key: cord- - ei ram authors: li, jingwei; shao, jun; wang, chengdi; li, weimin title: the epidemiology and therapeutic options for the covid- date: - - journal: precis clin med doi: . /pcmedi/pbaa sha: doc_id: cord_uid: ei ram an outbreak of coronavirus disease (covid- ), a disease caused by a novel pneumonia virus, has affected over countries and regions worldwide. with the increasing number of patients and deaths, who have declared it as a global pandemic currently, indicating a third large-scale epidemic coronavirus has appeared since the emergence of severe acute respiratory syndrome coronavirus (sars) and middle-east respiratory syndrome (mers) in the twenty-first century. considering the great harm it has caused, researchers throughout the world have been chasing to exploit the pathophysiology, characteristics, and potential remedies for covid- to better battle the outbreak. therefore, the current study revisits advances of the virology, epidemiology, clinical features, therapeutic options, and prevention of covid- . the features of asymptomatic carriers are also been explored. at the end of , a sudden outbreak of pneumonia occurred in wuhan, china, which was later confirmed to be caused by a coronavirus, severe acute respiratory syndrome coronavirus (sars-cov- ). , soon after, the virus spread rapidly around the world and affected human health as well as causing huge economic losses to society. [ ] [ ] [ ] on february , this novel disease was named coronavirus disease (covid- ) by who. since then, medical experts around the world have been trying to find the control measures and treatment for it. because covid- is highly contagious, the number of patients has increased rapidly. thus, realizing its basic characteristics and finding appropriate methods to detect and cure covid- is necessary for outbreak control. the detection and rehabilitation judgment of covid- are mainly through reverse transcriptionpolymerase chain reaction (rt-pcr), but experts have pointed out the low sensitivity will lead to missed diagnosis. so a combination of rt-pcr and other clinical features of covid- is important for diagnosis. the treatments for covid- are still unclear and mainly contain administration of oxygen, drug therapy, and emergency treatments such as ecmo. , as we know, few studies have summarized and classified therapies for covid- systematically. therefore, we review basic characteristics such as virology and epidemiology of covid- and classified explore antiviral therapy, symptomatic treatment, and traditional chinese medicines for curing covid- . considering no licensed vaccine exists for covid- , we also summarize the research and development of its vaccine. notice that the recent emergence of asymptomatic carriers has brought great difficulties for prevention and control of this disease, we highlight the characteristics of asymptomatic carriers and how to reduce their impact on the development of the covid- pandemic. in january , after the outbreak of covid- , scientists identified its pathogen and immediately confirmed it to be a novel coronavirus, which is found to be a β coronavirus of group b and was named -ncov by who initially. because % of its genetic sequences are similar to the sars-cov, it was later renamed sars-cov- . the origin of sars-cov- is unclear and is thought to be related to bat coronaviruses. zhou et al. compared gene sequence of sars-cov- with ratg , a bat coronavirus, and found the whole-genome sequence of sars-cov- is . % similar to ratg , indicating that sars-cov- may originate from a bat coronavirus. at the same time, wu and colleagues reported that the genome sequence of sars-cov- was closely linked with sl-covzc , another bat coronavirus, with . % similarity. however, despite the high similarity of sars-cov- to the virus from bats, the genetic differences will take at least a few decades of evolution to make up. thus, bats are unlikely to be the definitive hosts of it, and there may exist other intermediate hosts which brought the virus into humans. the relative synonymous codon usage analysis of viruses found sars-cov- used the translation machinery of several snakes effectively. therefore, snakes are a potential reservoir of the novel virus. apart from this, pangolins are thought to be the potential intermediate host of sars-cov- due to the sequence similarity of their spike receptor binding domains. furthermore, liu et al. declared that turtles were another possible host of sars-cov- . thus, more studies are necessary for confirming the intermediate host of sars-cov- . the pathogenic mechanism of sars-cov- is still unclear and thought to be closely related to viral sepsis, but structural biology has explained how viruses enter cells. angiotensin converting enzyme ii (ace ) has been demonstrated to be the only receptor for sars-cov- . the s protein on the surface of coronavirus was confirmed to mediate virus entry, which contains proteins s and s subunits. the receptor-binding domain (rbd) of s is responsible for the recognition of ace on the surface of human cells to complete the binding of viruses to cells. the s subunit mediates the fusion of the virus envelope and human cell membrane to complete the invasion process. there are two important conserved repeated amino acid sequences, hr and hr , in the s subunit of sars-cov- . together, they form a spiral structure called -hb, which is the key for the fusion of a coronavirus envelope with cell membrane. the serine protease tmprss triggers the s protein and promotes its fusion with the cell membrane. after that, the rna of the virus is released into the cytoplasm to complete its biosynthesis. sars-cov- is more contagious, although it has a similar structure of s protein to sars-cov, so virus-receptor-binding affinity is now being conducted in further studies. goh et al. found the rigidity and stability of sars-cov- shell are apparently higher than sars-cov, which increase its adaption to the environment. moreover, the structural difference of hr contributes to the higher structural stability for the -hb of sars-cov- , which has caused the better membrane fusion capacity of sars-cov- . thus, sars-cov- has a stronger infectious ability. it is worth noting that the expressions of ace in patients with some diseases such as diabetes are notably higher than those in healthy people, indicating that people with underlying diseases are more likely to be infected. on december , wuhan municipal health commission reported that pneumonia patients were associated with a south china seafood market, which was the earliest discovery of covid- . then, the quantity of covid- patients increased rapidly after chinese new year. up to may , covid- had affected more than countries and regions, and the quantity of confirmed patients had reached globally. after the breakthrough of covid- , experts began to predict the incubation stage of the sars-cov- . according to the data collected in january , the incubation stage of covid- patients ranges between and days, and its average is about days ( % credible interval: . - . ) when implementing the best-fit lognormal distribution. thus, experts recommended that suspected patients are quarantined for at least days. the mode of sars-cov- transmission is also an important part of epidemiological investigation. it is clear that humanto-human transmission of covid- occurs mainly via droplet respiratory particles, but whether sars-cov- can be transmitted via the eyes is still unclear. it should be noted that several studies have showed that chief complaint of some covid- patients were digestive symptoms, and nucleic acids of sars-cov- were even found in fecal samples or anal swabs of some patients, demonstrating the possibility of an oralfecal route. [ ] [ ] [ ] furthermore, mother-to-child transmission is also a potential route of covid- . , luckily, infection rates of children are relatively low, and most inpatient children only have mild symptoms even if they are infected, [ ] [ ] [ ] thus less damage would occur to them. up until now, the largest case series data of china has shown that . % of covid- patients were aged - years, % were aged under year old, % aged - years, and % were aged above years. among all patients, males account for %, and females account for %. furthermore, % of them are medical workers. in the united states, the elderly (aged over ) account for % of total covid- cases, % of inpatients, % of icu patients, and % of death cases. in terms of epidemiology, the basic reproductive number and mortality rate are indispensable. basic reproductive number (r ) is thought to be an important index for predicting the development of an outbreak. the main method of calculating r is using the data of infected people, such as serial interval distribution and latent period, to build a proper mathematical model for predicting the trend of the epidemic. a big epidemiological data of confirmed covid- patients reported that the basic reproductive number of sars-cov- was . , which means each patient could infect . other people. however, more recent research estimated that basic reproductive number was . . it is obvious that distinctions of r exist in these studies, and they result in data and model differences. the incubation period and serial interval distribution of former research are calculated only through confirmed cases and six pairs of cases in clusters, respectively. furthermore, the model of the former research is made merely on the basis of one region, thus its r distinctly lacks universality. by contrast, the latter study gathered the information of incubation period, serial interval, and infectious period from the individual cases reported throughout china and designed two models to infer the growth rate of the outbreak in different perspectives. so, its r better reflects the epidemic situation of china. similarly, the r of around . reported by imperial college covid- response team only represented the situation in europe. according to the data analysis of the chinese center for disease control and prevention, the overall mortality of covid- patients was approximately . %, which is obviously lower than severe acute respiratory syndrome (sars) and middle east respiratory syndrome (mers). however, because of the lager quantity of covid- patients, the number of covid- deaths is still high. furthermore, the data from the epidemic area indicated that people aged - years had the highest death rate of any age group, and the risk of symptomatic infection increased year by year. like most respiratory illnesses, covid- has many typical respiratory clinical symptoms. data from confirmed covid- patients have shown that . % had a fever, . % developed a cough, and . % received invasive mechanical ventilation, which is consistent with other studies. for some severe patients, acute respiratory distress syndrome (ards), shock, and arrhythmia are common complications. , apart from these symptoms, covid- patients sometimes have other non-respiratory symptoms such as fatigue, myalgia, headache, and digestive tract symptoms. , moreover, the main changes in laboratory results of covid- are decreases in lymphocytes and eosinophils as well as increases in d-dimer, c-reactive protein, prothrombin time, and procalcitonin. , computed tomography (ct) is one of the most efficient techniques for evaluating severity and differential diagnosis of pulmonary diseases, thus the ct characteristics ( fig. ) of covid- are another important clinical feature. this clinical evidence indicates that ground glass opacity (ggo), consolidation, and interlobular septal thickening are the most common ct characteristics of covid- , which occurs mainly in the posterior lung area and middle and lower lung regions. , compared to patients with mild symptoms, signs such as consolidation, thickened bronchial wall, linear opacities, extrapulmonary lesions, and higher ct scores are marked ct features of critically ill patients. therefore, ct is potentially used to diagnose and predict the prognosis of covid- patients. clinical symptoms are often used as indicators of clinically suspected cases. thus, when it comes to the clinical features above, it is easy to think about clinical diagnosis of covid- (table and fig. ). according to the diagnosis and treatment program of novel coronavirus pneumonia, only a suspected case has one of the pieces of evidence of etiology or serology, such as positive nucleic acid, confirmation of gene sequencing, and virus specific antibody, to be confirmed to be covid- patient, and the suspected cases were identified by a comprehensive analysis of epidemiological history and clinical manifestations. however, there are also many problems with this program. the most obvious problem is that rt-pcr patients have any epidemiological history and conform to at least two clinical manifestations, or patients without clear epidemiological history conform to three clinical manifestations. epidemiological history: i. travel or residence history of an affected area or close contact with a suspected or confirmed case within days before onset ii. have contact with covid- cases (nucleic acid positive) within days prior to onset iii. have contact with patients with fever or respiratory symptoms from an affected area, or from communities with covid- cases iv. cluster onset (two or more cases of fever and/or respiratory symptoms within weeks in a small area such as home, office, school, and class) clinical manifestations: i. fever and/or respiratory symptoms ii. with covid- imaging characteristics iii. normal or reduced number of white blood cells and/or lymphocytes in early covid- the suspected cases have at least one of the following etiological or serological evidences. i. the real-time fluorescent rt-pcr for specimens with a positive result of sars-cov- rna ii. virus gene sequences are highly homologous to sars-cov- iii. positive sars-cov- specific igm antibody and igg antibody in serum; the serum sars-cov- specific igg antibody changes from negative to positive or is four times higher in the recovery period than in the acute phase is the most common method for nucleic acid testing, but its sensitivity is not as high as expected, thus it possibly causes misdiagnosis of covid- . furthermore, although viral gene sequencing is an accurate diagnostic method and used on a small scale, its complex operation and time-consuming process make it difficult for wider clinical use. sars-cov- specific antibody detection is a simple detection method with higher sensitivity than rt-pcr, but its high sensitivity is only reflected after . days of symptom onset, so it is just a supplementary means to rt-pcr. luckily, the fast and convenient method, ct, was found to have a higher diagnostic sensitivity for covid- than other diagnostic methods such as rt-pcr and can predict the prognosis of patients, , thus it is meaningful for the initial screening. zhang et al. developed a deep learning system for image recognition of covid- patients. they collected ct images from patients for validation and found this system precisely identified the covid- and other forms of pneumonia, and it also divided these patients into high-and low-risk groups correctly, so rational use of artificial intelligence such as this may be better able to screen covid- patients and give them timely interventions to ensure a better prognosis. in addition, a crispr-cas -based technique was confirmed to be a faster test for covid- with higher sensitivity, thus it is possibly a replacement for the rt-pcr assay. the therapeutic schedule issued by the general office of national health committee of china on march has shown that therapy of covid- should be combined with etiological treatment and symptomatic treatment, and symptomatic treatment is especially important for severe and critical patients. furthermore, traditional chinese medicine can be also used for the whole treatment cycle of covid- patients. in the processes of covid- therapy, drugs and bioproducts play important roles (table ) . here, we summarize the main treatments of novel pneumonia. the etiological treatment for covid- means antiviral therapy for it, which depends on antiviral drugs and bioproducts. the processes of virus infection could be described as attachment, penetration, uncoating, biosynthesis, assembly, and release. after that, the virus complete its proliferation and causes damage to host cells. similarly, the mechanism of antiviral therapy is through disturbing these processes. thus, the medicines for antiviral treatment of covid- are divided into penetration and uncoating inhibitors, biosynthesis inhibitors, and assembly inhibitors. penetration and uncoating inhibitors of sars-cov- mainly include chloroquine, arbidol, and camostat mesilate. chloroquine is an efficient drug for treatment of malaria as well as autoimmune rheumatic diseases. wang and colleagues treated vero e cells that were infected by sars-cov- with several drugs in vitro and found a low half-maximal effective concentration at . μmol and a high selectivity index of chloroquine, indicating that chloroquine probably inhibits the viral infection. there have been tens of clinical trials to confirm the safety and efficiency of chloroquine in treating covid- patients, and its mechanism can be described as interfering with the glycosylation of ace or alkalizing the phagolysosome to inhibit viral replication, , which prevents the sars-cov- entering the host cells. the in vitro study indicated that chloroquine only had an antiviral effect under high doses. however, the clinical data of chloroquine showed the mortality of highdosage group was apparently higher than the low-dosage group, but there was no significant difference in efficacy, and the qt interval of some covid- patients was prolonged after hydroxychloroquine/azithromycin treatment, thus it might not be an effective medicine for covid- . arbidol is the other penetration inhibitor that suppresses the fusion of the virus lipid membrane and host cells to block the replication of the virus. arbidol also has the function of interferon (ifn) inducement, thus it has been widely used to treat a and b influenza viruses. it is promising that several studies of arbidol have shown a significant therapeutic effect for curing covid- patients. wang and colleagues found arbidol reduced the mortality and improved discharging rate by analysis of discharged covid- patients. furthermore, the other study compared the treatment effects between combination of arbidol and lopinavir/ritonavir, and simple lopinavir/ritonavir, finding that their ct scan improvement rates are % and %, and viral rna decrement rates are % and %, respectively. thus, arbidol perhaps serves as a specific treatment for covid- . however, another clinical report pointed out arbidol could not improve the symptoms or accelerate the clearance of sars-cov- . thus, further studies are needed to validate its antiviral efficiency. camostat mesylate is a specific drug for inhibiting tmprss , a protease used for s protein priming to promote the entry of sars-cov- , thus it is another potential penetration inhibitor. however, there is still lack of clinical evidence to prove its effectiveness. the biosynthesis inhibitors for sars-cov- chiefly contain remdesivir, sofosbuvir, ribavirin, and lopinavir/ritonavir. remdesivir is as kind of broad spectrum antiviral medicine that suppresses the virus replication through inhibiting the activity of rnadependent rna polymerase, , and its efficiency has been widely confirmed in coronaviruses such as sars-cov and mers-cov. recently, remdesivir has been found to be a potential drug to treat covid- . a previous study showed that half-maximal effective concentration of remdesivir was . in an in vitro test treating covid- with a high selectivity index, demonstrating its therapeutic effect. there, the first covid- case of america was reported to be cured completely after intravenous injection of remdesivir, and clinical data showed that remdesivir dramatically alleviated clinical symptoms and reduced mortality for severe patients, which demonstrated it is a potential drug for treating novel pneumonia. however, a patient died of hypotension and cardiac arrest after remdesivir treatment in a randomized controlled trial of ebola virus (ebov) treatment, and % covid- patients had side effects after using remdesivir, which indicated its security is worthy of further confirmation. up to now, several agencies have published conflicting clinical results from remdesivir. , thus, more research should be conducted to verify its curative efficacy. furthermore, in vitro tests showed that other broad-spectrum antiviral medicines such as sofosbuvir and ribavirin interacted with rna-dependent rna polymerase of sars-cov- , which prevents the replication of virus, thus they can also serve as antiviral drugs for covid- . lopinavir and ritonavir are suppressors of -chymotrypsin-like protease, a protease of coronavirus. furthermore, ritonavir suppresses the activity of cytochrome p isoenzymes and thus elevates plasma concentration of other medicines. therefore, combining lopinavir and ritonavir has a good inhibitory effect on virus biosynthesis, which was confirmed in the treatment of sars-cov and mers-cov. recently, many covid- patients have received lopinavir/ritonavir therapy and to good effect. moreover, the first report of the lopinavir/ritonavir clinical trial results have been published on march . in that study, patients were assigned to the lopinavir/ritonavir group and patients were treated with the routine therapy, and the median time of clinical improvement was advanced by day when given the lopinavir/ritonavir treatment. but it failed to accelerate clinical improvement significantly, and reduce mortality and viral rna detected in the throat. similarly, the clinical trial in severe covid- patients indicated lopinavir/ritonavir was of no benefit compared to standard care. therefore, further studies are needed to identify or exclude the possible benefits of lopinavir/ritonavir-based therapies. the most common antiviral products are ifns, which induce cells to synthesize antiviral proteins and thus inhibit all processes of the viral replication cycle. furthermore, it could also enhance immunity of patients, so it is widely used for therapy for multiple viruses such as mers-cov. in this outbreak, ifns combined with antiviral drugs were recommended to treat covid- , which has achieved good clinical therapeutic effect. xu et al. reported that the combination of ifns and arbidol or lopinavir/ritonavir cured covid- patients in the zhejiang province. in addition, a combination use of ifn beta- b, ribavirin, and lopinavir-ritonavir was found to be more effective than pure lopinavir-ritonavir. these therapies have been initiated into multiple clinical trials. convalescent plasma therapy (cpt) is based on the principle of using a certain titer of viral-specific antibodies in the recovered plasma to obtain passive immunity, neutralize specific pathogens, and eventually clear the pathogens in blood circulation, thus achieving the treatment expectation. luckily, key indicators of laboratory testing, clinical signs, and symptoms of several covid- patients were confirmed to improve significantly after cpt, so cpt is recommended for covid- treatment. currently, clinical trials are under way to further evaluate the efficiency and safety of cpt to covid- . the monoclonal antibody is a highly uniform antibody that is produced by a single b cell and specific to target the antigen epitopes, which have been confirmed to suppress viruses entering host cells extracellularly for many coronaviruses including sars-cov- . like most diseases, the main treatments of the complications of covid- are to strengthen supportive treatment, ensure adequate energy, and pay attention to water and electrolyte balance to maintain internal environment homeostasis. for covid- , hypoxia is a typical clinical symptom of covid- , thus oxygen inhalation is the essential treatment for both mild and severe patients. , it is worth noting that severe cases of covid- often develop severe inflammation, shock, combination of bacterial infection, and severe kidney damage as well as acute respiratory distress syndrome (ards), which often result in death. thus, timely complications treatment is necessary for critical patients. glucocorticoids such as methylprednisolone and dexamethasone have strong anti-inflammatory as well as antishock effects, so they are usually used to save critical patients, especially patients with ards. however, they suppress immunity, cause femoral head necrosis of patients, and cannot save patients with shock who have increased intrathoracic pressure, thus who did not recommend using glucocorticoids initially. for these situations, physicians suggested that short-term administration of glucocorticoids should be adopted to decrease the side effects. moreover, considering the immunosuppressive action, immune boosters such as α-ifn and thymosin are important for use in avoiding adverse events. for severe cytokine storms, simple glucocorticoids cannot suppress the inflammation efficiently, so potent blood purification measures such as an artificial liver system are essential. the processes of urgent antishock therapy mainly contain complements of blood volume, improving cardiac contractility and vascular activity, thus vasoactive agents and positive inotropic drugs such as epinephrine, dopamine, and norepinephrine are necessary for first aid of critical covid- patients. for patients with severe kidney damage, we should actively search for the primary cause and pay attention to the water, electrolyte, and acid-base balance. when homeostasis is decompensated and/or multiple organ failure occurs, continuous renal replacement therapy (crrt) should be adopted for treatment. ards is one of most critical complications for patients, which is known for its high mortality rate, especially for pregnant patients. for its therapy, ecmo is usually recommended and has a certain curative effect. however, its complex operation and low cure rate make it difficult to perform in a primary hospital. luckily, stem cells and their extracellular vesicles are able to repair the damage and relieve lung symptoms, thus they have been used to cure ards. currently, some covid- patients have been treated with umbilical cord mesenchymal stem cells and achieved good effects. therefore, stem cells may be the hope for the treatment of severe covid- patients. tens of clinical trials of stem cell treatment have been registered in chinese clinical trial registry. recently, many covid- patients were found to have thrombotic risk, therefore, antithrombotic treatments have potential application value in the treatment of covid- . furthermore, patients with underlying diseases such as hypertension, diabetes, and cardiovascular disease have a potential bad prognosis, - so care should be taken to cure these basic diseases during treatment. covid- patients with low immunity are susceptible to hospital-acquired bacterial infections, therefore, antibiotics such as amoxicillin are another symptomatic treatment medicine for covid- . traditional chinese medicine has been confirmed to play a vital role in treating many respiratory viruses such as sars-cov. furthermore, the general office of national health committee pointed out that chinese medicines such as qingfei paidu decoction, qingfei touxie fuzheng recipe, and sheganmahuang decoction could be used for the whole therapeutic process of covid- , thus they are widely used for covid- treatment currently. the present clinical evidence has shown that a combination of western and chinese medicines apparently improved curative effect. for example, wan et al. treated patients with multiple traditional chinese medicines such as suhuang zhike capsule and xuebijing, and found their respiratory symptoms were significantly improved in a shorter time. furthermore, four cases treated with antiviral drugs and shufeng jiedu capsule had an obvious improvement both in symptoms and blood biochemical indexes. however, lack of a control group means these results are not reliable enough. although treatment based on syndrome differentiation and lack of scientific evidence on mechanisms are typical characteristics of traditional chinese medicines, many of them are gradually found to have antiviral potential for sars-cov- . theaflavin is conventional ingredient of chinese medicine, which was found to have hydrogen bonds to rna-dependent rna polymerase with a binding energy of − . kcal/mol, thus it possibly inhibits the proliferation of sars-cov- . lianhuaqingwen was also confirmed to significantly inhibit the replication of sars-cov- and suppress the inflammatory factors tnf-α, il- , ccl- /mcp- , and cxcl- /ip- in vero e cells, so it is potentially a specific medicine for covid- both etiologically and symptomatically. the prevention and control of covid- can be divided into controlling the source of infection, cutting off the transmission route, and protecting susceptible people. controlling the source of infection in this outbreak mainly refers to timely isolation of suspected and confirmed cases, which greatly depends on wireless communication data. isolation of convalescent patients is also necessary, because some of them have a positive rt-pcr test even after days of recovery. cutting off the transmission route includes sterilizing and wearing suitable masks such as n , kn , and medical surgical masks. protecting susceptible people means self-segregation, improving constitution, and prophylactic vaccination. considering the strong infectivity of covid- , the secondary outbreak of covid- can be prevented only if the public has immunity to sars-cov- , thus vaccine is the key area among all prevention measures. therefore, scientists all over the world are working on the vaccine for sars-cov- , aiming to completely control the outbreak. after a long period of effort, the vaccine targets of the virus had been found and shared with the world. , soon afterward, medical institutions around the world adapted joint research and identified five development approaches, including a live attenuated vaccine, inactivated whole-virus vaccine, nucleic acid vaccine, protein vaccine, and viral vector-based vaccine (table ), and most of them used the s protein of sars-cov- as the main inducer of neutralizing antibodies directly, or inducing the expression of the whole s protein or receptor-binding domain of the s protein indirectly. by interaction of the s protein and ace of host cells, uncoating and penetration of sars-cov- are induced. thus, s-protein-based vaccines potentially inhibit the uncoating and penetration of the virus. whole-virus vaccines are conventional strategies to develop a vaccine for most viruses. by injecting artificially attenuated or inactivated viruses, pathogens trigger the body's immune response without causing disease. compared to other vaccines, these keep the inherent immunogenicity of sars-cov- and stimulate the body's innate immunity such as releasing toll-like receptors. however, live viruses have the potential to cause disease. furthermore, it has been reported that patients were more easily infected by sars-cov after immunization with a live attenuated vaccine or inactivated wholevirus vaccine. thus, sufficient experiments are necessary to verify their safety. currently, three inactivated novel coronavirus pneumonia vaccines have entered the phase i/ii clinical trials. [ ] [ ] [ ] nucleic acid vaccine nucleic acid vaccines, including dna vaccines and mrna vaccines, are to directly deliver foreign genes encoding antigenic proteins into host cells and synthesize the antigenic proteins by host cells to induce the immunity of hosts. nucleic acid vaccines of covid- mainly aim to induce the whole s protein or receptorbinding domain of s protein expression, and several of them have entered clinical trials. for example, researchers of inovio pharmaceuticals are conducting the clinical trial of a dna vaccine. in the meantime, the national institute of allergy and infectious diseases have developed a mrna vaccine, mrna- , which uses lipid nanoparticles to encapsulate the mrna encoding s protein of sars-cov- . interestingly, symvivo corporation have developed an oral dna vaccine to avoid invasive injection. it consists of live bifidobacterium longum, which contain the synthetic dna encoding s protein. although patients with typical symptoms are easily diagnosed and isolated, we still need to pay attention to asymptomatic carriers. in january , a family cluster of three covid- patients with one symptomatic and two asymptomatic carriers drew great attention. because any one of them could have the first one to transmit the virus to others, there may exist asymptomatic patients with high infectivity who have not been detected. at the same time, another family cluster of five patients was found to have contact with an asymptomatic carrier before onset of their symptoms. according to time sequence, it is obvious that the virus was transmitted by an asymptomatic carrier. hereafter, the phenomenon of asymptomatic infection has been reported in several articles. , on the basis of virology of sars-cov- , quantity of shedding sars-cov- from pharyngeal sources is very high in the first week of symptoms, and they also replicate actively during this time, thus the first week after onset of symptoms is when the patients have the highest infectivity. but in this time period, some patients only have mild symptoms or even no symptoms, so they might be invisible sources of infection. therefore, people who have traveled to endemic areas or had contact with patients should be isolated, monitored, and screened strictly, even if they are asymptomatic, to rule out the possibility of infection. covid- , a disease that seriously endanger the safety of human life and properties, is caused by sars-cov- , which attacks host cells through ace . the spread of covid- mainly depends on airborne and droplet transmission. some researchers pointed out the possibility of fecal-oral transmission and vertical transmission, but these opinions need further confirmation. an accurate diagnosis of covid- is essential for containing disease, thus combnation of rt-pcr and clinical characteristics is widely used for its detection currently. the typical clinical features of covid- patients include fever, cough, and dyspnea. moreover, ggo, consolidation, and interlobular septal thickening are also typical ct signals of covid- . using artificial intelligence to screen covid- early on is likely to be the future diagnostic directions of it. good treatment is necessary to reduce mortality, and drug therapy is the main treatment of covid- . thus, we summarize the chief medicines and bioproducts for its treatment. according to the current reports, combined use of the drugs and bioproducts to treat covid- both etiologically and symptomatically has received great clinical effect. however, not all antiviral drugs for covid- have passed the clinical trials. a few clinical trial reports demonstrated that lopinavir-ritonavir, chloroquine, and remdesivir did not work as well as expected, , , which reflects the fact that many antiviral drugs have gone through many extensive clinical trials with currently only modest effect. instead, some bioproducts such as monoclonal antibodies and stem cells are more likely to play important roles in treatment of severely affected patients in the future. furthermore, we should also focus on vaccine research and artificial intelligence-based studies for fighting the outbreak, both of which play vital roles in controlling the it. although antiviral effects of many drugs and vaccines have been obtained in vitro, it remains to be seen as to whether they have comparable activity in vivo. therefore, establishing efficient animal models as soon as possible is important for virology research, drug, and vaccine development. currently, rhesus macaques models have been established to study the transmission and distribution of sars-cov- as well as effects of viral infection on host prognosis, , which is meaningful for virology study. furthermore, hace transgenic mice have been found to own typical covid- clinical symptoms, which could not be found in wild-type mice, indicating this model may be used for development of therapeutic drugs and vaccines. thus, perhaps further researching effective animal models and making full 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and immunogenicity study of -ncov vaccine (mrna- ) for prophylaxis sars cov- infection (covid- ) evaluating the safety, tolerability and immunogenicity of bactrl-spike vaccine for prevention of covid- vaccines/vaxart-announces-initiation-of-cor onavirus-vaccine-program.html, accessed date evaluation of the safety and immunogenicity of a sars-cov- rs (covid- ) nanoparticle vaccine with/without matrix-m adjuvant ct ?term = vaccine&cond = covid- &draw = &r ank = , accessed date academy of military medical sciences, pla of china. a phase ii clinical trial to evaluate the recombinant novel coronavirus vaccine (adenovirus vector) (ctii-ncov immune medical institute. safety and immunity of covid- aapc vaccine immunity and safety of covid- synthetic minigene vaccine covid- : four fifths of cases are asymptomatic, china figures indicate presumed asymptomatic carrier transmission of covid- transmission of -ncov infection from an asymptomatic contact in germany evidence of sars-cov- infection in returning travelers from wuhan, china virological assessment of hospitalized patients with covid- respiratory disease in rhesus macaques inoculated with sars-cov- sars-cov- receptor ace is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues the pathogenicity of sars-cov- in hace transgenic mice this work was supported by the national natural science all authors declared that they had no conflict of interest. key: cord- -m awip y authors: sobh, eman; abuarrah, einas; abdelsalam, khloud gamal; awad, sohaila sabry; badawy, mohamed ahmed; fathelbab, mohamed a.; aboulfotouh, mohamed ahmed; awadallah, mohamed fawzi title: novel coronavirus disease (covid- ) non-respiratory involvement date: - - journal: egypt j bronchol doi: . /s - - - sha: doc_id: cord_uid: m awip y background: coronavirus disease (covid- ) is a newly emerging pandemic that affected millions of people worldwide caused by novel coronavirus sars-cov- . the first cases reported suffered from respiratory symptoms. main body: various extrapulmonary manifestations were linked to covid- in several reports including cardiovascular, genitourinary, gastrointestinal, and skin. it is important that every clinician should be aware of these non-respiratory manifestations for early diagnosis and prompt management. this review aims to summarize the different extrapulmonary manifestations of covid- disease and highlight the importance of multidisciplinary care. conclusion: covid- is a disease of multi-organ involvement. manifestations may vary depending on which organ is involved. coronavirus disease (covid- ) is caused by a novel single-strand ribonucleic acid (rna) coronavirus known as severe acute respiratory syndrome coronavirus- (sars-cov- ). it has been recognized by the world health organization (who) as an international pandemic [ , ] . sars-cov- primary attacks the lower respiratory system causing viral pneumonia, but it may also affect the heart, gastrointestinal system, liver, kidney, and central nervous system leading to multiple organ failure [ ] . several comorbidities have been identified as risk factors for severe covid- disease. the most prevalent comorbidities detected in different studies were hypertension (htn), diabetes mellitus (dm), respiratory diseases, and obesity [ ] [ ] [ ] [ ] . in this review, we will through light on extrapulmonary manifestations caused by covid- and their impact on outcome and case management which indicates a great need for multidisciplinary team. the exact mechanism of extrapulmonary manifestations is still under research; several factors have been proposed either direct or indirect injury secondary to the inflammatory response to the viral injury [ , ] . sars-cov- infection begins when the viral surface spike protein (s) binds to the human angiotensin-converting enzyme receptors (ace ) receptor following activation of the spike protein by transmembrane protease serine (tmprss ) that facilitates s protein priming [ ] . ace receptors are expressed in the lung (principally type ii alveolar cells), heart, intestinal epithelium, kidney, vascular endothelium, and smooth muscle cells of all organs providing a mechanism for the covid- multi-organ dysfunction [ ] [ ] [ ] . another mechanism is the severe inflammatory response induced by the viral infection in the lung as well as other organs [ ] . once inside the cells, sars-cov- activates t lymphocytes triggering an intense immune response and an inflammatory reaction leading to an inflammatory cascade with the release of cytokines: interleukin (il)- , il- , tumor necrosis factor-α (tnf-α), granulocyte-macrophage colony-stimulating factor (gm-csf), and interferon-γ (ifn-γ) known as cytokine storm resulting in tissue damage [ ] . recent studies found that cardiovascular comorbidities such as hypertension, coronary artery disease, and cerebrovascular disease are common in covid- cases and are linked to severe disease, poor prognosis, and death [ ] [ ] [ ] [ ] ] . besides, diabetes mellitus is a risk factor for heart failure as non-cardiovascular comorbidity [ ] . several existing reports suggested that sars-cov- infection leads to cv complications or exacerbation of preexisting cardiovascular disease (cvd) [ , ] . palpitations, cardiac arrhythmias, and cardiac arrest were common cv manifestations in patients with covid- infection in one study [ ] . zhou and colleagues reported that cardiomyopathy and heart failure were observed in . % of patients with covid- disease [ ] . researchers found that among covid- -related deaths . % of patients who did not have underlying cardiovascular disease had cardiac damage with elevated cardiac troponin i (catnip) or cardiac arrest during hospital admission [ ] . other researchers found elevated serum troponin levels in many patients infected with covid- , and it was associated with more severe disease and poor prognosis [ ] . another study showed that covid- non-survivors had significantly higher d-dimer and fibrin degradation products (fdp) levels and longer prothrombin (pt) compared to survivors on admission [ ] . prevalent cvd may be a marker of accelerated immunologic dysregulation and aging that may relate indirectly to covid- prognosis [ ] . the exact mechanism of cardiac injury in covid- is still under research. it was proposed that covid- interacts with the cardiovascular system on multiple levels, increasing morbidity in patients with existing cardiovascular conditions and provoking myocardial dysfunction and injury [ ] . the mechanism behind acute myocardial injury caused by sars-cov- infection might be related to human angiotensin-converting enzyme receptor (ace ) [ ] which are highly expressed in the heart [ ] . besides, severe respiratory infection and hypoxia, especially in the setting of severe infection and acute respiratory distress syndrome (ards) due to covid- , it is likely that many patients will develop injuries such as myocardial injury, myocarditis, and acute coronary syndrome [ ] . meanwhile, pneumonia may cause significant ventilation perfusion mismatch, leading to hypoxemia, which significantly reduces the energy supply for cell metabolism, increases anaerobic fermentation, and leads to intracellular acidosis and oxygen free radicals that destroy the phospholipid layer of the cell membrane [ , ] . also, the high prevalence of arrhythmia might be attributable to hypoxia, metabolic disarray, and neurohormonal or inflammatory stress in the setting of viral infection in patients with or without prior cvd [ ] . abnormal coagulation resulting in venous thromboembolism and disseminated intravascular coagulopathy (dic) are other contributing factors [ ] . the results of previous reports indicate that cardiac injury, arrhythmia, and venous thromboembolism should be considered in any suspected or confirmed covid- case and the patient should undergo a prompt clinical evaluation. thromboprophylaxis should be added to therapy to those with severe disease. there is evidence from previous studies that sars-cov- can invade the gastrointestinal (gi) tract through binding to ace receptors where they are highly expressed as in the glandular cells of gastric, duodenal, ileal, colonic, and rectal epithelia; ileum; and colon [ ] [ ] [ ] . ace expression is rarely seen in esophageal mucosa, probably because the esophageal epithelium is mainly composed of squamous epithelial cells, which express less ace than glandular epithelial cells [ ] . besides, genetic elements of the sars-cov- rna had been found in feces [ ] [ ] [ ] . importantly, it is observed that . % of patients continued to have positive results for sars-cov- in stool after showing negative results in respiratory samples [ ] . this may raise the possibility of a fecal-oral transmission route and the gi can serve as a route of transmission [ ] [ ] [ ] [ ] . patients suspected to have covid- presenting with gi symptoms such as nausea, diarrhea, and vomiting should be considered seriously [ ] . sars-cov- may cause acute gastritis and enteritis, as evidenced by nausea, diarrhea, and vomiting [ ] . previous studies reported that most patients had at least one gi symptom, most commonly anorexia and diarrhea [ ] [ ] [ ] [ ] [ ] . patients with gi symptoms have a significantly high rate of fever, fatigue, headache, shortness of breath, and increased incidence of ards, and they also tend to have more severe/critical disease when compared with those without gi symptoms [ ] . electrolyte disturbances such as decreased sodium level secondary to gi manifestations contribute to the severity of the disease [ ] . a study found that about % of patients admitted to the hospital presented with digestive symptoms without respiratory symptoms. they had a significantly longer time from onset of symptoms to hospital admission when compared with patients with no digestive symptoms [ ] . abnormal laboratory data in these patients included elevated levels of liver enzymes, alanine transaminase (alt) and aspartate transaminase (ast) [ ] . significant prolongation of prothrombin time was found in patients with digestive symptoms, whereas other indicators of coagulation function were not significantly different [ ] . gastrointestinal manifestations may be attributed to the inflammatory response of sars-cov- in the gut, which may directly or indirectly damage the cells. viral invasion of gi epithelial cells results in cytokine and chemokine release, activating acute intestinal inflammation characterized by infiltration of neutrophils, macrophages, and t cells. this inflammatory response is evidenced by diarrhea, elevated fecal calprotectin (fc), and systemic il- response. sars-cov- infection exerts gut tropism characterized by an acute inflammatory response. this inflammatory process could deteriorate already present gi disorders like inflammatory bowel disease (ibd) [ ] . in addition, the immunosuppressive drugs used to treat ibd may result in a more severe/critical course of covid- [ ] . considering the previous points, gi symptoms should be evaluated promptly, and suspected covid- infection should be considered to avoid complicated course and to prevent transmission to the community due to delayed diagnosis and treatment [ ] . meanwhile, both the sars-cov- virus and the antiviral therapy can induce liver injury so continuous monitoring of liver functions is mandatory [ ] . several studies reported acute kidney injury (aki) in covid- patients with variable incidence rate [ , , , , ] . worsening of preexisting chronic kidney disease (ckd) was also described in covid- patients [ , ] . kidney injury is more linked to severe disease, old age, and comorbidities [ , ] , and it is a risk factor for poor prognosis [ , ] . markers of kidney injury observed in covid- cases involved elevated serum creatinine and blood urea nitrogen, reduced glomerular filtration rate, proteinuria, and hematuria [ , , ] , in addition to decreased density of the kidney and edema as seen in computed tomography (ct) scanning of the involved patients [ ] . the etiology of kidney involvement in covid- patients is ambiguous, and several mechanisms are proposed: first, the covid- virus utilizes the ace receptor for entry to the cell as mentioned earlier [ , ] . human tissue rna sequencing revealed that the ace presence in the kidney is higher than that in the lung [ ] . therefore, the covid- virus may attack renal epithelial cells [ ] . this mechanism is verified by the presence of the virus rna in the patients' blood and urine [ ] . besides, a report of autopsies from patients showed severe acute tubular injury, inflammatory cell infiltration, arteriosclerosis, and accumulation of coronavirus-like particles in renal epithelial cells [ ] . second, kidney impairment may stimulate inflammation in the lung (collateral injury). meanwhile, inflammation following lung injury may result in the deposition of immune complexes of viral antigen or virus-induced specific immunologic response leading to acute kidney injury [ , ] . third, the virus-induced cytokine storm may affect the kidney as well as other organs [ ] . hyaline thrombi with small vessel damage are found in the kidney of covid- patients [ ] . prompt evaluation of kidney function is necessary in all cases of covid- disease; continuous follow-up of renal function and proper management of any abnormal clinical finding should take place early to avoid deterioration. the effect of sars-cov- on the genital and reproductive system is still unknown. however, there are some reports describing testicular injury and possible impaired male fertility [ ] . viral markers have been found in the testis and semen raising the possibility of sexual transmission [ ] . significant changes in sex hormones in patients with covid- were reported, which may be attributed to impaired gonadal function [ ] . mechanisms of the sars-cov- effect on the gonadal system are the same for other organs including ace receptor binding and utilization of tmprss protein [ ] [ ] [ ] which are highly expressed in the urogenital system [ ] . the systemic and local inflammation process associated with the viral infection and the released cytokines, interferon, and inflammatory mediators contribute to the destructive effect [ , ] . therefore, continuous follow-up of the reproductive system is important in covid- patients. there was no evidence for the presence of sars-cov- in amniotic fluid, cord blood, and breast milk samples. the intrauterine infection has not been reported [ ] . neurologic symptoms have been reported in patients with covid- . the symptoms included central nervous system (cns), peripheral nervous system (pns), and skeletal muscle injury. the most common cns symptoms were dizziness and headache, while the most common pns symptoms were taste and smell impairment. most neurologic manifestations occurred early in the illness (median time, - days) except for cerebrovascular disease and impaired consciousness. some patients presented to the hospital with neurologic symptoms; even some had acute cerebrovascular attacks without any typical symptoms (fever, cough, anorexia, and diarrhea) of covid- [ ] . several patients reported a partial or total loss of smell and/ or taste [ , ] . the extent of olfactory dysfunction is still not fully understood [ ] . the neurologic manifestations can be due to sars-cov- infection either directly or indirectly [ , ] . sars-cov- may enter the cns through the hematogenous or retrograde neuronal route [ , ] . the invasion of the nervous system occurs through binding to ace receptors that are expressed in the nervous system and skeletal muscles [ , ] . the researchers detected sars-cov- nucleic acid in the cerebrospinal fluid of those patients and in their brain tissue on autopsy [ , ] . specimens from patients with covid- showed brain tissue hyperemia, edema, and degeneration of some neurons [ ] . immune suppression contributes to the neurologic injury indicated by the presence of a low number of lymphocytes in patients with cns symptoms compared to those without cns symptoms. patients with severe infection had higher d-dimer levels than patients with the non-severe infection that makes patients with severe infection more likely to develop cerebrovascular disease [ ] . the true magnitude of olfactory affection cannot be estimated because of the absence/scarcity of validated quantitative olfactory testing and neuroimaging performed for covid- patients. the mechanism may be direct injury of the olfactory nerve or local inflammation of the nasal cavity [ , ] . therefore, we should pay close attention to neurologic manifestations in patients with covid- disease especially those with severe disease, and any patient with unexplained neurologic deficits should be evaluated for sars-cov- infection. a few cases with covid- in china have been reported a skin rash, eczema, rosacea, atopic dermatitis, dryness, erythema, and urticaria [ , ]. however, it is difficult to distinguish between the main causes of these symptoms [ ] . several factors can be behind skin manifestations including the immune response to infection, medications, or use of protective equipment in healthcare workers or even unknown [ ] [ ] [ ] . hundreds of healthcare workers in china were found to have skin symptoms on the hands, nose, cheeks, and forehead as a result of damage to the skin barrier due to the frequent use of disinfectants and prolonged wearing face masks, goggles, and gloves [ , [ ] [ ] [ ] . itching and skin infections can result from some drugs used to treat symptoms such as antimalarials, antivirals, and corticosteroids [ , ] . skin reactions may also appear as a form of the immune response against the fever [ , ] . although the relationship between covid- and skin diseases is still mysterious and needs more clinical evidence, there is still some concern because the skin is the first line of defense for the immune system [ ] . if one of these possibilities is correct, people with autoimmune disorders and chronic infections such as psoriasis, lupus, scleroderma, and vitiligo may be more susceptible to infection with the covid- [ ] . therefore, the china dermatological society and the national center for clinical research of dermatology and immunology have recommended taking preventive measures such as wearing goggles instead of a sanitary mask. use foam-free cleaning products and skin moisturizing creams after cleaning your hands and wearing gloves that contain hyaluronic acid, ceramides, or vitamin e [ ] . ocular involvement in covid- is uncommon, and conjunctival congestion was reported in less than % of cases [ ] . another study reported a higher rate of manifestations consistent with conjunctivitis ( out of patients, . %) especially in cases with severe pneumonia. these manifestations involved conjunctival hyperemia, chemosis, epiphora, and increased secretions. patients with eye manifestations had leukocytosis, neutrophilia, increased creactive protein (crp), lactate dehydrogenase (ldh), and procalcitonin [ ] . conjunctival congestion may be an early manifestation in covid- according to some case reports [ , ] . eye involvement may result from direct inoculation of the virus through respiratory droplets, migration through the nasolacrimal duct, or hematogenous spread [ ] . the virus can also be transmitted through contaminated hands. the possibility of transmission of sars-cov- through ocular secretions is still unknown. positive pcr for sars-cov- from conjunctival secretions was reported only in cases in wu study [ ] . ophthalmologists should be aware of the possibility of eye involvement in covid- and should take infection control precautions and refer suspected cases for specialists to be evaluated thoroughly. the relation between blood sugar and pulmonary diseases is well established [ ] . studies found that covid- may cause elevation of blood sugar in diabetics and some experience poor control [ ] . a preliminary data from sebeokian et al. study found that more than half of all cases confirmed or suspected covid- had hyperglycemia and nearly one third had diabetic ketoacidosis. in addition, some cases developed newonset diabetes [ ] . direct pancreatic involvement by sars-cov- was suspected in severe covid- cases due to the high expression of ace receptors in the pancreas, in addition to severe inflammatory reaction which may explain pancreatic failure [ ] . this may be associated with high serum amylase and/or lipase levels [ ] . so, strict control and follow-up of blood sugar in all cases of suspected or confirmed covid- is important to avoid flaring of infection and/or complications of uncontrolled diabetes. in severe cases, a panel of endocrine markers should be evaluated. every organ in the body is susceptible to injury caused by the sars-cov- virus, and at the current time, several symptoms may be 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definitions by international consensus authors' contributions es contributed to the literature review, writing the draft and final manuscript, and critical revision. ea, kga, ma, mfa, and mb participated in the literature review and writing the first draft. mfa participated in writing the final draft and critical revision. ea contributed to the references' revision. all authors participated in the idea design of the work, and all had read and approved the final version to be published. the authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors. ethics approval and consent to participate not applicable consent for publication not applicable the authors declare that they have no competing interests. key: cord- -yxqbe dj authors: ren, yunzhao r.; golding, amit; sorbello, alfred; ji, ping; chen, jianmeng; bhawana, saluja; witzmann, kimberly; arya, vikram; reynolds, kellie s.; choi, su‐young; nikolov, nikolay; sahajwalla, chandrahas title: a comprehensive updated review on sars‐cov‐ and covid‐ date: - - journal: j clin pharmacol doi: . /jcph. sha: doc_id: cord_uid: yxqbe dj this literature review aims to provide a comprehensive current summary of the pathogenesis, clinical features, disease course, host immune responses, and current investigational antiviral and immunomodulatory pharmacotherapies, in order to facilitate the development of future therapies and measures for prevention and control. this article is protected by copyright. all rights reserved the disease name -covid- ‖ and the associated virus name -sars-cov- ‖ were coined by the world health organization (who) and the coronavirus study group of the international committee on virus taxonomy, respectively, on february , . currently no specific drug has been approved by the fda for treating covid- , and the current management of patients is mainly supportive. fda has issued only emergency use authorizations (eua) to permit the emergency use of chloroquine phosphate, hydroxychloroquine sulfate, and remdesivir. therapeutic development for covid- includes repurposing existing medications and developing investigational candidates. the first reported confirmed covid- case was presented as atypical pneumonia on december , in wuhan, china. the patient was among a cluster of cases reported to who on january , . as of may , , sars-cov- has infected over . million people worldwide . covid- had resulted in a global death toll of more than , . an epidemiology study noted that of , confirmed covid- cases in china through february , . % and . % of patients were in severe and critical condition, respectively . the reported median incubation period of covid- is days , and the median period from symptom onset to hospital admission ranges from to days , . median time from onset of the first symptom to dyspnea is - days , ; to pneumonia, days ; to icu admission, days ; and to acute respiratory distress syndrome (ards), days . the median duration of hospitalization is days to days ; median length of icu stay, days ; median time from admission to invasive mechanical ventilation, . days ; and median time from admission to death was . days . the currently estimated reproductive number (r ) of sars-cov- , the average number of people to which one infected individual will pass the virus, ranges from . to . [ ] [ ] [ ] , whereas the reported r for sars-cov is approximately . sars-cov- is an airborne virus which can be transmitted by aerosol . a hospital survey detected the maximum transmission distance of sars-cov- aerosol might be meters from the covid- patients . in the contaminated area of the hospital, the viral nucleic acid positive rate was % for computer mice, % for floor swabs, % for trash cans, % for sickbed handrails, and % for doorknobs. in a virus viability test, authors used a nebulizer to generate artificial aerosols with small particle size (< μm) containing sars-cov- . the results showed that sars-cov- remained viable in the artificial aerosols for at least hours. the virus is most stable on plastic and stainless steel surfaces, on which viable virus had been detected for up to hours. no viable virus was detected after hours on copper and after hours on cardboard. the who, therefore, advises the public not to touch their eyes, nose, or mouth with their hands to limit self-contamination . in addition, the centers for disease control and prevention (cdc) recommends wearing cloth face coverings in public settings where other social distancing measures ( feet) are difficult to maintain . a case study reported that of passengers on a coach bus contracted the virus from an infected patient who did not wear a protective face mask. however, the same patient bought a mask and wore it before transferring to a mini-bus, and none of the passengers on the mini-bus contracted the virus . live sars-cov- was isolated from nasal/pharyngeal swabs and sputum, but not from stool, in patients with covid- . the live viral copies peaked during the early stage of symptom onset (≤ days); and could not be detected after day in samples from mild cases of infection. this discovery suggests that the viral transmission occurs primarily through the airborne route rather than the fecal-oral route during early stages of the disease. indeed, there have been sporadic case reports on the human-to-human transmission from asymptomatic or pre-symptomatic subjects [ ] [ ] [ ] . one study estimated that the transmissibility of the asymptomatic cases is comparable to that of symptomatic cases . an epidemiology report from china indicated that . % ( ) of , tested/suspected/diagnosed cases were asymptomatic . identification and isolation of asymptomatic subjects has helped reduce the pandemic in an italian village . these reports suggest that a panpopulation screening for viral exposure is an effective way to critically contain the spread of the disease. two meteorology models consistently found that higher relative humidity favored sars-cov- transmission , . the two models differed regarding the trend of temperature effect on viral transmission, probably due to the different ranges of temperature studied in china (winter) and brazil (autumn). an epidemiology study from china found that although the proportion of male patients ( . %) was comparable to that of females ( . %), male patients ( . %) comprised almost two-thirds of the total deaths . data from the cdc website as of may , showed that among approximately , covid- cases in the u.s., % were in children (< years old); % were in the elderly (≥ years old), and most ( %) were in patients between and years old . of hospitalized patients in u.s. states from march - , ( %) were non-hispanic white; ( . %) were non-hispanic black; ( . %) were hispanic; ( . %) were asian, two ( . %) were american indian/alaskan native, and ( . %) were of other ethnic origins or unknown . culture of bronchoalveolar lavage fluid collected from early wuhan cases identified the etiology of the virus to date, the virus phylogenetically closest to sars-cov- by genetic homogeneity is a coronavirus isolated from the horseshoe bat (bat cov ratg ) with an overall genome sequence identity of . %, which is higher than that of sars-cov (< %) . angiotensinconverting enzyme (ace ) was identified as a shared receptor required for cell entry both for sars-cov and sars-cov- , with higher binding affinity for sars-cov- . sequence comparison of spike (s) protein, the viral ligand of ace , identified three short insertions located at the n-terminus region that are conserved in sars-cov- and bat cov ratg , but not in sars-cov . examination of the receptor-binding domain (rbd) of s protein surprisingly identified that a malayan pangolin coronavirus had a higher degree of similarity ( . %) than bat cov ratg ( . %), indicating that recombination may have occurred during the evolution of sars-cov- . variation analysis based on sequences of sars-cov- up to february revealed very high homology (> . %) among different strains . another group estimated that the evolution rate of sars-cov- is approximately . × - per base per year , which indicates that sars-cov- transmission in humans is a recent event. the sars-cov- genome sequence can be found at https://www.ncbi.nlm.nih.gov/genbank/sars-cov- -seqs/. the direct diagnosis of covid- requires detection of sars-cov- -specific rna from patients' samples. reverse transcription-polymerase chain reaction (rt-pcr) is the most widely used technique for diagnosis. a commercial rt-pcr test kit usually uses to pairs of primers detecting the different regions of sars-cov- genomic rna to increase the test specificity. the sensitivity of this method is not optimal. one paper noted that the sensitivity of rt-pcr ( %), even after % of patients had multiple tests, was lower than that of a ct scan ( %) . a test report of , wuhan cases with typical covid- symptoms and history of close patient contact demonstrated that the positive rate was about % for nasal and pharyngeal swabs, % for sputum samples, and % to % for bronchoalveolar lavage fluid . another study screened subjects in wuhan and found that the positive rate from nasopharyngeal swabs was . -fold higher than that of oropharyngeal swabs . interestingly, pharyngeal swab viral nucleic acid screening results of , patients between january and february from a hospital fever clinic in hunan province (a neighboring province of hubei) demonstrated that the positive rate of sars-cov- ( . %) was lower than that of influenza a ( . %) and influenza b ( . %) . it is unclear whether the lockdown status of hubei province or the sensitivity of the detection methods between different viruses contributed to the result. the disease course also affects viral nucleic acid detection results. one study closely followed throat swab samples or deep nasal cavity swab samples from hospitalized covid- patients and found that the positive rate was the highest ( %) within week since the symptom onset . however, the positive rate reduced to about one-third at week . similar results were obtained from another study, in which the positive rate of throat swabs from patients was > % when tested within - days since symptom onset, but decreased to < % on day , and < % after day . other than the traditional rt-pcr, other viral rna detecting methods such as loop-mediated isothermal amplification (lamp) were expeditiously developed and approved by the fda . the apparent advantage of lamp is the much shorter waiting time for the results (< minutes) compared to the traditional rt-pcr ( hours). crispr, the powerful gene editing technique, premiered in this pandemic and was also approved by fda, though the commercial kit requires an isothermal amplification step . reports on the relationship between viral load in respiratory tracts and disease severity showed conflicting results. one study (n= ) reported that the high viral load from a patient's respiratory tracts is moderately associated with a high murray score for acute lung injury and low pao /fio . the same study also reported that the high viral load is associated with high plasma angiotensin ii concentration. however, two other studies (n= and n= ) did not find significant differences in viral load between mild and severe cases , . one study demonstrated that the speed of viral clearance differs significantly in mild and severe cases . the average time of viral nucleic acid turning positive to negative was about days in mild cases and days in severe cases. in non-survivors, persistent viral rna was detected until death . however, another study with intensive testing was able to detect viral nucleic acid in throat/deep nasal cavity swab samples from of hospitalized patients with mild-to-moderate confirmed covid- weeks after symptom onset . sars-cov- was detected in the whole blood and serum , . more studies are needed to investigate the correlation between viremia with blood viral load and disease severity. patients on admission, and discovered that the cutoff of . µg/ml had a sensitivity of % and a specificity of % in predicting in-hospital mortality . higher levels of hypersensitive troponin i in patients with severe covid- (table ) indicates an association of sars-cov- infection and cardiomyopathy , . a review summarized that cardiovascular complications associated with covid- include myocardial injury, myocarditis, acute myocardial infarction, heart failure, dysrhythmias, and thromboembolic events two covid- -associated kawasaki disease cases were reported in a -month-old girl and a -year-old boy, respectively il- , il- , tnf-α and ifn-γ were found between the two groups. whether the age differences between the two groups also contributed to these observed differences is unclear. two rsv-infected children ( . %) and one sars-cov- -infected child ( . %) developed severe pneumonia. all children survived. various case reports, case series, retrospective and case-controlled studies of pregnant women with covid- presented clinical and laboratory data on maternal and neonatal manifestations and outcomes [ ] [ ] [ ] [ ] [ ] . reviews and analyses of published reports provided additional insights [ ] [ ] [ ] [ ] . most of the pregnant women in these studies and reports were in their third trimester, and many of their babies were delivered by caesarean section. in general, they experienced signs and symptoms of covid- much like those in non-pregnant women. no maternal deaths were reported. fetal distress, premature births, premature rupture of membranes, respiratory difficulties, and low birth weight were observed among some babies born to mothers with covid- , , . no definitive cases of vertical transmission of the sars coronavirus (sars-cov- ) from mother to fetus have been identified, although two highly suspect cases have been reported. wang and colleagues described a male infant delivered by emergency cesarean section to a -year-old woman with covid- confirmed by pharyngeal swab . the infant had a viral nucleic acid detected from pharyngeal swab approximately hours after birth. tests of the cord blood, placenta, and the mother's breast milk were negative for sars-cov- . both mother and infant recovered. alzamora and colleagues reported on a -year-old diabetic woman with covid- -induced respiratory failure whose neonate was positive for sars-cov- nucleic acid from nasopharyngeal swab hours after a cesarean section delivery . serologies for sars-cov- were negative for the mother and the baby at the time of delivery. the mother converted to seropositive status on postpartum day ; whereas the neonate, who had not been breastfed, remained seronegative at that time. in relation to neonatal survival, zhu and colleagues reported one neonatal death in which a male baby born to a mother with confirmed covid- developed refractory shock, gastric bleeding, multi-organ failure, and disseminated intravascular coagulation approximately days after birth three publications reported findings with inconsistent results from systematic reviews or meta-analyses. a systematic review by vardavas and nikitara found an association between smoking and covid- illness progression . emami and colleagues in a meta-analysis reported a high prevalence of smoking ( . %) in hospitalized patients with covid- . however, a meta-analysis by lippi and henry found no association between smoking and covid- , although they acknowledged the findings reported by liu above . the inconsistent results on smoking may be attributed to lack of data on smoking quantity and duration, small population size and/or few smokers in certain studies, and the presence of other concurrent comorbid conditions. future research should consider including documentation of nicotine exposures through vaping and ecigarettes. the scientific community recently has debated a possible therapeutic role for nicotine in treating covid- . some epidemiologic data has shown lower numbers of smokers among patients with covid- , indicating that nicotine may mediate the viral transmission by lowering ace levels , . a randomized clinical study is being planned in france to more formally assess if nicotine could reduce the risk of contracting the disease . an analysis of deceased patients with covid- revealed that deaths were due to complications directly related to the viral infection . among them, ards was most prevalent ( %), followed by myocardial injury ( %), liver injury ( %), and renal insufficiency ( %). multiple organ dysfunction syndrome occurred in % of cases. autopsy and biopsy of covid- cases have been sporadically reported. a report of complete autopsy in consecutive covid- -positive deaths ( males and females with median age of years) in germany found that half of the cases had coronary heart disease and a quarter of the cases had respiratory diseases (asthma/copd) . the cause of death was found within the lungs or the pulmonary vascular system in all cases. deep venous thrombosis was identified in of patients ( %) in whom venous thromboembolism was not suspected before death. pulmonary embolism was the direct cause of death in patients. the histopathology examination of lungs found diffuse alveolar damage in cases. the lesions included hyaline membranes, activated pneumocytes, microvascular thromboemboli, capillary congestion, and protein-enriched interstitial edema, which were consistent with ards diagnosis. however, another immunohistology investigation of lung tissues from covid- patients who died with respiratory failure found that the pattern of covid- pneumonitis was predominantly a pauci-inflammatory septal capillary injury with significant septal capillary mural and luminal fibrin deposition and permeation of the inter-alveolar septa by neutrophils without hallmarks of classic ards three clinical studies recorded the baseline cytokine plasma concentrations in , , and patients with covid- on admission or from initial tests. the median time from symptom onset to admission in these three papers was - days , days , and - days , respectively. however, the cytokine examination date from a fourth study may be even later , since the median time for blood sample collection in this paper was days since subjects were transferred to a designated hospital. one study reported that ifn-γ, tnf-α, il- β, and il- plasma concentrations in covid- patients were significantly higher compared to results from four healthy in addition to the consistent trend of lower lymphocyte counts observed in severe cases of covid- (table ) from different studies, total t cells, cd + t cells, and cd + t cells also were significantly lower in severe/critical covid- cases than in non-severe cases , , . subgroups of cd + t cells did not show significant proportion changes of cd ra + naïve t cells and cd ro + memory t cells between severe cases and moderate cases . however, the proportion of cd ra + regulatory t cells in severe cases ( . %) was only half the value of that in moderate cases ( . %). one study noted a slight improvement of mean t cell counts (including cd + or cd + subpopulations) in comparison to baseline values after - days of in-hospital treatment . the count improvement appears baselineproportional, regardless of disease severity. several published studies have observed features of cellular exhaustion in t cells analogous to that described for nk cells . in two related studies, the authors showed that healthy individuals could be distinguished from mild and severe covid- t cells; specifically, the severe group had much lower levels of non-exhausted (pd- -ctla- -tigit -) cd + t cells , . they also found that cd + t cells in covid- patients exhibit many aspects of exhaustion and reduced function, such as once in the cell, the virus is not killed or neutralized; instead, it may continue to replicate, and/or stimulate or kill the target cells, causing more inflammation and damage. of note is that ade is not necessarily associated with past humoral response to a related pathogen, such as dengue virus , and can occur during the primary humoral response when the neutralizing antibody is at a suboptimal level. this was documented in some severe cases following sars-cov infection , . in a study reporting patients with sars, the lung radiographic worsening of some severe cases was correlated with the time of igg seroconversion . the pattern is consistent with that of covid- , in which the disease in some severe cases suddenly worsened around one to two weeks , , when seroconversion of anti-sars-cov- occurred (around to days after the onset of the first symptom) . in addition, the recovered sars patients had higher and sustainable or steadily increasing levels of both anti-n antibody and anti-s neutralizing antibody since the seroconversion . however, the titer of anti-n antibody in the sras non-survivors was low, and the titer of anti-s antibody decreased rapidly approximately days after the peak, an observation much like that in some patients with severe cases of covid- . in vitro studies demonstrated that human anti-s serum enhanced sars-cov infection in human monocyte-derived macrophages (mdm) . the infection mechanism is very different from that of the ace -mediated, endosomal/lysosomaldependent pathway, and can be blocked by anti-fcγr ii antibody on april , the national institutes of health (nih) issued general treatment guidelines for covid- , with the recommendations based on scientific evidence and expert opinion. we do not intend to repeat the previously well-documented work in our review, but prefer to focus on two important topics: antiviral and immunomodulatory pharmacotherapies. because results from clinical trials currently are being generated at such a blazing pace, this review was up to date at the time it was written. siddiqi hk et al. many viral cellular adherence/endocytosis blocking reagents were proposed. the cellular infection mechanism of sars-cov- is believed to be the same as sars-cov, which is an ace -mediated, endosomal-dependent pathway. chloroquine and hydroxychloroquine were first identified through in vitro drug screening to reduce viral titers from the supernatant of infected cell cultures. the mechanism probably is through interference with viral entry/endocytosis by increasing the ph of the endosome . two series of open-label, non-randomized studies in france reported only one death in patients with relatively mild disease treated with hydroxychloroquine sulfate ( mg tid for days) and azithromycin ( mg on day followed by mg qd) , . the authors justified the use of azithromycin because it had been shown to be effective against zika and ebola viruses in vitro. of note is that azithromycin also prolongs the qt interval. based on limited scientific information, it is reasonable to believe that hcq may be an effective treatment. fda issued an eua on march to permit the emergency use of chloroquine phosphate and hydroxychloroquine sulfate supplied from the strategic national stockpile to treat adults and adolescents who weigh kg or more and are hospitalized with covid- for whom a clinical trial is not available, or participation is not feasible . it should be noted that the fda's typical process for eua is to review its circumstances and appropriateness periodically. the review would include regular assessments, based on additional information from the sponsor, regarding progress on the unapproved product's -or unapproved use of an approved product's-approval, licensure, or clearance. an observational study in patients from new york city did not find a significant difference in the rate of intubation or mortality between patients who received hydroxychloroquine and those did not o intravenous immunoglobulin (ivig) has been used to treat sars patients [ ] [ ] [ ] the covid- pandemic is still ongoing, and a long time may pass before we can fully grasp the complete picture of the pathogen's characteristics; including its vulnerabilities, which can be used to inform development of effective and efficient treatments. development of antiviral therapeutics, led by dna/rna polymerase and protease inhibitors, has been streamlined since their invention in combatting hiv. given worldwide extensive efforts, we are hopeful that anti-sars-cov- 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favipiravir and other drugs for the treatment of the new coronavirus covid- illnessin native and immunosuppressed states: a clinical-therapeutic staging proposal. the journal of heart and lung transplantation remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus ( -ncov) in vitro hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting sars-cov- infection in vitro insights from nanomedicine into chloroquine efficacy against covid- hydroxychloroquine and azithromycin as a treatment of covid- : results of an open-label non-randomized clinical trial clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in covid- patients with at least a six-day follow up: a pilot observational study eua) of hydroxychloroquine sulfate supplied from the strategic national stockpile for treatment of covid- in certain hospitalized patients observational study of hydroxychloroquine in hospitalized patients with 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severe acute respiratory syndrome? covid- : the new challenge for rheumatologists covid- : consider cytokine storm syndromes and immunosuppression first case of covid- in a patient with multiple myeloma successfully treated with tocilizumab tocilizumab, an anti-il receptor antibody, to treat covid- -related respiratory failure: a case report acute respiratory distress syndrome in critically ill patients with severe acute respiratory syndrome management of hospital-acquired severe acute respiratory syndrome with different disease spectrum effect of regular intravenous immunoglobulin therapy on prognosis of severe pneumonia in patients with covid- recent developments in the management of haemophagocytic lymphohistiocytosis high-dose intravenous immunoglobulin as a therapeutic option for deteriorating patients with coronavirus disease continuous intravenous anakinra infusion to calm the cytokine storm in macrophage activation syndrome. acr open rheumatol interleukin- blockade with high-dose anakinra in patients with covid- , acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study emapalumab for the treatment of relapsed/refractory hemophagocytic lymphohistiocytosis direct antiviral mechanisms of interferon-gamma plasma therapy against infectious pathogens, as of yesterday, today and tomorrow the effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis treatment of critically ill patients with covid- with convalescent plasma guidance for industry: investigational covid- convalescent plasma we would like to thank joanne berger, fda library, and karen valentine, fda center for devices and radiological health, for editing the manuscript. procalcitonin (ng/ml) % vs. % , n/a % vs % key: cord- -eevqclsy authors: mehta, chitra; kataria, sushila; mehta, yatin title: management of coronavirus date: - - journal: nan doi: . /s- - sha: doc_id: cord_uid: eevqclsy coronavirus (covid- ) disease is the most recent global public health problem. it is caused by sars-cov- (severe acute respiratory syndrome related coronavirus ), which is a rna virus with a high mutation rate, belonging to the genus coronavirus . the objective of this communication is to provide an initial understanding regarding pathophysiology, clinical manifestations, management, and prevention of this devastating disease. an outbreak of pneumonia of unidentified etiology started in wuhan district of china in the month of december . soon, scientists were able to identify it as a novel coronavirus referred to as -ncov. it has been assigned a new name, that is, severe acute respiratory syndrome related coronavirus (sars-cov- ). disease caused by sars-cov- was termed as coronavirus disease (covid- ) by the world health organization (who) soon after. in a short span, covid- has afflicted populations across all boundaries globally. unlike the sars outbreak, where it took months after the outbreak to identify the etiological organism, identification of sars-cov- was within weeks of the outbreak. this allowed a rapid development of real-time polymerase chain reaction diagnostic test specific to sars-cov- . despite this, it has had a devastating effect worldwide and continues to do so till now. sars-cov- is a positive-sense single-strand rna virus that is distinct from other coronaviruses such as sars-cov and middle east respiratory syndrome coronavirus (mers-cov). the incubation period is not exactly known, but according to the who, it is between and days. understanding of the risk of transmission is not complete yet. person-to-person spread of sars-cov- occurs through contact, droplet, and, sometimes, airborne route. droplets travel around m, but apparently the virus can remain viable in aerosols for about hours. it is estimated that the virus persists for approximately days on plastic, paper, wood, and glass surfaces. transmission is more likely during the early stage of infection as viral rna level appears to be highest soon after the onset of symptoms. viral translation has been documented from asymptomatic persons as well or from individuals within the incubation period. sars-cov- has been isolated in blood and stool specimens as well. but fecal-oral transmission does not seem to play a role as per the current understanding. , more than , cases and , deaths from covid- have been reported globally. updated case counts can be checked on the who and centers for disease control and prevention (cdc) web sites. a suspected case has been defined as a patient with acute onset respiratory infection with fever, cough, sore throat, and an epidemiological link in the form of a history of travel days prior to the onset of symptoms to countries afflicted with covid- , or a close contact with a confirmed or probable case of covid- days prior to symptom onset, or some acute respiratory infection requiring hospitalization with no other etiology fully explaining the clinical presentation, as per who guidelines. a probable case has been defined as a suspected case in whom the laboratory testing for covid- has turned out to be inconclusive. it has been advised to repeat the test to days later in such cases. a confirmed case is a patient with laboratory confirmation of infection with covid- . this is irrespective of the patient's clinical signs and symptoms as per the who. these definitions are, however, dynamic, and therefore practitioners may follow updates closely. the primary pathophysiology is acute respiratory distress syndrome (ards). there may also be an associated exuberant cytokines storm reaction as well. viral infection seems to move through two stages. first is the replicative stage, when viral replication occurs and innate immune responses of an individual fail to contain it. it is followed by the adaptive immunity stage, where adaptive immune responses result falling titers of virus. this phase is associated with increased levels of inflammatory cytokines that may lead to tissue damage with clinical deterioration. there may be an associated hemophagocytic syndrome. clinical markers such as c-reactive protein (crp) or ferritin may be used to track disease and mortality. potential patients of covid- requiring critical care may present either to an emergency department or through an interfacility transfer. routine careful questioning about the risk of covid- exposure is a must to ensure that appropriate infection control precautions are taken by the attending staff. if in doubt, any patient with unexplained several respiratory illnesses should be treated with standard contact/ droplet ± airborne precautions. all intensive care units (icus) should have a "ready bed" for airborne isolation capacity. the following practices have been broadly recommended: • the patient should be isolated in a single room with negative pressure and frequent air exchanges. patients infected with covid- present with constitutional, upper and lower respiratory tract, and gastrointestinal symptoms. the frequency of fever varies between and %. the absence of fever does not rule out covid- though. sore throat occurs in up to % of patients. shortness of breath, cough, and sputum are seen in up to % of patients. gastrointestinal symptoms such as diarrhea and nausea can occur in up to % of patients and may, in fact, be the presenting symptom that precedes the development of fever and dyspnea. silent hypoxemia, that is, respiratory failure without dyspnea may also be a presenting feature in some patients, especially in the elderly age group. physical findings are usually nonspecific. the most associated comorbidities with icu admission have been found to be diabetes and hypertension. the china cdc report has divided clinical manifestation severity-wise as follows: • mild disease: mild or no pneumonia occurring in % of cases. • severe disease: this includes respiratory rate of more than per minute, oxygen saturation (spo ) of less than %, pao /fio ratio of less than mm hg, and lung infiltrates of more than % within to hours, occurring in up to % of cases. • critical disease: this includes respiratory failure, septic shock, acute kidney injury, and multiorgan failure, occurring in up to % of cases. the who has divided clinical syndromes associated with covid- into mild illness, pneumonia, severe pneumonia, ards, sepsis, and septic shock. risk factors for severe covid- disease are divided into three categories. epidemiological risk factors are age more than years, preexisting pulmonary disease, chronic kidney disease, diabetes mellitus with hba c more than . %, hypertension, coronary artery disease, immunosuppressed state due to hiv (regardless of cd count), posttransplant or history of immunosuppressive therapy, and severe obesity (body mass index > ). clinical risk factors identified are respiratory rate of more than per minute, heart rate of more than per minute, and oxygen saturation of less than % on room air. laboratory risk factors are d-dimer more than , ng, creatine phosphokinase more than twice the upper limit of normal, crp of more than mg/l, lactate dehydrogenase (ldh) of more than u/l, elevated troponins, admission absolute lymphocyte account less than point . , and serum ferritin levels of > g/l. , all routine investigations including d-dimer, crp, procalcitonin, ldh, ferritin, and troponins should be performed. routine blood and sputum cultures should be taken. arterial blood gas analysis may show mild acidosis with normal lactate and high anion gap. white blood cell counts tend to be normal. lymphopenia is observed in approximately % of patients. mild thrombocytopenia is common, but platelet counts are rarely below × /l. elevated d-dimer is seen with normal coagulation profile initially, with the progression of disease, severe thrombocytopenia, and disseminated intravascular coagulation set in, indicating a poor prognosis. liver function tests are abnormal in approximately % of patients. procalcitonin levels have been found to be less than . in % of patients in the largest series. , [ ] [ ] [ ] covid- infection, however, results in an increase in crp levels. this may be used to track the disease severity and prognosis. in a patient with severe respiratory failure and a normal crp, non-covid- etiologies such as heart failure may be considered. chest x-ray usually reveals bilateral diffuse infiltrates with gravitational distribution. pleural effusion is uncommon. the typical finding of a computed tomography (ct) scan is patchy ground-glass opacities, mainly peripheral and basal. the crazy-paving pattern may also be seen. covid- does not appear to cause cavitation on lymphadenopathy. lung ultrasound usually shows diffuse b lines and can be used bedside to optimize ventilatory settings and follow the disease. chest ct is not indicated routinely due to a high risk of transport and spread of the contagion. it should be reserved for patients in whom an alternative diagnosis needs to be ruled out. an echocardiogram may show dyskinesia due to stress cardiomyopathy secondary to the virus. elevated troponin should not give a false suspicion of acute coronary syndrome. the utility of bronchoscopy in covid- is quite dubious. it may be associated with an enormous risk of transmission and may result in clinical deterioration. it should be considered where it would otherwise normally be done like for fungal pneumonia. it should not be performed routinely in these patients. the initial approach should be early suspicion, early recognition, immediate isolation, and institution of infection control precautions of covid- patients. patients who meet the criteria should urgently undergo testing for sars-cov- in addition to testing for other respiratory pathogens such as influenza and respiratory syncytial virus. sars-cov- rna is detected by reverse transcriptase polymerase chain reaction (rt-pcr). a positive test confirms the diagnosis of covid- . in case the initial test is negative but suspicion is high, resampling from multiple respiratory tract sites is recommended by the who. the cdc recommends that nasopharyngeal swab specimen should be collected to test for sars-cov- . the who considers the collection of oropharyngeal swab also essential. if it is collected, then it should be placed in the same container as the nasopharyngeal specimen. other preferred samples are bronchoalveolar lavage, tracheal aspirate, and sputum. in confirmed patients, blood, urine, and stool samples may also be tested. the sample should be tested within days of symptom onset and no later than days. standard triple packing should be followed for the transport of the samples as per who. pcr seems to have a sensitivity of around %. for safety reasons, it is recommended that specimens from suspected or confirmed covid- patients should not be submitted for viral cultures. differential diagnosis of covid- is given in ►table . • no antiviral therapy has been proven to work against covid- in humans. several randomized control trials are ongoing. • it is unknown whether a single antiviral agent is enough or a combination of multiple antiviral agents is required. • earlier treatment, that is, within to days of admission may be more effective than reserving it for a later date when organ failure has already set in. • maximum patients should do well without any therapy except for supportive care. among hospitalized patients, to % of patients need icu admission, of which to % require intubation. such patients would likely benefit from early therapy. • predictors of poor outcome as previously discussed, if present, should be an indication to start early antiviral therapy. there is currently scant evidence regarding appropriate antivirals to be used in covid- . some of the therapies that are being used on a trial basis by practitioners world over are remdesivir, lopinavir/ritonavir with ribavirin, and chloroquine. lopinavir/ritonavir in combination with ribavirin is being used commonly in the doses of / mg twice daily plus a -g loading dose of ribavirin followed by to g thrice a day orally for days or mg per kg thrice a day intravenously for days in moderate and severe cases. remdesivir has been found to have a superior activity than lopinavir/ ritonavir in in vitro and animal studies on mers-cov, but the availability of this drug is a big issue. some institutes are using the following investigational therapies, but as per the who, these can be used only in approved, randomized controlled trials: • in mild illness, use of lopinavir/ritonavir plus hydroxychloroquine mg (two tablets) hourly for day followed by g (two tablets) orally daily for to days. • in patients with covid- with no symptoms, hydroxychloroquine alone is being used. • in patients with severe covid- infection requiring supplemental oxygen, lopinavir/ritonavir combination plus hydroxychloroquine plus favipiravir , mg (eight tablets) twice daily as a loading dose followed by mg (three tablets) every hours for days is being used. • in patients with covid- ards, intravenous (iv) remdesivir mg iv as a loading dose on day followed by iv remdesivir mg once daily for days is being given as a part of clinical trials at various centers such as cleveland clinic, abu dhabi. the surviving sepsis campaign guidelines on covid- recommend against the routine use of lopinavir/ ritonavir or any other antiviral or chloroquine. there is insufficient evidence to issue a recommendation as per them. similarly, in certain refractory or progressive patients, with infectious disease expert approval, interferon-β b and tocilizumab are being considered, although the surviving sepsis campaign guidelines do not support their use. [ ] [ ] [ ] [ ] [ ] [ ] oseltamivir and other neuraminidase inhibitors do not seem to be effective against covid- . initial empiric therapy may include this till the time influenza infection is ruled out. there is no role of prophylactic antibiotics in covid- infected patients, but they may be used empirically at the physician's discretion in the presence of atypical presentation. the surviving sepsis campaign guidelines support the use of empirical antibiotics over no antibiotics in these patients. antibiotics may, however, be required later as bacterial pneumonia can develop during the hospital course. in one series, % of patients developed secondary infection. the who and the cdc recommend not using glucocorticoids in patients with covid- pneumonia unless there are indications such as acute exacerbation of chronic obstructive pulmonary disease. the surviving sepsis campaign guidelines on covid- recommend the use of steroids in low doses in septic shock and in mechanically ventilated adults with covid- and ards. steroids may cause a delay in viral clearance. , although the citris-ali (vitamin c infusion for treatment in sepsis induced acute lung injury) trial did not show improved mortality with ascorbic acid, some studies still recommend the use of vitamin c in moderate doses (i.e., . g iv six hourly) along with mg of iv thiamine twice daily in such patients. there is no high-quality evidence at present to support the use of ascorbic acid in viral pneumonia routinely. the use of acetaminophen or paracetamol over other antipyretics is recommended for temperature control in covid- patients. , hemodynamic support patients with covid- have rarely been found to have shock. the surviving sepsis campaign guidelines and some institutional guidelines recommend using conservative fluid strategy over liberal fluid strategy for acute resuscitation of patients with covid- infection. the cause of death from covid- is almost always ards, and this may worsen by fluid administration. dynamic parameters are preferred over static parameters for assessing fluid responsiveness. resuscitation with balanced crystalloids is preferred. the use of hydroxyethyl starches and gelatin is contraindicated. noradrenaline should be used as the first-line vasoactive agent in case of septic shock. , epinephrine/vasopressin may be added as required. supplemental oxygen should preferably be provided through a mask than nasal prongs. use of high-flow nasal cannula (hfnc) is preferred over noninvasive positive-pressure ventilation (nippv) for treating covid- -related acute respiratory failure. nippv can be provided through a mask, although there is a high risk of droplet production and transmission. helmets have also been used for this purpose at some centers. all patients with acute respiratory failure should be closely monitored for worsening respiratory status, and early intubation in a controlled setting is recommended in such a situation. , bronchodilators, if required, should be administered through metered dose inhalers to decrease the risk of viral aerosolization. the principles of airway management , are given in ►table . lung protective strategy, which is the standard recommendation for ards, should be used. target a plateau pressure of less than cm of h o. covid- patients have been found to require high positive end-expiratory pressure (peep) and usually respond well to recruitment maneuvers. if recruitment maneuvers are used, the surviving sepsis campaign guidelines recommend against the use of staircase or incremental peep recruitment maneuver. in case of a pao /fio ratio of less than , early prone ventilation can be performed for a duration of at least to hours. intermittent or continuous neuromuscular blocking agent may be used to facilitate lung-protective ventilation. early airway pressure release ventilation could be useful in some patients. , mechanically ventilated covid- patients with refractory hypoxemia, despite the use of rescue therapies, can be put on vv or va extracorporeal membrane oxygenation depending on hemodynamic stability. , management of covid- mehta et al. this concept was created during the sars outbreak. this highlighted procedures that required extra precautions due to the associated risk of viral transmission and aerosolization. these high-risk procedures were identified as hfnc, bag-mask ventilation, cpap/bipap (continuous positive airway pressure/bilevel positive airway pressure) use, endotracheal tube insertion, bronchoscopy, gastrointestinal endoscopy, and cardiopulmonary resuscitation (cpr). the primary care provider team enters the room with full ppe with minimal team size to avoid viral exposure during resuscitation. , anticipated complications in covid- patients are ards, acute liver injury, acute cardiac injury, acute kidney injury, septic shock, and disseminated intravascular coagulation. acute liver injury is the second most commonly reported complication as per the recent case reports. around % of patients have been found to die due to fulminant myocarditis. heart failure and arrhythmia have been found to occur even when respiratory illness is recovering. troponin elevation seems to strongly predict mortality in these patients. renal failure occurs in less than % of covid- patients. , the patient can be shifted to a ward if his/her physiological condition has stabilized and there is no need for intensive monitoring. since the virus scan persists for to days in moderate cases and up to weeks in severe cases, the patient should be shifted to a single room with a closed door or to a cohort ward/area. however, it is important that the patient is noninfectious at the time of discharge from the hospital. the following criteria have been recommended as per the latest guidelines: • for symptomatic patients: patient should be afebrile for days with improvement in respiratory symptoms, lung imaging must show resolution of infiltrates, and the nucleic acid test should be negative for sars-cov- from two consecutive samples of nasopharyngeal swabs taken at least hours apart. • for asymptomatic patients who are quarantined: patients must be sars-cov- negative days after the first test, that is, at the time of quarantine. , additional considerations angiotensin-converting enzyme inhibitors/angiotensin receptor blockers there is currently no evidence to suggest that angiotensin-converting enzyme (ace) inhibitors/angiotensin receptor blockers (arbs) should be discontinued in a patient with covid- due to a risk of adverse events. , in fact, covid- virus enters the cells through aceii receptors, and patients on acei or arb may theoretically have some protective effects. adjunctive therapies theoretically, there may be a role of extracorporeal therapies such as cytosorb filter (cytosorbents europe gmbh, berlin, germany) in patients with covid- sepsis and septic shock. clinicians have used the same in some cases. it has been mainly used in wuhan, china, and germany. ulinastatin is a protease inhibitor, which has been tried in some patients. an expert consensus statement on covid- from shanghai recommends the use of ulinastatin in large doses to reduce pulmonary interstitial inflammation. seventeen patients have been admitted to our facility with covid- patients to date. out of these, patients have successfully recovered and discharged home. three patients were put on a combination of lopinavir and ritonavir for high crp levels (cutoff being taken as twice the normal value). the maximum crp level observed was mg/l. all patients received ascorbic acid in . -g six hourly iv dosages. out of these three patients, one patient was given interleukin- (il- ) inhibitor in lieu of hypotension and ards. this patient also received steroids in septic doses. after il- inhibitor therapy, a significant fall in crp levels was observed, which persisted for the next days. out of these three patients, one has been discharged, and the other two have stabilized as of now. other four patients received a combination of hydroxychloroquine and azithromycin due to worsening respiratory symptoms. this was following the recent french study published that showed a decrease in viral load with hydroxychloroquine, which got further strengthened with additional azithromycin. these patients are being closely monitored. the covid- outbreak story is still evolving at present and needs to be closely followed for further developments. there has currently been no breakthrough as far as any therapeutic or preventive therapy is concerned. it is highly contagious, and the most risky ones are the asymptomatic carriers. the only preventive measure is isolation and infection control precautions. supportive therapy remains the mainstay. the psychological impact of perceived risk on the attending hospital staff cannot be undermined. each institute should have protocols ready to take care of covid- patients and their health care workers. outbreak of a new coronavirus: what anaesthetists should know coronavirus disease (covid- ): management in adults practical recommendations for critical care and anesthesiology teams caring for novel coronavirus ( -ncov) patients novel coronavirus outbreak research team. epidemiologic features and clinical course of patients infected with sars-cov- in singapore clinical predictors of mortality due to covid- based on an analysis of data of patients from wuhan, china clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china critical care crisis and some recommendations during the covid- epidemic in china characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study clinical features of patients infected with novel coronavirus in wuhan, china clinical characteristics of coronavirus disease in china radiological findings from patients with covid- pneumonia in wuhan, china: a descriptive study severe sars-cov- infections: practical considerations and management strategy for intensivists laboratory testing for coronavirus disease (covid- ) in suspected human cases: interim guidance remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus ( -ncov) in vitro in vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus (sars-cov- ) a systematic review on the efficacy and safety of chloroquine for the treatment of covid- clinical management of severe acute respiratory infection when covid- disease is suspected. https:// www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected/unknown surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ) (e-pub ahead of print) china approves use of roche drug in battle against coronavirus complications critical care for covid- affected patients: position statement of the indian society of critical care successful recovery of covid- pneumonia in a renal transplant recipient with long-term immunosuppression cytosorbents provides update on cytosorb and covid- coronavirus activities covid- world news. expert consensus on comprehensive treatment of coronavirus disease in shanghai hydroxychloroquine and azithromycin as a treatment of covid- : results of an open-label non-randomized clinical trial none. key: cord- -yn pvb authors: nan title: full issue pdf date: - - journal: jacc case rep doi: . /s - ( ) -x sha: doc_id: cord_uid: yn pvb nan t he coronavirus disease- (covid- ) pandemic has revolutionized clinical practice in recent months unlike any other health emergency in recent years. jacc: case reports has taken this challenge very seriously, dedicating to it an entire issue. we have received excellent case reports from across the world. our goal is to provide a comprehensive report of representative cardiovascular involvement in covid- (central illustration). besides the concern regarding qt interval prolongation with hydroxychloroquine and azithromycin treatment, covid- is strongly associated with the occurrence of sudden unexpected arrhythmias. given the general ignorance of the pathophysiological mechanisms of the virus at the time of submission of these case reports, it is hard to state with certainty that covid- has been the cause of these arrhythmias, but they surely offer an interesting direction for future research in the field. included are cases of brugada type i pattern positivization ( ) in the context of fever, one of the most common presenting symptoms of the disease ( ); electrical ventricular storm ( ); transient atrioventricular block in the absence of myocarditis ( ); sinus node dysfunction requiring pacemaker implantation ( ) ; and finally a provocative report on the use of amiodarone as a possible treatment for covid- ( ) . overall, the cytokine storm has proved to have a strong impact on the conduction system. the clinical presentation of patients with covid- has ranged from asymptomatic to acute respiratory distress syndrome requiring mechanical ventilation. one cause of sudden respiratory deterioration is the increased risk for venous thromboembolic disease in these patients ( ) (figure ). these events have been noted both early and in the recovery phase of covid- . furthermore, thromboembolic events have occurred despite the use of prophylactic anticoagulation or even full anticoagulation ( ) . a majority of patients have elevated levels of d-dimer and laboratory findings consistent with sepsis-induced diffuse intravascular coagulation, suggesting a coagulopathic process, yet no prospective studies have demonstrated the predictive nature of these markers for the occurrence of a thromboembolic event, only a higher risk for mortality ( ) . the early recognition and treatment of venous thromboembolic disease has therefore been a dilemma. we therefore provide commentary and suggest treatment algorithms ( ) . we received case reports in general categories detailing an increased risk or arterial thrombosis during the covid- pandemic. causing stemi in infected patients ( , ) . second, there were a number of cases of stemi in patients younger than years without risk factors for atherosclerosis ( ) . this phenomenon occasionally occurred before covid- , but the increased incidence reminds us to always include myocardial infarction in the differential diagnosis of a younger patient with chest pain and to always consider performing screening electrocardiography. third, a number of cases of stemi mimics were submitted, including patients with st-segment elevation due to myopericarditis, brugada pattern, takotsubo cardiomyopathy, or endothelial dysfunction due to infection or cytokine storm. as many as % of patients with covid- and st-segment elevation may have normal coronary arteries on angiography, complicating the decision whether to administer fibrinolytic therapy to patients without early access to primary percutaneous coronary intervention. finally, there were reports of spontaneous thrombosis ( ) involving the ascending and descending aorta, the cerebrovascular arteries, the mesenteric and renal arteries, and the peripheral arteries, underscoring an increased systemic risk for arterial thrombosis in patients with covid- . the development of heart failure in patients infected with severe acute respiratory syndrome coronavirus- has been described to involve different, and overlapping, mechanisms. one is cytokine release resulting in myocardial inflammation (figure ) , and affected patients has demonstrated both inflammatory infiltrates and viral particles. the heart failure cases presented in this special issue, however, describe more varied presentations of patients, some with pre-existing heart failure and others with no known cardiac disease prior to becoming ill with infection. in addition to cases of direct myocardial injury, some with pathological evidence, we also present cases of takotsubo cardiomyopathy ( , ) two cases highlight the special circumstances faced by patients with left ventricular assist devices ( , ) , which include the inability to tolerate prone positioning to augment respiratory support because of the mechanical equipment and the hypothesis that mechanical circulatory support may provide a type of protection against the most serious hemodynamic consequences of severe acute respiratory syndrome coronavirus- infection. included also is a case series of pediatric patients who had hemodynamic collapse and cardiac dysfunction ( ) , a presentation that has been rare in this younger age group. the now well-recognized thromboembolic disorders encountered with this disease include a case in this issue of massive pulmonary embolism and resultant severe right heart failure ( ) . and separate reports describe patients with concomitant noncardiac disease, with human immunodeficiency virus infection ( ) and with influenza ( ) . all the cases of heart failure represent the investigators' best attempts at providing supportive and emerging therapies at a time when they had no established guidelines and no best practices to follow. from the beginning of the pandemic, we believed that it was very important to publish the "voices" of our frontline colleagues across the world, to help cardiologists to get acquainted with mechanical ventilation ( ) , to describe the first evidence of sex differences in covid- ( ) , and to discuss the significant changes in health care with telemedicine and virtual clinics. the impact of covid- on african americans has also recently been described in jacc (table ) revealed leukopenia, normocytic anemia, thrombocytopenia, and significant increase in c-reactive protein levels. a nasopharyngeal swab sample tested positive for severe acute respiratory syndrome-coronavirus- (sars-cov- ) using real time-reverse transcriptionpolymerase chain reaction. the patient had a medical history of bipolar disorder and hypothyroidism. he reported having fever for week. given the patient's presentation of prolonged asystole, differential diagnosis included metabolic disorders, pharmacologic agents and extracardiac diseases with special attention to thyroid hormone levels. to recognize cardiovascular complications among covid- patients. to demonstrate arrhythmic risk related to covid- disease. to manage sick sinus dysfunction in covid- disease. during the following days, the patient had episodes of asystole associated with hypotension but without loss of cardiac output ( figure ). moreover, alternating episodes of bradycardia and tachycardia note bilateral ground glass opacities. once reversible causes were excluded, symptoms were related to dysfunction of the intrinsic sinus node, and the patient underwent dual-chamber ratemodulated implantation of a pacemaker (pm) ( figure ). because of evidence of sinus tachycardia, bisoprolol was administrated. further and later pm control showed only this episode. transthoracic echocardiography was repeated before the patient was discharged and showed no differences from the previous one. in consideration of his progressive clinical improvement, the endotracheal tube was removed, and the patient began to breath spontaneously. on psychiatric indication, therapy for bipolar disorder was reintroduced. this could be due to hypoxia and electrolyte abnormalities, which could lead to episodes of cardiac arrhythmia, or due to central nervous system alterations caused by sars-cov- disease. increasing evidence shows that covs are not always confined to the respiratory tract but may also invade the central nervous system, inducing neurological diseases ( , ) , and some covs have been shown to be able to spread to the medullary cardiorespiratory center through chemoreceptors and mechanoreceptors in the lung and lower respiratory airways through a synapse-connected route ( ) . considering that most covs share a similar viral structure and infection pathway ( ) , the infection mechanisms previously found for other covs may also be applicable to sars-cov- . furthermore, the transsynaptic transfer also has been reported for avian bronchitis virus ( ) in fact, the intrinsic cardiac nervous system has regional control over different cardiac functions, such as sinus node electrical activation and propagation, as well as atrioventricular nodal conduction, and consists of ganglia composed of afferent, efferent, and interconnecting neurons to other cardiac ganglia. these ganglia coordinate the sympathetic and parasympathetic inputs received from the rest of the cardiac autonomic nervous system. generally, autonomic dysfunction refers to a disorder of an autonomic nervous system that may arise from intrinsic or extrinsic mechanisms. intrinsic autonomic dysfunction arises from diseases that directly affect the autonomic nerves, such as diabetes mellitus and the various syndromes of primary autonomic failure. extrinsic autonomic dysfunction often is secondarily induced by cardiac or other disease ( ) . patients with autonomic dysfunction commonly have poor long-term prognosis, and death can occur from pneumonia, acute respiratory failure, sudden cardiopulmonary arrest, or fatal arrhythmias related, for example, to ssd. specifically, ssd includes a spectrum of heart rhythm disturbances related to abnormal sinus impulse formation or propagation ( ) and has different presentations, such as bradycardia, alternating episodes of bradycardia and tachycardia and sinoatrial block. in some cases, ssd presents with sinus node arrest and prolonged asystole, such as in the present patient. symptoms related to ssd are generally fatigue and syncope or presyncope, but patients can be asymptomatic in the early phase of the disease. when symptoms are related to dysfunction of sinus node, pm implantation is required. currently, data regarding the neuroinvasive potential of sars-cov- with subsequent autonomic dysfunction are less described. furthermore, to these authors' knowledge, this is the first case in medical literature of ssd related to covid- infection. an improved understanding is crucial primarily for guiding the need for additional arrhythmia monitoring during hospitalization and after discharge ( ) . the present authors believe that recognition by the scientific community of these risks related to covid- disease may be helpful for strict monitoring of affected patients and also for furthering knowledge of such complications for global public health. diagnostic coronary angiography performed through the right radial approach revealed angiographically normal coronary arteries (figures and ) . ventriculography confirmed the globally mildly reduced ejection fraction. the patient was admitted to a dedicated coronavirus disease- (covid- ) intensive care unit. the covid- results became available within h and were positive. his condition continued to improve, and he required minimal supplemental oxygen to maintain arterial saturation. all serial troponin values were negative. two days later he developed a brief episode of supraventricular tachycardia that was successfully terminated with intravenous adenosine ( figure ). four days after the initial presentation, he was doing well without fever. the c-reactive protein level had decreased to . mg/l, and the ecg demonstrated nearly complete resolution of the initial brugada-like ecg pattern ( figure ). the patient was discharged to home after the -week hospital stay. diagnosis and treatment of st-segment elevation myocardial infarction during the covid- pandemic present multiple diagnostic and logistic challenges ( ) . myocardial injury, myocarditis, acute coronary syndromes, and arrhythmias have all been described in the setting of covid- infection ( ) . st-segment elevation in the right precordial leads and brugada-like ecg patterns have previously been associated with various conditions (e.g., fever, myocarditis toxicity, metabolic disorders, certain drugs). these brugada-like patterns usually disappear once the inciting event is removed ( ) . a brugada-like ecg pattern presents an additional diagnostic and therapeutic challenge because it may be seen in patients presenting with chest pain, thus mimicking st-segment elevation. atrioventricular nodal re-entrant tachycardia, such as developed in our patient, has similarly been associated with brugada syndrome ( ) . most recently, covid- infection has been described as unmasking brugada syndrome in a patient who presented with syncope ( ). our case is important because it demonstrates the need to differentiate between the brugada syndrome and the brugada-like ecg configuration. given that our patient had a covid- -associated brugada ecg pattern with no history of syncope, observation therapy was recommended because the risk of major adverse cardiac events is low ( ) . covid- manifests mainly as a respiratory syndrome that includes pneumonia and, in the worst case scenario, acute respiratory distress syndrome ( ) . we have also learned that, in a not negligible number of cases, the virus can provoke myocardial ischemia and/or inflammation, with or without an associated respiratory syndrome ( ) . there are already numerous cases of covid- manifesting as st-segment elevation myocardial infarction that have triggered activation of primary percutaneous coronary intervention protocols. the cause of this stsegment elevation is unknown: it has been linked to traditional plaque rupture in those patients who have required coronary angioplasty, but it has been suggested that myocarditis or microvascular thrombosis could be the cause when no obvious thrombus or coronary flow interruption is detected. if all this were not sufficient, here comes brugada type i pattern, interfering with and complicating the lives of interventional cardiologists. indeed, in the case reported by vidovich ( ) , the patient presented with shortness of breath, substernal chest pain, and fever. the electrocardiogram showed a brugada type i pattern in the right precordial leads with no reciprocal changes; the presence of chest pain, shortness of breath, and reduction of systolic left ventricular function, assessed with a -dimensional echocardiogram, led to urgent coronary angiography, which excluded an ongoing acute coronary syndrome. no significant electrolyte imbalance was found. vidovich's ( ) conclusion was that the brugada type i pattern, completely unknown to the patient until this admis- a link between fever and a brugada type i pattern is very well known and has been described extensively ( ) ( ) ( ) . in fact, the international guidelines on sudden cardiac death recommend lowering body temperature as soon as possible in those patients with an established diagnosis of bs, as well as in carriers of the mutations with a proved inducible brugada type i pattern ( ) . the increase in body temperature has indeed been proven to cause a higher degree of inactivation of sodium channels, both mutated and wild ones: in the subjects who are genetically predisposed, this reduced sodium flow can result in a dangerous transmural heterogeneity that is the basis for phase re-entry ventricular arrhythmias and sudden death ( , ) . it would also be of interest understand whether the virus itself could interact directly with the myocardial ion channels and provoke the electrocardiographic modification typical of bs. the take-home message is therefore that patients with bs and concomitant covid- infection should be monitored in the intensive care unit or in the telemetry ward until the fever is resolved, regardless of their respiratory conditions. further research will be needed to help clinicians to navigate this uncharted sea. a -year-old man presented to the emergency department with acute-onset high-grade fevers accompanied by dry cough and shortness of breath that had been ongoing for a week before presentation. he denied any associated nausea or vomiting, diarrhea, sore throat, congestion, or skin rash. of note, he had recently returned from a high-prevalence area for coronavirus disease- (covid- ) within the united states and was in self-quarantine. he was monitoring his symptoms; however, when his shortness of breath was not improving with his asthma medications (albuterol inhaler and cetirizine), he presented to the emergency department. on arrival, he was noted to be febrile at . f, he was tachypneic to breaths/min, he was normotensive at / mm hg, his heart rate was beats/min, and he was saturating % oxygen on room air. physical examination was remarkable for decreased breath sounds bilaterally. his past medical history was significant for mild intermittent asthma. our patient's clinical presentation was concerning for viral or bacterial lower respiratory tract infection. an electrocardiogram revealed normal sinus rhythm with normal pr ( ms) and qrs ( ms) intervals to anticipate and diagnose conduction disturbances associated with the novel coronavirus. to understand the mechanism responsible for high-degree av block associated with covid- without evidence of overt myocarditis. ( figure ). no acute st-t wave changes were noted. a single-view chest radiograph showed blunted costophrenic angles bilaterally with concern for right middle lobe opacity ( figure inflammatory markers were mildly elevated; the ferritin level was mg/ml (normal range to ng/ml), and c-reactive protein was elevated at . mg/dl (normal range to . mg/dl). the procalcitonin level was negative at . ng/ml (normal range to . ng/ml), and thyroid hormone levels were within normal limits. his nasopharyngeal swab tested positive for sars-cov- ribonucleic acid. given the patient's underlying asthma, which predisposed him to an increased risk for pulmonary patients were noted to have cardiac arrhythmias ( ) . covid- involvement of the heart has ranged from asymptomatic myocardial injury to acute coronary syndrome, mild to fulminant myocarditis, stress cardiomyopathy, and cardiogenic shock; however, the mechanism of cardiac involvement is not exactly clear ( ) . furthermore, underlying cardiovascular disease or risk factors and myocardial injury have been shown to portend poor prognosis in these patients ( ) . in this case, we present a patient with moderate covid- infection who showed evidence of transient conduction disturbances with highdegree atrioventricular (av) block. high-degree av block is known to be an uncommon presentation of acute myocarditis in adults, more commonly seen in cardiac sarcoidosis and giant cell myocarditis ( ) . however, because our patient did not have any other overt evidence of myocardial involvement, with normal cardiac biomarkers and a normal echocardiogram, his presentation is unusual and interesting. it is possible that covid- may have caused subclinical myocarditis leading to high-degree av block in this case. ace receptors are abundant in the heart and are present in multiple cell types, including macrophages, endothelial cells, smooth muscle cells, and cardiomyocytes ( ) . further, animal models have shown the presence of ace receptors in sinoatrial nodal cells in rats ( ) , and conduction disturbances and ventricular fibrillation have been noted with overexpression of the ace receptor in experimental mice models ( ) . hence, another possibility is that isolated involvement of the av node and infra-hisian conduction system by sars-cov- may have caused transient high-grade av block. whether this block is secondary to direct viral involvement or is an autoimmune response is unknown at this time. our patient did not have a recurrence of these conduction disturbances after he was started on supportive her medical history included mild asthma, heart failure with preserved ejection fraction, coronary artery disease (percutaneous coronary intervention ), paroxysmal atrial fibrillation (af), hypertension, obesity, and total hip arthroplasty -month prior. her differential diagnosis included bacterial/viral pneumonia, acute on chronic heart failure with preserved ejection fraction, pulmonary embolism, and coronavirus disease- (covid- ) . on arrival she was hemodynamically stable: heart rate beats/min, blood pressure / mm hg, respiratory rate of , and oxygen saturation % on l nasal canula. physical examination noted bilateral rales. chest x-ray showed patchy bilateral consolidations with mild interstitial edema ( figure ) . a computed tomography pulmonary angiogram revealed no pulmonary embolism but bilateral interlobular septal thickening and peripheral ground glass opacities most prominent in the posterior and lower zones. laboratory tests were remarkable for a white blood cell count of . k/ml, absolute lymphocyte count of /ml, the differential for electrical storm in covid- remains broad. myocarditis and cytokine storm may not be universal drivers of cardiac sequelae in covid- . management of these arrhythmias requires consultation with expert, multidisciplinary teams. hemoglobin . mg/dl ( . mg/dl month prior), hyponatremia to mmol/l, ferritin of , ng/ml, nterminal pro-brain natriuretic peptide of pg/ml, and c-reactive protein of . mg/dl (figure a ). remaining laboratory tests were within normal limits. a nasopharyngeal swab was sent for severe acute respiratory syndrome-coronavirus- (sars-cov- ) and respiratory viruses, blood cultures were collected, vancomycin and cefepime were started, and the patient was admitted to a negative-pressure room. were mildly elevated at admission and continued to rise with ast, reaching a peak on day of admission. similarly, alt peaked on day of admission. by discharge, the transaminase levels were downtrending ( figure ). an abdominal ultrasound showed normal liver size ( . cm) with increased liver echogenicity and a nodular contour suggestive of liver fibrosis, likely due to fontan associated liver disease (fald). his cbc was trended with normalization of his platelet count by day of hospitalization. in the emergency room, the patient was hypoxic with oxygen saturations of % on right atrium with accompanying dyspnea. he was placed on to l of oxygen via a nasal cannula, which led to an improvement in the oxygen saturations to low s. ggt (g-glutamyl transferase) being the most common ( ) . this patient had modest transaminitis likely due to the effects of covid- on his underlying fald ( ) . the patient was discharged after a -day hospitali- over the -month period preceding the sars-cov- -related stay-at-home order, a total of patients followed by the achd service at the university of washington medical center with defects of various severities died in an acute setting. in this report we unexpected mortality among patients with achd appears to have acutely increased at a single academic achd center during the sars-cov- pandemic. the ongoing sars-cov- pandemic appears to be contributing to increased achd mortality by delaying patient contact with health care. routine follow-up care for high-risk groups, including those with congenital heart disease, during the sars-cov- pandemic is critical to ensure appropriate triage and care for vulnerable populations. even with prior clinical stability, these populations remain at risk for acute cardiovascular complications and increased mortality. describe a series of acute-setting achd deaths that occurred within a single week at the time of the effective stay-at-home order. acute-onset death was defined as death that occurred either out of the hospital or within h of presentation to a medical facility. with the exception of patient (case ) who was called but did not answer the phone days prior to being found dead at home, none of the patients had a missed clinic appointment since the initiation of the stay-at-home order, and none had made contact with the medical system to report concerning symptoms prior to their deaths. a after the procedure, the impella cp catheter was removed without complications, and the femoral access was closed with the use of proglide closure systems (abbott vascular, santa clara, california). the staff allowed to enter the catheterization lab since its outbreak in italy in mid-february, covid- has spread rapidly, with over , cases and more than , deaths to date. epidemiologic analysis shows that the presence of comorbidities significantly increases mortality: . % in patients with cardiovascular diseases; . % in patients with diabetics; . % in patients with chronic respiratory diseases; % in patients with hypertension; and . % in oncologic patients ( ) . given the high number of infected patients, we often diagnose cardiovascular diseases at different stages during the viral pathology. in this perspective, some selected patients could benefit from treatments that deviate from current guidelines. we report the first case of a patient with covid- and acute coronary syndromes treated in italy for unprotected lmca stenosis with protected percutaneous coronary intervention. the use of the impella cp cardiac assist system to provide left ventricular support during high-risk percutaneous coronary interventions is recommended in such settings, because its efficacy is supported by randomizedcontrolled trials ( ) and large registries ( , ). nevertheless, this case also highlights the importance the patient had no significant medical history. he never smoked. there was no family history of cardiovascular disease (cvd). an early viral panel polymerase chain reaction was negative for multiple respiratory viruses. a severe acute respiratory syndrome-coronavirus- (sars-cov- ) nucleic acid amplification test early and rapid testing is critically necessary in patients with suspected covid- to prevent severe evolution. ecg st-segment elevations in inferior leads have been described in several covid- patients, with variable clinical significance. an accurate evaluation of the true incidence of acute myocardial injury related to covid- requires a standardized definition, which should include a combination of ecg changes, biochemical markers, and imaging abnormalities. given the very low pre-test probability for coronary artery disease and the absence of coronary calcifications on the chest ct scan, a coronary ct angiogram was not indicated, and the patient was not referred for invasive coronary angiography. the patient was treated conservatively, without thrombolytic agents or initiation of the acute coronary syndrome management protocol. the covid- pandemic represents the largest worldwide health care challenge to date. limited but rapidly emerging data have documented the role of cvd in increasing both the risk of infection and the severity of its clinical presentation ( ) ( ) ( ) ( ) . in particular, cvd is associated with a sharp increase in overall mortality, which reaches almost % of patients hospitalized ( ) . however, although such an association can be anticipated to a certain degree (on the basis of existing data from previous outbreaks of influenza and severe acute respiratory syndrome), the incidence of myocardial injury in covid- infection appears to be higher ( ) . furthermore, the definition of covid- -associated "myocardial injury" lacks standardization and is based primarily on elevated (and highly variable) serum levels of cardiac-specific troponins as the single most common defining markers. this myocardial injury has been associated with possibilities. logistically, we now understand that the decision to proceed with angiography carries a significant risk for nosocomial spread of the virus endangering hospital staff. we are also learning that acute kidney injury is quite prevalent and highly associated with mortality in covid- patients ( ). one should think twice before administering intravenous contrast medium in these patients. consensus documents from our professional societies that are based on early covid- observations have resurrected considering the use of fibrinolytic therapy for stemi ( ) . in a setting of limited staffing and resources, and where time to treatment is expected to be significantly delayed, fibrinolytic therapy provides a more rapid and logistically easier approach to reperfusion therapy while reducing staff exposure to infection. however, contraindications to fibrinolytic therapy have to be absent, and stemi mimics have to be excluded. the fibrinolytic strategy is probably most reasonable for hospitals without pci capability or immediate availability. at pci-capable hospitals with adequate staffing, primary pci is still preferred ( , ) . until there is universal availability of rapid testing (< min) for both the virus and the antibodies, our approach to stemi will have to be modified. this is primarily the result of new infection control considerations that will have to be included in our daily workflow. the current door-to-balloon time quality metric should be suspended by hospital quality improvement committees as a measure of system performance because of the current diagnostic and logistical challenges in delivering stemi care. in the american college of cardiology national cardiovascular data registry cathpci registry reporting form, noting a "system delay" as a reason for a prolonged door-to-balloon time will avoid any external quality of care penalties. we now work in the era of covid- stemi care. the patient remained asymptomatic, and no confirmatory tests were performed for the same reason as in the first patient. very late lad artery stent thrombosis was found, and a new des was implanted. the patient was asymptomatic, but because the covid- pandemic had reached its peak, a pre-admission polymerase chain reaction test was performed, with a positive result. the patient had a favorable course and was discharged days later. as antiplatelet therapy. ten days later, prasugrel was replaced by clopidogrel (after antiviral treatment was completed), and the patient was discharged. the covid- pandemic has significantly decreased worldwide interventional cardiology activity. in spain, cardiac catheterization procedures have been reduced by %, with a reduction of % for primary angioplasty ( ) . similar data have been reported in we present case of acute stent thrombosis and very late stent thrombosis cases ( table ) . despite no initial covid- testing in cases, symptoms and subsequent testing ( figures a to d ) supported that the patients were infected at the time of stent thrombosis ( table ) . the patient reported an active lifestyle with a history of playing competitive football and had a body mass st-segment elevation myocardial infarction with a high thrombus burden can appear as the first and only onset of covid- symptoms. plaque rupture in predisposed patients with cardiovascular risk factors can be enhanced by severe inflammation and worsened by prothrombotic characteristics of this new infectious disease. in the course of this covid- pandemic, sars-cov- infection should probably be ruled out in patients with unusual or severe thrombotic and ischemic events, even when there are no symptoms of covid- disease. index of kg/m . he had no significant medical history except for past smoking ( pack-years), which he had quit years before. he had no family history of cardiovascular disease and was taking no medication or drugs. no diagnosis other than a stemi was possible. the initial electrocardiogram displayed a sinus rhythm with an anterior st-segment elevation and q waves with negative t waves in the inferior leads the patient did not develop heart failure, or heart rhythm disturbances, or other complications of myocardial infarction. furthermore, he remained free of covid- disease symptoms. in the context of the covid- pandemic, unusual myocardial infarction presentations, such as in young individuals at low cardiovascular risk, should lead to with t-wave inversion in diii and avf ( figure ). the patient had no past medical history and was not on any medications. to describe the management of patients with refractory ards requiring coronary angiography. to describe the feasibility of coronary angiography with the patient in prone position. the differential diagnosis included acute myocardial infarction, myocarditis, and takotsubo syndrome. there was no evidence of obstructive coronary disease, and the final diagnosis was myocarditis, although we were not able to perform cardiac magnetic resonance in this highly unstable patient. with a rapid spread worldwide, covid- has become a public health emergency of international concern ( ). the clinical course of sars-cov- infection is mostly characterized by respiratory tract symptoms, including fever, cough, pharyngodynia, fatigue, and complications related to pneumonia and ards, often in a patient in prone position, the geometry and orientation of the heart as well as the coronary anatomy do not allow to obtain perfectly symmetric pictures of the coronary arteries using usual views. consequently, the interpretation of coronary angiography was simply done following the heart's shape. with unchanged cranial/caudal tilts ( , ) or using the double-inversion technique to normalize all angiographic pictures such as in a left-located heart ( ) is usually enough to perform and analyze coronary angiography in such patients. finally, even though we did not perform percutaneous coronary intervention, performing percutaneous coronary intervention with a patient in prone position would not be a critical issue for an experienced operator. pandemic, the most plausible diagnosis seemed to be a severe acute respiratory syndrome-coronavirus- (sars-cov- ) infection. tables and summarize the biochemical tests and atrial blood gas analysis before, during, and after amiodarone therapy. figure shows the illness clin- no adverse events were reported. the patient was discharged on day . infection in cell cultures and mouse models ( , ) . amiodarone is a widely available, low-cost antiarrhythmic drug that in the past has been considered as a possible antiviral medication ( ) . amiodarone and its main metabolite (mono-n-desethyl amiodarone) were shown to inhibit the entry of filoviruses (a family of single-stranded, negative-sense rna viruses that includes ebola virus) at the same serum concentration found in patients treated for arrhythmias ( , ) . amiodarone also proved able to remain to be investigated, and drug interaction with other treatments (e.g., hydroxychloroquine, lopinavir/ritonavir, atazanavir, and darunavir/cobicistat) are major concerns ( ) . notably, amiodarone toxicity at follow-up visit, days after discharge, the patient was asymptomatic. in this case, amiodarone was given for research purposes in a hospital setting. this is an approach still under investigation. do not try this at home. to diagnose acp in patients with sars-cov- -related ards. to appreciate potential role of almitrine in improving oxygenation and rv function. to understand sars-cov- -related atypical type of ards. medical history included only an overweight with a body mass index of . kg/m . the differential diagnosis included pulmo- and septal dyskinesia disappeared ( figure c ). moreover, rv global longitudinal strain improved from - . % to - . % ( figure d ). twelve hours following almitrine infusion, rvswi decreased from . to . g/m/beat/m . the clinical spectrum of sars-cov- -related cardiovascular complication includes myocarditis, pericarditis, vasoplegia, rv failure, and acute coronary syndromes ( , ) . in this case, we highlight the rv dysfunction another explanation is the impact of ards and mechanical ventilation on the rv. acp is a well-known complication of ards despite a protective ventilation, with an incidence of %. hence, acp may be related to a high driving pressure, leading to an increased rv afterload ( ) . moreover, the patient was on norepinephrine, which may increase rv afterload. another explanation is that hypoxia could lead to rv dysfunction in its own right ( ). ventilation-to-perfusion ratio ( ) . moreover, previous studies in the s showed that at a low dose, the deleterious effect on pulmonary vascular resistance was negligible, especially when associated with nitric oxide ( ) . hence, we hypothesized that almitrine use in the case of sars-cov- atypical ards might be useful. in the present case, almitrine infusion was associated with rv function improvement and decrease in pulmonary vascular resistance. this is probably due not only to a better oxygenation, but also to a better distribution of pulmonary vascular flow to aerated lung areas. before almitrine infusion, we observed a high rvswi with a normal-to-low range of ci, suggesting a hemodynamic disconnection between the rv and left ventricle. the reduction in rv afterload by almitrine infusion resulted in an improvement in this disconnection (decreased rvswi and improved ci). as almitrine infusion could induce reversible lactic acidosis and hepatic dysfunction ( ) to describe high-risk clinical features in a patient on durable lvad support who developed covid- . to illustrate potential complications and clinical dilemmas in managing covid- in a patient supported with a durable lvad. reverse transcription polymerase chain reaction results for severe acute respiratory syndrome-coronavirus- (sar-cov- ) was positive at the initial emergency department visit and at the authors' institution. serial laboratory and imaging tests are detailed in table . several markers of disease severity were abnormal including absolute lymphocyte count, c-reactive protein level, and cardiac enzymes. chest radiographs showed bilateral infiltrates concerning for atypical pneumonia (figure ). the patient was quarantined in a negative-pressure intensive care room. the host response to covid- infection is often localized in the lung parenchyma, but a surge in proinflammatory cytokines can occur ( , ) . known as a "cytokine storm," this phenomenon is described in dynamics. we should closely monitor for: ) rv failure and need for inotropic support; ) drops in lvad speed or suction events, low flow, or pulsatility index events due to vasoplegia associated with infection. to limit health care workers' exposure to covid- , nonessential testing such as echocardiograms, the antimalarial medication hydroxychloroquine, which was chosen as the initial treatment agent for our patient, was shown to reduce in vitro sar-cov- cell entry, and a retrospective study suggested its clinical benefit in covid- ( , ) . a major side effect is qtc prolongation, so the present protocol provides monitoring guidance of this complication. immunomodulatory biological agents such as tocilizumab are reserved for severe covid- , defined by the values in bold are in-hospital values that were consistent with baseline values. *last visit values were the latest values obtained within the previous months. baseline ldh, wbc, platelet, absolute polymorphonuclear leukocytes, and absolute lymphocytes were recorded as an average of the previous values measured within year. †this patient was placed on ventilator support on the night of hod and was given tocilizumab on the evening of hod . ‡this patient experienced pulseless electrical activity arrest after the return of spontaneous circulation. krelative change is the percentage of increase or decrease from baseline value. alt ¼ alanine aminotransferase; ards ¼ acute respiratory distress syndrome; ast ¼ aspartate aminotransferase; bnp ¼ b-type natriuretic peptide; ck-mb ¼ creatine kinase mb; cvp ¼ central venous pressure (obtained from right heart catherization at baseline, and from central venous line in the hospital); egfr ¼ estimated glomerular filtration rate; fio ¼ fraction of inspired oxygen; hod ¼ hospital day; ldh ¼ lactate dehydrogenase; lvad ¼ left ventricular assist device; map ¼ mean arterial pressure (obtained from doppler or arterial line); pao ¼ arterial partial pressure of oxygen; wbc ¼ white blood cell. presence of both worsening respiratory failure and a cytokine storm as shown by increasing inflammatory markers. still, caution is warranted as major adverse effects of tocilizumab include infection, infusion reactions, dyslipidemia, neutropenia, and potential malignancy ( ) . patients on lvad support are particularly vulnerable to infectious complications due to the inherent presence of hardware and driveline finally, prone ventilation is beneficial in cases of severe ards. the maneuver has been effective in improving lung mechanics and gas exchanges, and in some cases, it may prevent the need to escalate to venous-venous extracorporeal membrane oxygenation ( , ) . although there are no published outcomes, early experience in wuhan, china indicates that prone position was widely used in patients with covid- -related severe ards with possible benefits ( ) . nonetheless, it may be prohibitive in heart failure patients on lvad support. a -year-old woman presented with productive cough, fatigue, fever, and diarrhea for the previous days. physical abbreviations as in figure . ( ) . stress cardiomyopathy has also been reported with viral infections ( ) . histological studies have shown mild inflammatory infiltration ( , ) , and it is possible that heightened inflammation with viral infections, particularly that seen with covid- , may contribute to development of stress cardiomyopathy. overall, the prognosis of stress cardiomyopathy is favorable, with the majority of patients fully recovering lv function by months ( ). twitter: @ferrasdabbagh . he had a history of hypertension and was taking lisinopril. the differential diagnosis included sars-cov- causing severe ards and acute cardiac injury from direct viral toxicity (i.e., myocarditis), acute coronary syndrome (acs), demand ischemia, and stress cardiomyopathy. prevalence and prognostic implications of cardiac injury (defined as troponin elevation > th percentile upper reference limit) in covid- . considerations for differentiating causes of cardiac injury in covid- . management strategies for myocarditis and severe ards in covid- . and mortality benefit in animal models ( ) . improved airway inflammation has also been observed in animals treated with aris ( ) . other viral infections such as influenza and respiratory syncytial virus were considered, but the pre-test probability for covid- was high because other residents at the facility had been diagnosed with covid- recently. in the emergency department, the patient was tachypneic with an initial oxygen (o ) saturation %. table lists the results of his initial laboratory testing including normal levels of ferritin, procalcitonin, interleukin (il)- , and il- . levels of c-reactive protein, lactate dehydrogenase, and troponin were elevated. there was a reduced white blood cell count without lymphopenia. a chest radiograph had no air space or interstitial infiltrates (figure ). there was a single low-flow lvad alarm noted days prior to presentation. based upon the adequate room air saturation, absence of pulmonary infiltrates, and minimally abnormal inflammatory markers, the patient was classified as having a mild case of covid- . due to persistent breathlessness, hydroxychloroquine was initiated on day with qtc monitoring. to the best of our knowledge, this is the first re- in the current covid- pandemic, lopinavir/ritonavir was studied in a randomized, controlled trial in table ) . the patient was discharged to his nursing facility on hospital day once a room was available where he could be quarantined, and he continued to feel well days later. mahmood et al. to make a diagnosis of fulminant myocarditis concomitant with covid- pneumonia. to understand the value of serial cardiac magnetic resonance after myocarditis due to covid- . sinus tachycardia ( beats/min) with negative t waves from v to v . to be able to arrive at the differential diagnosis of acute cardiac dysfunction in the setting of severe covid- disease early after heart transplantation. to understand the need for individualized management, balancing risks of infection and rejection in heart transplantation recipients with severe infections early after transplantation. was discharged to isolation at home with pulse oximetry and plans for daily telemedicine assessments. three days later the patient presented to the emergency department with rapidly progressive respiratory distress and hypoxia. the patient had a history of end-stage non- figure . the patient reported continued gradual recovery by weekly telemedicine assessments after discharge. he had a history of pityriasis lichenoides chronica. he had no personal or family history of congenital heart disease, immunodeficiency, or autoimmune disease. the differential diagnosis included viralinduced myocarditis or underlying cardiomyopathy unmasked by an acute viral illness. table ) . the patient has had no recurrent episodes of chb since day of admission, and a repeat echocardiogram on day of admission demonstrated lownormal biventricular systolic function. and conduction abnormalities appears to be a rare manifestation of sars-cov- infection in children ( ) ( ) ( ) . nonetheless, evaluation for myocardial injury may be warranted in pediatric patients with symptomatic sars-cov- infection, particularly in patients whose clinical symptoms (e.g., dyspnea, hypoxia) seem out of proportion to chest imaging findings. on autopsy, histopathologic examination of the heart showed mild to moderate myocyte hypertrophy with mild to moderate diffuse interstitial and perivascular fibrosis (figures a and b) . the impact of influenza co-infection in this patient with covid- must also be considered because this virus is known to contribute to cardiovascular morbidity and mortality secondary to up-regulation of the inflammatory response and endothelial dysfunction ( ) . as such, influenza a likely had significant effects on her cardiac functioning. coinfection with sars-cov- is of great concern, with limited data delineating the the patient's medical history showed arterial hypertension, dyslipidemia, and impaired fasting blood sugar. covid- has extrapulmonary and cardiovascular manifestations. covid- may be associated with exaggerated inflammatory response with an abnormal activation of coagulation, so a screening of coagulation setup may be indicated. covid- may show up with takotsubo syndrome. the differential diagnosis included acute myocardial infarction, takotsubo syndrome, myocarditis, and coronary embolism. the patient was transferred to our center for an urgent coronary angiography, which revealed nonsignificant coronary atherosclerosis. figures and , videos and ). our priority was to treat the patient with enoxaparin , iu twice daily as per the patient's weight. during the first days of hospitalization, and taking into consideration that the patient was hypotensive (systolic blood pressure: mm hg; mean blood pressure: < mm hg), we treated the patient with chest radiography was repeated in the following days and showed progressive reduction of interstitial pneumonia. also, blood test results revealed an improvement of inflammation indexes ( table ) . on day of hospitalization, the nasopharyngeal swab was repeated, with a positive result. the first negative result was registered on day . on the th day, we performed another transthoracic echocardiography, which showed the resolution of the thrombi ( figure ) and a complete restoration of lvef ( %) (video ). his past medical history was notable for type diabetes mellitus, remote prostate cancer, and ventricular tachycardia. covid- and concern over prolonged separation from his family. our service is modeled after previously published "e-consultation" workflow recommendations in "peacetime" prior to the sars-cov- outbreak ( ). in phase , we implemented these processes, and all emergent cases were treated as puis. as we approach phase , our processes continue to undergo iterative improvements and all cases coming to the ccl will be considered puis. our approach to stat and routine tee is outlined in remote monitoring is used for electrophysiology clinic device checks, with patients triaged to present for evaluation if they develop concerning arrhythmias, heart failure alerts, or device-related issues. *vt storm that has failed medical treatment including at least antiarrhythmic drugs (including propranolol), treatment of underlying reversible condition if present (qtc prolongation due to ischemia, medications, or metabolic/electrolyte imbalance), general anesthesia, and left stellate ganglion block (if available). †not reversible or fails to respond to chronotropic drugs such as isoproterenol, dopamine, and/or scopolamine, and temporary pacing cannot be safely maintained in an intensive care setting. in this scenario a screw-in active fixation lead connected to an externalized generator or an active fixation temporary pacing lead may be considered depending on the patient's clinical condition and could be performed in the intensive care setting under fluoroscopic guidance (if available) or in an operating room with negative airflow capabilities and fluoroscopy. cied ¼ cardiac implantable electronic devices; eos ¼ end of service; eri ¼ elective replacement indicator; vt ¼ ventricular tachycardia. in the wake of this pandemic, formal medical student and trainee didactics were disbanded to allow for social distancing. additionally, several states expe- her past medical history included hypertension and diabetes mellitus. the differential diagnosis included communityacquired pneumonia, atypical pneumonia, and coro- figures a and b ). the patient was started on therapeutic enoxaparin and was closely monitored for hemodynamic instability. she declined to take hydroxychloroquine, recommended by some experts for management for covid- . she remained hemodynamically stable and was transitioned to oral anticoagulant therapy (apixaban) with plans to continue anticoagulation for months. the covid- outbreak is an unprecedented global public health challenge. since the end of december , when the first cases of sars-cov- infection were detected in wuhan, china, the disease has spread exponentially ( ). on january , , the world health organization declared covid- , the disease caused by the novel coronavirus, a public health emergency of international concern and later officially upgraded it to a global pandemic. as of april , , more than , , confirmed cases from more than countries and more than , deaths have been documented worldwide. the projected u.s. death toll is > , , with an estimated total burden of more than million covid- cases. in approximately % of cases, fever is the most common presentation, followed by cough ( %), vomiting ( %), and diarrhea ( . %) ( ) . in up to % of patients, the natural course of the disease is complicated by severe interstitial pneumonia, which can lead to acute respiratory distress syndrome, multiorgan failure including acute kidney injury, dissemi- to suspect pe early in the disease process in confirmed or suspected covid- patients. to identify high-risk patients early and to offer appropriate therapies while mitigating patient and provider risk. the patient was managed with intravenous unfractionated heparin (ufh) and dobutamine; infection. cdt is associated with early improvement in rv function and hemodynamics in deteriorating patients with lower doses of tpa ( , ) ; however, pui approximately times less frequent ( , ) . importantly, a substantial proportion of the thrombotic events were diagnosed very early during the hospital stay, suggesting that they had already occurred before admission ( ) . in view of the previously mentioned (preliminary) findings, and although it cannot yet be concluded with safety that the thrombosis risk among patients with severe covid- is substantially higher than that of patients with severe infection caused by other bacterial or viral pathogens ( , ) , thrombotic events are very likely to be a key aspect of covid- -associated morbidity and mortality ( ) . it is therefore now necessary to make the patient's medical history was notable only for obesity (body mass index kg/m ) and type diabetes. the primary differential diagnosis for the patient's the usual risk stratification schema for acute pe rely on a combination of hemodynamic clinical parameters, such as hypoxemia, tachycardia, and hypotension along with serum biomarkers, such as troponin or brain natriuretic peptide, followed by confirmatory imaging tests ( ) . severe covid- -related ards may present with many similar hemodynamic and biomarker derangements masking underlying vte. illness. figure ). an axillobifemoral bypass was performed, followed by therapeutic anticoagulation with good initial results. the patient died days after surgery from a major hemorrhage. case . the third patient was a -year-old male with history of hypertension, diabetes, and coronary artery disease ( table ) who was admitted for hypoxic ct angiography of patient shows a nonobstructive thrombus formation of descending aorta (arrow) in an axial view (a) and a sagittal view (b). disease. a recent paper attributes this state "to excessive inflammation, platelet activation, endothelial dysfunction, and stasis" ( ) . others have suggested that formation and polymerization of fibrin are responsible for this hypercoagulability ( ) . therefore, recent recommendations insist on thromboprophylactic measures to prevent thromboembolism ( , , ) . a recent publication found evidence of the presence of virus in endothelial cells ( ) . one explanation is that the angiotensin-converting enzyme receptor that the virus uses to infect cells is widely expressed in endothelial cells. this causes endotheliitis, which could explain why covid- patients seem prone to venous and arterial thrombosis. this paper ( ) blockade may also be considered ( ) . it should be noted that mild ards may be managed with noninvasive forms of ventilation. however, during the present pandemic, modifications to usual critical care may be necessary. given concern for viral transmission, current recommendations advise it is also important to monitor the patient's driving pressure, or difference between the peep and plateau pressure, as increased driving pressures have been associated with higher mortality in ards ( ) . with a basic understanding of these fundamentals, it is possible for all cardiologists to provide safe and effective care for our patients with covid- . as many of us prepare to use skill sets long forgotten, it will be important to remember to ask for help when needed. one of the few bright spots in this pandemic has been the resurgence of interdisciplinary team- and is thought to protect against lung injury. these functions may be due to differences in the location of the ace proteins, transmembrane or in the plasma ( ) . the ace gene is located on the x chromosome, which suggests that women might have higher ace levels and thus be protected against more severe disease compared to men ( ) . there has been recent concern in the cardiology community about the possible negative effect of italy, as it has done in the past, will improve its health and economic systems after this tragedy. probably nothing will be like before, and this catastrophe will be a great opportunity to further improve an efficient and effective national universal health system. heroes, we look like prey in heroes' capes. that kind of bravery, that work integrity, is not boundless. no one is so fearless or short-sighted as to discount all risks. when i try to figure out how i feel in this moment, the italian motto "andrà tutto bene" ("everything will be alright") that has been viral since the onset of the the ccl nursing staff was reinforced to speed up procedures. all noncritical equipment or supplies were removed from the ccl to facilitate cleaning and disinfection procedures. availability of ppe is a concern, so we created sets of ppe to best manage available resources: a mid-level kit and a fullprotection kit for suspected and confirmed cases. despite the concern of the medical community, we believe society has largely adhered to the social isolation recommendations, as we are looking at a constant drop in admissions to intensive care units and an increase in patients successfully discharged. the availability of masks for everyone is still not a reality as we are conceiving the first draft of a plan to reduce restriction measures. subsequently, as we are receiving more papers, we have decided to divide jacc: case reports publications into sections: acute coronary syndromes, heart failure, arrhythmias, thromboembolic events, and stories from the front line, in the format of "voices of cardiology" papers. all these papers have been highlighted in this issue ( ) . recognizing the value of not overloading our audience with publications, and in an effort to keep the quality high and up to the standards of jacc journals, we accepted approximately % to % of the manuscripts submitted. we selected the best of the best cases and brought together world-renowned specialists to write editorials. although we understand that clinical cases have been of crucial importance for our understanding of covid- , it is of equal importance that they cannot substitute for large studies and pharmacological trials. therefore, unless we were dealing with an impressive side effect of a medicine, we have been very cautious in publishing pharmacological evidence, as large trials would prove the benefits and side effects of these medicines currently under trial. another important task of jacc: case reports is that to ease navigation on the acc covid- hub, its content was organized into sections on clinical guidance, practice considerations, and frontline perspectives. given the novelty and rapidity of the covid- pandemic, most of the initial content was based on analyses of frontline experiences and expert opinion. the hub executive team and sqc worked to ensure that the content struck a balance between reasonable, actionable suggestions and acknowledgment that more rigorous research was needed to better inform the best approach to covid- management. going forward, the hub will continue to generate content but now turn its attention to highlighting the growing peer-reviewed research on covid- and cv disease. the acc has commissioned a task force to promote research in this area, and the hub will serve as a primary dissemination platform, in conjunction with jacc and other cardiology-focused journals. in addition, the hub will highlight best practices and frontline experiences from its membership on "reopening" protocols. with projections that covid- will ebb and flow worldwide over the next several years, our membership will need to navigate the best way to continue to treat cv disease during this time. the acc covid- hub has proved to be a useful resource to assembling and distributing information broadly during a rapidly evolving pandemic. lessons learned include the need to build a nimble process to commission, organize, and distribute content, an ability to engage with experts to generate content, a method to closely monitor of member and community needs to inform content development, and an emphasis on highlighting rigorously conducted research and expert consensus over mere opinion and speculation. sars-cov- infection in children available at: https:// picsociety.uk/news/pics-statement-regardingnovel-presentation-of-multi-system-inflammatorydisease covid- and the heart sars-cov- and viral sepsis: observations and hypotheses myocardial localization of coronavirus in covid- cardiogenic shock: covid- does not spare the heart cardiac involvement in a patient with coronavirus disease (covid- ) the cytokine release syndrome (crs) of severe covid- and interleukin- receptor (il- r) antagonist tocilizumab may be the key to reduce the mortality epidemiology of covid- among children in china cardiac 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worries doctors: where are the heart attacks and strokes? reduction in st-segment elevation cardiac catheterization laboratory activations in the united states during covid- pandemic sented at: international conference and exhibition on pediatric cardiology professor sir magdi yacoub and the aswan heart centre pitfalls of judgment during the covid- pandemic covid- faq's in pediatric cardiac surgery resource allocation and decision making for pediatric and congenital cardiac catheterization during the novel coronavirus sars-cov- (covid- ) pandemic: a u.s. multiinstitutional perspective covid- : crisis management in congenital heart surgery considerations for triaging lessons from sars: a retrospective study of outpatient care during an infectious disease outbreak effects of response to ebola outbreak on deaths from malaria, hiv/aids, and tuberculosis, west africa critical care utilization for the covid- outbreak in at the epicenter of the covid- pandemic and humanitarian crises in italy: changing perspectives on preparation and mitigation covid- and italy: what next? italy's health performance, - : findings from the global burden of disease study coronavirus infections-more than just the common cold the obelisk press-seurat editions, ; new address for correspondence: dr e-mail: george.collins@ucl.ac.uk. twitter: @drgeorgecollins clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china the use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease (covid- ): the experience of clinical immunologists from china exploring personal protection during high-risk pci in a covid- patient: impella cp mechanical support during ulmca bifurcation stenting for the american college of cardiology's interventional council and the society for cardiovascular angiography and interventions. catheterization laboratory considerations during the coronavirus (covid- ) pandemic: from the acc's interventional council and scai reacquainting cardiology with mechanical ventilation in response to the covid- pandemic the covid- pandemic and cardiovascular complications: what have we key: cord- -ce ovan authors: asselah, tarik; durantel, david; pasmant, eric; lau, george; schinazi, raymond f. title: covid- : discovery, diagnostics and drug development date: - - journal: j hepatol doi: . /j.jhep. . . sha: doc_id: cord_uid: ce ovan an epidemic of acute respiratory syndrome (covid- ) started in humans in wuhan in , and became a pandemic. groups from china identified and sequenced the virus responsible for covid- , named sars-cov- , and determined that it was a novel coronavirus (cov) that shared high sequence identity with bat- and pangolin-derived sars-like covs, suggesting a zoonotic origin. sars-cov- is a member of coronaviridae, a family of enveloped, positive-sense, single-stranded rna viruses that infect a broad range of vertebrates. the rapid release of the sequence of the virus has allowed the development of diagnostic tools (e.g., rt-pcr). additionally, serological tests can allow identification of persons who have been infected. in humans, covs tend to cause mild to moderate upper respiratory tract infections. the fatality rate is around - % for infected persons. an acute respiratory distress syndrome (ards) likely due to an uncontrolled immune activation (“cytokine storm”) occurs in patients with severe disease and poor prognosis. risk factors for mortality include: advanced age, obesity, diabetes, hypertension and other comorbidities. drug repurposing has been used to rapidly identify potential treatment for covid- , which could move quickly to phase- . better knowledge of the virus, its enzymes, will be mandatory to develop more potent and specific direct-acting antiviral agents (daa). in the long term, a vaccine to prevent infection would be crucial; however even if successful it might not be available before - . to date, with the exception of intravenous remdesivir and dexamethasone, which have modest effects in moderate to severe covid- , no strong clinical evidence supports the efficacy and safety of any other drugs against sars-cov- . the aim of this review is to provide insights on the discovery of sars-cov- , its virology, the diagnostic tools, and the ongoing drug discovery effort. the world health organization (who) announced on march th , that the outbreak of "coronavirus disease " (covid- ) , which initially started in asia, has become pandemic. on september th the etiologic agent "severe acute respiratory syndrome (sars)-cov- has spread all over the world with a global estimation of around million confirmed cases and around , deaths [ ] . the rapid availability of the virus rna genome sequence was instrumental in the development of diagnostic tools and for the identification of experimental treatments. in this review, we will clarify aspects related to the discovery of sars-cov- , virological features, diagnostic tools, complex pathogenesis, including a focus on the liver and gastro-intestinal lesions, and of course drug discovery. the causative agent of covid- is a novel coronavirus (cov) officially named sars-cov- . it was named after sars-cov- , because of a genomic homology [ ] . coronaviruses are enveloped, large positive-sense single-stranded rna viruses (+ssrna), gathered in the coronaviridae family. covs can infect a broad range of vertebrates, including bats, birds, pangolins, snakes, mice, and humans. due to sequence similarities with ratg bat and pangolin cov strains, it is currently thought that sars-cov has a zoonotic origin and has secondary acquired human-to-human spreading capacity [ ] . in particular, the acquisition of i) mutations in the receptor binding area, ii) a polybasic furin cleavage site (rrrar) at the junction of subdomain and of the spike protein and iii) a site of o-linked glycosylation in the same area, has enabled the virus to efficiently interact with high affinity (via its spike protein) with its bona fide cellular receptor (angiotensin-converting enzyme (ace- )) [ ] , to become more virulent and pathogenic, while potentially evading immune response by o-glycan epitope masking [ ] . where does the virus replicate? following replication and sub-genomic rna synthesis, the viral structural proteins, are translated and inserted into the endoplasmic reticulum (er). these proteins move along the secretory pathway into the er-golgi intermediate compartment. in infected cells, the cov rna-synthesizing machinery associates with modified er membranes that are transformed into the viral replication organelle; double-membrane vesicles appear to be the central hub for viral rna synthesis [ ] . otherwise, the duration of sars-cov- is significantly longer in stool samples than in respiratory samples [ ] . disrupted cell membrane [ ] . viral particles were observed in the epithelial cells by electron microscopy suggesting that these lesions might be partially caused by a direct cytotoxicity. a better understanding of the functions/roles of viral proteins, as well as of the virus replication cycle, with a particular attention on host-cell/virus interactions, will allow the identification of novel or a better characterization of targets for antiviral agent development. the success of drug development for hepatitis c virus (hcv) has inspired scientists to achieve the same for other viruses [ ] . entry process. many cell types could express ace and transmembrane serine protease (tmprss ), the two cellular factors important for virus entry [ ] , including nasal and lower airway epithelial cells (pneumocytes), lung resident immune cells, endothelial cells, as well as neurons, enterocytes, cardiomyocytes, hepatocytes, kidney cells [ ] [ ] [ ] . but the presence of mrna in these cell-types is not sufficient. study of the expression at protein levels of these entry factors, as well as the demonstration of bona fide viral entry and active replication in all these cell-types is yet missing. interestingly, it was very recently shown that ace is an interferon-stimulated-gene (isg) [ ] , meaning that the presence of ifns in the microenvironment of the virus replication site could further enhance the spreading of the virus. the molecular details of the entry process, involving the spike protein and host receptor/coreceptor, have already been studied [ ] . polybasic furin cleavage site at the junction of subdomain and of the spike protein, may explain the large number of cell types that may be infected by the virus with the consequent diverse organ manifestations, including, possibly the thrombotic complications as a result of possible endothelial cell infection. this research will facilitate the identification of neutralizing antibodies or small molecules, which could target this step of the life cycle. covs encode several enzymes that are crucial for the replication of the virus and ideal target for antiviral development, amongst which two proteases/proteinases (plpro and clpro), the rdrp, a helicase, an mrna-cap-methyltransferase, and an exoribonuclease. these enzymes have been well studied for sars-cov, and thanks to the high homology between the two sars covs, we could expect functional similarities and the possible repurposing of drugs [ ] [ ] ] . the rdrp (also identified as nsp ) bears the main enzymatic activity of the replicase complex. recent advance in antiviral research against hcv [ , ] , has confirmed that rdrp are major target for very specific antiviral discovery. similarly to hcv, sars-cov genome is characterized by a positive-sense single-strand rna and share a similar replication cycle requiring a rdrp. this polymerase displays resembling catalytic mechanisms and key conserved amino acids in the active site. the rdrp d structure has been readily characterized [ ] [ ] . interestingly it has a large nterminal extension containing a kinase-like fold. the polymerase domain, like hcv, is composed of three subdomains; a fingers subdomain, a palm subdomain, and a thumb subdomain. moreover, j o u r n a l p r e -p r o o f also the -chymotrypsin-like protease ( clpro) is vital to virus replication and the clpro cleavage sites are highly conserved, so it could be a promising drug target [ ] . plpro and clpro/mpro are essential enzymes for the proteolytic processing of cov replicase polyprotein; their activities are needed very early in the infection process to step-by-step release other viral enzymatic activities. they are also attractive targets for specific antiviral discovery. sars-cov and sars-cov share high amino-acid sequence identities for these two proteases and d structures are also available. moreover biochemical assays are also available for functional testing, at least for the sars-cov proteins [ ] . plpro is a cysteine protease, encoded by nsp , and involved in the release of nsp to , as well as in the regulation of host innate immunity functions to allow viral escape [ ] . although the similarity between plpro of sars-covs is not very high, the catalytic domain, around the triad cyst-his-asp, is well conserved; therefore drug already in the pipeline for sars-cov might be repurposed. ctpro/mpro is encoded by nsp , forms a functional homodimer, utilizes a catalytic dyad cys-his, and is involved in the release of nsp to from polyprotein. its activity is key for cov replication-cycle and its inhibition very efficient at stopping viral replication. due to the dimeric nature of this protease, not only catalytic inhibitors, but also allosteric ones can be developed increasing possibilities of success. moreover the very high similarity of ctpro/mpro sars-covs allow repurposing of drugs [ ] . some specific antiviral screenings have been promptly started on ctpro of sars-cov- and several drug candidates already identified [ ] [ ] . beside virologic aspects of covid- , it is also important to better understand immunologic ones, as well as their mutual amplification responsible for an increased pathogenesis in patients. if the virus can be studied in cell culture model, immunological aspects of covid- can only be studied either in relevant animal model or during clinical studies, using patient samples. it is now rather well established that in patients with poor outcome there is an uncontrolled "cytokine storm", featuring a local and systemic production of pro-inflammatory cytokines such as il- , tnf-α and il- β [ ] [ ] [ ] [ ] [ ] . recently, it has been reported that ace is a human interferon-stimulated gene (isg) in vitro using airway epithelial cells and extend the findings to in vivo viral infections. these data suggest that sars-cov- could exploit species-specific interferon-driven upregulation of ace , a tissue-protective mediator during lung injury, to enhance infection [ ] . more studies are needed to clarify the origin of this massive and uncontrolled cytokine production. covid- tests can be grouped as nucleic acid, serological, antigen, and ancillary tests, all of which play distinct roles in hospital, point-of-care, or large-scale population testing [ ] . methods for the detection of viral nucleic acid. pcr tests for sars-cov have been available since january . rt-qpcr-based assays performed on respiratory specimens has j o u r n a l p r e -p r o o f emerged as the cornerstone of covid- diagnostic testing. the usa centers for disease control and prevention (cdc) has developed a widely used sars-cov rt-qpcr assay [ ] . the kit contains pcr primer-probe sets for two regions of the viral nucleocapsid gene (n and n ), and for the human rnase-p gene to ensure the rna extraction was successful. this assay differs from the who's one, which target sars-cov rdrp and e genes [ ] . to avoid potential cross-reaction with other endemic covs, as well as potential genetic drift, at least two molecular targets should be included in the assay. evolution and potential mutations in sars-cov- genome strengthens the need to continue optimizing the oligonucleotides by global updated sharing of sars-cov- genomes [ ] . theoretical specificity of most rt-qpcr assays is % because the primer design is specific to the sars-cov- genome. occasional false positive results may occur due to technical errors or reagent contamination [ ] . a cycle threshold (ct) value of rt-qpcr less than is generally interpreted as positive when results are interpreted as qualitative [ ] [ ] . quantitative interpretation of ct as indicators of the copy number of sars-cov- rna in specimens needs an appropriate standard curve with adequate limit of detection [ ] . a rigorous assessment of the diagnostic accuracy of the many newly introduced sars-cov- assays is hampered [ ] [ ] . the sensitivity of viral rna testing varies with timing of testing relative to exposure. a false positive result erroneously labels a person infected, with consequences including unnecessary quarantine and contact tracing. false negative results are more consequential, because infected persons may not be isolated and can infect others. one modeling study estimated that the probability of a falsenegative result in an affected patient decreases from % on day to % on day [ ] . on the day of symptom onset, the median false-negative rate estimation was %. sample pooling strategy was suggested to offer a viable alternative to detect community transmission at a time when tests are in short supply globally [ ] [ ] [ ] . one potential limitation of pool testing is that the false-negative rate may increase owing to dilution of positive samples. point-of-care pcr kits can shorten the turnaround time for screening and diagnosing patients with suspected sars-cov- . these rapid tests typically have lower throughput and are generally more expensive than other tests. time efficient methods that do not require thermal cycling have been designed and are evaluated [ ] . crispr-cas /cas -based assay are also currently in development for point-of-care use [ ] [ ] . nature of samples tested. the current diagnostic strategy to identify patients with covid- is to test samples taken from the respiratory tract to assess for the presence of sars-cov- specific nucleic acid targets [ ] . a nasopharyngeal specimen is the preferred choice for testing, but oropharyngeal, mid-turbinate, or anterior nares samples are also acceptable [ ] . a pharyngeal virus shedding was shown to be very high during the first week of symptoms [ ] . infectious virus was readily isolated from throat-and lung-samples, but not from stool ones. serum and urine were usually negative for the presence of viral nucleic acid [ ] [ ] . the viral load in nasopharyngeal samples peaks within the first few days after symptom onset, before declining [ , [ ] [ ] . for nasopharyngeal specimen, samples should be obtained by using a flocked swab to enhance the j o u r n a l p r e -p r o o f collection and release of cellular material [ ] [ ] . samples taken from sputum, endotracheal aspirates, and bronchoalveolar may have greater sensitivity than upper respiratory tract specimens [ ] . inadequate sample collection may result in a false-negative test. bronchoalveolar lavage fluid specimens had the highest positive rates of sars-cov rt-qpcr assay [ ] . a single nasopharyngeal swab has become the preferred swab, as it is well tolerated and safe. saliva may also be an alternative specimen source that requires less personal protective equipment and fewer swabs, but requires further validation [ ] [ ] . serologic testing. if rt-qpcr-based molecular assays for detecting sars cov- in respiratory specimens remain the current reference standard for diagnosis, point-of care technologies, and serologic immunoassays have also rapidly emerged [ ] [ ] [ ] . serologic tests that identify antibodies to sars-cov- from clinical specimens may be less complex than molecular tests [ ] . as antibody responses to infection take days to weeks to be reliably detected [ ] , their utility for diagnosing acute infections is limited [ ] . serologic assays might be more relevant in surveying for asymptomatic infection or in scenarios in which patients present to medical care with late complications of disease, when rt-qpcr may be falsely negative [ , ] . seroconversion in most cases of sars occurs during the second week of symptoms [ ] . for sars-cov- infection, timing of seroconversion appears similar to or slightly earlier than in sars-cov- infection [ ] . in a study of patients with covid- , % of patients were tested positive for antiviral igg within days after symptom onset, with seroconversion for igg and igm occurring simultaneously or sequentially [ ] . negative results would not exclude covid- infection, particularly among those with recent exposure to the virus. the viral spike protein is perceived as the clear candidate for inclusion in an immunoassay that detects whether antibodies are present [ ; ] . the other protein that appears to be important antigen for the development of serological assays is the n protein (structural component of the nucleocapsid). indeed, antibodies to this protein are frequently detected in covid- patient [ ] [ ] , suggesting that n protein may be one of the immunodominant antigens in the early diagnosis of covid- [ , [ ] [ ] . it is now established that sars-cov- pre-existing immune reactivity can exist in the general population. serum samples from patients with covid- showed some cross-reactivity for the sars-cov- nucleocapsid antigens [ , [ ] [ ] . a recent study detected sars-cov- -reactive cd + t cells in % of unexposed individuals, suggesting cross reactive t cell recognition between circulating ''common cold'' coronaviruses and sars-cov- [ ] . t cell reactivity was highest against proteins other than the coronavirus spike protein, but t cell reactivity was also detected against spike. several monoclonal antibodies have been described that target the s glycoprotein of sars-cov- from memory b cells of an individual who was infected with sars-cov- in [ ] . one antibody (s ) potently neutralizes sars-cov- by engaging the receptor-binding domain of the s glycoprotein. enzyme-linked immunosorbent assays (elisa) and clia are common laboratory platforms that can measure antibody titers (igg and igm). a variation of these tests can use magnetic, proteincoated microparticles, known as a chemiluminescent microparticle immunoassay. being able to quantify antibodies will be important for identifying convalescent plasma donors with abundant titers and studying how the immune system responds to the virus. neutralizing antibodies (nabs) play important roles in virus clearance and have been considered as a key immune product for protection or treatment against viral diseases. in covid- , transfusion of convalescent plasma or serum from recovered patients was also considered as a promising therapy [ ] . the neutralization assay is a laboratory-based test that uses live virus and cell culture methods to determine if patient antibodies can prevent viral infection in vitro [ ] . because immunofluorescence assay is a labor-intensive method, a substantial number of the new commercial covid- antibody tests developed as screening tests are not elisa-based. they are lateral flow immunoassays (lfia), which provide no quantitative information. these qualitative lfia represent typically small, portable rapid diagnostic tests (rdt), and can be used at point of care. conclusions on serologic testing. antibody testing is ramping up quickly, with a growing list of commercial kits and test protocols from academic researchers [ ] . many questions will have to be answered. the first and most urgent is the validation of serologic tests. a recent meta-analysis showed wide range sensitivities from % in lfias to % in the clias [ ] ; sensitivities were higher with increased time after symptom onset. the specificities are excellent ( %). assays must be optimized further, independently validated, and used in an algorithm format to achieve the highest possible accuracy for decision making [ ] [ ] . second, there is insufficient data of the magnitude and duration of antibody responses after infections. although data suggest that neutralizing titers correlate with severity of infection [ ] , it remains elusive, whether this effect is caused by ongoing somatic hypermutation or ongoing production of highly potent antibodies that were initially generated. moreover, any documentation that limits individual freedoms on the basis of biology risks becoming a platform for restricting human rights [ ] . physiopathology. several potential pathogenic mechanisms may be involved including coagulopathy, endothelial dysfunction, and excessive release of pro-inflammatory cytokines. the endothelial dysfunction caused by infection activates an excessive thrombin generation and inhibits fibrinolysis, which designates hypercoagulability [ ] . lymphopenia is frequent in patients with covid- [ ] . the cytokine release syndrome could have a major role in patients with severe covid- as in acute respiratory distress syndrome (ards) [ ] . the pathological features of covid- related ards are diffuse alveolar damage with hyaline membrane formation with fibrin deposition and a few multinucleated enlarged cells [ ] [ ] . in patients who died from covid- associated respiratory failure, the histologic pattern in the peripheral lung was diffuse alveolar j o u r n a l p r e -p r o o f damage with perivascular t-cell infiltration [ ] . the lungs also showed distinctive vascular features, consisting of severe endothelial injury, but also widespread thrombosis with microangiopathy. alveolar capillary microthrombi were frequent, with a high amount of new vessel growth (intussusceptive angiogenesis). transmission by asymptomatic carriers. several findings are consistent with person-to-person transmission of this novel coronavirus in hospital and family settings . a case of sars-cov- infection acquired outside asia in which transmission appears to have occurred during the incubation period [ ] . furthermore, in a previously reported family cluster, some of the family members had positive rt-qpcr results without any symptoms [ ] . clinical characteristics. among , patients from china with laboratory-confirmed covid- , . % were admitted to the intensive care units (icu), . % underwent invasive mechanical ventilation, and . % died [ ] . the most common symptoms were fever and cough. the median incubation period was days. in another study including patients, with who died in hospital, half of the patients had a comorbidity, with hypertension being the most common, followed by diabetes and coronary heart disease [ ] . in-hospital death was associated with older age, higher sequential organ failure assessment (sofa) score, and d-dimer greater than μg/ml on admission. in another study of the , patients infected with sars-cov- admitted to icu in italy, the median age was years and % were male [ ] . among , patients with available respiratory support data, % needed respiratory support, including % who received mechanical ventilation and % who received non-invasive ventilation. finally, in this case series of critically ill patients admitted to icus, the majority were older men and icu mortality was %. moreover, data from previous coronavirus infections such as severe acute respiratory syndrome and middle east respiratory syndrome, as well as emerging data from the covid- pandemic, suggest there could be substantial fibrotic consequences following sars-cov- infection [ ] . imaging findings. the hallmarks of covid- were bilateral and peripheral ground-glass and consolidative pulmonary opacities [ ] . notably, % of patients with early disease had a normal ct. with a longer time after the onset of symptoms, ct findings were more frequent, including consolidation, bilateral and peripheral disease, greater total lung involvement, linear opacities, "crazy-paving" pattern and the "reverse halo" sign. bilateral lung involvement was observed in % in early phase and % in late phase of the disease. ct scans at the time of symptoms may increase diagnosis rate since rt-pcr sensitivity may be as low as % [ ] . also, chest x-ray findings in covid- patients frequently showed bilateral lower zone consolidation [ ] . coagulopathy disorders. sars-covid- -induced infection can be associated with a coagulopathy, findings consistent with infection-induced inflammatory changes as observed in patients with disseminated intravascular coagulopathy (dic) [ ] . the initial coagulopathy of covid- presents with elevation of d-dimer and fibrin/fibrinogen-degradation products. covid- -j o u r n a l p r e -p r o o f associated coagulopathy should be managed as it would be for any critically ill patient, using thromboembolic prophylaxis and standard supportive care measures for those with sepsis-induced coagulopathy or dic. current data do not suggest the use of high anticoagulation doses [ ] . among all the numerous clinical manifestations associated with covid- infection, we can recall cardiological lesions with acute myocardial injury [ ] ; neurological lesions with encephalitis and myalgia [ ] [ ] , cutaneous manifestations with rash and urticaria [ ] , and acute kidney injury [ ] . (figure ) . elevation of liver enzyme occurs in to % of patients. the pattern of liver injury is mainly at hepatocellular rather than cholestatic level [ ] [ ] , with hepatocyte degeneration, focal necrosis, capillary bile duct cholestasis and inflammation in the portal area, but interestingly sars-cov- cannot be detected in samples [ ] . frequently, the severity of liver injury had been correlated to the severity of covid- . the presence of underlying chronic liver diseases could render covid- patients at higher risk of severe liver injury, such as acute-on-chronic liver failure [ ] , with data suggesting that nafld/madld could be an independent risk factors for severe covid- [ ] [ ] . the virus was found in stool samples in around % of patients with covid- , with around % of them complaining of abdominal pain and diarrhea [ ] . it was demonstrated that sars-cov is capable to productively replicate in ace -positive enterocytes [ ] . due to the abundance of the virus in the small intestine, liver cell exposure through the hepatic reticular system is expected. hepatic default immune status might play a critical role in covid- infection. indeed, it has been shown that in patients with mafld, the polarization status of macrophage might be skewed due to metabolic stimuli such as fatty acids and thus affecting host-inflammatory response to signals generated from the gut-liver axis [ ] . in covid- , the "cytokine storm" bears resemblance to sars caused by the sars-cov- , where cytokine storm has been associated with disease [ ] [ ] [ ] . on the other hand, direct cytopathic damage by sars-cov- is also possible as there are entry receptors ace- in cholangiocytes [ ] . also, learning from sars experience, the use of antibiotics, antivirals, together with possible secondary bacterial infection, might lead to liver injury in covid- patients [ ] . moreover, tocilizumab is evaluated for the treatment of covid- patients with serious lung damage and accompanying elevated blood levels of il- [ ] . prophylactic nucleoside analogs against hepatitis b virus had been recommended for those hepatitis b surface antigen positive covid- patients planned for immunosuppressive therapy [ ] . liver damage, which lead to drug withdrawal, has been reported in patients treated with remdesivir. accordingly, it is not recommended for those covid- patients with alt> times uln or with liver decompensation to receive remdesivir [ ] . lastly, hypoxia and shock induced by covid- related complications may also cause hepatic ischemia [ ] . to manage liver injury related to covid- , several guidelines have been issued [ ] [ ] [ ] ] . suffered from gastrointestinal symptoms such as nausea or vomiting, diarrhea and anorexia [ ] , with similar incidence among adults and children [ ] . patients with gastrointestinal symptoms may require longer duration of hospitalization [ ] [ ] ] . in some patients, gastrointestinal without respiratory symptoms might be the presenting clinical features [ ] [ ] . the underlying mechanism may be related to the abundant expression of ace mrna and receptor protein in the enterocytes [ ] [ ] . histological changes with the presence of plasma cell and lymphocytes infiltration in patients' lamina propria of enterocytes suggested an immune-mediated response [ ] . the capability of sars-cov to infect enterocytes has also been demonstrated in human intestinal organoids [ ] . one of the major concerns of enteric infection is whether fecal source can lead to fomite transmission, especially when infective aerosols are generated from the toilet plume. indeed, cluster of cases infected with covid- , in analogy to "amoy garden" during the sars in , has recently been suggested in hong kong [ ] . in accordance to the surface stability study on plastic and different materials, sars-cov- could remain viable up to hours [ ] . in one study, in % of patients, sars-c v rna remained positive in feces despite clearance in the respiratory specimen [ ] . taking together, it is of great importance that the presence of sars-cov- in the stool need to be determined for the epidemiology control of covid- . there is a major concern with the potential concomitant infection of sars-cov- with influenza or other respiratory diseases such a respiratory syncytial virus, or tuberculosis or even bacterial infections or mycoplasma. co-infection with sars-cov- and influenza a virus in a patient with pneumonia has been reported in china [ ] . covid- might be underdiagnosed because of false-negative tests for upper respiratory specimens or co-infection with other respiratory viruses. prevention and transmission control measures. washing hands frequently, using mask and social distancing are important. china banned travel to and from wuhan city on january , and this shutdown was associated with the delayed arrival of covid- in other cities by approximately days [ ] . suspending intra-city public transport, closing entertainment venues and banning public gatherings were associated with reductions in case incidence. early on, the spatial distribution of covid- cases in china was explained well by human mobility data [ ] . following the implementation of control measures, this correlation dropped and growth rates became negative in most locations. a contact-tracing application, which builds a memory of proximity contacts and immediately notifies contacts of positive cases could achieve epidemic control if used by enough people [ ] . much like with influenza, antiviral drugs to be effective likely need to be started early in infection course. in turn, this represents a burden to identify drugs that are indeed effective against the virus in clinical trials. patients with early disease may benefit from antiviral agents to reduce viral load, patients with severe and late disease may benefit from anti-inflammatory j o u r n a l p r e -p r o o f drugs. furthermore, in the beginning of the disease, anti-inflammatory drugs might be harmful by increasing viral load. drug repurposing. drug repurposing (also called drug repositioning or reprofiling) is a strategy for identifying new uses for approved or investigational drugs that are outside the scope of the original medical indication [ ] . this strategy offers various advantages over developing an entirely new drug, with a reduction risk of failure because safety has already been evaluated. but also the time frame and the cost can be reduced, because most of the preclinical testing and safety assessment have been done. an extensive repositioning activity of approved drugs has been embarked for the covid pandemic. a selection of drugs being tested for covid- are represented in table . for example of large randomized ongoing trial the design of "solidarity", is provided in table . has also been combined with azithromycin, an antibiotic. hcq would inhibit sars-cov- entry into cells. few data are coming from reports and small studies [ ] . a systematic review on the efficacy and safety of hcq for the treatment of covid- concluded that there is currently no evidence from rcts to inform on hcq efficacy [ ] . in a multicenter, open label, randomized controlled trial, patients admitted to hospital with laboratory confirmed covid- were included in the intention to treat analysis ( patients assigned to hcq plus standard of care (soc), to soc [ ] . there was no difference in term of efficacy between the arms. adverse events were higher in hcq recipients than in non-recipients. lopinavir is an antiretroviral protease inhibitor used in combination with ritonavir in hiv therapy, which has shown some antiviral activity against sars-cov [ ] . a randomized, controlled, openlabel trial involving hospitalized adult patients with confirmed sars-cov- infection and severe respiratory illness covid- was performed [ ] . patients were randomly assigned to receive either lopinavir-ritonavir, in addition to soc, or soc alone. there were no differences between groups (virologic aspects, duration of disease, mortality), indicating that there is no benefit in hospitalized adult patients with severe covid- . cell culture data suggest that this compound demonstrates activity with an ec of . µm [ ] . one wonders why it was selected for clinical trials with such a weak activity. evaluating in humans repurposed drugs that are essentially ineffective in culture against sars-cov- is being repeated over and over again wasting time and resources. remdesivir is a prodrug of a nucleotide analog that is intracellularly metabolized to an analogue of adenosine triphosphate that inhibits viral rna polymerases. remdesivir has broad-spectrum activity against members of several virus families, including filoviruses (e.g., ebola) and coronaviruses (e.g., sars-cov and mers-cov [ ] . six large studies are ongoing ( table ) . unfortunately remdesivir must be given intravenously for at least days, although an aerosol formulation is being developed. were reported [ ] . from the patients whose data were analyzed, clinical improvement was observed in / patients ( %). a randomized, double-blind, placebo-controlled, multicenter trial was performed in china [ ] . mortality at day was similar between the two groups ( % died in the remdesivir group vs % in the placebo group). there was no difference in the two groups regarding clinical improvement and viral load decreased. this trial did not attain the predetermined sample size because the outbreak of covid- was brought under control in china, therefore, it is difficult to reach a definitive conclusion. gilead is conducting two randomized, open-label, multicenter, phase clinical studies to evaluate the safety and efficacy of two dosing durations - days and days -of remdesivir in adults diagnosed with covid- (the simple studies). the first simple study is involving hospitalized patients with confirmed sars-cov- infection, oxygen saturation of % or less while they were breathing ambient air, and radiologic evidence of pneumonia [ ] . in the second simple study patients were randomized to receive open-label remdesivir for or days or soc alone. at day , a higher proportion of patients in the -day treatment group achieved improvement in clinical status versus the soc group, achieving statistical significance for a ≥ -point improvement in ordinal scale (p= . )(gilead press release). however, most clinician would have preferred to see a decrease in mortality on treatment. clearly another controlled study will have to be performed soon. among other antiviral drugs being tested for covid- we can quote arbidol [ ] [ ] , favipiravir [ ] , famotidine [ ] [ ] , and camostat (tmprss inhibitor) [ ] . dexamethasone. glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. in a controlled, open-label trial of patients hospitalized with covid- , patients were randomly assigned to receive oral or intravenous dexamethasone ( mg once daily) for up to days or to receive soc alone [ ] . in the dexamethasone group, the incidence of death was lower than that in the soc group among patients receiving invasive mechanical ventilation ( . % vs . %) and among those receiving oxygen without invasive mechanical ventilation ( . % vs . %) but not among those who were receiving no respiratory support at randomization ( . % vs . %). in a recent trial involving patients with ards who were undergoing mechanical ventilation, mortality at days was percentage points lower among those receiving dexamethasone than among those receiving soc [ ] . in the early phase of the infection, anti-inflammatory drugs may not be efficient (maybe harm-full) increasing viral load. viral shedding in sars-cov- appears to be higher early in the illness and declines thereafter [ , , ] . the greater mortality benefit of dexamethasone in patients with covid- who are receiving respiratory support and among those recruited after the first week of their illness suggests that at that stage the disease may be j o u r n a l p r e -p r o o f dominated by inflammation, with active viral replication playing a secondary role. clearly a trial of the combination remdesivir and dexamethasone may yield interesting results. early triple combination of interferon beta- b, lopinavir-ritonavir, and ribavirin was safe and superior to lopinavir-ritonavir alone in alleviating symptoms and shortening the duration of viral shedding and hospital stay in patients with mild to moderate covid- . future clinical study with interferon beta- b as a backbone is warranted [ ] . tocilizumab (actemra), also known as atlizumab, and sarilumab (kevzara) are both immunosuppressive drugs, mainly for the treatment of rheumatoid arthritis. they are both humanized monoclonal against the interleukin- receptor (il- r), and are given by injection. clinical trials are ongoing. moreover other monoclonal antibodies or agents targeting other inflammatory cytokines (tnf-α, il- β...) should be soon tested. kinase inhibitors. the janus activating kinase (jak)-signal transducer and activator of transcription (stat) pathway has been implicated as a key driver in many inflammatory diseases. with the onset of small molecule inhibitors that can selectively and specifically target key jaks involved in controlling downstream inflammation, exploration for their utility across a broad range of diseases has become a rapidly expanding field [ ] [ ] , including viral infections (eg. hiv; [ ] [ ] [ ] ). baricitinib and ruxolitinib are two known jak inhibitors. recently, artificial intelligence enabled the identification of a group of approved drugs that could inhibit clathrin-mediated endocytosis and thereby inhibit viral infection of cells [ ] [ ] . the drug targets are members of the numbassociated kinase (nak) family. baricitinib was identified as a nak inhibitor, with a particularly high affinity for aak , a pivotal regulator of clathrin-mediated endocytosis. this drug is also known to target jak and could have a dual action against the virus and inflammation [ ] . the nih/niaid sponsored actt- study is still ongoing and compares remdesivir to remdesivir plus baricitinib in moderate to severe patients. in a small uncontrolled cohort of veterans affairs patients with moderate-severe covid- , treatment with baricitinib plus hydroxychloroquine was associated with recovery in of patients [ ] . two other kinase inhibitors, namely imatinib mesylate and dasatinib, could also be envisaged to treat covid- [ ] . furthermore, ruxolitinib (another jak inhibitor-incyte) is being evaluated in a multicenter phase-ii clinical trial [ ] . convalescent plasma. the immediate use of convalescent plasma provides a promising treatment. in a preliminary uncontrolled case series of critically ill patients with covid- and ards, administration of convalescent plasma containing neutralizing antibody was followed by improvement in their clinical status [ ] . the limited sample size of this study precludes a definitive statement about the efficacy of this treatment. vaccines are the most effective strategy for preventing infectious disease since they reduce morbidity and mortality, and they are more cost-effective than treatment. despite previous coronaviruses epidemics, there is still no approved vaccine for human coronaviruses [ ] . we will have to improve our understanding and knowledge regarding immune response to sars-cov . interestingly, in rhesus macaques, comparing the humoral and cellular immunity between primary infection and re-challenge revealed notably enhanced neutralizing antibody and immune responses [ ] . these results suggest that primary sars-cov- exposure protects against subsequent reinfection in rhesus macaques. in human, in a large study of the icelandic population observed that humoral response did not decline within months after infection, that % of persons who had been infected had not been diagnosed with pcr, and that the fatality rate was . % [ ] . we have also to recall that few cases of sars-cov- re-infection were reported. epidemiological, clinical, serological and genomic analyses confirmed that the patient had reinfection instead of persistent viral shedding from first infection [ ] . this case lead to several open questions: how frequent is reinfection? are reinfections less severe than the first? will vaccine protect against reinfections? these results suggest sars-cov- may continue to circulate among the human populations despite herd immunity due to natural infection or vaccination. further studies of patients with re-infection will shed light on protective correlates important for vaccine design. regarding vaccine development, among the different strategies, we can recall the use of recombinant subunit vaccine, dna or mrna vaccine. subunit vaccines are believed to be highly safe because they are expected to induce the immune system without introducing infectious viruses [ ] . a better knowledge of sars-cov- s or/and n protein organizations will be require to develop such vaccines. the sars-cov- spike (s) glycoprotein mediates host cell attachment and is required for viral entry; it is the primary vaccine target for many candidate sars-cov- vaccines. dna vaccines are based on direct injection of plasmids encoding the antigens, followed by a large range of immune responses. mrna-based vaccines contain mrnas encoding the antigens, which are translated at the host cellular machinery by vaccination [ ] . mrna vaccines have advantages over conventional vaccines, by the absence of genome integration, the improved immune responses, the rapid development, and the production of multimeric antigens [ ] [ ] . preliminary report of an mrna vaccine against sars-cov- was published [ ] . the candidate [ ] . long-term assessment will be relevant given that natural history studies suggest that sars-cov may not generate long-lived antibody responses [ ] . furthermore safety evaluation will be mandatory, since there have been concerns about the potential for vaccineassociated enhanced respiratory disease. of the three doses evaluated, the -μg dose elicits high neutralization responses and th -skewed cd t cell responses, coupled with a reactogenicity profile that is more favorable than that of the higher dose. the results of two early phase covid- vaccine trials were reported, one at oxford university (uk), with support from astrazeneca [ ] , and the second supported by cansino biologics in china [ ] . both groups used an adenoviral vector, and both report the vaccine achieving humoral responses to the sars-cov- spike glycoprotein receptor binding domain by day as well as tcell responses. both report local and systemic mild adverse events such as fever, fatigue, and injection site pain. in neither trial was a severe adverse event reported. although these preliminary data are encouraging sars-cov- is a novel pathogen in humans, and many of the technologies being used to build vaccines are relatively untested. there is still a long way to go and phase trials of these vaccines will require thousands of subjects in order to confirm efficacy and safety. the rapid sequencing of the virus has allowed the development of diagnostic tools. table summarize future directions. a test and trace programs will be essential. later, "test, trace and treat (t )" programs will become mandatory once effective drugs would have been identified and safe therapies developed (figure ) . several issues will be important to understand. it will be important to precise how transmissible and pathogenic is sars-cov- in the ongoing and future epidemic. furthermore, it will be important to improve diagnostic tools. ideally a single or combined test that provides virological and serological output would be ideal. in many countries, at the end of containment, strict recommended measures will be important to avoid new waves of contamination. however, few innovative treatment modalities have been discovered since the bulk of the effort to date has been focused on a vaccine. vaccines might not be enough to quell this pandemic. open-reading-frames (orfs), allowing structural, non-structural and accessory viral protein synthesis [ ] . sars-cov is , base-long and contains majors orfs, as well as additional accessory genes; the reference sequence is registered in genbank with id: mn . [ ] . (a and b) up to different polypeptides are potentially produced in fine from the different orfs and after polyprotein processing by viro-encoded proteases [ ] . if the rna genome contained in virions can already serve, after cell entry, as a template for the synthesis of non-structural proteins, which are to achieve sars-cov- elimination there will be a need to improve protection, testing, treating and preventing strategies. a test and trace programs will be essential. later, test, trace and treat (t ) programs will become mandatory once effective and safe therapies are developed j o u r n a l p r e -p r o o f immunoassays: detection/quatification of seroconversion: patient igm and igg specific to sars-cov- spike or nucleocapsid proteins. -neutralization assay: quantitative information on antibodies able to inhibit virus growth ex vivo, -enzyme-linked immunosorbent assay (elisa): quantification of antibodies specific to the virus, -immunochromatography assay: qualitative lateral flow assay (rapid diagnostic test) : detection of antibodies specific to the virus. rapid diagnostic tests (rdt): -works with venous whole blood, serum, or plasma; -rapid test ( min); no instrument required, -only qualitative: aid in the screening and diagnosis in combination with rt-pcr, -aid in risk stratification, and cohort study. who covid- situation report a pneumonia outbreak associated with a new coronavirus of probable bat origin the proximal origin of sars angiotensin-converting enzyme is a functional receptor for the sars coronavirus a unifying structural and functional model of the coronavirus replication organelle: tracking down rna synthesis viral load dynamics and disease severity in patients infected with sars-cov- in zhejiang province, china pathological findings of covid- associated with acute respiratory distress syndrome a novel coronavirus from patients with pneumonia in china pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid- treatment of 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single-blind, randomised controlled trial immunogenicity and safety of a recombinant adenovirus type- -vectored covid- vaccine in healthy adults aged years or older: a randomised, double-blind, placebo-controlled, phase trial define mechanisms determining establishment of sars-cov- infection: characterize all steps of the virus replication cycle . define structure and function of the sars-cov- enzymes and their interractions . understand physiopathology and immune response . improve methods for study of the replication cycle and virus-host interactions to reveal new targets for therapeutic approaches develop and validate diagnostic tools improving sensibility and specificity (serology, rapid diagnostic test) supported in part by nih grant r -ai- , the center for aids research/nih grant p -ai- and national science foundation grant (to rfs).j o u r n a l p r e -p r o o f j o u r n a l p r e -p r o o f key: cord- -v d c authors: yen, wei‐ting title: taiwan’s covid‐ management: developmental state, digital governance, and state‐society synergy date: - - journal: nan doi: . /aspp. sha: doc_id: cord_uid: v d c this article examines the reasons behind taiwan’s effective covid‐ response. while some have argued that taiwan’s success with covid‐ is based on its experience with sars, i argue that we should not attribute taiwan’s effective response solely to its sars experience. the country’s success mainly lies in three factors: ( ) reliance on the mask policy as the main disease prevention measure and the ability to quickly expand mask production capacity; ( ) use of big data and technology to enhance effective implementation of disease prevention and detection measures; and ( ) strong state‐society relations favoring transparency, communication, and collaboration. the first two factors can trace their roots to the country’s developmental state model. democracy provides the institutional underpinning for a vibrant civil society and the synergy between state and civil society, strengthening taiwan’s crisis governance legitimacy and increasing citizens’ voluntary compliance. d ue to its geographical proximity to china and the intensive flow of people from/to china, taiwan was believed to be at the highest risk for importation of covid- when news of the virus first broke in january (gardner, ) . yet, at the time of writing (june, ), taiwan only has covd- cases and seven deaths in total. what explains taiwan's success? what are the lessons policymakers can learn from taiwan's experience? the author appreciates li-ying liu, chia-chien chang, and tsung-hsin lee's feedback on the earlier version of this paper. building upon the crisis management framework, i argue that there are three major elements in taiwan's successful response. first, the government relies heavily on the face mask policy for disease prevention. the government ramped up the production capacity quickly by solving the coordination problem that could have emerged from the production process. second, the government fully leverages the digital governance infrastructure and big data for effective implementation of measures related to disease prevention and detection, albeit that intrusive tracking and tracing raise privacy concerns (ngerng, ) . these first two elements demonstrate how taiwan manages to overcome the coordination and surge capacity challenges, two key obstacles to effective crisis response (ansell, boin, & keller, ) . the developmental state model paved the foundation for these two elements. third, there is a strong two-way communication channel between the government and taiwan's vibrant civil society. the strong state-society relation also facilitates more synergy in fighting covid- . in some cases, the civil society took the lead in initiating solutions which the government then adopted. because the ongoing crisis is characterized by immense levels of uncertainty, transparency and communication are crucial for defining and making sense of the crisis for the society. the state-society collaboration also facilitates revision and refinement of crisis response. it increases citizens' voluntary compliance, which in turn helps enhance the overall effectiveness of taiwan's crisis management. a lively democratic regime provides the political underpinning for the demand and supply of transparency, communication, and collaboration between state and society. i organize the rest of the article in the following way. i first address sars's legacy in taiwan. taiwan's successful covid- response is widely attributed to its past sars experiences, but i contend that even though the sars experience has certainly had an impact, it cannot fully account for taiwan's remarkable achievements in . i then turn to the crisis management framework, discussing how the developmental state foundations and the democratic regime lead to taiwan's success on mask policy, digital governance, and strong state-society collaboration and communication. i end by providing some concrete policy suggestions for policymakers. there is a strong perception that taiwan's effective covid- response is mostly the result of its sars experience (e.g., graham-harrison, ) . it is worthwhile to address the extent to which sars affects taiwan's covid- response first before we move on to other factors. i contend that taiwan's covid- response benefits from sars's legacy mainly in two aspects: ( ) the creation of legal and institutional foundations for the future epidemic outbreak; and ( ) a cohort of experienced technocrats whose knowledge becomes valuable in the covid- fight. yet, besides sars, taiwan also possesses other unique factors that would prompt the country to take a more cautious and "self-help" approach to public health crises too, making it hard to tease out the causal effect of sars. sars left a painful mark on taiwan. like covid- , sars was a fatal respiratory disease caused by a coronavirus and was first discovered in southern china in . taiwan's handling of sars was initially viewed as a success as there were only sporadic cases in the first month. nevertheless, following the world health organization's (who) praise on taiwan's response, clusters started to appear and spread in hospitals, causing an immediate lockdown of a major hospital in taipei. within the next month, clusters were identified in another five hospitals (centers for disease control and prevention, ) . the sudden spike and ongoing local clusters sent society into outright panic. multiple nurses and doctors died of sars because of inadequate protection gears and unknowing exposure to the virus. taiwan's people criticized the government's sudden lockdown and the ill-prepared detecting and reporting mechanism. the who offered limited help too at the time because taiwan was not a who member (lin, wu, & wu, ) . in the end, taiwan became one of the most severely affected countries by sars. there were cases, of which % were associated with hospital clusters, and deaths (taiwan, ) . sars's direct legacy in taiwan was the creation of the national health command center (nhcc) and the overhaul of the communicable disease control act (cdc act). the new organization and the amended law are the central pillar in taiwan's covid- institutional design. responding to sars's regulatory failure, the nhcc became the centralized command point for any type of public health emergency moving forward, including epidemic outbreaks and bioterrorism. the central epidemic command center (cecc) is one of its subunits composed of experts from all fields, which became essential for taiwan's covid- fight. (taiwan cdc, ) . the streamlined response system helped shorten the government's reaction time, effectively mobilized and allocated resources, and facilitated communication with the public. during the covid- crisis, the cecc was quickly activated on january th, one day before the first case was detected in taiwan, and coordination was set at the ministerial level to maximize cecc's authority. the cdc act provides the legal framework for government actions, including how the central and local governments should coordinate with each other, procedures for resource mobilization, and compulsory measures on social behaviors. the law also grants the cecc the authority to penalize lawbreakers. even though there was criticism of granting the cecc too much authority, the post-sars institutional design authorizes the cecc with great power and discretion during public health emergencies (huang, ; lin et al., ) . another legacy of sars was that many government officials and experts in the covid- fight had direct experiences of sars. such experience created a cohort of technocrats who are more agile and cautious about any possible "second sars" in taiwan. from very early on in the covid- crisis, government officials constantly and repeatedly mentioned sars in media interviews. this consensus directed the administration to take a more preemptive approach toward covid- . for example, out of precaution, taiwan immediately sent doctors to wuhan china on january th to gather more information once experts suspected a new epidemic. there is also a strong consensus within the government that taiwan cannot and should not repeat the mistakes made during sars. the technocrats' sars experience leads to their emphasis on face mask policy. during the sars epidemic, panic buying of face masks became a major issue. as a result, the government foresaw that mask hoarding would occur again during this crisis. the government swiftly imposed export bans on n and surgical masks on january , one day after china decided to lockdown wuhan. to combat panic buying, the government also took over the private sector mask distribution lines and launched a mask rationing system. sars's panic buying was partially the consequence of inadequate face mask supply at the time. during covid- , to secure sufficient supplies of masks, the government leveraged its close public-private sector partnership to ramp up the mask production, a point i will elaborate more in the next section. even though sars certainly contributed to taiwan's quick reaction to covid- , there are other concurrent factors that contributed to taiwan's quick reaction. the first was taiwan's exclusion from the who. research shows that countries excluded from international organizations would make more cautious and responsible policies (lipscy & lee, ) . deprived of the who's support, taiwan must resort to the "self-help" approach, nudging the administration to be more prudent (chang, a) . another factor is china's growing hostile relations with taiwan. taiwan's trust toward china has come to a new low. two weeks before the wuhan lockdown, taiwan held its presidential election, during which president tsai ing-wen of the democratic progressive party, the party more antagonistic to china, won her second term with a landslide victory. voters endorse her firm stance against china. taiwan's distrust of china can also lead to a quicker response. observationally, it is hard to tease out the effect of sars, and it is likely that there are multi-factors leading to taiwan's quick reaction. as such, we should not exaggerate sars's legacy on the country's covid- response. taiwan is not unique in its quick response to the new coronavirus outbreak either. almost all china's neighboring countries (except for japan) activated their response system to a greater or lesser extent in early january after china notified the who about the potential coronavirus disease. some of these countries do not have painful sars memories. south korea is considered very successful in its comprehensive testing capacity; vietnam, as a country that directly borders china but with only less than cases in june , is also another remarkable example. neither of them suffered sars. moreover, not all sars veteran countries orchestrate successful crisis responses this time. judging from the number of covid- cases, past sars experiences do not fully shield singapore and canada, two sars veteran countries, from this crisis. even though a coronavirus is the cause of both epidemics, covid- and sars are still different. unlike sars, the defining features of covid- include longer incubation periods, higher transmission rates, more virus mutations, but lower death rates. patients can be asymptomatic when spreading the virus. relying solely on sars's experience would not be adequate for containing the crisis. in addition, covid- is a prolonged and ongoing crisis. orchestrating a successful multi-agency response requires complex and different policy tools at different stages. an early reaction itself would not be sufficient. therefore, while sars's legacy is important and the sars experience can be informative for the current crisis, we should not exaggerate sars's impacts on taiwan's success, or on any country's success. an effective covid- response still hinges on a country's governance structure, capacity, and legitimacy. covid- is a transboundary epidemic crisis. facing an epidemic, all governments must compose a response strategy combining disease prevention, detection, and treatment. disease prevention includes measures such as border control, regulations on mask wearing and social distancing, etc.; disease detection includes measures such as screening incoming travelers, contact tracing, quarantine policy, and testing policy, etc.; disease treatment measures focus on healthcare facility surge capacity and vaccine research and development. as a transboundary and unprecedented crisis, covid- also confronts all governments with a common governance challenge (ansell et al., ) . that is, how to cope with the uncertainty brought by or embedded in this crisis? how do the public perceive the risks? amid high uncertainty, how to make collective sense of this crisis as a society? the four tasks are part of the public health crisis management framework, as illustrated in figure . the framework suggests that there is no one-size-fits-all strategy, and there are multiple routes to effective crisis management. no matter what the strategies are, an effective response would balance resources between disease detection, treatment, and prevention, while minimizing the uncertainty and panic the public may feel. for an effective response, it is of vital importance that a government can mobilize resources to provide surge capacity and to coordinate a coherent response (ansell et al., ) . moreover, the capacity of a government to define and communicate the uncertainty the crisis brings is also an essential element in an effective response because collective sense-making can help increase citizens' voluntary compliance. of the three epidemic tasks, taiwan relies heavily on disease prevention and detection in their covid- response. relatively, the country spends fewer resources on disease treatment, such as increasing health care beds or investment in vaccine development. moreover, the synergy and transparent communication between the government and civil society strengthen governance legitimacy and citizens' cooperation. in this section, i will show that taiwan's developmental state lineage benefits the country through resource mobilization and inter-and intra-agency coordination for their disease prevention and treatment measures. its democratic regime and robust civil society also conducive to more • the screening of incoming travelers; quarantine policy; testing policy; contact tracing, etc. • healthcare facility surge capacity; vaccine research and development, etc. • disease sense making (how serious is the disease); uncertainty on origin, transmission, and disease features, etc. transparency and open communication with the society, which in turn enhances the country's governance legitimacy and cooperative compliance. taiwan adopts a border control and strict quarantine policy to block the outside-in transmission route for disease prevention. domestically, taiwan relies heavily on the mask policy to prevent the disease from spreading. as mentioned above, the government quickly imposed export bans on masks and introduced a rationing system after the cecc was activated, but a crucial piece to a successful mask policy is ensuring sufficient mask supplies. in normal times, taiwan imports facemasks from china. therefore, at the beginning of the crisis, domestic production was only . million masks per day, far short of the quantity needed. yet taiwan managed to ramp up its mask production eightfold in months to million per day (yen, ) . under the real-name rationing system, people can receive two masks per week in early february; by mid-april, the quantity was increased to nine masks per days. taiwan was even able to start "mask diplomacy" to supply masks to other countries (horton, li, & cheng, ) . facemask production is not a skill-intensive industry. nevertheless, one of the most baffling issues during covid- is the mask shortage around the globe. taiwan's ability to produce sufficient mask, in contrast, stands out. why can't other countries mass-produce facemasks like taiwan does? according to economics , if there is demand, there is supply. there is obviously huge demand for facemasks during this crisis, but why isn't there corresponding supply? the reasons why it is hard to rely on the market to sort out the demand and supply issue are that, first, developing a production line poses high transaction costs. even though facemasks are not a skill-intensive product, challenges still exist in sourcing raw materials, especially the melt-blown fabric for filtration, and re-tooling machines for rapid production. it would require a substantial amount of effort and time to coordinate and assemble a production line if the task was left to the private sector. second, from the private sector's perspective, it is not clear if investment in facemask machinery now can be profitable in the post-covid- world. china has been the major facemask supplier for the world because facemask is an industry of slim profit margins where other countries no longer have a comparative advantage. therefore, for private sector companies, investment without guaranteed returns or high yield would hamper their interest in massive investment in the first place. taiwan's mask policy success lies exactly in the government intervention in lowering transaction cost and enlarging future profitability for the private sector. the developmental state model, which governed taiwan's industrial policy from the post-war era, provided the foundations for resolving these issues. briefly speaking, a developmental state is characterized by the government's active role in the economic growth process. under this model, the government maintains a very close relationship with the private sector but keeps its autonomy in making policy (evans, ) . with the goal of rapid economic growth, the government would nudge specific industries by proactively solving growth-induced coordination problems, which, under a more market-oriented economy, are usually solved by the market's invisible hand. in general, there are three types of coordination the government helps overcome. first, the government coordinates the supply chain, linking upstream to downstream companies in an industry. second, the government would also coordinate between the financial sector and industry by channeling the capital needed to grow the targeted industries. last, to facilitate industrial upgrading, the government would support r&d and coordinate knowledge transfer between public research institutes and industries (haggard, ) . the developmental state logic is applied extensively behind the massive increase in mask production. first, to lower the transaction and coordination costs between different companies in the industry, the government directly intervened to coordinate the production line. the industrial development bureau of the ministry of economic affairs (moe) and the taiwan textile research institute, a government-funded agency supporting r&d for the textile industry, were both involved in the effort. in early february, the moe directly gathered all facemask-industry related manufacturers, including machine tool companies (for producing face mask machines), raw material providers, and the downstream facemask manufacturers. by the end of the lengthy meeting, an ambitious facemask production plan was drafted and agreed upon by all companies. the government coordinated all the machine tool companies to produce more facemask machines, matched raw materials suppliers with downstream facemask manufacturers, assigned quotas to every company, and set the purchasing price structure. it was not coincidental that taiwan successfully assembled and coordinated among relevant companies for mask production within such a short time. the long public-private partnership tradition made such a task possible. though the government played a big role in the process, it is still different from a planned economy in the sense that, in a developmental state, the government does not directly force the private sector to reach certain production capacities. instead, the government incentivizes or nudges (i.e., tax incentives, knowledge transfer, capital investment, etc.) industries to enhance voluntary compliance. in the covid- fight, the government incentivized the companies to participate in the government's plan through several measures that can guarantee and increase companies' future profitability. on the one hand, the government directly supported the infrastructure needed for rapid mask production, which essentially lowered the private sector's machinery costs. the government intervened with a us$ . million subsidy and built new mask production lines. when it realized that the production capacity still fell short of expectations, a second tranche of us$ million dollars was released to add another production lines. in total, taiwan's government added new production lines in months. in the traditional developmental state, the government would channel the capital the industry needs through financial institutions. in this crisis, direct government interventions solved both the capital and the basic infrastructure issues (yen, ) . on the other hand, the government relied on price setting and guaranteed demand to further guarantee companies' profitability in working with the government. at the onset, a big concern for the manufacturers is how to tackle the potential oversupply issue when the crisis demand wanes. amid the pandemic, the demand can easily be bigger than the supply, but in a post-covid world, that demand might disappear. oversupply could also create an undesirable price war situation between mask suppliers. to tame the concern and to incentivize production increase, taiwan's government set the purchasing price structure and guaranteed that face masks will become a national security necessity. the government will continue purchasing a fixed number of masks to ensure the demand stream (yen, ) . moreover, with the government-supplied facemask machines, the government promised that once the export bans are lifted, companies can re-start facemask export for more profit. the facemask export ban in taiwan was lifted in june, and the facemask companies are now realizing a substantial facemask profit margin given that the pandemic is still severe around the globe. the second element to taiwan's successful covid- response lies in its full utilization of digital governance. digital tools are not the main infrastructure to fight coronavirus, but when combined with other policy tools, digital governance reinforces the effectiveness of disease prevention and detection measures, such as gps tracking, which greatly expands the government's governance capacity. specifically, during covid- , digital governance helped improve disease detection through integrated databases of people's health records and travel history, through more accurate contact tracing, and through active surveillance tracking for people under quarantine. on disease prevention, the mask rationing system also benefited from the digitized mask distribution platform. the most important e-governance step the government took early on was to link individual international travel history to the national health insurance system on january th. the database integration relies on the inter-agency collaboration between the national health administration and customs. with the data integration, all healthcare facilities can have access to patients' immediate travel history (first limited to days and then extended to days) when seeing the patient. such measures enhance local health facilities' real-time classifying and monitoring capacity. meanwhile, taiwan asked incoming travelers to submit a mandatory health declaration form before entering the border. such information would be further integrated into the database. travelers could then be classified into different risk levels based on their flight origin and health symptoms, allowing proactive monitoring and testing. digital tools are also used for active surveillance of quarantined people. due to taiwan's geographical advantage as an island, the coronavirus risks come mostly from imported cases. therefore, taiwan imposed a strict quarantine policy with a high monetary penalty (compared to other asian countries) (duchâtel, godement, & zhu, ) . effective enforcement of the quarantine policy was further enhanced through active surveillance. taiwan's government works with telecom companies to track quarantined people's whereabouts through their phones' gps data. to ensure accurate implementation, the standard operating procedure is as follows: the cdc first compiles the quarantine list, which is then reviewed by local health facilities and local civil departments (i.e., village chiefs) to check the accuracy of the quarantine people's phones and addresses. the local authorities then call the individuals twice a day to check on their physical and mental wellbeing. the quarantined individuals can also self-report their health conditions to the centralized tracking system through the mobile chat app (e.g., line). meanwhile, local authorities send these numbers to the telecom companies who can start tracking the quarantined people's movement. if the individual could not be reached or if the phone location changed based on triangulating the base station data, an alarm would be triggered. the quarantined person and local authorities (i.e., village chiefs, police, etc.) would all receive a text message. local authorities would also pay an in-person visit to verify the individual's whereabouts (ngerng, ) . despite its effectiveness, active digital surveillance tools raised substantial concerns about individual privacy. the cecc claims such invasive monitoring is authorized by the cdc act and the special act on covid- prevention, relief, and restoration. based on the acts, the cecc can take any measures that deem necessary for disease prevention. however, this did not ease the public's concern. the government promised that all the data collected during the pandemic or for the quarantine purpose will be deleted after covid- . yet, the issue of how to strike a balance between individual privacy and public interest remains an issue all societies must confront in the digital governance era. to summarize, it is obvious that digital governance itself is not adequate for successful disease detection and prevention. the state is already capable of penetrating society and collecting people's information. for example, the prerequisite for database integration was the existence of such health data in the cloud space, which taiwan's national health insurance had already completed when it digitalized individual health records in recent years (ngerng, ) . another example is that the central government was capable of working with local authorities to check the quarantined. the function of digital governance infrastructure is to help facilitate and further enhance the effectiveness of government regulations. thanks to the digital governance infrastructure, taiwan achieved the intended policy goals more effectively. to some extent, taiwan's comprehensive digital infrastructure has its roots in the developmental state as well. under the government's intentional planning in the s, taiwan upgraded its economic engines to semiconductor and technology-related industries, leveling up the basic digital infrastructure in taiwan. the industrial transformation not only created the infrastructure hardware but also a population with high levels of digital literacy. the tech-savvy civil society also played a big role in the covid- fight. despite its impact on the world, we still know relatively little about covid- . for months, the world was learning whether and how the virus is transmitted from human to human and the complete range of symptoms. six months after the outbreak, it is still not entirely clear how contagious asymptomatic cases can be (yan, ) . the who also changed its policy from discouraging masks on healthy individuals to encouraging wide-spread mask use in june . still, it is unclear when or if a vaccine will become available. simply put, covid- is an epidemiological crisis with high levels of ongoing uncertainty. amid the immense level of uncertainty, governments around the world are confronted with two tasks. first, as the crisis and the inherent uncertainty are evolving, it is almost impossible for a government to identify best practices. governments are likely to make mistakes. the task at hand is to continue calibrating the national response after considering the structural and moving factors. second, since there are many unknowns, government responses are of vital importance. with an uncertain crisis, the public depends on the government to help define the nature of the crisis. this "meaning making" step is essential for how the public perceive the risk. different perceptions can result in different health-related behaviors and compliance levels (kushner gadarian, goodman, & pepinsky, ). taiwan's government dealt with such uncertainty through continuing and transparent communication with the country's vibrant civil society. active communication helped the government define the crisis as dangerous at an early stage. the cecc used the analogy of "war time mobilization" to warn the seriousness of covid- . it helped the society's collective sense-making of the virus. the major communication channel between the government and people during covid- has been a daily press conference. starting on january th, taiwan's cdc hosted a daily press briefing, during which the cecc provides the most recent update on covid- and responds to questions. moreover, the daily conference is used as an educational platform to address false information, social stigmas, and bias. for example, one case of covid was an illegal migrant caregiver, which triggered panic and demands for crackdowns on illegal migrant workers. the cecc used the conference platform to educate the public that every migrant worker, legal or illegal, should be included and treated the same during the coronavirus fight. the cecc stated that illegal foreign workers should not be excluded from the healthcare system, explaining that a crackdown would only result in a bigger loophole in the fight against covid . in another example, a schoolboy was bullied because he wore a pink mask; the cecc team all appeared wearing pink masks at the next press briefing, fighting gender stereotypes (chang, b) . these daily conferences are informative, educational, and morale boosting. it is not an exaggeration to say that the daily press briefing anchored and calmed taiwanese society. people listened to and followed the instructions provided in those daily briefings. communications are not only top-down but bottom-up, and a robust civil society is essential for the bottom-up effort. taiwan has developed a vibrant civil society since democratization in the late s. after the sunflower movement in , civil society networks have grown even stronger and can easily be mobilized. a democratic political structure is the institutional foundation that makes a strong civil society possible. not all democracies breed strong civil societies, but strong civil societies only exist in democratic settings. during the covid- fight, civil society sometimes challenges the government, sometimes collaborates with the government, and sometimes even pioneers and leads the government. instead of imposing rules and regulations on society, the government must persuade the society of the necessity of those regulations. the government has also benefited from the wisdom of the crowd as it sought to refine regulations. two-way communications between the government and societal actors have been a hallmark of the taiwanese response, rather than strictly topdown communications. during the covid- fight, there have been several collaborative efforts between digital civil society and the government. one example is fighting misinformation. of the active civil society, a civic-tech community, pioneered by the g v("gov-zero") movement, has grown rapidly. these "civic hackers" advocate for open government, transparency, and citizens' agenda-setting power (tang, ) . during the crisis, they worked with the government to quickly correct misinformation about covid- on the internet (quito, ) . such synergy was possible partially due to audrey tang, taiwan's current digital minister. tang was once a civic hacker and was one of the g v's core members. her long-term advocacy for big data and open government facilitated active collaboration between the government and the digital civil society. another example of civil society's energy is the "taiwan can help" campaign. during covid- , taiwan and the who had several disputes over taiwan's exclusion from the who. while taiwan's effective crisis response has gained attention, it remains isolated from the global health governance body. the dispute, at some point, developed into a heated fight over racist slurs. taiwan's civil society was furious about the response of who's director-general. in response, the civil society initiated the "taiwan can help" crowdfunded campaign. the goal was to place a full-page advertisement in the new york times to promote taiwan's effective crisis response and to increase cooperation with the international community despite being excluded from the who. the campaign received more than enough money within a few days. with the #taiwancanhelp hashtag on twitter, the campaign began a wave of activism works. later, when the government launched its mask diplomacy, the same hashtag #taiwancanhelp was used to promote its ability to contribute to the international community. in some cases, the tech-savvy community even pioneered better solutions that were later adopted by the government. one example is the optimization of mask distribution. as mentioned above, taiwan launched a mask rationing system. administration of the real-name rationing system was initially difficult, requiring long lines at pharmacies. civic hackers voluntarily created mask apps combining the stock at local pharmacies and google maps to show mask stocks in different locations to help shorten the waiting queues during the early stages of distribution. the government adopted the idea and later developed an online mask purchasing platform. people can now pre-order masks online either through the government website, the national health insurance app, or through the wide-spread convenience stores on the island. the state-society synergy indirectly contributed to e-governance expansion too. in the online purchasing platform example, to accommodate the surplus traffic, the national health insurance administration set up extra servers to expand the cloud capacity (duchâtel et al., ) . one myth about taiwan's success is that confucianism plays a role. some have argued that the successful asian experiences can be attributed to asian values, which emphasize social order and hierarchy. asian people do not question the government as often and are more submissive to strict government regulation. however, taiwan's experience suggests otherwise. in taiwan, governments are subject to frequent criticism. even when the government's measures are necessary, it does not mean that society accepts those decisions submissively. society questions the government, forcing the government to be transparent and be responsive. the positive consequence is that when the regulatory measures are perceived as necessary and approved by the civil society, it increases citizens' cooperation and compliance. governance legitimacy is reinforced through this interaction. in this article, i laid out some of the factors behind taiwan's success in fighting covid- . the legacy of the developmental state helped taiwan create the "mask economy" within a short period of time as well as contributing to the digital governance infrastructure. transparent communication helped define the nature of covid- early on in taiwan, decreasing public panic and increasing public trust in the government and citizens' compliance level. the tech-savvy civil society also collaborated with the government in refining crisis measures. the successful crisis management strategy has also had international repercussions, enhancing taiwan's standing on the international stage. the information presented above suggests a few policy lessons. first, while taiwan has relied on the face mask policies, there are multiple routes to a successful covid policy. central to success is governance capacity, given a society's social, cultural, and economic factors. a centralized command center benefits inter-and intra-agency coordination to produce more coherent response strategies and to mobilize and allocate resources more efficiently. second, for best crisis management outcomes, government legitimacy matters too. people must perceive regulatory measures as necessary to generate high cooperative behaviors. therefore, the way a government defines the crisis is of utmost importance. transparency and communication can also help generate higher cooperation and compliance. additional benefit transparency and communication bring to the table is to allow experts to debate and calibrate a more refined strategy moving forward. third, the wisdom of the crowd can be useful in the covid- fight. when possible, citizens' active engagement can be helpful for the government. through repeated interactions with the society, the government can also refine its crisis to manage strategies to better align the intended policy goals and people's behaviors. notes nhcc includes the central epidemic command center (cecc), the biological pathogen disaster command center, the counter-bioterrorism command center and the central medical emergency operations center ("nhcc" n.d.). originally, the chief commander was the director-general of taiwan's cdc, but soon after china locked down wuhan on january rd, the minister of ministry of health and welfare (mohw), the superior unit of taiwan cdc, became the new chief commander of cecc. leveling up the command center to the ministerial level helps ease inter-ministry cooperation. china also shortened its reaction time compared to the country's reaction time to sars. the first sars case in china appeared on november th, , but china only reported the outbreak to the who in february when there were already cases and deaths in china. during this crisis, the first reported official case appeared on december th , and china reported the outbreak to the who on december st when there were only reported cases (wu & mcgoogan, ) . countries that were affected the most by sars include china, hong kong, taiwan, singapore, and canada. the rationale behind the government's active role is to address the latecomer issue that many asian countries, taiwan included, had after world war ii. however, at the beginning, the pricing mechanism was set in a way that only a few manufacturers met their quota in the first week of production. after reviewing the gaps within the production line, the government identified ways to increase capacity and revise its purchasing and bonus structure to encourage suppliers to produce at maximum capacity. using the integrated database, the government was able to proactively re-test cases that were tested negative for influenza for covid- . out of the cases was covid- positive (jason wang, ng, & brook, ) . when permitted, the health authorities can also trace the infected or high-risk individuals' contact history to prevent any possible virus spread. in one navy ship cluster infection case, the government sent out , text messages to people who may have close contact with the infected individuals based on location information from mobile phones. with taiwan's national health insurance program, every legal resident living in taiwan for more than months (citizens or not) can have access to health resources. the illegal migrant workers are the only group with no access to health resources. to further fix the hole, from april through june , taiwan ran the second amnesty program for illegal migrant workers to encourage them to come forward (wei, ) . the website of the campaign. retrieved from https://taiwa ncanh elp.us/ retrieved from https://mask.pdis.nat.gov.tw/ retrieved from https://www.nhi.gov.tw/conte nt_list.aspx?n= f d f b c managing transboundary crises: identifying the building blocks of an effective response system severe acute respiratory syndrome -taiwan, (morbidity and mortality weekly report a discussion on imf's governance bias and global financial crisis: lessons for who and the covid- pandemic crisis [從imf與金融危機談國際組織、偏 差治理、與全球危機:兼論對who處理武漢肺炎危機 (covid- )的問題]. who governs taiwan pink (mask) is the new black: fighting gender stereotypes. taipei times fighting covid- : east-asian responses to the pandemic embedded autonomy: states and industrial transformation partisanship, health behavior, and policy attitudes in the early stages of the covid- pandemic update january : modeling the spreading risk of -ncov. the center for systems science and engineering (csse) at jhu experience of sars a key factor in countries' response to coronavirus. the guardian developmental states taiwan counters china's isolation campaign with mask diplomacy. nikkei asian review soft regulation and hard compliance in taiwan|the regulatory review. the regulatory review (blog) response to covid- in taiwan: big data analytics, new technology, and proactive testing reimagining the administrative state in times of global health crisis: an anatomy of taiwan's regulatory actions in response to the covid- pandemic the imf as a biased global insurance mechanism: asymmetrical moral hazard, reserve accumulation, and financial crises taiwan's digital response to covid- : impressive, but is privacy respected? the news lens international edition nhcc taiwan is using humor to quash coronavirus fake news taiwan cdc announces activation of central epidemic command center (cecc) for severe special infectious pneumonia to comprehensively prevent novel coronavirus pneumonia outbreak in china and ensure health of taiwanese public. taiwan cdc inside taiwan's new digital democracy coronavirus: taiwan making progress in getting illegal migrant workers to come forward. the straits times characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china fauci says the who's comment on asymptomatic spread is wrong. here's the difference between asymptomatic and pre-symptomatic spread the secrete behind . times of mask production in months: how did taiwan do it? room for industrial upgrade? key: cord- - kwfulqe authors: yue, jing-li; yan, wei; sun, yan-kun; yuan, kai; su, si-zhen; han, ying; ravindran, arun v.; kosten, thomas; everall, ian; davey, christopher g; bullmore, edward; kawakami, norito; barbui, corrado; thornicroft, graham; lund, crick; lin, xiao; liu, lin; shi, le; shi, jie; ran, mao-sheng; bao, yan-ping; lu, lin title: mental health services for infectious disease outbreaks including covid- : a rapid systematic review date: - - journal: psychological medicine doi: . /s sha: doc_id: cord_uid: kwfulqe the upsurge in the number of people affected by the covid- is likely to lead to increased rates of emotional trauma and mental illnesses. this article systematically reviewed the available data on the benefits of interventions to reduce adverse mental health sequelae of infectious disease outbreaks, and to offer guidance for mental health service responses to infectious disease pandemic. pubmed, web of science, embase, psycinfo, who global research database on infectious disease, and the preprint server medrxiv were searched. of reports identified, were included in this review. most articles of psychological interventions were implemented to address the impact of covid- pandemic, followed by ebola, sars, and mers for multiple vulnerable populations. increasing mental health literacy of the public is vital to prevent the mental health crisis under the covid- pandemic. group-based cognitive behavioral therapy, psychological first aid, community-based psychosocial arts program, and other culturally adapted interventions were reported as being effective against the mental health impacts of covid- , ebola, and sars. culturally-adapted, cost-effective, and accessible strategies integrated into the public health emergency response and established medical systems at the local and national levels are likely to be an effective option to enhance mental health response capacity for the current and for future infectious disease outbreaks. tele-mental healthcare services were key central components of stepped care for both infectious disease outbreak management and routine support; however, the usefulness and limitations of remote health delivery should also be recognized. the coronavirus disease pandemic is the largest threat to the world in this century (who, ) . to limit transmission, business and school closures are implemented, mass quarantines (brooks et al., ) are imposed and self-isolation and social distancing (kaplan et al., ) are highly recommended, and such measures have been implemented in almost all countries to differing extents (galea, merchant, & lurie, ; ho, chee, & ho, ; jung & jun, ; li et al., a li et al., , b . millions of people in the world have been infected, with ever increasing numbers under quarantine or in isolation. fear of illness, severe shortages of resources, social isolation, large and growing financial losses, and increased uncertainty will contribute to widespread psychological distress and increased risk for mental illness and behavioral disorders as a consequence of covid- (pfefferbaum & north, ) . the worldwide impact of the covid- pandemic on mental health has already been identified as including insomnia, anxiety, and depression among healthcare workers and other vulnerable populations tang et al., ; brooks et al., ; cao et al., ; gao et al., ; gonzalez-sanguino et al., ; holmes et al., ; king, delfabbro, billieux, & potenza, ; li et al., a li et al., , b shi et al., ; wang et al., a wang et al., , b wang et al., , c xiao, zhang, kong, li, & yang, ) . chinese healthcare workers exposed to the covid- pandemic reported symptoms of depression ( . %), anxiety ( . %), insomnia ( . %), and psychological distress ( . %) (lai et al., ) . these symptoms also manifest in the general population, whose prevalence of depression, anxiety, insomnia, and acute stress was . , . , . , and . %, respectively . similar types of symptoms have accompanied other infectious disease epidemics such as severe acute respiratory syndrome (sars), middle east respiratory syndrome (mers), and ebola virus disease (evd) (ho et al., ; jalloh et al., ; pfefferbaum & north, ; vyas, delaney, webb-murphy, & johnston, ; wu et al., ) . people discharged from hospital after recovering from covid- have reported high rates of posttraumatic stress disorder (ptsd) (bo et al., ) . a systematic review showed that after severe coronavirus infection, the point prevalence of ptsd was . % ( % ci . - . ), depression was . % ( . - . ), and anxiety was . % ( . - . ) (rogers et al., ) . some mental health problems persisted for years with a quarter of sars patients having ptsd, and . % having depression years after experiencing sars (mak, chu, pan, yiu, & chan, ) . early detection and recognition of covid- -related psychiatric symptoms is pivotal for tailoring cost-effective accessible interventions. mental health responses could enhance coping and lead to recovery from this massive worldwide psychological trauma of covid- and the pandemic. given the developing situation with coronavirus pandemic worldwide, policy makers urgently need an evidence synthesis to produce guidance for the development of psychological interventions and mental health response. the aim of this paper is to synthesize the data on mental health services and interventions for the infectious disease epidemics, and to enhance knowledge and improve the quality and effectiveness of the mental health response to covid- and future infectious disease epidemics. we sought to include any articles focusing on mental health interventions or services applied specifically for infectious disease outbreaks. we searched pubmed, web of science, embase, psycinfo on may , using a combination of text words and mesh terms: (sars or severe acute respiratory syndrome or middle east respiratory syndrome coronavirus or middle east respiratory syndrome* or mers-cov or mers or middle eastern respiratory syndrome* or merscov* or coronavirus or coronavirus infections or coronavirus* or covid- or -ncov or sars-cov- or ebola) and (mental disorders or mental health or mental health programs or mental health services or public health services or emergency services psychiatric or emotional trauma or psychosocial interventions or psychiatric interventions or psychological treatment or psychotherapy). we also searched who global research database on covid- using the term 'mental health', and the preprint server medrxiv with search terms 'sars or mers or ebola or coronavirus or covid- ' and 'mental health' on april . articles about mental health services (e.g. mental health system, mental health measures or strategies) and specific types of psychological interventions for infectious diseases such as sars, mers, evd, and covid- were included in the present review. we excluded articles on the epidemiology of psychological impacts, mental health responses to other types of diseases, and non-english publications. all articles were independently screened for eligibility by two reviewers (syk and yw) on title and abstract. all full-text articles identified were reviewed by yjl and byp. for each retrieved fulltext article, we hand searched the article's references and examined possible additional studies. original intervention trials were independently critically appraised using the cochrane collaboration's quality assessment tool by two reviewers (ssz and yk) (higgins et al., ; higgins & green, ) . consensus was used to resolve any disagreements. review authors' judgments evaluated selection bias, performance bias, detection bias, attrition bias, reporting bias, and other bias. in all cases, an answer 'l' indicates a low risk of bias and an answer 'h' indicates high risk of bias. if insufficient detail was reported of what happened in the study, the judgment will usually be 'unclear' risk of bias. the pubmed, web of science, embase, and psycinfo search identified , , , and articles, respectively. the who global research database on covid- identified articles and medrxiv identified articles. there were articles left after removing those articles which were duplicates from the six searches. hand searching of full-text articles yielded one additional reference to include in this review. in total, eligible articles were included in this review (see fig. ), most focusing on covid- , followed by evd, sars, and mers. of the articles, one used a randomized controlled trial (rct), seven used quasi-experimental methods or pre-post intervention or quantitative interview, reported processes of the delivery of care but did not rigorously evaluate outcomes ( reports, commentaries, and reviews) (see table ). twenty-three articles described mental health practices and services for covid- [china ( ), south korea ( ), singapore ( ), italy ( ), and one each for canada, germany, usa, uk, malaysia, iran, australia, and spain], seven articles for evd [sierra leone ( ), liberia ( ), and usa ( )], one article for sars (hong kong, china), and one article for mers (south korea). four different mental health practices were reported in this systematic review, including mental healthcare systems, psychosocial interventions, specific responses of psychiatric hospitals and digital mental healthcare (see fig. table ). table summarizes the assessment of risk of bias for five controlled trials. the majority of the intervention trials showed a low risk of bias, or we were unable to determine the risk. one trial had low risk of performance bias and detection bias, one trial had high risk of selection bias, and we were unable to determine the risk for other trials. all five trials had low risk of attrition bias, reporting bias, and other biases. as the other records included in this review were not controlled trials or were commentaries, we did not conduct quality assessments for them. governments have variously developed interventions and response systems to deal with the mental health problems caused the mental health professionals provided psychological counseling to individuals in quarantine. national hospitals and community mental health centers also provided mental health care services. leaflets promoting mental health care for the distress caused by infectious disease outbreaks were distributed. percudani et al. italy covid- report (-) regional health authorities authorized the continuation of mental health services for the general population. safety guidelines for both medical staff and patients were implemented, including remote psychosocial interventions and telemedicine. hospital admissions for acute psychiatric disorders in patients positive for covid- need a dedicated area in the psychiatric ward or alternatively, a medical ward supported by psychiatric staff. (continued ) jing-li yue et al. ( ), their families ( ) the community-based mental health system of detection, brief intervention, and refer to treatment was established for the quarantined mers patients and their families. service utilization rate, . % receive one consultation, . % required continuing services, . % received continuing services. albott et al. ( ) small group cbt developed to treat anxiety, depression, and functional impairment, eight sessions over weeks. at post-intervention, anxiety, depression, and functional impairment significantly reduced, helping . % of the participants to their personal goals or recovery. overall, the intervention was given a mean rating of . out of by the participants. ping et al. malaysia covid- report nurses on the covid- frontline ( ) ultra-brief psychological interventions for month including group problem-solving techniques, mindfulness skills and so on. the informal qualitative feedback has suggested that it has helped respond effectively to individuals with anger or frustration, anxiety secondary to the uncertainty of the daily fluctuations of covid- , panic and tension in committee meetings, and the general psychological wellness of hospital staff. kazerooni et al. iran covid- report medical junior students ( ) near peer mentoring via the social media platform. senior students under the supervision of expert faculty offered psychological supports for junior students such as stress relaxation techniques, time management, etc. % of junior medical students believed the platform had a significant impact on helping them adjust faster to these emergency conditions. decosimo et al. sierra leone children who were ebolasurvivors; living in ebola-infected homes or community ( ) a community-based psychosocial arts program (playing to live). activities included storytelling, musical freeze dance, art drawing, yoga, and dancing. contrasted a -month to a -month treatment. significant decrease in reported symptoms in both treatment groups pre-to post-intervention and a significant difference in total symptoms over time. waterman et al. sierra leone evd quantitative interview ex-etc staff ( ) -week group cbt program for depression and anxiety modeled on evidence-based low-intensity interventions. barriers (lack of motivation to attend, low literacy) and enablers (novelty of cbt, social network). waterman et al. sierra leone evd pre-post intervention ex-etc staff ( ) three-phased cbt-based intervention. improvement of ptsd, sleep, depression, anxiety, and alcohol usage. sierra leone the general public, inpatients general nurses were trained in pfa, case identification and referral pathways and provided basic counseling and problem-solving therapy for individuals in the need of mental healthcare. kohrt et al. liberia evd pre-post intervention mhcs ( );law enforcement officers ( ) adapting the cit model implemented a national community-based anti-stigma program, family support and advocacy activities, and facilitated partnerships to advance mental health policy, legislation, and funding. the anti-stigma and advocacy activities involved work with journalists, pharmacists, religious leaders, and other stakeholders. there is a need to develop formal collaborations with law enforcement for stigma reduction, service provision, and human rights protection. there was a significant increase in knowledge ( - % of items answered correctly), a significant increase in positive attitudes, and a significant decrease in social distance. (continued ) jing-li yue et al. the 'strength-focused and meaning-oriented approach to resilience and transformation' intervention using a cognitive redefinition was applied. after the -day group debriefing, participants showed significant decrease in depression level and changes in cognitive appraisal toward sars. such changes were sustained in a -month follow-up. garriga et al. (yoon, kim, ko, & lee, ) . various mental health centers such as public health centers, community mental health centers cooperatively delivered services for mers patients and the national center for crisis mental health management evaluated people using these services and subsequently transferred them to local community mental health centers for continuing case management and follow-up. the service utilization rate was high, but they also found that the referral system from the national level to regional or local levels did not work well (yoon et al., ) . while active detection of subjects with emotional difficulties and interventions following the covid- outbreak was a potential option, they needed a more efficient process for an open entry system at the local level rather than a triage system starting nationally from the top. a series of mental health-related actions were taken at the initial stage of the covid- outbreak in china (li et al., , b qiu, zhou, liu, & yuan, ; wang et al., a wang et al., , b wang et al., , c yao, chen, zhao et al., ; zhou, ) , singapore (ho et al., ) , south korea (jung & jun, ; park & park, ; yoon et al., ) , canada (agyapong, ) , germany (bauerle, skoda, dorrie, bottcher, & teufel, ) , italy (percudani, corradin, moreno, indelicato, & vita, ) , and the usa (schreiber, cates, formanski, & king, ) . specifically, mental health professionals including psychiatrists, psychiatric nurses, and psychologists were deployed to provide psychological counseling and support for vulnerable populations (e.g. frontline healthcare workers, confirmed covid- patients, suspected covid- cases and their families) in china and for people in quarantine in south korea. the national health center of china (nhc) issued several guidelines and plans (nhc-china, b , c , d . several national associations related to mental health and academic societies cooperated to establish expert groups on psychological interventions to older adults (wang et al., a (wang et al., , c . psychoeducational books, articles, and videos were made available for the public through e-platforms and mobile apps (e.g. wechat) at the early stage of the covid- outbreak in china (bao, sun, meng, shi, & lu, ; li et al., a li et al., , b pfefferbaum et al., ) . several hospitals, individual psychiatric departments, community psychiatric partners, and psychologists all provided online psychotherapy and counseling to psychiatric patients and the general public with covid-related psychological distress through videoconferencing platforms (e.g. zoom) in singapore (ho et al., ) . leaflets for the general public provided guidelines for coping with the covid- distress and hotlines provided information for covid- mental health crisis that might occur in south korea (park & park, ) . canada launched a support text message (text mood) program to respond to the psychological impact of covid- . this program provided free psychological supportive text messages daily for months (agyapong, ) . germany's 'coping with corona: extended psychosomatic care in essen' (cope) offered psychological support for distressed individuals, which included four steps: initial contact, triage and diagnosis, support via tele-or video-conference, and aftercare. this program offered psycho-educational information materials about resources, relaxation techniques, and mental health (bauerle et al., ) . increasing public mental health literacy is vital to prevent and overcome the mental health crisis during the covid- pandemic. education and support from the voluntary and professional mental health sectors should be a part of mental health prevention under large infectious disease outbreaks. psychological and physical supports tended to be specifically matched to different vulnerable populations, such as children, older adults, and health care workers. a national community-based anti-stigma and advocacy activity, which is a curriculum based upon the crisis intervention team (cit) model was launched in liberia during the evd outbreak, could significantly decrease mental health and public health problems including violence, self-harm and suicide (kohrt et al., ) . a mental health unit was created at connaught hospital in sierra leone during evd outbreak (kamara et al., ) . general nurses were trained in psychological first aid (pfa), case identification, and referral pathways, and provided basic counseling and problem-solving therapy for individuals with mental healthcare needs. a nurse-led approach within a nonspecialist setting appears to have been successful for delivering mental health and psychosocial support (mhpss) services during the evd outbreak. peer support programs or services led by nonprofessional mental health workers are potential ways to deliver care in areas with limited human resources and weak social welfare systems. an alternate strategy which was employed during the sars outbreak in hong kong (ng et al., ) was the strength-focused and meaning-oriented approach to resilience and transformation (smart). this intervention employed a body-mind-spirit framework with a strong emphasis on cognitive redefinition of the stressful situation and the individual's response. results of the rct (n = ) suggested that participants' depression levels and adaptive changes in cognitive appraisal of sars decreased significantly after the single-day group debriefing. as this intervention trial included only a small sample, its efficacy needs to be replicated in a larger sample, and should include a follow-up study. for children and adolescents a community-based psychosocial arts program created by playing to live (ptl) was established for children who were ebola-survivors or living in ebola-affected homes or communities (decosimo, hanson, quinn, badu, & smith, ) . the ptl group hired and trained ebola-survivors to run the ptl activities two to three times a week in their communities. they also hired psychosocial workers to provide weekly supportive talks to families, and information about childcare and child rights. the ptl activities included storytelling, musical freeze dance, art drawings, yoga, and dancing. results of the pre-post-evaluation (n = ) suggested that the -month program was associated with a % reduction in symptoms including social withdrawal, extreme anger, bedwetting, worry/anxiety, poor eating habits, violence, and continued sadness, whereas the -month intervention group showed a % reduction of such symptoms. for older adults for mental disorders of old age, particularly dementia, there have been limited reports of the effects of the covid- pandemic. we found only one report on mental health care for older adults among our included papers. given the high death rate among older adults infected with covid- and the added strain on families with older relatives and on the institutions caring for them, the chinese society of geriatric psychiatry in collaboration with the chinese society of psychiatry responded with an interdisciplinary solution. mental health professionals, social workers, nursing home administrators, and volunteers collaboratively delivered mhpss for older adults, especially for community-dwelling residents and nursing-home residents (wang et al., a (wang et al., , c . mental health care for older adults during this epidemic was not given enough attention in the early stage of outbreak. more specific age-appropriate interventions may need to be developed for older adults for effective intervention during pandemic in the future. for healthcare workers frontline health care workers are also shouldering a greater mental health burden, and thus need support in strengthening their resilience through peer support and other interventions . first, proper protection against their own infection is critical. for example, masks, personal protective equipment, and other essential medical equipment (e.g. ventilators) will help relieve the stress of having to treat people with infections, and improve their mental wellbeing. during this covid- crisis, various interventions were offered to healthcare workers, such as a peer-supported resilience intervention in the usa (albott et al., ) , e-package with agile methodology in the uk (blake, bermingham, johnson, & tabner, ) , and the ultra-brief psychological intervention in malaysia (ping et al., ) . the e-package in the uk included evidence-based guidance, support, and signposting relating to psychological wellbeing, and results of this pre-post intervention (n = ) revealed that % of healthcare participants used the information in their work or home lives (blake et al., ) . feedback from healthcare workers suggests that qualitative wellness is improved by providing a free online resource manual targeting psychological skills and interventions to reduce the distress caused by uncertainty during the pandemic (ping et al., ) . many countries have developed dedicated teams to provide mental health support for healthcare workers; however, the type of support needed depends on the stage of the pandemic, and can benefit from peer and professional counseling (isaksson rø, veggeland, & aasland, ) . the anticipate, plan, and deter responder risk and resilience model was used to assess and manage healthcare workers' psychological risk and resilience during the evd outbreak (schreiber et al., ) . the anticipate, plan, and deter model contains three components. first, pre-deployment training about the stressors that healthcare workers may face during deployment ('anticipate'). second, development of a personal resilience plan ('plan') and monitoring stress exposure during deployment using the web-based system. third, invoking the personal resilience plan when risk is elevated ('deter'), addressing responder risk early before the onset of impairment. psychological support was offered to junior medical students in iran via a novel social media platform during the covid- (rastegar kazerooni, amini, tabari, & moosavi, ) . in total, % of participants (n = ) believed the platform had a significant impact on helping them adjust faster to these emergency conditions. following the evd outbreak in sierra leone, cognitive behavioral therapy (cbt) was widely used among ebola treatment center (etc) staff (cole et al., ; waterman et al., ; waterman, cole, greenberg, rubin, & beck, ) . results of the pre-post intervention (n = ) showed that small group cbt could significantly reduce anxiety, depression, and functional impairment of etc staff after eight sessions over weeks (cole et al., ) . workshops with different themes such as pfa, stress, sleep, depression, anxiety, relationships, and behavior were developed in phase and . participants still displaying high anxiety and depression levels after phase and were enrolled in phase with low-intensity cbt strategies. significant improvements in the stress, anxiety, depression, and anger domains were reported, but no improvement in sleep (waterman et al., ) . cbt is an evidence-based intervention delivered through various means besides face-to-face interactions. for example, delivery over the internet or smartphone apps can be efficient for broad outreach to the populations at risk for mental health complications. the feasibility and effectiveness of training a national team to deliver a three-phase cbt-based group intervention to ex-etc staff suggested that this model protected healthcare workers from negative psychological consequences of potentially traumatic stressors (waterman et al., ; waterman et al., ) . however, the effectiveness of this model and its components needs more rigorous evaluation, because it relied on a single small sample during a unique epidemic (schreiber et al., ) . furthermore, most of the reviewed studies were pre-post measurements with substantial heterogeneity in the included participants, methods, study designs, and outcomes. standardized evaluations in randomized clinical trials were difficult to implement due to the urgent nature of the pandemics. evidence-based interventions that have shown efficacy in conditions differing from epidemics also might be effective approaches to combat covid- , but their effectiveness needs to be tested in controlled trials during the covid- pandemic. psychiatric hospitals in china prepared to cope with the covid- outbreak by establishing crisis psychological intervention teams across many psychiatric hospitals, including psychiatrists, clinical psychologists, and psychiatric nurses (li et al., , b shao, shao, & fei, ; xiang et al., ) . a specialized psychiatric ward was established in an infectious disease hospital in wuhan on february , and in turn isolation wards were established in psychiatric hospitals for mentally ill patients with suspected or confirmed covid- . nhc issued a set of guidelines in february to standardize the management of patients with severe mental disorders during the covid- outbreak (nhc-china, f ). subsequently, the chinese society of psychiatry published guidelines to the hospital administration applicable to both psychiatric hospitals and psychiatric units in general hospitals during the outbreak (chinese society of psychiatry, ). psychiatric hospitals reduced outpatient visits, tightened admission criteria, and shortened the length of inpatient hospitalizations. for newly admitted psychiatric patients, isolation wards were set up and visiting was suspended to minimize the potential risk of nosocomial infection. additionally, the majority of psychiatric hospitals used telemedicine to provide psychiatric consultations for infected patients and medical treatments for patients with preexisting mental disorders, and antipsychotic drugs were often delivered to patients' homes following the covid- outbreak in china. the italian society of epidemiological psychiatry also issued operational instructions for the management of mental health departments and similar measures were employed in italy (starace & ferrara, ) . the institute of mental health (imh) in singapore implemented a series of prevention and control strategies at the levels of hospital, ward, and individual (poremski et al., ) . except for restrictions on patients and visitors, medical staff were managed effectively, for example, electronic tracking of staff movement to facilitate contact tracing in singapore (poremski et al., ) and china (shao et al., ) . for community care centers and out-patient clinics, in-person visits were recommended for patients with a psychiatric emergency, risk of psychiatric relapse or new emergent cases with mental disorders, incorporating phone call follow-ups and telepsychiatry consultations in spain (garriga et al., ) . as per in-patients, early discharges of the psychiatry emergency rooms and acute wards were moved forward and the suspension of family visits was implemented. a novel mental health home hospitalization care was recommended (garriga et al., ) . the infection control measures needed to limit potential exposure to sars-cov- led to inaccessibility of some mental health interventions such as injectable medications and electroconvulsive therapy, and the relative risks and benefits of these treatment losses need to be evaluated . these losses should be assessed in the balance with many novel strategies involving digital telemedicine, mental health home hospitalization, commercial drug delivery, and electronic tracking. moreover, follow-up studies are needed on how effective these interventions were in mitigating the mental health impacts of other losses to mental services and patients. tele-mental health services were prioritized for individuals at higher risk of exposure to covid- infection such as frontline clinicians, infected patients, suspected cases of infection, their families, and policemen. there are well-documented reports of china proactively providing various tele-mental health services during the covid- outbreak zhou et al., ) . the nhc and the chinese psychological society provided guidelines on conducting online mental health services (li et al., , b nhc-china, a . these services were provided by the government, academic agencies (e.g. hospitals, universities, institutes), associations of mental health professionals, and non-government organizations. the services included counseling, supervision, training, as well as psychoeducation through e-platforms (e.g. hotline, wechat, weibo, tencent qq, alihealth, and haodaifu) (moe-china, ) . additionally, online self-help psychological interventions such as cbt for depression, anxiety, and insomnia were also developed . early reports indicated high interest and acceptance of these services by the target population. the 'national crisis intervention platform for covid- ' was created with mental health professionals. several hospitals set up their own crisis counseling system for staff and patients using telehealth in many provinces of china kang et al., ) . the australian government had delivered a wide range of telehealth services including telehealth consultations to general practitioners and specialists . however, to date, the australian government has focused on managing the physical health needs of the population during the epidemic, with less focus on mental health . access to other existing tele-mental health support services such as self-help platforms, videoconferencing, or mobile apps for depression, anxiety, and emotional problems should be made available for the general population . telehealth has become a cost-effective alternative for delivering mental health care during the covid- global pandemic when in person and face-to-face visits are not possible. solid evidence supports the effectiveness of telephone and web-based interventions, especially for alleviating symptoms of depression, anxiety, and ptsd (kerst, zielasek, & gaebel, ; turgoose, ashwick, & murphy, ) . videoconferencing, online programs, smartphone apps, text-messaging, and e-mails have been useful communication methods for the delivery of mental health services (torniainen-holm et al., ; zhou et al., ) . national and provincial digital mental health services (e.g. hotlines, websites, wechat, weibo) have been established as essential measures to address mental health needs of key target populations such as healthcare providers during the covid- outbreak. however, digital therapies might not be appropriate for older or demented people, people with reading difficulties, poor people, or people who are not technologically adept. the combination of online and offline psychological counseling is a key strategy for mental health services and intervention systems during the covid- pandemic. this paper provides a rapid review of the published literature on mental health practices and services during recent infectious disease epidemics. except for publications on some mental health intervention systems and psychosocial interventions, most other reports were not specifically designed to evaluate the feasibility and effectiveness of mental health interventions. more evidencebased psychosocial interventions with telehealth services and considering contextual adaptation, complexity, and resources requirements are needed during the covid- pandemic and future outbreaks of infectious diseases. during infectious disease outbreaks such as covid- , measures implemented for their prevention (e.g. quarantine and isolation, business or school closures) as well as the losses induced by them (e.g. finance, food, personal freedom, social connection, and relationships) contributed to significant emotional distress, reduced mental well-being, and may lead to psychiatric or behavioral disorders in both the short and long term. these consequences are of sufficient magnitude, requiring immediate efforts and direct interventions to reduce the impact of the outbreaks at both individual and population levels (galea et al., ) . psychoeducation and emotional support in particular help to normalize crisis reaction, mobilize resources, and increase adaptive coping strategies for progression to serious mental illness such as major depression or ptsd (north & pfefferbaum, ; north, hong, & pfefferbaum, ; reyes, ) . however, many countries have tended to focus on the physical health needs of covid- , often neglecting mental health needs with few designated organizations offering specific mental health services with easy access to those in need. the integration of mental health provisions into the covid- (and other infectious disease emergencies) response should be best addressed at the national, state, and local planning levels (pfefferbaum & north, ) . call for evidence-based psychosocial interventions to cope with the covid- pandemic prevention efforts in mental health were implemented primarily for people who were at risk or had greater vulnerability, such as frontline workers, confirmed covid- patients, infected family members, and those affected by the loss of loved ones (holmes et al., ) . mhpss programs through international organizations were used effectively in several low-and middle-income countries during infectious disease outbreaks (cenat et al., ) . for example, group-based cbt (waterman et al., ; waterman et al., ) , pfa, ptl (decosimo et al., ) , culturally adapted interventions such as smart (ng et al., ) , ultra-brief psychological interventions (ping et al., ) and peer supports (rastegar kazerooni et al., ) have been reported to effectively mitigate the emotional impacts of covid- , evd, and sars outbreaks. however, the quality of evidence was still restricted because limited studies have provided quantitative data, and most intervention studies included small numbers of participants. during the covid- pandemic, other evidence-based interventions can be applied, and their feasibility and effectiveness should be evaluated. for example, mindfulness-based interventions (hofmann & gomez, ) or cbt for insomnia (koffel, bramoweth, & ulmer, ; riemann et al., ; trauer, qian, doyle, rajaratnam, & cunnington, ) can be assessed for their effectiveness in the provision for individuals suffering from severe sleep problems or chronic anxiety symptoms. psychosocial interventions can provide support for individuals in the wake of a crisis and can increase the perceived safety of individuals, further ameliorating maladaptive stress reactions and reducing emotional distress (slavich, ) . people with major losses or those with more severe illnesses are more vulnerable to experience depression, suicidal ideation, or ptsd in the initial phase of the pandemic or even after it ends (north, suris, davis, & smith, ). evidence-based trauma-focused psychotherapies and pharmacotherapy are appropriate. for specific subgroups, family intervention may be recommended (dawson et al., ; forbes et al., ; north & pfefferbaum, ) . facing the pandemic, measures for identifying, triaging, referring, and treating severe psychosocial consequences, death notification, and bereavement care should be established (north & pfefferbaum, ; pfefferbaum & north, ; . moreover, for the lower income countries, with greater scarcity of mental health resources, implementation or modification of evidence-based psychological treatments, such as psychological treatments to be delivered by non-specialist providers including through task sharing, is urgently needed (barbui et al., ; singla et al., ) . evaluating the effectiveness of interventions to mitigate covid- 's mental health consequences on patients the degree of risk for infection with covid- for individuals with severe mental illnesses has not been clearly established; however, it is reasonable to presume such risk to be higher than that of the general population, because of disordered mental state, possible poor self-care, inadequate insight, or side effects of psychotropic medications (starace & ferrara, ; xiang et al., ) . furthermore, adverse social determinants brought about by the covid- pandemic, including poverty, food insecurity, and stigma, can be contributory (lund et al., ) . people with severe mental health problems commonly live in poverty which impacts their ability to socially distance themselves from neighbors or the local community and increases transmission risk. psychiatric inpatients confirmed or suspected covid- could be treated in specialized wards in infectious disease hospitals or in isolated wards in psychiatric hospitals or shelter hospitals equipped with psychiatric consultations. as for psychiatric hospitals, measures including strict triaging/precautionary procedures and admission criteria, and shorter hospitalization length of stay should be taken to prevent the clustering of covid- cases (chinese society of psychiatry, ; shao et al., ; starace & ferrara, ) . additionally, mental health home hospitalization care was recommended (garriga et al., ) , and medical staff management in psychiatric hospitals such as electronic tracking of staff movement might facilitate contact tracing (poremski et al., ) . however, follow-up studies on how effective these interventions were in mitigating covid- 's mental health impacts on mentally ill patients are needed. these studies should balance the risks and benefits of these alternative interventions on mental health services among patients and providers. the potential of digital therapy programs which can offer costeffective evidence-based therapies has not been fully realized. however, awareness of the disparities in access to the technology of poorer populations and cultural and linguistically diverse communities in low-and middle-income countries may have an impact on their implementation (naslund et al., ) . the effectiveness of digital mental health interventions in such countries has not been rigorously evaluated. online mental health services' utilization is still low in china and australia . however, telehealth remains a valuable way of reducing psychosocial distress without increasing the risk of infection. during infectious disease outbreaks, telemental health services can enable remote triaging of care, offer cognitive and/or relaxation skills to deal with stress symptoms, encourage access to online self-help programs, and deliver professional psychological interventions if necessary. simple communication methods such as e-mail and text messaging can and should be used more extensively in low-income countries. however, many of these interventions require more rigorous jing-li yue et al. assessments to determine their efficacy, effectiveness, treatment retention, and outcomes. investing in the collection of evidence on the outcomes, workforce requirements, patient engagement, and ethical uses of tele-mental health services will allow them to truly deliver their full potential . telehealth and digital services should not completely replace face-to-face treatment for patients in need, particularly those requiring intensive mental health treatment and support including wider deployment of injectable long-acting medications and hands-on interventions such as electroconvulsive and transcranial magnetic stimulation therapies, when in-person contact is once again safe. several limitations of this systematic review need to be considered. first, few rcts on the effectiveness of mental healthcare interventions on mitigating mental problems during any of these infectious disease outbreaks were identified, and more highquality rct studies are needed. second, due to the limited number of studies on psychological interventions during infectious disease outbreaks, and the heterogeneity of evaluation methods, we only could provide a systematic review without a formal meta-analysis. third, relatively few countries have reported mental health services and treatments during infectious disease outbreaks, more high-quality studies are in need to form culture-adapted efficient and nationally unique mental health responses for infectious disease outbreaks. the pandemic of covid- brings huge challenges for mental health systems worldwide which have to rapidly change, but also can offer an opportunity for improvement of mental health responses, and lead to long-term development of sustainable mental health care systems. despite differences in political, social, and health systems, mental health services worldwide have implemented acute responses that focus on care for mental health service users, and have facilitated access to mental health assessment and care for new-onset or high-risk patients. more evidencebased interventions should be implemented during epidemics especially for vulnerable populations such as children, older adults, and healthcare workers. the effectiveness of alternative digital interventions in mitigating the mental health consequences on mental services and patients should be assessed in follow-up studies. tele-mental health strategies and global cooperation are sound approaches to develop and implement 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coronavirus disease (covid- ) outbreak in january in china rethinking online mental health services in china during the covid- epidemic mitigating mental health consequences during the covid- outbreak: lessons from china system effectiveness of detection, brief intervention and refer to treatment for the people with posttraumatic emotional distress by mers: a case report of community-based proactive intervention in south korea psychological crisis interventions in sichuan province during the novel coronavirus outbreak the role of telehealth in reducing the mental health burden from covid- acknowledgements. we appreciate an-yi zhang, yi-jie wang, xiao-xing liu, xi-mei zhu, ze yuan, chen-wei yuan and meng-ni jing for their help with the data search. conflict of interest. none. key: cord- -mxvbbkc authors: wei, maoti; yang, ning; wang, fenghua; zhao, guoping; gao, hongwei; li, yuming title: epidemiology of coronavirus disease (covid- ) caused by severe acute respiratory syndrome coronavirus (sars-cov- ) date: - - journal: disaster medicine and public health preparedness doi: . /dmp. . sha: doc_id: cord_uid: mxvbbkc in december, , an infectious outbreak of unknown cause occurred in wuhan, which attracted intense attention. shortly after the virus was identified as severe acute respiratory syndrome coronavirus (sars-cov- ), the epidemic of coronavirus disease (covid- ) broke out, and an information storm occurred. at that time, important aspects, that is, the stages of spread and the components of the epidemic, were unclear. answers to the questions ( ) what are the sources, ( ) how do infections occur, and ( ) who will be affected should be clarified as the outbreak continues to evolve. furthermore, components of the epidemic and the stages of spread should be explored and discussed. based on information of sars, middle east respiratory syndrome (mers), and covid- , the components of the epidemic (the sources, the routes of infection, and the susceptible population) will be discussed, as well as the role of natural and social factors involved. epidemiologic characteristics of patients will be traced based on current information. s ince the end of , a novel coronavirus, namely severe acute respiratory syndrome coronavirus (sars-cov- ), which causes coronavirus disease (covid- ) , appeared in wuhan, hubei province, china. to date (april , ), china's number of officially reported cases include , confirmed, suspected, deaths, and , recovered cases. the mortality rate caused by covid- in china is . % ( / , ; % confidence interval [ci]: . - . %). at the same time, at least , accumulated cases have been reported in nearly all countries and regions outside of china with , deaths. to cope with the pandemic, the infection profile caused by the novel coronavirus was summarized from an epidemiological perspective. starting in december , more and more unexplained cases of infection were being found in wuhan, hubei province, china. the initial infection time reported in several studies is different. for example, the study by li et al. showed that, on december , , local hospitals used the term "unexplained pneumonia" for monitoring and found the first reported cases, all of which were related to the south china seafood wholesale market. the study by huang et al. reported that patients were found on december and , , and patient was related to seafood market exposure. in all, it was acknowledged that more and more cases were found after mid-december . published data showed that the progress of the epidemic started from mid-december with increasing numbers of cases. by december , , more than cases ( figure , small graph) were reported (note: there is a slight difference in timing reported by li et al. and huang et al., but a similar trend was observed in both studies; that means the epidemic started from mid-december). , since the official recognition of human-to-human (person-to-person) transmission, also with the continuous improvement of detection methods and technologies, the number of cases increased rapidly (exponential increase), suggesting that the epidemic is expanding (figure ). however, the trend of rising numbers of incident cases changed on february , , because strict control measures were enacted and enforced. these data allowed for a profile of the outbreak to emerge. according to daily released data figure epidemiological curve of covid- cases reported by timeline in published papers. , note: there is a difference in timing reported by li et al. and huang et al., but both studies acknowledged that the epidemic started from mid-december, . the data in the upper litter chart is from huang et al., and the data of the larger chart is from li et al. epidemiological curve of covid- cases in china from january , , to april , , by daily reported data (http://www.nhc.gov.cn/xcs/xxgzbd/gzbd_index.shtml). at noon on january , (chinese lunar new year's eve), the prevention and control headquarters of coronavirus infection in wuhan released announcement no. , which was an important step to prevent the spread of the epidemic. the announcement suspended the city's urban public transportation, subway, ferry, and long-distance passenger transportation, limiting departures from wuhan, and also temporarily closed the airport and railway station exit channels from the city. although there were follow-up announcements to limit the spread, with the successful development and distribution of diagnostic reagents in this stage, an exponential growth curve was observed for newly reported cases. at the same time, the world health organization (who) also declared china as an epidemic area, which has a huge impact on china, and the task of prevention and control became very arduous. shortly after the announcement of the lock-down of wuhan city, the central government initiated several measures for controlling the epidemic in wuhan as well as in other parts of china (from january , , until the time of this writing). briefly, wuhan citizens were asked to stay at home, and the government tried its best to offer logistics supplies; medical support was encouraged from other regions to help wuhan city; infected patients were isolated in fangcang shelter hospital. as in wuhan city, other regions of china also carried out strict control measures. the hard work in preventing the epidemic in wuhan and china paid off, and the incidence cases decreased day by day and a controlled profile was built. according to various reports, the initial source of infection is believed to be wild animals, possibly the chinese bat, rhinolophus sinicus. in an interview, academician zhong nanshan also mentioned that wild animals, such as bamboo rats and badgers, may also be possible sources. although there is no correlation between the initial case (december , ) and the follow-up cases (december , ), it may be arbitrary to exclude the first patient from the seafood market. it could take more than days to trace the patient's contact history in the study; also, the patient's forgetting or loss of personal contact history is reasonable. of course, the data also suggest that covid- may have originated far earlier than the time of that patient emerging. the analysis of available genomes of the virus shows that they had a "recent common ancestor" as early as october , . it is possible that the first infection case occurred far earlier before december . the virus could have spread among people in wuhan and other places quietly, and then concentrated and was detected in the seafood market; the virus may have been spreading within the population, and the seafood market may not have been the geographic source. , however, the route of transmission to humans at the start of this event remains unclear. bats are rare in markets in china but are hunted and sold directly to restaurants for food. the current most likely hypothesis is that an intermediary host at present, the existing data and the actual phenomenon of infections showed that covid- patients were the most important source of spread of infection, who could cause human-to-human transmission. , when the sars-cov- infection occurred, it may have been contagious before the appearance of symptoms. however, in sars-cov infection, it was reported that the more obvious symptoms were accompanied by a higher viral load, as well as stronger infectivity. whether covid- has the same characteristic needs further investigation. of course, this characteristic also needs close attention in prevention and control. recent results showed that sars-cov- persists longer with a higher viral load and peaks later in the respiratory tissue of patients with severe disease; this phenomenon highlights the need for the prevention and control of the epidemic. unlike sars, patients with covid- had the highest viral load near onset of symptom, which could account for the fast-spreading nature of this epidemic. some experts commented that people with mild or asymptomatic sars-cov- infection were not identified by epidemic prevention measures, thus accelerating the spread of the disease. according to published research results, the average interval from onset to the first medical visit was approximately - days ( . days, % ci: . - . ; and . days, % ci: . - . ), which is similar to the estimated incubation period (the average incubation period of confirmed cases is estimated to be . days ( % ci: . - . ). during that time, although there were mild or no symptoms, the disease could be contagious. this finding highlights the importance of contact history tracing and maintained isolation of patients, suspected patients, and those with whom they have come in contact. this feature of covid- is significantly different from that of the sars-cov infection outbreak in . it is reported that sars had no evidence of an incubation period and no shedding of virus. asymptomatic patients were reported often, and this meant that there may be so-called "recessive infection cases" or asymptomatic infections. , most of the so-called "recessive infection cases" or asymptomatic infected people would eventually have symptoms and become ill. to date, no super spreader of the sars-cov- infection has been observed, but experts still warned people to pay attention to the possibility of super transmission events. clustering cases were reported, but in limited scale. , these studies reported that a super spreader at a group gathering could cause - new cases of infection, with a maximum of people newly infected being reported. however, compared with sars-cov infection, there were fewer clustered cases of sars-cov- infection and fewer cases compared with middle east respiratory syndrome coronavirus (mers-cov) infection. however, other data showed that the transmission ability of covid- , with an r = . to . , indicates that there may be super spreaders of the virus. , for effective prevention of mass transmission, more must be learned about super spreaders of covid- . inhalation of droplets containing virus particles exhaled by infected persons is the main mode of transmission of covid- , and the most common route of infection. this mode of transmission is very similar to that of the sars-cov infection. this transmission is easy to achieve during daily contacts, such as close family contact, by public transportation, in medical institutions, and so on. the reported covid- cluster events may be explained by close family contact. , , it is generally believed that large size droplets play important roles in sars spread, especially droplets with sizes of μm- μm; so how about covid- ? because the symptoms of covid- are very similar to those of influenza or the common cold, they are easily misdiagnosed in the early stages of infection by clinicians, other medical staff, or rescue personnel. in the early stages of infection, cutting off the spread of droplets may play an important role in the control of covid- spread. during the epidemic of sars, aerosol transmission was way of transmission, which was highly suspected to be of the important transmission routes of outbreaks in hospitals and communities in severely affected epidemic areas. the epidemiological point here is that susceptible persons can be infected by inhalation of aerosols containing sars-cov without coming into contact with sars-infected patients. although the data of sars cases were analyzed by epidemiological models, the results showed that the spread of sars infection was not supported by aerosols, but by droplets. officers of who believed that the possibility of sars transmission through aerosols is very low. however, the propagation speed of covid- is so fast, whether it is related to aerosol propagation needs further confirmation. however, the respiratory transmission will be greatly reduced by various protective measures, such as wearing face masks and isolation clothing. through direct or indirect contact with the patient's secretions or body fluids, excreta, and other contaminated items, or working for, living with, treating, or visiting the patient, during the course of the sars epidemic, the possibility of transmission by means of the digestive tract cannot be ruled out because of lack of direct evidence. however, a study reported that there were digestive tract symptoms after covid- ; whether the transmission was achieved through the digestive tract was unknown and needs further epidemiological study. to date, it is confirmed that sars-cov- viral rna can be detected in feces after recovery, which is very similar to the sars-cov infection. it is unknown whether the virus is infectious at that time. however, enhanced control measures of the digestive tract products may reduce the risk of its spread during the epidemic. to date, there is no evidence of transmission by blood, sexual contact, vertically from mother to fetus, or other routes. there is no evidence that flies, mosquitoes, cockroaches, and other arthropods can transmit covid- . people are generally susceptible to infection by sars-cov, but the rate of infection in children is low, and the reason is unclear. some experts concluded that children are not easily infected. however, epidemiological data show that children are susceptible to covid- , and the low infection rate of children may be related to their having less exposure. the elderly and those with underlying diseases are seriously affected after infection. preliminary data showed that most patients who die are the elderly with underlying diseases. those persons in close contact with sars patients during the symptomatic period are at high-risk for sars-cov infection. however, persons coming in contact with an asymptomatic covid- patient may also be at high-risk of sars-cov- infection. persons caring for and visiting patients (medical staff, patients' family members and friends) were likely to have close and prolonged contact times. if sufficient protective measures were not taken, these persons are at higher risk of acquiring covid- . it is confirmed that humoral immunity can be induced after sars-cov infection. the serum anti sars-cov immunoglobulin (ig) g stays strongly positive at months after the onset of the disease. for covid- , whether the humoral immunity could have protective effects needs to be studied further. in the acute period of sars-cov- infection, the level of some cytokines increased: interleukin (il) - b, il- ra, il- , il- , il- , il- , basic fibroblast growth factor (fgf), granulocyte colony-stimulating factor (gcsf), granulocyte-macrophage colony-stimulating factor (gmcsf), interferon-gamma (ifn-γ), induced protein- (ip- ), monocyte chemoattractant protein- (mcp ), macrophage inflammatory protein- a (mip a), mip b, platelet-derived growth factor (pdgf), tumor necrosis factor-alpha (tnf-α), and vascular endothelial growth factor (vegf). however, there was no significant change in other cytokines, such as il- , il- p , il- , eotaxin, and rantes. certainly, these altered cytokines may be related to the development of this disease. a recently published study showed that the elevated il- concentration could be associated with poor prognosis. different from sars-cov infection, covid- can cause severe cellular immune dysfunction. according to data of respiratory diseases, poor ventilation, environmental conditions, and mass gathering indoors will favor the transmission of infectious diseases. some person-to-person transmissions may be explained by closed environments. , as is well known, the sars outbreak ceased with the coming of the summer, and it seems there is a direct relationship between the seasonal factors and the spread of this coronaviruses infection among human beings. therefore, further investigated is needed as to whether the epidemic of covid- relates to meteorological conditions, seasonality, geographical conditions, and ecological environment. the pandemic of covid- occurred in the northern hemisphere and the southern hemisphere, and this fact means that infections of sars-cov- may not be influenced by temperature. high population density, high mobility, poor health conditions, and poor health habits are important aspects prompting the spread of infectious diseases. large cities with concentrated populations and convenient transportation are prone to outbreaks and the prevalence of respiratory infectious diseases. ineffective prevention and control measures and improper personal hygiene habits and protective measures of medical staff may cause the occurrence of nosocomial infections. the rapid spread of sars is closely related to mass migrations using modern transportation. the prevalence of covid- increased rapidly in a short period, also demonstrating that current transportation modes are crucial for the spread of this disease. therefore, it is very important to cut off all responsible transmission routes (through various means) once the transmission routes of the disease are well defined. according to established prevention and control of infectious disease strategies, areas may be declared epidemic areas after an outbreak of an infectious disease, and corresponding control measures enacted. after the outbreak of covid- , wuhan city has been closed (locked down) since january , , and the control measures have been in effect from february , . also, according to a study, "close the city" has reduced the incidence of infection and death by nearly %. in addition, the state vigorously publicized the epidemic control measures, which also played an important role in the control of covid- in china. with the ending of the spring festival holiday, people began to return home to their cities (city-returning). there were relatively large zones where people were returning to, namely beijing, tianjin, and hebei; the yangtze river delta; the pearl river delta; and chengdu and surrounding areas. it was previously predicted that, with the large number of people moving back to specific areas, the number of new infections would also increase. therefore, the epidemic could worsen because of the breakdown of the prevention and control measures. fortunately, at the time of this writing, the epidemic of the covid- is under control in these regions, as well as in china. on april , , the national health commission (nhc) had received , total confirmed cases reported by provinces (autonomous regions, municipalities directly under the central government) and xinjiang production and construction corps, including confirmed ( in serious condition), deaths, , discharged cases, and suspected cases. the hottest epidemic area in mainland china was wuhan city, hubei province, followed by guangdong province, henan province, zhejiang province, hunan province, and so on. on the whole, infections were more likely in areas surrounding hubei province (figure ). from the first case in wuhan in november to the first case of covid- in thailand on january , (the first case outside china), covid- had successively appeared in other countries. with the spread of the epidemic, it was listed as a public health emergency of international concern (pheic) by who on january , . the epidemic curve of covid- worldwide showed that early cases occurred sporadically, but the number of cases increased significantly after february , ( figure ). the mode of infection increased gradually from the visit to wuhan to the contact with the residence. as shown in the data, most of the cases were initially exposed to hubei (or wuhan), or were related to taking transportation or going to hubei (or wuhan). however, some cases in the later period were related to contact with patients. at the time of this writing, the pandemic is roaring all around the world. official reports showed a rapid increase in cases of covid- was observed in the epidemic curve. with the coming of the city-returning peak (people returning to their home and work city after the spring festival holiday), it was warned that more cases would be reported in other places of china. an epidemic curve is presented (figure ), in which, an increase trend in the early course and a down trend in the later period. although some studies thought that numbers of cases were seriously underestimated, fortunately the down trend has maintained, and this means the epidemic is under control in china. occupation, age, and gender during the early period of the epidemic, limited data were obtained for describing the epidemiological characteristics of covid- . however, according to published studies, the source of infection was located to the huanan seafood market. for this reason, the personnel related to the seafood market could be roughly divided into categories: the first category was the dealers and the managers of the seafood market (who had close contact with the seafood market); the second category was the buyers at the seafood market (who had contact history with the seafood market); the third category was the secondary cases of the infections in the seafood market (who had no contact history with the seafood market). , , among the patients reported by li et al., the first time period was before january (the date of closing the huanan seafood wholesale market). the average age of patients was years ( - years) , and % of them were under years old. according to the common assumption, the first group (the dealers or the managers of the seafood market) should account for a large part of the affected population in this period, and there were no children under the age of at this stage. in the period after the closure of the seafood market, ie, the second and third stages in the study by li et al., groups of people (close contact, contact, and no contact with the seafood market) may exist. at this time, the average age of patients was years ( - years old) ( figure ). however, sars-cov- , as a new virus, the people with the highest risk were those people with low resistance, such as the elderly, especially the elderly with underlying diseases, where infections may be more severe. that means the weak more easily contracted infection, with more serious outcomes. this phenomenon has been observed in other binfluenza virus infections, such as the h n virus, which affected the elderly at a higher significantly rate than other common pathogens. epidemiology of covid- disaster medicine and public health preparedness therefore, it could be preliminarily considered that the main personnel before closure of the market were the dealers or the managers of the seafood market, the purchasers at the seafood market, and the secondary cases of the infected persons in the seafood market. after the closure of the market, onsets of the early stage of infections and secondary transmissions were more likely to affect the elderly with underlying diseases. therefore, in the follow-up prevention and control of the epidemic, more attention should be paid to the elderly, especially the elderly with underlying diseases; high death rates reported verified this hypothesis now. data showed that the proportion of men in the first period was higher ( %); in the second period, the proportion of men decreased ( %); and in the third period, the proportion of men was almost the same as women ( % proportion of the elderly is relatively large ( % of were over years old). with increased age, the fatality rate also increased. the patients with other diseases, such as hypertension, diabetes, heart disease, emphysema, and tumor, had the highest fatality rates. on february , , the number of deaths due to covid- reported by the state was , with a mortality rate of . % ( / ), which was lower than that of sars-cov and mers-cov infection. according to the current limited data ( case fatalities), the average age of the patients was ± years ( - years), and most of them had underlying diseases. although the data were not very comprehensive, it was speculated that the prognosis characteristics may be similar to that of sars-cov infection. in conclusion, in view of the infection caused by the covid- , this study used the research literature, data, and daily releases to summarize the epidemic process and the transmission stages of covid- . the infection source, transmission routes, susceptible populations, and natural and social factors affecting the epidemic of covid- were summarized. the epidemiological characteristics of covid- were analyzed and described. through this study, we hope to preliminarily clarify the epidemiology of infections caused by the new coronavirus and provide guidance for prevention and control. daily announcements of epidemic situation of china coronavirus disease (covid- ) situation report - early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia clinical features of patients infected with novel coronavirus in wuhan daily announcements of epidemic situation of china wuhan temporarily shuts down local transportation to curb virus. peoples government of hubei province website genetic evolution analysis of novel coronavirus and coronavirus from other species wuhan seafood market may not be source of novel virus spreading globally kraemer m. epidemiological data from the ncov- outbreak: early descriptions from publicly available data estimates of the clock and tmrca for -ncov based on genomes importation and human-tohuman transmission of a novel coronavirus in vietnam a familial cluster of pneumonia associated with the novel coronavirus indicating person-to-person transmission: a study of a family cluster determining sars sub-clinical infection: a longitudinal seroepidemiological study in recovered sars patients and controls after an outbreak in a general hospital viral load dynamics and disease severity in patients infected with sars-cov- in zhejiang province temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by sars-cov- : an observational cohort study a novel coronavirus outbreak of global health concern transmission of covid- infection from an asymptomatic contact in germany presymptomatic transmission of sars-cov- -singapore super-spreading events of mers-cov infection nowcasting and forecasting the potential domestic and international spread of the covid- outbreak originating in wuhan, china: a modeling study the presence of sars-cov- rna in the feces of covid- patients first case of novel coronavirus in the united states modelling the epidemic trend of the novel coronavirus outbreak in china coronavirus disease (covid- ) situation reports epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study epidemiological characteristics of confirmed avian influenza a (h n ) cases in mainland china-a preliminary report] (in chinese) daily announcements of epidemic situation of china we thank all staff members for collecting the data. without their valuable assistance, it would have been impossible to successfully complete this study. drs. wei and dr. yang contributed equally to this work. this study was supported by the national natural science foundation of china (grant no. ). key: cord- -lmws eed authors: rafiq, danish; batool, asiya; bazaz, m. a. title: three months of covid‐ : a systematic review and meta‐analysis date: - - journal: rev med virol doi: . /rmv. sha: doc_id: cord_uid: lmws eed the pandemic of novel coronavirus (sars‐cov‐ ), reminiscent of the ‐sars‐cov outbreak, has completely isolated countries, disrupted health systems and partially paralyzed international trade and travel. in order to be better equipped to anticipate transmission of this virus to new regions, it is imperative to track the progress of the virus over time. this review analyses information on progression of the pandemic in the past months and systematically discusses the characteristics of sars‐cov‐ virus including its epidemiologic, pathophysiologic, and clinical manifestations. furthermore, the review also encompasses some recently proposed conceptual models that estimate the spread of this disease based on the basic reproductive number for better prevention and control procedures. finally, we shed light on how the virus has endangered the global economy, impacting it both from the supply and demand side. the initial outbreak of the novel coronavirus in december was centered in wuhan, hubei province of the people's republic of china. [ ] [ ] [ ] [ ] [ ] it was initially named as novel coronavirus, soon after the international committee of taxonomy of viruses (ictv) named the virus as sars-cov- , because of the previously identified variant-severe acute respiratory syndrome coronavirus (sars-cov). the clinical illness it causes is termed as coronavirus disease . while several other human coronaviruses such as hcov-nl , hcov- e, hcov-oc , and hcov-hku cause mild respiratory disease, others like the zoonotic middle east respiratory syndrome coronavirus (mers-cov) and sars-cov tend to have a higher fatality rate (summarized in table ). they bear a core shell with surface projections that make them resemble a crown. they were first described by tyrell and bynoe in , from patients with the common cold. four subfamilies of coronaviruses have so far been discovered; • alpha: originate from mammals, particularly bats, cause asymptomatic or mildly symptomatic infections • beta: originate from mammals, particularly bats, can cause severe disease and fatalities. sars-cov- belongs to the betacoronaviruses and is closely related to the sars-cov virus. , sars-cov- is % identical to a bat coronavirus at the wholegenome level. • gamma and delta: originate from pigs and birds the genome size of coronaviruses varies between and kb with four major structural genes encoding the membrane glycoprotein (m), spike protein (s), nucleocapsid protein (n), and a small membrane protein (sm) (figure ). an additional membrane glycoprotein (he) occurs in the hcov-oc and hku beta-coronaviruses. sars-cov- has succeeded in transferring from bats to humans, presumably in the seafood market in wuhan, china. however, potential intermediate hosts remain to be identified and the precise route of transmission urgently needs to be clarified. because of the novelty of this virus, experts' understanding of exactly how it spreads is restricted. major respiratory outbreaks in last century it has also been suggested that the receptor-binding ability of sars-cov- is - times stronger than that of sars-cov. the patients may move through different stages of illness: • replicative stage -the virus may take several days to replicate. initially, it evokes the first line of defence, that is, innate immune response, but this fails to contain the virus resulting in fairly mild symptoms due to direct viral cytopathic effect. • adaptive immunity stage -the innate immune response is eventually followed by the adaptive immune response which tends to decrease the titer of the virus. meanwhile, the inflammatory cytokines show augmented levels culminating in tissue damage and consequent clinical deterioration. this explains the sudden deterioration of the patients after being relatively fine for several days. potentially clinical inferences can be drawn: • preliminary clinical symptoms are not essentially prognostic of future outcome. • antiviral therapies need to be given during the replicative stage to work optimally. • it is desirable to deploy any immunosuppressive therapies in the adaptive immune stage to blunt the immunopathologic response. the initial clinical sign of the covid- that allowed its case detection was pneumonia. while some reports suggest gastrointestinal symptoms associated with this disease, others describe asymptomatic infections, particularly among young children. sars-cov- may cause lower respiratory symptoms, upper respiratory symptoms, constitutional symptoms, and, less commonly, gastrointestinal symptoms. most patients show lower respiratory symptoms and constitutional symptoms (eg, cough and fever). • the incidence of fever is variable among studies (ranging from % to %). this may relate to different strains of virus or different levels of disease severity between several cohorts. regardless of the frequency, absence of fever in a patient does not exclude covid- . • about % of patients may have lymphopenia. , • mild thrombocytopenia is very common (but only rarely do platelet counts decline below ). • lower platelet count is a marker of poor prognosis. • also, up to % of patients can initially show gastrointestinal symptoms (eg, nausea and diarrhea), followed by dyspnea. • some patients, especially the elderly, may have "silent hypoxemia" and respiratory failure without dyspnea. • approximately, % of patients may develop pharyngitis or tonsil enlargement. | transmission and management typical of respiratory viruses like influenza virus, sars-cov- can spread through large droplets (with a transmission risk restricted tõ ft from the patient). the droplet containing viral particles (saliva or mucous droplets) can be ejected during coughing, sneezing, laughing, singing, breathing, and talking. if these droplets do not encounter anything along the way, they typically land on the ground or the floor. this transmission via large droplet can be reduced by using a normal surgical-style mask. this mode of transmission is usually overlooked, but it is very important. it works in four chains of reactions: there are currently no reports of intrauterine maternal-fetal transmission, but neonatal transmission can occur. research thus far has revealed more than agents including natural products, western medicines, and traditional chinese medicines with potential efficacy against covid- . some promising results have been achieved which are summarized below and listed in table , but formal randomized clinical trials will be required to prove efficacy and safety. lopinavir and ritonavir are protease inhibitors that work in conjunction to block viral replication. ritonavir, being a cyp a inhibitor, reduces the metabolism of lopinavir, thus boosting its levels. a ug/ml concentration of lopinavir was required for in vitro antiviral activity against sars while ug/mg of lopinavir was enough when used in combination with ribavirin. both protease inhibitors appear to function synergistically with ribavirin. combination of all three drugs has been used previously on sars and mers. recently, the combination of lopinavir/ritonavir has not proven impressive, suggesting that a cocktail of ribavirin/lopinavir/ritonavir might be required for efficacy. nevertheless, lopinavir/ritonavir is advantageous over ribavirin because of its wide availability and an established toxicity profile. originally developed for ebola, this drug was the most obvious fit for sars-cov- as it has already been tried out for ssrna viruses like sars and mers. remdesivir is a prodrug whose phosphoramide is cleaved off to leave the active compound gs- - with a oh. chloroquine, generally used for amebiasis and malaria, is currently being considered for treating covid- in view of its ability to interfere with the cellular receptor ace . it also impairs the acidification of endosomes, thereby impeding virus trafficking inside cells. although chloroquine has been unsuccessful in treatment of sarsinfected mice, recent reports from in vitro data show that chloroquine inhibits sars-cov- at a % inhibitory concentration of um. this suggests the possibility of achieving therapeutic levels in humans. it is worth mentioning that for sars, the % inhibitory concentration of chloroquine is near to um, several other potential drugs include bcr-abl kinase inhibitor imatinib and type-ii transmembrane serine protease (tmspss ) inhibitors. imatinib inhibits the fusion of virions with the endosomal membrane and as such possesses anti-coronavirus activity. ple. the interpretation of the results is given in table . the presence of sars-cov- viral proteins (antigens) in a sample from the respiratory tract of a person can also be detected within considering p as the total population, it is assumed that the susceptible population (s) is stably decreasing at a protection rate (α) and moving to compartment (s q ) that represents the quarantined individuals. those who are not quarantined and come in contact with infected persons belong to the compartment exposed (e) depending upon the transmission rate (β). an exposed individual, if protected from being infected (eg, by using protection of face mask or hand sanitizers) will move back to the susceptible (s) compartment at the safety rate (μ). the exposed individuals can get infected and move either to infectious and symptomatic (i) or infectious but not yet symptomatic/presymptomatic to (a) compartment depending upon the average latent time (γ − ) and (γ − ), respectively. the infected individuals can be detected and then hospitalized at a rate δ. from compartment (h), the patients can also move to the compartment recovery (r) at cure rate Λ(t) or die at mortality rate κ (t). however, the recovered persons are added back to the susceptible compartment (s) at a rate θ. it is important to mention that a percentage of people, though less, die in presymptomatic phase before being hospitalized. they also add to the death compartment at rate κ (t). the seir model described above can be modeled by a set of ordinary differential equations (odes) given as follows: these nonlinear coupled odes can be solved using an explicit/ implicit time stepping integrating scheme like the regular fourth-order runge-kutta scheme. in the past months, various mathematical models have estimated • later an updated estimation risk has been shown that included calculating the time-dependent contact and diagnosis rates. from a period of january , to february , . • the authors have argued that the estimation of r o mainly depends on the estimation technique involved and the modeling assumptions used. • both deterministic and stochastic models were included in the study. • the study showed that the maximum-likelihood (ml) value of basic reproductive number (r ) was . at an early stage on the ship for the covid- outbreak. • it was shown that if (r ) value was reduced by % and %, the • the value of (r ) was estimated using the next-generation matrix approach which came out to be . for reservoir to person and . for person to person. of covid- is presented in this study along with some useful insights from these models. • also, a susceptible-exposed-infected (sei) model framework was presented, and auxiliary strategies were described to prevent the covid- outbreak. the study showed that exposure time plays a significant role in spreading the disease. • the data were used for estimation of basic reproduction number using a susceptible infected recovered dead (sird) framework. • the estimated average value of r was~ . based on confirmed cases. the plot for the estimated value of the (r ) obtained by the above-mentioned studies is shown in figure . the plot shows a high reproductive number at the beginning of the outbreak in china with the maximum peak in mid-january . however, with passage of time, social distancing, self-quarantine, health care measures, and governmental actions had a substantial effect in containing the outbreak which is evident from the estimates of the (r ) in the months of february and march, . it is pertinent to mention that the estimates of the basic reproductive number mentioned in the above studies can be poor due to insufficient data, and different estimation techniques can result in different forecasts. however, further collection of data with robust modeling can result in close estimates. viral spread has borne out experts' downside fears, with consequences of possible containment measures, disrupted supply chains, and spill overs from the real economy to monetary markets. this overview provides the basic, biomedical, and translational research communities some key insights on covid- . we believe that the focus of future studies still lies in the progress of effective drugs in general and development of sars-cov- vaccines in particular. while uncertainty lingers, credible, coordinated, and coherent policy responses would deliver the best chance at limiting the fallout from this human tragedy. time alone can tell how the virus is going to affect our lives, but 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assessment of a novel coronavirus in wuhan estimating the effective reproduction number of the -ncov in china preliminary estimation of the basic reproduction number of novel coronavirus ( -ncov) in china, from to : a data driven analysis in the early phase of the outbreak how to cite this article: rafiq d, batool a, bazaz ma. three months of covid- : a systematic review and meta-analysis the authors declare no conflicts of interest. danish rafiq and asiya batool collected the data and wrote the manuscript, m. a. bazaz analyzed the data and helped in critical analysis and proof reading of the manuscript. not required. https://orcid.org/ - - - key: cord- - g ujfaf authors: qian, jing-yi; wang, bin; liu, bi-cheng title: acute kidney injury in the novel coronavirus disease date: - - journal: kidney dis (basel) doi: . / sha: doc_id: cord_uid: g ujfaf background: the novel coronavirus disease (co­vid- ) is a newly defined serious infectious disease caused by the sars-cov- virus. the epidemic started in wuhan, china, in december of and quickly spread to over countries. it has affected , , people, with , deaths worldwide by may , . covid- is characterized by acute respiratory disease, with % of patients presenting mild like flu-like symptoms; however, % of patients may have a severe or critical clinical presentation, which likely causes multiple organ injuries (e.g., kidney, heart, blood, and nervous system). among them, acute kidney injury (aki) is a critical complication due to its high incidence and mortality rate. here we present a review of the current understanding of aki in covid- . summary: co­vid- is a catastrophic contagious disease caused by the coronavirus, and the aki induced by covid- significantly increases the mortality rate. in this review, we summarize the clinical characteristics of covid- induced aki by focusing on its epidemiology, pathogenesis, clinical diagnosis, and treatment. key messages: multiple studies have shown that covid- may involve the kidneys and cause aki. this article reviews the characteristics of covid- -induced aki largely based on up-to-date studies in the hope that it will be helpful in the current global fight against and treatment of covid- . novel coronavirus disease (covid- ) is a newly discovered acute infectious disease caused by the sars-cov- virus, which is mainly manifested as acute respiratory diseases characterized by acute interstitial and alveolar pneumonia and can affect multiple organs such as the kidneys, the heart, the digestive tract, and blood [ ] . this disease is highly contagious, with diverse manifestations and complications, and poses a threat to public health, just like another coronavirus-induced diseases, i.e., severe acute respiratory syndrome (sars) and middle east respiratory syndrome (mers). although it mainly presents with acute pneumonia, acute kidney injury (aki) is the current outbreak of covid- started in wuhan, china, in early december of , and it has now spread to over countries [ ] . there are , cumulative confirmed cases, with , dead in china and , , cases with , dead outside of china by may , . in total, about - % of patients present severe or critical cases. the exact incidence of aki in covid- is still not fully clear. in the first study reported by huang et al. [ ] , the incidence of aki was %, and out of ( %) patients in the intensive care unit experienced aki. in another study of patients with covid- , seven cases developed various degrees of kidney injury with elevated serum creatinine (scr) and/or blood urea nitrogen (bun) levels, and of them were diagnosed with aki [ ] . wang et al. [ ] reported that . % of patients developed aki and patients received renal replacement treatment in his -patient cohort study. in a larger multicenter study with , cases, guan and zhong [ ] showed that the aki incidence rate was only . %. however, in a single-center study with consecutive hospitalized co-vid- patients, cheng et al. [ ] reported that the incidence rate of aki was . %; most strikingly, % of the patients with aki died. besides, patients with elevated baseline scr levels tend to develop more severe aki and have a higher death rate [ ] . so it appears that the overall incidence of aki in covid- is probably lower than that in sars and mers [ , ] . however, a recent study from yang et al. [ ] suggests that the aki incidence is quite high ( / ; %) in critically ill patients. quite similar results were also reported by diao et al. [ ] in their retrospective study, demonstrating that . % ( / ) of patients experienced aki, and elderly patients (age ≥ years) had a much higher incidence ( . %) of aki development [ ] . clearly, aki in covid- is very common, particularly in patients in severe or critical condition. our current understanding of the pathogenesis of aki in covid- is largely assumptive, based on previous studies and important coronavirus infection, i.e., sars and mers. renal impairment could be directly attacked by the coronavirus or a cytokine storm due to abnormal immunity. hypotension or dehydration, hypoxemia, sepsis, and nephrotoxic drugs could also be involved in the development of aki. angiotensin converting enzyme (ace ), a metallopeptidase, has been confirmed to effectively bind to the s domain of the spike protein on sars-cov. therefore, ace is considered to be a functional receptor of sars-cov [ ] . researchers described the full-length genome sequence of sars-cov- from patients and found that . % of sars-cov- sequences are homologous to sars -cov [ ] . moreover, they share the same functional receptor, i.e., ace , and have an affinity comparable that of human ace (hace ) [ , ] . recently the specific structure of ace was discovered by cryoelectronic microscopy and the multiple conformational states of the sars-cov- s glycoprotein were demonstrated at a . -Å resolution [ , ] . hace is not only expressed in lung tissue but it can also be detected in the kidneys, mainly in proximal tubules, afferent arterioles, collecting ducts, and the thick ascending limb of helen [ ] . in addition, viral nucleic acid could also be found in urine in out of ( . %), suggesting that the kidneys might be the target of this novel coronavirus [ ] . recently, diao et al. [ ] demonstrated that sars-cov- mainly induced acute tubular necrosis by infecting kidney tubules directly. immunohistochemistry demonstrated that the np antigen of sars-cov- was accumulated in the cytoplasm of kidney tubules instead of glomeruli based on the autopsy findings of covid- subjects with renal function impairment prior to death [ ] . besides, su et al. [ ] found the virus particles in the cytoplasm of renal proximal tubular epithelium and podocytes but less so in distal tubules. sars-cov nucleoprotein was analyzed in cases, and showed positive granular staining in a nuclear or cytoplasm pattern in tubular epithelium. these results provide direct evidence that the sars-cov- virus can directly infect the renal tubular epithelium and podocytes, which may induce aki in covid- patients [ ] . thus, the novel coronavirus can induce kidney injury directly via hace or other receptors like sars-cov, but the exact mechanism still needs to be clarified. immune activation accompanying the release of a large amount of proinflammatory factors may also play an important role in covid- -associated aki. previ-kidney dis doi: . / ous studies have demonstrated that sars-cov and mers-cov infection could lead to a significant upregulation of inflammatory factors and chemokines [ ] . it is noteworthy that cytokine storm syndrome (css) may play a critical role in multiple organ dysfunction syndrome in severe patients. laboratory examination showed that patients with covid- have a higher level of tnf-α, il- , il- , interleukin (il)- , and interferon (ifn)-α, suggesting that they may have experienced css. chen et al. recently a significant upregulation of il- and the il- receptor (il- r) was demonstrated in patients with covid- [ ] . the exact role of css in covid- needs to be further investigated. severely or critically illness patients with covid- often experience hypotension, hypoxemia, diarrhea, dehydration, electrolyte and acid-base balance disorder, cardiac insufficiency, and disseminated intravascular coagulation. meanwhile, drugs like nsaid, antiviral drugs, antibiotics, and (or) norepinephrine could all be attributable to the development of aki, specifically in aging patients with underlying diseases like diabetes, cardiovascular disease, or cancer. general manifestation covid- can affect a variety of organs and systems, including respiratory, urinary, digestive, cardiovascular, blood, and neurological systems, depending on the severity [ ] . the most common symptoms at the onset of the covid- illness are fever, cough, and fatigue, while other symptoms include sputum production, headache, hemoptysis, diarrhea, dyspnea, and lymphopenia. severe patients may experience a high fever, anhelation, chest distress, cyanosis, hypoxemia, hypotension, etc. the main feature of lung injury is acute interstitial pneumonia, i.e., alveolar pneumonia with a large amount mucinous secretion, which usually causes persistent hypoxemia. there are other relatively rare complications like acute respiratory distress syndrome and acute cardiac injury [ , , ] . patients with covid- may have various degree of renal dysfunction, characterized by elevation of bun, creatinine (cr), and renal structural changes [ ] . a study of patients with covid- found that % of patients developed massive albuminuria on the first day of admission and % of patients presented proteinuria during their stay in hospital [ ] . bun was elevated in % of the patients, and more importantly two thirds of the patients who died presented with increased bun and scr over μmol/l. kidney ct scans for showed the density was in the range of . - . hu, which is significantly lower than value in patients without kidney disease (i.e., hu). this result indicates that inflammation and edema of the renal parenchyma may occur in patients with covid- [ ] . cheng et al. [ ] recently reported that % of patients presented with proteinuria and hematuria and . % had hematuria on admission among consecutive hospitalized patients with covid- , and the prevalence of elevated scr and bun levels was . and . %, respectively. although the incidence of aki was . %, it is an independent risk factor for in-hospital death [ ] . recent autopsy data demonstrated that tubular epithelial cell necrosis and degeneration, with interstitial hyperemia, microthrombus, or focal fibrosis were the main pathological features, while glomerular lesions are not common [ ] . in the early stage of the disease, the number of peripheral blood leukocytes is normal or reduced; the lymphocyte count is reduced as well. some patients may suffer from liver disorder with abnormally elevated alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase levels. elevated troponin can be seen in some critically ill patients. c-reactive protein and erythrocyte sedimentation rates increased in most patients, and procalcitonin was usually normal. in severe cases, d-dimer increased and peripheral blood lymphocytes decreased progressively [ ] . chest ct showed multiple small patch shadows and interstitial changes in the early stage, which further developed into multiple ground glass shadows and infiltration shadows in both lungs. in severe cases, consolidation of the lung or white lung may occur, while pleural effusion is rare [ ] . moreover, a study of critically ill patients showed that lymphocytopenia occurred in more than % of covid- patients [ ] . however, a previous study claimed that % of noncritical patients infected with sars-cov- had mild lymphocytopenia [ ] , suggesting that the severity of lymphocytopenia reflects the severity of sars-cov- infection. a recently published case report analyzed the kinetics of immune responses of a nonsevere case of covid- , which suggest that immune parameters should be tested in covid- . early effective adaptive immune responses might correlate with better clinical outcomes [ ] . the diagnosis of aki complicated with covid- is based on the diagnosis of covid- and complied with the criteria of kdigo [ ] . aki is identified as one of the following: ( ) an scr increase ≥ . mg/dl (≥ . μmol/l) within h, ( ) an scr increase to ≥ . times baseline within the previous days; or ( ) a urine volume ≤ . ml/kg/h for h [ ] . for diagnosis of covid- , epidemiological factors, clinical manifestations, and laboratory examination (including a hemogram, a chest ct, a virological examination, etc.) should be combined [ ] . novel coronavirus nucleic acid detection, gene sequencing, or specific antibodies (both igm and igg) are all recommended approaches for confirmed diagnosis [ ] . however, false negativity may happen in some cases with a gene detection kit; it should therefore be used carefully and repeat analysis or combined use with other approaches is recommended [ ] . currently, detection kits like reverse transcription loop-mediated isothermal amplification (rt-lamp) with better sensitivity and specificity are under investigation [ ] . the main treatment of covid- with aki includes general management, antiviral therapy, renal replacement therapy, and other supportive therapies. all patients with confirmed covid- should be placed in effective quarantine and treated in designated hospitals. moreover, early admission to an intensive care unit (icu) is recommended for critical patients. patients are given rest, supportive treatment such as nutrients, and maintenance of homeostasis. oxygen therapy should be provided when necessary. fever is a common symptom of covid- , and nonsteroidal anti-inflammatory drugs (nsaid) are given cautiously. the management of critical cases should focus on the prevention and treatment of complications by maintaining hemodynamic stability. in addition, prevention of the secondary infection should also be emphasized. timely administration of high-flow oxygen, mechanical ventilation, or extracorporeal membrane oxygenation are key approaches for those with ards. it should be noted that assessing the patient's psychological situation and relieving the anxiety of patients are also integral parts of coping with this disorder [ ] . although antiviral therapy is critical, there is currently no confirmed effective antiviral drug for covid- . according to the updated version of guidelines recommended by the national health commission of the people's republic of china, aerosol inhalation of ifn-α and lopinavir/ritonavir are suggested for patients [ ] . the specific therapeutic value and safety of lopinavir/ritonavir in covid- patients are under investigation (chic-tr ). the efficacy of the nucleoside analog gs- (remdesivir) has been confirmed both in sars-cov and in mers-cov [ , ] . these studies suggested that remdesivir might be considered for a wider range of coronaviruses, including the current covid- . successful treatment with remdesivir has been reported in covid- patients [ ] , which quickly piqued the interest of chinese doctors. ta strictly designed clinical trial on the efficacy of remdesivir in covid- patients was started in china on february (nct and nct ) and will hopefully be finished in april of . blood purification comprises a group of techniques including plasma exchange, adsorption, perfusion, and continuous renal replacement therapy (crrt). among them, crrt is critical for severe covid- cases due to its unique technical features, specifically for those with aki, systemic inflammatory response syndrome, multiple organ dysfunction syndrome, and css. crrt is usually recommended for those with hyperkalemia, acidosis, pulmonary edema, or water overloaded [ ] . besides, it should be noted that crrt may play a crucial role in clearance of overloaded inflammatory cytokines in severe and critical patients [ ] . ghani et al. [ ] had showed the efficacy of high-volume hemofiltration ( l/h) treatment in sepsis, with not only removed inflammatory cytokines (il- , p = . ) but also improved sofa (sequential organ failure assessment) scores on day . park jt et al. [ ] also demonstrated that a high dose of crrt could significantly reduce the patient's serum il- and il- levels. in a randomized clinical trial, zarbock et al. [ ] demonstrated that early use of rrt (kdigo stage ii started in less than h) could significantly reduce the mortality rate in days compared to delayed use (kdigo stage iii started in over h) in critically ill patients [ ] . all of these studies suggested that timely use crrt might be an effective therapy in helping to clear the deadly cytokine storm in severe patients of covid- . other therapies convalescent plasma preliminary clinical studies in china have showed that early application of convalescent plasma in patients with covid- is an effective approach and could accelerate the patients' clinical recovery [ ] . however, van griensven et al. [ ] reported that transfusion of up to ml of convalescent plasma with unknown levels of neutralizing antibodies to patients with confirmed ebola virus disease did not show significant improvement in survival. the reason for this discrepancy is still unclear. now trials (an open-label, non-randomized clinical trial [nct ] and a multicenter, randomized, and parallel controlled trial [chictr ]) about the efficacy of convalescent plasma in patients with covid- are ongoing in china. monoclonal antibody directed against the rbd domain of the s protein of mers-cov has been verified to be effective in vitro [ ] . although the monoclonal antibody against covid- has not been developed, trastuzumab, as a monoclonal antibody against il- receptor, achieved encouraging results in a preliminary clinical observation. the safety and effectiveness evaluation of trastuzumab is ongoing in multicenter randomized controlled trials (chictr ). glucocorticoids are usually applied in severely ill patients with a viral infection. in the retrospective study im sars-cov, it was found that steroids could reduce the mortality and shorten the hospitalization time [ ] . however, the use of steroids is still quite controversial due to its potential inhibition of virus clearance and prolongation of the duration of viremia. sars, mers, and covid- , as the catastrophic contagious diseases caused by coronavirus in this century, pose great threats to public health and the safety of the world. aki as a complication of covid- could not only significantly increase the mortality rate of covid- but also, in the long run, increase the risk of developing chronic kidney disease. it is therefore important to pay more attention to finding aki in a timely manner and treat the patients properly when we are fighting covid- . clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china national health commission of the people's republic of china. guidelines for diagnosis 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injury rapid detection of novel coronavirus (covid- ) by reverse transcription-loopmediated-isothermal amplification. medrxiv coronavirus susceptibility to the antiviral remdesivir (gs- ) is mediated by the viral polymerase and the proofreading exoribonuclease prophylactic and therapeutic remdesivir (gs- ) treatment in the rhesus macaque model of mers-cov infection washington state -ncov case investigation team. first case of novel coronavirus in the united states practice of extracorporeal therapies for septic acute kidney injury patients in intensive care units in mainland china serum il- and il- -ra with sequential organ failure assessment scores in septic patients receiving high-volume haemofiltration and continuous venovenous haemofiltration. nephrology (carlton) high-dose versus conventional-dose continuous venovenous hemodiafiltration and patient and kidney survival and cytokine removal in sepsis-associated acute kidney injury: a randomized controlled trial effect of early vs delayed initiation of renal replacement therapy on mortality in critically ill patients with acute kidney injury-the elain randomized clinical trial joint defense and control mechanism of the state council. press conference of the joint defense and control mechanism of the state council ebola-tx consortium. evaluation of convalescent plasma for ebola virus disease in guinea generation and characterization of a monoclonal antibody against mers-cov targeting the spike protein using a synthetic peptide epitope-cpg-dna-liposome complex treatment of severe acute respiratory syndrome with glucosteroids: the guangzhou experience we would like to thank all of the medical staff at the institute of nephrology of zhong da hospital for their support in writing this article. the authors have no conflict of interests to disclose, and the results in this paper have not been published previously in whole or part. financially support for this work was provided by the key international cooperation program of the china national natural science foundation ( ) and the key research project of the ministry of china science and technology ( yfc ) to prof. bi-cheng liu as pi. bi-cheng liu designed this study, jing-yi qian carried out this study, jing-yi qian and bin wang wrote the draft, and bi-cheng liu revised this paper. key: cord- -jm lj t authors: uddin, md bashir; hasan, mahmudul; harun-al-rashid, ahmed; ahsan, md irtija; imran, md abdus shukur; ahmed, syed sayeem uddin title: ancestral origin, antigenic resemblance and epidemiological insights of novel coronavirus (sars-cov- ): global burden and bangladesh perspective date: - - journal: infect genet evol doi: . /j.meegid. . sha: doc_id: cord_uid: jm lj t sars-cov- , a new coronavirus strain responsible for covid- has emerged in wuhan city, china and still continuing its worldwide pandemic nature. considering the severity of the disease, a number of studies are underway, and full genomic sequences have already been released in the last few weeks to enable the understanding of the evolutionary origin and molecular characteristics of this virus. bioinformatics analysis, satellite derived imaging data and epidemiological attributes were employed to investigate origin, immunogenic resemblance and global threat of newly pandemic sars-cov- including bangladesh perspective. based on currently available genomic information, a phylogeny study was employed focusing four types of representative viral proteins (spike, membrane, envelope and nucleoprotein) of sars-cov- , hcov- e, hcov-oc , sars-cov, hcov-nl , hku , mers-cov, hku , hku and bufcov-hku . the findings clearly demonstrated that sars-cov- exhibited evolutionary convergent relation with previously reported sars-cov. it was also found that sars-cov- proteins were highly similar and identical to sars-cov proteins, though proteins from other coronaviruses showed lower level of similarity and identical patterns. the cross-checked conservancy analysis of sars-cov- antigenic epitopes showed significant conservancy with antigenic epitopes derived from sars-cov. the study also prioritized the temperature comparison through satellite imaging alongside compiling and analyzing the epidemiological outbreak information on the novel coronavirus based on several open datasets on covid- (sars-cov- ) and discussed possible threats to bangladesh. covid- has opened a new chapter of human civilization with a lots of tragedy stories. a new strain of coronavirus family, novel coronavirus or sars-cov- has emerged and infected thousands of humans. it is gaining importance due to daily increases in the deaths caused by this disease [ ] [ ] [ ] . the virus has already been reported from wuhan (china), thailand, japan, south korea, iran, and the us and is poised to occur in many more areas of the world community causing a pandemic scenario [ ] [ ] [ ] and globally increasing the potential for rapid horizontal spread geographically [ ] . determining the origin, evolution and antigenic resemblance of sars-cov- is urgently needed to study its molecular pathogenesis, perform surveillance, [ , ] were employed for the study. again, as some reports and analyses guessed bats as the probable original host of sars-cov- , we also considered two strains of bat-originated coronavirus (hku and hku ) in this study. from database and literature searches, only a single buffalo-originated coronavirus strain collected from bangladesh (bufcov-hku -m) [ ] was used for the comparative study with covid- strains isolated from wuhan, china [ ] . the global risk of the novel coronavirus (covid- [sars-cov- ]) has recently been addressed by many scientists [ ] [ ] [ ] [ ] . outside china,covid- transmission has been found in over countries and territories [ , ] . the us declared emergency funds because of coronavirus to the countries that are either affected or at high risk of spread, including bangladesh [ ] . as the outbreak of the novel coronavirus (covid- [sars-cov- ]) is expanding rapidly, analysis of epidemiological data of covid- is necessary to explore the measures of burden associated with the disease and to simultaneously gather information on determinants and interventions. therefore, we designed this study to compare the genetic materials of sars-cov- with different previously reported [ ] [ ] [ ] [ ] . accordingly, we also extracted population data of countries and provinces (china) from several websites [ ] [ ] [ ] . the retrieved protein sequences were subjected to multiple sequence alignment (msa) by clustalw [ ] and phylogenetic relationship (maximum parsimony, mp) studies by using mega x [ ] to understand the ancestral origin and antigenic resemblance of sars-cov- with other coronaviruses. in addition, pairwise sequence alignment of sars-cov- proteins with other viral strains was performed by the emboss needle online software, which uses the needleman-wunsch alignment algorithm to find the optimum alignment (including gaps) of two sequences along their entire length [ ] . moreover, sequence alignment was also visualized and analyzed by using jalview software (https://www.jalview.org/). targeting potential antigens from viral proteins is crucial for constructing peptide-based vaccine molecules that can interact with b lymphocytes [ ] . it was reported that peptide flexibility and j o u r n a l p r e -p r o o f journal pre-proof proper surface accessibility are prerequisites for being a potential b cell epitope. considering those parameters, the immunogenic peptide sequences from four types of viral proteins were determined by using the b cell epitope prediction tools of the immune epitope database (iedb) [ ], which employs the bepipred linear epitope prediction method [ ] . the vaxijen v . server (http://www.ddgpharmfac.net/vaxijen/) was used for screening out the most immunogenic peptides determined from iedb [ ] . however, epitope conservancy analysis is an important step to determine the degree of desired epitope distribution in its homologous protein set. in this study, the conservancy pattern of mostly immunogenic b cell peptide sequences of covid- was compared with other homologous sequences retrieved from the ncbi database by using blastp [ ] . moreover, the conservancy study of immunogenic peptides predicted from the sars-cov- proteins was also compared against other human coronavirus strains (hcov- e, hcov-oc , sars-cov, hcov-nl , hku and mers-cov). the epitope conservancy analysis tool (http://tools.iedb.org/conservancy/) of the iedb was used to continue the conservancy analysis [ ]. homology modeling of spike glycoprotein (p dtc ), membrane protein(p dtc ), envelope protein (p dtc ) and nucleoprotein (p dtc ) of sars-cov- was performed by using the i-tasser server [ ] . although d structures were generated by multiple threading alignments in the i-tasser server, refinement was conducted using modrefiner [ ] followed by the fg-md refinement server to improve the accuracy of the predicted d modeled structure [ ]. modrefiner allowed for significant improvements in the physical quality of the local structure based on hydrogen bonds, side-chain positioning and backbone topology of the native-state proteins. again, fg-md, a molecular dynamics-based algorithm for structure refinement, usually works at the atomic level. the refined protein structure was further validated by rampage [ ] and eraat analyses [ ] .structures were visualized and analyzed by pymol [ ] . j o u r n a l p r e -p r o o f we illustrated the number of cases and deaths of sars-cov- in a consecutive way through graphs to elucidate the pattern of occurrence of those outcomes. we covered country-wise cases and deaths, the onset of global and chinese cases by date, the global death toll per day, and province-wise cases and deaths in china. we calculated the crude mortality rate and case fatality according to the formulas suggested by the cdc [ ] as well as jacob and ganguli [ ] . here, we calculated the crude mortality rate for those countries and for chinese provinces, having death records per crore persons, for better interpretation. it is already known that the sars-cov- can multiply even at high temperatures, especially temperatures higher than ° c [ , ] ; however, sars-cov- is rapidly inactivated at °c [ ] . therefore, temperature plays a great role in its multiplication. for this purpose, recent environmental temperature data from the place of first occurrence as well as bangladesh were obtained from landsat- satellite data. this satellite provides high spatial resolution ( m) data at -day intervals. using the brightness temperature of band number (tir- ) and emissivity data temperature (in °c) of bands and (l data users handbook), a large area (a -km-wide swath) can be obtained for a time with minor deviation from in situ temperature data (maximum . degree celsius sd). therefore, cloudless or less cloudy images (less than %) were obtained from the usgs webpage (www.earthexplorer.usg.gov). a maximum of data points were available for one area in each month. however, neighboring path and row image borders shared some common areas, which provided more frequencies for those overlapped areas. level- tier- images, which are radiometrically and geometrically corrected, were used in this study. first, all images fulfilling the cloud-related conditions were downloaded. a total of images covering the land areas of wuhan, china, korea, italy and bangladesh were downloaded. then, dn of band data were converted to emissivity and simultaneously converted to brightness j o u r n a l p r e -p r o o f journal pre-proof temperature by using "equation " [ ] . then, the emissivity was converted to temperature by using "equation " [ ] . the estimated data were obtained by the landsat thermal infrared sensor (tirs) of band . this information was automatically obtained from metadata. the four phylogenetic trees constructed from four types of representative viral proteins (spike, besides, fewer level of similarity and identical patterns were found with other viral strains, including bufcov-hku of bangladesh origin ( table ) . were employed to determine the most antigenic sites by using the b cell epitope prediction tool of iedb and vaxijen scoring. the vaxijen server, which gave a result well above the threshold value ( . ), usually reveals the immunogenic potential to stimulate a protective response in host organisms [ ] . from the analysis, a total of epitopes from s proteins, epitope from m proteins, epitope from e proteins and epitopes from n proteins were found to be mostly immunogenic in sars-cov- , with almost % of peptides carrying more than the threshold value of the antigenic score of the vaxijen server ( and were subjected to conservancy analysis with the immunogenic epitopes from sars-cov- proteins. it was found that antigenic sites are almost conserved in all of the homologous protein sequences deposited in the ncbi database ( table ) . cross-checked conservancy analysis of covid- antigenic epitopes with sars-cov proteins showed that conservancy when crosschecked with other coronaviruses, including bufcov-hku of bangladesh origin, was not significant ( table ) . in china, of provinces experienced deaths from covid- , and the highest death toll occurred in hubei ( , ) province, followed by henan ( ) and heilongjiang ( ); in other provinces, the death toll was below ten up until march (supplementary file ) . upon analysis of mortality data over the time period from january to march , therefore, only the eastern part is shown here. similarly, during the study period in the midregion of korea, the temperature was very low, which was caused by the presence of heavy and widespread clouds in that region during satellite image acquisition. however, very few clouds covers were found for the landsat- image acquisition for february for the italy areas. in almost all areas temperature were lower than °c except a few places where the temperature did not exceeded °c. therefore, interpretations from the figures for these regions should be guarded in order to avoid errors. the novel coronavirus sars-cov- became a pandemic because of its global spread [ ] . as the genetic architecture of sars-cov- was highly divergent from that of bufcov-hku j o u r n a l p r e -p r o o f (figures and many of the scientists and pathologists revealed that high temperature and humidity able to j o u r n a l p r e -p r o o f restrict the spread of covid- and spread of disease will be suppressed as the weather warms [ , ] . this also supports our hypothesis. interestingly, coronaviruses that cause colds do tend to subside in warmer months. however, it is highly uncertain whether sars-cov- will behave the same way. current research by scientists is too early to predict how the virus will respond to changing weather [ ]. immunogenicity and epitope conservancy analyses of coronavirus proteins were performed to determine the potential b-cell epitopes that would interact efficiently with b lymphocytes to initiate the immune response against specific viral pathogens [ ] . the study identified a total of highly immunogenic b-cell epitopes from sars-cov- proteins ( epitopes table ). the antigenic sites of covid- were also crosschecked with other coronavirus-corresponding proteins ( table ) respectively. this calculation agrees with the report of wang et al. [ ] , who stated that the global case fatality was close to %. however, the global case fatalities of sars ( . %) and j o u r n a l p r e -p r o o f world health organization): coronavirus disease (covid- ) situation reports early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia international journal of infectious diseases the continuing -ncov epidemic threat of novel coronaviruses to global health -the latest novel coronavirus outbreak in development of genetic diagnostic methods for novel coronavirus (ncov- ) in japan transmission of -ncov infection from an asymptomatic contact in germany the global spread of -ncov : a molecular evolutionary analysis passengers' destinations from china: low risk of novel coronavirus ( -ncov) transmission into africa and south america a highly conserved wdypkcdra epitope in the rna directed rna polymerase of human coronaviruses can be used as epitope-based universal vaccine design occurrence of foot and mouth disease (fmd) during - in cattle of sirajganj district first genome sequences of buffalo coronavirus from water buffaloes in a novel coronavirus from patients with pneumonia in china nowcasting and forecasting the potential domestic and international spread of the -ncov outbreak originating in wuhan, china: a modelling study potential for global spread of a novel coronavirus from china preliminary assessment of the international spreading risk associated with the novel coronavirus ( -ncov ) outbreak in wuhan city global health policy:covid- coronavirus tracker outbreak of acute respiratory syndrome asssociated with a novel coronavirus . and rampage ramachandran plot analysis of sods in gossypium raimondii and g. arboreum protein-protein docking on molecular models of aspergillus niger rnase and human actin: novel target for anticancer therapeutics pymol: an open-source molecular graphics tool measures of risk, section : mortality frequency measures handbook of clinical neurology the effects of temperature and relative humidity on the viability of the sars coronavirus persistence of coronaviruses on inanimate surfaces and its inactivation with biocidal agents estimation of sea surface temperature (sst) using split window methods for monitoring industrial activity in coastal area retrieval of sea surface temperature over poteran island water of indonesia with landsat tirs image: a preliminary algorithm immunogenicity prediction by vaxijen: a ten year overview real-time estimation of the risk of death from novel coronavirus (covid- ) infection: inference using exported cases recombination, reservoirs, and the modular spike: mechanisms of coronavirus cross-species transmission severe acute respiratory syndrome coronavirus (sars-cov- ) temperature, humidity, and latitude analysis to predict potential spread and seasonality for covid- transmissibility of covid- and its association with temperature and humidity in silico vaccine strain prediction for human influenza viruses immunoinformatics approaches for designing a novel multi epitope peptide vaccine against human norovirus (norwalk virus) exploring t & b-cell epitopes and designing multiepitope subunit vaccine targeting integration step of hiv- lifecycle using immunoinformatics approach. microbial pathogenesis significance of rna sensors in activating immune system in emerging viral diseases. dynamics of immune activation in viral diseases world health organization (who) recombinant modified vaccinia virus ankara expressing the spike glycoprotein of severe acute respiratory syndrome coronavirus induces protective neutralizing antibodies primarily targeting the receptor binding region middle east respiratory syndrome coronavirus (mers-cov): mers monthly summary a novel coronavirus outbreak of global health concern human immunopathogenesis of severe acute respiratory syndrome (sars) conceptualization, data curation, formal analysis, investigation, methodology, software, validation, manuscript writing-original draft, review and editing abdus shukur imran:data curation, formal analysis, investigation, methodology, software, validation, manuscript writingoriginal draft formal analysis, methodology, project administration, software, supervision, validation, visualization, manuscript writing-original draft all authors read and approved the final version of the manuscript. the descriptions are accurate and agreed by all authors table : template proteins considered for d homology structure predictions by using i-tasser. table hcov -oc the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.j o u r n a l p r e -p r o o f key: cord- -er ehk authors: yang, kunyu; sheng, yuhan; huang, chaolin; jin, yang; xiong, nian; jiang, ke; lu, hongda; liu, jing; yang, jiyuan; dong, youhong; pan, dongfeng; shu, chengrong; li, jun; wei, jielin; huang, yu; peng, ling; wu, mengjiao; zhang, ruiguang; wu, bian; li, yuhui; cai, liqiong; li, guiling; zhang, tao; wu, gang title: clinical characteristics, outcomes, and risk factors for mortality in patients with cancer and covid- in hubei, china: a multicentre, retrospective, cohort study date: - - journal: lancet oncol doi: . /s - ( ) - sha: doc_id: cord_uid: er ehk background: patients with cancer are a high-risk population in the covid- pandemic. we aimed to describe clinical characteristics and outcomes of patients with cancer and covid- , and examined risk factors for mortality in this population. methods: we did a retrospective, multicentre, cohort study of patients with laboratory-confirmed severe acute respiratory syndrome coronavirus (sars-cov- ) infection and with a pathological diagnosis of a malignant tumour in nine hospitals within hubei, china, from jan to march , . all patients were either discharged from hospitals or had died by april , . clinical characteristics, laboratory data, and cancer histories were compared between survivors and non-survivors by use of χ( ) test. risk factors for mortality were identified by univariable and multivariable logistic regression models. findings: between jan and mar , , patients with cancer and laboratory-confirmed sars-cov- infection were enrolled (median age years [iqr – ; range – ]; [ %] women). ( %) had solid tumours and ( %) had haematological malignancies. the median duration of follow-up was days (iqr – ). the most common solid tumour types were breast ( [ %] patients), colorectal ( [ %]), and lung cancer ( [ %]). ( %) of patients received antitumour therapies within weeks before symptom onset. ( %) of patients were transferred to an intensive care unit and ( %) died during hospital admission. patients with haematological malignancies had poorer prognoses than did those with solid tumours: nine ( %) of patients with haematological malignancies died versus ( %) of patients with solid tumours (hazard ratio for death · [ % ci · – · ]; log rank p= · ). multivariable regression analysis showed that receiving chemotherapy within weeks before symptom onset (odds ratio [or] · [ % ci · – · ]; p= · ) and male sex (or · [ % ci · – · ]; p= · ) were risk factors for death during admission to hospital. interpretation: patients with cancer and covid- who were admitted to hospital had a high case-fatality rate. unfavourable prognostic factors, including receiving chemotherapy within weeks before symptom onset and male sex, might help clinicians to identify patients at high risk of fatal outcomes. funding: national natural science foundation of china. , caused by the severe acute respiratory syndrome coronavirus (sars-cov- ), was first detected in december, , in wuhan, china. it spread rapidly across the world during the following few weeks. , as of may , , cases have been confirmed worldwide, with deaths. , in wuhan, the initial centre of the epidemic, covid- cases and deaths have been confirmed, as of may , . patients with cancer are a vulnerable population during the covid- pandemic. they are often immunosuppressed because of their underlying illness, poor nutrition, and treatment-related side-effects. therefore, they are at increased risk of opportunistic infections, developing severe complications, requiring admission to an intensive care unit (icu), or even death. [ ] [ ] [ ] [ ] liang and colleagues analysed data from patients with cancer, from a sample of patients with covid- , and found a higher risk of covid- and poorer outcomes in patients with cancer than in those without. zhang and colleagues reported cases of sars-cov- infection in patients with cancer, with a case-fatality of · %. however, these studies were limited by small sample sizes. large studies are needed to comprehensively describe the characteristics and outcomes of patients with cancer and covid- . we collected and analysed data from patients with cancer and covid- who were admitted to nine local hospitals in hubei, china. we aimed to describe the clinical features and outcomes of patients with cancer diagnosed with covid- , and to identify risk factors associated with in-hospital mortality. this retrospective, multicentre, cohort study was led by wuhan union hospital (wuhan, china). the list of participating hospitals is as follows: cancer center of wuhan union hospital, west branch of wuhan union hospital, jin yin-tan hospital, wuhan red cross hospital, the central hospital of wuhan, huanggang central hospital, the first people's hospital affiliated to yangtze university, xianning central hospital, and suizhou central hospital (appendix p ). all hospitals involved in this study were officially designated for treatment of patients with covid- after the outbreak was declared. diagnosis of covid- followed who interim guidance. from jan to march , , we enrolled patients with a history of cancer, irrespective of when the cancer had been diagnosed. the inclusion criteria were strictly based on pathological diagnosis of a malignant tumour and laboratory confir mation of sars-cov- infection; patients clinically diagnosed with covid- were excluded. patients with a pathological diagnosis of a benign tumour were excluded because we chose to focus on malignancies that are usually linked to an immuno suppressive state. the presence of sars-cov- infection was confirmed by rt-pcr and next-generation sequencing analysis of samples collected from nasopharyngeal swabs. , we aimed to explore the clinical characteristics and outcomes of patients with covid- who had malignant tumours. there was no formal determination of sample size and all patients meeting the inclusion criteria were recruited. the cutoff date for our study was april , . ethics approval was obtained from the ethics committee of wuhan union hospital, tongji medical college, huazhong university of science and technology, wuhan, china, at the beginning of the study. written, informed consent was waived because of the urgency and unprecedented nature of the covid- pandemic. we obtained information about demographic data, clinical manifestations, cancer histories, laboratory findings, data are median (iqr) or n (%). copd=chronic obstructive pulmonary disease. spo₂=blood oxygen saturation. *data on time from onset of symptoms to admission were missing for eight patients. †hospital admission before feb , , is used to represent the time period of the covid- pandemic. ‡data on respiratory rate were missing for one patient. §data on spo₂ were missing for patients. laboratory tests (haemo globin, white blood cells, neutro phils, lympho cytes, platelets, albumin, creatinine, blood urea nitrogen, lactate dehydrogenase, creatine kinase, d-dimer, c-reactive protein, procalcitonin, electro lytes, and interleukin- ) were all collected at the time of admission. based on the tnm staging system, cancer stage was defined as early (i-ii) or late (iii-iv) stage for solid tumours (staging information for brain cancer was not recorded). haematological malignancies have various staging systems and are distinct from the tnm staging system, so information about cancer stage was not collected to avoid inaccuracies. we also recorded information about treatments for covid- (administration of anti biotics and antivirals, oxygen therapy, and mechanical ventilation), compli cations, and outcomes during admission to hospital. acute respiratory distress syndrome was defined according to the berlin definition. acute heart failure, acute kidney injury, septic shock, and secondary infection were defined according to previous studies. leucocytosis was defined as a white blood cell count of more than ¹⁰ cells per l. lymphopenia was defined as a lymphocyte count of less than ⁹ cells per l. coagulopathy was defined as an extension of prothrombin time for more than s or of activated partial thromboplastin time for more than s. a high neutrophil-lymphocyte ratio (nlr) was defined as a value greater than . we hypothesised that differences exist in demographic, clinical, and laboratory characteristics, treatments, and cancer history between survivors and non-survivors of data are median (iqr) or n/n (%), where n is the number of patients with available data. nlr=neutrophil-lymphocyte ratio. *data on haemoglobin were missing for eight patients. †data on albumin were missing for patients. ‡data on procalcitonin were missing for patients. §data on interleukin- were missing for patients. ¶data on calcium were missing for patients. covid- with cancer. quantitative variables were presented as medians (iqr), and qualitative vari ables were presented by frequencies and percentages (only available data were calculated). the mann-whitney u test, fisher's exact test, χ² test, and yates' continuity correction were applied to analyse the differences between groups according to the type of data. kaplan-meier analysis (log-rank test) and cox proportional hazards models were applied to analyse survival data. hazard ratios (hrs) and % cis were estimated with the cox model. risk factors associated with death and their odds ratios (ors) were analysed by the univariable logistic regression model. we chose receiving chemotherapy within weeks before symptom onset as the cutoff according to the number of patients within groupings and the significance of the logistic regression analysis (appendix p ). for the multivariable logistic regression analysis, we chose four variables to avoid overfitting of the regression model because of the small number of endpoint events (n= ) in our research. variable selection was based on significance from the univariable logistic regression analysis (p< · ), the correlation between indicators, basic baseline clinical characteristics, and the accuracy and availability of data. cancer stage was not chosen for the multivariable analysis as this variable was only collected in solid tumours (except for brain cancer). white blood cell count, lymphocyte count, and nlr were not chosen because they might have been influenced by chemotherapy. other laboratory tests, including creatinine, lactate dehydrogenase, creatine kinase, d-dimer, interleukin- , and c-reactive protein can be unavailable in emergency situations. these laboratory tests were not available for all patients in this study, and were excluded from the multivariable analysis. the time period of hospital admission was not included because some patients might have been admitted to other hospitals and been given treatment for covid- (eg, antibiotics, antiviral medication, oxygen therapy) before they were transferred to the current hospital. therefore, receiving chemotherapy within weeks before symptom onset, cancer type (solid vs haematological), time since cancer diagnosis, and sex were chosen in our multi variable logistic regression model. we used generalised linear mixed-effect models with a logit link function to adjust the between-centre differences. receiving chemo therapy weeks before symptom onset, time since cancer diagnosis, cancer type (solid vs haematological), and sex were included as fixed effects, and the study centre was treated as a random effect. we used ibm spss statistics . software for statistical analysis. the tests we used were all two-sided with less than % type i error. the differences between groups were considered to be significant when the p value was less than · . the funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. the corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. acquired pneumonia. more than half of patients had other comorbidities besides cancer, including hypertension, diabetes, coronary heart disease, and hepatitis b virus infection (table ) . compared with survivors, nonsurvivors had higher respiratory rates and lower levels of blood oxygen saturation. shortness of breath and dyspnoea were significantly more common in nonsurvivors than in survivors. no significant differences in age and other comorbidities were observed between survivors and non-survivors. data for abnormal blood cell counts in the patients for whom these data were available included ( %) cases of leucocytosis, ( %) of leucopenia, ( %) of neutro penia, ( %) of lymphocytopenia, and ( %) of thrombocytopenia (table ) . ( %) of patients had elevated concentrations of d-dimer, ( %) of patients had elevated concentrations of c-reactive protein, and ( %) of patients had increased lactate dehydro genase. all patients with available radiological data showed abnormal features. ( %) of patients had bilateral inflammatory infiltration, and ( %) pre sented with ground-glass opacities. compared with survivors (table ), non-survivors had higher nlr and higher concentrations of creatinine, blood urea nitrogen, lactate dehydrogenase, creatine kinase, d-dimer, c-reactive protein, procalcitonin, and interleukin- , and lower lymphocyte and platelet counts, and albumin and calcium concentrations. of the patients included, ( %) received intravenous antibiotics and ( %) received antiviral medications (table ) . intravenous corticosteroids were given to ( %) of patients. invasive mechanical ventilation was applied to ( %) of patients requiring mechanical ventilation. ( %) of patients were referred to the icu. complications occurred in ( %) of patients, including secondary infection and acute respiratory distress syndrome. compared with survivors (table ) , non-survivors were more likely to receive intravenous medication (antibiotics, immunoglobulin, or corticosteroids), receive oxygen therapy, require mechanical ventilation, be transferred to the icu, and develop complications such as acute respiratory distress syndrome, secondary infection, acute renal failure, and septic shock (table ) . ( %) of patients had been diagnosed with cancer within the past year, and ( %) of patients had an ecog score higher than before admission. ( %) of patients were diagnosed with solid tumours (table ; appendix p ). the most common types of cancers were breast, colorectal, and lung carcinomas. lymphoma was the most common haematological malignancy. ( %) of patients received antitumour therapy within weeks before symptom onset, and ( %) of received more than one treatment, including seven ( %) of who received both chemotherapy and targeted therapy. two patients with lung cancer received chest radiotherapy and chemotherapy, and one patient with breast cancer received chest radiotherapy. ( %) of patients with solid tumours were at an advanced stage (stage iii/iv). the case-fatality rate in patients with haematological malignancies was % (nine of (table continues on next page) example, two of three patients with multiple myeloma died; case-fatality rates were lower for patients with breast cancer, thyroid cancer, and cervical cancer. we did a comparative analysis of clinical characteristics, treatments, laboratory data, and radiological data from patients with solid tumours and those with haematological malignancies (appendix pp - ). patients with haematological malignancies were younger than those with solid tumours ( of patients) were more frequently seen in patients with haematological malig nancies than in those with solid tumours. ( %) of patients with haematological malignancies received antitumour treatments in the past weeks before symptom onset, compared with ( %) of patients with solid tumours. ( %) of patients with haematological malignancies and ( %) of patients with solid tumours received chemotherapy within weeks before symptom onset. in univariable logistic regression analysis, cancer type, time since cancer diagnosis, cancer stage, male sex, leuco cytosis, lymphopenia, high nlr, thrombocytopenia, lactate dehydrogenase, d-dimer, creatine kinase, c-reactive protein, creatinine, receipt of chemotherapy or targeted therapy within weeks before symptom onset, and hospital admission were associated with death (table ) . we included patients with complete data in the multivariable regression analysis ( survivors and non-survivors), in which we included four variables: sex, cancer type, receipt of chemotherapy within the previous weeks, and time since cancer diagnosis. there was no inter action effect between the selected variables (appendix p ). receiving chemotherapy within weeks before symptom onset (or · [ % ci · - · ]; p= · ) and male sex ( · [ · - · ]; p= · ) were associated with increased odds of death during admission to hospital (table ) . similar results were shown after adjusting for study centre or different cancer types (appendix p ). patients with cancer are a vulnerable population in the ongoing covid- pandemic. they are at high risk of infection and have a higher probability of severe illness and increased mortality once diagnosed with covid- . to our knowledge, this is the first multicentre, retrospective, cohort study to describe the clinical features, outcomes, and risk factors for mortality in patients with cancer and diagnosed with covid- . severe pneumonia occurred in ( %) patients and the in-hospital case-fatality rate in patients with covid- and cancer was %, which is much higher than the case-fatality rate for covid- in the overall chinese population ( %). in wuhan, the case-fatality rate of patients with cancer in our study was % ( of patients), which was higher than the overall case-fatality rate reported for patients with covid- ( %). in particular, male sex and receiving chemotherapy within weeks before symptom onset were identified as risk factors for death in patients with cancer who were diagnosed with covid- . the proportion of patients with cancer among those with covid- who were admitted to the nine hospitals in our study was · %, which was higher than that reported in the overall chinese population ( · %) and in a previous report of patients with covid- ( %). this finding suggests that patients with cancer are more susceptible to covid- than the general population. by contrast with four other human coronaviruses (hcov-nl , hcov- e, hcov-oc , and hku ), which induce only mild upper respiratory diseases, sars-cov- behaves like sars-cov and middle east respiratory syndrome coronavirus (mers-cov) to some extent, and leads to higher rates of severe respiratory syndrome. similar to our study, fever and cough were the most common clinical manifestations among patients with covid- . although older age and underlying diseases have been found to be risk factors for severe events in a previous study, this was not observed in our study. this difference might be due to the fact that our study already comprised an elderly population (median age years) with under lying diseases. we found bilateral lung lesions in % of patients with available records, which was higher than the figure reported previously by xu and colleagues (bilateral lung lesions in [ %] of patients with laboratory-confirmed sars-cov- infec tion), suggesting that patients with cancer were more vulnerable once they became infected with sars-cov- . men were found to be at a higher risk of mortality than women in this study. in addition to sex differences in smoking rate, differences in the immune and endocrine systems between men and women , might exert different responses against sars-cov- infection. moreover, case-fatality rates for patients with covid- who had breast, thyroid, or cervical cancer were low in our study. ( %) of women in our study had one of these three types of cancers. lymphocytopenia is one of the clinical features of covid- , indicating that the virus tends to diminish the antiviral immunity of the host. similar to other studies, we found that cytotoxic chemotherapy within weeks before symptom onset was associated with increased risk of mortality. patients receiving chemotherapy might develop long-lasting myelo suppression and impaired immunity. since we do not yet have highly effective drugs targeting sars-cov- , a patient's inherent immunity might be a determining factor for their prognosis after effective supportive care. it has been recommended that the mode of admin istration (from infusion to oral administration) and intervals of chemotherapy should be adjusted according to patients' conditions. although molecular-targeted therapy rarely impairs patients' immunity, those receiving maintenance molecular-targeted therapy all had advanced disease, and seven ( %) of received chemotherapy concurrently within weeks before symptom onset, which might have accounted for the increased risk of death. immunosuppressive treatments administered more than weeks before symptom onset might not worsen the outcome of covid- , which can be partially explained by the recovery of patients from side-effects of cytotoxic treatments. because of the small number of patients in our study who received chest radiotherapy weeks before onset of covid- , we were not able to analyse the effect of recent chest radiotherapy on patient outcomes. many haematological malignancies change how blood cells in the immune system function. lower respiratory tract diseases caused by human coronaviruses in patients with haematological malignancies have been associated with high rates of oxygen use and mortality. in our study, patients with haematological malignancies had poorer prognoses than those with solid tumours. besides the inherent differences between haematological malignancies and solid tumours, more patients with haematological malignancies received chemotherapy within weeks before symptom onset ( [ %] of vs [ %] of ), which might partly explain our finding of worse outcomes in these patients. in addition to lymphocytes, neutrophils are the mainstay in fighting off various infections. nlr is considered to reflect host inflammation and is a predictor of bacterial infection. it has also been found to be associated with clinical outcome and treatment efficacy in several cancers. in patients with covid- , high neutrophil counts have frequently been seen in refractory disease. in line with a previous study, we found a high nlr to be associated with poor prognosis in patients with cancer and covid- . sars-cov- infection and subsequent bacterial infection might have caused a deterioration of lung function and contributed to death, although this hypothesis requires further investigation. our study had some limitations. the sample size was not large enough to derive any firm conclusions. incomplete documentation and recall bias of cancer history added to the complexity of the study. we were not able to analyse the effect of treatment with immunosuppressants on the outcome of patients with cancer and covid- because this information was not collected. additionally, we did not compare the case-fatality rate, characteristics, outcomes, and treatment strategies of patients with cancer against a control group of patients without cancer. dynamic changes in the titre of the igm and igg antibodies, sars-cov- nucleic acid, and other laboratory tests such as tumour-related cytokines besides interleukin- (eg, tumour necrosis factor-α and interferon-γ) in the course of disease should be further recorded and analysed. finally, the impact of covid- on cancer needs to be evaluated with long-term follow-up of survivors. in conclusion, patients with cancer and covid- require urgent and special attention, since they are a vulnerable population with a much higher case-fatality rate than the general population. receiving chemotherapy weeks before symptom onset and male sex are two indicators that might help clinicians to identify patients with cancer who are at high risk of fatal outcomes at an early stage. gw and ky had the idea for and designed the study and provided financial support. jliu, jy, yd, dp, cs, jli, jw, yh, lp, mw, and yl were involved in acquisition of the data. ky and ys summarised the data. ch, yj, nx, kj, hl, rz, bw, lc, gl, and tz were involved in data interpretation. ys drafted the manuscript. gw, ky, bw, ch, yj, nx, kj, and hl critically revised the manuscript for important intellectual content. we declare no competing interests. first case of novel coronavirus in the united states transmission of -ncov infection from an asymptomatic contact in germany covid- ) pandemic clinical features of patients infected with novel coronavirus in wuhan, china epidemic situation of covid- (in chinese) there should be no eskape for 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cancer during the covid- spread in china clinical significance of human coronavirus in bronchoalveolar lavage samples from hematopoietic cell transplant recipients and patients with hematologic malignancies prognostic significance of neutrophil-to-lymphocyte ratio in patients with sepsis: a prospective observational study prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis clinical characteristics of refractory covid- pneumonia in wuhan, china dysregulation of immune response in patients with covid- in wuhan, china this work was supported by the national natural science foundation of china (nsfc , nsfc ). we thank all front-line healthcare workers for their efforts during the covid- pandemic. key: cord- -rcuzi u authors: liu, lilong; hu, junyi; hou, yaxin; tao, zhen; chen, zhaohui; chen, ke title: pit latrines may be a potential risk in rural china and low-income countries when dealing with covid- date: - - journal: sci total environ doi: . /j.scitotenv. . sha: doc_id: cord_uid: rcuzi u according to the latest reports, severe acute respiratory syndrome coronavirus (sars-cov- ), which caused coronavirus disease (covid- ), was successfully isolated from the excreta (stool and urine) of covid- patients, suggesting sars-cov- could be transmitted through excreta contaminated water. as pit latrines and the use of untreated excreta as fertilizer were common in rural china, we surveyed villages of jiangxi and hubei provinces and found that pit latrines could be a potential source of sars-cov- water pollution. recently, bats have been widely recognized as the source of sars-cov- . there were many possible intermediate hosts of sars-cov- , including pangolin, snake, bird and fish, but which one was still not clear exactly. here, we proposed a hypothesis to illustrate the mechanism that sars-cov- might spread from the excreta of infected humans in pit latrines to potential animal hosts, thus becoming a sustainable source of infection in rural china. therefore, we believe that abolishing pit latrines and banning the use of untreated excreta as fertilizer can improve the local living environment and effectively prevent covid- and other potential waterborne diseases that could emanate from the excreta of infected persons. although this study focused on rural areas in china, the results could also be applied to low-income countries, especially in africa. the ongoing pandemic of coronavirus disease is an emerging respiratory infectious disease caused by the severe acute respiratory syndrome coronavirus (sars-cov- ), which was named -ncov previously , posing an unprecedented challenge to global public health. the most common symptoms of covid- patients include fever ( %- %, % on average ), cough ( %- %, % on average), fatigue ( %), sore throat ( %- %, % on average), shortness of breath ( %- %, % on average), rhinorrhea ( %- %, % on average) and muscle ache ( %- %, % on average) (cai et al., ; chen et al., a; huang et al., ; wang et al., a) , while diarrhea ( %- %, % on average), nausea ( %), vomiting ( %) and abdominal pain ( %) were also reported (huang et al., , chen et al., a . significantly, sars-cov- ribonucleic acid (rna) was detected in the stool of %- % ( % on average) covid- patients (including patients with severe symptoms, asymptomatic status, and treated patients with no further sign of the symptoms), and the duration of positive stool ranged from one day to more than a month (cai et al., ; chen et al., b; holshue et al., ; lescure et al., ; pan et al., ; tang et al., ; wang et al., b; wu et al., c; xiao et al., a; xu et al., ; zheng et al., ) . among all patients, %- % ( % on average) of all age groups and % of children were still positive in stool even after the respiratory tract samples infections (leung et al., ; zhou et al., ) , zhou et al. ( a) isolated sars-cov- from differentiated bat small intestinal organoids and human intestinal organoids, an in vitro model of the human intestinal epithelium. they found that both bat and human intestinal organoids developed progressive cytopathic changes after sars-cov- inoculation and accompanied by a substantially increased viral load in the culture media (zhou et al., a) , suggesting that active replication of sars-cov- in human intestinal organoids. notably, infectious sars-cov- was successfully isolated from the stool specimen of a patient with diarrheal covid- (zhou et al., a) and patients without diarrhea (wang et al., d) . another study showed that infectious sars-cov- virus were successfully isolated from of patients with viral rna-positive, indicating that infectious virus in feces was a common manifestation of covid- and confirmed the potential of fecal-oral or fecal-respiratory transmission (xiao et al., b) . in addition, recent studies showed that human angiotensin-converting enzyme ii (ace ), which had been proved to be a cell receptor for sars- cov- (lu et al., ; zhou et al., b) , was highly expressed in glandular cells of human gastric, duodenal, and rectal epithelia, supporting the entry of sars-cov- into host cells (xiao et al., a) . moreover, viral nucleocapsid protein (np)-positive cells were not only observed in the cytoplasm of gastric, duodenal, and rectum glandular epithelial cells from the biopsy specimens of covid- patients (xiao et al., a) , but also in human intestinal organoids (zhou et al., a) . collectively, the available evidence demonstrated that the occurrence of sars-cov- infection in human intestinal organoids might recapitulate enteric infection of covid- patients, and the human intestinal tract might represent an additional route of sars-cov- transmission (zhou et al., a) . in the meantime, sars-cov- rna was also detected in the urine sample (sun et al., ) , sink, and toilet (ong et al., ) of covid- patients, and the positive urine duration j o u r n a l p r e -p r o o f journal pre-proof was more than one month (sun et al., ) . notably, sun et al. ( ) successfully isolated infectious sars-cov- from the urine of a covid- patient, suggesting that sars-cov- might be secreted through the human urinary system. considering that infectious sars-cov- virus was found in urine and stool samples from covid- patients on days - of the clinical process (jeong et al., ) , and the duration of sars-cov- rna positive in stool and urine would last more than one month (cai et al., ; chen et al., b; holshue et al., ; lescure et al., ; pan et al., ; tang et al., ; wang et al., b; wu et al., c; xiao et al., a; xu et al., ; zheng et al., ; sun et al., ) , we believed that sars-cov- might exist in the stool and urine of patients with covid- for a long time. according to the available literature, sars-cov- rna was detected in wastewater samples from the netherlands (lodder and de roda husman, ) , australia (ahmed et al., ), france (wurtzer et al., ) , usa (wu et al., a) , italy (la rosa et al., b), and spain (randazzo et al., ) , we inferred that sars-cov- contaminated water might be a potential sustainable source of infection, thus threatening the local individuals' health. previous studies have shown that water contaminated by bacteria, viruses, and chemicals was closely related to the use of pit latrines and septic tanks (gerba, ; graham and polizzotto, ; hammoud et al., ; ngasala et al., ) . herein, this study aims to comprehensively evaluate the potential risks of covid- in rural china through the investigation of rural geographical environment, the use of pit latrines, and the villagers' daily life, then try to find out the solutions. although this study focused on rural areas in china, the results could also be applied to other low-income countries, especially in africa. in order to prevent the spread of covid- , several versions of the prevention guidelines were issued in china, suggesting that people with a history of living or traveling in epidemic areas should carry out self-health monitoring twice a day for days from the time of leaving the epidemic area, and try to live alone or in a single room with good ventilation to minimize close contact with their families (national health commission of the people's republic of china, ). zhang et al. ( a) proposed a home confinement guideline for rural areas, emphasizing that people from the epidemic areas of covid- should use tableware and sanitary items alone to avoid or control the suspicious transmission of sars-cov- . however, the living conditions of some rural residents were difficult to meet the criteria for home confinement during the outbreak response. for example, some villagers who did not have flush toilets at home must leave their rooms and use the nearby shared pit latrines for defecation, which might increase the close contact between people and also increase the transmission of sars-cov- . in addition, sars-cov- could be transmitted through the human excreta as mentioned above. a field investigation was carried out in villages of jiangxi province, china, which contained returnees from wuhan. the survey included the sources of domestic water, the structure, distribution and use of pit latrines among villages, and the excreta management pattern in rural china, to find out whether there was a systematic disinfection process and analyze the possibility of fecal contamination of drinking water. in addition, we also conducted a detailed survey on the distribution of family houses and daily life routes of villagers with a history of being in epidemic areas in wuhan and other cities of hubei province to identify the impact of pit latrines on the risks of covid- j o u r n a l p r e -p r o o f journal pre-proof transmission. village committees are grass-roots mass organizations of self-governance elected by villagers of the administrative village under the jurisdiction of a township in mainland china, a village committee shall be composed of - members, including the chairman, vice-chairmen and members (chinese government, ). their functions mainly include self-management, self-education, self-service by villagers, and carry out democratic elections, democratic decision-making, democratic management and democratic supervision. the village committees handle the village's public affairs and public welfare undertakings, mediate civil disputes, assist in maintaining public order, and report to the people's government the opinions, requirements and suggestions of the villagers (chinese government, ) . thus, the village committees know the basic situation of the village very well. to understand the prevalence of pit latrines in rural china, we contacted to the village committees from villages in jiangxi and hubei provinces by phone, email and wechat to survey the number of households, the total population, the average household size, whether there are flush toilets at family, whether villagers use pit latrines, and whether villagers use untreated excreta as fertilizer among the rural households. here, we define flush toilets as flushing human excreta (urine and feces) chinese villages have long been known for their small bridges and flowing water, which means that chinese villages are usually built near streams, where great rivers originated. during the field investigation of villages in jiangxi province, china, we found that they all located upstream of the river, and many pit latrines are scattered around the rural houses throughout the villages. as shown in figure , a typical pit latrine in rural china consists of main parts: a shelter for creating a private space, a slab or floor with a small hole for villagers to defecate, and a cesspool for storing feces and urine. besides, there was usually a small window on the wall of cesspool for farmers to take the excreta as a natural fertilizer. to make it easier for farmers to get the excreta, some cesspools were built on the open next to the shelter. as described in available researches (heinonen-tanski and van wijk-sijbesma, ; lam et al., a; mamera et al., ) , human urine and feces as fertilizer could meet the needs of plants for potassium and phosphorus, and improve soil structure, and using human excreta as fertilizer is free, which leads to the villagers like to use excreta as fertilizer. through surveying villages in jiangxi and hubei provinces by contacting the village committees through phone, email and wechat, it was found that about %- % ( % on average) of rural households used the excreta directly from the pit latrines as crop fertilizer in recent years. in addition, according to the villagers, we learned that the excreta in the open cesspools may be washed to everywhere by rainwater, or be carried to everywhere by animal like dogs, cats, or field mouse, eventually polluting the local water. fortunately, the villagers' domestic water is all diverted from the mountain stream by water pipes rather than groundwater. although the water from mountain stream j o u r n a l p r e -p r o o f journal pre-proof was not treated before using, it was not polluted by excreta as the source of water was far away from the pit latrines. it was well documented that the bacteria, viruses, and chemicals within drinking water sources or agricultural soil posed a great threat to human health (gerba, ; gerba and bitton, ; graham and polizzotto, ; hammoud et al., ; jamieson et al., ; leung et al., ; mamera and van tol, ; mamera et al., ; nganje et al., ; tallon et al., ) . for example, wells in nearby septic tanks and pit latrines were found to be significantly contaminated in dar es salaam, tanzania, leading to more than % of wells contained with escherichia coli and % of wells with nitrate levels higher than who guidelines (ngasala et al., ) . it has been recognized that the consequent movement of pathogens along with subsurface drainage systems to surface water systems was the main route of pathogen transport (jamieson et al., ; prüss-ustün et al., ) , and it was possible that slimy bacteria form a thin coat over the pipelines to aid in the spread of sars-cov- (naddeo and liu, ). thus, sars-cov- , as a virus, may also be transmitted through water. a study from australia (ahmed et al., ) showed that the number of infected individuals in the catchment areas could be reasonably estimated by detecting the copy numbers of sars-cov- rna in the wastewater, which verified that early detection of coronavirus in wastewater might be a viable surveillance strategy for covid- infections (daughton, ; orive et al., ; wu et al., b) as previously demonstrated for hepatitis a virus, norovirus (hellmér et al., ) and poliovirus (asghar et al., ; lodder et al., ) . although there was no sufficient evidence that fecal-oral transmission of covid- was viable, while there was evidence showed that sars-cov- could be easily and sustainably transmitted in the community in shenzhen, china, because the proportion of covid- patients without definite exposure from january through february ( %) was much j o u r n a l p r e -p r o o f journal pre-proof higher than that before january ( %) . this suggests that there may be other potential routes of transmission, such as exposure to sars-cov- that survive in community environment. given that the infectious sars-cov- was found to be secreted through the human urinary system (sun et al., ) and intestinal tract (wang et al., d; xiao et al., b; zhou et al., a) , and sars-cov- rna was detected in wastewater worldwide (randazzo et al., ), many studies have suggested the possibility of wastewater transmission of covid- disease (adelodun et al., ; arslan et al., ; foladori et al., ) . however, the direct use of untreated excreta as a fertilizer and the flushing of excreta from open cesspools into the waters on rainy days might lead to serious water pollution, including the sars-cov- within human excreta. thus, the possibility of sars-cov- transmission through water contaminated with human excreta cannot be ignored. coronaviruses are present in a variety of animals and can cause respiratory, enteric, hepatic, and nervous system diseases of varying severity (lau et al., ) . the members of the coronavirus family, sars-cov (drosten et al., ) , mers-cov (chan et al., ) and the current sars-cov- (zhu et al., ) have caused severe respiratory illness and high mortality to humans since . studies have shown that both sars-cov and mers-cov were likely originated from bats and then crossed species barriers to infect humans through an amplification mammalian host, the paguma larvata for sars-cov and the camelus dromedarius for mers-cov (chan et al., ; cheng et al., ; lau et al., ) . similarly, recent studies have shown that sars-cov- might originated from bats with the genome of sars-cov- has %- % ( % on average) nucleotide j o u r n a l p r e -p r o o f journal pre-proof identity with several bat coronaviruses and %- % ( % on average) with human sars-cov, but might with more proximal origins from a potential intermediate animal host ji et al., ; lu et al., ; zhou et al., b) . it has been reported that pangolins (lam et al., b; lopes et al., ; wahba et al., ; xiao et al., c; zhang et al., b) and snakes (ji et al., ) might be the intermediate hosts of sars-cov- . however, the possibility of snakes as intermediate hosts of sars-cov- was questioned by the scientific community , and the existing evidence was not sufficient to either confirm or rule out the role of pangolins as an intermediate host (tiwari et al., ; wahba et al., ) . in other words, it is still not clear which animal is the intermediate hosts that brings sars-cov- to human hosts. (chan et al., ) . as described in the latest review (tiwari et al., ) , many coronaviruses have bats, birds, or pigs as the primary host, in addition to infecting animals such as civets, pangolins, and camels, coronaviruses also could be harbored by a range of animal species, such as fish, snake, cattle, horse, dog, cat, rabbit, rodent, ferret, minks, frog, marmot, and hedgehog. moreover, damas et al. ( ) had greatly expanded the potential number of intermediate hosts that might be infected by sars-cov- through ace receptors by protein structural analysis, which means that plenty of wild animals might be novel sars-cov- hosts. the results highlight the importance of wildlife and biosecurity in farms and wet markets, which may serve as the potential source and amplification centers for emerging infections (cheng et al., ; tiwari et al., ) . previous studies have elucidated that sars-cov could survive for days in diarrheal stool samples with an alkaline ph (lai et al., ) , days in sewage at degrees celsius and days at j o u r n a l p r e -p r o o f journal pre-proof degrees celsius (wang et al., ) , and retained its viability for over days at temperatures of °c - °c and relative humidity of %- % (chan et al., ) . kampf et al. ( ) analyzed studies and found that human coronaviruses such as sars-cov, mers-cov or endemic human coronaviruses could persist on inanimate surfaces like metal, glass or plastic for up to days. another study (casanova et al., ) found that two surrogate coronaviruses, transmissible gastroenteritis (tgev) and mouse hepatitis (mhv) remained infectious in water and sewage for days to weeks at degrees celsius, the time for % reduction was days for tgev and days for mhv even in the pasteurized settled sewage, suggesting that contaminated water might a potential vehicle for human exposure if aerosol was generated. notably, recent studies demonstrated that sars-cov- was highly stable at °c with only around a . log-unit reduction of infectious titre on day , but was sensitive to heat as the time for virus inactivation was reduced to minutes (chin et al., ) . besides, no infectious virus was detected from treated smooth surfaces on day (glass and banknote) or day (stainless steel and plastic), but a detectable level of infectious virus could still be present on the outer layer of a surgical mask on day (chin et al., ) . sars-cov- could be highly stable in a favorable environment (van doremalen et al., ) , for example, sars-cov- is extremely stable in a wide range of ph values at room temperature (ph - ) (chin et al., ) . infectious sars-cov- has been found in human excreta samples of covid- patient in many previous studies (sun et al., ; wang et al., d; xiao et al., b; zhou et al., a) , and the sars-cov- embedded in stool particles in septic tanks could escape from disinfection and slowly release into aqueous phase, behaving as a secondary source of sars-cov- and potentially contributing to its spread through drainage pipelines . former study has found that particles (kaolin clay, humic acid powder, and activated sludge) ＜ μm in diameter were large j o u r n a l p r e -p r o o f journal pre-proof enough to protect viruses from -nm ultraviolet (uv) light (templeton et al., ) , suggesting that the protection of faecal particles might make the survival of sars-cov- more easier. the sars-cov- within the excreta of covid- patients can be released into the water (natural environment) when farmers use untreated excreta as fertilizer in agricultural fields, and the excreta been washed into water by rainwater or be carried to water by animal. then the sars-cov- survived in the natural environment would be available absorbed by wild animals (such as bats, birds, fishes, and snakes) by drinking or contacting contaminated water, and become a secondary source of human sars-cov- infection. this hypothesis was consistent with another study that sars-cov- spilled into novel wild hosts in north america, as demonstrated by franklin and bevins ( ) through a conceptual model for the perpetuation of the pathogen. owing to the typically high mutation rates of rna viruses, coronaviruses (including sars-cov- ) can rapidly increase their virulence and adapt to new hosts (duffy, ; elena and sanjuán, ) . besides, the potential aquatic animals that may be infected with sars-cov- in the river may reach cities downstream of the river, then may be caught and eaten by city dwellers, further expanding the range of transmission. as excreta was directly used as fertilizer, fruits and vegetables grown in rural areas might be contaminated by sars-cov- and then eaten by wild animals, or purchased and eaten by rural and urban residents through wet markets. long-term exposure to contaminated environmental sources, such as the air pollutants, extended exposure to aerosols produced by contaminated water, and the inadequate cleaning processes of food and the surfaces of some materials, may resulted in an increased risk of sars-cov- transmission (adelodun et al., ; carraturo et al., ) . thus, it was seemly reasonable that the sars-cov- survives in nature could be a potential sustainable source of infection (figure ) , particularly for those people in rural areas who relied on untreated j o u r n a l p r e -p r o o f journal pre-proof drinking groundwater sources (hammoud et al., ; mamera and van tol, ; rosa and clasen, ) and who practiced open defecation (adzawla et al., ), the increased sars-cov- load in the natural environment might increase the possibility of human infection. through contacting the village committees by phone, email and wechat, a total of households were investigated in villages of jiangxi and hubei provinces, china, involving , persons with an average household size of . persons ( - persons per household) and an average number of . ± . households per village. the average proportion of households using pit latrines was % ( %- %) (figure , table ). existing reports indicated that pit latrines were one of the most common human excreta disposal systems in low-income countries (heinonen-tanski and van wijk-sijbesma, ; mamera and van tol, ; mamera et al., ) with approximately . billion of the world's population (graham and polizzotto, ) . according to a recent survey (mutyambizi et al., ) , pit latrines was the most common toilet facilities in informal settlements in south africa ( %), followed by flush toilets ( %), with approximately % reported not having access to any toilet facilities. similarly, the most common type of toilet facilities was shared pit latrine with a slab ( %) with no hand-washing facilities in kampala, uganda (ssemugabo et al., ) . in ghana, % of commonly used toilet facilities were dry toilets (pit latrines), and between and households, or and people shared one facility, (antwi-agyei et al., ) , and more than % of households engaged in open defecation (adzawla et al., ) . in short, toilet facilities in low-income countries are critical and need to be improved. in contrast to pit latrines, flush toilets have septic tanks that collect excreta through water-closed drainpipes, allowing for microbial degradation and disinfectant treatment of excreta when necessary (for example: to kill potential sars-cov- ). as generally considered that coronaviruses were very sensitive to oxidants, such as chlorine, ozonation, and uv irradiation (la rosa et al., a; quevedo et al., ; wang et al., c; zhang et al., c) , the sars-cov- released from human excreta during flush toilets-drainpipes-septic tanks could be inactivated by conventional disinfection. however, pit latrines with an open cesspool are not easy to be disinfected, because the excreta may be washed to everywhere by rainwater or be carried to everywhere by dogs or field mouse. coupled with the fact that villagers usually use untreated excreta as agricultural fertilizer, we believe that the use of pit latrines in rural china and other low-income countries increases the possibility of sars-cov- contaminating the surrounding natural environment and ultimately harms human health. human to human contact is the most important factor to increase the transmission rate of covid- . according to recent reports, the transmission routes of sars-cov- mainly include the respiratory tract by droplets or respiratory secretions, and contact with infected persons or contaminated surface and these measures were effective and have been confirmed by multiple reports (mwalili et al., ; ngonghala et al., ; teslya et al., ; tian et al., ) . during the field investigation of villages in jiangxi province, china, we found that it was common for villagers to live with scattered houses and share pit latrines, with to households (an average of . ) sharing one pit latrines. as shown in figure , of the households in a-h, only household a included a member with a history of being in epidemic areas (wuhan), family members of both c and h households all defecated in pit latrines, other households' members defecated in flush toilets at their home and occasionally used the pit latrines. the houses of a, b, and c households were scattered, naturally, the daily life routes of family members were significantly larger than those of other families. notably, the use of pit latrines expanded the daily life routes of c and h households' members and increased the possibility of close contact and exposure to sars-cov- between individuals. ultimately, it might increase the risk of covid- transmission. given that plentiful households shared toilet facilities (most of them were pit latrines) with poor ancillary facilities (such as hand-washing facilities) were common in low-income countries (antwi-agyei et al., ; ssemugabo et al., ) , we believed that the use of pit latrines in rural china and low-income countries would increase the contact between human, thus increasing the risk of covid- transmission to a certain extent. we proposed this hypothesis to illustrate the mechanism that sars-cov- might spread from the excreta of infected humans in pit latrines to potential animal hosts and then become a sustainable source of infection in rural china and other low-income countries. the widely use of pit latrines and j o u r n a l p r e -p r o o f journal pre-proof open cesspools coupled with agricultural fields application of untreated excreta could act as a potential route for the spread of covid- disease and other possible waterborne diseases that could emanate from the excreta of infected persons. we suggest for further implementation of the toilets revolution in rural china and also low-income countries in the world, completely replace pit latrines by flush toilets. next, according to the division of the residential area, using drainage systems to collect human excreta centrally and then used as agricultural fertilizer after unified disinfection treatment. through these preventive measures, the local living environment will be significantly improved and sars-cov- and other potential waterborne diseases will be effectively prevented. social determinants of health: the role of effective communication in the covid- pandemic in developing countries a case series of children with novel coronavirus infection: clinical and 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presence of severe acute respiratory syndrome coronavirus (sars-cov- ) viral rna in septic tanks of fangcang hospital guidance on the control and prevention of sars-cov- infection in primary healthcare institutions in rural china viral load dynamics and disease severity in patients infected with sars-cov- in zhejiang province, china infection of bat and human intestinal organoids by sars-cov- human intestinal tract serves as an alternative infection route for middle east respiratory syndrome coronavirus a pneumonia outbreak associated with a new coronavirus of probable bat origin a novel coronavirus from patients with pneumonia in china conceptualization, data curation, formal analysis, investigation, methodology, roles/writingoriginal draft. junyi hu: data curation, formal analysis, investigation, methodology, roles/writing -original draft. yaxin hou: investigation, methodology. zhen tao: conceptualization, investigation, methodology, writing -review & editing. zhaohui chen: conceptualization, formal analysis, methodology, writing -review & editing. ke chen: conceptualization, formal analysis, investigation, methodology key: cord- -oig qrr authors: brüssow, harald title: covid‐ : test, trace and isolate‐new epidemiological data date: - - journal: environ microbiol doi: . / - . sha: doc_id: cord_uid: oig qrr in the absence of an efficient drug treatment or a vaccine, the control of the covid‐ pandemic relies on classic infection control measures. since these means are socially disruptive and come with substantial economic loss for societies, a better knowledge of the epidemiology of the new coronavirus epidemic is crucial to achieve control at a sustainable cost, and within tolerable restrictions of civil rights. this article is protected by copyright. all rights reserved. comprising ' participants (gudbjartsson et al., ) . very similar information was reported in data describing household transmission in wuhan, where children showed a % infection rate compared with % in adults. . likewise, in a study from hunan children had a threefold lower infection risk than adults . in contrast, the infection risk in children from shenzhen, china was similar to that in adults (bi et al., ) . however, all studies concur that disease in children is generally mild, if not asymptomatic. asymptomatic cases raise problems for contact tracing and containment, but it is currently not clear to what extent infected children transmit the disease. three asymptomatic sars-cov- -positive adolescents showed transmission to family members (liao et al., ) while data for transmission from children are still absent. one special problem should still be mentioned in this context: in italy, pediatric hospitalization decreased substantially during the covid- epidemic. when the general population avoids hospitals for fear of infection, it can have a negative health impact. an increased number of deaths occurred in italy due to delayed arrival of children in hospitals, while no child died from covid- in italy (lazzerini et al., ) . the fear of hospitals has also been responsible for a deficit in the treatment against stroke in adults in the us (kansagra et al., ) . the statistics for the covid- epidemic have shown that the older population has suffered the greatest loss of life, and that nursing homes have been hotspots for transmission. two detailed studies from the us document these given facts. at the end of february , a cluster of epidemiologically linked covid- cases were reported in several long-term care facilities in washington state. of those, cases were residents (median age y), % of them were hospitalized, and % died. in comparison only cases had been visitors, % of whom were hospitalized, but none died. further cases were among the health care personnel, of whom only % were hospitalized, but again none died. factors favoring the outbreak were: health care personnel who showed up to work with symptoms; some of the personnel worked at more than one facility; and some residents were transferred between facilities. in the early stages of the epidemic, contributing factors to this outbreak were: an unawareness of the risk; a lack of diagnostic tests; and inadequate personal protection equipment (mcmichael et al., ) . currently, . million us americans reside in nursing homes. one in ten of > ' accredited nursing facilities reported covid- cases. an epidemiological survey in such a facility demonstrated the extent of the problem: the first infection in this nursing home was introduced by a symptomatic nurse, and then a week later the first resident tested positive. a further days later, half of the residents from this unit tested positive for viral rna. during the following weeks, to % of the residents in other units of this home became infected, along with % of the staff. notably, more than half of the residents were asymptomatic when they tested positive for viral rna. four days later, % of them had developed symptoms. the rest remained asymptomatic. mortality was high at %. importantly, asymptomatic, pre-symptomatic, and symptomatic residents did not differ with respect to viral load and infectious virus release. all viruses showed identical genome sequences guangdong cases. in guangdong province of china, all return visitors from wuhan/hubei province, their contacts, and all of the local hospitalized patients were tested for viral rna. . million tests were used to identify ' sars-cov- -positive cases; patients had had exposure to infected people from hubei. half of the local transmissions occurred within households. by mid-february, the local spread was controlled, but in march new cases were imported from abroad. sputum samples showed the highest viral titers, followed by oropharynx, stool, and finally nasopharynx samples. critical and severe cases showed higher viral titers than moderate and mild cases, but the differences were small. viruses from patients were sequenced and compared with sars-cov- sequences deposited in the database. single nucleotide polymorphism (snps) were detected at nucleotide positions scattered through the viral genome; variant sites were only seen in a single virus isolate. on a phylogenetic tree, the guangdong sequences were interspersed between the viral sequences from wuhan and those isolated abroad, documenting a recent, single source outbreak of a virus showing a low mutation rate (lu et al., a) . usa west-to-east spread. the first case of covid- in the us was reported on jan at the northwest coast of washington state and was imported from china. from march to the number of cases in the us increased from to ' . epidemiologists investigated the first nine covid- cases on the east coast (connecticut) that were observed in mid-march with genome sequencing. only one sequence exactly matched the viral sequences from china, but the patient had not traveled to china. the viral sequences from seven further patients, clustered with a large us clade known from washington state, documented a rapid west-to-east national spread of the novel coronavirus in the us. international air travel restrictions had no, or low, impact on the epidemic spread in the us. the viral genome was rooted in a single ancestor coronavirus in wuhan by fewer than mutations, and it had accumulated about nucleotide changes per month during its spread across the us, which is a low mutation rate for a ' nucleotide long viral rna genome. with the portable oxford nanopore technologies minion platform, viral genomes were sequenced within hours after having received the sample, theoretically allowing near real-time molecular epidemiology of the epidemic spread (fauver et al., ) . china. in wuhan, index cases of patients suffering from moderate covid- symptoms (fever, cough, fatigue) were investigated for secondary transmission to household contacts. the average household size was persons. the index case persons remained at home for a documented number of days before seeking medical advice. in total, contacts ( %) were infected, without symptoms, and the rest experienced moderate disease. the time lapse between primary and secondary infections was days. the transmission probability was age-dependent: it was % in children and % in adults. the highest transmission rate was seen in to year-olds, but not in > year-old household members. spouses experienced a % infection transmission rate. when the index case was quarantined directly after symptom onset, transmission rate was % . in shenzhen, cases were recorded, % of which were detected through the surveillance of symptoms. most cases were mild ( %) or moderate ( %). only % of infections were associated with severe disease, which correlated with male sex and older age; patients died. the researchers identified ' close contacts for the index cases; % of these had become infected. an increase to % in the rate of infection was seen in those who lived or traveled with index case persons. interestingly, infection risk was comparable for all age groups ranging from to y old. however, half of the children showed no fever, and severe infections were rare in people under the age of . notably, % of secondary infections were traced to only % of the index case persons (bi et al., ) suggesting an important role of "super-spreaders" in infection transmission. it would be helpful for public health if characteristic traits of super-spreaders were known. adding viral-specific igg antibody tests to the toolbox of covid- have allowed the connection between three previously separated infections clusters in singapore. an infected traveler from wuhan attended a church meeting, thereby infecting a secondary person (case x), who transmitted the virus to another subject during a family gathering, who then transmitted the virus to a large number of people in a second church. case x tested negative for viral rna and represented the missing link between the events. case x showed a strong serological response to sars-cov- , then connecting the links in the chain (yong et al., ) . iceland. from among high risk icelanders (persons who were symptomatic, or had contact with infected persons, or who traveled to a high risk country) % tested positive for sars-cov- rna. children under years from that high risk group showed a % rna detection rate compared with % in subjects older than y. before mid-march, travel exposure to austria and italy was a common denominator in the positive subjects. after mid-march, travel to uk was the biggest risk factor. in mid-march, a representative sample of ' subjects from the general population of iceland ( ' inhabitants) was tested, and . % tested positive for sars-cov- rna. in april, another sample of subjects from the general population showed a similar rate of viral excreters. in the general population, males were more frequently virus-positive than females. the highest prevalence was seen in y-old subjects, while no children under y were infected. five hundred viral genomes, isolated from infected icelanders, were sequenced. the genomes were clustered into distinct clades. during the early epidemic phase in iceland, nearly all sars-cov- isolates belonged to the a clade which was also frequently found in central european populations. viral genome sequencing identified networks of up to linked infections. transmission occurred in the early phase via international travel, but later via infection from family members (gudbjartsson et al., ) . airborne: cough, sneeze and speech. australian engineers evaluated the literature about the reach of pathogen transmission by coughing and sneezing. the to meter rule has been set since the s by photography, physical calculations, and through simulations. distinct models (turbulent jets vs. puffs) have been used, but not all used appropriate parameters for humidity and temperature. it remains unclear which conditions apply to the human respiratory excretions when handling infected patients in a clinic (bahl et al., ) . newer high speed pictures of a coughing volunteer show a turbulent jet plume that extends over . meter (tang and settles, ) . high speed pictures of a sneezing volunteer revealed exhaled air, muco-salivary filaments and drops. the turbulent puff cloud disintegrated into droplets that settled within to m distance. some droplets evaporate and become suspended in the puff and travel a room within a few minutes to land to m away from the sneezing person (bourouiba, ) speech generated droplets in front of the mouth increased with the loudness of the voice. holding a cloth in front of the mouth suppressed the droplet detection (anfinrud et al., ) . a who communication led to a controversy saying that there is not enough evidence that sars-cov- transmission is airborne. who defines airborne transmission as being via aerosols as opposed to transmission by droplets. since most covid- transmission seems to occur through close contact, droplets have been considered to be the more likely vehicles. whatever the exact transmission route by air, avoiding crowds, standing next to a person for too long, and increasing the rate of ventilation in closed rooms without air recirculation are reasonable precautions (lewis, ) . physicians recommended face mask use, even when scientific evidence for its effectiveness is lacking, in comments to leading medical journals. recent reviews have concluded that: no randomized trials with masks have been conducted; that the benefit of masks over no masks (but not of respirator masks over paper masks) was shown in an influenza epidemic in australia; that some benefit of masks was seen when worn by symptomatic, but not by asymptomatic cases during an influenza epidemic; that no data exist which directly support the use of mask wearing by the public; that no significant effect was seen for household use of masks against influenza transmission. therefore, who initially recommended masks only for symptomatic cases. cdc first advised against mask use by the public but have now changed their policy by recommending even self-made cloth masks for wide use. harm (e.g. increase of co level under the mask) is low if not used by small children or elderly people with disabilities (cheng et al., greenhalgh et al., ) . as assessed by viral rna detection, air and surfaces in a wuhan hospital were widely contaminated during the height of the epidemic in china. contamination levels were greater on the intensive care unit ward than on the general ward. the transmission of sars-cov- might reach up to meters distance. however, no medical staff in that particular hospital was infected. the authors admit two limitations of the study which prevent firm conclusions from being made. first, viral rna detection does not mean infectious virus detection, and second, the minimum infectious dose of sars-cov- for humans is unknown . when reviewing the official recommendations, the consensus seems to be to use a respirator for high risk interventions which create aerosols in the icu, and to use surgical masks on the general ward with low risk activities (bahl et al., ) . singapore hospital. the environment of three covid- patients from a ventilated hospital infection ward in singapore was tested for viral rna presence by rt-pcr. after routine cleaning of high touch areas and of the floor, no viral rna was found in the air, on hospital room surfaces or on the personal protection equipment of the treating physician. before routine cleaning, however, of room sites (table, chair, floor, window, toilet) and the shoe protection of a physician tested positive. room air samples and hospital corridor floors were, however, negative for viral rna. for infection control, regular room cleaning and handwashing were judged to be essential (ong et al., ) . primit study. it is more problematic to establish a control when a family member with mild infection remains at home. there is only one behavioral intervention study that has proved to reduce respiratory viral transmission within households, the primit germ defense study. the key interventions are web-based instructions about handwashing given to ' intervention subjects in uk, but not to ' controls. infection transmission was reduced by % and infection severity was also reduced, albeit modestly (little et al., ) . the rationale behind the idea was to reduce the viral load by which contacts are particularly exposed, such as through hand-to-eye contact, since the conjunctiva supports sars-cov- replication (hui et al., ; little et al., ) . in italy, the epidemic started in lombardy and veneto. lombardy strengthened their hospital capacity and increased icu beds, while veneto opted for strict containment and mass testing in % of the population. lombardy experienced ' more cases than veneto and also had a much higher crude case fatality rate ( % vs %). the higher death rate is probably explained by the delayed public health response (odone et al., ) as also seen in the us (anonymus, ) . the swedish government had recommended a number of trust based measures (social distancing from old people, handwashing, home office, travel reduction), but refrained from closing borders, schools, restaurants and bars, partly because the swedish law does not allow lockdowns. the case reduction of seasonal influenza and norwalk diarrhea provided documented effectivity of the measures taken (paterlini, ) . however, compared with neighboring finland and norway, sweden experienced a tenfold higher number of deaths for a . fold larger population, but the absolute numbers are still small ( vs. for sweden and finland, respectively, may ). in the us, the individual states and cdc have many legal options for quarantine (for the segregation of exposed people) and isolation (separation of infected people from the general population) in such cases as with sars. the establishment of broad sanitary cordons in which entire geographical areas are quarantined (as has happened in wuhan) will raise constitutional questions in the us. the us recommendations say that patients who show mild symptoms should stay home and notify their employer electronically. low-wage workers cannot afford to stay off work, but the us senate is in the process of establishing bills for paid sick leave and unemployment insurance (parmet and sinha, ) . kong. the control measures that stopped the epidemic locally have included: intense infection surveillance of incoming travelers; isolation of covid- cases in hospitals; contact tracing and quarantine in holiday camps; and school closure but no lock-down, thus preventing the crisis from having a negative economic impact. a total of cases were confirmed, half imported, and the rest locally transmitted with a reproduction number that quickly decreased to values around ; and % of virus-positive subjects were asymptomatic. the control measures also stopped an ongoing seasonal influenza epidemic. surveys showed that the population agreed to participate in the measures. they kept social distancing and made behavioral changes ( % wearing masks outside house, % increased hand hygiene, % staying at home as much as possible). the study could not differentiate the impact of each individual measure. unfortunately the full effect of school closure is still unknown because the susceptibility of children for covid- and their capacity to transmit the infection has not yet been established . china has contained the covid- epidemic through a combination of different measures including drastic ones. an international team of epidemiologists developed a computer model that described the dynamics of the epidemic and tested the impact of the different containment measures by using computer simulations. without any intervention, a -fold higher number of cases would have occurred in china, resulting in over million cases. without travel restrictions, the epidemic would have expanded more widely over the western provinces. early detection and isolation of patients reduced the number of cases by fold, while social distancing and contact reduction led to a . -fold reduction. however, without contact reduction, the epidemic would have, over time, increased exponentially across the regions. initiating the intervention one week earlier would have decreased the number of cases by % or, if done one week later the number of cases might have increased by -fold. a delay of or weeks would have increased cases by -and -fold, respectively. lifting travel restrictions will result in a new rise in case numbers, but even moderate levels of social distancing could keep this increase in check. partial maintenance of npi may prevent, or at least delay, the arrival of second wave infections (lai et al., ) . contact surveys were conducted in wuhan and shanghai during the height of the covid- epidemic in china. before the epidemic, people reported between - contacts (two-way conversations, physical contact) per day. this number was reduced to during the containment period. contact reduction was most significant for school-age children who, before the intervention, reported the greatest numbers of contacts out of all of the age groups, followed by adults at the workplace. during containment, contacts were mainly within families ( - %). the survey was consistent with data from inner city mobility. all contacts of patients in hunan province were placed under medical observation and tested for excretion of viral rna. from these contact data it was deduced that children (< y) had an infection rate that was only a third as high as adults ( - y), while older individuals had a % higher infection rate than young adults. based on these data and on a mathematical infection model, the authors concluded that social distancing alone is sufficient to control covid- spread. proactive school closure alone cannot interrupt transmission but can reduce the peak incidence of the disease by half, and it can delay the epidemic ). these are model simulations based on assumptions on infection transmission by children for which only few data are currently available. the reopening of schools in several countries will hopefully settle some questions with observational data. psychologists argue that contact-seeking is a basic human response to danger. this inclination takes over when an invisible infection threat is perceived. this instinct is only opposed by disgust when infected persons show appalling clinical signs which is not the case for sars-cov- infected subjects in pre-symptomatic or asymptomatic state. it will be increasingly difficult for health authorities to impose social distancing, as proven by the street demonstrations against containment measures in the us and in european countries by differently motivated opposition groups. the authors argue that the increased use of the internet as a substitute for contact can become an important public health tool to achieve physical distancing without social distancing (dezecache et al., ) . by may , the johns hopkins university registered . mio cases worldwide. the lion's share is from the us with . mio cases, compared with ' cases reported by china. one should interpret these data with caution. the definition for a confirmed case of covid- was changed five times in china, which accounts for the increase in knowledge about the epidemic. scientists from the who collaboration center in hong kong calculated that when the fifth version is applied, the total number of cases in china would increase from ' to ' , but the transmission patterns in mainland china would not change . the case number also depends on the intensity of viral testing and the capacity of the public health system to report the number of cases. with nearly ' deaths, the us number greatly surpasses the ' deaths reported in china. it is still difficult to assess the morbidity and mortality impact of the covid- pandemic on the population. even mortality rate is not a clear figure since it is reported differently in different countries. while death is a clear diagnosis, the cause of death isn't. it might not be evident whether somebody died with or from covid- , particularly in nursing homes. some countries attribute death to covid- if the virus was present at death. others attribute each death in nursing homes to covid- during the height of the epidemic -as was done in belgium, which explains its high mortality data. many deaths occurred while people also had underlying health problems (comorbidities), therefore they were already at increased risk of death. an international consortium of demographers called for the publication of excess mortality data. by comparing mortality statistics for a given epidemic period with a corresponding time period during previous years without that epidemic, the absolute impact of an infection can be assessed. such data are still largely lacking in the literature. excess mortality rates should best be calculated for both sexes and for each -y age range separately (leon et al., ) . first data have just now been reported: in march/april the care sector of england and wales alone has seen ' excess deaths over the figures of previous years. covid- deaths at care homes were three times as high as covid- deaths in hospitals (burki, ) . excess mortality calculations have been done globally for seasonal influenza, arriving at ' to ' influenza-associated deaths occurring annually (iuliano et al., ) . while the majority of influenza mortality applies to elderly people, the death rate is also substantial for children at an estimated ' deaths in . in comparison, the global death toll of covid- is now ' (status may ). a direct comparison of these two figures is difficult for two reasons: death levels are affected by vaccination campaigns against seasonal influenza and by strict containment measures for covid- . it seems plausible that without any containment measures covid- mortality would surpass greatly the number of deaths from seasonal influenza. the presumption that the covid- mortality is comparable to that of seasonal influenza deaths is fundamentally flawed because it compares numbers which are obtained by different methods. the death rate for covid- , which has just crossed the ' figure in the us, is an actual count of dead patients. in contrast, the ' to ' annual deaths from seasonal influenza quoted after influenza epidemics in the us are estimates by the cdc of influenza deaths based on calculations from models. the death counts actually reported to us health authorities ranged from ' to ' deaths per year during an influenza epidemic in the us. expressed as deaths per peak week, influenza claimed a maximum ' deaths per week, while covid- took about ' lives per week at its peak in the us (faust and del rio, ) . wuhan. an international consortium of epidemiologists has estimated that ' people were infected in wuhan and that have died; % were infected through household contact, % through public contact, and % in hospitals. from a peak number of new infections, wuhan currently has or fewer new infections per day. safe strategies are now needed for the exit from lockdown measures. when lifting the lockdown to a % pre-quarantine social contact level, a computer model showed that a % face mask wearing would be needed to ensure a complete elimination of infections. in contrast, with only % face mask use and a lifting date of strict measures before april to pre-quarantine level, the conditions in this model would lead to a major second wave of infection. maintaining a contact rate below pre-quarantine level combined with a high percentage of face mask wearing is essential while now the restrictions have been lifted in wuhan-at least until a vaccine becomes available. however, face mask provision for such large populations represents logistical challenges and must not cause a shortage of protective gear for health personnel (zhang et al., a) . in mainland china, ' confirmed cases and deaths were reported by march . in beijing and shenzhen, most cases have been imported from wuhan and the reproduction number r remained below . . in shanghai and wenzhou, local cases dominated but r rose to greater than for only one january week. case fatality was % compared with % in hubei. relaxing the restrictions could lead to a second wave of exponential infection from imported cases in a nonimmune, susceptible population. maximizing economic productivity under the < constraint can, according to this study, only be possible with a real time prevalence determination of new infections through extensive testing . other epidemiologists working on outbreak data from mainland china observed a sub-exponential increase of cases from the beginning, instead of an expected exponential growth for an unconstrained epidemic. model calculations showed that the containment measures (the quarantine of exposed, and the isolation of infected persons) which depleted the number of susceptible individuals for the virus, reproduced the actually observed case development. similar strategies are recommended in the event of a future outbreak (maier and brockmann, ) . harvard model. epidemiologists from harvard university derived projections from model calculations about the future dynamics of the covid- epidemic. when anticipating short term immunity (as observed for seasonal common cold coronaviruses), they predict annual winter epidemics for sars-cov- . with intermediate levels of immunity persistence, epidemics would become biannual. long-term immunity (as in the case of sars-cov) would lead to the extinction of the virus, even in the absence of social distancing. they also calculated that it needed weeks of social distancing to reduce the peak number of infected persons. if the reproduction of the virus is reduced by more than % through lockdowns, the infection peak is predicted to shift to the next winter season with high numbers because no herd immunity has been achieved (kissler et al., ) . a central concept of epidemiology is herd immunity; the percentage of persons with protective immunity needed in a population to stop the propagation of an infectious agent. when this threshold is crossed, the remaining susceptible persons are protected from infection. the threshold level depends on the "force" of the infectious agent which is expressed by the basic reproduction number r ,which is defined as the number of secondary infections caused by an index case. in infection modeling, herd immunity threshold and r are linked by a simple mathematical function. sars-cov- has a higher r "infectious force" than influenza virus, but a much lower one than "flying infections" such as chickenpox or measles. it is anticipated that a population needs a herd immunity of to % protected people to stop the covid- epidemic. the initial strategy of the uk government was to let the epidemic roll over the country to achieve this herd immunity, in contrast to containment policies which prevent exposure, but which also prevent immunity development in the population. this strategy has theoretical advantages (fewer economic losses when a lockdown is avoided, and a protected population in the event that no vaccine becomes available). however, it comes at a cost. if you allow, let's say, % of the population to get infected, you can calculate the cost of this strategy with the help of the infection fatality rate (ifr). in contrast to the case fatality rate (cfr) which expresses the number of deaths per clinically ill patients (which varies from . % to % for covid- ), ifr is the number of deaths per infected individual. the number is, of course, lower than crf. while we know, approximatively, the number of covid- deaths and covid- cases, we do not definitively know the number of infected persons, since this would require large and systematic seroprevalence studies, but which are lacking. current estimates suggest . % as a realistic approximation for ifr. with that figure, one can calculate that achieving herd immunity through natural infection with sars-cov- would cost the lives of ' uk citizen or more than ' ' us citizens. this death toll was considered as too high by the uk government, which then changed strategy by declaring a late containment strategy (randolphe and barreiro, ) . delays in imposing containment measures were predicted to lead to -fold or higher number of cases and fatalities. this prediction might explain why the us and uk have such high case and death statistics in international comparison. mobile phone technology. epidemiologists from the uk and us have developed a real-time datacapture platform applicable for mobile phone use for the self-guided collection of population-level data (cope consortium). the app queries location, age, health risk factors and asks daily for new symptoms and diagnostic test results. a test run with . million users in uk showed that the most common symptoms were fatigue and cough. anosmia (loss of smell) appeared as a strong predictor of covid- , while fever was not a diagnostic criterion unless combined with other symptoms. the reported symptoms predicted that there would be changes in the number of cases as indeed reported from health authorities to days later. the tool will be important for a controlled safe exit from confinement measures. also, long-term effects of the disease, and the impact of the covid- epidemic on social relations, mental health, and financial outcome can be evaluated with this tool. machine learning could also reveal new disease manifestations of the epidemic (drew et al., ) . anosmia is an interesting symptom. a preliminary evaluation of a covid- symptom tracker smartphone app from uk users showed that the loss of smell was reported by % of people with respiratory infection who tested positive for sars-cov- , compared with % of respiratory patients who tested negative. clinical criteria which allow a diagnosis of covid- without a viral rna test would be welcome for mass screening and telemedicine in an epidemic situation. french physicians have also reported that many covid- patients reported loss of smell and loss of taste, without nasal congestion. when these criteria were combined in a retrospective questionnaire this combination of signs had a sensitivity of % and a specificity of % for detecting covid- patients (bénézit et al., ) . these observations are not surprising since the highest expression level of the sars-cov- receptor ace- was shown in the respiratory tract, more specifically in the nasal epithelia. us physicians even suspected that sars-cov- might, in addition to the respiratory and alimentary tract, also infect cranial nerves (i.e. being neurotropic) which potentially explains the observation of neurological signs in % of covid- patients (chu et al., ) . seroprevalence studies. antibody tests are an important tool in a staggered release of population groups out of lockdowns because such tests identify people who have been exposed to the infection and who are potentially immune to infection. so far, only preliminary data became available from ' volunteers from santa barbara county in california. one out of ( . %) showed antibodies to sars-cov- . this number is -fold higher than the number of the official case count was for this area in early april. in a preliminary survey in geneva, less than % of a population sample showed viral-specific antibodies in preliminary surveys. in a town with ' inhabitants in germany, people were antibody tested following carnival parties and an infection rate of % was determined. these datasets cannot be extrapolated to the population at large. in addition, the antibody tests were only validated with a small set of positive and negative test samples, raising concerns about the reliability of the results (mallapaty, ; sood et al., ) . the next challenge will be the acquisition of reliable antibody data for representative samples from entire populations. the covid- epidemic continues to challenge our societies by its toll in deaths, by the disruption of social life; by its disastrous impact on the world economy; by increasing the debt of many nations; by endangering the survival of many industries; and by reversing the worldwide trend for poverty relief. for microbiologists, the covid- crisis has also revealed shortcomings in the public health sector, particularly in that of countries which were exemplary in this field during past decades. in the us, the covid- epidemic has taken more lives in one month than over years during the vietnam war. with more than . million cases, and more than ' deaths, the "america first" slogan has become sadly ironic in the context of covid- . an article in the leading us medical journal, the new england journal of medicine, attributes this calamity to insufficient diagnostic testing caused by the delivery of faulty tests by cdc; non-approval through the fda of working tests by who resulting in a delayed start of viral detection activities; and then followed then by a shortage of test reagents. public health workers were therefore blind to the unfolding of the us epidemic and unable to design efficient containment measures, short of a lockdown. epidemiologists were left without population data for modelling the epidemic in the us at a moment when the country started reopening economic and public activity. in comparison with other countries the us has tragically "failed the test". in the words of this article "the us once a leader, seem oddly lost" (schneider, ) . an editorial in the leading british medical research journal, the lancet, comes to the same conclusion: the cdc, once a pillar and international reference for combating diseases worldwide, instrumental in eradicating smallpox and coping with aids or ebola, has lost its technical competence and public trust due to contradictory scientific messages and the undermining of trust in scientific evidence by the current us administration. according to the lancet editors, the "us administration is obsessed with magic bullets-vaccines, new drugs-while only basic public health principles, like test, trace, and isolate, will see the emergency brought to an end" (the lancet, ). the situation is not better in the uk, once also renowned for its excellent public health research, particularly in the field of respiratory infections (remember the common cold research unit). at the end of may, the uk directly follows the us in the international mortality ranking list with more than ' covid- deaths. the late onset of large scale testing, the lack of personal protective equipment, and a delayed introduction of containment measures have certainly contributed to this high death toll. a correspondent to the lancet deplores that the situation in europe was no better with respect to the lack of a coordinated response to the pandemic. the european center for disease prevention and control (ecdc), which was established in to create a complement to the us cdc, failed to become a hub in europe of knowledge for covid- and a coordination center for europe-wide epidemic counter-strategies. ecdc is underfunded (cdc in : billion $, ecd million $) and understaffed (cdc: ' , ecdc: employees). an emergency structure for a pandemic was not set up, and ecdc played essentially no role in pandemic crisis management, which was done according to eu laws by national organizations without any european coordination (jordana and triviño-salazar, ) . even the city-state of singapore, where the early handling of the covid- was lauded as exemplary public health action, had "blind spots" on their screen in overlooking the miserable living conditions of migrant workers that became hotspots of covid- transmission. of special global health concern are refugee camps from bangladesh to europe. a refugee camp on lesvos/ greece has just one water tap per residents, making efficient handwashing an impossible mission (newland, ) . governments plan to spend billions on rescuing what they consider to be essential national industries. it will be important that they also find the money needed for covid- containment among migrant workers, refugees and populations at risk in developing countries . the beneficial epidemic effect of the lockdowns, obtained at enormous economic costs, would be canceled out if a second wave epidemic should start from these settings with relatively unrestrained viral transmission. at present it is not clear which institution, if not the united nations' suborganizations, will be able to implement such measures. when the leading nation of the western hemisphere leaves now the who, this is a disastrous signal for global public health at this crucial moment of the covid- pandemic. ) visualizing speech-generated oral fluid droplets with laser light scattering ' and counting. the economist presymptomatic sars-cov- infections and transmission in a skilled nursing facility airborne or droplet precautions for health workers treating covid- ? utility of hyposmia and hypogeusia for the diagnosis of covid- epidemiology and transmission of covid- in cases and of their close contacts in shenzhen, china: a retrospective cohort study investigation of a covid- outbreak in germany resulting from a single travel-associated primary case: a case series a sneeze england and wales see excess deaths in care homes wearing face masks in the community during the covid- pandemic: altruism and solidarity comparative tropism, replication kinetics, and cell damage profiling of sars-cov- and sars-cov with implications for clinical manifestations, transmissibility, and laboratory studies of covid- : an observational study impact assessment of non-pharmaceutical interventions against coronavirus disease and influenza in hong kong: an observational study ) pandemics and the great evolutionary mismatch rapid implementation of mobile technology for real-time epidemiology of covid- assessment of deaths 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interventions to contain covid- in china delayed access or provision of care in italy resulting from fear of covid- covid- : a need for real-time monitoring of weekly excess deaths first-wave covid- transmissibility and severity in china outside hubei after control measures, and second-wave scenario planning: a modelling impact assessment is the coronavirus airborne? experts can't agree the characteristics of household transmission of covid- epidemiological and clinical characteristics of covid- in adolescents and young adults an internet-delivered handwashing intervention to modify influenza-like illness and respiratory infection transmission (primit): a primary care randomised trial reducing risks from coronavirus transmission in the home-the role of viral load genomic epidemiology of sars-cov- in guangdong province sars-cov- infection in children effective containment explains subexponential growth in recent confirmed covid- cases in china antibody tests suggest that coronavirus infections vastly exceed official counts epidemiology of covid- in a long-term care facility lost in transition covid- deaths in lombardy, italy: data in context air, surface environmental, and personal protective equipment contamination by severe acute respiratory syndrome coronavirus (sars-cov- ) from a symptomatic patient children with covid- in pediatric emergency departments in italy covid- -the law and limits of quarantine closing borders is ridiculous': the epidemiologist behind sweden's controversial coronavirus strategy herd immunity: understanding covid- failing the test -the tragic data gap undermining the u.s. pandemic response seroprevalence of sars-cov- -specific antibodies among adults coughing and aerosols reviving the us cdc covid- : pcr screening of asymptomatic healthcare workers at london hospital effect of changing case definitions for covid- on the epidemic curve and transmission parameters in mainland china: a modelling study global burden of respiratory infections associated with seasonal influenza in children under years in : a systematic review and modelling study virological assessment of hospitalized patients with covid- connecting clusters of covid- : an epidemiological and serological investigation detection of covid- in children in early changes in contact patterns shape the dynamics of the covid- outbreak in china what is required to prevent a second major outbreak of sars-cov- upon lifting the quarantine of wuhan city, china. preprint to the lancet acknowledgements i thank jacqueline steinhauser and sophie zuber for critical reading of the manuscript. the author consults nestlé, his former employer, on the scientific aspects of the covid- epidemic, but he does not consider this as a conflict of interest. key: cord- -hffxb bm authors: cheung, ka shing; hung, ivan fn.; chan, pierre py.; lung, k. c.; tso, eugene; liu, raymond; ng, y. y.; chu, man y.; chung, tom wh.; tam, anthony raymond; yip, cyril cy.; leung, kit-hang; yim-fong fung, agnes; zhang, ricky r.; lin, yansheng; cheng, ho ming; zhang, anna jx.; to, kelvin kw.; chan, kwok-h.; yuen, kwok-y.; leung, wai k. title: gastrointestinal manifestations of sars-cov- infection and virus load in fecal samples from the hong kong cohort and systematic review and meta-analysis date: - - journal: gastroenterology doi: . /j.gastro. . . sha: doc_id: cord_uid: hffxb bm abstract background & aims infection with sars-cov- causes covid- , which has been characterized by fever, respiratory, and gastrointestinal symptoms as well as shedding of virus rna into feces. we performed a systematic review and meta-analysis of published gastrointestinal symptoms and detection of virus in stool, and also summarized data from a cohort of patients with covid- in hong kong. methods we collected data from the cohort of patients with covid- in hong kong (n= ; diagnosis from february through feb , ), and searched pubmed, embase, cochrane and three chinese databases through march , according to the preferred reporting items for systematic reviews and meta-analyses guidelines. we analyzed pooled data on the prevalence of overall and individual gastrointestinal symptoms (anorexia, nausea, vomiting, diarrhea, and abdominal pain or discomfort) using a random effects model. results among the patients with covid- in hong kong, patients ( . %) had gastrointestinal symptoms and patients ( . %) had stool that tested positive for virus rna. stool viral rna was detected in . % and . % among those with and without diarrhea, respectively (p=. ). the median fecal viral load was . log cpm in patients with diarrhea vs . log cpm in patients without diarrhea (p=. ). in a meta-analysis of studies, comprising patients, the pooled prevalence of all gastrointestinal symptoms was . % ( % ci, . %– . %); . % of patients with non-severe covid- had gastrointestinal symptoms ( % ci, . %– . %) and . % of patients with severe covid- had gastrointestinal symptoms ( % ci, . %– . %). in the meta-analysis, the pooled prevalence of stool samples that were positive for virus rna was . % ( % ci, . %– . %); of these samples, . % of those collected after loss of virus from respiratory specimens tested positive for the virus ( % ci, . %– . %). conclusions in an analysis of data from the hong kong cohort of patients with covid- and a meta-analysis of findings from publications, we found that . % of patients with covid- had gastrointestinal symptoms. virus rna was detected in stool samples from . % patients—even in stool collected after respiratory samples tested negative. healthcare workers should therefore exercise caution in collecting fecal samples or performing endoscopic procedures in patients with covid- —even during patient recovery. in december , a cluster of unidentified form of viral pneumonia cases was first reported in wuhan, china, which swiftly spread to the rest of china and then the rest of the world within a very short period. the virus was subsequently identified to be a novel coronavirus (cov) that belongs to the beta-coronavirus lineage b with more than % resemblance to the previously reported sars-cov in . up until march of , more than , cases were reported from more than countries or regions across the globe, with more than , cases in china, , cases in italy, , cases in iran and , cases from korea. although the number of new cases seem to be declining in china, the numbers of cases are rising in an exponential manner in europe, north america and middle east countries. the death toll has already reached more than , globally with more than , from the hubei province of china, where wuhan city is located. in response to the emerging threat posed by this virus, the world health organization (who) has declared a public health emergency of international concern on january , and further labelled it as a pandemic on march . the disease was named as covid- , which was an abbreviation for coronavirus disease , by the who and the virus was termed as the sars-cov- by the international committee on taxonomy of viruses (ictv). the sars-cov- is a positive-sense singlestranded rna virus and has strong genetic similarity to bat coronaviruses but the intermediate reservoir has yet to be identified. together with the other two previously identified coronaviruses sars-cov and mers-cov that cause severe acute respiratory syndrome and middle east respiratory syndrome (mers), this is the third coronavirus identified to cause severe viral pneumonia in humans ( table ) . similar to the other two coronaviruses, the sars-cov has very high infectivity as no one has immunity, resulting in an ongoing global health crisis. based on existing observation, the case fatality rate of covid- is lower than sars and mers and is estimated to be about - %, but is much higher in older patients. in addition to age, a high sequential organ failure assessment (sofa) score and d-dimer level > ug/l on admission are associated with poor prognosis. apart from respiratory symptoms, gastrointestinal manifestations are common in patients with sars, mers and the latest covid- . we previously reported the high prevalence of enteric symptoms in patients with sars and demonstrated acute viral replication in the small intestinal mucosa of sars patients. it is estimated that - % of patients had diarrhea during the course of sars illness. fecal shedding of sars-cov rna was found in - % of patients during day - of illnesses and could persist for > days of illness. , it was subsequently found that sars-cov bind to the angiotensin-converting enzyme (ace ) receptors of the intestinal and respiratory tracts, which is the entry point for the virus to the epithelial cells. similarly, up to a quarter of patients with mers also reported gastrointestinal symptoms such as diarrhea or abdominal pain. again, mers-cov could be detected in % of stool samples, and could persist for up to days after diagnosis. it was shown that the human intestinal tract including primary intestinal epithelial cells, small intestine explants, and intestinal organoids are highly susceptible to mers-cov. enteric manifestations of sar-cov not only pose important diagnostic challenge to clinicians when facing patients with mild covid- symptoms on initial presentation, but also signify potential fecal transmission of this virus. with increasing number of reported cases of covid- , there is a pressing need to systemically summarize the enteric manifestations of covid- and the temporal pattern of fecal shedding of the sars-cov- virus, particularly to gastroenterologists and endoscopists who may not be familiar with this disease. this study aimed to summarize the existing data on gastrointestinal manifestations of covid- and the temporal pattern of fecal shedding of sars-cov based on published data as well as the data from our recent cohort of covid- patients in hong kong. we included a cohort of patients with virologically confirmed covid- diagnosed between nd and th february in hong kong. the prevalence of gastrointestinal symptoms (including nausea/vomiting, diarrhea and abdominal pain/discomfort) and viral load in stool collected on admission was reported. three databases including pubmed, embase, and cochrane library were searched following the prisma guideline two authors (ksc, ifh) determined the eligibility of studies independently, and dissonance was resolved by the third author (wkl). the inclusion criteria included ( ) study population: covid- patients (including adult or pediatric patients and pregnant women); ( ) study design: case reports/case series, prospective/retrospective cohort study, case-control study, and randomized controlled trials. there was no language restriction. the exclusion criteria were ( ) patients without virological proof of sars-cov infection; ( ) asymptomatic patients infected with sars-cov ; ( ) studies that did not report gastrointestinal symptoms; and ( ) review articles, meta-analyses, editorials, and other forms (e.g. commentary). if all gastrointestinal symptoms were not reported and the number of events of any individual gastrointestinal symptom was less than one, it was regarded as "not available" and excluded from the meta-analysis of all gastrointestinal symptoms. however, this study was still included in the meta-analysis of individual gastrointestinal symptom if the proportion of patients with that symptom was reported. two additional studies , which did not report on gastrointesitnal symptoms but provided data on stool viral rna was included in the metaanalysis of stool viral rna only. for eligible articles, we recorded items including first authors, site of study, inclusion/exclusion criteria, sample size, age, sex, disease severity, any gastrointestinal symptoms (anorexia, nausea/vomiting, diarrhea, or abdominal pain), other symptoms (fever, cough, expectoration and dyspnea). severe disease was defined according to the american thoracic society and infectious disease society of america guidelines for communityacquired pneumonia, need of intensive care unit (icu) admission, and death. all statistical analyses were performed using r version . computing) statistical software. continuous variables were expressed as median (interquartile range [iqr]) or mean (± standard deviation [sd]). the prevalence of gastrointestinal symptoms was expressed as proportion and % confidence interval ( % ci) using the random effects model, and was presented as forest plot. we used cochran q test to detect heterogeneity among studies, with a p-value < . indicating significant heterogeneity. we calculate i statistic to measure the proportion of total variation in study estimates attributed to heterogeneity. i values of < %, - %, and > % indicate low, moderate, and high heterogeneity, respectively. subgroup analysis was performed according to whether studies were from china or other countries, in or outside of the hubei province, the disease severity, and patient group (adults, pediatric patients and pregnant women). on presentation, stool viral rna was positive in ( . %) patients, and the median viral load was . (range: . - . ) log copies per ml (cpm). the proportion of patients with detectable stool viral rna was higher among those with diarrhea than those without diarrhea table including the hospital admission period, places in which the patients were recruited, sample size, age, sex, disease severity, non-gastrointestinal symptoms (fever and respiratory symptoms) on presentation, and gastrointestinal symptoms (anorexia, nausea/vomiting, diarrhea and abdominal pain/discomfort). the median age of patients was . years (iqr: . - . ), and . % were male. among studies that reported disease severity, severe disease accounted for . - . %. significant heterogeneity among studies was seen for anorexia, nausea/vomiting, and diarrhea (p< . ; i = . - . %), while the heterogeneity was less for abdominal pain/discomfort (p= . ; i = . %). the pooled prevalence of all gastrointestinal symptoms was . % ( % ci: . - . ) and . % ( % ci: . - . ) in studies from china and other countries, respectively ( figure ). there was no significant subgroup difference between the studies based on country origin (p= . ). however, there was significant heterogeneity among the studies conducted in china (p=< . ; i = . %) but not among the studies from other countries (p= . ; among studies from china, the prevalence of all gastrointestinal symptoms in the single study of , patients from hospitals by guan et al was . % ( % ci: . - . ). ( figure ). for studies from hubei province, the pooled prevalence of all gastrointestinal symptoms was . % ( % ci: . - . ), whereas those from outside of hubei province was . % ( % ci: . - . ). there was a significant subgroup difference between the studies from and outside of hubei province (p< . ), and there was also significant heterogeneity among the studies (p=< . ; i = . % and i = . %). there were studies that compared the prevalence of all gastrointestinal symptoms according to the severity of covid- (number of patients with severe and non-severe disease was and , , respectively) (etable ). the pooled prevalence of all gastrointestinal symptoms was . % ( % ci: . - . ) and . % ( % ci: . - . ) in patients with severe and non-severe disease, respectively (figure ) . there was significant heterogeneity among the studies (p< . ; i = . % and i = . %). there were studies on adults, on pediatric patients, and on pregnant women. the corresponding pooled prevalence of all gastrointestinal symptoms in adults, pediatric patients, and pregnant women was . % ( % ci: . - . ), . % ( % ci: . - . ), and . % ( % ci: . - . ). there was no significant subgroup difference (p= . ). none of the studies tested stool viral rna on the day of hospitalization except our current study. there were studies which tested for viral rna in stool; the study by wang in this meta-analysis of , covid- patients from six countries, the pooled prevalence of all gastrointestinal symptoms (including anorexia, nausea/vomiting, diarrhea or abdominal pain) was . %. anorexia was the most common gastrointestinal symptom ( . %), followed by diarrhea ( . %), nausea/vomiting ( . %) and abdominal pain/discomfort ( . %). in the hong kong cohort, viral rna was detected in the stool of . % of patients on presentation, including patients without any gastrointestinal symptoms. moreover, patients with diarrhea on presentation had higher stool rna positivity and viral load than those without diarrhea. we also noted that . % of patients had detectable stool viral rna during the course of illnesses. more importantly, prolonged shedding of viral rna in stool rather than respiratory samples was observed in . % of patients, which could be up to ≥ days from illness onset. although diarrhea is one of the common gastrointestinal manifestations, the presence of constipation could not rule out covid- , as a case report of four patients reported that constipation was noted in two. despite the inclusion of > reports, the actual prevalence of any gastrointestinal symptoms could be underestimated as many earlier studies did not report other gastrointestinal symptoms except for diarrhea [ ] [ ] [ ] [ ] [ ] [ ] . moreover, majority of studies only reported gastrointestinal symptoms on the day of admission but not throughout the disease course. the issue is further complicated by the difference in the criteria on diagnosing diarrhea in various hospitals. with more than % resemblance to sars-cov, infection of the gastrointestinal tract by sars-cov- is not unexpected, which is proposed to be mediated via the ace cell receptors. ace receptors are highly expressed in the small intestine, especially in proximal and distal enterocytes, , and the binding affinity of ace receptors determines infectivity. as ace modulates intestinal inflammation, gastrointestinal manifestations were also commonly reported during the sars and mers outbreaks. in the previous sars outbreak in hong kong, % patients reported diarrhea. similarly, up to a quarter of patients with mers also reported gastrointestinal symptoms such as diarrhea or abdominal pain. in our covid- cohort in hong kong, % of patients reported diarrhea, which was slightly higher than our previous sars cohort. however, many of these patients were from a large outbreak during dinner gathering in the lunar new year, who might contract the virus through both fecal-oral and respiratory routes, thus partly explaining the higher frequency of gastrointestinal manifestations. previous studies during sars demonstrated that viral load in the stool was strongly associated with presence of diarrhea. in our covid- cohort, patients with diarrhea also had higher prevalence of detectable stool viral rna on presentation. importantly, gastrointestinal manifestations may be the only initial symptoms in some covid- patients. in the study by an et al, our meta-analysis showed that the prevalence of severe disease was more common in patients who had gastrointestinal symptoms than those who did not ( . % vs . %). wang et al reported that abdominal pain was more frequent in patients who required icu care than those who did not. healthcare professionals should be aware of the potential prognostic implications in patients with gastrointestinal symptoms, whom may require more close monitoring. in our covid- cohort in hong kong, we found that . % of patients tested positive for stool viral rna on the day of admission. as for the meta-analysis, we found that . % of patients had stool samples ever tested positive for viral rna during the illness. due to the lack of systematic stool collection protocol in currently published studies, the full extent of the stool positive rate remains to be characterized, particularly the peak timing and extent of fecal shedding. it is however alarming to note that . % of patients had stool viral rna remaining positive despite negative respiratory specimens. although it is uncertain at this moment whether these are live virus particles or just rna fragments released from the intestinal cells, this finding could raise a serious concern on the isolation policy for the covid- patients, particularly during the recovery phase. during the sars outbreak in , it was reported that the sewage system of the amoy gardens in hong kong served as the major source of infection from patients excreting coronavirus rna. the sewage concentrates of two hospitals receiving sars patients in beijing were also found to have sars-cov rna detected at that time. intuitively, proper handling of the excreta of covid- patients should still be strongly enforced despite repeatedly negative results in respiratory specimens. another interesting feature of covid- is the recurrent infection in some patients, i.e. recurrent symptoms after apparent recovery with positive respiratory specimens for viral rna again after initial clearance. it remains to be determined whether the persistence of viral rna in stool may be used as surrogate monitor for the recurrent infection in some patients. there are several strengths of our study. this is the first meta-analysis that summarized the rapidly emerging and sometimes confusing literature on covid- on the prevalence of the overall and individual gastrointestinal manifestations. the comprehensive inclusion of > studies allows a more precise estimation of the prevalence of gastrointestinal symptoms. subgroup analysis found that the presence of gastrointestinal symptoms was associated with a more severe disease course, highlighting the importance of a more detailed inquiry into gastrointestinal symptoms for both diagnostic and prognostic purposes. the alarmingly high prevalence of viral shedding in stool, particularly after viral rna negativity in respiratory specimens, prompts further research into the viral shedding dynamics in different systems, as well as the potential transmission risk via fecal-oral route, which carries significant infection control and public health implications. a few limitations of this study should be noted. as mentioned, gastrointestinal symptoms may be under-reported in some studies, which may lead to a lower pooled prevalence rate. second, studies of large sample size on ethnic groups other than chinese are currently lacking, precluding a more precise estimate of the prevalence of gastrointestinal manifestations in other ethnic groups. in this study, we found that gastrointestinal symptoms were present in . % of patients diagnosed with covid- . moreover, viral shedding in stool was detected in . % of patients, and could persist for up to ≥ days from illness onset even after viral rna negativity in respiratory specimens. gastrointestinal symptoms are color coded as shown (abdominal pain/discomfort, orange; vomiting, yellow; diarrhea, green). the details of "r-s+" patients are shown in case number : , , , , , , , , , , , and . abbreviations: covid- , coronavirus disease ; d, day of symptom onset; "r-s+", respiratory specimen negative for viral rna but stool specimen still positive for viral rna * nasopharyngeal/oropharyngeal and stool samples were tested for viral rna within - hours and - days after illness onset respectively in the study by cai j et al; the authors did not state the exact day from illness onset on which the respiratory and stool samples were tested for individual patients; in addition, all patients were tested negative for two consecutive respiratory specimens, but the exact day on 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records clinical analysis of neonates born to mothers with -ncov pneumonia pregnant women with new coronavirus infection: a clinical characteristics and placental pathological analysis of three cases diagnosis and treatment of novel coronavirus pneumonia in pregnancy with gastrointestinal symptoms as first manifestations author names in bold designate shared co-first authorship ( %) * severe disease was defined as the american thoracic society and infectious disease society of america guidelines for community-acquired pneumonia, need of icu admission, and death. # if all gastrointestinal symptoms were not reported and the number of events of any individual gi symptoms was less than one, it was regarded as "not available" and was excluded from the meta-analysis of all gastrointestinal symptoms. however, this study was still included in the meta-analysis of individual gastrointestinal symptom if the proportion of patients with that symptom was reported. abbreviations: covid- , coronavirus disease ; sd, standard deviation; iqr: interquartile range; gi, gastrointestinal; c, cough; e, expectoration; d, dyspnea; n.a., not available; n: nausea; v: vomiting; icu, intensive care unit; uk, united kingdom; usa, united states of america what you need to know: background and context: infection with sars-co- virus, which causes covid- , results in respiratory as well as gastrointestinal symptoms; virus rna has been detected in fecal samples. a meta-analysis of publications found that gastrointestinal symptoms have been reported in . % of patients with covid- . stool samples from . % of patients tested positive for virus rna; stool samples from . % of these patients tested positive for virus rna even after respiratory specimens tested negative. this study analyzed mostly data from reported cases from china; systematic data collection was lacking for most studies.impact: gastrointestinal symptoms occur in almost % of patients with covid- . virus rna can be detected in fecal samples-even those collected after respiratory samples test negative.lay summary: many patients with covid- develop gastrointestinal symptoms. the virus can be detected in stool, so patients and caregivers should take care to avoid fecal-oral transmission of the virus. key: cord- -e m m ut authors: samidurai, arun; das, anindita title: cardiovascular complications associated with covid- and potential therapeutic strategies date: - - journal: int j mol sci doi: . /ijms sha: doc_id: cord_uid: e m m ut the outbreak of coronavirus disease (covid- ), an infectious disease with severe acute respiratory syndrome, has now become a worldwide pandemic. despite the respiratory complication, covid- is also associated with significant multiple organ dysfunction, including severe cardiac impairment. emerging evidence reveals a direct interplay between covid- and dire cardiovascular complications, including myocardial injury, heart failure, heart attack, myocarditis, arrhythmias as well as blood clots, which are accompanied with elevated risk and adverse outcome among infected patients, even sudden death. the proposed pathophysiological mechanisms of myocardial impairment include invasion of sars-cov- virus via angiotensin-converting enzyme to cardiovascular cells/tissue, which leads to endothelial inflammation and dysfunction, de-stabilization of vulnerable atherosclerotic plaques, stent thrombosis, cardiac stress due to diminish oxygen supply and cardiac muscle damage, and myocardial infarction. several promising therapeutics are under investigation to the overall prognosis of covid- patients with high risk of cardiovascular impairment, nevertheless to date, none have shown proven clinical efficacy. in this comprehensive review, we aimed to highlight the current integrated therapeutic approaches for covid- and we summarized the potential therapeutic options, currently under clinical trials, with their mechanisms of action and associated adverse cardiac events in highly infectious covid- patients. coronavirus- is an emerging infectious disease caused by the novel single-stranded rna enveloped severe acute respiratory syndrome-coronavirus- (sars-cov- ). the first case of covid- was reported on december in hubei province of china [ ] and within a short span of time, the disease quickly spread to other parts of the world [ ] and has rapidly evolved as a global pandemic situation. the first confirmed case of covid- in the united states of america (usa) was reported on january in the state of washington when a -year-old man showed symptoms of sars-cov- infection after returning from wuhan, china [ ] . the first person-to-person transmission of a confirmed covid- case in usa was reported in illinois on january after an initial positive diagnosis of covid- on the patient's wife, who returned from wuhan, china in mid-january , and unfortunately, covid- is now widespread in all states across the usa [ , ] . according to johns hopkins coronavirus resource center, as of september , there are , , confirmed covid- cases and , confirmed deaths worldwide [ ] . usa is now the epicenter of the disease; the death toll has reached , with , , confirmed covid- cases [ ] . figure is the graphical representation of most affected regions of confirmed cases with reported deaths across the world. countries with more than , confirmed cases with reported deaths are presented in figure a ,b; and countries with more than , cases (but fewer than , ) and corresponding reported deaths are shown in figure c ,d. understanding the structure and the genetic makeup of sars-cov- is important to appreciate the ongoing efforts to address this disease and for the discovery of drugs and vaccines. sars-cov- is spherical in shape and consists of multiple components which are essential for their replication and transcription: ( ) several club shaped projections on the surface of the envelope, called spike glycoprotein (s), which helps in anchoring to the host cell and acts as an inducer to neutralize antibodies, ( ) a small membrane envelope protein (e), ( ) structural membrane protein (m), which spans the lipid bilayer, ( ) hemagglutinin-esterase glycoprotein (he), which destroys the sialic acid present on the host cell and helps the virus to inject its genetic material, ( ) nucleoprotein (n) and ( ) the key component, the positive-sense single-stranded genomic rna [ ] [ ] [ ] . the typical structure of covid- virus depicting the above-mentioned components is shown in figure a . the genome size of covid- is about . - . kb [ ] and is the largest among all known rna viruses in this category (sars-cov and middle east respiratory syndrome, mers). sars-cov- encompasses several open reading frames (orf) along with its utr and utr regions. orf a/b (frame shift) is the full-length gene ( . kb size) that encodes replicase polyprotein named pp a protein and accessary (non-structural proteins (nsps) and orf b codes for pp b and nsps [ ] [ ] [ ] [ ] . the structural proteins including spike (s), envelope (e), membrane protein (m) and nucleoprotein (n) are coded by orfs and present on the ' utr region. several other essential accessary proteins are coded by orf , orf a, orf b, and orf [ ] . the domain structure of sars-cov- is presented in figure b . the genomic sequencing data obtained from covid- -infected patients in china revealed the distinct features of sars-cov- [ ] . sequence comparison showed the novel sars-cov- was more distantly correlated with sars-cov (about %) and mers-cov (about %). some of the salient features of sars-cov- make it unique and virulent compared to previously known coronaviruses. reports suggest that sars-cov- lacks the orf a protein present in sars-cov and has variation in the c and b proteins [ ] . in addition, a single mutation at n t in the spike protein strengthened the binding efficiency of sars-cov- to angiotensin-converting enzyme (ace ), the primary mode of entry into host cell [ ] . structural details of sars-cov binding to the host cell through spike protein give us the clue about the importance of the mutation in this region [ ] . studies show that this mutation in the spike protein of sars-cov- increases its binding affinity to ace in human by - times higher than sars-cov [ ] . this mutation in the spike protein may be one of the key attributes of sars-cov- that led to its rapid spreading around the world in a very short period. there are six different strains of sars-cov- identified so far, namely, ( ) l strain (originated in wuhan, china and the parent orf -l s strain), ( ) s strain (mutation of orf , l s), ( ) v strain (variant of orf a coding protein ns , g v), ( ) g (mutation in spike protein, d g), ( ) gh strain (mutations in spike protein, d g and orf a, q h) and ( ) gr (mutation in nucleocapsid gene, rg kr) [ , ] . among these variants, g strain is the most widespread, has undergone several mutations since january , and branched into subtypes gr and gh. the g and gr strains are prevalent in europe, including in italy, whereas the gh strain is widespread in germany and france. the most predominant variant found in north america is the gh strain, and this subtype along with the gr clades accounts for % of all global sequences of sars-cov- genome [ ] . as of now, strains g, gh and gr are constantly increasing, globally, and it is yet to be determined whether the unique nature of these strains is associated with the disease intensity. covid- virus is predominantly transmitted from human to human through respiratory droplets or aerosols (> - µm in diameter) and contact routes. inhalation of respiratory droplets and aerosols from covid- -infected persons is the most likely potential mode of transmission of the disease [ ] . once in the host system, sars-cov- follows the traditional steps similar to any other virus for its mode of entry into the host cells [ ] . the spike protein anchors the virus to the surface of the host cell by binding to the ace receptor [ ] . the virus undergoes conformational changes to fuse to the cell membrane of the host cells and engulfs into the cytoplasm of the cell by endosomal pathway. once inside the cell, the virus releases its genomic rna and multiplies using the host's molecular machinery. experimental evidence using hela cells demonstrate that sars-cov- entry into host cell is activated by cell surface proteases and lysosomal proteases such as transmembrane serine protease (tmprss ) and lysosomal cathepsin [ ] . ace is expressed in type ii alveolar cells, the predominant portal of entry in the lungs; it is also expressed in the heart, intestine and kidney as well as on the epithelial cells of oral mucosa and the tongue [ , ] . sars-cov- primarily affects the respiratory tract, and infected patients suffer from pneumonia and flu-like symptoms ( figure ). the patients might need intensive care and artificial ventilation after developing acute respiratory syndrome (ards) or multiple organ dysfunction syndrome (mods). the abundance of sars-cov- compromises the normal function and leads to complications in lungs (inflammation, hypoxia, cytokine storm, pulmonary edema, acute respiratory distress syndrome) and in heart (myocardial infarction, heart failure, myocarditis and arrhythmia). ace , angiotensin i-converting enzyme; ace , angiotensin-converting enzyme ; acei, ace inhibitor; at r, angiotensin type receptor; at r, angiotensin type receptor; arbs, angiotensin ii type-i receptor blockers; ctni, cardiac troponin i; mas, mitochondrial assembly receptor; mras, mineralocorticoid receptor antagonists; tmprss , transmembrane serine protease . the lungs, being a major organ targeted by sars-cov- infection, are severely compromised in delivering their function. one of the common clinical manifestations of covid- at the late stage of the disease is shortness of breath, pneumonia-like symptoms and hypoxia, which ultimately is fatal to the patients. in the pulmonary vasculature, sars-cov- enters through endocytosis and activates adam metallopeptidase domain (adam ), which in turn cleaves ace , which indicates the loss of protection against the renin-angiotensin-aldosterone system (raas), which is mediated by cleaved ace [ , ] . the activation of adam also triggers acute pulmonary inflammation and infiltration of cytokines and leukocytes in the alveolar space and results in pulmonary edema [ , ] . overactive systemic inflammation as a response to covid- infection results in cytokine storm and leads to respiratory difficulties and accounts for majority of the deaths during end stage of the treatment [ ] . pulmonary complications associated with covid- infection include diseases such as acute respiratory distress syndrome (ards), vascular endothelialitis, sepsis, pulmonary edema and pulmonary embolism [ , ] . a multicenter cohort study involving hospitals from countries, which includes patients and cases of confirmed covid- , suggests that up to . % suffer severe pulmonary complications post-surgery and the majority of the deaths are largely due to pulmonary embolism [ ] . lung autopsy reports obtained from covid- patients who died due to ards showed severe alveolar damage and infiltration of perivascular t-cells. histology analysis also demonstrated increased thrombus formation, intussusceptive angiogenesis and microangiopathy in covid- patients compared to influenza [ ] . gene expression analysis using rna isolated from covid- patients showed several inflammatory markers and angiogenesis-related genes were differently regulated compared to healthy lungs. most importantly, there was a significantly increased positive count for ace in covid- tissues compared to control. covid- patients with ards were also characterized by an increased deposition of fibrin and high expression of d-dimers and fibrinogen, suggesting fibrinolysis as a determining factor of mortality [ ] . although pulmonary complication is the dominant clinical manifestation of covid- , underlying cardiovascular complication as well as developed acute cardiac injury enhances the vulnerability of the patient. acute respiratory complication/failure and cytokine storm may cause reduced oxygen supply, which could lead to acute myocardial injury in covid- patients [ ] . patients with cardiovascular disease (cvd) have an increased risk for severity and mortality with covid- infection, mainly because of the abundance of ace receptor in the cardiovascular system, which serves as a gateway for the entry of virus in lungs and heart [ ] . respiratory illness and acute cardiac injury are major clinical manifestations observed in patients infected with sars-cov- during the late stage complications of the disease [ ] . reasonably, patients with coronary artery disease or heart failure are vulnerable to developing major cardiac injury, and once such patients are infected with sars-cov- , they are at greatest risk of serious myocardial impairment or cardiac dysfunction, requiring hospitalization due to unexpected deterioration, and eventual mortality is greater among these patients. a brief view of cardiovascular complications associated with covid- is presented in figure . voluminous available clinical evidence confirms that the severity of covid- is pronounced in patients with a prevalence of underlying cardiovascular diseases, and in many of these patients, the virus causes severe myocardial injury [ ] , including myocardial dysfunction, cardiomyopathy, arrhythmias and heart failure during the course of critical illness [ ] [ ] [ ] [ ] [ ] [ ] [ ] . according to the death data of the cdc (centers for disease control and prevention), different health conditions contribute to the deaths of covid- patients in united states, which are summarized in figure [ ] . deaths that are associated with more than one underlying condition, e.g., deaths involving both diabetes and respiratory arrest or cardiovascular complications and respiratory arrest, etc. hypertension, diabetes, cardiac arrest, ischemic heart disease, and heart failure are the major risk factors and have contributed to the fatalities in covid- cases. the renin-angiotensin-aldosterone system (raas) consists of an enzymatic cascade that controls blood pressure by regulating circulatory homeostasis, body fluid and systemic vascular resistance, all of which are involved in the regulation of a myriad of cardiovascular system [ ] . ace (angiotensin i-converting enzyme) cleaves angiotensin i (ang-i) to angiotensin ii (ang-ii), which binds to and activates angiotensin type receptor (at r), which leads to vasoconstriction, inflammation, fibrosis and proliferation [ ] (figure ). ace converts ang-ii into angiotensin - (ang - ), which has vasodilating and anti-inflammatory effects by binding to mas receptor (mas-r). ace also cleaves ang-i into angiotensin- - , which is further converted into ang - by ace. therefore, ace regulates abnormal activation of the raas, which can prevent the development of hypertension, cardiac hypertrophy, and heart failure [ ] . an increase in ace /ace ratio protects against endothelial dysfunctions and vascular constriction, and exogenous ace activation attenuates thrombus formation and reduces platelet attachment to vessels [ , ] . the etiology of ace -dependent cardiovascular complications with covid- infection is rather complex. sars-cov- enters cardiovascular cells/tissue by binding to the membrane-bound form of ace (ace receptor). elevated levels of ace and its activity are the biomarkers of cardiovascular disease including patients with heart failure [ ] , which indicate that these patients may be more susceptible to covid- infection [ ] , with worsened prognosis of cardiovascular disease treatment [ ] . measuring plasma angiotensin peptides and plasma ace levels can provide a direct evaluation on the progress of treatment and the state of the raas in covid- patients [ ] . nevertheless, earlier clinical studies conveyed that treatment with soluble form of recombinant human ace (rhace ; apn ( . mg/kg, iv, bid for days), gsk : . mg/kg, iv, bid for days) neutralized the excessive sars-cov virus in the system and preserved the protective cellular effects of ace in ards patients [ , ] . consequently, scientists propose the therapeutic potential of soluble recombinant ace , which can overwhelm sars-cov- to prevent its binding to cellular ace [ ] . in addition, ace inhibitors (acei), which upregulate ace expression on the cell surface, have been proven to be successful, and improved the survival rate in patients undergoing covid- treatment [ ] . abundant expression of ace on the cell surface following virus infection may maintain ang-ii degradation, which could reduce at r activation and the risk of deleterious outcomes of covid- . while the ace gene is located on the x-chromosome, gender has an impact among covid- patients, where men are at increased risk of susceptibility to covid- infection and cvd complications due to their hemizygous allele for ace compared to heterozygous allele in female [ ] . interestingly, clinical data from european men and women with heart failure showed elevated level of circulating plasma ace in men than in female [ ] . this data complements with an observation of increased prevalence and susceptibility of covid- in males and demonstrates that abundance of ace receptor in cardiovascular cells can lead to severe clinical complications [ ] [ ] [ ] . considering the importance of ace in the development of hypertension and diabetes mellitus, patients with covid- exhibit severe comorbidities including hypertension and diabetes with poor prognosis. initial evidence from , confirmed cases in china showed . % with cvd and . % with hypertension. however, among the death rate, % had hypertension, . % had diabetes and . % suffered from chronic respiratory disease [ , ] . in another study involving a small population of patients, % had underlying cvd or cerebrovascular disease [ ] . interestingly, data from a small registry of admitted patients showed an alarming % were men, with a median age of [ ] . however, data involving patients (admitted during march to april ) with a median age of from new york city, the epicenter of covid- spread in the usa, showed a slightly different picture [ ] . the most common underlying comorbidities were hypertension ( %), obesity ( %), and diabetes ( %). figure depicts the statistics on distribution of underlying conditions among covid- patients based on the data from center for disease control department (cdc), usa. the data reveals that hypertension is a major comorbid factor for covid- fatalities. an increased risk of covid- death was associated with an age greater than years (mortality of %), cvds (coronary artery disease: . %; heart failure: . %; cardiac arrhythmia: . %), chronic obstructive pulmonary disease ( . %), and current smoking ( . %). another detailed observational meta-analysis ( , confirmed covid- case) of data available from public domains including databases from medline, embase and web of science showed patients with preexisting condition of cvd, diabetes and hypertension are significantly associated with a higher risk of developing severe complication with covid- disease. precisely, the analysis comparing the complications between severe vs non-severe (mild to moderate) covid- cases concluded that cvd was significantly associated with increased illness severity and adverse outcomes among covid- patients [ ] . recently, cdc suggests that children with certain medical conditions, like neurological, genetic, and metabolic conditions, or congenital heart disease might be at increased risk of severe illness from covid- compared to other children. additional study comprising patients from two hospitals in wuhan, china reported % of patients had underlying comorbidity factors: % with hypertension, % with diabetes and % with coronary heart disease [ ] . in another cohort with confirmed covid- patients (during february and march ) with an average median age of from lombardy, italy, % had at least one underlying comorbidity, hypertension ( %), cvd ( %), hypercholesterolemia ( %), or diabetes ( %) [ ] . moreover, a staggering % of the patients were male and the mortality rate was higher in elderly patients aged ≥ years compared to younger patients ( % vs. %). due to the high prevalence of hypertension in the older population, elderly male individuals may be at the highest risk of infection with worse outcomes, and an increased mortality rate with respect to younger patients. patients with hypertension are mostly treated with ace inhibitors (acei) and angiotensin ii type-i receptor blockers (arbs), which substantially increases the expression of ace , due to negative feedback activation caused by low level of ang-i in the system [ ] . considering ace as a preferential receptor of sars-cov- , the patient with antihypertensive therapy with acei/arbs may be at higher risk of developing severe covid- with poor prognosis [ ] . remarkably, clinical studies do not support this hypothesis and found no evidence to demonstrate use of acei or arb as a risk factor in covid- patients [ ] . multiple investigators have demonstrated the beneficial therapeutic effect of acei or arb in prevention of covid- infection [ , ] . independent studies conducted among hypertensive patients found no association between the use of acei or arb and increased risk of mortality in covid- -positive cases [ , ] . a population-based case-control study in the lombardy region of italy with a total of patients with covid- ( february and march ) reported that . % patients were receiving arb and . % patients were receiving acei [ ] . other antihypertensive drugs were also used more in covid- patients than in controls and they had a more frequent history of hospitalization due to cardiovascular complications. however, this study showed no evidence of association of use of anti-hypertrophic drugs including acei or arbs and susceptibility of covid- . another study with , patients in the new york university (nyu) langone health, in which patients were positive for covid- ( . %), reported patients had a history of hypertension ( . %) [ ] . among these hypertensive patients, ( . %) patients were positive for covid- ( . %). this study also identified no substantial adverse effect with the use of antihypertensive drugs including acei or arbs in the covid- positive patients. therefore, prospective research is warranted to clarify the accuracy of existing contradictory hypotheses regarding the use of acei or arbs to control of blood pressure in hypertensive patients during viral infections. fundamentally, after entering into the cells via ace receptors and excessive binding of the sars-cov- result in the downregulation of ace by intracellular degradation and shedding, which could reduce the ang-ii degradation and activation of at r with induction of myocardial hyper-inflammatory reaction in response to covid- [ , ] . due to acei or arb treatment, more ace may be localized in the cell surface after virus binding, which could facilitate ang-ii degradation with reduction of at r activation [ ] . apart from hypertension and age, acute cardiac injury, chronic heart damage and heart failure have all been observed in patients treated for covid- infection [ , ] . due to acute inflammation, procoagulant stimulus and endothelial cell dysfunction, various influenza rna viruses are involved in the development of human atherosclerotic plaques and progression of atherosclerosis. de-stabilization of vulnerable atherosclerotic plaques triggers acute myocardial infarction (mi) or cardiovascular death [ , ] . myocardial infarction, commonly known as heart attack, is a clinical condition, where oxygen supply to the heart is restricted and results in the irreversible loss of cardiomyocytes due to activation of cardiac apoptosis [ ] [ ] [ ] . a large population of patients diagnosed with covid- has died due to mi [ ] . data obtained from a laboratory in lombardy, italy suggest that . % ( out of cases) of patients with confirmed covid- and an existing condition of st-elevation myocardial infarction (stemi) had to undergo a repeated coronary angiogram and coronary lesion was identified as a major cause of the complication [ ] . myocardial injury was also identified as a major contributor of mortality in covid- patients, as derived using data from hospitals in wuhan, china [ ] . strikingly, the cardiac troponin i (ctni) level, a distinct marker of myocardial injury, was noticeably elevated in patients out of hospitalized patients with covid- ( . %) and the mortality was nearly % in these patients with elevated ctni. progressive increased levels of c-reactive protein and n-terminal pro-b-type natriuretic peptide (nt-probnp) coexisted with elevated ctni levels in these covid- patients, which enhance the severity of inflammation and ventricular dysfunction. among patients treated for covid- (admitted to zhongnan hospital of wuhan university during january ), patients had either acute myocardial injury or cardiac arrhythmia, as suggested by their elevated ctni level of . ng/ml versus . ng/ml for those who were treated in non-icu [ ] . several other retrospective multi-center cohort studies from china have also confirmed the significant elevation of biomarkers of myocardial injury over the course of covid- infection that were strongly associated with rapid surge of irreversible clinical deterioration and increased mortality [ , , , ] . although limited data are available on the incidence of heart failure in patients with covid- , the study with hospitalized patients with confirmed covid- (ranging in age from to years) in wuhan, china (until january ) reported that heart failure was identified in patients ( %), among them, ( %) patients died and ( %) patients recovered [ ] . cardiac injury, as a common complication ( . %), was associated with an unexpected high risk of mortality during hospitalization of elderly patients with covid- in wuhan, china [ ] . evidence indicated in another retrospective study that apart from ards and sepsis, acute cardiac injury ( %) and heart failure ( %) were the most common critical complications of death in deceased patients with covid- in wuhan, china [ ] . several other case reports also established that acute or end-stage heart failure was the main pathophysiological manifestation of covid- [ , , ] , which might be associated with hyperinflammation and oxidative stress [ , , ] . interestingly, one recent study indicated a decline in emergency department visits for heart failure during the covid- pandemic, partly due to effective remote clinician-patient interactions [ ] . since patients with cvd are considered to be more vulnerable to sars-cov- infection, with higher risk of negative consequences, these patients avoid frequent hospital visits and prefer alternative remote management. however, analyzing the clinical records during the covid- pandemic (between february and april ) of emergency department of san filippo neri hospital in rome, italy, a study revealed patients with acute heart failure often reported to the emergency department after significant clinical deterioration with high mortality due to failure of routine clinical assessment [ ] . emerging studies indicate that severe covid- -related death is associated with coagulopathy, venous thromboembolism ((vte) and disseminated intravascular coagulation (dic) [ ] . data obtained from the covid- patient population in wuhan, china indicate an abnormal coagulation pattern with prolonged prothrombin time [ ] . there were patients registered in this study and parameters such as (dic), antithrombin activity, prothrombin time (pt) and d-dimer, a fibrin degradation product, were measured and compared between survivors and non-survivors. the results showed elevated levels of dic and d-dimers and prolonged pt in non-survivors and suggest thrombus formation may have contributed to the mortality in these patients. this notion is strongly supported by the observation that treatment of covid- patients with anti-coagulation drug heparin resulted in reduced mortality rate [ ] . the -day mortality study between heparin users and nonusers indicated that only selected covid- patients with markedly higher sepsis-induced coagulopathy (sic) score or elevated d-dimer were benefited from the anticoagulant therapy. notably, anticoagulant treatment may endanger those patients without significant coagulopathy, because the activation of coagulation with local thrombosis/fibrin deposition could limit the survival and dissemination of microbial pathogens and reduce their invasion [ ] . myocarditis is a disease marked by the inflammation of the heart muscle, most often due to viral infection. this inflammation interferes with the electrical system and compromises the pumping capacity of the heart and results in arrhythmia and cardiac arrest [ ] . common diagnosis procedures include electrocardiogram (ecg), mri (magnetic resonance imaging) and a manifestation of increased cardiac troponin i (ctni) level. covid- patients with severe stage of illness manifest systemic hyperinflammation syndrome [ ] . this data suggests an effect of adverse inflammatory reaction or cytokine storm in response to covid- treatment and defines a strong role for ace signaling in covid- disease [ ] . several reports have shown that patients with covid- infection are diagnosed with myocarditis [ , , , ] . in a case report of a -year-old man admitted in lombardy, italy with respiratory difficulties and required mechanical ventilator, with worsening heart condition. transthoracic echocardiography showed mild left ventricle hypertrophy (lvh) with preserved left ventricular ejection fraction and normal wall motion and elevated plasma troponin level (at . ng/ml) [ , ] . cardiovascular mri was suggestive of myocarditis and the patient tested positive for covid- infection demonstrating sars-cov- infection was the most likely cause for the incidence of myocarditis [ ] . similarly, a -year-old healthy woman was diagnosed with acute myopericarditis upon covid- infection. cardiac mri showed a severe left ventricular dysfunction (ejection fraction- %). the patient also had myocyte necrosis with high-sensitivity cardiac troponin t (hstnt) level concentration of . ng/ml [ ] . these reports suggest that patient with covid- infection are prone to myocarditis, and physicians would suspect such conditions along with underlying morbidity factors like hypertension and other cvd. emerging clinical and epidemiological evidence suggests that metabolic disarray, hypoxia and accentuated myocardial inflammation due to sars-cov- infection plays a critical role in the pathophysiology of myocardial injury and prevalence of arrhythmic complications [ ] . in a clinical cohort with patients with covid- in wuhan, china, cardiac arrhythmias were considered a major complication in patients ( . %) who were transferred to the intensive care unit (icu) [ ] . specifically, cardiac arrhythmia was more common in icu patients than in non-icu patients ( . % vs. . %). a recent study from new york-presbyterian/columbia university irving medical center highlighted the spectrum of life-threatening arrhythmias observed in four patients with covid- infection [ ] . fulminant myocarditis with cardiogenic shock could also coexist with atrial and ventricular arrhythmias, which could increase the severity of covid- patients, including death [ , ] . therefore, the expected cardiac arrhythmogenic effect of covid- may be an important underlying risk of disease complication, which needs additional precautions and specialized management. based on the available clinical data, potential myocardial injury is a relevant challenge among hospitalized patients with covid- with increased risk of mortality; therefore, it is essential for multidisciplinary assessment, including blood pressure control in hypertensive patients as well as cardiovascular evaluation and therapy to reduce the morality for covid- infection. strikingly, a recent study in germany involving patients with an average age of years who recently recovered from covid- infection recognized the cardiovascular sequelae, irrespective of preexisting cardiac conditions [ ] . cardiovascular magnetic resonance imaging (cmr) revealed that patients had abnormal cardiac structural changes, had detectable levels of biomarker of cardiac injury, e.g., elevated level of high-sensitivity cardiac troponin t (hstnt), lower left ventricular ejection fraction, higher left ventricle volumes, higher left ventricle mass, and raised native t and t (quantitative assessments of the myocardium composition), commonly found after a heart attack, and had signs of inflammation. the exact molecular mechanism by which sars-cov- virus leads to cardiomyocyte injury is not completely understood. however, the abundant expression of ace- receptors in the heart plays an important role in the accumulation of sars-cov- virus in the cardiac tissue, which eventually results in hyperactivation of inflammation and cardiac tissue injury in patients. recently, autopsy results of patients, who died at early stage of covid- infection in germany, revealed the most likely localization of sars-cov- not to be in the cardiomyocytes, but in interstitial cells or macrophages invading the myocardial tissue [ ] . however, another emerging study using human induced pluripotent stem cell-derived cardiomyocytes (hipsc-cms) shows sars-cov- can directly enter and replicate in hipsc-cms and induce apoptosis, which results in cessation of cardiomyocyte beating after h of infection [ ] . the majority of the covid- patients suffering from cardiovascular complications show a significant elevation of ctni, nt-probnp and interleukin- (il- ) or other cytokines [il b, il ra, il , il , il , il , c-x-c motif chemokine (cxcl ), chemokine (c-c motif) ligand (ccl ), granulocyte-macrophage colony-stimulating factor (gm-csf), and tumor necrosis factor-α (tnf-α)] in their blood stream [ , , ] . severe hyperinflammation or cytokine storm due to immunological dysregulation may be the primary contributor to cardiomyocyte injury [ ] . epidemiological studies with other viral rnas indicated that after entering into the cytoplasm of cardiomyocytes, viral rna is further transcribed and translated into the viral structural proteins to form the complete infectious virion [ ] . ultimately, infected cardiomyocytes would be lysed, which could lead to activation of the innate immune response with induction of pro-inflammatory cytokines, inflammation-induced destabilization of coronary artery plaques and development of left ventricular dysfunction [ ] . collectively, uncontrolled hyperactivated t-lymphocytes with systemic inflammation appears to be the most common mechanisms of the cardiomyocyte injury in covid- patients with profound cardiovascular consequences. in addition to binding to ace of the host cell, the priming of the transmembrane spike (s) glycoprotein of sars-cov- by host proteases (furin, a signature protease of highly pathogenic viruses) through cleavage at the s /s and the s sites could enhance its transmissibility and pathogenicity [ ] . multiple evidences have revealed that the notch signaling plays a major role in maintaining the homeostasis of the cardiovascular system, including atherosclerosis progression and ventricular remodeling after myocardial infarction [ ] [ ] [ ] . furin is transcriptionally induced by notch signaling, but notch is cleaved at the cell membrane by adam /adam to enable final cleavage by γ-secretase to form active notch intracellular domain, which regulates the transcription of target genes in nucleus. therefore, targeting notch activation using inhibitor γ-secretase (gsi) could be a promising therapeutic strategy to block the virus entry into the cardiac cells by reducing furin and increase adam shedding. the notch signaling also modulates the activity of innate and adaptive immune responses by inducing macrophage polarization [ ] . in microphages, it directly binds to il- promoter in response to interferon (ifn)-γ and promotes il- production, which may cause severe myocardial injury due to triggered "cytokine storm" [ ] . our current understanding on the molecular mechanisms of cardiomyocyte injury for sars-cov- infection is limited and future in depth rigorous studies are warranted. early diagnosis of covid- infection in patients is crucial for the recommendation of appropriate treatment strategy and to address associated cvd complications. initial symptoms of sars-cov- infection include high fever or chills, cough, shortness of breath, headache, sore throat, new loss of taste or smell, diarrhea and fatigue that appears during - days after the exposure to the virus. these early indications, though similar to regular viral infection, should be taken seriously during this pandemic time and diagnosed further for the presence of covid- infection. currently, the established diagnostic test for the identification of sars-cov- infection is based on nucleic acid amplification testing (naat) or commonly called real-time reverse transcription-polymerase chain reaction (rt-pcr) assay, nucleic acid-based meta-genomic next-generation sequencing (mngs), reverse transcription loop-mediated isothermal amplification (rt-lamp) and antigen testing performed with nasopharyngeal swab specimen [ , ] . in the absence of any pharmaceutical interventions, traditional public health measures are considered to be the mainstay of management tools to curb this worldwide covid- epidemic. most widely accepted practices are hygienic precautions, isolation and quarantine, social distancing and community containment [ , ] . to minimize cardiovascular complications in highly infectious covid- patients, the patients with covid- infection require routine monitoring of cardiac parameters with echocardiography, telemetry to assess qt interval and electrocardiograph (ecg) to identify the development of cardiomyopathy, arrhythmia, ischemic heart disease and heart failure. potential therapeutic options to impede the propagation of covid- and its associated cardiovascular complication are desperately needed during this ongoing severe pandemic. researchers and clinicians are focusing on developing new drugs against coronavirus as well as repurposing already approved drugs for the treatment of covid- patients. unapproved antiviral drugs for sars-cov- and/or middle east respiratory syndrome coronavirus (mers-cov) diseases are also currently being reevaluated as treatment options for covid- . however, covid- poses unique problems that were not encountered with the previous known viruses. the major issue was to address the cvd complications, systemic and vascular inflammation, and to deal with comorbid risk like hypertension, diabetes and heart failure. initial approaches were to emphasis on obstructing the viral replication and inflammation by using antiviral drugs, such as, remdesivir, liponovir/ritonavir, hydroxy chloroquine (hcq), corticosteroids and broad-spectrum antibiotics like azithromycin, clarithromycin to address inflammation [ , ] . table summarizes the mechanisms of action and beneficial as well as adverse effects of drug treatments used for covid- . the antiviral drug, remdesivir (veklury, gs- ), initially developed for ebola, inhibits rna-dependent rna polymerase and prematurely terminates the viral rna transcription and shows broad-spectrum antiviral activity against rna viruses, including sars-cov- in vitro, and inhibits mers-cov, sars-cov- , and sars-cov- replication in animal models [ ] . remdesivir is a substrate for the drug metabolizing enzymes cyp c , cyp d , and cyp a , as well as a substrate for organic anion transporting polypeptides b (oatp b ) and p-glycoprotein (p-gp) transporters. remdesivir ( - mg/day for days) either treated alone or in combination with anti-inflammatory drugs was effective in curbing the virus and shortening the recovery time of patients undergoing treatment for covid- [ ] . a multicenter randomized, double-blind, clinical trial, involving patients with severe covid- , conducted in ten hospitals in wuhan, china, reported that seriously ill patients, receiving remdesivir ( mg on day followed by mg on days - in single daily infusions) within days of symptom onset, showed a numerically faster time to clinical improvement than those receiving placebo, without any antiviral effect [ ] . the study also reported early termination of the treatment due to multiple adverse events (including gastrointestinal symptoms, aminotransferase or bilirubin increases, and worsened cardiopulmonary status) in the remdesivir-treated patients ( %) ( table ) . in a small pilot study of four critically ill covid- patients with remdesivir, three patients tested negative for sars-cov- rna (swap test) after days of therapy. however, these reports also indicated some adverse side effects including liver injury [ , ] . lopinavir-ritonavir antiviral drugs such as lopinavir-ritonavir (mylan or kaletra; mg and mg, respectively, twice a day for days), hiv protease inhibitors, used in the clinical trial provided only a moderate benefit of reducing the recovery time by day [ ] . although in vivo animal study shows that a combination of remdesivir with lopinavir-ritonavir yields better outcome for coronavirus infection [ ] . however, the treatment with these protease inhibitors (lopinavir-ritonavir) develop cardio-metabolic complications including development of dyslipidemia with an adverse cholesterol profile, which could elicit inflammation with elevated reactive oxygen species (ros) production, altered myocardial ubiquitin proteasome and calcium-handling pathways together with decreased contractile function [ , ] (table ) . lopinavir-ritonavir treatment inhibits the myocardial ups (ubiquitin proteasome system) and leads to elevated calcineurin and connexin expression that may contribute to cardiac contractile dysfunction [ ] . without any benefit, lopinavir-ritonavir may also cause bradycardia, qt and pr interval prolongation due to the interaction with cytochrome p enzymes [ , , ] . baricitinib (olumiant®), an inhibitor of janus kinase (jak and jak ) molecule and a drug for the treatment of rheumatoid arthritis was tested ( mg or mg once daily) in covid- patients [ ] . this drug was repurposed in covid- treatment to curb the occurrence of inflammation process due to the use of ace inhibitors, which moderately reduced the lung inflammation and cytokine [ ] . the management of hyperinflammation or cytokine storm has been challenging and accounts for the majority of the mortality associated with adverse cases of covid- patients. clinical practices to address this complication involves treatment with monoclonal antibody against interleukin- receptor (il- r) such as tocilizumab (actrema®), siltuximab (sylvant®) and sarilumab (kevzara®) to control the infiltration of macrophages and cytokines in the respiratory system and suppression t-cell activation [ , ] . tocilizumab specifically binds membrane-bound (mil- r) and soluble interleukin- receptor (sil- r) and inhibits signal transduction. covid- patients treated with tocilizumab ( to mg/kg with recommended dose of mg with a maximum dose of mg) in addition to routine therapy showed significant improvement of the clinical outcomes, effectively controlled body temperature with improvement of peripheral oxygen saturation and reduction of inflammatory storm [ ] . considering the emergency to identify a drug that is effective in reducing the complications associated with covid- , efforts are also underway to repurpose old drugs that are proven to be clinically safe. data from recovery trial indicates that dexamethasone, a steroid drug generally used as an anti-inflammatory agent, is effective in reducing the mortality rate by one-third in covid- patients subjected to mechanical ventilation or who were on ventilators compared to patients receiving standard therapy [ ] . among registered covid- patients, of them who received mg of dexamethasone for days, had reduced mortality by % compared to patients who were on standard treatment. more importantly, patients on ventilator support during the critical stage of treatment responded better to dexamethasone compared to patients just receiving oxygen therapy. the outcome of this study is considered a breakthrough in the fight against covid- because dexamethasone is a commonly available drug and cost effective. however, further evidence is required to use dexamethasone in covid- patients. another drug that gained much attention for the treatment of covid- is hydroxychloroquine (hcq, plaquenil), an anti-malarial compound, which is also widely used for attenuation of systemic lupus erythematosus (sle), rheumatoid arthritis (ra), juvenile idiopathic arthritis (jia) and sjogren's syndrome [ ] . several clinical studies, including trials from nih (nct ), are testing this drug for covid- treatment, either alone or in combination with azithromycin [ ] . the treatments with hydroxychloroquine alone ( mg by mouth twice daily for day followed by mg by mouth twice daily for days) or in combination with azithromycin ( mg by mouth or intravenous daily for days) lead to a prolongation of the qt interval, possibly increasing the risk of sudden cardiac death [ ] (table ) . another retrospective multicenter cohort study was conducted involving patients admitted across various hospitals in the city of new york who were diagnosed with covid- (between - march ), those receiving either hcq alone (dose ranges: - mg; once or twice a day) or in combination with azithromycin (dose ranges: mg to mg; once or twice a day) or azithromycin alone. the results from the study showed that the probability of death for patients receiving hcq + azithromycin was . % ( out of ), while patients receiving hcq alone was . % ( out of ) and . % ( out of ) in azithromycin alone group. cardiac arrest was significantly high in patients receiving hcq + azithromycin combination than treatment with placebo or hcq alone [ ] . another cohort study performed at an academic tertiary care center in boston, massachusetts, showed similar high risk of qt prolongation with subsequently developed other ventricular arrhythmias in the hcq alone ( mg, twice on day , then mg daily on days through ) or with azithromycin-treated patients with covid- [ ] . an observational study of admitted patients to the hospital with covid- (between march and april ) in new york, revealed that hcq administration alone was not associated with either a greatly lowered or an increased risk of the composite end point of intubation or death [ ] . the treatment regimen of hydroxychloroquine was a loading dose of mg twice on day , followed by mg daily for additional days. however, recently, the u.s. food and drug administration (fda) revoked its approval to use hcq for covid- treatment due to disappointing results [ ] . data from randomized clinical trials suggest that hcq had no beneficial effects compared to placebo and was not successful in decreasing the mortality rate or in hospital stay (based on fda report, updated on july ) [ ] . therefore, rigorous, and large-scale studies with careful risk assessment of hcq should be conducted prior to initiating covid- therapeutics, with close monitoring cardiac manifestations including evaluation of cardiac biomarkers, routine electrocardiograms and electrolyte monitoring. there is an urgency for the development of a safe and effective vaccine for covid- ; however, no specific vaccines against sar-cov- are currently available [ ] . multiple inactivated vaccine candidates for sars-cov- , such as dna-, rna-based formulations, recombinant-subunits containing viral epitopes, adenovirus-based vectors and purified inactivated virus are under development [ , ] . several candidate vaccines are still in the preliminary stage of phase i clinical trial. the mrna-based vaccine prepared by the usa national institute of allergy and infectious diseases against sars-cov- is under phase trial [ ] . ino- , a dna-based vaccine, is also in pipeline and will soon be available for human trial. preliminary results from pilot studies and clinical trials on new vaccine are encouraging and gives hope for a successful availability of an effective vaccine by end of . several pharmaceutical companies, including pfizer, novartis and astrazeneca and moderna, are testing their candidate vaccine. university of oxford in collaboration with astrazeneca are in the development of covid- vaccine and expect to produce million doses in uk by september . jenner institute, oxford, uk is a leader in this effort and launched a phase iii clinical trial of more than people in may. however, due to the suspected adverse event in a person receiving the vaccine in the united kingdom, the clinical trials have been temporarily paused. moderna, a usa-based company in collaboration with switzerland's lonza, released positive outcomes from its phase i clinical trial of their mrna vaccine for sars-cov- [ ] . preliminary results are very promising, showing good immune response, and due to effectiveness and safety profiles, this vaccine is approved by the u.s. food and drug administration (fda) for phase ii and phase iii studies [ , ] . novartis announced its plans to initiate a phase iii clinical trial to study effects of canakinumab, an interleukin (il)- β blocker, in covid- patients with pneumonia [ ] . they aim to rapidly enroll patients at multiple medical centers across france, germany, italy, spain, uk and the usa and randomize them to receive either canakinumab or placebo on top of standard of care (soc) [ ] . pfizer, in partnership with biontech (bnt), has initiated its phase i/ii clinical trial in the usa for its mrna-based vaccine, the bnt prevent covid- [ ] . sinopharm, a wuhan, china-based pharmaceutical company received approval from the national medical products administration (china) and conducting phase ii clinical trials for its inactivated vaccine bbibp-corv. the company already tested doses of this vaccine and expect to release in the marker by the end of the year . sinovac is planning to enter its phase iii clinical trial in collaboration with instituto butantan in brazil after observing positive results in its preclinical trail with the vaccine coronavac [ ] . ad -ncov, an adenovirus type vector-based vaccine developed by cansiobiologics, china is also in phase iii clinical trial and demonstrated promising effects in the early phase of testing on participants [ ] . inovio pharmaceuticals in collaboration with university of pennsylvania and center for pharmaceutical research, kansas city, missouri, is testing its dna-based vaccine ino- [ ] . preclinical experiments conducted in guinea pigs showed antibody titer against ace receptor/sars-cov binding protein. when countries all over the world are racing to develop their own vaccine against covid- , russia has already approved a vaccine candidate for public use named sputnik v, that was developed in collaboration with gamaleya research institute of epidemiology and microbiology in moscow [ ] . the vaccines comprise either recombinant adenovirus type (rad ) or recombinant adenovirus type (rad ) vectors, which contain the gene for sars-cov- spike glycoprotein (rad -s and rad -s). initial results from the ongoing phase i and ii clinical trials are promising, which include total population size of healthy adult volunteers [ ] . among them volunteers were intramuscularly vaccinated with gam-covid-vac lyo (lyophilized vaccine formulation) and other participants were subjected to gam-covid-vac (frozen vaccine formulation) [ ] . both heterologous recombinant adenoviral (rad and rad ) vector-based covid- vaccines induced a strong humoral and cellular immune responses with reported safety profiles in participants. however, further investigations with larger scale population (including different underlying medical complications) are needed to demonstrate the effectiveness of this vaccine for prevention of covid- . nevertheless, scientists globally have serious concerns about unforeseen adverse effects of this vaccine without the outcomes of the phase iii trial. even though, for the development of an efficient vaccine for covid- , extensive preclinical studies and clinical trials are essential to carefully evaluate the adverse effect of vaccine, the aforementioned fast-paced preclinical data are encouraging for advancing the preventive strategies against covid- . several other treatment options such as convalescent plasma therapy (cpt) and monoclonal antibody therapy have been evaluated with some moderate success. cpt is a traditional method where plasma containing the antibody from recovered patients infected with covid- was transfused to the severely ill covid- patients [ , [ ] [ ] [ ] . studies showed that cp therapy was effective, and the level of neutralizing increased as high as : times in patients infected with sars-cov- [ ] . transfusing antibodies from covid- survivors into high-risk patients to neutralize sars-cov- could provide a quick treatment option until an optimistic vaccine will arrive to prevent this viral infection. efforts are also underway to design a monoclonal antibody that can target the specific epitope on the spike protein of sars-cov- and block the virus entry in to the host cell [ , , ] . such efforts are still in their preliminary stage [ ] and are time consuming; however, they could provide a long-lasting solution for dealing with sars viruses in general. recently, stem cell therapies with secreted extracellular vesicles (evs) offer a potential therapeutic benefit in covid- patients by attenuating inflammation with regeneration of the damaged lung. mesenchymal stem cells (mscs)-derived evs-based therapy could be the most promising reparative strategy in people with covid- , because of its high proliferation rate, low invasive nature, and the immunomodulatory, antioxidant and anti-inflammatory properties of mscs [ ] . there are several promising clinical trials with msc-derived evs underway, which could reveal convincing evidence in the encouraging prospect of msc-based therapies for respiratory complications of covid- patients [ , ] . despite the above-mentioned beneficial effects of different therapeutics, the safety profiles of these therapies have not been proficiently identified. specifically, the potential adverse cardiovascular effects of these drugs in covid- patients need urgent attention before rushing the approval of any new drug into clinical application. for most effective treatments for covid- , it is important to pay attention to emerging evidence about potential harmful risk of drug interactions. due to the highly transmissible novel coronavirus, sars-cov- , the covid- outbreak has become an unprecedented worldwide pandemic with a record number of infected individuals and an excess of mortality. the desperate need for effective therapeutics for covid- during this pandemic integrated scientist around the world across multiple research fields while sharing their research findings and knowledge to fast-track the process of drug discovery. considering the high mortality of covid- patients with cardiovascular comorbidities, it is important to understand whether it is attributable to underlying cardiovascular disease (cvd) or if cvd is the consequence of inflammatory response to sar-cov- infection or severe respiratory symptoms. the precise mechanisms linking cvds and worsened prognosis or higher mortality rate in covid- patients remain unknown. recent therapies under investigation for severe multi-organ failure in covid- patients may have adverse cardiovascular effects, while their clinical efficacy for combating covid- is yet to be established. new advanced technological tools, like information technology based on smart phone apps, social media, artificial intelligence (ai), machine learning, etc., accelerate the diagnosis/screening of patients with virus, analysis of available literature, and identification of potential therapeutic targets and other specific clinical features to tackle covid- pandemic. moreover, ai, particularly, plays an important role in predicting the harmful interaction between cardiovascular consequences with the drugs used for covid- , by automated interpretation of collected meta-data from various sources. in the context of disease progression with cardiovascular complications, the researchers are focusing on developing new drugs in parallel to repurposing already clinically approved drugs to avoid a massive surge of covid- patients with a 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distributed under the terms and conditions of the creative commons attribution (cc by) license key: cord- - cso cl authors: amatya, shaili; corr, tammy e.; gandhi, chintan k.; glass, kristen m.; kresch, mitchell j.; mujsce, dennis j.; oji-mmuo, christiana n.; mola, sara j.; murray, yuanyi l.; palmer, timothy w.; singh, meenakshi; fricchione, ashley; arnold, jill; prentice, danielle; bridgeman, colin r.; smith, brandon m.; gavigan, patrick j.; ericson, jessica e.; miller, jennifer r.; pauli, jaimey m.; williams, duane c.; mcsherry, george d.; legro, richard s.; iriana, sarah m.; kaiser, jeffrey r. title: management of newborns exposed to mothers with confirmed or suspected covid- date: - - journal: j perinatol doi: . /s - - - sha: doc_id: cord_uid: cso cl there is limited information about newborns with confirmed or suspected covid- . particularly in the hospital after delivery, clinicians have refined practices in order to prevent secondary infection. while guidance from international associations is continuously being updated, all facets of care of neonates born to women with confirmed or suspected covid- are center-specific, given local customs, building infrastructure constraints, and availability of protective equipment. based on anecdotal reports from institutions in the epicenter of the covid- pandemic close to our hospital, together with our limited experience, in anticipation of increasing numbers of exposed newborns, we have developed a triage algorithm at the penn state hospital at milton s. hershey medical center that may be useful for other centers anticipating a similar surge. we discuss several care practices that have changed in the covid- era including the use of antenatal steroids, delayed cord clamping (dcc), mother–newborn separation, and breastfeeding. moreover, this paper provides comprehensive guidance on the most suitable respiratory support for newborns during the covid- pandemic. we also present detailed recommendations about the discharge process and beyond, including providing scales and home phototherapy to families, parental teaching via telehealth and in-person education at the doors of the hospital, and telehealth newborn follow-up. introduction sars-cov- , a novel β-coronavirus, was first reported in december in wuhan, china, as "pneumonia of unknown etiology" [ ] prior to its isolation and identification by chinese authorities in january [ , ] . coronavirus disease (covid- ) is primarily a respiratory disease of varying severity [ ] , which presents more commonly as asymptomatic or mild disease in newborns when compared with adults [ ] [ ] [ ] . sars-cov- is transmitted through respiratory droplets, infected fomites [ ] [ ] [ ] , and from airborne transmission during aerosolization procedures [ ] . the american academy of pediatrics (aap) published initial guidance on the management of neonates born to mothers with covid- [ ] . another group recently published a practical resource for perinatalneonatal specialists, providing the most up-to-date information about covid- during pregnancy [ ] . since the epidemiological data for this pandemic are rapidly evolving, neonatologists need to continuously update management compared with adults, children are less susceptible to sars-cov- infection and experience less severe disease with significantly lower death rates [ , [ ] [ ] [ ] [ ] . the physiological mechanisms underlying these differences are as yet unknown, but several possibilities exist that should be explored in future studies. the immature developing immune system of children may respond to sars-cov- differently than adults, possibly resulting in a less damaging cytokine reaction. sars-cov- binds to angiotensin converting enzyme-ii (ace- ) receptors on type ii alveolar epithelial cells in the lower respiratory tract to gain entry into the lungs [ , ] , and ace- receptors may be functionally immature in children making them less susceptible to sars-cov- infection [ ] . although the reasons are unclear, and causation cannot be implied, about half of mothers with covid- delivered preterm infants [ ] . fetal growth during the third trimester does not appear to be affected in infected mothers [ , , , , ] . perinatal complications such as fetal distress and premature rupture of the membranes and postnatally, respiratory distress, tachycardia, shock, thrombocytopenia, and even death have been reported in some neonates (sars-cov- negative) born to mothers with covid- [ , , ] . two stillbirths have been reported [ , ] , one from a pregnant woman who had acute respiratory distress syndrome and multi-organ failure leading to extracorporeal membrane oxygenation (ecmo), and another from a mother who eventually died [ , ] . maternal morbidity due to the disease may lead to morbidity and mortality in fetuses/newborns who test negative for sars-cov- . a few newborns who tested positive soon after birth had dyspnea, fever, pneumonia, respiratory distress syndrome, and feeding intolerance, with overall mild disease and no deaths [ , ] . a large epidemiologic study from china of children with laboratory-confirmed or suspected covid- reported that . % of cases were in infants < year of age [ ] . another report from wuhan children's hospital reported similar results [ ] . a similar percentage ( . %) of pediatric cases in the united states occurred in infants < year of age [ ] . in china, a larger proportion of infants < year of age had severe/critical disease compared with older children ( . % vs . %) [ ] . similarly, in the united states, infants < year of age had the highest rates of hospitalization among pediatric patients [ ] . at penn state, universal covid- testing was implemented on april , for all patients admitted for delivery (fig. ) . the unexpectedly high asymptomatic carrier rates reported from other institutions as well as prolonged face-to-face patient care required during labor and delivery drove this decision, allowing for judicious personal protective equipment (ppe) use and decreased potential exposure for both healthcare workers and newborns. when patients refuse testing, a protocol of contact and droplet isolation for both mother and newborn is used, and during the delivery, healthcare workers wear n respirators. our obstetricians have cared for term covid- positive patients who delivered healthy newborns (viral testing negative), and one women who convalesced and was discharged, still pregnant, at weeks' gestation. pregnant women with confirmed or suspected covid- requiring hospitalization are admitted to negative-pressure rooms, preferentially with an adjoining patient room for newborn resuscitation. mode of delivery is based on the progression of labor and routine obstetric indications. operative vaginal deliveries are considered for women who require a shortened second stage of labor due to maternal exhaustion or respiratory distress. at penn state, cesarean deliveries occur in negativepressure operating rooms. the negative-pressure unit dedicated to covid- positive pregnant patients is the surgical anesthesia intensive care unit (saicu). although in close proximity to the operating rooms, we learned during the labor of one patient that transporting patients with covid- present many logistical challenges (need for multiple cleanings of patient equipment and for security to clear hallways) that would delay an emergency cesarean delivery. although this patient ultimately delivered vaginally, this scenario raised many questions about lowering the threshold for cesarean delivery for patients with covid- in the future. moreover, transport of the newborn, considered a person under investigation (pui) [ ] , out of the saicu was also delayed by the institution's covid- transport policy. this has since been remedied with updated policies that allow newborn puis to be transferred to their rooms in a transport isolette. due to frequent exposure to aerosolizing procedures during the second stage of labor, the possible use of general endotracheal anesthesia during emergency cesarean sections, and the possible need for neonatal intubation, labor, and delivery staff are at frequent risk of exposure [ ] . delivery providers and nurses wear full ppe ("full ppe" = isolation gown, n respirator or powered, air purifying respirator, face shield or goggles, and gloves) [ ] during the entire labor and delivery process of mothers with confirmed or suspected covid- , and mothers wear surgical masks. the triage begins with the laboring mother undergoing testing for sars-cov- to determine delivery location and disposition of the newborn to the appropriate location and care service. viral shedding [ , ] . the american college of obstetricians and gynecologists (acog) recommends the continued use of antenatal corticosteroids for asymptomatic women or those with mild covid- who are at risk of preterm birth within the next days at < / weeks' gestation [ ] . if the mother is ill [ ] , however, the risks to the mother and the potential benefits to the fetus must be weighed and discussed with the mother and family. the benefits of dcc for preterm and term neonates are well known [ ] . several reports, based on expert opinion, have recommended that dcc not be performed in neonates born to mothers with confirmed or suspected covid- in order to reduce the risk of secondary transmission [ , , ] . in contrast, the acog and the royal college of obstetricians and gynecologists, based on a lack of evidence that brief exposure to the mother causes neonatal infection, still recommends performing dcc [ , ] . another group recommends performing dcc with the newborn held by the obstetrician [ ] . at penn state, we now perform dcc with the obstetrician holding spontaneously breathing newborns rather than placing them skin-to-skin on the mother. at penn state, a covid- resuscitation team (neonatal delivery nurse, a respiratory therapist, and a neonatologist) is available for all deliveries of mothers with confirmed or suspected covid- . a pediatric infectious diseases consult is obtained on all neonates born to mothers with confirmed covid- (or symptomatic mothers who initially test negative) so that appropriate testing and discharge follow-up is established. for newborns not predicted to need extensive resuscitation, a neonatal delivery nurse (fully donned) enters the room immediately after delivery and evaluates gestational age, tone, color, and respiratory effort. if there is good tone with spontaneous breathing, the nurse wraps the newborn with warm blankets and places her/him into a prewarmed transport isolette. hospital staff caring for these newborns don a gown, surgical mask, face shield, and gloves. in order to minimize ppe use and potential exposures, routine newborn tests such as screening for congenital heart disease, obtaining the newborn screen, and hearing testing are performed together. for resuscitation of premature, high-risk, and newborns with anomalies born to mothers with cinfirmed or suspected covid- , a fully donned neonatal resuscitation team enters the room upon delivery. the newborn is quickly assessed, and if spontaneously breathing, is placed into the transport incubator. if resuscitation is required, necessary respiratory support is provided, and the newborn is transported to the neonatal intensive care unit (nicu) and admitted into a negative-pressure room with an antechamber. mechanical ventilation, ecmo, and surgeries can be performed in this room. care is provided by a neonatal nurse trained in donning and doffing ppe. a second nurse monitors donning and doffing to ensure that contamination of the primary nurse or medical provider does not occur. the minimum number of persons needed to provide care to these newborns are allowed to enter the room. healthcare workers who are pregnant or ≥ years of age do not care for these patients [ ] . at penn state, the initial sars-cov- test is performed within - h after birth. for newborns who initially test positive and remain in the nicu for extended periods, additional testing occurs on a case-by-case basis, likely every h, and based on signs and severity of covid- . the aap, acog, and chinese consensus experts recommend separating newborns from mothers with confirmed or suspected covid- into separate isolation rooms until the mother's transmission-based precautions are discontinued [ , , , ] . the presumed benefits of temporary separation, i.e., decreased risk of neonatal infection, should be discussed with families prior to delivery [ , ] . the centers for disease control (cdc) recently (april , ) changed their guidance regarding separating newborns from mothers with confirmed or suspected covid- [ ] . they now recommend that the decision to separate newborns should be made on a case-by-case basis, using shared decision-making between mothers and families and the healthcare team about the risks and benefits of cohabitating [ ] . if rooming in does occur according to the families' wishes, or because of facility constraints, care should be taken to practice social distancing, hand hygiene, and infection control, and the mother should wear a facemask during contact with her newborn [ ] . at penn state, due to facility infrastructure constraints, mothers with confirmed or suspected covid- and newborns are admitted to different hospital units; thus they are separated. while hospitalized, mothers with covid- remain in the hospital's covid unit. mothers who are discharged home prior to the infant's discharge may visit their newborns after they have been afebrile for days, symptoms have abated or are improving, and > days have passed since their symptoms first began. alternatively, they can visit if they have two negative tests (> h apart), are afebrile without antipyretics, and respiratory symptoms have improved [ , ] . other family support persons who are puis may not visit the baby until their own sars-cov- molecular testing is negative and any symptoms have abated [ ] . visitors are instructed on proper techniques for donning and doffing masks, gowns, and gloves. various technology platforms are used to video conference with families who are unable to visit. in the nicu, newborns who tests negative for sars-cov- and have no signs can be moved to a regular room [ ] . breast milk has innumerable benefits for newborns, including passive transmission of antibodies against various infections [ ] . antibodies to a similar virus, sars-cov, were detected in breast milk [ ] . to date, sars-cov- has not been detected in the breast milk of mothers with covid- [ ] , and it is possible that breast milk from these mothers will provide some degree of immunity. thus, most international associations highly recommend using breast milk from mothers with confirmed or suspected covid- [ , [ ] [ ] [ ] . careful collection techniques should be used for pumped breast milk [ ] , including providing mothers with a dedicated breast pump. mothers should wash their hands before and after pumping, and the breast pump should be properly disinfected per the manufacturer's instructions. if possible, expressed breast milk should be fed to newborns by a healthy caregiver. if a mother with confirmed or suspected covid- chooses to directly breastfeed, she should wear a surgical mask and perform hand and breast hygiene prior to feeding. when the mother is not breastfeeding, the newborn should remain > m (~ ft) away, be separated by a barrier, and/or be placed in an isolette. the world health organization and united nations children's fund recommend standard breastfeeding guidelines within an hour of birth using appropriate infection prevention precautions [ , ] . this advice may be most pertinent to areas where limited resources make breastfeeding the only viable option. since sars-cov- has been detected on plastic for up to h [ ] , staff receiving bottles of expressed milk from mothers with covid- should wear gloves. after securing the cap, bottles should be wiped with viricidal wipes or diluted bleach solutions and placed on a clean surface to air dry. after drying, bottles may be placed in hospital refrigerators in individual patient bins [ ] . for long-term nicu stays, donor human milk is an option if maternal breast milk is not available. human milk banking association of north america milk banks uniformly use heat treatment during holder pasteurization [ ] , which totally inactivates genetically similar viruses (sars-cov and mers-cov) [ , ] . while there is currently no evidence regarding sars-cov- , it is likely inactivated during heating. at penn state, during hospitalization, infected mothers are encouraged to provide expressed breast milk. unfortunately, due to being in separate units, direct breastfeeding is not currently possible. at other institutions, where there is an opportunity for cohabitation, the decision to directly breastfeed can be made using shared decision-making between mothers and healthcare teams about the risks and benefits of direct breastfeeding. aerosolization procedures increase the risk of airborne transmission, particularly to healthcare workers, since sars-cov- can remain in the air for > h and travel > m (~ ft) [ , ] . droplet transmission occurs when larger respiratory droplets are generated by infected individuals through coughing, sneezing, and talking. these larger droplets drop quickly and only travel a short distance, usually ≤ m (~ ft) [ ] . fortunately, there are very few reports of respiratory support needs in neonates with confirmed or suspected covid- [ , ] . most exposed neonates who received mechanical ventilation also had comorbidities such as prematurity, asphyxia, and non-covid- sepsis [ ] . guidance of respiratory care of patients with confirmed or suspected covid- remain fluid [ , , ] . since up to % cases in wuhan, china, occurred in healthcare workers [ ] , aerosolization properties and stability of sars-cov- in the environment cannot be overemphasized [ ] . therefore, common aerosolizing procedures in the nicu, such as intubation, extubation, open suctioning, noninvasive ventilation, and placement of naso-and oro-gastric tubes need to be conducted with a high degree of caution, using appropriate ppe in negative-pressure rooms [ , ] . institutional variation of what is considered an aerosol generating procedure and how that will affect professionals caring for covid- patients adds another layer of complexity [ , ] . a single center study showed that the team members who directly performed these procedures were at highest risk of becoming infected [ ] . institutions should critically assess the literature in light of their specific patient population and resources in order to determine what they consider aerosol generating procedures. noninvasive support such as nasal intermittent positive pressure ventilation, nasal continuous positive airway pressure (cpap), high flow nasal cannula, and nasal cannula oxygen therapy can be generated by several devices in the nicu. since they are open systems at the patient interface, there is a large risk for droplet and airborne transmission [ ] . masks covering both the nose and mouth, as well as using the lowest possible pressure, may minimize some of the risk. further, if noninvasive ventilation is generated by mechanical ventilators with high-efficiency particulate air (hepa) filters, the risk of aerosolization is likely lower. interestingly, during the sars epidemic, nurses caring for patients receiving noninvasive ventilation did not contract more disease than those who cared for patients on ventilators [ ] . rapid sequence intubation is recommended for those in respiratory failure with covid- [ ] . if bag-mask ventilation is needed, providers should place a hepa filter between the mask and the end tidal co device and oxygen source [ , ] , and wear full ppe [ ] . if ppe is likely to inhibit the ability to visualize the vocal cords, video laryngoscopy should be performed [ ] . pulmonary hygiene should be minimized [ ] . suctioning of endotracheal tubes should be performed using in-line suctioning catheters [ , ] . if a patient needs to be disconnected from the ventilator, the endotracheal tube should be clamped and the circuit disconnected with the heat moisture exchanger still attached to the patient [ , ] . conventional ventilators with dual limb circuits with expiratory hepa filters connected to cuffed endotracheal tubes [ ] are nearly closed systems that significantly decrease the risk of aerosolization. the high-frequency oscillator ventilator (hfov, sensormedics, yorba linda, ca), without specialized experimental circuits, is not able to filter the exhaled air, making its use especially worrisome to healthcare workers during a viral epidemic [ ] . during the sars outbreak, however, healthcare workers caring for patients on hfov did not become infected more than those caring for patients receiving conventional ventilation [ ] . the high-frequency jet ventilator (hfjv, bunnell, salt lake city, ut) has an expulsion set with a filter that prevents aerosol generation [ ] . at penn state, noninvasive ventilation (using a ventilator) for newborns with confirmed or suspected covid- is the preferred mode. if mechanical ventilation is needed, conventional ventilation is failing, or high-frequency ventilation is desired, neonates are placed on the hfjv. newborns ≥ g with confirmed or suspected covid- are placed on ventilators with capabilities to do both invasive and noninvasive ventilation, thus, respiratory care can be adjusted without contaminating multiple devices. in surge situations with inadequate number of ventilators, bubble or variable flow cpap may be used. the diagnosis of covid- in newborns includes physical examination, laboratory, and radiologic testing [ , , ] . a sars-cov- rt-pcr is done for asymptomatic puis [ ] . for symptomatic puis and covid- infected newborns, additional tests such as cbc and crp should be performed, as well as other tests that are clinically indicated [ ] . while the diagnostic role of serologic testing is currently unclear, it may be useful for future epidemiological purposes [ ] . the cdc recommends obtaining a nasopharyngeal swab (or a bronchoalveolar lavage sample if receiving invasive ventilation) for initial diagnostic testing [ ] . rt-pcr is currently recommended for the qualitative detection of sars-cov- nucleic acid in respiratory tract specimens [ ] . the emergency use authorization fda approved test used at penn state is the simplexa ® covid- direct kit (diasorin molecular, cypress, ca). it has excellent specificity. for newborns, the aap recommends obtaining throat and nasopharynx swabs at about and h after birth, although the optimal time of testing is unknown [ ] . the testing regimen should also take into account the risk of infection and limitations of resources. additional testing in symptomatic neonates should be considered because early test results may be negative due to the incubation period of the virus. a respiratory viral panel, to rule out other infections, should also be considered in symptomatic neonates [ ] . chest x-ray findings are variable and nonspecific including unilateral or bilateral ground-glass opacity, lobar or subsegmental areas of lung consolidation, pneumothorax, and are sometimes normal [ , , , [ ] [ ] [ ] . ct scans do not appear to provide additional diagnostic information [ , , , ] . given the limited sensitivity, specificity, and radiation exposure, imaging should only be performed if clinically indicated. healthy newborns ≥ weeks' gestation routine newborn criteria, including stable physical exam, ability to maintain body temperature, and feeding well with adequate hydration, are used to establish timing of discharge. all families, courtesy of the children's miracle network, are given a baby scale (baby/toddler electronic scale, model # , salter). if serum bilirubin (which may be done concurrently with the newborn screen) is in the high intermediate or high-risk zone [ ] , they are also loaned home phototherapy (bilibed ® , model , medela, baar, switzerland). advice regarding home isolation precautions follow the aap guidelines [ ] . neonates are ideally discharged into the care of an unaffected caregiver. covid- positive family members are instructed to limit exposure to the newborn, generally maintaining a m (~ ft) distance. if the mother is breastfeeding or provides newborn care, she is instructed on hand hygiene and use of a mask until afebrile for h without the use of antipyretics, and > days have passed since symptoms began [ ] . predischarge education is completed using video conferencing during the mother's hospital stay or at home following maternal discharge. on the day of discharge, the neonate is brought to a less trafficked entrance of the hospital by the discharging nurse (with a scale and home phototherapy, if needed) and is met by the family (likely still being quarantined) who are wearing gloves and a mask, for a complete in-person teaching session. during this interaction, parents and staff maintain m (~ ft) social distancing, and take turns moving in and out of the teaching space without exposing other staff or patients to the family and newborn. lastly, parents are instructed on the use of the scale and phototherapy, about monitoring for signs of neonatal illness, and details about medical follow-up and additional testing. infants are followed up - days after discharge via telehealth. an informal poll of local primary care providers indicated that only % had a plan in place to care for these newborns as outpatients. the focus of the video visit is to evaluate for developing signs of infection, review home isolation precautions, and discuss routine concerns such as feeding, hydration, and jaundice. neonates are weighed on the home scale during the encounter, allowing the pediatrician to visualize the neonate's tone, color, demeanor, and respiratory status. if the pediatrician is concerned about jaundice, or if the infant was discharged with home phototherapy, arrangements are made for a laboratory technician in full ppe to obtain a serum bilirubin sample in the home. alternatively, a chinese group developed an online bilirubin follow-up program for parents, with video education for using an online app to check transcutaneous bilirubin levels [ ] . if the pediatrician is concerned that the neonate appears ill, the family is directed to the emergency department. the timing of subsequent telehealth visits is determined by the initial visit and the neonate's prior history. at days after birth, a repeat test for sars-cov- is performed, although this is not recommended by the aap. this is done to identify neonates who may be at risk of infecting others. if the day test result is negative, routine baby care is transitioned back to the community primary care provider. if readmission for a neonate born to a mother with confirmed or suspected covid- is necessary for any reason, the neonate will undergo testing for covid- , regardless of the timing of previous tests, to ensure proper use of isolation rooms and ppe. this paper reports penn state's current guidelines, based on the most up-to-date literature, about managing mothers and newborns with confirmed or suspected covid- . while covid- generally has a mild course in newborns and children, the disease continues to evolve and has caused major morbidity and mortality worldwide. although vertical transmission is unlikely, monitoring of neonates born to mothers with confirmed or suspected covid- is imperative. while many facets of care remain the same, other practices such as antenatal corticosteroids, dcc, separation and visitation, breastfeeding, airway management and respiratory support, and neonatal follow-up have been impacted by covid- . while we hope our policies and procedures may be helpful to other institutions, each center must develop and revise their guidelines to provide optimal care for patients while conserving vital ppe and ventilators and protecting healthcare workers. given the low rate of disease in newborns to date, our policies may change in the near future to allow cohabitation, direct breastfeeding, and routine newborn care for newborn puis without signs of disease. the continuing -ncov epidemic threat of novel coronaviruses to global health: the latest novel coronavirus outbreak in wuhan, china world health organization. novel coronavirus-china. world health organization genomic characterisation and epidemiology of novel coronavirus: implications for virus origins and receptor binding a novel coronavirus from patients with pneumonia in china novel coronavirus infection in hospitalized infants under year of age in china why is covid- so mild in children? acta paediatr systematic review of covid- in children show milder cases and a better prognosis than adults early transmission dynamics in wuhan, 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key: cord- - by r authors: khalifa, shaden a. m.; mohamed, briksam s.; elashal, mohamed h.; du, ming; guo, zhiming; zhao, chao; musharraf, syed ghulam; boskabady, mohammad h.; el-seedi, haged h. r.; efferth, thomas; el-seedi, hesham r. title: comprehensive overview on multiple strategies fighting covid- date: - - journal: int j environ res public health doi: . /ijerph sha: doc_id: cord_uid: by r lately, myriad of novel viruses have emerged causing epidemics such as sars, mers, and sars-cov- , leading to high mortality rates worldwide. thus, these viruses represented a challenging threat to mankind, especially considering the miniscule data available at our disposal regarding these novel viruses. the entire world established coordinative relations in research projects regarding drug and vaccine development on the external range, whereas on the internal range, all countries declared it an emergency case through imposing different restrictions related to their border control, large gatherings, school attendance, and most social activities. pandemic combating plans prioritized all sectors including normal people, medical staff politicians, and scientists collectively shouldered the burden. through planning and learning the previous lessons from sars and mers, healthcare systems could succeed in combating the viral spread and implications of these new pandemics. different management strategies including social distance, social awareness and isolation represented successful ways to slow down the spread of the pandemic. furthermore, pre-preparedness of some countries for emergencies is crucial to minimize the consequences of the crisis. . comparison between total deaths and confirmed cases in some countries with different population from jan till april [ ] . most countries were forced to announce emergency measures to protect vulnerable people and block ways of transmission due to the continuous increase in confirmed cases by time as reported in figure [ ] [ ] [ ] [ ] [ ] [ ] . with regard to this escalating situation, governments have begun to develop strategies to resolve the pandemic cooperatively with international health agencies, i.e., centers of disease control (cdc) and world health organization (who) that declared many precautions based on previous lessons from mers and sars diseases, as will be outlined in this section. our review aims to evaluate strategies of the most affected countries from different continents all over the world (china, italy, germany, france, spain, america, canada, brazil, uk, india, japan, singapore, iran, korea, and australia) for confronting the epidemic as it explains the best practices that could help other countries to overcome current or any upcoming pandemic. most countries were forced to announce emergency measures to protect vulnerable people and block ways of transmission due to the continuous increase in confirmed cases by time as reported in figure [ ] [ ] [ ] [ ] [ ] [ ] . with regard to this escalating situation, governments have begun to develop strategies to resolve the pandemic cooperatively with international health agencies, i.e., centers of disease control (cdc) and world health organization (who) that declared many precautions based on previous lessons from mers and sars diseases, as will be outlined in this section. figure . change in numbers of confirmed cases over time [ ] [ ] [ ] [ ] [ ] [ ] . the chinese lunar new year holiday, which synchronized with the outbreak of covid- , is the most celebrative time of year in china. usually, a large global migration takes place, as individuals travel back to their homes. around five million people had left wuhan [ ] . around a third of those people travelled outside the province of hubei. restricting people's social contacts was critical to covid- regulation. key elements of such social distancing initiatives included that the chinese government promoted people to stay home, dissuaded mass gathering, postponed or the chinese lunar new year holiday, which synchronized with the outbreak of covid- , is the most celebrative time of year in china. usually, a large global migration takes place, as individuals travel back to their homes. around five million people had left wuhan [ ] . around a third of those people travelled outside the province of hubei. restricting people's social contacts was critical to covid- regulation. key elements of such social distancing initiatives included that the chinese government promoted people to stay home, dissuaded mass gathering, postponed or cancelled major events, and closed universities, factories, museums, libraries, schools, and governmental offices. chinese people began to take steps to shield themselves from covid- , i.e., wearing protective masks, if they had to commute in public. social distancing has been successful in limiting human to human transmission and cutting morbidity and mortality. more stringent steps are introduced such as isolation and quarantine. the lunar new year holiday was expanded by chinese government. the holiday deadline was shifted to march for hubei province and feb for other provinces, so that the holiday duration was long enough to cover the alleged covid- incubation time. diagnosed people were segregated in hospitals. in wuhan, in which a large number of infected people resided, people with mild or asymptomatic infections were quarantined at shelters called fang cang hospitals, which were public open areas, i.e., stadiums and convention centers that had been retooled for medical treatment. the chinese government promoted and funded grassroots screening for contact tracking and early detection and encouraged hand-washing and surface sanitization. home-based quarantine of people who were at the epicenters of epidemic and travelled to other places in china to curb the spread of virus to boarder populations. the government avoided panic amongst people by providing the updated information through media. free medical care was introduced by the state to motivate patients to visit doctors as soon as possible and in good time to prevent further deterioration of the condition. the state guaranteed people's daily needs [ ] . the state with the second highest numbers of viral deaths worldwide. the government declared a state of emergency lockdown that began in northern italy and spread throughout the world. the fatality rate ( . ) was much higher than that of china ( . ). all italian regions were known as "red zones" with extreme limits imposed on every public event. italy responded to the situation with screening even for those without symptoms. italy faced a persistent shortage of health care staff. the government announced a proposal to recruit , new doctors, nurses, and health workers to meet demand. retired doctors and students who had finished their medical degree and are in the final year of specialist training, were called upon [ ] . coordinated intensive care units were equipped for covid- positive patients. continuous training for health care staff was crucial with applying dedicated protocols and full isolation [ ] . the rules initially laid down approximately one month for schools' closures and restrictions on people's right to leave homes and two weeks for the suspension of business activities. the italian government proposed an extension of lockdown steps [ ] . to curb viral transmission, air travels were banned from china and italian passengers were quarantined in china. suspected cases were moved to pre-defined hospitals where the check for sars-cov- was available and infectious disease divisions were willing to isolate confirmed cases. emergency medical system of milan metropolitan area formed covid- response team with main goal of resolving the viral pandemic without encumbering regular emergency medical system activities. the response team examined the health and clinical conditions of persons being screened to evaluate the need for hospitalization or home testing and subsequent isolation. this response team designed algorithm to identify covid- suspected cases. the algorithm is continuously modified to comply with the regional directives [ ] . in a speech about the coronavirus pandemic, german chancellor angela merkel approached the citizens directly. she explained the situation this way "it is serious. take it seriously too!". "since world war ii, there has been no other challenge to the country, where national solidarity was as important as right now", she said. the german chancellor announced stricter steps and declared standards/rules for germany. the main objective was to "reduce public life to the extent warranted". this included restriction of the bare minimum connections, maintenance of a minimum distance to the public of at least . m, permission for people to go to work, doctors, shops, and play outdoor sports individually. however, gatherings in groups or meeting were no longer permitted [ ] . france, like other nations formed their pandemic influenza plan (pip) based on the recommendations for the contagion management by who. president macron clarified that only collective national campaign can prevent the spread of infection, restrict deaths, and avoid the submergence of health service. french pip aimed to alleviate pandemic by minimizing the number of civilian casualties and preserving machinations in particular economic activities. pip included stages: the st stage was to impede the introduction of outbreak to the world, nd stage to restrict viral growth and distribution in france, rd stage to attenuate the potential outbreak to minimum and th stage was returning to normalcy. first reported cases were chinese nationals visiting france, so steps were rapidly taken to keep these cases in isolation. contact tracing was held to identify people at risk of infection. the government cancelled all sporting events and schools were also closed. authorities have repeatedly pronounced individual habits and requested protective masks for those who show signs of infections and for health workers so, public and private sectors were mustered to produce masks and disinfectants. to prevent viral transmission, france pressured the european union to close the schengen treaty zone for all non-european citizens. despite the strategy's economic impacts, france scarified the entire society to combat covid- [ ] . on march, the spanish government started the applications of safety measures, in order to flatten the curve days after the exponential rate of virus start (r < ); the day in which new cases were registered for the first time. all people were forced to stay home through announcing the lockdown. spain has adopted some measures to control spread: social distance, closure of most activities, e.g., cinemas, clubs and schools to avoid crowding [ ] . under supervision of the president of the government, pedro sánchez, who described the crisis as: "unprecedented challenge", "a global threat that recognizes no borders, colors or languages", and an "extraordinary challenge that forces us to take exceptional measures". he assured the importance of application of distance learning as much as possible to slow down viral spread. they reduced non-essential work to conserve support to different sectors including the vulnerable categories, the elderly, families with the lowest resources, and small business owners. their strategy included increasing the awareness that each person in the community has a role in combating the virus; elderly people receive intensive care and the young follow the safety measures and social distancing. everyone had to care of others and the sense of social responsibility was increased. moreover, they had a continuously announced transparent data from the beginning beside their steps to prevent infection through following the guidelines and health monitoring protocol [ ] . the director-general of the world health organization (who) announced that the covid- pandemic had triggered an international public health emergency. the united states department of health and human service secretary announced on january a u.s public health emergency, and the u.s. president legitimated a "proclamation on suspension of entry as immigrants and non-immigrants of persons that pose a risk of transmitting novel coronavirus". this regulation restricts the entrance of american citizens and those with legal permanent residents and their families, especially those who have travelled to mainland china. the centers of disease control and prevention (cdc) and other governmental agencies, as well as state and local health centers, introduced proactive steps to limit covid- propagation in the u.s. [ ] . such steps included the recognition of cases and their contacts, and the suitable care of travelers coming from china to the u.s. the correct actions were taken to ( ) slow down virus spread; ( ) prepare health care systems and encourage public willingness for pervasive transmission; and ( ) clearly define infection and directly report to public health centers in order to make decisions and improve medical safeguards involving diagnosis, therapy, and vaccines [ ] . despite the fact that these initiatives were being enforced in anticipation of the virus in the u.s., the continued widespread dissemination of the virus was devastating. usa holds a negative record in regard to the pandemic, with the highest number of infections and deaths recorded worldwide. public health and disease prevention programs in canada were refashioned around guidelines and recommendations of naylor and his group that were used before against sars and entitled "learning from sars". experience with sars affected positively canada's response to the covid- outbreak. most notably, correspondence concerning public health was greatly improved and digital media was progressed. there were some technological gaps like contrasting directives on the use of personal protective equipment but this has been mainly resolved. in airports, procurement were organized and rolling tests became faster [ ] . previous preparedness before incidence of infection was phenomenal in brazil. on january , the health surveillance secretariat together with the ministry of health activated an emergency health operation center with low alerting level, which was raised later on january when the first suspected corona virus case appeared. national contingency plan (ncp) for the covid- and guidelines; based on information received from who were announced to be applied in all states. quarantine law was imposed for protecting people. isolation and exceptional restrictions on travelling was applied even before the appearance of the first case. currently, there is a rapid growth in cases in brazil; cases and deaths were registered only one month after the first confirmed case [ ] . trials to reduce cases were implemented and huge attention was paid towards availability of intensive care units (icus), diagnostic tests and ventilators needed for patients with covid- [ ] . brazil suffered from political flounder, which constituted distraction in the middle of crisis. the government restricted the use of rt-pcr examinations to people with more severe symptoms leading to higher mortality rates. this was due to high cost of materials and shortage in qualified people and labs able to do the rt-pcr test and the needed transportation for samples to places, where tests are performed. thus, people with mild symptoms or the asymptomatic caused the transmission of infection. dense populations on favelas made it impossible to follow the social distance. moreover, illegal mining and logging in amazon forests may have brought infections to remote areas. scientific organizations, such as the brazilian academy of sciences opposed bolsonaro due to the decreased science budget, general security, and shortage of public services. currently, there is increased production of personal protective equipment, ventilators, and diagnostic kits [ , ] . the united kingdom (u.k.) government followed health's department direct recommendations for travelling abroad with respiratory infections, especially travelling to wuhan [ ] . the u.k. national health service emphasized the importance of using personal protective equipment, obtaining a detailed history of travelling, and rapidly escalating suspicious cases with a dedication to isolate patients. any confirmed cases of covid- should be moved to an airborne high impact infectious disease center such as the two major centers in england (royal free hospital in london and newcastle royal victoria infirmary). u.k. chief medical officers told individuals who had toured wuhan or hubei province over the past days to stay at home and call national health service number . such recommendations were also applied to people, who have visited japan, thailand, hong kong, singapore, taiwan, macau, and malaysia [ ] . the world's second most densely-populated country after china made the situation worse, since population density beside some other factors contributed to the wide viral transmission [ ] . poverty and money-related problems complicated combating strategies. if the government imposed social distance ( m distance), many categories opposed the actions, especially craftsmen. ignorance from indians at first increased the number of infected people [ ] . then, the government imposed a strict lockdown for days except for some services such as fire departments, police, and hospitals. diagnostic kits were increased every day and in every state. train coaches were turned to mobile wards for isolation. a phone application was launched called aarogya setu (health bridge) aiming to track people's health [ ] . check points were built at borders to check people entering the country, and all borders were shut. the ministry of health and family welfare (mohfw), india, increased awareness, took actions to control covid- and guidelines on management; prevention and sample collection were announced. also a hotline was created with a h/ days-a-week service to help people [ ] . a huge budget of about us $ . billion was endowed for health sector to combat covid- . the department of science and technology, government of india tried to promote research in university institutes and started working in various directions to control the virus during the country's lockdown. the indian council of medical research (icmr) launched private labs with suitable safety regulations to test covid- samples. icmr reported that about , tests (as of april ) were performed in india. blood plasma therapy using the plasma of recovered patients with immunity against covid- was applied to infected individuals. the indian strategies paid the most attention for medical care requirements. thus, the number of infected people is less than other countries due to exerted efforts by authorities to impose the strict lockdown. yet even after lockdown removal (fully or partially) on may , the threats amplified [ ] . on june , the ministry of health and family welfare (mohfw) announced that , confirmed covid- cases and deaths from states especially the states of maharashtra, tamil nadu, delhi, and gujarat. hence, the case-fatality rate became . % [ ] . it is not the first time for japanese people to face a national crisis, as they previously experienced two atomic bombings in , the sarin gas in , and the h n epidemic in . thus, fear and anxiety was dominating. images, headlines, rumors and confirmation of human-to-human transmission in nara prefecture played a role. anxiety-related behaviors appeared significantly in shortage of masks and sanitizers in drug stores, social rejection, discrimination against affected people [ ] . however, preparedness and learning from previous lessons was effective. japan reported low numbers of covid- -related deaths due to the following measures. to prevent infection, emergency state was declared on april and continued for a month. people were asked to stay home and stop un-essential activities. japanese customs suited for social distancing, as they exclude handshaking, hugging, or kissing in greetings [ ] . usage of long-term care areas with the most vulnerable residents was temporarily suspended. japanese people were asked to avoid crowded places with bad ventilation and conservation of physical distances according to recommendations of an expert committee [ ] . travels were restricted from and to wuhan, and japanese citizens were asked to evacuate china. subsequently, three flights transported them back home. healthy individuals were isolated, prevented to move around and kept under medical observation at designated hotels, while others with disease symptoms upon arrival in japan were admitted to hospitals [ ] . singapore, the regional travel center in southeast asia, was one of the first places to be impacted by covid- . the singapore strategies were based on back experience with sars outbreak. an important lesson was to ensure cohesive response across all sectors, consistent leadership and guidance was crucial. therefore, a multi-ministerial task force was established to provide central leadership for all government crisis management, before singapore had its first covid- incident. an intensified surveillance system was developed to monitor covid- cases between hospital and primary care pneumonia patients. to promote this system, covid- rt-pcr laboratory tests were rapidly expanded to all singapore hospitals with tests per day for . million persons. suspected and confirmed cases were isolated in hospitals immediately to avoid further transmission. contact tracing was also started to determine their past locomotion before isolation to identify potential sources of infections. more than public health preparedness clinics has been set up to facilitate the control of primary care of respiratory diseases. incoming travelers were subjected to temperature and health checks at all airports and suspicious cases sent immediately to hospitals. singapore's community approach focused on social responsibilities while precautionary life kept going as usual. social education was a key empowerment strategy and carried out through print, broadcast, and social media. workers are empowered to continuously monitoring temperature and health and organizations are motivated to step forward their business plans. schools remained opened with precautions. even though these precautions were enforced, singapore retained normality of daily life [ ] . by march , the viral spread increased, and all provinces were affected. then, by april the number of confirmed cases reached , with deaths in iran. the government prohibited many activities: sale and export of face masks to legal entities were limited, commercial movements with china were prevented, and travel was banned. cancelation of all public gatherings, including cinemas, concerts, theaters, postponement of weddings, parties, conferences, seminars, camps and collective sports, school closure, and establishing e-learning, reduced office hours for h/day [ ] . people were guided for hand-washing and wearing masks. suspected and infected people with covid- were isolated for days [ ] . poor people were severely affected by quarantine; hence, the government financially supported them. the supreme council for health and food security together with a special council for covid- confessed essential deficiencies in policies regarding food security including delays in bills such as electricity, payment of bank loans. however, reductions in oil prices and oil selling due to sanctions significantly affected the ability of governmental support [ ] . the iranian ministry of health and medical education (mohme) compiled the who guidelines for covid- prevention and announced them through different platforms. hotlines to answer questions and give advice on nutrition and mental health were available. national campaigns for increasing awareness and information were held to improve public knowledge. a website was launched (salamat.gov.ir) to help people and answer their questions [ ] . the political situation in iran impacted the economic infrastructure, which indirectly affected the health sector and the first-line defense against the virus. thus, the burden scaled up. in addition, the weakness of the medical infrastructure, inadequate personal protective equipment and difficulties in importing them are all key factors. quarantining cities was rather ineffective due to viral distribution throughout the country [ ] . korea's infection alerting system has four levels: ( ) attention to the epidemic as the government began tracking, ( ) caution if an epidemic reached the country and the government maintained a program of cooperation, ( ) activation of response system that could be alerted regarding to spread of infection, and ( ) development of a national response program, as the outbreak progressed and became serious. four days after announcement of new cases in china, korea began screening and enforced quarantine program at the airports. everyone who had visited wuhan during the past days was asked to complete health questionnaire and to have days of self-quarantine. if there was fever or respiratory ailments, they should call korea cdc. early recognition helped korea remove the community infection and limit it to medical facilities which was an integral part of outbreak response. a -h rapid test was distributed in all health centers around the country. korea cdc started recording the crisis to provide reliable data. such reports included number and history of suspected cases with public guidance for prevention. travel to china was cancelled. korea goals were accomplished through key strategies: st outbreak based on suppression and mitigation, nd risk awareness to encourage community involvement, and rd science-based and reality driven behavior [ ] . australia built its response to covid- on the basis of its powerful healthcare system. australia realized that people involved in primary care, elderly care, home care, and disability care need the same degree of support and safety as people working in hospitals in attempt to preserve both public and vital health care system to sustain the workplace of services. good, coherent contact with the primary care staff and general public was very critical for the needed steps. borders were shut down, non-essential facilities were closed, precautionary measures were in the places with infection risk, stringent social distancing were enforced together with quarantining of individuals with suspected infection or confirmed infection. the prime minister of australia stated the implementation of the novel coronavirus emergency response program for australian medical sector. the four strategic goals of the targeted plan were: protecting people from covid- effects, maintain health care functional capacity, facilitate the most appropriate treatment of people with symptoms, manage, and control personal protective equipment. the australian government introduced . billion primary care packages to safeguard all australians. primary care approach has main components: telemedicine services, online infection control training provided to all caregivers, institution of general practice-led primary healthcare respiratory clinics ( clinic) to transfer affected people away from other general practices [ ] . most governmental strategies are summarized in figure . collectively, demographic diversity, standard of living of each country's citizens, political state and health systems in addition to other factors led to various strategies being implemented across the globe trying to cope with the crisis. however, the collaboration and sharing of responsibility for controlling the pandemic through exchange of information between countries was the most important step. taken together, countries facing covid- or any other pandemic should consider control or closure periods and whether required or compulsory closure of unneeded workplaces and public entities as a first line of social distance measures can reduce transmission rate. the closure times should be adapted to the unique characteristics of the novel disease, i.e., the incubation duration and transmission routes, and the nature of these outbreaks. the main purpose of the pandemic control closure phase is to avoid the spread of disease by people with asymptomatic infections. governments should use closure times to optimize effect, promotions, group screening, active communication, monitoring, isolation, and quarantine. some countries have promoted their people's consciousness across many channels, e.g., television, newspapers, and conferences. they have been resorting to the use of more modern health and education technologies i.e., e-learning and telemedicine to reduce the urge to go outside. such a hybrid strategy is also backed up by analyses of responses to previous pandemics, which have shown that average attack rate reductions were more noticeable if social distance policies and other disease prevention steps were combined to prevent transmission. sars-cov- spreads at an astonishing speed across the globe. on january , who collectively, demographic diversity, standard of living of each country's citizens, political state and health systems in addition to other factors led to various strategies being implemented across the globe trying to cope with the crisis. however, the collaboration and sharing of responsibility for controlling the pandemic through exchange of information between countries was the most important step. taken together, countries facing covid- or any other pandemic should consider control or closure periods and whether required or compulsory closure of unneeded workplaces and public entities as a first line of social distance measures can reduce transmission rate. the closure times should be adapted to the unique characteristics of the novel disease, i.e., the incubation duration and transmission routes, and the nature of these outbreaks. the main purpose of the pandemic control closure phase is to avoid the spread of disease by people with asymptomatic infections. governments should use closure times to optimize effect, promotions, group screening, active communication, monitoring, isolation, and quarantine. some countries have promoted their people's consciousness across many channels, e.g., television, newspapers, and conferences. they have been resorting to the use of more modern health and education technologies i.e., e-learning and telemedicine to reduce the urge to go outside. such a hybrid strategy is also backed up by analyses of responses to previous pandemics, which have shown that average attack rate reductions were more noticeable if social distance policies and other disease prevention steps were combined to prevent transmission. sars-cov- spreads at an astonishing speed across the globe. on january , who announced the outbreak of covid- an international public health emergency which impacted countries (status: march ) [ ] . the speed and extent of pandemic detection, particularly early diagnosis and notification of new cases, is an important measure to monitor this infectious disease. countries that have previous experience with viral infectious diseases (most commonly sars), powerful primary care systems with helpful infrastructures, guidance rules and instructions, and community awareness with social responsibilities prove to be more effective in controlling the spread of infection and reducing its deleterious impacts. numerous countries endeavor to construct an info-structure of national digital health in order to improve disease surveillance and link public health and clinical intelligence programs. clear and open contact between governments and healthcare staff would be pivotal. it was the time for hospitals or agencies that engage in healthcare delivery to audit its protocols and consumables for all selected patients. heads of state, global health leaders, private sector partners, and other stakeholders have accelerated global partnership to speed up the production of covid- diagnostic and preventive tools. all governments should prepare the public for a second wave or another outbreak. national policy discussions about the future of the respective society should be initiated. covid- is a tragedy for us all collectively, but it is also an opportunity to ask ourselves what kind of society we want after the pandemic fades away. reproduction numbers of infectious disease models molecular mechanisms of coronavirus rna capping and methylation genomic characterisation and epidemiology of novel coronavirus: implications for virus origins and receptor binding origin and evolution of pathogenic coronaviruses the novel zoonotic covid- pandemic: an expected global health concern systematic review: national notifiable infectious disease surveillance system in china study of surveillance data for class b notifiable disease in china from to three emerging coronaviruses in two decades: the story of sars, mers, and now covid- covid- ): situation report- covid- ): situation report- covid- ): situation report- coronavirus disease (covid- ) situation report- . available online coronavirus disease (covid- ) situation report- . available online coronavirus disease (covid- ) situation report- . available online coronavirus disease (covid- ) situation report- . available online the model of epidemic (covid- ) prevention and control in rural of china covid- control in china during mass population movements at new year on the front lines of coronavirus: the italian response to covid- hospital surge capacity in a tertiary emergency referral centre during the covid- outbreak in italy compliance with covid- social-distancing measures in italy: the role of expectations and duration the response of milan's emergency medical system to the covid- outbreak in italy merkel announces strict measures and tells germans to stay home in virus fighle adaptation of the national plan for the prevention and fight against pandemic influenza to the covid- epidemic in france effectiveness of the measures to flatten the epidemic curve of covid- . the case of spain president of the government calls for political and public unity to overcome coronavirus emergencyle proclamation on suspension of entry as immigrants and nonimmigrants of persons who pose a risk of transmitting novel coronavirus initial public health response and interim clinical guidance for the novel coronavirus outbreak-united states learning from sars. lancet characterization of the covid- pandemic and the impact of uncertainties, mitigation strategies, and underreporting of cases in south korea, italy, and brazil covid- in brazil covid- - million cases worldwide and an overview of the diagnosis in brazil: a tragedy to be announced covid- ): situation report- world health organization declares global emergency: a review of the novel coronavirus (covid- ) projections for covid- pandemic in india and effect of temperature and humidity covid in india: strategies to combat from combination threat of life and livelihood investigating the dynamics of covid- pandemic in india under lockdown the rise and impact of covid- in india covid- pandemic in india: present scenario and a steep climb ahead public responses to the novel coronavirus ( -ncov) in japan: mental health consequences and target populations why does japan have so few cases of covid- ? clusters of covid- in long-term care hospitals and facilities in japan the rate of underascertainment of novel coronavirus ( -ncov) infection: estimation using japanese passengers data on evacuation flights interrupting transmission of covid- : lessons from containment efforts in singapore covid- pandemic and comparative health policy learning in iran the challenges and considerations of community-based preparedness at the onset of covid- outbreak in iran ensuring adequate health financing to prevent and control the covid- in iran ir of iran national mobilization against covid- epidemic coronavirus disease (covid- ) outbreak in iran: actions and problems lessons learned from korea: covid- pandemic crossref] . world health organization. responding to community spread of covid- : interim guidance the authors declare no conflict of interest. key: cord- -ws xprt authors: ozoner, baris; gungor, abuzer; hasanov, teyyup; toktas, zafer orcun; kilic, turker title: neurosurgery practice during coronavirus disease (covid- ) pandemic date: - - journal: world neurosurg doi: . /j.wneu. . . sha: doc_id: cord_uid: ws xprt abstract coronavirus disease (covid- ), caused by severe acute respiratory syndrome coronavirus (sars-cov- ), is a highly contagious, life-threatening condition with unprecedented impacts for worldwide societies and healthcare systems. since the first detection in china, it has spread rapidly worldwide. the increased burden has substantially impacted the neurosurgery practice and intensive modifications were required in surgical scheduling, inpatient and outpatient clinics, management of emergency cases, and even academic activities. in some systems, non-overlapping teams were created to minimize transmission among healthcare workers. in case of a massive burden, neurosurgeons may be needed to reassign to the covid- wards, or teams from other regions may be needed to send to severely affected areas. in outpatient practice, if possible, appointments should be turned into telemedicine. all staff assigned in the non-covid treatment unit should be clothed in level personal protective equipment. if possible, postponement is recommended for operations that do not require urgent or emergent intervention. all patients indicated for surgery must receive a covid- screening, including nasopharyngeal swab, and thorax computed tomography. level protection measures would be appropriate during covid- negative patients' operations. operations of covid- positive patients, and emergency cases, where screening can not be obtained, should be performed following level protective measures. during surgery, the use of high-speed drills and electrocautery should be reduced to minimize aerosol production. screening is crucial in all patients since the surgical outcome is highly mortal in covid- patients. all educational and academic conferences can be turned into virtual webinars. coronavirus disease (covid- ) is an exceedingly infectious, life-threatening condition and its outbreak is now constituting unprecedented extraordinary threats and difficulties for worldwide societies and healthcare systems. [ ] [ ] [ ] since the first detection in china in late december , it has spread rapidly to countries around the globe and reached approximately . . confirmed cases with more than . deaths on april , . the increased burden of this pandemic disease has substantially impacted the entire health system, including the neurosurgery practice in most countries. [ ] [ ] [ ] in neurosurgery practice, intensive modifications were required in surgical scheduling, administration of inpatient and outpatient clinics, management of emergency cases, and even academic & educational activities. the major goal of this review is to compose a comprehensive guide using existing guides and recommendations for reorganizing daily practice and the academic routine of neurosurgery during the covid- pandemic. this study also aimed to refine the substantial information for neurosurgery practice about this pandemic disease. an outbreak of pneumonia of unknown origin showed up in wuhan city, the capital of hubei province in people's republic of china, in late december . , on january , china isolated a new coronavirus formerly called novel coronavirus ( -ncov) and presented virus genome data to the international society. later, coincidentally, on february , the coronavirus study group of the international committee on taxonomy of viruses gave a new name to the virus "severe acute respiratory syndrome coronavirus " (sars-cov- ) and the world health organization designed a name for epidemic disease "coronavirus disease " . virology sars-cov- , a positive-sense single-stranded rna virus, a member of the subgenus betacoronaviruses, is the seventh determined coronavirus that infects humans. , , the genetic sequence of the sars-cov- presents approximately % analogy to sars-cov. sars-cov- comprises four structural proteins: n (nucleocapsid), e (envelope), m (membrane), and s (spike) proteins ( figure ). the n protein supports the rna genome, and e, m, and s proteins compose the viral envelope. the s protein also is responsible for binding to the angiotensin-converting enzyme receptor on the human cell membrane. the median incubation period is approximately days and practically all cases experience symptoms in days after exposure to sars-cov- . transmission occurs mainly through direct contact with the infected material or via droplets spread by sneezing or coughing. sars-cov- primarily targets the respiratory system. the main clinical symptoms of covid- are fever, cough, myalgia or fatigue, expectoration, and dyspnea. , minor symptoms include headache or dizziness, diarrhea, and nausea & vomiting. , dyspnea may be observed in critical patients and may proceed to severe acute respiratory syndrome, sepsis, and multiple organ dysfunction syndrome. reduced total leukocyte and lymphocyte counts, increased c-reactive protein and lactate dehydrogenase are common results in the laboratory tests. , the typical appearance is bilateral, subpleural, ground-glass opacities with air bronchograms on thorax computed tomography (ct). the viral load is elevated throughout the upper respiratory tract mucosa, including the nasal cavity, and naso-oropharynx. the viral ribonucleic acid (rna) can be identified in the sputum, saliva, as well as in the serum. the blood-brain barrier works as a natural barrier against pathogenic microorganisms and reduces the risk of intracranial infection. some human coronaviruses can invade the central nervous system (cns) through hematogenous or neuronal retrograde dissemination, leading to encephalitis and exacerbation of existing neurologic diseases. the brainstem involvement of sars cov has been described in both clinic and experimental studies. [ ] [ ] [ ] given the high analogy between sars cov and sars cov- , it clarifies that the cns spread of sars cov- may be partly responsible for acute respiratory failure in covid disease. a recent study from wuhan city, china reported that some severe covid- patients developed neurologic manifestations, such as acute cerebrovascular diseases ( . %), and impaired consciousness ( . %). cerebrovascular accidents may occur due to a systemic highly prothrombotic state of covid- . furthermore, sars-cov- was isolated in cerebrospinal fluid (csf) by gene sequencing from a covid- patient in beijing ditan hospital, china on march . since results of encephalitis are highly mortal, early diagnosis is essential. severely affected and comatose patients with neurologic symptoms should undergo brain imaging and csf examination. magnetic resonance imaging (mri) would yield the definitive marks about the presence of infectious intracranial processes. the regional hyperintense abnormalities on t weighted(w), t -w, flair, and diffusion-weighted images are considered suspicious for viral encephalitis. in case of suspected cns infections, lumbar puncture is indicated. the obtained csf can be investigated to detect viral genetic material through a polymerase chain reaction (pcr) examination or using antibody testing. viral encephalitis may also be presented with neurologic deterioration related to massive cerebral edema. , in case of conservative management (corticosteroids, hyperventilation, hypertonics, hypothermia, and barbiturate coma) fails, decompressive craniectomy can be considered an option for the last chance therapy in selected cases. , faculty planning the regional disease burden surges during the pandemic and the disease also shows a significant transmission to healthcare professionals. in the algorithm proposed by the university of california san francisco (ucsf), surgical scheduling is organized according to the ''surge level'' that correlates with the rising viral transmission between local community. using this system, the green, yellow, red, and black levels represent the lowest, moderate, high and highest levels of the surge, respectively. in the green level (< covid- + inpatients, and no staffing shortages), all elective operations proceed as scheduled. in the yellow level ( - covid- + inpatients, or < % staffing shortages), the schedule is rearranged as yielding a % reduction in the capacity of all elective procedures and all outpatient procedures is designated to an off-site (covid- free) hospital. in the red level (> covid- + inpatients, or > % staffing shortages), a % reduction is done in elective scheduling. finally, at the black level, in which significant assistance required from outside institutions to resist the outbreak, only emergent surgical cases will be performed. ucsf recommends a system, based on the "paired coverage model", designed to minimize patient and provider viral exposure while providing continuous inpatient coverage for neurosurgical emergencies. in this model, each department is covered by nonoverlapping teams (rotating in d cycles: d on, d off), in which members will have contact only within the same team. this model is activated by a red level of surge and includes an assigned alternate pool of providers to replace who show covid- prodrome. in case of a massive increase in covid- cases, non-specialized physicians in respiratory or infectious diseases, including neurosurgeons, may need to be reassigned to the covid- wards to initiate supplementary emergency responses. remodeling the hospital system by identifying concentration centers for neurosurgical activities would be necessary for managing emergent and urgent cases. an instance of this circumstance is present in lombardy, northern italy. lombardy health system was rearranged as a ''spoke-and-hub system''. [ ] [ ] [ ] [ ] the local neurosurgical network was assembled in hub hospitals ( for cranial or spinal emergencies, and one for oncological emergencies ). all the other neurosurgery departments have converted the spokes. in this way, hub hospitals are available to manage neurosurgical emergencies, whereas spoke hospitals concentrate on covid- patients. [ ] [ ] [ ] [ ] in this system, a huge increase may be expected in the number of patients treated in hub hospitals. according to an early report from the university of insubria, italy, there was an increase of % and %, respectively, of hospitalized and surgically treated neurosurgical emergencies. healthcare professionals from other areas may need to be sent to regions that are heavily affected by pandemics. during the outbreak, more than , medical staff including teams from other regions of china have been dispatched to hubei province, of which teams are comprised of neurosurgeons. owing to the newly appointed teams, emergency operations could be performed even during worst times of the epidemic peak. robertson et al. suggested a ''task shifting and task sharing'' method that involves training, practice, and maintenance phases for increasing workforce capacity during the pandemic. according to this method, the most experienced neurosurgeons who are also from the most vulnerable age groups may practice on telemedicine encounters, guiding ethical decisions on appropriate neurosurgical interventions, or neurosurgery-specific cases. and, residents skilled in neurocritical care may receive intensive skills training in endotracheal intubation and mechanical ventilator management. , residents may serve remotely when possible to perform virtual visits, record notes, give orders, and call consults. according to the physicians' preference, patient follow-up and appointments should be turned into telemedicine, if possible. , besides, remote examinations are reported that they are often applicable. according to the harvard medical school experience, more than % of the outpatient visits have been able to be switched to telemedicine. also, in a validation study by neumarkt clinic, germany, remote neurological examination consisting of items performed via audio-visual telemedicine presented comparable results to bedside examination. on occasions, the assist of a person may be required for the patient to perform some parts of the examination, such as the laségue test for the spinal examination. the transmission of patients' radiological images to the outpatient team via a data transfer method before telemedicine appointment would be beneficial. actual visits should be preserved for selected patients, such as patients requiring wound control and stitch removal. also, the use of absorbable sutures in neurosurgical surgeries could be considered to decrease the contacts among clinicians and patients after discharge. besides, patients aged > years should be encouraged to shun visiting the out-patient clinic. the out-patient facilities and personnel should be separated in non-covid and covid treatment units during the pandemic. the work schedule should be organized with as minimal staff as possible using the proper protective equipment. physicians and staff assigned in out-patient facilities should be clothed in level personal protective equipment (ppe) during their practice. ppe according to handbook of covid- prevention and treatment is presented in table . accompanies for pediatric or non-ambulatory patients should be reduced to one person. and, ambulatory individuals should visit the outpatient clinics alone. the ''lockdown'' and the ''stay at home'' strategies during pandemic dramatically reduced the spinal and cranial traumas allowing the medical professionals to focus on covid- patients. , also a reduction in surgical treatments for degenerative pathologies is present. the drop of traumatic events can be explained by the reduced traffic and work activities. two potential reasons have been argued by dobran et al. for the demand decrease in surgical treatment for spinal degenerative pathologies: ( ) the prevalent fear in the community that regarding hospitals as a risky place for a possible infection; and ( ) the patients' overrating their impairments and pains that resulting in surgical overtreatment. a global study, which conducted on the impact of covid- on neurosurgeons and generated an acuity index for the triaging strategy for non-emergent operations, surveyed respondents from countries. % of respondents reported that all elective cases canceled and their clinics closed down. % of respondents reported that their operative density reduced more than %, and this rate was % in the most affected countries. if possible, medical care methods requiring less invasive interventions such as endovascular treatment in neurovascular conditions, and radiosurgery in certain neuro-oncological diseases may be considered. endotracheal intubation or high-speed drill use is not required during stereotactic radiosurgery, which reduces the risk of exposure to aerosols compared to open surgeries. the summary of measures during the covid- pandemic is presented in table . healthcare personnel including operation room staff are at high-level risk of exposure to the sars-cov- . up to % of the confirmed cases were healthcare staff in the initial cohort reports. later, according to the report of the chinese center for disease control and prevention, which included more than , cases, . % of the confirmed cases were medical staff, and . % of them were in critical or severe condition. minimal or no symptoms are observed during the incubation period (first - days) in the majority of the cases. still, these asymptomatic patients are able to spread the virus. so, all patients indicated for surgery must receive a covid- screening, including measuring body temperature, symptoms investigation, sars-cov- pcr and antibody test, nasopharyngeal swab, and thorax ct scan. different recommendations are present for covid negative patients for the protection of medical staff in the operating theatre. according to a surgical neuro-oncology team perspective, patients from low-risk areas who are verified covid- negative can be operated following level precautions. other perspectives from tongji medical college, wuhan, china and heinrich-heine university, düsseldorf, germany recommended that medical staff should take level protection measures due to the long incubation period. , for patients who are suspected or confirmed covid- positive, or patients from a high-risk area, the operations should be performed under level precautions. , in emergency cases, the results of sars-cov- tests may not be obtained before the surgery, therefore the surgery should be performed following strict measures (level protective measures) to reduce potential exposure. the route from the ward to the operation room, including the elevators, should be cleared during the transfer of a covid (+) patient. the transfer should be performed by the covid- ward nurses in full personal protective equipment (ppe ). the operation room of covid- (+) patients should be separated. an operation room with negative atmospheric pressure setting, and with independent access should be designated for all confirmed or suspected covid- (+) cases. , during the pandemic, the same operating room, and the same continuous flow anesthetic machine should be used for only covid- (+) patients. since the endotracheal intubation can generate aerosols, the intubation should be performed via the method with the maximum possibility of first-time success using a video-laryngoscope to avoid multiple attempts. during the operation of confirmed or suspected covid- patients, all operating room staff must wear level ppe under a surgical gown to prevent contamination. ppe is obligatory for all interventions involving close contacts, such as surgery, endotracheal intubation, intravenous cannulation, cardiac catheterization, and regional anesthesia. using powered air-purifying respirators (papr) by the surgical team is recommended. all personnel should be trained about wearing and removing ppe to prevent contamination. after extubation, it is recommended that the patient is worn a surgical mask as soon as possible. the viral exposure load of the operating room staff can be considered to be proportional to the duration of the surgery. during the pandemic period, the staff number in the operating theatre must be reduced to the absolute minimum. also, all neurosurgical procedures ought to be designed to reduce the operating theater time. if possible, only a single experienced neurosurgeon beyond her/his learning curve ought to carry out the procedure to reduce operation time and to prevent exposure of other physicians. powered instruments such as the high-speed drills, which are commonly used tools for cranial and spinal procedures, had been demonstrated to produce blood-containing aerosols with the identification of hemoglobin in the ambient air. and viruses, such as human immunodeficiency virus- , was showed to be survival in the aerosols produced by surgical power instruments. since the coronaviral rna can be determined in plasma or lymphocytes of confirmed or asymptomatic patients, so these aerosols produced during neurosurgical operations can be contagious. also, a recent study used the bayesian regression model (a statistical model uses probability to represent all uncertainty within the model) indicated that aerosol transmission of sars-cov- is plausible. so, attention should be paid to minimize aerosol generation in operations performed during the pandemic period. upholding the increase of using traditional hand drills and rongeurs would be beneficial. more meticulous irrigation and reduction of drill speed are some precautions that should be taken if cranial or spinal drilling is necessary. special caution should be taken during anterior skull base surgeries, to avoid breach frontal or ethmoidal sinuses. the use of electrocautery creates a gaseous by-product containing aerosol commonly referred to as ''surgical smoke''. viral transmission of human papillomavirus from patients to treating physicians through surgical smoke has been demonstrated. , due to potential transmission risk, using time of monopolar and bipolar electrocautery should be reduced and their power settings ought to be minimized to decrease aerosol dispersal during the pandemic period. endonasal procedures, using debriders and drills inside the nasal cavity, generate highly hazardous aerosols. otolaryngologists are among the worst affected medical professionals in wuhan city, china, and even n / (filtering face piece) ffp masks did not prevent transmission. , also, a patient with a mass lesion in the sellar region that underwent endonasal endoscopic surgery in neurosurgery department, tongji medical college, wuhan city, china was diagnosed with covid- after surgery, and disease was confirmed in healthcare professionals in the same clinic afterwards. according to an initial perspective from the society of british neurological surgeons, endonasal transsphenoidal endoscopic surgical approaches should be avoided during the pandemic period. alternatives routes to endoscopic surgery should be considered for patients whose surgery can not be postponed: ( ) craniotomy; and ( ) microscopic endonasal transsphenoidal surgery, with the submucosal approach and non-drill techniques used during the endonasal and sellar phase. another recent perspective from singapore suggests that endonasal procedures should be managed according to the covid- test results. they suggested wearing n / ffp mask, eye protection (goggles and full-face shield), and standard personal level equipment (gown and gloves) in patients whose test results are negative. and in patients with positive test results, they recommended doning an additional papr by the entire surgical and anesthesia team, including the circulating nurse and operating room attendant. they also recommended using rongeurs and chisels instead of power instruments during surgical exposure, and avoiding the use of nasal pledgets, whose removal may stimulate gagging or coughing in the postoperative phase. also, gowns, n / ffp masks, and face shelters are recommended to use during all outpatient nasal endoscopies. since the disease is asymptomatic in some patients, covid- screening is crucial in all patients before the operation. because, in addition to protecting healthcare professionals, high mortality risk is present in covid- patients who have undergone surgical intervention. university of brescia, italy was reported that the mortality rate of chronic subdural hematoma was % in covid- (+) patients. this rate was reported as . % in the control group treated before the pandemic. a meta-analysis including nearly covid- patients revealed that lower platelet count was associated with severe covid- . the thrombocytopenia can lead to re-bleeding that resulting in a poor outcome. also, in subclinical covid- patients, surgical intervention could impair the immune system, leading to the emergence of the covid- disease. , interstitial pneumonia progression after the surgical intervention may worsen the outcome. the conservative strategy should be preferred whenever operation could be postponed. this situation may be different for the baby and children population. the general observation is that newborns, infants, and children are relatively resistant to covid- . a case report from milan, italy presented that an -month-old infant with complex hydrocephalus underwent two consequent shunt revision interventions while his nasopharyngeal swab was positive for sars-cov- . the baby, who underwent two operations under general anesthesia without respiratory complications, showed a favorable neurological course. web-based conferencing systems have emerged and reached primacy. , all in-person conferences such as resident education lectures, multidisciplinary board meetings, and weekly morbidity & mortality conferences should be converted to video teleconferences with an individual person participating in the conference from one site. , , many elements of medical students' lectures may be converted into virtual webinars. involving of neurosurgery-willing students in department educational video teleconferences would intensify student learning and provide accessibility of the department to students. our country, turkey, is among the most-affected countries by the pandemic. in our country, the pandemic burden is being managed by in collaboration of state and private health institutions. a substantial or all part of the many hospitals were modified to covid- wards. when necessary, some of the operation rooms were used as intensive care units. during the pandemic period, most of the neurosurgeons attended in the front lines. the urgent and emergent surgeries were performed and the schedule for elective procedures was postponed. in india, one of the most affected countries in asia, a consensus was suggested for neuro-interventional teams to switch coverage model including days on work and days of self-isolation cycles. in this consensus statement, the categorization of the patients based on priority and postponing non-essential elective surgeries and outpatient visits are advocated. in an experience report from iran, one of the most-affected countries, it was reported that out-patient clinics were shut down, elective surgeries were canceled, and postponed, neurosurgery residents were reassigned in covid- wards. according to the iran university of medical sciences and health services experience, a significant decrease ( %) was noticed in elective and emergency neurological surgeries. an experience report from germany declared that spine cases fell . % below baseline ( ) levels. with the increasing burden of covid- pandemic worldwide, the need for various modifications in neurosurgery practice will proceed. during the pandemic period, strict measures are essential for both medical staff safety and patient care. in this paper, we outline substantial information and recommendations for the daily outpatient and inpatient practice, severe acute respiratory syndrome coronavirus (sars-cov- ) and 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spinal pathology via telemedicine during the covid- pandemic: early experience and unique challenges letter : the use of absorbable sutures in neurosurgical procedures in the time of covid- handbook of covid- prevention and treatment letter to the editor by dobran mauro, paracino riccardo, and iacoangeli maurizio regarding "neurosurgery during the covid- pandemic: update from lombardy, northern italy our darkest hours (being neurosurgeons during the covid- war) the impact of covid- on neurosurgeons and the strategy for triaging non-emergent operations: a global neurosurgery study the management of emergency spinal surgery during the covid- pandemic in italy safety instructions for neurosurgeons during covid- pandemic based on recent knowledge and experience letter: covid- pandemic: safety precautions for stereotactic radiosurgery clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china characteristics of and important lessons from the 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the covid- pandemic: the singapore perspective letter: precautions for endoscopic transnasal skull base surgery during the covid- letter : covid- infection affects surgical outcome of chronic subdural hematoma thrombocytopenia is associated with severe coronavirus disease (covid- ) infections: a meta-analysis the perioperative immune response does major surgery induce immune suppression and increase the risk of postoperative infection? clinical characteristics of novel coronavirus disease (covid- ) in newborns, infants and children correspondence neurosurgery in an infant with covid- editorial. covid- and academic neurosurgery academic neurosurgery department response to covid- pandemic: the university ofmiami/jackson memorial hospital letter : maintaining neurosurgical resident education and safety during the covid- letter : covid- impact on the medical student path to neurosurgery neurosurgery and neurology practices during the novel covid- pandemic: a consensus statement from india the authors would like to thank to mrs. senay guner ozoner for her illustrative figure work. all authors certify that they have no affiliations with or involvement in any organization or entity withany financial or non-financial interest in the subject matter or materials discussed in this manuscript key: cord- - se oz authors: gosain, rohit; abdou, yara; singh, abhay; rana, navpreet; puzanov, igor; ernstoff, marc s. title: covid- and cancer: a comprehensive review date: - - journal: curr oncol rep doi: . /s - - - sha: doc_id: cord_uid: se oz purpose of review: the outbreak of the novel coronavirus disease (covid- ) has emerged to be the biggest global health threat worldwide, which has now infected over . million people and claimed more than , lives around the world. under these unprecedented circumstances, there are no well-established guidelines for cancer patients. recent findings: the risk for serious disease and death in covid- cases increases with advancing age and presence of comorbid health conditions. since the emergence of the first case in wuhan, china, in december , tremendous research efforts have been underway to understand the mechanisms of infectivity and transmissibility of severe acute respiratory syndrome coronavirus- (sars-cov- ), a fatal virus responsible for abysmal survival outcomes. to minimize the mortality rate, it becomes prudent to identify symptoms promptly and employ treatments appropriately. even though no cure has been established, multiple clinical trials are underway to determine the most optimal strategy. managing cancer patients under these circumstances is rather challenging, given their vulnerable status and the aggressive nature of their underlying disease. summary: in this comprehensive review, we discuss the impact of covid- on health and the immune system of those affected, reviewing the latest treatment approaches and ongoing clinical trials. additionally, we discuss challenges faced while treating cancer patients and propose potential approaches to manage this vulnerable population during this pandemic. severe acute respiratory syndrome coronavirus- (sars-cov- ) marks the emergence of the third large-scale epidemic related to the coronavirus, after sars-cov in and middle-east respiratory syndrome coronavirus (mers-cov) in . coronavirus disease (covid- ) was first reported in wuhan, china, in december , among a group of individuals presenting with pneumonia of unknown etiology [ , ] . based on the sequencing and evolutionary data, bats are the proposed reservoir for the coronavirus [ , ] . after its initial discovery, the spread of sars-cov- worldwide was rapid, with over . million confirmed cases globally and more than , deaths as of april [ ] . the severity of this disease can range from asymptomatic disease to acute respiratory distress syndrome (ards) requiring aggressive measures to death [ , ] . current management strategies involve supportive treatment and protective measures to prevent further transmission of the virus [ , ] . though no potential cure has been reported, several trials are underway to determine the most appropriate treatment regimen. providing care to immunocompromised patients and those suffering from cancer, amidst this pandemic, has been extremely challenging. data from china thus far have shown that cancer patients infected with covid- are at . times the risk of requiring mechanical ventilation or icu admission, compared to the general population [ •] . additionally, the limitation of resources in outpatient settings, including administrative staff and specialists, has hindered the routine care of these patients [ •] . this review aims to evaluate current literature on the diagnosis and management of covid- patients, rohit gosain and yara abdou contributed equally to this work. and discuss approaches to managing cancer patients in this pandemic. coronaviruses (covs) were first identified by tyrell and bynoe in , in patients with viral-like upper respiratory illness [ ] . covs are enveloped, positive single-stranded rna viruses that can infect both humans and animals. their spherical morphology with core shell and glycoprotein projections from their envelope, as seen under an electron microscopy, makes them appear "crown-like," hence termed coronaviruses [ ] . some human covs can cause selflimiting upper respiratory infections in immunocompromised individuals, whereas other covs of beta-covs subgroup, such as sars-cov, sars-cov- (covid- ) , and mers-cov, can result in epidemics with increased mortality [ ] . the fatality rate for infected cancer patients in china is . % [ • ], compared to a . % fatality rate for all covid- patients [ ] . ace is the common binding site for both the sars-cov of the - sars epidemic and, reportedly, also for the sars-cov- strain underlying the current covid- epidemic [ ] . sars-cov- interaction with the renin-angiotensin-aldosterone system (raas) through angiotensin-converting enzyme- (ace ) is a key factor for infectivity [ ] . ace physiologically counters raas activation and also serves as a receptor for sars-cov- [ ] . ace is expressed broadly in numerous tissues; however, lung alveolar epithelial cells are considered the primary targets [ ] . once cov- gains entry into the target cell, the host response is a major determinant of severity of the ensuing pathogenesis ( fig. ) [ ] . the bronchial mucosa is lined by mucosal associated invariant t (mait) cells and γδ t cells [ ] . these innate-like lymphocytes respond rapidly to pathogen invasion and trigger a cytokine response essential for microbial killing [ ] . the critical role of the host immune system in patients with severe covid- infection is highlighted by the characteristics of patients who have died [ ] . clinical outcomes are dependent upon factors such as age, ace expression, and comorbidities. thus, cancer patients by virtue of being older (median age of a cancer diagnosis is years in the usa) [ ] and having higher ace expression (ace tends to increase with increasing age) [ ] and more comorbidities [ ] are at a higher risk of adverse outcomes when infected with sars-cov- . figure highlights the case-fatality rate by age group in the general population diagnosed with covid- in china along with possible roles of mentioned factors. after the initial innate response, a specific adaptive immune response is required to eliminate cov- [ ] . however, in cancer patients on active treatment or even during watchful observation, lymphopenia (an independent poor prognostic indicator in covid- patients) [ ] is common [ ] , and hence, the required immune response is impaired. persistent cytokine release (likely mediated by leukocytes other than t lymphocytes) [ ] may then lead to "cytokine storm" and cause significant lung damage. in addition to this damage, subpar specific immune response allows viral propagation, destruction of tissues, and progression to severe stages especially in ace -rich tissues, e.g., lung, intestine, and kidneys [ ] . therefore, strategies that augment immune response at this stage, e.g., immunoadjuvant therapies (ifnα or convalescent plasma) [ •, ] , block cytokines (il- , il- , or tumor necrosis factor alpha, tnfα) or early institution of antiviral agents may prove beneficial. less immunocompromised and nonlymphopenic cancer patients may mount an adequate response, with cytotoxic t lymphocytes (ctls) and natural killer (nk) cells being crucial for the control of viral infection. persistent adaptive immune activation leading to lymphocyte exhaustion is well described in cases of chronic infections, tumorigenesis [ ] , and reportedly, even with sars-cov- infection [ ] . functional exhaustion of ctls and nk cells is now reported with cov- infection with significantly higher levels of exhaustion markers, e.g., programmed death- (pd- ), as compared to healthy controls [ , ] . functional exhaustion of ctls correlates to [ ] and likely results in viral disease progression and rapid decompensation [ ] . reports of successful use of anti-pd- drugs to reinvigorate exhausted t cells by blocking pd- in cases of viral, bacterial, and fungal infections are becoming common [ ] . foreseeably, clinical trials to study the use of anti-pd agent against covid- are underway (table ) . tremendous efforts are underway for vaccine development targeting cov- [ ] . however, virus eliminating immune response may be difficult to illicit in immunocompromised cancer patients. vaccine effectiveness in general tends to be lower in patients with cancer, much lower for those with hematologic malignancies [ ] . utilization of long-term immune memory from convalescent individuals may provide alternate strategies for patients with hematological malignancies. the most common clinical symptoms of covid- range from fever, cough, dyspnea, fatigue, and in rare cases diarrhea and vomiting [ ] . based on current evidence, cancer patients also present with similar symptoms, though are at much higher risk of serious outcomes resulting in death when compared to the general population [ •, •, •]. emerging data highlighting concerns of coagulopathy in covid- patients is becoming available, but it is too early to infer if these are more or less common in cancer patients [ ] . some of the common laboratory findings seen in covid- patients are cytopenias, specifically lymphocytopenia, along with elevation in lactate dehydrogenase (ldh) [ , ] . covid- patients should additionally be screened for secondary hemophagocytic lymphohistiocytosis (shlh) via hscore [ ] . this is an often under-recognized hyperinflammatory syndrome characterized by a severe cytokine storm often with multiorgan failure. this is to identify the subgroup of patients who may benefit from immunomodulatory treatment. given general upper respiratory infection symptoms, diagnosis of covid- often entails ruling out other common respiratory viral infection (rvi) etiologies. nasopharyngeal swab is usually a collection method employed to obtain specimen for testing via polymerase chain reaction (pcr). increasing frequency of false negatives is being reported; as a result, hospitals are either repeating the test or treating patients empirically, if one presents with classical symptoms of fever, fatigue, and dyspnea of unknown etiology [ ] . remdesivir is a nucleotide analog that inhibits viral rna polymerases and has shown activity against sars-cov- in vitro [ ] . in a cohort of patients hospitalized for severe covid- who were treated with compassionate-use remdesivir, clinical improvement was seen in ( %) patients [ ] . this suggests that remdesivir may have clinical benefit in patients with severe disease, although the lack of a control group precludes definitive conclusions. a randomized controlled trial (rct) is currently underway (nct ). lopinavir-ritonavir (kaletra) is a human immunodeficiency virus (hiv) medication that has shown inhibitory activity against sars-cov in vitro. lotus-a rct in china showed no benefit with lopinavir-ritonavir treatment compared to standard care among patients with severe covid- [ ] . trials with drug combinations to enhance the antiviral effects of this drug are underway (nct , nct ). hydroxychloroquine sulfate and chloroquine phosphate, historically, anti-malaria drugs, have been shown to be safe and efficacious against covid- in clinical trials conducted in china [ , ] and france [ ] . the data from france showed a synergistic effect of azithromycin with hydroxychloroquine [ ] . however, evidence of efficacy is limited given there are only few small human trials with methodological limitations [ ] . additionally, there is limited safety data available for the use of these drugs in the context of covid- , especially in the setting of liver and renal impairment, which may increase the risk of toxicity from these agents [ ] . therefore, at present time, there is insufficient evidence to support the routine use of these drugs outside the context of a clinical trial. several studies have indicated a "cytokine storm syndrome" in patients with severe covid- , with the release of interleukin il- , il- , il- , and il- ; tnfα); granulocytemacrophage colony stimulating factor (gm-csf); ifnγ; and other inflammatory mediators [ ] . immunomodulators decrease the pulmonary inflammatory response, thereby improving the alveolar-capillary gas exchange (which tends be impaired due to cytokine-mediated hyperinflammation), and thus, can improve oxygenation and survival. il- and il- inhibitors may ameliorate severe damage to lung tissue caused by cytokine release in patients with serious covid- infections [ , ] . one clinical trial using tocilizumab, an il- inhibitor, reported improvement in clinical outcomes in patients with severe covid- [ ] . several interleukin inhibitors are being investigated, including a phase iii rct, covacta (nct ), to evaluate the efficacy of tocilizumab in severe covid- patients, and another double-blind, adaptive phase ii/iii rct (nct ) to evaluate the safety and efficacy of sarilumab (il- inhibitor) has almost completed accrual. acalabrutinib (calquence) is a next-generation, highly selective bruton tyrosine kinase inhibitor (btki) used to treat mantle cell lymphoma and cll, now being tested for use in covid- patients. the bruton's tyrosine kinase pathway has a role in the production of inflammatory cytokines [ ] , and early clinical findings showed that acalabrutinib may ameliorate the severity of respiratory distress caused by covid- infection through inflammation control. the calavi trial will be initiated as a randomized global clinical trial to assess the potential of acalabrutinib in the treatment of the cytokine storm associated with severely ill covid- patients [ ] . additionally, other trials are being considered with different btki, specifically ibrutinib, to reduce the inflammatory response [ ] . baricitinib, fedratinib, and ruxolitinib are selective janusassociated kinase (jak)-stat inhibitors that could potentially have anti-inflammatory effects in covid- patients with elevated cytokine levels [ ] . baricitinib is a jak inhibitor as well as an aak (ap -associated protein kinase ) inhibitor that can interrupt the entry of the virus into cells in addition to an anti-inflammatory effect [ ] . several clinical trials are ongoing to confirm the efficacy of these agents. gm-csf is a pro-inflammatory cytokine found to be elevated in the serum of covid- patients. there is evidence that gm-csf enhances the expression of pro-inflammatory cytokines in addition to promoting the differentiation of th cells and polarization of macrophages to m -like phenotype, resulting in pulmonary immunopathology and detrimental clinical manifestations in covid- patients [ ] . therefore, targeting gm-csf seems to be a promising strategy in ameliorating lung damage while allowing time for the virus to clear. mesenchymal stem cells (mscs) exert anti-inflammatory effects and promote endogenous repair of alveolar epithelium [ ] . a recent pilot study in seven covid- patients who received donor msc in china showed that the intervention was safe and may improve patient outcomes [ ] . the fda has approved msc treatments for use in critically ill covid- patients under the expanded access compassionate use. there is still controversy about the efficacy of glucocorticoids in treating covid- -associated pneumonia. the rationale is that steroids prolong the viral shedding time and maintain a systemic anti-inflammatory state that will minimize the precipitation of ards, dyspnea, and severe pneumonia. however, steroid therapy did not improve clinical outcomes for patients with sars or mers [ , ] . a small observational study (n = ) done in wuhu, china, showed no association between corticosteroids and outcomes in patients with mild disease [ ] . another study conducted in wuhan, china (n = ), showed that methylprednisolone decreased the risk of death from covid- -associated ards (hr . ; % ci . - . ) [ ] . multiple prospective rcts to explore the effectiveness and safety of glucocorticoids in the treatment of novel coronavirus pneumonia are ongoing. convalescent plasma originates from patients who have previously recovered from the viral infection and are now able to donate their anti-sars-cov- immunoglobulin-containing blood. once transfused into the patient, the antibodies from the convalescent plasma are thought to neutralize the virus and limit its replication. this treatment has been used to treat prior sars-cov. an exploratory meta-analysis of studies showed evidence of reduced mortality after receiving various doses of convalescent plasma in patients with severe acute respiratory infections of viral etiology [ ] . recent experience and data from china showed that human convalescent plasma is a potential therapeutic option to lessen the severity and/or shorten the length of illness caused by covid- [ ] . the true clinical effect of this intervention is being verified through several ongoing rcts. in addition, the fda is supporting a national expanded treatment protocol to provide convalescent plasma to covid- patients across the country, with the help from the red cross to identify prospective donors and manage the distribution of these products to hospitals. ace has been identified as the functional receptor for sars-cov invasion into the human body [ ] . this led to concerns about the use of raas inhibitors in covid- patients; however, published data in humans is inadequate to support or refute this concern [ ] . vaduganathan et al. proposed an alternative hypothesis that ace may be beneficial rather than harmful in patients with lung injury from sars-cov [ ] . clinical trials using raas modulators including losartan are currently underway (nct , nct , nct ). extracorporeal membrane oxygenation (ecmo) can be a life-saving intervention for covid- patients with refractory respiratory failure in the setting of ards. while this intervention has been used successfully in some patients [ , ] , concerns were raised about the potential harms of ecmo therapy including elevation in il- levels and decrease in the number of functioning lymphocytes [ ] . as a result, the immunological status needs to be considered when selecting patients for ecmo, especially in cancer patients who are on treatments that often result in lymphopenia. ards with concomitant dic was observed in % of those who die of covid- [ ] . there is evidence that fibrin deposition in the pulmonary microvasculature is a contributing factor for ards and fibrinolytic therapy was shown to improve survival in ards patients. three case reports of intravenous administration of tissue plasminogen activator (tpa) in critically ill, mechanically ventilated covid- patients show an improvement in their pao /fio ratio from to % [ ] . formal studies are planned to determine the efficacy of this agent [ ] . prior evidence has shown that low molecular weight heparin (lmwh) has anti-inflammatory properties and reduces the biological activity and levels of il- [ ] . a retrospective study looked at patients with severe covid- , of whom patients received heparin (mainly lmwh). results show that the heparinized group had lower mortality among patients who had an elevated sepsis-induced coagulopathy score and d-dimer [ ] . a smaller retrospective study looked at patients with covid- and analyzed the efficacy of lmwh in slowing their inflammatory response [ ] . the patients who received lmwh during hospitalization had significantly lower levels of il- , higher lymphocyte levels, and less coagulopathy compared to the patients who did not receive lmwh. no difference was seen in the duration of hospitalization between both groups. this data is promising; however, prospective studies are needed prior to its use in clinical practice. chinese medicine has played a key role in the treatment of several prior epidemic diseases including covid- pandemic [ ] . qingfei paidu decoction (qpd), for example, was used to treat cases with covid- in china. improvement and cure was seen in cases, and stability of symptoms was seen in cases [ ] . qpd is thought to alleviate excessive immune and inflammatory responses by regulating immune-related and cytokine action-related pathways [ ] . a rct to evaluate the effects of traditional chinese medicine on covid- patients is underway (nct ). a p r o s p e c t i v e , r a n d o m i z e d m u l t i c e n t e r s t u d y, immunoncovid, is currently recruiting patients with advanced or metastatic cancer who have sars-cov- infection in europe. the study aims to compare the efficacy of a chloroquine analog (gns ), an anti-pd- (nivolumab), and an il- inhibitor (tocilizumab) versus standard of care in this cohort of patients (nct ). more studies to evaluate the efficacy of such agents in our cancer population are needed. cancer patients require timely diagnosis, evaluation, and treatment even during a pandemic. however, it is important to consider that cancer patients are immunocompromised and are at increased risk of covid- -related serious events (intensive care admission, requirement for mechanical ventilation, or death) in comparison to the general population [ •, •]. given the current evolving situation, pragmatic approaches are needed to deal with the challenges of treating cancer patients, without jeopardizing their care. to assist healthcare facilities in these unprecedented times, oncology societies around the world, namely the european society of medical oncology (esmo), american society of clinical oncology, national comprehensive cancer network (nccn), and many more, have developed guidelines to mitigate the negative effects of the covid- pandemic on the diagnosis and treatment of cancer patients [ ] [ ] [ ] . the common theme of these proposed guidelines is to categorize patients into high, medium, or low priority based on the ontario health cancer care ontario criteria (table ) in order to plan their management course accordingly [ ] . figure briefly outlines cancer management in the era of covid- pandemic. in addition to these suggested priority-driven guidelines, hospitals around the world have issued internal guidelines for oncologists, aiming to decrease patient exposure to covid- . given the immunocompromised nature of the patient population, cancer centers have been adhering to strict infection control guidelines, in inpatient and outpatient settings. outpatient visits, including ambulatory clinics and chemotherapy infusion visits, have been reduced [ ] . utilization of oral therapy regimens is recommended instead of parenteral anticancer therapies, if considered equivalent. this strategy can hence reduce patients' risk of exposure to sars-cov- , without compromising oncological outcome, for instance, the use of capecitabine in place of -fluorouracil in patients receiving concurrent neoadjuvant chemoradiation therapy for rectal cancer [ ] . additionally, one must strongly consider delaying anticancer therapy in patients with stable cancer. zhang et al. studied the outcomes of cancer patients with covid- on active anticancer therapy and reported more than fourfold higher likelihood of experiencing severe events in those who received therapy in the preceding days of covid- diagnosis (hr = . , % ci . - . , p = . ) [ • ]. however, for aggressive cancers, it is warranted to have a risk-benefit assessment and proceeding with cancer treatment if benefits outweigh risks. as precisely mentioned by wang et al., the major risk factor for cancer patients during the covid- pandemic is their inability to receive sufficient medical support [ ] . to further minimize patient exposure to covid- , clinicians could consider the option of chemotherapy break and the possibility of performing home laboratory draws for toxicity assessment if feasible. to avoid patients' exposure to pharmaceutical departments, patients could use drive-through pick-up or hospitals could utilize a courier medication delivery service [ , ] . surgery is another vital component in cancer management. in the current pandemic, the centers for disease control and prevention (cdc) and the american college of surgeons (acs) have advised rescheduling elective surgeries if possible [ , ] . evidence suggests that patients who received surgery and concomitantly contracted covid- were at much higher risk of severe clinical events than those who did not have surgery [ •] . despite these advisories, it is important for clinicians and patients to have risk assessment discussions prior to making treatment decisions. part of the discussion should also entail resource availability, as surgeries often require post-operative care in the intensive care unit (icu). given the current shortage of icu beds, it is important to delegate resources efficiently. in instances, specifically early stage cancers where surgery is often the first step in management, patients could be offered neoadjuvant therapy, and surgery could be delayed without compromising patient outcomes [ ] . evidence suggests that -day delays in surgical intervention of early stage breast cancer has been documented without worsening oncological outcomes [ ] . unlike medical and surgical management, radiation therapy, which is another essential part of cancer management, has its unique challenges during a pandemic. given the nature of the treatment, patients have to attend radiation therapy (rt) sessions daily and the interruption of therapy is rather unacceptable [ ] . considering varied clinical scenarios, the american society for radiation oncology (astro) recently published brief guidelines for radiation oncologists dealing with covid- pandemic. as noted by astro, if considered reasonable, hypofractionated schedules are encouraged [ ] . additionally, in patients with rapidly progressing disease or potentially curable tumors where rt significantly impacts survival, treatment should be prioritized as benefits outweigh risks. on the contrary, patients receiving palliative rt for symptom control or where interrupting the radiation course would not cause potential harm, one should consider delaying the treatment [ , ] . hematopoietic stem cell transplant (hsct) recipients are at an increased risk of a variety of infections [ , ] . incidence of rvis is seen in about % of allogeneic and % of autologous transplant recipients, with majority of patients developing nosocomial rvis [ ] . additionally, hsct patients receive therapies which result in prolonged cytopenia, making the transplant patients who contract covid- very vulnerable for severe symptoms [ , ] . considering these profound implications, the european society for blood and marrow transplantation (ebmt) recommends evaluating recipients at risk closely, and in appropriate cases, deferring the transplant therapy until asymptomatic (table ) [ ] . clinical trials are an extremely important part of advancing medicine forward and introducing novel therapies. the food drug and administration (fda) plays a critical role in car, chimeric antigen receptor; pcr, polymerase chain reaction conducting these clinical trials, and ensuring participants' safety is paramount in any scenario. in the midst of the current crisis, the fda has issued guidance for the institutions to protect trial participants while administering investigational product with an altered monitoring approach [ ] . at our institution, clinical trial activity during covid- is tailored to the changing epidemic scenario. all nontherapeutic interventional trials that require in person specimen collection have been suspended until state "stay at home" order is lifted. therapeutic clinical trials are prioritized by the clinical research services (crs), with weekly meetings conducted to re-prioritize with the evolving epidemic. the clinical trials that have remained open continue to obtain all tests and data points required for the primary endpoint of the study. additionally, all correlative studies imbedded in the research plan, except questionnaires, are suspended until the state "stay at home" order is lifted. all the covid- -specific research studies have been prioritized and taken precedence in activation and conduct including the correlative endpoints. new studies and proposals continue to be reviewed and processed. clinical disease teams and the scientific review committees continue to meet virtually and advance the much needed care. the covid- pandemic is potentially the greatest public health crisis since the influenza pandemic of . this crisis has brought unprecedented challenges in the management of those who are afflicted, by overwhelming healthcare systems and causing great stress to the healthcare workforce. during such crises, generation of timely evidence for treatment options is crucial. the higher risk of covid- -related severe disease incurred by patients with cancer prompts the generation of a comprehensive set of pragmatic approaches specifically for cancer patients and an in-depth review of potential treatments options available to patients, including cancer patients. author contribution rg, ya, and as conceived the idea for the article; rg, ya, as, nr, ip, and mse performed the literature search and drafted the review; and rg, ya, as, nr, ip, and mse critically revised the work. conflict of interest igor puzanov has received compensation from amgen for service as a consultant. rohit gosain, yara abdou, abhay singh, navpreet rana, and marc s. ernstoff declare that they have no conflict of interest. human and animal rights and informed consent this article does not contain any studies with human or animal subjects performed by any of the authors. pneumonia of unknown aetiology in wuhan, china: potential for international spread via commercial air travel outbreak of pneumonia of unknown etiology in wuhan, china: the mystery and the miracle 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timing of breast cancer surgery-how much does it matter? covid- recommendations to radiation oncology practices covid- interim patient care guidelines flocked nasal swab versus nasopharyngeal aspirate for detection of respiratory tract viruses in immunocompromised adults: a matched comparative study community respiratory virus infections among hospitalized adult bone marrow transplant recipients european society for blood and marrow transplantation (ebmt) fda guidance on conduct of clinical trials of medical products during covid- pandemic. the food drug & administration publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- -vq uhj i authors: da silva, severino jefferson ribeiro; silva, caroline targino alves da; guarines, klarissa miranda; mendes, renata pessôa germano; pardee, keith; kohl, alain; pena, lindomar title: clinical and laboratory diagnosis of sars-cov- , the virus causing covid- date: - - journal: acs infect dis doi: . /acsinfecdis. c sha: doc_id: cord_uid: vq uhj i [image: see text] in december , a novel beta (β) coronavirus eventually named sars-cov- emerged in wuhan, hubei province, china, causing an outbreak of severe and even fatal pneumonia in humans. the virus has spread very rapidly to many countries across the world, resulting in the world health organization (who) to declare a pandemic on march , . clinically, the diagnosis of this unprecedented illness, called coronavirus disease- (covid- ), becomes difficult because it shares many symptoms with other respiratory pathogens, including influenza and parainfluenza viruses. therefore, laboratory diagnosis is crucial for the clinical management of patients and the implementation of disease control strategies to contain sars-cov- at clinical and population level. here, we summarize the main clinical and imaging findings of covid- patients and discuss the advances, features, advantages, and limitations of different laboratory methods used for sars-cov- diagnosis. t he recent emergence of a novel coronavirus in the human population has caused dramatic and unprecedented impact of the economy and prompted mobilization of public health authorities around the world to counter the rapid spread of the virus. coronaviruses (covs) are members of the coronaviridae family and are an important group of viruses that infect a large number of animals including mammalian and avian species. the coronavirinae subfamily is divided into four genera based on genetic features: alphacoronavirus (α-covs), betacoronavirus (β-covs), gammacoronavirus (γ-covs), and deltacoronavirus (δ-covs). the α-covs (hcov- e and hcov-nl ) and β-covs (hcov-oc and hcov-hku ) cause human infection and have been associated with mild respiratory diseases. in the st century, however, three β-covs have emerged from animal reservoirs to cause severe disease in humans: severe acute respiratory syndrome coronavirus (sars-cov), the middle east respiratory syndrome coronavirus (mers-cov), and the pandemic severe acute respiratory syndrome coronavirus (sars-cov- ). , the genome of covs consists of a single-stranded positive sense (+ssrna) of around kb in size. the genomic rna is capped at the ′ end and has a poly(a) tail at the ′ end, allowing it to act as an mrna for translation of the replicase polyproteins. , the ′ terminal region of the genome encodes a polyprotein that is cleaved into nonstructural proteins involved in the transcription and replication process, and the ′ terminal region encodes viral structural proteins. in december , the world was on alert due to a cluster of severe pneumonia cases of unknown origin in wuhan, hubei province, china. this outbreak was epidemiologically linked to a wholesale animal and seafood market where live and freshly slaughtered animals were kept and sold. of the initial patients hospitalized with pneumonia, two-thirds had a history of direct exposure to this market. on the basis of the clinical presentation and the link with the animal market, similar to sars epidemiology, a cov was suspected as the causative agent and therefore pan-cov pcr primers were used to test the samples followed by sequencing. the causative agent was identified as a novel cov, eventually named sars-cov- , and the respiratory syndrome associated with the infection was designated as coronavirus disease- (covid- ) by the world health organization (who). the sars-cov- genome has about % sequence identity to sars-cov (with whom it is classified into the species severe acute respiratory syndrome-related coronavirus) and % to mers-cov. the most closely related virus to sars-cov- found so far is a cov isolated from bats, named ragt cov, whose nucleotide identity is %, suggesting that sars-cov- is also of bat origin. however, it is not clear whether sars-cov- jumped to humans directly from bats or through an intermediate host. the rapidly increasing numbers of covid- prompted who to declare first a public health emergency of international concern (pheic) on january , and then a pandemic on march , . as of july , , more than million cases of covid- and deaths have been reported in countries and territories around the world. most of the cases have been reported by the usa, followed by brazil, india, russia, south africa, mexico, and peru. different from the other highly pathogenic covs, sars-cov- has acquired the ability to establish sustained humanto-human transmission. its basic reproductive number (r ), i.e., the number of secondary infections generated from one infected individual, is estimated to be between . and . , with a mean of . . ultimately, this metric will require further investigations and may vary across settings and locations. on the basis of the travel history and symptom onset of patients in china, the mean incubation period of covid- has been calculated to be . days, ranging from to up to days. clinically, the spectrum of covid- manifestations ranges from asymptomatic and mild to severe infections requiring oxygen therapy and ventilation support. , , since its emergence, a wide variety of methods have been developed for the purpose of the rapid and accurate diagnosis of covid- . on the basis of clinical criteria alone, sars-cov- cannot be reliably distinguished from infections with other pathogens that cause similar symptoms, including influenza, seasonal cov, adenovirus, bocavirus, human metapneumovirus, parainfluenza, respiratory syncytial virus rhinovirus, bordetella pertussis, legionella pneumophila, myco-plasma pneumonia, , and even the mosquito borne dengue virus. in this context, the laboratory-based diagnosis assumes a role for the clinical management of patients and the implementation of disease control measures. here, we review the clinical features, laboratory methods, and imaging findings that are used for covid- diagnosis. in addition, we explore the next steps of the methods under development for covid- diagnosis. a rapid presumptive diagnosis based on clinical assessment and epidemiological characteristics is critical to ensuring appropriate patient care and controlling viral transmission, thus contributing to disease control. as mentioned and as with other respiratory viral infections, the signs and symptoms of covid- are nonspecific and the clinical spectrum of disease can range from no symptoms to severe pneumonia and death. asymptomatic infection has been reported in many settings, but some patients develop clinical disease at a later stage of infection. the proportion of truly asymptomatic infections is unclear, but some estimates indicated that up to % of infections do not result in overt clinical signs of disease. a recent mathematical model suggested that undocumented infections might be major drivers of sars-cov- spread in the world. according to who criteria, a person is suspected of being infected with covid- in three scenarios: (i) a patient with acute respiratory illness (fever and at least one sign/symptom of respiratory disease, e.g., cough, shortness of breath) and a history of travel to or residence in a location reporting community transmission of covid- disease during the days prior to symptom onset; (ii) a patient with any acute respiratory illness who has been in contact with a confirmed or probable covid- case in the last days prior to symptom onset; and (iii) a patient with severe acute respiratory illness (fever and at least one sign/symptom of respiratory disease, e.g., cough, shortness of breath, and requiring hospitalization) and in the absence of an alternative diagnosis that fully explains the clinical presentation. if a patient then tests positive with a laboratory diagnostic, then the infection becomes a confirmed overall, % of laboratory-confirmed covid- patients develop mild to moderate disease, which includes nonpneumonia and pneumonia cases, % have severe disease (dyspnea, tachypnea, blood oxygen saturation ≤ %, and pao /fio ratio of % of the lung field within − h), and % of cases reach critical state (respiratory failure, septic shock, and/or multiple organ dysfunction/failure). risk factors for severe covid- include age ≥ years and people with preexisting concurrent conditions such as cardiovascular disease, hypertension, diabetes, chronic respiratory disease, immunodeficiencies, cancer, and obesity. − accurate estimates of the covid- case fatality rate are still lacking, but it is believed to be around % and can be as high as . % in patients > years of age. however, this number is dependent on the level of testing in countries, testing accuracy, and death-reporting policies. interestingly, men have a much higher risk of death than women. , table summarizes the clinical signs and symptoms of covid- patients seen in several studies. in general, the most common clinical manifestations are fever, dry cough, fatigue, sputum production, dyspnea, sore throat, headache, myalgia or arthralgia, and chills ( figure ). less common symptoms include nausea or vomiting, nasal congestion, diarrhea, hemoptysis, and conjunctival congestion. in children, sars-cov- infection is generally mild and in some cases asymptomatic; however, when presented, the main symptoms include fever (about %), cough ( %), and pharyngeal erythema ( . %). more recently, several studies have been suggested that covid- infection was associated with cutaneous manifestations in patients. − major manifestations observed in covid- patients including different types of lesions such as purpuric, papulovesicular, livedoid, urticarial, maculopapular, and thromboticischemic. a recent study in european covid- patients reported that . and . % of patients had olfactory and gustatory dysfunctions, respectively. these disorders persisted after the resolution of other symptoms. finally, a single retrospective case series in wuhan, china, reported neurologic manifestations in of hospitalized patients ( . %) with a laboratory-confirmed diagnosis of covid- . these symptoms were more common in severe cases, along with acute cerebrovascular events, headache, dizziness, and impaired consciousness. it is unclear whether the neurologic manifestations were caused by sars-cov- directly or by pulmonary disease or other organ damage indirectly or by cytokines. since this study included only hospitalized patients in a single location, the true percentage of neurological manifestations in covid- needs further evaluation. imaging techniques such as chest x-rays, pulmonary computed tomography (ct) scans, and lung ultrasounds are important tools in the early diagnosis of pneumonia in patients with covid- . although chest x-rays are less expensive and more convenient for follow up in pneumonia cases, the technique has low-resolution and projection overlapping, which could lead to many false-negative covid- cases. reports indicate that covid- patients submitted to chest ct scans on admission presented abnormal results (about %), showing bilateral multiple ground-glass and patchy opacity. a clinical laboratory findings and biomarkers in covid- patients. several studies have reported hematologic and blood chemistry alterations in patients infected by sars-cov- . , major laboratory findings in covid- patients identified by meta-analysis include leukopenia, leukocytosis, decreased albumin levels, increased levels of creactive protein, lactate dehydrogenase (ldh), creatinine kinase, and biliarubin, and a high erythrocyte sedimentation rate (esr). increased levels of creatine kinase and lactate dehydrogenase were associated with myalgia. a growing body of evidence suggests that sars-cov- infection can trigger the overproduction of cytokines in some patients, known as a cytokine storm, which is associated with poor outcomes. , − as for other severe viral infections, the exacerbated production of proinflammatory cytokines may be involved in some of the pathophysiology of covid- , including pulmonary edema and lung failure and damage to the liver, heart, and kidneys. compared to healthy adults, covid- patients had higher levels of il- β, il- ra, il- , il- , il- , il- , basic fgf, g-csf, gm-csf, ifn-γ, ip- , mcp- , mip- a, mip- b, pdgf, tnf-α, and vegf. serum biomarkers associated with severe disease included il- , il- , il- , g-csf, ip- , mcp- , mip- a, and tnf-α. a recent retrospective study of confirmed covid- cases ( fatal and discharged cases) in wuhan, china, identified several serological markers that were more elevated in lethal cases than in survivors: elevated ferritin, il- , myoglobin, creactive protein, and cardiac troponin. together, these findings suggest that covid- mortality might be due to infection-driven hyperinflammation. diagnostic virology of covid- . laboratory virology tests are essential for a correct diagnosis and the population level prevalence of covid- , given the number of asymptomatic cases or nonspecific clinical symptoms. results from these tests guide clinicians and health officials in the management, control, and prevention of covid- . several analytical parameters are used to determine the performance of covid- assays, including clinical sensitivity, clinical specificity, positive predictive value (ppv), negative predictive value (npv), and overall accuracy. the confirmation of a sars-cov- infection in the laboratory can be achieved by direct and indirect virology methods. while direct detection is more specific, indirect methods allow a greater opportunity for virus detection after the acute phase of the disease. in direct tests, the clinical sample is examined directly for the presence of particles, virus antigens, or viral nucleic acids, whereas indirect methods detect the serological response against the infection (figure ). samples. the world health organization (who) recommends that all procedures performed with covid- be done only by trained professionals and should take place in a laboratory with an appropriate level of biosafety. nonpropagative diagnostic assays, such nucleic acid amplification tests (naats), sequencing, and some serological tests (e.g., elisa type assays) can be performed in biosafety level (bsl- ) laboratories provided that the initial processing (before virus inactivation) of samples takes place in a validated biological safety cabinet. however, procedures that involve propagative virus work, such as virus culture, isolation, or neutralization assays, should be performed in laboratories equivalent to bsl- using validated practices. the work team must use appropriate personal protective equipment including eye protection (goggles or a disposable face shield), a respirator or facemask, a long-sleeved gown, and gloves and follow all standard operating procedures regarding sample collection and handling. respirators that offer a higher level of protection such as n respirators or powered air-purifying respirators should be used instead of a face mask when performing an aerosol-generating procedure. samples from patients with a suspected or confirmed case must be transported to un , a code referring to "biological substance category b"; however, virus-infected cultures or isolates must be transported as category a -un , "an infectious substance that affects humans". , specimens for diagnosis. choosing the correct sample for diagnosis tests is an essential step in a reliable diagnosis. sars-cov- infection can be detected in a variety of clinical specimens, such as nasopharyngeal or oropharyngeal aspirates or washes, nasopharyngeal or oropharyngeal swabs, sputum, tracheal aspirates, and bronchoalveolar lavage. − the median duration of sars-cov- shedding in respiratory samples is (irq, − ) days in survivors, but shedding can last for up to days. given the invasiveness and requirements for equipment and skilled labor, the collection of specimens other than sputum from the lower respiratory tract should be considered only in special situations. a nasopharyngeal swab collected with a fiberplastic shaft swab is the preferred choice for swab-based sars-cov- testing because it provides reliable results while not being too invasive. calcium alginate swabs and wooden shaft swabs are not recommended because they may contain substances that inactivate some viruses and inhibit pcr testing. when collection with a nasopharyngeal swab is not possible, oropharyngeal swabs, nasal midturbinate swabs, or anterior nares (nasal swab) swabs are also acceptable alternatives. swabs should be placed immediately after collection into sterile tubes containing to ml of a viral transport medium to preserve viral integrity. upon collection and with the appropriate storage medium, specimens can be stored at − °c for up to h. in cases of delayed testing or shipping, samples should be stored at − °c or below. inadequate sample collection, handling, and storage are important variables that may result in false-negative test results. in addition to respiratory tract specimens, sars-cov- can also be detected in other samples such as stool, anal swabs, and blood but not in urine. , , sars-cov- detection in blood is not frequent and is associated with disease severity. , the detection rate of sars-cov- rna in fecal specimens is similar to that of pharyngeal swabs; , however, importantly, fecal viral shedding appears to occur for a longer period of acs infectious diseases pubs.acs.org/journal/aidcbc review time. sars-cov- detection in stool is not associated with the presence of gastrointestinal symptoms or the severity of illness. − despite high virus rna levels in feces, successful isolation of sars-cov- from patient stool has been reported. the isolation of sars-cov- from urine and ocular secretions from infected patient has been described. , viral shedding in human breast milk and semen has been detected, , while in tears it has either been undetected or acs infectious diseases pubs.acs.org/journal/aidcbc review detected at very low frequency. serum and plasma samples are used for serological assays, especially week postinfection. the median seroconversion time for total anti-sars-cov- antibodies, igm and then igg, were days , , and , respectively. virus isolation. sars-cov- was first isolated from bronchoalveolar lavage from a patient with pneumonia in vero e and huh cells. the viral identity was confirmed by immunofluorescence using the now-known cross-reactive anti-sarsr-cov rp n antibody, rt-qpcr, and metagenomics sequencing. the cellular infectivity of the isolated virus was confirmed by virus neutralization assay using sera from convalescing patients. culture-based methods for sars-cov- detection have been used in research and public health laboratories in different parts of the world, but virus isolation is not recommended as a routine diagnostic procedure because it has low sensitivity, it is time-consuming, and it requires bsl- containment. sars-cov- is also culturable in several cell lines, including human airway epithelial, , vero e , vero ccl- , and huh- cells. , , , vero e cells express high levels of angiotensin-converting enzyme (ace ), which has been identified as a key a cell receptor for sars-cov- infection. similar to sars-cov- and mers-cov, sars-cov- isolation is enhanced in an engineered vero e that expresses tmprss (transmembrane serine protease ) levels that are -fold higher than in human normal lung tissue and other human cell lines, suggesting that tmprss protease is important for sars-cov- infection. recently, zang and colleagues demonstrated that tmprss and tmprss promote sars-cov- entry into enterocytes. harcourt and co-workers studied the susceptibility of several cell lines such as vero ccl- , vero e , hek- t, a , and huh- as well as the big brown bat kidney cell line (efk b) to support the productive replication of sars-cov- . no cytopathic effect (cpe) was observed in any of the cell lines except in vero e and vero ccl cells, in which the virus grew to > pfu/ml at h postinfection. huh- and hek- t cells showed only modest viral replication, whereas no virus replication was detected in either a or efk b cells. sars-cov- produced distinct plaques in vero e cells, but plaques in vero ccl- cells were not as clear, suggesting that vero e cells might be the best choice for the propagation, quantification, and study of plaque phenotypes of different sars-cov- strains. however, should virus isolation be attempted, vero e cells clearly stand out as a cell line that supports infection and virus production. a recent cross-sectional study used sars-cov- rt-qpcr confirmed specimens and evaluated their ability to infect vero cell lines. for the study, patient samples were incubated on vero cells (ccl- ) during days, and then the cytopathic effect was evaluated. of these, samples ( . %) demonstrated viral growth, but there was no growth in samples with a ct value > , which suggests using samples with low ct values for successful viral isolation. electron microscopy. human cov was first isolated in from a patient with a common cold. later, the virus was named "coronavirus" due to the virus' appearance under the electron microscope that resembles the solar corona. cov particles are pleomorphic, and their surfaces are covered with a distinct layer of projections, which corresponds to the long spike protein. given the virus' distinctive morphology, electron microscopy has been used to observe and identify virus particles after isolation in culture systems in the initial outbreak in wuhan and subsequently by others. , , the first attempts to recover sars-cov- virions with the characteristic fringe of surface spike proteins from the first covid- case in australia failed, but adding trypsin to the cell culture medium immediately allowed the visualization of the virus with characteristic cov morphology, with particles of − nm diameter displaying prominent spikes ( − nm) on the surface. real-time rt-qpcr. the gold standard diagnostic test for sars-cov- infection is viral rna detection by reverse transcription quantitative real-time polymerase chain reaction (rt-qpcr) given its sensitivity, specificity, and speed. rt-qpcr shows better performance than serology because it can identify positive cases in the early stage of infection, even during the incubation period of the disease and after symptoms have disappeared. many laboratory-developed tests based on the rt-qpcr assay have been published or are in development for sars-cov- detection. some of these developed assays are specific to the pandemic strain of the virus, and others also recognize genetically similar strains such as sars-cov. molecular targets for sars-cov- rt-qpcr include the genes that encode the nucleocapsid (n), envelope (e), spike (s), and rna-dependent rna polymerase proteins given their high degree of genetic conservation (figure ) . , most assays use two targets in the viral genome, but in the event of reagent shortages, rt-qpcr screening with only one set of primers instead of two may be considered after thorough validation in the individual laboratory. performing a sample preheating step instead of rna extraction can also be considered during a shortage of viral nucleic acid extraction kits. in a study with oropharyngeal swab samples ( positive and negative for sars-cov- ) in denmark, it was found that heating for min at °c resulted in a sensitivity, specificity, and accuracy of . , . , and . %, respectively, as compared with magna pure rna-extracted samples. although some laboratories have recommended heat inactivation of the virus ( − °c for − min) before rna extraction to protect laboratory personnel, this procedure adversely affects the efficacy of rt-qpcr for sars-cov- detection. high rates of false-negative sars-cov- rt-qpcr results and prolonged nucleic acid conversion have been reported in some studies, which have implications for returning to normal activities and covid- control. − in addition to in-house tests, many molecular assay kits have been approved by the food and drug administration's (fda) and have been made commercially available for the detection and amplification of the sars-cov- rna genome (https:// www.fda.gov/medical-devices/emergency-situations-medicaldevices/emergency-use-authorizations). however, diagnostic laboratories should rigorously validate these commercial kits before routine use since the analytical sensitivity of some commercial rt-qpcr tests differs substantially, which could lead to false-negative results. two of the most widely used assays in the western world have been developed by charite, hospital germany and the u.s. cdc. nalla and co-workers compared the performance of the charité(n, polymerase, and e targets) and the cdc (n , n , and n targets) primer/probe sets side-by-side using clinical samples. it was found that all assays were highly specific to sars-cov- , with no cross-reactivity with other respiratory viruses. the cdc n and the charitéhospital e-gene primer/probe sets performed equally well and were the most sensitive assays for detecting sars-cov- . we anticipate acs infectious diseases pubs.acs.org/journal/aidcbc review that this list will grow as several new rt-qpcr assays are being developed to promote the accurate and rapid detection of sars-cov- . the results demonstrated that the median duration between the onset of symptoms to nucleic acid conversion was days (iqr, − ) and that the longest duration was days after the onset of symptoms. it was found that higher viral loads (inversely proportional of the ct value) can be observed in upper respiratory samples soon after symptom onset and that the peak occurs within the first week of illness onset of covid- confirmed patients. , in another study, the authors evaluated the viral shedding patterns demonstrated in patients with mild and severe covid- disease using specimens from patients, including individuals classified as mild cases and classified as severe cases. the results showed that the viral load of severe cases was around times higher when compared with that of mild cases, indicating that higher viral loads might be associated with severe clinical findings. in addition, it was revealed that the ct values of severe cases were significantly lower than those of mild cases in infected patients at the time of admission and that early viral clearance was observed in patients classified as mild cases ( days after onset). sars-cov- -positive rt-qpcr detection has also been demonstrated even after the resolution of covid- symptoms. , for this reason, the cdc has recommended obtaining at least two negative upper respiratory tract samples, collected in intervals of h or longer, to document sars-cov- clearance. on the other hand, the viral shedding in asymptomatic patients with covid- also has been investigated. , zhou and co-workers analyzed the viral shedding pattern in patients that were confirmed to have covid- using rt-qpcr but were asymptomatic during admission to the hospital. subsequently, the study divided the patients into groups: patients who remained asymptomatic during hospitalization (aps) and patients who presented symptoms after admission to the hospital (apis). the results demonstrated that the median ct value of aps ( . , interquartile range [iqr] . − . ) was higher than when compared to apis ( . , iqr . − . ), showing a lower viral load in aps. also, it was found that the duration of viral shedding remained similar in the two patient groups, which reflects the possibility of sars-cov- transmission in the community during the asymptomatic period. in addition, the study findings revealed that the viral load of aps peaked during the first week after admission to the hospital while that of apis peaked during the second week of covid- infection. these findings alert professionals and health authorities to the possibility of transmission during the asymptomatic period of patients with covid- disease. however, further scientific studies with more patients are required to elucidate the real role of asymptomatic patients in the transmission chain. reverse transcription loop-mediated isothermal amplification (rt-lamp). the recent increase in the number of covid- cases in the world has encouraged a global effort to develop point-of-care platforms for diagnosing sars-cov- . reverse transcription loop-mediated isothermal amplification (rt-lamp) is perhaps one of the most promising platforms for rapid development and accessible sars-cov- testing and has many advantages, compared to rt-qpcr, such as high specificity and sensitivity, simple operation, rapid amplification, and low cost,. , rt-lamp assays have been developed for other covs of the same genus (betacoronavirus), including sars-cov , and mers-cov. , not surprisingly, several studies have already demonstrated the use of rt-lamp for sars-cov- detection. − crispr/cas-based diagnostic methods. the clustered regularly interspaced short palindromic repeats (crispr)/cas machinery has recently been adapted as a poc tool for the rapid detection of nucleic acids (dna or rna). , overall, this crispr machinery is programmed to cleave specific sequences in the dna/rna target where the results can be easily observed by combination with a lateral-flow strip. initially, zhang's team developed a crispr/cas-based platform called specific high-sensitivity enzymatic reporter unlocking (sherlock) that, combined with isothermal preamplification to detect strains of single-strand rna viruses, identifies mutations and human genotype dna, and distinguishes pathogenic bacteria. , more recently, using the same knowledge, they adapted a protocol using the sherlock system for sars-cov- detection. on the other hand, mammoth bioscience company developed another platform based on the crispr/cas system named the endonuclease-targeted crispr trans reporter (de-tectr) to detect any rna or dna target, which has now been used to detect the sars-cov- rna genome from respiratory swab rna extracts. the suitability of detectr technology for the detection of sars-cov- was evaluated using patient specimens, including patients with covid- infection and patients with other viral respiratory infections, and then compared with the cdc rt-qpcr as a reference method to confirm covid- infection. the sars-cov- detectr test had % positive predictive agreement and % negative predictive agreement when compared with rt-qpcr results. despite these promising results, crispr/cas-based diagnostic methods are not widely used by diagnostic laboratories and need further implementation. taken together, these results highlight the great potential of crispr-based diagnostic methods as a rapid, specific, portable, and accurate detection platform for the detection of the sars-cov- genome in patient samples. sensors. sensors represent another alternative detection method with rapid and high throughput. since the emergence of sars-cov- , several research groups from different parts of the world have also focused on alternative sensing modalities based on sensors for the diagnosis of sars-cov- that reduce the use of expensive laboratory equipment, trained laboratory personnel, and extensive sample preparation and provide fast and accurate results. in this context, qiu and co-workers developed a dual-functional plasmonic biosensor combining the plasmonic photothermal (ppt) effect and localized surface plasmon resonance (lspr) to detect sars-cov- . in another study, the authors used a field-effect transistor (fet)based sensor to detect sars-cov- from patient samples. in general, these recent research findings are based on technologies previously used for the detection of other viral pathogens that now can be adapted for the detection of sars-cov- . for instance, due to its high sensitivity and specificity, simple operation, low cost, and other advantages, the sensors using programmable biomolecular components named the toehold switch developed in response to previous ebola and zika outbreaks represent another powerful platform for detecting the sars-cov- genome. − genome sequencing. whole genome sequencing was used to identify potential etiological agents involved in the index cases of the covid- pandemic in wuhan. in addition to unequivocally confirming the diagnosis of a sars-cov- infection, regular sequencing of a percentage of patient samples from clinical cases can be used to monitor changes in the viral genome over time and trace transmission patterns. for this purpose, several sequencing protocols based on sanger and next-generation sequencing (ngs) are being applied to rapidly generate the genome sequences. , , lu and colleagues used a combination of sanger, illumina, and oxford nanopore minion sequencing technologies to obtain the whole-genome sequences of sars-cov- from six patient specimens from wuhan, china. holshue and colleagues reported the first case of the novel coronavirus in the united states and used a combination of the sanger method, illumina, and minion to generate the whole-genome sequences. whole-genome sequencing using minion technology coupled with phylogenetic analyses and travel history allowed the identification of sars-cov- entry routes into latin america during its emergence in brazil. as of july , , genome sequences had been deposited in genbank (https://www.ncbi. nlm.nih.gov/genbank/sars-cov- -seqs/), including complete genome sequences from different countries around the world and partial genome sequences. sars-cov- has evolved continuously since its emergence. the binding regions of primers and probes should be monitored continuously for matching to the virus genome as more sequence information becomes available. in this scenario, artesi and colleagues reported that changes within the sars-cov- primer binding region negatively affected the performance of commercial rt-qpcr assays (unpublished data, https://www.medrxiv.org/content/ . / . . . v ). in another study, rana and co-workers analyzed the whole genome sequence of patients with covid- and found variations in the primer and probe binding sites that could produce false-negative results. a comprehensive bioinformatics analysis of sars-cov- sequences from around the world identified the presence of mutations/ mismatches in the primer/probe binding regions of assays out of rt-qpcr assays studied, including the charite-orf b reverse primer and the us-cdc-n- probe. however, it should be noted that except at the ′ end, rt-qpcr can tolerate mismatches at the ′ extremity or in the middle of a primer. thus, oligonucleotide binding regions should be continuously monitored by bioinformatics and also by wet-laboratory experiments in order to identify changes that may influence rt-qpcr performance. , , taken together, whole genome sequencing and bioinformatics will be important in global efforts to combat the pandemic, with the resulting analyses being used to guide a wide range of studies, including diagnostics, , , molecular epidemiology studies, viral evolution, − elucidatation of possible hosts of the virus, , − identification of targets for drugs and vaccines, , molecular determinants involved in virulence and pathogenicity, , and factors related to the host's immune response to the virus. , serology. serological methods are being increasingly used and can be used for diagnosis, contact tracing, and herd immunity assessment, and vaccine efficacy evaluation. seroepidemiologic studies can assist in the investigation of the ongoing pandemic and the retrospective assessment to determine the attack rate or the progress of the pandemic through antibody detection. these studies can assist health authorities and governments in making sound decisions with respect to the implementation of public health measures during the course of the current pandemic. population-based serosurveys for sars-cov- has been applied in several sites to assess the burden of covid- and more accurately determine sars-cov- prevalence and transmission dynamics. − moreover, serology can also be useful in situations where rt-qpcr is negative and there is a strong epidemiological link to covid- infection. in these cases, paired serum samples collected in the acute and convalescent phase can be of diagnostic value. the adaptive immune response to sars-cov- infection has been studied, , , , despite several knowledge gaps in this area. long and co-workers studied the antibody responses to sars-cov- in patients with covid- in china. seroconversion for igm and igg occurred simultaneously or sequentially, and the median day of seroconversion for both immunoglobulins was days after covid- onset. the seroconversion rate for igg reached % days after symptom onset. in a related work, zhao and colleagues showed that the median seroconversion times for total antibodies, igm, and igg were , , and days after sars-cov- infection. severe patients tend to have higher antibodies titers than patients with mild covid- . , to investigate the antibody responses to sars-cov- in convalescing individuals, robbiani and co-workers analyzed plasma samples collected an average of days after the onset of symptoms from convalescing individuals. most convalescent plasmas obtained from recovered patients did not contain high concentrations of neutralizing activity. a related study with convalescing patients detected serum neutralizing antibodies in out of patients, and there was a strong correlation among neutralization antibody titers, the numbers of virus-specific t cells, and anti-s-rbd igg but not with anti-np igg. notably, the antibody response and viral clearance can be delayed in immune-compromised individuals and people posteriorly infected with sars-cov- . in the past few months, a variety of serological tests have been designed to detect sars-cov- , mainly enzyme-linked immunosorbent assays (elisa), immunofluorescence assays (ifa), chemiluminescence enzyme immunoassays (clia), and lateral flow assays (lfa). of these serological methods, elisa, clia, and lfa are used for the first-line screening of patient samples with covid- . most serological assays are based on the sars-cov- nucleocapsid protein (n), transmembrane spike protein (s), or s receptor-binding domain (rbd) because of their high antigenicity. − as mentioned before, sars-cov- enters host cells using its spike protein and represents the main target of neutralizing antibodies produced by the host. in this context, several studies have demonstrated that serological tests using the s antigen are more sensitive than those using n-antigen-based antibody assays. instead of a single antigen, some companies have combined n-and s-based antigens to develop serological assays for sars-cov- detection. cross-reactivity between sars-cov- and sars-cov- has been reported against the n protein but not against the s subunit of the s protein. cross-reactive antibodies between sars-cov- and sars-acs infectious diseases pubs.acs.org/journal/aidcbc review cov- have been detected in both the rbd region located in the s subunit and also in non-rbd regions. anderson and colleagues analyzed patient samples with sars-cov- and sars-cov- infections and showed that there is no detectable cross-neutralization by sars-cov- patient serum against sars-cov- , despite significant cross-reactivity between the n proteins from the two viruses many elisa-based assays have been developed to evaluate the human antibody response (iga, igm, and igg) against sars-cov- . , − cross reactivity to other coronaviruses has been reported, and therefore test results should be interpreted in light of the local epidemiological scenario. for example, it has been shown that igm elisa allows a higher detection efficacy than rt-qpcr after . days of symptom onset, and the combined use of igm elisa and rt-qpcr increases the positive detection rate to . % when compared with a single rt-qpcr test ( . %). the median time of appearance of igm and iga antibodies in plasma was days, while igg was detected days after symptom onset. in the same study, sars-cov- n elisa did not show any cross-reactivity with other covs, with the exception of sars-cov- , a virus that has not been in circulation since the to outbreak. perera and co-workers developed an elisa based on the receptor-binding domain (rbd) of the sars-cov- s protein to detect igg and igm antibodies in human sera and compared the elisa results with confirmatory microneutralization and % plaque reduction neutralization tests (prnt ). they found that prnt were more sensitive than microneutralization to detecting antibodies against sars-cov- , indicating that elisa should be used for screening and prnt should be used for confirmation in large-scale seroepidemiological studies. a magnetic chemiluminescence enzyme immunoassay (mclia) has also been developed for virus-specific antibody detection. in a study with covid- patients, sera from these patients did not cross react with the sars-cov spike antigen, but some cross-reactivity was found with the sars-cov nucleocapsid antigen. many lateral flow assays (lfa) have been developed to detect sars-cov- − and have obtained emergency use authorization from the fda (https://www.fda.gov/medicaldevices/emergency-situations-medical-devices/emergency-useauthorizations). a combined igm/igg assay seems to be a better choice in terms of performance and sensitivity to either antibody alone (igm or igg). recently, li and colleagues developed a rapid lfa to simultaneously detect igm and igg antibodies against sars-cov- within min in human blood. the assay uses the receptor binding domain of the sars-cov- s protein as the antigen. they validated the assay with blood samples previously screened by rt-qpcr, including positive and negative samples. the assay had a sensitivity of . % and a specificity of . % compared to rt-qpcr. in addition, several studies have been used to evaluate the clinical sensitivity of serological tests with covid- patient samples collected on different days after the onset of symptoms. − pan and colleagues evaluated a commercial lateral flow immunochromatographic test targeting viral igm or the igg antibody and compared it with rt-qpcr. the sensitivity of the assay for sars-cov- detection was . % in early-stage patients ( − days after onset), . % in intermediate-stage patients ( − days after onset), and . % in late-stage patients (more than days after onset). in similar study, tang and co-workers compared the diagnostic performance of two sars-cov- commercial serologic tests using specimens from pcr-confirmed sars-cov- patients and control specimens from different days after disease onset (< , − , − , and ≥ days). both assays had poor diagnostic sensitivity during the first days of symptoms, generating a high rate of false-negative results. the time of sampling since the onset of symptoms must be taken into account when performing the serological diagnostic test, and false-negative results can lead to the false assumption that a person is not infected, consequently bringing about serious challenges and implications for the spread or containment of the disease. most patients will seroconvert only in the second week after infection, and thus negative serological test results obtained during the first days of the disease should be interpreted with caution. as opposed to classical serum neutralization assays such as the microneutralization and plaque reduction neutralization test (prnt), pseudovirus neutralization assays for sars-cov- can be performed in biosafety level facilities. pseudovirusbased neutralizing assays for sars-cov- have been developed using vesicular stomatitis virus (vsv) and lentiviral pseudovirus systems. , such systems will facilitate the study of covid- humoral immunity and the development and evaluation of vaccines and therapeutics against sars-cov- once the reliability and cross reactivity have been assessed. antigen detection tests represent another alternative to detecting sars-cov- . antigen detection assays are developed to directly detect viral particles in biological samples such as nasopharyngeal secretions from infected patients. in this context, some rapid antigen assays have been proposed to detect sars-cov- . , − a fluorescence lfa antigen test based on the n protein has been developed and validated using nasopharyngeal and oropharyngeal samples from suspected covid- cases ( positive by rt-qpcr). compared with rt-qpcr, the test achieved a sensitivity of . % and % specificity. however, some commercially available point-of-care tests have very low sensitivity, which hinders their use in covid- diagnosis. , for the validation of serological tests, robust test validation with adequate clinical samples representative of a real-world scenario (e.g., timing from disease onset, different disease severities, different geographical locations, and patient age) is of paramount importance. particular attention should be paid to the low specificity of some assays and the high possibility of false-positive results. a low specificity of serological assays may have important consequences in terms of both diagnosis and population surveillance of covid- patients at the individual level and population level. , at the individual level, the risks posed by false-positive results can be of great concern. for instance, people who have never been infected may return to work or travel because they are considered to be immune to sars-cov- infection. at the population level, false-positive results may increase the prevalence of covid- disease and provide a distorted picture of the higher population immunity and lower mortality rate than what is actually happening, which can negatively affect seroepidemiological surveillance studies. thus, the independent validation of covid- serological tests using samples from different stages of the disease is urgently needed to encourage health care professionals and governments to make sound decisions. differential diagnosis. since the clinical manifestations of covid- are similar to those of other respiratory diseases, differential diagnosis is of paramount importance in assisting physicians in the therapeutic management of patients and health officials in establishing disease control policies. in an effort to do so, respiratory pathogens in patients suspected of covid- in italy have been investigated. here, researchers tested the nasopharyngeal swabs of suspected causes using sars-cov- rt-qpcr and a commercial multiplex respiratory cartridge that detects and differentiates viral and bacterial pathogens. only patients were confirmed to be infected with sars-cov- , and ( . %) were positive for other respiratory pathogens, including ( . %) positive for influenza a and ( . %) positive for influenza b. other pathogens detected in the patient samples were common cold cov (h-cov e, h-cov nl , and h-cov hku ), rhinovirus, enterovirus, metapneumovirus, adenovirus, mycoplasma pneumoniae, streptococcus pneumoniae, and legionella pneumophila. these results highlight the diagnostic differential and demonstrate the importance of using a spectrum of molecular kits for the rapid detection of respiratory pathogens in order to improve the clinical management and treatment of patients infected with covid- . in another study, yan and co-workers reported the cases of two patients in singapore who initially had moderate symptoms including myalgia, a mild cough, and diarrhea and presented with thrombocytopenia and a normal chest radiograph. dengue was suspected, and a rapid serological test for dengue produced false-positive results. as patient symptoms worsened, they were later diagnosed with covid- by rt-qpcr. taken together, these findings suggest that special attention is needed in the differential diagnosis between arboviruses and sars-cov- infection, especially in countries where is there a circulation of denv, zikv, and chikv. moreover, coinfection with sars-cov- and other respiratory viruses, such as common cold cov, influenza, and metapneumovirus, have been reported, highlighting the need for repeat testing based on clinical indications. − the rapid spread of sars-cov- around the world, with mounting cases of fatal pneumonia and the economic crisis, is a global concern. diagnostics represent one of the most powerful tools in mitigating these effects until a vaccine can be established. this needed is further highlighted by overlapping symptoms from other pathogens that can confound diagnosis based only on clinical criteria. as we have reviewed, many approaches have been established for the diagnosis of sars-cov- , and we anticipate the coming months to bring about many more innovative strategies. critically, the development of inexpensive point-of-care diagnostic platforms will accelerate the global response to the current pandemic, especially in countries with health systems devoid of adequate laboratory infrastructure. it will be important that widespread diagnostic development and validation continue in the coming months and that the large-scale implementation of these sars-cov- diagnostic platforms is successful as this pandemic evolves. reliable, easy-to-use assays will be absolutely critical, especially as the disease moves through low-and middle-income countries. 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coinfection of influenza virus and severe acute respiratory syndrome coronavirus (sars-cov- ) coinfection with sars-cov- and human metapneumovirus sars-cov- and influenza virus co-infection epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in emerging novel coronavirus ( -ncov) pneumonia china: a descriptive, cross-sectional, multicenter study prevalence and clinical presentation of health care workers with symptoms of coronavirus disease in dutch hospitals during an early phase of the pandemic clinical and virologic characteristics of the first patients with coronavirus disease (covid- ) in the united states clinical features, laboratory characteristics, and outcomes of patients hospitalized with coronavirus disease (covid- ): early report from the united states key: cord- -t y w ef authors: luo, zichao; ang, melgious jin yan; chan, siew yin; yi, zhigao; goh, yi yiing; yan, shuangqian; tao, jun; liu, kai; li, xiaosong; zhang, hongjie; huang, wei; liu, xiaogang title: combating the coronavirus pandemic: early detection, medical treatment, and a concerted effort by the global community date: - - journal: research (wash d c) doi: . / / sha: doc_id: cord_uid: t y w ef the world health organization (who) has declared the outbreak of novel coronavirus, known as -ncov, a pandemic, as the coronavirus has now infected over . million people globally and caused more than , fatalities as of april , . coronavirus disease (covid- ) causes a respiratory illness with symptoms such as dry cough, fever, sudden loss of smell, and, in more severe cases, difficulty breathing. to date, there is no specific vaccine or treatment proven effective against this viral disease. early and accurate diagnosis of covid- is thus critical to curbing its spread and improving health outcomes. reverse transcription-polymerase chain reaction (rt-pcr) is commonly used to detect the presence of covid- . other techniques, such as recombinase polymerase amplification (rpa), loop-mediated isothermal amplification (lamp), clustered regularly interspaced short palindromic repeats (crispr), and microfluidics, have allowed better disease diagnosis. here, as part of the effort to expand screening capacity, we review advances and challenges in the rapid detection of covid- by targeting nucleic acids, antigens, or antibodies. we also summarize potential treatments and vaccines against covid- and discuss ongoing clinical trials of interventions to reduce viral progression. the recent global outbreak of covid- has led to a public health emergency. as of april , , over . million confirmed cases were reported to who from countries and territories [ ] . on january , , who declared the covid- outbreak as the sixth public health emergency of international concern, following h n ( ), polio ( ), ebola in west africa ( ), zika ( ), and ebola ( ) [ ] . the rapid global expansion and rising fatalities have raised grave concerns on the viral spread across the globe. with the rapid increase in the number of confirmed cases, who classified the global covid- outbreak as a pandemic on march , [ ] . covid- can spread from person-to-person and animal, and transmission of infection may occur with exposure to symptomatic patients or asymptomatic individuals. coronaviruses (covs) (corona: crown-like shape) are enveloped, single-stranded rna viruses that belong to the order nidovirales in the subfamily coronaviridae. covs are divided into four genera: alpha (α), beta (β), gamma (γ), and delta (δ) (figure (a) ) [ ] . alpha-and beta-covs infect mammals, while gamma-and delta-covs primarily infect birds [ ] . before december , six types of covs had infected humans, including two α-covs (hcov- e and hcov-nl ) and four β-covs (hcov-oc , hcov-hku , sars-cov, and mers-cov). the first two β-covs (hcov-oc and hcov-hku ) mainly cause self-limiting upper respiratory infections, while the other two β-covs (sars-cov and mers-cov) are mostly associated with severe respiratory illness [ , ] . full-genome sequence analysis of -ncov confirms that it is a β-cov, distinct from sars-cov and mers-cov [ ] . investigations reveal that -ncov shares~ % sequence identity with sars-cov while maintaining~ % nucleotide identity to the sars-like covs (zc and zxc ) from bats [ ] . a recent report suggests that a bat cov (ratg ) is % identical to -ncov [ ] . a typical cov genome is a single-stranded, positivesense rna (+ssrna) (~ kb) enclosed by a ′-cap and ′ -poly-a tail [ ] . the genome size of -ncov is , nucleotides, encoding amino acids, with a g+c content of % [ ] . the -ncov genome contains two flanking untranslated regions (utrs) on ′ -and ′ -terminals, one single long open reading frame ab (orf ab) encoding a polyprotein and at least five other orfs encoding structural proteins, and eight accessory proteins (figure (c) ). the first orf (orf a/b) is about two-thirds of the whole-genome length and encodes the nonstructural proteins (nsp - ) . the other one-third of the genome contains four orfs encoding the spike (s), membrane (m), envelope (e), and nucleocapsid (n) proteins, whereas other orfs encode accessory proteins (figure (b) and (c)). most of the nonstructural proteins are essential for -ncov replication, while structural proteins are responsible for virion assembly and viral infection [ , ] . the m and e proteins are required in viral assembly, while the n protein involves rna genome assembly. the s protein, a surface-located trimeric glycoprotein of covs, is the primary determinant of cov tropism, as it binds to the membrane receptor on host cells, mediating viral and cellular membrane fusion [ ] . the s protein of -ncov reportedly binds to angiotensin-converting enzyme (ace ), a homolog of ace on host cell membranes, contributing to -ncov cell invasion [ ] . moreover, this particular s protein shows a higher binding affinity to ace than the s protein of sars-cov, enabling -ncov to invade host cells more effectively [ , ] . recently, a transmembrane glycoprotein, cd , also known as basigin or emmprin, has been confirmed as another receptor for binding of the -ncov s protein, thereby mediating viral invasion [ ] . the e protein is an integral membrane protein that regulates viral life cycles, including pathogenesis, envelope formation, assembly, and budding [ ] [ ] [ ] . among the four structural proteins, protein e appears to have the highest antigenicity and the most significant potential as an immunogenic target, highlighting the possibility of developing protein e-derived peptides as a -ncov vaccine [ ] . systemic studies of proteins s and e have inspired scientists to take creative approaches to design anti-covid- drugs. although some covid- patients show no symptoms, most patients have some common symptoms such as fever, cough, fatigue, sputum production, shortness of breath, sore throat, and headache. in some severe cases, infections can cause pneumonia, severe acute respiratory syndrome, kidney failure, and death. according to the who-china joint report [ ] , on average, people infected with -ncov develop mild respiratory symptoms and fever, - days after infection (mean incubation period, - days; range, - days). people over years of age and those with hypertension, diabetes, or cardiovascular diseases are at high risk for severe illness and death. in comparison, children under years appear to be infected minimally by -ncov (around . % of all reported cases). based on the chinese center for disease control and prevention (china cdc) report (from , patient records, dated february ), among the confirmed cases, . % of patients are - years of age, . % of patients have mild-to-moderate disease, . % have a severe illness, and . % are critically ill [ ] . notably, the mortality rate of children under years is . %, while people aged over years have the highest mortality rate of . %. currently, there are no effective antiviral drugs or specific vaccines against covid- . thus, there is an urgent need for rapid detection to prevent further spread, to reduce the intensity of the pandemic, and to slow the increase in cases. recently, several new technologies, including lamp-lfa, rpa-lfa, rpa-crispr, and other nanomaterial-based igg/igm kits, have been adopted for -ncov detection. a significant number of drug candidates, including chemical drugs, biological drugs, nutritional interventions, and traditional chinese medicine (tcm), have been proposed for clinical trials after the -ncov outbreak. in this review, we concentrate on the most significant developments in -ncov detection and provide an overview of medical treatments and vaccines currently in development to combat and contain the disease. properties of the virus and biomarkers that hosts exhibit after infection. these biomarkers include viral proteins and nucleic acids, as well as antibodies induced in response to viral infection. the most common -ncov detection methods include viral nucleic acid detection and serum antibody (igg or igm) detection. a confirmed case should have at least one of the following criteria: (i) a positive result for -ncov nucleic acid, using real-time pcr tests from respiratory or blood samples; (ii) a high homogeneity between viral gene sequencing from respiratory or blood samples and known -ncov; and (iii) serum samples positive for igm or igg to -ncov, or seroconversion in igg, or a fourfold or more significant increase in igg antibody titer to -ncov in the recovery phase than in the acute phase [ ] . . . . high-throughput sequencing ( nd -generation sequencing). high-throughput sequencing (hts) technology contains various strategies that depend on a combination of library preparation, sequencing and mapping, genome alignment, and data analysis [ ] (figure (a) ). unlike the sanger sequencing method ( st -generation sequencing) [ ] , nd -generation sequencing has been widely applied in genome sequencing, transcriptional profiling (rna-seq) disease mapping, and population genetic studies. the wholegenome nucleotide sequence of -ncov was identified and compared with the full-length genome sequence of coronavirus from bats [ ] through hts. hts-based technology is also applied to detect -ncov. for example, wang et al. developed a hts method based on nanopore target sequencing (nts) by harnessing the benefits of target amplification and long-reads for real-time nanopore sequencing [ ] . this nts strategy detects -ncov with higher sensitivity ( -fold) than standard qpcr, simultaneously with other respiratory viruses within - h. moreover, all targeted regions can be identified by nts in higher copies of samples ( - copies/ml) within min, indicating the potential for rapid detection of an outbreak in the clinic. for h sequencing data, reads mapped to -ncov differed remarkably from those of negative controls in all targeted regions at concentrations ranging from to copies/ml. importantly, nts can identify mutated nucleic acids. however, the nts platform cannot readily detect highly degraded nucleic acid fragments that are less than base pairs in length [ ] . moreover, the strategy requires tedious sample preparation and lengthy turnaround time. although hts technology provides fast, low-cost dna sequencing, it is not suitable for detection in clinics. on the other hand, the hts strategy may be suitable for amplicon sequencing or de novo sequencing of a whole genome [ ] . reaction (rt-pcr). rt-pcr is considered the gold standard to detect nucleic acids extracted from -ncov specimens qualitatively. positive results indicate infection with -ncov. rt-pcr is an advanced technique for coronavirus detection because of its optimized sensitivity, specificity, and simplicity for quantitative assay [ , ] . it provides accurate and reliable identification for confirmed and suspected cases. there are many commercial -ncov detecting kits with oligonucleotide primers and probes (sybr green or taqman chemistries) for detecting double genes of -ncov (nucleocapsid n gene and orf ab/e/orf b/s gene). this strategy usually requires four steps: sample collection (respiratory swabs), sample preparation (rna isolation), one-step qrt-pcr, and data analysis ( figure (b)) [ ] . real-time rt-pcr has been adopted as the gold standard diagnostic approach for -ncov worldwide. however, rt-pcr is time-consuming ( - h) and requires wellequipped laboratories and skilled technicians, thereby limiting full deployment in developing countries. . . . reverse transcription-isothermal amplification (rt-iamp)-based detection. isothermal amplification technology has been developed to eliminate the need for a high-precision instrument in rt-pcr assays. this approach can amplify dna at isothermal conditions without a thermocycler [ ] . there are mainly four isothermal amplification technologies for nucleic acid detection: lamp, rpa, nucleic acid sequence-based amplification (nasba), and transcriptionmediated amplification (tma) [ ] . in nasba and tma assays, input rna is converted to a double-stranded dna intermediate with a promoter region. detection of rna using dna polymerase-based amplification requires a reverse transcriptase step. lamp and rpa do not require thermal or chemical melting with the aid of enzymes. combined with a visual detection platform, such as a lateral flow assay (lfa) or organic dyes, lamp and rpa have been widely employed in viral detection kits. lamp is a rapid, one-step amplification technique that amplifies nucleic acids with high sensitivity and specificity at an optimal temperature of °c [ ] . lamp processing comprises three steps: an initial step, a cycling amplification step, and an elongation step (figure (a) ). lamp employs six primers to amplify targeted genes by creating stem-loop structures that promote new dna synthesis using a dna polymerase with strand displacement activity. the two inner primers (fip, bip) and two outer primers (f , b ), along with loop structures (lf, lb), create multiple initiating sites in the growing dna products, enabling rapid amplification. lamp is also highly specific since the amplification reaction occurs only when the primers correctly recognize all six regions. a reverse transcriptase step is included in the lamp reaction to allow rna targets to be detected [ ] . rt-lamp offers improved sensitivity and specificity in screening sars-cov, hcov-nl , and mers-cov compared to conventional real-time rt-pcr [ ] [ ] [ ] . recently, yu et al. used a commercial lamp kit to amplify fragmented orf ab genes of -ncov (figure (b) and (c)) [ ] . they optimized the lamp system through incubation at °c for different periods using a -ncov-positive rna sample as the template. results require a min reaction time at °c, and detection sensitivity is comparable to that of the taqman-based qpcr approach ( copies). rt-lamp employs two additional protocols for -ncov rna detection. park et al. performed rt-lamp at °c for min to identify the nsp , s, and n genes of -ncov using colorimetric detection [ ] . the sensitivity of this rt-lamp assay was copies of -ncov rna. the other rt-lamp protocol was conducted at °c for min to detect the orf ab, e, and n genes simultaneously [ ] . the results confirmed the specific nature of orf ab and the high sensitivity of the n gene. based on an analysis of clinical specimens, the sensitivity of this rt-lamp was similar to conventional rt-pcr, and the specificity was %. interestingly, ei-tholoth et al. designed a two-stage isothermal amplification procedure by combining rpa ( °c) with lamp ( °c) to detect synthesized dna fragments of -ncov [ ] . the test was performed in closed tubes within h using either fluorescence or colorimetric detection. this method has a sensitivity of times better than conventional lamp and rt-pcr, suggesting a rapid, sensitive, point-of-care test for use at home. rpa is an isothermal dna amplification method that utilizes a specific combination of enzymes and proteins (recombinase, single-strand binding (ssb) protein, and strand-displacing dna polymerase) to amplify target genes step : cycling amplification step : elongation step : initiation step : ssb binds to displaced strand step : bsu initiates polymerization step : parental strand is displaced and elongation continues step : recombinase binds primers step : ssb ds to displaced strand step : bsu tiates polymerization step : tal strand is displaced elongation continues step : recombinase binds primers rapidly at a constant low temperature between and °c in as little as min [ ] . rpa usually requires four steps to achieve dna amplification: formation of a recombinaseprimer complex, strand invasion, d-loop formation (stabilized by ssb, dna polymerization through the use of strand-displacing dna polymerase), and dna amplification ( figure (d)) [ ] . results of rpa can be detected by agarose gel electrophoresis, quantitatively measured using twis-tamp ™ probes, or simply applied in lateral flow assays. apart from dna target amplification, rpa formats have been developed for the detection of rna targets (rt-rpa) by adding a reverse transcriptase enzyme to reaction mixtures [ ] . because rpa-(rt-rpa-) based detection achieves more rapid and sensitive results and operates efficiently, it has been widely adopted to detect animal and human pathogens, such as hand, foot, and mouth disease (hfmd) virus, human immunodeficiency virus (hiv), bovine coronavirus, or mers-cov [ ] [ ] [ ] [ ] . currently, rpa has been applied to detect -ncov, in combination with other technologies, such as crispr or microfluidic technology. repeat-(crispr-) based detection. the crispr-associated protein (cas ) system (crispr/cas ) is a revolutionary gene-editing toolbox that can modify target genes with high precision and that can control various types of genetic diseases in preclinical studies [ ] [ ] [ ] [ ] . due to the collateral nucleic acid cleavage activity of cas effectors, crispr/cas systems have also been widely used in nucleic acid detection with fluorescent and colorimetric signals [ ] . there are mainly two kinds of crispr/cas systems for diagnostics, based on the cutting activity of cas protein on nucleic acids outside of the grna target site: the crispr/cas a and crispr/cas a systems. the crispr/cas a system (specific high-sensitivity enzymatic reporter unlocking (sherlock)) was developed by zhang's group, based on the collateral effect of an rnaguided and rna-targeting crispr effector, cas a (figure (a)) [ , ] . the detection system is highly sensitive and specific because it is capable of single-molecule nucleic acid detection. subsequently, they developed an enhanced sherlock version (sherlockv ) detection system with a . -fold improvement in detection sensitivity and lateral flow readout. sherlockv has been used to detect dengue and zika virus single-stranded rna or mutations in clinical samples, showing great potential for multiplexable, portable, rapid detection of nucleic acids [ ] . recently, they combined rt-rpa technology with the sherlock system (namely crispr diagnostics) to detect the s and orf ab genes of -ncov (figure (b) and (c)) [ diagnostics-based test can be conducted in hour and can be read using a dipstick. the analysis is performed at °c and °c, and its detection sensitivity is ten copies per microliter of input, exhibiting unique advantages, such as high sensitivity, specificity, speed, and suitability for point-of-care testing. however, this approach needs to be validated using real patient samples. unlike the crispr/cas a system, the crispr/cas a system is based on the collateral effect of cas a on singlestranded dna (ssdna). chen and colleagues combined cas a ssdnase activation with rpa technology to create a new approach, named dna endonuclease-targeted crispr trans reporter (detectr), with attomolar sensitivity for dna detection (figure (a)) [ ] . detectr was also validated with clinical samples, showing the capacity for rapid, specific detection of human papillomavirus (hpv) [ ] . recently, detectr was investigated to identify the nucleic acid of -ncov. lucia et al. applied the detectr (crispr-cas a and rt-rpa) to detect the rnadependent rna polymerase (rdrp), orf b, and orf ab genes of -ncov using synthetic rna fragments as samples [ ] . remarkably, all steps of the test were completed in h, and results were visible to the unaided eye. the limit of detection for orf ab was ten copies/μl. the advantages of this method are its portability and low cost (~us$ per reaction). but this proposed approach also needs to be validated with clinical samples before commercialization. another detectr-based -ncov detection strategy was developed by chiu's lab [ ] . they employed lamp, crispr/-cas , and lateral flow assay to detect the e and n genes of -ncov in clinical samples. this protocol supplied rapid (~ min), low-cost, and accurate ( % specific vs. % specific for qrt-pcr) detection of -ncov in respiratory swab samples. realistically, crispr/cas-based -ncov detection technology is highly specific, rapid, and low cost, but the detection strategy also needs to be validated using clinical samples. microfluidic-based detection. the abovementioned methods are based on relative quantification, because they require external calibration with genetic standards or inner reference dna templates, resulting in unavoidable errors and other uncertainties. on the contrary, methods that do not need standard curves can provide a quantitative analysis of nucleic acids using absolute quantification of genetic copies. recently, digital pcr and digital lamp have been achieved with microelectromechanical and microfluidic technologies [ , ] . microfluidic or lab-on-a-chip techniques use microsized channels to process or manipulate fluids. microfluidics has been widely utilized in various fields, including drug screening, tissue engineering, disease diagnostics, and nucleic acid detection [ , ] . based on its portability and ultralow sample consumption, microfluidics shows significant promises in clinical applications [ ] . regarding nucleic acid analyses, microfluidic devices aliquot diluted nucleic acid samples into hundreds to millions of discrete nanoliter chambers. the isolated chambers contain only one or zero target molecule according to a poisson distribution. consequently, the abso-lute copy number of target nucleic acid can be calculated from the number of positive and negative reactions, based on the poisson distribution formulas [ , ] . both digital pcr and digital lamp have employed microfluidics for pathogen analysis, which is suitable for covid- detection. for instance, ottesen and colleagues used digital pcr to amplify and analyze multiple genes on a microfluidic chip [ ] . this chip consisted of parallel chambers and micromechanical valves. the micromechanical valves segmented chambers into independent pcr reactors after the sample flowed into chambers through connection channels. the chip was able to detect several kinds of genes with parallel sample panels. digital pcr can also be conducted with droplets generated by the microfluidic chip. however, the detection of fluorescent signals in droplets requires special instruments, such as flow cytometers, which may limit its application in point-of-care testing. additionally, the high temperature in pcr amplification tends to evaporate the reaction liquid (nanoliter or even femtoliter), leading to unacceptable errors. using airtight devices or high pressure delays liquid evaporation but complicates the devices and increases testing costs. digital lamp is more compatible with microfluidics than digital pcr because it is executed at a moderate temperature. this simplifies microfluidic devices and reduces testing costs. many microfluidic devices have been reported for nucleic acid detection using digital lamp, such as self-digitization chips, self-priming compartmentalization chips, and dropletgeneration chips [ ] [ ] [ ] . as an example, xia et al. designed a mathematical model using the monte carlo method according to the theories of poisson statistics and chemometrics [ ] . the mathematical model illustrated influential factors of the digital lamp assay, guiding the design and analysis of digital lamp devices. based on the established mathematical model, they fabricated a spiral chip with chambers ( . nl) for pathogen detection ( figure (a)-(c)). this spiral chip operated at °c without visible liquid evaporation and achieved a quantitative analysis of nucleic acids over four orders of magnitude in concentration with a detection limit of copies per ml. this portable gadget shows significant promise in future point-of-care testing. microfluidics, combined with enzyme-dna nanostructures, is also applied to detecting -ncov. ho et al. developed a modular detection platform (termed envision) consisting of an integrated circuit of enzyme-dna nanostructures for direct and versatile detection of pathogen nucleic acids from infected cells [ ] . built-in enzymatic cascades in the envision microfluidic system supply a rapid color readout for detecting hpv. the assay is fast (< h), sensitive (limit of detection < attmol), and readily quantified with smartphones. recently, they adopted the envision microfluidic system to detect -ncov [ ] . preliminary results showed that the envision platform is sensitive, accurate, fast (within . - h), and inexpensive (less than $ per test kit). this novel platform works at room temperature and does not require a heater or special pumps, and it uses a minimal amount of samples, making it highly portable. however, this platform needs to be further validated with real clinical samples. antigen and antibody. as mentioned above, the primary diagnostic methods are virological detection involving viral nucleic acids. another approach to detection is with serological assays that measure antigens or antibodies present in the host. such testing provides vital information about host exposure to -ncov and is useful for detection and surveillance purposes. for instance, this method greatly helps medical professionals to determine whether some recovered patients have a higher risk of reinfection. however, the disadvantage is that one should be cautioned that in the early stages of covid- infection, the host's antibodies are often not within the detectable range of serological test kits. besides, there was no proven evidence on the duration of igm or igg antibodies circulating in the host after recovery. it could be merely a short time frame for detection. as such, serological tests should not be solely used for covid- diagnosis. early diagnosis of -ncov infection is of utmost importance both for medical teams to manage patients effectively and for policymakers to curb the viral spread. presently, elisa in cell culture extracts has proven to be the working "gold standard" for laboratory diagnosis of -ncov [ ] . elisa is a plate-based assessment method for detecting and quantifying biomolecules, including peptides, proteins, antibodies, and hormones. elisa techniques depend on specific antibodies to bind target antigens and a detection system to indicate the presence of antigen binding. in an elisa, an antigen must be immobilized to a solid surface and then complexed with an antibody that is linked to an enzyme. detection is accomplished by assessing the conjugated enzyme activity after incubation with a substrate to produce a measurable product [ ] . recently, coronavirus proteins have been widely used in elisa to diagnose sars-cov or other viruses within the coronavirus family [ ] . in a bold, novel approach, a team of infectious disease experts in singapore utilized an elisa against -ncov to ascertain that suspected subjects were infected with covid- and discovered the connection between two covid- clusters in the local community [ ] . using blood samples taken from alleged covid- patients, the researchers detected antibodies targeting the spike protein that prevented the virus from killing cells in laboratory tests. they verified that a couple allegedly infected with covid- had the disease because they had exceedingly elevated levels of virus-specific antibodies in their blood. interestingly, pcr tests on the couple yielded negative results. because the couple had recovered from the -ncov infection, they had no viral genetic materials in their bodies, but the antibodies persisted. there were also other reports of using elisa to diagnose -ncov infection [ , ] . each study confirmed the high reproducibility and specificity of elisa in diagnosing covid- patients accurately in clinics. research has established that the presence of immunoglobulin m (igm) indicates a primary defense against viral infections. this igm defense occurs before the production of high-affinity and adaptive immunoglobulin g (igg) that is critical for prolonged immunity and immunological memory [ ] . from a previous study on sars infections, both igm and igg antibodies could be detected in the patient blood after - days and beyond days, respectively [ ] . given that -ncov belongs to the same family of coronaviruses including mers and sars, -ncov should also generate igm and igg antibodies in infected humans. therefore, the detection of igm and igg antibodies may provide epidemiologists with crucial information on viral infection of test subjects, allowing them to adjust policies to combat the pandemic more effectively. point-of-care lateral flow immunoassays are performed qualitatively to quickly determine the presence of -ncov by detecting anti- -ncov igm and anti- -ncov igg antibodies in human plasma, serum, or whole blood. a typical device is shown in figure (a). reddishpurple lines in the readout indicate the presence of -ncov igm and igg antibodies in the sample. lfa is based on the lateral chromatographic flow of reagents that bind and interact with the sample. as the sample flows through the test device, starting at the sample pad region, the anti- -ncov igm and igg antibodies, if present, bind tightly to -ncov antigen-labeled gold nanoparticles, located on the conjugated pad. when conjugated products in the sample continue to move up the strip, anti- -ncov igm antibodies and anti- -ncov igg antibodies bind to anti-human igm (m line) or anti-human igg (g line), respectively. no visible lines can be seen when the specimen does not contain anti- -ncov antibodies because no labeled complexes bind at the test zone. igg-labeled gold colorimetric nanoparticles serve as the control when they bind to anti-rabbit igg antibodies at the control line (c) (figure (b) ). lfa has proven useful in detecting -nco-vigm/igg antibodies in clinical studies, demonstrating . % test sensitivity and . % specificity in human blood, serum, and plasma samples. results from six patients are shown in figure (c). common -ncov detection methods are summarized in table . in clinics, medical imaging tools are indispensable and form an essential component of viral diagnosis, as well as for monitoring viral progression [ ] . they have also been used for follow-up in outpatient settings for coronavirus-related pulmonary disorders. just like both sars and mers, pulmonary complications in covid- patients have been observed. learning from the well-documented sars and mers studies, ct imaging results in the acute and chronic periods of covid- are invariant, but not always present [ ] [ ] [ ] [ ] . evidence is found in previous studies on sars and mers. the glass opacities observed are not always found in covid- patients. crucially, preliminary imaging discoveries indicate that covid- yields nonspecific results as well [ ] [ ] [ ] . radiologists are presently striving to any characteristics specific to covid- , although present medical information remains limited. given the precarious situation, there is a pressing need for alternative, complementary diagnostics. ct is one example. covid- patients often develop "ground glass" lung opacities [ ] . as such, a ct imaging scan can readily identify lung abnormalities in human subjects, thereby enabling early treatment against covid- . ct has demonstrated some common imaging characteristics in covid- patients. these features include bilateral, multifocal, ground glass opacities, with a peripheral distribution (figure (a)) [ ] . crucially, more than half of patients under study presented multilobar involvement and lesions more prominently in the lower lobes of their lungs. given its feasibility and ease of use, ct has become an essential tool for the -ncov infection diagnosis. from a radiological perspective, the advantages of using ct imaging could expedite the rate of diagnosis. it also supports the current shortage and heavily reliant on technical knowhow during rt-pcr testings. nonetheless, one limitation is that it should be cautiously utilized as a diagnostic approach because there are no proven, evidence-based clinical benefits of using ct. it could also cause false securities if results are negative. other limitations include requirements of relatively high-dose ct scans and long-term, continuous usage, which can altogether be logistically challenging and deplete additional medical resources. transmission electron microscopy (tem) has been used for many years and has had a profound impact on our understanding of illnesses, including viral infections. the thousandfold enhanced resolution provided by tem enables investigators to visualize viral morphology and to classify viruses into families [ ] . mechanistically, tem operates based on interactions between electrons emitted from a source and materials under examination. in the present context, it is usually -ncov in a cellular sample [ ] . the detector collects a multitude of signals from transmitted electrons, before processing them to reveal viral morphology and location within cells [ ] . typical specimen preparation for tem includes sample fixation, embedding, sectioning, staining, and loading onto the tem copper grids [ , , ] . -ncov sampling typically uses supernatants from patient airway epithelial cells. infected cells are fixed and dehydrated before embedding in resin. a negatively stained, film-coated grid for examination is similarly prepared for contrast enhancement. -ncov virus particles seen with tem are shown [ ] (figure (b) ). tem enables microbiologists to rapidly diagnose patients with a single examination of a single tissue sample. there are three general approaches to develop potential antiviral treatments of the human coronavirus. firstly, standard assays may be used to evaluate existing broadspectrum antiviral drugs. secondly, chemical libraries containing existing compounds or databases may be screened. thirdly, specific, new medications based on the genome and biophysical understanding of -ncov can be designed and optimized. therefore, this section will discuss some of the potential -ncov therapeutics obtained through these general approaches. besides chemical and biologic drugs commonly used in antiviral therapies, we further elaborate on how nanomaterials, nutritional interventions, traditional chinese medicine, and stem cell therapy can be potentially used for treatment or as an adjuvant to reduce the mortality and morbidity rate of -ncov patients. finally, to end this section, we highlight vaccines as a key therapeutic option to eradicate covid- through herd immunity without getting the disease. . . chemical drugs. there are currently no approved antiviral drugs to treat covid- , and patients must depend upon their immune systems to combat the infection. a full-fledged treatment plan has yet to emerge, and both academia and pharmaceutical companies are racing to develop new treatments and vaccines to address covid- . research into the cellular and molecular pathogenesis of -ncov has provided essential insights with the hope of developing viable therapies. while researchers are working on cures or preventive measures for covid- [ ] , a more robust, efficient, and economical way to tackle the disease is to repurpose existing drugs into a viable therapeutic strategy. drug repurposing, also termed drug repositioning, refers to the process of discovering new therapeutic applications for existing drugs. it offers various advantages over traditional de novo drug discovery, i.e., reduced cost and drug development time, established drug characteristics, and, most importantly, established safe dosages for human use [ ] . repurposed drugs often negate the need for phase clinical trials and can be used immediately [ , ] . at present, repurposed drugs are the only option available at treatment centers for covid- patients. as covid- is a viral infection, the most obvious choices for repurposed drugs come from known antiviral drugs [ ] . antiviral creation strategies focus on two approaches: targeting viruses or targeting host cell factors. in this section, we will review antiviral drugs prescribed or proposed against covid- based on the antiviral drug creation strategies. when an infection occurs, the virus gains entry into a host cell by attaching itself to the host cell surface (figure ) [ ] . this relies on numerous interactions between the virion surface and the specific proteins on the cell membrane. in general, these surface proteins have other functions but are serendipitously recognized by the virus as entry receptors [ ] . molecules that prevent such recognition, either by competitive binding or by downregulating the receptors, are known as viral entry inhibitors (figure (a) ). these inhibitors are valuable as therapeutics since blocking infection early in the life cycle reduces cellular and tissue damage associated with viral replication and production of viral progeny. as mentioned above, coronavirus particles comprise four structural proteins: the s, e, m, and n proteins [ ] [ ] [ ] [ ] . the s protein is the most crucial in viral attachment, fusion, and entry [ ] . it comprises two subunits. s facilitates attachment to the host cell receptor, while s mediates membrane fusion of the virion and the host cell. as mentioned above, viruses have specific attachment sites. sars-cov recognizes ace as its host receptor, while mers-cov recognizes dipeptidyl peptidase [ , ] . like sars-cov, -ncov also targets host ace [ ] [ ] [ ] . biophysical and structural analysis indicates that the -ncov s protein binds ace with higher affinity than the sars-cov s protein [ ] . therefore, it is vital to target ace for the development of viral entry inhibitors. to the best of our knowledge, not much is known about ace -specific inhibitors that are commercially available or under commercial development [ ] . however, ace stimulators have been used in the treatment of hypertension, cardiac diseases, and diabetes mellitus to regulate the reninangiotensin system [ , ] . there are also ace inhibitors known for treating the diseases mentioned, but these lack inhibitory activity toward ace due to their distinct substrate-binding pockets [ ] [ ] [ ] [ ] . in brief, there are concerns that both ace stimulators and ace inhibitors can increase the expression of ace , which in turn may increase susceptibility to viral host cell entry [ , ] . much work needs to be done on ace -targeting drugs, and controversial issues that lie beyond the treatment pathway need to be addressed soon. a small antiviral molecule, umifenovir, has entry inhibitory effects on the influenza virus. umifenovir targets hemagglutinin for its anti-influenza virus effect [ ] [ ] [ ] . hemagglutinin, a viral cell surface protein, facilitates infection by undergoing a conformational change when the virus binds to host cells [ ] . umifenovir interacts with hemagglutinin to stabilize it against low ph-induced conformational change via the formation of an extensive network of noncovalent interactions that prevent hemagglutininmediated membrane fusion [ , ] . it also interacts with phospholipids by altering membrane fluidity [ ] , which is vital for the fusion process. this is most likely due to umifenovir's molecular interactions (bearing both the h donor and acceptor groups) with the interfacial region of the lipid bilayer by competing for the hydrogen bonding of phospholipid c=o groups with water molecules [ ] . this renders lipid bilayers of host cells less prone to viral fusion [ ] . no studies have shown that umifenovir is effective in inhibiting sars-cov or -ncov. wang et al. reported that patients with mild/severe covid- recovered after prescription of combined lopinavir/ritonavir, arbidol (umifenovir), and shufeng jiedu capsule (a traditional chinese medicine) [ ] . on the other hand, dong et al. found in an in vitro study that arbidol may effectively inhibit -ncov infection at a concentration of - μm [ ] . chloroquine, also a small molecule, is a quinine analog used to prevent and treat malaria. similar to umifenovir, chloroquine exhibits its inhibitory effect on influenza by ph stabilization. chloroquine is a weak base and becomes protonated intracellularly in a manner described by the henderson-hasselbalch law [ ] . it can raise lysosomal ph to facilitate autophagy intracellularly [ ] [ ] [ ] . chloroquine also alters the signaling pathway of enzymes, causing enzyme glycosylation, ultimately inhibiting viral replication in host cells [ , ] . liu et al. claimed that chloroquine could inhibit sars-cov entry by changing glycosylation of the ace receptor and s protein [ ] . chloroquine's effective inhibition of sars-cov was demonstrated in vitro on primate cells and human rectal cells [ , ] . hydroxychloroquine is a derivative of chloroquine with an additional hydroxyl group. these two chloroquines share similar struc-tures and mechanisms. both have shown in vitro antiviral activities toward -ncov [ ] [ ] [ ] . hydroxychloroquine was more effective than chloroquine in inhibiting -ncov in vitro on primate cells [ ] . until now, chloroquine has shown apparent efficiency and safety against -ncov in clinical trials conducted in china [ ] . currently, chloroquine or hydroxychloroquine has been administered to hospitalized -ncov patients on an uncontrolled basis in various countries, including china and the usa [ ] . however, it must be noted that chloroquine and hydroxychloroquine cause ocular toxicity [ ] . hydroxychloroquine is reportedly less toxic than chloroquine, making it more attractive as a prescription drug [ , ] . nevertheless, more investigation and clinical trials are needed to evaluate further their efficacy and safety in treating -ncov. proteases are essential enzymes that regulate cell life processes such as cell growth and death, blood clotting, inflammation, fertilization, and infection [ ] . viral entry into host cells requires s protein priming by host proteases, which subsequently enables the fusion of viral and cellular membranes [ ] . membrane fusion enables the release of the viral genome into the host cytoplasm, initiating rna translation into protein. most viruses also encode their proteases to protect viral proteins by modulating host cell responses. while proteases are vital for cell life processes, they have become promising targets for antiviral therapeutic agents. protease inhibitors prevent viral replication by binding selectively to viral proteases or blocking proteolytic cleavage of protein precursors necessary for the production of infectious particles [ ] . it is noteworthy that protease inhibitors were a major therapeutic breakthrough of antiviral drug design in the mid- s for the treatment of hiv. most hiv protease inhibitors have found prominent clinical use (figure (b) ). coronavirus s proteins can be primed by a multitude of proteases [ ] . hoffmann et al. demonstrated that the s protein of -ncov could be primed by serine protease tmrpss [ ] . similarly, both sars-cov and mers-cov can be activated by other tmprss family members [ ] . tmprss family proteases are widely expressed in the respiratory tract [ , ] , which is likely the reason that coronaviruses cause acute respiratory distress syndrome. upon successful priming, the viral genome encoding rna and several nonstructural proteins, including coronavirus main protease ( clpro), papain-like protease (plpro), and rdrp, are released [ ] [ ] [ ] . the single-stranded positive rna is translated into viral polyproteins by ribosomes in the host cell cytoplasm. the polyproteins are then cleaved into effector proteins by viral proteases: clpro and plpro. plpro also acts as a deubiquitinase that may remove specific host cell proteins (e.g., interferon regulatory factor (irf ) and nuclear factor kappa-light-chain-enhancer of activated b cells (nf-κb)), thus weakening the immune system [ , , ] . both host and viral proteases are essential therapeutic targets in the case of covid- . camostat mesylate is a small molecule that has shown an excellent therapeutic effect for chronic pancreatitis treatment by targeting proteases [ , , ] . camostat mesylate primarily inhibits enzymatic autodigestion of the pancreas [ ] . in vivo studies on rats with pancreatic fibrosis showed that camostat mesylate inhibits inflammation, cytokine expression, and fibrosis in the pancreas [ ] . it has an additional clinical benefit for pancreatic pain by preventing enzyme-evoked activation of pain receptors [ ] . as mentioned above, the tmprss family, especially tmrpss , is most likely the protease targeted by a coronavirus. camostat mesylate inhibits tmprss activity on primate cells in vitro, completely blocking membrane fusion between the host cell and the viral mers-cov particle [ ] . zhou et al. claimed that camostat mesylate displays an inhibitory effect in mice for sars-cov infection [ ] . recent research by hoffmann et al. showed a promising in vitro inhibitory effect of this serine protease inhibitor in sars-cov and -ncov on human lung cells, showing potential as a viable option for covid- treatment [ ] . unfortunately, in vitro and in vivo data for camostat mesylate against coronaviruses are limited. more investigation is required to evaluate camostat mesylate as a potential therapeutic against covid- . lopinavir-ritonavir is a coformulated antiretroviral drug with excellent efficacy against hiv- . the lopinavir has a core molecular structure identical to ritonavir. the thiazolyl end group and -isopropylthiazolyl group in ritonavir are replaced by the phenoxyacetyl group and a modified valine, respectively, in which the amino terminus has six-membered cyclic urea attached. in brief, lopinavir is a potent protease inhibitor developed from ritonavir with high specificity for hiv- protease [ ] . it represents a higher proportion of the coformulation. lopinavir contains a hydroxyethylene scaffold mimicking a standard peptide bond cleavable by hiv- protease [ ] . this results in the production of noncontagious viral particles. on the other hand, ritonavir binds to hiv- protease, interrupting the maturation and production of viral particles [ ] . a clinical study from hong kong has shown that the combination of lopinavir-ritonavir and ribavirin treatment for patients against sars-cov had an overall favourable clinical response [ ] . it has been demonstrated that lopinavirritonavir targets clpro of -ncov and further indicated that clpro might also be the targets of protease inhibitors for other coronaviruses [ ] . regrettably, a recent clinical trial using lopinavir-ritonavir in wuhan, china, reported that hospitalized adult patients infected with -ncov did not benefit from the treatment [ ] . given such conflicting clinical data, physicians must carefully weigh lopinavir-ritonavir as a covid- treatment. darunavir is another antiretroviral protease inhibitor drug effective against hiv- . darunavir is designed for multidrug-resistant hiv- protease variants, due to its molecular structure, which introduces more hydrogen bonds compared to conventional antiretroviral medicines. in general, changes in van der waals and hydrogen bonding interactions between inhibitors and proteases affect the potency of antiretroviral drugs [ ] . aside from enzymatic inhibition, darunavir inhibits protease dimerization [ ] . the dimerization of hiv protease is essential for the acquisition of its proteolytic activity for the maturation of viral particles [ ] . lin et al. claimed that darunavir inhibits -ncov. the group has used molecular modeling to evaluate darunavir binding to clpro and plpro proteases and found targeted activity against the latter [ ] . nevertheless, the therapeutic effect of darunavir in covid- clinical cases remains untested [ ] . this may be in part due to potential side effects, such as liver damage and severe skin rashes [ , ] . these contraindications must be carefully evaluated if darunavir is to be considered a potential therapeutic agent for covid- . polymerases are enzymes essential for viral replication to produce viral progeny. viral dna and rna polymerases are responsible for duplicating the viral genome and facilitating transcription and replication [ ] . replication inhibitors (figure (c)) interfere with the production of viral particles by blocking enzymatic activity, ultimately causing chain termination during viral dna or rna replication [ ] . there are four types of viral polymerases in viruses: rna-dependent rna polymerases, rdrp, dna-dependent rna polymerases, and dna-dependent dna polymerases. in the section protease inhibitors, we mentioned that rdrp is released upon successful priming. rdrp is a necessary polymerase that catalyzes the replication of rna from an rna template for coronaviruses [ ] . release of rdrp from the virus initiates the synthesis of a full negativestrand rna template to be used by rdrp to replicate more viral genomic rna, which eventually turns host cells into virus factories [ ] . therefore, rdrp is an attractive therapeutic target to prevent host cells from producing viruses. ribavirin is a synthetic guanosine nucleoside analog that mimics purines, including inosine and adenosine, and ribavirin has been used in the treatment of respiratory syncytial virus [ ] . it has only one ring at the heterocyclic base, compared with guanine's two rings. notably, ribavirin has a ribose sugar moiety with a hydroxyl group at the ′ -carbon position, enabling preferential activity in rna-related metabolism [ , ] . ribavirin inhibits cellular enzyme and inosine monophosphate dehydrogenase involved in purine nucleotide biosynthesis [ , ] . ribavirin is also known for its inhibitory effect on viruses by forcing viral genome replication to become catastrophically error-prone. it is likely that as a nucleoside analog, ribavirin is incorporated by rdrp into the newly synthesized viral genome, where it induces mutagenesis [ , ] . although ribavirin has proven effective against viral infections, its mechanism of action has not been firmly established, and there are several proposed mechanisms of action that require further validation [ , ] . ribavirin was initially used in treating sars; however, ribavirin treatment lacked an in vitro antiviral effect and caused adverse side effects including anemia, hypoxemia, and decreased hemoglobin levels [ ] . however, ribavirin was used as the primary treatment during the mers outbreak [ ] . in general, clinical studies of ribavirin treatment for sars and mers did not show strong evidence of efficacy against these coronaviruses [ ] [ ] [ ] . there have been no studies of ribavirin's efficacy against covid- . therefore, the use of ribavirin remains controversial and requires more investigation for a better understanding of its mechanism of action, efficacy, and toxicity, even though it is a widely available drug. favipiravir is a synthetic guanine analog frequently used for influenza treatment [ ] . structurally, favipiravir is closely related to ribavirin, in which it shares the same carboxamide moiety [ ] . while ribavirin interacts with the viral polymerase directly, favipiravir must be phosphoribosylated by cellular enzymes to its active form, favipiravir-ribofuranosyl- ′ -triphosphate (rtp) [ , ] . the viral polymerase mistakenly recognizes favipiravir-rtp for a purine nucleotide, thereby disrupting viral genome replication [ , ] . favipiravir has not been used against sars and mers previously, but interestingly, it has been shown to reduce viral infection of -ncov [ , ] . in a clinical study involving patients infected with -ncov, conducted in shenzhen, china, favipiravir showed better efficacy than lopinavir-ritonavir in terms of disease progression and viral clearance [ ] . another clinical study involving patients with covid- conducted in hubei province, china, also demonstrated that those treated with favipiravir had a higher recovery rate compared to those treated with umifenovir (preprint) [ ] . more clinical data are needed to validate favipiravir's efficacy and safety in -ncov treatment. remdesivir is a trial synthetic adenosine analog that has not yet been clinically approved [ ] . it was synthesized and developed by gilead science in for ebola virus infection [ ] . remdesivir needs to be metabolized into its active form, gs- , to initiate its activity. the active form of remdesivir inhibits viral rna polymerase and evades proofreading by viral exonuclease, causing an interruption in viral rna production [ , , ] . it has been demonstrated that remdesivir is effective against mers-cov infection in vivo and -ncov in vitro [ , ] , showing great potential as a therapeutic agent for -ncov. the drug is currently being validated in clinical trials [ ] . given that antiviral drugs have previously demonstrated reasonable inhibition of coronaviruses and therapeutic efficacy against coronavirus outbreaks, umifenovir, chloroquine, hydroxychloroquine, lopinavir-ritonavir, and ribavirin have been recommended in the latest guidelines for diagnosis and treatment of covid- , updated on february [ ] . recent studies also demonstrated that some antibiotics potentially inhibit -ncov replication. anderson et al. (preprint) recently developed the first bat genome-wide rna interference (rnai) and crispr libraries and identified mthfdi as the critical host factor for viral infections [ ] . mthfdi is a trifunctional enzyme involved in the one-carbon (c ) metabolic pathway, participating in the cellular production of purine, dtmp, and methyl groups [ ] . anderson et al. demonstrated that purine synthesis activity of mthfdi is an essential activity for viral replication, making mthfdi a potential target for developing antiviral drugs [ ] . they further explained that an mthfd inhibitor, carolacton, restricts replication of influenza virus, mumps virus, melaka virus, zika virus, and, most importantly, -ncov [ ] . carolacton is a secondary metabolite derived from the mycobacterium sorangium cellulosum. it is a macrolide ketocarbonic acid. carolacton has been studied as an antibacterial compound against biofilms of pathogenic streptococcus mutans and growth of pathogen streptococcus pneumoniae [ , ] . it has no toxic effect against eukaryotic cells [ ] . it has recently been identified as a potent inhibitor of mthfdi, and its mechanism of action is presumably due to the ability of carolacton to bind with mthfdi [ ] . more research is needed to validate the mechanism of action, efficacy, and safety of carolacton as a possible treatment for covid- . on the other hand, ivermectin is originally a medication used to treat parasite infestation. it comprises different analogs of avermectin: , -dihydroavermectin b a and , -dihydroavermectin b b, at a ratio of : [ ] . they are macrolide antibiotics isolated from the fungus streptomyces avermitilis. it has reportedly stopped hiv-i proliferation by inhibiting interaction of the retroviral integrase protein with adapter protein (importin), responsible for the nuclear protein import cycle [ ] . caly et al. reported that ivermectin successfully inhibited -ncov in vitro but the mechanism of action is unclear [ ] . since ivermectin is an approved drug, it shows great potential as a therapeutic agent for covid- . in vivo work or clinical trials need to be done to confirm its efficacy and safety for treatment against covid- . potential drugs for covid- are summarized in table . . . nanodrug delivery system. nanomaterials have recently been utilized for the treatment of diseases such as cancer [ ] [ ] [ ] and various types of infections [ , ] . the ease of modification of surface properties, large surface area [ ] , and multivalent interactions with targets [ ] imbues nanomaterials with massive potential as highly efficacious covid- therapeutic options. however, to the best of our knowledge, no nanoparticle treatment option has been applied to covid- . nonetheless, results obtained from nanoparticle research against other viruses have shown promising potential. for example, fujimori et al. utilized a cui nanoparticle to treat h n influenza through the generation of reactive oxygen species (ros) that inactivate the virus [ ] . silver nanoparticles also show much promise in treating covid- with their broad antiviral properties against a multitude of viruses, including hiv, hepatitis b virus, herpes simplex virus, respiratory syncytial virus, and monkeypox virus [ ] . the broad antiviral properties of silver nanoparticles and the generality of ros inactivation suggest that these nanoparticles can be utilized therapeutically without any modifications. nanoparticles could also be used for drug delivery. recently, herold and sander demonstrated the use of pulmonary surfactant-biomimetic nanoparticles to encapsulate a stimulator of interferon gene (sting) agonist, ′ , ′ -cyclic guanosine monophosphate-adenosine monophosphate, as an adjuvant in a variety of influenza vaccines [ ] . using nanoparticles as a delivery agent, immune cells were activated without excessive inflammation in the lung. this could provide a considerable benefit for use in covid- vaccines in the future, but as the field is still relatively new, especially in medicinal applications, safety should remain a key consideration in the adoption of nanoparticles in humans. in addition to chemical medicines, another vital form of therapy for covid- may be the use of biologics. currently, interferon-α b nebulization of , to , iu/kg twice a day for to days is one of the main treatments for covid- in children, and it has demonstrated efficacy in reducing the viral load during early stages of infection [ , ] . another promising biologic drug is convalescent plasma, the plasma of patients who have recovered from covid- [ , ] . antibodies in the donated plasma could confer temporary, passive immunity against covid- , allowing patients time to develop active immunity. clinical trials are currently ongoing [ , ] , and preliminary results announced from the chinese hospitals have been promising. on the other hand, human monoclonal antibodies or their fragments developed in the lab have shown encouraging results as well. tian et al. confirmed the binding of a human monoclonal antibody cr to the receptor-binding domain (rbd) of -ncov with high affinity [ ] , highlighting the therapeutic potential of cr toward covid- , though further in vitro and in vivo studies are required before it could be used clinically. another supportive treatment for covid- involves dietary interventions. various research studies have shown supplementation of multiple vitamins and minerals such as vitamins a, c, and d and zinc can reduce the severity of respiratory infections [ ] [ ] [ ] [ ] [ ] [ ] [ ] . however, most of these studies targeted children below the age of who were suffering from malnourishment or preexisting diseases. therefore, vitamin and mineral supplementation may offer more significant benefits to covid- patients in developing countries. moreover, aggressive supplementation of calories and protein in nutritionally at-risk patients has shown significant benefits in reducing mortality [ ] . using a modified nutrition risk in critically ill (mnutric) score, kalaiselvan and coworkers demonstrated that . % of mechanically ventilated patients have high nutritional risks (mnutric score ≥ ), accompanied by long intensive care unit (icu) stays and high mortality rates [ ] . an estimated % of covid- patients require icu care, and of these critically ill patients, most need mechanical ventilation [ , ] . therefore, nutritional intervention using aggressive calorie and protein supplementation may provide substantial benefits to a significant number of critically ill patients. evidence of such benefits may be provided by the clinical trial (nct ) that is expected to end in july . . . traditional chinese medicine. traditional chinese medicine (tcm) is considered a prospective supplementary treatment of covid- , due to its impressive performance in treating sars in [ ] . first, tcm shows a generalized antiviral effect through direct inhibition of viruses and control of inflammation. for example, weng et al. reported that the smabucus formosana nakai (a traditional medicinal herb) ethanol stem extract displayed strong anti-hcov-nl activity [ ] . moreover, tcm can alleviate damage induced by inflammatory reactions and immune responses initiated by viral infections. single and combined chinese medicines could mitigate the cytokine storm by clearing the heat and toxicity in the body. for instance, tcm approaches were adopted to prevent and treat sars in and h n influenza in [ ] . as of february , , over . % of total confirmed cases (over , cases) had been treated with tcm, showing that tcm yields excellent outcomes. notably, in a trial of cases with mild symptoms, tcm achieved remarkable therapeutic effects, demonstrated [ , ] in vitro antiviral activities against bat kidney cells [ ] not known none ivermectin genome replication antiparasitic drug (broad-spectrum). in vitro antiviral activities against -ncov on primate cells [ ] not known none n/a: not available. note: "coronaviruses" only target sars-cov and mers-cov. by faster clinical symptom disappearance and reduction of fever, shorter disease course, higher cure rate (by %), and lower rate of moderate-to-severe cases [ ] . to date, the national health commission (nhc) of the people's republic of china has published seven editions of the guidelines for diagnosis and treatment of covid- [ ] . since the fourth version, a list of tcm prescriptions (including tcm soup and tcm capsules) has been recommended for patients based on the stage of the disease and their symptoms [ ] . according to the th edition of the guidelines, there are three kinds of tcm prescriptions recommended for different stages of patients: the medical observation period, the clinical treatment period, and critical condition (details in table ) [ ] . among tcm recipes, the qing fei pai du decoction is strongly recommended for treatment of covid- by the nhc of the people's republic of china, because it gave a cure rate of over % of covid- patients in a clinical trial involving confirmed cases [ ] . another tcm recipe, xue bi jing injection is specifically recommended for treating critically ill covid- patients, because it suppresses severe sepsis, according to the china food and drug administration. it also promoted significant improvement in cases of severe community-acquired pneumonia (cap) [ ] . therefore, tcm could be an alternative prophylactic approach to covid- and a supplementary treatment in combination with western medicine to cure covid- . . . stem cell therapy. stem cell therapy is a promising treatment strategy for degenerative diseases, including huntington's disease, parkinson's and alzheimer's diseases, and chronic diseases such as cardiac failure and diabetes [ ] . a clinical study showed that transplantation of mesenchymal stem cells (mscs) significantly lowered the mortality of patients with h n -induced acute respiratory distress syndrome (ards), with no harmful effects [ ] . as h n and -ncov share similar genome structures and corresponding infection mechanisms, as well as related clinical symptoms (lung failure), msc-based therapy could be a possible alternative for treating covid- . currently, stem cellbased therapy for covid- is being conducted by different hospitals in china. doctors from baoshan hospital (yunnan province, china) used human umbilical cord mesenchymal stem cells (hucmscs) to treat a -year-old critically ill woman with covid- . two days after the rd injections of stem cells, the woman recovered, and the throat swab test for covid- turned negative [ ] . another clinical trial involving stem cell therapy was conducted in seven confirmed covid- patients in different clinical stages in beijing youan hospital (beijing, china). two to four days after intravenous transplantation of ce -mscs, all symptoms such as high fever, weakness, and shortness of breath disappeared in all seven patients without observed adverse effects, indicating that mscs can cure or significantly improve functional outcomes [ ] . there are at least other trials using stem cells to treat covid- in china, according to the who report. vaccines are another promising treatment to prevent or cure specific viruses. currently, there is no effective vaccine against -ncov. fortunately, two covid- vaccines are undergoing clinical trials. the first is moderna's mrna- , an mrna vaccine, which started at kpwhri in seattle, usa, on march , [ ] . it targets the spike protein of -ncov. the other vaccine, ad -ncov (a recombinant novel coronavirus disease vaccine (adenovirus type vector)), was conducted at tongji hospital in wuhan, china, on march , [ ] . the trial was jointly developed and administered by cansino biologics inc. and the academy of military medical sciences. ad -ncov, a genetically engineered vaccine, expresses the -ncov s protein using replication-defective adenovirus type as an expression vector, thereby inducing a virus-specific immune response to prevent covid- . there are also several other types of covid- vaccines, including deoptimized live attenuated vaccines, protein vaccine, dna vaccine, rna vaccine, and subunit vaccine, all of which are in the preclinical stage (table ) [ ] . notably, there is a new microneedle array (mna) approach based on delivering coronavirus s subunit vaccines against covid- . expedited by prior experience in developing vaccines against mers, this approach was developed within weeks and enabled long-term induction of potent virus-specific antibody responses. significantly, the mna work can be extended to other emerging infectious diseases. however, these will require further clinical studies for efficacy and safety, which requires more time. according to the th edition of the diagnostic criteria [ ] , patients severely or critically ill with covid- should receive comprehensive antiviral treatment, including lopinavir/ritonavir, arbidol, or shufeng jiedu capsule. meanwhile, they also need additional treatments, according to their symptoms, including respiratory support (oxygen therapy, high-flow nasal cannulas, or noninvasive ventilation, invasive mechanical ventilation, or extracorporeal membrane oxygenation-(ecmo-) based therapy), circulatory support, or continuous renal replacement therapy. the main therapeutic approaches proposed for covid- are summarized in table . as the most recent pandemic, covid- induces much fear. it is highly infectious and is transmitted asymptomatically. as such, our best options to slow and prevent transmission are to understand the origin of -ncov, its transmission route, and associated disease pathways and systems. generally, a pathogen must remain viable outside the host to allow for environmental spread [ ] . collective effects of many biotic and abiotic factors determine the period that the pathogen can survive [ ] . as of now, covid- is thought to be transmitted directly from person-to-person through liquid (droplets) and, more importantly, transmitted indirectly via contact with contaminated surfaces. -ncov remains viable for a fairly long period outside the human body (up to hours) and is more stable on plastic and stainless steel than on copper and cardboard [ ] . therefore, aerosol and fomite transmission of -ncov is possible, as the virus lingers among particles or fibers, in airborne liquid droplets, and on surfaces, in some cases for days [ ] . although there are currently insufficient data on the inactivation of environmental -ncov, data from other coronaviruses can be used as a reference. however, it should be noted that biocidal agents may only limit the survival of coronavirus in critical environments and have no efficacy for infected patients. given the high transmissibility of covid- , its propensity for asymptomatic transmission, and its persistent nature, confirmed patients could only be quarantined and treated in adequately equipped facilities. this also applies to anyone who has come into contact with these patients. as such, contact tracing is still a mainstay for disease control. confirmation can be achieved only when specific diagnostic methods have been employed. chest ct imaging is useful as an initial evaluation for covid- , as ct confirmation is often possible even before symptoms appear; therefore, it is recommended for suspected covid- cases [ ] . once the primary diagnosis reveals abnormal chest ct findings, a nucleic acid test should be performed to confirm whether a patient is infected. once a person is confirmed positive, tests such as c-reactive protein (crp), complete blood count, urinalysis, biochemical indicators (i.e., liver enzymes, myocardial enzymes, and renal function), blood coagulation function, arterial blood gas analysis, and cytokine levels should be performed to monitor the patient's condition [ ] . chest ct should be performed as a follow-up to treatment as well [ ] . the currently adopted procedure in identifying potential covid- cases in china is summarized in figure . on a community scale and beyond, strict controls over human traffic are essential to limiting disease transmission. by establishing lockdowns, china has been able to bring the crisis under control. other nations are now following the chinese's approach in restricting movement of residents within their borders. as evidenced globally, social distancing is essential to halt the spread of covid- . on the other hand, individuals have the responsibilities to follow the guidelines given by the authorities, to practice good hygiene, and to behave responsibly. covid- , like the past epidemics, does not recognize political boundaries, ethnicity, or gender. the disease has challenged the economic and medical infrastructure of the entire globe. as evidenced by events of the past few months, the impact of the outbreak depends upon how well we are prepared to face such a challenge. only with time will we be able to fully evaluate the measures that are being taken against covid- today. previous coronavirus epidemics like sars and mers have expedited the process of finding useful diagnostic and therapies against -ncov. it is of paramount importance for all countries to share essential information about -ncov to mitigate its spread. because of this strategic approach, research has been mobilized to rapidly develop diagnostic methods and worldwide implementation to minimize the impact of the pandemic. practical diagnostic tests have aided management and contact tracing of covid- cases in hotspot areas. in this regard, molecular virological techniques have assisted the scientific community in characterizing infectious agents for years. these include qrt-pcr, isothermal amplification, and crispr technology. on the other hand, serological assays for antibodies and antigens present essential tools to obtain valuable information about prior exposure to -ncov and the prevalence of infection. these include elisa and lfa technologies. serological screening also enables novel vaccines to be assessed and supports the design of functional vaccine approaches. other approaches, including chest computed tomography (ct) and transmission electron microscopy (tem), can boost existing detection approaches. notably, there has been a marked increase in the use of both ct and tem to detect -ncov and other coronaviruses. these complimentary tools reveal the progression of suspected infection, which cannot be accomplished by conventional diagnostic means. nonetheless, there is a pressing need for continuous development of rapid, accurate diagnostic devices and strategies to characterize unknown respiratory pathogens. despite these signs of progress, the present data suggest that current public health policies and improved diagnostic measures alone may not be sufficient to eradicate covid- in the short term. efficacious and novel treatments are desperately required. presently, large numbers of ongoing clinical trials of various drugs may succeed in minimizing morbidity and mortality. we have highlighted several of them in this review. some are highly promising, while others may require more time to demonstrate usefulness. while some drug candidates appear promising and have been used in treating covid- patients in desperation, it does not necessarily mean that they are proven safe and efficacious in the long run. as such, stringent criteria must be established by health regulatory agencies. however, in the long term, vaccines and prophylactics may be required to curb the spread of -ncov. the authors declare no conflicts of interest. covid- ) outbreak situation who, -ncov outbreak is an emergency of international concern who-director-general-s-openingremarks-at-the-media-briefing-on-covid more and more coronaviruses: human coronavirus hku discovery of seven novel mammalian and avian coronaviruses in the genus deltacoronavirus supports bat coronaviruses as the gene source of alphacoronavirus and betacoronavirus and avian coronaviruses as the gene source of gammacoronavirus and deltacoronavirus characterization and complete genome sequence of a novel coronavirus, coronavirus hku , from patients with pneumonia coronavirus as a possible cause of severe acute respiratory syndrome a novel coronavirus from patients with pneumonia in china return of the coronavirus: -ncov a pneumonia outbreak associated with a new coronavirus of probable bat origin genome composition and divergence of the novel coronavirus ( -ncov) originating in china genomic characterization of the novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting wuhan emerging coronaviruses: genome structure, replication, and pathogenesis ace expression by colonic epithelial cells is associated with viral infection, immunity and energy metabolism, medrxiv singlecell rna-seq data analysis on the receptor ace expression reveals the potential risk of different human organs vulnerable to -ncov infection cryo-em structure of the -ncov spike in the prefusion conformation structural basis for the recognition of sars-cov- by full-length human ace sars-cov- invades host cells via a novel route: cd -spike protein, biorxiv coronavirus envelope (e) protein remains at the site of assembly subcellular location and topology of severe acute respiratory syndrome coronavirus envelope protein a single polar residue and distinct membrane topologies impact the function of the infectious bronchitis coronavirus e protein design of multi epitope-based peptide vaccine against e protein of human -ncov: an immunoinformatics approach report of the who-china joint mission on coronavirus disease (covid- ) the epidemiological characteristics of an outbreak of novel coronavirus diseases (covid- )-china, national health committee of the people's republic of china, diagnosis and treatment guidelines for covid- april high-throughput determination of rna structures dna sequencing with chain-terminating inhibitors nanopore target sequencing for accurate and comprehensive detection of sars-cov- and other respiratory viruses rapid multiplex small dna sequencing on the minion nanopore sequencing platform mycobiome diversity: highthroughput sequencing and identification of fungi recent advances and perspectives of nucleic acid detection for coronavirus real-time rt-pcr in covid- detection: issues affecting the results quantification of mrna using real-time rt-pcr sars-cov- test to detect novel coronavirus receives fda emergency use authorization and is available in markets accepting the ce mark nucleic acid isothermal amplification technologies-a review isothermal nucleic acid amplification technologies for point-of-care diagnostics: a critical review loop-mediated isothermal amplification (lamp): a rapid, accurate, and cost-effective diagnostic method for infectious diseases development and application of reverse transcription loop-mediated isothermal amplification for detecting live shewanella putrefaciens in preserved fish sample a simple 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for rapid detection of foot-and-mouth disease virus rapid detection of hiv- proviral dna for early infant diagnosis using recombinase polymerase amplification a new approach for diagnosis of bovine coronavirus using a reverse transcription recombinase polymerase amplification assay reverse transcription recombinase polymerase amplification assay for the detection of middle east respiratory syndrome coronavirus development of a reverse transcription recombinase-aided amplification assay for the detection of coxsackievirus a and coxsackievirus a rna multiplex genome engineering using crispr/cas systems development and applications of crispr-cas for genome engineering crispr gene-editing tested in a person for the first time harnessing crispr/cas technology in cardiovascular disease nucleic acid detection with crispr-cas a/c c sherlock: nucleic acid detection with crispr nucleases multiplexed and portable nucleic acid detection platform with cas , cas a, and csm sherlock, a protocol for detection of covid- using crispr diagnostics crispr-cas a target binding unleashes indiscriminate single-stranded dnase activity an ultrasensitive, rapid, and portable coronavirus sars-cov- sequence detection method based on crispr-cas crispr-cas -based detection of sars-cov- digital pcr research highlights: digital assays on chip lab-on-a-chip: microfluidics in drug discovery the origins and the future of microfluidics the present and future role of microfluidics in biomedical research theoretical design and analysis of multivolume digital assays with wide dynamic range validated experimentally with microfluidic digital pcr monte carlo modeling-based digital loop-mediated isothermal amplification on a spiral chip for absolute quantification of nucleic acids microfluidic digital pcr enables multigene analysis of individual environmental bacteria digital lamp in a sample self-digitization (sd) chip self-priming compartmentalization digital lamp for point-of-care microfluidic continuous 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instrumentation matters unravelling biological macromolecules with cryo-electron microscopy here are the first images of how coronavirus replicates in cells preparation of viral samples within biocontainment for ultrastructural analysis: utilization of an innovative processing capsule for negative staining novel and potent inhibitors targeting dhodh, a rate-limiting enzyme in de novo pyrimidine biosynthesis, are broad-spectrum antiviral against rna viruses including newly emerged coronavirus sars-cov- innate immune cells and bacterial infection in zebrafish drug repurposing from an academic perspective drug repurposing approaches for the treatment of influenza viral infection: reviving old drugs to fight against a long-lived enemy chapter -antiviral drugs characterization of the receptor-binding domain (rbd) of novel coronavirus: implication for development of rbd protein as a viral attachment inhibitor and vaccine subunit vaccines against emerging pathogenic human coronaviruses vaccines for the prevention against the threat of mers-cov prospects for a mers-cov spike vaccine mechanisms of coronavirus cell entry mediated by the viral spike protein angiotensin-converting enzyme is a functional receptor for the sars coronavirus dipeptidyl peptidase is a functional receptor for the emerging human coronavirus-emc structure analysis of the receptor binding of -ncov functional assessment of cell entry and receptor usage for sars-cov- and other lineage b betacoronaviruses sars-cov- cell entry depends on ace and tmprss and is blocked by a clinically proven protease inhibitor structure-based discovery of a novel angiotensinconverting enzyme inhibitor the potential actions of angiotensin converting enzyme ii (ace ) activator diminazene aceturate (dize) in various diseases angiotensin-converting enzyme as a therapeutic target for heart failure diabetes and cvd risk during angiotensin-converting enzyme inhibitor or angiotensin ii receptor blocker treatment in hypertension: a study of patients ace inhibitor use and major cardiovascular outcomes in type diabetes treated with the dpp- inhibitor alogliptin evaluation of angiotensin-converting enzyme (ace), its homologue ace and neprilysin in angiotensin peptide metabolism covid- and angiotensinconverting enzyme inhibitors and angiotensin receptor blockers are patients with hypertension and diabetes mellitus at increased risk for covid- infection? structural basis of influenza virus fusion inhibition by the antiviral drug arbidol new small-molecule drug design strategies for fighting resistant influenza a characteristics of arbidol-resistant mutants of influenza virus: implications for the mechanism of anti-influenza action of arbidol mechanism of inhibition of enveloped virus membrane fusion by the antiviral drug arbidol membranotropic effects of arbidol, a broad antiviral molecule, on phospholipid model membranes clinical characteristics and therapeutic procedure for four cases with novel coronavirus 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epidemiologically related to a new coronavirus in the province of hubei, china. subsequently, there has been an increase in infections attributable to this virus throughout china and worldwide. the world health organization (who) has officially named the infection coronavirus disease (covid- ), and the virus has been classified as severe acute respiratory syndrome coronavirus (sars-cov- ). this appears to be a virus from rhinolophus bats, but the intermediate host has not yet been identified. the mechanism of infection of sars-cov- is not yet known; it appears to have affinity for cells located in the lower airways, where it replicates. the interhuman transmission of coronaviruses mainly occurs through saliva droplets and direct and indirect contact via surfaces. as of march , , the number of cases worldwide was , . along with severe acute respiratory syndrome (sars) and middle eastern respiratory syndrome (mers), covid- appears to cause a severe clinical picture in humans, ranging from mild malaise to death by sepsis/acute respiratory distress syndrome. the prognosis is worse in elderly patients with comorbidities. to date, there is no specific therapy for covid- . prevention of sars-cov- infection implies strategies that limit the spread of the virus. who and other international and national bodies have developed continuously updated strategic objectives and provisions to contain the spread of the virus and infection. background coronaviruses (covs) are a large family of respiratory viruses that can cause mild to moderate diseases, ranging from the common cold to severe respiratory syndromes [ ] . these viruses are common in many animal species, and, in some cases, albeit rarely, they can evolve and infect humans and then spread to the population [ ] . most of the numerous human pathogenic coronaviruses are associated with mild clinical symptoms, with two notable exceptions: severe acute respiratory syndrome (sars) and middle east respiratory syndrome (mers). sars is caused by a virus that emerged in southern china in november and led to [ human infections and deaths in countries in the - period [ ] ; mers is related to a virus detected for the first time in saudi arabia in , responsible for laboratoryconfirmed cases of infection and deaths since september [ ] . in december , some cases of viral pneumonia were epidemiologically linked to a new coronavirus in the province of hubei in china. in the following days a possible association with the huanan fish market in wuhan was identified. in fact, most of the initially identified patients had visited, worked at or lived near this market in the month preceding the infection. in early january, a new coronavirus, tentatively called -ncov, was isolated, and interhuman transmission was confirmed [ ] . on february , , the world health organization (who) officially named the new coronavirus infection coronavirus disease (covid- ) [ ] . subsequently the coronavirus study group (csg) of the international taxonomy committee of viruses (ictv) officially classified the virus as severe acute respiratory syndrome coronavirus (sars-cov- ) [ ] . this article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors. coronaviruses (covs) are rna viruses belonging to the subfamily of the coronavirinae, coronaviridae family, order nidovirales [ ] . their definition is related to the fact that covs are virions with projections resembling a crown. all covs share similarities in organization and genomic expression with nonstructural proteins and at least structural proteins (spike: s; envelope: e; membrane: m; nucleocapsid: n proteins) [ ] . they are divided into four genera: alphacov, betacov, gammacov and deltacov [ ] . covs can infect different hosts and have a different tissue tropism: generally, alphacovs and betacovs infect mammals while gam-macovs and deltacovs infect other animals such as birds, fishes and only a few mammals [ ] ( table ) . seven human covs are known to date, common worldwide. the first ones were identified in the mid- s, others more recently [ ] . the human covs are: e (alfacov), nl (alfacov), oc (betacov), hku (betacov), mers-cov (betacov, which causes mers), sars-cov (betacov, which causes sars) and -ncov/sars-cov- [ ] . in the past years, two major human cov epidemics have occurred: sars and mers. both viruses infect the lower airways and cause severe respiratory syndromes in humans. other covs have a global distribution with a seasonality characterized by a peak in winter and in spring and few cases in summer [ ] . the sars epidemic began in , starting from the town of foshan in the chinese province of guangdong, and then spread globally, involving countries in different continents. more than cases were recognized ( % in health workers) with a case fatality rate (cfr) of almost % [ ] and a basic reproduction number (r ) equal to - [ ] . in humans, the incubation period ranges between and days, and interhuman transmission is very effective, which is why the delay of months between the beginning of the epidemic and the first investigations has allowed a worldwide spread of the virus. the bat was identified as the natural reservoir of sars-cov and the civet as the intermediate host [ ] . despite active surveillance, no more sars cases have been recognized since july [ ] . mers was first identified in . from then until january , , cases were reported worldwide. these include deaths, with a cfr of % [ ] and an estimated r of . [ ] . most cases were found in the arabian peninsula and approximately % in saudi arabia [ ] . however, the virus was isolated in countries [ ] , and all patients outside the arabian peninsula had a travel history to or a contact with someone who had traveled to this region [ ] . in humans, the incubation period ranges between and days, and, unlike sars, interhuman transmission is limited. the virus is not easily transmitted from person to person, unless a close contact occurs. the bat was also identified as an animal reservoir for the mers-cov, while the intermediate host was the camel [ ] . both sars and mers have a broad spectrum of clinical pictures ranging from flu-like symptoms to acute respiratory distress syndrome (ards). age and comorbidities are prognostic predictors. sars mainly involved healthy young adults while half of mers cases were identified in subjects [ years of age. the clinical picture at hospital admission is characterized by fever, cough, dyspnea and myalgia in both sars and mers. atypical symptoms such as diarrhea and vomiting are common in both syndromes [ ] . epidemiology on december , , the who chinese office was informed about some cases of pneumonia of unknown origin in the city of wuhan, located in the chinese province of hubei [ ] . on january , , a new coronavirus was isolated from the bronchial wash samples of a patient from wuhan and was identified as the pathogen responsible for pneumonia [ ] . on january and , , the who received further details and information from the chinese national health commission regarding the possible association of this epidemic with exposure in a fish market in wuhan, and the chinese authorities shared the genetic sequence of a new coronavirus, subsequently identified as sars-cov- [ ] . new evidence shows the relation between sars-cov- and other covs that are circulating in bats, specifically in rhinolophus bats [ ] . these subspecies are abundant in southern china and asia, the middle east, africa and europe. the mode of transmission to humans is still unclear. bats are rare in chinese markets; however, they are captured and sold directly to restaurants as food. the most recent hypothesis is that there is an intermediate animal host that has played a role in the new sars-cov- infection [ ] . several animals have been considered as possible hosts, including pangolins [ ] . identifying the animal source of this new virus would help to prevent other new infections and to understand the initial dynamics of spreading in the wuhan market. in this regard, strengthening the control of food and hygiene within live animal markets is essential to prevent future new zoonosis [ ] . the mechanism of sars-cov- infection is not yet known. the key to human transmission is the ability of the virus to bind to human cells: covs use the spike protein to bind to cells, and it seems that sars-cov- , as sars-co virus, uses the same receptor for the conversion enzyme of angiotensin (ace ) [ , ] . a recent study showed that the binding affinity between the viral receptorbinding domain (rbd) and the host receptor ace , in the initial viral attachment step, determines the host susceptibility to sars-cov- . the greater transmissibility of sars-cov- than sars-cov is partly explained by the fact that, due to a higher affinity, the binding capacity of viral rbd increases and the number of viruses required to infect a cell is reduced [ ] . sars-cov- appears to have affinity for cells located in the lower airways, where it replicates, causing radiologic evidence of pneumonia in patients without any particular clinical symptoms [ ] . usually, the interhuman transmission of covs occurs through different pathways that include droplets, direct contact and indirect contact through surfaces [ ] . the virus has also been isolated in serum, blood, rectal swabs, saliva, urine and stool [ ] . fecal-oral transmission has not yet been proven [ , ] . a recent study indicates that the highest viral load is found immediately after the onset of symptoms and in greater quantities in the nose rather than in the throat. this analysis suggests that the spread of the sars-cov- virus resembles that of influenza more than that of sars. the viral load found in asymptomatic subjects was similar to that of symptomatic ones; this suggests the potential transmission role of asymptomatic subjects [ ] . despite several uncertainties, the evidence indicates that the cfr for hospitalized covid- patients is substantially lower than that for hospitalized sars, mers and pandemic flu h n patients ( %, %, % and %, respectively). taking into account covid- and influenza (pandemic and seasonal), it is important to carefully consider the differences in definition of cases, as these are relevant for cfr estimation [ ] . the r has been estimated between and [ ] , and the risk assessment calculated by who is very high for the whole world [ ] . as of march , , there were , confirmed cases of sars-cov- infection in the world, with new cases in the last h. in china, the country with the highest number of confirmed cases, , occurred, of which were within h with total deaths ( new in the last h) [ ] . the first case of sars-cov- laboratory-confirmed infection outside china was reported on january , , in thailand [ ] . as of march , , outside china there were , confirmed cases and deaths, and countries were involved [ ] . in the western pacific region, the countries with the highest number of cases were republic of korea ( ), japan ( ) and singapore ( ) [ ] . in the european region, italy counted cases; thus it was the second country with the most cases after china. france, germany and spain reported , and cases, respectively, while another countries reported \ cases [ ] . in the eastern mediterranean region, iran was the country with the highest number of cases ( ) [ ] . in the usa, cases were reported [ ] . of note, cases, including deaths, were reported in subjects on a cruise ship that had been anchored in japanese territorial waters [ ] . several clinical pictures have been associated with sars-cov- infection; they range from mild malaise to death, which occurs from sepsis and/or ards. early recognition of the clinical picture is essential to promptly start the adequate preventive measures and supportive treatments to avoid spreading of the virus and possible complications in patients [ ] (table ) . it seems that covid- presents with three worsening clinical pictures that evolve in few days: at the onset a slight malaise with symptoms of the upper respiratory tract, subsequently a mild pneumonia that can later worsen with a picture of ards [ ] . several retrospective studies show that hospitalization generally takes place on the th day after the onset of the symptoms (fever, fatigue and dry cough with dyspnea) [ , ] . other possible symptoms are myalgia, headache, anorexia, pharyngodynia and gastrointestinal complaints with diarrhea. many patients developed multiorgan dysfunction, radiologic signs of bilateral pneumonia with ards and acute renal failure; furthermore, mental confusion may occur [ ] . the incubation period lasts up to days ( - days as median incubation period) [ , ] . recently, the chinese center for disease control and prevention (ccdc) has published a work on a series of cases, currently the most numerous in the literature, concerning mainland china (updated on february , ). healthcare workers represent . % of cases; . % of these have been confirmed as serious or critical cases [ , ] . as for the distribution by age, %, % and % of cases were registered in young subjects (\ years and between and years of age), young adults (aged between and years) and adults and elderly people (age range -- years), respectively. elderly patients aged c years represented % of cases. regarding the spectrum of the disease, %, % and % of cases were affected by a medium intensity, severe and critical form, respectively [ , ] (table ) . according to these data, the overall cfr rate is . %. in detail, cfr was equal to % and . % in subjects aged between and years and in patients aged c years, respectively. no subject \ years of age died. no deaths have been registered in subjects suffering from mild or medium intensity forms, while cfr was equal to % in critical cases [ , ] (table ) . notably, cfr was high in subjects with comorbidities; in detail, cfr was equal to . %, . %, . %, . % and . % for cardiovascular diseases, diabetes, chronic respiratory diseases, hypertension and tumors, respectively [ , ] (table ). in conclusion people [ years of age and patients with comorbidities (most of all cardiovascular diseases) have a greater risk for a more severe clinical picture and for fatal outcome. furthermore, deaths occurred only in critical cases. fortunately, covid- seems to be relatively rare in children, whose clinical picture is often mild [ ] . according to another chinese study, the median age of patients is years, with a slightly higher percentage in males ( . % males vs. . % females). intensive care unit (icu) admission was needed in % of subjects, and . % of them died of multiorgan failure. once more, the worst clinical pictures refer to elderly subjects with comorbidities such as diabetes, high blood pressure and cardiovascular diseases [ ] . inter-human transmission was considered for % of patients: the infection seems related to previous exposure to the huanan fish market in . % of cases, family members in . % and healthcare workers in % [ ] . according to another study, some cases have also been reported in children aged -- months: the clinical picture was less severe than in adults, with fever and mild respiratory infections as prevalent symptoms. the transmission was mainly intra-familiar or through contacts with visitors to the huanan market [ ] . a recent study analyzed nine pregnant women with sars-cov- pneumonia. their clinical picture was similar to that of nonpregnant women affected by the virus. in all cases, a cesarean delivery was done, and no vertical transmission has been documented. therefore, it can be assumed that there is no evidence of vertical transmission during the third trimester of pregnancy [ ] . the diagnosis and confirmation of sars-cov- infection are carried out by specific tests recommended by who that are described on a dedicated webpage [ ] . the european centre for disease prevention and control (ecdc) also provided a specific webpage on laboratory support by a coronavirus-specialized laboratory in the european union [ ] . any person satisfying the criteria of a suspected case ( table ) should be tested for sars-cov- , and, when possible, samples from both the lower respiratory tract (bronchoalveolar lavage, endotracheal aspirate, expectorated sputum) and upper respiratory tract (nasopharyngeal swab, oropharyngeal swab, nasopharyngeal aspirate or nasal wash) should be collected [ ] . according to a recent chinese study, collecting specimens from different sites could be useful to improve the sensitivity and reduce false-negative test results. this study highlights that bronchoalveolar lavage fluid specimens showed the highest positive rates, followed by sputum, nasal swabs, bronchial biopsy, pharyngeal swabs, feces and blood [ ] . to date, there is no specific therapy for covid- . patients with covid- should receive supportive care to help relieve symptoms, and, for severe cases, treatment should include care to support vital organ functions [ , ] . several randomized clinical trials (rcts) are currently underway, not yet published, which are testing different therapies for covid- . one of the drugs, normally used in the treatment of rheumatoid arthritis, targets the interleukin receptor and has been included in the covid- treatment guidelines issued by the chinese national health commission [ , ] . in addition, several rcts are underway regarding the use of antiviral drugs for the treatment of covid- [ , [ ] [ ] [ ] [ ] . finally, a recent study evaluates the use of plasma from convalescent patients with previous sars-cov- infection as a potential therapeutic treatment [ ] . another study shows that the use of systemic corticosteroids for covid- is not recommended [ ] . the advent of covid- is unquestionably reminiscent of previous sars and mers epidemics. the increase in the number of cases and expansion of geographical areas have revealed issues regarding the future management of the infection: on march , , the who declared covid- a pandemic [ ] . at the beginning, efforts were made by the chinese government to limit the spread of the virus, such as suspension of public transport, closure of airports [ ] , cancellation of the lunar new year celebrations and closure of parks and cinemas. a ban on the wild animal trade within china was declared on january , [ ] . as the number of cases increased, more drastic containment measures were applied in china up to the suspension of all non-essential activities. these measures appear to have slowed the progression of sars-cov- infections in china, as can be seen from the progressive decrease in incidence in wuhan [ ] . since the beginning, the who and the emergency committee under international health regulations have stressed china's need to strengthen screening of exits from affected areas. in general, evidence in the peer-reviewed literature does not support entry screening as an effective measure for detecting infected travelers, especially when symptoms of the disease are very common/aspecific and the seasonal flu activity in europe and china is ongoing. however, some imported cases of covid- in asian countries have been detected through entry screening procedures at the destination airports [ ] . one of the screening methods for covid- is the measurement of body temperature, although current evidence shows that this method is not effective in controlling disease transmission [ ] . as of march , , who believes that restrictive measures for travelers and the exchange of goods must be proportional to the risk to public health, with the minimum duration possible and daily updates accordingly on the available epidemiology [ ] . currently, the us centers for disease control and prevention (cdc) has increased the level of traveler health alert and recommends avoiding non-essential travel [ ] . other countries are considering implementing restrictions for people traveling from and to the most affected countries. since the beginning of the pandemic, the who has developed a strategy and response plan to contain the impact of covid- . the main points included in this plan are related to blocking the chain of transmission (working on patients as well as close contacts), identifying and reducing transmission from animal sources, developing correct and scientifically sound risk communication and controlling the social and economic impact of the pandemic as much as possible to minimize it through multisectoral partnerships [ ] . the ecdc, taking into account the evolving epidemiologic situation, considers five possible scenarios (from to ). the objective is to avoid the health system disruption and to limit the impact of the pandemic as much as possible [ ] ( table ) . crucial general preventive measures should include: rigorous hand hygiene, avoiding coughing and/or sneezing without covering the mouth and the use of disposable tissues to mechanically block droplets [ ] . the who recommends hand washing with soap and water or use of alcohol-based solutions [ ] . the use of surgical face masks can reduce the risk of infection transmission; masks should be used by subjects with respiratory symptoms. there is no evidence of the usefulness of face masks by healthy subjects; besides, their use can be related to an increased risk due to a false sense of safety [ ] . isolation of symptomatic subjects can be considered to reduce transmission; patients (suspected or confirmed) should be asked to wear a surgical mask to reduce the spread of table different scenarios and options to limit the impact of the epidemic (modified from [ ] ) risk management and options for response localized outbreaks, which start to merge, becoming epidemiologically indistinct reduce burden on the health system and protect the population at risk scenario widespread sustained transmission and health care system over-burdened because of the large demand for services mitigate the impact of dissemination, protect the population at risk and reduce excessive mortality respiratory droplets, considered the most likely route of transmission [ ] . currently, many countries are considering or have already implemented relevant social measures such as school closures, smart working and cancelling meetings, sports and cultural events. social distancing is essential. it implies avoiding shaking hands and kissing, use of public and crowded means of transportation, and gatherings of people [ ] . strict compliance with all these measures is essential to lower the spread of infection to gain time to identify adequate therapeutic options and to design and hopefully develop a vaccine [ ] . italy is now the second country in the world in terms of case numbers [ ] . the first cases occurred in some areas of lombardy and the veneto regions and then spread all over the country. as of march , , considering that new cases of covid- registered in italy had started to increase considerably and national restrictive measures had not yet been put in place, the council of ministers issued a decree law with measures to prohibit access to and exit from the country as well as suspension of all the activities that were not strictly necessary [ , ] . the current italian situation confirms that a local outbreak, once started, can quickly spread and have a huge impact on the most vulnerable citizens, mainly elderly subjects with comorbidities [ ] . although to date no sars-cov- bloodborne transmission has been documented, the national blood center of the national institute of health (iss) has activated precautionary measures to prevent the spread of the new coronavirus sars-cov- from blood donors [ ] . ecdc reports that, as of march , , the risk of covid- infection in europe is currently moderate to high and can change. it should be considered that the transmission chain has not always been identified and that the epidemiologic situation is constantly evolving [ ] . the spread of the sars-cov- virus represents a global health emergency involving the health authorities of all countries, especially since the pandemic state was declared. many aspects of the infection have been studied. available epidemiologic, clinical and impact data have made it possible to outline preventive interventions that have been shared internationally. unfortunately, the spread of the virus is ongoing, and the impact of the infection is still growing, despite the application of preventive interventions, which in some contexts are very restrictive. the impact of the infection is evident not only from a clinical but also from an economic point of view. the considerable cost in terms of infected/ dead health workers, who operate on the front line and, as such, are particularly exposed to the risk of infection, should not be underestimated [ ] . strict observance of the rules issued by the who and the other international bodies (e.g., cdc, ecdc, etc.) is essential, as we need to understand the dynamics of virus spread in more detail, identify new diagnostic and therapeutic approaches and develop a vaccine reasonably quickly. the international effort is enormous and hopefully will allow preventing further spreading of the virus [ ] . epidemiologic daily updated cases can be found on the following web pages: https://www.who. int/emergencies/diseases/novel-coronavirus- / >situation-reports/. https://www.ecdc.europa.eu/ en/novel-coronavirus-china. funding. no funding or sponsorship was received for this study or publication of this article. authorship. all named authors meet the international committee of medical journal editors (icmje) criteria for authorship for this article, take responsibility for the integrity of the work as a whole and have given their approval for this version to be published. disclosures. erica d'anchera, federica sandri, marta savio and armando stefanati declare that they have no conflict of interest. giovanni gabutti declares that he does not have a specific conflict of interest related to this paper; however, he reports grants from sanofi pasteur msd, gsk biologicals sa, pfizer, sanofi pasteur italy, msd italy, emergent biosolutions and seqirus for taking part to advisory boards, expert meetings, for acting as speaker and/or organizer of meetings/congresses and as principal investigator and chief of o.u. in rcts. compliance with ethics guidelines. this article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors. data availability. data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. open access. this article is licensed under a creative commons attribution-noncommercial . international license, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit 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and safety of darunavir and cobicistat for treatment of pneumonia caused by -ncovfull text view-clinicaltrials the efficacy of lopinavir plus ritonavir and arbidol against novel coronavirus infection-full text view-clinicaltrials a randomized, open, controlled clinical study to evaluate the efficacy of asc f and ritonavir for -ncov pneumonia-full text view-clini-caltrials convalescent plasma as a potential therapy for covid- clinical evidence does not support corticosteroid treatment for -ncov lung injury director-general's opening remarks at the media briefing on covid- a novel coronavirus outbreak of global health concern updated who recommendations for international traffic in relation to covid- outbreak cdc. covid- information for travelers|cdc nuovo coronavirus, nuove misure di prevenzione dopo la trasmissione locale|centro nazionale sangue key: cord- -lh c izt authors: wang, chaofu; xie, jing; zhao, lei; fei, xiaochun; zhang, heng; tan, yun; nie, xiu; zhou, luting; liu, zhenhua; ren, yong; yuan, ling; zhang, yu; zhang, jinsheng; liang, liwei; chen, xinwei; liu, xin; wang, peng; han, xiao; weng, xiangqin; chen, ying; yu, ting; zhang, xinxin; cai, jun; chen, rong; shi, zhengli; bian, xiuwu title: alveolar macrophage dysfunction and cytokine storm in the pathogenesis of two severe covid- patients date: - - journal: ebiomedicine doi: . /j.ebiom. . sha: doc_id: cord_uid: lh c izt background: the novel coronavirus pneumonia covid- caused by sars-cov- infection could lead to a serious of clinical symptoms and severe illness, including acute respiratory distress syndrome (ards) and fatal organ failure. we report the fundamental pathological investigation in the lungs and other organs of fatal cases for the mechanistic understanding of severe covid- and the development of specific therapy in these cases. methods: the autopsy and pathological investigations of specimens were performed on bodies of two deceased cases with covid- . gross anatomy and histological investigation by hematoxylin and eosin (he) stained were reviewed on each patient. alcian blue/periodic acid-schiff (ab-pas) staining and masson staining were performed for the examinations of mucus, fibrin and collagen fiber in lung tissues. immunohistochemical staining were performed on the slides of lung tissues from two patients. real-time pcr was performed to detect the infection of sars-cov- . flow cytometry analyses were performed to detect the direct binding of s protein and the expression of ace on the cell surface of macrophages. findings: the main pathological features in lungs included extensive impairment of type i alveolar epithelial cells and atypical hyperplasia of type ii alveolar cells, with formation of hyaline membrane, focal hemorrhage, exudation and pulmonary edema, and pulmonary consolidation. the mucous plug with fibrinous exudate in the alveoli and the dysfunction of alveolar macrophages were characteristic abnormalities. the type ii alveolar epithelial cells and macrophages in alveoli and pulmonary hilum lymphoid tissue were infected by sars-cov- . s protein of sars-cov- directly bound to the macrophage via the s-protein-ace interaction. interpretation: infection of alveolar macrophage by sars-cov- might be drivers of the “cytokine storm”, which might result in damages in pulmonary tissues, heart and lung, and leading to the failure of multiple organs . funding: shanghai guangci translational medical research development foundation, shanghai, china the coronavirus disease- caused by sars-cov- infection can lead to a series of clinical settings from non-symptomatic viral carriers/spreaders to severe illness characterized by acute * correspondence authors. e-mail addresses: wangchaofu@ .com (c. wang), caijun@shsmu.edu.cn (j. cai), crjudy@ .com (r. chen), zlshi@wh.iov.cn (z. shi), bianxiuwu@ .net (x. bian). contributed equally to this work. contents lists available at sciencedirect ebiomedicine journal homepage: www.elsevier.com/locate/ebiom respiratory distress syndrome (ards). [ À ] a sizable part of patients with covid- have mild/moderate clinical symptoms at the early stage of infection, but the disease progression may become quite rapid in the later stage with ards as the common manifestation and followed by critical multiple organ failure, causing a high mortality rate of - % in the elderly population with non-communicable chronic disease (ncd). [ , , ] the pathological evidences in the lung of fatal cases are fundamental for the mechanistic understanding and treatment of severe patients with covid- . in this study, we investigated the critical pathological changes in the lung of severe covid- patients. we hope this work may contribute in a significant way to the understanding of the mechanisms underlying the phenotype of severe cases in covid- and appropriate development of treatment strategies. the autopsy and pathological investigations of specimens were performed on bodies of two deceased cases with covid- in wuhan jin yin-tan hospital, hubei, china. the diagnosis was established according to clinical symptoms (fever, cough and shortness of breath), rt-pcr testing of sars-cov- and chest xray or computed tomographic (ct) scanning examination (fig. s ). the severe respiratory and circulatory failure was considered the critical cause of death in the two patients. informed consent was obtained. this study was approved by the medical ethics committee of the national health commission of china. the autopsy procedures were performed in the negative pressure-ventilation p laboratory. we collected adequate pieces of each organ for analysis, special attention was given to the lungs and and pieces were collected respectively. the timelines were hours and hours from death to autopsy. hematoxylin and eosin (he) staining of the slides of % neutral formaldehyde-fixed, paraffin-embedded tissues was performed and carefully reviewed on each patient. alcian blue/periodic acid-schiff (ab-pas) staining and masson staining were carried out for the examinations of mucus, fibrin and collagen fiber in lung tissues. immunohistochemical staining was performed on the slides of lung tissues from two patients. a panel of primary antibodies were used, including the macrophage marker cd (monoclonal mouse anti-human cd , clone kp ; : ; dako omnis, agilent); t-lymphocyte marker cd (monoclonal rabbit anti-human cd , clone sp ; ready-to-use; dako omnis, agilent), cd (monoclonal mouse anti-human cd , clone b ; ready-to-use; dako omnis, agilent) and cd (monoclonal mouse anti-human cd , clone c / b; ready-to-use); b-lymphocyte markers cd (monoclonal mouse anti-human cd cy, clone l ; ready-to-use); natural killer cell/t cell (nk/t cell) marker cd (monoclonal mouse anti-human cd , clone c ; ready-to-use), and the markers of programmed cell death- (pd- monoclonal mouse anti-human pd- , clone umab ; ready-to-use) and programmed cell death-ligand (pd-l monoclonal mouse anti-human pd-l , clone c ; ready-to-use). antibodies specific for chemokine and inflammatory cytokines were also used, including interleukin (polyclonal rabbit anti-il- human; : ; abcam), interleukin (il- , polyclonal rabbit anti-human il- ; : ; abcam) and tumor necrosis factor a (tnfa, polyclonal rabbit anti-human tnfa; : ; abcam). in addition, ace protein was revealed using a mouse monoclonal anti-human ace antibody (clone g ; : ; origene) while the detection of sars-cov- was performed using the antibody against sars-cov- rp n-protein (rp -np) ( : ; the rp -np antibody was provided by prof. zheng-li shi, wuhan institute of virology, chinese academy of sciences). total rnas were extracted from paraffin-embedded lung and pulmonary hilum lymph nodes tissues, with amoydx Ò ffpe rna kit (adx-ff , amoydiagnostics, xiamen, china) according to manufactures' instructions. the sars-cov- was detected by real-time rt-pcr with taqman probes against the e gene, n gene and rdrp gene of sars-cov- according to manufactures' instruction of the -ncov nuclear acid detection kit (z-rr- - - , liferiver, shanghai, china). evidence before this study as the severe acute respiratory syndrome coronavirus (sars-cov- ) spreads increasingly worldwide, coronavirus disease (covid- ) outbreak has become a common challenge faced by humanity. it can lead to a series of clinical settings from non-symptomatic viral carriers/spreaders to severe illness characterized by acute respiratory distress syndrome (ards). so far, up to april , , we searched pubmed for articles using "novel coronavirus", "sars-cov- " and "pathology" as keywords, there were two case reports concerning the pathological changes of covid- . one case report showed the pathological characteristics of a patient who died from severe infection with severe acute respiratory syndrome coronavirus (sars-cov- ) by postmortem biopsies. another report described the early phase of the lung pathology of covid- pneumonia by lung lobectomies for adenocarcinoma. the former one has limitations for comprehensive observation of organs owing to the biopsy samples, and the latter one only shows the early changes of lungs in patients of covid- with mild symptoms. these reports revealed that the pathological features of covid- greatly resemble those seen in sars and middle eastern respiratory syndrome (mers) coronavirus infection. added value of this study we performed an anatomical and pathological study in two patients died from covid- and identified the distinct pathological feature of covid- . we found mucous plugs in all respiratory tracts, terminal bronchioles and pulmonary alveoli which could aggravate the dysfunction of ventilation and the viral infection of aggregated alveolar macrophages that could result in "cytokine storm" or cytokine release syndrome (crs). implications of all the available evidence these findings might shed light on the pathogenesis of covid- and potential therapeutic strategies against sars-cov- among severe patients. the excessive mucus secretion with serous and fibrinous exudation, which could aggravate the dysfunction of ventilation, might be one of the pathogenic mechanisms responsible for the hypoxemia that somehow different from sars patients. the accumulation of sars-cov- infected macrophages in the lungs resulted in releasement of cytokines including il- which is considered as one of the drivers in a special clinical setting known as crs. and these pathological findings supported the notion that anti-il- /il- r antibody treatment among severe covid- patients might benefit for the blockage of crs. the normal lung tissues used for preparation of cell suspension subject to flow cytometry analysis were those adjacent to lung tumors obtained from surgical operation. informed consent was obtained. the normal lung tissues were cut into slices and digested with type iv collagenase (#c , sigma) in dmem (gibico) supplemented with % fetal bovine serum (gibico) in °c for minutes. the indigestible tissues and debris were filtered with a mm cell strainer (# , bd falcon) and the cells were washed twice with pbs. the red blood cells were removed according to manufactures' instructions of red blood cell lysis buffer (# es , yeasen, china). the white blood cells were obtained from six health donors according to manufactures' instructions of red blood cell lysis buffer (# es , yeasen, china). after the removal of the red blood cells, white blood cells were washed twice with pbs. cells were firstly incubated with fc blocker (human bd fc block tm , # , bd biosciences). then they were washed and used incubation for reagents in two different settings: purified sars-cov- ( -ncov) spike protein (# -v h, sino biological, china), whereas the other with rabbit anti-human ace antibodies (# - -ap, proteintech, china) in dmem (gibico) supplemented with % fbs (gibico) for minutes at room temperature, followed by goat anti-rabbit igg (alexa fluor goat anti-rabbit igg (h+l) polyclonal antibody, thermofisher) as secondary antibodies according to manufactures' instructions. subsequently, cells treated with the above mentioned reagents in two experimental settings were respectively labeled simultaneously by antibodies against human cd (apc mouse anti-human cd monoclonal antibody, clone hit a, bd bioscience), cd (fitc mouse anti-human cd monoclonal antibody, clone rmo , beckman coulter), cd (pe/cy mouse anti-human cd monoclonal antibody, clone y / a, biolegend) and human igg (pe anti-human igg fc, clone m g , biolegend). bd lsrfortessa tm x- was used for flow cytometry analysis. the two deceased covid- patients, with the diagnosis confirmed by reverse transcriptase-polymerase chain reaction (rt-pcr) for sars-cov- , were a years old female (patient no ) and a years old male (patient no ) ( table ) . both had fever, cough and shortness of breath and received anti-viral treatment with arbidol and peramivir respectively. patient no also received methylprednisolone therapy (table ) . unfortunately, both patients progressed into acute respiratory distress syndrome (ards) due to severe pulmonary lesions, as confirmed by chest x-ray or computer-assisted tomography (ct) examinations (fig. s ). both patients had significantly decreased lymphocytes with elevated serum il- and c reactive protein (crp) levels (table s ), typical worse prognostic indicators in patients with critical disease described in several recent reports. [ À ] the female case had also co-morbidities of type diabetes and essential hypertension. finally, both cases died of respiratory failure and heart failure. the pathological investigations of severe patients are pivotal for the understanding of pathogenesis of covid- and assessment of clinical treatments. special attention was given to the abnormalities in lungs, which are the main damaged organ in severe covid- patients. the gross anatomy of the lungs showed moderate bilateral pleural effusion and fibrotic pleural adhesion in the two patients. the hepatization of pulmonary tissues was observed on the cut-surface of the collapsed and consolidated lungs. the microscopic manifestation of the lung injury was consistent with diffuse alveolar damage (dad). alveolar cavities were filled with a large number of macrophages with scattered neutrophils and lymphocytes (fig. a) . the massive serous (fig. b) and fibrinoid exudate in the alveolar spaces were shown by the masson staining (figs. cÀd) . the acidic mucopolysaccharides from a large amount of mucinous secretion were observed by the alcian blue-periodic acid-schiff (ab-pas) staining in the bronchi and bronchioles, terminal bronchioles and pulmonary alveoli (figs. eÀf) . a lot of mucus in the distal respiratory tract lined by mucous cells was shown, reminiscent of the morphology of mucoid adenocarcinoma (fig. g) . the peribronchiolar metaplasia (pbm) with interstitial fibrous hyperplasia but without invasive growth of atypical cells was observed. the bronchial plug combined with epithelial detachment was visible (fig. h) . the hyaline membranes and widened alveolar walls with collagen fibers proliferation and lymphocyte infiltration were observed in alveoli occasionally (figs. s a-b) . focal or patchy hemorrhage with fibrinous exudate was seen in the alveolar cavities and interstitial tissues (figs. s c-d). the broken alveolar walls flushed by huge hemorrhagic effusion formed the "blood lake". the endothelial cells of small pulmonary arteries were swollen and shed (fig. s e) . mixed thrombi were present in small veins (fig. s f) . intensive sloughing of bronchiole and alveolar epithelial cells was remarkable (figs. aÀb) while abundant swollen and degenerated alveolar cells desquamated in the alveoli (figs. cÀd) . patchy type ii pneumocytes proliferated with atypical changes, including enlarged nuclei, clearing of nuclear chromatin, prominent nucleoli and inclusion bodies (figs. eÀf) . the proliferation of type alveolar epithelial cells resembled the morphological changes of atypical adenomatous hyperplasia, in situ adenocarcinomas, or even invasive adenocarcinoma. thickened alveolar walls and widened interstitial tissues were accompanied by lymphocyte infiltration and fibroblast proliferation (figs. gÀh) . notably, the alveolar macrophages significantly increased and filled in a part of the alveolar cavities with scattered neutrophils and lymphocytes. cd , one of the scavenger receptors and a well-documented specific marker of macrophages, [ ] was highly expressed in alveolar macrophages. these cd positive macrophages were presented in diverse forms, including aggregation in small clusters (figs. aÀb), diffused distribution (fig. c) , single cell exhibiting intracytoplasmic phagocytosis, spherical acidophilic hyaline bodies or hemophagocytic phenomenon (figs. dÀe) , and multinucleated giant cells (fig. f) . furthermore, using immunohistochemistry approach, we examined several chemokine and inflammatory cytokines secreted by alveolar macrophages including il- , il- and tnfa with specific antibodies. il- and tnfa were moderately expressed in macrophages (figs. gÀi) , while the expression of il- was strong (fig. h) . besides, extensive and strong expression of programmed death-ligand (pd-l ) by alveolar macrophages was observed (fig. j) . of particular note, we found the expression of ace , a well-established receptor for both sars-cov and sars-cov- , by hyperplastic type ii alveolar epithelial cells and alveolar macrophages (fig. a) . macrophages in the cortical sinuses of pulmonary hilum lymph nodes were also shown to express ace (figs. d and g) . moreover, type ii alveolar epithelial cells and macrophages in alveoli and pulmonary hilum lymphoid tissue were infected by sars-cov- , as revealed by immunohistochemistry using rp -np specific antibodies (figs. b, e and h). this result was further confirmed by real-time rt-pcr detection (table s ). next, the distribution of lymphocytes in the pulmonary tissues was examined. a recent report had described the substantially reduced peripheral t cells and lymphocytes infiltration in lung tssue [ ] . contrarily to the situation of macrophages, the degree of lymphocytic infiltration was much inferior, although some focal infiltrations of lymphocytes were present (fig. s a) . cd -positive b lymphocytes (fig. s b) accounted for a large majority of the lymphocytes whereas a few cd -positive t lymphocytes (fig. s c) made up a small proportion including cd -strong positive for helper t cells and cd -positive for cytotoxic t cells (figs. s d-e) . among the inflammatory infiltrating cells, no cd -positive nk/t cells (fig. s f) were detected. neither programed cell death protein- (pd- ) nor pd-l proteins were shown on the surface of lymphocytes (figs. s g-h) . no obvious viral infection was found in the lymphocytes and mesenchymal cells by using rp -np antibody in immunohistochemistry staining (fig. s i) . to further address the topic that monocytes/macrophages could be the direct target cells of sars-cov- , cell suspension from the normal lungs were incubated respectively with purified s proteins or anti-human ace antibodies, followed by an incubation with directly labeled antibodies against cell surface markers cd (covering several blood cell lineages, but with strong binding with monocytes), cd (t cells) and cd (specific marker of macrophages). the labeled cells were then subject to flow cytometry analysis. of note, there were high levels of s protein binding on the lung macrophages (fig. a) . furthermore, ace was also highly expressed on the surface of the lung macrophages (fig. b) , suggesting sars-cov- could enter into the alveolar macrophage via the interaction between s protein and ace receptor [ ] . since the monocytes/macrophages in the peripheral blood are well established as sources of tissue macrophages, we tested s protein binding to white blood cell (wbc) samples from six healthy donors. the results of flow cytometry analysis showed that the s protein interacted with cd -expressing monocytes/macrophages but not with t lymphocytes (fig. c) . when the expression of ace was examined on the surface of blood monocytes/macrophages, an expression pattern similar to that of s protein was observed (fig. d) . we carefully examined, in the two deceased patients, the heart and kidney which were often found with damaged functions in sars-cov- infected people. no obvious gross abnormalities were observed. nevertheless, microscopical abnormalities were found in both organs. multifocal myocardial degeneration was present in the heart, together with myocardial atrophy and interstitial fibrous tissue hyperplasia (figs. s a-b) . a few cd -positive b cells and cd -positive t cells were scattered in the heart (figs. s c-d) . in the kidneys, normal renal structures were retained. nonetheless, the fibrotic glomeruli and edematous tubular epitheliums were focally present with a small amount of infiltrating b and t lymphocytes (figs. s e-h) . it is worth noting that no obvious viral infection was found in parenchymal cells in both heart and kidney using immunohistochemistry with antibodies against rp -np. overall speaking, pathological findings in pulmonary tissues of covid- shared similarities to those in sars outbreak of . in both diseases, extensive damage of type i alveolar epithelial cells and atypical hyperplasia of type ii alveolar cells were detected, with formation of hyaline membrane, focal hemorrhage, exudation and pulmonary edema, and pulmonary consolidation. the sloughing of epithelium, also a classic and common appearance of expected postmortem tissue changes, were extensively present in our cases and a recent report [ ] . it is one of common manifestations in the diffuse alveolar damage (dad) that existed in acute respiratory distress syndrome (ards) not only in covid but also in sars and mers. meanwhile, infiltration of macrophages, lymphocytes and plasma cells, as well as endothelial injury and thrombosis in small vessels and micro-vascular structures in the lungs were obvious in the two diseases. thus, like sars-cov, sars-cov- was capable of triggering the pathogenesis and resulting in severe dysfunction of ventilation and gas exchange obstruction in patients. [ À ] though the endothelial injury and thrombosis were not common in our cases, resent studied showed the high incidence of thromboembolic events in segmental/subsegmental pulmonary arterial vessels [ ] , pulmonary embolism and deep venous thrombosis [ ] , and microvascular thrombosis [ ] , suggested coagulopathy in severe covid- infection patients. however, the pathology of lungs in covid- also exhibited unique features as compared to sars. for example, in the previous autopsy study on sars, the hyaline membranes in alveoli were reported, [ ] which constituted the major anatomical abnormalities leading to gas exchange obstruction, whereas the hyaline membranes in alveoli were uncommon in our observations, which was in accordance with a recent report [ ] . in covid- , we found mucous plugs in all respiratory tracts, terminal bronchioles and pulmonary alveoli, which was not described in sars. [ , À , , ] one patient received -days non-invasive ventilator treatment while the other had nasal cannular oxygenation and mask oxygen inhalation instead of ventilator treatment (table ) , indicating the mucous plugs obstruction was not caused by the ventilator-induced lung injury (vili). another unique feature of covid- was the excessive mucus secretion with serous and fibrinous exudation, which could aggravate the dysfunction of ventilation. therefore, the pathogenic mechanisms responsible for the hypoxemia could be somehow different between covid- and sars patients. we assumed these lesions could play a part in the sputum suction failure in very severe covid- patients. in addition, the differences between covid- and sars could be found at the level of immune cell involvement. it was reported that sars-cov could occasionally be identified in the alveolar macrophages. [ ] in the case of covid- , the viral infection of aggregated alveolar macrophages was obvious from early phase to the late stage, according to our study and the results in recent reports of pulmonary pathology [ , ] . these observations suggest the alveolar macrophages might be crucial in the pathological changes in patients with critical disease manifestation, in that the aggregation and activation of these cells could result in "cytokine storm" or cytokine release syndrome (crs). the spectacular infiltration and activation of alveolar macrophages in covid- might represent the shift of classically activated phenotype (m ) to alternatively activated phenotype (m ) of these cells, whereas this shift, particularly in the case of antibody-dependent enhancement (ade), could contribute to the inflammatory injuries and fibrosis of respiratory tracts. [ ] and the specific subsets of macrophages should be identified in future studies. to further address the significance of accumulation of macrophages in lungs and to explore the potential function of monocytes/ macrophages in response to sars-cov- , we examined the possible interaction between spike (s) protein of sars-cov- and ace receptor on the surface of immune cells isolated from pulmonary tissues. these findings were in support of a direct viral entry into the monocytes/macrophages and highlighted the role of the aberrantly activated macrophages as host cells of sars-cov- in covid- disease mechanism. in agreement with abnormal activation of macrophages, an elevated serum il- was observed in the two cases in this study, consistent to recent reports by other groups [ ] . release of cytokines including il- by macrophages has been considered as one of the drivers in a special clinical setting known as crs in hemophagocytic lymphohistocytosis (hlh) or macrophage activation syndrome (mas). [ , ] the blockage of crs using anti-il- or il- r antibody, such as tocilizumab, has already been used in the treatment of mas or hlh. recently, the tocilizumab therapy was recommended in the guideline of diagnosis and treatment of covid- (version ) by the national health commission in china to control the crs. while potential benefits of this treatment still require definite evidence, our pathological findings tend to support the clinical practice of the anti-il- /il- r antibody treatment among severe covid- patients in order to inhibit the vicious cycle of alveolar macrophage activation and inflammatory injuries. on the other hand, the use of anti-viral effect of convalescent plasma from recovered patients has been shown to be effective in the treatment of severe cases of covid- . [ ] it is well known that elderly patients with ncd such as diabetes, cardiovascular disease and hypertension are vulnerable to covid- . we carefully examined, in the two deceased patients, the heart and kidney which were often found with damaged functions in sars-cov- infected people. no obvious gross abnormalities were observed. nevertheless, microscopical abnormalities were found in both organs. it is worth noting that no obvious viral infection was found in parenchymal cells in both heart and kidney using immunohistochemistry with antibodies against rp -np finally, some issues remain to be addressed in future studies. first, the precise molecular and cellular mechanisms underlying the infection of alveolar macrophages by sars-cov- should be unfolded so that a deeper understanding of the persistent viral infection and inadequate immune reaction in severe/critical cases of covid- can be obtained. these studies may accelerate and refine drug and vaccine design targeting vulnerabilities of viral entry and proliferation in affected cells/tissues. second, in the two cases studied here and in some other recent reports, there is a remarkable reduction of both cd and cd cells in the peripheral blood in covid- patients. a graded decrease of t cells was found with increased clinical severity. intriguingly, we recently observed a negative correlation between the extent of t lymphocytopenia and increased il- and il- levels in the serum. the causal relationship between these phenomena should be addressed. third, in this study, no ace -expression was found on the surface of t cells, which might be considered as an argument for the absence of direct toxic effect of sars-cov- on distinct t cell populations. however, the observation of only a small number of t lymphocytes in the inflammatory lung tissues at late disease stage might not reflect the status of t cell infiltration at relatively early phase of covid- . the possibility that the reduction of peripheral blood t cells result from a tremendous infiltration of these cells into lung tissues in early response to the effect of cytokines and a subsequent apoptosis of these cells cannot be ruled out. the study on detailed mechanism of t cell depletion in severe covid- over the whole disease process should be conducted among patients or in experimental animal models. the authors declare no competing interests. clinical features of patients infected with novel coronavirus in wuhan, china clinical characteristics of coronavirus disease in china clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study macrophage specificity of three anti-cd monoclonal antibodies (kp , ebm , and pgm ) widely used for immunohistochemistry and flow cytometry pathological findings of covid- associated with acute respiratory distress syndrome a pneumonia outbreak associated with a new coronavirus of probable bat origin autopsy report with clinical pathological correlation clinical progression and viral load in a community outbreak of coronavirus-associated sars pneumonia: a prospective study a novel coronavirus associated with severe acute respiratory syndrome identification of a new human coronavirus the clinical pathology of severe acute respiratory syndrome (sars): a report from china lung pathology of fatal severe acute respiratory syndrome pulmonary arterial thrombosis in covid- with fatal outcome: results from a prospective, single-center, clinicopathologic case series autopsy findings and venous thromboembolism in patients with covid- complement associated microvascular injury and thrombosis in the pathogenesis of severe covid- infection: a report of five cases pulmonary pathology of early phase covid- pneumonia in a patient with a benign lung lesion a major outbreak of severe acute respiratory syndrome in hong kong identification of a novel coronavirus in patients with severe acute respiratory syndrome pulmonary pathology of early-phase novel coronavirus (covid- ) pneumonia in two patients with lung cancer alveolar macrophages: plasticity in a tissue-specific context macrophage activation syndrome: characteristic findings on liver biopsy illustrating the key role of activated, ifn-gamma-producing lymphocytes and il- -and tnfalpha-producing macrophages cytokine responses in severe acute respiratory syndrome coronavirus-infected macrophages in vitro: possible relevance to pathogenesis effectiveness of convalescent plasma therapy in severe covid- patients we thank prof. zhu chen supplementary material associated with this article can be found in the online version at https://doi.org/ . /j.ebiom. . . key: cord- -xad zht authors: kumaravel, santhosh kumar; subramani, ranjith kumar; jayaraj sivakumar, tharun kumar; madurai elavarasan, rajvikram; manavalanagar vetrichelvan, ajayragavan; annam, annapurna; subramaniam, umashankar title: investigation on the impacts of covid- quarantine on society and environment: preventive measures and supportive technologies date: - - journal: biotech doi: . /s - - - sha: doc_id: cord_uid: xad zht the present outbreak of the novel coronavirus sars‐cov‐ , epicentered in china in december , has spread to many other countries. the entire humanity has a vital responsibility to tackle this pandemic and the technologies are being helpful to them to a greater extent. the purpose of the work is to precisely bring scientific and general awareness to the people all around the world who are currently fighting the war against covid- . it's visible that the number of people infected is increasing day by day and the medical community is tirelessly working to maintain the situation under control. other than the negative effects caused by covid- , it is also equally important for the public to understand some of the positive impacts it has directly or indirectly given to society. this work emphasizes the various impacts that are created on society as well as the environment. as a special additive, some important key areas are highlighted namely, how the modernized technologies are aiding the people during the period of social distancing. some effective technological implications carried out by both information technology and educational institutions are highlighted. there are also several steps taken by the state government and central government in each country in adopting the complete lockdown rule. these steps are taken primarily to prevent the people from covid- impact. moreover, the teachings we need to learn from the quarantine situation created to prevent further spread of this global pandemic is discussed in brief and the importance of carrying them to the future. finally, the paper also elucidates the general preventive measures that have to be taken to prevent this deadly coronavirus, and the role of technology in this pandemic situation has also been discussed. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. an unprecedented outbreak of mysterious etiology pneumonia, which occurred in december , has taken the whole world to a state of sorrow and worry about the future. the novel coronavirus (covid- ) is a respiratory illness and its outbreak primarily originated from wuhan, china. the epidemic is found to be caused by a zoonotic transmission event associated with a wide seafood market and soon became transmission from human to human (zhou et al. ). mostly the virus affects animals only, but the covid- virus is able to mutate into new forms that are immune to the vaccine. despite various efforts taken by every country like global containment, travel restrictions, and treating the infected person, the incidence of covid- continues to rise at a tremendous rate. at the same time, the lockdown has also made some impacts on human society such as negative psychological effects due to quarantine, loss in the economy of the world. but there are also positive aspects like reduction in pollution due to less movement of vehicles and closure of many industries. covid- is identical to coronavirus with severe acute respiratory syndrome (sars) and coronavirus with middle east respiratory syndrome (mers). this is also known as coronavirus (sars-cov- ) severe acute respiratory syndrome pneumonia. it's confirmed that the sars-cov- ( fig. ) originated by nature itself by comparing the available genome of the coronavirus strains said by kristia andersen, ph.d., an associate professor of immunology and microbiology at scripps research (science daily a). coronavirus is a big family of severe respiratory illness, first it was found in at china as sars and its second outbreak occurred in in saudi arabia as mers (science daily a). the coronavirus with spike protein-rbd (receptor binding domain) portion is the important part of the virus that has been evolved and binds to the cells and then cleaves the site of contact where the virus enters the human cells (science daily a). the articles revealed that the covid- is a group of beta-coronavirus and this is mutated from bat coronavirus hku - which is the ancestor of covid- . this mutant virus interacts strongly with the human ace receptor. the researchers state that the sars-cov- shares less than % nucleotide identity and has . % similarity genes of the previous sars-cov (qamar et al. ) . the transmission of sars-cov- is presented as in (fig. ) . the genome of sars-cov- is . % similar to the bat cov ratg and shares its identity from sars-cov . it is known that the main cause of this virus has started from bats and the virus is mutated to affect the humans and it is identified that there are six coronaviruses which affect the human body and some of them are α-covs hcov- e and hcov-nl , which are of low pathogenicity and cause mild respiratory symptoms. the covid- is a respiratory disease that spreads at a maximum rate through droplets of the infected people through the air (world health organisation a). the coronavirus is mutant by the previous process; it has been continuously spreading between the humans, rapidly through many modes of transmission they are as follows: • cough or sneeze by the infected person. • through close contact with the victims by touching the nose, eyes, and mouth. • the transmission of droplets occurs within m. • the transmission can also happen by indirect means such as handling the instruments of the infected person, for example, stethoscope, thermometer (world health organisation a). the affected persons were observed with common symptoms like cough, fever and in addition to it, some were noticed by muscle soreness, headache, dyspnea, and fatigue. thoracic radiology and ct (computed tomography) are the best evaluations of the infection covid- (bernheim et al. ) . also, most of the positive cases are asymptomatic, they are not aware that they are carrying the virus to spread it on. the world statistics of infected cases increased to , , , total deaths climbed to , , , and recovered cases were , , by th july (worldometers a) . in india, the total number of cases was , , , death cases were , and the recovered cases were , , as on july th (worldometers, a) . the fatality rate on july th, was estimated to be . % and it is calculated by (total deaths/(death + active cases)) (qamar et al. ) . the observed spread of covid- is more rapid than the calculated values. the number of death cases all over the world increased about times from march th till march th from deaths to , death cases(see fig. ). covid- is a deadly disease that had no mercy on the pregnant women and even the infants inside the womb of the mothers during this pandemic. the who (world health organisation) has said that the covid- affected pregnant women may die due to the infection and may spread the disease directly to the foetus and neonate. after testing the affected women who gave birth to infants, the reports state that the babies were healthy and the women were tested negative for the virus after various effective treatments . the infected patients were given chloroquine phosphate to block the covid- infection in low micromolar concentrations. china has tested the safety and efficacy of the chloroquine that can be used to treat covid- in ten hospitals . the reproductive rate of covid- is ranging from . to . and the average reproductive rate is . and the estimates were calculated by different personnel in different methods (liu et al. a, b) and in india, the reproduction rate of coronavirus is estimated to be . (india's covid- ro value ). the purpose of this review is to convey the impacts on society due to the pandemic and also how to tackle this pandemic situation with the available technologies. this review shares the knowledge about the technologies that help out the industrialists, students, and doctors to fight against and run the routine life even during the lockdown. this review would also elucidate the environmental impacts that changed the world during the quarantine of the people and the preventive measures taken by the governments for the safety of the people in the world. in this review, the knowledge regarding the importance of quarantine and social distancing is gathered first. statistics obtained from who and worldometers is used for this review to demonstrate the quarantine effect. then, it discusses the social nature of the disease. statistics on the fatality incidence derived from standard research articles have also been used here. also, the environmental effects related to the epidemic were discussed in a detailed manner. data on the condition of air quality and bird status during the lockdown scenario is obtained from online reports and journal articles. the preventive measures for covid- were also discussed. data is also obtained based on the equipment used during the lockdown process. the knowledge obtained from academic or grey literatures were helpful to carry out this comprehensive analysis. a keyword search based method was used to collect the information along with a structured process of sorting the data. in the beginning, the keywords are made to be determined through detailed discussions. the keywords used for searching the data are covid- , environmental impacts, technologies, pollution, and quarantine. the academic literatures discussed in this work here comprises of regular papers and conferences while the grey literatures discussed here contain web sources and professional studies. this analysis took google scholar, scopus, and scopus indexed extended as the most important research sites for framing the important sections of the work. when gathering the data and details, we ensured that only the peer-reviewed publications and online sites to be referred to. for this review, about articles and official web resources were studied. the articles were further reviewed to identify the most suitable papers for this analysis. finally, references from scholarly journals and references from web resources, a total of references found to be the most suitable for this work, and those were included in this review analysis. when reviewing the relevant papers, a manual procedure is followed to determine the appropriateness of the papers for this study. the systematic framework for data collection adopted in this review paper is shown in (fig. ). the spread of covid- disease was announced by the world health organization (who) as a public health emergency of international concern on th january (world health organisation b). there are currently no appropriate treatments and vaccines for this virus (wilder-smith and freedman ). also, evidence shows that much of the human to human transmission occurs during covid- ′s asymptomatic incubation interval, which will be approximately between and days (rothe et al. ; sohrabi et al. ) . therefore we rely entirely on public health strategies such as quarantine to restrict the spread of this respiratory disease. quarantine essentially involves isolating or limiting the mobility of people who have come from other countries or have been exposed to this infectious disease. in this scenario, covid- infected persons are isolated from non-infected persons and this isolation usually takes place in the hospital. by quarantine, we can prevent the human-to-human spread of disease to break the chain of transmission (wilder-smith and freedman ). quarantine facilities must be provided to infected persons who do not have an appropriate homely environment (cetron and landwirth ) . but the infected patients would also be able to transmit the disease to another person before the symptoms appear to them. the incubation time for the covid- has a median of days . so quarantine is often too late to effectively stop the transmission and control this influenza pandemic (wilder-smith and freedman ). thus, it remains unknown when the transmissibility attains its peak and how frequently pre-symptomatic cases get transformed into secondary cases. quarantine was implemented successfully to halt the transmission during the sars epidemic in (goh and chew ) . it is one of the important steps in this pandemic disease plan. the quarantine can be done to an individual or at the group level and usually, it involves restriction to the home or a particular area. during the quarantine period, all the persons should be monitored regularly for the occurrence of any symptoms. if any symptoms occur, the infected individual must be immediately isolated in a designated place with all essential treating equipment. by quarantining, the detection of cases becomes easier, so that contacts can be listed and traced out within a short period of time frame (wilder-smith and freedman ). also, quarantine includes the following benefits: • the isolation of persons prone to reported cases will avoid a large proportion of diseases and deaths relative to those without control. • there was little impact of quarantining travelers from a country with a reported epidemic to prevent infection and death. • in addition, the incorporation of lockdown with other treatment and prevention measures such as school closures, travel restrictions, and social distancing has had a greater impact on spread prevention, cases requiring critical care beds, and deaths compared with quarantine alone. so in controlling the covid- outbreak, more systematic and early implementation of preventive and control measures may be more successful (science daily b). after an effective lockdown of months, the cases in china were reduced. this can be clearly viewed in fig. . it gives a clear overview of the covid- attack and how china resolved its pandemic situation. when covid- cases are increasing rapidly all over the world, china had got slowly relieved from this infectious disease with its severe methodologies and treatments. this also shows the effect of massive lockdown in mainland china. chinese health (worldometers b) authorities have declared that the country had passed the peak of coronavirus outbreak on march th, (impact of lockdown in china ). another component to prevent transmission is 'social distancing'. this must be introduced to minimize people-topeople communication in a larger population, where individuals may be contagious but have not yet been recognized as an infected person and therefore not isolated. so social distancing of people will effectively reduce the transmission of this kind of infectious disease (wilder-smith and freedman ). this involves avoiding unnecessary travel and social gatherings. there must always be a m gap between people in public, independent of viral transmission (social distancing in uk ). social distancing is useful where community spread is suspected to have occurred, but where the relationship between the infected persons are uncertain and restrictions imposed only on individuals known to be exposed are considered inadequate to prevent further disease transmission (centres for disease control and prevention ) . social distancing includes closure of schools or office buildings, public markets, and the cancellation of gatherings. community-wide isolation is an initiative extended to the entire city, town or area to restrict human interactions, except for limited interactions to ensure that vital resources reach human beings. in the absence of medicinal drugs for this covid- disease, the only solution is that by reducing the contact of affected people and the things used by affected people are to be totally avoided (lewnard and lo ) . but implementing community-wide containment is far more complex because it involves a large number of people (rothe et al. ) . it is important to use social media wisely during community-wide containment, which provides us with an opportunity to communicate the reasons for quarantine, to provide realistic advice, to avoid misinformation and getting panic. the implementation of the above mentioned public health initiatives also includes cooperation with law enforcement officials at local and state level, and it involves checkpoints and may need legal penalties if quarantine violations occur (rothe et al. ) . a community-wide containment is currently happening in america. quarantine is one of the unpleasant experiences for those who undergo it. since quarantine includes separation from loved ones, loss of rights, confusion about the status of disease and boredom can have drastic effects (brooks et al. ). this quarantine period can extend for an unpredictable long time. the possibility of psychological and mental problems increases due to quarantine (xiao ) . the psychological negative effects include symptoms of post-traumatic stress, uncertainty, irritation, disappointment, insufficient knowledge, financial loss, and stigma. studies show that post-traumatic stress in children who are quarantined is found to be four times higher than children who were not quarantined (brooks et al. ) . many who are quarantined often experience a great degree of psychological distress and signs of disease. also due to lockdown in several countries across the world, the production of several essential commodities has been decreased. consumer goods companies are facing various problems like the absence of labour, stranded trucks, and permissions for manufacturing products (drop in production of essential goods ). the government has taken several measures to make the people stress-free. they are arranging the markets to nearby places. they are allocating funds to the poor people who are depending on money for food. they are taking several actions to make this quarantine not affect people's minds. throughout the outbreak of communicable diseases such as covid- , the limitations placed on daily behaviours as part of social distancing requirements to avoid the disease spread. the immediate response should include maintaining community shelters and community kitchens, supplying other relief supplies, stressing the need for social isolation, reporting the cases of infected people, and adhering to guidelines for treating these cases. it is significant to remember that isolation doesn't just freeze your brain with boredom. when people like those kept in solitary confinement, know their sentence is nearly up, their mood lifts again in anticipation. those who experience social isolation because of covid- can no longer get it. open, clear, and reliable connectivity is what governments and organizations should achieve the most (prem et al. ) . protect yourself, and help other people. helping others in their time of need will benefit both the individual who receives assistance and the helper. managing your mental health, psychological, and social well-being during this period is just as essential as managing your physical health. keep regular routines and schedules including regular exercising, cleaning, daily chores, singing, painting or other activities. individual approach to each other can cause significant social disruption, it is necessary to know the degree of intervention which is required to minimize transmission and the burden of disease (lewnard and lo ) . people who are living together can share many ideas to prevent this disease and also they can care for each other during this quarantine. at the same time, they should also take care of elderly people. in joint families, people will share the financial burden during this situation. they can also play with the children and always keep them engaged without feeling their loneliness. people must be sanitized and should maintain hygiene by periodically washing their hands with soap and water for at least s. ensure that your home and workplaces are regularly cleaned and sprayed with a disinfectant, with particular attention to electronic devices. there is currently no vaccine or antiviral drug for coronavirus in humans and animals. so it is important to be healthy during the -ncov quarantine period (lu ) . symptoms of prodromal -ncov infection include nausea, dry cough and malaise are non-specific (wang et al. a, b, c) . through not exchanging personal things like food, water bottles, and utensils. families can implement these improvements now. people can also use a separate room in your home that can be used to isolate the affected member from the safer ones. affected people must use a separate bathroom. in case your caretaker is sick, it is important to have the one who is really very healthy. caregivers and their care recipients will be required to work closely and also ensure that they will not be affected by covid- . the caregiver will monitor the situation and regularly inquire about the wellbeing of the other tenants (rocklöv and sjödin ). the outbreak is predicted to spread among larger sections of the society than the mers-cov (yoo ) . in this period people must utilize their time to gain knowledge by reading books via the internet. because of the coronavirus outbreak, the technology and industry have become their new best friend for people hunkering down, with a number of lifestyle options that make "social distancing" easier. many of them wish to avoid crowds; they can have restaurant meals delivered, socialize online with friends, and work remotely. lifestyle approaches inspired by the latest technologies to gain momentum as more people are motivated to work from home, as more conferences and events are cancelled. many online streaming platforms have gained more users, as people are feeling very bored during this quarantine (increase of online usage ). internet usage has been increased; more people are using mobile phones to watch the news as it is very handy and portable. to make this quarantine useful online classes were launched, which has let students learn from home and gain information. nowadays, children are great at surfing and browsing the data. they are learning to play games and handle mobile phones at a younger age. this will be useful if they are acquiring knowledge but at the same time, many inappropriate content can misguide their path. so parents must watch their kid's daily activities (web safety for kids ). they love to play online games because they cannot play outside during this quarantine. children can use the same internet for their self-development. various videos are available on the internet platform to develop their skills (omar et al. ). the internet is a blessing to the present generation as it was not available to the previous generations. it is based on how people are using the internet whether it is to be treated as a blessing or curse. the same internet is considered as a blessing in disguise as it helps people. without the internet, people will get mentally weakened by facing the four walls during this quarantine. as a result of the covid- calamity, the trend in social media has grown, with more people going online to remain linked to families, friends, and colleagues. recent research from kantar's insights and advisory company shows just how many advantages those applications gain. according to a survey conducted between and th march with more than , customers in markets, whatsapp is the social media application that earned huge attraction from the covid- perspective (rapid increase in web usage ). people are continuously using whatsapp during this quarantine. as people are required to communicate with their relatives who are in distant places they are using different kinds of communication mediums. its handling capacity has risen from an initial % rise in the earlier days of the pandemic to % in the mid-phase. whatsapp handling has increased by % for countries now in the later phase of the pandemic (rapid increase in web usage ). fatality rates were calculated by dividing the total number of deaths in persons who tested positive for sars-cov- (numerator) by the total number of sars-cov- cases (denominator) and this is expressed as a percentile in both ( fig. ) and (fig. ) (outbreak of covid- ). when societies prepare for potential covid- diseases, regardless of underlying health problems, the risks of older people and those with weakened immune systems need to be remembered. from this figure, we come to the conclusion that people with greater than or equal to years of age had the highest fatality rate ( . %) than all the other age groups. such type of people are at higher risk of severe covid- infection or even death. since fatality and extent of illness have a connection with the age factor and comorbidities from (fig. ) and (fig. ) , we must make sure that these high-risk groups of people have sufficient protection from infections and they should be subjected to early access to medical care when infected. these measures are important for improving their chances of survival (outbreak of covid- ). fatality rates were calculated by evaluating n = , it was found that confirmed cases in mainland china in both ( fig. ) and (fig. ) as of february th, (outbreak of covid- ). patients with no comorbid conditions had just . % of mortality, whereas patients with comorbid conditions had much higher rates. so it is found that people, who are older, with higher sequential organ failure assessment (sofa) score and elevated d-dimer at admission, were at high risk for death due to covid- (zhou et al. ). the case fatality rate is considered as a great tool to express the fatality rate (spychalski et al. ) . covid- infected persons are identified by reverse transcriptase polymerase chain reaction (rt-pcr) testing. this method is used to test the patients on the throat swabs (onder et al. ). but it is reliable only in the first week of covid- disease because after the first week it slowly starts to disappear on the throat and begins to multiply in the lungs. after the second week, the suction catheter is used to collect samples from the deep air breath of the affected person. due to this pandemic covid- spread, this transition has brought some unforeseen consequences in the environment. compared to the last year, emission rates in many countries have fallen gradually. this shows how the environment is affected by regular day to day activities. this is considered as one of the best positive impacts of the quarantine during covid- . so the environmental impacts of covid- are seen in various forms of pollution, the condition of birds and animals, and the disposal of harmful medicinal waste. the coronavirus outbreak had led the world to shut down many cities, companies, and industries to ensure the safety of the workers. this had a great impact on the environmental changes in the quality of air, water bodies, etc. cleaner air has saved several lives in the last few months. there was a decline in the level of air pollution because of countries that are imposing strict quarantine and travel restrictions, the unintended decline in air quality from the virus outbreak is only temporary (british broadcasting council ). the long-term impact of the coronavirus pandemic on the world will depend on how countries respond to an economic crisis. at the end of november , delhi, a city in india was found to have a bad or unhealthy quality of air. data intelligence unit (diu) reviewed the central pollution control board (cpcb) and the aqi (air quality index) bulletin of delhi. the -h average aqi (november rd, pm to november th, pm) showed that jind in haryana had analysed the most polluted air in cities. the average aqi at jind was and aqi of delhi was at (polluted cities ). during the period of quarantine, the air quality of delhi increased drastically and the aqi dropped to from , this shows that the environment has a good impact due to the coronavirus outbreak (improvement of air quality ). as the vehicle's movement has reduced during this quarantine, horn usage also decreased. generally, unnecessary horn sounds will irritate people. this has reduced very much. birds' sounds are heard more than any other sound during this lockdown. birds are enjoying nature on their own by tweeting and chirping (natural effect on this pandemic ). sound which is unnecessary and higher than the audible frequency level is considered as noise. the entire city soundscapes are reduced, which may be pleasant to all the living creatures. the noise reduction helped the people who have high blood pressure and the disruption in sleep. many people started to recall their peaceful childhood days because at that time vehicles were less (natural effect on this pandemic ). due to the shutdown of industries, the noise level has reduced to a great extent. if we follow the standards of transportation and reduce unnecessary noise, we can make this globe a pleasant and peaceful place to live in the near future too. water pollution has also decreased much, this will lead to an improvement in the purity of freshwater sources. the famous water bodies such as ganga and yamuna in india have seen much improvement in freshness and its purity during the lockdown of the entire country (impact on water bodies). these rivers are the two important freshwater sources, these should be protected. freshness and purity should be maintained (water quality improvement during the lockdown ). due to the reduction in transportation of oil and goods via oceans, the chances of pollution of water like spilling of oils and waste into the ocean is reduced. (effects of water pollution ). many countries now have biomedical waste management regulations, the central pollution control board (cpcb) guidelines have been issued to ensure the scientific disposal of the waste generated while people research and treat covid- patients. biomedical waste is created during diagnosis, care, immunization of humans, animals or research, etc. (biomedical waste regulations ). biomedical waste disposal regulations show how the waste produced during human diagnosis, treatment or immunization should be disposed of (hegde et al. ). the waste consists of human skin, blood-contaminated products, body fat, and blood or body fluid pollution of the bedding. sacks of blood, needles, syringe or all other sharp items infected (hegde et al. ). for isolation wards in which covid- patients are quarantined, it is noted that double-layered bags can be used as a precaution to capture waste in addition to regulations on biomedical waste to ensure adequate intensity and no leakage (guidelines for waste disposal ). across a number of nations, when quarantine roll calls, people will spend more money on movies, social media, drama, and books. nonetheless, nature does its thing and the people are experiencing an unforeseen quarantine result. in countries such as japan, italy, and thailand, animals were observed roaming in the streets because of human absence. due to quarantine both the birds and animals are feeling free to roam outside, the roads are completely empty there is no rush as normal days. it is considered as the natural environmental change for both the birds and animals (freedom of animals ). manufacturing products use energy and natural resources which creates pollution and waste production, some wastes like plastic bags and bottles in rivers, lakes which lead to negative consequences for endangered species and other animals. now due to the covid- pandemic situation birds and animals are feeling completely happy (freedom of animals ). although there are no exact vaccines for treating covid- as of now, some methods of treatment or antiviral drugs have been effective in curing the patients. so to get rid of quarantine or to get discharged from hospital, the following conditions have to be met: • body temperature is supposed to be normal for longer than days. • it is important to strengthen the body and overcome respiratory symptoms. • the radiological abnormalities or acute exudative lesions on chest computed tomography (ct) images must be enhanced to a greater version. • two consecutive results of rt-pcr (reverse transcription-polymerase chain reaction) should be negative and these results must be at least h apart (lan et al. ; pan et al. ). no medicinal drugs have yet been proved safe and effective for the covid- diagnosis. a variety of medicinal products have been proposed as possible research therapies, some of which are currently being tested in clinical trials during this pandemic situation which are cosponsored by who and other participating countries (world health organisation b). (table ) provides common and potential antiviral drugs. in some countries, doctors are treating covid- patients with drugs that were not approved for this disease. the use of licensed drugs for indications that are not approved by a national regulatory authority for medicinal products is marked "off label" use. table represents some of the common and potent antiviral drugs used in clinical practice previously for some of the diseases. medicinal drugs prescribed by doctors for off label use may be subjected to national laws and regulations (world health organisation b). both healthcare staff should be aware of the laws and regulations regulating their practice and comply with them. in addition, the stipulation should be made on a case-by-case basis. it is necessary to avoid excessive stockpiling and creating shortages of approved medicines that are needed to treat diseases. based on the past experience of battling the sars-cov and mers-cov outbreaks, we have discussed certain prevention approaches against covid- . chloroquine is one of the drugs tested in china for covid- . it was reported on february th, , to inhibit sars-cov- in vitro. national health commission of the people's republic of china, included this drug in the covid- treatment guidelines on february th, . according to this guideline, the recommended dose for adults is about mg twice per day and it should not be continued for more than days (wong et al. ) . also, for adults, g of chloroquine becomes lethal (riou et al. ). chloroquine is a repurposed drug that is very effective in the treatment of covid- . chloroquine is previously used as an antimalarial and autoimmune disease drug. this drug has now been identified as a possible antiviral drug of broad range (wong et al. ). this drug acts as a novel class of autophagy inhibitor, which prevents further viral replication. also, a combination of remdesivir and chloroquine was found to be effective in the treatment of covid- . hydroxychloroquine which is an analogue of chloroquine has been found to have an anti-sars-cov activity. it is also found that azithromycin added to hydroxychloroquine was found to be more efficient for eliminating the virus. the study revealed a higher proportion of people diagnosed with hydroxychloroquine and azithromycin relative to patients treated with hydroxychloroquine alone (gautret et al. ). the kabasuraneer choornam is a siddha medicine that is used to cure many types of fever, flu, and respiratory illness (ayurveda benefits ). it is specially used when there is table common and potent antiviral drugs goldhill et al. ( ) fever associated with cold, cough, and difficulty in breathing as it is used for treating various cases of flu (ayurveda benefits ). the kabasuraneer choornam contains nearly types of medicinal herbs and they are chukku (dried ginger), thippili (piper longum), cirukancori ver (tragiainvolucrata), seenthil (tinospora cordifolia), karpooravalli (anisochilus carnosus), lavangam (syzygiumaromaticum), adathodai ver (root of justiciabeddomei), korai kizhangu (cyperus rotundus), kostam (costus speciosus), akkara (anacyclus pyrethrum), vatta tiruppur (sida acuta), mulliver (hygrophila auriculata), nilavembu (andrographis paniculata), kanduparangi (clerodendrum serratum) and kadukkaithol (terminaliachebula) is found to be efficient in prevention and treatment of swine flu (natural remedies to treat swine flu ). the kabasuraneer choornam is prepared from the extract of kabasura kudineer choornam, it is added to water and heated to about - ºc till the water reduces to / th of the volume. the kabasuraneer choornam is a siddha medicine practised in india and mostly in southern india which is prescribed to increase the immunity against swine flu in (saravanan et al. ) . atleast eight of the herbs used in the preparation of the kabasuraneer choornam could neglect the replication of the virus and gives protection for the human body from covid- , said by sanjeev biomedical research centre (benifits of kabasura kudineer ). phytocompounds bind to the coronavirus spike protein or surface protein and prevent it from binding to the human cell membrane receptors that serve as a barrier until it starts to replicate. if the kabasuraneer choornam is consumed before the virus is contracted, the phytocompounds will bind to the respiratory epithelial cells and strengthen the immune system and it also prevents the virus from linking with the human cells and replicating after the person gets affected by covid- . the benefits of kabasuraneer choornam includes several phytochemical components that are responsible for antiinflammatory, antipyretic, analgesic, antiviral, antifungal, antioxidant, hepato-protective, anti-diabetic, anti-asthmatic, immunomodulatory, anti-diarrhoeal activity (saravanan et al. ) . it is said that the kabasuraneer choornam can be used against the covid- virus by siddha practitioners in india because it is a preventive remedy against various types of fever, flu and also increases the immunity of the human body (ayurveda benefits ). however, a siddha practitioner, g. sivaraman director of arogya healthcare said that this drug cannot be used as treatment for covid- and this drug is used to treat pneumonia like diseases in siddha medicine (remedy given by siddha field ). astrazeneca has joined serum institute of india (sii), the world's biggest immunization makers by the number of portions created and sold, to deliver the possible antibody in india. the human trials of oxford covid- immunization have just begun in brazil. if any of these vaccines have proved its success, then we can slowly reduce this pandemic to a normal situation (research updates on the vaccine ). some of the developers of vaccines that are in the clinical evaluation stage as on th july, are shown in (fig. ). in this section, the preventive measures for both people and medical staff given by central governments from the world health organisation will be elucidated. preventive measures should be taken otherwise, the risk of disease transmission will be more. according to the english proverb "prevention is better than cure", prevention is the best thing that we can follow, until the proper medicine or vaccination is found. the preventive measures that can be adopted to prevent human from getting covid- infection, they are as follows: • hygiene should be maintained. • % alcohol-based hand rub, liquid soap can be used by people. • avoid touching each other and maintain social distancing for m. • stay home, seek medical attention if you have the symptoms of cold, fever, and problems in respiration. follow the guidelines of the local health authority. • personal protective equipment [ppe] such as sterile gloves, face shields, aprons, sterile gloves, gowns, protective goggles, scrubs, masks (n or ffp ) must be used by medical staff. (adams and walls ). • medical staff and paramedical workers should self-quarantine themselves for alternate weeks. • doctors should sterilize themselves before and after attending the patients. • reducing the contacts with the family members during the crisis. • screening people and risk assessment should be well planned and managed. • environmental cleaning and spraying disinfectant in local areas is a must. • spreading awareness among people through online videos can be done. • overcrowding in the areas of essential places such as markets should be strictly avoided (world health organisation, c). since the covid- pandemic has forced to close educational institutions and industries, we have to depend on cloud based technologies to connect students with educational institutions and also artificial intelligence-enabled robots can prove to be helpful for many industries to work during these pandemic. without these advancements in technologies, this lockdown would be hard for individuals to cope up. individuals will feel exhausted at their home. presently, they are engaged with their movies on online streaming platforms. if there was isolation during the olden days, people would fig. technologies used during covid- ). these technologies helped mankind to invent new products like face masks (developed by d printing), ir thermometer (bio sensors) to provide safety for human beings and for the front line workers feel stressed without cell phones and media transmission. but nowadays, individuals are getting occupied with these innovations. technologies also played a vital role in data collection (artificial intelligence and big data), online classes (virtual reality) etc. some of the other technologies were also used to tackle this pandemic condition as shown in (fig. ). artificial intelligence has a feasible contribution in fighting against covid- as well as existing constraints. in terms of life and economic destruction, the risk of a pandemic is terrible. improving artificial intelligence and data analytics technologies have evolved continuously over the last decades. because of the lack of evidence, artificial intelligence has not been impactful against covid- yet. overcoming these constraints requires careful consideration of data privacy and public health issues as well as the interaction between human artificial intelligence. it will be necessary to gather diagnostic data from infectious people to save lives and reduce the economic havoc due to containment (mccall ). the goal of artificial intelligence is to deploy decision support using predictive analysis. artificial intelligence can help people by predicting the case of covid- which helps them to identify persons affected and take actions in a faster manner. patients with confirmed n-cov infection suffer from respiratory illness, fever, and cough. incubation time ranges from days to weeks (carlos et al. ) . supervised training is a practice and learning process. accordingly, the computers are equipped with sample data and then used for predicting new sampling of the results. the vast collection of health data from a wide range of outlets types include genome screening, electronic health records (ehr), and wearables contributed to biomedical big data (elavarasan and pugazhendhi ) . artificial intelligence was praised for its possible contribution to the development of new medicines. artificial intelligence helps in finding new drugs and a covid- vaccine. artificial intelligence creates an aid clinical preliminaries which are ought to perceive the ailment in patients, distinguish the quality targets and foresee the impact of the particle structured just as the on-and off-target impacts (mak and pichika ) data is used to run artificial intelligence models; it helps to handle the pandemic more efficiently. early warning is a much better way to cure the pandemic. a basic urine test is expected to assist clinical experts in recognizing future decompensation of covid- disease (early warnings ). the case of the artificial intelligence model based in canada, blue dot, has already become legendary. this shows that blue dot, a fairly low-cost artificial intelligence platform. it can predict infectious disease outbreaks in humans (predetermining artificial intelligence ). blue dot predicted the outbreak of the infection by the end of , according to accounts, where it identified the top destination cities where wuhan passengers will arrive. this warned that those cities may be at the forefront of the disease's global spread. patients with suspected -ncov were admitted and quarantined, and samples of the throat swab were obtained and the same data is sent to the -ncov chinese centre for disease control and prevention using a quantitative polymerase chain reaction test and the surveyed data was very much useful for the analysis of the covid- disease (chang et al. ) . artificial intelligence can be used to monitor and predict how covid- will spread over the period of time. for instance, a dynamic neural network was built to predict its spread following a previous pandemic, zika-virus of . algorithms were formulated to predict seasonal flu are now being retrained on new covid- data at carnegie mellon university. the atypical case of pneumonia, caused by a novel coronavirus ( -ncov), was first documented and confirmed on st december in wuhan, china ). fast and accurate covid- diagnosis will save lives, limit disease spread, and generate data on which to train models of artificial intelligence. artificial intelligence may provide valuable feedback in this regard, in particular with a diagnosis based on images (predetermining artificial intelligence ). according to a recent study by researchers working with un global pulse of artificial intelligence applications against covid- , studies have shown that artificial intelligence can be as reliable as human beings, can save the time of radiologists and diagnose faster and cheaper than regular covid- tests (predetermining artificial intelligence ). the field of biology and modern medicine is making more tremendous upgraded technology which is becoming data-intensive, by using these data and the field of deep learning technology is more helpful in treating the patients (ching et al. ). deep learning is useful when a problem arises with a patient of a particular disease, the data which is input to the computer represents the disease in the patient, the computer analyses many logical symptoms in the patient and the treatment is given according to the results of the computer (hinton ) . machine learning has proved effective in many analytical areas of risk. machine learning probably matters in three major areas, with clear medical risk (machine learning in healthcare ). • danger of infection what is the risk of having covid- for a specific person or group? • risk of severity what is the risk of extreme covid- symptoms or complications requiring hospitalization or intensive care of a specific patient or group? • result probability what is the probability of the ineffectiveness of a medication for a specific person or group? theoretically, learning by computer can aid in detecting all three risks. although it is still too early to get some covid- -specific machine learning research completed and written, early findings are very positive. we can also understand how machine learning can be used in related fields and how it can assist with covid- risk prediction (machine learning in healthcare ). early statistics indicate that important risk factors that decide the probability of a person contracting covid- include: sex, pre-existing illnesses, general grooming practices, social behaviour, amount of interaction between individuals, duration of interactions, place, and climate, socioeconomic status(machine learning in healthcare ) (see fig. ). machine learning has the potential to support clinicians' work processing and management of large amounts of medical data contained in electronic health records and used in clinical applications which includes recognizing high-risk patients in need of icu, the identification of early signs of lung cancer, determination of patient's respiratory status from x-rays in the chest, such deep learning approaches employ neural networks to predict the input-output data relationship. another potential feature of ml is its ability to reduce the cost of operation and product, automate, and enhance customer support (elavarasan and pugazhendhi ) . deep learning works more similar to machine learning where it can be separated into two types as "supervised applications-where the predicted goal is achieved accurately and unsupervised applications-where the goal is to summarize the data outcomes and identify the patterns of the outcome data" (hinton ) . deep neural network (fig. ) is learned and trained over a large set of data and they work on the multiple layers for the specified results and they are more accurate because they are learning from the previous outcomes of the data obtained (healthit analytics ; hinton ). machine learning and the rapid advancement of deep learning based technologies have demonstrated their ability to transform these big data in biomedical applications to a functional form. in general, ai and ml are introduced at the healthcare has increased patient safety, and successful treatment, and healthcare costs also has got reduced (elavarasan and pugazhendhi ) . when data on covid- is collected and analysed by a deep learning network it would save as many lives as possible and the computers would suggest the doctors for the treatment. deep learning helps in the classification of each and every task by the use of multiple layer strategy in the patients with the risk abnormalities found earlier with the same symptoms and by means of medical imaging (table ) (switching healthcare ). deep learning is a key technology where predictive healthcare systems can be developed, which can have access to a billions of data of the patients for the next generation (hinton ) . table provides a list of deep learning data and its uses in diverse medical fields and where data can be gathered and therapies provided to patients. there are several applications used for helping the government. some of the important apps used in india to control the pandemic condition is shown in (table ) and some of the top applications used in the world to tackle the covid- is shown in (fig. ) . these applications give clear monitoring status, feedback and also give guidelines to be followed by the people. it gives several updates about contact tracing which will be very much useful to the people. these applications utilise the telephone's bluetooth and gps capacities. it will track the affected persons by utilizing bluetooth. (hinton ) types of data application references electronic health records • it helps in indicating different population subtypes and to differentiate symptoms of gout and acute leukemia from uric acid lasko et al. ( ) • assigns the diagnosis process for the patients by previous clinical status liang et al. ( ) • to know about heart failure and chronic pulmonary illness in advance cheng et al. ( ) • advanced treatments over the onset of diseases by predicting from lab results razavian et al. ( ) • end-to-end method for forecasting after discharge unplanned readmission nguyen et al. ( ) clinical imaging • advanced imaging using magnetic resonance imaging (mri) scan to detect alzheimer's disease brosch and tam ( ) • it is used to meet the requirement of people during this pandemic gizbot ( ) these applications will also utilize a gps to track the record of an individual. these data will be updated on the mobile application if any person is tested with positive covid- . this will be done on the basis of an appraisal review of every individual. in such infected cases, the records will be transferred to the servers (tracking apps for covid- ). table provides the information about the list of applications and their functionality developed by the indian government to handle the pandemic condition. the internet of things (iot) could be a well-defined platform of interconnected computing strategies, computerized, and mechanical gadgets having the capability for transmission of information over the defined network without having any human inclusion at any level (singh et al. ). in addition, no research in the current literature attempts to analyze the position of emerging technologies like iot. it is a well-developed scheme of interconnected computing techniques, physical and mechanical devices with data communication capabilities over the specified one. network without any degree of human involvement (singh et al. ) . iot is a way beyond concept which develops a general architectural history, which allows for integration and fig. top applications used in the world to control the pandemic (covid watch ), (central and eastern europe legalblog ) , (immuni ) , (covid- smartphone applications ) fig. working of iot in health care domains which minimizes the contact between the affected individuals and the frontline workers effective exchange of data between needy persons and service providers. in the latest problematic pandemic scenario, the number of globally infected patients are growing day by day, and there are a large number of the sufficient and well-organized facilities provided with the methodology of iot. in addition iot already is also used for the purposes being demanded in various domains in healthcare (mohammed et al. ) (see fig. ). plasma is the fluid piece of blood that is gathered from patients who have recouped from the covid- . this disease is brought about by the infection named sars-cov- . covid- patients create antibodies in the blood against the infection. antibodies are proteins that may help to fight against the contamination (food and drug administration ). individuals who have completely recuperated from covid- in the last days are urged to consider giving plasma, which may help the lives of different patients. covid- based healing plasma should possibly be gathered from recuperated people in the event that they are qualified to give blood. people should have an earlier analysis of covid- recorded by a research centre test and meet other contributor models. people must have a total goal of manifestations for the past days before plasma donation. a negative lab test for dynamic covid- ailment is not required for plasma donation (food and drug administration ). there are many technologies that are used to reduce the effect of this pandemic, some of them are as follows, big data investigation helps in studying the infected individuals very effectively. these frameworks can control the development of the pandemic and also aids in observing individuals who are isolated. it also keeps an eye on individuals to check whether they are infected or they have been in contact with a contaminated individual. (management during pandemic ). self-driving vehicles, automated drones, and robots would be able to avoid human interaction. automated vehicles can be used to move impaired people to and from the medical service offices, without bargaining individual's lives. robots can be utilized in the circulation of food, warming, medical clinic sanitization, and road watching. these technologies help people who are facing many difficulties during these lockdown period (management during pandemic ). currently, digital learning is gaining its popularity and also it the trend which is heading forward in modern educational activities, models, and processes. this will be the big moment for the online learning and educational approaches that will be re-planned much like the businesses that are going to operate remotely (work from home) because of the covid- . the present scenario has pushed scholars and educational institutions towards online learning plans and technology (online education ). e-learning training is very useful in this pandemic situation because it is instantly accessible and it also offers flexible scheduling for the training (computer aided elearning team ). since virtual classrooms are important for student-faculty interaction, video conferencing platforms like google meeting and webex are getting used extensively by many educational institutions. also, software like proctorio, a google chrome extension that monitors whether students take their online exams regularly, which has helped the educational institutions to keep track of the students, who take up their online exams regularly. so, the learning has become digitized and this will help us to get rid of the use of paper and costly textbooks (online education ). these online classes offer a highly effective learning atmosphere for students so that they can learn from their respective locations (computer-aided e-learning team ). such initiatives and steps taken by the educational institutions are important because extended school closure and home isolation during a pandemic could have negative effects on the physical and mental health of children (wang et al. a, b, c) . with more than million web clients, india is the second biggest online market among all countries, positioned distinctly behind china. it was evaluated that by , there would be more than million web clients in the nation. regardless of the huge base of web clients, the web entrance rate in the nation remained at around % in . this statistics imply that around half of the . billion indians started using internet accessibility that year. there has been a steady increase in web accessibility but it is contrasted with only the past years, when the web entrance rate was around % (statistical usage ). though india is the second biggest online market among all countries, some children in rural areas are lagging behind, without the internet facility. this would rule out a large proportion of children from rural areas in internet usage (online education ). since the confirmed cases and deaths due to covid- are rapidly increasing day by day, both medical staff and the public have been undergoing psychological problems, like depression, stress, and anxiety. also, the transmission of viruses takes place at a faster rate between people. this obstructs face-to-face psychological interventions. therefore, internet services and telecommunication helped health care professionals to provide mental health support online during the covid- outbreak (liu et al. a, b) . since epidemic contagious diseases mostly interrupt the movement of people, transportation systems, and mobility of commodity, the use of drones in this situation will relieve humanitarian aid. the use of drones and quadcopters will generally help to do certain things like (i) evaluate and analyse the infected area by aerial monitoring (ii) epidemic cargo and logistic delivery (estrada ) (iii) aerial spray and disinfection (drone technologies ). unmanned aerial vehicles are used to monitor the people, who were unnecessarily roaming in the streets. those people can be warned and sent back through this facility. disease transmission can be controlled to a greater extent and it is cost-efficient. by travelling, a high quantity of fuel will be wasted and it is not practically possible to monitor all the areas. aerial monitoring systems will be helpful for the reduction of covid- transmission (benefits of drones ). drones were used in china and dubai to spray disinfectant chemicals in public places and on vehicles for disease prevention so that the transmission mechanism gets reduced. justin gong, co-founder of an agricultural drone company said that spraying disinfecting chemicals using drones has been more effective in comparison with hand spray (drone technologies ). the use of drones is a great boon for the workers and it reduces the risk of being infected by the pandemic in the infected areas. in india, these drones are effectively used to control the spread of the disease. if the people are seen outside doing mischievous activities they would be spotted and punished or warned. drones are very much useful to monitor a highly populated country like india. otherwise, the disease transmission rate would be even higher. the covid- outbreak has shown the pathway of hygiene for people all over the world. we must learn from mother nature to give equal rights to all living beings in the world and we must uphold it as a superior sense. it is our duty to protect nature for ourselves and for future generations. the pandemic has demonstrated the world's best new technologies that can hold children up to date with lectures, courses, and more online learning and educational exams that have contributed to a landscape of modern interfacing within months. the advanced ai and machine learning systems tend to operate the industries while the whole planet is being shut down due to the epidemic and the industrial goods are already being processed by these systems. the lockdown of cities has reinforced the relationship within a family by obtaining more freedom to communicate with each other, and it has been found that the use of traditional medicines has a great influence on the society. also during the quarantine period, people have learnt a great lesson from the epidemic of a novel coronavirus, the sophisticated technology supports the community with drones disinfecting the cities, interfacing robots, and gathering data from the infected communities without transmitting the virus to the physicians. the risk of being affected is high to the workers in the frontline, also people who travelled from other countries can be quarantined for the safety of their family, and the surroundings. the people who ever recognize the symptoms can admit themselves to test them for the disease, rather than being detected at the final stage of the illness. the human race had faced many outbreaks of many contagious diseases and had 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data-driven analysis in the early phase of the outbreak clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study using deep learning for energy expenditure estimation with wearable sensors the authors thank dr.s.sivaramakrishnan ms ortho and dr. m. jayalalitha mbbs, shanthi ortho care hospital, tiruchirappalli, tamil nadu, india. they have helped us by suggesting some practical issues that are faced by the corona virus affected patients and the doctors working in the hospital during the covid- period. the inputs received has helped the authors in framing certain important sections of the paper. the authors declare that they have no conflict of interest. key: cord- -ncdy qgb authors: wang, ji-gan; cui, hai-rong; tang, hua-bo; deng, xiu-li title: gastrointestinal symptoms and fecal nucleic acid testing of children with coronavirus disease: a systematic review and meta-analysis date: - - journal: sci rep doi: . /s - - - sha: doc_id: cord_uid: ncdy qgb in order to understand the clinical manifestations and incidence of gastrointestinal symptoms of coronavirus disease (covid- ) in children and discuss the importance of fecal nucleic acid testing.we retrospectively analyzed studies on gastrointestinal symptoms and fecal nucleic acid detection in pediatric covid- patients from january , to august , , including prospective clinical studies and case reports. the results of fecal nucleic acid detection were analyzed systematically. stata . software was used for meta-analysis.the results showed that the most common gastrointestinal symptoms in children with covid- were vomiting and diarrhea, with a total incidence of . % ( % cl . – . %). however, the prevalence of gastrointestinal symptoms in other countries ( . %, % ci . – . %) was higher compared to china ( . %, % ci – . %). in wuhan, the pooled prevalence was much higher ( . %, % ci . – . %) compared to areas outside wuhan in china ( . %, % ci . – . %). the positive rate of fecal nucleic acid testing in covid- children was relatively high at . % ( / ). additionally, . % ( / ) were still positive for fecal nucleic acid after respiratory tract specimens turned negative. one and two weeks after the respiratory tract specimens turned nucleic acid-negative, . % ( / ) and . % ( / ) patients, respectively, remained fecal nucleic acid-positive. the longest interval between the respiratory tract specimens turning negative and fecal specimens turning negative exceeded days. conclusions and relevance: gastrointestinal symptoms in pediatric covid- are relatively common. attention should be paid to the detection of fecal nucleic acids in children. fecal nucleic acid-negative status should be considered as one of the desegregation standards. literature screening and data extraction. two researchers independently searched and screened the literature and collected and cross-checked the relevant data. if there was any dispute, it was discussed or resolved with the help of a third researcher. inclusion criteria . research types: cohort study, case-control study, and case analysis; . subjects: children with covid- ; . observation index: clinical manifestations of covid- in children including gastrointestinal symptoms such as diarrhea and vomiting. exclusion criteria . repeated publication of the same research; . studies on adults; . incomplete or missing data or analysis, and inability to obtain the data literature. we included a case series study, using the national institute for clinical optimization. clinical excellence (nice) for quality evaluation . the evaluation items were as follows: the cases included in the case series should ( ) come from different levels of medical institutions that carry out multi-center research; ( ) clearly describe the research hypothesis or purpose; ( ) have clear exclusion criteria; ( ) have a clear definition of the measurement of results; ( ) present collected data that achieves the expected purpose; ( ) accurately describe that patients are continuously recruited; ( ) describe the main findings clearly; ( ) analyze and report the results in layers. one point is given for each item, and a total score ≥ out of points is considered as highquality research. two researchers independently evaluated the quality and cross-checked the results. statistical analysis. meta-analysis was performed using the stata . software. first, the original ratio (r) was transformed by double arcsine to make it conform to a normal distribution, and then the transform ratio (tr) was analyzed by meta-analysis. subsequently, the final rate (r) with the % confidence interval (ci) were obtained by converting the results with the formula r = (sin[tr/ ]) . meta-analysis was carried out by using the random effect model for all studies. the funnel chart was utilized to assess publication bias, and the metaanalysis significance level was designated as α = . . as this is a systematic review, ethical approval was not required. gastrointestinal symptoms of covid- . figure summarizes the article retrieval and abstraction method using the prisma guidelines. most research data are concentrated in articles published by china, the united states, and europe. a total of studies were included in this analysis - , of which described the gastrointestinal symptoms of patients (supplementary table s ). a total of patients were evaluated in the study, among whom had digestive tract symptoms, accounting for . % ( % ci . - . %) of the patients (fig. ) . vomiting and diarrhea were the most common gastrointestinal symptoms. when analyzing by country (studies from china versus studies from other countries), the prevalence of gastrointestinal symptoms in countries outside china was . % ( % ci . - . %), which was higher than that in china ( . %, % ci - . %). among patients in wuhan, the pooled prevalence was much higher at . % ( % ci . - . %) than in areas outside wuhan in china ( . %, % ci . %- . %) ( table ) . a majority of studies did not describe the stool characteristics or number of bowel movements. wang duan et al. reported that in the six northern provinces of china, patients had bowel movements - times per day, while wu huaping found that in the jiangxi province of china, the frequency of diarrhea in affected children was - times per day . subgroup analysis. the heterogeneity of this study was relatively large. to explore the source of heterogeneity, we analyzed according to the region (country or region) where the research object was located. it was discovered that the analysis results of each subgroup were basically consistent with the overall results, and there were no significant differences between the heterogeneity of each subgroup and the overall heterogeneity. therefore, was considered that the region of the research object was not the main source of heterogeneity (table ) . fecal testing for viral nucleic acid. thirteen reports included in the present study described fecal nucleic acid examination ( . however, in a study on three neonates , respiratory tract and fecal nucleic acid tests were positive and days after birth, respectively, and the fecal and respiratory tract specimens were negative on the th day after birth. publication bias. the funnel plot (fig. ) shows the presence of a possible publication bias. most of the research quality scores were not high. our confidence in the pooled estimates of prevalence was reduced because of concerns regarding risk of bias (selection bias, detection bias, and attrition bias), heterogeneity of the tested incidence of gastrointestinal symptoms. in the early stages of the pandemic, there was a shared misconception that children were not easily infected . however, with the spread of the pandemic, the number of infected children is increasing and several severe pediatric cases have been reported . it is sometimes difficult to distinguish the gastrointestinal symptoms of pediatric covid- from those caused by another viral illness, side effects of drugs, and digestive tract symptoms such as nausea and diarrhea caused by the disturbance of gastrointestinal flora by the fever itself. some studies have found that . % children use antibiotics that cause diarrhea, and the diarrhea is more severe in younger patients with lower respiratory tract infections treated with intravenous antibiotics. moreover, we discovered that the total incidence of gastrointestinal symptoms in children with covid- was . %; unfortunately, not all the studies described a control group when investigating the incidence of gastrointestinal symptoms in an antibiotic treatment group and non-antibiotic treatment group. in a meta-analysis of predominantly adult studies, studies (including patients with covid- ) were analyzed and the incidence of gastrointestinal symptoms was found to be . %, which is almost equal to . % found in this study. in addition, we discovered that the incidence of gastrointestinal symptoms in other countries ( . %) was significantly higher than that in china ( . %). one reason may be that the gastrointestinal symptoms were not paid attention to in the early stage of the epidemic. however, once the literature was published, gastrointestinal symptoms were described in detail. regarding the mechanism of infection of the severe acute respiratory syndrome coronavirus (sars-cov- ), it is currently believed that the major determinant of sars-cov- infection is the s protein, which binds to membrane receptors on host cells and mediates the fusion of the virus and cell membrane. angiotensin converting enzyme (ace ) is a homolog of ace and one of the important receptors on the cell membrane of host cells. the interaction between the s protein and ace promotes the invasion of host cells by sars-cov- . the structure of the sars-cov- s protein is highly similar to that of the sars coronavirus (sars-cov) s protein; however, sars-cov- s protein binds to ace with a higher affinity than the sars-cov s protein, indicating that sars-cov- possesses a stronger invasion ability . ace can control intestinal inflammation and diarrhea, and the interaction between sars-cov- and ace may lead to diarrhea . ace is highly expressed in the small intestine, especially in the proximal and distal intestinal epithelial cells; therefore, the small intestine is more vulnerable to sars-cov- infection. previous investigations may have underestimated the incidence of diarrhea among those infected with sars-cov- . further research is needed to determine whether diarrhea has diagnostic value for sars-cov- . in case of the middle east respiratory syndrome coronavirus (mers-cov), which is highly homologous to sars-cov- , it is believed that the intestinal tract is another route of infection and the incidence rate of diarrhea is - % . pathological examination. till date, there have been no endoscopic and pathologic studies of the digestive tract in pediatric covid- cases. however, a study in adults demonstrated that there was no obvious damage to the mucosal epithelium of the esophagus, stomach, duodenum, and rectum. in the inherent layers of the stomach, duodenum, and rectum, a large number of infiltrating plasma cells and lymphocytes were seen accompanied by interstitial edema. ace , the virus host receptor, is mainly found in the cytoplasm of gastro- positive rate and significance of fecal nucleic acids. in a recent study on hospitalized adult patients in china, the feces of . % of the patients were positive for the viral rna, the duration for which positive fecal results were obtained ranged from to days, and . % of the patients were still fecal nucleic acid-positive after being confirmed respiratory nucleic acid-negative. compared with adults, the present study found that the nucleic acid positivity rate of feces in children was higher ( . %). a study reported that among patients with covid- in hong kong, ( . %) had gastrointestinal symptoms and nine ( . %) had positive stool viral rna test results. the detection rates of fecal viral rna were . % and . % in people with and without diarrhea, respectively . at present, there is no relevant study on whether there is a difference in the positive rate of fecal nucleic acid testing in covid- children with and without diarrhea. in a recent study conducted from january , to february , , the chinese cdc reported pediatric covid- patients (including confirmed and suspected cases), of whom were asymptomatic ( . %) . however, a recent study from new york claimed that ( . %) out of pregnant women who tested positive for sars-cov- on admission did not have symptoms of covid- at the time of treatment. this is very worrying data, because it shows that there are more asymptomatic than symptomatic patients; therefore, controlling asymptomatic patients is the key to controlling the pandemic. in children with asymptomatic covid- , there is no relevant study on whether the nucleic acid sensitivity of respiratory specimens is higher than that of feces. furthermore, it remains unknown whether the children in whom the symptoms have resolved and respiratory tract specimens are negative while the stool samples remain positive for viral nucleic acids, are asymptomatic infectious sources. consequently, it is important to recommend that after recovery and discharge, pediatric patients be isolated at home for more than weeks. in terms of prognosis, a retrospective comparative study was carried out in patients over years old in the united states . the experimental group included patients with fever and cough due to covid- , and the control group included patients with fever and cough attributable to a common respiratory tract infection. the incidence of gastrointestinal symptoms in the two groups was . % and . %, respectively (p = . ). in the patients with covid- , the course of gastrointestinal symptoms was longer, but the mortality rate and rate of severe disease were lower in patients with gastrointestinal symptoms than in those without such symptoms. at present, there is no prognostic study on children with covid- . prevention and treatment. transmission through respiratory droplets and contact are currently considered to be the main routes of transmission of covid- . nevertheless, there is now increasing evidence of fecal-oral transmission . in clinical practice, doctors mostly pay attention to the manifestations of respiratory infection in children with covid- such as fever, cough, fatigue, etc. for patients in the gastroenterology department who have no respiratory symptoms, it is recommended to adopt the appointment system and timedivision diagnosis and treatment to reduce patient aggregation and avoid cross infections. the clinic should be well-ventilated and disinfection of the clinic should be performed daily at the beginning and end of the clinic. although gastrointestinal symptoms are often ignored, in children with diarrhea, abdominal pain, nausea, vomiting, and other gastrointestinal symptoms accompanied by a low fever, attention should be paid to their epidemiological history with screening of suspected patients. nucleic acid examination should be performed using throat swabs and anal tests. in daily life, the risk of transmission can be reduced by good hygiene practices, such as washing hands frequently and closing the toilet lid when flushing. at present, there is no specific drug for covid- . plasma therapy from convalescent patients is considered for those with severe disease ; however, this treatment is controversial . dexamethasone has now been proven to be a good treatment option for the covid- . diarrhea in covid- patients is mostly self-limiting, and symptomatic treatment such as montmorillonite powder can be used. for critically ill patients, intestinal microecological regulators may be used to maintain the balance of the intestinal flora and prevent secondary infection by intestinal bacterial translocation. the number of studies included in the meta-analysis was relatively small, with a relatively large proportion of case reports. most studies did not report on the duration of the gastrointestinal symptoms preceding the presentation. additionally, the number of patients was relatively small and the description of the gastrointestinal tract of children in the included studies was not sufficiently detailed. the heterogeneity is large and subgroup analysis can not find the source of heterogeneity, which will affect the accuracy of the results. therefore, it is necessary to conduct a large-scale double-blind randomized controlled study and include additional research factors such as stool frequency, stool characteristics, number of patients with gastrointestinal symptoms and positive fecal nucleic acid test results, length of hospitalization of fecal nucleic acid-positive patients, severity of illness, and the interrelation between respiratory tract sample nucleic acid and stool nucleic acid findings. 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meta-analysis ace and covid- and the resulting ards diarrhoea may be underestimated: a missing link in novel coronavirus human intestinal tract serves as an alternative infection route for middle east respiratory syndrome coronavirus evidence for gastrointestinal infection of sars-cov- epidemiology of covid- among children in china universal screening for sars-cov- in women admitted for delivery gastrointestinal symptoms and coronavirus disease : a case-control study from the united states covid- : gastrointestinal manifestations and potential fecal-oral transmission effectiveness of convalescent plasma therapy in severe covid- patients the use of dexamethasone in the treatment of covid- j.w. and h.t. contributed to the study design, while h.c. and x.d. contributed to the data collection. statistical analyses and interpretation of results were performed by j.w. and h.c., whereas j.w. and h.t. drafted the manuscript and edited the language. all the authors participated in the critical revisions, and approved the final version of the manuscript. the authors declare no competing interests. supplementary information is available for this paper at https ://doi.org/ . /s - - - .correspondence and requests for materials should be addressed to j.w.reprints and permissions information is available at www.nature.com/reprints.publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/ . /. key: cord- -j i ozsz authors: mccreary, erin k; pogue, jason m title: coronavirus disease treatment: a review of early and emerging options date: - - journal: open forum infect dis doi: . /ofid/ofaa sha: doc_id: cord_uid: j i ozsz severe acute respiratory syndrome coronavirus (sars-cov- ), the cause of coronavirus disease (covid- ), has spread across the globe resulting in a pandemic. at the time of this review, covid- has been diagnosed in more than patients and associated with over deaths (centers for disease control and prevention, world health organization). on behalf of the society of infectious diseases pharmacists, we herein summarize the current evidence as of march , to provide guidance on potential covid- treatment options. it is important to caution readers that new data emerges daily regarding clinical characteristics, treatment options, and outcomes for covid- . optimized supportive care remains the mainstay of therapy, and the clinical efficacy for the subsequent agents is still under investigation. antimicrobial stewardship programs, including infectious diseases pharmacists and physicians, are at the forefront of covid- emergency preparedness. we encourage all readers to continue to assess clinical data as it emerges and share their experience within our community in a well-controlled, adequately powered fashion. in december , several patients in wuhan, hubei, china were diagnosed with pneumonia secondary to an unknown virus. in response, an epidemiological alert was placed with the world health organization (who) dated december , . by january , chinese scientists had isolated severe acute respiratory syndrome coronavirus (sars-cov- ) [ ] . in the months that followed, sars-cov- , the cause of coronavirus disease (covid- ) , spread across the globe resulting in the current pandemic. at the time of this review, covid- has been diagnosed in more than patients and associated with over deaths (centers for disease control and prevention [cdc] , who). on behalf of the society of infectious diseases pharmacists, we herein summarize the current evidence as of march , to provide guidance on potential covid- treatment options. it is important to caution readers that new data emerges approximately every hour regarding clinical characteristics, treatment options, and outcomes for covid- . optimized supportive care remains the mainstay of therapy, and the clinical efficacy for the subsequent agents is still under investigation. most existing preclinical and clinical data on antiviral therapy are derived from other viruses, including sars-cov- (first reported in ), middle east respiratory syndrome coronavirus ([mers-cov] first reported in ), and non-coronaviruses (eg, ebola virus disease). it is unclear how well these data can be extrapolated to sars-cov- . furthermore, the clinical relevance of antiviral in vitro activity (defined as half-maximal effective concentration [ec ] values) remains unclear given an absence of pharmacokinetic/pharmacodynamic or clinical data that equates achievable exposures relative to these values to a treatment effect. finally, in vitro data should be compared cautiously across studies given the potential variability in testing methodologies that could impact perceived activity. antimicrobial stewardship programs, including infectious diseases pharmacists and physicians, are at the forefront of covid- emergency preparedness [ ] . we encourage all readers to continue to assess clinical data as it emerges and share their experience within our community, preferentially evaluating these agents in the context of randomized, controlled trials. gilead sciences, inc. in response to the ebola outbreak in west africa from to . in its active triphosphate nucleoside form, remdesivir binds to ribonucleic acid (rna)-dependent rna polymerase and acts as an rna-chain terminator. it displays potent in vitro activity against sars-cov- with an ec at hours of . µm in vero e cells [ ] . similar activity has been demonstrated against other zoonotic coronaviruses with ec values of . µm demonstrated for both sars-cov- and mers-cov [ ] [ ] [ ] [ ] . remdesivir is highly selective for viral polymerases and is therefore expected to have a low propensity to cause human toxicity. accordingly, sheahan et al [ ] demonstrated a wide therapeutic index for remdesivir in a human airway epithelial cell model. the drug also displays a high genetic barrier to resistance in coronaviruses and has a long intracellular half-life that allows for once-daily dosing [ , ] . the dose under investigation for treatment of covid- is mg intravenously (iv) on day followed by mg iv daily for up to days, infused over - minutes ( table ) . the therapeutic efficacy of remdesivir was first described in an animal model against ebola among infected rhesus monkeys in which once-daily dosing resulted in suppression of viral replication and protection from lethal disease [ ] . however, in a human study, remdesivir-treated patients with ebola experienced a -day mortality rate of % in a randomized controlled trial of experimental therapies conducted in response to the democratic republic of congo outbreak of , resulting in early termination of this study arm [ ] . it is worth noting that this trial did not have an active control arm, and mortality rates for the other experimental treatments were . % (zmapp), . % (mab ), and . % (regn-eb ). against mers-cov, sheahan et al [ ] evaluated the therapeutic efficacy of remdesivir among infected mice and found treatment significantly reduced virus lung titers, weight loss, lung hemorrhage, and lung injury scores. the authors proposed the importance of early therapy initiation to diminish virus replication and promote pulmonary repair because remdesivir demonstrated less clinical benefit with high-titer virus inoculum. most notably, the authors also noted that prophylactic remdesivir diminished mers-cov replication and disease, which was similar to their findings in a murine model with sars-cov- [ , ] . the first report of a remdesivir-treated patient with covid- in the united states was a -year-old male in snohomish county, washington who received treatment on hospital day (illness day ) due to developing pneumonia and persistent fevers [ ] . the patient experienced clinical improvement and negativity of oropharyngeal swab on hospital day , although nasopharyngeal swab remained positive. no adverse events to remdesivir were reported for the patient, which is consistent with previous case reports of use in other viruses [ , ] . among the first patients confirmed by the cdc to have covid- in the united states, were treated with remdesivir via compassionate use protocol [ ] . all patients reported transient gastrointestinal symptoms and aminotransferase elevation. all patients are reportedly recovering, but the authors were unable to assess the efficacy or safety of remdesivir based on the lack of comparator and confounding treatments, including concomitant use of corticosteroids in one patient. there are clinical trials currently enrolling patients in the united states (table ) . two additional trials recruiting only in china have been registered on clinicaltrials.gov nct (severe disease) and nct (mild/moderate disease). remdesivir may also be obtained through compassionate use and the emergency investigational new drug (eind) application process. at the time of this review, requests for compassionate use must be submitted online via https://rdvcu.gilead. com/. compassionate use is only considered for hospitalized patients with polymerase chain reaction (pcr)-confirmed sars-cov- requiring mechanical ventilation in whom enrollment in a clinical trial is not feasible. patients are excluded from the compassionate use program if they do not meet the above criteria, have evidence of multiorgan failure, are receiving vasopressors for hypotension, have liver disease defined as alanine aminotransferase (alt) > × upper limit of normal (uln) or renal impairment defined as creatinine clearance (crcl) < ml/min, or receiving dialysis or continuous venovenous hemofiltration. inclusion and exclusion criteria for compassionate use may change, so applicants are encouraged to review the most up to date criteria for all potential patients. clinicians should be cognizant that it typically takes a minimum of hours for institutions to receive emergency institutional review board authorization (if required), protocol, and consent forms from gilead, us food and drug administration (fda)-approval for the eind, and eventual drug shipment. clinicians should coordinate with their local information technology teams to build a medication order sentence into the electronic health record during this time. patients may receive other antiviral therapies during the waiting period but must immediately discontinue them if they receive remdesivir for compassionate use. it is interesting to note that the adaptive clinical trial protocol originally stated "remdesivir is a prodrug that is metabolized to its active form as a substrate of cyp- a ". this implies the existence of a drug-drug interaction with cyp a substrate inhibitors such as ritonavir or voriconazole. however, the protocol also stated "although remdesivir is a substrate for cyp c , cyp d , and cyp a in vitro, coadministration with inhibitors of these cyp isoforms is unlikely to markedly increase remdesivir levels, as its metabolism is likely to be predominantly mediated by hydrolase activity." unlike the former, the latter statement is substantiated by well described chemistry of the molecule. the national institute of allergy and infectious diseases was contacted about this discrepancy and in collaboration with gilead, this has been corrected. there is no reason to believe that any significant drug interactions between remdesivir and cyp a inhibitors or inducers are likely [ ] . emerging clinical evidence and available in vitro data suggest remdesivir is a promising agent for the treatment of covid- . institutions should explore clinical trial enrollment or compassionate use remdesivir for moderate-to-severe patients. additional clinical data are eagerly anticipated and should help further define the role of this agent in covid- . chloroquine, an antimalarial agent with anti-inflammatory and immunomodulatory activities, has gained significant interest as a potential therapeutic option for the management of covid- . in early february, wang et al [ ] demonstrated potent in vitro activity of chloroquine against sars-cov- with an ec at hours of . µm in vero e cells. these data were consistent with previous data for chloroquine's inhibitory activity against sars-cov- and mers-cov in various cell lines, where ec values of - . and . µm were demonstrated, respectively [ ] . these findings have supported the clinical use of chloroquine, at a dose of mg by mouth twice daily, in numerous clinical trials in china during this outbreak. although the rationale for this dosing regimen remains unclear, and peer reviewed data from the trials are currently unavailable, it was announced in mid-february that promising early results have been demonstrated. per gao et al [ ] , "thus far, results from more than patients have demonstrated that chloroquine phosphate is superior to the control treatment in inhibiting the exacerbation of pneumonia, improving lung imaging findings, promoting a virus-negative conversion, and shortening the disease course according to the news briefing. severe adverse reactions to chloroquine phosphate were not noted in the aforementioned patients. " although this development has been encouraging, supply issues in the united states and cardiovascular toxicity concerns limit the use of chloroquine. as an alternative, hydroxychloroquine, a compound that differs from chloroquine only by a single hydroxyl group, has garnered interest. hydroxychloroquine is perceived as having better tolerability than chloroquine, which has led to long-term usage in rheumatological disorders. historically, very limited data were published assessing the activity of hydroxychloroquine against coronaviruses. in , biot et al [ ] assessed the comparative inhibitory activity of chloroquine and hydroxychloroquine against sars-cov- in vero cells. the authors demonstrated that chloroquine had an approximately -fold increased potency (ec of . ± . µm) compared with that of hydroxychloroquine (ec of ± µm). against sars-cov- , yao et al [ ] performed a -part study assessing the comparative in vitro activity of chloroquine and hydroxychloroquine and performed pharmacology-based pharmacokinetic (pbpk) modeling to assess comparative exposure and predicted activity of these compounds in the lung. in vitro analyses in vero cells demonstrated that the potency of hydroxychloroquine (ec of . µm) was greater than that of chloroquine (ec of . µm) against sars-cov- [ ] . to inform optimal dosing of hydroxychloroquine, the investigators then performed pbpk modeling. in this analysis, the investigators utilized human population pharmacokinetic and rat lung penetration data for each compound to estimate free trough concentrations in the lung to ec ratios (r ltec ) [ ] . because mg of chloroquine by mouth twice daily has been reported to demonstrate efficacy against sars-cov- , the target r ltec for hydroxychloroquine regimens was set to ≥ . (day ), . (day ), and . (day ), which were the r ltec values predicted with the "efficacious" mg by mouth twicedaily dosing of chloroquine [ ] . various dosing regimens were simulated, but are particularly notable. the first was an oral loading dose of mg (divided mg then mg) on day , followed by mg daily. this regimen led to significantly higher r ltec on day ( . ), day ( . ), and day ( ) than those values demonstrated with chloroquine. the second regimen was a loading dose of mg ( mg × ) on day followed by mg twice daily. this was also associated with higher r ltec values than chloroquine on day , , and (corresponding to . , . , and . , respectively) [ ] . the authors concluded that these data support the lower dose regimen because r ltec values were significantly higher than those with the "proven efficacious" regimen of mg of chloroquine by mouth twice daily. clinicians should note that both chloroquine and hydroxychloroquine have half-lives of ~ days [ ] , and therefore short durations would likely provide prolonged courses of therapy. this was exemplified in the pbpk modeling in which r ltec values with hydroxychloroquine were predicted to still be above the targeted efficacy threshold on day , even with a -day course of therapy. although these data are encouraging for the potential role of hydroxychloroquine against sars-cov- , we caution against solely relying on these data to support dosing regimens for patients. the use of mg of chloroquine by mouth twice daily as the reference for efficacy is rational given initial reports from china [ ] , but it is important to note that this dosing still requires validation, and the improved r ltec values reported are largely driven by the finding that hydroxychloroquine was . times more potent than chloroquine in vitro. although this enhanced potency may very well prove true as more data become available, this report is counter to the relative potency demonstrated with the structurally similar sars-cov- strain in in which chloroquine was approximately times more potent than hydroxychloroquine. in addition, a recently published study has demonstrated that the ec value for chloroquine is . µm [ ] , similar to the value reported for hydroxychloroquine in the analysis by yao et al [ ] . because there are currently no efficacy data available for hydroxychloroquine in covid- , additional consideration should be given to the optimal dosing strategy. we use the following example to illustrate this point. if one were to consider these compounds to be equally potent (identical ec values) and utilize the pbpk data from yao et al [ ] , the mg load, mg daily regimen for hydroxychloroquine would yield r ltec values of . , . , and . on day , , and , respectively. these r ltec values would be slightly lower than those achieved with mg by mouth twice daily of chloroquine on day and significantly lower than those on day , suggesting the potential need for a higher dose to have similar activity. although the mg daily regimen is the most common regimen currently being assessed in clinical trials, the rationale for that dose is currently unclear, and at least clinical trial in china is using a higher dose of mg by mouth daily. to this point, gautret et al [ ] recently published their initial experience on the impact of mg of hydroxychloroquine by mouth every hours on viral eradication in patients with covid- . the authors reported on patients ( hydroxychloroquine and control) who were covid- positive and able to have nasopharyngeal sampling for the first days of therapy (in the treated arm). the investigators demonstrated that hydroxychloroquine ( of , %) was superior to standard of care ( of , . %; p = . ) in eradicating sars-cov- from the nasopharynx. it is interesting to note that patients were prescribed azithromycin "to prevent bacterial super-infection" and the investigators found that viral eradication was numerically superior in this subgroup ( of , %) compared with those who received hydroxychloroquine alone ( of , %). the authors concluded that azithromycin "reinforced" the sars-cov- viral load achieved by hydroxychloroquine. although these data are intriguing, certain limitations to this data set must be acknowledged. first, although viral eradication is an important endpoint, the authors did not report clinical outcomes in these patients. second, the cohort initially contained hydroxychloroquine patients, but of them were removed from the analysis due to early cessation of hydroxychloroquine therapy including pcr-positive patients who were transferred to the intensive care unit (icu), pcr-negative patient who passed away, and pcr-positive patient who discontinued hydroxychloroquine due to nausea. finally, the hydroxychloroquine monotherapy arm included patients with significantly higher viral loads, represented by lower cycle threshold (c t ) values than those who received combination therapy. if the hydroxychloroquine monotherapy patients with c t values < are separated from those with c t values ≥ , there is a notable discordance in viral eradication rates ( of , % vs of , %), with this latter number approaching the of demonstrated with hydroxychloroquine and azithromycin combination therapy in which all patients had c t values ≥ . given this finding, the small numbers in this study, the lack of clinical outcomes presented, the potential for additive toxicity with hydroxychloroquine and azithromycin, and the desperate need to practice good antimicrobial stewardship during the covid- pandemic, we would caution clinicians against using these data to support combination therapy. despite all of the unknowns, the initial experience in china is encouraging for the potential role of chloroquine, or alternatively hydroxychloroquine, for the management of covid- . clinicians are encouraged to closely follow subsequent peer-reviewed publications from the ongoing chloroquine and hydroxychloroquine trials, because others have raised concerns regarding the apparent in vitro and/or in vivo discordance witnessed with chloroquine in other viral infections [ ] . furthermore, if hydroxychloroquine is utilized, careful consideration for dose selection should be given in accordance with the aforementioned data, as well as considerations for when to initiate during the course of illness. lopinavir is a human immunodeficiency virus (hiv)- protease inhibitor administered in fixed-dose combination with ritonavir (lpv/r), a potent cyp a inhibitor that "boosts" lopinavir concentrations. lopinavir seems to block the main protease of sars-cov- , inhibiting viral replication [ ] . in , chu et al [ ] evaluated a series of antivirals for in vitro activity against sars-cov- . they reported lopinavir at µg/ml and ribavirin at µg/ml inhibited sars-cov- after hours of incubation and that the agents were synergistic when used together [ ] . de wilde et al [ ] later described the antiviral activity of lopinavir against sars-cov- and demonstrated an ec . ± in vero e cells, which is near the upper range of lpv plasma concentrations previously measured in patients with hiv [ ] . sheahan et al [ ] evaluated the in vitro efficacy of lpv/r in combination with interferon beta (infb) against mers-cov and found the addition of lpv/r did not significantly enhance antiviral activity of infb alone (ec = vs iu/ml, respectively). they also described the ec of lpv/r ( . µm) and lpv alone ( . µm), suggesting similar activity to that described for sars cov- . despite in vitro activity against mers-cov, therapeutic doses of lpv/r + infb in mice models failed to reduce virus titer and exacerbated lung disease [ ] . this is notable because this was the same study in which remdesivir demonstrated both more potent in vitro activity as well as in vivo efficacy. however, the in vivo animal data for mers-cov appears equivocal given that a nonhuman primate model demonstrated improved clinical and pathological features after lpv/r treatment [ ] . a randomized controlled trial of lpv/r and recombinant interferon-β b versus placebo is currently enrolling for patients with mers-cov, which might help clarify the apparent discrepancy between in vitro and animal models [ ] . based on in vitro findings, chu et al [ ] utilized combination therapy with lpv/r, ribavirin, and corticosteroids for any newly diagnosed patient with sars-cov- without acute respiratory distress syndrome (ards) starting in april . patients receiving lpv/r combination therapy (n = ) were matched to historical patients receiving ribavirin plus corticosteroids (n = ), and a significant reduction in the development of ards or death at days was observed ( . % vs . %, p < . ). this was corroborated by an expanded case-control matched study of lpv/r-treated patients from the same center that demonstrated a significant reduction in pulse steroid use ( . % vs . %), intubation ( % vs %), and mortality ( . % vs . %) among patients who received lpv/r combination versus no lpv/r, respectively, as initial therapy [ ] . more important, the benefits of lpv/r were only demonstrated in patients who received initial treatment with lpv/r (defined as initiation of drug at time of sars-cov- diagnosis). there was no observed benefit when lpv/r was added as rescue or salvage therapy (death rate . % vs %). this compelling mortality difference in sars-cov- and continued investigation in mers-cov led to inclusion of lpv/r in the chinese sars-cov- guidelines at a dose of mg/ mg ( capsules/tablets) by mouth twice a day for no more than days even though to our knowledge, no in vitro data for lpv/r in sars-cov- exist [ ] . in pediatric patients weighing - kg, the recommended dose in the united states is mg/kg suspension by mouth twice daily. there are ongoing registered clinical trials in china, korea, thailand, and hong kong evaluating lpv/r as monotherapy or in combination with other antivirals (eg, ribavirin, interferon beta- b) or traditional chinese medicine for treatment of covid- . real-world data for treatment of covid- with lpv/r are emerging. young et al [ ] reported outcomes of the first patients infected with sars-cov- in singapore, of whom received lpv/r monotherapy. three patients had reduction in oxygen requirements after treatment initiation; deteriorated to respiratory failure. two of patients ( %) experienced clearance of viral shedding on treatment, and of ( %) experienced adverse events that precluded completion of the planned -day treatment course. other published case reports or case series from korea and china comprising total patients describe decreased viral load and clinical improvement after lpv/r initiation. these data are difficult to interpret in light of concomitant drug therapies, varied time points of therapy initiation, heterogeneous severity of illness amongst patients, and the lack of comparator treatments [ ] [ ] [ ] . finally, early reports from wuhan have described some patients receiving lpv/r in addition to other therapies (including corticosteroids), but clinical outcomes and adverse events are either not described or not delineated by treatment group [ ] [ ] [ ] . most recently, cao [ ] et al reported the results of an openlabel randomized trial comparing lpv/r / mg twice daily (n = ) to standard care (n = ) for the treatment of covid- pneumonia. the primary endpoint was defined as the time from randomization to an improvement of points on a -category ordinal scale or discharge from the hospital. secondary outcomes included -day mortality, time until discharge, and virologic response on repeat oropharyngeal swabs over the course of the study. the median time from symptom onset to randomization was (interquartile range [iqr], - ) days, and this did not differ between the groups. there was no significant difference in time to clinical improvement ( [iqr, [ ] [ ] [ ] [ ] [ ] , − . % to . %) between patients receiving lpv/r and standard care. when the patients who died after randomization but before receiving lpv/r were removed, there remained no difference in mortality ( . % vs . %; absolute difference, − . percentage points; % ci, − . to . ). more important, there was no difference between treatment arms in reduction of viral loads over time between the groups. with the available data, it is difficult to assess whether lpv/r has a role for the treatment of covid- either as monotherapy or in combination. the data from sars-cov- are encouraging, but this must be weighed against the inferior performance in mouse models against mers-cov, the less potent in vitro activity compared with remdesivir and chloroquine for sars-cov- , and limited data suggesting no advantage over standard care for sars-cov- . more important, it warrants comment that in the recent randomized controlled trial in covid- pneumonia, the median time from symptom onset to initiation of therapy was days, and in the sars-cov- experience, therapy appeared effective if started early, but not as rescue and/or salvage. if used, drug interactions must be screened, and gastrointestinal toxicities, including diarrhea, nausea, and vomiting, and hepatotoxicity, require close monitoring, particularly because elevated aspartate transaminase or alt may exclude patients with covid- from clinical trials. the lpv/r tablets can be taken without regard to food but should not be crushed because this decreases systemic exposure; solution should be used in patients who cannot receive intact tablets [ ] . nitazoxanide has demonstrated potent in vitro activity against sars cov- , with an ec at hours of . µm in vero e cells [ ] . this potent activity is consistent with ec values for nitazoxanide and its active metabolite, tizoxanide, against mers-cov in llc-mk cells in which ec values of . and . µm, respectively, have been demonstrated [ ] . nitazoxanide displays broad-spectrum in vitro antiviral activity against influenza, respiratory syncytial virus, parainfluenza, rotavirus, and norovirus among others in addition to coronaviruses [ ] . this broad-spectrum antiviral activity is believed to be due to the fact that the mechanism of action is based on interference with host-regulated pathways involved in viral replication rather than virus-specific pathways [ ] . due to its broad-spectrum antiviral activity, nitazoxanide is being investigated for the management of influenza and other acute respiratory infections. positive results were demonstrated in a phase b/ study for the outpatient management of influenza, in which a dose of mg by mouth bid of nitazoxanide was associated with a ~ -day improvement in time to resolution of symptoms when compared with placebo (p = . ) [ ] . three phase randomized controlled trials in uncomplicated influenza have since been completed (clinicaltrials. gov identifier nct [march ], nct [april ], and nct [september ]), although results are unavailable. nitazoxanide failed to reduce the duration of hospitalization or the time to symptom alleviation in a phase randomized controlled trial in patients with severe acute respiratory illnesses requiring hospitalization, predominantly caused by respiratory viruses [ ] . although the in vitro activity of nitazoxanide against sars-cov- is encouraging, more data are clearly needed to determine its role in the management of covid- . tocilizumab is a humanized monoclonal antibody that inhibits both membrane-bound and soluble interleukin- (il- ) receptors. interleukin- , which is secreted by monocytes and macrophages, is one of the main drivers of immunologic response and symptoms in patients with cytokine-release syndrome (crs). although tocilizumab was first approved by the fda in for the treatment of rheumatoid arthritis, it has gained traction in recent years for treatment of patients with crs following chimeric antigen receptor t-cell (car t) therapy as a corticosteroid-sparing agent [ ] . indeed, it received fda approval for severe or life-threatening car t-associated crs in due to its efficacy and safety profile. although criteria for grading crs severity varies by cancer center, it has been proposed to administer tocilizumab to crs patients with any of the following: oxygen requirement < %, hypotension responsive to fluids or a low dose of a single vasoactive agent, or grade organ toxicity as defined by the common terminology criteria for adverse events [ ] . interleukin- antagonism may make a patient more susceptible to bacterial infection and has been associated with neutropenia and thrombocytopenia in patients receiving chronic therapy with tocilizumab for giant cell arteritis or rheumatoid arthritis. in a case series of adult patients with relapsed or refractory b-cell acute lymphoblastic leukemia, grade crs or higher was associated with increased risk of subsequent infection, but it was unclear whether tocilizumab or corticosteroid use promoted this risk [ ] . there were no reported adverse events in the tocilizumab-treated patients submitted to the fda for the crs indication, which recommends a maximum of doses for treatment [ ] . hyperinflammatory states and cytokine storming, including elevated il- , has been reported in severe covid- and were associated with increased mortality in patients in china [ ] . a preprint (nonpeer reviewed) case series of patients treated with tocilizumab between february and , in china reported marked success, including rapid resolution of fever and c-reactive protein, decreased oxygen requirements, and resolution of lung opacities on computerized tomography imaging [ ] . the authors state the patients all had "routine treatment for a week" before tocilizumab, which was described as "standard care according to national treatment guidelines" including lopinavir, methylprednisolone, and other supportive care. all patients had il- analyzed before tocilizumab administration with a mean value of . ± . pg/ml (normal < pg/ml). it should be noted that in the united states, il- monitoring is a send-out laboratory for most institutions with a turnaround time of - days. no adverse events were described in the chinese cohort; however, long-term assessment was not done. immunotherapy with tocilizumab is listed as a treatment option for severe or critical cases of covid- with elevated il- in the th edition of the national health commission of the people's republic of china covid- diagnosis and treatment guide [ ] . the recommended dose is - mg/kg or mg standard dose iv once, with the option to repeat a dose in hours (not to exceed a total dose of mg). there are ongoing trials in china evaluating safety and efficacy of tocilizumab for patients with covid- pneumonia, but none registered in the united states. we anticipate that more data regarding tocilizumab use in patients with covid- will emerge, and it will be imperative for clinicians to evaluate it closely. the optimal timing of tocilizumab administration during the disease course is not yet defined, nor is there a known il- threshold for progression to severe disease. it is imperative to continue to follow the longterm outcomes in these patients to assess the risk versus benefit of tocilizumab. similar to other severe respiratory tract infections, there is significant interest and controversy surrounding the role of corticosteroids for the management of severe pneumonia due to coronaviruses. the potential benefit of these agents to blunt the inflammatory cascade seen in severe disease needs to be carefully weighed against the concerns for secondary infections, adverse events, and other complications of corticosteroid therapy. the data assessing the role of corticosteroids as adjunctive care for severe coronavirus (sars-cov- , mers-cov, and sars-cov- ) pneumonia are difficult to interpret. given the retrospective observational nature of these analyses, there is significant confounding by indication that is difficult to control or correct for in addition to limited sample sizes. patients who receive corticosteroids have a higher severity of illness, are more likely to require invasive interventions, and are more likely to be receiving intensive care. in addition, there is significant heterogeneity with regard to timing of corticosteroid initiation, which can significantly impact disease progression and likelihood of response. all of these features lead to patients who receive steroids being at increased risk for poor outcomes. in addition, there is great variation in agent and dosage used, which can impact both safety and efficacy. therefore, clinicians making any therapeutic decisions based on the literature for corticosteroids need to keep these considerations in mind. the clinical data for use of corticosteroids in sars-cov- infections are mixed. multiple analyses show no impact on outcomes [ ] , one report demonstrates decreased mortality in critically ill patients [ ] , and others have documented worse outcomes for patients receiving steroids, including increased time to viral clearance [ ] or an increase in the composite endpoint of icu admission or death [ ] . in mers-cov, receipt of corticosteroids has been associated with a delayed time until viral clearance in a large cohort (n = ) of infected patients [ ] . however, this same data set showed a nonsignificant reduction in -day mortality in patients receiving corticosteroids (adjusted odds ratio = . ; % ci, . - . ) after accounting for differences between the groups in a regression model accounting for time-varying exposures. finally, recent evidence in sars-cov- suggested a decrease in mortality in patients with ards with the receipt of corticosteroids ( of [ %] vs of [ %] without; hazard ratio, . ; % ci, . - . ) [ ] . as demonstrated, the data for corticosteroids are inconsistent, confusing, and inconclusive. although target patients in whom corticosteroids will improve outcomes may exist (eg, those with cytokine-related lung injury who may develop rapidly progressive pneumonia), that population remains ill-defined [ ] . clinicians need to carefully weigh the risks and benefits of corticosteroids on the individual patient level. this need for a risk-benefit assessment in individual patients and careful consideration of dose is exemplified in the covid- diagnosis and treatment guide from the national health commission of the people's republic of china where the authors state, "based on respiratory distress and chest imaging, may consider glucocorticoid that is equivalent to methylprednisolone - mg/kg/day for - days or less. note that large-dose glucocorticoid suppresses immune system and could delay clearance of sars-cov- ." [ ] a recent consensus statement from the chinese thoracic society recommends a lower dose, ≤ . - mg/kg per day methylprednisolone for ≤ days in select patients, after careful consideration of risks and benefits [ ] . randomized controlled trial data are urgently needed to clearly define the role of corticosteroids in covid- . ribavirin, a guanosine analog that terminates rna synthesis, was first approved in the s and has been used clinically for respiratory syncytial virus, viral hemorrhagic fever, and in combination with interferon for hepatitis c. as mentioned previously (see lpv/r section), it was evaluated against sars-cov- in and used clinically in combination with corticosteroids and/or interferon in the absence of other treatment options; however, outcomes were either poor or ill-defined [ , ] . the doses required for antiviral activity against sars range from . to . grams by mouth every hours, which are associated with excessive toxicity to patients [ ] . wang et al [ ] evaluated the in vitro activity of ribavirin against sars-cov- and found an ec of . µm, which was over times less potent than remdesivir. the risk of hematologic toxicity at high doses likely outweighs potential clinical benefit, and therefore ribavirin was not considered a viable candidate for further investigation by the who research and development plan for sars-cov- given its lack of in vitro efficacy, toxicity profile, and poor outcomes. interferons (α, β) may stimulate innate antiviral responses and are expected to have in vitro activity against sars-cov- , given the previously described activity demonstrated against mers-cov (ec iu/ml). however, toxicities are substantial including severe cytopenias, hepatotoxicity (including fatality), neuropsychiatric events, and risk of developing fatal or life-threatening ischemia or infection, particularly when combined with ribavirin. this combination was not associated with improved mortality or enhanced viral clearance in a retrospective analysis of patients infected with mers-cov who were initiated on combination therapy within - days of icu admission [ ] . despite the limited to poor data, chinese guidelines recommend ribavirin mg iv - times daily in combination with lpv/r or inhaled interferon-α ( million units nebulized twice daily) as one of the "standard treatment" options for covid- . various combinations of ribavirin, interferon, and other antiviral agents are currently being studied in several clinical trials. based on the poor in vitro activity, an absence of animal or human data supporting its use, and a significant toxicity profile, we recommend avoiding use of ribavirin in patients with covid- at this time. although interferons may be useful as adjunctive care, they pose a significant risk to critically ill patients, and in the absence of supportive data they also cannot be currently recommended. given their antiviral activity against influenza, considerable attention has been paid to oseltamivir, and to a lesser degree baloxavir, as potential treatment options for covid- . this was exacerbated by the initial report from huang et al [ ] in wuhan where patients managed with covid- received oseltamivir in addition to broad-spectrum antimicrobials. it is important to note that use of oseltamivir was not as targeted therapy of sars-cov- but rather driven by the lack of a knowledge of the causative pathogen at the time of treatment and the desire to empirically treat influenza. the authors do not suggest the use of oseltamivir for covid- in that publication, and there are no data that suggest in vitro activity of oseltamivir against sars-cov- . in fact, the only data assessing oseltamivir activity against coronaviruses demonstrated it to be ineffective at inhibiting sars-cov- , even at a concentration of µm/l [ ] . coronaviruses do not utilize neuraminidase, and thus there is no enzyme to be inhibited by oseltamivir. this would hold true for zanamivir, peramivir, or any other neuraminidase inhibitor agents. similarly, neither a defined mechanism nor in vitro data have suggested that baloxavir would demonstrate activity against sars-cov- or other coronaviruses. therefore, given the critical need for these agents in the management of influenza and concern for drug shortages with oseltamivir, these agents should be avoided in patients with covid- once influenza has been ruled out. table lists agents that are being investigated and/or theoretically considered for the management of sars-cov- -infected patients. at this time, no recommendation can be made for any of these agents. in general, they should be avoided without additional supporting evidence. appropriate management strategies for patients with covid- are a rapidly evolving therapeutic challenge, and the optimal agents (if any) to treat infection or prevent progression to critical illness remain ill-defined. although certain agents listed in this review are encouraging, and the potential benefit of therapy likely outweighs the relatively minor risk of adverse events from short-course therapy, the evidence remains inconclusive and changes almost daily. patient populations who warrant therapy and the timing of initiation of therapy need to be defined. given that disease progression can occur rapidly in stable patients and that viral loads are highest early in the infection course, the authors of this review opine that rapid initiation of therapy in high-risk populations (patients who are hospitalized or outpatients who are at high risk of complications) is rational and should be considered, ideally in the context of a well-controlled, adequately powered trial. more important, however, this strategy is not without risk and needs to be weighed against potential adverse events (that remain poorly defined) and impending drug shortages with increases in use of these agents. to help address these concerns, careful consideration should be given to duration of therapy with many clinical trials and institutional protocols recommending - days for uncomplicated disease. duration of therapy should be individualized to the patient and the progression of disease. clinicians must continually monitor and adapt as new literature becomes available. caution should be applied because the bulk of the available clinical data are uncontrolled, not peer reviewed, or even unpublished. given these [ ] . the safety and efficacy of convalescent plasma transfusion in sars-cov- -infected patients has not been established, and no protocols exist currently in the united states. protocols are reportedly being developed at the johns hopkins university hospital. darunavir/cobicistat hiv- protease inhibitor currently being evaluated in a clinical trial (nct ), but no in vitro or human data exist to support use at this time. thiuram derivative that blocks alcohol oxidation. demonstrated ability to competitively inhibit the papain-like proteases of sars; however, no clinical data exist [ ] . no in vitro or clinical data exist for covid- . humanized, monoclonal igg antibody that binds to complement protein c and prevents formation of membrane attack complex (mac). being evaluated in a clinical trial (nct ) for covid- to quell immune response, no data exist at this time to support use. favipiravir rna-dependent rna polymerase inhibitor with broad-spectrum antiviral activity; however, demonstrated high ec (decreased potency) against sars-cov- but was effective in protecting mice against ebola virus despite similarly high ec values [ ] . currently being evaluated in clinical trial nct for patients with covid- . this agent is not fda approved or available in the united states. galidesivir (bcx ) nucleoside rna polymerase inhibitor with reported wide spectrum of antiviral activity, currently in pipeline of biocryst pharma and previously evaluated for ebola and other hemorrhagic fever virus infections. algae-derived lectin and potent hiv entry inhibitor agent that demonstrated in vitro activity against sars-cov- [ ] . ivig ivig remains on critical national shortage in the united states. the benefit in patients with covid- is unclear. nelfinavir, an hiv- protease inhibitor, might be active against sars-cov- based on a preprint publication that utilized homology modeling [ ] . no clinical data exist. anthelminthic drug with in vitro efficacy against sars-cov- ; however, low absorption and oral bioavailability resulting in a wide range of serum concentrations in healthy volunteers after a single dose may limit utility as antiviral treatment [ ] . human monoclonal antibody discovered by regeneron that reportedly binds to the s protein of mers-cov. currently in phase trial in healthy volunteers (nct ). the company reportedly announced recruitment for phase and trials for sars-cov- ; however, these are not registered on clinicaltrials.gov. sarilumab il- receptor antagonist fda-approved for rheumatoid arthritis. recently announced a us-based trial will begin enrolling at medical centers in new york for patients with severe covid- disease. sofosbuvir antiviral used to treat hepatitis c, in vitro activity against sars-cov- , no clinical data exist [ ] . a novel, fully human anti-il r by tiziana life sciences. the company recently announced they are moving forward with clinical development for patient use in patients with covid- and excessive il- production. vitamin c there is an ongoing clinical trial of grams iv bid vitamin c in china for treatment of covid- (nct ). use of this agent is not recommended at this time. chinese herbal medicine extract infusion formulation given at ml iv twice daily, suggested as a "may consider" treatment for severe and critical cases in the national health commission of the people's republic of china: the covid- diagnosis and treatment guide, th edition. this previously demonstrated improved mortality in patients with severe community acquired pneumonia in china [ ] . limitations, it is critical that institutions and clinicians 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niclosamide and its therapeutic potential anti-hcv, nucleotide inhibitors, repurposing against covid- xuebijing injection versus placebo for critically ill patients with severe community-acquired pneumonia: a randomized controlled trial we acknowledge and thank jovan borjan, julie ann justo, liza vaezi, ryan shields, and jason gallagher for thorough review of this manuscript.potential conflicts of interest. all authors: no reported conflicts of interest. all authors have submitted the icmje form for disclosure of potential conflicts of interest. key: cord- -gy kfhy authors: peng, fujun; tu, lei; yang, yongshi; hu, peng; wang, runsheng; hu, qinyong; cao, feng; jiang, taijiao; sun, jinlyu; xu, guogang; chang, christopher title: management and treatment of covid- : the chinese experience date: - - journal: can j cardiol doi: . /j.cjca. . . sha: doc_id: cord_uid: gy kfhy with over , , cases and , deaths globally, covid- is one of worst infectious disease outbreaks in history. the objective of this paper is to critically review the available evidence regarding the lessons learned from the chinese experience regarding covid- prevention and management. the steps that have led to a near disappearance of new cases in china included rapid sequencing of the virus to establish testing kits which allowed tracking of infected persons in and out of wuhan. in addition, aggressive quarantine measures included the complete isolation of wuhan and then later hebei and the rest of the country, as well as closure of all schools and non-essential businesses. other measures included the rapid construction of two new hospitals and the establishment of fangcang shelter hospitals. in the absence of a vaccine, the management of covid- included antivirals, high flow oxygen, mechanical ventilation, corticosteroids, hydroxychloroquine, tocilizumab, interferons, intravenous immunoglobulin and convalescent plasma infusions. these measures appeared to provide only moderate success. while some measures have been supported by weak descriptive data, their effectiveness is still unclear pending well-controlled clinical trials. in the end, it was the enforcement of drastic quarantine measures that stopped sars-cov- from spreading. the earlier the implementation, the less likely resources will be depleted. the most critical factors in stopping a pandemic are early recognition of infected individuals, carriers and contacts, and early implementation of quarantine measures with an organized, proactive and unified strategy at a national level. delays result in significantly higher death tolls. since mid-december , there has been a worldwide outbreak of coronavirus disease (covid)- , caused by sars-cov- (formerly -ncov or and first detected in wuhan, china. the incubation period is to days (mean: - days) in most cases, but can be as long as days. the most commonly seen characteristics of covid- are fever, cough and abnormal chest computed tomography (ct). , at present, the chinese chrysanthemum bat is thought to be the origin of sars-cov- based on sequence homology of % between sars-cov- and bat-cov-ratg . , the pangolin has been proposed as an intermediate host, but this has not been confirmed. , human-to-human transmission of sars-cov- occurs mainly via respiratory droplets, direct contact, asymptomatic transmission, , and intrafamilial managing the spread of the epidemic the most important strategy to combat a pandemic is to prevent it from even happening. this shortage of personal protection equipment (ppe), which was mitigated by using reserve supplies, acquiring donations, and production increases (appendix and figure s ). wuhan is shown in figure . table s . emergency staffing was arranged as needed within a half hour. do not require supplemental oxygen, and hyperoxemia may induce further respiratory injury and even higher mortality. the indications for supplemental oxygen should be pharmacologic agents we summarize the treatment of pooled cases of severe cases with covid- ( (table ) . , interferon-α b inhalation, ( %) patients received arbidol and lopinavir/ritonavir, and ( %) received interferon-α b by inhalation. chen et al reported that of confirmed patients in wuhan received antiviral treatment, including oseltamivir, ganciclovir, and lopinavir and ritonavir. the duration of antiviral treatment was - days. zhou et al proposed that hydroxychloroquine could serve as a better therapeutic agent than chloroquine due to reduced toxicity, fewer side effects, lower cost and relative safety in pregnancy. yao et al used physiologically-based pharmacokinetic (pbpk) models and found that hydroxychloroquine was more potent than chloroquine at inhibiting sars-cov- in vitro. they recommended hydroxychloroquine sulfate mg twice daily for day, followed by mg twice daily for days to treat sars-cov- infection. the efficacy and safety data of chloroquine or hydroxychloroquine from high-quality clinical trials are urgently needed. a retrospective study found that low-to-moderate dose glucocorticoid therapy had no effect on the time to viral clearance in patients with covid- . glucocorticoids are not recommended in mild cases because there was no improvement in the rate of radiographic recovery. however, a single-center in wuhan shared that early, low-dose and short-term ( - mg/kg/d for - days) corticosteroids was associated with a faster improvement of clinical symptoms and absorption of focal lung lesions in severe cases of covid- . another study analyzed critical cases and suggested that a low dose and short duration of corticosteroids (methylprednisolone < mg/kg, less than days) may be beneficial for critically ill patients with covid- . vaccine development the development of a vaccine for sars-cov- has been accelerated as a priority project. improve sample collection and the accuracy of sars-cov- nucleic acid detection. the patients' position should be assessed and changed regularly to avoid decubitus skin injury. due to the fact that cardiac insufficiency can lead to a coagulation disorder and that severe covid- patients were reported to have increased level of d-dimer, low molecular weight heparin was recommended to treat covid- patients in the early phase of disease. as in sars-cov, ace has similarly been identified as the receptor for sars-cov- to enter cells. the use of angiotensin converting enzyme inhibitors (acei) may not be of any benefit because it does not bind to the ace receptor. this also means that discontinuing acei in patients with covid- is not necessary. with regard to angiotensin receptor blockers (arbs), there is evidence that arbs could lead to increased expression of ace , thus worsening disease, but this effectiveness and importance of public health interventions the who-china joint mission report reported that china's vigorous public health measures to prevent the covid- are the most "ambitious, agile and aggressive disease containment effort in history". the drastic measures taken are listed in table . if not for a national strategy once it is recognized that there is a new, potentially lethal virus, the virus needs to be isolated, the viral genome sequenced, and testing kits validated and released for rapid distribution. infected individuals and their contacts need to be tracked and isolated. the earlier this is done, the less impact there will be on the personal and professional lives of people and the economy, and the less resources will be needed. when more people are infected, the drastic measures including shutting down cities and restricting travel will need to be more widespread, healthcare resources will be exhausted and the economy will take a bigger hit. adult who meet any of the following criteria: (i) respiratory distress (≥ breaths/ min); (ii) oxygen saturation ≤ % at rest; (iii) arterial partial pressure of oxygen (pao )/fraction of inspired oxygen (fio )≤ mmhg (l mmhg = . kpa) §, or whose chest imaging shows obvious lesion progression within - hours > % child who meets any of the following criteria: (i) tachypnea|| independent of fever and crying; (ii) oxygen saturation ≤ % on finger pulse oximeter taken at rest; (iii) labored breathing ¶, cyanosis, and intermittent apnea; (iv) lethargy and convulsion; (v) difficulty feeding and signs of dehydration;(vi) hrct show infiltration in both lungs or multiple lobes, lesion progress in a short time or pleural effusion same as above mild, and respiratory support (high-flow nasal oxygen and non-invasive ventilation or invasive mechanical ventilation) patients who meet any of the following criteria: (i) respiratory failure and requiring mechanical ventilation; (ii) shock; (iii) with other organ failure that requires icu care clinical characteristics of coronavirus disease in china clinical characteristics of hospitalized patients with -ncov infection china-who new coronavirus pneumonia (covid- ) joint inspection report a pneumonia outbreak associated with a new coronavirus of probable bat 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viral pneumonia cryo-em structure of the -ncov spike in the prefusion conformation inhibition of sars-cov- infections in engineered human tissues using clinical-grade soluble human ace recommendations from the peking union medical college hospital for the management of acute myocardial infarction during the covid- outbreak experiences and lesson strategies for cardiology from the covid- outbreak in wuhan, china, by 'on the scene' cardiologists covid- : too little, too late? the impact of transmission control measures during the first days of the covid- epidemic in china. medrxiv abbreviations: na: not available; hrct: high-resolution computed tomography; ards: acute respiratory distress syndrome; icu: intensive care unit; map: mean arterial pressure; sbp: systolic blood pressure; sd: standard deviation; hr: heart rate; bpm: beats per minute; sec: second; *: the elderly and immunosuppressed may present with atypical symptoms. symptoms due to physiologic adaptations of pregnancy or adverse pregnancy events, such as dyspnea, fever, gastrointestinal symptoms or fatigue, may overlap with covid .†: fast breathing (in breaths/min): < months: ≥ ; - months: ≥ ; enforcement laws including <law of the people's republic of china on the prevention and treatment of infectious diseases>, <surveillance protocol for pneumonia cases from novel coronavirus (second edition)>, <preventive measures against infectious diseases in business and service business sites>, <provisions on the emergency handling of entry-exit inspection and quarantine for public health emergencies at border ports>, etc. temperature screening on the public occasions, such as hospitals, supermarket purchasing daily necessities on a regular schedule delivering food and disinfectants for every family real time disinfection of public areas. key: cord- -wav d ws authors: patel, sanjay k. s.; lee, jung-kul; kalia, vipin c. title: deploying biomolecules as anti-covid- agents date: - - journal: indian j microbiol doi: . /s - - - sha: doc_id: cord_uid: wav d ws severe acute respiratory syndrome coronavirus (sars-cov- ) known as covid- has emerged as a major threat to human existence. covid- seems to have undergone adaptive evolution through an intermediate host, most likely bats. the flu leads to severe pneumonia that causes respiratory and multi-organ failure. the absence of any known treatment procedures, drugs, or vaccines has created panic around the world. the need is to develop rapid testing kits, drugs and vaccines. however, these proposals are time-consuming processes. at present social distancing along with previously known traditional medicines can act as quick and short-term alternatives for treating this viral flu. biologists have revealed that the populations of more than % of all vertebrates have been declining during the last few centuries. it has been realized that there is a need to curb the basic drivers for these immense losses. there have been cases of catarina pupfish going extinct without making news headlines. christmas island pipistrelle, a vesper bat vanished without a whisper. human races have been under threat of ''extinction'' having seen some of the worst pandemic disasters. human immunodeficiency virus infection and acquired immune deficiency syndrome (hiv/aids) has taken around million human lives during the last four decades. even at present, more than million people are living with hiv. constant efforts to find treatments and generating awareness has helped to decline the death rate due to hiv/aids from . million to . million (https://www.mphonline.org/worst-pandemicsin-history/). the flu pandemic of caused due to influenza a virus spread from hong kong to vietnam, india, the philippines, singapore, europe, the united states, and australia, with less than weeks of its first report. despite a low mortality rate of %, it resulted in killing million people, of which % were residents of hong kong. from to , asian flu caused by influenza a (subtype h n ) with its origin in china caused million deaths in china, hong kong, singapore, and the united states (https://www.mphonline.org/worst-pan demics-in-history/). among the worst pandemics recorded during the twentieth century was the flu of - , which infected around % of the world's population resulting in a death toll of - million people, equal to a mortality rate of - %. the most disturbing aspect was that it struck even healthy young adults. prior to that, between and , cholera pandemic with its origin in india was spread to russia, eastern europe, north africa, and the middle east. it had taken the lives of more than . million people with more than % being from india alone (https://www.who.int/). in the nineteenth century, influenza and cholera have been striking a human being quite frequently causing millions of deaths (https:// www.who.int/). the emergence of a novel severe acute respiratory syndrome coronavirus (sars-cov- , renamed as covid- ) in from wuhan, china has led to a global crisis and it has been declared as a pandemic emergency by world health organization (who) due to its fast rate of transmission among human beings [ , ] . sars-cov- exhibits unique spiked protein (s glycoprotein) and belongs to the family of coronaviridae [ ] . about , viral genomic sequences are available via the global initiative on sharing all influenza data (https:// www.gisaid.org/). sars-cov- enters the host cell by attaching s glycoproteins to angiotensin-converting enzyme (ace ) that is mediated via serine protease tmprss [ ] . the possible candidate drugs have been based on ( ) inhibition of binding ace to sars-cov- via inhibition of the ace and tmprss , ( ) polyclonal antibody against s glycoproteins, and ( ) inhibition of replication [ , ] . non-availability of any treatment procedures, drugs, or vaccines has created panic around the world. in this review, we have described the present scenario on covid- and discussed the use of traditional medicines-based biomolecules in its mitigation. covid- (previously labelled as -ncov) is the main causative organism responsible for acute pneumonia. coronaviruses (covs) are a group of genetically distinct viruses, which originated from broad ranges of hosts, including animal and bird species, and primarily cause respiratory and intestinal infections to humans and animals [ , [ ] [ ] [ ] [ ] . in - , covs surfaced as a severe acute respiratory syndrome (sars) with cases of 'atypical pneumonia' in china and hong kong [ ] . sars originating from bats caused a major threat to humans through interspecies transmission through another host such as raccoon dogs or himalayan palm civets. it led to around infections in countries and a high fatality rate of %. in , covs of animal origin-known as middle east respiratory syndrome coronavirus (mers) emerged with rarely transmitting history between humans [ ] . it had a much higher fatality rate up to . % globally till november . these infections posed a severe public health risk and caused substantial damage to the economy of those e affected. for genetically heterogeneous sarslike covs (alphacoronavirus and betacoronavirus) bats seems to be the natural reservoirs, in different parts of china. these covs are well-known for their emergence from natural hosts [ , ] . transmission of covid- possibly involved an adaptive evolution through an intermediate host (bat) before infecting humans. although the exact mechanism of transmission of covid- to humans is yet to be elucidated. -however, the primary evidence to support this route is the genomic identity of up to % nucleotides with a bat (betacov/ratg / ) [ ] . the phylogenic comparison has also pointed out towards convergent evolution or multiple recombination events, between the two virus strains of diverse evolutionary origins. the major determining factor of the cell tropism is the spike protein, leading to the transmission of covs among different species [ , ] . in fact, the virus is bound to the cellular receptor through this protein, which in turn catalyzes its entry by membrane fusion. although, no antiviral agents are known to act against this virus, however, monoclonal antibodies and convalescent sera are known to inhibit mers or sars in model systems. however, these sera and antibodies may not prove very effective in handling the present outbreak [ ] . in the recent outbreak of covid- , with possible transmission from bats, initially had shown pneumonia-like symptoms with unspecified etiology [ ] . covid- infected person showed flu-like symptoms with fever, cough, headache, muscular soreness, and dyspnea with an incubation period of about - days [ , , ] . in a few cases, patients exhibited atypical symptoms, including vomiting and diarrhea. the epidemiology curve of covid- broadly has been classified in different phases: ( ) the start of the outbreak through exposure at a market (december ) to new cases ( confirmed) beyond wuhan, china (january , ) between humans transmission occurrence by close contact, ( ) a rapid increase in confirmed cases by spreading of the virus within hospitals and family transmission outside china, which was nearly -folds than phase first till january , [ ] . this resulted in the traditional mass movement of people (about million people), which has contributed significantly in spreading of confirmed cases of covid- , and ( ) finally, a cluster of cases marked on january , was the beginning of the third phase. the global covid- mortality rate of . % has been reported by who [ ] (tables , ) covs are viruses with single stranded rna genome sizes between to kb [ ] . initially, the screening of covid- infection has done through measurements of temperature and related symptoms. the laboratory testing for covid- detection includes methods based on the presence of the virus and the measurement of antibodies (serology) produced in response to infection [ ] . the virus was confirmed using:-( ) pcr based reverse transcription (rt)-pcr detects covs specific rna from either nasopharyngeal and throat swabs or sputum samples within a few hours to days, and ( ) high throughput nucleic acid sequencing, ( ) non-pcr based technique of isothermal nucleic acid amplification has a testing period of min [ ] [ ] [ ] . similarly, chest ct scans and radiographs to detect it were not found to be accurate for covid- confirmation at early stages [ ] . the antibody test targets the production of antibodies such as iga, igm, and igg in response to covid- infection in blood samples, which takes around days after infection or needs to wait for the onset of symptoms. the procedure, however, takes only min to detect the infection. various approaches are under investigation for developing a rapid and low-cost detection kit with high specificity and selectivity for covid- [ ] [ ] [ ] . the infections of covid- are not selective to any age group, such that even newborn infants have been among the confirmed cases. covs genomes exhibit high genomic plasticity enabling it to possess high recombination capacities [ ] . these features have led to a high probability of adaptive mutations for utilizing multiple cellular receptors for efficient binding and entry by spike proteins into various hosts. this ability of covs may assume an alarming tendency to expand to wider host-species. since, multiple species of covs are present in wildlife animals, who constantly interact among themselves, their expansion or transmission to humans is inevitable. this feature evidenced by the transmission of covid- from humans to dogs, cats, and even tigers. thus, surveillance is expected to prevent the virus from establishing in other hosts, which live in the vicinity of human beings [ , ] . covid- has exhibited a much higher infection than sars or mers cases. initially, to minimize the global spread after cases in china various approaches such as airport screening and traveling restrictions were largely implemented in a few countries [ , ] . due to the asymptomatic behavior of covid- such as a longer incubation period suggested that quick tracking of the infected person is essential for limiting the human-to-human transmissions. the initial quaternity period of about days for travelers was considered desirable [ ] . but, even longer periods for incubations were required for visualizing of symptoms made the realization that it was a more critical scenario for its spread. the minimization of social interaction by limiting activities at workplaces, education centers public functions were suggested to be more effective in reducing the rapid spreading of infection [ , , ] . early enough, it was observed that age groups and the frequency of physical interaction may be influenced by geographical locations. computational analysis of the data generated from measures of social distancing at the workplace, educational institutes, and lock-down suggested that either a days lockdown or periodic shutdowns of and days, may prove effective to counter the covid infection in countries like india. alternatively, periodic two lockdowns of - weeks followed by a shorter lock-down with a gap of days, or a long-term lock-down of weeks may help to minimize the transmission of this infection among human beings [ ] . these four approaches are likely to yield different -mortality cases with a maximum of , in the first strategy followed by , , and in the later three approaches [ ] . it thus implied that social distancing along with lock-down can counter covid infection in any part of the world, including india, where medical facilities are limited. at present, no vaccines or drugs are available for specifically targeting this rapidly spreading disease. the most common practices are supportive care in combination with certain previously known but non-specific drugs. these seem to be the only options, at present. the strategy being envisaged right now is to take advantage of the similarities in the following features -epidemiological, genomic, and pathogenetic-of the sars-cov and sars-cov- . conventionally sars-cov- infection are treated using a combination of therapeutic agents: ( ) ventilation for oxygen supply, ( ) combinations of antibiotics amoxicillin, azithromycin, and fluoroquinolones, ( ) antivirals such as chloroquine, favipiravir (t- ), interferon, lopinavir/ritonavir, oseltamivir, remdesivir, and ribavirin, ( ) corticosteroids, and ( ) convalescent plasma [ ] . among these various possibilities, remdesivir may prove to be an effective drug for handling covid- , as it has been already shown to be helpful in treating rna viruses such as mers and sars [ , ] . certain methods like antibody and plasma therapy through the donation of plasma by covid- patients had been adapted in the cases of covs such as mers and sars. other possibilities are using the neutralizing potential of monoclonal antibodies [ ] . melatonin has been suggested as a potent drug for this treatment [ ] . ivermectin seems to have the potential to inhibit covid- in vitro [ ] . few pharmaceutical drugs, including hiv drugs and stem cells are under clinical trials, however, there are still major challenges to be handled [ , [ ] [ ] [ ] [ ] [ ] [ ] . invivo biosystem has developed ace humanized genetic models using caenorhabditis elegans for covid- research (https://tgx.elegans@invivobiosys tems.com). in the absence of the availability of specific anti-viral drugs or vaccines, a few asian countries such as china, thailand, and india have been relying on the use of traditional medicines. this expertise gained over at least a few centuries can have a short-term effect on covid- . almost % of covid- patients in china are treated using traditional medicines such as herbal formulations yu ping feng san and sang ju yin, which modulate the t-cells and enhance host defense mechanisms [ , ] . a few other combinations of traditional medicines such as lian hua qing wen capsule, shuang huang lian, and ma xin gan shi tang can be expected to be effective as therapeutics against viral infections [ , , ] . many traditional herbal extracts and compounds have shown potential activity against cov, these include: ( ) ( ) for prevention such as fortunes bossfern rhizome [ ] . liquorice root (glycyrrhiza glabra) a native of europe and asia showed an anti-viral property towards sars-covs that might be beneficial in this treatment because of the phytochemicals, including flavonoids (glycyrrhizin, liquiritigenin, and glabridin) and triterpenoids (glycyrrhizic acid, and glycyrrhetinic acid) [ ] . thailand's medical board has recommended licorice root for covid- treatment. more efforts are needed untill vaccine discovery takes place. indian ministry of ayurveda, yoga and naturopathy, un ani, siddha, and homoeopathy (ayush) also advise on the use of traditional medicine arsenicum album although not supported by strong scientific evidence. intake of anti-malarial drug ayush (without side effects), sesame oil in the nose, and tulasi, ginger, guduchi (tinospora cordifolia, and turmeric in the diet have been suggested. ayurveda has worked towards enhancing immunity against a host of infections and homeopathy has been reported for treating cholera, spanish influenza, yellow fever, and typhoid. it was also offered during the outbreak of ebola in (guinea, west africa) due to a lack of vaccine or anti-virals (https://m.economictimes.com/ news). infectious diseases are caused by pathogens, which have resistance to antibiotics. genomics plays a crucial role in diverse biotechnological applications including developing antipathogens [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the emergence of covid- continues to plague the whole world. from about countries, over one million confirmed cases with a high mortality rate of . % have been reported (https:// www.worldometers.info/coronavirus/). lock-down for social distancing in mitigating covid- has been found to be suitable for preventing pandemic scenario but it involves a heavy economic burden on the maintenance of essential services for health [ ] . this strategy offers a short-term relief in delaying the transmissions. for a permanent remedy, investigations need to continue: ( ) rapid and reliable testing kits, ( ) short-term therapeutics and, and ( ) finally vaccine for complete eradication. genomic data are likely to provide insights into the evolutionary trends and their potential transmission among diverse hosts. apart from various alternative approaches, traditional medicines known since long for curing such infections without side effects may prove beneficial. understanding sars-cov- : genetic diversity, transmission and cure in human coronavirus -ncov: a brief perspective from the front line candidate drugs against sars-cov- and covid- natural product-derived phytochemicals as potential agent against coronaviruses. a review comparative genomic analysis of rapidly evolving sars cov- viruses reveal mosaic pattern of phylogeographical distribution world health organization declares global emergency: a review of the novel coronavirus (covid- ) covid- : epidemiology, evolution, and cross-disciplinary perspectives the possible of immunotherapy for covid- : a systematic review running title: immunotherapy for covid- coronavirus disease : coronaviruses and blood safety review of the novel coronavirus (covid- ) based on current evidence molecular immune pathogenesis and diagnosis of covid- covid- infection: origin, transmission, and characterization of human coronaviruses potential interventions for novel coronavirus in china: a systemic review bat-to-human: spike features determining 'host jump' of coronaviruses sars-cov, mers-cov, and beyond mutated covid- , may foretells mankind in a great risk in the future age-structured impact of social distancing on the covid- epidemic in india traditional chinese medicine in the treatment of patients infected with -new coronavirus (sars-cov- ): a review and perspective broad-spectrum antiviral gs- inhibits both epidemic and zoonotic coronaviruses in silico screening of chinese herbal medicines with the potential to directly inhibit novel coronavirus covid- : melatonin as a potential adjuvant treatment the fda-approved drug ivermectin inhibits the replication of sars-cov- in vitro coronavirus disease (covid- ): a primer for emergency physicians new insights on the antiviral effects of chloroquine against coronavirus: what to expect for covid- ? treatment options for covid- : the realty and challenges severe acute respiratory syndrome coronavirus (sars-cov- ) and coronavirus disease- (covid- ): the epidemic and the challenges yu ping feng san, an ancient chinese herbal decoction, induces gene expression of anti-viral proteins and inhibits neuraminidase activity immunomodulatory effects of a traditional chinese medicine with potential antiviral activity: a self-control study the chinese prescription lianhuaqingwen capsule exerts anti-influenza activity through the inhibition of viral propagation and impacts immune function liquorice may tackle sars identification of myricetin and scutellarein as novel chemical inhibitors of the sars coronavirus helicase, nsp natural bis-benzylisoquinoline alkaloids-tetrandrine, fangchinoline, and cepharanthine, inhibit human coronavirus oc infection of mrc- human lung cells inhibition of sars-cov cl protease by flavonoids quorum sensing inhibitors: an overview quorum sensing inhibitors as antipathogens: biotechnological applications quenching the quorum sensing system: potential antibacterial drug targets genomic analysis reveals versatile organisms for quorum quenching enzymes: acyl-homoserine lactone-acylase and-lactonase evolution of resistance to quorum-sensing inhibitors extending the limits of bacillus for novel biotechnological applications inhibition of microbial quorum sensing mediated virulence factors by pestalotiopsis sydowiana a lesson learned from the outbreak of covid- in korea key: cord- - du s p authors: ciuca, ioana m title: covid- in children: an ample review date: - - journal: risk manag healthc policy doi: . /rmhp.s sha: doc_id: cord_uid: du s p the aim of this review was to describe the current knowledge about coronavirus disease (covid- , which is caused by severe acute respiratory syndrome coronavirus [sars-cov- ]) in children, from epidemiological, clinical, and laboratory perspectives, including knowledge on the disease course, treatment, and prognosis. an extensive literature search was performed to identify papers on covid- (sars-cov- infection) in children, published between january , and april , . there were relevant papers on covid- in children. the results showed that covid- occurs in . – . % of children. clinical signs and symptoms are comparable to those in adults, but milder forms and a large percentage of asymptomatic carriers are found among children. elevated inflammatory markers are associated with complications and linked to various co-infections. chest computed tomography (ct) scans in children revealed structural changes similar to those found in adults, with consolidations surrounded by halos being somewhat specific for children with covid- . the recommended treatment includes providing symptomatic therapy, with no specific drug recommendations for children. the prognosis is much better for children compared to adults. this review highlights that covid- in children is similar to the disease in the adult population, but with particularities regarding clinical manifestations, laboratory test results, chest imaging, and treatment. the prognosis is much better for children compared to adults, but with the progression of the pandemic; the cases in children might change in the future. the recently declared coronavirus pandemic represents the "sword of damocles" in societies used to protocols and guidelines. it started at the end of , when many adult patients with a new form of pneumonia that was frequently fatal were admitted to chinese hospitals; this illness was caused by severe acute respiratory syndrome coronavirus (sars-cov- ). in this time of modern medicine, when evidence-based medicine prevails, we find ourselves in the face of a difficult situation, where the necessary evidence is lacking; while there are some large studies for the adult population, for the pediatric population, the evidence is extremely limited. the new coronavirus was initially named -ncov but was later renamed severe acute respiratory syndrome coronavirus (sars-cov- ). the virus is a single-stranded, zoonotic rna virus that is a member of the group of respiratory tract viruses. it is related to middle east respiratory syndrome coronavirus (mers-cov) and severe acute respiratory syndrome coronavirus (sars-cov). the disease, known internationally as coronavirus disease (covid- ) , affects a significant proportion of people, but it has been reported less frequently in children, especially in the initial studies, in which only . % of the positive cases involved children < years. the current transmission is from human to human, and both intra-family and intra-community spread occurs, although it is assumed that it was initially from bats and had an animal intermediate host. the virus is excreted via the respiratory and digestive routes. it has been found that the virus is excreted via the digestive route even at days after a negative respiratory sample is obtained, which may be due to a longer time requirement for clearing the virus from the digestive route compared to the respiratory route. , contamination occurs via pffluge drops (produced by coughing, sneezing, and talking) or by contact with contaminated surfaces, with contamination of feces also occurring. because having children (especially toddlers) follow sanitary practices is extremely difficult (depending on their age), it is expected that child carriers transmit the infection easily. major problems among children include the high degree of contagiousness, the healthy status of carriers of the virus (leading to an increased potential for transmission), and the lack of knowledge we have about the disease. not much is known about mother-to-child transmission, but there are studies reporting on positive newborns being born to positive mothers. in these cases, it is not clear whether infection occurred intranatally or perinatally (via secretions such as pflugge drops or milk), with no clear transmission route having been established. [ ] [ ] [ ] this study aimed to review the current data on sars-cov- infection in children, from epidemiological, clinical, and laboratory perspectives, including data on the disease course, treatment, and prognosis. "covid- " or "sars-cov- " and "children" were used as the keywords in the search and the additional terms included epidemiology, diagnosis, clinic, laboratory, treatment, and outcome. the search period was january , to april , . litcovid (the us national library of medicine's curated hub of scientific literature on sars-cov- , https:// www.ncbi.nlm.nih.gov/research/coronavirus) was searched, along with searching for additional records in medline (pubmed interface), springer link and web of science. all retrieved records (including original articles, letters to editor, editorials, and case reports) in english and records with english translation were downloaded and evaluated. preprints, in-press articles, and accepted-for-publication studies were also evaluated, given the current scarcity of evidence. subsequently, the abstracts were evaluated for eligibility, duplicates were removed, and the data were analyzed. a total of published papers were found on sars-cov- in general populations, full-text articles that involved children were published between january , and april, and considered relevant were reviewed for this study. epidemiology sars-cov- has triggered a significant number of illnesses; (as of st of april ), the world health organization (who) reported , , confirmed cases, with , deaths. although data on the pediatric population are currently limited, there are several studies that provide valuable information. based on the first published research, the disease was diagnosed in only . % of children. a later chinese study of , patients of all ages reported the virus in % of children. a large-scale testing study in korea (involving children representing % of the country's population) reported that the proportion of children with covid- among the confirmed cases was . %. after the initiation of more widespread testing, lu et al conducted a recent study in china and reported that the incidence of confirmed covid- among children rose to . % ( out of the children assessed), with a mean an average age of . years. dong et al studied cases of children with covid- in a large study in china ( . % of cases were confirmed by laboratory testing and . % were clinically diagnosed). the average age of these children was . years. there was no significant difference in the proportion of males ( %) and females, but other research has shown a slightly higher prevalence in adult males. it was presumed that children were infected via exposure to infected family members, , without specifying from which family member the infection occurred, whether the infection was contracted simultaneously by all family members, or the incubation period in children. xia et al conducted a small study of children with covid- and reported that % had clear contact with a family member, while the contact was indeterminate for the remainder of the children. pediatric symptoms are variable, depending on the stage of the disease, the prior health status, and the presence of comorbidities and other individual features. the clinical picture in children includes fever, cough, dyspnea, and malaise, which is the tetrad of symptoms frequently reported in adults. in children, fever is present in . % to % of cases, being reported by most studies as a significant symptom, associated with both cough and common symptoms of rhinopharyngitis (such as sore throat and rhinorrhea). , based on the who case definition, in the majority of countries, only patients (including children) with respiratory symptoms would be suspected of having covid- . however, dong et al reported that . % of children were completely asymptomatic, while . % had mild forms such as rhinopharyngitis. digestive symptoms are also present in - % of cases involving children, including abdominal pain or discomfort, diarrhea, and vomiting; these symptoms may precede respiratory symptoms. cardiac manifestations specific to myocarditis were also found in children: sinus tachycardia and minor right bundle branch block (rbbb); however, the prevalence was not significantly different from that in the general pediatric population. depending on the affected organs, manifestations of the associated complications may be adjoining. the physical signs of covid- include rhinorrhea, pharyngeal congestion, and pulmonary rales, associated with pneumonia. compensatory signs such as polypnea, dyspnea, chest retractions, and other signs of respiratory failure have been observed, but specific covid- signs were not highlighted. thus far, there have been no confirmed cases of hemoptysis or anosmia in children, unlike in adults, but this might be because of the difficulty of describing the absence of smell by children. pediatric outcomes are usually excellent due to the mild forms of disease often present in children, although deaths have also been registered among children. asymptomatic carriers among the pediatric population have been described, raising concerns, because infected children might be asymptomatic spreaders of the disease. recently, the occurrence of a multisystemic inflammatory syndrome in children was reported. it was initially named "kawasaki like-disease" and then renamed pediatric multisystem inflammatory syndrome (pims), and it is similar to the vascular multisystem inflammatory involvement in adults with covid- .the disease onset is usually preceded by gastrointestinal symptoms, which are followed by systemic vasculitis with prolonged, nonresponsive fever associated with rash, palmar erythema, conjunctivitis, oral mucositis, and laterocervical lymphadenopathy, and sometimes complicated with myocarditis and/or severe coronaritis. pims has been reported in the uk, france, italy, and the usa but, fortunately, the treatment for kawasaki vasculitis has proven to be effective. however, dong et al reported that . % of children were completely asymptomatic, while . % had mild forms such as rhinopharyngitis. additionally, a recent study in china of children with covid- found that % of them had mild or moderate forms of the disease. the clinical manifestations of the virus in children have been mild and less severe than those in adults, being linked to their age and development. , , , , this needs to be kept under close supervision, and identifying the asymptomatic carriers is paramount for limiting the virus spread. although the clinical manifestations in children are more indistinct and less severe than in adults, this age category is distinct and must be considered with special care, particularly as early diagnosis influences the diseases outcome and, crucially, detecting asymptomatic carriers can limit the transmission of the disease. most studies suggest that the same risk factors in adults apply to children, including comorbidities such as diabetes, chronic pulmonary disease, and cardiac pathology, and unfavorable outcomes are more frequent in adults with comorbidities such as hypertension, diabetes, kidney disease, immunosuppression (drug-induced immunosuppression and hiv), and chronic obstructive pulmonary disease (including asthma). prompt diagnosis is vital, given the evolution of the disease, with ards potentially occurring at week after symptom onset. the most frequent complications observed in children with severe forms of covid- were septic shock, toxic encephalopathy, multiple organ dysfunction syndrome, disseminated intravascular coagulation, and status epilepticus. fortunately, in a study that included children, only one child (aged years) died, but the proportion of severe and critical cases was . % among infected infants, and this decreased with increasing age to . % for infected - -year-olds. more severe forms were more common in children < year of age ( . %) compared to in children aged - years ( %) infected with the virus, suggesting that younger children are more at risk of having severe forms than older children, but the study did not report if underlying diseases were pre-existent among any of the children. another study reported the death of a -month-old baby with associated intestinal occlusion. the comorbidities associated with severe cases in the study were leukemia (taking chemotherapy), intestinal occlusion, and hydronephrosis. as of march , , four deaths among children caused by covid- were reported in the international media. a -year-old died in france, and then a -year-old girl died in belgium and a -year-old boy died in the uk (https://www.euronews.com/ / / /). the presence of clinical signs and symptoms in a relevant epidemiological context (eg, an endemic area) indicates a suspected case of covid- , especially if contact with a confirmed covid- case is known. the diagnosis can be confirmed by viral detection laboratory tests. it is important to ascertain the timing of the onset of infection, based on the incubation period of - days, with a mean of - days. there may be suspicion of a case of covid- in a child if at least one of the following exists: . fever, specific respiratory symptoms, digestive symptoms, or fatigue . suggestive biological findings: normal leukocyte level, leukopenia, and increased c reactive protein (crp) and procalcitonin (pct) levels . specific imaging findings (based on chest x-ray [cxr] and ct scans) in a suspected case, the confirmation involves laboratory confirmation, although some clinicians would advocate that in the presence of clinical signs and symptoms and contact with a covid- case, a diagnosis can be made. the laboratory diagnosis is performed by detecting a nucleic acid antigen (sars-cov- rna) from nasopharyngeal or pharyngeal secretions using reverse transcription polymerase chain reaction (rt-pcr). the tests involving nasopharyngeal secretions had a better sensitivity ( %) compared to the tests involving pharyngeal swabs ( %). this is why the us centers for disease control and prevention (cdc) recommend screening involving nasal secretions or nasopharyngeal aspirate. the timing of the sample collection is very important: screening tests should ideally involve nasopharyngeal secretions collected at the beginning of the disease (when there are signs of rhinopharyngitis), as the viral load decreases in the upper airway and increases in the lower airways with the onset of lung disease; thus, after the onset of lung disease, sputum samples are recommended. using nasopharyngeal secretions leads to a lower sensitivity than using bronchial secretions, but the required bronchoalveolar lavage for children without sputum excretion is invasive and may increase the risk of infection among the medical personnel and so is not indicated. screening tests based on the detection of specific immunoglobulin m, a, and g (igm, iga, and igg) in serum have been developed, but igm and iga only become positive from the fifth day from covid- onset, so the diagnosis is made retrospectively and the tests cannot be used for early diagnosis. , igg levels can be detected after days of disease evolution. unfortunately, the number of screening tests is limited internationally due to the widespread nature of the pandemic, which makes it very difficult to establish precise diagnoses and to identify the healthy carriers acting as viral reservoirs. biological investigations are not specific, as expected in viral diseases. as in other viral infections, in covid- , several hematological disorders have been reported. several studies have reported the presence of leukopenia in adults and children, associated with lymphopenia and neutropenia. , another study reported normal leukocyte levels with leukopenia among children. sun et al reported normal leukocyte levels (lymphocytes and neutrophils), platelets, and hemoglobin in some patients, but leukopenia with lymphopenia, thrombocytopenia, and anemia were linked with severe outcomes. increased inflammatory markers such as crp, erythrocyte sedimentation rate, and pct have been noticed in some children with covid- , signifying a bacterial coinfection and associated complications. , , it has been shown that a large percentage ( %) of children had abnormal pct values, requiring antibiotics, but no deaths were registered among these children. pct was normal in children with mild and moderate covid- . , , while studies involving adults revealed that pct and leukopenia were risk factors for increase mortality rates, this connection was not confirmed in children. increased troponin was present in adults with myocarditis, and myoglobin (also known as myohemoglobin) and muscle enzymes were increased in adults due to covid-associated muscular injury , , but these findings were not reported in children. high crp and ferritin levels were associated with a poor prognosis in adults as well as increased d dimers and thrombocytopenia. , , other biological findings included idiopathic metabolic acidosis and increased serum levels of proinflammatory cytokines such as interleukin (il)- . increased transaminases, muscle enzymes, and lactic dehydrogenase , , , can occur, depending on the affected organ, and alanine transaminase and direct bilirubin were associated with severe disease in children. , chest imaging chest imaging, including chest xray (cxr), ct, and lung ultrasonography (lus), is often used for evaluation and monitoring of respiratory diseases. therefore, it may be advisable to use one of the imaging techniques for covid- assessment. however, it would not be appropriate to use ct as a screening diagnosis tool for covid- diagnosis in children because of the lack of specificity of the lesions, which can occur in other viral lung diseases. ai et al published a study on adults that concluded that ct scans should be considered for covid- diagnosis, based on the good sensitivity of ct for detecting lung changes, which was biased by the fact that ct is the gold standard for the detection of morphological changes. a comprehensive report stated that chest ct scans would be normal in - % of pediatric covid- patients with minor upper airway respiratory symptoms, which implies an unjustifiably high percentage of children, without injuries, who would be exposed to ct radiation if chest ct scans were used. to be used for screening, chest ct scans should detect lung changes in asymptomatic children as well as in symptomatic cases, but the median sensitivity of ct of % in pediatric patients with confirmed covid- is not sufficient to expose asymptomatic children to harmful radiation. as it is unusual to perform ct scans in cases of viral non-complicated pneumonia, there are currently no valid arguments for the use of ct scans as a screening tool in the pediatric population with asymptomatic sars-cov- infection. because ct scans lack specificity for covid- , caution was recommended by an expert panel regarding imaging choices, especially when they necessitate patient transport. in most cases of pneumonia, cxr is a key diagnostic tool, but its diagnostic utility for covid- is limited. the initial and mild stages of covid- can lead to a normal cxr image. , , however, uni-or bilateral patchy or diffuse asymmetric airspace opacities, interstitial alterations, and nodularity can be detected in severe covid- cases. nevertheless, cxr is neither an indispensable nor a mandatory covid- diagnostic tool due to its lack of specificity. ct is highly sensitive at detecting pulmonary lesions in all lung pathologies, including covid- . however, many studies described covid- lesions on ct scans that are nonspecific and bear some resemblance to other lung pathologies. [ ] [ ] [ ] ground-glass opacities were described, mostly subpleural and predominantly in the lower lobes, while fine-mesh shadows occurred in the early stages of the disease. , , , among children with moderate forms of covid- , there was a bilateral multi-lobular distribution with diffuse ground-glass, crazy-paving pattern, and consolidation. , , as the infection progressed, severe lesions and dense consolidation became more prevalent. xia et al reported that consolidation surrounded by a halo was found in half of children with severe or moderate covid- lung disease, suggesting that there is some specificity regarding these lesions in children. lesions such as ground-glass opacities and fine-mesh shadows were also described in children, while "patch-like shadows" and "white lung" have been found in severe cases. a recently developed covid- ct score showed a reliable, sensitive association with decreased mortality risk in adults. despite studies indicating that non-contrast chest ct scans could be used as an early diagnostic tool compared to rt-pcr (ct being frequently delayed because of the high burden of cases during pandemics), ct is not recommended as a first-line diagnosis technique in children. this is due to irradiation risks, lack of specific lesions, and the potential increased contamination risk during patient transport. the results of a study by fang et al support the use of chest ct scans for screening in patients with clinical and epidemiological features compatible with covid- , particularly when rt-pcr test results are negative. various studies have demonstrated that lus is a valuable tool for identifying changes that can occur in covid- such as consolidations, pleural effusions, small subpleural consolidations, areas of white lung, and b lines in a variety of patterns including focal, multifocal, and confluent lesions. , lus can indicate suggestive signs of interstitial-alveolar damage involving variable consolidations, irregularities of the pleura, nontranslobar consolidation, and consolidation with air bronchogram. however, lus can detect lung artefacts that are not specific to covid- , including consolidations with air bronchogram that occur in pneumonia, subpleural consolidations that occur in pneumonia and bronchiolitis, pleural line irregularities that occur in bronchiolitis, lung fibrosis, pleural malignancies, and copd, - and b-lines that occur in interstitial alveolar inflammation present in bronchiolitis and viral interstitial cases of pneumonia, as well as in chronic lung pathologies such as fibrosis, cystic fibrosis, and bronchiectasis. the limitations of lus is relied to the lesion localization, deeper lung lesions have no contact with the pleura and cannot be easily detected as the air is a very weak conductor of ultrasound. however, in contrast to other methods of investigation, lus is easily available at the bedside and portable probes that are easy to disinfect can be used, involving less exposure to infection among medical staff. there are currently no etiological treatments or prophylactic for covid- . the treatment of mild cases addresses current symptoms, and isolation to prevent human-to-human transmission is the most important prophylactic treatment. , for moderate and severe covid- , the therapeutic recommendations involve supportive therapy, supplemental oxygen and, if bacterial infection (which is frequent in children) is suspected, empirical antibiotics. , , , very severe cases involving refractory hypoxia and respiratory failure will need admission to an intensive care unit for mechanical ventilation; fortunately, children do not require this as often as adults. , , non-invasive ventilation (niv) and high-flow oxygen therapy (hfot) are associated with a high risk of virus aerosolization, and the virus can be spread via mask leaks, so niv and hfot may only be used in specific cases and when the mask is precisely positioned, with an optimal fit. retrospective studies on covid- suggest starting antiviral medication in the initial treatment window, when the evolution of the disease can still be changed, due to the lack of treatment efficiency once complications occur. etiological treatment would require the administration of antivirals targeting rna viruses. so far, no antiviral has been shown to be effective for the treatment of covid- in humans, but there are multiple randomized clinical trials in progress. some antiretroviral drugs (such as lopinavir/ritonavir, darunavir/cobicistat, favipiravir, remdesivir, ribavirin, oseltamivir, tocilizumab, and umifenovir as well as angiotensin-converting enzyme [ace] inhibitors) have been indicated in adults. , however, as there are no studies to demonstrate the benefit of any antivirals in children with covid- , the use of this type of medication would not be recommended. chloroquine and its derivatives (including hydroxychloroquine and chloroquine phosphate) have been successfully used for sars-cov and ebola, and have also been shown to be effective in children with sars-cov- . co-administration of azithromycin increases the therapeutic success, according to a french study. most of the therapeutic regimens for children include chloroquine (or derivatives) and lopinavir/ritonavir, which have been reported to show a degree of efficiency and a safety profile that is acceptable for children. ribavirin has been reported to have been used to treat severe covid- in children. , inhaled interferon-alpha has been used to treat covid- in children, but the efficiency and safety remain to be determined. , non-specific immunity-boosting treatments such as immunoglobulins and intravenous interferon have been used to treat severe cases in adults, but additional consideration is required before it is used for children. , , corticosteroids are recommended for the treatment of covid- complications such as ards, septic shock, encephalopathy, and bleeding disorders, and in other specific pathologies, steroids are required. the multicentric citris-ali trial demonstrated the effectiveness of high-dose ascorbic acid for treating ards due to other causes, lowering the mortality rate, and this could be extrapolated to covid- . antibiotics are recommended for secondary chest infections associated with covid- . the majority of studies suggest using empirical broad-spectrum antibiotics until culture results become available. , given the frequency of mycoplasma infections in children , and the well-described anti-inflammatory properties of azithromycin, this could be the antibiotic of choice in children with covid- and bacterial superinfection. further studies should be carried out to gather evidence on the best therapeutic options. prevention, aimed at reducing transmission in the community, remains the only proven efficient option to combat covid- , until further discoveries are made. according to several studies, covid- has a milder clinical course with faster recovery and a better prognosis in children compared to in adults. , , however, a recent study reported similarly severe forms of covid- in children with good outcomes. the reasons for these particularities are still being investigated. some researchers have hypothesized that lung epithelial cells in children may express fewer or perhaps even differently shaped ace proteins, leading to a lower morbidity rate, but further studies are needed to understand the mechanisms of the diverse manifestations of covid- in children. it has been shown that influenza virus, parainfluenza virus, respiratory syncytial virus (rsv), rhinovirus, or adenovirus, which are the most common viruses that cause acute lower respiratory infections in young children, might cross-react with coronavirus, giving children partial protection against covid- , but co-infections were also reported. the most common co-infections in children involved mycoplasma pneumoniae, influenza a and b, rsv, and cytomegalovirus. children of all ages are predisposed to acquire covid- , considering the human-to-human transmission, but the majority of them have mild forms of covid- and a favorable evolution. prognosis is much better in children compared to in adults, yet asymptomatic carrier transmission is presumed to be more common among the pediatric population. nevertheless, with the progression of the pandemic, the cases in children might change in the future. this review highlights that even if covid- is rare in children, asymptomatic sars-cov- infection is more frequent than in adults. collecting further high-quality evidence is essential to understand covid- in children and to determine the most efficient case management strategies. infection prophylaxis through isolation of infected children is essential, involving proper monitoring, early detection of disease complications, and the opportunity for on-time treatment and limiting secondary spread. being caught up in a pandemic involving the "sword of damocles" and a "crown" of sars-cov- proteins, children might be a key element in the battle. risk management and healthcare policy is an international, peerreviewed, open access journal focusing on all aspects of public health, policy, and preventative measures to promote good health and improve morbidity and mortality in the population. the journal welcomes submitted papers covering original research, basic science, clinical & epidemiological studies, reviews and evaluations, guidelines, expert opinion and commentary, case reports and extended reports. the manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use. visit http://www.dovepress.com/testimonials.php to read real quotes from published authors. submit your manuscript here: https://www.dovepress.com/risk-management-and-healthcare-policy-journal global pediatric pulmonology alliance. diagnosis, treatment, and prevention of novel coronavirus infection in children: experts' consensus statement 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applications, role, value and limitations lung b-line artefacts and their use the reliability of lung ultrasound in assessment of idiopathic pulmonary fibrosis how useful is the lung ultrasound in cystic fibrosis? ultrasound of the chest in children (mediastinum excluded) wfumb position statement: how to perform a safe ultrasound examination and clean equipment in the context of covid- available from pharmaceutical care recommendations for antiviral treatments in children with coronavirus disease severe sars-cov- infections: practical considerations and management strategy for intensivists international pulmonologist's consensus on covid- advance of promising targets and agents against covid- in china hydroxychloroquine and azithromycin as a treatment of covid- : results of an open-label non-randomized clinical trial effect of vitamin c infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: the citris-ali randomized clinical trial facing the pandemic of novel coronavirus infections: the pediatric perspectives virus-virus interactions impact the population dynamics of influenza and the common cold why is covid- so mild in children? the author acknowledges dr maria-mirabela lukic, dr flavian nicolae-mircov, dr ramona chelcea, dr diana ragobete, and dr maria budnic for the help in searching the papers and dr patricia nascu for reviewing the paper. the review did not have any source of funding. the author reports no conflicts of interest in this work. key: cord- -xit najq authors: van damme, wim; dahake, ritwik; delamou, alexandre; ingelbeen, brecht; wouters, edwin; vanham, guido; van de pas, remco; dossou, jean-paul; ir, por; abimbola, seye; van der borght, stefaan; narayanan, devadasan; bloom, gerald; van engelgem, ian; ag ahmed, mohamed ali; kiendrébéogo, joël arthur; verdonck, kristien; de brouwere, vincent; bello, kéfilath; kloos, helmut; aaby, peter; kalk, andreas; al-awlaqi, sameh; prashanth, ns; muyembe-tamfum, jean-jacques; mbala, placide; ahuka-mundeke, steve; assefa, yibeltal title: the covid- pandemic: diverse contexts; different epidemics—how and why? date: - - journal: bmj glob health doi: . /bmjgh- - sha: doc_id: cord_uid: xit najq it is very exceptional that a new disease becomes a true pandemic. since its emergence in wuhan, china, in late , severe acute respiratory syndrome coronavirus (sars-cov- ), the virus that causes covid- , has spread to nearly all countries of the world in only a few months. however, in different countries, the covid- epidemic takes variable shapes and forms in how it affects communities. until now, the insights gained on covid- have been largely dominated by the covid- epidemics and the lockdowns in china, europe and the usa. but this variety of global trajectories is little described, analysed or understood. in only a few months, an enormous amount of scientific evidence on sars-cov- and covid- has been uncovered (knowns). but important knowledge gaps remain (unknowns). learning from the variety of ways the covid- epidemic is unfolding across the globe can potentially contribute to solving the covid- puzzle. this paper tries to make sense of this variability—by exploring the important role that context plays in these different covid- epidemics; by comparing covid- epidemics with other respiratory diseases, including other coronaviruses that circulate continuously; and by highlighting the critical unknowns and uncertainties that remain. these unknowns and uncertainties require a deeper understanding of the variable trajectories of covid- . unravelling them will be important for discerning potential future scenarios, such as the first wave in virgin territories still untouched by covid- and for future waves elsewhere. late in , a cluster of acute respiratory disease in wuhan, china, was attributed to a new coronavirus, - later named severe acute respiratory syndrome coronavirus (sars-cov- ). it was soon discovered that the virus is easily transmitted, can cause summary box ► severe acute respiratory syndrome coronavirus (sars-cov- ), the virus that causes covid- , has spread to nearly all countries of the world in only a few months. it is unique that an emerging respiratory virus becomes a pandemic, and can continue human-to-human transmission unabated, probably permanently. ► depending on the context, the trajectory and the impact of the covid- epidemic vary widely across affected countries. this is in fact the case with most infectious diseases. ► despite limited initial knowledge on covid- , most societies have deployed draconian measures, including lockdowns, to contain the virus and mitigate its impact. this had variable success, but invariably with profound socioeconomic collateral effects. ► through research and rapid sharing of its findings, progressively more insights on sars-cov- and covid- have been uncovered (knowns), mainly based on evidence from china, europe and the usa; however, important knowledge gaps remain (unknowns). ► the different covid- epidemics and the responses unfolding in the global south are little described, analysed or understood. insights from these less researched contexts are important for discerning potential future scenarios, not only for the first wave in virgin territories still untouched by covid- , but also for future waves. ► more understanding of lived experiences of people in a variety of contexts is necessary to get a full global picture and allow learning from this variety. ► bmj global health and emerging voices for global health have launched a call for such on-the-ground narratives and analyses on the epidemics of, and responses to, covid- . severe disease and can be quite lethal especially in the elderly and those with comorbidities. [ ] [ ] [ ] [ ] the new human disease is called covid- . soon it became clear that its global spread was unstoppable. even with draconian containment measures, such as strict movement restrictions, the so-called lockdown, it spread, and within a few months reached almost all countries and was declared a pandemic by the who. table summarises key events in the unfolding of the covid- pandemic, from december to may . this progression is quite unique. new human pathogens emerge frequently from an animal host, but most cause only a local outbreak. human-to-human transmission stops at some point, and the virus can only re-emerge as a human pathogen from its animal host. only very rarely does an emerging pathogen become a pandemic. over the past decades, a totally new pathogen emerged, caused serious disease, and spread around the globe continuously only once before: the hiv. it seems increasingly likely that sars-cov- transmission will be continuing. all countries are now facing their own 'covid- epidemic'. in only a few months, the scientific community has started to learn the virus's characteristics and its manifestations in different contexts. but we fail to understand fully why the virus spreads at different speeds and affects populations differently. our main objective is to make sense of those different expressions of the covid- pandemic, to understand why covid- follows variable trajectories in ways that are often quite different from the collective image created by the mediatisation of the dramatic covid- epidemics in densely populated areas. we start by exploring the role of context, followed by a brief summary of what is already known at the time of writing about sars-cov- and covid- . we then bmj global health compare these knowns with what is known of some other viral respiratory pathogens and identify the critical unknowns. we also discuss the coping strategies and collective strategies implemented to contain and mitigate the effect of the epidemic. we finally look ahead to potential future scenarios. the unfolding covid- pandemic: importance of context initially, human-to-human transmission was documented in family/friends clusters. [ ] [ ] [ ] [ ] [ ] [ ] progressively, it became clear that superspreading events, typically during social gatherings such as parties, religious services, weddings, sports events and carnival celebrations, have played an important role. [ ] [ ] [ ] [ ] dense transmission has also been documented in hospitals and nursing homes possibly through aerosols. sars-cov- has spread around the world through international travellers. the timing of the introduction of sars-cov- has largely depended on the intensity of connections with locations with ongoing covid- epidemics; thus, it reached big urban centres first and, within these, often the most affluent groups. from there, the virus has spread at variable speeds to other population groups. as of may , the most explosive covid- epidemics observed have been in densely populated areas in temperate climates in relatively affluent countries. the covid- pandemic and the lockdowns have been covered intensively in the media and have shaped our collective image of the covid- epidemic, both in the general public and in the scientific community. the covid- epidemic has spread more slowly and less intensively in rural areas, in africa and the indian subcontinent, and the rural areas of low and lower-middle income countries (lics/lmics). not only the media but also the scientific community has paid much less attention to these realities, emerging later and spreading more slowly. the dominant thinking has been that it is only a question of time before dramatic epidemics occur everywhere. this thinking, spread globally by international public health networks, has been substantiated by predictive mathematical models based largely on data from the epidemics of the global north. however, what has been observed elsewhere is quite different although not necessarily less consequential. the effects of the covid- epidemic manifest in peculiar ways in each context. in the early stages of the covid- epidemic in sub-saharan africa, the virus first affected the urban elites with international connections. from there, it was seeded to other sections of the society more slowly. in contrast, the collateral effects of a lockdown, even partial in many cases, are mostly felt by the urban poor, as 'stay home' orders abruptly intensify hardship for those earning their daily living in the informal urban economy. governments of lics/lmics lack the budgetary space to grant generous benefit packages to counter the socioeconomic consequences. international agencies are very thinly spread, as the pandemic has been concurrent everywhere. donor countries have focused mainly on their own covid- epidemics. the epidemic is thus playing out differently in different contexts. many factors might explain sars-cov- transmission dynamics. climate, population structure, social practices, pre-existing immunity and many other variables that have been explored are summarised in table . although all these variables probably play some role, many uncertainties remain. it is difficult to assess how much these variables influence transmission in different contexts. it is even more difficult to assess how they interact and change over time and influence transmission among different social groups, resulting in the peculiar covid- epidemic in any particular context. we do not attempt to give a complete overview of viruses but select only those viruses that emerged recently and caused epidemics such as ebola, that have obvious similarities in transmission patterns such as influenza and measles, or that are closely related such as other coronaviruses. respiratory viruses such as severe acute respiratory syndrome coronavirus (sars-cov), middle east respiratory syndrome coronavirus (mers-cov) and avian influenza a and also ebola have originated from animal hosts and caused human diseases (table ) . these viruses do not continuously circulate from human to human. they create an outbreak only when there is interspecies cross-over transmission, most frequently from bats to another animal host. the first human case of a disease from an emerging viral pathogen, the 'index case' or 'patient zero', is invariably someone in close contact with the originating animal host or an intermediary animal host. if this contact occurs in a remote rural community, the spread is usually slow, at low intensity, and could fade out before the pathogen gets a chance to spread to another community. the spread can suddenly intensify if seeded in a densely populated community, frequently in a particular context such as a hospital or during a social event, often referred to as a superspreading event. when the spread reaches a city, it can become a major outbreak, from where it can spread further; this happened with sars-cov in hong kong in and with ebola in conakry, freetown and monrovia in - . but at some stage human-to-human transmission is interrupted and the outbreak stops. only very exceptionally can a new viral pathogen sustain continuous human-to-human transmission. other viral diseases such as measles and influenza are 'old' diseases; they have been studied in great depth. what can we learn from them? measles and influenza: the importance of context it is thought that measles emerged thousands of years ago in the middle east. it is assumed that a cross-over occurred from the rinderpest virus, to become the human measles virus. measles has since spread around the globe in continuous human-to-human transmission. when measles, along with other viruses such as smallpox and influenza, was introduced in the americas by european conquerors, it contributed to a massive die-off of up to % of the original population. the transmission dynamics of sars-cov- can be compared with influenza. influenza typically causes yearly epidemics in temperate climates during winter with less seasonal patterns in tropical or subtropical regions. in hotter climates, such as in sub-saharan africa or south and southeast asia, it is transmitted year round, often not identified as influenza. such different epidemic patterns of influenza are still incompletely understood but thought to be associated with temperature and humidity and human behavioural factors such as indoor crowding. but, in contrast to sars-cov- , the influenza virus is not new. influenza is a very old disease, certainly circulating for several centuries. it has infected most human beings living on the planet already, many of them several times, leaving some immunity but no durable protection. the virus also mutates, giving rise to a new dominant strain every influenza season. influenza is every year a slightly different virus (due to antigenic drift as a result of progressive mutations) with major differences every few decades (antigenic shift as a result of recombination with novel strains). one such antigenic shift resulted in the h n 'spanish' influenza pandemic, which had an estimated case fatality rate (cfr) of %- %, killing millions. box summarises some key facts about h n , including factors thought to be associated with its high cfr. a major difference between covid- and influenza is that sars-cov- is a new pathogen and influenza is not. at the time of writing (may ), sars-cov- has triggered an immune response in over million confirmed infections (and probably in many more), definitely too few to create anything close to herd immunity. calculations using an estimated reproductive number (r ) for sars-cov- suggest that herd immunity would require at least % of the population to have protective immunity (see box ). like covid- , measles and influenza have different epidemic patterns in different contexts. this also is the case for cholera, tuberculosis, hiv/aids and most infectious diseases. the difference in patterns is most pronounced and so is easily understood with vectorborne and water-borne diseases. epidemic patterns are also different for air-borne infections, although they are less easily understood. transmission of respiratory viruses is influenced by factors related to the virus and box pandemic h n influenza, - ► the h n virus probably infected one-third of the world's population at that time (or ~ million people). ► the pandemic had three waves in quick succession; the second wave, in , was worse than the first wave. ► high mortality, especially in younger persons ( - years; ~ % of total deaths) in the pandemic, may have been due to antibody-dependent enhancement and 'cytokine storms'. another possible explanation is that older persons had some protective cross-immunity from previous influenza outbreaks while younger persons did not. ► h n continued to circulate along with seasonal influenza viruses, often recombining to produce more severe local outbreaks, including other pandemics between and , giving it the nickname 'mother of all pandemics'. ► the original h n strain was replaced by a(h n )pdm virus that resulted from an antigenic shift and caused the h n influenza pandemic. ► the h n virus originated in pigs in central mexico in march and was responsible for an estimated deaths worldwide with an estimated cfr< . %. ► during the pandemic, mortality was much lower than in the pandemic. higher mortality in persons younger than years was related to cytokine storms. a role of protective crossimmunity from previous influenza strains in older persons has been suggested. ► after august , the a(h n )pdm virus appeared to have integrated with circulating strains of influenza and continues to cause localised seasonal influenza outbreaks worldwide. box on the use of mathematical models during epidemics a dominant way of studying the transmission dynamics of an infectious disease such as covid- , and predicting the amplitude and peak of the epidemic in a population (city, province, country) and analysing the effect of control measures is using mathematical models. based on available data and several assumptions, a model attempts to predict the course of the epidemic, the expected number of infections, clinical cases and deaths over time. critical is the effective reproductive number (rt). when rt > , the number of cases in a population increases; when rt < , the number of cases decreases. a relatively simple and widely used model is the susceptible-exposed-infectious-recovered model, as used in the two papers recently published in bmj global health on covid- in africa. there are many more types of models, with varying degrees of complexity. the use of such models has strengths and limitations. building a mathematical model implies trade-offs between accuracy, transparency, flexibility and timeliness. a difficulty, in general, is that the parameters on which the model is based, the so-called assumptions are frequently uncertain (table ) and predictions can vary widely if any of the parameters are modestly different. this uncertainty is captured in a sensitivity analysis, leading to various possible quantitative outcomes, usually expressed as a range of plausible possibilities, between 'worst-case' and 'best-case' scenarios. with a new disease such as covid- , certainly at the start of the outbreak, the parameters had to be based on very limited data from a particular context. however, many variables can widely differ across communities as they critically depend on contextual factors (table ) . in mathematical models, all such uncertainties and unknowns are somehow hidden in the complex formulae of the model, as a quasi 'black box'. few people have the knowledge and skill to 'open up the black box'. as uncertainties in covid- are large, the range of possibilities produced by a model is wide, with the worst-case scenario typically predicting catastrophic numbers of cases and deaths. such predictions are often misunderstood by journalists, practitioners and policy-makers, with worst-case estimates getting the most attention, not specifying the huge uncertainties. bmj global health the human host but also by factors related to the natural and human environment (table ) . however, we are quite unable to explain fully which factor has which influence, how these factors vary among different social groups and how interdependent or isolated they are. we are certainly unable to fully model all these variables mathematically to explain the epidemic pattern across a variety of different contexts. too many variables and their interrelations are difficult to quantify, and when all these factors change over time while the pathogen continues to spread in diverse societies, the complexity becomes daunting. understanding transmission dynamics is a bit less daunting for measles, as several variables are well known and rather constant across individuals and contexts. the natural transmission pattern of measles, before the introduction of vaccines, has been well described. measles is mostly a childhood disease, but this is not the case in very remote communities, where measles transmission had been interrupted for extended periods (such as the faroe islands). measles affected all age groups when reaching new territories, causing dramatic first-wave epidemics, a phenomenon called 'virgin soil epidemic'. the latest stages of the global dissemination of measles have been well documented, including in australia, the fiji islands and the arctic countries, where such virgin soil epidemics occurred in the th and the mid- th centuries. fortunately, measles infection creates robust protective immunity and after a first wave becomes a typical childhood disease, affecting only those without any prior immunity. human-to-human transmission of measles virus in a community stops when the virus cannot find new susceptible human hosts and the so-called herd immunity is reached. but transmission of measles continues elsewhere on the planet from where it can be reintroduced a few years later when the population without protective immunity has grown large enough to allow human-to-human transmission again. the epidemic patterns of measles are easily understood as measles is highly infectious, creates disease in almost every infected person and leaves lifelong natural immunity. measles circulation, prior to vaccination, was continuous only in large urban areas with high birth rates. everywhere else reintroduction occurred typically every - ► genetic stability or variability (affecting the potential of long-lasting immunity). ► viral load determines the incubation period with the formula high load ->short incubation period ->high severity. human host ► human susceptibility to the virus; transfer of parental immunity to newborns. ► route and efficiency of human-to-human transmission. ► presence and capacity of asymptomatic carriers to transmit the virus. ► immunity created after infection, its robustness and how long-lasting it is. ► severity and duration of the disease: proportion symptomatic, lethality (cfr). ► pathogenicity and disease spectrum; disease pattern according to age and comorbidities, and related potential to spread. natural environment ► temperature, humidity and seasonal changes in climate affecting the stability and transmission potential of the virus and human susceptibility. ► increasing extreme weather conditions such as droughts and severe storms, as well as global climate change may also affect transmission patterns. ► air pollution may also play a role in the transmission and stability of the virus. human environment/social geography ► demographic variables such as population density, age structure and household composition. ► mixing patterns within households, including bed sleeping patterns, related to housing conditions and hygiene practices. ► house construction with solid walls or permeable walls (thatched walls, straw mats). ► mixing patterns among households related to settlement patterns: social networks, urban-rural differences, working conditions, religious practices and commuting patterns. ► variables related to built environments, road infrastructure and socioeconomic conditions. ► mobility between communities, including international travel. ► crowding institutions: for example, elderly homes, extended families, boarding schools, child institutions, seclusion during tribal ceremonies, hospitals, nursing homes, military barracks and prisons. cfr, case fatality rate. years but sometimes only after or years in isolated rural communities (such as among nomadic groups in the sahel), causing epidemics among all those without acquired immunity and having lost maternal antibodies. these diverse patterns of measles epidemics have been fundamentally changed by variable coverage of measles vaccination. they can still help us make sense of the diversity of covid- epidemics being observed in . measles illustrates convincingly that the transmission pattern of a respiratory virus is strongly influenced by the demographic composition, density and mixing pattern of the population and the connectedness to big urban centres. measles transmission is continuous only in some large urban areas. it presents in short epidemics everywhere else with variable periodicity. this transmission pattern may well be a bit similar for covid- . but it took thousands of years for measles to reach all human communities while sars-cov- spread to all countries in only a few months, despite measles being much more transmissible than sars-cov- . factors such as increased air travel and more dense community structures play bigger roles for sars-cov- than they did for measles. comparison with other pathogenic coronaviruses sars-cov- has many close relatives. six other human coronaviruses (hcovs) are known to infect humans. sars-cov and mers-cov (causing sars and mers, respectively) are very rare and do not continuously circulate among humans. the other four (hcov- e, hcov-oc , hcov-hku and hcov-nl ) cause the common cold or diarrhoea and continuously circulate and mutate frequently. they can cause disease in the same person repeatedly. the typical coronavirus remains localised to the epithelium of the upper respiratory tract, causes mild disease and elicits a poor immune response, hence the high rate of reinfection (in contrast to sars-cov and mers-cov, which go deeper into the lungs and hence are relatively less contagious). there is no cross-immunity between hcov- e and hcov-oc , and new strains arise continually by mutation selection. coping strategies and collective strategies how a virus spreads and its disease progresses depend not only on the variables described above (table ) but also on the human reactions deployed when people are confronted with a disease outbreak or the threat of an outbreak. all these variables combined result in what unfolds as 'the epidemic' and the diverse ways it affects communities. what a population experiences during an epidemic is not fully characterised by the numbers of known infections and deaths at the scale of a country. such numbers hide regional and local differences, especially in large and diverse countries. the epidemic reaches the different geographical areas of a country at different moments and with different intensities. it affects different communities in variable ways, influencing how these communities perceive it and react to it. what constitutes a local covid- epidemic is thus also characterised by the perceptions and the reactions it triggers in the different sections of the society. even before the virus reaches a community, the threat of an epidemic already causes fear, stress and anxiety. consequently, the threat or arrival of the epidemic also triggers responses, early or late, with various degrees of intensity and effectiveness. the response to an epidemic can be divided into individual and household actions (coping strategies), and collectively organised strategies (collective strategies). coping strategies are the actions people and families take when disease threatens and sickness occurs, including the ways they try to protect themselves from contagion. collective strategies are voluntary or mandated measures deployed by organised communities and public authorities in response to an epidemic. these include, among others, isolation of the sick or the healthy, implementation of hygiene practices and physical distancing measures. they can also include mobility restrictions such as quarantine and cordon sanitaire. coping strategies and collective strategies also include treatment of the sick, which critically depends on the availability and effectiveness of diagnostic and therapeutic tools, and performance of the health system. collective strategies also include research being deployed to further scientific insight and the development of diagnostic and therapeutic tools, potentially including a vaccine. implementation of these measures depends not only on resources available but also on the understanding and interpretation of the disease by both the scientific community and the community at large, influenced by the information people receive from scientists, public authorities and the media. this information is interpreted within belief systems and influenced by rumours, increasingly so over social media, including waves of fake news, recently labelled 'infodemics'. coping strategies and collective strategies start immediately, while there are still many unknowns and uncertainties. progressively, as the pandemic unfolds and scientists interpret observations in the laboratory, in the clinic, and in society, more insights are gained and inform the response. table lists measures recommended by the who for preventing transmission and slowing down the covid- epidemic. - 'lockdown' first employed in early in wuhan, china, is the label often given to the bundle of containment and mitigation measures promoted or imposed by public authorities, although the specific measures may vary greatly between countries. in china, lockdown was very strictly applied and enforced. it clearly had an impact, resulting in total interruption of transmission locally. this list or catalogue of measures is quite comprehensive; it includes all measures that at first sight seem to reduce transmission opportunities for a respiratory virus. however, knowledge is lacking about the effectiveness of each measure in different contexts. as a global health bmj global health agency, the who recommends a 'generic catalogue' of measures from which all countries can select an appropriate mix at any one time depending on the phase of the epidemic, categorised in four transmission scenarios (no cases, first cases, first clusters, and community transmission). however, under pressure to act and with little time to consider variable options, public authorities often adopted as 'blueprint' with limited consideration for the socioeconomic context. the initial lockdown in china thus much inspired the collective strategies elsewhere. this has been referred to as 'global mimicry', : the response is somehow partly 'copy/paste' from measures observed previously (strong path dependency). some epidemiologists in northern europe (including the uk, sweden and the netherlands ) pleaded against strict containment measures and proposed that building up herd immunity against sars-cov- might be wiser. towards early april , it became increasingly clear that reaching herd immunity in the short term was illusive. most countries thus backed off from the herd immunity approach to combating covid- and implemented lockdowns. the intensity of the lockdowns has been variable, ranging from very strict ('chinese, wuhan style'), over intermediary ('french/italian/new york city style' and 'hong kong style'), to relaxed ('swedish style'), or piecemeal. the effectiveness of lockdowns largely depends on at what stage of the epidemic they are started, and how intensively they are applied. this is quite variable across countries, depending on the understanding and motivation of the population and their perceived risk ('willingness to adhere'), on the trust they have in government advice ('willingness to comply'), and on the degree of enforcement by public authorities. the feasibility for different population groups to follow these measures depends largely on their socioeconomic and living conditions. it is obviously more difficult for people living in crowded shacks in urban slums to practise physical distancing measures and strict hand hygiene when water is scarce than for people living in wealthier parts of a city. collateral effects of the response every intervention against the covid- epidemic has a certain degree of effect and comes at a cost with collateral effects. each collective strategy ( ) has intended and unintended consequences (some are more or less desirable); ( ) is more or less feasible and/or acceptable in a given context and for certain subgroups in that society; ( ) has a cost, not only in financial terms but in many other ways, such as restrictions on movement and behaviour, stress, uncertainty and others. these costs are more or less acceptable, depending on the perception of the risk and many societal factors; ( ) can be implemented with more or less intensity; and ( ) can be enforced more or less vigorously. the balance between benefit and cost is crucial in judging whether measures are appropriate, which is very context specific. furthermore, benefits and costs are also related to the positionality from which they are analysed: benefits for whom and costs borne by whom? more wealthy societies with strong social safety nets can afford increased temporary unemployment. this is much more consequential in poorer countries, where large proportions of the population live precarious lives and where public authorities cannot implement generous mitigation measures at scale. the adherence to hygiene and distancing measures depends not only on living conditions but also on risk perception and cultural norms. mass masking has been readily accepted in some asian countries, where it was already broadly practised even before the covid- bmj global health epidemic. it remains more controversial in western societies, some of which even have legal bans on veiling in public places. lockdowns are unprecedented and have triggered intensive public debate. not surprisingly, the impact of lighter lockdowns on the transmission is much less impressive; they decrease transmission but do not stop it. quite rapidly, the justification for lockdowns shifted from stopping transmission to 'flattening the curve'. also, once a lockdown is started, rationalised, explained and enforced, it is difficult to decide when to stop it. exit scenarios, usually some form of progressive relaxation, are implemented with the knowledge that transmission will be facilitated again. what we already know the available information on sars-cov- and the spectrum of covid- disease is summarised in tables and . it is increasingly becoming clear that most transmission happens indoors and that superspreading events trigger intensive dissemination. the virology and immunology of sars-cov- / covid- are being studied intensively. this is critical not only to understand what will potentially happen in future waves but also for the development of a vaccine. some scientists and companies are very upbeat about the possibility of producing a vaccine in record time. having a vaccine is one thing, but how effective it is, is quite another. as acquired immunity after a natural infection is probably not very robust (table ), it will also be challenging to trigger robust immunity with a vaccine, but perhaps it is not impossible. many questions remain, some of which are summarised in table . regarding the severity of covid- , initial fears of very high mortality have also lessened. it has progressively become clear that many infections remain asymptomatic, that severe disease is rare in children and young adults, and that mortality is heavily concentrated in the very old and those with comorbidities. table summarises a fuller overview of the present state of knowledge regarding covid- . with covid- epidemics unfolding rapidly, several of the variables in the transmission of sars-cov- and the disease spectrum of covid- could be quantified. this allows for mathematical modelling. several models have been quickly developed, leading to predictions of the speed of transmission and the burden of covid- (box ). predictive models developed by the imperial college ; the center for disease dynamics, economics & policy and johns hopkins university ; the institute for health metrics and evaluation ; harvard university ; and the who, including an 'african model', are a few that are influencing containment strategies around the world. although the covid- pandemic triggered unprecedented research efforts globally, with over scientific papers published between january and april , there are still critical unknowns and many uncertainties. tables and summarise many of the knowns, but their relative importance or weight is not clear. for instance, the virus can spread via droplets, hands, aerosols, fomites and possibly through the environment. however, the relative importance of these in various contexts is much less clear. these factors undoubtedly vary between settings, whether in hospitals, in elderly homes, or at mass events. the weight of the variables also probably differs between the seeding and initial spread in a community and the spread when it suddenly amplifies and intensifies. the importance of each variable probably also depends on climatic conditions, not only outdoors, but also on microclimates indoors, influenced by ventilation and air conditioning and built environments. we summarise the critical unknowns in table along some elements to consider in addressing the unknowns and thoughts on their importance. uncertainty remains, leading to controversy and directly influencing the choice of containment measures. controversy continues regarding when and where lockdown or more selective measures are equally effective with lower societal effects. relationship between the dose of the initial infectious inoculum, transmission dynamics and severity of the covid- disease new evidence is being discovered rapidly. some evidence comes from field observations and ecological studies; other evidence results from scientific experiments or observations in the laboratory and the clinic. sense-making by combining insights from different observations and through the lens of various disciplines can lead to hypotheses that can be tested and verified or refuted. one such hypothesis is that there is a relationship between the dose of virus in the infectious inoculum and the severity of covid- disease. several intriguing observations in the current pandemic could be (partially) explained by such a relationship. we develop this hypothesis in box , as an example of possible further research, to create new insight which may influence control strategies. this viral inoculum theory is consistent with many observations from the early stages of the covid- pandemic, but it is not easy to test scientifically. as covid- is a new disease, we should make a distinction between ( ) the current - 'virgin soil pandemic' caused by sars-cov- , specifically in how it will further spread around the globe in the first wave, and ( ) the potential future transmission in subsequent waves. in some countries, transmission will continue at lower levels. in other countries, such as china, the virus bmj global health may have been eliminated but can be reintroduced in identical or mutated form. for the current first wave, using influenza and the common cold as reasonable comparisons, it is possible that the major epidemics, as witnessed in wuhan, northern italy, or new york, will typically occur in temperate climates in the winter season. some predict that such epidemics will last between and weeks (but this is just a plausible and reasonable comparison in analogy with seasonal influenza). it is possible that in hotter climates the transmission may become continuous, year round at lower levels. it is increasingly clear that hot climate does not exclude superspreading events as observed in guayaquil, ecuador and in various cities in brazil. ventilation, air-conditioning and crowded places may still create favourable environments for intensive transmission. it is also quite possible that the more difficult spread of sars-cov- in such climates may, in certain table knowns, uncertainties and unknowns about severe acute respiratory syndrome coronavirus (sars-cov- ), as of may origin of sars-cov- ► most probably from bats via intermediate animal hosts to index case. all subsequent cases resulted from human-to-human transmission. transmission ► mainly through respiratory droplets from infected persons ; by hands, after contamination at nose, mouth or eyes; also through air on exposure to sneezing or coughing from an infected person at close distance. ► through aerosols, while singing/talking loudly in congregations, groups, parties, karaoke, and so on, especially in poorly ventilated spaces. ► through fomites. ► possibly via faecal-oral route ; detection in sewage. [ ] [ ] [ ] ► related to peak in upper respiratory tract viral load prior to symptom onset in presymptomatic (paucisymptomatic) persons. ► transmission dynamics in asymptomatic persons not fully elucidated although viral shedding occurs. influence of climate and/or air pollution on transmission ► influence of climate on the capacity of the virus to survive outside human body (in air, in droplets, on surfaces, etc.) and to spread has been speculative. ► may spread more readily in milder/colder climate ; although variability of the reproductive number could not be explained by temperature or humidity. ► existing levels of air pollution may play a role; air pollutants, such as particulate matter, nitrogen dioxide and carbon monoxide, are likely a factor facilitating longevity of virus particles. ► elevated exposure to common particulate matter can alter host immunity to respiratory viral infections. immunity-protective antibodies ► igm and iga antibody response - days after onset of symptoms, does not depend on clinical severity, correlates with virus neutralisation; igg is observed ~ days after onset of symptoms, may or may not correspond to protective immunity. whether antibody response is long lasting has remained unclear. ► rechallenge in rhesus macaques showed immunity post primary infection. how protective immunity after first infection is against subsequent infection with an identical or mutated strain has been uncertain. ► incidental reports showed recovered persons positive by real-time pcr, later attributed to testing errors. seroprevalence to sars-cov- ► reported estimates for seroprevalence range between . % and . % ; differences in timing of the serosurvey, the use of assay kits with varying sensitivity/specificity, and different methods for detection may contribute to this large variation. ► seemingly high seroprevalence may be due to cross-reactive epitopes between sars-cov- and other hcovs. ► whether seroprevalence implies immune protection is unclear, yet, some countries have considered use of 'immunity passports'. ► for herd immunity to be effectively achieved, an estimated seroprevalence of % of the population will be required. other studies estimate between . % and % seroprevalence in different countries. communities, be compensated for by human factors such as higher population density, closer human contacts and lesser hygiene (as, for instance, exist in urban slums in mega cities in low income countries). how all this plays out in sub-saharan africa, in its slums and remote areas, is still largely unknown. with sars-cov- , transmission scenarios are mainly based on mathematical models despite their serious limitations (box ). as the virus continues to circulate, it will progressively be less of a 'new disease' during subsequent waves. the immunity caused by the first epidemic will influence how the virus spreads and causes disease. whether later waves will become progressively milder or worse, as observed in the - spanish influenza, is a matter of intense speculation. both views seem plausible and the two are not necessarily mutually exclusive. indeed, immunity should be defined on two levels: individual immunity and herd immunity. individual immunity will dictate how mild or severe the disease will be in subsequent infections. herd immunity could be defined in different communities/regions/ disease spectrum ► many different estimates: ► initially, it was estimated that among infected, % remained asymptomatic, %- % had mild/moderate disease, %- % had severe disease, and %- % became critically ill. - ► very variable estimates for remaining totally asymptomatic (estimated %- % [ ] [ ] [ ] [ ] ). ► what determines that an infection remains asymptomatic? ► quasi-absence of disease in children: why? case fatality rate (cfr) ► initial estimates cfr: %- %; comparisons: influenza . %; common cold: %; sars: %- %; mers: %. ► calculated infection fatality rates (cifr) and calculated cfr (ccfr) on the princess diamond were . % and . %, respectively (for all ages combined), and projected cifr and ccfr for china were between . %- . % and . %- . %, respectively. in gangelt, germany: ccfr of . %. ► cfr is influenced significantly by age; male sex; comorbidities; body mass index and/or fitness; and adequacy of supportive treatment, mainly oxygen therapy. if a vaccine is developed? ► what type of vaccine will it be (live/non-live, classic killed, dna, or recombinant)? ► will it need special manufacture and transport conditions (such as cold chain)? ► how robust will be vaccine-acquired immunity? after how many doses? ► how protective will it be against infection? ► for how long will vaccine-acquired immunity last? and hence: how often will the vaccine have to be administered? only once? or yearly? ► will there be any adverse effects? acquired immunity is not very strong; hence, what is the consequence regarding herd immunity? ► to achieve herd immunity, how efficient will the vaccine need to be? ► what proportion of the population (critical population) will need to be vaccinated? ► how long will it take to effectively vaccinate the critical population? ► will vaccination be acceptable in the population? or will vaccine hesitancy reduce uptake? what are the socioeconomic implications? ► which countries will get the vaccine first (implications for lics/lmics)? ► how expensive will the vaccine be? ► will vaccination be made mandatory, especially for international travel? the various degrees of societal disruption and the collateral effects on other essential health services (eg, reluctance to use health services for other health problems, because of 'corona fear'). our growing knowledge may enable us to progressively improve our response. learning from the variety of ways the covid- epidemic is unfolding across the globe provides important 'ecological evidence' and creates insights into its epidemiology and impacts. until now, the insights gained on covid- have been largely dominated by the covid- epidemics in the global north. more understanding of lived experiences of people in a variety of contexts, where the epidemic is spreading more slowly and with different impacts, is necessary to get a full global picture and allow learning from this variety. this is an important missing piece of the covid- puzzle. bmj global health and emerging voices for global health have launched a call (https:// blogs. bmj. com/ bmjgh/ / / / from-models-to-narratives-andback-a-call-for-on-the-ground-analyses-of-covid- spread-and-response-in-africa/) for such on-the-ground narratives and analyses of the spread of and response to covid- , local narratives and analyses that will hopefully help to further enrich our understanding of how and why the covid- pandemic continues to unfold in multiple local epidemics along diverse trajectories around the globe. table some critical unknowns in sars-cov- transmission which transmission patterns will occur and will human-to-human transmission continue permanently? ► seasonal transmission in temperate climate? ► continuous tides, with ups and downs? ► the experience from china and some other countries showed that 'local elimination' is possible but risk of reintroduction remains. ► increasingly unlikely that elimination everywhere is possible. this will strongly depend on: how strong will the acquired immunity after a first infection with sars-cov- be and how long will it last? ► evidence of acquired immunity against subsequent infections has been limited. ► measurable antibodies have been observed in most persons who have recovered from covid- , and research in animal models has suggested limited possibility of reinfection. ► it is still unclear as to how robust the immunity is and how long it will last. ► debate on use, practicality and ethics of 'immunity passports' for those recovered from covid- has been ongoing. how stable is the virus (mutation) and do the different clades seen worldwide have any effect on the transmission potential/severity of the disease? ► if the virus mutates quickly and different strains develop, then antibodydependent enhancement might be an important risk, as in dengue with its four different strains. if so, then in subsequent waves progressively more severe cases could occur. ► this has been reported for the spanish influenza, where the second and third waves were characterised by a more severe disease pattern. what is the role of children in transmission? ► children have quasi-universally presented less severe disease. however, their susceptibility to infection remains unclear, with large heterogeneity reported between studies. ► their role in transmission has remained unclear, but evidence points to a more modest role in transmission than adults. how significant are asymptomatic carriers in transmission? ► there have been several reports of asymptomatic transmission and estimates based on modelling. ► increasing consensus that asymptomatic carriers play an important role in transmission. box relationship between the dose of the initial infectious inoculum, transmission dynamics and severity of the covid- disease hypothesis: the dose of the virus in the initial inoculum may be a missing link between the variation observed in the transmission dynamics and the spectrum of the covid- disease. it is plausible that: ► viral dose in inoculum is related to severity of disease. ► severity of disease is related to viral shedding and transmission potential. this hypothesis plays out potentially at three levels: ► at individual level: a person infected with a small dose of viral inoculum will on average develop milder disease than a person infected with a high viral inoculum and vice versa. ► at cluster level: a person with asymptomatic infection or mild disease will on average spread lower doses of virus in droplets and aerosols and is less likely to transmit disease; when the person transmits, the newly infected person is more likely to have milder disease than if infected by a severely ill person, who spreads on an average higher doses of virus. this causes clusters and chains of milder cases or of more severe cases. ► at community level: in certain contexts, such as dense urban centres in moderate climates during the season when people live mostly indoors, the potential for intensive transmission and explosive outbreaks is high, especially during indoor superspreading events. in other contexts, such as in rural areas or in regions with hot and humid climate where people live mostly outdoors, intensive transmission and explosive outbreaks are less likely. outbreak of pneumonia of unknown etiology in wuhan, china: the mystery and the miracle new-type coronavirus causes pneumonia in wuhan: expert a novel coronavirus from patients with pneumonia in china coronaviridae study group of the international committee on taxonomy of viruses. the species severe acute respiratory syndrome-related coronavirus: classifying -ncov and 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isn't mutating quickly, suggesting a vaccine would offer lasting protection. the washington post genomic epidemiology of novel coronavirus implications of test characteristics and population seroprevalence on 'immune passport' strategies systematic review of covid- in children shows milder cases and a better prognosis than adults susceptibility to and transmission of covid- amongst children and adolescents compared with adults: a systematic review and meta-analysis presumed asymptomatic carrier transmission of covid- transmission of -ncov infection from an asymptomatic contact in germany acknowledgements we would like to thank johan leeuwenburg, piet kager, and luc bonneux for useful comments on a previous draft, the teams of the riposte corona, inrb, kinshasa and the belgian embassy in kinshasa for welcoming and hosting wvd during his unscheduled extended stay in kinshasa during the lockdown, march-june . we are thankful to mrs. ann byers for editing the manuscript at short notice. funding the authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.competing interests none declared. provenance and peer review not commissioned; externally peer reviewed. open access this is an open access article distributed in accordance with the creative commons attribution non commercial (cc by-nc . ) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. see: http:// creativecommons. org/ licenses/ by-nc/ . /. key: cord- - wam aa authors: bevova, m. r.; netesov, s. v.; aulchenko, yu. s. title: the new coronavirus covid- infection date: - - journal: mol doi: . /s sha: doc_id: cord_uid: wam aa in december , the first cases of pneumonia of unknown etiology were found in wuhan (china). later, the pneumonia was associated with a new coronavirus; in february , the world health organization (who) gave the name covid- to the new disease, while the international committee on taxonomy of viruses (ictv) gave the name sars-cov- to the virus causing it. by march , , when the virus had spread to countries, the number of diagnosed patients had reached thousand and the number of deaths was , the who declared the outbreak of the disease a pandemic. in this review, we summarize the relevant information about the origin and spread of sars-cov- , its epidemiology and diagnostics, and the clinical course and treatment of covid- . in december , cases of pneumonia of unknown etiology appeared in china in hubei province. almost all the first cases of the disease were found in individuals working in the market or visiting the seafood market in wuhan. in january , a new coronavirus was detected in patients with pneumonia [ ] . in february , the world health organization (who) gave the name covid- to the new disease, while the international committee on taxonomy of viruses (ictv) gave the name sars-cov- to the virus. by february , , the number of individuals who had been diagnosed with covid- in china exceeded thousand, while a few (less than , except for singapore and the cruise ship diamond princess) cases of the disease were observed in other countries [ ] . despite the quarantine measures that were taken, the disease spread rapidly. on , the who declared the outbreak of the disease to be a pandemic [ ] ; by this time, the virus had spread to countries, with the number of diagnosed patients having reached thousand and the number of deaths thousand [ ] . when this article was written (april , ), the pandemic spanned countries; in the world, there are more than million cases and more than thousand deaths from covid- [ ] . in many countries, the number of cases and deaths are growing exponentially. the current statistics is available on the who website (https://www.who.int/ emergencies/diseases/novel-coronavirus- /situation-reports/), on a russian site (https://www.coro-navirus-monitor.ru), and on a web aggregator supported by johns hopkins university, united states (https:// gisanddata.maps.arcgis.com/apps/opsdashboard/index. html#/bda fd b e ecf ). by mid-april, after china, the largest number of cases occurred in the united states, italy, spain, germany, france, and the united kingdom. while the epidemic in china had been brought under control by this time, with less than new patients per day being detected, the center of the pandemic had moved to the united states and europe, where tens of thousands of new cases were diagnosed in total every day. in the russian federation, there had been more than thousand cases and more than deaths as of april , [ ] . the reproduction number (the number of secondary cases of infection caused by one infected individual, r ) is estimated for covid- as . ( % confidence interval from . to . ) [ ] . for comparison, seasonal influenza usually has a reproduction number of about . [ ] . covid- is transmitted by airborne droplet, airborne dust, and contact ways. it has been demonstrated that infection can be transmitted, including from asymptomatic carriers and infected individuals, already in the incubation period of their disease or even within a few days after clinical recovery [ ] [ ] [ ] . outside the human organism, sars-cov- virus can maintain an ability to infect for up to days on surfaces made of plastic and stainless steel, up to h on cardboard, and up to h on copper surfaces [ ] . the virus genome was for the first time sequenced in china and uploaded to genbank on january , [ ] . the first ten sequenced genomes were identical by . %, which indicates a single initial source of the epidemic. the sequence of sars-cov- was % identical to those for the bat cov ratg virus, % identical to those for the javan pangolin pangolin-cov virus [ ] , % to those for the sars-cov virus, and % to those for the mers-cov virus. it is now believed that bats are a natural reservoir of the virus, but, apparently, there was an intermediate host, which is not currently identified; pangolins, cats, and dogs are under suspicion. phylogenetic analysis of the genomes of virus isolates as compared with genomic sequences of more than natural strains and constructed laboratory strains confirms that sars-cov- virus has a natural origin [ ] [ ] [ ] . sars-cov- virus belongs to the riboviria realm, nidovirales order, cornidovirineae suborder, coronaviridae family, orthocoronavirinae subfamily, betacoronavirus genus, sarbecovirus subgenus, sars-coronavirus species [ ] . sars-cov and mers-cov viruses causing severe acute respiratory syndrome (sars) and middle east respiratory syndrome (mers) belong to the same genus, subgenus, and species. coronaviruses have a single-stranded plus rna genome ranging in size from to kb [ , ] and are divided into four genera: α, β, γ, and δ [ ] . of them, αand β-coronaviruses are mainly pathogens of mammals, while γand δ-viruses infect mammals and birds. sars-cov- belongs to the groups of β-coronaviruses. sars-cov- virus is the seventh known coronavirus that can cause disease in human beings. of them, α-covs hcov- e, hcov-nl , β-covs hcov-hku , and hcov-oc viruses usually have a low pathogenicity and mainly cause mild or moderate respiratory disease similar to influenza, although sometimes can cause severe pneumonia. sars-cov- and mers-cov viruses also belong to the genus of β-coronaviruses. sars-cov- virus caused the outbreak of atypical pneumonia in - [ ] , while mers-cov virus caused the outbreak of middle east respiratory syndrome in and subsequent years [ ] . to penetrate into human cells, sars-cov- uses the same receptor as sars-cov- -namely, angiotensin-converting enzyme (ace ). the fusion of cell and virus membranes takes place with the involvement of cellular serine protease tmprss [ ] . in vitro, sars-cov- viral particles can penetrate into the same cell cultures as sars-cov- , for example, cultures of hek- t human cells, vero e and vero ccl green monkey cells, mdckii dog cells, human adenocarcinoma cells (a ), and liver cells (huh . ) [ ] . in studies of viral replication and cytotoxicity, a number of cell lines were inoculated with the virus with a high multiplicity and was studied h thereafter. no cytopathic effect was observed, except for in vero cells, in which virus titers reached > pfu h after infection. in contrast to this, huh . and hek- t cells demonstrated only a low level of replication, while a cells were not infected at all. upon observation, the plaques were more distinguishable and visible on vero e culture. two days after infection with a stronger dilution, veroe cells produced separately distinguishable plaques clearly visible when stained with neutral red. in contrast to this, less transparent plaques were obtained on vero ccl cells more distinguishable when stained with neutral red days after infection [ ] . for in vivo studies of sars-cov- , such animals as rhesus macaques and transgenic (humanized) hace laboratory mouse line were used. however, neither macaques nor mice develop a severe respiratory form of infection [ ] . it was demonstrated that sars-cov- can replicate in the upper respiratory tract of ferrets, minks and domestic cats, while cats can infect other cats. at the same time, dogs, pigs, chickens, and ducks are little susceptible to infection [ ] . according to the results of studies of chinese scientists, most patients ( %) were - years of age; %, less than years; %, - years; and %, over years [ , ] . the estimation of the case-fatality rate (portion of deaths divided by the total number of cases) for the disease varies from to % [ , ] depending on the sex and age composition of the population; strategies of testing, diagnostics, and treatment; bureaucratic peculiarities of healthcare in a particular country; and congestion of healthcare systems. on march , , the who estimated the mortality rate to be . % [ ] . however, the results of observations of the crew and passengers of the cruise ship diamond princess, on which out of patients died [ ] , lead to an estimation of the case-fatality rate of . % (a % confidence interval from . to . %). many studies have already demonstrated that the course of the disease and mortality are highly dependent on the patient's age and the presence of other diseases. in children, isolated cases of death have been registered. in the group up to years, the mortality is about . %; after years, the risk increases by three to four times with each additional decade, reaching approximately % in patients aged - years and - % after years [ ] [ ] [ ] . in addition to the elderly, individual with chronic diseases are in the high risk group. it has been demonstrated that arterial hypertension, heart diseases, diabe-tes, and obesity with a body mass index above worsen the prognosis [ , ] . at the same time, a severe course with a fatal outcome is also observed in individuals of middle age ( years or older) without concomitant diseases. it is likely that these individuals have unknown risk factors-for example, an unfavorable genotype. at present, there are insufficient data on the course of covid- in pregnant women and on the effect of the disease on fetal and newborn development. preliminary data from small samples have not shown the course of the disease to be more severe during pregnancy. the course of the disease was mild or moderate in most pregnant women [ ] and newborns [ ] [ ] [ ] [ ] . there are no data on the effect of covid- on fetal development in the first and second trimesters of pregnancy. the incubation period of covid- is from to days, with an average time of the onset of symptoms about days [ ] . cases of the disease with an incubation period of more than days have been described [ ] , but they are isolated and it is likely that they involved repeated and unrecorded contacts with virus carriers. the clinical picture of the disease varies from asymptomatic cases to severe cases requiring hospital and resuscitation treatment. the typical clinical symptoms of covid- include fever, dry cough, shortness of breath, myalgia, and fatigue. other symptoms include headache, confusion, sternal pain, and diarrhea [ ] . in more severe cases, bilateral pneumonia, acute respiratory distress syndrome (ards), multiple organ failure, and sepsis develop [ ] . according to severity, the forms of the disease are classified into mild, moderate, and extremely severe [ ] . most clinical cases ( %) of covid- are classified as mild and moderate. in % of patients, the disease is severe with the presence of shortness of breath, a respiratory rate of ≥ /min, blood oxygen saturation of ≤ %, and a presence of infiltrates in the lungs of > % for - h. about % of patients have the disease in an extremely severe form. the development of respiratory failure, septic shock, and failure of other organs are observed in them [ , ] . after discharge, some patients are still virus carriers, this being confirmed by positive results of laboratory tests. moreover, a relapse of the disease is observed in some patients [ ] . thus, at least in some patients, the immune response does not develop sufficiently to eliminate the virus. this may mean that vaccination can be inefficient for a certain group of individuals. on the basis of clinical symptoms, it is impossible to distinguish covid- from other respiratory infections-in particular, from a cold or other acute respiratory viral infection. the collection of epidemiological data (travel history, patient contacts, etc.) is a key factor in differential diagnostics. the final diagnosis is made according to the results of laboratory tests, such as polymerase chain reaction (pcr), serological tests, and instrumental diagnostics (computed tomography). the diagnostics is based on the amplification (reproduction) of specific viral genome regions by the reverse transcription pcr (rt-pcr) method [ , ] . a nasopharyngeal and/or oropharyngeal swab is the main biomaterial for this study. at present, pcr diagnostics is used for many infectious diseases. its advantages include the possibility of rapid development and production of the test as soon as the genomic sequence of the virus becomes known, as well as a very high sensitivity (up to just ten rna molecules in the sample) and specificity of tests. the testing of sars-cov- is performed on the n, s [ ] , orf ab, and e genes and their combinations. for example, the chinese center for disease control and prevention recommends the use of primers to the orf ab and n genes. the test is considered positive if both genome regions are determined [ ] . a number of russian manufacturers registered their test systems at the end of march and already established production. using serological tests, it is possible to detect the presence of specific antibodies to the virus or the presence of an antigen in an organism. at the same time, combined testing using igm and igg antibodies to the virus is most frequently used. testing for immunoglobulins m allows the fact of recent infection with a virus to be determined, while testing for immunoglobulins g detects either a late stage of infection or immune response after recovery. an antibody test is very useful in the assessment of the immune status of the population and can allow an individual exit from the quarantine, as well as is required to estimate the immune status after vaccination. the minimum testing time is min, while final sensitivity and specificity during testing have been found to be . and . %, respectively [ ] . an enzyme immunoassay test for a viral antigen, especially its express version, helps to identify a coronavirus etiology in the acute phase of infection. however, exact information about these tests or their sensitivity and specificity was unavailable at the time of writing this article. there are no data in the published literature yet concerning the possibility of differentiat- ing different human coronaviruses using serological tests. at present, tests based on the crispr method (for example, sherlock and detectr) are being developed. tests are based on the ability of the crispr system to recognize specific genome regions and cut them. the specific high sensitivity enzymatic reporter unlocking (sherlock) method is based on the use of cas for detecting viral rna at a concentration from to rna molecules per microliter. the results are visualized using an indicator test strip for h. the detectr method uses cas to detect cdna and is faster in execution (about min), but less sensitive, determining the presence of a viral genome in the sample with an initial concentration of - viral rna molecules per microliter. at the time of writing this article, both tests were undergoing clinical trials [ ] . quick tests based on both simple pcr and isothermal pcr (including cartridge, for a field use) have also been developed. however, their sensitivity may be lower than in standard pcr tests. the analysis time for these tests is about min, which is acceptable for testing passengers at airports. a computed tomography is also used for the diagnosis of pneumonia caused by covid- [ ] . bilateral infiltrates in the form of ground glass opacities or consolidation with the primary distribution in lower and middle zones of the lungs are detected with pneumonia caused by coronavirus [ ] . treatment at the moment, there is no specific antiviral therapy for the treatment of covid- . mild cases do not require special treatment. with the development of respiratory failure and pneumonia, the patient is hospitalized and a symptomatic therapy is provided. in severe cases, the treatment is aimed at maintaining the functions of vital organs. when attaching secondary bacterial infections, antibiotics can be prescribed [ ] . oxygen therapy is the main symptomatic treatment in severe cases. ards can develop against the background of a viral infection in severe patients. such patients are transferred to mechanical ventilation (on a mechanical ventilator), and extracorporeal membrane oxygenation is used in more severe cases. with the severe form of the disease, the median time from the first symptoms to the development of shortness of breath is days, to hospitalization days, and to the development of ards days [ ] . at present, a large number of clinical trials for a number of drugs are being carried out. testing drugs commonly used to treat other diseases is of special interest. these drugs were selected from among drugs with a potential antiviral activity or based on the hypotheses about the mechanism of virus action. in particular, the effect of such drugs as favipiravir (inhibitor of viral rna polymerases produced in japan), remdesivir (or gs- , nucleotide analogue, inhibitor of viral rna polymerase developed by gilead sciences co. (united states), but still at an earlier stage of clinical trials compared to other drugs) [ ] , combination of lopinavir and ritonavir (protease inhibitors used in the treatment of hepatitis c and hiv infection), and antimalarial drugs chloroquine and hydroxychloroquine (increase endosomal ph and violate terminal glycosylation of ace ) are being widely investigated. preliminary studies did not confirm the efficiency of treatment with lopinavir and ritonavir [ ] . the efficiency of remdesivir and chloroquine was proven in experiments in vitro [ ] . the efficiency of hydroxychloroquine was demonstrated in preliminary, yet very limited, clinical trials [ ] that are currently criticized for unreliability. it should be noted that hydroxychloroquine can have severe side effects and interact with other drugs. at present, the who has initiated a global clinical study of these drugs, named solidarity [ ] . scientists from different countries are engaged in the development of vaccines against the disease caused by sars-cov- . there are several approaches to the development of antiviral vaccines. in particular, vaccines based on attenuated or inactivated virus, viral vectors, recombinant mrna and dna, and recombinant proteins are undergoing preclinical trials [ ] . phase i clinical trials started on volunteers in united states for a vaccine based on recombinant mrna (modetna co.) and in china for a vaccine based on recombinant live adenovirus (fifth serotype) (can-sino biologics co.). in the event of success in the phase i trial, the phases ii and iii will be held in outbreaks in united states and china in summer. full cycles of testing for the efficiency and safety of vaccines will take at least a year. there are currently no answers to many questions about the covid- disease and the sars-cov- virus itself. there are no accurate estimations of the portion of virus-infected individuals who are asymptomatic carriers or carry the disease in a mild form without getting into the official statistics. if this portion is high and such individuals transmit the disease, then, on the one hand, it will be very difficult to stop infection by currently taking quarantine measures, which, in many countries, are based on isolation of symptomatic cases and their contacts. on the other hand, this means that the estimations of the number of patients requiring hospital treatment and mortality rate are overstated. according to one such estimate, the portion of asymptomatic carriers may be as high as % of the total number of infected individuals [ ] , and at least some asymptomatic infected individuals can infect other individuals [ ] . although the existing estimations of the mortality rate and the amount of patients requiring hospitalization and intensive therapy may be overstated, it is clear that the number of covid- patients who simultaneously need hospitalization and resuscitation measures is many times higher than the rates of habitual infections such as seasonal influenza. this is clear from the fact that the healthcare systems of the regions in hubei and northern italy, in which sars-cov- spread uncontrollably for some time, were close to collapse. the number of patients simultaneously requiring medical assistance is affected by the virulence and the rate of infection in the population. an exact estimation of epidemiological parameters of covid- is important for the development of mathematical models that are used by experts to predict the development of the situation. defining a set of quarantine measures is one of the main tasks solved by these methods. quarantine measures are aimed at suppressing or slowing down the spread of the virus, thus optimizing healthcare opportunities and minimizing the mortality and economic effect from the pandemic [ ] . in particular, the number of patients requiring hospitalization is an important target parameter. their number should not exceed the number of available hospital beds in the healthcare system. a reliable identification of the dynamics of the number of infected individuals is extremely important for making government decisions and for understanding how efficient the measures taken are. at present, the who is calling for as many tests for sars-cov- as possible to control the spread of the disease [ ] , since, apparently, it is impossible to cope with the pandemic without it. establishing the exact number of infected individuals is extremely difficult due to the difficulties of total and repeated screening of the population. the experience of the netherlands and denmark, where monitoring of the dynamics of the number of infected individuals is carried out by determining the content of viral rna in the sewer, is interesting [ ] . however, the efficiency and accuracy of this approach to fighting the epidemic is still unclear. there is also no clear answer to the question of how stable immunity to covid- is. news sites have disseminated information on several cases in which a patient repeatedly contracted covid- [ ] . it is unclear whether these are cases of reinfected individuals, a relapse of the disease, or a result of the first test result being a false positive. however, a recent study on rhesus monkeys showed that reinfection is unlikely [ ] (it should be noted that, by the moment of writing this review, this article had appeared in the form of a reprint and had not yet been reviewed). the issue of the seasonality of covid- remains unclear. there is an hypothesis that the reproductive number will decrease with the onset of summer in the northern hemisphere, which will lead to a slowing down of the spread of infection. there is also a hypothesis that, due to isolation of seriously ill patients, the most pathogenic variants of the virus will not be distributed and will be displaced by weakly pathogenic variants from asymptomatic carriers. the current virus will then become just another coronavirus causing ordinary acute respiratory viral infection. these hypotheses will be tested by nature and life itself in the next - months. it is interesting to note that, although children are infected with the virus, they get sick in a milder form as compared with adults [ ] ; there are currently no data on death of children under the age of years [ ] . it is hypothesized that children may have a fresher immune response to antigenically similar infection, as well as a different level of ace receptors on lung cells [ ] . experiments on model animals indeed demonstrated that specific number of ace receptors plays an important role in the prevention of the development of acute respiratory failure [ ] , while the level of ace decreases with age [ , ] . however, no changes in the activity of ace with age were observed in human beings in studies of ards [ ] . the use of recombinant ace was not efficient in the treatment of human ards [ ] . in the future, it will be important to study the association of the symptoms and severity of the disease with 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date: - - journal: semergen doi: . /j.semerg. . . sha: doc_id: cord_uid: almssg resumen a finales de diciembre del , se reportaron una serie de casos de neumonía atípica, en ese momento, de origen desconocido en wuhan, china. días más tarde se identificó al agente etiológico como un nuevo coronavirus. a este nuevo coronavirus, se le llamó sars-cov- y a la enfermedad que produce se le denominó covid- . el origen de este nuevo virus se presume zoonótico siendo los murciélagos su probable vector. debido al acelerado número de contagios y muertes que se produjeron primero en china y posteriormente alrededor del mundo, la infección de este virus pasó rápidamente de ser un brote aislado en una región china, a convertirse en una emergencia sanitaria de preocupación internacional y posteriormente, en una pandemia. el propósito de esta revisión es estudiar la información más relevante y actual del patógeno, así como la epidemiología, patología, características clínicas, transmisión, prevención y tratamiento de la enfermedad. abstract in late december , some cases of atypical pneumonia, at that time of unknown origin, were reported in wuhan, china. days later, the etiologic agent was identified as a new coronavirus. this new coronavirus was called sars-cov- and the disease it produces was named covid- . the origin of this new virus is presumed zoonotic, with bats being its probable vector. due to the rapid number of infections and deaths that occurred first in china and later around the world, the infection of this virus quickly went from being an isolated outbreak in a chinese region to becoming a health emergency of international concern and later, a pandemic. the purpose of this review is to study the most relevant and current information on the pathogen, as well as epidemiology, pathology, clinical features, transmission, prevention, and treatment of the disease. j o u r n a l p r e -p r o o f radiológicas incompatibles con las de una neumonía causada por las bacterias y virus más comunes - . el surgimiento de estos casos levantó sospechas, sobre todo posterior a que varios de los pacientes que presentaban este cuadro clínico, referían tener de antecedente trabajar como distribuidores o vendedores en el mercado de mariscos y vida animal silvestre de huanan. debido al surgimiento de este brote, la autoridad sanitaria en china alertó a la organización mundial de la salud (oms) el día de diciembre del , sobre la aparición de casos de neumonía atípica de origen desconocido con la sospecha de una posible zoonosis , . a pacientes originalmente identificados que padecían de esta neumonía, se les tomaron múltiples muestras del tracto respiratorio, sangre y heces. las cuales fueron analizadas a través de la reacción en cadena de la polimerasa en tiempo real (rt-pcr, del inglés "real time pcr") en la cual se identificó un nuevo coronavirus que fue aislado en el fluido resultante del lavado broncoalveolar, de las muestras del tracto respiratorio inferior de pacientes. en ese momento, a este nuevo coronavirus se le llamó -ncov (del inglés: -novel coronavirus) y fue identificado por las autoridades sanitarias chinas como el agente causal de estos casos de neumonía atípica , , . los coronavirus son un grupo amplio de virus envueltos de material genético tipo arn, los cuales deben su nombre a la apariencia de una corona, que es observada en su superficie a través de la microscopía electrónica , . existen diferentes tipos de coronavirus los cuales pueden llegar a causar múltiples afecciones respiratorias, gastrointestinales o incluso la muerte. entre los síntomas respiratorios, pueden causar desde un resfriado común hasta una neumonía, aunque en la mayoría de los casos, los síntomas suelen ser menores y mitigables con facilidad , . no obstante, a lo largo de la historia se han documentado cepas que pueden causar afecciones y enfermedades severas , . tal es el caso del sars-cov (del inglés: severe acute respiratory syndrome coronavirus) identificado por primera vez en las infecciones por el nuevo coronavirus comenzaron a tomar progresivamente protagonismo a nivel internacional cuando el día de enero del , la oms reportaba el primer caso de infección fuera de china, ocurrido en tailandia . a partir de este punto, y previniendo que el virus se propagara a escala internacional, la oms ofreció su asesoramiento y guía para el manejo de esta nueva infección . no obstante, y a pesar de estos esfuerzos durante el mes de enero, el número de infectados aumentó rápidamente y se reportaron las primeras muertes . hacia final de mes, el día de enero la oms declaró la enfermedad causada por el nuevo coronavirus como una emergencia de salud pública de preocupación internacional, ya que para aquel momento se habían reportado casos en todas las regiones de la oms en solo un mes , . a poco más de un mes del inicio del brote, la oms anunció que la enfermedad causada por el nuevo coronavirus aislado en wuhan, china sería llamada "covid- " que responde a la forma corta del nombre "coronavirus disease ". mientras que el agente causal fue denominado sars-cov- por el comité internacional de taxonomía de virus . a partir de este punto, la línea cronológica de eventos ,así como la de infectados, se tornó muy precipitada(figura. ). conforme el paso de los días, el sars-cov- se fue propagando en todas las regiones del mundo y progresivamente el número de infectados y muertos se aceleró bruscamente por los meses subsiguientes. hasta el punto de que la oms caracterizó esta enfermedad como pandemia el día de marzo los coronavirus son un grupo grande de virus los cuales están envueltos de arn en sentido positivo no segmentado, que pertenecen a la familia coronaviridae del orden de los nidovirales. a su vez, los coronavirus son clasificados en géneros: alfa, beta, gamma y delta , . de estos géneros, se sabe que el género alfa y beta infectan a los seres humanos ocasionando generalmente afecciones y síntomas tanto respiratorios como gastrointestinales, aunque raramente también pueden ocasionar alteraciones hepáticas y neurológicas , , , , . page of j o u r n a l p r e -p r o o f en cuanto a su morfología y estructura, son reportados por la literatura microbiológica como virus de forma aproximadamente esférica de una capacidad moderada al pleomorfismo. en cuanto sus dimensiones, se reporta que el diámetro de este tipo de virus varía de entre - nanómetros , . mediante el estudio de la superficie de estos virus a través de microscopía electrónica, se ha descubierto la existencia de estructuras sobre la superficie del virión, las cuales están dispuestas de manera de proyecciones largas, separadas las unas de las otras. estas estructuras están constituidas por complejos triméricos de la glicoproteína viral s (spike) , , . adicionalmente se han identificado sobre la superficie del virión, otro tipo de proyecciones las cuales, en contraste con las anteriores, son cortas y están formadas por complejos diméricos de las proteínas hemaglutina-esterasa (he). en lo referente a la envoltura viral, se sabe que está reforzada por la proteína más abundante de la superficie del virión, la cual es llamada glicoproteína de membrana (m), y que además se encuentra ensimismada en la membrana por dominios transmembranales - . además de los componentes ya mencionados de la estructura del virus, existe la proteína de envoltura (e), esta se encuentra en menor proporción que las demás, ya que es de menor tamaño y tiene como característica principal ser altamente hidrofóbica hasta este momento, se plantea que el origen de este coronavirus es debido a una zoonosis , , . es sabido que los coronavirus entre sus diferentes géneros están presentes y circulan entre un amplio espectro de seres vivos, entre ellos los mamíferos y consecuentemente los seres humanos. según se ha observado, la mayor variedad de coronavirus está presente en los murciélagos, por lo que se lo que ocasiona el comienzo de su patogenicidad , . el motivo por el que se piensa que la transmisión sintomática es la que mayor número de contagios ocasiona, es debido a que estudios han demostrado que durante los primeros días de la infección, esta se encuentra mayormente localizada en las vías respiratorias superiores (nariz y garganta), lo que genera que las gotitas de flügge, portadoras del virus, sean más fáciles de expeler . el periodo de incubación del sars-cov- es de días, pudiendo incluso llegar a extenderse hasta por días según se asevera en distintas fuentes , , . a este periodo de tiempo también se le conoce como periodo presintomático. la transmisión presintomática ocurre cuando un persona ya infectada, es capaz de contagiar a otras personas aun cuando esta no haya presentado hasta ese momento síntomas de la infección , - . en cuanto a la transmisión asintomática, se le refiere a la ocurrida cuando una persona sana es contagiada por alguien que analíticamente resulta positivo al virus pero que en ningún momento del curso de la infección manifiesta síntomas . hasta este momento, se cuenta con información muy limitada en cuanto a este tipo de transmisión. sin embargo, la literatura médica actual ha demostrado la contagiosidad de esta infección a partir de individuos asintomáticos y la proporción de enfermos que este tipo de transmisión aporta a la pandemia aún está sujeta a estudio - . cabe además destacar el tipo de transmisión intrahospitalaria que se ha reportado en todo el mundo. donde personal médico y personal asociado a la atención sanitaria, se ha contagiado por el estrecho e inevitable contacto con los pacientes infectados y su espacio vital, pese a las medidas de prevención y el uso de equipo sanitario desechable de protección individual a base de batas, guantes, mascarillas y gafas , - . ante una pandemia de las características de covid- , es importante conocer el índice de contagio, es decir, la capacidad de transmisión que tiene un patógeno. para tal efecto, se utiliza internacionalmente el número reproductor básico (r ) el cual es un parámetro teórico que proporciona información sobre la velocidad con la que una enfermedad infecciosa puede propagarse en una población determinada; y que además es utilizado para medir la dinámica promedio de casos secundarios que se producen a partir de un caso inicial , la propia tormenta de citocinas que genera el slc causa daño en el sistema microvascular lo cual activa el sistema de coagulación e inhibición de la fibrinólisis. esta alteración del sistema microvascular conduce a la aparición de la coagulación intravascular diseminada (cid) la cual es señalada como una de las principales causantes de falla orgánica en pacientes graves y que analíticamente es observada a través del aumento progresivo del dímero d y fibrinógeno . según los primeros informes epidemiológicos generados en china, la edad media de los pacientes que contrajeron la infección se ubicó entre los - años, con una ligera predominancia entre individuos del género masculino. casos en individuos menores a los años se observaron, pero estos fueron reportados como casos aislados. entre las comorbilidades o condiciones médicas coexistentes más prevalentes entre estos pacientes, se reportó: hipertensión, diabetes, enfermedades cardiovasculares, consumo de tabaco, enfisema pulmonar y obesidad , , . a partir de estas comorbilidades, se determinó que los pacientes de mayor riesgo para presentar un cuadro clínico severo, son aquellos que padezcan alguna de las condiciones médicas anteriores, así como adultos mayores de años, personas inmunocomprometidas, mujeres embarazadas y asmáticos , , , . en españa mediante la red nacional de vigilancia epidemiológica (rnve), se ha comprobado que los primeros informes sobre las características demográficas, clínicas y epidemiológicas, originados en los países asiáticos, no difieren mucho de lo que se ha observado en el país durante la pandemia, por lo que en muchos aspectos los datos son superponibles(tabla. a) . los síntomas producidos por covid- son inespecíficos. no obstante, el espectro clínico puede ir desde un cuadro clínico asintomático hasta una neumonía severa que produzca insuficiencia respiratoria a causa del síndrome de distrés respiratorio del adulto (sdra). la presencia del sdra, está asociado al slc y a la cid; mismos que han sido descritos por la literatura médica actual como las principales causas del daño multiorgánico que presentan estos pacientes y que consecuentemente originan la alta mortalidad de covid- en pacientes de alto riesgo , , , . la neumonía es la manifestación clínica más severa que comúnmente se ha presentado durante el transcurso de la enfermedad en pacientes graves. esta es caracterizada principalmente por presentar fiebre, tos, disnea e infiltrados en las imágenes de tórax. sin embargo, así como sucede con otras infecciones respiratorias virales, no existen síntomas que sean específicos para poder diferenciar una neumonía ocasionada por otros virus, a la ocasionada por sars-cov- , , , . entre los principales síntomas inespecíficos de covid- que han sido reportados en china, europa y en muchas otras partes del mundo son: fiebre, tos seca, astenia, mialgias, artralgias, escalofríos, cefalea, odinofagia y disnea (presente en casos graves). siendo menos frecuente la presentación de anosmia, ageusia, diarrea, vómitos, congestión nasal y hemoptisis , , , , , . en cuanto a la presentación de los síntomas de covid- en españa, los datos son nuevamente equiparables con los reportados en la literatura médica e informes de la oms. concretamente la rnve en su informe n° del día de mayo enumera los principales síntomas presentados por el conjunto de la población española, hasta la fecha y a base de una muestra de , casos, de la siguiente manera: entre estos hallazgos, es comúnmente observar la leucopenia y linfopenia, siendo esta última característica de covid- . ya que el slc propicia la detección de il- , hiperferritinemia y la depleción linfocitaria. se ha reportado elevación de la enzima lactato deshidrogenasa (ldh) y creatinquinasa (ck) en respuesta al estado de sepsis que desarrollan los casos severos de la enfermedad. la mitad de los pacientes llegan a padecer algún grado de función hepática anormal manifestada con la elevación de las enzimas aspartato aminotransferasa (ast) y alanina aminotransferasa (alt). puede coexistir además la elevación en suero de la proteína c reactiva, pero sin elevación de la procalcitonina. y hasta un tercio de los pacientes, sobre todo los que se encuentran en estado crítico, pueden presentar elevación del dímero d, en respuesta de la activación de la coagulación y sus mediadores procoagulantes, los cuales causan fenómenos trombóticos observados los hallazgos imagenológicos han demostrado una alta eficiencia cuando estos hallazgos son adecuadamente integrados con la clínica del paciente. no obstante, hay que tener en cuenta que las manifestaciones radiológicas son diversas y que estas progresan rápidamente , . entre los estudios de imagen que se han sido utilizados, destacan las radiografías de tórax (rx-tx), así como las tomografías computarizadas de tórax con ventana pulmón (tc-tx). como es sabido, las rx-tx tienen una sensibilidad menor a las tc-tx. sin embargo, las primeras logran ser útiles en los casos donde un tomógrafo no se encuentra disponible, como sucede en sistemas sanitarios en países menos desarrollados. en general, el hallazgo imagenológico principal tanto en las rx-tx y tc-tx es el de una neumonía atípica u organizada(figura. a). en las rx-tx se suelen observar opacidades asimétricas irregulares como en vidrio esmerilado, datos de consolidación, con distribuciones bilaterales, periféricas y de los campos pulmonares inferiores. la afección pulmonar tiende a progresar en el trascurso de la infección por lo que estos hallazgos pueden variar según el momento de evolución en el que el cuadro clínico se encuentre; aunque según la literatura médica, hasta un % de los casos no presentan ni presentaran estos hallazgos radiológicos en ningún momento de la enfermedad(figura. b) , . en cuanto a lo referente a las tc-tx, los hallazgos predominantes son las opacidades en vidrio esmerilado y las consolidaciones distribuidas irregularmente, como si fueran parches, principalmente en la zona medial y externa de los campos pulmonares. entre los hallazgos tomográficos menos comunes, se han reportado: derrame pleural, cavitaciones, adenopatías y neumotórax , , . según un estudio, las anormalidades tomográficas alcanzan su punto máximo en la mayoría de los pacientes hacia el día de la infección, cuando además de los hallazgos ya mencionados, se puede observar un patrón reticular con una importante distorsión anatómica y en fases tardías, bronquiectasias por tracción(figura. c) . como se menciona en los informes de la oms y la experiencia adquirida desde el inicio del brote hasta este momento, aproximadamente el % de los pacientes enfermos de covid- cursarán con un cuadro clínico medio a moderado sin neumonía o con una neumonía leve no complicable. mientras que aproximadamente el % restante cursará con un cuadro severo de la enfermedad y un . % del total de los enfermos morirá , , , . por esta situación, los pacientes pueden ser clasificados en grupos clínicos en función de la severidad de su estado(tabla. b). esta clasificación ayuda a establecer quiénes son los pacientes que mayor soporte médico requieren, y contribuye a que la atención médica sea priorizada a quienes más la necesiten sin que se saturen los servicios médicos existentes , . la sospecha de encontrarnos ante un caso de covid- debe ser primordialmente basada en la historia clínica del paciente y en la evolución de su cuadro clínico. un paciente que presente los síntomas asociados de covid- o que refiera datos de alguna enfermedad de vías respiratorias sin que se haya identificado una causa concreta, debe ser estudiado como caso sospechoso. más aún si al interrogatorio, el paciente refiere haber tenido contacto cercano con un caso confirmado o sospechoso de covid- en los últimos días o si manifiesta residir o haber viajado en los últimos días a cualquier lugar del mundo dónde se conozca que existe la transmisión comunitaria del virus . como se ha evidenciado en la literatura revisada, la tc-tx ha demostrado ser una herramienta muy útil de apoyo para establecer el diagnóstico. estudios han puesto a prueba la capacidad de utilizar la tc-tx a la par de la rt-pcr y se ha reportado que la tc-tx tiene una sensibilidad diagnóstica de %, con un valor predictivo positivo de % y negativo de %. en un estudio comparativo similar, con una muestra menor, se obtuvieron resultados parecidos donde la tc-tx tuvo una sensibilidad del % . para el diagnóstico definitivo de covid- , es indispensable la realización de una rt-pcr. este es el método diagnóstico que ha sido ampliamente utilizado j o u r n a l p r e -p r o o f en el caso de las pruebas rápidas por determinación de anticuerpos, estas surgen desde la idea de que el sistema inmunitario desarrolla inmunoglobulinas (ig) frente al virus, dependiendo de la fase de la infección en la que el individuo se encuentre. siendo la igm la inmunoglobulina de fase aguda, mientras que la igg es la de fase crónica, de memoria o de recuperación . aunque hasta la fecha no existe consenso entre la comunidad médica sobre el tiempo en el que los títulos de igm e igg aumentan para ser detectables, se ha postulado que la igm comienza a elevarse entre - días posterior al momento del contagio (siendo su pico detectable entre - días) mientras que la igg se vuelve detectable a partir del día al , . las pruebas rápidas adquieren su mayor utilidad cuando son empleadas para detectar oportunamente la infección por sars-cov- , sobre todo cuando la rt-pcr no se encuentra disponible o no se puede realizar de forma masiva. sin embargo, es imprescindible que estas sean valoradas junto con la situación epidemiológica y clínica del paciente (tabla. a). hasta este momento, no se dispone de un tratamiento específico contra el covid- , ni de una vacuna capaz de prevenir la infección por sars-cov- . motivo por el cual, las medidas masivas de salud pública, optadas por gran parte de la comunidad internacional, han sido y han demostrado ser las únicas formas efectivas para la contención de la propagación de la enfermedad y su mitigación. tales medidas masivas de salud pública se han basado principalmente en el distanciamiento social y la cuarentena . entre las recomendaciones generales de la oms para la prevención de la enfermedad(tabla. b), es importante hacer énfasis en de estas medidas; el lavado de manos y el uso de mascarilla. el lavado de manos se tiene que realizar bajo una técnica adecuada según la técnica de la oms, donde las manos se tienen que frotar durante - segundos y de - segundos si las manos se notan sucias. además, es importante que estas sean lavadas con agua y con jabón, o con una solución a base de alcohol %. ya que, se demostró que el sars-cov- puede estar presente en superficies inanimadas hasta por días, y que una solución de alcohol al - % disminuye su infectividad en las superficies después de su exposición de al menos minuto , . por lo que es importante también lavar las manos frecuentemente, sobre todo después de que estas hayan estado en contacto con alguna superficie. en el caso específico del personal de salud, el lavado de manos además se tiene que realizar después de estar en contacto con el paciente o con su medio, ya sea directa o indirectamente, así como después de realizar cualquier procedimiento médico . el uso de mascarillas por parte de la población general ha sido un tema ampliamente discutido como medida efectiva de prevención, ya que hasta la fecha no existe evidencia científica concluyente que demuestre que el uso de mascarillas en el ámbito comunitario reduzca el contagio de sars-cov- o alguna otra infección respiratoria aguda viral . ante esto, la oms ha recomendado el uso de mascarillas solo a la población infectada y no recomienda su uso generalizado. entre otras cosas, porque optar únicamente por esta medida no es suficiente para evitar el contagio. ya que esta medida por sí sola no confiere el adecuado nivel de protección. por lo tanto, otras medidas deberían también ser adoptadas . el uso de mascarillas quirúrgicas entre el personal sanitario que atiende pacientes con covid- , no es efectivo debido a que las partículas virales son capaces de penetrar a través del material del que están hechas. por lo que la oms recomienda el uso de respiradores de alta eficiencia, los cuales cuentan con un filtro de partículas de entre a micras de diámetro. entre los ejemplos más conocidos de respiradores de alta eficiencia a nivel mundial, se encuentran los ffp y ffp que poseen una eficiencia de % y . % respectivamente, los cuales están avalados por la unión europea y por tanto son los utilizados en los países europeos. en contra parte existen los respiradores n , n y n con una eficiencia de %, % y  otros agentes: interferón-α/β utilizados junto con otros de los fármacos anteriores.  otras terapias coadyuvantes: anticuerpos monoclonales contra citocinas proinflamatorias como il- (tocilizumab) y terapia de inmunoglobulinas con inmunoglobulinas extraídas del plasma de pacientes recuperados de la infección. tratamientos bajo investigación para su uso estándar en covid- : favipiravir: con experiencia clínica limitada en covid- . sin embargo, con resultados alentadores en otros coronavirus. remdesivir: utilizado por primera vez en la pandemia de ébola . medicamento que hasta la fecha tiene mayor expectativa de ser utilizado como de uso estándar. protocolos de ensayos aleatorizados, doble ciego controlado con placebo se han realizado sobre este medicamento y uno de ellos demostró un ligero acortamiento en el tiempo de estancia intrahospitalaria de los pacientes que fueron tratados oportunamente con este medicamento, aunque no se pudo asociar en este estudio ningún otro beneficio clínico . a raíz de una serie de ensayos aleatorizados realizados por la farmacéutica gilead y el national institute of allergy and infectious diseases (niaid), el día de mayo la fda (u.s. food and drug administration) emitió una autorización de uso urgente de este medicamento en presentaciones graves de la enfermedad. aunque se aclara que esta autorización es temporal y que el medicamento tendrá que transitar por el procedimiento normal para la aprobación de medicamentos de la fda . desde el comienzo del brote y su progresión pandémica, la expectativa mundial está concentrada en el desarrollo de una vacuna. sin embargo, el desarrollo de vacunas no es un proceso corto, ya que se tiene que contar con una base teórica fuerte, tecnología necesaria y su prueba en animales pequeños y en humanos; para lo cual se necesita contar con ciertas regulaciones actualmente el mundo se encuentra luchando arduamente en contra de la que quizás es la pandemia más severa a la que se haya enfrentado la humanidad. esta lucha se encuentra liderada por la oms en apoyo de los gobiernos del mundo y respaldada por miles de científicos y médicos quienes invaluablemente han ofrecido sus conocimientos y experiencia para el control de la pandemia y para evitar más muertes. las medidas de distanciamiento social y la cuarentena han sido claves para mitigar la pandemia debido a que hasta la fecha no se dispone de un tratamiento médico eficaz o de alguna vacuna. la contribución de la población aislándose, ha representado un importante sacrificio pero que conforme pasan las semanas, ha demostrado un impacto significativo en el desarrollo positivo de la pandemia. es importante que el médico de familia conozca las generalidades de la clinical features of patients infected with novel coronavirus in wuhan, china. the lancet brotes epidémicos: neumonía de causa desconocida -china. publicado: enero brotes epidémicos: actualización. nuevo coronavirus 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study. the lancet infectious diseases profiling early humoral response to diagnose novel coronavirus disease (covid- ) antibody responses to sars-cov- in patients of novel coronavirus disease quarantine alone or in combination with other public health measures to control covid- : a rapid review persistence of coronaviruses on inanimate surfaces and their inactivation with biocidal agents world health organization. technical documentation. water, sanitation, hygiene and waste management for covid- . publicado: marzo revisión rápida del uso de cubrebocas quirúrgicos en ámbito comunitario e infecciones respiratorias agudas advice on the use of masks in the context of covid- . publicado: abril world health organization. interim guidance. infection prevention and control during health care when novel coronavirus (ncov) infection is suspected. publicado: marzo world health organization. who guidelines. infection prevention and control of epidemic-and pandemic prone acute respiratory infections in health care pharmacologic treatments for coronavirus disease remdesivir in adults with severe covid- : a randomised, double-blind, placebo-controlled, multicentre trial. the lancet fda news release. coronavirus (covid- ) update: fda issues emergency use authorization for potential covid developing covid- vaccines at pandemic speed the covid- vaccine development landscape world health organization. draft landscape of covid- candidate vaccines. publicado: mayo key: cord- -w sk m authors: caduff, carlo title: what went wrong: corona and the world after the full stop date: - - journal: med anthropol q doi: . /maq. sha: doc_id: cord_uid: w sk m this article examines the global response to the covid‐ pandemic. it argues that we urgently need to look beyond the virus if we want to understand the real seriousness of what is happening today. how did we end up in a space of thinking, acting, and feeling that has normalized extremes and is based on the assumption that biological life is an absolute value separate from politics? the author suggests that today's fear is fueled by mathematical disease modeling, neoliberal health policies, nervous media reporting, and authoritarian longings. it is as though mankind had divided itself between those who believe in human omnipotence (who think that everything is possible if one knows how to organize masses for it) and those for whom powerlessness has become the major experience of their lives. ---hannah arendt the measures that governments across the world have taken to contain the spread of coronavirus disease are massive and unprecedented. as a result of these measures, life has come to an almost complete standstill, with many countries under lockdown. never in the history of humanity have such drastic interventions into the lives of populations occurred in the name of health on such a scale and in such a short period of time. as a result of the world's largest and perhaps most stringent lockdown, millions of daily wage laborers have lost their source of income in india. health care workers have been attacked and evicted from their homes because they are seen as potential spreaders of contagious disease (kalra and ghoshal ) . neighborhoods have been scared into panic when an ambulance appears on the street. due to the sudden ban on any form of transportation, migrant workers have been stranded between the cities where they used to work and the villages where their families are living (daniyal et al. ) . cancer patients have been unable to receive essential medical care because they cannot reach the hospital. it is the poor, the marginalized, and the vulnerable who are most affected by drastic measures, exacerbating already existing inequalities. in kenya, the police enforced a coronavirus curfew using teargas and excessive force against presumable violators of lockdown law (namwaya ) . in bangladesh, the government created a special unit to monitor social media and arrest people for spreading "misinformation" about the virus (hrw ). in hungary, parliament passed a law allowing prime minister orbán to limit freedom of speech, defer elections, and suspend rules and regulations by decree (gebrekidan ) . in india, state governments released companies from the purview of labor laws, including occupational health laws, to stimulate the economy (sharma ) . in lebanon, the currency collapsed, leaving % of the population in need of food aid (chulov ) . in the united states, over million people have filed for unemployment benefits (rushe and aratani ) . unfortunately, as of the writing of this article, many things remain completely unknown in this pandemic despite intensive investigation. for example, we don't know what helped contain the outbreak in china, and particularly whether government interventions reduced the spread of the virus or if the virus burned out there before moving on to other susceptible populations. the fact is: we simply don't know. nevertheless, many actors and institutions have proceeded as if they did know, imposing extreme measures that have affected billions of people and that have pushed societies to the edge of collapse by creating poverty, hunger, misery, debt, and unemployment. today, many wonder how we ended up where we are. how was it possible for a virus to trigger such a massive response that continues to threaten society and the economy, with so little discussion about the costs and consequences of extreme measures? why is there widespread agreement that aggressive interventions to "flatten the curve" were necessary and justified? it seems that this unprecedented public health experiment occurred without sufficient consideration of the social, political, and economic consequences. the failure to consider the impact of extreme measures that have become the norm in many places in the covid- pandemic has been stunning. the destruction of lives and livelihoods in the name of survival will haunt us for decades. the coronavirus disease outbreak seems to have started in the chinese city of wuhan in december . in january, the chinese government put wuhan and other major cities in the province under lockdown. a lockdown of million people "is unprecedented in public health history, so it is certainly not a recommendation the who has made," dr. gauden galea, the world health organization's (who) representative in beijing, emphasized at the time (reuters ). in other provinces, the chinese government implemented tailored measures, including factory shutdowns and school closures, but not a lockdown or restriction of movement to limit the spread of disease. major media outlets in the united states called china's locked-city strategy deployed in and around wuhan "harsh," "extreme," "severe," and "controversial," emphasizing that it offered "no guarantee of success" (qin et al. ) . a new york times article noted that "china is trying to halt a coronavirus outbreak using a tactic … with a long and complicated history fraught with social, political and ethical concerns" (levenson ) . experts quoted in the article called the lockdown of cities "an unbelievable undertaking" that would be "patently unconstitutional in the united states." "that type of thing," said james hodge, a professor of law, "is obviously an excessive response." another expert cited in the article, historian howard markel, pointed to the "darker side of quarantine-its use as a social tool rather than its scientific use as a medical tool." in the united kingdom, newspaper articles suggested that the chinese government would not be able to keep the city of wuhan "closed for business indefinitely" (graham-harrison ). in february, the virus continued to circulate and soon appeared in other countries. in march, the who declared the covid- outbreak a global pandemic. despite the criticism of china's approach, a crude and extreme version of lockdown became the international norm promoted by experts, officials, and the media across the world. concerns with the dark side of quarantine faded rapidly. a few countries like south korea veered from this norm and chose instead a classic infectious disease intervention: test-trace-isolate, with a highly centralized approach to public health intelligence gathering. emphasizing mass testing and meticulous contact tracing to interrupt the chain of transmission, south korean health officials closed schools and managed the crisis successfully without any lockdowns or roadblocks, and few restrictions of movement. significantly, south korea learned from earlier outbreaks of infectious disease (sars in particular), and imposed central control, used digital technologies, and enforced quarantines, and it witnessed one of the lowest covid- mortality rates. by the end of april , around , cases of infection had been detected there, but only people had died. germany developed its own testing protocol, which was published on january by the who (beaumont ) . when the first case was detected on january , germany launched mass testing, systematic contact tracing, and early hospitalization, keeping the mortality rate low and hospitals functional even when cases of infection increased (mohr and datan-grajewski ) . health officials relied on an extensive network of laboratories and were able to conduct over , sars-cov- (covid- ) tests per week (buck ) . along with south korea, germany put testing and contact tracing at the heart of the response. despite the who's emphasis on testing and south korea's and germany's early success in reducing the spread of the virus, most countries considered testing at scale as a low priority and relied on an extreme version of the chinese approach of lockdown. however, in china, the approach was tailored and regionalized; as a who report noted, "specific containment measures were adjusted to the provincial, county and even community context, the capacity of the setting and the nature of novel coronavirus transmission there" (who ). the lockdown focused on the major cities in the most affected province, constraining the life of million people in a country of . billion. in other words, it was a limited lockdown affecting % of china's total population. in contrast to the tailored and regionally differentiated intervention that sought to minimize the socio-economic impact of the response, many other governments across the world imposed nationwide lockdowns that went far beyond china's locked-city approach. in practice, these lockdowns amounted to curfews (often legalized after the fact by emergency laws). italy was the world's first country with a nationwide lockdown/curfew. many countries followed suit, partly motivated by shocking images of overwhelmed hospitals in italy's north and partly driven by a disease model report released in the united kingdom a few days after italy's surprising national lockdown announcement . this moment of shock and surprise triggered a chain reaction in the pandemic response. the horizon shifted, the inconceivable became possible, and life suddenly felt surreal. the u.k.'s disease model garnered a lot of attention, creating a sense of urgency that amplified the political pressure because the numbers were alarming . published by a group of experts without peer review on an institutional website, the report compared covid- with the great pandemic of , which killed over million people worldwide and suggested, without any evidence, that sars-cov- was "a virus with comparable lethality to h n influenza in ." most frightening in all this was not so much the lethality of the sars-cov- virus but the license to rush forward with predictions, abandon basic standards of science, and make dramatic claims to scare people. for covid- , the report predicted , deaths in the united kingdom and . million deaths in the united states. it presented possible strategies to reduce the impact of the pandemic, but the focus was exclusively on "non-pharmaceutical interventions." there was no discussion of testing and contact tracing. a proven public health strategy known to be effective was systematically sidelined in one of the most influential reports to emerge in the covid- pandemic. significantly, the report claimed to focus on "feasibility" of measures and promoted the idea that systematic suppression of transmission would work best-in other words, lockdowns. however, it excluded from any consideration the social, political, and economic implications of lockdowns, noting that "no public health intervention with such disruptive effects on society has been previously attempted for such a long duration of time." in addition to ignoring testing and contact tracing as a possible strategy, disregarding the social, political, and economic implications of lockdowns, and conceding that there is no "easy policy decision to be made," the authors of the report felt confident enough to claim that "suppression" was the "preferred policy option" and the "only viable strategy" that countries across the world needed to implement "imminently." the lockdowns that were required for suppression would need to be maintained "until a vaccine becomes available" (which they predicted to be "potentially months or more"). a crude, extreme, and ultimately unsustainable version of the chinese approach became the international norm. shutting down society and the economy until a preventive medical treatment becomes available was advanced as an appropriate response and the only possible way of dealing with the crisis, despite the costs and consequences. italy figured as an important but fundamentally ambivalent model, shifting the locked-city into a locked-country approach. the italian scenario was sobering and frightening but also inspiring and motivating. to avoid italy's disaster, governments appropriated the italian approach of mass confinement and rigid restriction of movement as a one-size-fits-all intervention. in many places throughout the world, including italy and france, the locked-country approach took a militarized form with massive deployment of the police to enforce lockdown restrictions. the locked-country approach seemed to obviate the necessity of justifying a differentiated strategy that might have looked unequal and unfair and that might have intensified social and political conflicts along multiple internal fractures and fault lines. to avoid the political fallout of a differentiated strategy, which would have required systematic testing, government officials in europe and elsewhere invoked the politically expedient image of a total threat and suggested that "we are all in the same boat" and that "we are all in this together." the idea that regional lockdowns would not be possible and that it was best to treat the virus as a global threat that would uniformly impact all people involved conjuring an image of a united nation confronting a total threat that required everyone's sacrifice. this image relied on a false assumption of equality. solidarity came to mean not mutual support in a situation of uneven risk, but rather generalization of a sense of danger across a national population perceived as a homogeneous body under attack. the ideology of national pandemic solidarity-putting everybody under confinement and treating everyone the same-obscured the reality that lockdowns mean different things to different people, and that not everyone is equally exposed or equally vulnerable. both the virus and the lockdown disproportionately affected those who were already vulnerable along lines of age, class, and race. dramatic references to the magnitude of the threat served as justification for nationwide lockdown policies. this extreme and unprecedented blanket approach systematically imposed on entire populations was driven by a number of factors that variously prevailed in different countries across the world: a growing sense of panic, constant media sensationalism, deep authoritarian longings, increasing political pressure to contain the spread of the virus, disturbing accounts of overwhelmed hospitals unable to cope with the surge of patients, misleading mortality calculations, and, most importantly, a trust in the power of mathematical disease modeling. throughout the covid- pandemic, there has been an abiding assumption among observers and the public that it is clear what is happening; that everyone knows what is going on because everyone can see it on television. however, what an endless stream of media reports from around the world have continued to obscure is the fact that it is impossible to know what is happening in a population when there is no systematic testing. the lack of testing created a void that was filled by the flexible evidence of disease modeling. in the absence of robust data, disease modeling emerged as the presumably best and only available science to inform policy. media hyperbole focused on absolute numbers independent of context and made covid- deaths politically visible. flexible disease modeling (often based on data derived from viruses such as influenza) took the place of accurate epidemiological surveillance. scientific papers published online without peer review made scary projections and painted a grim picture. widely reported simulation models created shock effects that shaped government policies. a narrow focus on numbers played an important role in understandings of the magnitude of the threat, fueling fear and panic in the absence of actual evidence. a distinct imaginary took hold, "the imaginary of an unprecedented event," which seemed to require an unprecedented response (kelly ). there was a widespread sense, among experts and the media, that the sars-cov- virus was much more lethal than influenza. that this pandemic was different from influenza and thus necessitated a different approach was typically claimed on the basis of the case-fatality rate, the number of deaths as a subset of those infected with sars-cov- . the casefatality rate played a crucial role in the justification of the public health experiment now unfolding before our eyes. estimates of the case-fatality rate initially varied hugely from . % to %. in an article published in the lancet, scientists claimed the case-fatality rate could even be as high as % (baud et al. ). in early march , the who directorgeneral stated that the case-fatality rate for sars-cov- was . %. he added: "by comparison, seasonal flu generally kills far fewer than % among those infected." whatever the estimates, the fact remains that it is impossible to calculate the case-fatality rate in the absence of systematic testing. given the lack of evidence, the only scientifically valid statement at the time would have been to say that we simply don't know how lethal the virus is. early on in this pandemic, it became clear that over % of infected people were experiencing no symptoms at all at the time of testing (gudbjartsson et al. ) . this means that a surveillance regime where only people with symptoms were tested will automatically exclude a large number of infections. additionally, patients with symptoms are much more likely to die than asymptomatic people. the result is an exaggerated case-fatality rate. testing strategies differed across countries and changed within countries over time. for example, on february , , the italian ministry of health published a revised policy for testing, prioritizing patients with severe clinical symptoms (and thus higher chances of dying). this change in policy resulted in an apparent increase in the case-fatality rate of . % on february to . % on march (onder et al. ) . suddenly, the virus seemed to have become much more deadly. however, this increase was a numerical illusion-a statistical artifact. there was no change in the lethality of the virus. changes in testing policy occurred in many countries and even across regions where different tactics for counting deaths were used. in china, test-positive asymptomatic patients were excluded from being counted as cases of infection (wu et al. ) . in belgium, deaths were counted independent of any testing (schultz ) . of % of all deaths, only . % turned out to be confirmed by laboratory test as covid- positive. almost half of all victims were merely suspected to be linked with the virus but had never actually been tested. there was and remains no agreement among experts and officials on what counts as a death caused by the virus. in italy, covid- -related deaths were defined as those occurring in test-positive patients, "independently from preexisting diseases that may have caused death" (onder et al. ) . this is particularly concerning in terms of data quality because the vast majority of deaths occur in patients who are older than with one or more comorbidity. test-positive patients who die because of heart disease or terminal cancer are not necessarily dying because of sars-cov- infection. yet they appear in the statistics of some countries. this confusion between patients who die with the virus and those who die from it has had an impact on the data and their quality, making comparisons between countries impossible. further, almost all tests that are done use rna tests, which can detect an infection only as long as the virus is present in the body. these tests, however, cannot tell whether a person had the virus in the past. only serological tests for antibodies against the virus can provide an accurate picture of how many people have been infected in a given population. and yet, such systematic serological studies were and are missing. given the lack of testing and taking into account the role of selection bias, the large number of asymptomatic cases, the confusions in case definitions, the changes in testing policies, and the difficulty of knowing who is dying with versus dying from the disease, the denominator for calculating actual death rates cannot be reliably determined. without a denominator, it is mathematically impossible to calculate the case-fatality rate. nevertheless, despite the lack of data, experts, officials, and the media have remained transfixed by the assumption of clarity and reliability of numbers, and they continued to circulate wild estimates, unleashing a pandemic of scary charts with exponential curves. over the last weeks of march, more and more testing was done globally, and more testing continues as of the time of this publication. not surprisingly, estimates of the case-fatality rate have come down significantly, because the denominator has gone up due to the increase of testing. in iceland, % of the population has been tested using rt-pcr-based tests independent of symptoms, suggesting a case-fatality rate of . %. this figure is six times lower than who's official estimate for covid- . the center for evidence-based medicine at the university of oxford noted that if one assumes that % of iceland's population is infected, then the corresponding infection-fatality rate would be . %. a study using both rt-pcr-based and serological tests conducted in one of germany's most affected regions indicated a case-fatality rate of . % and an infection-fatality rate of . % (streeck et al. ) . we know from epidemics and pandemics of the past that the case-fatality rate is often massively overestimated at the beginning of an outbreak because case detection is limited, largely based on hospital patients and typically biased toward the severest cases of disease. when the h n swine flu pandemic occurred in , the estimated case-fatality rate varied between . % to . % in the first weeks of the outbreak. in , a decade after the pandemic, the who reported that the swine flu pandemic turned out to have a case-fatality rate of . %. this means that the actual casefatality rate was five times lower than the lowest estimate. social science scholarship has shown how numbers can deceive. numbers have the ability to reveal as well as conceal. therein lies their magic. they appear as seemingly neutral bearers of truth. they offer a sense of mathematical precision, making things seem more certain than they actually are and displacing attention away from the conditions under which they were produced. abstracting from limitations on the conditions of their production and treating numbers as absolute is dangerous because it makes things comparable that are not comparable, because it suggests scientific knowledge where there is lack of evidence, and because it creates the sense of a major threat obscuring the differential nature of risk. what using numbers this way fails to account for is the fact that not everyone is at risk in the same way. among the more interesting figures of the sars-cov- pandemic is the number of deaths per million inhabitants per country. this number is probably more reliable than the case-fatality rate because deaths are less likely to be missed (ignoring for now the case of belgium and the difficulty of defining deaths caused by sars-cov- ) and because the denominator, a country's population, is known. here are the current numbers of deaths per million inhabitants for five countries as of may , : spain: italy: france: germany: south korea: the staggering differences between countries cannot solely be explained by demography or rates of infection (some countries seem to have more infected people per million inhabitants than others and so might be overwhelmed, though this is also a question of time-how many cases per week per region). what the differences might reveal (and it is important to note that they may well change) is that some health care systems are able to deal with the crisis in a better way than others. the structural fragilities of an underfunded, understaffed, overstretched, and increasingly privatized and fractured health care system contribute to higher mortality rates (adams ) . in a sense, each society has the mortality it deserves (canguilhem : ) . where medical care is easily accessible, with sufficient and well-trained staff, and with capacity flexibility, patients are more likely to receive better care and survive. in this sense, it matters that spain turns out to have beds per , inhabitants, italy . , france , germany , and south korea . . although beds per inhabitants is a crude indicator, it is noteworthy that germany can rely on over , staffed intensive care beds, out of which only , were occupied in early april (see mohr and datan-grajewski ) . this at a time when there were more cases in germany than in france and the united kingdom and slightly less than in spain and italy. germany's was clearly not a health care system overwhelmed by a sudden surge of patients. ironically, organizations such as the oecd frequently scolded germany's health care system in the past for "oversupply" of hospital beds and its "inability" to "rationalize hospital capacity" (kumar and schoenstein ) . this means that the case-fatality rate is not just dependent on the biological nature of the virus and the age and health profile of the population (people most at risk of death are older than with one or more comorbidity). the case-fatality rate also depends on systematic testing, meticulous contact tracing, well-trained health care workers, nursing homes with adequate resources, and the ability of the health care system to cope with the crisis (excess as well as surge capacity) and provide high-quality medical care, particularly keeping medical workers safe and healthy. in this sense, the pandemic has and will continue to brutally expose policy failures and structural health care system deficits. the situation in many hospitals in italy, spain, and france is troubling, especially in densely populated areas. but it is important to understand why some of these highly visible institutions of care were overwhelmed. lombardy, italy's most affected region, has long been an experimental site for health care privatization: community-centered care "has been all but wiped out" (bagnato ) . the lack of general practitioners and the defunding and low emphasis on community care have increased the pressure on hospitals in urban centers. these hospitals have neither excess nor surge capacity to cope with a sudden rise in demand. over the past five years, hospitals across europe held numerous strike actions "with doctors and health workers complaining of funding cuts, a government reduction in the number of beds and a serious lack of medical staff leading to dire working conditions for emergency room staff" (chrisafis ). hospital systems in italy, spain, and france were on the brink of collapse even before the virus arrived. the most telling demonstration of the structural contradictions of pandemic preparedness under neoliberalism occurred, not surprisingly, in the united states. as american newspaper articles reported, hospitals across the country deferred regular medical services to free up space, equipment, and staff for the pandemic response. when patients started to avoid hospitals due to fear of infection, a main source of income was drastically cut off, "causing huge losses that have forced some hospitals to let go of health care workers as they struggle to treat infected patients" (harris and schneider ). facing a "financial nightmare," hospitals filled their intensive care units with patients who did not really need intensive care so that they could charge more and make up for the financial loss. additionally, administrators cut salaries, laid off hundreds of staff, and sent others on unpaid leave, weakening the health care system further in the midst of the pandemic response. when a new virus appears, things start to fall apart. once everyone gets scared, extreme measures are implemented, in a more or less improvised manner, and trillions of dollars, euros, and pounds are pumped into the economy to make up for the loss. once the worst is over, however, the normal crisis continues, and the structural fragilities remain (caduff ) . this pandemic will haunt us all for decades in ways that we can barely imagine at this point. the nature and sheer scale of the interventions that we have witnessed are staggering, and the consequences-social, political, and economic-remain unforeseeable. there are no systematic accounts of the implications and repercussions seen so far, nor do we have any idea about the number of indirect deaths due to the lockdowns/curfews, the social distancing and the self-isolation. we have yet to see a realistic plan that would outline how we might learn to live with a virus that is unlikely to disappear any time soon (sullivan and chalkidou ) . in the meantime, i suggest that we reframe the corona conversation to cut through the confusion and dimness that is pervading this pandemic in the following ways: the emergence of new viruses in human populations is normal. it has happened before; it will happen again. coronaviruses are common and circulate widely in humans. they have infected people and killed thousands year after year, especially in winter. worldwide, between , to , people die from influenza viruses every year. the sars-cov- virus has killed , people so far. there is no doubt, sars-cov- is causing a serious infectious disease, but so far it is still in the range of what we observe in terms of mortality during a severe influenza season. the main difference is the speed of infection, the clinical picture of the disease, and the impact on demographically older populations causing massive compression of morbidity and mortality that is overwhelming weak health care systems with no excess and little surge capacity. the influenza pandemic killed between and million people worldwide, and the influenza pandemic killed between and million people. as of the writing of this article, covid- has killed , people, according to the official numbers. clearly, the world has witnessed worse pandemics, including . million deaths due to tb each year, , deaths due to hiv infections each year, and , deaths due to malaria, all preventable and treatable conditions. this observation does not mean that influenza and covid- are clinically similar or that nothing should be done to contain the spread of sars-cov- and mitigate the consequences. however, it raises the question of why fear and panic are spreading like wildfire, provoking such extreme measures, and why experts and government officials are willing to mount an unprecedented effort for sars-cov- but have never considered similar interventions for the , - , people who die every year due to influenza. influenza is a relatively well-known virus. to say that sars-cov- is an unknown virus doesn't automatically justify the most extreme measures that the world has ever seen. what makes this pandemic unprecedented is not the virus but the response to it. extreme measures to contain the spread of the virus have resulted in extreme fallouts. it is difficult to overestimate what we are witnessing today. the pandemic response has pushed the world into a space of fragility and uncertainty. there hovers a "perhaps" over everything now (caduff ) . blinded by the urgency of the immediate moment, the response has created an opening for actors and institutions to push agendas and reorder the world. we will grapple for years to come with the changes that are happening today. the response to the disease is driven by a fantasy of control that overestimates and overreacts. this fantasy has caused and is causing enormous harm. it is unrealistic, misleading, and bound to fail. a pandemic like this cannot be controlled; it can only be managed. if we keep using words such as control, we are only setting ourselves up for disappointment. this pandemic is far from having found a language that is adequate to the problems it is posing. we urgently need new concepts but seem to have little imagination. the urgency of the crisis has displaced reliance on basic standards for quality and control of quality of scientific research. papers are published without peer review. claims are made without evidence. perhaps not surprisingly, given the fragile health care infrastructures in some countries, speed appears to be more important than quality, rigor, and integrity. underscrutinized science, lack of data, speculative evidence, strong opinions, deliberate misinformation, exaggerated mortality rates, the / news media attention, and the rapid spread of dramatic stories on social media have led to poor political choices and major public anxiety. we are afraid of covid- . we are not afraid of influenza. we see one thing as a public health emergency and another as a fact of life. today, we are learning an old insight the hard way: not every life and not every death are equal. some deaths are more important than others, drawing more attention, triggering a bigger response and mobilizing more resources. in the covid- pandemic, the belief seems to have taken root that health is an absolute value and that every life needs to be saved by all means. meanwhile, millions of people are dying of influenza, tb, hiv, malaria, and diarrhea, not to mention chronic diseases and accidents. there seems to be less political urgency for these preventable deaths. some health care systems were overwhelmed in this pandemic. others were not. for decades, governments have underfunded, understaffed, and privatized health care systems across the world, and these trends have exacerbated the impact of the pandemic. the response to sars-cov- took a particular shape, converging in extreme measures that have become the norm in many countries. questions that remain include: was it the only possible way of managing the crisis? why has a crude version of china's approach become the dominant model? at the heart of this pandemic was and is the widespread assumption that there were and are no alternatives to extreme measures implemented on entire populations with little consideration of cost and consequences. this is not true. as some countries have shown, adequate testing and less drastic policies of social distancing work well to manage the pandemic. it seems that some officials saw covid- as a disease that could be contained. as the who director-general suggested in early march , "we don't even talk about containment for seasonal flu-it's just not possible. but it is possible for covid- ." this perception may have contributed to the radically different approach seen across many countries. the idea of "flattening the curve" is often seen as the optimal solution, but there is no guarantee that the effort to do this will actually impact the total number of deaths over the long run of the disease's presence in any community. it may ultimately simply spread the same number of deaths over a longer period of time and thus perhaps reduce the pressure on hospitals but not overall mortality. nationwide lockdowns are not a solution. they prevent infection as long as they are in place, but they also keep people susceptible. this is particularly concerning in a pandemic where the virus has become endemic. once lockdowns are lifted, the number of infected people may well rise again later. this is why it has been so hard for countries who adopted this strategy to return to normal life-the strategy is not sustainable over the long run. as andrea bagnato noted about the stay-at-home strategy: "it is not in the harshness of its lockdown, but in the effectivity of separating the infected from the non-infected, that china's response has excelled: a centralized system of dedicated structures (called fangcang) was built in no time, where all patients and their contacts were treated and divided in four groups according to severity. instead, lombardy simply closed everything down. and it becomes clearer by the day that the main landscapes of infection were not public spaces, but hospitals, retirement homes, workplaces, and indeed private homes" (bagnato ). in germany, % of the people who died due to covid- are years or older (mohr and datan-grajewski ) . a majority of the patients who died have one or more underlying health condition such as hypertension, diabetes, cardiovascular disease, chronic respiratory disease, or cancer. this means that the pandemic is killing predominantly people with an already reduced life expectancy. the key question then becomes excess deaths-the difference between the statistically expected number of deaths and actually occurring deaths over a period of time. there is no doubt that there will be excess deaths due to covid- , but it is unclear how large that number will be. the pandemic response has produced a substantial rise in the number of people who now live with untreated illness. prohibition of public transport has made it difficult for patients and staff to reach hospitals. patients with conditions other than covid- avoid doctors because they are afraid of getting infected. emergency room attendance dropped substantively the world over. cancer referrals decreased and cancer screening services stopped entirely. rural health services in countries such as india crashed. essential public health programs have been paused; many resources have been reallocated. this means that patients are neglected, receiving no or less medical care, leading to untreated illness and a rise in mortality. a virus causes disease, not hunger. it is not the pandemic, but the response to it that threatens the livelihood of millions of people. in many countries, both rich and poor, the trends are shocking. in india, children die of starvation. farmers commit suicide because they are unable to harvest crops. stranded daily wage laborers drop dead after walking hundreds of miles. the poor, marginalized, and vulnerable bear the brunt of the pandemic response. the lockdown is a political mechanism not simply for the prevention but for the redistribution of negative effects. lockdowns shift negative effects away from hotspots of public attention to places where they are less visible and presumably less serious. in this way, they are part and parcel of a politics of inequality. this pandemic is not just about health, it is about fear, and the objects that are singled out and then made the ground and motivation of systematic thought and action. to be afraid has become an obligation, a responsibility, a duty. people are afraid not just because of what they experience but because they are told to be afraid and encouraged to inhabit the world with fear of "foreign bodies" and "invisible enemies." public discourse is highly moralized. looking for someone to blame, individuals are exposed as "super-spreaders" responsible for the rising number of cases. on social media, "lockdown warriors" accuse citizens of lack of patriotism and failure to "do their duty" in the face of danger. in this highly moralized public discourse, life is considered an absolute value that can justify almost every form of disciplinary intervention in the name of health. public health needs to be front and center in any infectious disease intervention. investing in strong public health infrastructures should happen even when there is no pandemic. mathematical disease modeling cannot replace systematic epidemiological surveillance on the ground. the most effective way to manage an infectious disease outbreak is to test, trace, and isolate. interventions need to be phased over time; they need to be dynamic, regionally targeted and risk based. all interventions must take into account the social, political, and economic impact, as well as the indirect impact on other health conditions. interventions that do this will create management strategies that work to minimize collateral damage. absolute numbers cannot be used for policy, they only fuel fear and panic. national lockdowns are not a solution. they protect people temporarily, but they also leave them susceptible. once restrictions are lifted, cases of infection are likely to increase again. there is no exit from the pandemic; there is only an exit from the response to it. we are still at an early stage of understanding how best to clinically manage covid- both as a disease and as a risk factor to potentially vulnerable populations. it is vital to find better ways of sharing quality data and effective practice to ensure health systems learn and adapt quickly. what this pandemic shows is a lack of preparedness. this will come as a surprise, given the billions of dollars, euros, and pounds that were spent over the last years on pandemic preparedness, including experience with past epidemics and pandemics such as ebola and swine flu. how can it be that hospitals ran out of n masks in week one? where did all the billions spent on preparedness go? outsourced production capacity and insufficient stockpiles of personal protective equipment put nursing home residents, community health care workers, and hospital staff at risk, weakening health care systems further. key preparedness concepts need to be at the heart of the response. fifteen years of pandemic preparedness seem to have evaporated into thin air in this pandemic. instead of activating existing plans and drawing on concepts such as the pandemic severity assessment framework, countries imposed a massive, untested, and unproven generic lockdown with unforeseeable social, political, and economic repercussions. sars-cov- is less lethal than every single scenario exercise that has been conducted for preparedness planning by governments and non-governmental organizations in europe and america. it will be important to understand why key preparedness concepts were sidelined in this pandemic, despite the attention that preparedness received and the substantial resources it consumed for over a decade. the fear of death is powerful in societies eager to repress the inescapable reality of death. in such a context, it is important to flatten the curve of extreme speaking, feeling, and acting. what was and will always be urgently needed is moderation and perspective. to continue to engage in today's competition for ever more extreme predictions is dangerous. it will only support those who ignored the virus initially and who are more than willing to blame it now for the mess. equally dangerous is a public health populism of clapping hands that leaves out any consideration of the social, political, and economic costs and consequences of sweeping interventions. attempts to obscure political failures are growing rapidly. those who contribute to extreme predictions and apocalyptic readings of the current situation are only contributing to the obfuscation of the policy failures and underlying structural issues that are responsible for many of today's problems. there are already attempts in countries such as the united kingdom and the united states to rewrite failure as success. not surprisingly, governments are calling on citizens to participate in public performances, demonstrate national unity in the face of danger, and celebrate collective strength and resolve. fighter jets soaring through the sky and helicopters showering rose petals on "frontline warriors" are militarized state spectacles. but health care workers deserve more than patriotic feelings and symbolic gestures; they deserve better health care policies. to challenge and critique now is essential. the story of how the chinese approach became a model for generic lockdowns in the global north and then exported to countries in the global south is important to note, particularly considering the dramatic consequences for millions of people struggling to survive without any source of income. ironically, these extremely restrictive lockdowns were sometimes demanded by people eager to criticize the authoritarianism of the chinese state. across the world, the pandemic unleashed authoritarian longings in democratic societies, allowing governments to seize the opportunity, create states of exception and push political agendas. commentators have presented the pandemic as a chance for the west to learn authoritarianism from the east. this pandemic risks teaching people to love power and call for its meticulous application. pandemic time is an auspicious time for all kinds of political projects. as a result of the unforeseeable social, political, and economic consequences of today's sweeping measures, governments across the world have launched record stimulus bills costing trillions of dollars, pounds, pesos, rand, and rupees. earmarked predominantly for individuals and businesses, these historic emergency relief bills are pumping staggering amounts of money into the economy, but, ironically, they are not intended to strengthen the public health infrastructure or improve medical care. the trillions that governments are spending now as stimulus packages surpass even those of the financial crisis and will need to be paid for somehow. today, there is a massive global recession in the making. if austerity policies of the past are at the root of the current crisis with overwhelmed health care systems in some countries, the rapidly rising public debt is creating the perfect conditions for more austerity in the future. the pandemic response will have major implications for the public funding of education, welfare, social security, environment, and health in the future. if you think something good will come out of this crisis, you should think again. today we are just driving faster and with a much bigger car, but it is the same road with the same destination. wolf bukowski notes that the political discussion in italy is now dominated by an "uncritical 'responsibility'" that cannot find a place outside the imperative to contain the virus. "the right intuition that 'we should not question the reality of the epidemic' shifts all too easily into 'we should not question the government's response to the epidemic'" (bukowski ). in such a context, any control intervention imposed by the state is perceived as lawful, and no democratic discussion and debate appears necessary ("let the experts speak!"). in other places, critique has become difficult for other reasons. the tragedy of today's political moment in the united states, the united kingdom, and brazil is that right-wing politicians pushed many into embracing measures that one thought were only possible in authoritarian regimes. here, an engagement in critical analysis has become almost impossible because it is seen as playing into the hands of trump, johnson, and bolsonaro, political figures who seem unconcerned with public health and the staggering inequalities that afflict our world and whose public statements have reached an unmatched level of ignorance and incompetence. however, it is important to understand that the strategic combination of confusion, contradiction, and the play of extreme opposites is foundational for authoritarian rule. everything that instills a sense of disorder and that intensifies the crisis magnifies the desire for decisive action. in this article, i have tried to carve a path through the morass of fear, panic, and desire for control to see how one can sustain a critical analysis of the pandemic response. as scholars and citizens, we have the obligation to think beyond the crisis, create openings in the world, and consider, critically and democratically, how we want to govern ourselves. as veena das underscores, it is important that we do not let our "love for the subtle and nuanced understanding of issues disappear on the grounds of needs for the rough and the ready in an emergency" (das ) . the pandemic and the response to it will require us to reimagine lives, rebuild conditions of existence, and find better ways of doing science and politics. like every engagement in a serious pedagogical project, it will entail a reconsideration of the objects we desire. today's fear is fueled by four main forces: mathematical disease modeling-a flexible and highly adaptable tool for prediction, mixing calculations with speculations, often based on codes that are kept secret and assumptions that are difficult to scrutinize from the outside. neoliberal policies-systematic disinvestments in public health and medical care that have created fragile systems unable to cope with the crisis. nervous media reporting-an endless stream of information, obsessed with absolute numbers, exploiting the lack of trust in the health care infrastructure and magnifying the fear of collapsing systems. authoritarian longings-a deep desire for sovereign rule, which derives pleasure from destruction and tries to push the world to the edge of collapse so that it can be rebuilt from scratch. this set of forces inspires thought, action, and passion in powerful ways. energized by the thrilling experience of witnessing "history in the making," actors and institutions have seized the opportunity to reorder the world, push political agendas in the name of survival, and shape life for years to come. the pandemic has become an auspicious moment to change the rules of engagement and expand the scope of scientific, medical, and political authority over bodies and populations. it is an occasion to publish papers and make dramatic statements, to feel relevant and important to the world, and enjoy the moment in the limelight. in the midst of death and destruction, the pandemic creates opportunities for innovation, domination, and profit-making. this unexpected opening connects elites in science, politics, and the media, releasing shocks of information, instruction, and command that are pushing hard against our confined, anxious, restless bodies. mathematical disease modeling, neoliberal policies, nervous media, and authoritarian longings fuel a fatal spiral centered around the fear of collapse. this fear is now literally in the air; it moves in and out of us with every breath; it operates as animating medium of our intense isolation and immobility. pandemic fear is unnerving and mentally exhausting. yet for those who embrace the feeling, it has the power of sustaining a state of excitement-excitement derived from the secret pleasure of spoiling a precious thing, wasting enormous resources, and engaging in an all-consuming project with total dedication. what we might call the provocation of the crisis-its intensification, expansion, and totalization beyond any notion of utility-seems so excessive and extreme that it borders on sheer madness. what could be more dangerous, more daring, more exciting than a walk on the wild side, an excursion to the other side of reason? melodramatic phrases such as "beating the virus," "winning the war," and "defeating the darkness" are rhetorically powerful and contagious. equally popular notions like "corona heroes" and "lockdown warriors" are symptoms of overidentification in a hegemonic discourse of power. all these terms reveal how this pandemic is "fabulously textual, through and through," and, at the same time, is lacking a source of symbolization strong, creative, and disturbing enough to move our engagement with the world beyond the most conventional of tropes (derrida ) . the language that we are asked to adopt today, in the midst of this outbreak, is contaminated with words that are stiff, stale, and corrupt like putrid air. given that so much of today's response is based on and driven by mathematical disease modeling and that millions of lives and livelihoods are being destroyed before our eyes, it is not an option anymore to exclude the "externalities" of a pandemic response that lacks imagination and that has resorted to the crudest interventions of all: the full stop. for those with permanent jobs, a comfortable couch, and no daycare duties, this unforeseen interruption may feel like a gift, a welcome relief from the non-stop world of global capitalism. but for millions of people living in less privileged parts of the planet, the pause button spells unemployment and hunger, not breaktime and downtime. without income, food, and access to basic health care, people are not making the most of the confinement outside in the garden; they are desperate and dying. we urgently need to look beyond the virus if we want to understand the real seriousness of what is happening today. how did we end up in this strange space of thinking, acting, and feeling that has normalized extremes and that is based on the assumption that biological life is an absolute value separate from politics? never has it been more important to insist that another politics of life is possible. the latest imperial college disease model report summarizes the staggering blindness that has prevailed in this pandemic: "we do not consider the wider social and economic costs of suppression, which will be high" (walker et al. ) . the time to suppress the costs of suppression and cast the consequences of interventions as an externality to model-based policy is over. these claims are utterly misleading, ignoring the influenza pandemics of and , including the hiv/aids pandemic, ebola, and many other infectious disease outbreaks that have killed millions of people worldwide with no vaccine available. last but not least, the toll of covid- is not even close to the toll of the influenza pandemic. . the report distinguishes between two strategies these days i sometimes catch myself wishing to get the virus-in this way, at least the debilitating uncertainty would be over… a clear sign of how my anxiety is growing is how i relate to sleep. till around a week ago i was eagerly awaiting the evening: finally, i can escape into sleep and forget about the fears of my daily life… now it's almost the opposite: i am afraid to fall asleep since nightmares haunt me in my dreams and awaken me in panic-nightmares about the reality that awaits me disasters and capitalism … and covid- . somatosphere website staying at home. e-flux real estimates of mortality following covid- infection. the lancet coronavirus testing: how some countries got ahead of the rest. the guardian website germany's coronavirus anomaly controllo e autocontrollo sociale ai tempi del covid- the pandemic perhaps: dramatic events in a public culture of danger the normal and the pathological french medics warn health service is on the brink of collapse. the guardian website anger and poverty grip lebanese city. the guardian as covid- pandemic hits india's daily-wage earners hard, some leave city for their home towns. scroll.in website facing covid- : my land of neither hope nor despair no apocalypse, not now impact of non-pharmaceutical interventions (npis) to reduce covid- mortality and health care demand. imperial college website for autocrats and others corona virus is a chance to grab even more power. the new york times website wartime conditions" as global coronavirus deaths reach . the guardian website spread of sars-cov- in the icelandic population cash-starved hospitals and doctor groups cut staff amid pandemic. the washington post bangladesh: end wave of covid- "rumor" arrests. human rights watch website indian doctors evicted over coronavirus transmission fears, says medical body. the wire website, march ebola vaccines, evidentiary charisma and the rise of global health emergency research managing hospital volumes germany and experiences from oecd countries scale of china's wuhan shutdown is believed to be without precedent. the new york times so stark ist die krankenhaus-auslastung mit corona-patienten. mdr website kenya police abuses could undermine coronavirus fight. human rights watch website . case-fatality rate and characteristics of patients dying in relation to covid- in italy china tightens wuhan lockdown in "wartime" battle with coronavirus. the new york times website shows commitment to contain virus: who representation in china. reuters website us unemployment rises another m, bringing total to m since pandemic began. the guardian website india moves big labour law changes to limit coronavirus impact others make these changes. financial express website why belgium's death rate is so high: it counts lots of suspected covid- cases. npr website vorläufiges ergebnis und schlussfolgerungen der covid- case-cluster-study urgent call for an exit plan: the economic and social consequences of response to covid- pandemic. centre for global development website the global impact of covid- and strategies for mitigation and suppression who. . report of the who-china joint mission on coronavirus disease (covid- estimating clinical severity of covid- from the transmission dynamics in wuhan, china is barbarism with a human face our fate? critical inquiry blog stavrianakis, nancy tamini, and laurence tessier. i am particularly grateful for conversations with richard sullivan. maria josé de abreu insisted i start writing and put thoughts on paper. for suggestions, i would like to thank the editor of medical anthropology quarterly, vincanne adams, and the two anonymous reviewers. none of these colleagues and friends are responsible for the arguments in this article. key: cord- -kwu otpi authors: judson, gregory l.; kelemen, benjamin w.; njoroge, joyce n.; mahadevan, vaikom s. title: cardiovascular implications and therapeutic considerations in covid- infection date: - - journal: cardiol ther doi: . /s - - - sha: doc_id: cord_uid: kwu otpi the ongoing severe acute respiratory syndrome coronavirus (sars-cov- ) pandemic has profoundly impacted all fields of medicine. infection with sars-cov- and the resulting coronavirus of (covid- ) syndrome has multiorgan effects. the pandemic has united researchers from bench to bedside in attempts to understand the pathophysiology of the disease and define optimal treatment strategies. cardiovascular disease is highly prevalent and a leading cause of death across gender, race, and ethnic groups. as the pandemic spreads, there is increasing concern about the cardiovascular effects of the viral infection and the interaction of infection with existing cardiovascular disease. additionally, there are concerns about the cardiac effects of the numerous treatment agents under study. it will be essential for cardiologists to understand the interplay between underlying cardiac comorbidities, acute cardiovascular effects of covid- disease, and adverse effects of new treatments. here we describe emerging evidence of the epidemiology of sars-cov- infection and underlying cardiovascular disease, the evidence for direct myocardial injury in sars-cov- infection, the specific presentations of cardiovascular involvement by sars-cov- , and the cardiac effects of emerging treatments. coronavirus disease of is caused by the severe acute respiratory syndrome coronavirus (sars-cov ) and was first reported in wuhan, china, in december of [ ] . initial presentations from wuhan were consistent with viral pneumonia and subsequent deep sequencing confirmed a novel rna-based virus of the coronaviridae family. as of june , , there are . million confirmed worldwide cases of covid- with over , deaths [ ] . covid- has become a worldwide pandemic and has mobilized healthcare workers in all disciplines. since the initial presentation of covid- , much has been learned about the pathophysiology and specific cardiovascular manifestations of the disease. early in the pandemic, there was evidence that those with preexisting cardiovascular conditions were over-represented in cases of severe infection [ ] . since that time, it has become clear that certain racial and ethnic groups are disproportionately affected by covid- [ ] . additionally, covid- appears to have several unique cardiovascular manifestations that cardiologists must understand, including worsening of heart failure, myocarditis, a proclivity for thrombosis, and arrythmia. finally, the speed at which clinical trials for covid- are being conducted, using both repurposed and new therapies, means that cardiologists must be aware of potential cardiovascular side effects for agents that are not commonly used in cardiovascular practice. this article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors. pathophysiology sars-cov- is a novel rna coronavirus that has emerged as the causative infection responsible for the current covid- pandemic. other viruses from the coronavirus family include the mers-cov virus, responsible for the middle east respiratory syndrome (mers) outbreak, and the sars-cov virus, responsible for the severe acute respiratory syndrome (sars) outbreak [ ] [ ] [ ] [ ] . initial infection with sars-cov- is a process that is still being understood but is known to involve viral s proteins and host angiotensin-converting enzyme (ace ) receptor and the transmembrane protease, serine (tmprss). sars-cov- expresses numerous spike (s) proteins on the surface of the viral envelope, which facilitates viral entry into the host cell. tmprss, a serine protease expressed on the host cell, primes the viral s proteins to enable interaction with the host ace receptor [ ] . the primed s protein then binds the s subunit of the host ace receptor allowing for viral entry into the cell [ ] . the role of the ace receptor in human physiology remains under investigation but it is believed to provide counter regulation to the renin-angiotensin system [ , ] . the ace receptor is commonly found in the lungs in type alveolar cells but is also expressed in vascular endothelium, gut epithelium, and in the proximal tubule in the kidneys [ ] [ ] [ ] . the location of the ace receptor is implicated in a multitude of disease presentations associated with sars-cov- infection. after binding the ace receptor, the virus is internalized, and the viral rna is released. immediately, the rna-dependent rna polymerase is translated, which allows for viral replication and spread of the infection. the role of the ace receptor expression and blockade within both sars-cov- infection and disease severity remains controversial, with both protective and deleterious effects hypothesized. the united states has surpassed other countries worldwide in case numbers with over . million cases as of june , [ ] . the epicenter has spread from china to many european countries and now the usa, with significant clusters around the country. the number of covid- -related deaths worldwide has now climbed past , . due to the heterogeneity of testing strategies and case ascertainment, mortality rates remain controversial, with estimates ranging from . to . %. covid- has a broad spectrum of severity and phenotypic presentation. the most typical presentation involves consequences of direct respiratory infection ranging from cough and dyspnea to hypoxia to acute respiratory distress syndrome (ards). the initial cohort study of covid- patients included data from hospitals in china with patients with covid- disease [ ] . the study reported that the most common symptoms at presentation were cough ( . %), fatigue ( . %), and temperature c . °c ( . %). in the largest published cases series of sequential covid- cases from the united states in new york city, of the patients admitted to different hospitals, % of patients presented with an initial fever and % presented with hypoxia [ ] . tachypnea was present in . % and tachycardia in . %. mechanical ventilation was required in . % of patients and early mortality was seen in . %, with . % of patients surviving to discharge and . % remaining in the hospital. thus, sars-cov- infection most commonly causes respiratory illness with a wide range of severity and outcomes that is relatively consistent in presentation (cough, dyspnea, fever, and hypoxia) across the globe. the preexisting burden of comorbid chronic disease is well recognized to contribute to the severity of sars-cov- infection and there are concerns that underlying comorbid illnesses play a role in the diverse spectrum of phenotypic presentation. the initial study of patients in wuhan, china, demonstrated a predominance of male patients ( %) with pre-existing comorbidities including diabetes ( %), hypertension ( %), and cardiovascular disease ( %) [ ] . the median age of patients in this group was years old. only % of these initial patients had a history of tobacco use. however, since these initial studies, a number of prospective and retrospective studies out of china have demonstrated higher rates of underlying comorbid conditions. common underlying comorbidities include hypertension ( - %), diabetes ( - %), and cardiovascular and coronary artery diseases ( - %) [ ] [ ] [ ] . smoking history or obstructive lung disease diagnoses were low, when documented ( - %). in these studies, these comorbidities were associated with worse severity of illness and mortality. a review of , confirmed covid- cases from wuhan, china, demonstrated increased mortality in patients with cardiovascular disease ( . %), diabetes ( . %), and hypertension ( %), which was significantly higher than the overall case-fatality rate of . % [ ] . in the united states, there are similarities and notable differences from the european and chinese experience. among patients admitted with covid- , . % were men and . % were over the age of years, with the majority ( . %) being over years old [ ] . comorbidities included hypertension ( . %), obesity ( . %), diabetes mellitus ( . %), chronic lung disease ( . %), cardiovascular disease; including coronary disease and heart failure ( . %), and, less frequently, renal disease ( . %) and immunocompromised conditions ( . %). these initial cases series have shown a similar relationship between underlying cardiac comorbidities with a higher prevalence of hypertension, diabetes, coronary artery disease, and obesity in patients requiring mechanical ventilation [ ] . a concerning trend is the alarming rate at which black and hispanic/latino americans are being infected and dying from covid- [ ] . there were early data from cities and states across the country indicating higher mortality from covid in black and hispanic/latino populations. these included milwaukee, wi, experiencing a % mortality rate in black patients who make up % of the population; chicago, il ( % of the mortality with % of the population); and the states of louisiana ( % of the mortality with % of the population) and michigan ( % of the mortality with % of the population). in the covid-net catchment population of the usa, a higher percentage of black patients were infected ( %) compared to the percentage of overall population being black ( %) [ ] . this trend has been repeated across the country and has brought into stark reality the devastating impact covid- has had on communities of color [ ] . while it is well known that black and hispanic/latino patients have a higher incidence of diabetes and hypertension, this alone does not explain the increased infected and mortality rates. studies during prior epidemics have continued to demonstrate similar healthcare disparities on smaller scales likely related to multiple factors including access to care, racial and ethnical stigmas among medical professionals, crowded living conditions, income instability, and continued rates of exposure and protection [ ] [ ] [ ] [ ] . it is crucial to acknowledge the institutionalized barriers to health as a first step to incite change and narrow the outcome gap and improve healthcare for marginalized individuals. de novo cardiac injury has also been described in patients presenting with covid- disease. initial studies provide insight into the prevalence and incidence of acute cardiac injury patients presenting with covid- . early studies reported a prevalence of acute cardiac injury of % in the entire cohort as defined by either high sensitivity troponin (hs tn) or the mb fraction of creatinine kinase (ck-mb) [ th percentile or new echocardiographic or electrocardiographic abnormalities with greater elevations in cardiac biomarkers among patients requiring icu care [ , ] . a metaanalysis further clarified the prevalence of acute cardiac injury among chinese patients presenting with covid- disease reporting a similar prevalence of acute cardiac injury defined as ck-mb or hs tn exceeding the th percentile [ ] . case cohort studies included data in patients for whom the outcome and illness course helped further elucidate the role of cardiac injury in covid- disease. zhou et al. showed that the initial hs tn was not dramatically elevated at illness onset, but that in non-survivors there was a rapid rise starting after day that was not seen in survivors [ ] . ruan et al. reported the cause of death in the non-survivors with the majority ( %) due to respiratory failure but a clinically significant number related to combined respiratory/cardiac failure ( %) and cardiac failure ( %) [ ] . based on these studies, the authors hypothesize that myocardial injury occurs frequently in patients with severe covid disease and that myocardial dysfunction is involved in the pathophysiology of severe disease. as the pandemic progressed and patient outcomes were defined, investigators sought to evaluate the association of myocardial injury with mortality. in a multivariable cox regression, acute cardiac injury at any point during hospital stay was associated with an increased risk of mortality (hr . , % confidence interval . - . ). guo et al. examined the association of cardiac comorbidities and acute cardiac injury as defined by hs tn above the th percentile with mortality in a retrospective cohort of patients [ ] . in this cohort, % of patients had acute cardiac injury. the proportion of non-survivors was increased in the groups with underlying cardiac comorbidities (hypertension, coronary artery disease, and cardiomyopathy) or myocardial injury and highest in groups with both. the authors did not assess measures of association beyond descriptive statistics. thus, myocardial injury occurs not infrequently with covid- disease and that the presence of myocardial injury portends both more severe disease and higher mortality. the mechanism of this acute cardiac injury remains elusive. data from zhou et al. and guo et al. have shown that the rise in troponin typically occurs late in the disease process, typically occurring - days after the onset of symptoms and coincides with progressive respiratory decline and multiorgan failure [ , ] . this would suggest that myocardial injury may be a marker for more severe infection and not causally associated. however, there are few reports of systematic cardiac testing of patients with covid- disease, and cardiac injury limited our ability to understand causal associations. a number of mechanisms have been proposed including direct myocardial injury and myocarditis, systemic hyperinflammatory response leading to cytokine storm and myocardial injury, microvascular thromboses, acute plaque rupture physiology, stress cardiomyopathy, and extreme oxygen supply-demand mismatch due to critical illness [ , ] . the relative mystery surrounding the pathophysiology of acute cardiac injury has resulted in conflicting recommendations regarding the use of troponin to screen and evaluate cardiac dysfunction in patients with covid- disease. a communication by the american college of cardiology (acc) recommended against routine cardiac biomarker testing in patients presenting with covid- disease [ ] . subsequent review papers have advocated for systematic use of high-sensitivity troponin as a biomarker of severe illness with proven prognostic value in covid- disease [ , ] . however, this risk prediction strategy has not yet been evaluated prospectively. sars-cov has been implicated in cases of myocarditis and acute decompensated heart failure. initial reports of myocarditis from china described cases of cardiogenic shock and reduced left ventricular ejection fraction among covid- patients [ , ] . these patients had extremely elevated levels of cardiac biomarkers (namely troponin, ck-mb, and bnp) and required inotropy or extracorporeal membrane oxygenation (ecmo) to maintain adequate cardiac output. based on the clinical presentation and on these elevations in biomarkers, these cases were deemed ''fulminant myocarditis'' and were treated with a combination of steroids, ivig, antivirals, antibiotics, anti-inflammatory agents, renal replacement, and mechanical ventilation. during other outbreaks of similar coronaviruses in the last years, namely sars-cov and mers, there was evidence to support direct myocardial involvement. among patients who died from sars-cov in toronto, canada, viral rna was detected in % of samples and the presence of viral rna was associated with increased levels of interstitial fibrosis and macrophage activity within the myocardium, thus potentially leading to a more rapid clinical course compared to patients without viral rna in the myocardium [ ] . however, hemodynamically significant myocarditis appears to have been a relatively rare complication of sars, with one case series noting only one instance of potential myocarditis requiring inotropy among cases [ ] . myocarditis also appears to have been a potential complication during the mers outbreak, with mri findings consistent with myocarditis reported [ ] . there is now additional evidence that sars-cov has a similar effect on the myocardium as sars-cov and mers. myocardial involvement has been confirmed in sars-cov- -positive patients via mri and endomyocardial biopsy [ ] [ ] [ ] . cardiac biopsy findings in covid- patients have shown inflammatory infiltration of the myocardium with t-lymphocyte and macrophages, interstitial edema, and in some cases, evidence of cytoplasmic vacuoles indicating direct viral involvement of myocardial cells [ , ] . in a post-mortem case series of patients from china, % of covid- patients died of circulatory failure with some degree of myocardial involvement, as marked by elevations in troponin [ ] . however, it is unclear if these cases can truly be classified as myocarditis given the lack of ejection fraction assessment via tte, mri, or biopsy. from a different case series in seattle, wa, troponin elevation was seen in % of patients, but none of the patients who underwent tte had evidence of a reduced ejection fraction [ ] . there is currently no standardized approach to treatment of covid- cardiomyopathy. in cases of more severe ''fulminant'' myocarditis resulting in cardiogenic shock, treatments with immunomodulating drugs, namely steroids and ivig, but also more specific agents like tocilizumab to inhibit il- , are being used. clinical trial data is as of yet lacking on the efficacy of such therapies in covid- -related myocarditis and are being extrapolated from other causes of fulminant myocarditis, namely giant cell subtype. decompensation of pre-existing heart failure appears to be a more common cardiovascular manifestation of sars-cov- infection than clinically significant myocarditis. prior to the covid- pandemic, influenza-like respiratory infections significantly increased the risk of hospitalization for decompensated heart failure, and in high influenza activity months, may contribute to % of heart failure hospitalizations across the united states [ ] . the relationship between respiratory infection and decompensated heart failure appears to also be true for covid- -like seasonal influenza. in two retrospective case series from china of and patients, heart failure was observed in % and % of deaths, respectively [ , ] . there appears to be a broad spectrum of disease severity, ranging from stable to fulminant heart failure requiring inotropes, and potentially mechanical circulatory support for refractory shock and or hypoxia. the use of ecmo in covid- cases is being studied in a prospective manner as part of the extracorporeal life support organization (elso) registry. as of june , , ecmo has been used in covid- -confirmed cases worldwide, with % discharged alive, and the vast majority of patients receiving veno-venous ecmo for respiratory support [ ] . there is interest in the role of acei/arb in both the overall risk of covid- and the severity of lung disease with studies suggesting both the possibility of deleterious and beneficial effects [ , ] . major guideline committees have continued to advocate for the use of ace/ arb medications in hemodynamically stable heart failure patients, hypertension, and those with ischemic heart disease [ , ] . covid- has been hypothesized to increase the risk of acute coronary syndromes (acs) and systemic thrombosis. this premise is based on prior experience with viral infections such as influenza, which predisposes patients to developing acs, and may increase the risk of myocardial infarction (mi) by at least sixfold in the week following infection [ ] . this increase in mi incidence is also seen following infection with other respiratory infections such as respiratory syncytial virus, and for non-viral respiratory illnesses such as bacterial pneumonia. many mis due to covid- disease are likely related to supply-demand mismatch from hypoxia resulting in myocardial injury and troponin release. however, mi from acute atherothrombotic events were first reported in wuhan, china, soon after the onset of the pandemic. as such, chinese hospitals soon developed treatment algorithms aimed at providing urgent reperfusion to covid- -suspected patients while maintaining the safety of catheterization lab staff. in the setting of st-elevation mi (stemi) and suspected sars-cov- infection, thrombolytics were often the first choice for acute reperfusion therapy in china [ ] . following this early experience in china, acc/scai released a joint recommendation outlining care for covid- -suspected patients [ ] . this document highlights the need for adequate personal protective equipment for catheterization lab staff, the need to differentiate true acs from supply-demand mismatch, consideration of deferring invasive angiography in low-risk non-st elevation myocardial infarction (nstemi) patients until hospital resources improve, and the potential use of thrombolytics for st segment elevation myocardial infarction (stemi) cases where the risks of exposing staff to sars-cov outweigh the benefits of a primary percutaneous coronary intervention (pci)-based approach. however, the authors still expect primary pci to remain the standard of care for patients with stemi and possible covid- and thrombolytics reserved for non-pci-capable hospitals [ ] . further adding to the complexity of treating these patients, st-segment elevations are seen in covid- patients who are then found to have non-obstructive coronary disease. in a case series of patients in new york, ny, who developed st-segment elevations, nine patients underwent invasive angiography. of these nine patients, three had no obstructive coronary artery disease and / with obstructive disease underwent pci ( after receiving thrombolytics) [ ] . these cases of st-segment elevation with no obstructive coronary disease on angiography may be related to peri-myocarditis, although the pathophysiology remains under investigation. importantly, the mortality among patients without no obstructive coronary lesion was higher ( %) than among those with obstructive coronary lesions ( %), although the absolute numbers were limited. a similar incidence of obstructive to non-obstructive coronary lesions was reported in a population of italian patients with stemi [ ] . the high prevalence of stemi mimics in this population further emphasizes the need for angiography (either invasive or non-invasive) as opposed to empiric fibrinolytic therapy given the potential for harm when administering fibrinolytics for non-acs presentations. while covid- may potentially increase the risk of acs, activations for stemi in the united states have decreased significantly during the pandemic. among nine high-volume centers in the us, there was a % reduction in stemi activations compared to the -month period before the pandemic [ ] . this finding is similar to the % reduction in stemi activations seen in spain [ ] . it is unclear what is responsible for the significant reduction in stemi activations, but it may be related to patients' fear of exposure to sars-cov when presenting to the hospital. in hong kong, china, patients who presented with stemi during the height of the outbreak presented to the hospital significantly longer after onset of symptoms compared to a year prior ( vs. min) [ ] . it is currently unknown how many people worldwide may not be seeking medical care for possible acs due to fear of covid- . it is possible that due to delays in seeking appropriate medical care, patients may eventually present to the hospital with heart failure, cardiogenic shock, or mechanical complications from acs. studies must be performed to assess the impact covid- could have on cardiovascular mortality through such indirect mechanisms. sars-cov infection is theorized to predispose to a hypercoagulable state through inflammation, immune dysregulation, and activation of cytokines. this process has been implicated in acs, but also in cases of thrombosis outside the coronary arteries. among icu patients in the netherlands, % were diagnosed with pulmonary embolism, deep-vein thrombosis, ischemic stroke, myocardial infarction, or systemic embolism-all while receiving standard prophylactic doses of anticoagulation as recommended by the who [ ] . remarkably, none of the patients in this study developed disseminated intravascular coagulopathy (dic), a known risk factor for the development of arterial and venous thromboembolism in critically ill patients. ddimer levels above ng/ml had a sensitivity of % and specificity of % for detecting venous thromboembolism in a cohort from china [ ] . some centers have advocated for the use of treatment dose anticoagulation for select patients with covid- and elevated d-dimer levels, however this practice has yet to be well validated. among patients with confirmed sars-cov- in wuhan, china, arrhythmia occurred in . % of all patients admitted [ ] . elevated troponin t was a statistically significant prognostic marker with % having either ventricular tachycardia or fibrillation. it is unclear whether elevated troponin preceded or succeeded the arrhythmic events. furthermore, among patients admitted to a single hospital in wuhan, china, arrhythmia (type not specified) was reported in % with the majority ( %) occurring in critically ill patients in the intensive care unit [ ] . among patients who suffered a cardiac arrest, the predominant rhythm was asystole/pulseless electrical activity ( %), followed by shockable ventricular tachycardia/fibrillation ( %) [ ] . similar rates in the new york city population were reported by goyal et al. arrhythmia was seen in . % of the entire cohort, with higher rates in the patients receiving icu care ( . %) as compared to non-icu care ( . %) [ ] . arrhythmias may be induced by the presence of acidosis and metabolic disturbances, as seen in critical illness with multiorgan dysfunction or catecholaminergic pressor infusion for hypotension and shock. finally, qt-prolonging agents given to some covid- patients may increase the susceptibility to arrhythmia as discussed below [ , ] . unfortunately, with the limited data available, no trends have been apparent as of yet [ , ] . there is suspicion that the aggressive nature of the coronavirus pneumonia is related to an exaggerated immune response mediated by interferon and interleukins, as has been seen in prior coronavirus infections [ , ] . targets for covid- therapies are therefore not only focused on the intrinsic viral make up (including proteins such as ace- cell surface receptor, -chymotrypsin-like protease, spike, rna-dependent rna polymerase, and papain-like protease) but also the human immune system [ ] . the ongoing covid- pandemic poses an enormous threat globally. given the high prevalence of existing cardiovascular disease worldwide, it is not surprising that cardiovascular comorbidities significantly impact disease severity. the unique properties of the sars-cov- infection and pathophysiology further raise concern for de novo cardiac injury with covid- . the cardiovascular presentations of covid- are still being elucidated, but appear to at least include decompensated heart failure, myocarditis, acs, arrhythmia, and thrombosis. the effect of the covid- pandemic on cardiovascular systems of care and whether patients are delaying necessary treatment will be of great importance to understand as the pandemic progresses in the months and years to come. lastly, emerging therapeutic approaches have expected and unexpected cardiac effects that must be monitored as treatment algorithms expand. cardiologists will play a vital role in the care of covid- patients worldwide and in the ongoing research into the pathophysiology and population-based effects of the sars-cov virus. funding. no funding or sponsorship was received for this study or publication of this article. authorship. all named authors meet the international committee of medical journal editors (icmje) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. disclosures. gregory l. judson, benjamin w. kelemen, joyce n. njoroge, and vaikom s. mahadevan have nothing to disclose in relation to this article. compliance with ethics guidelines. this article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors. data availability. data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. open access. this article is licensed under a creative commons attribution-noncommercial . international license, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from 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statement from the chloroquine cardiomyopathy-a review of the literature a trial of lopinavirritonavir in adults hospitalized with severe covid- kaletraÒ oral film coated tablets, oral solution, lopinavir ritonavir oral film coated tablets, oral solution discovery and synthesis of a phosphoramidate prodrug of a pyrrolo[ , -f][triazin- -amino] adenine c-nucleoside (gs- ) for the treatment of ebola and emerging viruses a randomized, controlled trial of ebola virus disease therapeutics methylprednisolone infusion in early severe ards: results of a randomized controlled trial low-dose corticosteroid therapy does not delay viral clearance in patients with covid- the effect of corticosteroid treatment on patients with coronavirus infection: a systematic review and meta-analysis effective treatment of severe covid- patients with tocilizumab treatment of critically ill patients with covid- with convalescent plasma key: cord- -ko eda w authors: zheng, ruijun; zhou, yuhong; fu, yan; xiang, qiufen; cheng, fang; chen, huaying; xu, huiqiong; fu, lan; wu, xiaoling; feng, mei; ye, lei; tian, yongming; deng, rong; liu, shanshan; jiang, yan; yu, chunhua; li, junying title: prevalence and associated factors of depression and anxiety among nurses during the outbreak of covid- in china: a cross-sectional study date: - - journal: int j nurs stud doi: . /j.ijnurstu. . sha: doc_id: cord_uid: ko eda w background: coronavirus disease (covid- ) is a public health emergency of international concern and has caused traumatic experience for nurses worldwide. however, the prevalence of depression and anxiety symptoms in nurses, and how psychosocial factors influence nurses in this public crisis are unknown. objectives: to determine the effect of covid- on the mental health of nurses and the prevalence of anxiety and depression symptoms among nurses in china during the outbreak. design: a cross-sectional study. settings and participants: a total of , nurses in sichuan province and wuhan city were selected by convenience sampling. all participants were invited to complete the questionnaire through wechat from january to february , . methods: a self-reported questionnaire combining depression and anxiety scale was used to collect data anonymously. binary and multivariate logistic regression was applied to measure the odds of psychosocial factors of anxiety and depression and perceived health, respectively. results: the total incidence of depression ( . %) and anxiety ( . %) during the covid- outbreak was lower than that during the sars outbreak; however, the rate of depression in our study ( . %) was high and similar in a recent study ( . %) about the health care workers exposed to covid- in china. the results indicated that covid- -related stress, relationship quality with family, and demographic characteristics were associated with depression, anxiety, and perceived health status. furthermore, the prevalence of depression was similar between nurses working in low-risk covid- wards was as high as working in high-risk covid- wards (or, . ; % ci, . – . ). conclusions: our study revealed the high prevalence of depression and anxiety among nurses during the outbreak of covid- . covid- factors and psychosocial factors were associated with mental health of nurses. the results suggest that hospitals should implement effective mental health promotion programs focused on occupational safety and family support to improve the well-being of nurses. the municipal health commission of wuhan, the capital of hubei province in china, notified an outbreak of atypical pneumonia caused by a novel coronavirus, designated severe acute respiratory syndrome coronavirus (sars-cov- ) by the international committee on taxonomy of viruses (gorbalenya et al., ) . this entity was named coronavirus disease (covid- ) by the world health organization (who) on february , , and the type of pneumonia was designated novel coronavirus pneumonia. covid- spread to countries or territories, and caused . million confirmed cases of pneumonia as of july , (who, ). sars-cov- is the third most pathogenic human coronavirus that has emerged in the last two decades (perlman, ) , after severe acute respiratory syndrome coronavirus (sars-cov) and middle east respiratory syndrome coronavirus (mers-cov) (de wit et al., ; cui et al., ) . since december , when covid- emerged in wuhan and rapidly spread throughout china, the government has suspended all public transportation services in wuhan on january , , to prevent viral spread. many details of the emergence of sars-cov- such as its origin and transmission dynamics remain unknown (munster et al., ; . as of february , confirmed cases of infection of medical staff were reported, with six deaths (cdc of china, ) . has caused depression, anxiety, and fear across china during the outbreak of this public crisis. there are an estimated million people with depressive symptoms and million with anxiety worldwide (who, ) . moreover, nurses experienced higher rates of depression compared to the general population, especially in the face of health emergencies (dyrbye et al., ) . during the sars outbreak, % of nurses working in hong kong developed symptomatic depression (tam et al., ) , - % had high levels of distress in canada (maunder, ) , and % had high levels of stress in taiwan (tzeng, ) . sars-cov infections among medical staff represented more than % of all infection cases in hong kong, leading to negative emotions such as depression and anxiety (who, ) . specific stressors associated with emotional distress include the lack of effective treatment (lau et al., ) , high work demands (rau et al., ) , low job control (dragano et al., ) , effort-reward imbalance (pikhart et al., ) , work-family conflict (chandola et al., ) , and the life-threatening nature of the disease, especially direct exposure to sars patients (su et al., ) . severe psychological problems may compromise physical, mental, and social health, increasing suicide risk (kapur et al., ) . sars, mers, and covid- have caused fear and anxiety worldwide wu et al., ; knawy et al., ; lai et al., ) . understanding the impact of covid- infection control on personal and family health helps plan emergency responses to future infectious disease outbreaks. first, nursing workload and long working hours are significant predictors of mental health (helen et al., ) . nurses who are assigned unfamiliar tasks appear to suffer a higher risk of anxiety than other nurses doing familiar work . a study reported that health care workers at high risk of contracting sars were more likely to have a higher prevalence of depression and anxiety, and develop post-traumatic stress during the sars epidemic (mcalonan et al., ) . in addition, the relationship quality with family is important since it can improve psychological distress. some studies reported that work-family satisfaction was negatively correlated with psychological distress (ford et al., ; barnett et al., ; oshio et al., ) . social support is known to reduce depression and anxiety, and family support is associated with lower anxiety levels among nurses (chen et al., ) . although the transmission of sars-cov- in the early phase of the outbreak remains largely unknown, there is evidence that the risk of sars-cov infection and the level of emotional exhaustion is higher among nurses (brooks et al., ) . therefore, work stress, family dissatisfaction, and infectious disease exposure are more strongly related to psychological distress. managing psychological distress can improve the physical, mental, and social health of nurses. the objective of this study is to assess the prevalence rates of depression and anxiety in nurses during the first covid- epidemic through a questionnaire survey. the factors associated with the mental health of nurses were determined to provide the basis for establishing psychological intervention programs for these professionals. in this study, we hypothesize that covid- -related stress, relationship quality with family, and perceived health status are associated with the risk of depression and anxiety. a total of , nurses in sichuan province and wuhan city were selected in this cross-sectional study by convenience sampling. all participants were invited to complete the questionnaires from january , , to february , . we invited volunteers( coordinators of regional hospital network established by west china hospital， and members of the nursing academy specialty committee) from hospitals to investigate their hospital nurses. a professional questionnaire survey platform called "wenjuan xing" was used to investigate psychological health of participants through wechat groups (number of participants range from to ). we defined pneumology, infection, fever clinics, isolation wards, or icus as high-risk covid- wards, and general outpatient or emergency wards as middle-risk covid- wards, defined other wards as low-risk covid- wards. in this study, a self-made questionnaire combining the self-rating depression scale (sds) and self-rating anxiety scale (sas) was used to conduct an anonymous survey with the permission of the research ethics committees of the participating hospitals. participants were informed about the aims of the study and importance of enrollment. a total of , nurses answered the questionnaire, corresponding to a response rate of . %. demographic data, including gender, age, education level, hospital department, job position, type of hospital, city of residence, and exposure level, were collected. high exposure level are defined as nurses who care for, close contact, or live with covid- patients; elevated exposure level are defined as one covid- patient or more are found in nurses" department, public transportation, or community; normal exposure level are defined as no covid- patient is found in nurses" department, public transportation, or community. we have developed a self-reported questionnaire (table ) base on psychosocial factors during the sars and covid- epidemic (nickell et al., ; reznik et al., ) . the questionnaire contained ten main items: unknown origin of covid- , fear of infection, lack of effective treatment, poor patient compliance, nursing workload, poor social support, parent-child relationship quality, couple relationship quality, relationship quality with other family members, and perceived health status. the -item sds was used to evaluate depressive symptoms (zung, ) . the sds evaluates affective, psychological, and somatic symptoms associated with depression in adults and served as a reliable and valid tool to assess depressive symptoms in the chinese population (gong et al., ) . responses were scored from (never or rarely) to (usually or always). items on positive symptoms and items on negative symptoms. the total score ranged from to and was obtained by multiplying the total original score by . , with higher scores indicating more severe depression. depression was classified as mild ( - points), moderate ( - points), and severe (> points). in this study, cronbach"s α coefficient for this scale was . . the -item sas (zung, ) was utilized to evaluate anxiety symptoms. the sas is widely used and has good accuracy to evaluate psychometric properties in the chinese population (tao et al., ) . responses were scored from (never or rarely) to (usually or always), and the total score ranged from to . the total score was determined as the original score multiplied by . . anxiety was classified as none ( - points), mild ( - points), moderate ( - points), and severe ( - points). the cronbach"s α coefficient of this scale was . . data were analyzed using spss software version . . descriptive statistics were used to determine the distribution of demographic characteristics, including gender, age, education level, hospital department, exposure level, and so on. continuous variables were reported as means and standard deviations. categorical variables were expressed as absolute values and percentages. bivariate and multivariate logistic regression was used to measure the risk factors of anxiety, depression and perceived health, respectively. the bivariate logistic regression analyses were used to estimate the odds ratio for each independent variable, to assess which of the factors associated with depression and anxiety. multivariate logistic regression analysis was used with potential associated characteristics (demographic characteristics, covid- -related stress, and relationship quality with family) as independent variables and perceived health status as dependent variable. a two-sided p-value of less than . was considered statistically significant. the participating hospitals" research ethics committees approved this study. the first section of the questionnaire mainly included informed consent, participants will read the informed consent at first, if they agree to participate in the study they will click "i agree" to complete the following survey. the questionnaire survey was anonymous, and personal information was not disclosed, except for demographic data. a total of nurses were enrolled, and their demographic characteristics are summarized in table . most of the study population were women, accounting for . % of the total, and . % of them were aged  years old. in addition, . % of the participants worked in high-risk covid- wards, . % exposed to high level of covid- , and . % worked in wuhan. the rate of depression and anxiety in the study sample is shown in table . the total prevalence of depression and anxiety among nurses were . % and . %, respectively. the rates of depression and anxiety in nurses who cared for the covid- patients was . % and . %, respectively. the results from the binary logistic regression analysis are presented in nurses working in high-risk and low-risk covid- wards were at a higher level of depression than those working in middle-risk covid- wards. the city of residence and type of hospital also influenced the risk of depression, and this risk was higher among those working in wuhan and general tertiary hospitals. the results from the binary logistic regression analysis of the factors associated with anxiety are shown in ci, . - . ) were associated with anxiety symptoms. staff with a high exposure level were more likely to experience anxiety symptoms. it is widely recognized that psychological and social factors are linked to work-related stress (laferton et al., ) , and these factors strongly affect nurses" health (gigli et al., ) and clinical care quality (burton et al., ) , especially during health crises. this large cross-sectional study compared the psychosocial effects of covid- on distress symptoms and self-perceived health among nurses. to our knowledge, few studies have investigated the relationship between psychosocial factors and distress symptoms and perceived health status among nurses during public health crises. the main findings indicated that nurses experiencing covid- -related stress and poor relationship quality with family were more likely to develop depression and anxiety symptoms and have health concerns. furthermore, more than one-third of the nurses manifested psychiatric symptoms of depression and anxiety based on sds and sas scores. our study found that the total prevalence of either depression or anxiety among nurses ( / , . %) was lower than that among nurses caring for sars patients ( . - %) (chan et al., ; chong et al., ) , and the health care workers exposed to covid- (lai et al., ) . however, the rate of depression among nurses who cared for the patients was almost the same as lai et al study (lai et al., ) , and higher than that of nurses caring for sars patients in china (lung et al., ; su et al., ; chen et al., ; nickell et al., ; lin et al., ) . this phenomenon may be due to the stage of the pandemic, nurses" expertise, knowledge, and experience with sars. most of the previous studies (chan et al., ; chong et al., ; lung et al., ; su et al., ; chen et al., ; lin et al., ) had focused on nurses" mental health at the mid-stage and final-stage of sars pandemic, comparing with our study at the early stage of covid- pandemic. this led to our result was inconsistent with previous studies. this result may be in part due to the fact that hospitals provided a large amount of high-quality personal protective equipment to nurses in china. the national health commission of china also established mental health teams to promote the emotional stability of nurses caring for covid- patients in designated hospitals. this study found that covid- -related stress and relationship quality with family were associated with depression and anxiety scores, which agrees with previous findings (nickell et al., ) . unknown origin of sars-cov- and fear of infection were associated with higher levels of depression and anxiety in our cohort. given that nurses were concerned about being infected, as was the case during sars (lau et al., ) . caring for sars patients without being infected helped them to cope with challenging tasks and reduced the level of distress (rima et al., ) . tens of thousands of people were infected with sars-cov- in less than months. nurses who cared for covid- patients for more than month were quarantined for weeks. this measure affected nurses" relationships with their partner, children, and other family members, and led to feelings of loneliness (lau et al., ) . our results showed that prevalence and scores of depression and anxiety were higher there was no significant difference in the prevalence of depression between nurses in high-risk and low-risk covid- wards; however, the finding disagrees with previous studies on sars (chan et al., ; rima et al., ; su et al., ; chen et al., ; chong et al., ; lin et al., ) . this discrepancy may be due to four reasons. first, the proportion of non-severe covid- patients reported in a previous study was high ( / ) . therefore, we may have neglected the fact that sars-cov- -infected patients were asymptomatic or had mild cases in low-risk covid- wards. furthermore, the average incubation period of sars-cov- is days. consequently, whether patients in low-risk covid- wards were infected with sars-cov- during the incubation period is unknown. second, epidemiological evidence indicated that there were thousands of close contacts around us in china (national health commission of china, ). therefore, nurses may have a high risk of infection in hospitals or public areas . third, sars-cov- was detected by high-throughput sequencing or real-time reverse-transcriptase polymerase-chain-reaction (rt-pcr), which has a high false-negative rate . the period from symptom onset to diagnostic confirmation is several days. therefore, nurses had to be on high alert in light of the risk of infection from asymptomatic patients. fourth, personal protective equipment (ppe) was in short supply and, therefore, was initially offered to nurses working in high-risk covid- wards, and not nurses working in low-risk covid- wards, which may explain the same high level of depression in the two groups. our data highlighted the psychosocial factors were associated with mental health of frontline nurses who had covid- -related stress and poor relationship quality with family, including unknown origin, the fear of infection, poor social support, poor quality couple relationship, parent-child relationship conflict, and poor-quality relationship with other family members. these nurses are more likely to have personal and family health concerns. there is no effective treatment or vaccine for covid- to date. consequently, nurses are concerned about becoming infected through asymptomatic transmission (chen et al., ) , lack of effective treatment (chen et al., ) , inadequate supply of ppe (chan et al., ; lau et al., ) , and stigmatization xiang et al., ) . our findings agree with previous studies indicating that having work stress and poor relationship quality with family are high-risk factors for psychosocial distress (chan et al., ; nickell et al., ) . a review study showed that perceived stress from the sars epidemic was also influenced by the timing of the survey (su et al., ) . the nurses believed that their work environment was safer after the first peak of the sars epidemic (su et al., ) . nurses who experienced a high level of stress due to the rapid spread of covid- might not have sufficient time to become better adjusted to caring for affected patients and became more concerned about personal and family health during the outbreak. our results revealed that perceived health status was related to age and gender. younger female frontline nurses tended to become more concerned about personal or family health. younger age increased the odds of mental health and ptsd during the sars epidemic (su et al., ; sim et al., ) . in addition, female nurses were more likely to suffer from ptsd among trauma-exposed adults (brewin et al., ; gelder et al., ) , which may explain why younger female nurses who had more covid- -related stress during the covid- outbreak. therefore, this population should be given more social support to reduce symptom severity. frontline nurses need timely mental health care. our group recommends emergency mental health management, which has been recently used in our hospital . for this purpose, our hospital established multidisciplinary mental health promotion teams, including psychiatrists, psychiatric nurses, clinical psychologists, and counselors . the department of psychiatry developed the huaxi emotional-distress index (hei) for screening depression and anxiety among medical staff and patients in our hospital (wang et al., ) . one or two clinical psychologists and counselors ("sunny angels") from each non-psychiatric ward received systematic psychiatric training. after that, these professionals provided specialized psychiatric treatment for medical staff and patients. these workers continued to serve the medical staff and patients during the covid- pandemic, especially nurses in general inpatient wards. second, mental health promotion programs include free-of-charge psychological counseling during health crises through mobile phones and wechat. this safe communication channel is beneficial to individuals with mild mental problems and those with suicidality or psychological crisis, because of its accessibility and flexibility. furthermore, medical staff and patients can benefit from psychological counseling during the covid- pandemic. third, among the psychological treatment options, our team members usually apply cognitive-behavior therapy (cbt) because evidence has indicated that cbt can address multiple conditions, including anxiety (asnaani et al., ) , major depression (felder et al., ) , and post-traumatic stress disorder (shalev et al., ) . furthermore, cbt is appropriate for people of all ages (warwick et al., ; mccrae et al., ) . our previous study revealed that short-term group cbt could improve negative emotions and sleep, and consequently improve the quality of life of cancer patients (zheng et al., ; yuan et al., ) . fourth, clear communication with rapid information updates on the covid- outbreak was beneficial for disease control and prevention and for addressing public fear. china has built a daily press release system to ensure efficient and accurate disclosure of covid- epidemic information . the chinese government has implemented effective policies to expedite the production of personal protective equipment. in addition, chinese hospitals accept public donations to reduce shortage of personal protective equipment. this study has some limitations. first, the cross-sectional design does not allow establishing a definitive causal link between covid- -related stress, relationship quality with family, and distress symptoms. therefore, longitudinal studies and prospective controlled studies are necessary to confirm our conclusions. second, the participants completed the questionnaires using the wechat application and mobile devices, which might lead to self-selection bias. third, our self-designed questionnaire was not validated due to time constraints. we should test the reliability and validity of this scale in future research. fourth, the sample size of wuhan was small. therefore, our findings need to be tested in other high risk areas for covid- . our findings demonstrate that the covid- pandemic had significant psychosocial effects on nurses. covid- -related stress, relationship quality with family, and demographic characteristics were associated with depression, anxiety, and perceived health status. in addition, the prevalence of depression was similar between nurses working in low-risk and high-risk covid- wards. nurses working in a city where the disease is spreading rapidly are more likely to develop distress symptoms than those working in less affected 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exposure, risk perception, and altruistic acceptance of risk timely mental health care for the novel coronavirus outbreak is urgently needed group cognitive behavioral therapy modulates the resting-state functional connectivity of amygdala-related network in patients with generalized social anxiety disorder short-term group cognitive behavioral intervention in cancer patients zung self rating depressive scale a rating instrument for anxiety disorders this study was supported by the west china nursing discipline development special key: cord- -c qh y authors: monteleone, pedro aa; nakano, mayra; lazar, victor; gomes, alecsandra p; de martin, hamilton; bonetti, tatiana cs title: a review of initial data on pregnancy during the covid- outbreak: implications for assisted reproductive treatments date: journal: jbra assist reprod doi: . / - . sha: doc_id: cord_uid: c qh y the current outbreak of the novel coronavirus disease (covid- ) started in china in december and has since spread to several other countries. on march , , a total of , cases had been confirmed globally with , cases in brazil, showing the urgency of reacting to this international public health emergency. while in most cases, mild symptoms are observed, in some cases the infection leads to serious pulmonary disease. as a result, the possible consequences of the covid- outbreak for pregnant women and its potential effects on the management of assisted reproductive treatments, demand attention. in this review, we summarize the latest research progress related to covid- epidemiology and the reported data of pregnant women, and discuss the current evidence of covid- infections during pregnancy and its potential consequences for assisted reproductive treatments. reported data suggest that symptoms in pregnant women are similar to those in other people, and that there is no evidence for higher maternal or fetal risks. however, considering the initial data and lack of comprehensive knowledge on the pathogenesis of sars-cov- during pregnancy, human reproduction societies have recommended postponing the embryo transfers and do not initiate new treatment cycles. new evidence must be considered carefully in order to adjust these recommendations accordingly at any time and to guide assisted reproductive treatments. the current outbreak of the novel coronavirus disease (covid- ) caused by severe acute respiratory syndrome coronavirus (sars-cov- ) emerged in china in december and subsequently spread to many other countries. on january , the emergency committee of the world health organization (who) declared a global health emergency, and less than one month later, almost , cases were confirmed in china and more than , cases outside of china. numerous countries have reported increasing numbers of confirmed cases and deaths per day, and despite all efforts, spreading of covid- currently continues; therefore, on march , the who declared covid- a pandemic (who, a) . in numerous countries, current disease dynamics resemble those observed in china following the emergence of covid- . on march , an issue of euro surveillance journal reported the first confirmed covid- case in europe (spiteri et al., ) , according to the who case definition (who, b) . on march , covid- cases have been detected in all countries of the european union/european economic area and in the united kingdom with a total of , cases and , deaths, of which , cases and , deaths occurred in italy alone (european centre for disease prevention and control, ) . the brazilian health ministry confirmed the first covid- case on february in são paulo. the patient was a -year-old man who had recently returned from northern italy, where a significant outbreak had occurred. this was also the first confirmed case in south america, a continent with a population of over million people who have previously experienced significant outbreaks of infections such as zika, dengue, and measles. the number of covid- cases has been increasing constantly since the first reported case, and while initial cases were associated with travelers arriving from countries with ongoing covid- epidemics, since march , the stage of 'community transmission' was announced to be reached in são paulo and rio de janeiro. at the time this manuscript was drafted (march ), , cases have been confirmed in brazil, and the pandemic continues to increase worldwide, with currently , confirmed cases and , deaths in countries (who, c) . sars-cov- shows rapid community transmission, and nosocomial infections are common (novel coronavirus pneumonia emergency response epidemiology, ). evidence suggests that when the number of initial cases reaches , the likelihood of losing control is high, and the number of infections should double within a week, on average, which highlights the urgency of early detection and rapid response measures (hellewell et al., ) . china enacted a program of strict social isolation to control further spreading of covid- , with measures including isolation of cases and limited contact, lock-down of cities, mass quarantine, social distancing mandates, school closures, and intense case identification and contact tracing executed by health care professionals (chen et al., a) . these steps helped control local outbreaks, and chinese authorities reported absence of community transmission cases in china as of march . following this strategy, numerous countries also adopted social isolation regulations to contain the pandemic (who, b). however, it is important to emphasize that transmissibility of sars-cov- is high and infection growth rates are exponential, ranging from . to . . the rapid increase in suspected and confirmed cases of covid- suggests that virus transmission may occur by droplet infection and a fecal-oral route. moreover, transmission from people with mild or no symptoms or before symptom onset may reduce the effect of such isolation strategies (khan et al., ; niud & xu, ; rothe et al., ) . coronaviruses are a large family of viruses known to cause symptoms ranging from a common cold to more severe diseases, such as the severe acute respiratory syn a review of initial data on pregnancy during the covid- outbreak: implications for assisted reproductive treatments pedro aa monteleone , , mayra nakano , , victor lazar , alecsandra p gomes , (drosten et al., ; ksiazek et al., ) , and mers coronavirus (mers-cov) was the pathogen responsible for severe respiratory disease outbreaks in the middle east in (zaki et al., ) . sars-cov- is the seventh identified member of the family of coronaviruses which infect humans, and the main symptoms including fever, cough and fatigue are similar to those following sars-cov and mers-cov infection (liu et al., a) . coronaviruses are large, enveloped, positive-sense single-stranded rna viruses that infect humans and a wide range of animals. sars-cov- belongs to the genus beta-coronavirus, and it may originate from a virus of bats, as the genome sequence of sars-cov- is to approximately % identical with that of a bat coronavirus. in contrast, sars-cov- sequences show only about % sequence identity with sars-cov and about % with mers-cov zhou et al., ) . sars-cov- has four key structural proteins: the nucleocapsid protein (n), spike protein (s), small membrane protein (sm), and membrane glycoprotein (m). the angiotensin-converting enzyme (ace ), which is expressed on type-i and type-ii alveolar epithelial cells, is the main sars-cov- receptor, and infection causes respiratory symptoms and eventually the acute respiratory syndrome. this receptor is also expressed in the gut, albeit at a low abundance, and infection may lead to diarrhea and vomiting, despite it is less frequent. the s protein is required for the virus to fuse with the host cell through the receptor-binding domain. this protein includes two subunits, s and s , and while s determines cellular tropism, s mediates virus-cell membrane fusion. after membrane fusion, viral rna is released into the cytoplasm, and viral replication is initiated. newly formed viral particle buds then fuse with the plasma membrane through virion-containing vesicles to release the virus sun et al., ) . it is noteworthy that sars-cov also uses ace as a receptor for cell entry; however, receptor binding ability of sars-cov- is -to -fold higher than that of sars-cov, and the number of infections with sars-cov- has exceeded that of sars infections during the outbreak in china in / , indicating higher transmission rates. moreover, men typically have higher ace levels than women, and asians show higher levels of ace expression in alveolar cells than caucasian and african american people, which would suggest asian males to be most susceptible to infection . sars-cov- is predominantly transmitted from person to person through droplets and close contact . after contact with a virus-shedding patient, the mean incubation period is about days, ranging from to days . the spectrum of clinical presentations of sars-cov- infections has been reported to range from asymptomatic infections to severe respiratory failure. however, most cases experience a similar course of disease as sars and mers patients, with the most common symptoms including fever and cough which frequently leads to lower respiratory tract disease with poor clinical outcomes in elderly patients and in those with preexisting health conditions. confirmation of infection requires nucleic acid testing of respiratory tract samples (e.g., pharyngeal swabs), whereas clinical diagnoses can be made based on symptoms, exposure to infection, and chest imaging (wu & mcgoogan, ) . the study describing approximately . cases of covid- in china showed that in most cases ( %), the course of disease was mild (i.e., no or mild pneumonia), and it was severe in % (i.e., dyspnea, respiratory frequency ≥ /min, blood oxygen saturation ≤ %, partial pres-sure of arterial oxygen to fraction of inspired oxygen ratio < , and/or lung infiltrates > % within - hours) and critical in % (i.e., respiratory failure, septic shock, and/or multiple organ dysfunction or failure). the overall case fatality rate was . %, but it was . % in patients aged - years and . % in patients aged years and older; no deaths occurred in patients aged years or younger and among mild and severe cases. however, case fatality rates were higher in patients with preexisting comorbid conditions, varying from . % to . %, depending on comorbidity (wu & mcgoogan, ) . sars and mers infections, which also showed widespread transmission, produced fatality rates of . % and %, respectively . despite considerably higher case-fatality rates in sars and mers patients, covid- seems to be more transmissible and has led to a higher number of deaths due to the large number of cases. in addition, the true number of covid- cases can be presumed to be higher than the number of reported cases owing to inherent difficulties in identifying mild and asymptomatic cases in addition to insufficient covid- testing capacities in all affected countries (wu & mcgoogan, ) . immunosuppression and other physiological changes during pregnancy cause high susceptibility to respiratory pathogens and severe pneumonia in pregnant women (jamieson et al., ) which may require hospitalization in intensive care units and ventilatory support (goodnight & soper, ) . hormone levels and immune competence show considerable variation throughout pregnancy. early pregnancy seems to be more risk-prone due to adaptive changes in response to fetal antigens, but conditions typically stabilize with gradual adjustment of the mother's immune and endocrine systems, with highest stability in the late stages of pregnancy. early pregnancy is a crucial period of fetal organ development, and the immune system is particularly sensitive at this stage, which likely affects the course of infections (wong et al., ) . experience with previous respiratory virus epidemics may offer some insights regarding covid- susceptibility and complication rates during pregnancy. swine-origin influenza a (h n ) virus is an influenza virus type a, which also causes respiratory disease that can develop into an acute respiratory syndrome. during the h n epidemic in , pregnant women were found to be at higher risk of complications as they were four times more likely to be hospitalized than the rest of the population (jamieson et al., ) . regarding other coronaviruses, the sars epidemic in / produced , cases and deaths, and studies have shown that clinical outcomes during this epidemic were worse in pregnant women than in non-pregnant women. in addition, increasing rates of premature births and abortions have been associated with sars-cov infections (schwartz and graham, ) . approximately % of pregnant women suffering from sars required intensive care, and approximately % needed mechanical ventilation. the death rate of pregnant women suffering from sars reached % (wong et al., ) . from the mers epidemic which produced , confirmed cases and caused deaths, we can affirm that mers progresses much more quickly to respiratory failure and results in higher mortality rates than sars. however, there was no evidence of vertical transmission of mers or sars. based on this evidence, there is no doubt that sars-cov and mers-cov infections, as even the h n , are associated with higher rates of complications in pregnant women (schwartz and graham, ) . despite that covid- epidemic is ongoing and the data are limited, recent reports indicate that clinical char covid- and assisted reproductive treatments -monteleone et al. jbra assist. reprod. | v. | nº | apr-may-jun/ acteristics reported in pregnant women with confirmed sars-cov- infections are similar to those of non-pregnant women with covid- pneumonia, and no evidence of vertical transmission of sars-cov- in late pregnancy has been produced so far. nine studies reported covid- in pregnant women, with a total of patients; however, some of these patients may have been included in more than one study (table ). the reported cases included five patients in the second trimester of pregnancy, and all other patients were in the third trimester. most women showed mild or moderate symptoms, and three of them required intensive care. preterm birth occurred in out of women who gave birth (chen et al., b; chen et al., c; fan et al., ; liu et al., b; liu et al., c; wang et al., a; wen et al., ; zhu et al., ) . a joint investigation carried out by the who and china evaluated pregnant women in china ( confirmed and suspected covid- cases and an asymptomatic patient), % showed severe symptoms, and % showed a critical course of disease. it was concluded that pregnant women with covid- were not at a higher risk of developing severe symptoms (who, d). most likely, there are many other pregnant women with no or mild symptoms who were not included in these statistics. one case of a neonate infected with sars-cov- was confirmed hours after birth; however, it is unclear whether this was due to vertical transmission from mother to child (wang et al., b) . regardless of the small number of reported cases, the combined data suggest that susceptibility to infection and frequencies of severe courses of disease due to sars-cov- infection in pregnant women are similar to those in other young adults, and no case of vertical transmission has been reported. moreover, according to the who definition of preterm delivery as birth occurring before weeks of gestation and an estimated rate of preterm births of % (who, ), preterm birth rates in pregnant women affected by covid- seems to follow the general rate. regarding premature births, it should be considered that many pregnant patients who are hospitalized near term presenting symptoms of covid- , the anticipation of delivery by elective cesarean section can be a medical decision that is influenced by the patient and epidemic pressure and is not necessarily a result of current sars-cov- infection. no studies on severe covid- and obstetric complications during the first trimester of gestation are available so far; therefore, we lack information on potential effects of infection on pregnancy during the initial stages. regarding other coronaviruses, sars and mers epidemics showed no correlation with frequencies of malformations. moreover, data from the current epidemic should be considered for managing covid- infections during pregnancy, as the clinical course of this disease and the response to treatments seem to differ from those of previous outbreaks of other types of coronaviruses (chen et al., d; liang & acharya, ) . further research is needed in order to understand pathogenesis and epidemiology of sars-cov- during pregnancy, including aspects such as the time of maternal infection, gestational age, effects of comorbidity factors, and frequencies of adverse outcomes; however, preliminary observations of pregnant women infected with sars-cov- suggest an optimistic outlook regarding the clinical course. it is important to consider that the covid- pandemic elicited psychological stress and anxiety in the general population, including pregnant women. several concerns regarding potential infection during pregnancy have been raised, including (i) presence of family members given quarantine constraints, (ii) potential sars-cov- exposure during visits to physicians, (iii) potential requirement of early termination of pregnancy through elective cesarean section; (iv) constant use of sodium hypochlorite and alcohol as disinfectants which may exert toxic effects, and (v) potential postpartum complications, e.g., during breastfeeding or neonatal care (rashidi fakari & simbar, ) . in view of the current covid- pandemic and uncertainties regarding effects of sars-cov- on mothers and fetuses during pregnancy, human reproduction societies published suggestions for managing patients who currently are or will be undergoing infertility treatments through assisted reproductive technologies (art). the international federation for fertility societies (iffs) recommended on march that patients who are considering pregnancy or who are currently undergoing fertility therapies should consult with their personal physician for planning further steps (iffs, ). the same day, the american society for reproductive medicine (asrm) published a bulletin suggesting that patients who are highly likely to suffer from covid- (i.e., patients who were tested sars-cov- positive or who have been exposed to confirmed covid- cases within days of onset of their symptoms) should consider freezing oocytes or embryos and avoid embryo transfer until they are symptom-free; however, this recommendation was emphasized to not necessarily apply to suspected covid- cases as symptoms of covid- closely resemble those of other more common forms of respiratory disease (asrm, a). on march , the asrm published a new document named "patient management and clinical recommendations during the coronavirus (covid- ) pandemic" in which the key recommendations were: . suspend initiation of new treatment cycles, including ovulation induction, intrauterine inseminations (iuis), in vitro fertilization (ivf) including retrievals and frozen embryo transfers, as well as non-urgent gamete cryopreservation. . strongly consider cancellation of all embryo transfers whether fresh or frozen. . continue to care for patients who are currently "in-cycle" or who require urgent stimulation and cryopreservation. . suspend elective surgeries and non-urgent diagnostic procedures. . minimize in-person interactions and increase utilization of telehealth (asrm, b). the european society of human reproduction and embryology (eshre) issued a statement on march detailing that so far, only few cases of covid- during pregnancy have been reported, thus the respective data must be interpreted with caution as no information is available regarding potential effects of covid- infection during the initial stages of pregnancy; furthermore, medical treatment administered to severe covid- cases may include drugs that are contraindicated during pregnancy (eshre, ). the same publication advised that all patients considering or planning treatments, independently of confirmation or suspicion of covid- infections, should avoid becoming pregnant at this time and consider deferring pregnancy by freezing oocytes or embryos for embryo transfer at a later point (eshre, ) . the brazilian society for human reproduction (sbrh), the brazilian society for assisted reproduction (sbra), and the latin american network of assisted reproduction (redlara) also published statements concerning patients undergoing assisted reproductive treatments. the sbrh stressed that there is no cause for panic in pregnant women and urged that the asrm recommendations for women undergoing or planning infertility treatments be followed. however, treatment plans should be individually discussed with physicians as postponing of treatments may, in some cases, reduce chances of success (sbrh, ). the sbra and the redlara published a joint note on march , firstly suggesting that infertility treatments should continue as planned to avoid reducing prospects of success in infertile women but that the advice of international societies to postpone embryo transfers should be followed (sbra & redlara, ) . then, an update launched on march recommended that ongoing cycles should be finalized and new procedures should not be initiated. embryo transfer must be assessed individually with strict controls on the patients and teams involved and the exceptions lies on oncological and others situations in which the postponement may cause loss to the patient, since the decision need to be shared (sbra & redlara, ) . it is important to cite the brazilian health ministry published a technical note on covid- and pregnancy on march . based on available evidences until this moment reporting no difference of clinical course, as well as rates of complications and evolution to severe diseases of pregnant compared to young adults; it was recommended that the covid- diagnostic in pregnant women follow the protocol for the general adult population, as the prenatal care for all asymptomatic pregnant women. however, it is highlighted the importance the prevention of agglomerations, best hygiene practices and home screening and isolation of suspected cases of flu syndrome. also, despite the literature shows the unlikely vertical transmission of sars-cov- , they suggests it is prudent to perform morphological ultrasonography in the second trimester in mothers with sars-cov- infection, when available, since the data in infected women in the first trimester of pregnancy are not available (brasil -ministério da saúde, ). taken together, we currently face a pandemic with a novel virus, and considerable uncertainty remains regarding sar-cov- infections and consequences of infection during pregnancy. hence, most of human reproduction societies are restrictive suggesting to postpone embryo transfer independently of confirmation or suspicion of covid- and suspend all cycle's initiations, with rare exceptions. however, whilst every effort must be made to reduce services over coming weeks or maybe months, it is necessary to think forwards towards a resumption of services and a number of questions need to be answered around the management of art: should we cancel all art cycles at this moment? should we keep the treatments and postpone all embryo transfers? should we keep only embryo transfers for couple whose success of treatment can be impaired or those who desire transfer the embryos? based on most recent epidemiologic data on covid- and pregnancy, there is no evidence to suggest increased risk for mothers or fetuses. it appears that the course of disease after infection with sars-cov- in pregnant women does not differ from that in other young adults. moreover, recent evidence suggests no association of vertical transmission and malformations, and the management of pregnant patients should be individualized based on obstetrical indications and maternal/fetal health status. it is important to consider that the current covid- pandemic causes psychological stress and anxiety in pregnant women, which may exert adverse effects. furthermore, it is important to emphasize the recommendations regarding social isolation and quarantine as issued by health authorities in order to avoid further spreading of sars-cov- . therefore, deciding between initiating/resuming or postponing assisted reproductive treatments depends more strongly on social isolation than on covid- and its potential effects during pregnancy, bearing in mind potential emotional effects on patients. however, considering the lack of knowledge regarding sars-cov- pathogenesis during pregnancy, the current pandemic requires caution and human reproduction societies generally recommended postponing embryo transfers of current cycles and do not initiate any new cycles, with rare exceptions. nevertheless, we must be alert to new evidence, which can change these recommendations at any time, in order to adjust the management of assisted reproductive treatments. asrm -american society for reproductive medicine. covid- : suggestions on managing patients who are undergoing infertility therapy or desiring pregnancy. a. available at statements/patient-management-and-clinical-recommendations-during-the-coronavirus-covid- -pandemic brasil -ministério da saúde. secretaria de atenção primária à saúde a familial cluster of pneumonia associated with the novel coronavirus indicating person-to-person transmission: a study of a family cluster early containment strategies and core measures for prevention and control of novel coronavirus pneumonia in china pregnant women with new coronavirus infection: a clinical characteristics and placental pathological analysis of three cases expert consensus for managing pregnant women and neonates born to mothers with suspected or confirmed novel coronavirus (covid- ) infection identification of a novel coronavirus in patients with severe acute respiratory syndrome perinatal transmission of covid- associated sars-cov- : should we worry? the origin, transmission and clinical therapies on coronavirus disease (covid- ) outbreak -an update on the status feasibility of controlling covid- outbreaks by isolation of cases and contacts the continuing -ncov epidemic threat of novel coronaviruses to global health -the latest novel coronavirus outbreak in wuhan, china iffs -international federation for fertility societies. up-dates and resources related to the coronavirus pandemic and covid- . . available at novel influenza a (h n ) pregnancy working group. h n influenza virus infection during pregnancy in the usa emerging infections and pregnancy the emergence of a novel coronavirus (sars-cov- ), their biology and therapeutic options sars working group. a novel coronavirus associated with severe acute respiratory syndrome early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia novel corona virus disease (covid- ) in pregnancy: what clinical recommendations to follow? overlapping and discrete aspects of the pathology and pathogenesis of the emerging human pathogenic coronaviruses sars-cov, mers-cov, and -ncov pregnancy and perinatal outcomes of women with coronavirus disease (covid- ) pneumonia: a preliminary analysis clinical manifestations and outcome of sars-cov- infection during pregnancy genomic characterisation and epidemiology of novel coronavirus: implications for virus origins and receptor binding deciphering the power of isolation in controlling covid- outbreaks novel coronavirus pneumonia emergency response epidemiology team. the epidemiological characteristics of an outbreak of novel coronavirus diseases (covid- ) in china coronavirus pandemic and worries during pregnancy; a letter to editor. arch acad emerg med transmission of -ncov infection from an asymptomatic contact in germany redlara -red latinoamericana de reproducion assistida covid- : acompanhamento de pacientes submetidas às terapias de reprodução assistida ou que desejam engravidar potential maternal and infant outcomes from (wuhan) coronavirus -ncov infecting pregnant women: lessons from sars, mers, and other human coronavirus infections first cases of coronavirus disease (covid- ) in the who european region understanding of covid- based on current evidence a case of novel coronavirus in a pregnant woman with preterm delivery a case report of neonatal covid- infection in china a patient with sars-cov- infection during pregnancy in qingdao who -world health organization. preterm birth coronavirus disease (covid- ) situation report - . a. available at technical-guidance/surveillance-and-case-definitions who -world health organization. novel coronavirus (covid- ) situation. c pregnancy and perinatal outcomes of women with severe acute respiratory syndrome characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention. jama. . epub ahead of print isolation of a novel coronavirus from a man with pneumonia in saudi arabia preliminary estimation of the basic reproduction number of novel coronavirus ( -ncov) in china, from to : a data-driven analysis in the early phase of the outbreak a pneumonia outbreak associated with a new coronavirus of probable bat origin clinical analysis of neonates born to mothers with -ncov pneumonia the authors gratefully acknowledge the contributions of the team of monteleone centro de reprodução humana, são paulo, brazil, for technical and emotional support with patients and procedures during the covid- pandemic. the authors declare no conflict of interest. key: cord- -knelqmzx authors: villas-boas, gustavo r.; rescia, vanessa c.; paes, marina m.; lavorato, stefânia n.; de magalhães-filho, manoel f.; cunha, mila s.; simões, rafael da c.; de lacerda, roseli b.; de freitas-júnior, renilson s.; ramos, bruno h. da s.; mapeli, ana m.; henriques, matheus da s. t.; de freitas, william r.; lopes, luiz a. f.; oliveira, luiz g. r.; da silva, jonatas g.; silva-filho, saulo e.; da silveira, ana p. s.; leão, katyuscya v.; matos, maria m. de s.; fernandes, jamille s.; cuman, roberto k. n.; silva-comar, francielli m. de s.; comar, jurandir f.; brasileiro, luana do a.; dos santos, jussileide n.; oesterreich, silvia a. title: the new coronavirus (sars-cov- ): a comprehensive review on immunity and the application of bioinformatics and molecular modeling to the discovery of potential anti-sars-cov- agents date: - - journal: molecules doi: . /molecules sha: doc_id: cord_uid: knelqmzx on march , , the world health organization (who) officially declared the outbreak caused by the new coronavirus (sars-cov- ) a pandemic. the rapid spread of the disease surprised the scientific and medical community. based on the latest reports, news, and scientific articles published, there is no doubt that the coronavirus has overloaded health systems globally. practical actions against the recent emergence and rapid expansion of the sars-cov- require the development and use of tools for discovering new molecular anti-sars-cov- targets. thus, this review presents bioinformatics and molecular modeling strategies that aim to assist in the discovery of potential anti-sars-cov- agents. besides, we reviewed the relationship between sars-cov- and innate immunity, since understanding the structures involved in this infection can contribute to the development of new therapeutic targets. bioinformatics is a technology that assists researchers in coping with diseases by investigating genetic sequencing and seeking structural models of potential molecular targets present in sars-cov . the details provided in this review provide future points of consideration in the field of virology and medical sciences that will contribute to clarifying potential therapeutic targets for anti-sars-cov- and for understanding the molecular mechanisms responsible for the pathogenesis and virulence of sars-cov- . . continental map of sars-cov- infection cases. data were collected on . . [ ] . designed by freepik. currently, in the absence of any efficient therapy known for the treatment of covid- infections and, also, to the process of developing new drugs is time-consuming and cumbersome, the use of bioinformatics as a tool can redirect old drugs against covid- , helping to identify treatments with known pharmacokinetic, pharmacodynamic and toxicity profiles [ ] . some recent studies have provided critical insights using bioinformatics and molecular modeling to help the rapid development of treatments that can be tested in clinical trials [ , ] . for example, using xml-like web effort (q-uel) systems to access relevant and emerging literature and interact with standard publicly available bioinformatics tools on the internet helped quickly identify sequences of amino acids that are well conserved across many coronaviruses, including sars-cov- . the theory behind q-uel has been described and developed in several essentially mathematical papers [ ] . q-uel is a biomedical and pharmaceutical data mining tool that comprises knowledge bearing tags as "probabilistic statements" from relatively structured data sources [ ] and specialist text [ ] , as well as "common sense" and general wisdom from thesauruses and encyclopedias, and automatic surfing of the internet [ ] . research using this type of tool can contribute to the proposition of specific synthetic vaccine epitope and peptidomimetic agents (see [ ] ). the role of bioinformatics in conjunction with molecular modeling in the search for methods of diagnosis, treatment and prevention of covid- is unquestionable. processes such as screening of bioactive compounds, modeling of biomacromolecule structures, primer selection and genetic sequencing compounds can be faster, more accurate and less expensive when aided by computer . . [ ] . designed by freepik. currently, in the absence of any efficient therapy known for the treatment of covid- infections and, also, to the process of developing new drugs is time-consuming and cumbersome, the use of bioinformatics as a tool can redirect old drugs against covid- , helping to identify treatments with known pharmacokinetic, pharmacodynamic and toxicity profiles [ ] . some recent studies have provided critical insights using bioinformatics and molecular modeling to help the rapid development of treatments that can be tested in clinical trials [ , ] . for example, using xml-like web effort (q-uel) systems to access relevant and emerging literature and interact with standard publicly available bioinformatics tools on the internet helped quickly identify sequences of amino acids that are well conserved across many coronaviruses, including sars-cov- . the theory behind q-uel has been described and developed in several essentially mathematical papers [ ] . q-uel is a biomedical and pharmaceutical data mining tool that comprises knowledge bearing tags as "probabilistic statements" from relatively structured data sources [ ] and specialist text [ ] , as well as "common sense" and general wisdom from thesauruses and encyclopedias, and automatic surfing of the internet [ ] . research using this type of tool can contribute to the proposition of specific synthetic vaccine epitope and peptidomimetic agents (see [ ] ). the role of bioinformatics in conjunction with molecular modeling in the search for methods of diagnosis, treatment and prevention of covid- is unquestionable. processes such as screening of bioactive compounds, modeling of biomacromolecule structures, primer selection and genetic sequencing compounds can be faster, more accurate and less expensive when aided by computer tools. experts from all over the world believe in the potential of bioinformatics in combating the covid- pandemic. bioinformatics contributes to understanding the variations in sars-cov- proteins and molecules , , of how the virulence of this pathogen can increase. based on this, this tool can also clarify how the virus subverts the immune system. our know-how about the molecular elements involved in triggering this type of response can bring to light essential points that may otherwise be neglected. in addition to issues related to bioinformatics and molecular modeling, understanding the participation of innate immunity in the infectious process is crucial for the screening of new target molecules for the treatment and diagnosis of covid- . it is well established in the current literature that innate immunity plays a central role in determining the outcome of viral infections in general [ ] . therefore, the present review explicitly focuses on this aspect of the immune system, demonstrating its role in the formation of the adaptive immune response downstream and its importance as a therapeutic target for the development of new drugs for the treatment of patients with severe covid- . researchers put much effort to understand the origin and pathophysiology of this novel coronavirus and have been testing multiple drugs to screen for therapeutic effective substances [ ] . despite little understanding about the pathophysiology and high pathogenicity of sars-cov- infection, early studies have shown that increased amounts of proinflammatory cytokines in serum (e.g., (interleukin il) il- β, il- , il- , interferon-γ (ifnγ), interferon-inducible protein (ip ), and monocytic chemotactic protein (mcp )) were associated with pulmonary inflammation and extensive lung damage in patients with severe acute respiratory syndrome (sars) [ ] . besides, research has shown that infection by mers-cov leads to a significant increase in serum levels of pro-inflammatory cytokines (ifnγ, tnf-α, il , and il ) [ ] . patients who required intensive care unit (icu) admission had higher concentrations of gcsf, ip , mcp , mip a, and tnf-α than those who did not require icu admission, suggesting that massive cytokine synthesis and secretion are associated with the severity of the disease [ ] . given the above, the present study aimed to develop a comprehensive review of aspects of bioinformatics and molecular modeling as auxiliary tools to pharmacology and immunology in the discovery of potential anti-sars-cov- agents. understanding these aspects streamlines the biomedical research process, without any operational costs. besides, we researched and gathered evidence of the interactions between sars-cov- and innate immunity. discovering new therapeutic targets and understanding pathophysiological processes are the key to the development of effective treatments and efficient management of patients who progress to severe sars-cov- infection, which can save lives worldwide. most coronavirus (cov) infections in humans are caused by low-pathogenicity species, causing common cold symptoms; however, they can eventually lead to serious infections in higher risk groups such as the elderly, children, patients with comorbidities (hypertension, diabetes mellitus, asthma, among others) and/or those suffering immunosuppression. prior to , two highly pathogenic and animal-derived coronavirus species (sars and mers) were responsible for outbreaks of severe acute respiratory syndromes. regarding human infection by sars-cov- , the clinical spectrum is not fully described, and the lethality, mortality, infectivity, and transmissibility pattern is not yet fully elucidated. in addition, there is no specific treatment with antivirals that are effective against sars-cov- or available vaccines and, currently, treatment is supportive and nonspecific for covid- in hospitalized patients with fever, accompanied by cough or sore throat and with dyspnea or o saturation below % or respiratory discomfort [ ] . cov, of the order nidovirales, coronavirin subfamily and coronaviridae family, is a single-stranded rna virus with diameter of - nm [ ] with appearance of crown under electron microscope ("coronam" is the latin term for "crown") due to the presence of glycoproteins in the viral envelope [ ] . it is a virus capable of infecting humans and a wide variety of other mammalian hosts (e.g., mice, swine, rats, dogs, cats, rabbits, horses, cattle, cetaceans and bats) and birds (chickens, pheasants and molecules , , of turkeys) and develop respiratory, enteric, liver and central nervous system (cns) diseases. based on its genotypic and serological characteristics, cov is classified into subfamilies, previously called groups , and . group and were composed of cov that has mammals as hosts and group was composed, until recently, only of avian cov [ ] [ ] [ ] [ ] [ ] . currently, the study group of the international committee for viral taxonomy (icvt) has proposed replacing the traditional groups by subfamilies alfacoronavirus (α-cov) (group ), betacoronavirus (β-cov) (group ) and gamacoronavirus (γ-cov) (group ). after that, the presence of a fourth cov subfamily was detected in birds and pigs and called deltacoronavirus (δ-cov) [ , ] . the most common human covs (hcov) are hcov-oc , hcov-hku , both β-covs of strain a, and hcov- e and hcov-nl , both α-covs. generally, they cause common colds and self-limited upper respiratory infections in immunocompetent individuals, that is, they are eliminated in a short period of time by the immune system without the need for intervention through specific pharmacotherapy. in immunocompromised and elderly individuals, lower respiratory tract infections may also occur. other hcov include sars-cov, sars-cov- (or sars-cov- ) and mers-cov (β-covs of lineage b and c, respectively). these cov categories can cause epidemics of varying clinical severity, with respiratory and extra-respiratory manifestations. regarding sars-cov, mers-cov, mortality rates are up to % and %, respectively [ ] and sars-cov- belongs to β-cov subfamily. an important feature of the sars-cov epidemic between and was the virus efficiency in transmitting from species such as masked palm civet (paguma larvata), raccoon dog (nyctereutes procyonoides) and the chinese ferret-badger (melogale moschata) and infect human populations (fig a) [ ] . it is postulated that sars-cov is the result of the recombination of covs transmitted from these animals to humans. however, research has shown that sars-cov has not been detected in domestic or wild masked palm civet [ ] , suggesting that these, and other animals marketed in wholesale seafood markets in china, were not the main reservoirs of the virus [ ] . cov similar to sars-cov was isolated from the chinese horseshoe bat (rhinolophus spp.) [ , ] , which were also marketed in live-animal markets, strongly suggesting that the virus may have recently been transmitted from bats to other mammals, such as masked palm civets, and later to humans (figure a ) [ ] . in addition to sars-cov, there are other situations of cross-transmission of covs among different animal species. bovine coronavirus (bcov) and hcov-oc have broad similarities. bcov is believed to have been transmitted from bovine hosts to humans a hundred years ago [ ] . previous studies have demonstrated the isolation of bcov from alpaca that showed signs of enteritis and in captive wild ruminants [ , ] , strongly suggesting that this cov has been transmitted to others species (figure b) . previous studies have shown that canine (ccov), feline (fcov) and swine coronaviruses exchanged genetic material at random, showing that they were infecting the same host. recombination processes among the first ccov and fcov (ccov-i and fcov-i) strains and an unknown cov resulted in two new groups of viruses, ccov-ii and fcov-ii. in addition, studies have shown that the sequence of the transmissible gastroenteritis virus (tgev) genetic material shows that this cov was originated through cross-transmission of ccov-ii species from an infected dog (figure c ) [ ] . molecules , , x for peer review of swine, rats, dogs, cats, rabbits, horses, cattle, cetaceans and bats) and birds (chickens, pheasants and turkeys) and develop respiratory, enteric, liver and central nervous system (cns) diseases. based on its genotypic and serological characteristics, cov is classified into subfamilies, previously called groups , and . group and were composed of cov that has mammals as hosts and group was composed, until recently, only of avian cov [ ] [ ] [ ] [ ] [ ] . currently, the study group of the international committee for viral taxonomy (icvt) has proposed replacing the traditional groups by subfamilies alfacoronavirus (α-cov) (group ), betacoronavirus (β-cov) (group ) and gamacoronavirus (γ-cov) (group ). after that, the presence of a fourth cov subfamily was detected in birds and pigs and called deltacoronavirus (δ-cov) [ , ] . the most common human covs (hcov) are hcov-oc , hcov-hku , both β-covs of strain a, and hcov- e and hcov-nl , both α-covs. generally, they cause common colds and selflimited upper respiratory infections in immunocompetent individuals, that is, they are eliminated in a short period of time by the immune system without the need for intervention through specific pharmacotherapy. in immunocompromised and elderly individuals, lower respiratory tract infections may also occur. other hcov include sars-cov, sars-cov- (or sars-cov- ) and mers-cov (β-covs of lineage b and c, respectively). these cov categories can cause epidemics of varying clinical severity, with respiratory and extra-respiratory manifestations. regarding sars-cov, mers-cov, mortality rates are up to % and %, respectively [ ] and sars-cov- belongs to β-cov subfamily. an important feature of the sars-cov epidemic between and was the virus efficiency in transmitting from species such as masked palm civet (paguma larvata), raccoon dog (nyctereutes procyonoides) and the chinese ferret-badger (melogale moschata) and infect human populations (fig a) [ ] . it is postulated that sars-cov is the result of the recombination of covs transmitted from these animals to humans. however, research has shown that sars-cov has not been detected in domestic or wild masked palm civet [ ] , suggesting that these, and other animals marketed in wholesale seafood markets in china, were not the main reservoirs of the virus [ ] . cov similar to sars-cov was isolated from the chinese horseshoe bat (rhinolophus spp.) [ , ] , which were also marketed in live-animal markets, strongly suggesting that the virus may have recently been transmitted from bats to other mammals, such as masked palm civets, and later to humans (figure a ) [ ] . . this virus has spread and adapted to wild animals, for example, masked palm civet, which is marketed for human consumption in wholesale seafood markets in china. the employees of these markets that manipulate these wild animals have been infected; however, they did not present important clinical signs, and symptoms were minimal. the process of adapting the virus to new hosts resulted in strains with efficient replication capacity in human hosts, which cause diseases with clinical conditions ranging from mild to severe and with great ability to spread from person to person; (b) oc coronavirus, whose natural reservoir are humans (hcov-oc ) and bovine coronavirus (bcov) are closely related. it is postulated that these coronaviruses originated in another animal species and subsequently have crossed their species. bcov has effectively spread among other animal species, for example, alpaca (south american mammal of the camelid family) and wild ruminants (such as deer); (c) currently, some canine viruses are believed to have common ancestors with feline species. this occurs with coronaviruses that infect these species. currently, feline coronavirus i (fcov-i) and canine coronavirus i (ccov-i) are believed to share a common ancestor. a recombination process (random exchange of genetic material) of ccov-i with an unknown coronavirus gave rise to a second type of canine coronavirus (ccov-ii). the recombination of ccov-ii with fcov-i in an unknown host gave rise to a second type of feline coronavirus (fcov-ii). there is evidence that ccov-ii was transmitted to pigs, originating the transmissible gastroenteritis virus (tgev) [ ] . note: this image was developed using the coreldraw software ( corel corporation id ). in addition to sars-cov, there are other situations of cross-transmission of covs among different animal species. bovine coronavirus (bcov) and hcov-oc have broad similarities. bcov is believed to have been transmitted from bovine hosts to humans a hundred years ago [ ] . previous this virus has spread and adapted to wild animals, for example, masked palm civet, which is marketed for human consumption in wholesale seafood markets in china. the employees of these markets that manipulate these wild animals have been infected; however, they did not present important clinical signs, and symptoms were minimal. the process of adapting the virus to new hosts resulted in strains with efficient replication capacity in human hosts, which cause diseases with clinical conditions ranging from mild to severe and with great ability to spread from person to person; (b) oc coronavirus, whose natural reservoir are humans (hcov-oc ) and bovine coronavirus (bcov) are closely related. it is postulated that these coronaviruses originated in another animal species and subsequently have crossed their species. bcov has effectively spread among other animal species, for example, alpaca (south american mammal of the camelid family) and wild ruminants (such as deer); (c) currently, some canine viruses are believed to have common ancestors with feline species. this occurs with coronaviruses that infect these species. currently, feline coronavirus i (fcov-i) and canine coronavirus i (ccov-i) are believed to share a common ancestor. a recombination process (random exchange of genetic material) of ccov-i with an unknown coronavirus gave rise to a second type of canine coronavirus (ccov-ii). the recombination of ccov-ii with fcov-i in an unknown host gave rise to a second type of feline coronavirus (fcov-ii). there is evidence that ccov-ii was transmitted to pigs, originating the transmissible gastroenteritis virus (tgev) [ ] . note: this image was developed using the coreldraw software ( corel corporation id ). in general, statistical data suggest that % of the population are asymptomatic cov carriers and that these viruses are responsible for about % to % of acute respiratory infections [ ] . as for transmission and infection, rarely animal covs infect people and spread among them, as occurred with sars-cov and mers-cov. at first, many of the patients with outbreaks of respiratory diseases caused by sars-cov- in wuhan, china, had some connection with a large seafood and live-animal market, strongly suggesting that the spread occurred from animal to people. however, after the outbreak began, an increasing number of patients supposedly did not have exposure to the animal market, also indicating the occurrence of spread from person to person [ ] . the possibility of sars-cov- transmission from seafood to humans is unlikely. as the wuhan seafood wholesale market also sells other animals, the sars-cov- natural host remains unknown [ ] . the sustained spread from people to people is occurring in the globe. this culminated in the statement that the now-pandemic sars-cov- outbreak constitutes a public health emergency of international concern (pheic) by who on january , in geneva, switzerland. person-to-person transmission cases have already been reported worldwide. transmission in health institutions, such as hospitals, has frequently occurred, having already been reported in almost all countries where sars-cov- is present. regarding the person-to-person spread that occurred with sars-cov or mers-cov, the main means is believed to have been through respiratory droplets produced when an infected person coughs or sneezes, similar to the way influenza and other respiratory pathogens are disseminated. in addition, aerosol transmission has been identified in patients undergoing airway procedures, such as endotracheal intubation or airway aspiration. in the population, sars-cov and mers-cov dissemination among people usually occurs after close contacts, and health professionals involved in assisting these patients are particularly vulnerable [ ] . a recent study conducted with women who were in the third trimester of pregnancy and who were confirmed with sars-cov- infection showed no evidence of vertical transmission, that is, from mother to child. despite that, all pregnant women underwent cesarean section and it remains unclear whether transmission can occur during normal delivery [ ] . further studies with pregnant women in other gestation periods and even in the third trimester should be carried out, since the sample used was small. studies like this are crucial for the care of pregnant women, since they are relatively more susceptible to respiratory pathogen infection and severe pneumonia. recent studies have shown that interpersonal sars-cov- transmission has occurred since mid-december in wuhan (china) and from there, considerable efforts to reduce transmission and control the current pandemic will be necessary, since the transmission dynamics is very similar in all places where the number of infected and dead people is high. furthermore, these results suggest that measures to prevent or reduce transmission should be urgently implemented in populations at risk [ ] . for this reason, all government spheres worldwide, together with regulatory agencies from the health area, recommended complete social distancing as an emergency measure to contain the spread of sars-cov- through interpersonal contact. it is important to highlight that, through the experience of chinese and italians, the possibility of sars-cov- transmission before the onset of symptoms cannot be excluded and although it seems uncommon, there is evidence that individuals who remain asymptomatic can transmit the virus. these data suggest that the use of isolation is the best way to contain the sars-cov- -associated pandemic [ ] . china's cdc and local cdcs used the chinese experience in the sars-cov- outbreak to conduct investigations that determined the viral incubation time. they demonstrated that this period can vary from to days to weeks, since the longest time from infection to symptoms was . days ( % ci, . - ) [ ] . in addition, these results showed that the new pandemic doubled every seven days, while the basic reproduction number (r -r zero) is . , that is, each patient transmits the infection to an additional . individuals, on average. it is important to note that the r estimates of the sars-cov epidemic in - were approximately [ ] . for viral infection to occur, the connection of the virus to a receptor expressed by host cells is the first step, followed by fusion with the cell membrane. specifically for sars-cov- , it is possible to deduce that the epithelial cells of lungs are its main target, since in part of infected patients, covid- progresses as an acute respiratory infection [ ] . previous studies have shown that human-to-human sars-cov transmission occurs by the association between the binding domain to the spike receptor located on the viral envelope and the cell receptor. recently, it was identified that cell receptor for sars-cov is the angiotensin-converting enzyme (ace ) [ , ] . it is important to note that the sequence of the binding domain to the spike receptor of the sars-cov- viral envelope is similar to that of sars-cov. these data strongly suggest that the entry into host cells occurs through the ace receptor ( figure ) [ ] . infection to an additional . individuals, on average. it is important to note that the r estimates of the sars-cov epidemic in - were approximately [ ] . for viral infection to occur, the connection of the virus to a receptor expressed by host cells is the first step, followed by fusion with the cell membrane. specifically for sars-cov- , it is possible to deduce that the epithelial cells of lungs are its main target, since in part of infected patients, covid- progresses as an acute respiratory infection [ ] . previous studies have shown that human-to-human sars-cov transmission occurs by the association between the binding domain to the spike receptor located on the viral envelope and the cell receptor. recently, it was identified that cell receptor for sars-cov is the angiotensin-converting enzyme (ace ) [ , ] . it is important to note that the sequence of the binding domain to the spike receptor of the sars-cov- viral envelope is similar to that of sars-cov. these data strongly suggest that the entry into host cells occurs through the ace receptor ( figure ) [ ] . it is assumed that covs that cause covid- in humans are related to bats (upper left corner). this selected subset of viruses has the necessary resources to infect the human respiratory tract (lower left corner), with a certain tropism for this system. infection (right panel) requires the interaction of spike proteins present in the sars-cov- viral envelope (s proteins) with host sites for type angiotensin-converting enzyme (ace ) present in the lung. subsequently, proteases present on the surface of pneumocytes cleave the s region of the s protein, the subunit responsible for the fusion of the s protein with the cell membrane. after cleavage, a series of conformational changes are triggered, resulting in the fusion between viral envelope and the target cell membrane. the structural features of sars-cov- that can facilitate infection in humans include: ( ) presence of reasons for binding to the s b receptor (rbms) (in purple) that bind to ace orthologous receptors. ace is believed to be orthologous because it exhibits homology to s b rbms (since they complement each other to the point of binding) and were probably duplicated from a common ancestor, shared by the two underlying sister species, where in the course of evolution, both receptors gradually differentiate but continue to have affinity for each other; ( ) an s a domain that provides additional interactions with the host and; ( ) a cleavage substrate for a furin protease (represented by the green starry shape bound to the protease at the bottom right of the figure . infection of pneumococytes during covid- . it is assumed that covs that cause covid- in humans are related to bats (upper left corner). this selected subset of viruses has the necessary resources to infect the human respiratory tract (lower left corner), with a certain tropism for this system. infection (right panel) requires the interaction of spike proteins present in the sars-cov- viral envelope (s proteins) with host sites for type angiotensin-converting enzyme (ace ) present in the lung. subsequently, proteases present on the surface of pneumocytes cleave the s region of the s protein, the subunit responsible for the fusion of the s protein with the cell membrane. after cleavage, a series of conformational changes are triggered, resulting in the fusion between viral envelope and the target cell membrane. the structural features of sars-cov- that can facilitate infection in humans include: ( ) presence of reasons for binding to the s b receptor (rbms) (in purple) that bind to ace orthologous receptors. ace is believed to be orthologous because it exhibits homology to s b rbms (since they complement each other to the point of binding) and were probably duplicated from a common ancestor, shared by the two underlying sister species, where in the course of evolution, both receptors gradually differentiate but continue to have affinity for each other; ( ) an s a domain that provides additional interactions with the host and; ( ) a cleavage substrate for a furin protease (represented by the green starry shape bound to the protease at the bottom right of the figure), which can provide greater sensitivity to cleavages by host proteases. anti-cov antibodies (shown at the bottom right of the figure) can prevent infection through the following mechanisms: (a) binding to s brbms of the virus, blocking access to ace receptor and consequently preventing the continuation of the process of virus fusion with the target cell; (b) distal connection in relation to rbms, generating steric impairment and, consequently, blocking the connection between the virus rbms and the ace receptor of the host cell; (c) binding in the s a region of the viral spike, blocking alternative connections to different receptors; and (d) binding to s , the region responsible for the fusion of the virus with the membrane of the target cell, consequently preventing fusion. as future perspectives, future research should aim at the development of protease inhibitor antiviral compounds, which play a crucial role in the fusion of the virus to the host cell membrane, suppressing the entry of the virus [ ] . note: this image was developed using the coreldraw software ( corel corporation id ). in a recent study, [ ] demonstrated the interactions of sars-cov- with the host organism, specifically interactions between spike proteins ("coronan") located in the viral envelope (s proteins), projected from the envelope, and the host ace receptors. covs derived from the most virulent bats are those in which s proteins have tropism by distinctly human receptors, as is the case with sars-cov- . after the first contact with humans, the virus migrates to lungs and s proteins interact with various proteins and receptors, which are factors of host susceptibility. such interactions cause substantial changes in the conformation of proteins involved in the infection process of host cells, triggering the fusion between virus and human cells and, consequently, the infection. it is noteworthy that specific antibodies against s proteins and antiviral agents that block the link between virus and human susceptibility factors can prevent sars-cov- infection [ ] (figure ). studies like these have shown that there is a wide spread of covs in their natural reservoirs and by demonstrating interactions between virus and human hosts and, consequently, how the infectious process occurs, they drive the development of vaccines and antiviral drugs. in addition, further studies should be aimed at the active surveillance of these viruses in geographic regions that go beyond the beginning of the sars-cov- pandemic outbreak. in the long term, broad-spectrum antiviral drugs and vaccines should be developed with the aim of controlling emerging infectious diseases caused by covs. in addition, regulatory agencies in the health sector should develop specific regulations to control domestication and consumption of wild animals. the emergence of the highly pathogenic sars-cov- led to the need for deeper knowledge on the biology and pathogenesis of cov. an emerging theme in the cov pathogenesis and covid- pathophysiology is the interaction between specific viral genes and the host's immune system, which acts as a key determinant in the regulation of disease virulence and development results. viral interactions with innate immune system play a key role in determining the course of the infection. the initial control of viral replication by type i interferons (ifn), complement system proteins and other innate immune mediators limit viral spread in the host during the early stages of the disease [ ] . in addition, the initial innate response also plays a key role in the development of the subsequent adaptive immune response [ ] . despite that, it is well established in current literature that the hyperactive innate immune response can also result in pathology and subsequent tissue damage. regarding innate immunity, there are two main pathways by which cells detect viruses that invade the organism and activate the ifn pathway [ ] . toll-like receptors (tlrs), which include tlr , tlr , tlr and tlr , are responsible for detecting viruses in endosomal compartments as they penetrate host cells. the cytoplasmic domain of tlrs (called card) contains two specific rna-helicases, rig-i and mda , which detect viral rna in the cell cytoplasm. for activation of both pathways, interactions between sensors with pathogen-associated molecular patterns (pamps) are required, such as, for example, single-stranded rnas associated with viral genomes or double-stranded rna, which is a by-product of viral replication, being common targets. different adapter proteins participate in signal transduction in the induction pathways of tlrs and cytoplasmic ifn. the tlr-dependent pathway uses tir-domain-containing adapter-inducing interferon-beta adapter proteins (trif) and/or the myeloid differentiation factor (myd ) and the ifn cytoplasmic induction pathway uses the mavs/ips- /visa/cardif mitochondrial adapter protein [ ] (figure ). the tlr-dependent pathway uses tir-domain-containing adapter-inducing interferon-beta adapter proteins (trif) and/or the myeloid differentiation factor (myd ) and the ifn cytoplasmic induction pathway uses the mavs/ips- /visa/cardif mitochondrial adapter protein [ ] ( figure ). after internalized, the virus exposes the genomic rna to the dsrna detection mechanism in the cell, that is, tlr , rigi and mda . these proteins are responsible for the irf- cascade signaling, leading to ifnb induction and, consequently, the production of ifnβ protein. the newly synthesized ifnβ can bind to ifn receptors on the surface of the same cell or surrounding cells and induce the synthesis of more ifn molecules. binding to ifn receptors activates the signal transducer and activator of transcription (stat ) signaling pathway to activate several distinct antiviral genes located in isre promoter elements [ , ] . note: this image was developed using the coreldraw software ( corel corporation id ). the complement system plays a crucial role in the innate immune response to viruses. it represents one of the main factors responsible for the development of pro-inflammatory reactions during these diseases [ , ] . research has shown that, just as in human infection, intranasal sars-cov infection in c bl/ j mice, results in virus replication with high rates in the lung, in addition to induction of inflammatory cytokines and chemokines and infiltration of immune cells in the pneumocytes [ ] . using c -deficient mice (c -/-), these researchers demonstrated that animals c -/-infected with sars-cov lost less weight and obtained a significant reduction in respiratory dysfunction when compared to control groups, despite viral loads equivalent in the lung. besides, a significantly lower rate of neutrophils and inflammatory monocytes were present in the lungs of c -/-mice than in the c bl/ j controls, and subsequent studies showed that lung injury was reduced, as were cytokine (il- , mainly) and chemokine levels in lungs and serum of c -/-mice than when purchased from animals in the control group [ ] . this suggests that c inhibition may significantly reduce the pulmonary inflammatory complications of sars-cov- infection. the decrease in neutrophilic infiltration in the lungs and the reduced levels of intrapulmonary and plasma il- that have been observed in mice with c -/-infected with sars-cov suggest a potential treatment that combines c inhibitors and anti-il- drugs [ ] . besides, as c is one of the first proteins synthesized by the complement system in the innate immune cascade, the anti-inflammatory potential for c blockage is broader. drugs like amy- are being investigated for this [ ] , which is currently being tested in patients with covid- [ ] . c blockade can simultaneously inhibit the synthesis of c a and c a. furthermore, this block reduces the intrapulmonary activation of c and the release of il- after internalized, the virus exposes the genomic rna to the dsrna detection mechanism in the cell, that is, tlr , rigi and mda . these proteins are responsible for the irf- cascade signaling, leading to ifnb induction and, consequently, the production of ifnβ protein. the newly synthesized ifnβ can bind to ifn receptors on the surface of the same cell or surrounding cells and induce the synthesis of more ifn molecules. binding to ifn receptors activates the signal transducer and activator of transcription (stat ) signaling pathway to activate several distinct antiviral genes located in isre promoter elements [ , ] . note: this image was developed using the coreldraw software ( corel corporation id ). the complement system plays a crucial role in the innate immune response to viruses. it represents one of the main factors responsible for the development of pro-inflammatory reactions during these diseases [ , ] . research has shown that, just as in human infection, intranasal sars-cov infection in c bl/ j mice, results in virus replication with high rates in the lung, in addition to induction of inflammatory cytokines and chemokines and infiltration of immune cells in the pneumocytes [ ] . using c -deficient mice (c -/-), these researchers demonstrated that animals c -/infected with sars-cov lost less weight and obtained a significant reduction in respiratory dysfunction when compared to control groups, despite viral loads equivalent in the lung. besides, a significantly lower rate of neutrophils and inflammatory monocytes were present in the lungs of c -/mice than in the c bl/ j controls, and subsequent studies showed that lung injury was reduced, as were cytokine (il- , mainly) and chemokine levels in lungs and serum of c -/mice than when purchased from animals in the control group [ ] . this suggests that c inhibition may significantly reduce the pulmonary inflammatory complications of sars-cov- infection. the decrease in neutrophilic infiltration in the lungs and the reduced levels of intrapulmonary and plasma il- that have been observed in mice with c -/infected with sars-cov suggest a potential treatment that combines c inhibitors and anti-il- drugs [ ] . besides, as c is one of the first proteins synthesized by the complement system in the innate immune cascade, the anti-inflammatory potential for c blockage is broader. drugs like amy- are being investigated for this [ ] , which is currently being tested in patients with covid- [ ] . c blockade can simultaneously inhibit the synthesis of c a and c a. furthermore, this block reduces the intrapulmonary activation of c and the release of il- from alveolar macrophages or other cells that express c a receptors (c ars) and/or c a receptors (c ars), causing the beneficial evolution and cure of lung injury [ ] . the role of complement system activation in the development of severe acute respiratory syndrome associated with sars-cov- infection is not yet fully understood, and clinical data are scarce. recent research has shown that the sars-cov, mers-cov, and sars-cov- "n" proteins bind to masp- , the essential serine protease in the complement activation lectin pathway, leading to over complement activation and lung injury severe inflammatory disease. thus, it is evident that the blockade between the interaction of protein n with masp- can significantly reduce the hyperactivation of complement induced by protein n and lung injury in vitro and in vivo. complement overactivation is present in patients with covid- , and a promising suppressive effect has been seen in patients with severe lung injury treated with an anti-c a monoclonal antibody [ ] . due to the cascade organization of the complement system, inhibitors that target c or its upstream activators may be more effective and, potentially, may prevent the initial stages of the infectious process that lead to severe lung inflammation. despite this, no substance that acts with these mechanisms of action has been approved for use in humans, although phase ii clinical studies are already underway [ ] . figure outlines the moment when complement system inhibitors can be used in lung injury associated with sars-cov- . molecules , , x for peer review of figure . a possible scheme for using complement system inhibitors in lung injury associated with sars-cov- : (a) sars-cov- penetrates the host's pneumocytes and uses the cellular machinery for protein synthesis and replication of the genetic material and causing activation of the complement system through different pathways; (b) complement activation contributes to the massive inflammatory response of pneumocytes observed in some patients with severe covid- . the inhibition of c or c can have significant therapeutic potential [ ] . note: this image was developed using the coreldraw software ( corel corporation id ). the mechanism of natural sars-cov- infection occurs very similar to previously studied sars-cov [ ] and produces adaptive immune responses against the structural antigens of these viruses in humans and animals [ ] . spike glycoproteins located in the viral envelope (s proteins) are figure . a possible scheme for using complement system inhibitors in lung injury associated with sars-cov- : (a) sars-cov- penetrates the host's pneumocytes and uses the cellular machinery for protein synthesis and replication of the genetic material and causing activation of the complement system through different pathways; (b) complement activation contributes to the massive inflammatory response of pneumocytes observed in some patients with severe covid- . the inhibition of c or c can have significant therapeutic potential [ ] . note: this image was developed using the coreldraw software ( corel corporation id ). the mechanism of natural sars-cov- infection occurs very similar to previously studied sars-cov [ ] and produces adaptive immune responses against the structural antigens of these viruses in humans and animals [ ] . spike glycoproteins located in the viral envelope (s proteins) are responsible for binding to the cell receptor and fusing the virus membrane with the host's cell membrane [ ] . these glycoproteins also act as antigens responsible for the activation of t cells and development of humoral and cellular immunity [ ] . literature data have demonstrated that the majority of antigenic peptides are located in structural proteins (mainly s protein) [ , ] . it is believed that hypervirulent cov variants, such as sars-cov- , have the capacity to develop viremia, producing systemic disease, being often fatal [ , [ ] [ ] [ ] [ ] [ ] [ ] . previous studies have shown that sars-cov infection of macrophages and dendritic cells leads to an aberrant cytokine/chemokine expression pattern [ ] , so that the ability to infect and replicate in such phagocytes appears to be a determinant factor for establishing the course of viral infection. in addition, it has recently been reported that sars-cov- causes lymphocyte depletion, resulting in high viral titers [ , , , ] . previous studies demonstrate the spread of sars-cov to lymphoid organs such as spleen, thymus, peyer plaques and mesenteric lymph nodes, developing intense lymphoid depletion [ , , ] . it is already well established in literature that lymphocytes and their subtypes are essential to maintain the immune system function in basal activity or during infectious processes. viral infections, immunodeficiency syndromes and other infectious diseases, such as tuberculosis, are known to determine abnormal plasma counts in lymphocyte levels and their subtypes [ ] [ ] [ ] ; and for such infections to evolve into more serious events, lymphopenia is crucial, since the reduction of this cell type is necessary for the survival and persistence of many microorganisms. in wuhan, where sars-cov- infection started, % of patients with covid- had significant lymphopenia induction [ ] . although the mechanisms that cause lymphopenia in cov infections are not fully understood, it is already known that lymphocytes can undergo lysis by direct or indirect viral action [ ] . previous studies have shown that indirect events, secondary to viral infection, are the main responsible for cell lysis through the synthesis of soluble factors such as ifn, cytokines and chemokines by host cells [ , ] . as already mentioned, very recent studies have identified that the sars-cov cell receptor is ace and that the sequence of the binding domain to the spike receptor of the sars-cov- viral envelope is similar to that of sars-cov, suggesting that the entry into host cells occurs through the ace receptor [ ] . however, the presence of ace receptors has been identified in the oral mucosa, in type ii pneumocytes, along the intestine and in the renal and cardiac endotheliums [ ] , with no evidence of the presence of these receptors in circulating mature lymphocytes. for this reason, it is believed that the cytolytic effect of sars-cov- that led infected patients to develop lymphopenia is not direct, that is, caused by the virus itself, since the receptor determines the tropism of the pathogen by the tissue. in addition, previous studies have demonstrated the presence of cov rna in lymphoid tissues, such as the thymus, in infected patients. this suggests that one of the lymphopenia mechanisms in these patients may be related to the reduction in the production of mature lymphocytes by the thymus, which is the target organ in several infectious diseases, including coronavirus [ ] . since these viruses infect the thymus and cause tissue damage, there is an important interference in the lymphocyte differentiation process, which can cause lymphopenia [ ] . it is well established in literature that t cells are crucial to produce immunoglobulins and, consequently, for the development of humoral and memory immunity. therefore, pharmacological treatments or the use of integrative and complementary practices that prevent the reduction or increase the levels of cells of the immune system can be essential tools in combination with treatment and/or prevention of sars-cov- infection. the use of bioinformatics and other computational tools in addition to molecular modeling has helped researchers from different areas in the search for strategies for diagnosing viral infection, in the development of vaccines for its prevention, as well as in the discovery of new anti-sars-cov- agents. the knowledge of the genome of a species based on the genetic sequencing technique is the starting point for the structure and function of its genes to be understood. in the context of diseases transmitted by microorganisms, such as sars-cov- , the mapping of the genome of microorganisms collected from infected patients in different regions of the world also allows tracing a transmission profile, including its dissemination in different regions and countries, contributing to the search for strategies to combat the disease and monitor mutations [ , ] . data from the ncbi genbank ® gene sequence database https://www.ncbi.nlm.nih.gov/genbank) accessed on / / indicated more than , nucleotide sequences inserted since december for sars-cov- , most of them coming from cities in china and the usa. in february , researchers from the university of são paulo and instituto adolf lutz, in brazil, together with researchers from the university of oxford, in the united kingdom, managed to elucidate and publish the complete gene sequence of the virus (genbank accession number mt ) obtained from of the first confirmed cases of the disease in brazil within just two days from the confirmation of the diagnosis [ ] . the speed in obtaining this information is only possible through the application of bioinformatics techniques. bioinformatics showed great advance in the s, mainly in view of the development of the genomics area, which generated large amount of biological data incompatible to be quickly analyzed in a manual way. the rapid and adequate manipulation of these data has been possible through the application of data comparison and analysis software and easy access to previously available data from the sharing and storage of information in virtual databases [ ] . in view of experimentally obtained sequences, it is possible to perform the alignment of these sequences to other sequences available in virtual databases, leading to the knowledge of the family to which the microorganism is related [ , , ] . in one of the first studies on the new virus that caused respiratory infections in china, the researchers were able to determine from the sequencing of rna obtained from bronchoalveolar fluid samples that the etiologic agent was rna virus of the coronaviridae family. in addition, using bioinformatics tools, it was possible to perform a phylogenetic analysis, revealing . % similarity of the nucleotide sequence of this virus with a group of coronaviruses of the genus betacoronavirus already identified in bats in china, which gave evidence of the virus origin [ ] (figure ). one of the algorithms most widely used for comparing biological sequences, whether from nucleotides to nucleic acids or from amino acids to proteins, is the blast (basic local alignment search tool) [ ] . the diversity of information on biological sequences from organisms of different degrees of complexity allows blast to be a starting point to understand the genetic relationship with other species, also tracing a possible origin. the use of such tool allowed [ ] to identify high similarity between sars-cov- genomic sequence extracted from ncbi genbank ® (genbank accession number mn ) and viral metagenomas found in the pangolin mammal present in the database. these studies, in turn, guided analyses that led to findings of high amino acid identity of s, e, m and n genes of pangolin coronavirus with those isolated from humans, suggesting that the virus capable of infecting humans may have emerged from a recombination of coronaviruses isolated from bat and pangolin. the large capacity for storing information in virtual databases made possible by advances in the field of information technology allows these databases to be continuously updated with new genomic sequences to be universally available. in the context of covid- , this characteristic was important for a better understanding of the origin of sars-cov- from the comparative analysis of genomic data of the new virus with others from the same family, suggesting its origin from natural selection, with modifications in its spike protein, more specifically in the host receptor binding domain, which may have enhanced its interaction and recognition by the human cell [ , ] . related [ , , ] . in one of the first studies on the new virus that caused respiratory infections in china, the researchers were able to determine from the sequencing of rna obtained from bronchoalveolar fluid samples that the etiologic agent was rna virus of the coronaviridae family. in addition, using bioinformatics tools, it was possible to perform a phylogenetic analysis, revealing . % similarity of the nucleotide sequence of this virus with a group of coronaviruses of the genus betacoronavirus already identified in bats in china, which gave evidence of the virus origin [ ] ( figure ). figure . bioinformatics as technologies applied to health as allies to coping with the disease: bioinformatics is a technology that assists researchers in coping with diseases by investigating genetic sequencing and seeking structural models of potential molecular targets present in sars-cov- . note: this image was developed using the coreldraw software ( corel corporation id ). one of the algorithms most widely used for comparing biological sequences, whether from nucleotides to nucleic acids or from amino acids to proteins, is the blast (basic local alignment figure . bioinformatics as technologies applied to health as allies to coping with the disease: bioinformatics is a technology that assists researchers in coping with diseases by investigating genetic sequencing and seeking structural models of potential molecular targets present in sars-cov- . note: this image was developed using the coreldraw software ( corel corporation id ). the rt-pcr test is considered the gold standard for diagnosing covid- [ ] . by this technique, the reverse transcriptase enzyme initially participates in transforming the viral rna into complementary dna (cdna). then, the genetic material is amplified. in this process, the regions of the genetic material to be amplified are recognized by polymerase by means of oligonucleotides complementary to the region of interest called primers [ ] . the step of primer selection is essential to ensure the quality of the analysis and requires a thorough analysis of the reference genetic sequence [ ] . it is also important to consider that recognition is specific, and the method can be applied worldwide, that is, genetic material conserved regions should be prioritized over regions of low similarity. in this context, bioinformatics can contribute by allowing the design of primers based on the comparison of different genetic sequences from different geographic regions, available in virtual databases, identifying regions conserved in the genome, which would enhance the method's specificity [ ] . in the work of [ ] , which is also recommended by who as a reference in primers to be used in rt-pcr tests, researchers used complete and partial genetic sequences of sars-related viruses present in the ncbi genbank ® database for the design of primers and, in view of the first publications of sars-cov- sequence on virological.org [ ] and gisaid [ ] , it was possible to align the primers proposed for these sequences and to select those with greater correspondence. several online servers and software have been used in order to optimize this process [ , , ] . one of the main strategies to control viral diseases has been vaccination prevention. the development of a vaccine involves the identification of either synthetic or natural antigens that can prevent or even treat a disease. for viral diseases, the most explored strategies involve the use of attenuated viruses in their composition, use of viral structures that can be neutralized by the immune system, or application of part of the viral genetic material related to the expression of proteins that can behave as antigens for the development of antibodies against the pathogen of origin [ ] . regardless of strategy to be used, knowledge about the viral genome and the structure and function of virus proteins is essential for a vaccine to be successfully developed. in this context, bioinformatics tools have also contributed to greater quality and speed in the process. the proposal of vaccines based on b and t-cell epitopes has been a possible strategy for obtaining vaccines for covid- prevention. such epitopes can be predicted from the analysis of amino acid sequences of proteins of the sars-cov- pathogen and comparison with virtual epitope databases [ , ] . even without studies on specific immune responses against sars-cov- , the genetic similarity between this virus and sars-cov obtained from sequential alignment and phylogenetic analysis of genomes indicates that possible common epitopes related to structural s and n proteins could be incorporated into vaccines to be developed, in view of the immunological response already observed against sars-cov structures [ ] . the search for regions conserved in genetic sequences of different coronavirus species aided by bioinformatics tools has also been a way to identify sequences of amino acids that can be models for the design of specific synthetic epitopes to compose vaccines for covid- prevention [ ] . the discovery and planning of new drugs that can be used in the treatment of covid- benefited from the several advances observed over the last decades in the field of bioinformatics. a potential antiviral agent should target processes or macromolecules essential for maintaining the cycle of viral replication and infection of new host cells [ ] . to do so, knowing the genetic sequence of the virus is not enough, but it is also important to determine the functions related to each of the genes that compose it. the sequential identity between genetic materials of different organisms may indicate equivalent genes in terms of function [ ] , which encode common proteins that can be exploited as molecular targets for the action of drugs aimed at the treatment of viral infections, for example [ ] . prior knowledge of potential molecular targets in other coronaviruses combined with the similarity of genetic sequences among viruses of this family opens several doors for the discovery of new bioactive compounds aided by computational tools [ ] . to modulate the action of a molecular target, it is important to know its three-dimensional structure. the determination of this structure is essential for the understanding of how its connection site is organized, how it interferes with its mechanism of action and, given this information, how agents that interfere with its functioning can be proposed. information on the structural organization of a protein is obtained by various techniques such as x-ray crystallography [ ] , cryogenic electron microscopy [ ] and nuclear magnetic resonance (nmr) [ ] . however, bioinformatics tools are those that enable the detailed analysis of data obtained by these techniques and, consequently, the proposition and refinement of three-dimensional models, also exploring comparative analyses with models already proposed [ ] . in the same way that there are virtual databases powered by genetic sequences, advances in bioinformatics have also enabled the creation of virtual databases of models of three-dimensional structures of biomacromolecules, which data are freely accessible and can be downloaded and viewed using visualization and molecular modeling software. the most popular three-dimensional structure database is the protein data bank (pdb-www.rcsb.org), with more than , structures inserted so far [ ] . so far, more than structural models of sars-cov- macromolecules were deposited in the pdb. most refer to structures proposed for the main protease complexed or not with possible inhibitors [ , ] , but structural models can also be found for the nucleocapsid protein, non-structural proteins nsp , nsp , nsp , nsp [ ] and nsp and spike glycoprotein [ , ] . the determination of structural models of the main sars-cov- protease, an important enzyme in the processing of polyproteins translated from viral rna in free forms and complexed with the α-ketoamide b inhibitor [ ] started from obtaining crystallographic data via x-ray diffraction. structural models were then determined by the molecular substitution method, using as reference a structural model from sars-cov already available in pdb, with % sequential identity. previously determined sars-cov spike glycoprotein models were also used as a reference in the construction of models of the same sars-cov- protein, whose structural data had been obtained from cryogenic electron microscopy [ ] . the construction of structural models using crystallographic data as a reference allows the knowledge of the real arrangement of the structure under given experimental condition. when determining the structure of the main protease complexed with b inhibitor, [ ] were able to "visualize" at molecular level, aided by computational tools, the main points of interaction between inhibitor and enzyme, which may contribute to direct structural modifications that lead to the optimization of the compound's inhibitory activity. likewise, the knowledge of interactions involved in the protein-protein complex between the rbd domain of the sars-cov- spike glycoprotein and the human cell ace receptor helps to better understand how viral recognition occurs and the consequent search for epitopes conserved in this viral protein that can be targets of neutralizing antibodies to enable the production of vaccines [ ] . obtaining crystals from biomolecules; however, can be a laborious or even unfeasible process [ ] . in these situations, we choose to build structural models using homology modeling. by this technique, a macromolecule of known three-dimensional structure with considerable degree of sequential identity to that to be determined is used as reference for the construction of this structural model [ ] . comparative studies between models determined with the aid of crystallography and models obtained by homology modeling indicate that they have high prediction quality and can be widely applied in studies of interaction between ligand and molecular target [ ] [ ] [ ] . considering the urgency of obtaining structural models of potential molecular targets present in sars-cov- and the availability of models of three-dimensional protein structure, mainly of other viruses of the coronaviridae family, with sequential similarity to those of the virus that causes covid- , homology modeling is the fastest, cheapest and most accessible way for structural determination. thus, many research groups have used this strategy to obtain structural models of different sars-cov- proteins, such as the nucleocapsid protein [ ] , envelope protein, orf a protein [ , ] , non-structural proteins (nsp) [ , , ] , clpro [ , ] and spike glycoprotein [ , , ] , which have been used for the discovery of antiviral agents and the development of vaccines against covid- . the use of molecular modeling at the early stages of searching for new bioactive compounds has contributed for the faster development of new drugs at reduced costs. in view of the urgency for effective treatments of covid- , virtual screening methods for bioactive compounds end up by optimizing this discovery pathway by allowing the initial selection of those that present steric and electronic similarities with compounds of known activity (drug planning based on the ligand) or that have the potential to strongly bind to the molecular target of interest (structure-based drug planning) [ ] . in view of the low number of compounds with known anti-sars-cov- activity and considering the availability of structural models of potential molecular targets of the virus, the strategy based on the structure of the molecular target has been further explored, in which molecular docking techniques play a key role in this planning method. molecular docking consists of anchoring a molecule at the binding site of a molecular target, evaluating its assumed conformations, always searching for the one that generates the lowest-energy complex or the most stable with the target [ ] . the binding energy of this complex can be related to its ability to interact and thus modulate the target's action. based on this information, it is possible to select, from virtual databases with a multitude of compounds, potential inhibitors, agonists, or antagonists, against a specific target, which will be hit compounds for more targeted structural changes. in this process of identifying new hit compounds via virtual screening, virtual libraries of chemical compounds, such as zinc databases (https://zinc.docking.org/) [ ] and pubchem (https: //pubchem.ncbi.nlm.nih.gov/) [ ] , offer a great diversity regarding structural patterns and origin (natural or synthetic), which can contribute to higher quality in the search process. these two databases were explored by [ ] to identify possible inhibitors of the sars-cov- main protease. from these chemical libraries, researchers selected compounds that already had the ability to inhibit proteases found in other organisms, totaling more than tested compounds, which were submitted to molecular docking studies against the main protease (pdb id lu ), thus determining the interaction energy of the target-ligand complex. in this study, the pubchem cid , compound (figure a) showed the greatest potential for inhibiting the enzyme, forming the most stable complex with the main protease. there are published works that have focused on the screening of compounds of natural origin, which have great historical importance in the process of discovering new drugs [ ] . libraries of phytochemical compounds with antiviral action from traditional chinese medicine plants have already been virtually screened against different sars-cov- molecular targets such as the clpro protein [ , ] , papain-like protease (plpro) and spike glycoprotein [ ] . among selected compounds, pubchem cid , , [ ] and quercetin [ ] showed strong interaction with clpro; dihydrotanshinone i with the spike glycoprotein; and cryptotanshinone, with both plpro there are published works that have focused on the screening of compounds of natural origin, which have great historical importance in the process of discovering new drugs [ ] . libraries of phytochemical compounds with antiviral action from traditional chinese medicine plants have already been virtually screened against different sars-cov- molecular targets such as the clpro protein [ , ] , papain-like protease (plpro) and spike glycoprotein [ ] . among selected compounds, pubchem cid , , [ ] and quercetin [ ] showed strong interaction with clpro; dihydrotanshinone i with the spike glycoprotein; and cryptotanshinone, with both plpro and clpro proteins [ ] (figure a ). in addition to phytochemicals, compounds of marine origin have also been in silico evaluated against the sars-cov- main protease [ ] . the virtual screening strategy adopted by the authors involved the initial construction of a pharmacophoric model based on the structure, which was created from information on the structure of the enzyme cocrystallized with n inhibitor (pdb id lu ). in this work, the virtual screening of structures from libraries of marine compounds was then carried out using the pharmacophoric model created as a molecular filter to select those that presented structural characteristics corresponding to the created model. subsequently, the selected compounds were submitted to anchoring at the active site of the enzyme as a way of assessing complementarity with the target. different compounds were identified as potential main protease inhibitors in this analysis, highlighting the compound with the greatest potential heptafuhalol a (figure a ). in addition to the virtual screening strategies adopted, another that has stood out among works searching for new anti-sars-cov- agents is the one that uses drug groups already approved, preferably those with antiviral action, such as search libraries, characterizing a drug repositioning strategy. the interest in studying compounds already in pharmaceutical use for other purposes has the advantages of reducing time and costs mainly related to the stage of drug discovery, but above all the fact of knowing the toxicological profile of the compound, previously attested in clinical trials [ ] . in two studies found in literature, the use of a set of drugs obtained from the zinc database [ ] was observed as a library of screening compounds. in the work of [ ] , the interaction between this set of drugs and the sars-cov- spike glycoprotein was evaluated, highlighting as a result the high potential for interaction between digitoxin and zorubicin (figure b ). in the work of [ ] , the set of drugs obtained from zinc was virtually evaluated regarding their interaction with different probable molecular targets of the virus, highlighting the potential of ribavirin against plpro; limecycline against clpro and valganciclovir against rna-dependent rna polymerase (rdrp) (figure b ). in the study by [ ] , the drugs analyzed were obtained from the sweetlead database [ ] and screened against the spike glycoprotein, with drug pemirolast (figure b ) being indicated as a promising inhibitor of the action of this glycoprotein. [ ] conducted in silico evaluation against sars-cov- rdrp only the potential inhibitor of drugs or compounds in clinical trials with anti-hcv action. among drugs tested, the potential of ribavirin is highlighted, which had also demonstrated potential antiviral action in the work of [ ] , but acting against the plpro target ( figure b ). currently, a comprehensive and standardized repository of knowledge of the interaction mechanisms between sars-cov- and the host has been created. the repository is called covid- disease map and was built with the contribution of experts using the results of published research, including bioinformatics data. this technology is a platform that contributes to the computational analysis of molecular processes involved in the -ncoc input and replication interactions in the host. besides, information about the immune system's performance, recovery of host cells, and repair mechanisms can be obtained through the covid- disease map [ ] . figure demonstrates the objective and the initial layout of the map and its operating cycle. a recent study involving the phylogenetic analysis of complete genomes of covid- , researchers revealed three central variants distinguished by changes in amino acids, which were called variants a, b, and c, with a being the ancestral type according to the bat outgroup coronavirus. viral strains a and c have been identified in many countries outside east asia, that is, in europe and the united states of america. in contrast, variant b is the most common type in east asia, and there is no evidence that its ancestral genome spread outside east asia without first undergoing mutations [ ] . this update is carried out according to the materials available in databases on the subject to support visual and computational exploration, as well as efforts to model diseases [ ] . note: this image was developed using the coreldraw software ( corel corporation id ). a recent study involving the phylogenetic analysis of complete genomes of covid- , researchers revealed three central variants distinguished by changes in amino acids, which were called variants a, b, and c, with a being the ancestral type according to the bat outgroup coronavirus. viral strains a and c have been identified in many countries outside east asia, that is, in europe and the united states of america. in contrast, variant b is the most common type in east asia, and there is no evidence that its ancestral genome spread outside east asia without first undergoing mutations [ ] . a phylogenetic analysis carried out in turkey, with the first genomes isolated from sars-cov- in this region, showed that the introduction of the virus in the country occurred before the first reported case of infection. the study demonstrated that the virus circulated in turkey from several independent international introductions and revealed a hub for inland transmission [ ] . another phylogenetic analysis carried out recently sequenced nine viral genomes of patients with covid- previously reported in connecticut, united states. the research placed most of these genomes with viruses sequenced from washington state. interestingly, when the researchers combined the genomic data obtained in the study with national and international travel patterns, they found that domestic introductions probably drove the initial transmission of sars-cov- in connecticut. this study provides evidence for the sustained and widespread transmission of sars-cov- in the usa and highlights the critical need for local surveillance [ ] . important research on the evolutionary and epidemiological dynamics of the current outbreak of covid- analyzed genomes of sars-cov- strains collected from china and other countries with sampling dates between december and february . the phylogenetic study results showed that the time to the most recent common ancestor was november , and the evolutionary rate of sars-cov- was . × − substitutions per site per year. these results highlight that the use of phylodynamic analyzes is crucial to provide insights into the possibilities of interventions to limit the spread of sars-cov- worldwide [ ] . disease map is selected and reviewed from databases and knowledge continuously. this update is carried out according to the materials available in databases on the subject to support visual and computational exploration, as well as efforts to model diseases [ ] . note: this image was developed using the coreldraw software ( corel corporation id ). a phylogenetic analysis carried out in turkey, with the first genomes isolated from sars-cov- in this region, showed that the introduction of the virus in the country occurred before the first reported case of infection. the study demonstrated that the virus circulated in turkey from several independent international introductions and revealed a hub for inland transmission [ ] . another phylogenetic analysis carried out recently sequenced nine viral genomes of patients with covid- previously reported in connecticut, united states. the research placed most of these genomes with viruses sequenced from washington state. interestingly, when the researchers combined the genomic data obtained in the study with national and international travel patterns, they found that domestic introductions probably drove the initial transmission of sars-cov- in connecticut. this study provides evidence for the sustained and widespread transmission of sars-cov- in the usa and highlights the critical need for local surveillance [ ] . important research on the evolutionary and epidemiological dynamics of the current outbreak of covid- analyzed genomes of sars-cov- strains collected from china and other countries with sampling dates between december and february . the phylogenetic study results showed that the time to the most recent common ancestor was november , and the evolutionary rate of sars-cov- was . × − substitutions per site per year. these results highlight that the use of phylodynamic analyzes is crucial to provide insights into the possibilities of interventions to limit the spread of sars-cov- worldwide [ ] . from studies like these, it is possible to suggest that phylogenetic networks developed with bioinformatics aid can also be used successfully to trace undocumented sources of covid- infection. after that, cases can be reported and quarantined to prevent the disease's recurrent spread worldwide [ ] . the contributions of bioinformatics and molecular modeling in elucidating essential targets for the planning and development of new drugs, and the analysis of already known compounds, support the search for safer and more effective treatments against sars-cov- infection. identifying targets, planning interactions, understanding the structure-activity relationship, coupling, and molecular dynamics allow a projection of the mechanism of antiviral action in silico. an example of this is the prospect of using molecules of natural origin tested in vitro or in vivo and which showed significant antiviral activity. therefore, the use of software to identify viral targets and the prediction of their interaction with the molecule under analysis is necessary so that that research can proceed safely and with a higher probability of success. the verification of the performance of these compounds through computational analysis can predict physical-chemical properties, which are related to pharmacodynamic and pharmacokinetic parameters, whose knowledge is crucial when it comes to the planning of new drugs [ ] . table presents studies where the researchers tested natural compounds from plants and fungi against sars-cov- . the table shows the results of these analyzes on viral replication. it provides an essential overview of the antiviral action of phytochemicals that can be studied in bioinformatics and molecular modeling for the design of new anti-sars-cov- therapies. in an attempt to mitigate the symptoms of covid- , accelerate recovery, and reduce the mortality rate, several known drugs are being tested against sars-cov- , aiming at an antiviral action, the development of effective treatments, and prevention of infections by opportunistic microorganisms. the interaction of these drugs with proteins and viral receptors can be clarified through bioinformatics, which can identify the target and, with the support of molecular modeling, test the structural overlap, chemical interactions, and molecular coupling. studies like these are fundamental to elucidate the antiviral action mechanism of the compounds, favoring the projection of molecular modifications that modulate the affinity and specificity of the drug and, consequently, its aspects of pharmacological potency and safety. proposals for the repurposing of drugs known are a more reliable option for the development of an efficient and developed therapy with the urgency that the moment requires, to reduce the number of deaths [ ] . table presents studies on the effects of using drugs already known, and therapies with combinations of drugs, and the results of these research on the clinical condition of that infected and viral replication. these studies serve as a basis for more accurate analyzes of the drug's mechanism of action and the test outcome. in the context of the covid- pandemic, some studies and clinical reports describe the clinical worsening of some patients. the condition became known as cytokine storm or hypercytokinemia and is associated with increased mortality in infected patients. among the proposed pharmacological strategies, is the use of anti-cytokine molecules, such as anti-interleukin drugs and inhibitors of ifn-γ and tnf-α (see figure ) , capable of reducing the inflammatory process. the elucidation of the mechanisms associated with the action of immunomodulatory drugs on hypercytokinaemia is essential for the knowledge of safety regarding the use of these drugs, the best pharmacotherapeutic management, and the effectiveness to reduce the risk of death. bioinformatics, when applied to the analysis of inflammatory mediators, is a tool capable of evaluating the virus's performance and its ability to trigger an intense inflammatory response and how anti-cytokine molecules can normalize this condition. in this sense, bioinformatics aims to plan therapies that prevent the disease from worsening without causing immunodeficiency [ , ] . table shows the research results that used anti-cytokine compounds on respiratory function and inflammatory indexes in patients with covid- . the table reveals the clinical outcomes of the use of these substances, which can be investigated with the aid of bioinformatics and molecular modeling as a potential therapy against hypercytokinaemia resulting from sars-cov- infection, significantly reducing patient mortality. humans mg of aztm once daily on day , followed by mg once daily for the next days no benefit was seen [ ] mg/kg intravenously days improvement in respiratory and laboratory parameters [ ] mg/kg once daily days the treatment associated with hemoadsorption, improved gas exchange and reduced levels of inflammatory mediators [ ] sarilumab humans mg intravenously days treatment was associated with faster recovery [ ] days reduction of inflammation and rapid recovery [ ] mg _ clinical improvement and lower mortality [ ] [ ] it is crucial to mention that several of the drugs mentioned in this review have already received temporary regulatory approval. for example, remdesivir, hydroxychloroquine, chloroquine, and azithromycin are being used with consent in treatment protocols, depending on the country. the combination of these substances has also been used. despite this, studies on its effectiveness in the different stages of sars-cov- infection are controversial, and additional research is needed to elucidate the efficacy of these substances in infected patients. the use of molecular modeling at the early stages of searching for new bioactive compounds contributes to the faster development of new drugs at significantly reduced costs. given the low number of compounds with known anti-sars-cov- activity and considering the availability of structural models of potential molecular targets of the virus, the strategy based on the structure of the molecular target has been further explored, in which molecular docking techniques play a crucial role in this planning method. the compound pubchem cid , showed the highest potential to inhibit sars-cov- proteases during studies in search of possible molecular targets against the virus. about phytochemicals, the virtual libraries that store information about these compounds have already been extensively explored. among the selected compounds, pubchem cid , , and quercetin showed a strong interaction with clpro from sars-cov- . also, dihydrotansinone i interact strongly with spike glycoprotein and cryptotanshinone, with proteins plpro and clpro. marine compounds were also evaluated in silico against the main sars-cov- protease. the results identified different compounds as potential inhibitors of this protease, highlighting heptafuhalol a as the most promising. another virtual screening strategy that stands out among the research is the one that uses groups of drugs with antiviral action already approved for use in humans, characterizing a drug repositioning strategy. it was shown that digitoxin and zorubicin have a high potential for interaction with the sars-cov- spike glycoprotein. another highlight was the potential for ribavirin to interact with the plpro, lymecycline against clpro, and valganciclovir against rna-dependent rna polymerase, essential proteins for the survival of sars-cov- . besides, the present review showed that the pemirolast is promising as an inhibitor of the action of spikes glycoproteins. in addition to issues related to bioinformatics and molecular modeling, the details provided in the present review envision future points of consideration in the field of virology and medical sciences that will contribute to understanding the molecular mechanisms responsible for the pathogenesis and virulence of sars-cov- well as the development of the human acute severe respiratory syndrome. it is well established that the pathophysiology and lung injury caused by sars-cov- is related to innate immunity and factors such as the release of pro-inflammatory cytokines and the complement system action. besides, we strongly emphasize that: ( ) the complement system is an essential element of protective immunity against pathogens, but its excessive or unregulated activation can result in critical tissue damage and; ( ) the viral s subunit can be an important target for future antiviral compounds. thus, anti-s antiviral compounds may be potential treatments for sars-cov- infection. during this unprecedented period, we encourage scientists to actively contribute to understanding the role of the complement system in the development 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from real life asl napoli nord experience this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license we especially thank the research groups: research group on development of pharmaceutical products (p&dprofar); research group on biomolecules and catalyze; research group on biodiversity and health (biosa). the map for figure was "designed by freepik". we appreciate the opportunity to enrich our work with your art. we are grateful for the participation of everyone who contributed to the writing and revision of this manuscript. the authors declare no conflict of interest. key: cord- - bd adip authors: nepal, gaurav; rehrig, jessica holly; shrestha, gentle sunder; shing, yow ka; yadav, jayant kumar; ojha, rajeev; pokhrel, gaurab; tu, zhi lan; huang, dong ya title: neurological manifestations of covid- : a systematic review date: - - journal: crit care doi: . /s - - -z sha: doc_id: cord_uid: bd adip introduction: severe acute respiratory syndrome coronavirus (sars-cov- ) is responsible for the global spread of coronavirus disease (covid- ). our understanding of the impact this virus has on the nervous system is limited. our review aims to inform and improve decision-making among the physicians treating covid- by presenting a systematic analysis of the neurological manifestations experienced within these patients. methods: any study, released prior to may , , that reported neurological manifestations in patients infected by sars-cov- was systematically reviewed using the prisma (preferred reporting items for systemic review and meta-analysis) statement. results: our systematic review included data from articles: twelve retrospective studies, two prospective studies, and the rest case reports/series. the most commonly reported neurological manifestations of covid- were myalgia, headache, altered sensorium, hyposmia, and hypogeusia. uncommonly, covid- can also present with central nervous system manifestations such as ischemic stroke, intracerebral hemorrhage, encephalo-myelitis, and acute myelitis, peripheral nervous manifestations such as guillain-barré syndrome and bell’s palsy, and skeletal muscle manifestations such as rhabdomyolysis. conclusion: while covid- typically presents as a self-limiting respiratory disease, it has been reported in up to % of patients to progress to severe illness with multi-organ involvement. the neurological manifestations of covid- are not uncommon, but our study found most resolve with treatment of the underlying infection. although the timeliness of this review engages current challenges posed by the covid- pandemic, readers must not ignore the limitations and biases intrinsic to an early investigation. coronavirus disease is caused by the novel virus, severe acute respiratory syndrome coronavirus (sars-cov- ) [ ] . since its recent discovery in wuhan, china, coronavirus disease has spread across the world, leaving physicians challenged by its variable clinical manifestations. most patients infected by sars-cov- have presented with a mild clinical course: beginning with fever and dry cough, progressing to a form of mild or moderate respiratory disease, and resolving without specific treatment [ ] . serious complications of the infection, however, remain a central concern. acute respiratory distress syndrome, acute heart injury or failure, acute kidney injury, sepsis, disseminated intravascular coagulation, and lifethreatening metabolic derangements have all been reported in covid- patients, particularly among those with underlying comorbidities or advanced age [ , ] . as knowledge of sars-cov- and its clinical appearance continue to grow, the literature has shown a significant number of infected patients exhibit neurological symptoms [ , ] . in this systematic review, we evaluate various neurological manifestations reported in covid- patients and hypothesize their underlying pathophysiology. we deem the timeliness of this systematic review relevant, given the state of the covid- pandemic, but encourage readers to consider the implications of early review and analysis in the clinical setting. our systematic review utilized the prisma (preferred reporting items for systemic review and meta-analysis) statement in conjunction with the prisma checklist and flow diagram for manuscript format development [ ] . the following databases were reviewed for published studies prior to may , : pubmed, google scholar, and china national knowledge infrastructure (ckni). we also searched pre-print servers including research square, medrxiv, ssrn, and chinaxiv. boolean logic was used for conducting database search and boolean search operators "and" and "or" were used to link search terms. the following search strategy was adopted: covid- or sars-cov- or -ncov or ncov or novel corona and neurological or neurologic or brain or cns or nervous and manifestation or symptoms or presentation. titles, abstracts, and full text were screened to ensure they met eligibility criteria. two authors (gn and jhr) screened, retrieved, and excluded reports. additional investigators were consulted if uncertainty arose during the review process. we included any study, published in any language, which reported neurological manifestations in patients infected by sars-cov- . this included case reports and pre-print publications. we excluded all review articles, hypotheses papers, and papers reporting neurological symptoms in mers-cov and sars-cov patients. data was manually extracted from eligible studies by the research investigators. the following variables were included: first author, type of design, site of study, year of publication, published journal or pre-print server, sample size, and reported neurological manifestations. our outcome was to elucidate the neurological manifestations of covid- reported in the medical literature. the results were divided into three categories: central nervous system manifestations (e.g., headache, encephalopathy, and stroke), peripheral nervous system impairment (e.g., dysfunction of taste, dysfunction of smell, neuropathy), and skeletal muscle manifestations (e.g., myalgia). in total, our literature search yielded articles. after excluding duplicates and those not meeting inclusion criteria, papers were included in our systematic review. figure displays the results of our literature search and selection. the characteristics of each study are summarized in table . there were twelve retrospective studies [ , , , , - , , ] , two prospective studies [ , ] , and the rest were case reports/series. one article was a multicenter study [ ] , were from mainland china, six from the usa [ , , , , , ] , five from iran [ , , , , ] , four from italy [ , , , ] , and one each from japan [ ] , switzerland [ ] , and spain [ ] . out of all included studies, one was published in a premier news agency of china [ ] , eight were unpublished scientific articles deposited in pre-print servers [ , , , , [ ] [ ] [ ] [ ] , and the remaining were journal publications. eight retrospective studies reported covid- patients presenting with headache. we found that an overall average of . % of patients experienced headache (fig. ) . mao et al. reported that some of covid- patients with neurologic manifestation initially presented with fever and headache only. however, several days later, they developed cough, throat pain, lymphopenia, and a ground-glass appearance on their respective chest computed tomography (ct) images. real-time reverse-transcription pcr (rt-pcr) analysis of nasopharyngeal swabs confirmed covid- infection in these patients [ ] . a retrospective study from china reviewed cases of covid- , of which ( . %) developed hypoxic encephalopathy which progressed to death in ( . %) and recovery in ( . %) [ ] . a separate study from china reported encephalopathy in ( . %) out of cases, out of which one was obtunded, one was delirious, and six were comatose [ ] . among the deceased cases in both studies, there were high rates of acute respiratory distress syndrome (ards), respiratory failure, heart failure, and sepsis. three other case reports of covid- encephalopathy have been documented, one each from the usa [ ] , iran [ ] , and italy [ ] , with an age group spanning - . all three cases presented with symptoms of fever and cough for a duration of approximately days before the onset of confusion and asthenia. ct and magnetic resonance imaging (mri) of the brain were unremarkable. electroencephalogram (eeg) was employed in the usa and italy case which revealed diffuse slowing consistent with encephalopathy [ , ] . chloroquine, lopinavir, and ritonavir were administered in the first two cases. at the time of the report, the first patient was critically ill and the second had complete resolution of her symptoms [ , ] . the third patient showed dramatic response to high-dose steroids and with slightly more than a week of therapy, he was back at baseline mentation with a normal neurological examination [ ] . a retrospective observational study from wuhan, china, reported that six ( . %) patients, out of the reviewed covid- cases, developed ischemic stroke. of these six patients, two arrived at the emergency department owing to sudden onset of hemiplegia without any fever or upper respiratory tract symptoms. five of the six patients were severe cases of covid- . d-dimer levels were high in patients with severe disease, compared to non-severe, as well as in those with cns manifestations, compared to those without [ ] . a retrospective observational study from a different center in wuhan, china, found eleven ( . %) patients, out of reviewed covid- cases, developed acute ischemic stroke. those who had covid- infection with new onset of ischemic stroke were more likely to have a severe sars-cov- presentation, an advanced age ( . ± . years versus . ± . years), and preexisting cardiovascular risk factors including hypertension, diabetes, and previous cerebrovascular disease. an increased inflammatory response and hypercoagulable state, typified by raised crp and d-dimer levels, was also more common among these patients [ ] . three other cases of ischemic stroke were reported in china among covid- patients aged - . each of them initially presented with a dry cough. at least week later, they developed limb weakness, dysarthria, and tongue deviation. a ct scan of the brain revealed basal ganglia infarction in one case; normal findings were reported in the other two cases. laboratory studies showed elevated d-dimer, decreased fibrinogen level, prolonged prothrombin time (pt), and activated partial thromboplastin time (aptt). additionally, serum cytokine levels including il- , il- , and il- , were markedly elevated. all three patients recovered with good functional outcomes after stroke treatment and supportive therapy [ , ] . oxley et al. reported five cases of large-vessel stroke in patients younger than years of age from the usa. only three cases were symptomatic for covid- . the mean nihss score was at admission. ct brain, ct angiography, and/or mri revealed severe large-vessel stroke in all patients. all but one underwent mechanical thrombectomy. among these patients, d-dimer, ferritin, pt, and aptt were raised while the fibrinogen level was reduced. one was discharged home, two were transferred to a rehabilitation facility, and two were in the icu/stroke unit at the time of the report [ ] . a retrospective observational study from wuhan, china, reported one ( . %) patient, out of reviewed covid- cases, who developed intracerebral hemorrhage. he was a -year-old male cigarette smoker who presented to the hospital with a severe case of covid- . about a week later, he developed an intracranial hemorrhage and died. of note, his blood pressure averaged / mmhg during treatment [ ] . there are two case reports from iran, one of a year-old male with no medical history of hypertension or anticoagulation therapy [ ] and another of a year-old lady with a history of hypertension [ ] . both presented with an acute loss of consciousness preceded by fever and dry cough. initial glasgow coma scale (gcs) for them was seven and ten, respectively. coagulation studies were normal for both. the ct brain revealed massive intracerebral hemorrhage in the right hemisphere accompanied by intraventricular and subarachnoid hemorrhage for the former, and bilateral subacute basal ganglia hemorrhage in the latter, and a lung ct scan showed bilateral ground-glass opacities in both cases. the respective authors suspected the intracranial hemorrhage was secondary to infection with sars-cov- in both cases. six cases of encephalitis have been described to date; two from china [ , ] , two from switzerland [ ] , one from japan [ ] , and one from america [ ] . their ages range from early s to late s. all of them had preceding symptoms of fever and cough followed by a rapidly deteriorating level of consciousness. meningeal irritability in the form of nuchal rigidity, kernig's, and brudzinski's was reported in two out of the six cases [ , ] . where lumbar puncture (lp) was performed, it showed lymphocytic pleocytosis typical of a viral meningo-encephalitis [ , , ] . sars-cov- was detected in the cerebrospinal fluid (csf) in only one chinese patient [ ] and japanese patient [ ] . for one of the switzerland patients who presented with psychosis and focal status epilepticus, an eeg was done which showed abundant bursts of anterior low-medium voltage irregular spike and waves superimposed on an irregularly slowed theta background. this was managed with intravenous (iv) clobazam and valproate, and she had a marked improvement h after admission with the resolution of her symptoms [ ] . ct brain was normal in all but the case of the american whose scan demonstrated symmetric hypoattenuation within the bilateral medial thalami. she had a follow-up mri brain which revealed hemorrhagic, rimenhancing lesions within the bilateral thalami, medial temporal lobes, and subinsular regions. in her case, a presumptive diagnosis of covid- -associated acute necrotizing hemorrhagic encephalopathy was made, and she was thereafter started on intravenous immunoglobulin (ivig) [ ] . the mri of the patient from japan revealed right lateral ventriculitis and encephalitis mainly involving the mesial temporal lobe and hippocampus [ ] . mri brain performed for the switzerland patients were normal [ ] . at the time of writing, the chinese and switzerland patients recovered completely with supportive therapy [ , , ] , and the outcome of the patients from america and japan is not known. one case of acute disseminated encephalomyelitis (adem) has been reported in new jersey, america [ ] . the case was a female in her early s who presented with a -day history of dysphagia, dysarthria, and encephalopathy preceded by headache and myalgia. covid- nasal swab rt-pcr was positive. a lumbar puncture (lp) showed a csf with normal cell counts, protein, and glucose. ct brain showed multifocal patchy areas of white matter hypoattenuation and mri brain showed extensive patchy areas involving bilateral frontoparietal white matter, anterior temporal lobes, basal ganglia, external capsules, and thalami. she was treated with hydroxychloroquine, ceftriaxone, and a -day course of ivig. improvement was noted at the -day mark of therapy. one covid- case from wuhan, china, came with the presentation of acute myelitis. a -year-old male, with a -day history of fever, was admitted to the hospital after outpatient oral moxifloxacin hydrochloride and oseltamivir failed to improve his symptoms. ct scan of the chest found patchy changes in both lungs, and nasopharyngeal swab tested positive for sars-cov- . after a night of high fever, he developed bilateral weakness of his lower limbs, with urinary and bowel incontinence, rapidly progressing to flaccid lower extremity paralysis and paresthesia and numbness below t . planters were down going bilaterally. a clinical diagnosis of post-infectious acute myelitis was made. he received treatment with ganciclovir, lopinavir/ritonavir, moxifloxacin, dexamethasone, ivig, and mecobalamin. his bilateral lower extremity paralysis ultimately improved, and he was discharged to a rehabilitation facility [ ] . five studies assessed the prevalence of smell disorder. an overall average of . % of patients experienced olfactory disturbance (fig. ) . additionally, four studies assessed the prevalence of taste disorder. an overall average of . % of patients experienced taste disorder (fig. ) . a multicenter prospective study by lechien et al., reported time course of the aforementioned disorders. the olfactory dysfunction appeared before, in unison, and after the appearance of general symptoms in . , . , and . % of the cases, respectively. this olfactory abnormality persisted after the resolution of other symptoms in . % of cases [ ] . in an iranian study by moein et al., majority of patients with olfactory dysfunction reported that the onset of the olfactory dysfunction occurred at the same time or immediately after the onset of their other covid- symptoms [ ] . in china, a -year-old woman was admitted to the hospital for a left facial droop preceded by a -day history of pain in the mastoid region. there was no preceding fever, cough, or respiratory symptoms. physical examination showed a left lower motor neuron facial nerve paralysis. mri brain showed no abnormality. however, a throat swab rt-pcr turned positive for sars-cov- virus and the ct chest revealed ground-glass shadows in the right lower lung. the left facial paralysis was relieved after antiviral treatment with umifenovir and ribavirin [ ] . toscano et al. reported cases of guillain-barré syndrome (gbs) in covid- patients. the interval between the onset of viral illness and the first symptoms of gbs was between and days. the first symptoms of gbs were lower limb weakness and paresthesia in four patients and facial diplegia followed by ataxia and paresthesia in one patient. generalized, flaccid quadriparesis or tetraplegia evolved over a period of h to days in four patients; three received mechanical ventilation. csf analysis showed raised protein levels in two patients and raised lymphocytes in all five patients. csf rt-pcr for covid- was negative in all patients. neurological examination and nerve conduction studies were consistent with a demyelinating neuropathy in two patients, while the others were diagnosed as axonal variants of gbs. all five patients were treated with ivig; two received a second course of ivig and one required plasma exchange. four weeks after treatment, two patients remained in the icu and were receiving mechanical ventilation, two were undergoing physical therapy, and one was discharged without any residual symptoms [ ] . four other case reports of gbs, one in america [ ] , iran [ ] , italy [ ] , and china [ ] , respectively, were reported. age ranged from mid- s to s. all but the chinese patient presented with flu-like symptoms preceding weakness and/or numbness of the lower limbs with a progressive ascending paralysis; the chinese patient presented with neurological symptoms first and respiratory symptoms only on day of admission [ ] . in all cases, neurological examination and nerve conduction studies were consistent with a demyelinating neuropathy [ , [ ] [ ] [ ] . where lp was done, an albuminocytologic dissociation was revealed [ , ] . ivig was administered in the above case reports with variable response. two gbs variants have been described in a case series from spain. specifically, one case of miller fisher syndrome and one case of polyneuritis cranialis associated with covid- was described. the former case was a -year-old man who presented with anosmia, ageusia, right internuclear ophthalmoparesis, right fascicular oculomotor palsy, ataxia, areflexia, albuminocytologic dissociation, and positive testing for gd b-igg antibodies. five days prior, he had developed a cough, malaise, headache, low back pain, and a fever. the latter case was a -year-old man who presented with ageusia, bilateral abducens palsy, areflexia, and albuminocytologic dissociation. three days prior, he had developed diarrhea, a low-grade fever, and a poor general condition. the oropharyngeal swab for covid- by rt-pcr was positive in both patients and negative in the cerebrospinal fluid. the first patient was treated with ivig and the second with acetaminophen. two weeks later, both patients made a complete neurological recovery, except for residual anosmia and ageusia in the first case [ ] . an overall average of . % of patients reported experiencing myalgia in seven retrospective studies (fig. ) . the character and course of myalgia was not detailed in any of those studies. mao et al. reported that out of covid- patients, skeletal muscle injury occurred in ( . %). compared with the patients without muscle injury, patients with muscle injury had significantly higher levels of creatine kinase (median u/l [range . to , . ] versus median . u/l [range . - ]; p < . ). in addition, patients with muscle injury had higher c-reactive protein (crp) levels and d-dimer levels-manifestations of increased inflammatory response and associated coagulopathy. furthermore, patients with muscle injury showed more signs of multiorgan damage, including more serious liver and kidney abnormalities, than patients without muscle injury [ ] . a case report by jin et al. described a -year-old man in wuhan who presented with a -day history of fever and cough and a ct chest which showed bilateral ground-glass opacities. rt-pcr analysis of the patient's throat swab specimen indicated sars-cov- infection. he was treated supportively and with antivirals and antibiotics. on day of admission, the patient complained of pain and weakness in his lower limbs, and tenderness was noted on examination. urgent laboratory reports indicated raised myoglobin (> , . μg/l), creatine kinase ( , u/l), lactate dehydrogenase ( u/l), alanine aminotransferase ( u/l), and aspartate aminotransferase ( u/l). the patient's kidney function and electrolytes were normal. urinalysis revealed a lightyellow color of the urine, with positive occult blood and positive urine protein. these results indicated the onset of rhabdomyolysis. in addition to ongoing supportive therapy, the patient was treated with hydration, alkalization, plasma transfusion, and gamma globulin. the patient improved subsequently [ ] . coronavirus contains four structural proteins, including the spike protein (s), envelope protein (e), membrane protein (m), and the nucleocapsid protein (n). among them, the s protein plays the most important role in virus attachment, fusion, and entry. sars-cov- , like sars-cov, recognizes the angiotensin-converting enzyme (ace ) as a host cell entry receptor [ ] . high expression of the ace receptor is seen in type ii alveolar cells of the lung, intestine, esophagus, cardiomyocytes, proximal tubular cells, and urothelial cells [ ] . glial cells and neurons have been reported to express ace receptors, making the brain a potential target of covid- infection [ ] . how the virus enters the central nervous system is still a subject of debate. one plausible route of entry is through the olfactory nerve. retrograde transfer into the axon, whether through synapses, endocytosis, or exocytosis, could explain viral migration into the brain [ , ] . experimental studies using transgenic mice suggest that sars-cov and mers-cov may enter the central nervous system intranasally through the olfactory nerve. once in the brain, they have the potential to spread to the thalamus and brain stem, two regions highly involved in coronaviridae infections [ ] [ ] [ ] . a study evaluating specific receptors in the nasal mucosa, however, suggest sars-cov- may reach the brain through mechanisms independent of axonal transport via olfactory sensory nerves [ ] . another theory suggests if sars-cov- gained access to the general circulation, it could potentially invade the cerebral circulation and continue viral spread [ ] . slow movement in the cerebral microvasculature may promote interaction of the sars-cov- s protein and capillary endothelium ace receptor. once bound, the virus would have the potential to infect, damage, and bud from the capillary endothelium, thereby facilitating viral entry into the cerebrum [ , ] . sars-cov- could also cause damage to the central nervous system indirectly. viruses do not have to enter the brain to cause damage; they can activate an immune response that triggers subsequent damage within neuronal tissue. sars-cov- has been reported to cause a massive release of cytokines, a syndrome known as "cytokine storm"-downstream effects of this immune response include endothelial damage, disseminated intravascular coagulation, and disrupted cerebral autoregulation [ , ] . common symptoms elucidated from our systematic review include myalgia, headache, altered sensorium, hyposmia, and hypogeusia. acute viral respiratory tract infections have already been shown to cause the aforementioned neurological symptoms [ ] . peri-and postinfectious hyposmia and hypogeusia is hypothesized to be secondary to olfactory nerve and/or apparatus damage from direct insult of viral infection [ ] . according to the multicenter prospective european study by lechien et al., it appears that a large number of covid- patients experience olfactory and gustatory symptoms. in their study, olfactory and gustatory dysfunction occurred in . and . % of patients, respectively, with a majority of patients ( . %) experiencing abnormalities in olfaction after the appearance of their general symptoms [ ] . we found that in covid- patients, altered sensorium and encephalopathy were not uncommon. the basic pathological change seen in this disease is cerebral edema, with key clinical features being headache, confusion, delirium, loss of consciousness, seizure, and coma. covid- patients with encephalopathy were, by large, older male patients with cardiovascular comorbidities and severe infection with systematic inflammation and multi-organ dysfunction. early identification of covid- patients with altered sensorium is critical, as underlying potential reversible causes, including impending respiratory failure, require timely intervention [ ] . the pathophysiology behind the cerebral dysfunction is hypothesized to be in part inflammatory-mediated [ ] . this is supported by the fact that the encephalopathic italian patient had a dramatic response to high-dose steroids [ ] . ischemic stroke is another clinical entity which can present in patients with covid- infection. this presentation may arise secondary to a cytokine storm syndrome [ ] , which can cause endothelial damage, disseminated intravascular coagulation, and disrupted cerebral auto-regulation [ ] . through the ace receptor of the vascular endothelium, the virus's extensive invasion of the vascular endothelium obviously may cause extensive endotheliitis, increasing the risk of thrombosis leading to ischemic stroke. critically ill patients with severe sars-cov- infection often show elevated levels of d-dimer, a fibrin-degraded product which serves as a marker of dysfunctional activation of the coagulation system, such as in acute ischemic stroke [ , , ] . however, it is observed that the stroke prevalence in covid- patients and non-covid- patients are similar. two retrospective studies in wuhan, china, reported prevalence rates of between . - . % of acute ischemic stroke [ , ] which is consistent with the stroke prevalence in northeast china prior to the outbreak [ , ] . although the biochemistry suggests an association of covid- with disorders of the coagulation system, further studies are warranted to establish a relationship. for the three cases of covid- -associated intracerebral hemorrhage, a few potential explanations exist. it is known that the expression and the ability of ace receptor to lower blood pressure is reduced in patients with hypertension. in sars-cov- infection, the presence of s protein could further reduce the expression and function of ace proteins. this could potentially lead to uncontrolled hypertension, arterial wall rupture, and cerebral hemorrhage in infected patients [ ] . moreover, if the virus disseminates within the cerebral microvasculature, subsequent damage of capillary endothelial cells could result in a tear of the vasculature sufficient enough to cause parenchymal hemorrhage [ ] . additionally, covid- patients have been reported to have thrombocytopenia and coagulopathy, both of which are contributory factors for secondary brain parenchymal hemorrhage [ , ] . it is still unknown how covid- causes encephalomyelitis. it is thought that once viral particles gain entry into the milieu of the neuronal tissue, their interaction with the ace receptors in neurons could initiate a cycle of viral budding accompanied by neuronal damage. this can occur without substantial inflammation [ ] . in other cases, it may cause an acute inflammatory demyelination resulting in adem, which was described in one covid- case [ ] , and previously in mers-cov [ ] . covid- is also thought to cause acute hemorrhagic encephalitis through the mechanism of a cytokine storm [ ] . acute hemorrhagic leukoencephalitis is a rare demyelinating disorder that is usually fatal; icu care, use of high-dose corticosteroid therapy, immunoglobulins, plasma exchange, and dehydrating agents have led to survival in only some patients [ ] . this has been seen in one covid- case thus far [ ] . three neuro-immunological entities related to covid- infection surfaced in our systematic review: acute transverse myelitis, gbs and its variants, and bell's palsy [ , , ] . the time course of the disease is alike what is known for other viruses known to cause the above in that the symptoms of respiratory or gastrointestinal infection usually precede that of the neuroimmunological phenomena [ ] . this was seen in all cases in this report with the only exception being the gbs case report from china [ ] . this suggests that the underlying mechanism of such neuro-immunological phenomena in covid- patients is likely to be grounded by the hypothesis of molecular mimicry, where mimicry between microbial and nerve antigens is thought to be a major driving force behind the development of the disorder [ ] . there are a number of limitations in our study. most of the studies included in this systematic review are case reports/series and retrospective observational studies. the larger retrospective studies included were limited to the documentation of common neurological symptoms, such as headache, myalgia, and a loss in sense of taste and/or smell. furthermore, the timeliness of our systematic review presents potential for premature analysis of data trends in the literature. given the current pandemic, the authors of this study felt that the benefits of systematic data retrieval and review outweighed current risks of inaccurate predications. our aim was to synthesize data to aid physicians currently treating the novel covid- , knowing time constraints inhibited their own analysis of the evolving literature on neurological manifestations. our systematic review comprehensively detailed the neurological manifestations of covid- known to date. respiratory symptoms remain the hallmark of early identification, cohorting, and treatment of covid- , bearing in mind that in a number of cases it has been observed that neurological manifestations may precede it in the course of the disease. clinical characteristics of coronavirus disease in china clinical features of patients infected with novel coronavirus in wuhan covid- in critically ill patients in the seattle region-case series neurologic complications of 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neuronal death in the absence of encephalitis in mice transgenic for human ace non-neural expression of sars-cov- entry genes in the olfactory epithelium suggests mechanisms underlying anosmia in covid- patients. biorxiv preprint neurotropism of sars-cov : mechanisms and manifestations preventing covid- -induced pneumonia with anticytokine therapy inflammatory cytokines and ischemic stroke risk: the regards cohort aneta nitsch-osuch and ls. pathophysiology of clinical symptoms in acute viral respiratory tract infections hypogeusia, dysgeusia, hyposmia, and dysosmia following influenza-like infection covid- : icu delirium management during sars-cov- pandemic nervous system involvement after infection with covid- and other coronaviruses surviving sepsis campaign: guidelines on the management of critically ill adults with coronavirus disease (covid- ) prevalence of stroke and associated risk factors: a population based cross sectional study from northeast china prevalence, incidence, and mortality of stroke in china: results from a nationwide populationbased survey of adults coagulopathy and antiphospholipid antibodies in patients with covid- severe neurologic syndrome associated with middle east respiratory syndrome corona virus (mers-cov) acute hemorrhagic leucoencephalitis guillain-barré syndrome publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none we received no funds for conducting this study. ethics approval and consent to participate not applicable. not applicable. none of the authors has any conflict of interest to disclose. we confirm that we have read the journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. key: cord- -e ao j authors: han, dongsheng; li, rui; han, yanxi; zhang, rui; li, jinming title: covid- : insight into the asymptomatic sars-cov- infection and transmission date: - - journal: int j biol sci doi: . /ijbs. sha: doc_id: cord_uid: e ao j the existence of a substantial but unclear number of asymptomatic sars-cov- patients worldwide has raised concerns among global public health authorities. in this review, according to the published literature, we provided the evidence that asymptomatic infections can result in person-to-person transmission. four studies suggested that the virus can be transmitted by asymptomatic patients for at least two consecutive generations, indicating its strong infectivity. asymptomatic infection tends to be, but is not only, identified among young people (< years old). the majority of asymptomatic patients appear to have a milder clinical course during hospitalization, but the severity of the symptoms of the secondary patients infected by sars-cov- from asymptomatic patients varies with their physical constitution. the proportion of asymptomatic individuals among all confirmed cases widely differed (from . % to . %) according to the study setting and the populations studied. the increasing large-scale tests are expected to give more information about the true number of asymptomatic infections in the population. in china and other countries, various guidelines for management of asymptomatic cases have been issued. importantly, early detection, early reporting, early isolation and early treatment of asymptomatic patients require the joint efforts of policy makers, clinicians, technicians, epidemiologists, virologists and patients. the covid- pandemic caused by the sars-cov- virus is now straining or overwhelming health care systems worldwide. the clinical manifestations of covid- are protean, including asymptomatic carrier, acute respiratory disease, and pneumonia of varying degrees of severity [ ] . through the joint efforts of government administrations, academic institutions, medical workers, technology enterprises and ordinary community residents, the epidemic in china has been basically brought under control. however, in many countries, new infections and deaths are still increasing. as of july , , over million confirmed cases and more than , fatalities at a global scale have been attributed to covid- infection. as the situation is rapidly evolving, it is unclear what the final scope and impact of this pandemic will be. in addition to the potent transmissibility of the virus itself, there is increasing evidence that unnoticed, asymptomatic cases in the infected population may greatly accelerate the spread of sars-cov- from person to person [ ] [ ] [ ] . therefore, strict screening and management of patients with asymptomatic infection may be a key breakthrough to control the spread of the pandemic [ ] . asymptomatic covid- patients are those who carry the virus but do not show any symptoms (e.g., fever, gastrointestinal or respiratory symptoms), and no ivyspring international publisher significant abnormalities on chest radiograph at time of laboratory confirmation [ , , ] . however, asymptomatic cases are difficult to identify because they seem to be normal except for the presence of viruses in their bodies, making the transmission caused by these silent patients difficult to prevent. moreover, in the early stage of the outbreak, all medical resources tended to be used for the identification and management of critically ill patients, and asymptomatic patients have not attracted attention. these factors have led to a lack of systematic awareness of the prevalence and potential role of asymptomatic disease. due to heightened concerns of the risks posed by these stealth virus carriers, china has published the numbers and conditions of asymptomatic people every day since april and has further promulgated guidance for the management of asymptomatic covid- cases nationwide [ ] . in this review, based on the findings of existing studies and reports, we summarize the clinical and epidemiological characteristics and discuss current screening and management strategies for asymptomatic patients. this knowledge is critical to design and implement efficient and globally coordinated interventions. according to recently published studies, we reviewed the clinical, virological and epidemiological characteristics of asymptomatic infections, which were usually determined by reverse transcriptionpolymerase chain reaction (rt-pcr) ( table ) . we found that ( ) some asymptomatic cases at the time of the earliest test remained asymptomatic throughout the whole duration of laboratory and clinical monitoring, while others, which may account for approximately %, experienced clinical symptoms at a later stage of infection (presymptomatic patients) [ ] [ ] [ ] [ ] ; ( ) the viral load in respiratory specimens of asymptomatic patients was similar to that in symptomatic patients, ranging from × to × copies per milliliter [ , ] ; ( ) the period of positive nucleic acid tests of asymptomatic patients (the interval from the first day of positive nucleic acid tests to the first day of continuous negative tests) could be up to weeks (ranging from - days) [ , ] ; ( ) hoehl et al. successfully isolated sars-cov- from throat swabs of two asymptomatic patients in a cell culture of caco- cells, suggesting the potential for presymptomatic transmission [ ] ; ( ) increasing studies show clear epidemiological evidence of human-to-human asymptomatic spread of covid- (described in the following section); ( ) asymptomatic infection tends to be, but is not only, identified among young people (< years old) [ , , [ ] [ ] [ ] ; and ( ) the majority (> %) of asymptomatic patients appears to have a milder clinical course during hospitalization [ ] , but the severity of the symptoms of the secondary patients infected by sars-cov- from asymptomatic patients varies based on their physical constitution [ , ] . these findings may be adjusted as the pandemic continues to unfold. with the accumulation of more research data, researchers will thoroughly clarify the occurrence, development and outcome of asymptomatic infections, providing reliable evidence for finalizing prevention, diagnosis and treatment strategies. asymptomatic transmission could be defined as the transmission of sars-cov- from an asymptomatic person (source or index patient) to a secondary patient, as ascertained by exposure and symptom onset dates, with no evidence that the secondary patient had been exposed to anyone else with covid- [ ] . asymptomatic transmission is driven by two groups of patients, one with no self-perceived symptoms or clinically detectable signs throughout the days of quarantine and the other in the incubation period (i.e., the time period between getting infected and showing symptoms) (presymptomatic transmission). as early as january , chan et al. reported evidence of human-to-human transmission of sars-cov- in family settings, suggesting that asymptomatic patients might serve as a possible source to propagate the outbreak [ ] . by estimating the epidemiological data of distinct outbreak clusters from singapore and tianjin, china, tindale et al. identified that the serial interval (i.e., the number of days between symptom onset in a primary case and a secondary case) was shorter than the incubation period of sars-cov- by - days, supporting the likelihood that sars-cov- viral shedding can occur in the absence of symptoms and before symptom onset [ ] . similar findings were reported by other researchers [ ] [ ] [ ] . to date, epidemiologic studies have clearly documented sars-cov- transmission during the asymptomatic period. the evidence was mostly observed in cluster outbreaks, especially in family cluster outbreaks that occurred in china (figure ). in general, in these clusters, there is a clear history of contact between the source patients and the secondary patients; there is no other explanation for the infection; and according to the epidemiological survey, the source patients were asymptomatic when transmitting the virus to the secondary patients. for example, a study reported in january identified five patients with covid- pneumonia infected by a -year-old asymptomatic woman (the source patient) who was thought to have acquired sars-cov- infection from the epidemic center of wuhan [ ] . this source patient showed no symptoms during the entire period of monitoring and isolation ( figure a) . tong et al. identified covid- patients (patients a and d) after their exposure to an asymptomatic person from wuhan who was later confirmed to be positive for sars-cov- [ ] . patients a and d later transmitted sars-cov- to family members (patients b, d and e) ( figure b) . li et al. confirmed asymptomatic and human-to-human transmission through close contacts in familial and hospital settings by analyzing the epidemiologic, laboratory, and clinical data of covid- patients in a -family cluster [ ] . the epidemiological survey showed that the source patient ( -year-old man) had stayed at hankou station in wuhan, china for hours on his way from guangzhou to xuzhou ( figure c ). qian and colleagues reported a family cluster of asymptomatic covid- transmission in zhejiang china [ ] . two source patients became infected with sars-cov- after a visit to a temple and then transmitted the virus to four other family members before experiencing symptoms. the four secondary patients then unknowingly (because they were asymptomatic) infected three other relatives through close contact ( figure d) . importantly, the latter three reports provided by tong et al., li et al. and qian et al. together with another report from luo et al. [ ] , showed that sars-cov- can be spread through sustained transmission (at least two generations of spread) through asymptomatic/presymptomatic individuals ( figure b-e) , suggesting that the virus has a strong infectivity. in another study in mainland china, the source patient (case ), who had a travel history to the city of huanggang, hubei province on jan - , and was diagnosed as an asymptomatic covid- carrier, transmitted the virus to his cohabiting family members [ ] ( figure f ). in addition, the transmission of sars-cov- infection from asymptomatic contacts has also been reported in other countries outside china, such as germany [ ] , the usa [ ] and singapore [ ] . . the label (letter or number) on each person represents the person's id in the original literature. the cluster outbreaks are as follows: a is from reference [ ] , b is from reference [ ] , c is from reference [ ] , d is from reference [ ] , e is from reference [ ] , and f is from reference [ ] . in all the above reports, the source patients remained without any symptoms of infection during the clinical course ( figure a, d and f) , or developed varying degrees of pneumonia ( figure b, c and e) . through comprehensive analysis of asymptomatic covid- patients screened among close contacts, the authors reported that asymptomatic carriers among the close contacts were prone to mild illness during admission. however, the communicable period could last as long as days, and the communicated patients could develop severe illness [ ] . in four clusters of covid- in singapore, asymptomatic transmission occurred approximately - days before the source patient developed symptoms [ ] . since asymptomatic transmission is an established fact, how many individuals in the infected population are attributed to asymptomatic transmission? several studies have made preliminary assessments. for example, using available data of confirmed covid- cases compiled from online reports from provincial centers for disease control and prevention (cdc) in china, du et al. identified that presymptomatic transmission might be responsible for . % ( ) of confirmed cases [ ] . in the singapore outbreak, . % ( / ) of locally acquired cases were attributed to presymptomatic transmission [ ] . another study published by scientists in belgium and the netherlands showed that up to % ( % ci: - %) of the included covid- cases in singapore and % ( % ci: - %) of the included covid- cases in tianjin, china contracted the infection from someone who was presymptomatic [ ] . now that the transmission of sars-cov- through asymptomatic patients via person-to-person contact has been confirmed, reliable estimations of the proportion of asymptomatic infections among all covid- patients are crucially needed to guide public health policy, especially to clarify the intensity and range of social distancing strategies to be implemented to prevent the spread of covid- [ ] . robert redfield, director of the us cdc, warned that up to a quarter of covid- patients may not display any symptoms [ ] . we summarized the data of currently published literature. overall, the detected asymptomatic proportion widely differed (from . % to . %) in the available studies with more than confirmed individuals (table ) . this situation is similar to the reported asymptomatic proportion of mers-cov (another coronavirus that infects humans) infections, which is varied from . % to . % based on the populations studied [ ] . although reliable comparison may not be possible due to the differences in the study setting and the included populations, it can be seen, in general, that the asymptomatic proportions of sars-cov- infections reported in china (< %) and singapore (< %) are lower than those reported in japan (> %), iceland (> %) and the united states (> %) ( table ) . according to the national health commission (nhc) update, as of april , a total of , asymptomatic infections were reported nationwide in china, close to % of all confirmed sars-cov- cases (approximately , cases) [ ] . in pediatric patients (< years of age) with covid- , a nationwide epidemiologic survey in china showed that . % ( / ) of cases were asymptomatic [ ] . in wuhan city, . % ( / ) of diagnosed children did not exhibit any symptoms of infection or radiologic features of pneumonia during the course of hospitalization [ ] . the latest implemented universal sars-cov- testing in all pregnant patients presenting for delivery in new york city revealed that at this point in the pandemic, . % of the patients who were positive for sars-cov- at delivery were asymptomatic, underscoring the risk of covid- among asymptomatic obstetrical patients [ ] . several studies suggested that the vast majority of cases (approximately %) that were asymptomatic at the time of testing would eventually develop into symptomatic cases [ ] [ ] [ ] , highlighting the importance of timely detection, treatment and management of asymptomatic patients. however, most of the above results were not obtained by random sampling or testing all individuals in the population, but mainly through the analysis of screening data from high-risk groups (i.e., individuals who have symptoms, have traveled to areas infected with the virus or have been in contact with infected patients). thus, these early results might not accurately reflect the real situation of the entire population. the large-scale population tests launched in increasing countries/regions are expected to reveal the true number of sars-cov- infections in the population and the contribution of asymptomatic individuals. recently, iceland reported the results of its population screening based on nucleic acid testing, and found that % of the participants who tested positive had no symptoms [ ] . importantly, before large-scale testing begins, full consideration should be given to the rationality of the research design, the standardization of the experimental operation, and the reliability of the quality of the reagents/kits. this is the premise to ensure the reliability of the final results. the current first-line laboratory diagnostic tests for covid- worldwide include nucleic acid testing (mainly rt-pcr) and rapid serological antibody (mainly igm and igg) testing. as the transmission of sars-cov- may occur in the early course of infection and a high viral load in respiratory samples could be detected [ ] , rt-pcr testing for this virus is more suitable for screening at earlier stages of infection in key populations, such as patients with obvious symptoms and close contacts of asymptomatic patients [ ] . however, due to various factors (such as nonstandard sampling, inadequately trained personnel, unqualified reagents, etc.), false negative results in nucleic acid testing are almost inevitable [ ] . it has been reported that the detection rate of currently available rt-pcr methods is between % and % [ ] [ ] . the issues contributing to false negative results in nucleic acid assays include insufficient viral load in infected persons, nonstandard sampling and handling, imperfect sensitivity of in vitro diagnostic reagents, and inadequate clinical laboratory testing capabilities [ ] . for some cases, multiple samples and repeated testing may be required to obtain a final diagnosis [ ] . in addition, in the early stages of outbreaks, many countries did not have sufficient reagents to carry out large-scale testing, which led to nucleic acid testing being more inclined to be performed on persons with obvious symptoms and reduced the detection for asymptomatic infections [ ] . in theory, nucleic acid testing will miss individuals who have been asymptomatic for past infections (convalescent cases). these reasons make the true number of infected individuals, including asymptomatic individuals, in the population is currently unclear. detecting serum antibodies is an effective supplement to nucleic acid assays. data show that the positive rate can be increased from . %, for a single rt-pcr test, to . % when combining an igm antibody assay with an rt-pcr test [ ] . serological assays are rapidly being developed and have proven to be useful in confirming covid- infection [ , ] . in view of its simple operation and low cost, serological detection is suitable for large-scale screening [ ] . a study showed that the median time of igm antibody response was days (interquartile range [iqr], - ), while the appearance of igg antibody occurred on day (iqr, - ) after symptom onset [ ] . thus, serological testing is unlikely to play an important diagnostic role in the early stage of sars-cov- infection, but is more suitable in retrospective investigations for accurately determining the burden of infection, the contribution of asymptomatic infection, the basic reproduction number and total mortality, which have important implications for public health [ , ] . eran et al. carried out serologic testing for sars-cov- antibodies in , people in santa clara county, northern california, suggesting that the actual number of infected people may be -to -fold the reported number of confirmed cases [ ] . however, the reliability of antibody kits they used was been questioned by some scientists because of the lack of rigorously assessment. on april - , a random seroprevalence survey of residents in los angeles county, california suggested that only . % ( / ) of the tested people have sars-cov- antibodies, suggesting that most people are still susceptible to contracting covid- [ ] . at present, large-scale serological screening projects are running in many countries and regions [ ] [ ] [ ] , if the study design is rigorous (full consideration is given to variation factors such as sampling, research population, reagent quality, etc.), the results of which will have important guiding significance for understanding the true number of asymptomatic infections and controlling the current disease outbreak worldwide. asymptomatic cases are easily neglected in disease screening and epidemic prevention. the asymptomatic covid- patients who have been identified include close contacts of covid- cases during their medical observation period, individuals involved in cluster outbreaks, people who were unknowingly exposed to infected patients and were identified when the infection source was being traced, and individuals who recently traveled to areas/ countries/regions with high infection rates (i.e., imported cases) [ , ] . however, in reality, there may be more undetected asymptomatic patients. these cases may not be aware that they have been infected and therefore will not actively self-isolate or seek medical attention [ ] , or they may be misdiagnosed during the screening and thus transmit the virus to others unknowingly. this situation complicates fighting the pandemic, forcing healthcare workers around the world to shift their focus from containing the infection to mitigation [ ] . as the large-scale domestic epidemic has passed, one of china's current core tasks is to strictly screen, report and manage patients with asymptomatic infections to prevent possible future outbreaks. the actions china takes next will provide experience for the rest of the world to respond to the subsequent sars-cov- outbreak. on april , , china's state council issued guidance for the management of asymptomatic covid- cases [ ] . briefly, the guidelines call for standardized reporting of asymptomatic cases, which means that all healthcare facilities should report asymptomatic cases detected by them within hours through direct online reporting. county-level cdcs are required to complete a case investigation within hours after receiving the report of an asymptomatic case and report all the close contacts of the case. then, the asymptomatic case and all the close contacts need to undergo a -day centralized quarantine for medical observation. similarly, days of active monitoring or quarantine for contacts of asymptomatic cases are also recommended by other countries [ , , ] . once the individuals complete the -day quarantine and test negative twice in a row with one test every hours, they are released from medical observation. those who show no symptoms and still test positive will be kept under centralized medical observation. if asymptomatic cases display clinical manifestations during the period of centralized medical observation, they shall be immediately transferred to designated medical institutions for standardized treatment in accordance with the confirmed cases [ ] . furthermore, the guidance also pointed out that those who are released from centralized quarantine still need to be under medical observation for another fortnight. this strategy is useful in monitoring the risk of possible recurrence of the virus in recovered covid- patients [ , ] . these series of management measures for asymptomatic patients in china are very strict compared to those of other countries. in the united states and the united kingdom, asymptomatic patients might discontinue isolation if they still have no symptoms within one week of the first positive covid- diagnostic test [ , ] . there are currently no proven pharmaceutical treatments (vaccines or antivirals). rigorous implementation of traditional public health measures such as isolation and quarantine, social distancing and community containment is now the preferred option to reduce transmission of the virus [ , ] . since the sars-cov- outbreak began, china has implemented all these nonpharmaceutical measures, such as case isolation, contact tracing and quarantine, physical distancing and community containment, with unprecedented efforts and successfully curbed the spread of the virus across the country in a relatively short period of time [ , ] . other countries are also aware of the necessity of implementing such measures. once community transmission is detected, implementing the combined intervention of isolating infected individuals and their family members (including voluntary isolation at home); closing schools, factories or office buildings; suspending public markets; cancelling gatherings; and even locking-down affected cities are recommended [ , , , [ ] [ ] [ ] . related studies have also suggested the importance of these measures in reducing sars-cov- spread, including the spread from asymptomatic individuals [ , [ ] [ ] [ ] . furthermore, for personal protection, wearing masks is another important public health intervention for limiting the spread of respiratory pathogens. as transmission from asymptomatic infected individuals has been documented for covid- , wearing masks in public places would help to intercept the transmission and prevent the spread by these apparently healthy infectious sources (asymptomatic patients) [ ] [ ] [ ] . other suggestions should be accepted as well, such as restricting movement in affected cities, avoiding close contact with patients who are symptomatic, avoiding unnecessary gatherings, and washing hands frequently (with soap and water for at least s) [ ] [ ] [ ] . when coming into contact with confirmed/suspicious patients, people should proactively inform health authorities and seek testing to determine whether they are infected. addressing covid- is now an urgent health and social concern. however, controlling the pandemic only by detecting, isolating and treating symptomatic or critically ill patients is not sufficient because accumulating evidence has confirmed the asymptomatic transmission of sars-cov- . several studies have even suggested that the virus can be transmitted by asymptomatic patients for at least two consecutive generations, indicating its strong infectivity. therefore, it is of great public health significance to screen and manage asymptomatic patients and their close contacts via multiple strategies to contain potential outbreaks. several scattered studies have evaluated the contribution of asymptomatic patients in the population. however, there is no comparability between their results due to the differences in the distribution and size of the studied populations, so the true scale of asymptomatic infections remains unclear. ongoing large-scale population screening is expected to answer this question. studies have provided a cautionary warning that sars-cov- virus may be transmitted through multiple routes in addition to the most common respiratory droplet spread. it is necessary to fully consider the sample type and sampling time to improve the detection rate. in addition, a combination of molecular and serological tests is needed to identify virus carriers when necessary. asymptomatic patients themselves should complete the standard isolation and treatment process as required by governments and doctors. additionally, when considering that the spread of sars-cov- may occur through respiratory droplets, contact with contaminated objects or fecal viral shedding, which is currently being investigated [ , ] , individuals should also 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infected pneumonia (standard version) preventing the spread of covid- in a variety of settings throughout your community characteristics of pediatric sars-cov- infection and potential evidence for persistent fecal viral shedding the epidemiological characteristics of infection in close contacts of covid- in ningbo city suppression of a sars-cov- outbreak in the italian municipality of vo'. nature. . in press spread of sars-cov- in the icelandic population prevalence of sars-cov- infection in residents of a large homeless shelter in boston this work was supported by the "aids and hepatitis, and other major infectious disease control and prevention" program of china under grant (no. zx ) and the national natural science foundation of china under grant (no. ). the funder had no role in study design, data collection, analysis, interpretation, or writing of the paper. the authors have declared that no competing interest exists. key: cord- -g v xc authors: yang, wenjing; sirajuddin, arlene; zhang, xiaochun; liu, guanshu; teng, zhongzhao; zhao, shihua; lu, minjie title: the role of imaging in novel coronavirus pneumonia (covid- ) date: - - journal: eur radiol doi: . /s - - - sha: doc_id: cord_uid: g v xc almost the entire world, not only china, is currently experiencing the outbreak of a novel coronavirus that causes respiratory disease, severe pneumonia, and even death. the outbreak began in wuhan, china, in december of and is currently still ongoing. this novel coronavirus is highly contagious and has resulted in a continuously increasing number of infections and deaths that have already surpassed the sars-cov outbreak that occurred in china between and . it is now officially a pandemic, announced by who on the th of march. currently, the novel coronavirus (sars-cov- ) can be identified by virus isolation or viral nucleic acid detection; however, false negatives associated with the nucleic acid detection provide a clinical challenge and thus make the imaging examination crucial. imaging exams have been a main clinical diagnostic criteria for the novel coronavirus disease (covid- ) in china. imaging features of multiple patchy areas of ground glass opacity and consolidation predominately in the periphery of the lungs are characteristic manifestations on chest ct and extremely helpful in the early detection and diagnosis of this disease, which aids prompt diagnosis and the eventual control of this emerging global health emergency. key points • in december , china, an outbreak of pneumonia caused by a novel, highly contagious coronavirus raised grave concerns and posed a huge threat to global public health. • among the infected patients, characteristic findings on ct imaging include multiple, patchy, ground-glass opacity, crazy-paving pattern, and consolidation shadows, mainly distributed in the peripheral and subpleural areas of both lungs, which are very helpful for the frontline clinicians. • imaging examination has become the indispensable means not only in the early detection and diagnosis but also in monitoring the clinical course, evaluating the disease severity, and may be presented as an important warning signal preceding the negative rt-pcr test results. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. in december of , the city of wuhan, located in the hubei province of china, became the epicenter of an outbreak of a pneumonia of unknown cause. this pneumonia was later confirmed to be secondary to infection by a novel coronavirus. this virus was originally called the novel coronavirus ( -ncov), but on february , , the disease was named covid- by the world health organization (who), and the virus was named "severe acute respiratory syndrome coronavirus " (sars-cov- ) by the international committee on taxonomy of viruses (ictv). it is believed that the covid- outbreak has a zoonotic origin and began in the huanan wet seafood wholesale market in wuhan. sars-cov- has proven to be extremely contagious and spreads easily from person to person. cases of covid- have now spread beyond wuhan to many other provinces in china as well as other countries, which has raised international attention and concern. as of march , , more than , human infections with sars-cov- and at least deaths related to covid- have been confirmed in china alone. although the epidemic situation in china has been relatively under control, the situation outside china is getting worse. so far, the covid- viral disease that has swept into at least countries with more than , cases diagnosed and more than people killed is now officially a pandemic, as who director-general tedros adhanom ghebreyesus announced in geneva on march . at first, covid- appeared in a few clusters and was more likely to affect persons with advanced age or other comorbidities, but it is now more widespread. infection can result in severe pneumonia and even fatal respiratory diseases such as acute respiratory distress syndrome (ards) [ , ] . the main clinical presentation includes fever, dry cough, fatigue, and malaise and/or non-specific upper respiratory tract infection symptoms that may not be particularly noticeable. as previously reported [ ] , patients with severe illness can develop dyspnea and some even developed ards and required icu admission and oxygen therapy. laboratory findings of patients infected with sars-cov- include lymphopenia, elevated crp, and erythrocyte sedimentation rate. genetic sequencing of sars-cov- has enabled the rapid development of point-of-care real-time rt-pcr diagnostic tests specific for covid- [ , ] . novel coronavirus nucleic acids are detected in throat swabs, sputum, lower respiratory tract secretions, and blood. at present, the diagnosis of covid- is primarily based on the patient's epidemiological history, clinical symptoms, chest imaging findings, and etiological evidence. viral nucleic acid testing is an important diagnostic criterion; however, it has some limitations. false negatives from viral nucleic acid testing arise from the uneven quantity of detection technology, disease characteristics (asymptomatic patients), and status of epidemic prevention and control, as well as errors in clinical sampling [ ] . covid- is highly contagious; thus, early detection and diagnosis are of paramount importance to isolate suspected cases and contacts to control the outbreak. the challenges in identification of pathogens by viral nucleic acid testing have made some frontline clinicians propose ct as a diagnostic method for identifying covid- patients. this review aims to briefly introduce the novel coronavirus pneumonia and highlight the value of imaging in its diagnosis. coronaviruses typically result in respiratory and enteric infections and affect both animals and humans. six coronavirus species are known to cause human infection, two of which typically can cause severe respiratory illness and fatalities: sars-cov (severe acute respiratory syndrome coronavirus) which had an outbreak in guangdong, china, between and and mers-cov (middle east respiratory syndrome coronavirus) which had an outbreak in outbreaks in the middle east [ , ] . by january , , chinese scientists had isolated the novel coronavirus from patients in wuhan [ ] . it has been reported [ ] that sars-cov- was more similar to two bat-derived coronavirus strains (bat-sl-covzc and bat-sl-covzxc ) than to known human-infecting coronaviruses, including the virus that caused the sars outbreak of . molecular modeling has shown structural similarity between the receptor-binding domains of sars-cov and sars-cov- , which suggests that sars-cov- may use angiotensin-converting enzyme (ace ) as a receptor. the differences of the etiological characteristics among sars-cov, mers-cov, and sars-cov- are shown in table . on december , , the health commission of hubei province in china announced that patients were afflicted with this mysterious disease, which was subsequently discovered to be covid- . the outbreak is believed to zoonotic in origin and likely started at the huanan wet seafood wholesale market in wuhan. sars-cov- is highly contagious and the basic reproductive number of the virus was estimated to be · [ , ] . covid- has spread beyond wuhan to other cities in china and other countries. in recent days, there is a significant growth trend in other countries, especially in south korea, japan, italy, and iran. the current global situation as of march , of covid- is shown in fig. . in the available reports, the bat is the most possible host of the sars-cov- and another animal may act as an intermediate host between bats and humans [ , ] . to this point, the main infection sources were the patients infected with sars-cov- . covid- mainly spread via human-to-human transmission through respiratory droplets and contact. the human population in general is susceptible, while the elderly as well as people with underlying diseases show more serious conditions after infection [ ] . although most people were reported to have a good prognosis of covid- , it is unknown whether there are potential impacts on the patients in the future and the sequelae are not available. in the case of the sars outbreak, significant impact on pulmonary function, functional capacity, and quality of life was found during patient followup [ , ] . the additional and detailed information about "etiology and epidemiology" is provided in electronic supplementary material (esm). according to current diagnostic criteria, identification of the viral pathogen via nucleic acid detection (usually from swab test) is considered as the gold standard and formative assessment for the diagnosis of covid- [ ] . however, due to various problems of virus detection in the clinical setting such as a shortage of supply test kits, irregular sampling of samples, laboratory error, insufficient viral material in the specimen, improper extraction of nucleic acid from clinical materials, and contaminatory and technical problems, there have been false negatives. health care workers on the front line have found the diagnostic value of imaging to be increasingly valuable, which has translated over into clinical diagnosis of covid- patients [ ] . in the clinical work of this epidemic, the radiologists play a crucial role in the rapid identification and early diagnosis of a suspected patient-this can be of great benefit not only to the patient but also to the larger public health surveillance and response systems. chest radiograph of covid- is not routinely recommended in clinical practice currently because they are insensitive to detecting covid- in the early stage. however, chest radiography may have some utility, with the potential to serve as a screening tool on the frontlines in medical settings with limited resources or in cases where the patient's physical condition does not allow for transport to the radiology department ct scanner. as the disease progresses beyond the early stage, chest radiography can detect multiple patchy opacities throughout the lungs. these opacities eventually become confluent and severe cases may appear as a "whited out lung" [ ] . in more advanced cases, in addition to the ground glass opacity and consolidation, even pleural fluid (in a severe case) has been reported on the chest radiographs [ , ] . progressive opacities and consolidation have been observed on chest radiographs over the time course of the illness [ ] . in the first case of covid- reported in the usa, there were no obvious abnormalities on the chest radiograph during the early stages after the onset of symptoms. however, on day of the illness, an increased area left basilar opacity was visible on chest radiography. then, stable streaky opacities in the lung bases were visible, and the opacities have steadily increased over time [ ] . computed tomography (ct) imaging is strongly recommended because it is very sensitive to detecting early disease, assessing the nature and extent of lesions, and discovering subtle changes that are often not visible on chest radiography. the imaging features of lesions are always described with the following factors: distribution, quantity, shape, pattern, density, and concomitant signs [ ] . the typical chest ct imaging characteristics of covid- include multiple, peripheral, bilateral, patchy, sub-segmental, or segmental ground glass opacities and areas of consolidation, which are mostly distributed along the bronchovascular bundles and subpleural space. the presence of associated interlobular septal thickening in the areas of ground glass opacity can give a crazy paving appearance. air bronchograms with the areas of consolidation and bronchial wall thickening are often present. more rarely, there is a thickening of the adjacent pleura or interlobar pleura, and a small amount of pleural effusion. there is no obvious lymphadenopathy [ ] ( tables , ). the imaging features mentioned above are consistent with the findings from patients in a recently reported article, in which the predominant pattern of abnormality observed was bilateral, peripheral, ill-defined, and ground glass opacification, mainly involving the right lower lobes [ ] . furthermore, in the currently available reports, the most common chest ct findings in covid- patients are the peripheral areas of ground glass opacity/consolidation (without subpleural sparing) which are bilateral in distribution [ ] [ ] [ ] . in one study, of patients, most had more than two lobes affected ( of , %) with bilateral involvement ( of , %) [ ] . another study showed that the most common patterns of covid- on thin-section ct images are pure ground glass opacity, ground glass opacity with intra-and/or interlobular septal thickening, and ground glass opacity with consolidation and consolidation, with prominent distribution in the posterior and peripheral part of the lungs [ ] . in a large research cohort study, chest ct findings showed a bilateral distribution of patchy ground glass opacity and consolidation in patients [ ] . typical chest radiograph and chest ct of covid- are shown in figs. and . in "expert recommendations from the chinese medical association radiology branch," chest ct manifestations of covid- are divided into three stages: early, advanced, and severe, based on the extent of lesion involvement [ ] . this current clinical guideline recommends dividing covid- into four stages according to the time of onset and the response of body to the virus with additional dissipation stage (fig. ). early stage: chest ct shows single or multiple scattered patchy or conglomerate ground glass opacities, predominantly in the middle and lower lungs and along the bronchovascular bundles. these ground glass lesions are often located in peripheral and subpleural areas of the lung. intra-and interlobular septal thickening sometimes present in the areas of ground glass opacity can give a crazy paving pattern. the pathological process during this stage is dilatation and congestion of the alveolar septal capillary, exudation of fluid in alveolar cavity, and interlobular interstitial edema [ ] . one patient had normal chest ct at initial presentation; however, days later the disease progressed and developed a solitary rounded ground glass lesion in the right lower lobe, indicating this pattern may represent the very first radiologically visible manifestation in patients infected with sars-cov- [ ] . . advanced stage: at this stage, chest cts will show new lesions that are similar to the earlier lesions described above. in addition, findings from the early stage of disease increase in density and extent, coexisting with the new areas of disease. as areas of consolidation grow, air bronchograms are often present in the areas of consolidation. a previous case report described a patient who had evolved into a mixed pattern of ground glass opacities and consolidation by after onset of symptoms [ ] . the pathological features in this stage are the accumulation of a cell-rich exudate in the alveolar cavity, vascular expansion, and exudation in the interstitium. the fibrous exudation connects each alveolus through the interalveolar space to form a fusion state [ ] . severe stage: as the disease further progresses, chest ct shows diffuse consolidation of the lungs of varying density secondary to the fibrous exudate into the alveolar cavity, air bronchograms, and bronchial dilation. nonconsolidated areas of the lung appear as patchy ground glass opacity. when most of the lungs are involved, the lungs appear as a "whited out lung." the pleura is thickened and there can be a small amount of pleural effusion. . dissipation stage: images show gradual resolution of the ground glass opacity and consolidation in the lungs with some residual curvilinear opacities compatible with fibrosis. after isolation and treatment, a majority of patients infected by covid- stabilize and gradually recover and on imaging the areas of disease decrease correspondingly. however, in a small number of patients with underlying disease or advanced age, the disease progresses during the treatment with the scope of the lesions in the lungs expanding and increasing density, eventually appearing as "whited out lungs." on the frontlines of fighting the covid- epidemic, chest imaging (particularly chest ct) now has an irreplaceable role in the early diagnosis of covid- as well as monitoring the disease's clinical course. covid- has characteristic manifestations in the lung that are readily detected on chest ct as described in some recent publications [ , , ] . in several prior reports, chest ct showed progression of disease that corresponded with worsening clinical symptoms and also disease resolution as the patients clinically recovered [ , , ] . in a recent report [ ] , the predominant pattern of abnormality in covid- observed on the basis of the interval between symptom onset and the first ct scan has some differences. lesions quickly evolved from focal unilateral to diffuse bilateral ground glass opacities that progressed to or coexisted with consolidations within - weeks, indicating the change through clinical course which was also reflected on the number of involved lung segments. in a prior study of patients, the absolute number of lung findings increased with the time from symptom onset and lesions with consolidations including ground glass opacities with consolidation and pure consolidation showed mildly positive correlation with the time between symptom onset and the ct [ ] . another report demonstrated mild or moderate progression of disease as manifested by increasing extent and density of lung opacities during follow-up [ ] . in the context of typical clinical presentation and exposure history, some patients may present with negative results of rt-pcr for covid- but have characteristic imaging features of covid- on chest ct. subsequently, these patients whose labs were initially negative for covid- did test positive later with repeat swab tests. thus, in patients at high risk for covid- , chest ct evidence of viral pneumonia may precede negative rt-pcr test results and present as an important warning signal. a combination of repeated swab tests and ct scanning may be helpful for individuals with high clinical suspicion of covid- but negative rt-pcr screening [ , ] . chest ct has a high sensitivity for diagnosis of covid- . in a report of patients with chest ct and rt-pcr assay performed within days, the sensitivity of chest ct was greater than that of rt-pcr for covid- at initial patient presentation ( % vs %, respectively, p < . ) [ ] . in another study of the appearance frequency of each ct characteristic is described in order from low to high as (+~++++); e, a, s, and d stand for stage early, advanced, severe, and dissipation patients, % had positive rt-pcr results, and % had positive chest ct scans. the sensitivity of chest ct in suggesting covid- was % based on positive rt-pcr results. between % and % of cases had initial positive ct consistent with covid- prior (or parallel) to the initial positive rt-pcr results [ ] . in addition, chest ct can evaluate disease severity. in terms of the percentage of pneumonia lesions in the entire lung volume, the difference between the earlier stage patients and the severe stage patients is statistically significant [ ] . in an initial prospective analysis of the clinical features of patients, chest ct images of icu patients on admission showed bilateral multiple lobular and subsegmental areas of consolidation, and overall had more imaging abnormalities than non-icu patients [ ] . older patients may have more systemic symptoms, more extensive lung involvement, and worse prognosis than younger patients [ ] . thus, the typical ct findings of covid- can not only help early screening suspected cases, but can also monitor the clinical progression and may predict severe complications such as acute respiratory diseases. with high sensitivity for covid- , chest ct would play a very important role in the diagnosis and treatment of covid- in the high-risk regions and year-old male show multiple patchy areas of pure ground glass opacity (ggo) and ggo with reticular and/or interlobular septal thickening [ ] . chest ct image of a -year-old male (b) shows multiple patches, grid-like lobule, and thickening of interlobular septa, typical "paving stone-like" signs [ ] . an axial ct image obtained in -year-old female (c) shows bilateral ground glass and consolidative opacities with a striking peripheral distribution [ ] . ct image of a -year-old male (d) shows large consolidation in the right middle lobe, patchy consolidation in the posterior and basal segment of right lower lobe, with air bronchogram inside [ ] fig. chest radiograph (a) in a -year-old man shows bilateral patchy, somewhat nodular opacities in the mid to lower lungs [ ] . unenhanced computed tomography (ct) images (b) in a -year-old woman., images show multiple ground glass opacities in the periphery of the bilateral lungs. the bilateral, peripheral patterns of opacities without subpleural sparing are common and characteristic ct findings of the novel coronavirus pneumonia [ ] . chest ct image of a -year-old male (c) shows consolidation in the peripheral right upper lobe and a patchy area of ground glass opacity with some associated consolidation intra-and interlobular septal thickening within the left upper lobe [ ] countries. in some extreme situations in very high-risk areas (wuhan, china), ct was the one of main diagnostic criteria for this disease due to the relatively high false negative of rt-pcr. for some low-risk regions and countries, positive predictive value of ct alone or adding ct to rt-pcr should be adjusted. the proposition of ct could be tempered to some degree. therefore, to be more accurate, the role of chest ct in covid- should be assessed based on the prevalence of the disease in each area. the ct appearance of covid- shares some similarities with other diseases that cause viral pneumonia, including influenza viruses, parainfluenza virus, adenovirus, respiratory syncytial virus, rhinovirus, human metapneumovirus, etc. (table ). in particular, those within the same viridae (sars and mers) have great similarities in imaging findings because they belong to the same coronaviridae family, and thus need to be excluded through clinical manifestations and laboratory pathogen detection. imaging in mers pneumonia can also show ground glass lesions in the subpleural and basal parts with consolidation, and fibrosis changes can be left after healing [ ] . in the pneumonia patients infected by respiratory syncytial virus, chest ct mainly manifested as small centrilobular nodules and areas of consolidation which are often asymmetrically distributed in the lungs. adenovirus pneumonia shows bilateral multifocal ground glass opacities with patchy consolidations on ct images and may show lobar or segmental distribution. human parainfluenza virus pneumonia may show centrilobular nodules with bronchial wall thickening that differentiates it from the imaging appearances of the other viruses. radiographs in patients with influenza pneumonia show bilateral patchy areas of ground glass opacity with or without focal areas of consolidation, usually in the lower lobes [ ] . in a report on h n influenza infection, in addition to the most common findings of ground glass opacity, interlobular septal thickening, and centrilobular nodules were the second most frequent findings [ ] . rapidly progressive ground glass opacities and consolidations with air bronchograms and interlobular septal thickening, with right ground glass opacity, interlobular septal thickening, and centrilobular nodules h n ground glass opacity and consolidation with air bronchograms and interlobular septal thickening human parainfluenza virus centrilobular nodules with bronchial wall thickening, findings which differentiate it from other viral infections respiratory syncytial virus small centrilobular nodules and areas of parenchymal consolidation; asymmetrically distributed in the lungs adenovirus pneumonia bilateral multifocal ground glass opacities, patchy consolidation in a lobar and/or segmental distribution lower lobe predominance, are the main imaging findings in h n pneumonia [ ] . viruses are a common cause of respiratory infection and recognition of viral pneumonia patterns may help in the differentiation among viral pathogens, while the definite diagnosis is achieved by laboratory detection of virus. in addition, covid- also needs to be distinguished from mycoplasma pneumonia, chlamydia pneumonia, and bacterial pneumonia. other diseases that need to be identified are vasculitis, acute interstitial pneumonia, connective tissue-related lung disease, and cryptogenic organizing pneumonia [ ] . the covid- initially began in china; however, it is extremely contagious and has spread beyond china to many other countries, raising concerns and posing not only a huge threat to global public health but also a huge economic burden and panic to society. early disease recognition can prompt early patient isolation and early diagnosis and treatment. in the current situation, imaging of covid- , particularly with chest ct, has a very high value because it shows characteristic manifestations and has enabled frontline clinicians to have primary diagnosis in their first contact with suspected patients, even in the presence of initially false negative lab results. earlier diagnosis with the aid of imaging allows for early containment and response to this communicable disease as well as overcoming the outbreak as soon as possible through a joint effort. clinical features of patients infected with novel coronavirus in wuhan, china epidemiological and clinical characteristics of cases of 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family cluster radiographic and ct features of viral pneumonia initial hrct findings of novel influenza a (h n ) infection emerging h n influenza a (novel reassortant avian-origin) pneumonia: radiologic findings publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations acknowledgments we are very grateful to the worldwide front-line medical staff for their dedication in the fighting against the outbreak of covid- , despite the potential threat to their own lives and the lives of their families. and we also believe this pandemic will be controlled by the efforts of all mankind. guarantor the scientific guarantor of this publication is minjie lu. the authors have no conflict of interest to disclose.statistics and biometry no complex statistical methods were necessary for this paper.informed consent written informed consent was not required for this study because this is a review of literature.ethical approval institutional review board approval was not required because this is a review of literature. • n/a key: cord- -pn nwl authors: helmy, yosra a.; fawzy, mohamed; elaswad, ahmed; sobieh, ahmed; kenney, scott p.; shehata, awad a. title: the covid- pandemic: a comprehensive review of taxonomy, genetics, epidemiology, diagnosis, treatment, and control date: - - journal: j clin med doi: . /jcm sha: doc_id: cord_uid: pn nwl a pneumonia outbreak with unknown etiology was reported in wuhan, hubei province, china, in december , associated with the huanan seafood wholesale market. the causative agent of the outbreak was identified by the who as the severe acute respiratory syndrome coronavirus- (sars-cov- ), producing the disease named coronavirus disease- (covid- ). the virus is closely related ( . %) to bat coronavirus ratg , based on phylogenetic analysis. human-to-human transmission has been confirmed even from asymptomatic carriers. the virus has spread to at least countries, and more than , , confirmed cases and , deaths have been recorded, with massive global increases in the number of cases daily. therefore, the who has declared covid- a pandemic. the disease is characterized by fever, dry cough, and chest pain with pneumonia in severe cases. in the beginning, the world public health authorities tried to eradicate the disease in china through quarantine but are now transitioning to prevention strategies worldwide to delay its spread. to date, there are no available vaccines or specific therapeutic drugs to treat the virus. there are many knowledge gaps about the newly emerged sars-cov- , leading to misinformation. therefore, in this review, we provide recent information about the covid- pandemic. this review also provides insights for the control of pathogenic infections in humans such as sars-cov- infection and future spillovers. coronaviruses are enveloped, single-strand rna viruses that can infect a wide range of hosts including avian, wild, domestic mammalian species, and humans. coronaviruses are well known for their ability to mutate rapidly, alter tissue tropism, cross the species barrier, and adapt to different coronaviruses are enveloped, icosahedral symmetric particles, approximately - nm in diameter containing a non-segmented, single-strand, positive-sense rna genome of about - kb in size [ ] . coronaviruses (covs) are one of the largest groups of viruses that belong to the order nidovirales, suborder cornidovirineae, and family coronaviridae. coronaviridae is classified into two subfamilies, namely, letovirinae and orthocoronavirinae. letovirinae includes the alphaletovirus genus, while orthocoronaviridae is further classified on the basis of phylogenetic analysis and genome structure into four genera: alphacoronavirus (αcov), betacoronavirus (βcov), gammacoronavirus (γcov), and deltacoronavirus (δcov), which contain , , , and unique species, respectively (ictv ). the most recent classification of the coronaviridae is shown in table . corona in latin means crown, and this name was attributed to the virus due to the presence of spike projections from the virus envelope that give it the shape of a crown under the electron microscope; nido means nest and refers to the ability of the viruses of this order to make a nested set of subgenomic mrna [ , ] . coronaviruses infect a wide range of wild and domestic animals; αand βcovs infect mammals, while γand δcovs primarily infect birds (table ) . a human coronavirus (hcov) was first isolated in from hospitalized patients who suffered from common cold symptoms and was named b [ ] . so far, the seven different hcovs that infect humans are e, nl , which belong to α covs, and hku , oc , sars, mers, sars-cov- , which belong to βcovs. in - , a pandemic caused by sars-cov (lineage b βcov) originated in china [ ] . in the middle east, mers-cov (lineage c βcov) emerged in [ ] . in , a newly emerged sars-cov- , closely related to bat sars-related covs, was clustered with lineage b βcov. chan et al. [ ] demonstrated that sars-cov- represents a distinct lineage in the subgenus sarbecovirus (previously, lineage b of βcov) [ ] . additionally, other coronaviruses have caused pandemic diseases in domestic and wild mammals and birds, leading to high mortality rates and severe economic losses. these viruses include ibv in chickens [ ] , beluga whale coronavirus sw (bwcov-sw ) [ ] , bat coronaviruses cdphe and hku (ictv ), porcine epidemic diarrhea virus (pedv), tgev, and sudden acute diarrhea syndrome (sads-cov) [ ] . since the emergence of sars-cov- in wuhan city, china, in december , many laboratories have been working on sequencing the genome of the causative agent. as of april , there are a total of complete genomes from countries in the global initiative on sharing all influenza data (gisaid) database [ ] (table ) . a reference genome is now available in the ncbi genome database ( , nucleotide, reference sequence: nc_ . ) [ ] . to date, there are a total of sequences including one refseq sequence and complete genomes at ncbi. sars-cov- is a monopartite, single-stranded, and positive-sense rna virus with a genome size of , nucleotides, making it the second-largest known rna genome. the virus genome consists of two untranslated regions (utrs) at the and ends and open reading frames (orfs) that encode proteins (table ) . the first orf (orf /ab) constitutes about two-thirds of the virus genome, encoding non-structural proteins (nsps), while the remaining third of the genome encodes structural proteins and at least accessory proteins. the structural proteins are spike glycoprotein (s), matrix protein (m), envelope protein (e), and nucleocapsid protein (n), while the accessory proteins are orf a, orf , orf a, orf b, orf , and orf , as shown in figure [ , , , ] . the ′utr and ′utr of sars cov- are comprised of and nucleotides, respectively. orf ab is , nucleotides and encodes either replicase proteins pp a of amino acids (aa) (nsp -nsp ) or pp ab of aa (nsp -nsp ), according to ribosomal frameshift. of these proteins, ( ) nsp suppresses the antiviral host response, ( ) nsp is a papain-like protease, ( ) nsp is a clpro ( c-like protease domain), ( ) nsp makes a complex with nsp to form a primase, ( ) nsp is responsible for rna/dna binding activity, ( ) nsp is an rna-dependent rna polymerase (rdrp), ( ) nsp is confirmed as a helicase, ( ) nsp is a ′- ′ exonuclease (exon), ) nsp is a poly(u)-specific endoribonuclease (xendou). the remaining nsps are involved in transcription and replication of the viral genome [ , , ] . single-stranded rna viruses exhibit a faster biological mutation rate due to the lack of proofreading activity of viral rna polymerases [ ] ; however, unlike other mutation-prone rna viruses, with the exception of the arenaviridae family, covs do have limited proofreading capabilities, with the nsp protein allowing for the enhanced genome size of cov family members [ ] . recombination is another mechanism of evolution in coronaviruses [ ] . a high recombination frequency was demonstrated in murine hepatitis virus during mixed infection, where the majority of viruses recovered after three passages were recombinants [ ] . recombination was also reported for mers-cov and sars-cov. seven putative recombination regions were detected in orf ab and s protein between sars-cov and six other coronaviruses by in silico analysis of their genomes [ ] . similarly, bioinformatic analysis of mers-cov genomic data revealed recombinant sequences from humans and camels [ ] . recombination in sars-cov- is not yet clearly understood. initial studies suggested that it may have occurred in the course of sars-cov- evolution [ ] , while other researchers excluded the possibility of recombination based on a full genome evolutionary analysis investigating putative recombination events [ ] . to better understand the evolution of sars-cov- , we performed a phylogenetic analysis of representative coronaviruses from countries including sars-cov, sars-cov- , hcov, bat sars . the other third of sars cov- includes four genes (in green) that encode four structural proteins (s, m, e, n), and six accessory genes (in blue) that encode six accessory proteins (orf a, orf , orf a, orf b, orf , and orf ). the utr and utr of sars cov- are comprised of and nucleotides, respectively. orf ab is , nucleotides and encodes either replicase proteins pp a of amino acids (aa) (nsp -nsp ) or pp ab of aa (nsp -nsp ), according to ribosomal frameshift. of these proteins, ( ) nsp suppresses the antiviral host response, ( ) nsp is a papain-like protease, ( ) nsp is a clpro ( c-like protease domain), ( ) nsp makes a complex with nsp to form a primase, ( ) nsp is responsible for rna/dna binding activity, ( ) nsp is an rna-dependent rna polymerase (rdrp), ( ) nsp is confirmed as a helicase, ( ) nsp is a - exonuclease (exon), ) nsp is a poly(u)-specific endoribonuclease (xendou). the remaining nsps are involved in transcription and replication of the viral genome [ , , ] . single-stranded rna viruses exhibit a faster biological mutation rate due to the lack of proofreading activity of viral rna polymerases [ ] ; however, unlike other mutation-prone rna viruses, with the exception of the arenaviridae family, covs do have limited proofreading capabilities, with the nsp protein allowing for the enhanced genome size of cov family members [ ] . recombination is another mechanism of evolution in coronaviruses [ ] . a high recombination frequency was demonstrated in murine hepatitis virus during mixed infection, where the majority of viruses recovered after three passages were recombinants [ ] . recombination was also reported for mers-cov and sars-cov. seven putative recombination regions were detected in orf ab and s protein between sars-cov and six other coronaviruses by in silico analysis of their genomes [ ] . similarly, bioinformatic analysis of mers-cov genomic data revealed recombinant sequences from humans and camels [ ] . recombination in sars-cov- is not yet clearly understood. initial studies suggested that it may have occurred in the course of sars-cov- evolution [ ] , while other researchers excluded the possibility of recombination based on a full genome evolutionary analysis investigating putative recombination events [ ] . to better understand the evolution of sars-cov- , we performed a phylogenetic analysis of representative coronaviruses from countries including sars-cov, sars-cov- , hcov, bat sars cov, bat sars-like cov, and mers-cov. the viral genomes were obtained from the gisaid and ncbi databases. multiple sequence alignment was performed using kalign [ ] . a phylogenetic tree was constructed based on whole-genome sequences (coding sequences of all genes) in iq-tree, using the maximum likelihood method, ultrafast bootstrap approximation, and modelfinder [ , ] . the tree was drawn to scale, with branch lengths measured in the number of substitutions per site. the bootstrap values were determined by , replicates. the tree was visualized in mega x [ ] ( figure ). cov, bat sars-like cov, and mers-cov. the viral genomes were obtained from the gisaid and ncbi databases. multiple sequence alignment was performed using kalign [ ] . a phylogenetic tree was constructed based on whole-genome sequences (coding sequences of all genes) in iq-tree, using the maximum likelihood method, ultrafast bootstrap approximation, and modelfinder [ , ] . the tree was drawn to scale, with branch lengths measured in the number of substitutions per site. the bootstrap values were determined by , replicates. the tree was visualized in mega x [ ] ( figure ). in the analysis we performed, all sars-cov- samples from the countries clustered together and were close to bat sars or sars-like coronaviruses, with wuhan bat cov ratg being the closest virus. in addition, mers-cov and human cov hku were very distant from sars-cov- ( figure ). within mers-cov samples, the south china mers-nl clustered separately from other mers-covs. the two bat sars-like covs (bat-sl-covzc and bat-sl-covzxc ) were the second closest viruses from bats to sars-cov- ( figure ). all sars-covs from china, canada, england, and the us were in a single cluster. the tree was constructed in iq-tree using the maximum likelihood method, modelfinder, and ultrafast bootstrap approximation ( replicates). the tree is drawn to scale, with branch lengths (numbers below the branches) measured in the number of substitutions per site. branch lengths less than . are not shown. numbers above the branches represent the percentage of replicate trees in which the associated viruses clustered together in the bootstrap test. the tree is rooted with two human coronavirus species from the genus alphacoronavirus as an outgroup (hcov- e and hcov-nl ). in the analysis we performed, all sars-cov- samples from the countries clustered together and were close to bat sars or sars-like coronaviruses, with wuhan bat cov ratg being the closest virus. in addition, mers-cov and human cov hku were very distant from sars-cov- ( figure ). within mers-cov samples, the south china mers-nl clustered separately from other mers-covs. the two bat sars-like covs (bat-sl-covzc and bat-sl-covzxc ) were the second closest viruses from bats to sars-cov- ( figure ). all sars-covs from china, canada, england, and the us were in a single cluster. zhou et al. [ ] conducted a phylogenetic analysis of sars-cov- against previously identified coronaviruses based on their whole-genome sequences, main structural protein genes, and non-structural protein genes. sars-cov- clustering was different depending on whether the whole genome or specific genes were used in the analysis. for example, sars-cov- clustered with the members of the subgenus sarbecovirus including the sars-cov ( . % identical) that caused the global pandemic in and other bat sars-like viruses ( % identical at the whole-genome level), but the topological position within the sarbecoviruses changed when individual genes (orf ab, s, e, m, and n) were used for clustering [ , ] . based on the whole-genome sequence alignment, sars-cov- shares % identity with bat sars-like covzxc , % with sars-cov, and . % with bat cov ratg [ , ] . alignment of the predicted protein sequences of sars-cov- to those of sars-cov or sars-like coronaviruses revealed a total of amino acid substitutions between these viruses [ ] . these amino acid substitutions were distributed as follows: mutations in nonstructural proteins (orf ab, a, b, a, b, b, and orf ), in s protein, and in n protein. no amino acid substitutions were detected in e or m proteins, indicating that e and m proteins are highly conserved among these viruses. it has been reported that sars-cov- uses the same cellular receptor, hace , as sars-cov to gain entry into the cell [ , , ] . the analysis of the receptor-binding domains (rbd) of sars-cov and sars-cov- s protein revealed similar binding affinities [ ] . wu et al. [ ] found a total of amino acid substitutions in the s protein but not in the receptor-binding motif (rbm) that directly interacts with hace , which may affect host tropism. these substituted residues were distributed as follows: in the s subunit [ in the rbd and in the subdomain (sd)] and in the s subunit. wan et al. [ ] reported similarity in the spike protein rbd, including rbm, of both sars-cov and sars-cov- , in addition to the presence of several residues in sars-cov- rbm that favor the interaction with human ace . these results agree with the genomic analysis of sars-cov- , according to which the s subunit of the spike protein shares % identity with those of two bat sars-like covs (sl-covzxc and zc ) and of human sars-cov [ ] . while the sars-cov- s subunit was conserved, the s subunit shares an overall % identity with those of bat and human sars-cov. the rbd core domain of s is highly conserved, with most of the amino acid differences located in the external subdomain that is responsible for the direct interaction with host receptors [ ] . investigators have also reported the presence of a polybasic cleavage site and predicted o-linked glycans that are unique to sars-cov- s protein. differences in sars-cov- s protein and the high contagious nature of this virus suggest that sars-cov- has evolved via natural selection for binding to human ace receptor [ ] . orf b also differs in sars-cov- . orf b deletion mutations in sars-cov do not affect viral replication in vitro [ ] . orf b may play a role in viral pathogenicity in addition to its inhibitory effects on interferon (ifn) expression and signaling [ , ] . recently, a novel short putative protein was identified in orf b of sars-cov- [ ] ; however, the function of this novel protein is still not known. sars-cov- orf is closer to those of bat sars cov zxc and zc and distant from that of human sars-cov [ ] . the assessment of genetic diversity among complete or semi-complete genomes of sars-cov- viruses revealed three deletions in the genome of isolates from japan, usa, and australia in addition to many other substitution mutations. the deletion mutations were in the orf ab gene ( -nucleotide and -nucleotide deletion) and at the end of the genome ( -nucleotide deletion). of the substitution mutations, changed the amino acid sequence of structural and non-structural proteins [ ] . the and -nucleotide deletions in orf ab are expected to reduce the protein sequence by and amino acid residues, respectively, without changing the reading frame, but the functional effects have yet to be investigated. the alignment of sars-cov- reference s protein gene against all sars-cov- sequenced genomes from china, usa, japan, australia, and taiwan revealed . - % identity, with % query coverage (also confirmed by our phylogenetic analysis, figure ), while the identity and coverage for sars-cov s protein gene were . % and %, respectively. also, the s protein gene from bat sars and sars-like coronavirus isolates shared . - % identity with that of sars-cov- . this agrees with previous conclusions regarding the evolutionary analysis of sars-cov- [ , ] . in the phylogenetic analysis we performed, sars-cov- viruses were in the same cluster regardless of the geographic region ( figure ). these results strongly suggest the possibility of a recent common ancestor for all sars-cov- or the transmission of the same virus strain across countries. the outbreak of covid- originated from wuhan city, hubei province, in china. fifty-five percent of the infected cases before january were linked to the huanan seafood wholesale market. however, the first human-to-human case of sars-cov- infection reported on december did not have any exposure to this market [ , ] . in mid-january , sars-cov- spread to other provinces of china due to the spring festival travel season. sars-cov- was transmitted from china to other countries via international travelers. on january , the first case of sars-cov- infection was confirmed outside china in thailand, and on january the first infected case was confirmed in japan. these cases were also linked to the huanan seafood wholesale market. by january , the number of confirmed cases had risen to , including , in china, thailand, hong kong, macau, australia, malaysia, singapore, france, japan, south korea, taiwan, the us, vietnam, nepal, and sweden. on january , china reported a sharp rise in the number of infected cases, with the presence of infection in more than countries. therefore, who declared the sars-cov- outbreak to be a public health emergency of international concern [ ] . as of march , more than countries and territories have been affected, with major outbreaks in central china, south korea, italy, iran, france, and germany [ ] . there were , confirmed cases of sars-cov- infections, with deaths and about % estimated mortality rate. more than % of these cases have been reported in mainland china [ ] . at this time, the number of global cases has shown a drastic increase within a short time, confirmed cases and deaths in china have not increased too much, while confirmed cases and deaths in other countries have drastically increased ( table ). the number of confirmed cases increased from to , in one week (between january and february), and the number of infected countries doubled (from to ). due to the rapid increase of the number of infected cases and infected countries, the who declared sars-cov- a pandemic on march and on march , the who declared europe to be the new center of the pandemic due to the massive increase of confirmed cases there [ ] . on , , were in italy). one week later ( april ), the number of confirmed cases of sars-cov- increased . times (up to , confirmed cases), and the number of deaths increased . times (up to , deaths) in the usa alone. the number of confirmed cases, deaths, and infected countries are shown in table . the origins of more than % of coronavirus infections are considered zoonotic, i.e., animals are the main source of the outbreaks. for example, sars-cov was transmitted from palm civets to humans, and mers-cov from dromedary camels to humans. bats are currently considered a reservoir for all human coronaviruses, as mentioned above [ , ] . many coronaviruses are circulating in animals but have not yet infected humans. the type of animal that sars-cov- originated from is still unclear. at the beginning of the outbreak in wuhan, china, many patients were linked to the huanan seafood wholesale market, suggesting animal-to-person spread. after retrospectively studying case reports, the number of patients that did not have exposure to animal markets has risen, indicating person-to-person spread was also occurring at that time [ ] . sars-cov- is closely related to bat coronaviruses and sars-cov [ ] . a group of researchers reported early in the outbreak that the novel sars-cov- has the highest similarity of codon usage bias with snakes [ , ] ; however, this method to determine initial host origins is dubious. interestingly, researchers also reported one amino acid difference in the receptor-binding domain of the s protein of pangolin-cov compared to that of sars-cov- , suggesting that pangolins might play a role as an intermediate host (xiao et al., data currently under review). another group of researchers reported that the virus originated from bats based on the genome sequence of sars-cov- , which is % identical to bat coronavirus ratg . there were speculations that sars-cov- is a laboratory-engineered cov and leaked directly from a laboratory in wuhan where a bat cov (ratg ) was recently reported. however, there is no evidence to support this allegation [ ] . recently, a group of researchers found that sars-cov- replicates poorly in dogs, pigs, chickens, and ducks but efficiently in ferrets and cats [ ] . scientists are still trying to find the main source of the disease outbreak and identify the definitive intermediate hosts. both established (sars-cov, mers-cov) and novel (sars-cov- ) coronaviruses were reported to spread from an infected person to a non-infected person through direct or indirect contact. sars-cov- infection was reported to be transmitted directly from person to person like most respiratory viruses via close contact with an infected person or through respiratory droplets (aerosol) produced when an infected person coughs or sneezes. these droplets can be inhaled to reach the lung. the virus can be indirectly transmitted via touching a surface or an object that was previously contaminated with the virus and then touching the face, eyes, or mouth [ ] and possibly via the fecal-oral route [ , ] . asymptomatic carriers (during the incubation period of the virus) and patients after recovery from the acute form of the disease are also considered a potential source of virus transmission to healthy persons [ , ] . interestingly, human coronaviruses are able to survive on steel, metal, wood, aluminum, paper, glass, plastic, ceramic, disposable gowns, and surgical gloves for - days. high temperature (≥ • c) can reduce the persistence period, while low temperature ( • c) increases the persistence time up to days [ ] . transmission of the virus vertically from mother to fetus or via breast milk has not been confirmed yet [ ] . the transmission cycle of coronavirus among animals and humans is shown in figure . both established (sars-cov, mers-cov) and novel (sars-cov- ) coronaviruses were reported to spread from an infected person to a non-infected person through direct or indirect contact. sars-cov- infection was reported to be transmitted directly from person to person like most respiratory viruses via close contact with an infected person or through respiratory droplets (aerosol) produced when an infected person coughs or sneezes. these droplets can be inhaled to reach the lung. the virus can be indirectly transmitted via touching a surface or an object that was previously contaminated with the virus and then touching the face, eyes, or mouth [ ] and possibly via the fecal-oral route [ , ] . asymptomatic carriers (during the incubation period of the virus) and patients after recovery from the acute form of the disease are also considered a potential source of virus transmission to healthy persons [ , ] . interestingly, human coronaviruses are able to survive on steel, metal, wood, aluminum, paper, glass, plastic, ceramic, disposable gowns, and surgical gloves for - days. high temperature (≥ °c) can reduce the persistence period, while low temperature ( °c) increases the persistence time up to days [ ] . transmission of the virus vertically from mother to fetus or via breast milk has not been confirmed yet [ ] . the transmission cycle of coronavirus among animals and humans is shown in figure . there are many factors that affect sars-cov- transmission and spread. these factors include, but are not limited to: ( ) travel to or contact with individuals who have recently visited wuhan, china, or other places experiencing an outbreak; ( ) close contact with persons who are diagnosed positive for the disease, such as healthcare workers caring for patients with sars-cov- ; ( ) contact with droplets and secretions (produced by sneezing or coughing) from an infected person and eating or handling wild animals native to china such as bats. additionally, the risk of infection is higher for the elderly and for patients suffering from pre-existing illnesses such as cardiovascular disease, hypertension, diabetes, and chronic respiratory disease [ ] . the reported fatality rate based on age is . % for people ˃ years of age, % for people between and years, . % for people between and years, . % for people between and years, . % for people between and years, there are many factors that affect sars-cov- transmission and spread. these factors include, but are not limited to: ( ) travel to or contact with individuals who have recently visited wuhan, china, or other places experiencing an outbreak; ( ) close contact with persons who are diagnosed positive for the disease, such as healthcare workers caring for patients with sars-cov- ; ( ) contact with droplets and secretions (produced by sneezing or coughing) from an infected person and eating or handling wild animals native to china such as bats. additionally, the risk of infection is higher for the elderly and for patients suffering from pre-existing illnesses such as cardiovascular disease, hypertension, diabetes, and chronic respiratory disease [ ] . the reported fatality rate based on age is . % for people > years of age, % for people between and years, . % for people between and years, . % for people between and years, . % for people between and years, . % for people between and years; no fatalities have been reported for children under years of age. notably, the fatality rate is higher in males ( . %) than in females ( . %) [ , ] . the estimated incubation period of the novel coronavirus ranges from to days. however, some cases had an incubation period of , , or days [ ] . the complete clinical picture of sars-cov- is still unclear. the disease begins with flu-like symptoms that include fever, fatigue, dry cough, sore throat, shortness of breath, headache, chest tightness, chest pain, and muscle pain. some of sars-cov- patients have runny nose, nausea, vomiting, and diarrhea [ ] . people can be infected without showing symptoms, which allows the virus to spread more effectively from person to person. complications can occur due to covid- leading to severe infections, such as pneumonia (infection of the lungs), kidney failure, and death [ ] . the mild phase of the disease can last up to weeks, while severe or critical disease lasts approximately to weeks (this analysis was conducted on , confirmed cases). additionally, the time from the disease onset to the development of severe disease is one week, while the time from the onset of symptoms to death ranges from to weeks [ ] . based on the data analysis of , confirmed cases of sars-cov- in wuhan city, china, by february, . % of the cases were mild with flu-like symptoms, and patients recovered at home, . % were severe with pneumonia and shortness of breath, . % were critical with respiratory failure and septic shock resulting in organs failure, and approximately % of the cases were fatal [ ] . another study was conducted on hospitalized patients, and symptoms were classified as follow: fever ( %), cough ( %), shortness of breath ( %), muscle ache ( %), confusion ( %), headache ( %), sore throat ( %), runny nose ( %), chest pain ( %), diarrhea ( %), and nausea and vomiting ( %) [ ] . the rapid diagnosis of sars-cov- infection is the cornerstone of disease control. it depends on several criteria including case history, clinical symptoms, serology, molecular diagnosis, and computed tomography (ct) imaging. on march , who published interim guidance for laboratory testing of suspected human cases, with precautions for specimen collection, packing, shipment, and amplification of nucleic acid to detect viral genes (n, e, s, and rdrp) [ ] . sars-cov- uses the same cell entry receptor, hace , as sars-cov. therefore, oral swabs, bronchoalveolar lavage fluid (balf), blood, as well as anal swabs are the best samples used for virus diagnosis [ ] . a proper diagnosis depends primarily on the factors described below. the strict monitoring of case history in clinically suspicious patients is considered the first step in the early diagnosis of sars-cov- infection. clinically suspicious patients are those who suffer from fever and lower respiratory tract infection symptoms (for details, see the clinical characteristics section) and reside within or have traveled to endemic regions or had close contact with a confirmed or suspected case. additionally, sars-cov- can be transmitted by symptomatic and asymptomatic patients especially to the high-risk group mentioned above (for details, see the risk assessment section) [ ] . the blood profiles of patients suffering from sars-cov- infection revealed the following: ( ) increased c-reactive protein and erythrocytes, ( ) increased myohemoglobin, liver enzymes, and muscle enzymes, with a high level of d-dimer in severe cases, and ( ) normal or decreased white blood cell counts and lymphocytes in the early stage of the disease, with advanced lymphocytopenia in severe cases [ ] . in icu patients, high levels of plasma granulocyte colony-stimulating factor (gcsf), ip , il , il , il , tnf-α, and mip a were reported [ ] . electron microscope examination of sars-cov- revealed the typical coronavirus morphology. further, sars-cov- was successfully isolated from human respiratory epithelial cells or balf samples of infected patients using huh cells and vero e cells. the isolated strain was confirmed by immunofluorescent antibody techniques using the cross-reactive nucleoprotein (np) antibody. serum neutralization tests (snt) using vero e cells were conducted to confirm the neutralization activity in igg-positive viral samples [ ] . igm and igg elisa detection kits using bat sarsr-cov rp np were developed with no cross-reaction against human coronaviruses except sarsr-cov [ ] . using these serological tools, viral antibody titers were increased in sars-cov- -infected patients [ ] . the procedures of elisa for the determination of sars-cov- igg were described before [ ] . nucleic acid detection is the main, fastest, and most sensitive test for the diagnosis of sars-cov- infection. recently, two nested rt-pcr and two real-time rt-pcr assays have been developed with successful detection of the first positive cases of infection in japan [ ] . three real-time rt-pcr techniques have been designed based on the e, rdrp, and n genes [ ] . also, scientists established molecular detection tools for sars-cov- based on the s gene [ ] . chest x-ray examination in the early stage of the disease shows interstitial changes and multiple small plaque shadows. chest ct scans play an important role in the diagnosis of acute respiratory disease syndrome (ards) and pneumonia as well as in the early detection of lung parenchymal abnormalities in patients at risk and provide an impression of secondary infection (figure ). electron microscope examination of sars-cov- revealed the typical coronavirus morphology. further, sars-cov- was successfully isolated from human respiratory epithelial cells or balf samples of infected patients using huh cells and vero e cells. the isolated strain was confirmed by immunofluorescent antibody techniques using the cross-reactive nucleoprotein (np) antibody. serum neutralization tests (snt) using vero e cells were conducted to confirm the neutralization activity in igg-positive viral samples [ ] . igm and igg elisa detection kits using bat sarsr-cov rp np were developed with no cross-reaction against human coronaviruses except sarsr-cov [ ] . using these serological tools, viral antibody titers were increased in sars-cov- -infected patients [ ] . the procedures of elisa for the determination of sars-cov- igg were described before [ ] . nucleic acid detection is the main, fastest, and most sensitive test for the diagnosis of sars-cov- infection. recently, two nested rt-pcr and two real-time rt-pcr assays have been developed with successful detection of the first positive cases of infection in japan [ ] . three real-time rt-pcr techniques have been designed based on the e, rdrp, and n genes [ ] . also, scientists established molecular detection tools for sars-cov- based on the s gene [ ] . chest x-ray examination in the early stage of the disease shows interstitial changes and multiple small plaque shadows. chest ct scans play an important role in the diagnosis of acute respiratory disease syndrome (ards) and pneumonia as well as in the early detection of lung parenchymal abnormalities in patients at risk and provide an impression of secondary infection ( figure ). assessing these lungs parenchymal abnormalities conveys disease severity to clinicians. using artificial intelligence models in the future may be useful in mass screening, to allow risk prioritization and help to minimize turnaround time [ ] . pan et al. [ ] conducted a retrospective study to elaborate the time course of lung changes during recovery from infection. they described assessing these lungs parenchymal abnormalities conveys disease severity to clinicians. using artificial intelligence models in the future may be useful in mass screening, to allow risk prioritization and help to minimize turnaround time [ ] . pan et al. [ ] conducted a retrospective study to elaborate the time course of lung changes during recovery from infection. they described findings using international standard nomenclatures such as ground-glass opacity (ggo), consolidation, and crazy paving patterns. they established a semi-quantitative scoring system of grades to quantify the degree of involvement based on an area ranging from % to > %. the total score ranged from to (max), and involvement was subpleural, random, or diffuse. they found that in early stages ( - days after the onset of symptoms), ggo was the main finding in lower lung lobes; in progressive stages ( - days), the progression of lung disease involved three patterns of ground-glass, consolidation, and crazy paving, while in peak stages ( - days) , dense consolidation became the prevalent feature; in absorption stages (> days), ggo was detected with no crazy paving and resolution of consolidations [ ] . more than % of sars-cov- -affected patients suffered from bilateral lung involvement, and % have multilobe involvement. ct examinations of patients showed % consolidation and % ggo in the chest [ , , , ] . another study examined cases by ct and reported that % showed pure ggo, % exhibited ggo with reticular and/or interlobular septal thickness, % had ggo with consolidation, while % revealed pure consolidation. bilateral lung involvement was reported in % of cases; in % of the cases the posterior part of the lung was involved, while in %, the periphery was involved [ ] . in january , the who issued guidance for the clinical management of sars when sars-cov- infection was suspected. in this guidance, the start of emergency treatments, immediate implementation of prevention and control strategies, early supportive therapy and prevention of sars-cov- complications were described in detail [ ] . so far, there are no approved specific antiviral drugs for sars-cov- infection. therefore, preventive measures and inactivation of the virus are essential to stop and control the spread of the disease. human coronaviruses can be inactivated using . % hydrogen peroxide, - % ethanol, . % sodium hypochlorite, . - % formaldehyde, % glutaraldehyde, or . % povidone iodine within minute. other disinfectants such as . % chlorhexidine digluconate, . % orthophtalaldehyde, or . - . % benzalkonium chloride are less effective [ ] . in light of the urgent clinical demand, many drugs are approved to be used for clinical trials against sars-cov- infection, such as lopinavir/ritonavir, arbidol, interferon-alpha, favipiravir, chloroquine phosphate, darunavir/cobicistat, oseltamivir, and methylprednisolone. the most used antiviral drugs [ ] are summarized in table . generally, coronaviruses are not sensitive to current antiviral drugs, and high concentrations of drugs effective on these viruses cannot be used in vivo. therefore, combinations of different therapies have been used for the treatment of coronavirus infections [ ] . some drug combinations that could be successful for the treatment of sars-cov- patients are lopinavir and ritonavir [ , ] , lopinavir/ritonavir plus arbidol [ ] , and ribavirin and interferon [ , ] . the use of anti-inflammatory drugs such as glucocorticoids, il- antagonist, janus kinase inhibitors (jak), and choloroquine/hydrocholoroquine in sars-cov- patients is a dilemma, especially in patients suffering from an impaired immune system. balancing the risk-benefit ratio is a critical issue. corticosteroids may delay the elimination of the virus and increase the risk of secondary infection. in addition, drugs targeting pro-inflammatory cytokines can only inhibit specific inflammatory factors and thus may not be very effective in curbing the cytokine storm (excessive and uncontrolled release of pro-inflammatory cytokines). moreover, some anti-inflammatory drugs such as jak block inf-α production, which is important in fighting the virus [ ] . additionally, fecal transplantation was approved for clinical trials as a therapeutic option for sars-cov- -related pneumonia based on the promising results obtained from fecal microbiota transplantation in patients suffering from antibiotic-associated diarrhea, active ulcerative colitis, and other viral infections [ ] [ ] [ ] [ ] . recently, it was found that intestinal microbiota-derived ifn in lung stroma confers protection against viral diseases such as avian influenza and respiratory syncytial virus [ ] . moreover, based on historical records of the effect of antiviral herbs on sars and influenza h n , chinese herbal formulas could be an alternative approach for the prevention of sars-cov- in a high-risk population [ ] , if no scientifically based therapeutics are available. it was found that sambucus formasana nakai exhibited a strong antiviral effect against human coronavirus nl [ ]. increases ph in host cell lysosomes and negatively influences virus-receptor binding, as well as interferes with the glycosylation of cellular receptors of sars-cov -exhibited a promising antiviral effect against sars-cov- in vitro -improved covid- -pneumonia patients and shortened the course of the disease [ ] remdesivir a monophosphoramidate of adenosine prodrug that incorporates into nascent viral rna chains causing pre-mature termination -used against a wide range of rna viruses such as filoviridae, paramyxoviridae, pneumoviridae, and coronaviridae; used successfully in covid- treatment in the united states and showed no adverse events [ ] darunavir and cobicistat inhibit c-like protease ( clpro). -used for the treatment of mers-cov in experimental animals -used for the treatment of hiv- patients [ ] to date, there is no vaccine to prevent sars-cov- infection, and trials for vaccine development are in the preliminary stages of research. several vaccine candidates such as live attenuated, adenovirus-vectored, recombinant protein, and nucleic acid (dna and mrna) vaccines are in the pipeline [ ] . the epidemiology of sars-cov- is still unclear, and data availability is limited. therefore, it is imperative to follow preventive measures and safety precautions issued by health authorities to limit exposure to the virus and to reduce further spread. general hygienic measures should be implemented, such as ( ) washing hands often with soap and water or an alcohol-based hand sanitizer, ( ) cough or sneeze etiquette, recommending covering of the mouth, ( ) avoiding touching eyes, nose, and mouth if the hands are not clean, ( ) avoiding close contact with sick persons, ( ) avoiding sharing dishes, glasses, bedding, and other household items with sick people, ( ) cleaning and disinfection of surfaces that are often touched, and ( ) staying home from work, school, and public areas when feeling sick. the transmission route of sars-cov- is probably not only through cough, respiratory droplets, and/or contaminated surfaces [ , ] , but also through fecal-oral transmission [ ] . therefore, strict hygienic measures should be followed, especially in dense cities or agricultural spaces [ ] . since the sars-cov- spread is primarily driven by travel, screening of travelers who arrive at airports from pandemic areas for possible sars-cov- infection and entry-screening procedures are necessary. also, general hygienic precautions during travel are highly recommended. travelers who suffered from acute respiratory infection should be tested and reported to the respective public health authorities [ ] . in addition, people should be motivated to notify and report about travel history and close contacts in case of sars-cov- infection. asymptomatic carriers (during the incubation period) and patients after recovery from the acute form are also considered potential sources of the virus [ , ] . strict hygienic measures should be implemented to avoid virus transmission to healthcare workers and other contacts, i.e., placement of sars-cov- suspected or confirmed patients in single-person rooms and wearing personal protection equipment (ppe) such as masks, goggles, and protective gowns. because early diagnosis and detection of asymptomatic carriers of sars-cov- are successful factors for the treatment and prevention of transmission, health authorities should designate laboratories to implement tests for a rapid and accurate diagnosis [ ] . the control of coronaviruses is based on biosecurity regarding animals as well as on shifts in food habits, including discouraging the consumption of bushmeat and of animal products without appropriate cooking [ ] . ban of wet marketplaces where live or dead animals are handled should be implemented. surveillance among people who have contact with wildlife and improvement of biosecurity regarding wildlife trade are urgently needed to prevent the next pandemic outbreak [ ] . the epidemiology of sars-cov- is still unclear. many unresolved questions related to sars-cov- epidemiology and pathogenicity pose great challenges for researchers. these unresolved questions include: what is the origin of sars-cov- ? what is the intermediate host that transmitted the virus from bats? why does the virus cause severe disease and mortality in the elderly or those with co-morbidities, while it is milder in children? are aerosol, saliva, feces, urine, and foodborne the only routes of transmission? what are the other unknown routes of transmission? control of the sars-cov- outbreak and future epidemics requires global efforts among medical and veterinary clinicians, diagnosticians, epidemiologists, public health experts, vaccinologists, pharmaceutical industries, economists, and governments to implement a one-health approach [ , ] . these measures must include: ( ) writing policies and supporting funds required for the implementation of one health, prevention, and control measures, ( ) hiring well-trained and professional personnel, ( ) performing rapid and accurate diagnosis and treatment of infected persons, ( ) developing and providing vaccines for virus control in humans, ( ) conducting surveillance among wildlife for the identification and characterization of possible reservoirs and surveillance among people who are in contact with wildlife to identify risk factors in human behaviors and living environment, ( ) improving hygienic measures, ( ) assessing the social and economic impacts of covid- on the population, ( ) utilizing veterinary experience in the disinfection of premises and gatherings under the supervision of health authorities to decrease outbreaks in humans, ( ) providing antiviral drugs for the treatment of the disease in humans, and ( ) increasing public health awareness about the virus and its transmission. the sars-cov- outbreak started in wuhan city, china, in december . it is now a global pandemic, with , , confirmed cases, , deaths, and , recoveries (as of april ). the virus has the potential for rapid and extensive spread between people and countries. there are a lot of misleading information and knowledge gaps on the newly emerged sars-cov- . therefore, we reviewed the latest updates about different aspects including epidemiology, source of infection, transmission dynamics, zoonotic potential, virus characteristics, and discovery of novel strategies for disease control to avoid spillover of infection in the future. bats play an important role in the transmission of the infection to humans. coronaviruses are genetically diverse and have a high tendency towards frequent genetic mutations and gene recombination, which increases the risk of interspecies transmission. information about the incubation period can help in establishing an effective quarantine for asymptomatic carriers, thus preventing the virus spread. from our perspectives and based on the currently available information about the virus and its epidemiology, the control of the sars-cov- requires an effective and global disease coordination effort including multidisciplinary research efforts (one-health approach) through collaboration between 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phylogenetic tree construction is based. the authors declare no conflict of interest. key: cord- -lkrmg qr authors: xie, yewei; wang, zaisheng; liao, huipeng; marley, gifty; wu, dan; tang, weiming title: epidemiologic, clinical, and laboratory findings of the covid- in the current pandemic: systematic review and meta-analysis date: - - journal: bmc infect dis doi: . /s - - - sha: doc_id: cord_uid: lkrmg qr background: the covid- pandemic has affected the world deeply, with more than , , people infected and nearly , deaths. this review aimed to summarize the epidemiologic traits, clinical spectrum, ct results and laboratory findings of the covid- pandemic. methods: we scoped for relevant literatures published during st december to th july based on three databases using english and chinese languages. we reviewed and analyzed the relevant outcomes. results: the covid- pandemic was found to have a higher transmission rate compared to sars and mers and involved stages of evolution. the basic reproduction number (r( )) is . ( % ci: . – . ), the incubation period was . days ( % ci: . – . , studies) on average, and the average time for symptoms onset varied by countries. common clinical spectrums identified included fever ( . – . °c), cough and fatigue, with acute respiratory distress syndrome (ards) being the most common complication reported. body temperatures above . °c, dyspnea, and anorexia were more common symptoms in severe patients. aged over years old, having co-morbidities, and developing complications were the commonest high-risk factors associated with severe conditions. leucopenia and lymphopenia were the most common signs of infection while liver and kidney damage were rare but may cause bad outcomes for patients. the bilateral, multifocal ground-glass opacification (ggo) on peripheral, and the consolidative pulmonary opacity were the most frequent ct results and the tendency of mortality rates differed by region. conclusions: we provided a bird’s-eye view of the covid- during the current pandemic, which will help better understanding the key traits of the disease. the findings could be used for disease’s future research, control and prevention. the emergence of covid- has made it the first infectious disease pandemic in the twenty-first century. as of th july , a total of , , people got infected, and , were confirmed dead in countries, territories, and areas globally [ ] . while more than countries had issued the highest level of response, the sars-cov- (pathogen of continues to spread in different regions around the world [ ] . however, the key information on the virus epidemiology, clinical spectrum, and on the pathogen was delayed in response during the early outbreaks in many countries. to fill the research gaps mentioned above, this review article systematically summarizes global findings on the natural history, clinical spectrum, transmission patterns, laboratory findings, ct results, and risk factors of the covid- . we searched for publications in epidemiology and clinic domains of the covid- broadly. the databases we searched were: chkd v . of the cnki [in chinese], pubmed, and medrxiv, by using such search terms as 'covid- , sars-cov- , and ncov' (see additional file ). the publication date was restricted from st dec to th jul . both english and chinese were applied for the search. only the full-text available human studies were eligible for selection. like the realtime data, other data were obtained from health departments of multiple countries, global ngos, and reputable media sources. the searched records were firstly screened by reading titles and abstracts. then, the rest records were screened again by full-text reading. if there were disagreements initially, the records then submitted to the whole team for further discussions. besides, a prisma diagram was conducted to illustrate the entire flows of the review (fig. ). the data for the quantitative analysis was extracted and managed by using microsoft excel (microsoft©, redmond, wa, usa). the meta-analysis was performed by the r version . and rstudio ( ) [ ] . the cochrane handbook for systematic reviews of interventions suggested review authors collect missing data from investigators. considered that using the imputation method to tackle the missing data problem could not reduce bias, we only analyse data available to us if we could not collect the missing data from the investigators [ ] . the heterogeneity of the included studies was assessed by using i . the p-value was generated by wald-type test and likelihood-ratio test. the overlapping confidence intervals (cis) were displayed by the forest plots (see additional file ). we categorized and combined the data about epidemiologic traits, clinical spectrums, laboratory, and imageology findings in a narrative. then we further analyze the data about common symptoms, reproduction number, and incubation period through meta-analysis. the quantitative outcomes were combined with the narrative of epidemiological and clinical findings. we collected , records after removing duplications. after three batches of screening, records were included in this review (see screening details in fig. ). in a china based study involving , covid- patients, the majority of patients were aged - ( . %) with only . % of the patients being years and below. the median age of the patients was (ranged days- years old) [ ] . similarly, in the united states, more than half of patients were aged between and years ( %), with only % of patients being under years old. older aged patients were more prone to getting infected compared to the young [ ] . by gender, the male to female ratio of confirmed cases was . : . in china [ ] . however, in south korea and iceland, the male population had a higher incidence rate than the female population [ , ] . males had twice the secondary attack rate than females [ ] . the covid- transmission stages could be categorized into four temporal stages according to the chronological order of case reports. the first stage: people with exposure histories to huanan seafood market (hsm) got infected [ ] . forty-one patients were found to be having sars-like symptoms in december , and the hsm was believed to be one of the origins of the virus. however, of the patients reported no prior exposure to the hsm thus indicating that the origin of the virus needed further investigation [ ] . the second temporal stage is the transition from community transmissions to the outbreak in wuhan [ ] . the virus was mainly spread to multiple communities directly and indirectly by people with hsm exposure histories. the interpersonal transmissions and clustered transmissions formed community transmissions [ ] . an earlier study showed that the proportion of patients with hsm exposure histories decreased from to . % within days, indicating when people who did not have exposure histories to the hsm became infected [ , ] . the third stage: the epidemic in china. at this stage, transmissions began to expand to communities outside wuhan and the hubei province as a whole [ ] . on th jan , a study involving covid- patients outside wuhan found that all the patients had been exposed to wuhan, which demonstrated an established local transmission outside wuhan [ ] . the fourth temporal stage is the global pandemic. on th jan , the first case outside china was reported in thailand [ ] . on th jan , the who declared a public health emergency of international concern (pheic) [ ] . it subsequently took about days for transmission to escalate from the first reported case to the , th reported case outside china. globally, it took days for the number of reported cases to increase from , th cases to , th cases, days from , th cases to , th cases, only days from , th cases to , , th cases and days from , , th cases to , , th cases [ ] . the main transmission route of this virus was by human-to-human spread, since only . % patients among confirmed patients had history of direct contact with wild animals [ ] . the vital transmission routes were through respiratory droplets and contact transmissions. there remains the possibility of aerosol transmission when exposed to high concentrations of aerosols for a long time in a relatively closed environment [ ] . mother-to-child transmission has been confirmed, whiles fecal-oral transmission was also considered possible but lacked direct evidence until now [ , ] . other suspected routes of transmission still needed further clarification. community transmission, nosocomial transmission, household transmission, and transmission in closed environments were four typical transmission patterns of the covid- . firstly, community transmission was considered to be an important pattern in covid- spread [ ] . in the netherlands, community transmissions were found in the noord-brabant regions [ , ] . in north america, community transmissions were reported in winnipeg, canada, and eastern idaho, united states [ , ] . secondly, the potential risk of transmission among medical personnel and through medical facilities was deemed high and thus extreme attention should be paid. transmissions between patients and health workers were in higher proportions during the sars outbreak, while transmission through medical facilities was higher in proportion during the mers outbreak [ ] . in wuhan, the proportion of severely infected medical workers was higher than the national average [ ] . in italy, health workers were reported infected with the covid- before th march and accounted for . % of the total number of cases nationwide. the number however increased to by th march and represented % of the country's total number of cases [ , ] . in spain, the number of diagnosed cases among medical workers increased to within days and more than % of the country's confirmed cases remained among medical workers until march th [ ] . update from another source reported an increase in the number of cases from to % among spain healthcare workers by st march and this was attributed to lack of medical supplies, such as masks and gowns. other reasons accounting for these high infection rates among medical personnel varied according to different country's circumstances. an italy study pointed out hospitals as a potential hotspot for infection. facilities and medical personnel turned into untested vectors and patients [ , ] . in the us for example, the reasons that turned hospitals into infection hotspots included the overload of covid- patients and inappropriate management against the pandemic in hospitals [ ] . similar to the us, medical workers got infected in a county hospital in romania due to inadequate hospital management. in egypt, a serious wave of emigration by physicians for years led to patient overload for remaining medical workers and placed them at higher risk of infection through continuous exposure. the emigration wave was purportedly caused by low salary, undesirable working conditions, lack of legal protection, and shortage of medical supplies and equipment [ ] . thirdly, household transmission contributed to cluster infections and was the major transmission pattern observed in china. for instance, among reported cases in guangdong and sichuan provinces, most cluster infections occurred in families ( - %) [ ] . the who in this regard issued a statement that household transmission highly occurred among medical workers' families than health facility infection in china. household transmission was also a significant pattern observed in south korea and the us [ , ] . the european centre for disease prevention and control (ecdc) had provided guidance for the control of household transmission in european countries [ , ] . what made household transmission worse was that some groups (age < and > ) had high risk got infection within households than the general population [ ] . so, children and elderly living with medical workers at a higher risk of getting than other populations. fourthly, transmissions in a closed environment besides the home should also be of a keen focus on the prevention and control of this outbreak. a japanese health department reported that a closed environment could promote super-spreading events because the transmission of the sars-cov- in a closed environment was the same as large-scale transmission, such as the ski chalet-cluster infection in france and the church-hospital infection clusters in south korea [ ] . for example, outbreaks of the covid- were observed in multiple prisons in china, the uk, and the us [ , , ] . cluster infections also happened on cruise ships, such as the diamond princess, grand princess, golden princess, ruby princess, phoenix reisen, ms westerdam, and punta arenas [ ] . further studies are however required to identify and assess other potential transmission patterns for further prevention, especially since some cases were asymptomatic [ , ] . in addition, patients who were considered cured and no longer needed quarantine still tested rt-pcr positive after to days [ ] . we systematically used the data of the incubation period and the reproduction numbers for meta-analysis (see details of selected studies on additional file ). the result suggested that the mean incubation period was . days ( % ci: . - . , studies), and ranged from to . days [ ] [ ] [ ] [ ] [ ] . however, the incubation period in some special cases could be as long as days [ ] . the result also illustrated that the basic reproduction number (r ) of sars-cov- was . ( % ci: . - . , studies) and varied between . - . [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . this finding suggested that the transmission ability of sars-cov- was stronger than sars ( ) and mers (≤ ) [ , ] . moreover, the median time from the first symptom to first hospital admission was days with the median duration from illness development to severe symptoms development being: - days for dyspnea, - days for ards, . days for mechanical ventilation and icu admission [ , ] . for covid- related deaths, the duration from the onset of symptoms to death averaged days in china and in italy (median) [ ] , and days in south korea (median) [ ] . by th july , nations had reported over , covid- cases in each of the countries, together contributed to . % of the confirmed cases and . % of death in the world . the world case fatality rate (cfr) was . % on th july; however, it was apparently different by country. one third of these countries had a cfr of over . %. france ( . %), united kingdom ( . %), italy ( . %), and mexico ( . %) were the top four countries with over % cfr while qatar ( . %) and saudi arabia ( . %) were the two countries with no more than % cfr. most countries experienced an increase of cfr at first, and the number was then gradually becoming stable during the disease outbreak (fig. ) . however, the cfr was high in iran ( . % on th february) and the united states ( . % on th march) at first, experienced a sharp decrease to . % on th march and . % on th march, and rebounded to . and . % on th july, respectively. bangladesh was the only country that had high cfr of around % at the beginning and then continuously decreased until . % on th july. as the pandemic outbreak continued, more surveillance is needed for the cfr of covid- [ ] . the mortality is higher among elderly, patients requiring intensive care unit admission and male. however, mortality rate among younger age group and patients with mildly disease is less. the us's data indicated that patients younger than had milder covid- illness, with almost no hospitalizations or deaths reported [ ] . based on a worldwide data, the elderly (aged over ) were at a high risk of developing into death [ , , , ] . the mortality in icu was extremely higher than non-icu patients, varied from to % [ ] [ ] [ ] [ ] . about the gender ratio, there is a seemingly unquestionable pattern that covid- killed more men than women [ ] . unlike the less report in the research from china, south korea or other asia areas, the reports from europe and american reflect the male gender is the risk factor for heavy illness. to figure out the general situation around the world, here we analyzed the data from countries, compiled centrally and individually verified by authors against country-specific reports [ ], shown that the case-fatality rate among male is about % higher than female (ir = . based on the data collected from selected articles [ , , , , (details of selected articles were put in the additional file ), we conducted the meta-analysis using a random-effects model to identify the clinical feature of covid- . fever ( . , % ci: . - . %) and cough ( . , % ci: . - . %) were the most fig. case fatality rate of countries reported over , cases, *. *data was collected until july (i.e. the th day of year ). the cfr of a country was not included on those dates when the country reported less than cases, with the consideration that the cfr may not be reliable if the size of infected population was small common symptoms. other common symptoms included: olfactory ( . %), gustatory ( . %), dyspnea ( . %), fatigue ( . %), sputum production ( . %), sore throat ( . %) and headache ( . %). all the other data showed in table . besides, studies pointed out that most patients had more than one symptom [ , , ] . additionally, there were . % of patients without viral pneumonia symptoms [ ] , which was opposite to previous studies [ , ] . the asymptomatic cases varied from . - . % [ , , , ] . the top common symptoms among mild and severe patients are summarized and displayed in a figure (fig. ) [ , , , , [ ] [ ] [ ] [ ] . fever was found to be the most common symptom in all patients. in a study, . % of patients had fever initially and the proportion increased to . % following hospitalization [ ] . the body temperatures of - . % of patients ranged between . - . °c. the higher body temperatures (above . °c), dyspnea and anorexia were more frequent among patients in severe conditions [ , , ] . cough and fatigue were more widely reported among mild and severe patients. additionally, another study reported that dyspnea ( %) was the most common symptom among severe patients in the united states [ ] . the proportion of patients who needed icu care varied based on the local pandemic circumstances. for example, the who speculated that around . % of patients were in severe conditions in china [ ] . however, - % of patients needed icu care in wuhan [ , , ] . currently documented covid- related complications include ards, arrhythmia, septic shock, acute cardiac injury, myocarditis, acute coronary syndrome, cardiomyopathy, acute respiratory injury, and acute renal injury, etc. [ , , , , , ] . the ards was the most common complication, among both mild and severe patients [ , , , , ] . most icu patients had a higher risk of developing ards and having complications [ , ] . the progress of some patients with ards to septic shock was fast and quickly evolved into multiple organ failure finally [ ] . among covid - patients, a decrease in leukocytes such as eosinophil and lymphocyte were commonly reported. this might be because the cytokine storm caused by the novel virus changes the peripheral of white blood cells and immune cells [ , , , , , ] . severe lymphopenia was also common among the dead patients [ , ] . myocardial zymogram abnormality was found in many patients. for instance, % of patients had an increase in lactate dehydrogenase, while % of patients had increases in creatine kinase [ ] . the level of c-reactive protein was important to evaluate the infection [ ] . most patients were found to have a higher level of c-reactive protein ( %) and serum ferritin ( %) compared to the normal range [ ] . the biomarkers related to liver and renal damage were found to be abnormal among covid- patients. the abnormality of liver-related biomarkers was not widespread but yet still common in severe cases [ , , , ] . besides, although only % of patients showed renal biomarker abnormalities, renal damage might contribute to the final multi-organ failure and death outcome [ , ] . the icu patients showed higher levels of white blood cells, neutrophil counts, d-dimer, creatine kinase, and creatine with longer prothrombin times [ , , ] . compared to patients who survived, the patients who died had higher levels of d-dimer, high-sensitivity cardiac troponin i, serum ferritin, lactate dehydrogenase, il- , blood urea, creatinine, white blood cell counts and neutrophil counts. severe lymphopenia was also common among dead patients [ , ] . the computed tomography scan (ct scan) was widely used for disease diagnosis, prognosis, and management during the covid- [ ] . the ct was found more sensitive for identifying sars-cov- patients than the rt-pcr assay ( % vs. %) in a study [ ] . the ct evidence for confirming the highly suspected patients' positive may precede the rt-pcr results [ , ] . most patients had ggo and the bilateral lung involvement [ , , [ ] [ ] [ ] . one study found that bilateral lung involvement was more frequently shown in the intermediate course and late course, compared to the earlier clinical course [ ] . the clinical course could be divided into four stages based on ct scan findings [ ] . in the first stage (pre-symptom), ggo, unilateral and multifocal were observed among most patients in this stage [ , ] . in the second stage (symptoms ≤ week), lesions soon developed into bilateral and diffused except for ggo. this stage was considered a period from transition to consolidation. a mixed pattern of transition and consolidation develops during this stage. in the third stage (symptoms - weeks), the ggo was still common and the consolidation pattern showed. findings indicated an interstitial change, which was considered as the development of fibrosis. in the fourth stage (symptom - weeks), consolidation and mixed patterns were more common, and the ggo started to shrink [ ] , the consolidation was gradually absorbed among patients who recovered at last [ ] . among icu patients, the bilateral multiple lobular and sub segmental areas of consolidation were considered typical findings [ ] . patients in severe condition showed diffuse lesions, with density increasing in both lungs. ct scans showed 'white lung' appearances, indicating the serious influence the infection has on patients' lung functions [ ] . being old (≥ years old), male sex, having a higher bmi value (> kg/m ), having co-morbidities (e.g. hypertension, diabetes, cardiovascular and cerebrovascular diseases, etc.), and developing complications were vital risk factors for patients to develop severe conditions [ , , , , , , ] . the cytokine storm, raised inflammatory markers, elevated cardiac troponins, the requirement of mechanical ventilation, and the requirement of intensive care unit stay predict the bad outcome of admission patients [ ] . findings from multiple studies showed that patients who are more than years of age, with co-morbidities such as diabetes and heart diseases had a high mortality rate [ , , [ ] [ ] [ ] . late hospitalization and bacterial infections were also considered high risk factors for disease progression [ , , ] . smoking history could be a potential risk factor for developing severe conditions [ , ] . people with underlying disorders were considered to be at a high risk of getting infected [ ] . our review identified several research gaps. firstly, large amounts of data from african were missing from this review. as the number of people in african suffering from malnutrition, anemia, malaria, hiv/aids and tuberculosis is high, a large "low immunity population" has been created which has made the control and prevention of covid- in the region a challenge. the situation could be worsened by the limited health resources region [ ] and hence, more african focused research is required to support africa in fighting the epidemic. secondly, the proportion of asymptomatic patients is large but the current transmission ability by asymptomatic patients might be weak. however, further exploration of risks posed by the group is needed as limited studies exist on the subject matter [ ] . meanwhile, data on the distribution of asymptomatic patients in large-scale community groups is also lacking, prompting the need for large scale of active screening and testing to help identify them [ , ] . this approach is however difficult and expensive for most countries to undertake as accurate strategies to identify asymptomatic currently are non-existent. further research focus on asymptomatic patients is needed. third, a 'super-spreader' was defined as infected individuals who infected numerous others during the sars outbreak. for example, a nephrotic hospitalized patient who infected people was classified as a 'superspreader' during the sars in china. in those patients were medical workers who came in contact with the 'super-spreader'. the incidence rate among the medical workers was . % ( / ) in the nephrotic department [ ] . in the covid- era, the emergence of 'super-spreaders' were found in multiple places worldwide. a saudi arabian study linked the concept of 'super-spreaders' to 'super spreading' events noting that 'super-spreaders' might cause unexpected transmissions during the pilgrimage [ ] , as huge numbers of people gather. reasons causing the super-spreading events might include: immune suppression, increased disease severity and viral load, asymptomatic individuals, and extensive social interactions [ ] . however, the characteristics and features of how an individual becomes a super-spreader are still not clear [ ] . summarizing the features of the 'super spreader' concept, as well as their characteristics and role in transmissions, are needed in future disease control [ ] . fourth, it has been reported that some cured patients covid- retested positive by pcr after being discharged and quarantined at home in multiple places [ , ] . the reason for this phenomenon is still unclear and hence further investigations are required for future pandemic control [ ] . there existed some limitations in this review. firstly, this review was based on english and chinese resources only. as the covid- transformed from a regional outbreak to a global pandemic, comprehensive collection of the related information worldwide is needed. secondly, the clinical spectrum presented in this review is based on general population only, and thus a further subgroup analyzes in future may help to figure out more on 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-status of diagnostic test, significance of "super spreaders problems to be solved in sars research in china fu yang": there is no unified conclusion, and discharge management is being strengthened at present, it seems that fuyang patients are not infectious what is kawasaki disease and its possible link with covid- in children? publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we thank mr. peizhen zhao for technical support.authors' contributions wt designed the study protocol. yx, zw, and hl did the literature search. the titles, abstracts, and full texts were screened and selected by yx, zw, and hl. the data were extracted and analysed by yw, zw and hl. yx, zw and hl drafted the manuscript. yx, zw, gm, dw, and wt edited the draft. all authors read and approved the final manuscript. key: cord- -pem zk authors: zhang, ling-pu; wang, meixian; wang, yanping; zhu, jun; zhang, nannan title: focus on a -novel coronavirus (sars-cov- ) date: - - journal: future microbiology doi: . /fmb- - sha: doc_id: cord_uid: pem zk a new coronavirus, severe acute respiratory syndrome coronavirus , was first discovered in wuhan, china, in december . as of april , , the new coronavirus has spread quickly to countries and aroused the attention of the entire world. no targeted drugs have yet been available for intervention and treatment of this virus. the sharing of academic information is crucial to risk assessment and control activities in outbreak countries. in this review, we summarize the epidemiological, genetic and clinical characteristics of the virus as well as laboratory testing and treatments to understand the nature of the virus. we hope this review will be helpful to prevent viral infections in outbreak countries and regions. clinical symptoms fever ( %), sough ( %), dyspnea ( . %), myalgia ( . %), malaise ( %) and so on fever (Ͼ %), cough ( %- %),chills or rigor ( %- %), diarrhea %, dyspnea ( %) fever ( %), cough ( %), dyspnea ( %), sputum production ( %), odynophagia ( %), digestive system /signs ( %), hemoptysis ( . %), myalgia ( %) and headache ( %) [ , , ] radiology critically ill patients with bilateral multiple lobular and subsegmental areas of consolidation; mild patients with bilateral ground-glass opacity and subsegmental areas of consolidation almost % patients with abnormal ct unilateral/bilateral ground-glass opacities or focal unilateral/bilateral consolidation. chest radiography or ct abnormal rate was Ͼ % unilateral/bilateral patchy densities or infiltrates, bilateral hilar infiltration, segmented/lobar opacities, ground-glass opacities and possible small pleural effusions. chest radiography or ct abnormal rate was between % to % was named severe acute respiratory syndrome coronavirus (sars-cov- ) by the international committee on taxonomy of viruses on february [ ] . the disease caused by sars-cov- was named covid- by the world health organization (who). on january , the who declared the outbreak of covid- to be a global health emergency and further labeled it a pandemic on march . the virus can be transmitted not only from animals to humans but also from humans to humans [ ] . a lancet report demonstrated that the virus could have recently acquired the ability to transmit between humans [ ] . a report of five patients in a family cluster who traveled to wuhan and were infected with sars-cov- was the first report directly illustrating that the virus is capable of person-to-person transmission in hospital and family settings [ ] . sars-cov- can spread via direct contact and respiratory droplets. respiratory particles are spread while breathing, speaking, coughing or sneezing [ ] . in addition, aerosol and fomite transfer may promote transmission of the virus according to a study in the new england journal of medicine [ ] . aerosolized virus may be generated by respiratory and surgical procedures. the study showed that the half-life of the virus is about . - . h, and it remained viable for h in aerosols. meanwhile, the virus on plastic, stainless steel, copper and cardboard remained stable for - h [ ] . these results indicate that aerosol or fomites may be able to spread sars-cov- [ ] . a fluid-resistant (type-r) surgical face mask is used to protect against droplets. fecal-oral transmission may also play an important role in sars-cov- spread [ ] . xiao and colleagues showed that . % of hospitalized covid- patients had sars-cov- rna in stool specimens, and the duration time of positive stool results ranged from to days [ ] . in addition, viral nucleic acid in . % patients remained positive in the feces after sars-cov- rna in pharyngeal swabs turned negative. furthermore, positive sars-cov- rna in stool specimens was not associated with gastrointestinal symptoms [ ] . together, these findings indicate the possibility of sars-cov- via the fecal-oral transmission. the basic reproduction number (r ) of this virus reflects the dynamics of transmission during this coronavirus outbreak. the who has estimated that sars-cov- has a reproduction number of . - . . however, a recent study shows the average r to be . (median: . ; interquartile range [iqr]: . ), an r considerably higher than the who estimate at . [ ] . in an earlier phase of the outbreak, li et al. reported that the mean incubation period of the virus is . days ( % ci: . - . ), the epidemic doubled in size every . days, and the r was estimated to be . ( % ci: . - . ) [ ] . zhao and collaborators estimated an r ranged from . ( % ci: . - . ) to . ( % ci: . - . ) [ ] . in another study, r was computed to oscillate between . ( % ci: . - . ) and . ( % ci: . - . ) [ ] . in addition, the study reported a transmission rate within wuhan of . days ( % ci: . - . ), an infectious period of . days ( % ci: . - . ) and an r value of . ( % ci: . - . ) [ ] . based on the nowcasting and forecasting approach, wu et al. showed an estimated reproduction number of . ( % ci: . - . ), and an epidemic doubling time of . days [ ] . recently, tang et al. calculated the r as . ( % ci: . - . ), using mathematical seir-type epidemiological model [ ] . nevertheless, sars-cov- has demonstrated a higher transmission rate than that of sars-cov and mers-cov. variation in viral transmissibility should be considered, and estimates of the reproduction number may change in the future. sars-cov- is similar to sars-cov. both single-stranded rna viruses share % nucleotide identity, and sars-cov- shares % identity with sars-like covzxc [ ] . the genome of sars-cov- has , nucleotides encoding , amino acids. genetically, sars-cov- is similar to sars-cov (about %) and mers-cov (about %) [ ] . the virus contains a replicase, spike (s) protein, envelope (e) protein, membrane (m) protein and nucleocapsid [ ] (figure a & b) . however, sars-cov- lacks the hemagglutinin-esterase gene, which is found in lineage a β-covs. sars-cov- has open reading frames (orfs) encoded by nine subgenomic mrnas that carry nine transcription regulatory sequences, two terminal untranslated regions (utr) and a conserved leader sequence [ ] . the large replicase polyprotein pp a contains ten nonstructural proteins (nsp -nsp ), and pp ab contains nonstructural proteins (nsp -nsp , nsp -nsp ), which are all encoded by orf a and orf ab [ ] (figure a ). with the exception of nsp and nsp , which are cysteine proteases, most nonstructural proteins play an important role in the transcription and replication of sars-cov- [ ] . pp ab has different lengths in covid- , sars-cov and mers-cov of , bp ( aa), , bp ( aa) and , bp ( aa), respectively ( figure a) . furthermore, there is no obvious difference between sars-cov- and sars-cov nonstructural proteins and orfs. the spike glycoprotein plays an important role in binding to receptors on host cells and, therefore, is involved in host tropism [ ] . sars-cov- , sars-cov and mers-cov have s proteins containing , , , and , aa, respectively ( figure a ) [ ] . the s protein mediates entrance into human respiratory epithelial cells by interacting with the cell-surface receptor angiotensin-converting enzyme (ace ) [ , ] . it is comprised of s and s subunits ( figure c ), and the s subunit shares approximately % identity with that of human sars-cov and bat sars-like covs (sl-covzxc and zc ). the s subunit has an n-terminal domain and a receptorbinding domain (rbd) that are both responsible for the binding of virions to host cells [ ] . both sars-cov- and sars-cov bind to ace through the c-terminal domains (ctd) of their s subunits, and mers-cov utilizes the ctd to bind proteinaceous dipeptidyl peptidase (dpp ) [ ] . the rbd of sars-cov- has % identity to that of sars-cov [ ] . the transmissibility of the sars-cov- virus is greater than that of sars-cov, which may be because the rbd of sars-cov- is slightly different from that of sars-cov. the s subunit shares % identity with two bat sars-like covs and human sars-covs [ ] . the s subunit contains a fusion peptide (fp) and heptad repeats (hrs) and ( figure c ). after the s rbd binds to the ace receptor on the host cell, the fp of s is inserted into the host cell membrane, and then hr and hr form a six-helix bundle ( -hb), which helps the virus fuse with host cell membranes [ , ] . sars-cov- envelope (e) protein, matrix protein, accessory proteins p and p , nonstructural protein (nsp ), and nsp are homologous with those of sars virus [ ] . therefore, the sars-cov- virus has a high level of identity with sars-cov. this suggests that an anti-sars-cov antibody, which could cross-react with the sars-cov- s protein, may be useful to treat patients with the virus. sars-cov- infection has caused clusters of severe respiratory illness similar to that of sars-cov. the virus causes symptoms such as fever, cough, shortness of breath, leukopenia and pneumonia in both lungs [ ] . the symptoms are observed approximately . days after the sars-cov- infection [ ] . in a study published in the lancet, of patients who were identified as positive for sars-cov- infection presented with pneumonia and abnormal chest computed tomography (ct) [ ] . covid- symptoms included fever ( %), cough ( %) and myalgia or fatigue ( %). less common symptoms such as sputum production ( %), headache ( %), hemoptysis ( %) and diarrhea ( %), were also observed [ ] . another clinical study containing patients showed that common symptoms were fever, fatigue, dry cough, lymphopenia, prolonged prothrombin time and an increased lactate dehydrogenase level (table & figure ) [ ] . common complications included shock, acute respiratory distress syndrome, acute renal injury, acute liver failure, arrhythmia, rnaaemia and acute cardiac injury [ ] . in addition, it is now understood that sars-cov- can infect children as well as adults [ ] . one study showed that during the early infection period, most patients had normal white blood cell counts; however, . % of patients had leukopenia in cases of serious infection [ ] . patients with dyspnea were more frequently admitted to the intensive care unit (icu) [ ] . most chest computed tomography (ct) showed bilateral patchy shadows or ground-glass opacity (ggo) in the lungs [ , ] . in another study, % of patients showed ggo by chest ct, and % of patients had consolidation [ ] . following the appearance of ggo, % of patient lung cts showed reticular or interlobular septal thickening [ ] . however, no direct cavitation, pleural effusion, lymphadenopathy or nodules were observed in the lungs of covid- patients [ ] (table ). in view of the large amounts of cytokines produced during sars-cov infection, infection with sars-cov- similarly induces the production of proinflammatory cytokines such as, interleukin beta (il- β), interferon gamma (ifn-γ), ip and monocyte chemoattractant protein (mcp). moreover, the levels of granulocyte colony stimulating factor (gcsf), ip , mcp , mip α and tumor necrosis factor-alpha (tnf-α) were found to be higher in intensive care unit (icu) than non-icu patients [ ] . however, secretion of immunosuppressive cytokines (e.g.,interleukin [il- ] and interleukin [il- ] by t-helper type [th ] cells was also increased during sars-cov- infection [ ] ) ( table ) . the mortality rate of sars-cov- -infected patients varies in different studies. a study of patients showed a mortality rate of % [ ] , and the fatality of patients in a clinical study was . % [ ] . however, chen showed that the mortality was %, a number closer to the official national statistics of china ( . %) [ ] . these differences in mortality rates are possibly due to the difference in sample size. the reported mortality rate of sars-cov was %, and that of mers-cov was about % [ ] . the currently estimated mortality rate of sars-cov- is therefore lower than that of sars-cov and mers-cov [ , ] (table ). in summary, sars-cov- spreads more rapidly but has a relatively lower fatality rate as compared with two other related coronaviruses. the number of total leukocytes, lymphocytes and monocytes has been detected from hospitalized patients with covid- [ ] . approximately % of cases formed leucopenia [ ] . moreover, lymphopenia was observed in - . % of patients [ , ] . cd + or cd + t-cell numbers decreased as the disease severity increased [ , ] . patients with severe cases had more prominent abnormalities than those with non-severe cases. patients infected with covid- had some unique clinical features including rhinorrhoea, sneezing, sore throat. most patients had haemoptysis dyspnea, fever, headache, fatigue, sputum production, pneumonia and ground-glass opacities. however, only a low percentage of patients developed intestinal symptoms such as diarrhea and vomiting. leucopenia, lymphopenia, pro-inflammation cytokines increasing, acute respiratory distress syndrome and acute organs damages (such as cardiac, liver or kidney) were common features in some intensive care unit patients. virus from throat swabs, blood, urine, stool or respiratory tracts have been assessed by fluorescent reverse transcription-polymerase chain reaction (rt-pcr) methods [ ] . primers and probes targeting rdrp/helicase (hel), e, s, n and replicase orf a/b genes were designed and tested for sars-cov- [ ] . rt-pcr showed that primers of the e and rdrp genes demonstrated better sensitivity than that of the n gene, and the limit of detection (lod) of rdrp/hel and n gene was lower than that of s gene and rdrp-p [ ] . chan et al. showed that the covid- -rdrp/hel assay (rdrp/hel probe, fam-ttaagatgtggtgcttgcatacgtagac-labkfq) was significantly more sensitive than the rdrp-p assay for the detection of sars-cov- rna, and detection targeted orf a/b, orf b-nsp , rdrp, s, e or n genes was with less specificity for sars-cov- [ ] . moreover, a previous study showed that the specific probe rdrp sarsr-p (fam-caggtggaacctcatcaggagatgc-bbq) detected only the sars-cov- rna transcript but not the sars-cov rna [ ] . however, a novel rt-pcr assay showed that targeting rdrp was a non-specific assay for sars-cov- , because this detected other betacoronaviruses such as sars-cov [ ] . the covid- -rdrp/hel assay had the lowest lod in vitro and higher sensitivity and specificity, which helped to reduce the false-negative rate and improve the laboratory diagnosis of covid- [ ] . sars-cov- viral load is detectable from throat-and lung-derived samples; however, blood and urine have not yet yielded virus [ ] . patients with covid- produced the highest viral load near symptom presentation, which may be the reason for the fast spread of the virus [ ] . an observational cohort showed that viral load in saliva was highest following symptom onset in the first week, then gradually declined with time [ ] . endotracheal aspirate viral load was available from day after symptom onset and did not significantly decline thereafter [ ] . following symptom onset, virus load in % patients could be detected for days or longer in that study. viral load in respiratory tract specimens was about sixfold higher than that in the nonrespiratory tract specimens [ ] . in addition, elder patients reportedly had a greater virus load than that of younger patients. studies showed that higher initial viral load was related to the severity of covid- symptoms [ ] . although the positive test ratio was only . % in previous study, it was improved by novel assay methods [ ] . the sample quality, collection time, detection kits and technical abilities of clinical doctors may affect the accuracy of detection. therefore, precise diagnosis of covid- should be combined with ct scans and nucleic acid testing. bronchoalveolar lavage fluid or throat swabs from patients have been sequenced, and viral genomes were searched via blast with the sars-cov- sequence [ , ] . genome sequencing has also been used to identify patients with suspected infection. in addition to hematological detection and nucleic acid testing, serological diagnosis is important for patients who present late with a very low viral load, below the detection limit of rt-pcr assays [ ] . igm and igg titers were relatively increased on day and rapidly raised days after symptom onset in most patients [ , ] . the igm-positive rate increased from to %, whereas the igg-positive rate increased from to % [ ] . in addition, the igm-and igg-positive rates were not significantly different before and after patients were found to be virally negative [ ] . therefore, virus-specific igm and igg serological testing may be used to confirm current or previous infection with sars-cov- . an ideal animal model for covid- would reflect the clinical signs, viral replication and pathology displayed in humans. non-human primate models (rhesus, cynomolgus macaques, african green monkeys, common marmoset, squirrel monkeys and mustached tamarins) have all been evaluated as models of sars-cov infection [ ] . all non-human primates had pneumonia, cough and respiratory distress after virus infection [ ] . mice (balb/c, c bl and s strains) supported sars-cov replication and showed clinical signs of sars [ ] . rag −/− mice, cd −/− mice, stat −/− mice and beige mice have been used to determine the role of immune effectors of the virus [ ] . ac and ac transgene-positive mice also showed clinical manifestation after sars-cov infection, demonstrating their usefulness to study the pathogenesis and evaluation of vaccines and other therapeutics [ ] . hamsters also have been used to study immuno-prophylaxis and drug research as they harbored high viral titers and pulmonary histopathology upon virus infection [ ] . ferrets are another appropriate animal model to study this respiratory virus because the clinical symptoms, viral titers and histologic changes were similar to those of patients with virus infection [ ] . ace , the receptor of sars-cov, was also identified as the functional receptor for sars-cov- , therefore, mice, hamsters and ferrets may be animal models for studying the sars-cov- [ ] . an article reported in science shows that sars-cov- can replicate in the upper respiratory tract of ferrets, indicating that ferrets represent an ideal animal model for evaluating antiviral drugs or vaccine candidates against covid- [ ] . in addition, the domestic cat has shown multifocal pulmonary consolidation with infection of sars-cov, and sars-cov- can replicate efficiently in cats and transmit between cats via the airborne route [ ] . by contrast, dogs, pigs, chickens and ducks are poorly susceptible to sars-cov- [ ] . no specific therapeutic medicine has been approved for the treatment of sars-cov- infection. all patients are given empirical antibiotic or antiviral drugs. moxifloxacin or levofloxacin are empirically used to treat early coinfections with bacteria [ ] . linezolid is effective against streptococcus pneumoniae and staphylococcus aureus and is combined with nemonoxacin in cases of severe infection [ ] . a combination of lopinavir and ritonavir has been used to treat covid- because the lopinavir/ritonavir (lpv/r) combination has been confirmed to be effective against sars-cov and mers-cov [ , , ] . another antiviral drug, remdesivir (rdv), was predicted to be efficacious against covid- by target-based virtual ligand screening [ ] . rdv is a novel nucleotide analog prodrug that is in development and has demonstrated effective pan-cov therapy. the first case of sars-cov- infection in the usa was successfully treated with rda. moreover, a randomized, double-blind, parallel-controlled phase iii clinical trial was conducted to recruit sars-cov- -infected patients [ , ] . favipiravir is a nucleoside analog that can lead to lethal viral mutagenesis, chain termination or the inhibition of nucleotide biosynthesis [ ] . favipiravir in combination with oseltamivir, which was given to patients infected with sars-cov- , has been used to treat severe influenza [ ] . oseltamivir, a neuraminidase inhibitor, is recommended as an antiviral treatment for influenza and has been widely used to inhibit covid- in china [ , ] . other neuraminidase inhibitors, zanamivir and peramivir, are also effective treatments for mers-cov [ ] . at this time, these are all empirical therapies for covid- . however, whether oseltamivir or zanamivir are effective treatments for covid- also needs further study. arbidol (arb) was licensed for the treatment of influenza and other respiratory viral infections in russia and china [ , ] . blaising and coauthors consider arb to be a broad spectrum antiviral drug [ ] . in addition, arb has been reported to inhibit sars-cov in vitro. therefore, a clinical trial of arb-treated covid- -positive patients has been registered [ ] . glucocorticoids have been commonly used in patients with sars-cov or mers-cov infection [ , ] . glucocorticoids prolonged the survival time of sars cases [ ] . patients with covid- were given glucocorticoids in some hospitals in china. however, the mortality rate did not decrease with corticosteroid treatment in patients infected with sars-cov- , and viral clearance was not delayed [ , ] . therefore, it is still controversial whether corticosteroids should be used to treat sars-cov- infections [ ] . chloroquine/hydroxychloroquine was used as an antimalarial, broad spectrum antiviral drug, and has been broadly used in autoimmune diseases including lupus and rheumatoid arthritis [ ] . a recent study indicates that chloroquine and the antiviral drug rdv-inhibited sars-cov- in vitro [ ] . clinical symptoms of patients treated with chloroquine were obviously relieved: for example, more rapid decline in fever and improvement of lung ct [ ] . chloroquine was suggested to treat covid- in the sars-cov- treatment guidelines by the chinese medical advisory. chloroquine has been highly effective in reducing sars-cov- viral replication by increasing endosomal ph and interfering with the glycosylation of cellular receptors [ ] . moreover, chloroquine was probably the first molecule to be used to treat covid- . another antiviral drug, nelfinavir, an hiv protease inhibitor, was predicted to be a potential inhibitor of covid- [ ] . in addition, cytokine immunotherapy with ifn-α, a broad spectrum antiviral drug, has been used to inhibit hbv. ifn-α was used to treat patients infected with sars-cov- according to established guidelines [ ] . ifn-α combined with lpv/r was shown to be beneficial for treatment of covid- [ ] . tocilizumab is a humanized anti-il- -receptor (il- r) monoclonal antibody that inhibits il- signaling and is used as a treatment in rheumatoid arthritis [ ] . il- is one of the most important cytokines involved in covid- -induced cytokine storms. tocilizumab (tcz) has been used to treat covid- in china and italy. tcz was recommended for covid- patients to prevent or treat cytokine storms and could reduce the mortality of covid- [ ] . other drug types such as rna synthesis inhibitors (tdf and tc) and an fp (ek ), have also effectively inhibited sars-cov- in vitro. in addition, traditional chinese medicines (lian hua qing wen capsules, shu feng jie du capsules) have also been used to treat covid- in the latest version of the diagnosis and treatment of pneumonia induced by covid- [ ] . in addition, human seroalbumin and γ-immunoglobulin were given to some patients with severe infections [ ] . in conclusion, there are specific vaccines or antiviral drugs for covid- . all of the drugs described above have shown some usefulness in treating sars-cov- infections, and their efficacy merits further study. covid- is a serious human infectious disease of global concern. as of april , sars-cov- has infected a total of , patients globally at least ( figure d & g) . the covid- outbreak poses a serious challenge to china and the whole world; it has profoundly affected public health. although the overall mortality rate of sars-cov- appears to be lower than that of sars-cov and mers-cov (table ) , the transmissibility of covid- is more rapid. moreover, the fatality rate of elderly patients with reduced immunity or chronic diseases is as high as % [ ] . in addition, asymptomatic carriers may be a potential source of infection, sustaining a local epidemic and global spread [ ] . therefore, covid- may cause disruptions to the global public health system for an extended period of time. the outbreak of covid- has shown that there are still shortcomings in the prevention of public health diseases such as the lack of awareness of the frontline doctors and the early vigilance and attention from the government. meanwhile, the awareness of the general public to health concerns also must be improved. individuals should develop good living habits: for example, keeping away from wild animals, not consuming wild animals, maintaining hand hygiene -among others. in addition, the development of targeted antiviral drugs should be anticipated and accelerated in the future. certainly, vigorous measures to prevent contagion have been taken in china and other countries. to prevent the spread of infection, the chinese government imposed a full lockdown and canceled public events such as the new year festival; contact with wild animals was also restricted, and travel was reduced with screening at airports, railway stations and subway stations [ ] . moreover, two emergency hospitals in wuhan were constructed, and army medical units and medical staff from other areas were deployed to help prevent infections in wuhan [ ] . the who and various governments advised people to reduce public activity, maintain social distance, wear masks, wash their hands frequently, and practice respiratory hygiene. as of april , the number of fully recovered patients was , worldwide ( figure e & h) , and the number of recovered patients was , in china ( figure b ). therefore, we are confident that the outbreak of covid- will be effectively curbed. most countries have isolated any suspected cases as rapidly as possible to contain infection and prevent local outbreaks. the ability to rapidly test patients suspected of having a sars-cov- infection is the cornerstone of case isolation. the experience gained from sars-cov and mers-cov by the health community over the last years could also help in dealing with sars-cov- infections throughout the world. to date, no sars-cov- -specific antiviral drugs or vaccines have been described for covid- . therefore, a safe and stable vaccine for covid- is urgently needed, and it is expected to be ready within months [ ] . vaccines specific for sars-cov- will immunize people worldwide in the future. it is hoped that drugs specifically targeted for covid- also will be widely developed. meanwhile, the origin, intermediate host, structure and pathogenesis of sars-cov- will be the focus of future research. moreover, prediction of whether the similar coronaviruses can infect humans will be import for all the world. we hope that vaccines specific for the similar coronaviruses will be developed in advance to prevent epidemics in the world. • coronavirus disease (covid- ) was first reported in china and currently poses a serious challenge worldwide. the pneumonia was caused by a novel coronavirus named sars-cov- . • more than , , cases of covid- and , deaths have been reported as of april , according to data from johns hopkins resource center. • sars-cov- belongs to betacoronavirus, a large genus of viruses prevalent in nature. sars-cov- has % nucleotide identity with human sars-cov and % nucleotide identity with bat sars coronavirus (sarsr-cov-ratg ). • the fatality rate of covid- has been approximately . % and the r has ranged from . to . . compared with previous coronavirus outbreaks, has been reported to have a lower mortality rate and more rapid transmissibility and caused severe acute respiratory syndrome similarly to sars. • the main symptoms are fever, cough, shortness of breath, leukopenia and pneumonia. • diagnostic laboratory testing of covid- includes hematology testing, nucleic acid testing, viral genome sequencing and serology testing. to date, no specific antiviral drugs or vaccines for covid- have been developed. therefore, empirical antiviral drugs (lopinavir/ritonavir, favipiravir, oseltamivir, zanamivir and peramivir, arbidol), antibiotic drugs (moxifloxacin, levofloxacin, linezolid), chloroquine/hydroxychloroquine, glucocorticoids, monoclonal anti-inflammatory antibody (tocilizumab), have been used to treat sars-cov- infection. traditional chinese medicines are also used for therapy during infection with sars-cov- . • this review is presented in the hope of helping the public effectively recognize and combat covid- and to provide a reference for future studies or outbreaks. the authors gratefully acknowledge all doctors who participate in the fight against covid- on the frontline. financial & competing interests disclosure no writing assistance was utilized in the production of this manuscript. . /fmb- - future microbiol. 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novel coronavirus (covid- ) outbreak: a call for action novel coronavirus pneumonia emergency in zhuhai: impact and challenges focus on middle east respiratory syndrome coronavirus (mers-cov) key: cord- -v kk i authors: dhama, kuldeep; khan, sharun; tiwari, ruchi; sircar, shubhankar; bhat, sudipta; malik, yashpal singh; singh, karam pal; chaicumpa, wanpen; bonilla-aldana, d. katterine; rodriguez-morales, alfonso j. title: coronavirus disease –covid- date: - - journal: clin microbiol rev doi: . /cmr. - sha: doc_id: cord_uid: v kk i in recent decades, several new diseases have emerged in different geographical areas, with pathogens including ebola virus, zika virus, nipah virus, and coronaviruses (covs). recently, a new type of viral infection emerged in wuhan city, china, and initial genomic sequencing data of this virus do not match with previously sequenced covs, suggesting a novel cov strain ( -ncov), which has now been termed severe acute respiratory syndrome cov- (sars-cov- ). although coronavirus disease (covid- ) is suspected to originate from an animal host (zoonotic origin) followed by human-to-human transmission, the possibility of other routes should not be ruled out. compared to diseases caused by previously known human covs, covid- shows less severe pathogenesis but higher transmission competence, as is evident from the continuously increasing number of confirmed cases globally. compared to other emerging viruses, such as ebola virus, avian h n , sars-cov, and middle east respiratory syndrome coronavirus (mers-cov), sars-cov- has shown relatively low pathogenicity and moderate transmissibility. codon usage studies suggest that this novel virus has been transferred from an animal source, such as bats. early diagnosis by real-time pcr and next-generation sequencing has facilitated the identification of the pathogen at an early stage. since no antiviral drug or vaccine exists to treat or prevent sars-cov- , potential therapeutic strategies that are currently being evaluated predominantly stem from previous experience with treating sars-cov, mers-cov, and other emerging viral diseases. in this review, we address epidemiological, diagnostic, clinical, and therapeutic aspects, including perspectives of vaccines and preventive measures that have already been globally recommended to counter this pandemic virus. o ver the past decades, coronaviruses (covs) have been associated with significant disease outbreaks in east asia and the middle east. the severe acute respiratory syndrome (sars) and the middle east respiratory syndrome (mers) began to emerge in and , respectively. recently, a novel coronavirus, severe acute respiratory syndrome coronavirus (sars-cov- ), causing coronavirus disease (covid- ) , emerged in late , and it has posed a global health threat, causing an ongoing pandemic in many countries and territories ( ) . health workers worldwide are currently making efforts to control further disease outbreaks caused by the novel cov (originally named -ncov), which was first identified in wuhan city, hubei province, china, on december . on february , the world health organization (who) announced the official designation for the current cov-associated disease to be covid- , caused by sars-cov- . the primary cluster of patients was found to be connected with the huanan south china seafood market in wuhan ( ) . covs belong to the family coronaviridae (subfamily coronavirinae), the members of which infect a broad range of hosts, producing symptoms and diseases ranging from the common cold to severe and ultimately fatal illnesses, such as sars, mers, and, presently, covid- . sars-cov- is considered one of the seven members of the cov family that infect humans ( ) , and it belongs to the same lineage of covs that causes sars; however, this novel virus is genetically distinct. until , six covs were known to infect humans, including human cov e (hcov- e), hcov-nl , hcov-oc , hcov-hku , sars-cov, and mers-cov. although sars-cov and mers-cov have resulted in outbreaks with high mortality, others remain associated with mild upper-respiratory-tract illnesses ( ) . newly evolved covs pose a high threat to global public health. the current emergence of covid- is the third cov outbreak in humans over the past decades ( ) . it is no coincidence that fan et al. predicted potential sars-or mers-like cov outbreaks in china following pathogen transmission from bats ( ) . covid- emerged in china and spread rapidly throughout the country and, subsequently, to other countries. due to the severity of this outbreak and the potential of spreading on an international scale, the who declared a global health emergency on january ; subsequently, on march , they declared it a pandemic situation. at present, we are not in a position to effectively treat covid- , since neither approved vaccines nor specific antiviral drugs for treating human cov infections are available ( ) ( ) ( ) . most nations are currently making efforts to prevent the further spreading of this potentially deadly virus by implementing preventive and control strategies. in domestic animals, infections with covs are associated with a broad spectrum of furthermore, it acts as a critical factor for tissue tropism and the determination of host range ( ) . notably, s protein is one of the vital immunodominant proteins of covs capable of inducing host immune responses ( ) . the ectodomains in all covs s proteins have similar domain organizations, divided into two subunits, s and s ( ) . the first one, s , helps in host receptor binding, while the second one, s , accounts for fusion. the former (s ) is further divided into two subdomains, namely, the n-terminal domain (ntd) and c-terminal domain (ctd). both of these subdomains act as receptorbinding domains, interacting efficiently with various host receptors ( ) . the s ctd contains the receptor-binding motif (rbm). in each coronavirus spike protein, the trimeric s locates itself on top of the trimeric s stalk ( ) . recently, structural analyses of the s proteins of covid- have revealed amino acid substitutions within a , -amino-acid stretch ( ) . six substitutions are located in the rbd (amino acids to ), while four substitutions are in the rbm at the ctd of the s domain ( ) . of note, no amino acid change is seen in the rbm, which binds directly to the angiotensinconverting enzyme- (ace ) receptor in sars-cov ( , ) . at present, the main emphasis is knowing how many differences would be required to change the host tropism. sequence comparison revealed nonsynonymous changes between the early sequence of sars-cov- and the later isolates of sars-cov. the changes were found scattered over the genome of the virus, with nine substitutions in orf ab, orf ( substitutions), the spike gene ( substitutions) , and orf a (single substitution) ( ) . notably, the same nonsynonymous changes were found in a familial cluster, indicating that the viral evolution happened during person-to-person transmission ( , ) . such adaptive evolution events are frequent and constitute a constantly ongoing process once the virus spreads among new hosts ( ) . even though no functional changes occur in the virus associated with this adaptive evolution, close monitoring of the viral mutations that occur during subsequent human-to-human transmission is warranted. the m protein is the most abundant viral protein present in the virion particle, giving a definite shape to the viral envelope ( ) . it binds to the nucleocapsid and acts as a central organizer of coronavirus assembly ( ) . coronavirus m proteins are highly diverse in amino acid contents but maintain overall structural similarity within different genera ( ) . the m protein has three transmembrane domains, flanked by a short amino terminus outside the virion and a long carboxy terminus inside the virion ( ) . overall, the viral scaffold is maintained by m-m interaction. of note, the m protein of sars-cov- does not have an amino acid substitution compared to that of sars-cov ( ) . the coronavirus e protein is the most enigmatic and smallest of the major structural proteins ( ) . it plays a multifunctional role in the pathogenesis, assembly, and release of the virus ( ) . it is a small integral membrane polypeptide that acts as a viroporin (ion channel) ( ) . the inactivation or absence of this protein is related to the altered virulence of coronaviruses due to changes in morphology and tropism ( ) . the e protein consists of three domains, namely, a short hydrophilic amino terminal, a large hydrophobic transmembrane domain, and an efficient c-terminal domain ( ) . the sars-cov- e protein reveals a similar amino acid constitution without any substitution ( ) . the n protein of coronavirus is multipurpose. among several functions, it plays a role in complex formation with the viral genome, facilitates m protein interaction needed during virion assembly, and enhances the transcription efficiency of the virus ( , ) . it contains three highly conserved and distinct domains, namely, an ntd, an rna-binding domain or a linker region (lkr), and a ctd ( ) . the ntd binds with the = end of the viral genome, perhaps via electrostatic interactions, and is highly diverged both in length and sequence ( ) . the charged lkr is serine and arginine rich and is also known as the sr (serine and arginine) domain ( ) . the lkr is capable of direct interaction with in vitro rna interaction and is responsible for cell signaling ( , ) . it also modulates the antiviral response of the host by working as an antagonist for interferon (ifn) and rna interference ( ) . compared to that of sars-cov, the n protein of sars-cov- possess five amino acid mutations, where two are in the intrinsically dispersed region (idr; positions and ) , one each in the ntd (position ), lkr (position ), and ctd (position ) ( ) . besides the important structural proteins, the sars-cov- genome contains nsps, nsp to nsp and nsp to nsp , and accessory proteins ( a, b, p , a, b, b, b, and orf ) ( ) . all these proteins play a specific role in viral replication ( ) . unlike the accessory proteins of sars-cov, sars-cov- does not contain a protein and has a longer b and shorter b protein ( ) . the nsp , nsp , envelope, matrix, and p and b accessory proteins have not been detected with any amino acid substitutions compared to the sequences of other coronaviruses ( ) . the virus structure of sars-cov- is depicted in fig. . sequence percent similarity analysis. we assessed the nucleotide percent similarity using the megalign software program, where the similarity between the novel sars-cov- isolates was in the range of . % to %. among the other serbecovirus cov sequences, the novel sars-cov- sequences revealed the highest similarity to bat-sl-cov, with nucleotide percent identity ranges between . and . %. meanwhile, earlier reported sars-covs showed . to . % similarity to sars-cov- at the nucleotide level. further, the nucleotide percent similarity was . %, . % to . %, . % to . %, and . % to . % to the other four subgenera, namely, hibecovirus, nobecovirus, merbecovirus, and embecovirus, respectively. the percent similarity index of current outbreak isolates indicates a close relationship between sars-cov- isolates and bat-sl-cov, indicating a common origin. however, particular pieces of evidence based on further complete genomic analysis of current isolates are necessary to draw any conclusions, although it was ascertained that the current novel sars-cov- isolates belong to the subgenus sarbecovirus in the diverse range of betacoronaviruses. their possible ancestor was hypothesized to be from bat cov strains, wherein bats might have played a crucial role in harboring this class of viruses. splitstree phylogeny analysis. in the unrooted phylogenetic tree of different betacoronaviruses based on the s protein, virus sequences from different subgenera grouped into separate clusters. sars-cov- sequences from wuhan and other countries exhibited a close relationship and appeared in a single cluster (fig. ). the covs from the subgenus sarbecovirus appeared jointly in splitstree and divided into three subclusters, namely, sars-cov- , bat-sars-like-cov (bat-sl-cov), and sars-cov (fig. ) . in the case of other subgenera, like merbecovirus, all of the sequences grouped clinical microbiology reviews than italy. a john hopkins university web platform has provided daily updates on the basic epidemiology of the covid- outbreak (https://gisanddata.maps.arcgis.com/ apps/opsdashboard/index.html#/bda fd b e ecf ) ( ) . covid- has also been confirmed on a cruise ship, named diamond princess, quarantined in japanese waters (port of yokohama), as well as on other cruise ships around the world ( ) (fig. ) . the significant events of the sars-cov- /covid- virus outbreak occurring since december are presented as a timeline in fig. . at the beginning, china experienced the majority of the burden associated with covid- in the form of disease morbidity and mortality ( ), but over time the covid- menace moved to europe, particularly italy and spain, and now the united states has the highest number of confirmed cases and deaths. the covid- outbreak has also been associated with severe economic impacts globally due to the sudden interruption of global trade and supply chains that forced multinational companies to make decisions that led to significant economic losses ( ) . the recent increase in the number of confirmed critically ill patients with covid- has already surpassed the intensive care supplies, limiting intensive care services to only a small portion of critically ill patients ( ) . this might also have contributed to the increased case fatality rate observed in the covid- outbreak. the novel coronavirus was identified within month ( days) of the outbreak. this is impressively fast compared to the time taken to identify sars-cov reported in foshan, guangdong province, china ( days) ( ) . immediately after the confirmation of viral etiology, the chinese virologists rapidly released the genomic sequence of sars-cov- , which played a crucial role in controlling the spread of this newly emerged novel coronavirus to other parts of the world ( ) . the possible origin of sars-cov- and the first mode of disease transmission are not yet identified ( ) . analysis of the initial cluster of infections suggests that the infected individuals had a common exposure point, a seafood market in wuhan, hubei province, china (fig. ). the restaurants of this market are well-known for providing different types of wild animals for human consumption ( ) . the huanan south china seafood market also sells live animals, such as poultry, bats, snakes, and marmots ( ) . this might be the point where zoonotic (animal-to-human) transmission occurred ( ) . although sars-cov- is alleged to have originated from an animal host (zoonotic origin) with further humanto-human transmission (fig. ), the likelihood of foodborne transmission should be ruled out with further investigations, since it is a latent possibility ( ). additionally, other clinical microbiology reviews potential and expected routes would be associated with transmission, as in other respiratory viruses, by direct contact, such as shaking contaminated hands, or by direct contact with contaminated surfaces (fig. ) . still, whether blood transfusion and organ transplantation ( ) , as well as transplacental and perinatal routes, are possible routes for sars-cov- transmission needs to be determined (fig. ). from experience with several outbreaks associated with known emerging viruses, higher pathogenicity of a virus is often associated with lower transmissibility. compared to emerging viruses like ebola virus, avian h n , sars-cov, and mers-cov, sars-cov- has relatively lower pathogenicity and moderate transmissibility ( ) . the risk of death among individuals infected with covid- was calculated using the infection fatality risk (ifr). the ifr was found to be in the range of . % to . %, which is comparable to that of a previous asian influenza pandemic ( to ) ( , ) . notably, the reanalysis of the covid- pandemic curve from the initial cluster of cases pointed to considerable human-to-human transmission. it is opined that the exposure history of sars-cov- at the wuhan seafood market originated from humanto-human transmission rather than animal-to-human transmission ( ) ; however, in light of the zoonotic spillover in covid- , is too early to fully endorse this idea ( ). following the initial infection, human-to-human transmission has been observed with a preliminary reproduction number (r ) estimate of . to . ( , ) , and recently it is estimated to be . to . ( ) . in another study, the average reproductive number of covid- was found to be . , which is significantly higher than the initial who estimate of . to . ( ) . it is too early to obtain the exact r value, since there is a possibility of bias due to insufficient data. the higher r value is indicative of the more significant potential of sars-cov- transmission in a susceptible population. this is not the first time where the culinary practices of china have been blamed for the origin of novel coronavirus infection in humans. previously, the animals present in the liveanimal market were identified to be the intermediate hosts of the sars outbreak in china ( ) . several wildlife species were found to harbor potentially evolving coronavirus strains that can overcome the species barrier ( ) . one of the main principles of chinese food culture is that live-slaughtered animals are considered more nutritious ( ) . after months of struggle that lasted from december to march , the covid- situation now seems under control in china. the wet animal markets have reopened, and people have started buying bats, dogs, cats, birds, scorpions, badgers, rabbits, pangolins (scaly anteaters), minks, soup from palm civet, ostriches, hamsters, snapping turtles, ducks, fish, siamese crocodiles, and other animal meats without any fear of covid- . the chinese government is encouraging people to feel they can return to normalcy. however, this could be a risk, as it has been mentioned in advisories that people should avoid contact with live-dead animals as much as possible, as sars-cov- has shown zoonotic spillover. additionally, we cannot rule out the possibility of new mutations in the same virus being closely related to contact with both animals and humans at the market ( ) . in january , china imposed a temporary ban on the sale of live-dead animals in wet markets. however, now hundreds of such wet markets have been reopened without optimizing standard food safety and sanitation practices ( ) . with china being the most populated country in the world and due to its domestic and international food exportation policies, the whole world is now facing the menace of covid- , including china itself. wet markets of live-dead animals do not maintain strict food hygienic practices. fresh blood splashes are present everywhere, on the floor and tabletops, and such food customs could encourage many pathogens to adapt, mutate, and jump the species barrier. as a result, the whole world is suffering from novel sars-cov- , with more than , , cases and , deaths across the globe. there is an urgent need for a rational international campaign against the unhealthy food practices of china to encourage the sellers to increase hygienic food practices or close the crude live-dead animal wet markets. there is a need to modify food policies at national and international levels to avoid further life threats and clinical microbiology reviews economic consequences from any emerging or reemerging pandemic due to close animal-human interaction ( ) . even though individuals of all ages and sexes are susceptible to covid- , older people with an underlying chronic disease are more likely to become severely infected ( ) . recently, individuals with asymptomatic infection were also found to act as a source of infection to susceptible individuals ( ) . both the asymptomatic and symptomatic patients secrete similar viral loads, which indicates that the transmission capacity of asymptomatic or minimally symptomatic patients is very high. thus, sars-cov- transmission can happen early in the course of infection ( ) . atypical clinical manifestations have also been reported in covid- in which the only reporting symptom was fatigue. such patients may lack respiratory signs, such as fever, cough, and sputum ( ) . hence, the clinicians must be on the look-out for the possible occurrence of atypical clinical manifestations to avoid the possibility of missed diagnosis. the early transmission ability of sars-cov- was found to be similar to or slightly higher than that of sars-cov, reflecting that it could be controlled despite moderate to high transmissibility ( ) . increasing reports of sars-cov- in sewage and wastewater warrants the need for further investigation due to the possibility of fecal-oral transmission. sars-cov- present in environmental compartments such as soil and water will finally end up in the wastewater and sewage sludge of treatment plants ( ) . therefore, we have to reevaluate the current wastewater and sewage sludge treatment procedures and introduce advanced techniques that are specific and effective against sars-cov- . since there is active shedding of sars-cov- in the stool, the prevalence of infections in a large population can be studied using wastewater-based epidemiology. recently, reverse transcription-quantitative pcr (rt-qpcr) was used to enumerate the copies of sars-cov- rna concentrated from wastewater collected from a wastewater treatment plant ( ) . the calculated viral rna copy numbers determine the number of infected individuals. the increasing reports of virus shedding via the fecal route warrants the introduction of negative fecal viral nucleic acid test results as one of the additional discharge criteria in laboratory-confirmed cases of covid- ( ) . the covid- pandemic does not have any novel factors, other than the genetically unique pathogen and a further possible reservoir. the cause and the likely future outcome are just repetitions of our previous interactions with fatal coronaviruses. the only difference is the time of occurrence and the genetic distinctness of the pathogen involved. mutations on the rbd of covs facilitated their capability of infecting newer hosts, thereby expanding their reach to all corners of the world ( ) . this is a potential threat to the health of both animals and humans. advanced studies using bayesian phylogeographic reconstruction identified the most probable origin of sars-cov- as the bat sars-like coronavirus, circulating in the rhinolophus bat family ( ) . phylogenetic analysis of whole-genome sequences of sars-cov- showed that they are related to two covs of bat origin, namely, bat-sl-covzc and bat-sl-covzxc , which were reported during in china ( ) . it was reported that sars-cov- had been confirmed to use ace as an entry receptor while exhibiting an rbd similar to that of sars-cov ( , , , ) . several countries have provided recommendations to their people traveling to china ( , ) . compared to the previous coronavirus outbreaks caused by sars-cov and mers-cov, the efficiency of sars-cov- human-to-human transmission was thought to be less. this assumption was based on the finding that health workers were affected less than they were in previous outbreaks of fatal coronaviruses ( ) . superspreading events are considered the main culprit for the extensive transmission of sars and mers ( , ) . almost half of the mers-cov cases reported in saudi arabia are of secondary origin that occurred through contact with infected asymptomatic or symptomatic individuals through human-tohuman transmission ( ) . the occurrence of superspreading events in the covid- outbreak cannot be ruled out until its possibility is evaluated. like sars and mers, covid- can also infect the lower respiratory tract, with milder symptoms ( ) . the basic reproduction number of covid- has been found to be in the range of . to . based on real-time reports and . to . based on predicted infected cases ( ) . coronavirus infection in humans is commonly associated with mild to severe respiratory diseases, with high fever, severe inflammation, cough, and internal organ dysfunction that can even lead to death ( ) . most of the identified coronaviruses cause the common cold in humans. however, this changed when sars-cov was identified, paving the way for severe forms of the disease in humans ( ) . our previous experience with the outbreaks of other coronaviruses, like sars and mers, suggests that the mode of transmission in covid- as mainly human-to-human transmission via direct contact, droplets, and fomites ( ) . recent studies have demonstrated that the virus could remain viable for hours in aerosols and up to days on surfaces; thus, aerosol and fomite contamination could play potent roles in the transmission of sars-cov- ( ) . the immune response against coronavirus is vital to control and get rid of the infection. however, maladjusted immune responses may contribute to the immunopathology of the disease, resulting in impairment of pulmonary gas exchange. understanding the interaction between covs and host innate immune systems could enlighten our understanding of the lung inflammation associated with this infection ( ) . sars is a viral respiratory disease caused by a formerly unrecognized animal cov that originated from the wet markets in southern china after adapting to the human host, thereby enabling transmission between humans ( ) . the sars outbreak reported in to had , confirmed cases with total deaths ( . %) ( ) . the outbreak severely affected the asia pacific region, especially mainland china ( ) . even though the case fatality rate (cfr) of sars-cov- (covid- ) is lower than that of sars-cov, there exists a severe concern linked to this outbreak due to its epidemiological similarity to influenza viruses ( , ) . this can fail the public health system, resulting in a pandemic ( ) . mers is another respiratory disease that was first reported in saudi arabia during the year . the disease was found to have a cfr of around % ( ) . the analysis of available data sets suggests that the incubation period of sars-cov- , sars-cov, and mers-cov is in almost the same range. the longest predicted incubation time of sars-cov- is days. hence, suspected individuals are isolated for days to avoid the risk of further spread ( ) . even though a high similarity has been reported between the genome sequence of the new coronavirus (sars-cov- ) and sars-like covs, the comparative analysis recognized a furin-like cleavage site in the sars-cov- s protein that is missing from other sars-like covs ( ) . the furin-like cleavage site is expected to play a role in the life cycle of the virus and disease pathogenicity and might even act as a therapeutic target for furin inhibitors. the highly contagious nature of sars-cov- compared to that of its predecessors might be the result of a stabilizing mutation that occurred in the endosome-associated-protein-like domain of nsp protein. similarly, the destabilizing mutation near the phosphatase domain of nsp proteins in sars-cov- could indicate a potential mechanism that differentiates it from other covs ( ) . even though the cfr reported for covid- is meager compared to those of the previous sars and mers outbreaks, it has caused more deaths than sars and mers combined ( ) . possibly related to the viral pathogenesis is the recent finding of an -nucleotide (nt) deletion in orf , which appears to reduce the replicative fitness of the virus and leads to attenuated phenotypes of sars-cov- ( ) . coronavirus is the most prominent example of a virus that has crossed the species barrier twice from wild animals to humans during sars and mers outbreaks ( , ) . the possibility of crossing the species barrier for the third time has also been suspected in the case of sars-cov- (covid- ) . bats are recognized as a possible natural reservoir host of both sars-cov and mers-cov infection. in contrast, the possible intermediary host is the palm civet for sars-cov and the dromedary camel for mers-cov infection ( ) . bats are considered the ancestral hosts for both sars and mers ( ) . bats are also considered the reservoir host of human coronaviruses like clinical microbiology reviews hcov- e and hcov-nl ( ) . in the case of covid- , there are two possibilities for primary transmission: it can be transmitted either through intermediate hosts, similar to that of sars and mers, or directly from bats ( ) . the emergence paradigm put forward in the sars outbreak suggests that sars-cov originated from bats (reservoir host) and later jumped to civets (intermediate host) and incorporated changes within the receptor-binding domain (rbd) to improve binding to civet ace . this civetadapted virus, during their subsequent exposure to humans at live markets, promoted further adaptations that resulted in the epidemic strain ( ) . transmission can also occur directly from the reservoir host to humans without rbd adaptations. the bat coronavirus that is currently in circulation maintains specific "poised" spike proteins that facilitate human infection without the requirement of any mutations or adaptations ( ) . altogether, different species of bats carry a massive number of coronaviruses around the world ( ) . the high plasticity in receptor usage, along with the feasibility of adaptive mutation and recombination, may result in frequent interspecies transmission of coronavirus from bats to animals and humans ( ) . the pathogenesis of most bat coronaviruses is unknown, as most of these viruses are not isolated and studied ( ) . hedgehog coronavirus hku , a betacoronavirus, has been identified from amur hedgehogs in china. studies show that hedgehogs are the reservoir of betacoronavirus, and there is evidence of recombination ( ) . the current scientific evidence available on mers infection suggests that the significant reservoir host, as well as the animal source of mers infection in humans, is the dromedary camels ( ) . the infected dromedary camels may not show any visible signs of infection, making it challenging to identify animals actively excreting mers-cov that has the potential to infect humans. however, they may shed mers-cov through milk, urine, feces, and nasal and eye discharge and can also be found in the raw organs ( ) . in a study conducted to evaluate the susceptibility of animal species to mers-cov infection, llamas and pigs were found to be susceptible, indicating the possibility of mers-cov circulation in animal species other than dromedary camels ( ) . following the outbreak of sars in china, sars-cov-like viruses were isolated from himalayan palm civets (paguma larvata) and raccoon dogs (nyctereutes procyonoides) found in a live-animal market in guangdong, china. the animal isolates obtained from the live-animal market retained a -nucleotide sequence that was not present in most of the human isolates ( ) . these findings were critical in identifying the possibility of interspecies transmission in sars-cov. the higher diversity and prevalence of bat coronaviruses in this region compared to those in previous reports indicate a host/ pathogen coevolution. sars-like coronaviruses also have been found circulating in the chinese horseshoe bat (rhinolophus sinicus) populations. the in vitro and in vivo studies carried out on the isolated virus confirmed that there is a potential risk for the reemergence of sars-cov infection from the viruses that are currently circulating in the bat population ( ) . the disease caused by sars-cov- is also named severe specific contagious pneumonia (sscp), wuhan pneumonia, and, recently, covid- ( ) . compared to sars-cov, sars-cov- has less severe pathogenesis but has superior transmission capability, as evidenced by the rapidly increasing number of covid- cases ( ) . the incubation period of sars-cov- in familial clusters was found to be to days ( ) . the mean incubation period of covid- was found to be . days, ranging from . to . days ( ) . among an early affected group of patients, years was the median age, of which more males were affected ( ) . similar to sars and mers, the severity of this ncov is high in age groups above years ( , ) . symptoms of covid- include fever, cough, myalgia or fatigue, and, less commonly, headache, hemoptysis, and diarrhea ( , ) . compared to the sars-cov- -infected patients in wuhan during the initial stages of the outbreak, only mild symptoms were noticed in those patients that are infected by human-to-human transmission ( ) . the initial trends suggested that the mortality associated with covid- was less than that of previous outbreaks of sars ( ) . the updates obtained from countries like china, japan, thailand, and south korea indicated that the covid- patients had relatively mild manifestations compared to those with sars and mers ( ). regardless of the coronavirus type, immune cells, like mast cells, that are present in the submucosa of the respiratory tract and nasal cavity are considered the primary barrier against this virus ( ) . advanced in-depth analysis of the genome has identified amino acid substitutions between the amino acid sequences of sars-cov- and the sars/sarslike coronaviruses. these differences in the amino acid sequences might have contributed to the difference in the pathogenic divergence of sars-cov- ( ) . further research is required to evaluate the possible differences in tropism, pathogenesis, and transmission of this novel agent associated with this change in the amino acid sequence. with the current outbreak of covid- , there is an expectancy of a significant increase in the number of published studies about this emerging coronavirus, as occurred with sars and mers ( ) . sars-cov- invades the lung parenchyma, resulting in severe interstitial inflammation of the lungs. this is evident on computed tomography (ct) images as ground-glass opacity in the lungs. this lesion initially involves a single lobe but later expands to multiple lung lobes ( ) . the histological assessment of lung biopsy samples obtained from covid- -infected patients revealed diffuse alveolar damage, cellular fibromyxoid exudates, hyaline membrane formation, and desquamation of pneumocytes, indicative of acute respiratory distress syndrome ( ) . it was also found that the sars-cov- infected patients often have lymphocytopenia with or without leukocyte abnormalities. the degree of lymphocytopenia gives an idea about disease prognosis, as it is found to be positively correlated with disease severity ( ) . pregnant women are considered to have a higher risk of getting infected by covid- . the coronaviruses can cause adverse outcomes for the fetus, such as intrauterine growth restriction, spontaneous abortion, preterm delivery, and perinatal death. nevertheless, the possibility of intrauterine maternal-fetal transmission (vertical transmission) of covs is low and was not seen during either the sars-or mers-cov outbreak ( ) . however, there has been concern regarding the impact of sars-cov- /covid- on pregnancy. researchers have mentioned the probability of in utero transmission of novel sars-cov- from covid- -infected mothers to their neonates in china based upon the rise in igm and igg antibody levels and cytokine values in the blood obtained from newborn infants immediately postbirth; however, rt-pcr failed to confirm the presence of sars-cov- genetic material in the infants ( ) . recent studies show that at least in some cases, preterm delivery and its consequences are associated with the virus. nonetheless, some cases have raised doubts for the likelihood of vertical transmission ( ) ( ) ( ) ( ) . covid- infection was associated with pneumonia, and some developed acute respiratory distress syndrome (ards). the blood biochemistry indexes, such as albumin, lactate dehydrogenase, c-reactive protein, lymphocytes (percent), and neutrophils (percent) give an idea about the disease severity in covid- infection ( ) . during covid- , patients may present leukocytosis, leukopenia with lymphopenia ( ), hypoalbuminemia, and an increase of lactate dehydrogenase, aspartate transaminase, alanine aminotransferase, bilirubin, and, especially, d-dimer ( ) . middle-aged and elderly patients with primary chronic diseases, especially high blood pressure and diabetes, were found to be more susceptible to respiratory failure and, therefore, had poorer prognoses. providing respiratory support at early stages improved the disease prognosis and facilitated recovery ( ) . the ards in covid- is due to the occurrence of cytokine storms that results in exaggerated immune response, immune regulatory network imbalance, and, finally, multiple-organ failure ( ) . in addition to the exaggerated inflammatory response seen in patients with covid- pneumonia, the bile duct epithelial cell-derived hepatocytes upregulate ace expression in liver tissue by compensatory proliferation that might result in hepatic tissue injury ( ) . coronavirus can cause disease in several species of domestic and wild animals, as well as humans ( ) . the different animal species that are infected with cov include horses, camels, cattle, swine, dogs, cats, rodents, birds, ferrets, minks, bats, rabbits, snakes, and various other wild animals ( , , , , , , ) . coronavirus infection is linked to different kinds of clinical manifestations, varying from enteritis in cows and pigs, upper respiratory disease in chickens, and fatal respiratory infections in humans ( ) . among the cov genera, alphacoronavirus and betacoronavirus infect mammals, while gammacoronavirus and deltacoronavirus mainly infect birds, fishes, and, sometimes, mammals ( , , ) . several novel coronaviruses that come under the genus deltacoronavirus have been discovered in the past from birds, like wigeon coronavirus hku , bulbul coronavirus hku , munia coronavirus hku , white-eye coronavirus hku , night-heron coronavirus hku , and common moorhen coronavirus hku , as well as from pigs (porcine coronavirus hku ) ( , ) . transmissible gastroenteritis virus (tgev), porcine epidemic diarrhea virus (pedv), and porcine hemagglutinating encephalomyelitis virus (phev) are some of the coronaviruses of swine. among them, tgev and pedv are responsible for causing severe gastroenteritis in young piglets with noteworthy morbidity and mortality. infection with phev also causes enteric infection but can cause encephalitis due to its ability to infect the nervous system ( ) . bovine coronaviruses (bocovs) are known to infect several domestic and wild ruminants ( ) . bocov inflicts neonatal calf diarrhea in adult cattle, leading to bloody diarrhea (winter dysentery) and respiratory disease complex (shipping fever) in cattle of all age groups ( ) . bocov-like viruses have been noted in humans, suggesting its zoonotic potential as well ( ) . feline enteric and feline infectious peritonitis (fip) viruses are the two major feline covs ( ) , where feline covs can affect the gastrointestinal tract, abdominal cavity (peritonitis), respiratory tract, and central nervous system ( ) . canines are also affected by covs that fall under different genera, namely, canine enteric coronavirus in alphacoronavirus and canine respiratory coronavirus in betacoronavirus, affecting the enteric and respiratory tract, respectively ( , ) . ibv, under gammacoronavirus, causes diseases of respiratory, urinary, and reproductive systems, with substantial economic losses in chickens ( , ) . in small laboratory animals, mouse hepatitis virus, rat sialodacryoadenitis coronavirus, and guinea pig and rabbit coronaviruses are the major covs associated with disease manifestations like enteritis, hepatitis, and respiratory infections ( , ) . swine acute diarrhea syndrome coronavirus (sads-cov) was first identified in suckling piglets having severe enteritis and belongs to the genus alphacoronavirus ( ) . the outbreak was associated with considerable scale mortality of piglets ( , deaths) across four farms in china ( ) . the virus isolated from the piglets was almost identical to and had % genomic similarity with horseshoe bat (rhinolophus species) coronavirus hku , suggesting a bat origin of the pig virus ( , , ) . it is also imperative to note that the sads-cov outbreak started in guangdong province, near the location of the sars pandemic origin ( ) . before this outbreak, pigs were not known to be infected with bat-origin coronaviruses. this indicates that the bat-origin coronavirus jumped to pig by breaking the species barrier. the next step of this jump might not end well, since pigs are considered the mixing vessel for influenza a viruses due to their ability to be infected by both human and avian influenza a viruses ( ) . similarly, they may act as the mixing vessel for coronaviruses, since they are in frequent contact with both humans and multiple wildlife species. additionally, pigs are also found to be susceptible to infection with human sars-cov and mers-cov, making this scenario a nightmare ( , ) . it is only a matter of time before another zoonotic coronavirus results in an epidemic by jumping the so-called species barrier ( ) . the host spectrum of coronavirus increased when a novel coronavirus, namely, sw , was recognized in the liver tissue of a captive beluga whale (delphinapterus leucas) ( ) . in recent decades, several novel coronaviruses were identified from different animal species. bats can harbor these viruses without manifesting any clinical disease but are persistently infected ( ) . they are the only mammals with the capacity for self-powered flight, which enables them to migrate long distances, unlike land mammals. bats are distributed worldwide and also account for about a fifth of all mammalian species ( ) . this makes them the ideal reservoir host for many viral agents and also the source of novel coronaviruses that have yet to be identified. it has become a necessity to study the diversity of coronavirus in the bat population to prevent future outbreaks that could jeopardize livestock and public health. the repeated outbreaks caused by bat-origin coronaviruses calls for the development of efficient molecular surveillance strategies for studying betacoronavirus among animals ( ) , especially in the rhinolophus bat family ( ) . chinese bats have high commercial value, since they are used in traditional chinese medicine (tcm). therefore, the handling of bats for trading purposes poses a considerable risk of transmitting zoonotic cov epidemics ( ) . due to the possible role played by farm and wild animals in sars-cov- infection, the who, in their novel coronavirus (covid- ) situation report, recommended the avoidance of unprotected contact with both farm and wild animals ( ) . the live-animal markets, like the one in guangdong, china, provides a setting for animal coronaviruses to amplify and to be transmitted to new hosts, like humans ( ) . such markets can be considered a critical place for the origin of novel zoonotic diseases and have enormous public health significance in the event of an outbreak. bats are the reservoirs for several viruses; hence, the role of bats in the present outbreak cannot be ruled out ( ) . in a qualitative study conducted for evaluating the zoonotic risk factors among rural communities of southern china, the frequent human-animal interactions along with the low levels of environmental biosecurity were identified as significant risks for the emergence of zoonotic disease in local communities ( , ) . the comprehensive sequence analysis of the sars-cov- rna genome identified that the cov from wuhan is a recombinant virus of the bat coronavirus and another coronavirus of unknown origin. the recombination was found to have happened within the viral spike glycoprotein, which recognizes the cell surface receptor. further analysis of the genome based on codon usage identified the snake as the most probable animal reservoir of sars-cov- ( ) . contrary to these findings, another genome analysis proposed that the genome of sars-cov- is % identical to bat coronavirus, reflecting its origin from bats ( ) . the involvement of bat-derived materials in causing the current outbreak cannot be ruled out. high risk is involved in the production of bat-derived materials for tcm practices involving the handling of wild bats. the use of bats for tcm practices will remain a severe risk for the occurrence of zoonotic coronavirus epidemics in the future ( ) . furthermore, the pangolins are an endangered species of animals that harbor a wide variety of viruses, including coronaviruses ( ) . the coronavirus isolated from malayan pangolins (manis javanica) showed a very high amino acid identity with covid- at e ( %), m ( . %), n ( . %), and s genes ( . %). the rbd of s protein in cov isolated from pangolin was almost identical (one amino acid difference) to that of sars-cov- . a comparison of the genomes suggests recombination between pangolin-cov-like viruses with the bat-cov-ratg -like virus. all this suggests the potential of pangolins to act as the intermediate host of sars-cov- ( ) . human-wildlife interactions, which are increasing in the context of climate change ( ) , are further considered high risk and responsible for the emergence of sars-cov. covid- is also suspected of having a similar mode of origin. hence, to prevent the occurrence of another zoonotic spillover ( ), exhaustive coordinated efforts are needed to identify the high-risk pathogens harbored by wild animal populations, conducting surveillance among the people who are susceptible to zoonotic spillover events ( ) , and to improve the biosecurity measures associated with the wildlife trade ( ) . the serological surveillance studies conducted in people living in proximity to bat caves had earlier identified the serological confirmation of sars-related covs in humans. people clinical microbiology reviews living at the wildlife-human interface, mainly in rural china, are regularly exposed to sars-related covs ( ) . these findings will not have any significance until a significant outbreak occurs due to a virus-like sars-cov- . there is a steady increase in the reports of covid- in companion and wild animals around the world. further studies are required to evaluate the potential of animals (especially companion animals) to serve as an efficient reservoir host that can further alter the dynamics of human-to-human transmission ( ) . to date, two pet dogs (hong kong) and four pet cats (one each from belgium and hong kong, two from the united states) have tested positive for sars-cov- ( ) . the world organization for animal health (oie) has confirmed the diagnosis of covid- in both dogs and cats due to human-to-animal transmission ( ) . the similarity observed in the gene sequence of sars-cov- from an infected pet owner and his dog further confirms the occurrence of human-to-animal transmission ( ) . even though asymptomatic, feline species should be considered a potential transmission route from animals to humans ( ) . however, currently, there are no reports of sars-cov- transmission from felines to human beings. based on the current evidence, we can conclude that cats are susceptible to sars-cov- and can get infected by human beings. however, evidence of cat-to-human transmission is lacking and requires further studies ( ) . rather than waiting for firmer evidence on animal-to-human transmission, necessary preventive measures are advised, as well as following social distancing practices among companion animals of different households ( ) . one of the leading veterinary diagnostic companies, idexx, has conducted large-scale testing for covid- in specimens collected from dogs and cats. however, none of the tests turned out to be positive ( ) . in a study conducted to investigate the potential of different animal species to act as the intermediate host of sars-cov- , it was found that both ferrets and cats can be infected via experimental inoculation of the virus. in addition, infected cats efficiently transmitted the disease to naive cats ( ) . sars-cov- infection and subsequent transmission in ferrets were found to recapitulate the clinical aspects of covid- in humans. the infected ferrets also shed virus via multiple routes, such as saliva, nasal washes, feces, and urine, postinfection, making them an ideal animal model for studying disease transmission ( ) . experimental inoculation was also done in other animal species and found that the dogs have low susceptibility, while the chickens, ducks, and pigs are not at all susceptible to sars-cov- ( ) . similarly, the national veterinary services laboratories of the usda have reported covid- in tigers and lions that exhibited respiratory signs like dry cough and wheezing. the zoo animals are suspected to have been infected by an asymptomatic zookeeper ( ) . the total number of covid- -positive cases in human beings is increasing at a high rate, thereby creating ideal conditions for viral spillover to other species, such as pigs. the evidence obtained from sars-cov suggests that pigs can get infected with sars-cov- ( ). however, experimental inoculation with sars-cov- failed to infect pigs ( ) . further studies are required to identify the possible animal reservoirs of sars-cov- and the seasonal variation in the circulation of these viruses in the animal population. research collaboration between human and animal health sectors is becoming a necessity to evaluate and identify the possible risk factors of transmission between animals and humans. such cooperation will help to devise efficient strategies for the management of emerging zoonotic diseases ( ) . rna tests can confirm the diagnosis of sars-cov- (covid- ) cases with real-time rt-pcr or next-generation sequencing ( , , , ) . at present, nucleic acid detection techniques, like rt-pcr, are considered an effective method for confirming the diagnosis in clinical cases of covid- ( ) . several companies across the world are currently focusing on developing and marketing sars-cov- -specific nucleic acid detection kits. multiple laboratories are also developing their own in-house rt-pcr. one of them is the sars-cov- nucleic acid detection kit produced by shuoshi biotechnology (double fluorescence pcr method) ( ) . up to march , the u.s. food and drug administration (fda) had granted in vitro diagnostics emergency use authorizations (euas), including for the rt-pcr diagnostic panel for the universal detection of sars-like betacoronaviruses and specific detection of sars-cov- , developed by the u.s. cdc (table ) ( , ) . recently, full-length genomic sequences of saras-cov- strains available in the national center for biotechnology information and gisaid databases were subjected to multiple-sequence alignment and phylogenetic analyses for studying variations in the viral genome ( ) . all the viral strains revealed high homology of . % ( . % to %) at the nucleotide level and . % ( . % to %) at the amino acid level. overall variation was found to be low in orf regions, with variation sites recognized in a, b, s, a, m, , and n regions. mutation rates of . % ( / ) and . % ( / ) were observed at nt (orf ) and nt (orf a) positions, respectively. owing to such selective mutations, a few specific regions of sars-cov- should not be considered for designing primers and probes. the sars-cov- reference sequence could pave the way to study molecular biology and pathobiology, along with developing diagnostics and appropriate prevention and control strategies for countering sars-cov- ( ) . nucleic acids of sars-cov- can be detected from samples ( ) such as bronchoalveolar lavage fluid, sputum, nasal swabs, fiber bronchoscope brush biopsy specimen, pharyngeal swabs, feces, blood, and urine, with different levels of diagnostic performance (table ) ( , , ) . the viral loads of sars-cov- were measured using n-gene-specific quantitative rt-pcr in throat swab and sputum samples collected from covid- -infected individuals. the results indicated that the viral load peaked at around to days following the onset of symptoms, and it ranged from to copies/ml during this time ( ) . in another study, the viral load was found to be higher in the nasal swabs than the throat swabs obtained from covid- symptomatic patients ( ) . although initially it was thought that viral load would be associated with poor outcomes, some case reports have shown asymptomatic individuals with high viral loads ( ) . recently, the viral load in nasal and throat swabs of symptomatic patients was determined, and higher viral loads were recorded soon after the onset of symptoms, particularly in the nose compared to the throat. the pattern of viral nucleic the results of the studies related to sars-cov- viral loads reflect active replication of this virus in the upper respiratory tract and prolonged viral shedding after symptoms disappear, including via stool. thus, the current case definition needs to be updated along with a reassessment of the strategies to be adopted for restraining the sars-cov- outbreak spread ( ) . in some cases, the viral load studies of sars-cov- have also been useful to recommend precautionary measures when handling specific samples, e.g., feces. in a recent survey from confirmed cases of sars-cov- infection with available data (representing days to after onset), stool samples from nine cases ( %; days to after onset) were positive on rt-pcr analysis. although the viral loads were lower than those of respiratory samples (range, copies per ml to . ϫ copies per ml), this has essential biosafety implications ( ) . the samples from sars-cov- -positive patients in singapore who had traveled from wuhan to singapore showed the presence of viral rna in stool and whole blood but not in urine by real-time rt-pcr ( ) . further, novel sars-cov- infections have been detected in a variety of clinical specimens, like bronchoalveolar lavage fluid, sputum, nasal swabs, fibrobronchoscope brush biopsy specimens, pharyngeal swabs, feces, and blood ( ) . the presence of sars-cov- in fecal samples has posed grave public health concerns. in addition to the direct transmission mainly occurring via droplets of sneezing and coughing, other routes, such as fecal excretion and environmental and fomite contamination, are contributing to sars-cov- transmission and spread ( ) ( ) ( ) ( ) . fecal excretion has also been documented for sars-cov and mers-cov, along with the potential to stay viable in situations aiding fecal-oral transmission. thus, sars-cov- has every possibility to be transmitted through this mode. fecal-oral transmission of sars-cov- , particularly in regions having low standards of hygiene and poor sanitation, may have grave consequences with regard to the high spread of this virus. ethanol and disinfectants containing chlorine or bleach are effective against coronaviruses ( ) ( ) ( ) ( ) . appropriate precautions need to be followed strictly while handling the stools of patients infected with sars-cov- . biowaste materials and sewage from hospitals must be adequately disinfected, treated, and disposed of properly. the significance of frequent and good hand hygiene and sanitation practices needs to be given due emphasis ( ) ( ) ( ) ( ) . future explorative research needs to be conducted with regard to the fecal-oral transmission of sars-cov- , along with focusing on environmental investigations to find out if this virus could stay viable in situations and atmospheres facilitating such potent routes of transmission. the correlation of fecal concentrations of viral rna with disease severity needs to be determined, along with assessing the gastrointestinal symptoms and the possibility of fecal sars-cov- rna detection during the covid- incubation period or convalescence phases of the disease ( ) ( ) ( ) ( ) . the lower respiratory tract sampling techniques, like bronchoalveolar lavage fluid aspirate, are considered the ideal clinical materials, rather than the throat swab, due to their higher positive rate on the nucleic acid test ( ) . the diagnosis of covid- can be made by using upper-respiratory-tract specimens collected using nasopharyngeal and oropharyngeal swabs. however, these techniques are associated with unnecessary risks to health care workers due to close contact with patients ( ) . similarly, a single patient with a high viral load was reported to contaminate an entire endoscopy room by shedding the virus, which may remain viable for at least days and is considered a great risk for uninfected patients and health care workers ( ) . recently, it was found that the anal swabs gave more positive results than oral swabs in the later stages of infection ( ) . hence, clinicians have to be cautious while discharging any covid- infected patient based on negative oral swab test results due to the possibility of fecal-oral transmission. even though the viral loads in stool samples were found to be less than those of respiratory samples, strict precautionary measures have to be followed while handling stool samples of covid- suspected or infected patients ( ) . children infected with sars-cov- experience only a mild form of illness and recover immediately after treatment. it was recently found that stool samples of sars-cov- -infected children that gave negative throat swab results were positive within ten days of negative results. this could result in the fecal-oral transmission of sars-cov- infections, especially in children ( ) . hence, to prevent the fecal-oral transmission of sars-cov- , infected covid- patients should only be considered negative when they test negative for sars-cov- in the stool sample. a suspected case of covid- infection is said to be confirmed if the respiratory tract aspirate or blood samples test positive for sars-cov- nucleic acid using rt-pcr or by the identification of sars-cov- genetic sequence in respiratory tract aspirate or blood samples ( ) . the patient will be confirmed as cured when two subsequent oral swab results are negative ( ) . recently, the live virus was detected in the selfcollected saliva of patients infected with covid- . these findings were confirmative of using saliva as a noninvasive specimen for the diagnosis of covid- infection in suspected individuals ( ) . it has also been observed that the initial screening of covid- patients infected with rt-pcr may give negative results even if they have chest ct findings that are suggestive of infection. hence, for the accurate diagnosis of covid- , a combination of repeated swab tests using rt-pcr and ct scanning is required to prevent the possibility of false-negative results during disease screening ( ) . rt-pcr is the most widely used test for diagnosing covid- . however, it has some significant limitations from the clinical perspective, since it will not give any clarity regarding disease progression. droplet digital pcr (ddpcr) can be used for the quantification of viral load in the samples obtained from lower respiratory tracts. hence, based on the viral load, we can quickly evaluate the progression of infection ( ) . in addition to all of the above findings, sequencing and phylogenetics are critical in the correct identification and confirmation of the causative viral agent and useful to establish relationships with previous isolates and sequences, as well as to know, especially during an epidemic, the nucleotide and amino acid mutations and the molecular divergence. the rapid development and implementation of diagnostic tests against emerging novel diseases like covid- pose significant challenges due to the lack of resources and logistical limitations associated with an outbreak ( ) . sars-cov- infection can also be confirmed by isolation and culturing. the human airway epithelial cell culture was found to be useful in isolating sars-cov- ( ). the efficient control of an outbreak depends on the rapid diagnosis of the disease. recently, in response to the covid- outbreak, -step quantitative realtime reverse transcription-pcr assays were developed that detect the orf b and n regions of the sars-cov- genome ( ) . that assay was found to achieve the rapid detection of sars-cov- . nucleic acid-based assays offer high accuracy in the diagnosis of sars-cov- , but the current rate of spread limits its use due to the lack of diagnostic assay kits. this will further result in the extensive transmission of covid- , since only a portion of suspected cases can be diagnosed. in such situations, conventional serological assays, like enzyme-linked immunosorbent assay (elisa), that are specific to covid- igm and igg antibodies can be used as a high-throughput alternative ( ) . at present, there is no diagnostic kit available for detecting the sars-cov- antibody ( ) . the specific antibody profiles of covid- patients were analyzed, and it was found that the igm level lasted more than month, indicating a prolonged stage of virus replication in sars-cov- -infected patients. the igg levels were found to increase only in the later stages of the disease. these findings indicate that the specific antibody profiles of sars-cov- and sars-cov were similar ( ) . these findings can be utilized for the development of specific diagnostic tests against covid- and can be used for rapid screening. even though diagnostic test kits are already available that can detect the genetic sequences of sars-cov- ( ), their availability is a concern, as the number of covid- cases is skyrocketing ( , ) . a major problem associated with this diagnostic kit is that it works only when the test subject has an active infection, limiting its use to the earlier stages of infection. several laboratories around the world are currently developing antibody-based diagnostic tests against sars-cov- ( ). chest ct is an ideal diagnostic tool for identifying viral pneumonia. the sensitivity of chest ct is far superior to that of x-ray screening. the chest ct findings associated with covid- -infected patients include characteristic patchy infiltration that later progresses to ground-glass opacities ( ) . early manifestations of covid- pneumonia might not be evident in x-ray chest radiography. in such situations, a chest ct examination can be performed, as it is considered highly specific for covid- pneumonia ( ) . those patients having covid- pneumonia will exhibit the typical ground-glass opacity in their chest ct images ( ) . the patients infected with covid- had elevated plasma angiotensin levels. the level of angiotensin was found to be linearly associated with viral load and lung injury, indicating its potential as a diagnostic biomarker ( ) . the chest ct imaging abnormalities associated with covid- pneumonia have also been observed even in asymptomatic patients. these abnormalities progress from the initial focal unilateral to diffuse bilateral ground-glass opacities and will further progress to or coexist with lung consolidation changes within to weeks ( ). the role played by radiologists in the current scenario is very important. radiologists can help in the early diagnosis of lung abnormalities associated with covid- pneumonia. they can also help in the evaluation of disease severity, identifying its progression to acute respiratory distress syndrome and the presence of secondary bacterial infections ( ) . even though chest ct is considered an essential diagnostic tool for covid- , the extensive use of ct for screening purposes in the suspected individuals might be associated with a disproportionate risk-benefit ratio due to increased radiation exposure as well as increased risk of cross-infection. hence, the use of ct for early diagnosis of sars-cov- infection in high-risk groups should be done with great caution ( ) . more recently, other advanced diagnostics have been designed and developed for the detection of sars-cov- ( , , ( ) ( ) ( ) . a reverse transcriptional loopmediated isothermal amplification (rt-lamp), namely, ilaco, has been developed for rapid and colorimetric detection of this virus ( ) . rt-lamp serves as a simple, rapid, and sensitive diagnostic method that does not require sophisticated equipment or skilled personnel ( ) . an interactive web-based dashboard for tracking sars-cov- in a real-time mode has been designed ( ) . a smartphone-integrated home-based point-of-care testing (poct) tool, a paper-based poct combined with lamp, is a useful point-of-care diagnostic ( ) . an abbott id now covid- molecular poct-based test, using isothermal nucleic acid amplification technology, has been designed as a pointof-care test for very rapid detection of sars-cov- in just min ( ) . a crispr-based sherlock (specific high-sensitivity enzymatic reporter unlocking) diagnostic for rapid detection of sars-cov- without the requirement of specialized instrumentation has been reported to be very useful in the clinical diagnosis of covid- ( ) . a crispr-cas -based lateral flow assay also has been developed for rapid detection of sars-cov- ( ) . artificial intelligence, by means of a three-dimensional deep-learning model, has been developed for sensitive and specific diagnosis of covid- via ct images ( ) . tracking and mapping of the rising incidence rates, disease outbreaks, community spread, clustered transmission events, hot spots, and superspreader potential of sars-cov- /covid warrant full exploitation of real-time disease mapping by employing geographical information systems (gis), such as the gis software kosmo . , web-based real-time tools and dashboards, apps, and advances in information technology ( - ). researchers have also developed a few prediction tools/models, such as the prediction model risk of bias assessment tool (probast) and critical appraisal and data extraction for systematic reviews of prediction modeling studies (charms), which could aid in assessing the possibility of getting infection and estimating the prognosis in patients; however, such models may suffer from bias issues and, hence, cannot be considered completely trustworthy, which necessitates the development of new and reliable predictors ( ) . recently emerged viruses, such as zika, ebola, and nipah viruses, and their grave threats to humans have begun a race in exploring the designing and developing of advanced vaccines, prophylactics, therapeutics, and drug regimens to counter emerging viruses ( ) ( ) ( ) ) . several attempts are being made to design and develop vaccines for cov infection, mostly by targeting the spike glycoprotein. nevertheless, owing to extensive diversity in antigenic variants, cross-protection rendered by the vaccines is significantly limited, even within the strains of a phylogenetic subcluster ( ) . due to the lack of effective antiviral therapy and vaccines in the present scenario, we need to depend solely on implementing effective infection control measures to lessen the risk of possible nosocomial transmission ( ) . recently, the receptor for sars-cov- was established as the human angiotensin-converting enzyme (hace ), and the virus was found to enter the host cell mainly through endocytosis. it was also found that the major components that have a critical role in viral entry include pikfyve, tpc , and cathepsin l. these findings are critical, since the components described above might act as candidates for vaccines or therapeutic drugs against sars-cov- ( ) . the majority of the treatment options and strategies that are being evaluated for sars-cov- (covid- ) have been taken from our previous experiences in treating sars-cov, mers-cov, and other emerging viral diseases. several therapeutic and preventive strategies, including vaccines, immunotherapeutics, and antiviral drugs, have been exploited against the previous cov outbreaks (sars-cov and mers-cov) ( , , ( ) ( ) ( ) ( ) . these valuable options have already been evaluated for their potency, efficacy, and safety, along with several other types of current research that will fuel our search for ideal therapeutic agents against covid- ( , , , , ) . the primary cause of the unavailability of approved and commercial vaccines, drugs, and therapeutics to counter the earlier sars-cov and mers-cov seems to owe to the lesser attention of the biomedicine and pharmaceutical companies, as these two covs did not cause much havoc, global threat, and panic like those posed by the sars-cov- pandemic ( ) . moreover, for such outbreak situations, the requirement for vaccines and therapeutics/drugs exists only for a limited period, until the outbreak is controlled. the proportion of the human population infected with sars-cov and mers-cov was also much lower across the globe, failing to attract drug and vaccine manufacturers and clinical microbiology reviews producers. therefore, by the time an effective drug or vaccine is designed against such disease outbreaks, the virus would have been controlled by adopting appropriate and strict prevention and control measures, and patients for clinical trials will not be available. the newly developed drugs cannot be marketed due to the lack of end users. the s protein plays a significant role in the induction of protective immunity against sars-cov by mediating t-cell responses and neutralizing antibody production ( ) . in the past few decades, we have seen several attempts to develop a vaccine against human coronaviruses by using s protein as the target ( , ) . however, the developed vaccines have minimal application, even among closely related strains of the virus, due to a lack of cross-protection. that is mainly because of the extensive diversity existing among the different antigenic variants of the virus ( ) . the contributions of the structural proteins, like spike (s), matrix (m), small envelope (e), and nucleocapsid (n) proteins, of sars-cov to induce protective immunity has been evaluated by expressing them in a recombinant parainfluenza virus type vector (bhpiv ). of note, the result was conclusive that the expression of m, e, or n proteins without the presence of s protein would not confer any noticeable protection, with the absence of detectable serum sars-cov-neutralizing antibodies ( ) . antigenic determinant sites present over s and n structural proteins of sars-cov- can be explored as suitable vaccine candidates ( ) . in the asian population, s, e, m, and n proteins of sars-cov- are being targeted for developing subunit vaccines against covid- ( ) . the identification of the immunodominant region among the subunits and domains of s protein is critical for developing an effective vaccine against the coronavirus. the c-terminal domain of the s subunit is considered the immunodominant region of the porcine deltacoronavirus s protein ( ) . similarly, further investigations are needed to determine the immunodominant regions of sars-cov- for facilitating vaccine development. however, our previous attempts to develop a universal vaccine that is effective for both sars-cov and mers-cov based on t-cell epitope similarity pointed out the possibility of cross-reactivity among coronaviruses ( ) . that can be made possible by selected potential vaccine targets that are common to both viruses. sars-cov- has been reported to be closely related to sars-cov ( , ) . hence, knowledge and understanding of s protein-based vaccine development in sars-cov will help to identify potential s protein vaccine candidates in sars-cov- . therefore, vaccine strategies based on the whole s protein, s protein subunits, or specific potential epitopes of s protein appear to be the most promising vaccine candidates against coronaviruses. the rbd of the s subunit of s protein has a superior capacity to induce neutralizing antibodies. this property of the rbd can be utilized for designing potential sars-cov vaccines either by using rbd-containing recombinant proteins or recombinant vectors that encode rbd ( ) . hence, the superior genetic similarity existing between sars-cov- and sars-cov can be utilized to repurpose vaccines that have proven in vitro efficacy against sars-cov to be utilized for sars-cov- . the possibility of cross-protection in covid- was evaluated by comparing the s protein sequences of sars-cov- with that of sars-cov. the comparative analysis confirmed that the variable residues were found concentrated on the s subunit of s protein, an important vaccine target of the virus ( ) . hence, the possibility of sars-cov-specific neutralizing antibodies providing cross-protection to covid- might be lower. further genetic analysis is required between sars-cov- and different strains of sars-cov and sarslike (sl) covs to evaluate the possibility of repurposed vaccines against covid- . this strategy will be helpful in the scenario of an outbreak, since much time can be saved, because preliminary evaluation, including in vitro studies, already would be completed for such vaccine candidates. multiepitope subunit vaccines can be considered a promising preventive strategy against the ongoing covid- pandemic. in silico and advanced immunoinformatic tools can be used to develop multiepitope subunit vaccines. the vaccines that are engineered by this technique can be further evaluated using docking studies and, if found effective, then can be further evaluated in animal models ( ) . identifying epitopes that have the potential to become a vaccine candidate is critical to developing an effective vaccine against covid- . the immunoinformatics approach has been used for recognizing essential epitopes of cytotoxic t lymphocytes and b cells from the surface glycoprotein of sars-cov- . recently, a few epitopes have been recognized from the sars-cov- surface glycoprotein. the selected epitopes explored targeting molecular dynamic simulations, evaluating their interaction with corresponding major histocompatibility complex class i molecules. they potentially induce immune responses ( ) . the recombinant vaccine can be designed by using rabies virus (rv) as a viral vector. rv can be made to express mers-cov s protein on its surface so that an immune response is induced against mers-cov. the rv vector-based vaccines against mers-cov can induce faster antibody response as well as higher degrees of cellular immunity than the gram-positive enhancer matrix (gem) particle vector-based vaccine. however, the latter can induce a very high antibody response at lower doses ( ) . hence, the degree of humoral and cellular immune responses produced by such vaccines depends upon the vector used. dual vaccines have been getting more popular recently. among them, the rabies virus-based vectored vaccine platform is used to develop vaccines against emerging infectious diseases. the dual vaccine developed from inactivated rabies virus particles that express the mers-cov s domain of s protein was found to induce immune responses for both mers-cov and rabies virus. the vaccinated mice were found to be completely protected from challenge with mers-cov ( ) . the intranasal administration of the recombinant adenovirus-based vaccine in balb/c mice was found to induce long-lasting neutralizing immunity against mers spike pseudotyped virus, characterized by the induction of systemic igg, secretory iga, and lung-resident memory t-cell responses ( ) . immunoinformatics methods have been employed for the genomewide screening of potential vaccine targets among the different immunogens of mers-cov ( ) . the n protein and the potential b-cell epitopes of mers-cov e protein have been suggested as immunoprotective targets inducing both t-cell and neutralizing antibody responses ( , ) . the collaborative effort of the researchers of rocky mountain laboratories and oxford university is designing a chimpanzee adenovirus-vectored vaccine to counter covid- ( ) . the coalition for epidemic preparedness innovations (cepi) has initiated three programs to design sars-cov- vaccines ( ) . cepi has a collaborative project with inovio for designing a mers-cov dna vaccine that could potentiate effective immunity. cepi and the university of queensland are designing a molecular clamp vaccine platform for mers-cov and other pathogens, which could assist in the easier identification of antigens by the immune system ( ) . cepi has also funded moderna to develop a vaccine for covid- in partnership with the vaccine research center (vrc) of the national institute of allergy and infectious diseases (niaid), part of the national institutes of health (nih) ( ) . by employing mrna vaccine platform technology, a vaccine candidate expressing sars-cov- spike protein is likely to go through clinical testing in the coming months ( ( ) . the process of vaccine development usually takes approximately ten years, in the case of inactivated or live attenuated vaccines, since it involves the generation of long-term efficacy data. however, this was brought down to years during the ebola emergency for viral vector vaccines. in the urgency associated with the covid- outbreaks, we expect a vaccine by the end of this year ( ) . the development of an effective vaccine against covid- with high speed and precision is the combined result of advancements in computational biology, gene synthesis, protein engineering, and the invention of advanced manufacturing platforms ( ) . the recurring nature of the coronavirus outbreaks calls for the development of a pan-coronavirus vaccine that can produce cross-reactive antibodies. however, the success of such a vaccine relies greatly on its ability to provide protection not only against present versions of the virus but also the ones that are likely to emerge in the future. this can be achieved by identifying antibodies that can recognize relatively conserved epitopes that are maintained as such even after the occurrence of considerable variations ( ) . even though several vaccine clinical trials are being conducted around the world, pregnant women have been completely excluded from these studies. pregnant women are highly vulnerable to emerging diseases such as covid- due to alterations in the immune system and other physiological systems that are associated with pregnancy. therefore, in the event of successful vaccine development, pregnant women will not get access to the vaccines ( ) . hence, it is recommended that pregnant women be included in the ongoing vaccine trials, since successful vaccination in pregnancy will protect the mother, fetus, and newborn. the heterologous immune effects induced by bacillus calmette guérin (bcg) vaccination is a promising strategy for controlling the covid- pandemic and requires further investigations. bcg is a widely used vaccine against tuberculosis in high-risk regions. it is derived from a live attenuated strain of mycobacterium bovis. at present, three new clinical trials have been registered to evaluate the protective role of bcg vaccination against sars-cov- ( ) . recently, a cohort study was conducted to evaluate the impact of childhood bcg vaccination in covid- pcr positivity rates. however, childhood bcg vaccination was found to be associated with a rate of covid- -positive test results similar to that of the nonvaccinated group ( ) . further studies are required to analyze whether bcg vaccination in childhood can induce protective effects against covid- in adulthood. population genetic studies conducted on genomes identified that the sars-cov- virus has evolved into two major types, l and s. among the two types, l type is expected to be the most prevalent (ϳ %), followed by the s type (ϳ %) ( ) . this finding has a significant impact on our race to develop an ideal vaccine, since the vaccine candidate has to target both strains to be considered effective. at present, the genetic differences between the l and s types are very small and may not affect the immune response. however, we can expect further genetic variations in the coming days that could lead to the emergence of new strains ( ) . there is no currently licensed specific antiviral treatment for mers-and sars-cov infections, and the main focus in clinical settings remains on lessening clinical signs and providing supportive care ( ) ( ) ( ) ( ) . effective drugs to manage covid- patients include remdesivir, lopinavir/ritonavir alone or in a blend with interferon beta, convalescent plasma, and monoclonal antibodies (mabs); however, efficacy and safety issues of these drugs require additional clinical trials ( , ) . a controlled trial of ritonavirboosted lopinavir and interferon alpha b treatment was performed on covid- hospitalized patients (chictr ) ( ) . in addition, the use of hydroxychloroquine and tocilizumab for their potential role in modulating inflammatory responses in the lungs and antiviral effect has been proposed and discussed in many research articles. still, no fool-proof clinical trials have been published ( , , , ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . recently, a clinical trial conducted on adult patients suffering from severe covid- revealed no benefit of lopinavir-ritonavir treatment over standard care ( ) . the efforts to control sars-cov- infection utilize defined strategies as followed against mers and sars, along with adopting and strengthening a few precautionary measures owing to the unknown nature of this novel virus ( , ) . presently, the main course of treatment for severely affected sars-cov- patients admitted to hospitals includes mechanical ventilation, intensive care unit (icu) admittance, and symptomatic and supportive therapies. additionally, rna synthesis inhibitors (lamivudine and tenofovir disoproxil fumarate), remdesivir, neuraminidase inhibitors, peptide (ek ), antiinflammatory drugs, abidol, and chinese traditional medicine (lianhuaqingwen and shufengjiedu capsules) could aid in covid- treatment. however, further clinical trials are being carried out concerning their safety and efficacy ( ) . it might require months to a year(s) to design and develop effective drugs, therapeutics, and vaccines against covid- , with adequate evaluation and approval from regulatory bodies and moving to the bulk production of many millions of doses at commercial levels to meet the timely demand of mass populations across the globe ( ) . continuous efforts are also warranted to identify and assess viable drugs and immunotherapeutic regimens that revealed proven potency in combating other viral agents similar to sars-cov- . covid- patients showing severe signs are treated symptomatically along with oxygen therapy. in such cases where the patients progress toward respiratory failure and become refractory to oxygen therapy, mechanical ventilation is necessitated. the covid- -induced septic shock can be managed by providing adequate hemodynamic support ( ) . several classes of drugs are currently being evaluated for their potential therapeutic action against sars-cov- . therapeutic agents that have anti-sars-cov- activity can be broadly classified into three categories: drugs that block virus entry into the host cell, drugs that block viral replication as well as its survival within the host cell, and drugs that attenuate the exaggerated host immune response ( ) . an inflammatory cytokine storm is commonly seen in critically ill covid- patients. hence, they may benefit from the use of timely anti-inflammation treatment. anti-inflammatory therapy using drugs like glucocorticoids, cytokine inhibitors, jak inhibitors, and chloroquine/hydroxychloroquine should be done only after analyzing the risk/benefit ratio in covid- patients ( ). there have not been any studies concerning the application of nonsteroidal anti-inflammatory drugs (nsaid) to covid- -infected patients. however, reasonable pieces of evidence are available that link nsaid uses with the occurrence of respiratory and cardiovascular adverse effects. hence, as a cautionary approach, it is better to recommend the use of nsaids as the first-line option for managing covid- symptoms ( ) . the use of corticosteroids in covid- patients is still a matter of controversy and requires further systematic clinical studies. the guidelines that were put forward to manage critically ill adults suggest the use of systemic corticosteroids in mechanically ventilated adults with ards ( ) . the generalized use of corticosteroids is not indicated in covid- , since there are some concerns associated with the use of corticosteroids in viral pneumonia. stem cell therapy using mesenchymal stem cells (mscs) is another hopeful strategy that can be used in clinical cases of covid- owing to its potential immunomodulatory capacity. it may have a beneficial role in attenuating the cytokine storm that is observed in severe cases of sars-cov- infection, thereby reducing mortality. among the different types of mscs, expanded umbilical cord mscs can be considered a potential therapeutic agent that requires further validation for managing critically ill covid- patients ( ) . repurposed broad-spectrum antiviral drugs having proven uses against other viral pathogens can be employed for sars-cov- -infected patients. these possess benefits of easy accessibility and recognized pharmacokinetic and pharmacodynamic activities, stability, doses, and side effects ( ) . repurposed drugs have been studied for treating cov infections, like lopinavir/ritonavir, and interferon- ␤ revealed in vitro anti-mers-cov action. the in vivo experiment carried out in the nonhuman primate model of clinical microbiology reviews common marmosets treated with lopinavir/ritonavir and interferon beta showed superior protective results in treated animals than in the untreated ones ( ) . a combination of these drugs is being evaluated to treat mers in humans (miracle trial) ( ) . these two protease inhibitors (lopinavir and ritonavir), in combination with ribavirin, gave encouraging clinical outcomes in sars patients, suggesting their therapeutic values ( ) . however, in the current scenario, due to the lack of specific therapeutic agents against sars-cov- , hospitalized patients confirmed for the disease are given supportive care, like oxygen and fluid therapy, along with antibiotic therapy for managing secondary bacterial infections ( ) . patients with novel coronavirus or covid- pneumonia who are mechanically ventilated often require sedatives, analgesics, and even muscle relaxation drugs to prevent ventilator-related lung injury associated with human-machine incoordination ( ) . the result obtained from a clinical study of four patients infected with covid- claimed that combination therapy using lopinavir/ritonavir, arbidol, and shufeng jiedu capsules (traditional chinese medicine) was found to be effective in managing covid- pneumonia ( ) . it is difficult to evaluate the therapeutic potential of a drug or a combination of drugs for managing a disease based on such a limited sample size. before choosing the ideal therapeutic agent for the management of covid- , randomized clinical control studies should be performed with a sufficient study population. several classes of routinely used antiviral drugs, like oseltamivir (neuraminidase inhibitor), acyclovir, ganciclovir, and ribavirin, do not have any effect on covid- and, hence, are not recommended ( ) . oseltamivir, a neuraminidase inhibitor, has been explored in chinese hospitals for treating suspected covid- cases, although proven efficacy against sars-cov- is still lacking for this drug ( ) . the in vitro antiviral potential of fad-approved drugs, viz., ribavirin, penciclovir, nitazoxanide, nafamostat, and chloroquine, tested in comparison to remdesivir and favipiravir (broad-spectrum antiviral drugs) revealed remdesivir and chloroquine to be highly effective against sars-cov- infection in vitro ( ) . ribavirin, penciclovir, and favipiravir might not possess noteworthy in vivo antiviral actions for sars-cov- , since higher concentrations of these nucleoside analogs are needed in vitro to lessen the viral infection. both remdesivir and chloroquine are being used in humans to treat other diseases, and such safer drugs can be explored for assessing their effectiveness in covid- patients. several therapeutic agents, such as lopinavir/ritonavir, chloroquine, and hydroxychloroquine, have been proposed for the clinical management of covid- ( ) . a molecular docking study, conducted in the rna-dependent rna polymerase (rdrp) of sars-cov- using different commercially available antipolymerase drugs, identified that drugs such as ribavirin, remdesivir, galidesivir, tenofovir, and sofosbuvir bind rdrp tightly, indicating their vast potential to be used against covid- ( ). a broadspectrum antiviral drug that was developed in the united states, tilorone dihydrochloride (tilorone), was previously found to possess potent antiviral activity against mers, marburg, ebola, and chikungunya viruses ( ) . even though it had broad-spectrum activity, it was neglected for an extended period. tilorone is another antiviral drug that might have activity against sars-cov- . remdesivir, a novel nucleotide analog prodrug, was developed for treating ebola virus disease (evd), and it was also found to inhibit the replication of sars-cov and mers-cov in primary human airway epithelial cell culture systems ( ) . recently, in vitro study has proven that remdesivir has better antiviral activity than lopinavir and ritonavir. further, in vivo studies conducted in mice also identified that treatment with remdesivir improved pulmonary function and reduced viral loads and lung pathology both in prophylactic and therapeutic regimens compared to lopinavir/ritonavir-ifn-␥ treatment in mers-cov infection ( ) . remdesivir also inhibits a diverse range of coronaviruses, including circulating human cov, zoonotic bat cov, and prepandemic zoonotic cov ( ) . remdesivir is also considered the only therapeutic drug that significantly reduces pulmonary pathology ( ) . all these findings indicate that remde-sivir has to be further evaluated for its efficacy in the treatment of covid- infection in humans. the broad-spectrum activity exhibited by remdesivir will help control the spread of disease in the event of a new coronavirus outbreak. chloroquine is an antimalarial drug known to possess antiviral activity due to its ability to block virus-cell fusion by raising the endosomal ph necessary for fusion. it also interferes with virus-receptor binding by interfering with the terminal glycosylation of sars-cov cellular receptors, such as ace ( ) . in a recent multicenter clinical trial that was conducted in china, chloroquine phosphate was found to exhibit both efficacy and safety in the therapeutic management of sars-cov- -associated pneumonia ( ) . this drug is already included in the treatment guidelines issued by the national health commission of the people's republic of china. the preliminary clinical trials using hydroxychloroquine, another aminoquinoline drug, gave promising results. the covid- patients received mg of hydroxychloroquine daily along with azithromycin as a single-arm protocol. this protocol was found to be associated with a noteworthy reduction in viral load. finally, it resulted in a complete cure ( ) ; however, the study comprised a small population and, hence, the possibility of misinterpretation could arise. however, in another case study, the authors raised concerns over the efficacy of hydroxychloroquine-azithromycin in the treatment of covid- patients, since no observable effect was seen when they were used. in some cases, the treatment was discontinued due to the prolongation of the qt interval ( ) . hence, further randomized clinical trials are required before concluding this matter. recently, another fda-approved drug, ivermectin, was reported to inhibit the in vitro replication of sars-cov- . the findings from this study indicate that a single treatment of this drug was able to induce an ϳ , -fold reduction in the viral rna at h in cell culture. ( ) . one of the main disadvantages that limit the clinical utility of ivermectin is its potential to cause cytotoxicity. however, altering the vehicles used in the formulations, the pharmacokinetic properties can be modified, thereby having significant control over the systemic concentration of ivermectin ( ) . based on the pharmacokinetic simulation, it was also found that ivermectin may have limited therapeutic utility in managing covid- , since the inhibitory concentration that has to be achieved for effective anti-sars-cov- activity is far higher than the maximum plasma concentration achieved by administering the approved dose ( ) . however, ivermectin, being a host-directed agent, exhibits antiviral activity by targeting a critical cellular process of the mammalian cell. therefore, the administration of ivermectin, even at lower doses, will reduce the viral load at a minor level. this slight decrease will provide a great advantage to the immune system for mounting a large-scale antiviral response against sars-cov- ( ). further, a combination of ivermectin and hydroxychloroquine might have a synergistic effect, since ivermectin reduces viral replication, while hydroxychloroquine inhibits the entry of the virus in the host cell ( ) . further, in vivo studies and randomized clinical control trials are required to understand the mechanism as well as the clinical utility of this promising drug. nafamostat is a potent inhibitor of mers-cov that acts by preventing membrane fusion. nevertheless, it does not have any sort of inhibitory action against sars-cov- infection ( ) . recently, several newly synthesized halogenated triazole compounds were evaluated, using fluorescence resonance energy transfer (fret)-based helicase assays, for their ability to inhibit helicase activity. among the evaluated compounds, -(cyclopent- -en- -ylamino)- -[ -( -iodophenyl) hydrazinyl]- h- , , -triazole- -thiol and -(cyclopent- -en- -ylamino)- -[ -( -chlorophenyl) hydrazinyl]- h- , , -triazole- -thiol were found to be the most potent. these compounds were used for in silico studies, and molecular docking was accomplished into the active binding site of mers-cov helicase nsp ( ) . further studies are required for evaluating the therapeutic potential of these newly identified compounds in the management of covid- infection. monoclonal antibodies (mabs) may be helpful in the intervention of disease in clinical microbiology reviews cov-exposed individuals. patients recovering from sars showed robust neutralizing antibodies against this cov infection ( ) . a set of mabs aimed at the mers-cov s protein-specific domains, comprising six specific epitope groups interacting with receptor-binding, membrane fusion, and sialic acid-binding sites, make up crucial entry tasks of s protein ( , ) . passive immunization employing weaker and strongly neutralizing antibodies provided considerable protection in mice against a mers-cov lethal challenge. such antibodies may play a crucial role in enhancing protective humoral responses against the emerging covs by aiming appropriate epitopes and functions of the s protein. the cross-neutralization ability of sars-cov rbd-specific neutralizing mabs considerably relies on the resemblance between their rbds; therefore, sars-cov rbd-specific antibodies could cross-neutralized sl covs, i.e., bat-sl-cov strain wiv (rbd with eight amino acid differences from sars-cov) but not bat-sl-cov strain shc ( amino acid differences) ( ) . appropriate rbd-specific mabs can be recognized by a relative analysis of rbd of sars-cov- to that of sars-cov, and cross-neutralizing sars-cov rbd-specific mabs could be explored for their effectiveness against covid- and further need to be assessed clinically. the u.s. biotechnology company regeneron is attempting to recognize potent and specific mabs to combat covid- . an ideal therapeutic option suggested for sars-cov- (covid- ) is the combination therapy comprised of mabs and the drug remdesivir (covid- ) ( ) . the sars-cov-specific human mab cr is found to bind with sars-cov- rbd, indicating its potential as a therapeutic agent in the management of covid- . it can be used alone or in combination with other effective neutralizing antibodies for the treatment and prevention of covid- ( ) . furthermore, sars-cov-specific neutralizing antibodies, like m and cr , failed to bind the s protein of sars-cov- , indicating that a particular level of similarity is mandatory between the rbds of sars-cov and sars-cov- for the cross-reactivity to occur. further assessment is necessary before confirming the effectiveness of such combination therapy. in addition, to prevent further community and nosocomial spread of covid- , the postprocedure risk management program should not be neglected ( ) . development of broad-spectrum inhibitors against the human coronaviral pathogens will help to facilitate clinical trials on the effectiveness of such inhibitors against endemic and emerging coronaviruses ( ) . a promising animal study revealed the protective effect of passive immunotherapy with immune serum from mers-immune camels on mice infected with mers-cov ( ) . passive immunotherapy using convalescent plasma is another strategy that can be used for treating covid- -infected, critically ill patients ( ) . the exploration of fully human antibodies (human single-chain antibodies; huscfvs) or humanized nanobodies (single-domain antibodies; sdab, vh/vhh) could aid in blocking virus replication, as these agents can traverse the virus-infected cell membranes (transbodies) and can interfere with the biological characteristics of the replicating virus proteins. such examples include transbodies to the influenza virus, hepatitis c virus, ebola virus, and dengue virus ( ) . producing similar transbodies against intracellular proteins of coronaviruses, such as papain-like proteases (plpro), cysteinelike protease ( clpro), or other nsps, which are essential for replication and transcription of the virus, might formulate a practical move forward for a safer and potent passive immunization approach for virus-exposed persons and rendering therapy to infected patients. in a case study on five grimly sick patients having symptoms of severe pneumonia due to covid- , convalescent plasma administration was found to be helpful in patients recovering successfully. the convalescent plasma containing a sars-cov- specific elisa (serum) antibody titer higher than : , and neutralizing antibody titer more significant than was collected from the recovered patients and used for plasma transfusion twice in a volume of to ml on the day of collection ( ) . at present, treatment for sepsis and ards mainly involves antimicrobial therapy, source control, and supportive care. hence, the use of therapeutic plasma exchange can be considered an option in managing such severe conditions. further randomized trials can be designed to investigate its efficacy ( ) . potent therapeutics to combat sars-cov- infection include virus binding molecules, molecules or inhibitors targeting particular enzymes implicated in replication and transcription process of the virus, helicase inhibitors, vital viral proteases and proteins, protease inhibitors of host cells, endocytosis inhibitors, short interfering rna (sirna), neutralizing antibodies, mabs against the host receptor, mabs interfering with the s rbd, antiviral peptide aimed at s , and natural drugs/medicines ( , , ) . the s protein acts as the critical target for developing cov antivirals, like inhibitors of s protein and s cleavage, neutralizing antibodies, rbd-ace blockers, sirnas, blockers of the fusion core, and proteases ( ) . all of these therapeutic approaches have revealed both in vitro and in vivo anti-cov potential. although in vitro research carried out with these therapeutics showed efficacy, most need appropriate support from randomized animal or human trials. therefore, they might be of limited applicability and require trials against sars-cov- to gain practical usefulness. the binding of sars-cov- with ace leads to the exacerbation of pneumonia as a consequence of the imbalance in the reninangiotensin system (ras). the virus-induced pulmonary inflammatory responses may be reduced by the administration of ace inhibitors (acei) and angiotensin type- receptor (at r) ( ) . several investigations have suggested the use of small-molecule inhibitors for the potential control of sars-cov infections. drugs of the fda-approved compound library were screened to identify four small-molecule inhibitors of mers-cov (chlorpromazine, chloroquine, loperamide, and lopinavir) that inhibited viral replication. these compounds also hinder sars-cov and human covs ( ) . therapeutic strategies involving the use of specific antibodies or compounds that neutralize cytokines and their receptors will help to restrain the host inflammatory responses. such drugs acting specifically in the respiratory tract will help to reduce virus-triggered immune pathologies in covid- ( ) . the later stages of coronavirus-induced inflammatory cascades are characterized by the release of proinflammatory interleukin- (il- ) family members, such as il- and il- . hence, there exists a possibility that the inflammation associated with coronavirus can be inhibited by utilizing anti-inflammatory cytokines that belong to the il- family ( ) . it has also been suggested that the actin protein is the host factor that is involved in cell entry and pathogenesis of sars-cov- . hence, those drugs that modulate the biological activity of this protein, like ibuprofen, might have some therapeutic application in managing the disease ( ). the plasma angiotensin level was found to be markedly elevated in covid- infection and was correlated with viral load and lung injury. hence, drugs that block angiotensin receptors may have potential for treating covid- infection ( ) . a scientist from germany, named rolf hilgenfeld, has been working on the identification of drugs for the treatment of coronaviral infection since the time of the first sars outbreak ( ) . the sars-cov s subunit has a significant function in mediating virus fusion that provides entry into the host cell. heptad repeat (hr ) and heptad repeat (hr ) can interact and form a six-helix bundle that brings the viral and cellular membranes in close proximity, facilitating its fusion. the sequence alignment study conducted between covid- and sars-cov identified that the s subunits are highly conserved in these covs. the hr and hr domains showed . % and % overall identity, respectively ( ) . from these findings, we can confirm the significance of covid- hr and hr and their vital role in host cell entry. hence, fusion inhibitors target the hr domain of s protein, thereby preventing viral fusion and entry into the host cell. this is another potential therapeutic strategy that can be used in the management of covid- . other than the specific therapy directed against covid- , general treatments play a vital role in the enhancement of host immune responses against the viral agent. inadequate nutrition is linked to the weakening of the host immune response, clinical microbiology reviews making the individual more susceptible. the role played by nutrition in disease susceptibility should be measured by evaluating the nutritional status of patients with covid- ( ) . for evaluating the potential of vaccines and therapeutics against covs, including sars-cov, mers-covs, and the presently emerging sars-cov- , suitable animal models that can mimic the clinical disease are needed ( , ) . various animal models were assessed for sars-and mers-covs, such as mice, guinea pigs, golden syrian hamsters, ferrets, rabbits, nonhuman primates like rhesus macaques and marmosets, and cats ( , ( ) ( ) ( ) ( ) ( ) ( ) . the specificity of the virus to hace (receptor of sars-cov) was found to be a significant barrier in developing animal models. consequently, a sars-cov transgenic mouse model has been developed by inserting the hace gene into the mouse genome ( ) . the inability of mers-cov to replicate in the respiratory tracts of animals (mice, hamsters, and ferrets) is another limiting factor. however, with genetic engineering, a - ϩ/ϩ mers-cov genetically modified mouse model was developed and now is in use for the assessment of novel drugs and vaccines against mers-cov ( ). in the past, small animals (mice or hamsters) have been targeted for being closer to a humanized structure, such as mouse dpp altered with human dpp (hdpp ), hdpp -transduced mice, and hdpp -tg mice (transgenic for expressing hdpp ) for mers-cov infection ( ) . the crispr-cas gene-editing tool has been used for inserting genomic alterations in mice, making them susceptible to mers-cov infection ( ) . efforts are under way to recognize suitable animal models for sars-cov /covid- , identify the receptor affinity of this virus, study pathology in experimental animal models, and explore virus-specific immune responses and protection studies, which together would increase the pace of efforts being made for developing potent vaccines and drugs to counter this emerging virus. cell lines, such as monkey epithelial cell lines (llc-mk and vero-b ), goat lung cells, alpaca kidney cells, dromedary umbilical cord cells, and advanced ex vivo three-dimensional tracheobronchial tissue, have been explored to study human covs (mers-cov) ( , ) . vero and huh- cells (human liver cancer cells) have been used for isolating sars-cov- ( ) . recently, an experimental study with rhesus monkeys as animal models revealed the absence of any viral loads in nasopharyngeal and anal swabs, and no viral replication was recorded in the primary tissues at a time interval of days post-reinfection in reexposed monkeys ( ) . the subsequent virological, radiological, and pathological observations indicated that the monkeys with reexposure had no recurrence of covid- , like the sars-cov- -infected monkeys without rechallenge. these findings suggest that primary infection with sars-cov- could protect from later exposures to the virus, which could help in defining disease prognosis and crucial inferences for designing and developing potent vaccines against covid- ( ). in contrast to their response to the sars outbreak, china has shown immense political openness in reporting the covid- outbreak promptly. they have also performed rapid sequencing of covid- at multiple levels and shared the findings globally within days of identifying the novel virus ( ) . the move made by china opened a new chapter in global health security and diplomacy. even though complete lockdown was declared following the covid- outbreak in wuhan, the large-scale movement of people has resulted in a radiating spread of infections in the surrounding provinces as well as to several other countries. large-scale screening programs might help us to control the spread of this virus. however, this is both challenging as well as time-consuming due to the present extent of infection ( ) . the current scenario demands effective implementation of vigorous prevention and control strategies owing to the prospect of covid- for nosocomial infections ( ) . follow-ups of infected patients by telephone on day and day are advised to avoid any further unintentional spread or nosocomial transmission ( ) . the availability of public data sets provided by independent analytical teams will act as robust evidence that would guide us in designing interventions against the covid- outbreak. newspaper reports and social media can be used to analyze and reconstruct the progression of an outbreak. they can help us to obtain detailed patient-level data in the early stages of an outbreak ( ) . immediate travel restrictions imposed by several countries might have contributed significantly to preventing the spread of sars-cov- globally ( , ) . following the outbreak, a temporary ban was imposed on the wildlife trade, keeping in mind the possible role played by wild animal species in the origin of sars-cov- /covid- ( ) . making a permanent and bold decision on the trade of wild animal species is necessary to prevent the possibility of virus spread and initiation of an outbreak due to zoonotic spillover ( ) . personal protective equipment (ppe), like face masks, will help to prevent the spread of respiratory infections like covid- . face masks not only protect from infectious aerosols but also prevent the transmission of disease to other susceptible individuals while traveling through public transport systems ( ) . another critical practice that can reduce the transmission of respiratory diseases is the maintenance of hand hygiene. however, the efficacy of this practice in reducing the transmission of respiratory viruses like sars-cov- is much dependent upon the size of droplets produced. hand hygiene will reduce disease transmission only if the virus is transmitted through the formation of large droplets ( ) . hence, it is better not to overemphasize that hand hygiene will prevent the transmission of sars-cov- , since it may produce a false sense of safety among the general public that further contributes to the spread of covid- . even though airborne spread has not been reported in sars-cov- infection, transmission can occur through droplets and fomites, especially when there is close, unprotected contact between infected and susceptible individuals. hence, hand hygiene is equally as important as the use of appropriate ppe, like face masks, to break the transmission cycle of the virus; both hand hygiene and face masks help to lessen the risk of covid- transmission ( ) . medical staff are in the group of individuals most at risk of getting covid- infection. this is because they are exposed directly to infected patients. hence, proper training must be given to all hospital staff on methods of prevention and protection so that they become competent enough to protect themselves and others from this deadly disease ( ) . as a preventive measure, health care workers caring for infected patients should take extreme precautions against both contact and airborne transmission. they should use ppe such as face masks (n or ffp ), eye protection (goggles), gowns, and gloves to nullify the risk of infection ( ) . the human-to-human transmission reported in sars-cov- infection occurs mainly through droplet or direct contact. due to this finding, frontline health care workers should follow stringent infection control and preventive measures, such as the use of ppe, to prevent infection ( ) . the mental health of the medical/health workers who are involved in the covid- outbreak is of great importance, because the strain on their mental well-being will affect their attention, concentration, and decision-making capacity. hence, for control of the covid- outbreak, rapid steps should be taken to protect the mental health of medical workers ( ) . since the living mammals sold in the wet market are suspected to be the intermediate host of sars-cov- , there is a need for strengthening the regulatory mechanism for wild animal trade ( ) . the total number of covid- confirmed cases is on a continuous rise and the cure rate is relatively low, making disease control very difficult to achieve. the chinese government is making continuous efforts to contain the disease by taking emergency control and prevention measures. they have already built a hospital for patients affected by this virus and are currently building several more for accommodating the continuously increasing infected population ( ) . the effective control of sars-cov- /covid- requires high-level interventions like intensive contact tracing, as well as the quarantine of people with suspected infection and the isolation of infected individuals. the implementation of rigorous control and preventive measures together might control the r number and reduce the transmission risk ( ) . clinical microbiology reviews considering the zoonotic links associated with sars-cov- , the one health approach may play a vital role in the prevention and control measures being followed to restrain this pandemic virus ( ) ( ) ( ) . the substantial importation of covid- presymptomatic cases from wuhan has resulted in independent, self-sustaining outbreaks across major cities both within the country and across the globe. the majority of chinese cities are now facing localized outbreaks of covid- ( ) . hence, deploying efficient public health interventions might help to cut the spread of this virus globally. the occurrence of covid- infection on several cruise ships gave us a preliminary idea regarding the transmission pattern of the disease. cruise ships act as a closed environment and provide an ideal setting for the occurrence of respiratory disease outbreaks. such a situation poses a significant threat to travelers, since people from different countries are on board, which favors the introduction of the pathogen ( ). although nearly cruise ships from different countries have been found harboring covid- infection, the major cruise ships that were involved in the covid- outbreaks are the diamond princess, grand princess, celebrity apex, and ruby princess. the number of confirmed covid- cases around the world is on the rise. the success of preventive measures put forward by every country is mainly dependent upon their ability to anticipate the approaching waves of patients. this will help to properly prepare the health care workers and increase the intensive care unit (icu) capacity ( ) . instead of entirely relying on lockdown protocols, countries should focus mainly on alternative intervention strategies, such as large-scale testing, contract tracing, and localized quarantine of suspected cases for limiting the spread of this pandemic virus. such intervention strategies will be useful either at the beginning of the pandemic or after lockdown relaxation ( ) . lockdown should be imposed only to slow down disease progression among the population so that the health care system is not overloaded. the reproduction number (r ) of covid- infection was earlier estimated to be in the range of . to . ( ); recently, it was estimated to be . to . ( ) . compared to its coronavirus predecessors, covid- has an r value that is greater than that of mers (r Ͻ ) ( ) but less than that of sars (r value of to ) ( ) . still, to prevent further spread of disease at mass gatherings, functions remain canceled in the affected cities, and persons are asked to work from home ( ) . hence, it is a relief that the current outbreak of covid- infection can be brought under control with the adoption of strategic preventive and control measures along with the early isolation of subsequent cases in the coming days. studies also report that since air traffic between china and african countries increased many times over in the decade after the sars outbreak, african countries need to be vigilant to prevent the spread of novel coronavirus in africa ( ) . due to fear of virus spread, wuhan city was completely shut down ( ) . the immediate control of the ongoing covid- outbreaks appears a mammoth task, especially for developing countries, due to their inability to allocate quarantine stations that could screen infected individuals' movements ( ) . such underdeveloped countries should divert their resources and energy to enforcing the primary level of preventive measures, like controlling the entry of individuals from china or countries where the disease has flared up, isolating the infected individuals, and quarantining individuals with suspected infection. most of the sub-saharan african countries have a fragile health system that can be crippled in the event of an outbreak. effective management of covid- would be difficult for low-income countries due to their inability to respond rapidly due to the lack of an efficient health care system ( ) . controlling the imported cases is critical in preventing the spread of covid- to other countries that have not reported the disease until now. the possibility of an imported case of covid- leading to sustained human-to-human transmission was estimated to be . . this can be reduced to a value of . by decreasing the mean time from the onset of symptoms to hospitalization and can only be made possible by using intense disease surveillance systems ( ) . the silent importations of infected individuals (before the manifestation of clinical signs) also contributed significantly to the spread of disease across the major cities of the world. even though the travel ban was implemented in wuhan ( ) , infected persons who traveled out of the city just before the imposition of the ban might have remained undetected and resulted in local outbreaks ( ) . emerging novel diseases like covid- are difficult to contain within the country of origin, since globalization has led to a world without borders. hence, international collaboration plays a vital role in preventing the further spread of this virus across the globe ( ) . we also predict the possibility of another outbreak, as predicted by fan et al. ( ) . indeed, the present outbreak caused by sars-cov- (covid- ) was expected. similar to previous outbreaks, the current outbreak also will be contained shortly. however, the real issue is how we are planning to counter the next zoonotic cov epidemic that is likely to occur within the next to years or even sooner (fig. ) . several years after the global sars epidemic, the current sars-cov- /covid- pandemic has served as a reminder of how novel pathogens can rapidly emerge and spread through the human population and eventually cause severe public health crises. further research should be conducted to establish animal models for sars-cov- to investigate replication, transmission dynamics, and pathogenesis in humans. this may help develop and evaluate potential therapeutic strategies against zoonotic cov epidemics. present trends suggest the occurrence of future outbreaks of covs due to changes in the climate, and ecological conditions may be associated with humananimal contact. live-animal markets, such as the huanan south china seafood market, represent ideal conditions for interspecies contact of wildlife with domestic birds, pigs, and mammals, which substantially increases the probability of interspecies transmission of cov infections and could result in high risks to humans due to adaptive genetic recombination in these viruses ( ) ( ) ( ) . the covid- -associated symptoms are fever, cough, expectoration, headache, and myalgia or fatigue. individuals with asymptomatic and atypical clinical manifestations were also identified recently, further adding to the complexity of disease transmission dynamics. atypical clinical manifestations may only express symptoms such as fatigue instead of respiratory signs such as fever, cough, and sputum. in such cases, the clinician must be vigilant for the possible occurrence of asymptomatic and atypical clinical manifestations to avoid the possibility of missed diagnoses. the present outbreak caused by sars-cov- was, indeed, expected. similar to clinical microbiology reviews previous outbreaks, the current pandemic also will be contained shortly. however, the real question is, how are we planning to counter the next zoonotic cov epidemic that is likely to occur within the next to years or perhaps sooner? our knowledge of most of the bat covs is scarce, as these viruses have not been isolated and studied, and extensive studies on such viruses are typically only conducted when they are associated with specific disease outbreaks. the next step following the control of the covid- outbreak in china should be focused on screening, identification, isolation, and characterization of covs present in wildlife species of china, particularly in bats. both in vitro and in vivo studies (using suitable animal models) should be conducted to evaluate the risk of future epidemics. presently, licensed antiviral drugs or vaccines against sars-cov, mers-cov, and sars-cov- are lacking. however, advances in designing 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recent advances and emerging trends point-of-care rna-based diagnostic device for covid- rapid colorimetric detection of covid- coronavirus using a reverse transcriptional loop-mediated isothermal amplification (rt-lamp) diagnostic plat-form: ilaco mapping the incidence of the covid- hotspot in iran-implications for travellers covid- : preparing for superspreader potential among umrah pilgrims to saudi arabia geographical tracking and mapping of coronavirus disease covid- /severe acute respiratory syndrome coronavirus (sars-cov- ) epidemic and associated events around the world: how st century gis technologies are supporting the global fight against outbreaks and epidemics policy decisions and use of information technology to fight novel coronavirus disease prediction models for diagnosis and prognosis of covid- infection: systematic review and critical appraisal consider pregnancy in covid- therapeutic drug and vaccine trials rational vaccine design in the time of covid- bacillus calmette guérin (bcg) vaccination use in the fight against covid- -what's old is new again? sars-cov- rates in bcg-vaccinated and unvaccinated young adults high throughput and comprehensive approach to develop multiepitope vaccine against minacious covid- on the origin and continuing evolution of sars-cov- covid- : the race for a vaccine all authors substantially contributed to the conception, design, analysis, and interpretation of data and checking and approving the final version of the manuscript, and we agree to be accountable for its contents.this compilation is a review article written, analyzed, and designed by its authors and required no substantial funding to be developed.all authors declare that there are no existing commercial or financial relationships that could, in any way, lead to a potential conflict of interest. with years of research and teaching experience in the areas of microbiology, immunology, virology, public health, medicine, and biomedicine as an eminent researcher, he has developed several diagnostics, vaccines, immunomodulatory modules, and hypotheses to counter infectious diseases of animals, poultry, and public health concerns. he has to his credit publications, books, and book chapters. dr. dhama has been recognized as an extremely productive researcher in the journal nature. he has been honored with best paper awards and other recognitions. he is an naas (national academy of agricultural science, india) associate and has worked as nodal officer, wto, and member, wildlife health specialist group (iucn). he is actively serving as editor-in-chief, co-eic, editor, and member, editorial board, of nearly scientific journals. his google scholar h-index is and scopus h-index is . sharun khan, m.v.sc., is currently working as a researcher in the stem cell laboratory, division of surgery, icar-indian veterinary research institute, izatnagar, india. his area of interest is regenerative medicine with a focus on understanding cell biology and molecular pathways involved in the maintenance and differentiation of stem cells originating from different tissues. he has particular interest and knowledge in the fields of veterinary medicine, pharmacology, infectious diseases of animals, wildlife diseases, diagnosis and therapy of animal diseases, nutrition, and biomedicine. with excellent academic records, he has received awards and recognitions (fellowships and scholarships) and participated in national and international workshops, training programs, and courses. he has a keen interest in learning excellent scientific writing skills and has published papers, including in international journals of repute. he is highly enthusiastic about gaining knowledge of advancements in educational and scientific research areas.ruchi tiwari is currently working as assistant professor in the department of veterinary microbiology, college of veterinary sciences, duvasu, mathura, india. she is currently pursuing her ph.d. (hons) degree from duvasu. with an excellent academic record and years of research and teaching experience, she has expertise in the field of diagnosis, prevention, and control of important livestock/poultry diseases/pathogens having public health significance, along with particular reference to veterinary microbiology, immunology, ethnoveterinary medicine, alternative and complementary therapies, and bacteriophage therapy. dr. tiwari has published research/review articles and book chapters. she has been honored with the young scientist award, best paper awards ( ) key: cord- -qu bmov authors: reddy, gireesh b.; greif, dylan n.; rodriguez, jose; best, thomas m.; greditzer, harry g.; jose, jean title: clinical characteristics and multisystem imaging findings of covid- : an overview for orthopedic surgeons date: - - journal: hss j doi: . /s - - - sha: doc_id: cord_uid: qu bmov the covid- pandemic holds widespread implications for global public health, economies, societies, and the practice of orthopedic surgery. as our knowledge of the transmissibility of sars-cov- and the symptomatology and management of covid- expands, orthopedic surgeons must remain up to date on the latest medical evidence and surgical perspectives. while covid- primarily manifests with pulmonary symptoms, cardiovascular, neurologic, and other major organ systems may also be affected and present with hallmark imaging findings. this article reviews initial and emerging literature on clinical characteristics and imaging findings of covid- . electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. since december , infections with severe acute respiratory syndrome coronavirus (sars-cov- ), a novel betacoronavirus strain responsible for coronavirus disease (covid- ) , rapidly progressed from an isolated cluster of cases in the hubei province of east central china to a pandemic, with significant global health and economic repercussions [ , , , , , , , , , , ] . by mid-june , the world health organization (who) had declared over . million people infected worldwide, with nearly , deaths. in the usa, despite unprecedented social distancing and public health measures, over . million people were infected, with more than , deaths [ ] . musculoskeletal chief complaints account for % of all healthcare visits in the usa [ ] , with nearly million orthopedic procedures performed annually worldwide, of which five orthopedic procedures comprise % of all operations in the usa [ ] . public safety restrictions on semi-elective and elective office visits and surgical procedures during the covid- pandemic have created a tremendous backlog (estimated at more than million cases in years) for orthopedic practices and have taken many practices to a tenuous economic precipice [ , ] . as restrictions are eased nationally [ ] , it is critical that orthopedic surgeons remain aware of the clinical and radiographic findings associated with covid- to best evaluate surgical patients. in addition to the widely known pulmonary symptoms, covid- patients may initially present with atypical neurologic, gastrointestinal, cardiac, and musculoskeletal imaging findings (table ) , which are more likely to be undiagnosed. we summarize the most recent literature describing the clinical and imaging findings in order to assist orthopedic surgeons in navigating a clinical and practice management landscape permanently transformed by the pandemic. the most common symptoms of patients presenting with covid- are cough, dyspnea, and fever, while the most common reasons for admission are pneumonia and hypoxemia [ , , , , ] . approximately % of patients develop more severe symptoms, including acute hypoxic respiratory failure and acute respiratory distress syndrome (ards), while the mortality rate for patients requiring invasive mechanical ventilation is high ( . % in new york city) [ , ] . in a recent retrospective review of chest radiographic findings in patients with covid- , wong et al. reported consolidation ( %) and ground glass opacities (ggo) ( %) as the most common findings, usually in a peripheral ( %) or lower lobe ( %) distribution, with bilateral lung involvement in % ( fig. ) [ ] . pulmonary nodules, pleural effusions, lymphadenopathy, and lung cavitation (thick-walled abnormal gas-filled spaces within the lung) were usually absent [ ] . chest computed tomography (ct) is the gold imaging standard for diagnosing covid- . in a retrospective cohort study from wuhan, including some of the earliest diagnosed patients, ct scans were reviewed sequentially from prior to symptom onset to weeks after onset [ ] . the authors found that even before symptom onset, ct scans demonstrated unilateral ggo that progressed to bilateral diffuse ggo, with or without consolidation [ , ] . early reports from china described the most common imaging findings on ct as ggo ( . %) and bilateral patchy shadowing ( . %) [ ] . in another recent review, pan et al. correlated time course of lung changes on ct scans with covid- disease progression [ ] . in the "early stage" of the disease ( to days after onset of symptoms), ggos in subpleural locations unilaterally or bilaterally were observed (fig. ) . during the "progressive stage" (days to ), ct scans demonstrated multilobe distribution of diffuse ggos and crazy-paving pattern (ggos with superimposed inter-and intralobular septal thickening), and consolidation was observed, without mediastinal lymphadenopathy ( fig. ) [ ]. in the "peak stage" ( to days), consolidations became denser, with worsening diffuse ggos, crazypaving, and residual parenchymal bands (fig. ) . if patients clinically improved, they entered the "absorption stage" (usually more than days after symptom onset). in this stage, ggos persisted, but the crazy-paving resolved, and consolidations improved. if the patient worsened, with increased oxygen requirements, need for more invasive ventilation, and other intensive care unit (icu) care, a transition to a denser alveolar consolidation pattern on radiographic imaging was noted. at this point, acute respiratory distress syndrome was likely to occur, and a low clinical threshold was necessary for transfer to an icu for advanced respiratory support [ ] . there is a characteristic change in imaging of the chest, not only temporally from symptom onset but also with increasing disease severity. in a retrospective study of patients, patients with more severe manifestations of covid- had higher thin section ct score, incidence of consolidation, mediastinal lymph node enlargement, septal thickening, pleural effusion, and pericardial effusion than those with less severe presentations [ , ] . salehi et al. reviewed the imaging findings of patients and corroborated this progression of severity [ ] . other uncommon findings that occur later in the progression of covid- may also include bronchiectasis, pleural thickening, enlargement of intralesional pulmonary vessels greater than mm in diameter, cavitation, or ct halo signs (ggos surrounding a pulmonary nodule or mass) [ , ] . finally, as mentioned, disease resolution is seen with the gradual disappearance gastrointestinal manifestations ct and us abdomen (figs. and ) • small and large bowel wall thickening, due to gastroenteritis or ischemia • bowel and mesenteric infarction and necrosis, with associated non-enhancing bowel, pneumatosis, portal venous gas, and bowel perforation • portal vein thrombosis • distended gallbladder containing sludge suggestive of cholestasis • solid organ inflammation and infarction, including the pancreas (pancreatitis), liver (hepatitis), kidneys, and spleen ct computed tomography mri magnetic resonance imaging . chest x-ray findings of covid- pneumonia: frontal radiograph of the chest demonstrates low lung volumes with bilateral perihilar ground glass opacities and peripheral airspace consolidations (blue arrows) in a predominately mid and lower lobe distribution. of consolidative opacities and decreased number of lesions and/or involved lobes. a recent meta-analysis of articles [ ] found that chest ct has a sensitivity and specificity of % and %, respectively, in detecting covid- [ , ] . imaging characteristics of covid- are distinctive enough that chinese and american radiologists were able to differentiate covid- (n = ) from respiratory viral pneumonia (n = ) when presented with respective imaging [ ] . early reports from italy and china indicated that although pulmonary diseases including ards and diffuse pneumonia comprise the predominant lethal complications of covid- , patients have also presented with or developed significant cardiac signs and symptoms [ ] . in one of the first series of covid- patients from wuhan, huang et al. [ ] found that five of ( %) had some form of acute cardiac injury, determined either by elevated cardiac biomarkers above the th percentile or new abnormalities/arrhythmias on electrocardiography or echocardiography as seen in patients with myopericarditis ( fig. ) or myocardial infarction (fig. ) [ ] . a case report from italy described a covid- patient without a cvd history who presented with electrocardiographic and biomarker changes indicative of acute cardiac injury [ ] . transthoracic echocardiography (tte) and gadoliniumenhanced cardiac magnetic resonance imaging (gd-cardiac mri) demonstrated increased wall thickness, diffuse biventricular hypokinesis, severe left ventricular dysfunction, biventricular myocardial interstitial edema (on short-tau inversion and t -mapping sequences), acute myocarditis, and pericardial effusion, especially around the right cardiac chambers. the above suggests that covid- may be related to cardiac injury of undetermined pathophysiology. cardiac injury in the context of viral infections has been studied in the past. in a self-controlled case series involving admissions in ontario, canada, laboratory-confirmed respiratory viral infections were associated with . % increase in the incidence of acute myocardial infarction within days of viral detection [ ] . viral respiratory tract infections may lead to complications such as acute coronary syndrome (acs) or venothrombotic events (vtes) secondary to immune system hyperactivation and generation of a thrombogenic state [ , ] . global reports of covid- -associated coagulopathy with multifocal thromboembolic disease are rapidly growing and include pulmonary emboli, limb ischemia, and cerebral infarct; often associated with poorer prognosis [ , , , , , ] . several european studies have demonstrated higher rates of vte in the covid- population [ , ] . in a study of covid- icu patients, nearly ( %) had a thrombotic event, including pulmonary embolism (fig. ) and continuous renal replacement therapy (crrt) circuit clotting [ ] . in a study of covid- icu patients at two institutions, an alarming % were positive for dvts, despite almost all being on prophylactic anticoagulation [ ] . another study of icu patients screened for dvts using duplex ultrasonography found that % were positive, with % positive despite being on therapeutic anticoagulation [ ] . up to % of covid- patients with pulmonary symptoms were diagnosed with acute pulmonary embolus on pulmonary ct angiogram over a month period in a tertiary care center and all with higher levels of d-dimer ( μg/l) and c-reactive protein (crp) than usually encountered, suggesting an independent association between d-dimer level and disease severity [ , ] . antiphospholipid antibodies in the setting of multifocal cerebral infarct have also been observed in covid- patients [ ] . while noted in other infections, antiphospholipid antibodies have not been associated with thrombotic events in these circumstances [ , ] . covid- musculoskeletal and neurologic manifestations are being reported with increased frequency, particularly in patients with more severe respiratory disease, indicating coronavirus neurotropism possibly directly related with higher viral loads, which are now detectable in cerebrospinal fluid [ ] . angiotensin-converting enzyme (ace- ) receptors may be responsible for covid- cerebral involvement via entry through the cribriform plate [ ] . reportedly, up to % of icu covid- patients demonstrate neurologic symptoms [ , ] . neuroimaging findings beyond those of acute infarction, hemorrhage, and vessel thrombosis include meningoencephalitis and acute necrotizing encephalopathy (ane). there is mounting evidence of increased leptomeningeal enhancement, fluidattenuated inversion recovery (flair) cortical signal abnormalities, cortical diffusion restriction, and cortical blooming artifact, suggesting either infectious, autoimmune, or critical illness-related encephalitis, hypoxia, hypoglycemia, and seizure [ ] . in a limited series over a -week period in march at a single institution, five patients under the age of years suffered large vessel arterial cerebral infarct (with preferential involvement of the middle cerebral artery), a dramatic increase compared with a pre-covid- average of . strokes per weeks in patients younger than years (fig. ) [ ] . in a study by mao . % had neurologic symptoms, including acute ischemic stroke, intra-cranial hemorrhage ( fig. ), impaired consciousness, and skeletal muscle injury defined as pain with elevated serum creatinine kinase levels [ , ] . from italy, of an estimated covid- patients admitted over month, five developed rapidly progressive guillain-barré syndrome (fig. ) that began with lower extremity paresis that progressed to flaccid tetraparesis and tetraplegia [ ] . mahammedi et al. reported that of ( %) consecutive hospitalized covid- patients had neurologic symptoms requiring neuroimaging in italy, and of those, ( %) had altered mental status, and ( %) had ischemic stroke; % of those patients had acute neuroimaging abnormalities that included acute ischemic stroke, intracranial hemorrhage (possibly due to cerebrovascular endothelial rupture), cerebral venous thrombosis, multiple sclerosis plaque exacerbation, encephalopathy, guillain-barré syndrome, miller-fisher syndrome, and posterior reversible encephalopathy syndrome [ , ] . in an observational study of encephalopathic covid- patients with ards, had upper motor neuron signs, while eight of who underwent mri demonstrated leptomeningeal enhancement (fig. ), two of had focal acute ischemic strokes, and of displayed frontotemporal hypoperfusion abnormalities on profusion studies [ ] . anosmia, possibly related to ace- involvement, has also been reported [ ] . limited reports of covid- isolated musculoskeletal manifestations are currently available. similar low incidence case series of critical illness myopathy or myositis (fig. ) [ ] and critical illness polyneuropathy following middle east respiratory syndrome (mers) and severe acute respiratory syndrome (sars) have also been reported, at times with an association with concurrent myocarditis [ , , ] . in all of these cases, patients typically present with myalgia and muscle weakness, with rhabdomyolysis and elevated creatine kinase (ck) levels representing more severe manifestations [ , , ] . elevated ck levels are associated with increased rates of mortality and interstitial pneumonia in covid- patients [ ] . evidence suggests that some patients with severe covid- might have a cytokine storm syndrome, which can be seen by testing for serum cytokine levels [ ] . recently, ane, a rare complication of viral infections related to intracranial cytokine storms that result in blood-brain barrier breakdown without direct viral invasion or demyelination, has been reported as a result of covid- [ ] . the most common findings of ane include hypoattenuating lesions on ct and t /flair hyperintense lesions on mri, in a bilateral symmetric multifocal distribution predominantly involving the thalami and to a lesser extent the brain stem, cerebral white matter, and cerebellum. in addition, findings of leukoencephalopathy, including ct hypoattenuation of the bilateral cerebral hemispheric white matter and corpus callosum, as well as mri diffuse confluent white matter t / flair hyperintensities, scattered micro-hemorrhage in the corpus callosum, and posterior circulation hyperperfusion without diffusion restriction or abnormal enhancement have been reported [ ] . it is uncertain if covid- -related white matter injury findings are the result of icu anesthesia-related toxicity, covid- -associated cytokine release syndrome, or covid- -related endotheliitis with thrombotic microangiopathy [ ] . beyond neurologic manifestations, cytokine storm also has pulmonary manifestations, namely, pulmonary and interstitial damage caused by nonspecific inflammatory cell infiltration [ ] . for covid- , in addition to the previously described radiographic findings, this syndrome may lead to the development of bilateral pneumonia or ards much faster in thus subgroup of patients, as well increased rates of icu admission, mechanical ventilation, and subsequent mortality [ ] . even without pulmonary or neurologic manifestations, cytokine storm can lead to multi-organ system failure, which explains reports of elevated liver enzymes, creatine, and other important markers in covid- patients who do not present with the above manifestations [ ] . this is due to the systemic exposure to large amounts of pro-inflammatory cytokines that leads to the immune system "attacking" the body, particularly interstitial and parenchymal spaces [ ] . vascular compromise due to extensive endothelial damage is also possible [ ] . though not as severe, gastrointestinal symptoms have been reported in up to % of covid- patients [ ] . this may be due to the increased gastrointestinal wall permeability to viral pathogens, which promote malabsorption by infected enterocytes [ ] . the most common symptoms include diarrhea, abdominal pain, or vomiting, though preliminary data suggests that patients with these symptoms tend to have an improved prognosis independent of patient age or sex [ ] . constipation, melena, and anorexia have also been reported but less commonly [ , ] . more severe manifestations of gastroenteritis can be seen on ct scan and can be the only presenting symptom (fig. ) [ , ] . patients can have pertinent laboratory findings, namely, elevated lipase and/or alkaline phosphatase levels, which are associated with poor prognosis as they reflect a greater systemic inflammatory response [ ] . the most common abdominal imaging findings in covid- icu patients include small and large bowel wall thickening, non-enhancing bowel, pneumatosis, portal venous gas, and bowel perforation, all related to bowel and mesenteric ischemia, infarction, and necrosis ( fig. ) [ ] . portal vein thrombosis and distended gallbladder containing sludge suggestive of cholestasis have also been observed. in addition, evidence of inflammation and infarction in other solid organs, including the pancreas, liver, kidneys, and spleen, have been reported, particularly in icu covid- patients. although the exact pathophysiology is uncertain, these findings are thought to be multifactorial in origin, resulting from a combination of direct sars-cov- infection and indirect systemic derangements associated with critical illness, including small vessel thrombosis related to icu hypercoagulopathy and nonocclusive ischemia related to an icu hyperinflammatory effect [ , ] . though preliminary in nature, current findings may suggest that sars-cov- can be detectable in both hepatic tissue and cholangiocytes due to ace- expression [ ] . elevated liver enzymes have been found in blood samples of covid- patients, but it is important to note that elevated liver enzymes do not necessarily mean liver damage is present [ ] . imaging is currently not indicated for evaluation of hepatic pathology in covid- patients, but hepatic steatosis and mild lobular and portal inflammation may be seen. whether these are indeed due to covid- or the consequence of drug-induced hepatic injury is still unknown [ ] . recent studies suggest that covid- may cause acute renal failure, as both podocytes and proximal convoluted tubular cells express certain genes (ace- and transmembrane serine protease [tmprss ]) that increase the host viability for sars-cov- [ ] . the viral cytopathic effect on these cells has been linked as the cause of acute renal failure, which is secondary to ards as one of the more common fatal presentations in patients with covid- [ ] . separately, a case report found that patients who developed rhabdomyolysis throughout the course of their disease are also at risk for acute renal failure, with manifestations of lower extremity pain and fatigue (separate from generalized myositis) followed by rising plasma creatine level [ ] . renal imaging studies currently have little to no diagnostic role in covid- patients, though one would theoretically expect to note increased parenchymal echogenicity via ultrasound [ ] . in fact, it is more important to keep in mind that while covid- patients primarily present with respiratory findings, acute renal injury should be suspected until proven otherwise, as contrast-induced nephropathy secondary to contrast-enhanced ct or mri imaging studies may exacerbate already present renal damage secondary to covid- [ ] . clinical and basic science research, as well as national public health guidance, regarding covid- is rapidly and continuously evolving. it has been described as a novel, "once-in-a-century" disease. along with our medicine and public health colleagues, orthopedic surgeons and orthopedic care providers should remain up to date on the latest covid- peer-reviewed evidence, not only to better respond to changes in our clinical practice and to accurately counsel surgical patients but also to ultimately practice safe and efficacious surgery for patients in a new and changing clinical environment. in addition to the widely known pulmonary symptoms, covid- may affect the neurologic, gastrointestinal, cardiac, and musculoskeletal systems ( table ) . musculoskeletal issues remain underrecognized at this point, which may be due to the low prevalence of this disease at this time. overall, it is imperative that all healthcare professionals have a broader understanding of all of the possible clinical and imaging manifestations of this global pandemic to improve patient and community outcomes. open access this article is licensed under a creative commons attribution . international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright opening up america again. the white house covid- digestive system involvement and clinical outcomes in a large academic hospital in correlation of chest ct and rt-pcr testing in coronavirus disease (covid- ) in china: a report of cases economic impacts of the covid- crisis: an orthopedic perspective what will be the economic impact of covid- in the us? rough estimates of disease scenarios performance of radiologists in differentiating covid- from viral pneumonia on chest ct evidence of the covid- virus targeting the cns: 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pneumonia in china key: cord- -eju wnb authors: sheervalilou, roghayeh; shirvaliloo, milad; dadashzadeh, nahid; shirvalilou, sakine; shahraki, omolbanin; pilehvar‐soltanahmadi, younes; ghaznavi, habib; khoei, samideh; nazarlou, ziba title: covid‐ under spotlight: a close look at the origin, transmission, diagnosis, and treatment of the ‐ncov disease date: - - journal: j cell physiol doi: . /jcp. sha: doc_id: cord_uid: eju wnb months after the outbreak of a new flu‐like disease in china, the entire world is now in a state of caution. the subsequent less‐anticipated propagation of the novel coronavirus disease, formally known as covid‐ , not only made it to headlines by an overwhelmingly high transmission rate and fatality reports, but also raised an alarm for the medical community all around the globe. since the causative agent, sars‐cov‐ , is a recently discovered species, there is no specific medicine for downright treatment of the infection. this has led to an unprecedented societal fear of the newly born disease, adding a psychological aspect to the physical manifestation of the virus. herein, the covid‐ structure, epidemiology, pathogenesis, etiology, diagnosis, and therapy have been reviewed. in december , a cluster of insidious coronavirus infections was reported in the huanan seafood market, located in wuhan state of hubei province in china. unlike the name, livestock animals were also traded in the market alongside their marine relatives. days later, the cluster turned into a local network and set off the alarm for the chinese government. it was then that a pneumonia epidemic of unknown cause became the focus of global attention (sahin et al., ) . chinese authorities announced on january , that a new type of cov (novel cov, ncov) was isolated (imperial college london, ; world health organization, ). on december , , a pneumonia case of unknown origin was reported in wuhan, china. initial laboratory tests ruled out influenza and infection with recognized covs. following the incident, new cases of pneumonia of viral origin were officially reported on december , . a week later on january , , the chinese authorities announced that a new species of cov was isolated in the country (zumla, hui, azhar, memish, & maeurer, ) . given the whereabouts of the first case ever reported, the infection was speculated to have been contracted from a zoonotic agent. etiologic investigations on patients who had been hospitalized with a similar medical history supported the likelihood of a viral infection transmitted from animals to humans (sahin et al., ; world health organization, ; yin & wunderink, ) . ncov was duly reported to have been originated from wild bats. falling in the category of group β-covs, the novel coronavirus only shares a % similarity in genetic sequence with its predecessor, sars-cov, which also belongs to the exact same family (gralinski & menachery, ) . the tantalizing surge in the number of cases infected with sars-cov- in china, despite the closure of markets and evacuation of the vicinity, fulfilled the burden of proof that the virus can also be transmitted from human to human. soon thereafter, peculiar cases of acute respiratory syndrome started appearing in other asian countries, ultimately spreading to north america and europe. (sahin et al., ; world health organization, ; yin & wunderink, ) . following an emergent briefing on january , , the world health organization (who) declared the outbreak of covid- as a public health emergency of international concern (organization, ) . the epidemic began to emerge with the advent of the chinese new year, a traditionally important festival that is heavily celebrated across the country. the coincidence paved the way for sars-cov- to turn into an unprecedented massive coronavirus outbreak, which required extensive measurements to be contained. with a population of million, wuhan city also served as an important pathway for millions of people traveling in celebration of the spring festival. accordingly, the number of cases to be diagnosed with showed an overwhelming increase between january - , . despite the arbitrary speculations, not only did the recent outbreak of covid- egress the country of origin, it also proceeded to become a global concern in the form of a pandemic . covid- is an acute self-resolving respiratory disease in most of the cases, however, it can also be fatal in some cases. the disease was initially reported to have a mortality rate of %. if severe, covid- might result in death as a result of the preceding extensive alveolar damage, and failure of the lungs . as of february , , a total of , cases had been confirmed, with over , deaths. however, there have no specific reports on pathology, as performing an autopsy or biopsy was not possible in most of the cases (chan et al., ; huang et al., ) . table march , (www.who.int). a total of , sars cases and deaths across countries were reported for an overall case-fatality rate (cfr) of . %. mers is still not contained and is thus far responsible for , confirmed cases and deaths across countries for a cfr of . %. despite the much higher cfr of . % and . % for sars and mers, the novel coronavirus epidemic has led to a larger death toll. the chinese government had reported , confirmed cases, with , deaths, as of february , . these statistics yield a crude cfr of . %. however, one should not haste to generalize this number, as most possibly the total number of patients with covid- is much higher. that is, because the cases are not readily identifiable, as many asymptomatic patients are missed during the process yan et al., ) . despite the higher transmissibility than sars and mers, covid- is still a relatively unknown disease and requires further investigations to be fully understood (yan et al., ) . after making a successful entry, the rna-based genome starts replicating itself, and expressing specific sequences that results in production of useful accessory proteins; facilitating the adaptation of cov to its human host (viralzone., ). alterations in genetic make-up that result from recombination, exchange, insertion, or deletion of genes, are frequently reported among covs; a phenomenon that might have played a part in the past epidemics (sahin et al., ) . therefore, the classification of covs is continuously being changed. based on the most recent classification provided by the international committee on taxonomy of viruses, there are four genera of covs, that comprise a total of unique species (subissi et al., ) . thus, variable mechanisms could be involved in the process of pathogenesis. for instance, sars-cov binds to angiotensin i converting enzyme (ace ). on the other hand, mers-cov is more inclined to attach the cellular receptor of dipeptidyl peptidase (lambeir, durinx, scharpé, & de meester, ) . following a cascade of signals after binding, the viral genome is successfully injected into the target cell. the genomic rna that regulates the expression of structural and nonstructural polyproteins, is polyadenylated and encapsulated. these proteins are then cleaved by certain proteases that exhibit chymotrypsin-like activity (lambeir et al., ; viralzone, ) . through replication and transcription, the resulting protein complex drives the production of negative-sense rna or (−) rna. full-length (−)rnas produced by replication are ultimately used as templates for generation of positive-sense rna or (+) rna (luk, li, fung, lau, & woo, ; viralzone, ) . all of the structural proteins are then translated from a subset of - subgenomic rnas, which are products of discontinuous transcription. the resulting protein complex is the assembled together to envelope the viral genome, making a nucleocapsid in the process, that will bud into the lumen of the endoplasmic reticulum to finally complete the intracellular cycle. newly formed virions are then expelled from the infected cell through exocytosis. the covs released thereafter are now capable to infect a wide spectrum of human cells, including lung, renal, hepatic, intestinal, and lower respiratory tract cells, as well as t lymphocytes (chhikara, rathi, singh, & poonam, ; lambeir et al., ) . . | respiratory system sars-cov- tends to infect the respiratory tract, thus, pneumonia is a primary clinical finding in patients with covid- li, guan, et al., ; zhu et al., ) . however, pneumonia is only a component of the sars that might develop in some cases. the resulting sars may then be aggravated and lead to serious conditions that are extremely difficult to control, for example, septic shock, metabolic acidosis, and coagulation dysfunction (kofi ayittey, dzuvor, kormla ayittey, bennita chiwero, & habib, ) . investigation on the radiological findings of covid- associated pneumonia have yielded little, if any, information that are mostly unspecific. progressive lung lesions are usually detected in patients with covid- , about week after the onset of signs and symptoms (ooi et al., ) . the lesions then become aggravated during the nd week, and lead to formation of irregular reticular opacities mixed with ground glass opacities (ggos), which can be detected by ct at the fourth week. in a recent cohort study, . % ( / ) of subjects with covid- -associated pneumonia showed disease progression, defined by an increased extent of ggo, on early follow-up ct . pulmonary fibrous cords was reported in one particular patient that displayed signs of improvement, as the inflammatory secretions had been absorbed . long-term complications of covid- in patients with severe pneumonia might include an array of fibrotic changes often observed in the late stages of lung injury, for example, reticulation, interlobular septal thickening, and traction bronchiectasis (kim, ) . there have been several reports that indicated meager cytolethal distending toxin-induced lymphocytes, with a density as low as cells/mm in three patients with sars-cov infection zhou et al., ) . as in the case of sars-cov- , it has been suspected that infection with this type of cov might lead to f i g u r e presents a schematic of viral structure and the entry mechanism of sars-cov- sheervalilou et al. | inflammatory cytokine storm zumla et al., ) ; a life-threatening condition characterized by elevated levels of interleukin (il- ) in plasma. a number of investigations recently conducted on covid- have reported that il- levels was actually higher in the patients with severe disease (cai, ; chen, liu, et al., ; xiang et al., ) . this could highlight the importance of il- as a biomarker for evaluation of disease severity . impaired liver function tests have been reported for a number of patients with sars-cov- infection, suggesting hepatic damage as an extrapulmonary complication of covid- in almost one half of the patients (chen, zhou, et al., ; wang, hu, et al., ) . a recent study has concluded that liver function abnormality might stem from infection of bile duct cells with sars-cov- . nonetheless, the alkaline phosphatase value, which is an index of bile duct damage, were not specific in patients with covid- (chen, zhou, et al., ; wang, hu, et al., ) . investigation of liver biopsy specimens was accompanied by new pathological findings. scientists have reported moderate microvascular steatosis, and mild lobular and portal activity in these patients, that suggests liver damage may have arisen from either sars-cov- infection or drug-induced liver . an essential player in maintenance of electrolyte balance and blood pressure, ace is regarded by many as the principal counterregulatory arm in the axis of renin-angiotensin-aldosterone system (raas; santos, ferreira, & simões e silva, ) . upon infection, sars-cov- binds ace . this results in degradation of ace , which subsequently dampens the counter-effect of ace on raas. the final effect of ace in an otherwise healthy adult is to increase reabsorption of sodium and the reciprocal excretion of potassium ions (k + ). the concomitant re-uptake of water with sodium reabsorption prompts an increase in blood pressure (weir & rolfe, ) . potassium is the predominant intracellular ion, that is majorly involved in regulation of cell membrane polarity. too low levels of k+ in blood, known as hypokalemia, can result in cellular hyper-polarity. a hyper-polarized cell membrane tends to be depolarized faster than normal, causing aberrancy in the function of cardiac cells (bielecka-dabrowa et al., ) . in a recent cohort study, patients diagnosed with covid- were categorized into three groups: severe hypokalemia, hypokalemia, and normokalemia. the study reported that % of patients with a severe clinical condition had hypokalemia. scientists did not find a direct link between gastrointestinal symptoms and hypokalemia among patients with both severe or moderate hypokalemia. further investigations established an association between parameters such as body temperature, creatine kinase (ck), creatine kinase myocardial band (ck-mb), lactate dehydrogenase (ldh), and c-reactive protein (crp) with the severity of hypokalemia. reportedly, hypokalemia was most often observed with patients who had elevated levels of serum ck, ck-mb, ldh, and crp. potassium (k + ) loss in the urine was determined to be the primary cause of hypokalemia. hypokalemia requires strenuous efforts to be corrected. this is chiefly due to the incessant loss of k + in the urine, as a result of ace degradation. in the case of covid- -associated hypokalemia, however, the patients seemed to respond well to potassium supplements when the critical phase had passed [ ] . therefore, one should consider the impact of hypokalemia in covid- morbidity, and its effect on the outcomes of treatment. this is a condition that must be carefully addressed for, as patients with covid- are more inclined to develop dysfunctions in heart, lungs, and other vital organs (li, hu, su, & dai, ) . several studies have sought to compare the sex differences in the clinical findings of severe covid- . in one study, scientists investigated patients with covid- , ( . %) of whom were men. procalcitonin (pct) level was reported to be higher in men than in women. the results also showed higher amounts of serum n-terminal-pro brain natriuretic peptide, as increased levels of the molecule were detected in men . % than women . %. furthermore, . % of male patients were reported test-positive for influenza a antibody, whereas no such records were registered for female patients. during a -week stay at the hospital, . % of male, and . % of female patients deteriorated, and hence were reassigned to the critical-type group. there was no mortality reports among women, whereas . % of male patients had deceased due to covid- complications. a total of . % and . % of female and male patients successfully recovered, and were discharged from the hospital. based on the current evidence, men are more likely to develop complications, and experience worse in-hospital outcomes compared with women . a group of researchers led by chen investigated the clinical characteristics of sars-cov- infection in nine pregnant women. their aim was to evaluate the likelihood of intrauterine/vertical transmission of sars-cov- from mother to baby. all of the women who were being investigated had cesarean section in the third trimester of their previous pregnancies. seven patients were febrile, and variably presented other symptoms such as cough, sore throat, myalgia, and malaise. fetal distress was reported in two cases. lymphopenia and increased aminotransferase activity were observed in five and three patients, respectively. there was no mortality cases, as none of the patients in the study developed severe covid- -associated pneumonia. nine livebirths were recorded. the newborns displayed no signs of asphyxia. a -min apgar score of - , and a -min apgar score of - were calculated for all nine newborns. samples collected from six patients, including amniotic fluid, cord blood, neonatal throat swab, and breastmilk proved test-negative for sars-cov- . the clinical features of covid- -associated pneumonia observed in these pregnant women shared a great similarity to characteristics reported for covid- -associated pneumonia in nonpregnant adult patients . in a recent investigation, scientists in china looked into the pattern of blood type distribution in , patients in three hospitals, who had been confirmed to have sars-cov- infection. accordingly, they compared their findings regarding the blood type of patients with that of the healthy population who lived in the same area as the patients in the study. apparently, there was a higher prevalence of blood type a among the patients with covid- than in the normal population. on the contrary, it seemed that individuals with o blood type were spared somehow, as there were fewer patients with this blood type in this study (both p < . ). a series of meta-analyses on the available data indicated a significantly higher risk for covid- in people with blood type a, relative to individuals with non-a blood types. however, an opposite scenario seemed to be true for the blood type o community, since, according to the literature, are less susceptible for contracting infectious diseases such as covid- . according to the literature, the pathogen and area of origin were similar in both sars and covid- outbreaks. however, despite this similarity, the raised public awareness and extensive interventional procedures that might have once proved effective for sars containment, have been rendered ineffective against the novel coronavirus; as the disease is already more widespread than sars (liu, gayle, wilder-smith, & rocklöv, ) . a large family of viruses, covs are common among many different animal species, including cattle, civets, camels, and bats. however, these covs are not solely restricted to animal populations, as they can occasionally infect humans, bringing epidemics such as sars, mers, and in recent memory, covid- (sahin et al., ) . recent investigations conducted on the origins of covs responsible for the past epidemics have reported bats as the primary reservoir for both sars-cov and mers-cov; suggesting that other animal species were involved in the process merely as intermediate hosts. accordingly, the majority of batassociated covs belong to α-cov and β-cov genera, while almost all of the avian covs fall in the other two genera; γ-covs and δ-covs (yin & wunderink, ) . it has been suggested that species responsible for the recent epidemic is reminiscent of the cov isolated in bats. trafficking of wild animals in huanan seafood market, located in wuhan state of hubei province in china, where the first cases were reported, further supports this finding. only days following the first outbreak, secondary cases started emerging. although the new cases had no contact with the marketplace, they did have a history of social contact with the salesmen and people who had previously been there. the growing pile of confirmed cases from healthcare workers in wuhan city is an strong indicator of human-tohuman transmission in the case of sars-cov- (sahin et al., ) . transmission of the virus from human to human occurs mostly with close contact. the short distance between individuals in close social contacts makes it possible for respiratory droplets of the infected person, released by coughing and sneezing, to reach other people in the proximity. this is similar to the transmission of influenza and other respiratory infection. it still remains unclear if the virus can be contracted by touching surfaces, and then touching mouth, nose, or even eyes (who, ). apparently, covid- is considered most contagious when individuals infected with the virus is symptomatic. however, there have been cases who reportedly had contracted the disease from asymptomatic patients in the prodrome period of covid- . transmission of the novel coronavirus has yet to be clarified by more investigations. (rothe et al., ) . investigation on a familial cluster of five patients concluded that sars-cov- might have actually been transmitted by an asymptomatic carrier in the family (bai et al., ) . surprisingly, the first reverse transcription polymerase chain reaction (rt-pcr) test of the asymptomatic family member was reported negative; a noteworthy example of a false-negative result. unwanted false-negative results are inevitably reported due to a number of factors, for example, quality of the test kit, sufficiency of the collected sample, or performance of the test by clinicians. to this date, rt-pcr has widely been used as a reliable diagnostic method (corman et al., ) . thus, her second rt-pcr result, reported positive, was unlikely to have been a false-positive result; hence, it was accepted as the definite evidence that the suspected person had indeed been infected with sars-cov- (bai et al., ) . there was also another study that reported an asymptomatic young boy with covid- infection. however, ct scans obtained from the subject exhibited abnormalities, indicative of an on-going pulmonary pathology (chan et al., ) . if we presume that the findings regarding asymptomatic carrier-based transmission of covid- can be replicated, this would prove covid- an overwhelmingly challenging issue to be controlled (bai et al., ) . the incubation period for the asymptomatic patient in the case of familial cluster was days. despite being a long period, it still perfectly falls in the suggested incubation period of - days (bai et al., ; guan et al., ) . a proper diagnosis of covid- is made based on the following criteria, which have been recently suggested based on the initial investigations: (a) clinical signs and symptoms, (b) history of traveling or close contact with people suspected to be infected, (c) positive test result for the pathogen, and (d) pathologic findings on ct images. the key clinical features of covid- , though nonspecific, include fever, dry cough, dyspnea, and pneumonia (chen, zhou, et al., ; huang et al., ; li, guan, et al., ; wang, hu, et al., ) . rapid screening of patients with acute respiratory symptoms, initiation of an appropriate quarantine program, and development of therapeutic measures have been suggested as a top-priority strategy to control the spread of covid- wang, kang, et al., ) . according to the data gathered by individual-level surveillance, it is strongly recommended that the elderly and male patients should be diagnosed in a timely manner, as progression of the respiratory pathology to pneumonia might result in catastrophic outcomes (jian-ya, ). understanding the otherwise nonspecific clinical signs and symptoms of covid- is a crucial step toward appropriate management of the disease. patients mostly complain of fever, non-productive cough, and body ache or extreme tiredness. in some cases, diarrhea and nausea precede fever by a few days, suggesting that fever might not be the initial manifestation of infection. a small number of patients reportedly had headache, or even developed hemoptysis wang, hu, et al., ) . some patients remained asymptomatic, despite being tested positive for the disease (chan et al., ) . according to several studies, infection with sars-cov- in the elderly, especially the male community, is more likely to result in severe alveolar damage and respiratory failure (chen, zhou, et al., ) . occasionally, the disease may be demonstrated with a fulminant natural history, rapidly progressing to organ dysfunction, and even death in critical cases. organ dysfunction includes conditions such as shock, ards, acute cardiac injury, and acute kidney injury wang, hu, et al., ) . from a laboratory point of view, lymphopenia, thrombocytopenia, impaired prothrombin time (pt), and elevated serum levels of crp stand among the findings that can be reported for patients with covid- (chen, zhou, et al., ; guan et al., ; huang et al., ; wang, hu, et al., ) . overall, any patient with fever and acute respiratory symptoms, who is reported to have lymphopenia or leukopenia on lab examination, should be suspected. a history of travel to wuhan or having close contact with local residents is a strong indicator for careful management of the patient (zu et al., ) . shortly after the onset of the epidemic, the national health commission of china (committee, a; organization, a) initiated the diagnosis and treatment program of covid- -associated pneumonia, following the guidelines provided by who on sars and mers (azhar & ei-kafrawy, ; organization, organization, , b . according to the newly formulated criteria, a "suspected case" is defined as a patient with epidemiological history, that is traveling and contact, and two clinical findings pertinent to the disease. if, however, an epidemiological history is not confirmed, then the patient must present at least three clinical findings to be considered as a edition, the term "clinical diagnosis" was removed and replaced with "etiological diagnosis" (organization, a). according to the recent revision, it is imperative that an etiological diagnosis of covid- is made at first, which can then be complemented by a positive real-time rt-pcr assay for sars-cov- , which is duly performed on the sputum or blood sample of the patient. after the final diagnosis is made, confirmed patients are categorized into mild, moderate, severe, and critical types, based on the severity of disease (zu et al., ). . | covid- detection tests: pathogenic laboratory testing, real-time rt-pcr, and sequencing of nucleic acid table (ai et al., ; bai et al., ; chen, zhao, et al., ; shi et al., ; tian et al., ; wang, kang, et al., ; wu & mcgoogan, ; yan et al., ; yang et al., ) and table represent studies on diagnosis of covid- infected patients and related clinical trials, respectively. despite being the diagnostic gold standard, pathogenic lab testing is a rather time-consuming procedure, with unavoidable false-positive results (wang, kang, et al., ) . it is recommended that lab testing should be performed, as soon as the patient is identified as a "person under investigation" (pui). viral nucleic acid required for an rt-pcr test is usually extracted from secretions of the lower respiratory tract, for example, bronchoalveolar lavage; however, tracheal aspirate or sputum can also be used corman et al., ) . since the onset of the epidemic, several factors have been found to affect the final efficiency of nucleic acid testing, that is, availability, quality, stability, and reproducibility of detection kits. in most of the cases, the tests need to be repeated for several times (wang, kang, et al., ) , as the estimated detection rate of the test falls in an underwhelming range of - % corman et al., ; zhang et al., ) . in spite of being a valuable asset, the undesirable false-negative results of rt-pcr have prompted careful clinical and etiological evaluation of covid- in suspected cases as the first-line diagnostic method (zu et al., ) . ct has proved to be of great value in diagnosis of the covid- associated pneumonia, as it provides major evidence, that cannot readily be obtained with alternative methods. it is true that ct is a reliable imaging modality in subtle detection of viral pneumonia and screening of suspected cases; however, it should be noted that many pulmonary diseases of inflammatory nature share similar radiographic findings (wang, kang, et al., ) . the majority of patients with covid- present with ggo in their chest ct, which later progress into multilobar consolidations. there have been several reports of rounded opacities, which are sometimes peripherally distributed in the lung (chung et al., ; huang et al., ) . in contrast to ct, plain chest radiography (cxr) has not been recommended as a first-line imaging method, because this modality does not provide the clarity viewed on ct scans, especially in the early stages of pulmonary infection (ng et al., ) . nevertheless, cxr is capable of recording pathologic changes in patients with severely progressed covid- , as the bilateral multifocal consolidations present in these patients are too dense to be missed. the notorious "white lung" appearance can be optimally viewed on cxrs of critically ill patients (zu et al., ) . ct resulted in diagnosis of , new cases as of february , (zu et al., ) . therefore, slice chest ct is an adequately sensitive and reliable method in early detection of pneumonia in patients with covid- (chan et al., ; ng et al., ) . depp learning, as a novel ai-based modality might be able to analyze radiographic features of covid- , and help clinicians provide an accurate clinical diagnosis based on a precedented pattern (wang, kang, et al., ) . as part of recent advancements, convolutional neural network (cnn), a class of deep neural networks, has been shown to be capable of medical image analysis. to this date, cnn has been successfully employed in investigations on the nature of pulmonary nodules reported in ct images, diagnosis of pneumonia in children based on cxr, and image recognition in cystoscopy videos (choe et al., ; kermany et al., ; negassi, suarez- the st century has seen many ai-based models to be incorporated in several scientific fields, particularly imaging studies. diagnostic ai-based models might actually be a forward leap in tasks that simply cannot be handled by manpower, especially risk prioritization, that can greatly help improve patient turnaround time. given the shortage of human resources and inadequate number of hospital beds in a country like china, ai-based models for analysis of cxr and ct scans can be useful in ruling out irrelevant cases, and resource-wise admission of patients to the hospitals (kim, ) . . table ( chen, zhao, et al., ; yan et al., ) and table represent studies on prognosis of covid- infected patients and related clinical trials, respectively. scientists have made strenuous efforts to come up with an effective regimen for successful treatment of covid- (gao, tian, & yang, ) . table fan et al., ; han et al., ; lan et al., ; li, zhang, et al., ; li, hu, et al., ; lim et al., ; wu & mcgoogan, ) , tables and combination therapy is a more extensive and rigorous approach mainly aimed at correction of life-threatening events such as shock, hypoxemia, secondary or super infection, and maintenance of homeostasis, that is, electrolyte, acid and base balance. as a palliative practice, antiviral treatment in the early stages of covid- might lessen the severity and prevent further progression of the disease. trials on combination therapy with lopinavir/ritonavir and arbidol (umifenovir) have reported satisfactory results in treatment of covid- . alongside a proper antiviral treatment, patients may also benefit from an artificial liver blood purification system, which is capable of rapidly removing the inflammatory factors from blood, thus, halting the disastrous cytokine release syndrome. this system can also facilitate the sustenance of critically ill patients by preserving the balance of bodily fluid. administration of glucocorticoids in moderate doses is another intervention that has recently been indicated for patients with severe covid- -associated pneumonia. however, secondary fungal infection should be considered. patients with an oxygenation index of less than mmhg might benefit more from oxygen therapy than noninvasive ventilation. a rational prescription of antimicrobial medicines has been cautioned only for patients with remittent fever and elevated antimicrobial prophylaxis a new therapeutic for treating immune-mediated diseases, msc therapy might have the capability to terminate the inappropriate release of cytokines in covid- . through its anti-inflammatory effects, msc therapy has been reported to improve respiratory function in murine models with acute lung injury. evidence suggests that mscs might be doing so by repressing the aberrant release of inflammatory factors (hu & li, ; wang, yao, lv, ling, & li, ; xiang et al., ) . in particular, a study by chinese scientists concluded that transplantation of mscs could be considered as a novel approach in treatment of viral pneumonia, noting promissory implications of this method in management of h n -induced ards. since h n and sars-cov- can result in similar complications, for example, ards and respiratory failure, msc-based therapy might lead to a new path in treatment of covid- -associated pneumonia . it has long been known that the traditional circulation-based delivery of therapeutic agents is not as effect, prompting pharmaceutical industries to develop novel platforms for delivery of molecules to hard-to-reach tissues in human body. conjugation of antiviral agents, particularly nucleoside analogs, with specific nanoparticles has proved to be effectual in treatment of resistant hiv infection (agarwal, chhikara, doncel, & parang, ; agarwal, chhikara, quiterio, doncel, & parang, ) . today, an appreciable number of drug delivery platforms based on nanotechnology are available that can be experimentally used with custom therapeutic formulations for treatment of covid- (chhikara & varma, ) in hopes of shortening the course of the disease (chhikara et al., ) . progression of covid- , similar to any other disease, can result in suffering of the patients, prompting psychological symptoms, which will require special interventions. it has been well-established today that individuals who fall victim to public health emergencies, for example, disease outbreaks, develop variable degrees of stress disorders. the problem persists even after the individual has recovered and discharged from the hospital (cheng, wong, tsang, & wong, ; fan, long, zhou, zheng, & liu, ) . with that in mind, one should consider several factors for classification of patients who will most probably benefit from psychological interventions; that is overall course of the disease, severity, and quality of hospitalization (e.g., home, ordinary wards, icu, etc.) (duan & zhu, ) . in large-scale outbreaks such as covid- epidemic, healthcare workers become the frontline at providing psychological cares for patients who battle against the disease. primary medical and mental care should be provided for those individuals who are recognized as "suspected case" and duly quarantined at home. (duan & zhu, ) . interventions should be discreetly formulated following a thorough evaluation of risk factors involved in emerging of these psychological issues, including a history of impaired mental health, bereavement after a deceased family member, panic, separation from loved ones, and a low income (kun, han, chen, yao, & anxiety, ). the following criteria must be met in order for a patient to be discharged from hospital or released from quarantine: (a) having been afebrile for at least consecutive days, (b) remission of respiratory distress, (c) regression of infiltrations/consolidations on chest ct images, and two consecutive negative reports of rt-pcr test performed at least day apart (d). despite these thoroughly formulated criteria, one study reported positive rt-pcr test results - days after hospital discharge for four patients with covid- , who met all of the criteria above before they were discharged. these findings are important in that they imply the slight possibility that even a fully recovered patient might still be a silent carrier of the virus. in this scenario, however, no family members were reported to be infected, since all of the four patients with bizarrely late positive tests were medical professional, and followed all of the guidelines while they were at home quarantine. with due attention to this incident, the current criteria for hospital discharge may need to be reconsidered (lan et al., ) . deemed a global health emergency, covid- outbreak has continued to be the headline of the news. the number of confirmed cases is on the rise, and the seamless spread of the virus has become a plight for general population, and the entire medical community. in spite of the extreme preventive measures while near a patient, clinicians are still at great risk for contracting the disease from the visitors. else, it is vividly known that quarantine alone is not the optimal choice for containing of the virus. on the other hand, the devastating potential impact of the outbreak is a much feared topic around the world. science has always been the ultimate arsenal of weaponry when it comes to battling obstinate pathogens; however, time is needed for conduction of proper investigations on human-to-human and animal-to-human transmission of sars-cov- . with no access to requisite information on the structure and life cycle of the novel coronavirus, research and development programs on therapeutic agents become a far-fetched milestone, rendering the tried-and-true primary prevention measures the only proper means to confront sars-cov- . as of today, few existing drugs have been considered for treatment of covid- , with scant reports on benevolence of the results. as our meager knowledge of sars-cov- is advancing, one may speculate the advent of an effectual vaccine, alongside treatment options that might include antiviral agents, and even monoclonal antibodies. at the time of writing this manuscript, no definitive treatment option has been 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uddin, md. sahab; hossain, md. farhad; abdulhakim, jawaher a.; alam, md. asraful; ashraf, ghulam md; bungau, simona g.; bin-jumah, may n.; abdel-daim, mohamed m.; aleya, lotfi title: ncovid- pandemic: from molecular pathogenesis to potential investigational therapeutics date: - - journal: front cell dev biol doi: . /fcell. . sha: doc_id: cord_uid: akr f p in december , a severe acute respiratory syndrome coronavirus (sars-cov- )-related epidemic was first observed in wuhan, china. in , owing to the highly infectious and deadly nature of the virus, this widespread novel coronavirus disease (ncovid- ) became a worldwide pandemic. studies have revealed that various environmental factors including temperature, humidity, and air pollution may also affect the transmission pattern of covid- . unfortunately, still, there is no specific drug that has been validated in large-scale studies to treat patients with confirmed ncovid- . however, remdesivir, an inhibitor of rna-dependent rna polymerase (rdrp), has appeared as an auspicious antiviral drug. currently, a large-scale study on remdesivir (i.e., mg on first day, then mg once/day) is ongoing to evaluate its clinical efficacy to treat ncovid- . good antiviral activity against sars-cov- was not observed with the use of lopinavir/ritonavir (lpv/r). nonetheless, the combination of umifenovir and lpv/r was found to have better antiviral activity. furthermore, a combination of hydroxychloroquine (i.e., mg times/day) and azithromycin (i.e., mg on first day, then mg/day from day – ) also exhibited good activity. currently, there are also ongoing studies to evaluate the efficacy of teicoplanin and monoclonal and polyclonal antibodies against sars-cov- . thus, in this article, we have analyzed the genetic diversity and molecular pathogenesis of ncovid- . we also present possible therapeutic options for ncovid- patients. coronaviruses (covs) belong to the large family of positivesense, enveloped, highly diverse, and single-stranded rna viruses (fehr and perlman, ) . indeed, covs have been found to infect both humans and animals, therefore causing various respiratory, gastrointestinal, neuronal, and hepatic diseases (weiss and leibowitz, ; chan et al., ; zumla et al., ) . former epidemics of covs include severe acute respiratory syndrome (sars)-cov and middle east respiratory syndrome (mers)-cov, these outbreaks caused severe health problems in humans . a group of individuals was admitted to hospitals in late december of with a primary diagnosis of pneumonia due to an unknown cause (bogoch et al., ; lu et al., ) . it was assumed by the earlier reports that the onset of a potential cov epidemic provided the estimation of a reproduction number for the novel coronavirus (ncovid- , named by world health organization (who) on feb , ) which was thought to be considerably > (ranges from . - . ) . this severe acute respiratory syndrome coronavirus (sars-cov- ) can be transmitted largely via droplets and due to the close contact. it has been found that elderly people and individuals with chronic diseases or comorbidities are particularly high-risk populations (li et al., a) . there are various symptoms of ncovid- including cough ( %), fever ( %), diarrhea ( . %), and vomiting ( %) (mungroo et al., ) . the mode of transmission of sarscov- is supposed to take place from human to human through respiratory secretions released by the infected people when sneezing and coughing (mungroo et al., ) . ncovid- patients can be asymptomatic, which is making the control of the transmission more difficult (gao et al., ; li et al., a) . since february of , strict infection control approaches were executed by the centers for disease control (cdc) in order to limit the spread of sars-cov- . in a recent study, mentioned that ncovid- patients had the highest viral load (measured in saliva samples) near presentation. they also summarized that as viral load is quite high during the time of hospital admissions, use of potent antiviral agents at an early stage might prove abbreviations: ace , angiotensin converting enzyme ; ap, antigen presentation; apcs, antigen presentation cells; apn, aminopeptidase n, arbs, angiotensin ii receptor blockers; ards, acute respiratory distress syndrome; cdc, centers for disease control; ncovid- , novel coronavirus disease ; covs, coronaviruses; dpp , dipeptidyl peptidase ; dsrna, double-strand rna; ec , half maximal effective concentration; ed, emergency department; elisa, enzymelinked immunosorbent assay; eua, emergency use authorization; fda, food and drug administration; ggo, ground-glass opacity; hcv, hepatitis c virus; hiv, human immunodeficiency virus;, mhc, major histocompatibility complex; or hla, human leukocyte antigen; icu, intensive care unit; il- , interleukin ; lpv/r, lopinavir/ritonavir; mabs, monoclonal antibodies; mers, middle east respiratory syndrome; n -mtase, n -methyltransferase; nsaids, nonsteroidal anti-inflammatory drugs; prrs, pattern recognition receptors; pui, patient under investigation; rdrp, rna-dependent rna polymerase; rsv, respiratory syncytial virus; s protein, spike protein; sam, s-adenosyl-methionine; sars, severe acute respiratory syndrome; sars-cov- , severe acute respiratory syndrome coronavirus ; tmprss , transmembrane serine protease ; who, world health organization. beneficial in managing the severity of ncovid- infection . previously, sars was found to be partially linked with environmental factors (lin et al., ) . in a study, it was revealed that air pollution was linked with mortality in sars patients in china (cui et al., ) . in this regard, it was mentioned that lung functions can be compromised owing to long-or shortterm exposure to certain environmental pollutants (cui et al., ) . air temperature is another factor that is also needed to be considered. it has been revealed by lin et al. ( ) that the occurrence of sars was much higher ( times) at lower air temperatures as compared to higher temperatures. researchers also showed that respiratory disorders are more likely to take place in colder environments since virulence of agents are likely to deteriorate at higher air temperatures because they might not endure the alterations in the environment (d'amato et al., ) . in addition to this, they also summarized that sars-cov's transmissibility is comparable with the transmissibility of influenza virus. moreover, the occurrence of influenza markedly elevates with high relative humidity and low temperatures (park et al., ) , which is further suggesting that viral transmission can be significantly affected by environmental factors. there are no therapeutic agents that have been approved to treat ncovid- . various medicines including immunomodulatory or antiviral drugs such as remdesivir, favipiravir, ribavirin, chloroquine, hydroxychloroquine, azithromycin, nitazoxanide, teicoplanin etc. have been advised as potential investigational drugs, many of which are now being studied in animals and humans who, c) . on march , , the food and drug administration (fda) gave an emergency use authorization (eua) for emergency use of oral administrations of chloroquine phosphate and hydroxychloroquine sulfate to treat sars-cov- infection (fda, ) . along with oxygen and mechanical ventilation, a guideline has also been published by belgium which involved recommendations from four other european countries, including switzerland, netherlands, france, and italy that recommended the use of remdesivir, lopinavir/ritonavir, tocilizumab, and chloroquine or hydroxychloroquine (sciensano, ) . in addition, japan and china approved the use of favipiravir (an antiviral agent) to treat influenza, which is now under investigation to treat ncovid- (fujifilm, ) . in this article, we have critically appraised the genetic diversity, molecular pathogenesis, symptoms, diagnosis, and prevention of ncovid- . furthermore, we also specially reviewed the mechanisms, efficacy, and use of various drugs that might be beneficial in combating ncovid- infection. in nature, nucleotide substitution is considered as a vital step for viral evolution (lauring and andino, ) . the rapid spreading of sars-cov- raised a suspicion that mutations are driving its evolution. in a recent study, from gisaid, phan ( a) collected complete or near-complete sars-cov- genomes to estimate its genetic variation. in addition to this, these strains of sars-cov- were identified in patients with confirmed ncovid- from usa ( ), china ( ), japan ( ), australia ( ), england ( ), singapore ( ), france ( ), germany ( ), belgium ( ), south korea ( ), vietnam ( ), and taiwan ( ). clustalx was used to align the pair-wise nucleotide sequence (saitou and nei, ) . as a reference genome, the sequence of the strain "china/whu / /epi_isl_ " was used. interestingly, similar to other beta coronaviruses, the genome of sars-cov- contains a long orf ab polyprotein at the ′ end, followed by main structural proteins, such as nucleocapsid protein, matrix protein, small envelope protein, and spike surface glycoprotein (phan, b) . in addition to this, it was also observed that there were deletions in the genomes of sars-cov- from australia (victoria), usa (wisconsin), and japan (aichi). in contrast, deletion ( nucleotides) was found in the ′ end of the genome, while deletions ( nucleotides and nucleotides) were found in the orf ab polyprotein. furthermore, it was also observed from the nucleotide sequence alignment that there were missense mutations in the entire genomes of novel coronavirus (table ) . except for the envelope protein, mutations were detected in all of the main structural and non-structural proteins. whereas, missense mutations were observed in the nucleocapsid protein, in the matrix protein, in the orf ab polyprotein, and in the spike surface glycoprotein. interestingly mutations (i.e., phe , tyr , and asp ) were found in the spike surface glycoprotein receptor-binding domain. indeed, spike surface glycoprotein contributes significantly in binding to receptors on the host cell and eventually regulates host tropism (fung and liu, ) . furthermore, this spike glycoprotein is the main target of neutralizing antibodies . conformational changes of spike glycoprotein can be induced by the mutations, which can lead to altered antigenicity. up until now, no study has identified the amino acids that are involved in conformational alterations of spike glycoprotein. therefore, further studies are required to identify these important amino acids. various wild and domestic animals such as bats, cats, cattle, and camels might play a role as hosts for coronaviruses (adhikari et al., ) . in general, animal coronaviruses do not spread among human beings (cdc, a) . nevertheless, exceptions have been noticed in case of mers and sars, where these diseases were found to be transmitted owing to the contact with respiratory droplets from sneezing or coughing of ncovid- patients. initial ncovid- patients were detected in china, where there was an association with the seafood market of wuhan, which is indicating that these initial infections took place because of the animal-to-person transmission. later on, ncovid- was also detected in healthcare professionals and also in other individuals where there was no history of contact with that affected area of wuhan, which is further suggesting the human-to-human transmission (gralinski and menachery, ; huang et al., ; li et al., b; liu et al., ; who, d) . as per the recent guidelines from health authorities of china (adhikari et al., ; who, e) , there are major routes of ncovid- transmission including droplets transmission, aerosol transmission, and contact transmission. transmissions via droplets were found to take place when respiratory droplets of infected individuals are inhaled or ingested by people who are in close contact. whereas, contact transmission might take place when a person touches a virus-contaminated-object or surface and then that person touches his/her nose, mouth, or eyes. on the other hand, aerosol transmission might take place when respiratory droplets mix into the air, thus forms aerosols and might result in infection when a high dose of aerosols are inhaled into the lungs in a comparatively closed environment (adhikari et al., ; who, e) . in a study, it was revealed that the digestive system is also a possible route for sars-cov- transmission. symptoms like diarrhea and abdominal discomfort have been observed in individuals with confirmed ncovid- , this observation led to studies which revealed that ace (to which sars-cov- binds) is highly expressed in enterocytes of colon and ileum . the effect of temperature on the health of humans can be varied depending on the countries or even areas (hajat and kosatky, ) . in line with this aforesaid finding, it was also reported that temperature can affect the transmission of respiratory syndromes-causing viruses including sars-cov- (ma et al., ) and influenza virus (park et al., ) . studies have also revealed that novel coronavirus and influenza virus can survive only in some specific environmental conditions and their transmissions also depend on temperatures (chan et al., ; jaakkola et al., ) , which is also applicable for sars-cov- transmission (wang et al., c) . it was observed in case of influenza virus that it can transmit more readily at lower temperatures (lowen and steel, ) , since host immunity is likely to remain weakened in cold weather, this can further increase the vulnerability toward infection (kudo et al., ) . as the transmission process of coronaviruses is comparable with the influenza virus transmission (lin et al., ) , thus it can be expected that these processes are also applicable for the sars-cov- transmission (wang et al., c) . several other environmental factors can affect the link between mortality and temperature including air pollution (cai et al., ) , humidity (jaakkola et al., ; kudo et al., ) , latitude (bao et al., ) . in this regard, socio-demographic factors including income, age, and gender (bao et al., ) have also been reported to play roles. in a study, chan et al. ( ) revealed that individuals who live at lower latitudes showed a strong adaptive capacity toward heat, and a relatively weak adaptive capacity was observed toward cold. these researchers also observed that the viability of sars-cov was much lower at higher relative humidity and higher temperatures (for example, relative humidity: over %, and temperature: • c). in a different study, it was revealed that humidity and temperature are linked with an increased risk of ncovid- (wang et al., c) . interestingly, coronaviruses can persist on inanimate surfaces including plastic, glass, or metal for up to days (kampf et al., ) . ncovid- patients exhibit various clinical symptoms including cough, fever, fatigue, radiographic evidence of pneumonia, dyspnea, decreased or normal leukocyte counts, and myalgia . these aforesaid symptoms are also similar to mers-cov and sars-cov infections (peiris et al., ) . even though ncovid- pathogenesis is not well-understood, however the similar mechanisms used previously by mers-cov and sars-cov can provide a lot of information regarding sars-cov- pathogenesis (figure ). spike protein (s protein) of coronavirus determines the viral entry into the host cells (de wit et al., ) . interestingly, the envelope spike glycoprotein binds to its cellular receptor, angiotensin converting enzyme (ace ) for sars-cov (li et al., b) and sars-cov- (figure ) , dipeptidyl peptidase for mers-cov (raj et al., ) , and cd l for sars-cov [ ] . although it was initially identified that sars-cov enters into cells by direct fusion of plasma membrane and virus (simmons et al., ) . however, belouzard et al. ( ) revealed that a vital proteolytic cleavage process takes place at sars-cov s protein at position (s ′ ) that facilitated the membrane fusion and infectivity of the virus. for membrane fusion, mers-cov also has evolved an aberrant steps furin activation (mille and whittaker, ) . other than membrane fusion, entry of sars-cov was also found to be mediated by the clathrin-independent and -dependent endocytosis (wang et al., ; kuba et al., ) . following the entry of virus into the cells, rna genome of sars-cov is released into the cytoplasm and is translated into polyproteins and structural proteins, subsequently the viral genome starts to replicate (perlman and netland, ). the newly generated envelope glycoproteins are then inserted into the membrane of the endoplasmic reticulum or golgi apparatus, and the it has been found that s protein is cleaved into s and s by a cell-derived protease, where s binds with ace receptor, and s is activated by the host serine protease tmprss and results in a fusion with the cell membrane. following the entry into the host cell, sars-cov- takeovers the host cell machinery to transcribe, replicate, and translate its rna genome and structural proteins before being reassembled, encapsulated, and exocytosed from the host cell. following exocytosis, sars-cov- is presented to host antigen presenting cells (apcs), which eventually leads to the generation of various cytokines including, tnf-α, cxcl- , il- , and il- (invivogen, when the sars-cov- enters into the cells, its antigen will be presented to the antigen presentation cells (apcs) (figure ) , this process is crucial for the anti-viral immunity of the human body (kumar et al., ) . peptides of antigens are presented via major histocompatibility complex (mhc; or human leukocyte antigen (hla) in humans) and then identified by virusspecific cytotoxic t lymphocytes. therefore, the understanding of antigen presentation (ap) of the virus will provide a better understanding of the pathogenesis of ncovid- . however, not much information is available regarding this, thus we can obtain information from previous studies on mers-cov and sars-cov. ap of sars-cov- mostly relies on mhc i molecules (liu et al., ) , nonetheless mhc ii also plays roles in its presentation. former studies revealed that many hla polymorphisms associate with the susceptibility of sars-cov, for instance hla-cw * (chen et al., b) , hla-b * , hla-dr b * , and hla-b * (keicho et al., ) , while hla-a * , hla-dr , and hla-cw alleles are associated with the protection from sars infection (wang et al., ) . in case of mers-cov, it was observed that mhc ii molecules (for example hla-dqb * : and hla-drb * : ) were linked with the susceptibility to mers-cov infection (hajeer et al., ) . other than mannose-binding lectin gene polymorphisms linked with ap are associated with the risk of sars-cov infection (tu et al., ) . indeed, the aforementioned findings will give us an important idea regarding the mechanism, prevention, and treatment of ncovid- . ap subsequently induces the human body's humoral and cellular immune responses, which are then facilitated via virus-specific b and t cells. like other common acute viral infections, antibodies including igg and igm are produced against sars-cov virus. it is estimated that at the end of week , sars-specific igm antibodies disappear. whereas, sars-specific igg antibody can stay for a longer period, which is suggesting that igg mainly has a protective function (li et al., a) . furthermore, it was also found that sars-specific igg antibodies mainly are nspecific and s-specific antibodies (de wit et al., ) . most of the studies have focused on cellular immune responses, as compared to the humoral immune responses in case of coronavirus. recent findings have revealed that the levels of cd + and cd + t cells in the peripheral blood of ncovid- individuals were significantly decreased, as confirmed by increased percentages of cd (cd . %) and hla-dr (cd . %) double-positive fractions . likewise, acute phase response in individuals with ncovid- is linked with a marked decrease of cd + t and cd + t cells. interestingly, it was found that although there is no presence of antigen, cd + , and cd + memory t cells can last for years in individuals who have recovered from sars-cov and can perform ifnγ generation, delayed-type hypersensitivity response and t cell proliferation (fan et al., ) . after years of infection with sars-cov, specific t-cell memory responses to the sars-cov s peptide library can still be identified in of recovered sars individuals (tang et al., ) . in mouse models, specific cd + t cells also exhibited similar activity in the clearance of mers-cov (zhao et al., ) . indeed, these results might be useful in the rational designing of an effective vaccine against sars-cov- . acute respiratory distress syndrome (ards) is considered as the major cause of ncovid- -related death. in the early stages of the epidemic, out of the admitted patients with confirmed ncovid- died owing to ards . this ards is found to be the main immunopathological characteristic of sars-cov, mers-cov, and sars-cov- infections . cytokine storm is the major characteristic of ards. this storm is a fatal uncontrolled systemic inflammatory response that takes place because of the high secretions of chemokines (i.e., c-x-c motif chemokine like sars-cov, mers patients showed increased levels of cxcl- , cxcl , ccl , ifn-α, and interleukin (il- ) in serum as compared to individuals with the mild to moderate disease (min et al., ) . in the human body, a powerful cytokine storm will induce an aggressive attack by the immune system, which will lead to multiple organ failure and ards, and will ultimately result in death in severe novel coronavirus infection, as like mers-cov and sars-cov infection . various strategies are used by viruses including sars-cov and mers-cov to evade immune responses for their better survival in host cells. the pattern recognition receptors (prrs) can identify the evolutionarily conserved microbial structures called pathogen-associated molecular patterns. nonetheless, mers-cov and sars-cov can stimulate the generation of doublemembrane vesicles lacking prrs and subsequently can replicate in these vesicles, thus evading the host detection of their doublestrand rna (dsrna) (snijder et al., ) . ifn-i (ifn-β and ifn-α) plays a protective function on mers-cov and sars-cov infection, however the ifn-i mechanism is suppressed in infected mouse models (channappanavar et al., (channappanavar et al., , . interestingly, by directly interacting with the dsrna, mers-cov's accessory protein a might block the stimulation of ifn at the level of melanoma differentiation-associated protein activation (niemeyer et al., ) . ifn β promoter activation and transportation of ifn regulatory factor to the nucleus can be inhibited by the orf , orf b, orf a, and membrane proteins of mers-cov (yang et al., ) . sars-cov- can also affect the ap. in this regard, for instance, gene expression associated with ap is downregulated following mers-cov infection . therefore, it is vital to terminate the immune evasion of coronavirus to develop specific and effective therapies. following an incubation period of around . days, the symptoms of sars-cov- infection appear . it takes around to days from the first appearance of the symptoms to death, along with a median of days (wang et al., d) . however, the aforesaid durations depend on various factors including the patient's age and status of the immune system. this duration was found to be shorter for individuals older than -years old as compared to the individuals who are under the age of (wang et al., d) . at the onset of the disease, the most commonly observed symptoms are cough, fatigue, and fever (figure ). in addition to this, various other symptoms including headache, lymphopenia, dyspnea, sputum production, diarrhea, and hemoptysis (graham carlos et al., ; huang et al., ; ren et al., ; wang et al., d) . pneumonia has also been identified by computed tomography scan in ncovid- patients, unfortunately, various aberrant clinical features including ground-glass opacity (ggo), acute cardiac injury, and ards led to death . occasionally, in subpleural areas of both lungs, the multiple peripheral ggos were detected (lei et al., ) and these triggered both localized and systemic immune responses, which collectively raised the level of inflammation. unfortunately, treatment with interferon inhalation did not result in any clinical benefit, rather it aggravated the condition via facilitating pulmonary opacities (lei et al., ) . indeed, some of the symptoms of ncovid- are similar to the earlier betacoronavirus including dyspnea, dry cough, fever, and bilateral ggos . nonetheless, there are some unique clinical manifestations of ncovid- such as sore throat, sneezing, rhinorrhea (lee et al., ; assiri et al., ) . as revealed by chest radiographs following admission, in some cases it was observed that an infiltrate in lung's upper lobe is linked with growing dyspnea with hypoxemia (phan et al., ) . although ncovid- exhibited digestive disorders like diarrhea, only a small proportion of sars-cov or mers-cov showed similar gastrointestinal symptoms. thus, testing urine and fecal samples are important to eliminate a possible alternative mode of transmission (lee et al., ; assiri et al., ) . henceforth, developing methods to detect different routes of transmission for example urine and fecal samples are immediately required to develop ways to suppress and/or minimize the transmission and also to discover therapies to treat ncovid- . recently, it has been observed that ncovid- might predispose to both arterial and venous thromboembolic disease because of immobilization, hypoxia, inflammation, and diffuse intravascular coagulation guan et al., ; klok et al., ; wang et al., a; zhou et al., ) . furthermore, it was also revealed that respiratory failure in the disease is not only driven by the ards, rather microvascular thrombotic activities might also contribute in this regard (grillet et al., ) . therefore, klok et al. ( ) have strongly suggested to administer pharmacological agents in a prophylactic manner to all the intensive care unit (icu) ncovid- patients. for any given emergency department (ed) visiting patients with the symptoms of fever and respiratory diseases, healthcare workers must need to get a travel history in detail from that patient. if a patient shows flu-like symptoms and has a travel history to a country or area with confirmed ncovid- cases or if the patient came into close contact with a confirmed ncovid- patient in the last days then the patient ought to be considered as a patient under investigation (pui) (npr, ) . it needs to be noted that here close contact means any individual who was within six feet of an individual with confirmed ncovid- for an extended period. furthermore, any individual who came into direct contact with the secretions of any ncovid- patient will also be considered as a close contact. individuals who have traveled from high-risk countries or areas with confirmed ncovid- cases and members of a family who are suffering from ncovid- and not staying at home care or not maintaining isolation precautions are regarded as highrisk exposures. while medium risk exposures involve individuals who have traveled from low-risk countries or areas and family members are stringently maintaining appropriate home care and adhering with proper isolation precautions (who, e). in contrast, low-risk exposures involve those individuals who were in the same indoor environment (for example in a waiting hall) for a longer period with ncovid- patients but did not come into close contact. molecular assays of respiratory specimens are performed for diagnosis purposes usually at the regional referral laboratories designated by who (kaiser health news, ). for regional testing, the cdc started distributing ncovid- test kits on february (who, a). ncovid- test is getting more widely available day by day. for hospitals or institutions where ncovid- test is not available, the only option is the testing by cdc. ncovid- should be tested on an urgent basis for the pui cases. an individual should be removed from pui status only if that individual is fully evaluated clinically and has consulted with proper healthcare professionals. the mode of sars-cov- transmission is still complex. guidelines for ncovid- prevention is mainly based on the previously developed guidelines for sars and mers and also on the intervening guidelines provided by cdc and who (cdc, a,b; who, a) . before or upon arrival in ed, a pui ought to be identified by the hospitals to protect the healthcare professionals and other patients. prevention measures should involve maintaining hand and respiratory hygiene and also screening questions including travel history. following a pui identification, both local health department and hospital infection control ought to be immediately notified to avert further spread among healthcare professionals and other patients. a surgical mask must need to be given to any pui and need to be isolated in a private room or if possible in a negative pressure room (who, a). as like sars and mers, ncovid- is also found to spread through the airborne route. therefore, surgical face masks might be beneficial to prevent sneeze and cough-related larger fluid droplets, however they are less likely to prevent small airborne contaminants (yee et al., ) . in this regard, respirators containing air filters and adequate seal should be more beneficial (tran et al., ; smith et al., ) . in healthcare settings, right use of respirators and personal protective equipment and proper hand hygiene are likely to prevent transmission (cowling et al., ; radonovich et al., ; yee et al., ) . if a patient requires hospital admission and there is no private or separate room for that patient, then that patient needs to be taken to an adequate facility containing institution. isolated rooms and care provide would need to be customized in a way that reduces the exposure of healthcare providers to the patient. indeed, along with an eye shield, all the healthcare providers must take measures to prevent contact with droplets and to maintain airborne precautions. since the risk of transmission is much higher during the aerosol-generating procedures (such as intubation), in these cases the importance of ppe is enormous (raboud et al., ; cdc, a) . still, it remains not known, regarding how long ncovid- can stay airborne following a patient leaves the room. respiratory protection is essential to enter into the vacated room. since still there is no specific drug to treat ncovid- , therefore the best approach will be taking preventative measures at a personal level including avoiding public transport, unnecessary travel, contact with ncovid- suspected individuals, and so on. indeed, the significance of maintaining frequent and proper hand hygiene is paramount. like other coronaviruses, sars-cov- has a lipid envelope, thus proper hand-washing with soap can break apart that lipid envelope and therefore can make it difficult or even impossible for the virus to infect humans. so far, this proper hand-washing is considered as the most effective preventative measure. in addition, duration of hand-washing with soap is also equally important. cdc has recommended that effective hand-washing should last at least for s. in a study, borchgrevink et al. ( ) showed that out of , individuals in a college town environment, only % of those individuals properly followed the hand-washing rules (i.e., washing, rubbing, and rinsing). this finding indicates that there is a poor understanding of the significance of proper handwashing among the general people. therefore, awareness among people should be increased about the importance of frequent and proper hand-washing. in order to form a physical barrier, the who has recommended the use of a face mask by those individuals who are showing respiratory symptoms (who, b). however, healthy people are not required to use face masks. a typical surgical mask only provides one-way protection and can avert the spreading of droplets during coughing and sneezing to the surrounding areas. healthcare professionals who are treating or in contact with a suspected or confirmed ncovid- patient must need to wear a specialized respirator (for example n or its equivalent) to effectively prevent the droplets entry and thus can reduce the chance of acquiring the infection (bae et al., ; who, b) . strict precautionary measures must need to be taken by the individuals during handling affected individual's body secretions including sputum, urine, or stools (yeo et al., ) . remdesivir out of all the investigational drugs, remdesivir (figure ) has appeared as the most effective and promising antiviral drug (li and de clercq, ) . this antiviral drug targets rnadependent rna polymerase (rdrp) of the virus while escaping proofreading via viral exoribonuclease, (agostini et al., ) which can ultimately lead to early termination of viral rna transcription as given in figure . interestingly, remdesivir is a phosphoramidate prodrug and has a wide range of activities against numerous virus families, such as pneumoviridae, paramyxoviridae, filoviridae, and orthocoronavirinae (for example pathogenic mers-cov and sars-cov) (sheahan et al., ; martinez, ) . in a covid- mouse model, when remdesivir was administered prophylactically and as early therapeutic intervention, it significantly decreased the pulmonary viral load, which ultimately reduced the progression of the disease and significantly improved respiration (sheahan et al., ) . in tissue culture models, brown et al. revealed that remdesivir showed half-maximal effective concentration (ec ) of . mm and . mm for mers-cov and sars-cov, successively . furthermore, remdesivir (within the submicromolar ec s) also effectively inhibited zoonotic cov and human covs (hcov- e and hcov-oc ) ko et al., ) . similar results were also observed when remdesivir was administered therapeutically ( h post-inoculation) and prophylactically ( h before prior inoculation) in mers animal (rhesus macaque) model (de wit et al., ) . even amino acid substitutions (v l and f l) in the non-structural protein polymerase were found to show lower-level of resistance toward remdesivir (agostini et al., ) . in humans, pharmacokinetic data of remdesivir is not available. however, it has been revealed in rhesus monkeys that intravenous remdesivir administration at the dose of mg/kg increased the intracellular concentration (over mm) of active triphosphate form in peripheral blood mononuclear cells for a minimum of h, which is indicating its clinical significance in ncovid- treatment. furthermore, human safety data of remdesivir are available online (mulangu et al., ) . in usa, the first patient with confirmed ncovid- was effectively treated with remdesivir for the advancement of pneumonia on th day of hospital admission in january, (holshue et al., ) . moreover, to assess its efficacy and safety to treat individuals with confirmed ncovid- , phase iii clinical trials (clinicaltrials.gov, e) have been started in march . in that study, individuals received mg of remdesivir on first day, subsequently received mg/day. although remdesivir showed promising in vitro and clinical activity against coronavirus (sheahan et al., ; holshue et al., ) , recently it has been reported that there are some uncertainties because of its multiple adverse effects including hepatotoxicity, rectal hemorrhage (jean et al., b) . in japan, favipiravir (figure ) was primarily developed and approved as an anti-influenza drug (shiraki and daikoku, ; wang et al., b) . this antiviral drug has a wide range of activities against various rna viruses including rhinovirus, respiratory syncytial virus (rsv), and influenza. former studies revealed that favipiravir was successfully used to treat infections associated with rabies, lassa virus, and ebola virus (shiraki and daikoku, ) . furthermore, favipiravir was also found to be effective to treat severe fever with thrombocytopenia syndrome (shiraki and daikoku, ) . nevertheless, favipiravir was found to be ineffective against dna viruses. favipiravir is a potent antiviral drug that selectively suppresses the rdrp of rna viruses (figure ) favipiravir is likely to produce resistant viruses, as compared to oseltamivir (shiraki and daikoku, ) . indeed, this feature of favipiravir can be beneficial in the treatment of ncovid- . to treat influenza, favipiravir's recommended oral dose is , mg two times on first day, subsequently mg twice/day from day to , and mg once/day on the sixth day. in recent times, initial findings of clinical trials have revealed that favipiravir exhibited significant activity in treating chinese ncovid- patients ( table ) (xinhua news agency). in china, favipiravir has been approved to treat ncovid- in march . furthermore, in china, randomized controlled trials involving ncovid- patients are also assessing the efficacy of favipiravir plus baloxavir marboxil (an antiviral drug) and favipiravir plus ifn-α (arab-zozani et al., ). ribavirin (figure ) is a rdrp inhibitor (figure ) used to treat various viral infections, for example, infections caused by rsv and hepatitis c virus (hcv) (ogawa and morisada, ) . it was revealed by in vitro studies that when ribavirin was administered at a concentration of mg/ml, it showed effective antiviral activity against sars-cov (chan et al., ) . unfortunately, this antiviral drug was found to decrease the level of hemoglobin, therefore it can be detrimental for individuals with respiratory distress (martinez, ) . umifenovir umifenovir (figure ) is a potent antiviral agent that has a wide-range of activities against various viruses including hcv, influenza a and b viruses (boriskin et al., ) . umifenovir's mechanism slightly varies with different viruses. it has been revealed that umifenovir suppresses the fusion of the virus with the host cell membrane (figure ) , thus the subsequent viral entry into the host cell is inhibited (boriskin et al., ) . in a clinical trial, it has recently been observed that lopinavir/ritonavir (lpv/r, figure ) protease inhibitors that are mainly used in human immunodeficiency virus (hiv) treatment did not significantly improve the ncovid- symptoms . furthermore, in a different study, effect of umifenovir plus lpv/r was compared with the sole treatment with lpv/r to treat ncovid- (deng et al., ) . the findings of that study revealed that better effects were observed with the treatment of umifenovir plus lpv/r in comparison with the sole lpv/r treatment (deng et al., ) . however, more studies are required to evaluate the incidence of resistance and efficacy. as coronavirus becomes activated on the membrane of the host cell, thus combination of lpv/r and umifenovir are likely to inhibit/prevent the viral entry into the host cell (figure ) . besides, there is also a need regarding a better chloroquine chloroquine (figure ) is mainly used as an antimalarial drug. furthermore, chloroquine is also used to treat various autoimmune disorders including rheumatoid arthritis and lupus erythematosus. in an animal model, it has recently been observed that chloroquine can also play a role as a potent antiviral drug against various viruses including influenza h n (yan et al., ) . interestingly, chloroquine can prevent the viral fusion with the cell membrane of host cell by increasing endosomal ph (figure ) . glycosylation of sars-cov's cellular receptors can also be interfered by chloroquine (vincent et al., ; wang et al., b) . even though findings from in vitro studies regarding chloroquine is auspicious (ec = . mm, used ncovid- -infected vero e cells), however use of chloroquine to treat ncovid- infection is a completely off-label use. furthermore, this drug is not strongly indicated due to some of its safety reasons including qt prolongation with ventricular dysrhythmia and adverse reactions on the renal, hepatic, and hematologic systems (cortegiani et al., ) . hydroxychloroquine (a chloroquine derivative, figure ) is also mainly used as antimalarial and anti-inflammatory drugs (sinha and balayla, ) . it has been proposed that hydroxychloroquine controls cytokine storm (figure ) , which takes place in critically ill late phase ncovid- patients (yao et al., ) . as compared to chloroquine, hydroxychloroquine is more potent and their ec values are . and . , successively. in addition to this, hydroxychloroquine is less likely to interact with other drugs as compared to chloroquine. moreover, in comparison with chloroquine phosphate, pharmacokinetic data confirmed that hydroxychloroquine is much more effective ( days before) at inhibiting sars-cov- in vitro (yao et al., ) . it has been declared on march , by taiwan cdc that hydroxychloroquine has a significant role in the treatment of ncovid- patients. however, treatment with hydroxychloroquine is contraindicated for the patients who are pregnant or breastfeeding, allergic to hydroxychloroquine, glucose- -phosphatase deficient, and for individuals with prolonged qt interval in electrocardiograms and retinopathy (gautret et al., ) . azithromycin previously, azithromycin (figure ) showed excellent in vitro activity against ebola virus (madrid et al., ) . it was found that azithromycin was administered to individuals with viral infection, it prevented severe infections of respiratory tract in pre-school children (bacharier et al., ) . in a recent study, when azithromycin was administered (i.e., mg on first day, then mg per day from day - ), it remarkably reinforced the hydroxychloroquine's efficacy (when mg was administered times/day for days) to treat severely ill ncovid- patients (figure ) . the mean serum concentration of hydroxychloroquine was . ± . mg/ml. it is assumed that this excellent virus eliminating activity was achieved owing to the use of the aforesaid combination therapy (gautret et al., ) . therefore, use of azithromycin along with hydroxychloroquine can be an effective future alternative to remdesivir in ncovid- treatment. however, in this regard, a possible complication related to prolonged qt interval should be taken into consideration. teicoplanin is a glycopeptide antibiotic and it has been revealed by zhou et al. (zhou et al., ) that teicoplanin exerted inhibitory activity (ic as low as nm) against replication-and transcription-competent virus-like particles. studies confirmed that teicoplanin can suppress the entry of mers and sars envelope pseudotyped viruses zhou et al., ) . in terms of its mechanism, teicoplanin can selectively suppress the effects of cathepsins b and l in host cell. these proteases are involved with cleaving the viral glycoprotein permitting exposure of the receptor-binding domain of its core genome and then release into the cytoplasm of host cells (zhou et al., ; baron et al., ) . therefore, teicoplanin blocked the entry of ebola virus in the late endosomal pathway. also, the derivatives of teicoplanin including telavancin, dalbavancin, and oritavancin, were also found to block the entry of sars, mers, and ebola viruses (zhou et al., ) . collectively, these findings suggest that teicoplanin and its derivatives might play a vital role in inhibiting the viruses that are dependent on cathepsin l ( table ) . ivermectin ivermectin (figure ) is an antiparasitic agent and it has broadspectrum of activity (caly et al., ) , recent in vitro studies have revealed that this drug also has an antiviral effect against dengue and hiv viruses . it has been found that the preformed impα/β heterodimer is accountable for the transport of viral protein into the nucleus and ivermectin can dissociate this heterodimer. since this transport of viral protein into the nucleus is important for the replication cycle and suppression of the host's antiviral response, thus targeting this viral protein transport might prove as a significant target in the development of therapeutic agents against rna viruses (caly et al., ; yang et al., a) . following h of ncovid- infection, a recent in vivo study has been demonstrated that ivermectin can decrease the level of viral rna (figure ) up to , -times (caly et al., ) . since ivermectin has an established safety profile as an antiparasitic agent, thus now it is needed to establish a safe and effective dose of this drug in clinical trials to treat ncovid- infection. nitazoxanide (figure ) is an effective antiparasitic and antiviral drug (rossignol, ) . this drug has a broad-spectrum in vitro antiviral activity against a range of viruses including rsv, rotavirus, parainfluenza, influenza, and coronavirus (rossignol, ) . in vero-e cells, nitazoxanide exerted a potent in vitro antiviral activity against sars cov- (ec = . µm, at h) . furthermore, this strong antiviral effect is in line with the observed ec values for nitazoxanide (ec = . µm) and tizoxanide (an active metabolite of nitazoxanide) (ec = . µm) against mers-cov in llc-mk cells (rossignol, ) . in terms of its mechanism of action, it is believed that nitazoxanide has potent antiviral effect because of its ability to interfere with the host-regulated pathways associated with viral replication instead of the virus-specific pathways (rossignol, ) . therefore, studies were carried out to evaluate the ability of this drug to treat influenza and other related acute respiratory infections. in the phase iib/iii of a clinical trial, positive effects of nitazoxanide were observed in the management of influenza symptoms, where mg of nitazoxanide was orally administered twice a day (haffizulla et al., ) . unfortunately, in phase ii clinical trial it was observed that nitazoxanide neither alleviated the symptoms nor decrease the length of stay in hospitals of individuals infected with respiratory viruses (gamiño-arroyo et al., ). however, in vitro data regarding the activity of nitazoxanide against coronavirus is promising. therefore, further studies are required to estimate its potential in ncovid- treatment. baricitinib most commonly used in rheumatoid arthritis treatment. this drug is a reversible and selective inhibitor of janus kinase (jak ) and jak . it has been found that these latter mentioned enzymes transduce intracellular signals for growth factors and cytokines associated with immune response, inflammation, and haematopoiesis. moreover, this jak inhibitor blocks the activities of ap -associated with protein kinase , which ultimately prevents viral binding with the alveolar epithelium (mayence and vanden eynde, ) . it has also been indicated that baricitinib might be used as an additional therapy for the covid- treatment (richardson et al., ) . in order to determine the safety and efficacy of sarilumab, hydroxychloroquine, lopinavir/ritonavir, and baricitinib to treat , hospitalized covid- patients, a non-randomized phase ii clinical study has recently been started (scavone et al., ) . other selective jak inhibitors including ruxolitinib, fedratinib, and sunitinib might also be effective against covid- in decreasing endocytosis of virus, inflammation, and levels of cytokines including il- and ifn-γ (bekerman et al., ; clinicaltrials.gov, f; favalli et al., ; scavone et al., ; stebbing et al., ) . previously, convalescent plasma therapy was used as a terminal therapy to increase the survival rate of individuals with a range of viral infections including sars, severe infection caused by ebola virus, pandemic influenza a h n , h n avian influenza shen et al., ) . convalescent plasma therapy can be effective because viremia can be suppressed due to the presence of plasma immunoglobulin antibodies in recovering patients. in a study, shen et al. ( ) evaluated the effect of convalescent plasma therapy in severely ill ncovid- patients with ards. in that study, convalescent plasma was transfused in those patients with a novel coronavirus-specific antibody (neutralization titer > and binding titer > : ). the used convalescent plasma of that study was obtained from five ncovid- -recovered individuals. the obtained convalescent plasma was then administered to the patients (in between and days following admission) along with methylprednisolone and antiviral drugs. after convalescent plasma transfusion, clinical conditions of the patients were found to be improved, including decreased viral loads (patients became ncovid- negative within days), elevated level of sars-cov- -specific enzyme-linked immunosorbent assay (elisa), neutralizing antibody titers, normalized body temperature (within days in four/five patients), improved ards (four patients at days following transfusion), successful weaning from mechanical ventilation (three participating individuals within weeks of therapy), increased partial pressure of oxygen/fraction of inspired oxygen, and reduced score in sequential organ failure assessment. out of the participants, of them were in stable condition (at days following transfusions), while of them were discharged from the hospital (following , , and days of staying in the hospital) (shen et al., ) . finally, the researchers summarized that although there were a small number of participants in this study, they suggested the therapy with convalescent plasma can be effective in the ncovid- treatment (shen et al., ) . as a prophylactic measure and therapy, monoclonal and polyclonal antibodies (targeting hemagglutinin binding) have been recommended to treat various viral infections including influenza (beigel et al., ) . the effectiveness of these antibodies against mers-cov largely encouraged the recent efforts to develop monoclonal and polyclonal antibodies against coronaviruses (sheahan et al., ) . for instance, in a phase i trial, sab- (a human polyclonal antibody) which was produced in transchromosomic cattle was found to be safe and better tolerated in healthy participants (beigel et al., ) . in a study, cockrell et al. ( ) revealed in mouse models that human monoclonal antibodies (mabs)-based immunotherapy only mediated protection in the early stage of mers (martinez, ) . many in vitro analyses showed that s protein of sars-cov is crucial to mediate the viral entry into the host cells. in addition to this, the cleavage and subsequent activation of the s protein of sars-cov via a host cell's protease is vital for the entry of the virus (glowacka et al., ) . in cell cultures, it has been noticed that transmembrane serine protease (tmprss ) is a vital protease of host cells that causes activation of s protein of sars-cov, therefore it was studied as an important target for antiviral drugs (sheahan et al., ) . previously, camostat mesylate (an inhibitor of serine protease) showed inhibitory activity against tmprss (kawase et al., ) . furthermore, k (a cysteine protease inhibitor) exhibited significant inhibitory activity (at submicromolar range) against replication of mers-cov and sars-cov (zhou et al., ) . sarilumab is a human monoclonal antibody and clinical trials are ongoing to assess the safety and efficacy of this antibody (alone or along with other standard therapies) in nearly , covid- patients (clinicaltrials.gov, a,d,f; scavone et al., ) . eculizumab (a monoclonal antibody) is approved to treat neuromyelitis spectrum disorders, refractory generalized myasthenia gravis, and atypical hemolytic uraemic syndrome. this monoclonal antibody inhibits the terminal portion of the inflammatory response-associated complement cascade. although the function of the complement cascade in ncovid- pathogenesis is not clear, numerous studies revealed that its suppression may effectively function as a therapeutic technique (ip et al., ; yuan et al., ; gralinski et al., ) . due to these findings, eculizumab will be tested in the solid-c clinical trial to treat individuals with severe ards and ncovid- (clinicaltrials.gov, b). currently, emapalumab (a monoclonal antibody) is being studied in an openlabel, randomized, phase ii/iii study to evaluate the safety and efficacy of this antibody in decreasing respiratory distress and hyper-inflammation in ncovid- patients (clinicaltrials.gov, c) . in china, stem cells are currently being studied as a treatment for ncovid- . tocilizumab (a mab) is an immunosuppressive agent and is used to treat rheumatoid arthritis (kaneko, ) . this agent was designed to suppress the il- binding with its receptors to alleviate cytokine storm syndrome. tocilizumab is now being studied as a potential ncovid- treatment (jean et al., b; slater, ) . in ncovid- high-risk populations, traditional chinese medicines were also regarded as a preventative measure, based on the traditional uses and anecdotal evidence of prevention of h n pdm and sars. nonetheless, there is a lacking of clinical data regarding the effectiveness of these herbal medicines as an ncovid- treatment (cunningham et al., ; luo et al., ) . in china, several traditional medicines were widely used during the ncovid- epidemic and of these herbal medicines include lianqiao (fructus forsythia), jinyinhua (lonicerae japonicae flos), gancao (glycyrrhizae radix et rhizoma), baizhu (atractylodis macrocephalae rhizoma, rhizome of atractylodes macrocephala koidz), fangfeng (saposhnikoviae radix, dried root from the perennial herb saposhnikovia divaricate), and huangqi (astragali radix, dried root of astragalus membranaceus bge. var. mongholicus). indeed, stringent clinical studies are required with a large number of participants to demonstrate the preventive role of these traditional chinese medicines (cunningham et al., ; luo et al., ) . the occurrence of co-infection can widely vary among the patients with confirmed ncovid- . various reports suggest that several co-pathogens including viruses (such as rhinovirus, influenza, and hiv) and bacteria (for example candida species, mycoplasma pneumonia) can co-exist in these patients. among them, influenza a virus was most commonly found to coexist (jean et al., b) . furthermore, ncovid- patients with pneumonia were found to be commonly treated by the coadministration of anti-influenza drugs and antibiotics (jean et al., b) . therefore, careful selection of potential broadspectrum antibiotic(s) is required for the long-stay (over days) hospitalized patients (chou et al., ; jean et al., a) . mixed clinical findings were observed with the use of corticosteroids to treat sars-cov infections. although various reports suggested that there was no significant contribution of corticosteroids in clinical outcomes (stockman et al., ) . in contrast, it was suggested by a report that decreased mortality rate was observed due to the use of corticosteroids in critically ill patients (chen et al., a; wu et al., a) . unfortunately, several reports suggested worse outcomes including longer time for viral clearance, or elevated composite endpoint of icu admission or even death, owing to the use of corticosteroids (auyeung et al., ) . in a cohort (n = ), a longer time in viral clearance was observed in the corticosteroids-receiving mers-cov patients (arabi et al., ) . nevertheless, in the same study, it was observed that there was an insignificant decrease in -day mortality in corticosteroids-receiving patients. recent reports suggested that there was a decreased rate of mortality in ncovid- patients with ards due to the use of corticosteroids (wu et al., a) . these findings suggest that use of corticosteroids resulted in inconsistent outcomes. however, corticosteroids might be beneficial for patients with cytokine-linked lung injury and those who might rapidly develop progressive pneumonia . indeed, healthcare professionals need to carefully assess the risk and benefit ratio of corticosteroid use for each patient. this necessity to assess risk and benefit of corticosteroid use in individual patients and its careful dose consideration has been demonstrated in diagnosis and treatment guidelines from china's national health commission. as per that guideline, glucocorticoid (equivalent to methylprednisolone - mg/kg per day for three-five days or less) may be considered based on chest imaging and respiratory distress. large-dose of glucocorticoids can suppress the immune system, this can result in delayed sars-cov- clearance (mccreary and pogue, ) . recently, chinese thoracic society recommended a lower dose of methylprednisolone (≤ . - mg/kg per day) for a maximum of days in selected patients, prior to treatment these selected patients should be carefully assessed for potential risks and benefits . more clinical studies are immediately required to elucidate the function of corticosteroids in ncovid- . in a study, yang et al. ( b) mentioned that diabetes and cerebrovascular diseases were the commonly observed comorbidities in the non-survivors of ncovid- in icus. furthermore, guan et al. ( ) also observed similar results in their study and these ncovid- patients received angiotensin ii receptor blockers (arbs) or ace inhibitors. indeed, sars-cov- and sars-cov can bind with the ace receptors on the epithelial cells of lung, kidney, and intestine (fang et al., ) . therefore, when ards is not present, arb or ace inhibitors can be administered to ncovid- patients. increased activity of ace was found to be linked with decreased severity of ards among individuals with rsv-caused lower respiratory tract infection (wösten-van asperen et al., ) . interestingly, fedson ( ) revealed in their study that statins mainly target host response to infection, instead of the virus itself. these researchers also indicated that combination therapy with statins and arb may induce the reversal of homeostatic processes, which will allow the self-recovery of individuals (fedson et al., ) . there is an argument regarding the usage of non-steroidal anti-inflammatory drugs (nsaids) like ibuprofen since it can increase the ace receptors (day, ) . if the severely ill ncovid- individuals suffer from fever, acetaminophen can be a good option to control body temperature as compared to other nsaids (therapeutics initiative, ). tang et al. ( ) confirmed that anticoagulant therapy by heparin (an anticoagulant) specially with low molecular weight heparin improved the prognosis in severely ill patients with ncovid- . furthermore, -day mortality of heparin receivers was found to be lower as compared to the non-users among individuals with sepsis-stimulated coagulopathy scores or ddimer > -times the upper limit of normal . in human body, vitamin a plays various important functions including protecting mucosal and epithelium integrity, mediating growth and development, and proper maintenance of vision (huang et al., ) . vitamin a is also essential for enhancing immune response and maintaining regulatory action in both humoral and cellular immune responses (huang et al., ) . in case of infants, supplementation with vitamin a was found to ameliorate antibody response following several vaccines including anti-rabies (siddiqui et al., ) and measles vaccination (huang et al., ) . moreover, an improved immune response to influenza virus vaccination has also been reported in children ( - years) who had a deficiency of vitamin a and d at baseline, following supplementation with vitamin a and d (patel et al., ) . vitamin d has a significant contribution in modifying both adaptive and innate immune responses (aranow, ) . it has been revealed by epidemiological studies that there is a link between deficiency of vitamin d and elevated susceptibility to acute viral respiratory infections (monlezun et al., ) . it has also been suggested that vitamin d significantly modulates the innate immune responses against various viral respiratory infections including rsv, parainfluenza and , and influenza a and b (zdrenghea et al., ) . indeed, studies have revealed that there is a strong relationship between vitamin d deficiency and elevated risk of both lower and upper respiratory tract infections (jolliffe et al., ) . nonetheless, conflicting and heterogeneity in dosage regimens and baseline vitamin d conditions in study populations were observed in randomized controlled trials (rcts) (jolliffe et al., ) . in a study, aglipay et al. ( ) observed no significant difference between the action of high-dose ( iu per day) vs. standard-dose ( iu per day) vitamin d supplementation on viral upper respiratory tract infections (aglipay et al., ) . nevertheless, only one-third of the study subjects received vitamin d at doses below ng/ml. vitamin d increased the plasma level of tgfβ without ameliorating antibody generation in a rct on the effect of vitamin d administration on influenza vaccine response in deficient elderly person (goncalves-mendes et al., ) . in addition to this, it was also indicated in the latter mentioned rct that vitamin d administration perhaps directed the polarization of lymphocyte toward a tolerogenic immune response (goncalves-mendes et al., ) . in a different rct, monthly administration of high-dose of vitamin d ( , iu/month) decreased the occurrence of acute respiratory infections in older long-term care residents as compared to a standard dose group ( , iu/month) (ginde et al., ) . therefore, it is quite clear that the effect of vitamin d on antiviral immunity against respiratory infections is dependent on an individual's vitamin d status. moreover, it has been confirmed that vitamin d supplementation is also useful in case of other viral infections, for instance, vitamin d addition to conventional peg-α- b/ribavirin therapy for treatment-naive individuals with chronic hcv genotype infection considerably ameliorated the viral response (abu-mouch et al., ) , and similar action was also seen in individuals with hcv genotype - (nimer and mouch, ) . vitamin e possesses strong antioxidant property and it can modify host immune responses [ ] . the deficiency of this vitamin can lead to impairment of both cellular and humoral immune responses (moriguchi and muraga, ) . some studies revealed that administration of vitamin e may exert harmful activities in case of infectious disease. vitamin e increased the risk of pneumonia among - years old adult smokers (hemilä and kaprio, ) . similarly, vitamin e supplementation ( iu/day) did not significantly reduce the respiratory tract infections in elderly nursing facility residents (meydani et al., ) . nevertheless, in a small pilot rct, positive activities of vitamin e were seen in the treatment of chronic hepatitis b, where vitamin e administration markedly normalized the liver enzymes and hbv-dna negativization (andreone et al., ) . similarly, in a rct, vitamin e supplementation increased anti-hbe seroconversion and virological response in the pediatric population (fiorino et al., ) . vitamin c plays a significant role as an enzymatic cofactor in numerous physiological reactions including immune potentiation, collagen synthesis, and hormone generation . in mouse models, it was revealed that vitamin c plays important role in the antiviral immune responses against the influenza a virus (h n ) via the elevated generation of ifn-α/β, particularly at the early stages of infection . nonetheless, no significant benefit has been observed in using mega-dose of vitamin c as a prophylactic measure to lower the incidence of common cold caused by viral infections (hemilä and chalker, ) . zinc (an essential trace element) contributes significantly in the growth, development, and maintenance of immune responses (prasad, ; read et al., ) . the deficiency of zinc is linked with an enhanced susceptibility toward infectious diseases, for example, viral infections. an individual's zinc status is a vital factor that can affect the immune response against viral infections. indeed, zinc-deficient individuals are at greater risk of developing infections including hcv or hiv (read et al., ) . acevedo-murillo et al. ( ) reported that there was a noticeable clinical improvement in the children ( month− years) with pneumonia in the zinc-receiving group as compared to placebo (acevedo-murillo et al., ) . the researchers also confirmed that there was a rise in the cytokine response in th pattern (inf-γ and il- ) only in the zinc-receiving group, along with th cytokines (il- and il- ) being increased or remained elevated in both groups. following stem cell transplantation, oral administration of a high dose of zinc ( mg/day) increased thymic activity and output of new cd + naive t cells, which eventually helped in the prevention of torque teno virus reactivation (iovino et al., ) . nonetheless, provinciali et al. ( ) summarized that prolonged administration of zinc ( mg/day) or zinc plus arginine ( d/day) in the elderly (age - years) people restored zinc concentrations in plasma, which was ineffective in stimulating or improving the antibody response or number of cd , cd , or cd lymphocytes following influenza vaccination. selenium (a trace element) also exerts a range of important functions including antioxidant effects, various pleiotropic activities, and anti-inflammatory effects (rayman, ) . selenium deficiency is found to be linked with cognitive impairment, poor immune response, and elevated risk of mortality, whereas an increased level of selenium or treatment with selenium has exhibited antiviral actions (rayman, ) . broome et al. ( ) assessed whether an increased selenium administration ( - µg/day) ameliorated immune response in adults with a borderline concentration of selenium (broome et al., ) . treatment with selenium elevated the plasma selenium levels, and also increased the activities of cytosolic glutathione peroxidase and lymphocyte phospholipid. furthermore, selenium also increased the cellular immune responses (elevated level of ifn-γ and other cytokines), along with an increased level of t-helper cells and earlier peak tcell proliferation. nonetheless, it was observed that humoral immune responses were not affected (broome et al., ) . moreover, selenium treatment in participants also induced rapid poliovirus clearance. copper (another essential trace element) has a significant contribution in the differentiation and development of immune cells (li et al., ) . it has also been confirmed that copper exerted in vitro antiviral effects. intracellular copper was found to regulate the life cycle of influenza virus (rupp et al., ) , while thujaplicin-copper chelates inhibited the replication of human influenza viruses (miyamoto et al., ) . in a study, turnlund et al. ( ) determined the effects of chronic administration of copper on immune response, oxidative stress, and indices of copper status. these researchers observed that when copper was administered at a dose of . mg/day, copper significantly increased the level of superoxide dismutase, benzylamine oxidase, and plasma ceruloplasmin activity as compared to . mg/day dose, which further suggesting an enhancement in antioxidant status. nonetheless, increased copper administration ( . mg/day) markedly decreased the proportion of antibody titer, serum il- r, and circulating neutrophils against the beijing strain of influenza (turnlund et al., ) . magnesium (an essential mineral) has a significant contribution in regulating immune response via significantly affecting the t helper-b cell adherence, macrophage response to lymphokines, immunoglobulin m (igm) lymphocyte binding, adherence with immune cells, antibody-dependent cytolysis, and immunoglobulin synthesis (liang et al., ) . it has also been reported in in vivo and in-vitro studies that magnesium may have a contribution in the immune function against viral infections (chaigne-delalande et al., ) . still now there is no specific antiviral drug to treat ncovid- , but some of the investigational drugs were found to be useful. various drugs are being analyzed in vitro studies or clinical trials. although ribavirin is a potent antiviral drug, its clinical effects are not clear and its side effects ought to be carefully considered. on the other hand, chloroquine has been studied in interventional studies. furthermore, in the chinese clinical trial registry, the derivatives of chloroquine were prospectively registered; and more studies are required to evaluate their antiviral effects and to estimate the recommended dose in ncovid- patients . along with antiviral drugs, glucocorticoids ought to be utilized carefully and in a timely manner in ncovid- patients. in addition to this, extracorporeal support need to be considered under strict contraindications and indications, otherwise, there will be numerous additional complications and also a waste of resources . in order to manage the current ncovid- outbreak, extensive measures are needed to be taken to lower the personto-person transmission of the virus. in addition to this, special efforts and attention are required to reduce or protect the susceptible populations such as elderly people, health care providers, and children. more studies are also essential to understand the mechanisms related to ncovid- pathogenesis. this better understanding will help the development of specific and effective therapies against sars-cov- . since the respiratory tract is mainly affected by sars-cov- , thus special consideration is required to deliver the drug into the respiratory tract. more studies in animals and clinical trials on drug repositioning can also be considered to identify potential drugs to treat ncovid- . still there is no available specific drug or vaccine to treat ncovid- , thus effective preventative measures are recommended. specific drugs are urgently required to inhibit the entry of the virus and subsequent replication to overcome this outbreak. currently, as mentioned in this article, multiple investigational drugs and clinical trials are ongoing. the discovery of new drugs will ultimately enable us to better control this outbreak. furthermore, in silico studies can also be considered to faster the drug development process. finally, sharing findings or data will be effective to fight against ncovid- globally. mk and mu conceived the original idea and designed the outlines of the study and prepared the figures for the manuscript. mk wrote the initial draft of the manuscript. mu revised and improved the draft. mh, ja, ma, ga, sb, mb-j, ma-d, and la participated in the literature review of the manuscript. all authors have read and approved the final manuscript. vitamin d supplementation improves sustained virologic response in chronic 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coronavirus (sars-cov) protease inhibitors targeting coronavirus and filovirus entry coronaviruses-drug discovery and therapeutic options the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © kabir, uddin, hossain, abdulhakim, alam, ashraf, bungau, bin-jumah, abdel-daim and aleya. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord- -t p le authors: elgin, t.g.; fricke, e.m.; hernandez reyes, m.e.; tsimis, m.e.; leslein, n.s.; thomas, b.a.; sato, t.s.; mcnamara, p.j. title: the changing landscape of sars-cov- : implications for the maternal-infant dyad date: - - journal: journal of neonatal-perinatal medicine doi: . /npm- sha: doc_id: cord_uid: t p le the covid- pandemic represents the greatest challenge to date faced by the medical community in the st century. the rate of rapid dissemination, magnitude of viral contagiousness, person to person transmission at an asymptomatic phase of illness pose a unique and dangerous challenge for all patients, including neonatal and obstetric patients. although scientific understanding of the pathophysiology of the disease, nature of transmission, and efficacy of mitigation strategies is growing, neither a cure or vaccine have been developed. while covid- is primarily a disease of older patients, infection is now seen across all age demographics with reports of illness in pregnant patients and infants. altered hormone status and predominance of th- immune helper cells may result in increased predisposition to sars-cov- . case reports of pregnant patients demonstrate a clinical presentation comparable to non-pregnant adults, but evidence of vertical transmission to the fetus is controversial. neonatal reports demonstrate an inconsistent and non-specific phenotype, and it is often difficult to separate covid- from the underlying conditions of prematurity or bacterial infection. the development of international registries to enable risk profiling of covid- positive pregnant mothers and/or their offspring may facilitate the development of enhanced mitigation strategies, medical treatments and effective vaccinations. in december of cases of an unknown viral pneumonia were reported from wuhan, hubei, china although much uncertainty remains, regarding the natural history and demographics of covid- , the virus appears to primarily cause infection in adults over with case fatality rates increasing dramatically with age [ ] . appearance of symptoms, which usually include fever, cough, fatigue, and dyspnea with occasional gastrointestinal tract symptoms [ ] , typically occurs following five days of incubation [ ] . in addition to pulmonary infection, the virus appears to have manifestations in the central nervous system [ ] and heart [ ] .the published literature largely focuses on the biologic effects of covid- in adults, the burden to adult health care systems, and repercussions on society. the impact on perinatal health care is unique; specifically, the risks to maternal health may extend not only to health care providers in the delivery room, but to the newly born infant, and neonatal intensive care unit providers. as the disease spreads and testing capabilities expand, the likelihood of encountering covid- positive pregnant women and/or neonates increases. the true magnitude of the pandemic to maternal, fetal, and neonatal health will only be realized as the case mix rises. the goal of this review is to examine the pathobiology of maternal covid disease and possible effects on the developing fetus, provide an overview of published evidence related to the mother, and to appraise strategies to modulate the burden of illness. genetic sequencing identified that the virus belongs to the coronavirus family. coronaviridae are enveloped, positive sense, single stranded rna viruses with a large genome [ ] . coronavirus often infects bats and other mammalian hosts but, particularly the genera betacoronavirus, has the potential to infect human populations. severe acute respiratory syndrome (sars-cov) and middle east respiratory syndrome (mers-cov) are betacoronaviruses that have led to recent epidemics. sequencing has determined that the cause of covid- , officially named sars-cov- , is also a member of the betacoronarvirus genera [ ] , and its genome is nearly % identical to sars-cov. sars-cov- is a novel enveloped rna betacoronavirus, which infects host respiratory epithelial cells. it is thought to act through angiotensin-converting enzyme (ace ), a membrane-bound aminopeptidase, which functions as its putative receptor. whilst ace is predomi-nantly expressed within type ii alveolar cells of the lung, the receptor is also present in several extrapulmonary sites including the mucosa of the oral cavity [ ] . sexual diamorphism has been hypothesized based on cellular studies which reveal attenuated expression of ace in females. in general, the magnitude of the physiological and mechanical changes induced by pregnancy place the mother at increased risk of infection. these are likely to be exaggerated when respiratory health is adversely compromised or in an advanced stage of pregnancy when functional residual capacity decreases steadily, due to diaphragmatic splinting by the gravid uterus. both the spanish ( ) and asian ( ) flu pandemics were characterized by increased mortality in pregnant mothers and infants less than one year. on the contrary, sars-cov- appears to be less pathogenic in these patients. there is immunologic evidence that the pregnancy bias towards t-helper (th ) system dominance and fetus protection leaves the mother vulnerable to viral infections, which are more effectively contained by the th system. in pregnancy, the attenuation in cell-mediated immunity by th cells due to the physiological shift to a th cell dominant environment contributes to increased maternal susceptibility to intracellular pathogens like viruses [ ] . non-pregnant patients with covid- demonstrate activation of both th and th immunity, characterized by the presence of both microbicidal/pro-inflammatory cytokines (ifn␥ and il- ␤) in addition to anti-inflammatory cytokines (il- and il- ) [ ] . in pregnant mothers with covid- the immune responses may be variable and characterized by early adaptive immune responses predictive of milder disease severity [ ] . it has been postulated that the combined effects of changes in the hormonal milieu of pregnancy which negatively influence immunological responses to viral pathogens [ ] and the biological transition to a th predominant environment, result in a less severe covid- clinical phenotype compared to non-pregnant female. these biologic factors may place pregnant mothers, their fetus and health care workers who take care of them at increased risk compared to individuals of a comparable age, although there is no published evidence to substantiate these concerns. while respiratory secretions appear to be the primary means, evidence exists to suggest that transmission may occur through multiple routes, including ocular and fecal oral routes [ ] . patients with active covid- have been reported to have elevated inflammatory markers, d-dimer, and proinflammatory cytokines [ ] . of particular concern are the risks of covid- infection to healthcare workers and the ability of spread to occur through asymptomatic patients; for example in lombardi, italy up to % of health care workers became infected [ ] . coivd- is highly transmissible and infection can occur with a very short exposure time. diagnosis of covid- has largely been based on the combination of a clinical presentation, lab data and viral testing; however, computerized tomography (ct) imaging has played an additional supportive role. the radiologic findings ( fig. ) are non-specific and include bilateral ( ( %) patients), peripheral ( ( %) patients), ill-defined ( ( %) patients), and ground-glass opacification ( ( %) patients), and mainly involving the right lower lobes in ( %) of affected patients [ ] . ct findings have been categorized into different phases: an early phase defined as - days from symptom onset, and a late phase defined as - days from symptom onset [ ] . early phase appearance has been categorized predominantly by bilateral peripheral ground glass opacities. as the disease progresses to the late phase, there is increased lung involvement and the development of linear opacities, ground glass opacities with reticulation ("crazy paving" pattern) and "reverse halo" sign [ ] .the overall sensitivity for ct to identify the signs of pneumonia is high, however, its ability to perform as a diagnostic tool specific for covid- remains unknown. data from a chinese cohort revealed that the sensitivity, specificity, positive predictive value (ppv), and negative predictive (npv) value of a chest ct in diagnosing covid- are %, %, %, and % respectively [ ] . the clinical utility of ct needs further characterization, particularly in pregnant females where the adverse effects of ionizing radiation to the mother and the fetus need to be considered. in total, pregnant women who have been positive for covid- have been reported in the literature, all of whom were diagnosed in the third trimester [ ] . of those infected, there have been no published cases of maternal death and two cases of severe infection [ , ] . a recent review draws attention to two maternal deaths, secondary to ards following delivery, reported by the iranian ministry of health and medical education; however at the time of this publication these cases were not listed on pubmed [ ] . most evidence supports that pregnant women present with symptoms like non-pregnant adults [ ] . there are, however, emerging case reports of pregnant mothers who test positive for covid- infection and who remain either completely asymptomatic [ ] and or manifest mild symptoms in the subsequent hours following delivery. recent data from universal screening in a new york urban center revealed [ ] china case control no difference in rates of fetal distress, meconium, preterm birth or neonatal asphyxia. significantly higher rates of uterine atony requiring uterotonics di mascio et al. [ ] italy, usa metanalysis pooled analysis of above studies concluded significantly higher rates of preterm birth, preeclampsia and perinatal death breslin et al. [ ] usa case series asymptomatic carriers are present in substantial numbers and respiratory deterioration is relatively rapid yu et al. [ ] china case series symptoms included fever (n = ), cough (n = ), sob (n = ), diarrhea (n = ). lab abnormalities included lymphopenia, thrombocytopenia, elevated liver function tests, elevated c-reactive protein, elevated d-dimer. all delivered by cesarean section. all treated with oxygen but no icu admissions. no adverse neonatal outcomes abbreviations: dic, disseminated intravascular coagulation; sob, shortness of breath. that . % of asymptomatic women were positive for sars-cov- [ ] . in sick patients, symptoms include low grade fever and mild respiratory symptoms [ ] . from a diagnostic standpoint, pregnant women appear to have similar findings on laboratory evaluation, chest x-ray and ct scan. imaging findings include peripheral airspace shadowing, bilateral multi-lobar ground-glass opacities or consolidation [ ] . table provides a summary of all case series of pregnant mother illness at the time of the current review. a retrospective review, published in lancet, described the clinical findings in nine covid- positive women. seven of the nine woman presented with fever, four presented with cough, but none developed severe pneumonia or required intubation. six women developed lymphopenia and elevated c-reactive protein and three had elevation of liver enzymes [ ] . zhu et al. reported similar characteristics from nine covid- positive mothers and their neonates. fever and cough were the predominant presenting symptoms, and six of the nine women had symptoms appear either before or on the day of delivery [ ] . in these two reports, premature delivery was common but attributed to maternal illness. although, four of nine [ %, range - + weeks gestation] and six of ten [ %, range - + weeks gestation] were delivered preterm, no fetal or neonatal deaths were reported. breslin et al. report that two of seven women presenting in new york were asymptomatic, despite positive covid- testing [ ] . a retrospective study by yu et al., involving seven pregnant women admitted to tongji hospital, reveals additional clinical information [ ] . their average age was years, illness incubation period was days, and gestational age at delivery was + weeks. all received oxygen via nasal cannula, however none required critical care. symptoms included fever (n = ), cough (n = ) shortness of breath (n = ) and diarrhea (n = ). three women had coinfection with influenza h n or legionella pneumophilia, and ct imaging for six of the women demonstrated bilateral pneumonia. all women underwent caesarian section, and all were discharged home. only one infant tested positive. this neonatal symptoms have been reported, but it important to note that distinguishing the phenotype and separating the etiology of the symptoms as specific to covid- , rather than bacterial infection or prematurity, has yet to occur. patient was hours of age at the time of diagnosis, was transferred to a local children's hospital, remained well and was ultimately discharged home after weeks and repeat negative testing [ ] . pregnancy complications associated with covid- include miscarriage ( %), intrauterine growth restriction ( %), and preterm birth ( %) [ ] . there is little evidence to date regarding the impact of covid- infection on the developing fetus in the st or early nd trimester. concern exists, however, based on evidence from prior viral epidemics that early gestation may represent a period of increased fetal and maternal risk [ ] . during the sars outbreak in , there were several reported first trimester spontaneous miscarriages and evidence suggests that ongoing pregnancies were complicated by intrauterine growth restriction and neonatal ischemic gut injury [ ] . there is a high rate of cesarean section among those affected; however, this may relate to delivery trends in china which predated the pandemic or maternal illness. of those who attempted vaginal delivery, there is some evidence of higher rates of fetal distress, although there is no reported increased rate of hypoxic-ischemic encephalopathy or need for therapeutic hypothermia [ ] . the impact of covid- on preterm birth has recently been examined in a meta-analysis of pregnant patients from three coronavirus-related outbreaks, which includes data from six studies on pregnant mothers who were infected with covid- [ ] . the authors concluded increased risk of preterm birth in covid- positive pregnant mothers. unfortunately, the relatively high rate of preterm birth was not subdivided into spontaneous and iatrogenic preterm delivery, which is vital to discerning the role of covid- on development of preterm labor. the incidence of pre-eclampsia and perinatal death was also elevated in the covid- cohort, although the strength of this association was attenuated. of note, as with the individual series mentioned previously, pooled proportions show that > % of patients presented with some form of pneumonia and the cesarean section (cs) rate was %. in contrast, outcomes such as preterm premature rupture of membranes (pprom) and fetal growth restriction (fgr) were not significantly elevated in the covid- group. neither sars nor mers demonstrated evidence of vertical transmission, however the mortality rate in pregnant women reached % and %, respectively [ ] . the risk of vertical transmission of covid- , however, is biologically plausible given wide expression of the ace receptor in the placenta [ ] . although clinical evidence is lacking, the case numbers to date of covid- in pregnancy remain very low [ ] and case reports of two neonates who tested positive for sars-cov- shortly after birth lends some credence to the concern. the methods of perinatal transmission through other maternal- symptoms were mild and none died. case -born at weeks' gestation via c/s due to meconium-stained amniotic fluid and maternal covid- pneumonia. infant was admitted to nicu on day with lethargy and fever. cxr showed pneumonia. procalcitonin was elevated. nasopharyngeal and anal swabs were positive for sars-cov- on days and but negative on day . case -born at weeks' gestation via c/s for maternal covid. infant presented with fever, lethargy, vomiting on postnatal day . lab testsleucocytosis/lymphocytopenia. cxr showed pneumonia. nasopharyngeal/anal swabs were positive for sars-cov- on days , but negative on day . case -born at weeks' gestation by c/s due to fetal distress and confirmed maternal covid- pneumonia. resuscitation was required. apgar scores were , , and at , , and minutes. cxr revealed respiratory distress syndrome and pneumonia. symptoms resolved by postnatal day after treatment with non-invasive ventilation, caffeine, and antibiotics. he also had sepsis, with an enterobacter agglomerates-positive blood culture, leukocytosis, thrombocytopenia, and coagulopathy, which improved with antibiotic treatment. nasopharyngeal and anal swabs were positive for sars-cov- on days , but negative on day . dong et al. [ ] fetal-neonatal exposures remain unclear. samples of amniotic fluid, cord blood, breast milk,and neonatal throat swabs have failed to yield any viral isolates [ ] and there has been no evidence of covid- in placental specimens. in summary, pregnant women represent a population at risk for the development of covid- related illness. alterations to the immune system and increased susceptibility to respiratory pathogens during pregnancy represent known risk factors for intrapartum sepsis. the magnitude of the impact of covid- remains unclear, due to the limited number of cases reported, however in most cases the illness is mild. future studies should investigate the currently presumed differential impact of sars-cov on the health of pregnant mothers, compared to prior pandemics, the effect of illness earlier in preg-nancy, and long-term consequences to both maternal and infant health. as of may th, there has yet to be a single published report of a case of neonatal covid- illness in the unites states, although anecdotal evidence suggests otherwise. the evidence for neonatal transmission, immune susceptibility, viral penetrance, and clinical phenotype remains scarce. to date, limited case studies describe the clinical phenotype of early onset neonatal infection which would appear to be mild (fig. ) . in one of the largest maternal case series from china, of infants born to covid- positive mothers only three ( %) infants tested positive [ ] . all mothers had evidence of pneumonia on ct and had positive nasopharyngeal (np) swabs for sars-cov- . none required the provision of intensive care. all infants were delivered by caesarian section and noted to be appropriately grown, without dysmorphic features or malformation sequences. nasopharyngeal and anal swabs were positive on postnatal days and , but negative between days and . two of the three infants were born at term and all survived. the third infant was born by caesarian section, secondary to maternal distress, at week's gestation. the infants apgar scores were , and at , and minutes respectively. a clinical diagnosis of respiratory distress syndrome (rds) was made and the infant required intubation. the infant developed a sepsis-like illness with hemodynamic instability and coagulopathy. routine blood culture was, however, positive for an enterobacter species which was managed with antibiotics. the infant's symptoms could not be solely attributed to covid- , due to concurrent prematurity, sepsis and relative asphyxia. in a research letter, dong et al. reported a possible case of vertical transmission in a year old women with radiographic evidence of pneumonia and a positive np swab for covid- [ ] . the mother received antibiotics, oxygen, corticosteroids, and antiviral drugs prior to delivery. the mother wore an n mask and did not hold the infant following the delivery. the infant was asymptomatic at birth, had apgar scores of and and was immediately quarantined. of note, the infant demonstrated elevated sars-cov- igm and igg levels at two hours of life, but serial np swabs for sars-cov- were negative. at time of discharge, immunoglobin levels were still elevated. the presence of igg levels at two hours of life could be explained by elevated maternal levels, however igm antibodies do not freely cross the placenta [ ] . it is difficult to determine whether the elevated igm was due to fetal infection, delivery, or an unrelated process. without testing amniotic fluid or placenta specimens, no definitive conclusions can be drawn. increased availability of igg and igm testing has improved the quality of surveillance and detection of sars-cov- . zeng et al. reported immunoglobulin levels from six infants born to covid- positive mothers between february th and march th [ ] . all mothers underwent caesarian section and the infants were immediately isolated following delivery. neonatal viral throat and serum swabs were all negative for sars-cov- , but igg and igm were elevated in five and two respectively, out of the six infants. while the sample size is small and no evaluation of the placenta or amniotic fluid occurred, the report raises concern of placental involvement and fetal exposure to the virus. in the series published by zhu et al., the clinical status of neonates were reported. none of the infants born to covid- positive mothers demonstrated a positive throat swab pcr [ ] . one infant, born at weeks' gestation, developed hemorrhagic shock, secondary to profound gastrointestinal bleeding and ultimately died secondary to multi end organ failure. a second infant, born at week's gestation, developed fever and gastrointestinal (gi) bleeding, but responded to supportive therapies. with negative testing, and without evaluation of placental tissue or amniotic fluid, it is difficult to draw any conclusions regarding the biologic nature of the gi symptoms or any putative relationship to covid- exposure. clinical symptoms in neonates are non-specific and appear similar to the classic presentation of respiratory distress syndrome [ ] . additionally, radiologic imaging may demonstrate pneumonia, which is difficult to distinguish from premature lung disease. it is important to have a high degree of suspicion when managing neonates born to positive mothers, while recognizing more information is needed to truly develop a consistent neonatal phenotype. there is currently no specific treatment for covid- infection, nor access to an available vaccine. the american academy of pediatrics (aap) and the centers for disease control (cdc) have developed guidelines to aid in the care of infants born to covid- positive mothers (table ) . recent guidelines prioritize universal maternal testing and recommend a shared decision-making process related to whether the infant should stay with the mother or be isolated. treatment of patients with active sars-cov- illness has focused on the provision of supportive care according to illness severity. this may range from oxygen therapy and/or prone positioning to intubation, icu support in patients with shock or adult respiratory distress syndrome (ards). table provides an overview of current strategies that have been implemented or are under investigation to either mitigate the risk of transmission or modulate the disease course. [ , ] shortening of the disease course [ ] lopinavir no antiretroviral protease inhibitor [ ] rct, no benefit in clinical improvement demonstrated [ ] rct, randomized controlled trial; fda, food and drug administration. prevention has been used as a primary means to control the growth of covid- . as virus spread primarily relates to"person to person" interaction and has demonstrated familial clustering [ ] , limitation strategies that minimize human interaction, or social distancing, may help diminish transmission. it has been difficult to accurately determine the basic reproduction number (r o ) of sars-cov- , which is used to determine how quickly the virus can spread throughout a population [ ] , across various countries and cities with differing population densities. currently studies indicate the virus has a r o of . , meaning each infected individuals has the potential to spread the virus to . other individuals. until the r o drops to less than the outbreak is likely to continue with aggressive spread. mitigation measures such as social distancing, school closures, quarantine of exposed individuals have been determined through simulation and observational studies to have the potential to reduce transmission of previous pandemics, although there is no published evidence of the efficacy of this strategy in the setting of the current pandemic. vaccination research has started, with several academic centers and pharmaceutical companies having taken on the challenge, however the timeline needed to ensure patient safety remains considerable [ ] . modulation of the spread within the health care system is of vital importance. wu et al. reported that . % of their positive covid- population in china were infected health care personnel [ ] . the impact to health care workers in italy is even greater; in some situations, hospitals have closed because of the magnitude of transmission among health care workers [ ] . protection of healthcare workers has been made especially challenging due to an insufficient global supply of personal protective equipment and disruptions within the supply chain. to help combat this shortage, given that pregnant mothers may be either be asymptomatic carriers or undiagnosed due to limited testing, the vague or mild nature of symptoms, andthe potential for comorbid disease states, it is incumbent on healthcare systems to ensure that neonatal teams have efficient processes to protect vulnerable front-line workers and mitigate both covid- spread and access to healthcare delivery for other neonatal icu patients. an array of medications are in current use to treat patients with covid- . anti-viral agents such as oseltamivir, ganciclovir, lopinavir/ritonavir and remdesivir have been used for critically ill patients. remdesivir is a nucleotide analogue that interferes with viral replication. a clinical trial is currently in progress at multiple centers in wuhan province. additionally, the anti-malarial agent chloroquine phosphate has been used to treat pneumonia symptoms, as it possesses anti-viral and anti-inflammatory properties and has demonstrated positive clinical effect in the treatment of covid- [ ] . clinical trials of the efficacy of chloroquine are also being conducted in china. finally, lopinavir has demonstrated inhibition of protease activity in coronavirus species and is currently under investigation [ ] . there are no reports of use of these agents in pregnant mothers or their infants. use of convalescent plasma, as a means of generating passive immunity, has been the subject of recent investigation. this therapeutic strategy was previously investigated during the sars and mers outbreaks; specifically, a metanalysis demonstrated a significant reduction in mortality compared to placebo [ ] . in addition, clinical experience from five covid- positive individuals in china with ards demonstrated clinical improvement following the receipt of convalescent plasma [ ] . while this was not a randomized controlled study, the report is compelling and suggests biological and therapeutic plausibility. while many of the current treatments under investigation hold promise, due diligence and scientific rigor are essential to minimize the potential of unintended or unanticipated patient harm. there is currently no scientific evidence to justify any approach to treatment in pregnant mothers or in neonates. centers should develop institutional guidelines based on best available evidence and resources available to them. the covid- pandemic represents one of the greatest threats to human existence seen in the last one hundred years, with rapid spread across the globe and throughout the united states. the impact of rapid case escalation on the italian and spanish health care systems has forced the establishment of triaging committees to determine access to mechanical ventilation and intensive care resources. although knowledge increases daily, it is incumbent on health care professionals, medical societies and governing bodies to establish comprehensive registries to track disease progression and enable an enhanced understanding of clinical presentation and risk profiles for those patients greatest at risk. these registries are even more relevant for obstetrics and neonatology where individual centers are likely to see low volumes of maternal cases, and even lower volumes of neonatal illness. covid- does not appear to be particularly aggressive in pregnant women, neonates or children, based on the limited data that is available. due to the dynamic nature and rapid evolution of our scientific understanding of this condition, these premises are likely to change as knowledge grows. the clinical experiences from countries (e.g. italy, spain, iran) where covid- has crippled icu resources and preventative strategies from countries (e.g. south korea, singapore) where rapid dissemination has been limited will enable the development of standardized guidelines and frameworks for practice that may be universally adopted across the world. the ramifications of the pandemic to society have yet to be assessed, but are likely to be profound from personal, fiscal, and global health perspectives. the world beyond covid- is likely to be a very different place. no additional acknowledgements outside of authorship. no honorarium, grant, or other form of payment received to produce the manuscript. clinical features of patients infected with novel coronavirus in wuhan understanding of covid- based on current evidence world health organization. who director-general's opening remarks at the media briefing on covid- - coronavirus disease (covid- ) in italy ct features of coronavirus disease (covid- ) pneumonia in patients in wuhan the epidemiology and pathogenesis of coronavirus disease (covid- ) outbreak evidence of the covid- virus targeting the cns: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms covid- and the cardiovascular system high-resolution 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potential vaccines: lessons learned from sars and mers epidemic characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention italian doctors call for protecting healthcare workers and boosting community surveillance during covid- outbreak breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of covid- associated pneumonia in clinical studies a systematic review of lopinavir therapy for sars coronavirus and mers coronavirus-a possible reference for coronavirus disease- treatment option the effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis treatment of critically ill patients with covid- with convalescent plasma lack of vertical transmission of severe acute respiratory syndrome coronavirus an uncomplicated delivery in a patient with covid- in the united states novel coronavirus in a -day-old neonate with clinical signs of sepsis, a case report zhonghua er ke za zhi=chinese journal of pediatrics potential therapeutic agents against covid- : what we know so far chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion a trial of lopinavir-ritonavir in adults hospitalized with severe covid- considerations for inpatient obstetric healthcare settings: u.s. department of health and human services no animal research was involved in this manuscript. key: cord- -svwtfshi authors: fabio, ciceri; antonella, castagna; patrizia, rovere-querini; francesco, de cobelli; annalisa, ruggeri; laura, galli; caterina, conte; rebecca, de lorenzo; andrea, poli; alberto, ambrosio; carlo, signorelli; eleonora, bossi; maria, fazio; cristina, tresoldi; sergio, colombo; giacomo, monti; efgeny, fominskiy; stefano, franchini; marzia, spessot; carlo, martinenghi; michele, carlucci; luigi, beretta; maria, scandroglio anna; massimo, clementi; massimo, locatelli; moreno, tresoldi; paolo, scarpellini; gianvito, martino; emanuele, bosi; lorenzo, dagna; adriano, lazzarin; giovanni, landoni; alberto, zangrillo title: early predictors of clinical outcomes of covid- outbreak in milan, italy date: - - journal: clin immunol doi: . /j.clim. . sha: doc_id: cord_uid: svwtfshi background: national health-system hospitals of lombardy faced a heavy burden of admissions for acute respiratory distress syndromes associated with coronavirus disease (covid- ). data on patients of european origin affected by covid- are limited. methods: all consecutive patients aged ≥ years, coming from north-east of milan's province and admitted at san raffaele hospital with covid- , between february th and march th, were reported, all patients were followed for at least one month. clinical and radiological features at admission and predictors of clinical outcomes were evaluated. results: of the patients admitted to the emergency unit, patients were hospitalized and analyzed: median age was (iqr – ) years, and the majority of patients were males ( . %). median (iqr) days from covid- symptoms onset was ( – ) days. at hospital admission, fever (≥ . °c) was present in . % of patients. median oxygen saturation (spo ) was % (range – ), with median pao( )/fio( ) ratio, (iqr – ). median radiographic assessment of lung edema (rale) score was (iqr – ). more than half of the patients ( . %) had comorbidities, with hypertension, coronary heart disease, diabetes and chronic kidney failure being the most common. the probability of overall survival at day was %. multivariable analysis showed older age, coronary artery disease, cancer, low lymphocyte count and high rale score as factors independently associated with an increased risk of mortality. conclusion: in a large cohort of covid- patients of european origin, main risk factors for mortality were older age, comorbidities, low lymphocyte count and high rale. since the emergence of the severe acute respiratory syndrome coronavirus (sars-cov- ) in wuhan, hubei, china, in december , its potential to become a serious public health threat worldwide was apparent. the sars-cov- causing the coronavirus disease (covid- ) spread very rapidly and took a heavy death toll, with nearly . confirmed cases and more than deaths in the first month . extraordinary measures were established to control the outbreak in wuhan exceeding by far the classic definition of local confinement, lockdown and isolation. nevertheless, the sars-cov- has spread globally, and on march th , covid- was declared a pandemic by the world health organization (who). the first cases in europe were reported at the end of january . despite the time lapse since the outbreak in china, european healthcare systems were not prepared to cope with the steep increase in incidence and the large number of patients needing intensive care. the first confirmed case in europe, a patient with no travel history to china was reported on february, st in the lombardy region of northern italy. several more cases were reported in the following hours, with no apparent contact with the first patient nor with anyone known to have covid- . as of may th, , . individuals were known having been infected with sars-cov- in italy, of whom . died. clinical manifestations of covid- disease include a variety of presentations, spanning from asymptomatic disease to severe interstitial pneumonia with acute respiratory distress s yndrome (ards), and death. [ ] [ ] [ ] in the largest retrospective cohort study from china, hospitalized patients with covid- were relatively young (median age years), with males and females in similar proportions. older age and presence of comorbidities have been associated with increased mortality. , , however, demographic and anthropometric characteristics differ between asian and european populations , and these factors may impact clinical outcomes in patients with ards , . of note, the unexpected rapid spread of the covid- pandemic caused a dramatic overload of hospitals and intensive care unit (icus) in western countries. therefore, data on characteristics and outcomes of covid- patients in europe are crucial to the understanding of j o u r n a l p r e -p r o o f journal pre-proof the disease, to develop specific treatment plans, and to potentially optimize resource allocation by allowing early prognostic stratification. to date, available data from europe include those from a large retrospective cohort study of patients admitted to icu in italy , and a small case series of patients diagnosed with covid- in france. in this report we describe the demographical, clinical, radiological and laboratory characteristics, as well as the clinical outcomes and the risk factors for mortality, of the first patients with covid- admitted to san raffaele scientific institute, a tertiary care academic hospital in milan, italy. the study was approved by the institutional review board (irb), protocol number /int/ ). data were analyzed and interpreted by the authors, who also reviewed the manuscript and vouch for the accuracy and completeness of the data and for the adherence of the study to the protocol. informed consent was obtained according to the irb guidelines. all consecutive patients aged ≥ years admitted to the emergency department (ed) at irccs san raffaele with covid- infection between february th and march th, were enrolled in this cohort. patient data were censored at the time of data cut off, which occurred on may st, . an infection case was defined as a sars-cov- positive real-time reverse-transcriptase polymerase chain reaction (rt-pcr) from a nasal and/or throat swab together with signs, symptoms, or radiological findings suggestive of covid- pneumonia. the re-organization of the hospital to face the covid- outbreak has been recently reported. the hospital guidelines for j o u r n a l p r e -p r o o f journal pre-proof the management of respiratory failure are listed in table s supplementary appendix. lopinavir/ritonavir, remdesivir, hydroxychloroquine, azithromycin, were prescribed following italian recommendation (www.aifa.gov.it). in addition, we used immunomodulatory therapies with either anakinra (il- receptor antagonist), tocilizumab or sarilumab (anti-il receptor monoclonal antibodies), mavrilimumab (anti-human granulocyte macrophage colony-stimulating factor receptor monoclonal antibody), a novel anti-inflammatory agent that blocks complement (amy ) , reparixin (il inhibitor), or high-dose steroids in patients who displayed a hyper inflammatory laboratory profile in the context of expanded access programs or clinical trials. data were collected from medical chart review or directly by patient interview, and entered in a dedicated electronic case record form (ecrf) specifically developed on site for the covid-biob study. the geographical distribution of patients place of residence has been evaluated to represent the areas of patients referral. before analysis, data were data were cross-checked with medical charts and verified by data managers and clinicians, for accuracy. routine blood tests included: complete blood count (cbc) with differential, serum biochemical tests, including c-reactive protein (crp), electrolytes, renal and liver function tests. in addition, coagulation profile with d-dimer, lactate dehydrogenase (ldh), troponine, n-terminal prohormone of brain natriuretic peptide (nt-probnp), interleukin-(il-) and procalcitonin (pct) were available for a subgroup of patients. conventional chest x-ray (cxr) images were acquired in the postero-anterior (pa) or anteroposterior (ap) projections. cxr obtained at admission were blindly reviewed by consensus of two physicians (fdc and cm), with further review by an expert radiologist in case of disagreement. the following radiographic features were evaluated: ground glass opacities (ggo) and consolidation as defined by the fleischner society glossary of terms , hilar enlargement and pleural effusion. furthermore, lung opacity distribution was assessed and categorized in peripheral predominance, peri-hilar predominance, or neither. radiographic assessment of lung edema (rale) score was used to quantify the extent and severity of lung opacities. each radiographic quadrant was reviewed and assigned a score based on the extent of opacities ( - ) and their density ( - ); the final rale score (maximum score ) was then obtained by summing the product of the consolidation and density scores for each of the four quadrants. lastly all cxrs were analyzed by the artificial intelligence (ai) software (qxr v . , qure.ai technologies, india) designed to interpret covid- patients' plain radiographs and quantify the disease extension. each lung involvement percentage (cut-off %) was reported from the ai software analysis. median values with respective inter-quartiles ranges (iqr), were used to express continuous variables while frequencies in percentages were used for categorical variables. patient-related variables of survivors and non survivors were compared using the chi-square or fischer's exact test for categorical variables, and the wilcoxon rank sum or kruskal-wallis test for continuous variables. imputation for missing data was not performed. the ability of the two radiological score in predicting death was determined by the area-under-thecurve (auc) of receiver operating characteristics (roc) curves. for each score, the optimal cut-off value, predicting death, was determined on the highest youden index value (sensitivity + specificity - ). to evaluate the diagnostic accuracy of each radiological score, sensitivity, specificity, negative and positive predictive values with the corresponding % confidence intervals ( %ci) were estimated for both cut-off values. total accuracy was also assessed by the percentage of patients that were correctly classified by each score according to the corresponding optimal cut-off value. repeated-measures analyses using univariate mixed linear models (allowing correlated errors for a patient's multiple determinations) were used to estimate and compare laboratory changes among survivors and non-survivors. these models were fitted for each laboratory parameter to the j o u r n a l p r e -p r o o f available values, in the raw scale, determined during hospitalization; the models were fitted with random slope and intercept for each patient and the crude mean changes (slopes) were reported with the corresponding % confidence interval. kaplan-meier curves were used to estimate the probability of survival. the time-to-events was calculated from the date of hospital admission to the date of the event, or the date of last available visit, whichever occurred first. kaplan-meier curves on the time to death were estimated according to a number of covariates (on validated reference cut-offs or, if not available, on the overall median value) and compared by the log-rank test. to evaluate the association between patients characteristic and in-hospital death univariable and multivariable cox proportional hazards models were calculated. the effect estimates were reported as hazard ratio (hr) with the corresponding % ci, estimated according to the wald approximation. to avoid overfitting in the multivariable model, and considering the total number of events, the following variables deemed conceptually important, and known risk factors of covid- were included in the cox model: age (median value), sex, hypertension, coronary heart disease, diabetes, kidney failure, rale score, baseline lymphocyte count (median value) and c-reactive protein level (median value). the variables included in the models were fitted as time-fixed and measured at baseline. although we acknowledge that some factors are subject to change over time (e.g. laboratory parameters) and affect the considered outcomes, we did not fit a model with time - a total of patients were hospitalized and analyzed. all patients were followed for at least one month from the last patient admitted. the baseline characteristics, laboratory testing and cxr evaluation at admission of the patients who were hospitalized into the general covid- dedicated wards or into the icu are summarized in table for the subgroup of patients with available information at baseline (table ) overweight or obesity was reported in % of the patients. more than half of the patients ( . %) had comorbidities, with hypertension, coronary heart disease, diabetes and chronic kidney failure being the most common. overall, patients were under treatment for malignant diseases. as multivariable analysis ( our study describes a large series from an academic center reporting the clinical characteristics of patients from milano, lombardy, italy, one of the regions most affected by the covid- outbreak in europe. with a clinical observation longer than one months from the last patient admitted, w e were able to identify early predictors of mortality related to patient characteristics, radiological and laboratory findings at hospital admission for covid- . the results presented in this analysis reflect the first attempt to cope with a new dramatic disease as the covid- , with its atypical ards features. we aimed to provide a real life picture of the initial pandemic wave of the infection breakthrough which imposed a radical reshaping of the clinical activity at our tertiary care academic hospital. we increased the hospital capacity for treating covid- patients, moving rapidly from regular icu beds to covid- dedicated icu beds and repurposing a total of beds to covid- dedicated units. in this perspective, these results will be a reference to evaluate the potential benefits of further developments, new drugs and additional therapeutic measures in the near future. currently, the vast majority of clinical reports available on the covid- are from asian populations. , our study is the first addressing early risk factors associated with mortality in a j o u r n a l p r e -p r o o f population of european origin. we confirmed findings previously observed in patients from china and united states, including older age, associated comorbidities such as coronary artery disease, history of hypertension, diabetes, chronic obstructive lung disease and chronic renal failure . some other comorbidities, like cancer, were also identified as associated with increased mortality . the identification of underlying conditions of risk of vascular diseases is the first hallmark of our series and may reflect the increased risk of severity of the covid- spectrum in the caucasian cohort. these results translate into practical implications, on the targeting of such very high-risk population, and establishment of dedicated policies of social and work measures. in view of the upcoming post-pandemic long-wave with recurrent infection outbreaks , these findings are also of utmost importance for reducing the burden of the general health system, targeting the effort for adequate screening of the patients at risk. with regard to gender, we observed a large prevalence of male patients in our cohort, as already reported by others , but the mortality risk was not different, and this may be in part explained by the stronger effect of older age in our population. furthermore, we recognize a significant mortality in a cluster of elderly patients ( % of non survivors were years aged or more) with high burden of comorbidities and admitted with an advanced phase of respiratory distress. however the mortality in our elderly population is in line with the general lethality rate currently reported in italy, and highlights the need for early hospital referrals for this very high risk patients. a novel finding from our report is the high predictive value for mortality by the chest x-ray quantitative rale score at the admission, a marker of lung edema with high accuracy in the diagnosis of ards. rale score maintained a strong hazard ratio for mortality also in the multivariable analysis, suggesting this chest x-ray quantitative assessment as a simple tool for predicting clinical outcome very early, at the first patient evaluation at the ed . similarly, we have also demonstrated on a relevant proportion of patients, the prognostic impact of hyper-inflammation in covid- . at clinical presentation, non survivors had increased inflammatory markers which did not normalize throughout the entire hospitalization, suggesting a possible specific mechanism related with the pathogenesis of covid- . sars-cov- infection is likely responsible for a direct cellular damage and it also seems to enhance the host innate immune responses towards further tissue and vascular endothelial injuries . our data support the hypothesis of a covid- associated trombo-inflammatory syndrome, involving the endothelium and vessels primarily in the lung (microclots) , as one possible mechanism of the severe sars-cov- disease manifestations. of interest, the analysis of these markers may drive specific therapeutic interventions targeting selected inflammatory pathways , . one strength of our single center study is the observation time of more than one month that allowed us to capture the history of this new disease and describe in details the relevant events. this translates into a public interest in making our results and experience available, to contribute to a better targeting of patients at risk. importantly, we have set up a plan of systematic intervention of outpatient follow up visits, which includes sample collection for a biobanking in order to ensure a better understanding of the natural history and the biology of this new disease and to warrant the highest level of care for these patients. although we are confident that the major confounders were considered, we cannot exclude that residual confounding factors may still be present. we were unable to analyze the impact of socioeconomic status as a potential indirect factor for mortality. indeed, we can affirm that its effect in our results would have been mitigated by the national care system-based access for people living in italy. in conclusion, our results clearly identify risk factors for mortality in patients from a definite territorial area treated at the time of the covid- pandemia breakthrough in italy. we identified j o u r n a l p r e -p r o o f director-general's opening remarks at the media briefing on covid- the effect of control strategies to reduce social mixing on outcomes of the covid- epidemic in wuhan, china: a modelling study novel coronavirus( -ncov) situation report - clinical features of patients infected with novel coronavirus in wuhan, china clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china clinical characteristics of coronavirus disease in china clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study body composition phenotypes in pathways to obesity and the metabolic syndrome ards in obese patients: specificities and management acute respiratory distress syndrome baseline characteristics and outcomes of patients infected with sars-cov- admitted to icus of the lombardy region clinical and virological data of the first cases of covid- in europe: a case series fast reshaping of intensive care unit facilities in a large metropolitan hospital in milan, italy: facing the covid- pandemic emergency fleischner society: glossary of terms for thoracic imaging severity scoring of lung oedema on the chest radiograph is associated with clinical outcomes in ards early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the the novel coronavirus disease (covid- ) threat for patients with cardiovascular disease and cancer projecting the transmission dynamics of sars-cov- through the postpandemic period epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study functional exhaustion of antiviral lymphocytes in covid- patients complex immune dysregulation in covid- patients with severe respiratory failure microvascular covid- lung vessels obstructive thromboinflammatory syndrome (microclots): an atypical acute respiratory distress syndrome working hypothesis pharmacologic treatments for coronavirus disease (covid- ): a review the first case of covid- treated with the complement c inhibitor amy- the authors thank the entire staff of the san raffaele scientific institute, working every day to ensure the best quality of care to patients and their families. we dedicate this work to the memory of the italian health care workers who have given their lives in the care of patients with covid- . key: cord- -is pol authors: he, jingjing; guo, yifei; mao, richeng; zhang, jiming title: proportion of asymptomatic coronavirus disease (covid‐ ): a systematic review and meta‐analysis date: - - journal: j med virol doi: . /jmv. sha: doc_id: cord_uid: is pol objective: we aim to systematically review the characteristics of asymptomatic infection in the coronavirus disease (covid‐ ). methods: pubmed and embase were electronically searched to identify original studies containing the rate of asymptomatic infection in covid‐ patients before may . then mate‐analysis was conducted using r version . . . results: a total of patients from studies with confirmed covid‐ were included. the pooled percentage of asymptomatic infection is . % ( % ci: . %‐ . %). ten included studies contain the number of pre‐symptomatic patients, who were asymptomatic at screening point and developed symptoms during follow‐up. the pooled percentage of pre‐symptomatic infection among initially asymptomatic patients is . % ( % ci: . ‐ . %). the pooled proportion of asymptomatic infection among covid‐ children from studies is . % ( % ci: . – . %), which is much higher than patients from all aged groups. abnormal ct features are common in asymptomatic covid‐ infection. for patients from studies that ct results were available, ( . %) patients had bilateral involvement and ( . %) had unilateral involvement in ct results. reduced white blood cell count, increased lactate dehydrogenase, and increased c‐reactive protein were also recorded. conclusion: about . % of confirmed covid‐ patients are asymptomatic. nearly half of the patients with no symptoms at detection time will develop symptoms later. children are likely to have a higher proportion of asymptomatic infection than adults. asymptomatic covid‐ patients could have abnormal laboratory and radiational manifestations which can be used as screening strategies to identify asymptomatic infection. this article is protected by copyright. all rights reserved. the current covid- pneumonia pandemic, caused by a novel coronavirus sars-cov- that belongs to the beta-coronavirus lineage b, is spreading globally at an accelerated rate. first reported in a seafood market in wuhan province china in december , this disease is now affecting more than countries around the world. as of june th , , a total number of laboratory-confirmed cases have been documented globally, leading to deaths , which is far more than two clinical manifestation of covid- is protean. significant clinical presentations of covid- include fever, respiratory and gastrointestinal symptoms, pneumonia , and other symptoms such as myasthenia, ageusia, and anosmia . however, patients infected with sars-cov- could also be asymptomatic, confirmed by positive nucleic acid testing results during the illness. as a potential source of covid- infection, asymptomatic patients with subclinical manifestation could be missed by detection strategies and put a threat to infection control via person-to-person contact. asymptomatic cases inevitably distorting the covid- epidemiologic reality. while a variety of studies on asymptomatic infection have been reported, the proportion of asymptomatic patients in confirmed covid- cases is not well characterized. we conducted this meta-analysis to better understand the asymptomatic infection of covid- . two databases including pubmed and embase were searched before may following the prisma guideline. we included the following items: records were identified through database searching. confirmed covid- was defined as one that had a throat-swab or other specimen tested positive for sars-cov using real-time rt-pcr assay. asymptomatic infection was defined as patients who developed no symptoms such as fever, cough, or diarrhea during illness. a presymptomatic case was defined as a patient who has no symptoms at diagnosis time but developed symptoms during follow-up. patients with no symptoms at screening point were defined as the number of asymptomatic patients plus the number of pre-accepted article symptomatic patients. two authors (he and guo) extracted data independently. disagreements were resolved by discussion until consensus was reached or by consulting a third author. including criteria included: ) study objectives: patients confirmed infected with sars-cov- (including adult, pediatric patients, and pregnant women). ) study types: prospective/retrospective cross-section cohort studies. there was no language restriction. original articles reporting asymptomatic infection in confirmed covid- patients were included for meta-analysis. the methodological quality of the studies included in meta-analysis was assessed using an -item checklist which was recommended by agency for healthcare research and quality (ahrq). if an item was answered 'no' or 'unclear' it would be scored ' ' and if it was answered 'yes', then the item scored ' '. article quality was assessed as follows: low quality = - ; moderate quality = - ; high quality = - . after removing the duplicates, the abstract review was conducted through titles and abstracts. the following data were extracted: author, date of publication, site of study, study group, total number of people included in the study, age, sex, the number of all statistical analysis was performed using r version . . (r foundation for statistical computing) statistical software and rstudio. packages "meta", "metafor", and accepted article "weightr" were used. the proportion of asymptomatic infection was transformed using the logit transformation to make it conform to the normal distribution. a random effects model was applied to calculate the effect size and its % confidence interval ( % ci) by the method of moments (the dorsmanin and laird method) and as presented by forest plot. the tau and i statistic was used to estimate the proportion of the observed heterogeneity. studies containing the number of pre-symptomatic patients were extracted to analyze the proportion of pre-symptomatic infection in patients with no symptoms at screening point. untransformed proportions and a random effects model by the method of moments (the dorsmanin and laird method) were applied to calculate the effect size and its % confidence interval ( % ci) and as presented by forest plot. leave-one-out diagnostics and regression diagnostics were used to identify influential studies that pronouncedly contribute to heterogeneity in meta-analytic data. meta-analysis via linear was conducted to find the factor attributing to the overall heterogeneity, which was described in the article published by wang in . subgroup summary proportion analysis were conducted to explain the factor contributing to heterogeneity. then subgroups forest plot was created by different study group: all, children, pregnant women or elderly people, and different place: china or outside of china. publication bias was detected with funnel plot and egger's regression test. study process is depicted in supplementary materials: figure america: , europe region: , uk: , brunei: , iraqi kurdistan: , thailand: , and japan: ). all studies were of high ( ) or moderate ( ) quality. there were no articles with low quality rating. there was a total of studies containing the number of patients who were identified as silent covid- patients but developed symptoms during follow-up. a total of initial no-symptoms covid- patients were included. the pooled percentage of pre-symptomatic infection among patients with no symptoms at screening point is . % ( % ci: . - . %) with heterogeneity noted among studies (p < . , i : %) ( figure ). there were studies of people in study cohorts from all age groups, (figure ). there was a significant subgroup difference between the studies (p= . ). the pooled prevalence of asymptomatic infection was . % ( % ci: . - . %) and . % ( % ci: . - . %) in studies from china and other countries respectively ( figure ). the p value between these two groups is . with no significance. there was significant heterogeneity among the studies conducted in china (p< . ; i = . %) and fewer heterogeneity studies from other countries (p< . ; i = . %). leave-one-out diagnostics (supplementary materials: figure egger's regression test indicate that there may be publication bias (t= . , p < . ). fifty-nine patients from studies included in the meta-analysis , - and additional case series study ( , ) . in those two studies, . % ( / ) of asymptomatic patients had reduced white blood cell count, . % ( / ) of patients showed increased lactate dehydrogenase, and . % ( / ) of patients recorded increased c-reactive protein. increased creatine kinase-mb, both decreased lymphocyte count and increased lymphocyte count were also recorded in those two studies. noticeably, one study from wuhan showed that / ( . %) nucleic acid testing negative patients had lgg positive results, suggesting possible recovery from asymptomatic sars-cov- infection . a study from germany also demonstrates the importance of serological tests in covid- . in / ( . %) healthcare workers sars-cov- -igg antibodies could be detected. four of the five subjects were tested negative for sars-cov- via pcr. one subject was not tested via pcr since he was asymptomatic . all those results suggest that asymptomatic patients could use serological tests to detect covid- infection. asymptomatic infection was believed to be less contagious as a consequence of a decreased virulence throughout the successive transmission, like sars-cov. in the study conducted by schwierzeck et.al, the viral load of asymptomatic patients is lower than symptomatic cases . this result was supported by a mass screening by rivett et.al of health care workers as well as their contacts in the uk. viral loads were significantly lower for asymptomatic health care workers screening group than in those individuals tested positive due to the presence of symptoms . however, it's accepted article still too early to conclude that asymptomatic patients are less likely to transmit the virus. relatively high viral load was also detected in asymptomatic patients , and the stool sample was tested positive in a well infant of covid- , a man in his s probing into asymptomatic infection proportion is a useful quantity to understand the true burden of disease transmission. 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patient: epidemiological and clinical challenge in settings with limited community transmission detection of novel coronavirus by rt-pcr in stool specimen from asymptomatic child, china. emerging infectious diseases clinical characteristics of asymptomatic infections with covid- screened among close contacts in nanjing, china. science china life sciences familial cluster of covid- infection from an asymptomatic presumed asymptomatic carrier transmission of covid- potential presymptomatic transmission of sars-cov- the present study was supported by the shanghai pujiang pujiang program ( pjd ) and the national natural science foundation of china ( , , and ). the authors have declared that no competing interest exists. the data that support the findings of this study are available from the corresponding author upon reasonable request. key: cord- - aq authors: cajamarca-baron, jairo; guavita-navarro, diana; buitrago-bohorquez, jhon; gallego-cardona, laura; navas, angela; cubides, hector; arredondo, ana maría; escobar, alejandro; rojas-villarraga, adriana title: sars-cov- (covid- ) in patients with some degree of immunosuppression date: - - journal: nan doi: . /j.reumae. . . sha: doc_id: cord_uid: aq background it is not clear whether patients with some degree of immunosuppression have worse outcomes in sars-cov- infection, compared to healthy people. objective to carry out a narrative review of the information available on infection by sars-cov- in immunosuppressed patients, especially patients with cancer, transplanted, neurological diseases, primary and secondary immunodeficiencies. results patients with cancer and recent cancer treatment (chemotherapy or surgery) and sars-cov- infection have a higher risk of worse outcomes. in transplant patients (renal, cardiac and hepatic), with neurological pathologies (multiple sclerosis (ms), neuromyelitis optica (nmods), myasthenia gravis (mg)), primary immunodeficiencies and infection with human immunodeficiency virus (hiv) in association with immunosuppressants, studies have shown no tendency for worse outcomes. conclusion given the little evidence we have so far, the behaviour of sars-cov- infection in immunosuppressed patients is unclear, but current studies have not shown worse outcomes, except for patients with cancer. in december , a group of five patients with severe pneumonia of unknown origin were reported to have had contact with a seafood market in the city of wuhan, hubei province, china, as an epidemiological link. the chinese centre for disease control and prevention (china cdc), deployed a rapid response for the epidemiological and aetiological investigation of cases and identified a new coronavirus with the ability to cause severe lung disease that can rapidly progress to death in affected patients. , given its rapid progression and the poor knowledge of the infection, how it behaves in patients with multiple comorbidities is not clear, especially patients with some degree of immunosuppression, due either to their underlying disease or to the use of immunosuppressants to manage it. in this review, we will focus on describing the literature on sars-cov- infection in patients with some degree of immunosuppression, other than rheumatological diseases, among these, cancer patients, transplant recipients, primary immunodeficiency, and hiv patients. initially the virus was termed the new coronavirus ( -ncov) and variations of same. sars-cov- is the name currently used for the virus, which shares genetic similarities with the sars-cov virus. covid- (coronavirus disease ) is the name of the disease generated by sars-cov- infection. j o u r n a l p r e -p r o o f epidemiology from december th to th, samples of bronchoalveolar lavage fluid were collected from patients hospitalized for severe pneumonia in the city of wuhan, the epicentre of the pandemic, and the new coronavirus was isolated. results for viruses such as severe acute respiratory syndrome (sars-cov), middle east respiratory syndrome coronavirus (mers-cov), influenza, avian influenza, and other common respiratory pathogens were negative. , on january , a case series of confirmed sars-cov- patients treated at a wuhan hospital was released. most were male ( %), with a median age of years, and less than half had comorbidities ( %) such as diabetes mellitus ( %), hypertension ( %), and cardiovascular disease ( %). of these patients, % had a history of exposure to the seafood market. in another case series of hospitalized patients in wuhan, china, % of the infected patients were presumed to have been infected by nosocomial transmission, % of the patients required icu hospitalization, and mortality was about . %. the infection rapidly escalated and was declared a public health emergency by the world health organization (who) on january , . as of today, june , affected countries have been reported, and the number of confirmed cases worldwide is close to ten million ( , , ) , with a total of , deaths and , , cases that have recovered. the country with the most confirmed cases is currently the united states, followed by brazil and russia. china, the first country affected, has a declining case curve and is now in twentieth place worldwide. in the americas, there are , , confirmed cases with , deaths; the united states and brazil together account for % of all cases and % of all deaths currently reported in the region. infection in children is less frequent and most reported cases are among family members and, to a lesser extent, from close contact with infected patients. j o u r n a l p r e -p r o o f the coronaviruses (cov) are a group of viruses discovered in that have a single strand of rna (~ - kb in length) that codes for structural, envelope, membrane and nucleotide proteins, as well as for non-structural proteins. they belong to the coronaviridae family which in turn is part of a larger family, the nidovirals. the coronaviridae family is divided into two subfamilies: orthocoronavirinae and torovirinae. the former is classified into four genera: alphacoronavirus, betacoronavirus, gammacoronavirus and deltacoronavirus. they are zoonotic viruses, bats have been acknowledged as natural hosts, but six types have been recognized as having the ability to infect humans: two alpha-coronaviruses ( e and nl ) and four betacoronaviruses (oc , hku , sars-cov and mers-cov). , , in , there was an outbreak of sars-cov that caused deaths worldwide. in , mers-cov was discovered in middle eastern countries with a fatality rate of . %. sars-cov- is a betacoronavirus, subgenus sarbecovirus and from the subfamily orthocoronavirinae with an envelope composed of a lipid bilayer derived from the host membrane. the genome encodes for spike glycoprotein (s), small envelope protein (e), membrane protein (m), and nucleocapsid protein (n). it also encodes accessory proteins that interfere with the host's immune response. its name is due to its similarity to a crown, given the spherical morphology of the virus and the projections on its surface that correspond to the s protein, which is glycosylated and mediates the viral entry into the host cells. the m protein gives the shape to the viral particle and together with the e protein directs the assembly of the virus and its maturation. the n protein participates in the packaging of the viral rna during assembly. haemagglutinin is one of the accessory proteins, which binds to sialic acid in host glycoproteins, improving entry into the cell. like sars-cov, sars-cov- uses the receptor for the angiotensin converting enzyme (ace ) as a means of entry into the cell where it binds by means of the s protein, however, unlike the other viruses, sars-cov- binding is much stronger since this protein undergoes a residue substitution in its c-terminal domain that increases affinity for the receptor. , the s protein has two subunits, s which determines the cell tropism and s which mediates the fusion of the virion to the membrane so that it can enter the cell where it rapidly translates two polyproteins that form the replication/transcription complex into a double-membrane vesicle; the virion contained in these vesicles fuses with the plasma membrane to be released later. the viral genome found in cytoplasm acts as pathogen-associated molecular patterns (pamps) and are recognized by the molecular pattern recognition receptors (prrs) that are toll-like receptors (tlr , tlr , tlr and tlr ). the rig-i receptor (retinoic-acid inducible gene-i), the cytosolic receptor mda- (melanoma differentiation-associated gene ) and cgas (nucleotidyltransferase cyclic gmp-amp synthase) recognize viral rna and recruit adaptive molecules that trigger a response cascade leading to the activation of the nuclear transcription factor- and interferon regulatory factor (irf ), producing interferon  and  and pro-inflammatory cytokines. different elevated cytokines have been found in patients with covid- : il- , il , il- , il- , il- , il- , il- , il- , macrophage colony-stimulating factor (mcsf), mcp- , hepatocyte growth factor (hgf), ifn- and tnf-. this supports the fact that lung damage is secondary to a cytokine storm induced by the inflammatory response, resulting in the person entering a critical condition. , the transmission dynamics are not yet fully known. the intermediate host between the natural reservoir and humans is unknown. however, it has been possible to confirm person-to-person transmission, which contributes to the rapid spread of the disease, and this is confirmed by the data found in the case series, which show that as of january , % of cases were linked to the seafood market in wuhan (china); however, of the cases reported after this date, only . % had this link. to date, person-to-person transmission has been considered to occur via respiratory droplets produced by coughing or sneezing. however, the presence of the virus has been detected in other fluids such as blood, faeces, and saliva. , initially, it was believed that spread was by people with clinical manifestations. however, it has been shown that asymptomatic carriers also transmit, and some people have even been recognized as "super spreaders", infecting many people, including health workers. vertical transmission of the virus in pregnancy has not been proven, however it is not known whether there is a risk during delivery through the vaginal canal. clinical manifestations can range from being asymptomatic to acute respiratory distress syndrome and multiorgan dysfunction. the incubation period is estimated at . days; however, this can vary. in the first case series of zhu et al. and ren et al. of patients treated at a hospital in hubei, the predominant symptoms were dry cough, dyspnoea, and fever. lung opacities consistent with a pneumonic process, worsening rapidly (two to four days) and requiring invasive mechanical ventilation, are recorded. , in general, the most common clinical manifestations are fever (although not present in all cases), cough, odynophagia, fatigue, and myalgia. other less frequent symptoms are sputum production, headache, haemoptysis, and diarrhoea. cases of keratoconjunctivitis and fulminant myocarditis have also been described. , , in early stages of the disease, chest x-ray can be normal, but as the disease progresses, bilateral ground glass opacity or consolidation can be found in more than % of patients. chest ct is much more sensitive than radiography. these findings can be found in asymptomatic patients. , it has been reported that up to % of patients will have no radiological changes. as for laboratory findings, lymphopenia was common, found in more than % of patients, with less frequent evidence of thrombocytopenia and leukopenia. a large proportion presented with elevated c-reactive protein, and in fewer cases, elevated alanine aminotransferase, aspartate aminotransferase, creatine kinase, and d-dimer were found. disturbances are pronounced in patients with severe disease. in the different case series and epidemiological reports published since the appearance of sars-cov- , comorbidities have been highlighted as risk factors associated with severity. it has also been established that patients admitted to the intensive care unit have more comorbidities than those in general hospitalization. the most prevalent underlying diseases are high blood pressure, diabetes mellitus, cardiovascular and cerebrovascular disease. , the results of nine metaanalyses in patients with covid- published to date are summarised in tables and . table presents the prevalence of comorbidities in patients with covid- , most of them hospitalized, and analysed through seven meta-analyses. in turn, table shows the risk associated with severity, death, or fatality due to the presence of comorbidities, through seven meta-analyses. the meta-analysis by wang et al. is noteworthy, which identifies arterial hypertension, diabetes mellitus, chronic obstructive pulmonary disease (copd), cardiovascular and cerebrovascular disease as factors that negatively impact mortality. specifically, copd increases by . times the risk of progression and deterioration of patients with covid- . these data are supported by the results of another meta-analysis by zhao et al. where the severity of covid- is four times higher in copd patients; they also assessed the impact of active smoking, which increases the risk of severe covid- two-fold. it has been widely demonstrated that patients suffering from diabetes mellitus are admitted more frequently to the intensive care unit and have a higher mortality, as shown in table . the results of a primary study by roncon et al. are highlighted (or . , % ci . - . ; p < . , i = %). these patients tend to present a more severe pneumonic process, with greater inflammatory response and tissue damage, which makes them more prone to cytokine storm leading to rapid deterioration, which is why patients with this history should be strictly monitored. cardiovascular disease is a risk factor per se increased by covid- infection that generates or aggravates myocardial damage, but when associated with myocardial injury the results are usually fatal for patients. , among other comorbidities, chronic kidney disease is associated with in-hospital mortality, as are cancer and cerebrovascular disease, demonstrated through two meta-analyses that included over fifteen thousand patients ( table ) ; studies suggest that superficial fungal infections and psoriasis confer vulnerability to covid- ; a body mass index (bmi) > kg/m is an independent risk factor for complications from the infection; and there are discouraging results regarding underlying neurological disease and sars-cov- . [ ] [ ] [ ] [ ] in general, the presence of comorbidities should imply strict follow-up of patients to detect early complications; however, more attention should be paid to certain comorbidities where strong associations have been found with covid- infection and its severe outcomes. overall mortality is . % to %, but it changes to % to % among patients requiring hospitalization and increases to % in critically ill patients. studies have shown two peaks, at and days. among the causes of death, respiratory failure prevails, followed by shock due to myocardial dysfunction and finally, the combination of the two. it is important to maintain a high degree of diagnostic suspicion in patients with fever or respiratory symptoms who have travelled to affected areas or have had close contact with j o u r n a l p r e -p r o o f suspected or confirmed cases days before the onset of symptoms. in this scenario, confirmation by molecular testing is required. real-time reverse transcription polymerase chain reaction is performed on specimens collected from the lower or upper respiratory tract if the former cannot be obtained. there are several assays that are performed on serum or plasma for the detection of both viral proteins and antibodies. the most widely used are to detect immunoglobulin g (igg) and immunoglobulin m (igm) antibodies, which are produced in the second week of infection. there are several therapeutic goals and they are directed at different levels: inhibition of virus entry into the cell, inhibition of fusion of the viral envelope to the membrane, transcription inhibition, inhibition of viral proteins and blockade of il- signalling to prevent the cytokine storm. at first, chloroquine (clc) and hydroxychloroquine (hcq) were shown to block sars-cov- in vitro, with better results for the latter and therefore its use was indicated for the management of covid- infection. promising results have been shown in case series; however, the studies have limitations such as the sample size used. however, preliminary results were recently published from the recovery study, a randomized clinical trial to evaluate potential drugs for management of the infection in the united kingdom, in which they concluded no beneficial effect of the use of antimalarials in hospitalized patients, and therefore they stopped including patients for this treatment arm and the recommendation that it should not be used has been extended worldwide. additional results have recently been published in several articles on the efficacy and safety of the antimalarials chloroquine and hydroxychloroquine for the treatment of different phases of sars-cov- infection. however, the data are controversial, some not demonstrating efficacy or reporting a high number of adverse events, primarily associated with cardiac arrhythmias. it is important to note that a number of criticisms and concerns have been raised regarding the accuracy of the data from these studies and they have therefore been withdrawn. to date there are more than clinical trials underway with hcq, and with clq, several of which are in prophylactic use in healthcare workers and others post-exposure. , lopinavir/ritonavir has studies in sars and mers, the data published for covid- are reports and retrospective studies with which the effect cannot be established with certainty. there is a clinical j o u r n a l p r e -p r o o f trial of patients with covid- with no difference in mortality, hospital discharge or recovery. however, despite this, in some centres it is still being used at doses of mg/ mg twice a day for days. ribavirin, like lopinavir/ritonavir, has activity against other coronaviruses and was considered to be a possible treatment for sars-cov- ; however, studies carried out for sars show limited, highdose activity leading to a high rate of haematological and hepatic adverse events, therefore its use is now limited. , other antivirals such as oseltamivir were used in the first cases in hubei, china, because it was suspected to be seasonal influenza; they are now not indicated for use in sars-cov- . remdesivir is a nucleoside analogue that showed in vitro activity against sars-cov- , used later in a -patient cohort in canada, the united states, europe, and japan, achieving a satisfactory response in patients. based on preliminary studies, some drug regulatory agencies (united states and japan), conducted emergency approvals for use in hospitalized patients. results from ongoing studies are expected to evaluate efficacy and safety. currently umifenovir or arbidol is under study, an antiviral that aims to inhibit the interaction between protein s and ace . the use of corticosteroids is limited in sars-cov- infection to scenarios of chronic obstructive pulmonary disease exacerbation and refractory shock, taking into account previous studies in influenza pneumonia where they were associated with increased mortality. recently, preliminary results from the recovery study showed that the use of dexamethasone reduced mortality in one-third of critically ill patients who were on mechanical ventilation, while reduction was onefifth in those receiving non-invasive oxygen. definitive results are expected from this and the more than clinical trials currently underway to define the particular subgroups that would benefit from this treatment. monoclonal antibodies against il- are another therapy studied, in phases of adult respiratory distress syndrome (ards), with promising results in small case series. convalescent plasma is another therapy used as salvage in sars and mers. at the beginning of the pandemic, a case series of five critical patients from china, who were given convalescent plasma, showed improvement in their clinical status. more recently, several case series and preliminary trial results have demonstrated clinical benefits and decreased mortality with its use, particularly in hospitalized patients with moderate to severe involvement; however, results from more than j o u r n a l p r e -p r o o f clinical trials are awaited to clarify the characteristics of the plasma, the donors, and the specific individuals who could benefit. despite the abovementioned therapies, there is still no specific treatment and therefore the recommendations are symptomatic management in mild cases, supportive therapy in cases of critical illness and management of ventilation in cases of ards. immunosuppression and sars-cov- given the suddenness of the pandemic, and its rapid spread, little is known about sars-cov- infection and certain types of condition or disease, this is the case for people with some type of immunosuppression (either primary, associated to underlying or pharmacological diseases), which given the physiopathogenesis of sars-cov- infection known so far, would raise two hypotheses: it could be a possible benefit, since this state of immunosuppression could avoid that uncontrolled immune response or "cytokine storm", but on the other hand, it is equally clear from previous studies that immunosuppressant use or status is associated with increased risk of infection. in epidemics such as the abovementioned sars-cov, immunosuppressed patients, especially transplant recipients, did not have worse outcomes than the general population. , similar findings were presented in the mers epidemic, being male, advanced age and comorbidities such as diabetes mellitus, obesity, pulmonary pathology and renal disease being found as risk factors, and immunosuppression status not being associated as a factor of poor prognosis. to date, the centres for disease control and prevention (cdc) and other international agencies have included as poor prognostic factors patients with some degree of immunosuppression, including people with a history of cancer treatment, smokers, transplant recipients, people with immunodeficiencies, poorly controlled hiv or aids and people with prolonged use of steroids or immunosuppressive drugs, all based on previous studies that associate such diseases with respiratory infections, especially of viral aetiology. current evidence of conditions associated with immunosuppression and sars-cov- infection j o u r n a l p r e -p r o o f c a n c e r on march , liang et al., published a study collecting data from hospitals in china, up until january , , on patients with sars-cov- , comparing those with a history of cancer and those without. they collected , patients, ( %) with a history of cancer. the most frequent neoplasm was lung (five cases [ %]), and of the total cancer patients, four ( %) had undergone chemotherapy or surgery within the previous month, and the rest were cancer survivors, with strict follow-up. in terms of sociodemographic characteristics, the cancer patients were older, had a greater history of exposure to cigarettes, presented more polypnoea and had more severe pulmonary tomographic manifestations. in the analysis of outcomes, they showed that patients with a history of cancer and sar s-cov- infection were at greater risk of serious events (defined as the percentage of patients admitted to the intensive care unit requiring invasive ventilation or death) compared to patients without cancer (seven ( %) of patients vs. ( %) of , patients; p = . ). in addition, patients who underwent chemotherapy or surgery in the last month had a higher risk (three ( %) out of four patients) of clinically severe events than those who had not undergone chemotherapy or surgery (six ( %) out of patients). these data were confirmed by logistic regression (odds ratio (or) . ; % ci . - . ; p = . ) after adjusting for other risk factors such as age and smoking history. in addition, the patients with cancer deteriorated more rapidly than those without cancer (median time to severe events days (ci - vs. days, -unreached; p <. ). furthermore, desai et al., recently published a meta-analysis, in which they included studies, finding a prevalence of cancer in patients with covid- of % (ci . %- . %; i = . %). we should clarify that some authors consider that the current evidence is insufficient in this field, however, the number of research results has been increasing, showing similar results. , taking into account the results mentioned, it can be stated that cancer and its recent treatment are bad prognostic factors for sars-cov- infection. therefore, special recommendations should be considered for these patients, such as postponing adjuvant chemotherapy or elective surgery in people with "stable" cancer, especially in endemic areas, adopting stricter personal protection measures for cancer patients or cancer survivors, and considering stricter surveillance or treatment when cancer patients are infected with sars-cov- . in general, decisions should be made on a "patient-to-patient" basis. , t r a n s p l an t we highlight the study of a case series, two heart and kidney transplants and one liver (paediatric population). the heart transplant patients were confirmed by pcr to be infected, one of them was years old, came with immunosuppression with tacrolimus mg per day and mycophenolate g per day, and attended consultation for fever, fatigue and liquid stools, with characteristic findings of sars-cov- infection on chest tomography. he presented criteria of severe pneumonia, immunosuppression was discontinued, and he was managed with immunoglobulin (ivig) g/day and methylprednisolone mg/day and made adequate medical progress. the second patient, years old, in immunosuppression with tacrolimus . mg a day and mycophenolate g a day, attended with fever and fatigue, had lymphopenia, did not require hospitalization, nor discontinuation of immunosuppression, and was managed with ceftriaxone and ganciclovir, with an adequate outcome. their adequate clinical course suggests that in patients with this type of transplant the disease has a similar presentation to non-transplanted patients. it should be noted that in a series of seven cases (two liver, three kidney, one lung and one heart) an initial attenuated inflammatory response was evident, suggesting that although patients with transplant immunosuppression may have higher susceptibility to sars-cov- infection, their clinical course could be similar to that of immunocompetent patients. with regard to the renal transplantation patients, until the time of the report, a -year-old patient remained in icu managed with lopinavir/ritonavir, requiring suspension of immunosuppression who came under management with tracrolimus, everolimus and prednisolone at intermediate doses. he was admitted for fever and vomiting that progressed to respiratory symptoms, and had thrombocytopenia, lymphopenia, and elevated d-dimer as factors of poor prognosis. the second, a -year-old, under immunosuppression with tacrolimus, mycophenolate, and prednisolone, consulted for fatigue, abdominal pain, dyspnoea, fever, and dry cough, presented lymphopenia and imaging findings typical of sars-cov- infection. he was managed with ivig ( g, then g/day x days), methylprednisolone mg/day and interferon α ( million/u day), in addition to suspension of immunosuppression, and responded adequately to treatment. with regard to this type of transplant, the atypical presentation of the first case is noteworthy, and the adequate response of the second that could be associated with the use of multiple therapies, without it being possible conclude whether renal transplantation is associated or not with a worse prognosis. gandolfini et al., publish two cases of renal transplant and covid- , a -year-old male and a -year-old female patient under management with tacrolimus, corticoids and mycophenolate, who developed severe pneumonia; in addition to suspending immunosuppressants, management with hydroxychloroquine, lopinavir/ritonavir and colchicine was started, due to the unavailability of tocilizumab. the administration of colchicine achieved an impact in decreasing il- serum levels, thanks to its interfering with inflammasome assembly which leads to the production of il- b and other interleukins such as il- . in italy, the paediatric liver transplant group of hospital papa giovanni xxiii bergamo followed up liver transplants (two in the last three months), associated with autoimmune liver diseases ( patients), three additionally in chemotherapy (for hepatoblastoma). of the total number of transplant recipients, three were confirmed to be infected with sars-cov , and all remained asymptomatic without requiring hospitalization or suspension of immunosuppression. additionally, qin et al. , report the case of a patient with hepatocellular carcinoma who underwent liver transplantation and suffered an undetected sars-cov- infection in the perioperative period; immunosuppression was initiated with tacrolimus and glucocorticoids; however, persistence of fever led to confirmation of sars-cov- infection; management with oseltamivir and immunoglobulin was initiated, and despite a prolonged convalescence, they did not present multiorgan failure, thus immunosuppression was maintained. the importance of sars cov- detection is highlighted for organ receptors and donors to reduce the transmission and risk of severe infection or rejection due to adjustments in immunosuppression. given the above, it is not clear whether transplantation and use of immunosuppressants in this context is a risk or severity factor for sars-cov- infection. likewise, in the event of sars-cov- infection, the adjustment or suspension of immunosuppressors should be assessed, and we should always seek to protect graft function with the administration of glucocorticoid doses and support measures, among others. neurology is a continuously growing specialty. many diseases have a component that compromises autoimmune aggression to a greater or lesser extent and therefore go on to require immunosuppressant or immunomodulatory management. within the multiple entities, two diseases have become relevant in recent times, multiple sclerosis and optical neuromyelitis, due on the one hand to their physiopathological mechanism that involves neurodegeneration and inflammation by excessive activity of the immune system derived from antigenic epitopes and proinflammatory molecules, and on the other hand the use of therapies that trigger regulation of immune cells, affecting in some cases innate and adaptive immunity in most cases. if we consider that the response mechanisms to viral infections are based on inhibition of the infection by type i interferons and the death of the infected cells by nk lymphocytes (innate immunity), the generation of antibodies that block the union and entry of the virus into the cells, and the elimination of cells infected by cytotoxic t cells (adaptive immunity), the different drugs currently used could to a greater or lesser extent alter the immune response to sars-cov- infection, and this is why there are now different considerations when initiating or continuing therapies. people with ms are at higher risk of admission to the intensive care unit due to infections, and higher mortality at one year after admission than the general population. the use of diseasemodifying therapies implies a higher risk of infections, however, to date there is no data to indicate that patients with ms are at higher risk of sars-cov- infection, or more severe infection. it is even possible that such disease-modifying therapies and their immunosuppressive effect may play a protective role during -covid infection by preventing or dampening hyperimmune activity that, in some cases, could lead to clinical deterioration; there is even a report of a patient with primary progressive multiple sclerosis receiving treatment with ocrelizumab and becoming infected with sars-cov- , in the context of lymphopenia and hypogammaglobulinema expected for this type of treatment, without generating major clinical complications, this hypothesis is obviously limited for now only to academic deductions and limited information. , in recent results of the multicentre registry covisep, which includes information from patients with ms and covid- , it was demonstrated that age, obesity and highest score in the expanded disability status scale, were independent risk factors for severity of covid- . it is suggested that people with ms and related disorders receiving immunotherapy continue to receive the therapy during mild viral infections. in those with documented mild sars-cov- infection, it may be reasonable to continue treatment. neurologists should have a lower threshold for suspending treatment in people taking therapies with greater immunosuppressant effects. consideration should be given to suspending treatment in those who are hospitalized with severe or complicated sars-cov- infection. treatment may be restarted after four weeks or when symptoms have completely resolved, considering the risk of rebound of ms activity with s p modulators and natalizumab. neurologists should alert intensive care physicians to the importance of fever management in people with ms. in people with ms and disease-modifying treatment, the decision to start, continue, temporarily suspend, or defer doses should be individualized, taking into account factors such as disease activity and the possibility of disease progression, as well as considerations of the mechanism of action of the drugs and their ability to deplete lymphocytes. recommendations from experts suggest not suspending first-line drugs (interferons, glatiramer acetate, teriflunomide, or dimethyl fumarate) and considering deferring therapies such as cladribidine and alemtuzumab based on their ability to deplete lymphocyte counts rapidly and aggressively. , a survey of patients with nmosd or ms from china, from centres, did not find an increased risk of infection by covid- , suggesting as a possibility the role of self-care and protective measures taken by patients and their healthcare team, regardless of their condition and immunosuppression drug. relapses in patients with nmosd can be devastating and patients should be encouraged to continue therapies for the prevention of attacks, including corticosteroids, azathioprine, mycophenolate mofetil, rituximab, tocilizumab and eculizumab. if there is a clinical need to discontinue or delay treatment in patients with nmosd, corticosteroids may be used in moderate doses to prevent relapses in the short-term, it is important to consider individualized therapy and comorbidities when deciding on management of this condition during the covid- pandemic. my a s t h e n i a g r a v i s / l a mb e r t -e a to n my a s t h e n i c s y n d r o me ( mg / l e ms ) because most patients with myasthenia gravis (mg) are on immunosuppressant or immunomodulatory therapies and may also have muscle weakness and ventilatory failure, there is a theoretical concern that they may be at increased risk for infection or experience severe manifestations of sars-cov- infection. in a series of five cases with mg hospitalized for covid- infection, a variable clinical course was demonstrated, with three requiring mechanical ventilation and one presenting mg crises, and although it is difficult to assess the latter due to intubation and sedation in two of the cases, none had a fatal outcome. two additional cases have been reported, one developing crises due to myasthenia and the other with chronic refractory mg, with good outcome, without complications or worsening of their baseline condition. there are numerous recommendations circulating that attempt to provide clarity and guidance. however, the differences between the recommendations have created confusion, because decision-making varies in different countries, and due to the lack of databases with an adequate number of patients. patients with mg/lems should continue their treatment and are advised not to discontinue any existing medications; there is no scientific evidence to suggest that symptomatic therapies such as pyridostigmine increase the risk of infection and they should not be discontinued unless there are other clinical reasons to do so, given the risk of increased disease activity and/or mg exacerbation or crisis. with regard to certain therapies (immunoglobulins, plasmapheresis) there is no information pointing to increased risk of infection, however, the use of immunoglobulin should be based on the individual need of the patient and indiscriminate use should be avoided. in general, these therapies should be reserved for patients with acute exacerbation and if required as maintenance therapy on an exceptional basis, additional precautions should be taken. in patients with severe sars-cov- infection, temporary suspension of immunosuppression may need to be considered. it is important to note that decisions to intensify or change treatment should be individualized based on the relative severity of the sars-cov- infection. there is very little data regarding the impact of sars-cov- infection on primary immunodeficiencies (pi), which is why several international organizations such as the european society for immunodeficiency (esid), the reference centre for hereditary immunodeficiencies (le centre de référence déficits immunitaires héréditaires, ceredih) organization for primary immunodeficiencies (ipop) are collecting data through a survey of physicians in order to gather information and provide them better care. both the idf (immune deficiency foundation) and the ascia (australasian society of clinical immunology and allergy) and other agencies have considered their patients' increased risk of severe respiratory infections or of experiencing a more severe disease course, however, they recognize that it cannot be said whether people with primary immunodeficiencies are at higher or lower risk of severe sars-cov- infection. ascia and ipopi promote measures to prevent the spread of the virus, social isolation, and call for early consultation with medical services when infection is suspected, and recommend maintaining continuity of medication, especially in those receiving immunoglobulin. , virtual resources with patient and medical community education are available in the idf. these experts on the subject have theorized the possible effects of sars-cov- in different populations, for example, in the group of t lymphocyte (tl) immunodeficiency (combined immunodeficiency, digeorge syndrome, among others) measures of isolation and protection must be maximised, since the action of these defence cells is necessary for the control of the virus; in b-lymphocyte deficiency (agammaglobulinaemia, common variable immunodeficiency) the risk of infection is not thought to be higher than in the community, except in patients with structural involvement at the lung level, and in the phagocytosis deficiency immunodeficiency group (neutropenia and chronic granulomatous disease) although neutrophils are not as important in controlling the virus, the possibility of co-infection needs to be considered, while the chronic granulomatous disease group is not thought to be at increased risk of infection or severe manifestation. other recommendations according to the ipopi joint statement on the current coronavirus pandemic, are the use of pcr tests for diagnosis, since for some forms of pi there is no production of antibodies, and therefore tests based on immunoglobulins are not effective. in this same publication, as of april , , sars-cov- cases in different types of pi, exhibiting typical symptoms (fever, cough, and upper respiratory symptoms), of which were under years of age; seven required hospitalization (two developed adult respiratory distress syndrome) and all were under years of age. in the most recent update, based on collected (unpublished) data, there does not appear to be an increased risk of sars-cov- infection, especially in its severe form, however, given the still limited information and risk for these patients, isolation and infection prevention measures should be maintained as much as possible. another important aspect for these patients is the impact during the sars-cov- pandemic on their health-related quality of life (hrqol), requiring strict isolation and a remote care programme. in an italian cohort of patients with pi due to a bl defect, two scales were evaluated, one specific to health-related quality of life, cvidqol (common variable immune deficiency quality of life), and another generic scale to assess anxiety and depression, ghq- ( -item general health questionnaire); finding that the remote care programme does not affect hrqol, however, in the group of patients at risk of anxiety/depression there is impaired quality of life, emphasizing the importance of individualizing each patient and psychosocial support. hu during the stay at this institution infection was documented by nasopharyngeal sample associated with amplification of the betacoronavirus e gene and the specific sars-cov- rdrp gene by pcr, comorbidities such as hypothyroidism and asthma were also identified in these patients. all came under antiretroviral treatment, with cd cell count (> cell/mm in four of the patients). prior classification according to the patient's clinical status as mild, moderate or severe, under the precept that protease inhibitors could have activity against coronavirus protease, cobicistat + darunavir was considered appropriate in two of them, starting ritonavir + lopinavir in the rest combined with hydroxychloroquine, azithromycin, corticosteroids, interferon β- b and even tocilizumab, according to duration and progression. the survival of all is documented up to the time of publication and the conclusion is that patients in advanced stages of the disease should be guaranteed differential diagnosis by opportunistic pulmonary agents, inferring that they may have a poorer outcome, as well as an ominous prognosis. , in a recent study of incidence and severity of covid- involving hiv clinics in spain ( , patients), patients were diagnosed with covid- , were hospitalized, required intensive therapy and died. it was found that patients receiving tenofovir disoproxil fumarate (tdf)-emtricitabine (ftc) reverse transcriptase inhibitors had a lower risk of developing covid- and of hospitalization compared to groups receiving other treatments. there are isolated cases in which patients coinfected with hiv and covid- in management with lopinavir and ritonavir had a favourable clinical response, considering that this reaction can have two effects: inhibition of sars-cov- replication, as well as inhibition of hiv replication, allowing a slight activation of the immune system capable of responding to sars-cov- without the progression of the patient to hyperinflammatory status, even highlighting that lymphopenia would not be considered a marker of poor prognosis but a protective immune effect, being considered an disturbance of the overactive response of the immune system, avoiding serious clinical manifestations. other hypotheses raised as a favourable clinical response dependent on the patient's immune status, coinfection or history of opportunistic infections, mainly at the pulmonary level, the risk or benefit in relation to the use of glucocorticoids and even the benefit of introducing tocilizumab early were not omitted. in patients with hiv and sars-cov- infection it can be concluded that the immune response, prognosis and outcome are highly variable and / or subjective according to the antiretroviral treatment in place, duration in relation to diagnosis and viral suppression, because hiv patients without treatment, newly diagnosed or with no viral suppression may have a compromised immune system (mediated by a low cd count), even being vulnerable not only to the worst outcomes due to sarv-cov- , but alleged coinfection by other agents in pulmonary opportunists. patients with adherence to antiretroviral treatment, who have achieved viral suppression and do not have low cd count, will be affected by sars-cov- with the same chances as immunocompetent patients who develop mild manifestations, regardless of change in antiretroviral treatment or adjustment with ritonavir and lopinavir, however, it is important to emphasize the divergences in approach, management and choice versus antiretroviral treatment documented to date. for this type of patients, as well as those mentioned previously, recommendations have already been published on their management with covid- . the degree of pharmacological immunosuppression is assessed according to the patient's immunological risk, the type of protocol used, the type of target at which the drug or group of drugs is directed, and the type of disease for which it is indicated (e.g., neoplasms, transplants, immunological, etc.). although in all cases it is not easy to directly assess the degree of immunosuppression, some biomarkers have been developed that reflect the individual's response to immunosuppressants, which can range from general tests such as liver function enzymes, to the use of specific genotypes, including cell counts of specific lymphocyte populations, cytokines, leukocyte markers and target enzymes, among others. in other cases, the degree is assessed according to the number of immunosuppressant drugs, dose and time employed, being low when a drug is used in low or moderate doses for a short time, and increasing to a higher degree when two or more immunosuppressants are used in combination, regardless of the dose. there are many drugs used in different medical specialties that are associated with a certain degree of immunosuppression and that render patients vulnerable to one or another infectious process. however, in the field of sars-cov- infection, the data are scarce and unknown. as mentioned throughout the review, comorbidities are the most important risk factors compared to drugs used. the literature search predominantly reveals information about possible drug interactions that can occur with the treatment of covid- , which can clearly also generate damage and worsen the clinical picture. to date there are no data on specific drugs that are associated to a greater or lesser degree with infection by the new coronavirus. there is a warning about possible drug interactions between immunosuppressive drugs and those under investigation for the treatment of covid- , generating alerts and guidelines for the development of this complex task by clinicians. remdesivir, an antiviral with promising results in the treatment of covid- as mentioned, has no data so far on possible drug interactions with immunosuppressive drugs, unlike chloroquine/hydroxychloroquine and lopinavir/ritonavir, which although their use is declining, were initially an active part of treatment, suggesting major interactions with calcineurin inhibitors, mtor (mammalian target of rapamycin inhibitors) and corticosteroids, especially lopinavir/ritonavir. there are recommendations about discontinuing mycophenolate in critically ill transplant recipients, which would also apply to covid- , bearing in mind that during the h n pandemic it was documented that this drug decreased the serological response in transplant recipients. however, given the scarcity of data, this decision must be tailored to each patient in this special subgroup. in reference to calcineurin inhibitors (tacrolimus, cyclosporine), a dose minimization scheme is proposed, with the possibility of increasing the interval for its administration, suggesting safety in these regimens, particularly in individuals with kidney transplantation and covid- . multiple recommendations and guidelines have been generated around the use of immunosuppressors or cytostatics in the oncology field, such as cyclophosphamide, doxorubicin, cytarabine, vinblastine, as well as immunotherapy and the use of biological drugs in the context of cancer, according to the type of neoplasm in the context of risk or presence of covid- infection, suggesting in general a decrease in dose, but always balancing individual cases according to the type of neoplasm, stage and immunosuppressive scheme proposed. the recommendation is to avoid high doses of corticosteroids since they could, as observed in patients with mers-cov, prolong viral replication in patients with covid- . as mentioned above, their use would be reserved for specific subgroups of critically ill patients other drugs, not immunosuppressants, but associated with the physiopathogenesis of the disease, such as angiotensin-converting enzyme inhibitors or renin-angiotensin-aldosterone system j o u r n a l p r e -p r o o f inhibitors, have not been shown to increase the risk of sars-cov- infection, and conversely, their withdrawal could be harmful. considering the evidence available to date on sars-cov- infection outcomes in patients with immunosuppression (either due to their disease or the use of immunosuppressants) its behaviour is not clear in this type of individuals. we can highlight that patients with cancer and recent treatment of cancer (chemotherapy or surgery) have a higher risk of worse outcomes, with faster deterioration than those without cancer, an increased risk of severity and mortality having been shown through two meta-analyses. with regard to transplant patients (kidney, heart and liver), patients with neurological disease associated with the use of immunosuppression (ms, nmods, mg), primary immunodeficiencies and hiv, studies have not shown a tendency to poorer outcomes than patients without these diseases or drugs and have sars-cov- infection, similar to that found in rheumatological diseases. this could perhaps be explained in that the severity of sars-cov- infection has been associated with an aberrant inflammatory response (cytokine storm). for the time being and as more information is obtained, and based on the aforementioned literature and 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useful in renal transplant recipients affected by sars-cov- ? when a global pandemic complicates cancer care severe covid- in a renal transplant recipient: a focus on pharmacokinetics clinical course of covid- in a series of patients with chronic arthritis treated with immunosuppressive targeted therapies key: cord- - ateeei authors: vannabouathong, christopher; devji, tahira; ekhtiari, seper; chang, yaping; phillips, steven a.; zhu, meng; chagla, zain; main, cheryl; bhandari, mohit title: novel coronavirus covid- : current evidence and evolving strategies date: - - journal: j bone joint surg am doi: . /jbjs. . sha: doc_id: cord_uid: ateeei covid- is a global pandemic that has currently infected &gt; , globally. fever and cough are the most common symptoms of the disease, and it is important to remember that the virus can even be transmitted by individuals who test positive for the disease but do not have any symptoms. currently reported mortality rates vary because of the rapid spread of the disease and different approaches to calculating this estimate, but it is clear that the risk of death is associated with age and the presence of underlying conditions. risk mitigation techniques (i.e., hand washing, social distancing, and self-isolation) have already been emphasized across major news outlets. it is essential that we continue these practices, as the outbreak is currently expected to last for many more months and we must be mindful of the lessons learned from past pandemics to prevent a second wave from occurring. the outbreak of a novel coronavirus, referred to as severe acute respiratory syndrome coronavirus- (sars-cov- ) or coronavirus disease- , with its sentinel case in wuhan, people's republic of china, in december , has spread rapidly beyond the people's republic of china. on march , , the world health organization (who) declared covid- a worldwide pandemic, at which time > , people across countries, territories, and areas had been infected by this virus . covid- has rapidly become a global public health threat, endangering the health and well-being of all people, but especially vulnerable populations , . the pandemic has also precipitated social disruption, exceptional health-care utilization, and economic instability worldwide. controlling the spread of covid- has become the singular focus of several countries, with unprecedented international collaboration and rapid dissemination of emerging scientific evidence. table i summarizes what we know about covid- . we performed a search of electronic databases (pubmed, embase, google scholar) for relevant research articles on march , . we accessed the medrxiv database for any unpublished papers, as research in this field is quickly emerging. we also searched the world health organization (who), the u.s. centers for disease control and prevention (cdc), and other government health agency websites for relevant information. what is covid- ? covid- is the disease caused by the sars-cov- virus, which belongs to the family of coronaviruses . coronaviruses are positive-sense, single-stranded ribonucleic acid (rna) viruses that infect a variety of mammalian hosts, causing a range of symptoms that primarily affect the respiratory and gastrointestinal systems . coronaviruses tend to cause mild symptoms in humans, although several strains, including the viruses responsible for the severe acute respiratory syndrome (sars) and middle east respiratory syndrome (mers) outbreaks, have been linked to more severe symptoms and mortality . sars-cov- was isolated from several patients in wuhan, people's republic of china, and was identified as a novel coronavirus hitherto unknown to the medical field . the virus was named from its phylogenetic and taxonomic similarities to the sars coronavirus (sars-cov), the cause of the sars outbreak in to . sars-cov- represents the seventh known coronavirus. the transmission characteristics of sars-cov- were originally unclear, but it soon became apparent that the virus originated from an unknown animal source and was now spreading from human to human . the major route of transmission is through direct routes, such as respiratory droplets produced through coughing or sneezing, between people who are in close contact with one another, and through contact with contaminated surfaces or objects . although much of the focus has been on isolating symptomatic patients, there has been some potential evidence of transmission in asymptomatic patients (i.e., patients who are infected but not exhibiting symptoms associated with covid- ) [ ] [ ] [ ] . at the time of this writing, grow-ing evidence suggests that asymptomatic, pre-symptomatic, or mildly symptomatic individuals could be drivers of the community spread of the virus. some recent reports on asymptomatic cases have suggested that viral shedding can last close to a month , , although it is unclear how great the risk of transmission might be throughout this period. emerging mathematical models analyzing the outbreaks in singapore and tianjin, people's republic of china, also support the existence of asymptomatic and pre-symptomatic transmission of covid- . researchers analyzing the outbreak data from tianjin and singapore found that infection was transmitted, on average, . days prior to symptom onset in tianjin and . days prior to symptom onset in singapore in each cluster . several studies have sought to establish the basic reproductive number (r ) for sars-cov- . the r represents the number of new cases that can be expected to stem from each unique case. an early examination of the first patients in wuhan found that the r was . ( % confidence interval [ci], . to . ), meaning that each person infected with covid- can be expected to infect at least other people by definition , "a pandemic is the worldwide spread of a new disease." it can be transmitted between people and spread worldwide because of the absence of preexisting immunity against the new virus in humans . figure illustrates a timeline of important events associated with covid- . chinese laboratories successfully isolated a new type of coronavirus, after conducting tests on all suspected cases on january , . from the middle to late january , thailand, japan, south korea, and the united states reported their first cases of confirmed covid- , . by the end of january , , confirmed cases were identified globally across countries . on the second meeting of the international health regulations emergency committee on january , , the who declared a public health emergency of international concern (pheic) . the term pheic is defined as : "an extraordinary event which is determined to constitute a public health risk to other states through the international spread of disease; and to potentially require a coordinated international response." also, according to the who , "this definition implies a situation that is serious, unusual, or unexpected; carries implications for public health beyond the affected state's national border; and may require immediate international action." eleven days later, on february , , there were, cumulatively, , confirmed cases and deaths globally across countries, and the majority were identified in the people's republic of china . on february , , the who announced a name for the new coronavirus disease: covid- . timeline of important covid- events. since then, the numbers of confirmed cases and deaths have been escalating globally. by march , , there were > , cases and > , deaths across countries . one day later, on march , , in remarks to the media, the who director-general, dr. tedros adhanom ghebreyesus, announced covid- to be a pandemic based on > , cases in countries and , deaths due to the disease , . the countries with the highest prevalence, to date, are the people's republic of china, italy, iran, south korea, and spain . the current understanding of the incubation period, the period between exposure and the appearance of the first symptoms of infection, for covid- is limited. the current best evidence from an analysis of confirmed covid- cases detected from provinces, regions, and countries outside of hubei province between january , , and february , , estimated the median incubation period to be . days ( % ci, . to . days) . of all infected cases, researchers estimate that < . % of cases will show symptoms within . days ( % ci, . to . days) of exposure and that . % of cases will show symptoms within . days ( % ci, . to . days) . currently, real-time reverse transcription-polymerase chain reaction (rt-pcr) is considered the reference standard for detection of the sars-cov- virus in respiratory specimens. mass screening procedures (testing those with and without symptoms) and documented illness of covid- have demonstrated that the clinical spectrum of infection with sars-cov- appears to be wide, with a range including asymptomatic infection, mild upper respiratory tract illness, severe viral pneumonia with respiratory failure, and death , , . table ii presents a list of common symptoms among patients with covid- from an unpublished systematic review of retrospective studies including a total of , patients who were positive for sars-cov- . the authors found that, although fever was the most common symptom in these patients, only , patients ( . %) had fever as their onset symptom. radiographic findings revealed that , ( . %) of , patients had abnormalities on a chest computed tomographic (ct) scan, with either unilateral or bilateral ground-glass opacity and/or consolidation, with a peripheral distribution. lymphocytopenia (lymphocyte count < . · /l) was present in , ( . %) of , patients, and , ( . %) of , patients had elevated levels of c-reactive protein . because of the disease's rapid increasing case profile, the presence of asymptomatic and untested cases, and its varying effects across different patient demographic characteristics, the estimates of the mortality risk have been wide-ranging. on average, at the time of this writing, the who reported that the time between symptom onset and death ranges from to weeks , . as of march , , the who reported a mortality estimate of . % in confirmed cases globally; however, the highest incidence rate was in italy at . % . baud et al. suggested that a more representative estimate of mortality should not be relative to the number of confirmed cases (as patients are infected much earlier), but should be based on the total number of patients who were infected at the same time as those who died . to re-estimate the risk of mortality based on this approach using data as of march , , baud et al. divided the number of deaths in day by the number of confirmed cases days prior. this analysis led to mortality rates of . % ( % ci, . % to . %) for the people's republic of china and . % ( % ci, . % to . %) outside of the people's republic of china; globally, this estimate was . % ( % ci, . % to . %) . in a similar analysis on patients in wuhan, the estimate was . % . overall, when not considering the timing of infection, baud et al. argued that the risk of mortality can be underestimated . in contrast, some believe that this risk is actually overestimated because of the number of undiagnosed cases. klompas and wilson et al. suggested that currently reported estimates are inaccurate as asymptomatic positive cases have not been considered in these calculations. in addition, the risk of death increases with age and the presence of comorbidities , , . in a cross-sectional analysis that included , covid- -related deaths in the people's republic of china, the novel coronavirus pneumonia emergency response epidemiology team found that > % were patients ‡ years of age; when extending this range to those who were ‡ years of age, this number increased to > % . in terms of comorbidities, in this same study, the authors found that the mortality rate in patients with no comorbidities was about . %, whereas it was . % in patients with cardiovascular disease, . % in patients with diabetes, . % in patients with respiratory disease, and . % in patients with cancer . moreover, in a report by the who-china joint mission, they estimated that the risk of death in those without comorbidities was . %, and the incidence was higher in those with . approximately % of confirmed cases are diagnosed with mild to moderate disease (pneumonia and non-pneumonia cases), about % of cases experience severe disease (dyspnea and other respiratory problems), and the remaining % of cases are deemed critical cases (respiratory failure, septic shock, or multiple organ failure); similar to the risk of death, patients who are ‡ years of age and those with preexisting conditions are at the greatest risk of having severe disease , , . in a retrospective study on covid- patients in chongqing, people's republic of china, qi et al. evaluated patients who were categorized as severe or non-severe cases and found that patients with severe cases were significantly older (median age of . years compared with . years for patients with non-severe cases) and were more likely to have comorbid conditions ( % compared with %) . several reports have suggested that the median time from symptom onset to intensive care unit (icu) admission is approximately days , , . in a recent systematic review, fang et al. found that ( . %) of , patients were admitted to the icu . in the study by huang et al. , among confirmed cases in wuhan, % were admitted to the icu, strictly because of respiratory issues that required high-flow nasal cannula or higher-level oxygen support. in an updated study by chen et al. on patients, the icu admission rate was %, with % needing invasive mechanical ventilation and % needing noninvasive mechanical ventilation. in a larger study on , patients in china, % were admitted to the icu and . % underwent invasive mechanical intervention . in contrast, when looking at patients with severe illness only, qi et al. showed that ( %) of cases required noninvasive mechanical ventilation, % needed high-flow nasal cannula oxygen, and % required invasive mechanical ventilation . although the current evidence shows that older patients and those with underlying health conditions are at higher risks of severe disease and death, younger and, presumably, healthier individuals should still be concerned about experiencing severe outcomes if infected with covid- . the cdc recently published a report on u.s. patients with covid- , using data from february , , to march , , and, although their case-fatality rate may be low (i.e., < %), patients in the younger age groups had appreciable risks of both hospitalizations and icu admissions (fig. ) . among the cohort of patients included in the who-china joint mission report, the median time from onset to recovery (of those who survived) for mild cases was about weeks, whereas this was between and weeks for those who had severe or critical disease . the development of severe disease was about week from onset and deaths occurred at to weeks . as the number of cases continues to rise rapidly across the world, there is growing concern that health-care systems will quickly become saturated and unable to adequately respond to the outbreak. the soaring number of cases in italy (estimated at , as of march , ) requiring medical attention and hospitalization has overwhelmed the health-care system; some hospitals are filled to capacity, and there are a shortage of beds and a lack of medical equipment such as ventilators for those patients with more serious illness. in epidemiology, preventing and slowing the virus's spread so that fewer individuals require medical treatment at any given time are referred to as "flattening the curve" of the pandemic. without precautions or measures to slow the rate of infection, the projected number of people who will contract covid- over a period of time will likely increase exponentially. infection curves with a steep rise place greater demands on health-care systems, overwhelming limited health-care resources and forcing agonizing decisions about which patients will receive life-saving treatment and which patients will not. however, a flatter curve assumes the same or fewer absolute number of cases but over a longer period of time . a slower rate of infection reduces the burden on health-care systems and allows patients to receive appropriate care. a major issue faced by policymakers and health-care professionals is the apparent evidence that the virus can be spread by asymptomatic and pre-symptomatic patients [ ] [ ] [ ] . early evidence from pre-published studies of cohorts indicate that the virus is spread, on average, to days before symptoms present , . as there is no current vaccine that can protect against infection, preventing the spread of the virus, particularly in patients without symptoms, requires a comprehensive approach through collective action. international, national, and local public health authorities have made prevention and control recommendations based on current understanding of modes of transmission of the virus (table iii) . practicing proper hygiene includes frequent hand washing; avoiding touching the eyes, nose, and mouth; coughing or sneezing into a bent elbow or tissue; and wearing of masks for symptomatic individuals . social distancing involves taking deliberate steps to minimize close contact between people to limit covid- transmission in the community. examples of social-distancing measures include but are not limited to cancelling events and mass gatherings, closing schools or switching to online learning, working from home, and reducing public services such as access to community centers. additionally, many countries have begun advising their citizens to avoid all nonessential travel outside of the country, as well as banning or severely limiting incoming international flights. this seeks to limit the spread from countries with higher cases of covid- to the resident country. finally, an isolation from other individuals by a distance of m (or feet in the united states) is suggested. individuals who do not have symptoms but may have been exposed to the virus through close contact with someone diagnosed with covid- or those who have traveled outside their home country are recommended to self-isolate for days. the -day self-isolation recommendation is due to the time frame for symptoms to present, as previous studies have found that the presentation of symptoms occur by days . therefore, by isolating for days, a person would theoretically present with symptoms and would be able to be tested, while not actively spreading the virus in the community during the self-isolation period. the race for a covid- vaccine has become the focus of several research teams globally as researchers work to develop and test a vaccine that can potentially prevent future cases of the disease in vaccinated patients. groups in canada, germany, the people's republic of china, and the united states are all at varying stages of vaccine development, with human trials likely under way by the time of this article's publication [ ] [ ] [ ] [ ] . at least phase-i trials are registered on clinicaltrials.gov, including in the united states and the people's republic of china (clinicaltrials.gov identifier: nct , nct , nct , nct ) ( table iv) . one of the key lessons from previous attempts at the development of a sars coronavirus vaccine is the concern for immunopotentiation. in other words, whole-virus vaccines led to an undesired increase in infectivity or eosinophilic infiltration . johnson & johnson, the university of hong kong, and codagenix are all exploring whole-virus sars-cov- vaccine options. however, given the aforementioned concerns with regard to increased infectivity following immunization and the general dangers associated with live virus vaccines, extensive testing will be needed before these vaccines are available for clinical use . another potential vaccine strategy is subunit vaccines, which rely on eliciting an immune response against the spike (s) protein to prevent its docking with the host angiotensinconverting enzyme (ace ) receptor . a number of entities, including the university of queensland, novavax, clover biopharmaceuticals, and baylor college of medicine, have all made progress toward either a sars-cov or sars-cov- subunit vaccine. given the limited potential for host immunopotentiation and the similarities between sars-cov and sars-cov- amino acid expression, the potential for a subunit vaccine may be the most promising in the short term. the final option is a nucleic acid vaccine, for which several major biotechnology companies already have platforms. to date, there has not been a successfully licensed human nucleic acid vaccine, although promising results in animal studies have continued . overall, although there has been impressive and rapid progress toward a vaccine already, a vaccine that is ready for widespread use is still likely months, possibly years, away, given the testing, regulatory, and manufacturing hurdles that will need to be cleared. the race for a vaccine provides hope, but should not be relied on to compensate for a lack of containment strategies in the meantime. aggressive measures aimed at slowing viral spread will necessarily be the primary public health strategy for the near future. no specific treatment is currently recommended for covid- . similar to many other viral illnesses, the current mainstays of treatment include early recognition and isolation, along with symptomatic and oxygen therapy . considerations for the advanced levels of care including critical care depend on the development of further symptoms, including pneumonia or acute respiratory distress syndrome (ards). the use of systemic corticosteroids and antibiotics is not recommended except when targeting specific comorbid conditions . no antiviral treatments are currently approved, but alphainterferon ( million units inhaled twice daily), lopinavir-ritonavir (kaletra), remdesivir, and chloroquine have all been proposed as potentially beneficial and may be trialed if available in severe cases [ ] [ ] [ ] . a randomized controlled trial (rct) of lopinavirritonavir compared with standard care included patents with covid- . eligible patients were adult patients with covid- , pneumonia, and compromised oxygen saturation. there was no significant difference between the groups in terms of time to clinical improvement or mortality, with more adverse events in the intervention group . no high-quality evidence exists on remdesivir in this context, but it has been shown to effectively inhibit sars-cov- in vitro, particularly in combination with chloroquine . at least ongoing rcts are evaluating the efficacy of remdesivir in covid- (nct and nct ). chloroquine has been found to inhibit sars-cov- in vitro , and a number of trials are ongoing to test its clinical efficacy. although no formal results are yet available, early results have reportedly been promising, so much so that the expert consensus from the department of science and technology of guangdong province in the people's republic of china has recommended chloroquine mg twice daily for patients with mild to severe covid- who do not have any contraindications . convalescent plasma from recovered patients is also being actively investigated, based on positive experience with previous coronavirus outbreaks. however, there is a lack of evidence for convalescent plasma in covid- , and there is a risk of thrombotic events as well as attenuation of the immune response, which can leave patients at a potentially higher risk for reinfection or other infections. lessons from history: the first and second waves as discussed above, we are now experiencing our third human coronavirus epidemic of the century, with occurring in each decade so far. in addition, the pandemics of h n and the influenza (also known as the spanish flu) may provide clues into what may be expected moving forward. one of the common threads seen in both outbreaks was the phenomenon of multiple waves (fig. ) . both epidemics began in the late winter and early spring, at which point the relevant governments and public health systems began to take steps to limit the viral spread. in the case of the influenza pandemic, the death rates of the first wave were limited, and, between august and october , there were very few deaths occurring from the disease. however, the second wave, which was by far the deadliest of the waves, occurred between september and november . many theories have been proposed for the nature and timing of this second wave, including less favorable transmission conditions (rising temperatures, improved airflow, and less indoor crowding) in the summer months, although the exact reasons remain unclear . a smaller, third wave followed in early . the influenza pandemic also provides an example of the importance and effectiveness of the aforementioned practice of social distancing (fig. ) . a study compared the public health policies of philadelphia and st. louis during the pandemic, in which st. louis enacted public health measures such as social distancing in a rapid and strict fashion, and philadelphia enacted some less stringent measures weeks after the appearance of the first case . in fact, despite the first case being reported on september , , a citywide parade was held in philadelphia days later. the difference in outcomes between the cities was striking, with philadelphia showing weekly death rates of per , and cumulative peak death rates of per , and st. louis showing weekly death rates of per , and cumulative peak death rates of per , . similarly, the sars epidemic, which was first recognized in late february , also had a spring peak. on may , , the who removed toronto from the sars concern list, as there had been no new cases of community spread or death for days . shortly after, as hospitals began to dismantle their precautions, a second peak of cases developed in middle to late may ; most of these cases were clustered around a single hospital, with probable and suspect cases during this second wave . we do not have any clear understanding whether the coronavirus will recur in waves; the future behavior is unknown. the mers epidemic did not present with a second wave, and the timings of the second waves for the influenza epidemic and sars were very different. perhaps the most important lessons that can be taken from these previous outbreaks are simply a continued vigilance and preparedness for a possible second wave and a high index of suspicion for any new cases of undifferentiated respiratory illness in the weeks to months following a slowdown in new cases. finally, the past can also provide context with regard to the size and impact of past pandemics. table v contains a list of selected past pandemics with their absolute and relative (as a proportion of the global population) death tolls. we are in the midst of an unprecedented pandemic, the likes of which we have not seen in over a century. although the global response has been vigilant and focused, research continues to evolve and our understanding of the ultimate impact of covid- remains largely unknown. it is impossible to accurately predict the trajectory of covid- because of its rapidly evolving nature , , but some groups have recently attempted to forecast this using advanced modeling techniques , . these models are likely gross overestimates, given that they assume no containment measures are in place. even with aggressive containment procedures, the outbreak is unlikely to see meaningful resolution for weeks to months. peng et al. used public data from the national health commission of china from january , , to february , , and estimated that, for the majority of the people's republic of china, anti-epidemic success will be seen around mid-march ; however, in wuhan, this is expected to occur closer to the beginning of april . in another model by wu et al., the authors performed a generalized logistic growth model (data from infected cases between january , , and march , ) and estimated that, in japan, there will be a total of , cases by the end of march and , cases by the end of june and that around . % of italy (> , people) will be infected by the end of the outbreak. understanding big data sets will be key to future innovations and prevention. this outbreak has created millions of data points and provides an opportunity to test the promise of machine learning and artificial intelligence. the allen institute for ai (artificial intelligence) in seattle, washington, has recently partnered with other researchers to create the covid- open research dataset (cord- ) . this free resource contains relevant articles about covid- and related viruses, allowing researchers to apply advanced methods, such as natural language processing, to try to generate new information about the disease. the covid- pandemic has led to a heavy burden on the health-care system, leaving many surgeons with questions as to how to handle this situation, in terms of their practice and caring for their patients. a number of major institutions, surgical associations, and physicians with direct experience treating patients with suspected or confirmed covid- have recently released statements or published recommendations to offer guidance to surgeons, in particular, and all frontline health-care workers [ ] [ ] [ ] [ ] [ ] [ ] [ ] . we summarize their guidance here: . assess all planned elective or nonemergency surgical procedures and clinic visits to determine whether or not they can be postponed or cancelled, keeping in mind that it may be another to weeks (or more) until we see some resolution. . shift urgent inpatient diagnostics and surgical procedures to outpatient settings, when possible. . minimize the use of essential items (e.g., beds, personal protective equipment, cleaning supplies, ventilators). . plan for the potential surge of critical care patients and have additional space and supplies readily available. . create multiple teams that are completely insulated from each another. . limit or cancel nonessential travel, not only to prevent the spread of the disease, but also to ensure that you are available to help your local health-care system to manage a possible increase in patient admissions or to reorganize the workforce if a colleague becomes infected. . if they cannot be cancelled altogether, complete conferences, educational courses, panels, meetings, and even follow-up patient examinations virtually or remotely. . if a surgical procedure is necessary for a patient with suspected or confirmed covid- , use an operating room with a negative-pressure environment, frequent air exchange, and a separate access. airborne spread is a concern during aerosol-generating procedures, so it is also important to understand the airflow within an operating room and have the proper equipment and protocols in place to limit the spread of infection in this setting. anterooms in which to put on and remove protective equipment should be available, or even constructed, adjacent to the operating room. use disposable surgical items and protective equipment. use double caps, n masks, medical goggles, and boots. minimize entry into and exit from the operating room during surgical procedures. allocate time between procedures to allow staff and the operating room to go through proper decontamination procedures. . keep posted on updates provided by the cdc and the who on a regular basis. summary covid- is a global pandemic that has currently infected > , globally. fever and cough are the most common symptoms of the disease, and it is important to remember that the virus can even be transmitted by individuals who test positive for the disease but do not have any symptoms. currently reported mortality rates vary because of the rapid spread of the disease and different approaches to calculating this estimate, but it is clear that the risk of death is associated with age and the presence of underlying conditions. risk mitigation techniques (i.e., hand washing, social distancing, and self-isolation) have already been emphasized across major news outlets. it is essential that we continue these practices, as the outbreak is currently expected to last for many more months and we must be mindful of the lessons learned from past pandemics to prevent a second wave from occurring. n coronavirus disease (covid- ) situation report - chinese ibd quality care evaluation center committee. 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pneumonia emergency response epidemiology team similarity in case fatality rates (cfr) of covid- /sars-cov- in italy and china epidemiological and clinical features of -ncov acute respiratory disease cases in chongqing municipality characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention detection of sars-cov- in different types of clinical specimens epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study severe outcomes among patients with coronavirus disease (covid- ) -united states public health interventions and epidemic intensity during the influenza pandemic estimating the generation interval for covid- based on symptom onset data. medrxiv responding to community spread of covid- interim guidance coronavirus: when will a covid- vaccine be ready? global news canadian company announces covid- vaccine candidate. global news. . accessed coronavirus: first person to begin covid- vaccine trial in us, government official says germany's curevac says low-dose coronavirus vaccine could allow for mass production roadmap to developing a recombinant coronavirus s protein receptorbinding domain vaccine for severe acute respiratory syndrome the sars-cov- vaccine pipeline: an overview. curr trop med rep di napoli r. features, evaluation and treatment coronavirus (covid- ) coronavirus puts drug repurposing on the fast track accessed of chloroquine and covid- novel coronavirus outbreak research team. epidemiologic features and clinical course of patients infected with sars-cov- in singapore a trial of lopinavir-ritonavir in adults hospitalized with severe covid- remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus ( -ncov) in vitro multicenter collaboration group of department of science and technology of guangdong province and health commission of guangdong province for chloroquine in the treatment of novel coronavirus pneumonia a perspective on multiple waves of influenza pandemics influenza: the mother of all pandemics. emerg infect dis sars: lessons from toronto investigation of the second wave (phase ) of severe acute respiratory syndrome (sars) in toronto, canada. what happened? can commun dis rep paules ci, marston hd, fauci as. coronavirus infections-more than just the common cold epidemic analysis of covid- in china by dynamical modeling. medrxiv generalized logistic growth modeling of the covid- outbreak in provinces in china and in the rest of the world. medrxiv covid- open research dataset (cord- ). . accessed surgical care and coronavirus disease (covid- ). . accessed what we do when a covid- patient needs an operation: operating room preparation and guidance practical recommendations for critical care and anesthesiology teams caring for novel coronavirus ( -ncov) patients key: cord- -v yg jw authors: chen, yuxin; tong, xin; wang, jian; huang, weijin; yin, shengxia; huang, rui; yang, hailong; chen, yong; huang, aijun; liu, yong; chen, yan; yuan, ling; yan, xiaomin; shen, han; wu, chao title: high sars-cov- antibody prevalence among healthcare workers exposed to covid- patients date: - - journal: j infect doi: . /j.jinf. . . sha: doc_id: cord_uid: v yg jw the seroprevalence of severe acute respiratory syndrome coronavirus (sars-cov- ) was examined among healthcare workers (hcws) exposed to four patients who were laboratory confirmed with coronavirus disease (covid- ), the disease caused by sars-cov- infection. these hcws were immediately under quarantine for days as soon as they were identified as close contacts. the nasopharyngeal swab samples were collected on the first and (th) day of the quarantine, while the serum samples were obtained on the (th) day of the quarantine. with the assay of enzyme immunoassay (eia) and microneutralization assay, . % ( / ) of hcws were seropositive, while their swab samples were found to be sars-cov- rna negative. risk analysis revealed that wearing face mask could reduce the infection risk (odds ratio [or], . , % confidence interval [ci] . , . ), while when exposed to covid- patients, doctors might have higher risk of seroconversion (or, . , % ci . , . ), compared with hcws exposed to colleagues as well as nurses and general service assistants who exposed to patients. our study revealed that the serological testing is useful for the identification of asymptomatic or subclinical infection of sars-cov- among close contacts with covid- patients. the ongoing pandemic of novel coronavirus, known as severe acute respiratory syndrome coronavirus (sars-cov- ), was first reported in wuhan, china in late dec ( ) . due to its escalating spread globally, as of may , , more than , patients were confirmed with coronavirus disease (covid- ), the disease caused by sars-cov- , across countries and regions, causing a total of , deaths. a wide spectrum of disease severity of laboratory confirmed covid- has been depicted ( , ) , including asymptomatic or minimally symptomatic cases ( , ) . the proportion of asymptomatic sars-cov- infected patients is unknown, which remains a critical epidemiological puzzle ( ) . whether one may seroconvert to sars-cov- with minimal or without symptoms still needs to be answered. meanwhile, an efficient human-to-human transmission of sars-cov- mostly occurs among close contacts ( ) . serological testing to close contacts with covid- patients will help define the local transmission rate and the risk factors of infection, especially identify asymptomatic or subclinical infections. healthcare workers (hcws) have been on the frontline for fighting this covid- pandemic worldwide, which placed themselves at high risk of catching covid- . understanding risk factors of sars-cov- infection during clinical setting is urgently needed, which not only provides the hcws with essential guidance of self-protection, but also helps policymakers to formulate appropriate measures to control infection in hospital setting. this present study aimed to evaluate the seroprevalence of sars-cov- in a cohort of hcws exposed to covid- patients using both enzyme immunoassay (eia) and microneutralization assay. furthermore, risk factors of sars-cov- seroconversion among these hcws were identified with epidemiological investigation. our study shed lights on the subclinical infection of covid- and provided information for pandemic mitigation efforts. from jan th to feb th , , four patients were diagnosed with covid- in nanjing drum tower hospital, china. patient (a -year-old male surgeon) was occupationally exposed to sars-cov- , and patient (a -year-old female nurse) is his wife. both of them were diagnosed with covid- on jan th. patient (a -year-old male) was diagnosed in the th day of his hospitalization, while patient (a -year-old male)was in the emergency room (er) for days before diagnosis. the exposure history, the symptom onset timeline of the covid- patients and the cycle threshold [ct] values of nucleic acid results were retrieved from their electronic medical records (figure ). because of direct contact with the four aforementioned covid- patients during the past weeks, the hcws were immediately quarantined for -day observation. at the first day of their quarantine, each hcw was asked to complete a questionnaire designed by local center for disease control and prevention (cdc) during the past two weeks. the questionnaire included clinical symptom, relationship with the patients and exposure history. the relationship between hcws and coivd- individuals was categorized as colleague, doctor, nurse, or general service assistant. the exposure history included the time of exposures, date for each exposure, activity, location, distance, duration, with or without face mask (disposable non-surgical face mask, surgical mask or n respiratory if wearing face mask) during the past two weeks. disposable non-surgical face mask refers to the face mask made of non-woven textile in two or three layers, which generally lacks the capability of filtering particles, viruses and bacteria. additionally, during their quarantine, their body temperature and clinical symptoms were also recorded twice a day. nasopharyngeal swab specimens were collected on the first and th day of their quarantine by professional certified nurses who have received the training of nasopharyngeal swab collection. blood samples were only obtained on the th day of the quarantine. this study was approved by ethics committee of nanjing drum tower hospital. information consent was waived as part of a public health outbreak investigation. viral rna was extracted from nasopharyngeal swab samples using the qiaamp rna viral kit (qiagen), and quantitative reverse transcriptionpolymerase chain reaction (qrt-pcr) assay was performed (bioperfectus technologies, china). two sets of primers and probes targeting the open reading frame ab (orf ab) and nucleocapsid protein (np) genes of sars-cov- were used as recommended by the chinese cdc ( ) following who guidelines ( ) . the primers and probe set for orf ab are: forward primer ( '-ccctgtgggttttacacttaa- '); reverse primer ( '-acgattgtgcatcagctga- '); probe: ( ʹ-vic-ccgtctgcggtatgtggaaaggttatgg-bhq - ʹ). the primers and probe set for np are: forward primer ( '-ggggaacttctcctgctagaat- '); reverse primer ( '-cagacattttgctctcaagctg- '); probe: ( ʹ-fam-ttgctgctgcttgacagatt-tamra- ʹ). the thermal cycling condition was °c for min, °c for min, followed by cycles of °c for s and °c for s. the ct value of the amplification curve was defined as positive if less than and negative if greater than . to determine the seroprevalence among close contacts with covid- patients, an in-house enzyme immunoassay (eia) was conducted as previously described ( ) . two sars-cov- proteins, recombinant spike protein receptor binding domain (rbd) protein and recombinant nucleocapsid protein (np) were used as detecting antigens, respectively. the genes encoding spike rbd (amino acid residues to of spike protein) and full-length np were codon-optimized and synthesized (genewiz, china). the gene encoding spike rbd was cloned into mammalian expression vector pcdna . in frame respective and upstream of a series of six histidine residues, and np gene was cloned into prokaryotic expression vector pet- (b). rbd protein was expressed in f cells while np protein was expressed in escherichia coli, followed by affinity purification. the purity of np and rbd protein was determined with % sodium dodecyl sulphate (sds) polyacrylamide gel electrophoresis. briefly, -well plates were coated with ng/ml of recombinant rbd or np protein overnight, incubating with diluted were also collected and the nasopharyngeal swab samples from these patients have been repeatedly tested as negative for sars-cov- rna at least twice at a two-day apart. furthermore, serum samples from covid- patients were also collected at different time points for assay validation. pseudovirus expressing the sars-cov- spike protein was obtained as a general gift from the institute of biological product control from national institute for food and drug control, china. sars-cov- pseudovirus was prepared by using vsv g pseudotyped virus (g*Δg-vsv) that packages the expression cassette for firefly luciferase instead of vsv-g in the vsv genome, and the serum neutralization capability was determined as described recently ( ) . briefly, the sars-cov- pseudovirus was preincubated with serum samples at : dilution at °c for one hour, together with the pseudovirus control and cell control wells. serum samples from healthy controls were served as negative control in hexaplicate. then, the -well plates were seeded with μg of freshly trypsinized huh cells ( x cells/well). after hours of incubation in a % co environment under °c,the luminescence was measured using luciferase substrate (one-glo tm luciferase assay system, promega, e ) and the percentage of neutralization was calculated with the following formula as: [(relative light units (rlus) of virus control wells -rlus in cell control wells)-(rlus of serum incubated with virus wells-rlus of the cell control wells)]/ (rlus of virus control wells -rlus of cell control wells) x %. the percentage of neutralization over % was considered to have neutralization activity. all statistical analyses were performed using spss . . the medians (interquartile range (iqr)) were used to present the continuous variables, and the categorical variables were described as the counts and the percentages. the man-whitney u test (non-normal distribution) was used to compared the continuous variables between groups. chi-square test or fisher exact test was used to compare categorical variables. variables with p values < . in the univariate analysis were further used for a multivariate logistic regression analysis. pearson's correlation coefficients between different assays were calculated. the threshold for statistical significance was established at a p value < . . the demographic and epidemiological characteristics of the hcws were summarized in table . the median age of these hcws was years old (iqr - ) and ( . %) of them were female. during the quarantine, ( . %) hcws were reported having one or more general symptoms, including fever ( / , . %), headache ( / , . %), sore throat ( / , . %), cough ( / , . %), myalgia ( / , . %), diarrhea ( / , . %) and rhinorrhea ( / , . %). all swab specimens collected on the first and th day of the quarantine showed negative results for sars-cov- , and none of these close contacts developed covid- later. an eia-based sars-cov- antibody assay was developed to detect igm and igg antibodies against rbd and np protein, respectively ( figure a ). different groups of serum samples were used to determine the specificity and sensitivity of our assay. specifically, as negative control, all the exposure history of covid- patients between seropositive and seronegative hcws was summarized ( table ). the exposure events occurred in the early period of the outbreak of covid- in china, so the understanding to the sars-cov- was still limited at that time. all hcws did not wear personal protective equipment (ppe), including n respirators, surgical masks, face shield or googles. first, the proportion of doctors who were exposed to patients was higher in seropositive group than in seronegative group ( . % vs. . %, p= . ). it was identified that there was higher percentage of hcws exposed to patient in seropositive group ( . % vs. . %, p= . ) than in seronegative group, which might be caused by the relatively high level of viral shedding from patient , revealed by a low ct value for her respiratory swab samples at the hospital admission. besides, more seropositive hcws had a previous experience of exposure for over minutes within a distance of meter ( . % vs. . %, p= . ), and less seropositive hcws contacted covid- patients with disposable non-surgical face mask wearing ( . % vs. . %, p= . ), compared to that in seronegative group. neither swab sample collection nor multiple times of exposure with covid- patients showed any differences in seroconversion. risk factors associated with sars-cov- seroconversion were assessed ( table ). the univariate analysis showed that the exposure for more than minutes at a distance of less than meter (odds ratio [or], . ， % confidence interval [ci] . , . ), close contact with patient (or, . , % ci . , . ) and doctors exposed to their patient (or, . , % ci . , . ) led to higher risk of seropositivity, while contact with covid- patient wearing mask (or, . , % ci . , . ) was associated with a reduced risk of seroconversion. in multivariate analysis, there existed higher risk of seroconversion for close contacts with patient (or, . , % ci, . , . ) and doctors exposed to their patient (or, . , % ci . , . ), while the lower risk of seroconversion was closely related to direct contact with covid- patients wearing face mask (or, . , % ci . , . ). similar to sars-cov, sars-cov- has been reported to be highly communicable in hospital setting ( , ). high attack rate of sars-cov- among healthcare workers with direct patient care has been observed worldwide, including china, italy, and united states, etc. our study examined the seroprevalence of the hcws exposed to covid- patients without wearing ppe at early period of outbreak in a tertiary hospital of china. of note, hcws were exposed to covid- patients as colleagues, while hcws were exposed during performing direct care for patient or general service. despite the swab samples from all hcws collected at twice were negative for sars-cov- rna, our serological analysis indicated . % of asymptomatic or subclinical infection of sars-cov- in hospital setting. consistent with the efficient transmissibility of sars-cov- , our serological analysis in the hospital setting highlighted a higher percentage of asymptomatic or subclinical sars-cov- infection than that of sars-cov ( ) ( ) ( ) ( ) and mers-cov ( ) . our data suggested that those with asymptomatic or subclinical infection of sars-cov- were able to be seroconverted. all the nasopharyngeal swab samples collected twice were found to be negative for sars-cov- . this could because that the modest level of viral load from nasopharyngeal swabs was beyond detection. also, the nasopharyngeal swab samples were not longitudinally collected and the positive samples might be missed. therefore, serological testing is an ideal approach to assess the proportion of people who might experience the asymptomatic or subclinical infection of sars-cov- , which is critical to understand the viral transmissibility and disease burden during covid- pandemic. previous studies on human coronaviruses have shown that np protein and rbd region are highly immunogenic, which have been successfully applied in eia-based approach for serological analysis ( , , ) . in order to eliminate the possibility of cross-reactivity with other human coronaviruses, rbd and np protein were used as two antigens in our assay, similar to a recent published study ( ) . we found that all the healthy controls in and the non-covid- pneumonia patients were % found to be negative, while . % of serum from covid- patients were proved to be positive, suggesting our elisa assay has high sensitivity and fine specificity. by using eia assay, samples were discovered positive for detectable igm or igg responses to both rbd and np protein, while the antibody responses among these hcws were relatively lower compared with covid- patients. meanwhile, out of sera samples displayed neutralization activities. consistent with recent findings ( ), the level of neutralization activity was associated with anti-np igg response and anti-rbd igg response. whether those seropositive hcws acquired protective immunity from sars-cov- infection remains unknown. active surveillance and longitudinal followup to close contacts should be attached more importance. firstly, our analysis showed that the secondary attack rate to each covid- patients was distinct. in our study, higher percentage of close contacts with patient were seroconverted. such efficient transmission might be caused by higher level of viral load of patient , which was determined by the low ct value of nucleic acid assay. it is also possible that sars-cov- was evolved in patient after infection, which might further modulate the viral transmissibility and virulence ( ) . besides, our data support an essential need to wear face mask, including the disposable non-surgical face mask, because it might provide effective protection against sars-cov- . of note, since these exposure events occurred at the very first of the outbreak in china, all the hcws in our study only worn the disposable non-surgical face mask, rather than n respirator or surgical masks. therefore, our data suggested that the disposable non-surgical face mask might be also beneficial to the reduction of the potential nosocomial infection. consistently, a recent study in hong kong revealed that the community-wide wearing of the face mask plays a critical role in the control of covid- , not only by preventing the dispersal of droplets from subclinical or mild individuals with covid- , but also by reducing the environmental contamination of sars-cov- ( ) . moreover, among four relationships with the covid- patients, there is higher risk for doctors who were exposed to covid- patients to have seroconversion. it is possible that doctors might share more conversations with covid- patients within relatively close distance, which could generate large amount of infected saliva or respiratory droplets. our findings might shed light on the implementation of appropriate infection prevention and control measures, especially at hospital setting. this study has several limitations. firstly, our cohort is limited to only inclusion of hcws exposed to covid- patients. however, our cohort is representative since they are either colleagues or health professionals in terms of the relation with the covid- patient. and different extents of exposure history in our cohort allow us to identify the potential exposure risk factors. secondly, the serum samples were only collected on the th day of the quarantine, while the serum samples on the first day of the quarantine were not obtained. therefore, the dynamic antibody responses were not determined in our study. thirdly, the nasopharyngeal swab specimens were only collected twice on first and th day of the quarantine, which were not serially collected especially during the early period of the quarantine, and thus the positive nasopharyngeal swab samples might be missed. in summary, the serological testing among hcws exposed to covid- patients illustrated that . % ( / ) might have experienced asymptomatic or subclinical infection of sars-cov- . our study proved that the serological testing is useful for the identification of asymptomatic or subclinical infection of sars-cov- among close contacts with covid- patients. whether these asymptomatic or subclinical infections play a role in transmission dynamics still remains to be determined. our findings have important implications for the implementation of pandemic mitigation strategies. early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia clinical findings in a group of patients infected with the novel coronavirus (sars-cov- ) outside of wuhan, china: retrospective case series clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china epidemiologic and clinical characteristics of novel coronavirus infections involving patients outside wuhan, china a family cluster of sars-cov- infection involving patients in nanjing, china association of public health interventions with the epidemiology of the covid- outbreak in wuhan, china. medrxiv. coronavirus disease (covid- ) technical guidance: laboratory testing for -ncov in humans a novel rabbit monoclonal antibody platform to dissect the diverse repertoire of antibody epitopes for hiv- env immunogen design establishment and validation of a pseudovirus neutralization assay for sars-cov- supporting the health care workforce during the covid- global epidemic surface environmental, and personal protective equipment contamination by severe acute respiratory syndrome coronavirus (sars-cov- ) from a symptomatic patient healthcare worker seroconversion in sars outbreak severe acute respiratory syndrome-associated coronavirus infection relative rates of non-pneumonic sars coronavirus infection and sars coronavirus pneumonia sars-cov antibody prevalence in all hong kong patient contacts surveillance of the middle east respiratory syndrome (mers) coronavirus (cov) infection in healthcare workers after contact with confirmed mers patients: incidence and risk factors of mers-cov seropositivity characterization of anti-mers-cov antibodies against various recombinant structural antigens of mers-cov in an imported case in china temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by sars-cov- : an observational cohort study genomic diversity of sars-cov- in coronavirus disease patients. clin infect dis. . mar ; ciaa the role of community-wide wearing of face mask for control of covid- ) epidemic due to sars-cov- the authors have declared that no conflicts of interest. key: cord- -yi mx a authors: kaur, satinder; bherwani, hemant; gulia, sunil; vijay, ritesh; kumar, rakesh title: understanding covid- transmission, health impacts and mitigation: timely social distancing is the key date: - - journal: environ dev sustain doi: . /s - - -x sha: doc_id: cord_uid: yi mx a covid- is a highly infectious disease caused by sars-cov- , first identified in china and spread globally, resulting into pandemic. transmission of virus takes place either directly through close contact with infected individual (symptomatic/asymptomatic) or indirectly by touching contaminated surfaces. virus survives on the surfaces from few hours to days. it enters the human body through nose, eyes or mouth. other sources of contamination are faeces, blood, food, water, semen etc. parameters such as temperature/relative humidity also play an important role in transmission. as the disease is evolving, so are the number of cases. proper planning and restriction are helping in influencing the trajectory of the transmission. various measures are undertaken to prevent infection such as maintaining hygiene, using facemasks, isolation/quarantine, social/physical distancing, in extreme cases lockdown (restricted movement except essential services) in hot spot areas or throughout the country. countries that introduced various mitigation measures had experienced control in transmission of covid- . python programming is conducted for change point analysis (cpa) using bayesian probability approach for understanding the impact of restrictions and mitigation methods in terms of either increase or stagnation in number of covid- cases for eight countries. from analysis it is concluded that countries which acted late in bringing in the social distancing measures are suffering in terms of high number of cases with usa, leading among eight countries analysed. the cpa week in comparison with date of lockdown and first reported case strongly correlates (pearson’s r = − . to − . ) to cases, cases per unit area and cases per unit population, indicating earlier the mitigation strategy, lesser the number of cases. the overall paper will help the decision makers in understanding the possible steps for mitigation, more so in developing countries where the fight against covid- seems to have just begun. covid- is caused by novel strain of virus sars-cov- emerged from china and now declared as pandemic due to its presence across the continents in more than countries. based on genetic analysis sars-cov- is grouped in a family coronaviridae, genus betacoronavirus and subgenus sarbecovirus (benvenuto et al. ; lau et al. ; lu et al. ) . coronaviruses are known to infect series of animals, birds, rodents, reptiles and humans (ji et al. ) . similarly, sars-cov- is also zoonotic in nature by showing animal to human transmission. sars-cov- is reported to share % nucleotide identity with horseshoe bat (rhinolophus affinis), suggesting it as a natural host (andersen et al. ; paraskevis et al. ) . it is further assumed that sars-cov- moved from bats to an intermediate host malayan pangolin (manis javanica) sharing % nucleotide identity and then to humans (lam et al. ; zhang et al. a, b, c) . the capability of coronaviruses for host switching demonstrates strong adaptive capacity, suggesting that there can be other possible intermediate hosts (smith and denison ) . more elaborate research and studies are required to examine wide variety of animals as an intermediate host. sars-cov- is deadly due to its high transmission and fatality rates (carleton and meng ) . at present average fatality rate from covid- is reported to be . % (rajgor et al. ) . structural modelling depicts that sars-cov- readily binds with human cell receptor present in lungs, intestine, kidney, and heart (clerkin et al. ) . this cell receptor serves as the entry point for some coronaviruses present in a diverse group of animals (zhou et al. ) and regulates cross-species transmission (wan et al. ). sars-cov- enters the body primarily through nose, eyes and mouth. from the time of initial exposure, it takes two weeks ( days) for a person to develop symptoms called as incubation period, but, in some cases, it may be as long as days (abduljalil and abduljalil ) . first it infects upper respiratory tract causing dry cough and fever (jiang et al. ) progressing to lower respiratory tract causing bronchitis and pneumonia ) and gastrointestinal tract causing nausea and diarrhoea (han et al. ) . pneumonia causes lung damage preventing oxygen movement to other organs. in such cases ventilators are required for oxygen supply to avoid death due to multiple organ failures . at present many countries are in crisis due to increased number of cases and limited ventilators. transmission of covid- may occur from both symptomatic and asymptomatic patients. it is believed that asymptomatic patients carry a similar amount of virus as the symptomatic (zou et al. ); therefore, it is possible to spread the virus even before symptoms emerge, termed as silent transmission. the possibility of asymptomatic individual spreading the virus cannot be overruled, and such individual needed to be isolated/quarantined at specialized facilities . some people having travel history to infected countries/areas voluntarily quarantined themselves in their homes after informing officials. it is believed that one infected person will on average spread the virus to - individuals in normal condition (without lockdown) (cdph ). patients with covid- are diagnosed by rrt-pcr, blood test, antibody test, ct scans (bi et al. ) . understanding the transmission of the infection and evaluating the effectiveness of control measure is crucial for assessing outbreak in new areas and in future (kucharski et al. ) . the novelty of the paper is that it discusses in detail the transmission, health impacts and mitigation strategies in detail at one place in order to help in better understanding of the problems and solutions related to covid- . the paper further analyses the impact of lockdown and social distancing measures on the spread of this contagious virus using bayesian probabilistic modelling which is unique in its own way. limited literature is available on using such type of modelling for strategic applications related to covid- . cpa analysed through this model helps in understanding the role of outbreak, its spread and outcome of mitigative strategies of selected country. covid- had shown four phases of transmission throughout the world. phase-i had shown controlled transmission with few cases having travel history to infected countries. such cases were immediately isolated and treated in the designated hospitals. but at this moment there was no knowledge about the spread of virus through asymptomatic patients; therefore, disease progressed into next phase. phase-ii is the local transmission where virus spreads in local surroundings through symptomatic or asymptomatic patients having travel history. phase-iii is the community transmission where individuals having no connection with the asymptomatic and symptomatic patients start showing symptoms. at this phase other modes of transmission are also responsible for spread of disease and situation becomes uncontrollable. in the phase-iv disease crossed borders resulting into inter-/intrastate transmission where number of cases and deaths had shown sudden increase resulting into epidemic. covid- finally reached phase-v where initial outbreak in china spread rapidly, affecting other countries in europe, america, africa, asia and middle east resulting into pandemic. initial transmission took place when infected individual travelled outside from wuhan later declared as epicentre of covid- outbreak (ji et al. ) . in december , first patient (termed as index patient or patient zero) was reported with pneumonia in wuhan, china, who believed to have visited seafood market. later in last week of december, similar cases emerged and wuhan municipal health commission announced pneumonia outbreak of unknown cause. meantime, chinese lunar new year started in january where people travelled out of the city, and in some cases, overseas resident travelled to china. first few cases outside of china were reported in bangkok, thailand, korea, japan. population of wuhan was placed under lockdown, means no interstate and intrastate movement. by the end of january , singapore, vietnam, usa, nepal, australia, malaysia, canada, cambodia, germany, sri lanka, united arab emirate (uae), finland, philippines, uk, russia, sweden, spain and india confirmed their first covid- cases. who declared covid- as disease of emergency that needed international attention. covid- cases were reported with individuals having no travel history, suggesting that local transmission occurred in these countries. in march , more than countries reported cases of covid- and were declared pandemic by who. airports were put on screening to detect symptomatic people returning from infected countries. in the second half of march , china had shown decrease in new cases by adopting various mitigation measures, whereas italy and iran emerged as new hot spots. europe became epicentre of the pandemic with more cases and deaths than rest of the world. by the end of march , italy surpassed china with maximum number of deaths. on the other hand, usa had experienced maximum number of confirmed cases in the world. italy announced the need to extend the lockdown from march to april. by now all european countries were affected and reason for transmission was open border system. in march, usa had overtaken china and italy with the highest number of confirmed cases. april experienced rising number of cases in all the african and asian countries. usa became the country with the highest official death toll for covid- . by the end of april russia emerged to become new hot spot with % of population infected and africa decided to ease restrictions in some areas. in may , africa reported % cases and % deaths with eight regions showing community transmission. on may , the first new cluster of cases in wuhan was reported since the government lifted the lockdown. all the above information of covid outbreak is retrieved from devex.com. rise in number of cases in different weeks is presented in table where it can be observed that india, france and japan had experienced increase in fifth week, that in usa and spain in the fourth week, italy in the third week except for iran and china in second week. cpa is performed in table in order to understand the most impacting week for the countries in terms of either increase or stagnation in number of covid- cases. many ongoing studies are trying to find out nature and path of transmission of sars-cov- . as covid- is progressing, transmission modes of sars-cov- are also showing variations (as shown in fig. ). covid- is presumed to spread via droplets or aerosol spurted during coughing or sneezing, and airborne transmission happens when the residue from evaporated, infected droplets gets suspended in the air and infects those who breathe in it (gautam and trivedi ; santarpia et al. ) . droplet transmission is nosocomial droplet nuclei carrying pathogens from the infectious individual to recipient or falls on the surface (yang et al. ). an individual can also become infected by touching a contaminated surface resulting into fomite transmission (liu et al. a, b) . coronaviruses have been observed to remain viable for few hours on aerosols, copper, printing papers, tissue papers and for few days on cardboard, stainless steel, plastics, treated wood, glass, banknotes (chin et al. doremalen et al. ). recently, a study in italy reports adherence of sars-cov- on particulate matter in conditions of stable atmosphere and high concentration (setti et al. ). this can result into carrier transmission of the virus for a longer distance. in such case, it is important to perform quantitative risk assessment to find out possible health problem caused by inhalation of dust carrying sars-cov- . sars-cov- was also reported in the stool samples of patients, suggesting that viral shedding in stool could be a potential route of faecal-oral transmission (ong et al. ) . therefore, there are chances of virus transfer from toilet product to food and water through soiled hands (zhang et al. a, b, c) . virus has also been reported in blood samples, but chance of blood-borne transmission is not clear. although during blood donation, proper care should be taken to identify asymptomatic patient (chang et al. ) . scientists are collecting plasma and serum of infected patients for further studies on covid- . during pregnancy immune system is low resulting into manifestation of covid- symptoms (dong et al. ) . with regard to vertical transmission, i.e. transmission from mother to baby, there is no case reported where foetus is infected from mother. however, infants could become infected during delivery or while breastfeeding from infected mother. hospitals are also at risk for transmission of virus among health workers through medical equipments, apparels and procedures. the highest concentration of sars-cov- was observed inside the patient toilet room (liu et al. a, b) when compared other areas where patient lives. there are other multiple sources from where transmission of sars-cov- can take place such as home, transport, restaurant, theatre, shopping mall and supermarket. transmission in the mall was traced among workers and customers via elevator buttons or restroom taps, elevators etc. . researchers around the world were speculating seasonal transmission, where covid- will exist in winters, and as soon as temperature will rise, there are chances of less transmission. therefore, spread of cases is dependent on temperature and humidity (bherwani et al. a) . it was estimated that °c rise in temperature reduces transmission by % (carleton and meng ) . doubling time correlates positively with temperature and inversely with humidity (oliveiros et al. ) . but increase of temperature would alone not necessarily lead to decline in cases, but it should also be coupled with other mitigation measures. it was believed that developing countries with lack of medical facilities will face more mortality than developed countries. but in reality, given the present scenario developed countries had more cases and mortality as opposed to developing countries. it is believed that higher mortality in developed countries is due to the presence of elder populations, whereas developing countries have a younger population (walker et al. ) . it was reported that children are least affected, whereas the elderly are experiencing highest rate of deaths . children tend to make more social contacts than adults and therefore contribute more to transmission than adults (davies et al. ) . it was also evident that more symptoms were visible with age above years and there were no cases in children below years of age (li et al. a, b; zhang et al. a, b, c) . average recovery time for covid- is estimated to be days with days for young people and days for older groups (bi et al. ) . it was reported that mortality rate in italy ( . %) was higher than china ( . %) due to the presence of elderly population (abduljalil and abduljalil ) . cases were more in males and between the ages of - years (bi et al. ) . recent study in china surprisingly reported sars-cov- in the semen of male patients raising new debate on sexual transmission of the disease (li et al. a, b) . with every passing time new development related to covid- is stated with respect to transmission mode and transmission rate. other possibilities of transmission from human to pet transmission, waterborne transmission, transmission through air etc. (gautam and hens ; gautam a ) are speculated but remain uncertain. it is an initial phase of this pandemic and is believed that covid- will take longer time to get completely eradicated. however, control measures can slow down the speed as well as mortality rate. immediate and strategic response to mitigation plays an important role in influencing the trajectory of this pandemics across the world. in case of wuhan, china, there was decline in transmission when control measures were introduced (kucharski et al. ) . it was estimated that the absence of mitigation measure would lead to billion infections and billion deaths (walker et al. ) . various measures are undertaken to prevent infection such as maintaining hygiene, using facemasks, isolation/quarantine, social distancing, in extreme cases lockdown in hot spot areas. proper hygiene practices were encouraged such as covering the nose/mouth with tissue or elbow while coughing/sneezing and avoid touching surfaces (bruin et al. ). the use of hand sanitizer or washing hand with soap for secs after sneezing or touching contaminated surfaces was essential. surfaces were decontaminated with many solutions such as ethanol, isopropyl alcohol, sodium hypochlorite bleach, hydrogen peroxide. face masks became an essential component but was recommended only when having symptoms or treating patients. its importance was apparent from the fact that one patient without facemask transmitted virus to five other people while travelling in a vehicle in china (liu and zhang ; liu et al. a, b) . in developing countries, due to lack of sufficient medical mask, people started use of local cloth mask. cotton mask could be a potential substitute for medical mask as there is no significant difference for reducing droplet transmission. cotton mask is washable and re-usable also (ho et al. ) . health, transportation, safety, security and infrastructure workers were at highest risk of getting infected and therefore were provided first priority for personal protective equipment (ppe). source control by masking of patients and visitors by using n or higher-level respirators, using telemedicine, designating separate locations/rooms for care also helped in reducing risk of sars-cov- transmission in health workers (heinzerling et al. ) . the virus may be resuspended from the contaminated ppe surface to the air; therefore, sanitization before they are taken off was carried out to reduce the infection risk for health and other workers (gautam b; liu et al. a, b) . at present, there is no definite vaccine present to treat covid- , but many medicines such as remdesivir, chloroquine, lopinavir and ritonavir were successfully used as an alternative (gabriella et al. ; guo et al. ) . social/physical distancing was encouraged by avoiding groups and keeping safe distance of - m (bruin et al. ) . social distancing when coupled with isolation/restrictions likely to control the disease within - weeks and reduced peak incidence by - % was estimated (chang et al. ; zhang et al. a, b, c) . isolation practices can be effective for preventing secondary transmission of viruses (basile et al. ) . about % of individuals needed to be traced and isolated to attain % control over outbreak (hellewell et al. ) . in hot spot areas with highest number of cases lockdown was imposed in many countries. it included complete closure of public transport, public places, educational institution, hotels, offices, factories, etc. lockdown resulted into decline of transmission of disease to half (kucharski et al. ) . china initiated lockdown to control the disease followed by italy, france, spain, philippines, india and other countries. technology intervention such as the use of digital technologies for screening infected individuals was vital in controlling transmission and slowing pace of the disease in taiwan it is recognized that the sars-cov- is highly contagious and till the medications are being explored, and social/physical distancing along with hygiene is the only saviours (bherwani et al. a) . cpa is performed in table in order to understand the most impacting week for the countries in terms of either increase or stagnation in number of covid- cases. the countries were chosen based on better availability of data. pythonbased pymc is used for cpa. the above probabilistic programming of python is used to fit bayesian models using varied numerical methods (salvatier et al. ). here this model is used as per the concept that more than frequency of any parameter, the reasonability and expectation of an event are more important. in such circumstances bayesian probability is usually used. proportional logic is used to derive the reasoning of interaction. the assessment could have been carried using other methods of probability; however, the above method suits the best under the given circumstances. similar approaches have been used in past as well (aminikhanghahi and cook ; bherwani et al. c ). the model is built for series of data (table ) , and cpa is determined for each country, viz. india (a), usa(b), france(c), italy(d), japan(e), iran(f), spain(g), and china(h). the results of cpa are shown in fig. a -h and summarized in table . the raw images of fig. are given in appendix. the orange line indicates the point where drastic change has occurred in the number of covid- cases in each of the respective countries, referred to as change point (cp). it can be seen that each country had shown a different response to the pandemic except china is showing a band rather than a point of change, as the cases suddenly increased and stabilized in the country. cpa is further analysed in reference to the first cases which are observed in respective countries and the day on which lockdown is initiated as shown in table . this is important in order to understand if the lockdown is initiated before or after change point. the difference gives a significant information. table indicates the list of countries which were able to act fast and start physical distancing measures before the catastrophe (point of change) occurred in terms of exponential rise of covid- cases. countries including india, italy, japan, spain and china acted relatively fast. while italy and spain have suffered with many cases and fatalities, india, japan and china have been able to contain the spread and flatten the curve given their steady rise in cases. usa, which acted very late, has borne the brunt of the virus which is visible in their exponential rise and sheer magnitude of number of cases in such a short time. while the cpa indicates the importance of social distancing, it is worthwhile to explore its linkage with covid- by adding one more parameter of population, i.e. normalized population and population density. table gives a comparative analysis of the same. table is arranged in decreasing order of cases per unit population density (cpd), which is an indicator of penetration of covid- into the country. it can be clearly seen that the countries which acted late have more cases per unit population density. usa and iran with the slowest response have the maximum cpd. iran is standing below usa, probably due to lower absolute population. furthermore, spain had an earlier response than italy and was able to control cpd better despite having higher population and population density. india and japan had an ascendency in terms of delta (d), indicating the early action, and are the lowest in terms of cpd. india is best among the lot probably because of executing one of the most stringent lockdowns ever. china is an exception due to facts stated above. the results are represented in fig. with log values of cpd considered for normalization of scale. it indicates that with increase in the values of delta, there is steady drop in log cpd values. further analysis is carried out for countries having positive delta (except china) in terms of their linear correlation with population parameters. the results are shown in the form of lower triangular matrix in table . from table , it can be inferred that d is in strong inverse correlation with number of cases, cpp and cpd with factors of − . , − . and − . , respectively. this indicates that more the value of delta, lesser are the cpp, cpd and c values which establishes the hypothesis that lockdown and physical distancing are playing a major role in reducing the intensity and magnitude of cases of covid- . also, population density is an important factor when it comes to the spread of the virus which reconfirms the causation that the virus is highly contagious in nature and physical distancing is one of the most efficient ways to control its spread. while there is sufficient evidence that the extremely contagious nature of this virus and population density are playing an important role in spread of covid- , it is important to note that as the world moves through this pandemic, the models will have to be adapted to improve the predictions and the same is true for the above modelling exercise as well. covid- has proven to be once in lifetime pandemic that a generation will ever experience. it is a silent war that a human is fighting with an organism of nanosize. developed countries claiming their efficiency in health and other facilities have given up to the atrocities created by this virus. the virus which is named as sars-cov- has its presence in every country and continent across the world. it is transmitted from horseshoe bat (natural host) through malayan pangolin (intermediate host) finally to the humans. first detected in china and then spread rapidly in other countries initially from people having travel history to infected countries. airborne, droplet and fomite transmission are held responsible for local transmission. population were encouraged to use hand sanitizers, soap, facemask/face covering, etc., to prevent from covid- . it is believed that increase in temperature in coming months will also help to slow the pace of covid- and death rates will decrease. it is reported that covid- mostly effects and elderly population (fig. ) . the paper explores the efficacy of the lockdowns and social distancing polices followed by eight countries suffering from covid- pandemic. while lockdown has a strong effect on the economy and many people will lose their jobs, creating financial insecurity, lockdown seems to be an efficient way of controlling the spread (bherwani et al. fig. transmission of covid- symptom, mitigation measures adopted and effect on population b). cpa showed that social distancing and lockdown have helped many countries to bring down their number. the countries which were able to act before the curve became exponential and implemented their social/physical distancing measures have been able to contain their numbers. a strong inverse correlation between the time of action, represented by delta, and the number of cases (pearson's r = − . ), cases per unit population and population density (pearson's r = − . ), are representative of depth of penetration of the disease. it is evidently seen the countries like india and japan are among those who introduced lockdowns and distancing measures way early during the spread have much less cases, rate of increase of cases, while on the other hand, countries like usa, italy, spain and france have been suffering due to the late action on the above mitigation measures. the outcome of the research not only helps the countries which are still struggling with the virus, especially developing countries, but also it is helpful for the expected second wave of the virus. the analysis can be used to develop strategies related to mitigation and control of the spread of virus as it indicates the population density is one of the major factors driving the spread. future research on similar lines can be carried out to understand the effect of life style and pre-existing conditions similar to population density using the above given novel approach. . covid- daily cases of india data available online: https ://www.india today .in/india / story /coron aviru s-cases -in-india -covid -state s-citie s-affec ted- - - - accessed on ( may ) covid- daily cases of usa data available online covid- daily cases of france data available online covid- daily cases of italy data available online covid- daily cases of japan data available online covid- daily cases of iran data available online covid- daily cases of spain data available online covid- daily cases of china data 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python using pymc transmission potential of sars-cov- in viral shedding observed at the university of nebraska medical center sars-cov- rna found on particulate matter of bergamo in northern italy: first preliminary evidence implications of altered replication fidelity on the evolution and pathogenesis of coronaviruses. current opinion in virology the global impact of covid- and strategies for mitigation and suppression. imperial college covid- response team receptor recognition by the novel coronavirus from wuhan: an analysis based on decade-long structural studies of sars coronavirus person to person droplets transmission characteristics in unidirectional ventilated protective isolation room: the impact of initial droplet size changes in contact patterns shape the dynamics of the covid- outbreak in china probable pangolin origin of sars-cov- associated with the covid- outbreak isolation of -ncov from a stool specimen of a laboratory-confirmed case of the coronavirus disease (covid- ) a pneumonia outbreak associated with a new coronavirus of probable bat origin sars-cov- viral load in upper respiratory specimens of infected patients publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- - fl gwp authors: ouassou, hayat; kharchoufa, loubna; bouhrim, mohamed; daoudi, nour elhouda; imtara, hamada; bencheikh, noureddine; elbouzidi, amine; bnouham, mohamed title: the pathogenesis of coronavirus disease (covid- ): evaluation and prevention date: - - journal: j immunol res doi: . / / sha: doc_id: cord_uid: fl gwp coronavirus disease (covid- ) has become a major health problem causing severe acute respiratory illness in humans. it has spread rapidly around the globe since its first identification in wuhan, china, in december . the causative virus is called severe acute respiratory syndrome coronavirus (sars-cov- ), and the world health organization (who) named the new epidemic disease coronavirus disease (covid- ). the incidence of covid- continues to increase with more than three million confirmed cases and over , deaths worldwide. there is currently no specific treatment or vaccine against covid- . therefore, in the absence of pharmaceutical interventions, the implementation of precautions and hygienic measures will be essential to control and to minimize human transmission of the virus. in this review, we highlight the epidemiology, transmission, symptoms, and treatment of this disease, as well as future strategies to manage the spread of this fatal coronavirus. coronaviruses belong to the coronaviridae family in the nidovirales order. corona represents crown-like spikes on the outer surface of the virus; thus, it was named coronavirus. coronaviruses are minute in size ( - nm in diameter) and contain a single-stranded rna as nucleic material, with a size ranging from to kilobases (kb) in length. the subgroups of the coronavirus family are alpha (α), beta (β), gamma (γ), and delta (δ) [ ] . several coronaviruses can infect humans, like the globally endemic human coronaviruses hcov- e, hcov-nl , hcov-hku , and hcov-oc that tend to cause mild respiratory disease, and the zoonotic middle east respiratory syndrome coronavirus (mers-cov) and severe acute respiratory syndrome coronavirus (sars-cov) that have a higher case fatality rate [ ] . in late december , a cluster of patients was admitted to hospitals with an initial diagnosis of pneumonia of an unknown etiology. these patients were epidemiologically linked to a seafood and wet animal wholesale market in wuhan, hubei province, china [ , ] . the pathogen has been identified as a novel coronavirus. initially tentatively named novel coronavirus ( -ncov), the virus has now been named sars-cov- by the international committee of taxonomy of viruses (ictv) [ ] . this virus can cause the disease named coronavirus disease (covid- ) [ ] . the sars-cov- belongs to the same coronavirus group (betacoronavirus) as sars and mers viruses that caused two of the more severe epidemics in recent years. as with sars and mers, this new coronavirus, -ncov, is believed to be of zoonotic origin, but may also be transmitted through the respiratory tract, by direct contact, and possibly via patients excreta which may contain the living virus [ ] . since the emergence of the novel coronavirus ( -ncov) infection in wuhan, china, it has rapidly spread across china and many other countries [ ] . the outbreak of covid- has affected more than three million patients in countries, areas, or territories with a mortality rate of . % and has become a major global health concern [ ] . based on the evidence of a rapidly increasing incidence of infections and the possibility of transmission by asymptomatic carriers [ , ] , sars-cov- can be transmitted effectively among humans and exhibits high potential for a pandemic [ ] [ ] [ ] . to date, the disease has spread worldwide and become a serious infectious disease affecting human health worldwide [ ] . in the absence of specific therapeutic drugs or vaccines for novel coronavirus disease , it is essential to detect the diseases at an early stage and immediately isolate the infected person from the healthy population. in this paper, we attempt to review and document the current data related to corona virus disease (covid- ) including etiology, epidemiology, clinical characteristics, and measures of treatment of covid- , with a special focus on infection control and prevention. in december , wuhan city, province of china, became the center of an outbreak of novel contagious coronavirus disease (covid- ) of unknown etiology [ , ] . efforts are underway to continue to better understand more about transmissibility, severity, and other features associated with covid- [ ] . it appears that an infected animal may have first transmitted the virus to humans at a seafood market [ , ] . soon, a secondary source of infection was found to be human-to-human transmission of the covid- virus [ ] . it became clear that the covid- infection occurs among close contacts and exposure to the virus [ ] . recent studies showed that people aged ≥ years and the population with poor immune function such as diabetes, cardiovascular disease, chronic respiratory disease, cancer, renal, and hepatic dysfunction are at higher risk for severe covid- than children who might be less likely to become infected or, if so, may show milder symptoms or even asymptomatic infection [ ] . coronavirus disease (covid- ) is spreading rapidly across china and is being exported to a growing number of countries, some of which have seen onward transmission. according to the world health organization (who), covid- continues to emerge and represents a serious problem to public health. on may of march , more than three million confirmed cases of covid- reported by the world health organization. of these, more than have been fatal. about , cases were confirmed in china, and deaths were confirmed ( figure ) [ ] . the growing global tally includes spikes in korea, iran, italy, spain, france, and germany. the virus is also continuing to spread to african countries including algeria, south africa, senegal, burkina faso, cameroon, nigeria, and côte d'ivoire. in addition to the confirmed case, moroccan's health ministry says that morocco has more than confirmed cases of the coronavirus. the sars-cov- was found to be a positive-stranded rna virus belonging to the genus betacoronavirus with a crown due to the presence of spike glycoproteins on the envelope ( figure ) [ ] . other than sars-cov- , there are six types as humans coronaviruses have been identified, namely, hcov- e, hcov-oc , sars-cov, hcov-nl , hcov-hku , and mers-cov [ ] . phylogenetic analysis revealed that the sars-cov- is closely related, with - % similarity, to two bat-derived severe acute respiratory syndrome-(sars-) like coronaviruses, bat-sl-covzc (accession no. mg . ), and bat-sl-covzxc (accession no. mg . ), but it is more distant from sars-cov, with about % similarity, and mers-cov, with about % similarity [ ] [ ] [ ] . the sars-cov- has an envelope; its particles are round or elliptic and often polymorphic form, and a diameter of nm to nm [ ] . additional studies based on the genetic sequence identity and the phylogenetic reports confirmed that covid- is different from sars-cov, and it can thus be considered as a new betacoronavirus that infects humans [ ] . the source of the -ncov is still unknown. however, the growing outbreak has been linked to the huanan south china seafood market [ ] . scientists are trying to find the animal host of this novel coronavirus in hopes of eradicating the spread, but so far, no one is certain. most sources agree that the possible host of the -ncov is bats, pangolins, or seafood [ , , ] . the task at hand is to find the intermediate host that is responsible for transmitting the coronavirus to humans. it is important to determine the source of the virus, to help the discovery of the zoonotic transmission patterns [ ] . sars-cov- presents a high transmissibility and pathogenicity [ ] . it could be transmitted from human to human by droplets and contact [ ] . several reports have suggested that symptomatic people are the most frequent source of covid- spread. it primarily spreads between people through respiratory droplets by coughing or sneezing from an infected individual [ ] . moreover, there are suggestions that individuals who remain asymptomatic could transmit the virus. further, studies are needed to clarify and understand the mechanisms of transmission, the incubation period, and the duration of infectivity of this virus. in patients with coronavirus disease (covid- ), the most common clinical symptoms are fever and cough, shortness of breath, and other breathing difficulties in addition to other nonspecific symptoms, including headache, dyspnea, fatigue, and muscle pain [ , ] . moreover, some patients also report digestive symptoms such as diarrhea and vomiting [ , ] . covid- was similar to sars and mers in some clinical manifestations [ ] . fever occurred in - % of patients with sars or mers, compared to . % of patients with covid- [ , , ] . . % of patients had no fever at admission, suggesting that the absence of fever could not rule out the possibility of covid- [ ] . although patients initially have fever with or without respiratory symptoms, various degrees of lung abnormalities develop later in all patients, and these can be seen on chest ct (ct) [ , ] . although diarrhea is present in approximately - % of patients infected with mers-cov or sars-cov, intestinal symptoms have rarely been reported in patients with covid- [ ] . patients receive chest ct scans that provide reliable data on the dynamic x-ray pattern. typical mild covid- pneumonia begins primarily with small, subpleural, unilateral, or bilateral frosted glass opacities in the lower lobes, which then develop into a crazy-paving pattern and subsequent consolidation. after more than two weeks, the lesions are gradually absorbed with residual frosted glass opacities and subpleural parenchymal bands. in these patients who have recovered from covid- pneumonia [ ] . at admission, the majority of patients had lymphopenia and platelet abnormalities, neutrophils, aspartate aminotransferase (ast), aspartate aminotransferase (ast), lactate dehydrogenase (ldh), and inflammatory biomarkers. according to the results of the ct or x-ray, the patients had bilateral pneumonia and pleural effusion that occurred in . % of the patients. compared to patients in general, refractory patients had a higher level of neutrophils, ast, ldh, and reactive protein c and a lower level of platelets and albumin. in addition, refractory patients had a higher incidence of bilateral pneumonia and pleural effusion [ ] . in general, hospitalized patients are classified in two categories, the general covid- which has been defined according to the following criteria: obvious relief of respiratory symptoms (for example, cough, chest distress, and shortness of breath) after treatment, maintaining normal body temperature for more than three days without the use of corticosteroids or antipyretics, improving radiological abnormalities in the chest scanner or x-rays after treatment, a hospital stay of less than days. otherwise, it was classified as covid- refractory. in the admission severity assessment, a serious illness was defined if it met at least one of the following: respiratory rate /min, pulse oximeter oxygen saturation (spo ) % at rest, and partial arterial oxygen pressure (pao ) at the inspired oxygen fraction (fio ) mmhg [ ] . after the diagnosis of sars-cov infection was made, the prevention and quarantine are considered as the most way to stop the fast spreading of the virus, because there is no effective vaccine, drugs, or antiviral to prevent and treat this disease despite the great efforts made by the scientists and researchers around the world to develop vaccines and treatments of coronavirus. furthermore, several strategies were carried out to help patients with covid- as oxygen therapy (major treatment intervention), antivirals (lopinavir, ritonavir, ribavirin, favipiravir (t- ), remdesivir, oseltamivir, chloroquine, and interferon) [ , , ] . most importantly, unselective or inappropriate administration of antibiotics should be avoided. moreover, corticosteroids treatment should not be given for the treatment of sars-cov [ ] . convalescent plasma can journal of immunology research be used to help people recover from viral infection without the occurrence of severe adverse events [ ] . among the difficulties that avoid finding the treatment for covid- is that the spike protein of the virus interacts with the host cell receptor including grp (glucose regulating protein ). consequently, the inhibition of this interaction would probably decrease the rate of the infection [ ] . lopinavir (protease inhibitor used to treat hiv) or lopinavir/ritonavir has shown in vitro anti-coronavirus activity [ ] . in addition, the utilization of lopinavir/ritonavir showed a reduction of viral loads and it was found that it is able to improve virus symptoms during the treatment period [ ] . other reported antiviral treatments form human pathogenic covs include neuraminidase inhibitors like oral oseltamivir has been used in china hospitals for covid- cases [ ] . no study has demonstrated the effectiveness of oseltamivir in the treatment of sars-cov- [ ] . in wuhan, on february , a clinical trial was initiated of remdesivir (newly discovered antiviral drug) on sars-cov- . this compound showed an inhibition of the replication of sars-cov and mers-cov in tissue cultures and efficacy in animal models [ ] . however, given the related issues of security, safety, and efficacy, it is necessary to take some time to develop the vaccine and the antiviral drugs [ ] . for a thousand years, traditional chinese medicine has gained an important experience in the infection healing. currently, this kind of medicine has provided significant therapies for many current diseases as a h n influenza, a h n influenza, ebola virus, and sars-cov [ ] [ ] [ ] . consequently, it can be also developed and applied in the treatment of covid- . in fact, the decoction combination of ma xing gan shi (combination includes ephedrae herba, armeniacae semen amarum, glycyrrhizae radix and rhizoma, and gypsum fibrosum) with da yuan yin that includes arecae semen, magnoliae officinalis cortex, tsaoko fructus, anemarrhenae rhizoma, dioscoreae rhizoma, scutellariae radix, glycyrrhizae radix, and rhizoma had showed in an important and a significant impact on sars. the state administration of traditional chinese medicine advised on february , the utilization of qing fei pai du decoction that includes ephedrae herba, gypsum fibrosum, pinelliae rhizoma, aurantii fructus immaturus, and zingiberis rhizoma recen. this decoction has been shown to be % effective in the treatment of sars-cov- [ , ] actually, there is no specific treatment or vaccine of covid- ; all of the drug options come from experience treating influenza, hiv, sars, or mers. at present, current efforts are focused on developing vaccines or specific antiviral drugs for covid- . according to what was published by the world health organization and a number of international health institutes, there are many restrictions that must be followed, either on a personal level or on the environmental level, including early recognition by the patients; carrying out additional precautions for persons suspected of infection, as well as for people who had contact with patients before their patients were revealed; applying standard precautions for all patients and imposing administrative measures from various authorities, such as the environment and health authorities [ , ] . in the current situation and to limit the spread of the covid- virus, all countries should publish an awareness declaration of the symptoms of infection in all cities, especially in remote areas. also, publish the easiest and fastest way for the methods that every patient should follow in the event of a patient. in addition, encourage hcws to have a high level of clinical suspicion [ , ] . the who confirmed that the rational, correct, and consistent use of personal protective equipment (ppe) also helps reduce the spread of pathogens. ppe effectiveness depends strongly on adequate and regular supplies, adequate staff training, appropriate hand hygiene, and appropriate human behaviour [ , , ] . at the level of additional precautions for patients, patients should be isolated in private quarantine rooms; everyone who contact with the patients, whether family, friends, or visitors, should be placed in a quarantine and a distance for contacting between them should be established [ ] ; the patients should cover their mouth and nose during sneezing by using masks or tissue as well as the persons covid- suspected should place medical masks in public places and closed rooms and after every sneeze; the patient must wash their hands well (with an alcohol-based hand rub or with soap and water), as a result of coming into contact with respiratory secretions; a proper and careful approach should be taken to eliminate all waste from patient uses [ ] , reducing as much as possible the exchange of equipment between patients and sterilizing them well when transporting them from one patient to another and after patient care, appropriate doffing and disposal of all ppe and hand hygiene should be carried out journal of immunology research [ ] . at the level of additional precautions for health care workers (hcws), a specialized team must be identified to deal with the patients to limit the spread of infection through protection methods, including the use of a medical mask, use of gloves, wearing of eye protection or facial protection, and wearing a clean, nonsterile, and long-sleeved gown; health care workers are prohibited from touching their eyes and nose with gloves or uncovered hands and limit the number of hcws, family members, and visitors who are in contact with suspected or confirmed covid- patients [ , ] . at the level of additional precautions for the environment surrounding patients, the surfaces and places that patients come in contact with should be sterilized regularly; ensure adequate ventilation in the health care facility; separation of at least one meter should be maintained between all patients and manage laundry, food service utensils, and medical waste in accordance with safe routine procedures [ , ] . the last section is on administrative policies and regulations that include educating caregivers on how to dealing patients, developing policies and plans through which early recognition of acute respiratory infection potentially caused by covid- virus, preventing overcrowding in public places as much as possible, ensuring that the necessary equipment for health care is provided in sufficient quantities and permanently, providing protection to quarantine areas by the authorities to reduce patients' contact with healthy people, and imposing sanctions on those who violate the provisions that have been put in place by the authorities to limit the spread of the covid- virus [ ] . in conclusion, covid- has become a high risk to the general population and healthcare workers worldwide. however, scientific research is growing to develop a coronavirus vaccine and therapeutics for controlling the deadly covid- . hence, health education on knowledge for disease prevention and control is also important to control and reduce the coronavirus infection rate. further research should be directed toward the study of sars-cov- on animal models for analyzing replication, transmission, and pathogenesis in humans. the authors declare that there is no conflict of interest regarding the publication of this 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managing epidemics: key facts about major deadly diseases, who,world health organization world health organization, how to put on and take off personal protective equipment (ppe), world health organization world health organization, who guidelines on hand hygiene in health care world health organization, infection prevention and control of epidemic-and pandemic-prone acute respiratory infections in health care world health organization, decontamination and reprocessing of medical devices for health-care facilities, world health organization physical interventions to interrupt or reduce the spread of respiratory viruses this work was supported by grants from the cnrst of morocco, (project ppr / / ppr ). key: cord- -y sqee authors: cho, ryan h. w.; yeung, zenon w. c.; ho, osan y. m.; lo, jacky f. w.; siu, alice k. y.; kwan, wendy m. y.; to, zion w. h.; chan, anthony w. h.; chan, becky y. t.; fung, kitty s. c.; abdullah, victor; tong, michael c. f.; ku, peter k. m. title: pearls of experience for safe and efficient hospital practices in otorhinolaryngology—head and neck surgery in hong kong during the novel coronavirus disease (covid- ) pandemic date: - - journal: j otolaryngol head neck surg doi: . /s - - - sha: doc_id: cord_uid: y sqee the novel coronavirus disease (covid- ) epidemic originated in wuhan, china and spread rapidly worldwide, leading the world health organization to declare an official global covid- pandemic in march . in hong kong, clinicians and other healthcare personnel collaborated closely to combat the outbreak of covid- and minimize the cross-transmission of disease among hospital staff members. in the field of otorhinolaryngology—head and neck surgery (ohns) and its various subspecialties, contingency plans were required for patient bookings in outpatient clinics, surgeries in operating rooms, protocols in wards and other services. infected patients may shed severe acute respiratory syndrome coronavirus- (sars-cov- ) particles into their environments via body secretions. therefore, otolaryngologists and other healthcare personnel in this specialty face a high risk of contracting covid- and must remain vigilant when performing examinations and procedures involving the nose and throat. in this article, we share our experiences of the planning and logistics undertaken to provide safe and efficient ohns practices over the last months, during the covid- pandemic. we hope that our experiences will serve as pearls for otolaryngologists and other healthcare personnel working in institutes that serve large numbers of patients every day, particularly with regard to the sharing of clinical and administrative tasks during the covid- pandemic. the novel coronavirus disease (covid- ) epidemic originated in wuhan, a province of china, and spread rapidly throughout the world thereafter. in march , the world health organization (who) officially declared covid- a pandemic. the th situation report issued by the who on march , listed , confirmed covid- cases and , deaths worldwide, and these statistics encompassed countries, areas and territories in china, southeast asia, the middle east, europe, the united states and africa [ ] . at the time of preparing this article, although the mortality rate of covid- in china ( . %) was lower than the rates associated with severe acute respiratory syndrome (sars) and middle east respiratory syndrome (mers) ( . and . %, respectively) [ , ] , the global mortality caused by covid- had exceeded mortality during the sars outbreak ( cases) by more than times [ ] . sadly, an otolaryngologist who worked at a hospital in wuhan, china was infected by sars-coronavirus- (sars-cov- ), the causative pathogen of covid- , and died in january . by the time of preparation of this article, more otolaryngologists in the u.k. had become infected via transmission from local patients and died of covid- , and at least otolaryngologists in iran had been admitted to the hospital with covid- . many more similar incidents have been reported in european countries [ ] . consequently, many additional healthcare personnel have been quarantined due to close contact with the infected otolaryngologists. the most commonly reported symptoms of covid- include fever, cough that may be productive, dyspnea and myalgia with fatigue [ ] . however, patients suffering from covid- may also present with symptoms of upper respiratory tract infection, such as a sore throat ( - %) and/or rhinorrhea ( %) [ , ] . carriers of covid- may shed a heavy viral load into the environment even if they are asymptomatic or present with very subtle symptoms [ , ] . recently, anosmia, hyposmia and dysgeusia, which affect patients' senses of smell and taste, were identified as symptoms of covid- , with high prevalence in europe, korea and china [ ] . patients who develop a symptom related solely to their sense of smell or taste before developing respiratory symptoms consistent with covid- may seek consultation with otolaryngologists and receive treatment for rhinitis or neuritis. an asymptomatic patient may still have infectious potential, therefore it is important to have a high level of suspicion and adopt safe practices and precautions. in outbreak of sars in hong kong, the initial phase of outbreak began in prince of wales hospital with a carrier of coronavirus in a medical ward causing widespread infection to patients and medical staff through the use of nebulizer for bronchodilators which facilitated the transmission of the virus through aerosol spread. this alerted the precaution of drug administration and aerosol generating procedures in subsequent outbreak of viral disease and the application of appropriate personal protective equipment for safety of healthcare personnel. at the beginning of the outbreak of covid- , all suspected and confirmed cases were admitted to hospital for covid- test and those patients with negative result were discharged. this created a considerable workload to hong kong public healthcare system and suspension of non-urgent service. with a large number of the suspected cases returning to hong kong from mainland china, europe, united states and asian countries with high prevalence of covid- , all people were quarantine at home or isolation camps for observation. only those with subsequent symptoms after arrival to hong kong or suspected history and positive test for covid- were admitted to hospital. this had significantly reduced the congestion in the public healthcare system and preserved the capacity to see those patients in need of treatment. in this article, we share our experience of planning and logistics over a -month period to achieve safe and efficient ohns hospital practices through during the covid- pandemic. in particular, we discuss the clinical and administrative issues encountered during the outbreak. we hope that our experiences will provide pearls for otolaryngologists and physicians in other clinical specialties who work together at institutions that serve large numbers of patients every day. the provision of health education for healthcare personnel played a very important role at the beginning of the covid- outbreak, when information about the disease was scarce and official guidelines for practice, including otolaryngology practice, were not yet available. health seminars on covid- , which were organized by the infection control team to all hospital staff on daily basis across the whole month, provided a direct platform from which to educate healthcare personnel about the virus, its mode of transmission, the course of the disease, management and the mortality rate. these seminars also enabled otolaryngologists and their nursing staff to share information with the infection control team, particularly regarding proper concepts of infection control in terms of hand hygiene, the donning and doffing of personal protective equipment, the handling of suspected or confirmed cases of covid- , contact tracing, the proper disposal of clinical waste and the handling of specimens for any laboratory investigations. this was particularly important, as the ohns specialty involves a large number of surgical procedures targeting the nose, pharynx and airway, which are performed in clinics, wards and operating rooms. these procedures are often aerosol and respiratory droplet generating. since the first week of february , special arrangement was made to vigorously reduce patient flow to minimize the risk of cross-transmission and preserve manpower for deployment to other clinical teams. specifically, the outpatients' visits were reduced to - % of the normal services to ensure that only those with urgent and semi-urgent conditions, such as head and neck cancers, airway emergencies, head and neck abscesses, acute otitis media, acute mastoiditis, complicated sinusitis, sudden hearing loss, facial paralysis or facial trauma, would be seen. during a -week period, the ohns clinic rescheduled more than cases with no complaints; only a minority of patients wanted to keep their original appointments, whereas more than % of patient visits were successfully rescheduled. drug refills were provided to stable patients without consultation by an otolaryngologist, depending on each patient's clinical condition, and new follow-up appointments were offered. patients were triaged at clinic fulfilling the ftocc criteria: fever, travel history, occupational exposure, contact history and clustering phenomenon were segregated and managed in a separate room with surgical mask on while calling the infection control team for assistance. the travel history to high risk areas was updated in response to the evolving pandemic according to our local guideline from the centre for health protection. in ohns, endoscopy is a high-risk procedure that can induce intra-procedural coughing, sneezing and choking. in our institutes, our group of otolaryngologists also reached a consensus for definitions of several common procedures associated with a potential risk of aerosol generation ( table ) . as a negative-pressure airborne infection isolation room (aiir) was not available at our clinic, endoscopic procedures were performed in a designated room equipped with an iqair® healthpro® (incen ag, switzerland) . this device contains a hepa class h filtration system that can filter . % of all particles > . μm. additionally, patients were asked to wear a surgical mask at all times before entry to the hospital area, except during the examination to minimize the dispersal of droplet nuclei during patient transfer [ ] . in the clinic, all of the fiberoptic endoscopes were labeled with code numbers that were recorded for contact tracing. we strongly preferred to perform endoscopic procedures while wearing high-level personal protective equipment (ppe) (e.g., face shield, n respirator, long-sleeved disposable fluid-resistant gown and disposable gloves) ( table ). from july to december , our clinic performed an average of fiberoptic endoscopy procedures and rigid endoscopy procedures per month. from february to march , however, the rescheduling of services and very conservative provision of endoscopy examinations reduced the number of fiberoptic and rigid endoscopy procedures to only and per month, respectively, which corresponded to service reductions of and %, respectively. the hospital adopted the strategy of video consultation via the zoom video communications software platform. this technology allowed clinicians to see some patients who did not require an extensive physical examination. video consultation was especially suitable for the followup of patients with nasal symptoms, hearing impairments, tinnitus, treated sleep apnea, hoarseness with benign causes, dizziness and some facial plastic conditions. our preliminary trial of this technology was promising, with preoperative and postoperative patients reporting excellent overall satisfaction with a mean score of . / , effective communication . / , satisfactory many ent examinations and procedures are aerosolgenerating (e.g., incision and drainage of peritonsillar abscess, hemostasis of epistaxis). therefore, healthcare personnel in the ward were required to wear high-level ppe when examining any patients. the number of staff in the ward procedure room was strictly limited to reduce the potential exposure to sars-cov- , and a team of one otolaryngologist with one or two healthcare assistants was preferred. patients who required urgent consultations with the accident and emergency or other clinical departments and presented with fever and respiratory symptoms were subjected to a covid- polymerase chain reaction (pcr) test unless their situation was desperate (fig. ) (table ) . to reduce patient flow and reserve hospital beds and staff during the covid- outbreak, the number of elective ohns operations was reduced to a minimum. a total of elective surgeries were cancelled or postponed in february and march . only essential elective operations involving head and neck cancer surgery or work-up, airway management and infective conditions were maintained. using this approach, we reduced our elective surgeries by % without complaint. an insufficient supply of surgical masks, protective gowns, face shields and n respirators posed a real threat to all healthcare personnel during the period under study, as the demand for these items far exceeded the global supply due to an interruption of the supply chain [ ] . consequently, our department adopted the extended use of ppe such as n respirators and protective gowns [ ] . specifically, healthcare personnel used only one n respirator and protective gown during the same session of clinical duty, irrespective of the number of patients who were seen, provided that the ppe was not grossly contaminated by blood or body secretions. face shields were used to protect the contamination of surgical masks or n respirators so that extended use was possible. a plastic apron was worn over the protective gown and disposed if it became contaminated, thus eliminating the need to remove the inner protective gown. these ppe-saving measures were required despite the above-described administrative measures intended to reduce patient visits. using this strategy, the weekly consumption of isolation gowns, n respirators and full-face shields decreased from to pieces, to pieces, to pieces, which represented a reduction of , and % respectively, relative to the initial levels. endoscopic nasal surgery was noted to increase the risk of exposure for the surgeons and healthcare personnel in the operating room. indeed, china newsweek reported that healthcare personnel were infected with sars-cov- while assisting with a single endoscopic pituitary surgery [ ] . endoscopic nasal surgical procedures that involve the use of powered endoscopic debriders with irrigation and suction or microdrills can generate aerosols loaded with viable virus particles, which spread in the environment. as reports suggest that aerosols may remain in the air for h, healthcare personnel faced a high risk of exposure if they did not wear high-level ppe [ ] . recommendations for any endoscopic nasal surgery may involve the required routine testing of covid- twice with a -h interval to confirm infection negativity before proceeding to surgery, as n respirators may not be sufficient to protect healthcare personnel in the operating room [ ] . with our initial measures in surgery arrangement and infection control, no otorhinolaryngologists or healthcare workers in hong kong had a nosocomial covid- infection. according to a report by the chinese center for disease control and prevention that included approximately , confirmed cases of covid- , approximately % of the patients surveyed developed critical disease involving respiratory failure, shock or multi-organ dysfunction that required ventilation [ ] . tracheostomy may be required for any patient subjected to prolonged intubation due to respiratory failure associated with covid- . during the sars outbreak, the ohns team performed tracheostomy in only ( . %) of the confirmed cases under treatment at the prince of wales hospital [ ] . from previous experience in sars, the decision on tracheostomy was jointly made by intensivist, anesthesiologist and otorhinolaryngologist for patients intubated for more than weeks in general, as ample time was required for evaluation of possible extubation for recovering patients. during tracheostomy, the number of healthcare personnel in the operating room should be limited. senior anesthetists and experienced otolaryngologists should perform the surgery in a negative-pressure aiir, and all operating room staff members should wear highlevel ppe and adopt contact-and airborne-protective measures. anesthetists should ensure that the patient is fully paralyzed to facilitate a smooth intubation. two disposable high-efficiency bacterial and viral hydrophobic filters should be placed in the expiratory circuit of the ventilator. airway suction must be performed in a closed system during the procedure. moreover, the apnea technique should be adopted during fenestration of the tracheal wall and insertion of the tracheostomy tube. a well-fitting cuffed tracheostomy tube should be inserted with the cuff inflated to prevent air leakage and minimize the frequency of post-operative tube changing. good communication between the anesthetists and nurses is essential throughout the procedure. in our ohns department, cancer operations were prioritized according to the aggressiveness of the tumor, presence of complications (e.g., airway obstruction, dysphagia and bleeding) and potential impact on reconstructive methods. previous studies have clearly documented the high doubling rate of head and neck squamous cell carcinoma, and a wait time longer than weeks may lead to worse prognostic outcomes, such as the development of new lymph node metastasis ( % of cases) and progression according to the tumor, node, metastasis (tnm) classification ( %) [ ] . patients with head and neck squamous cell carcinoma were therefore assigned a high priority, followed by those with highgrade salivary gland cancer and undifferentiated nasopharyngeal carcinoma. in contrast, papillary thyroid cancer, which has a much more favorable prognosis and a -year survival rate > %, was considered a lower priority [ ] . early operations were allocated to the resection of bulky tumors in the larynx or hypopharynx, as this might avoid complete airway obstruction requiring an emergency tracheostomy. small oral cavity tumors were also prioritized, as a delay in treatment might necessitate a more complex reconstruction (e.g., free flap reconstruction), which would lead to more significant morbidity, a longer operating time and a longer hospital stay. with the available weekly operative list for patients suffering from head and neck cancers, cases were operated in february and march . emerging evidence from china indicates that children usually develop mild symptoms of covid- [ ] . moreover, covid- patients as young as days have been reported [ ] . in a case series of pediatric patients in china, all of the children recovered spontaneously and did not require oxygen therapy. nonetheless, the severity of symptoms should not determine the level of precaution, as asymptomatic or mildly symptomatic patients may be as infectious as their more severely affected peers [ ] . pediatric airway procedures or even simple examinations are considered highly likely to generate droplets or aerosols via crying and/or coughing vigorously during a fiberoptic endoscopic examination. therefore, it is critical to maintain a high level of precaution during pediatric examinations. in this context, the healthcare personnel were required to wear highlevel ppe in anticipation of aerosol generation during the examinations and procedures. to save time and reduce the risk of cross-infection during the covid- pandemic, teleconsultations with otorhinolaryngologists and maxillofacial surgeons were arranged for stable patients of the combined sleep surgery clinic [ ] . in-patient polysomnography (psg) studies were replaced by home studies, including watch-pat and nox- studies, as these methods have exhibited high clinical correlations with the goldstandard psg method [ , ] . drug-induced sleep nasal endoscopy was suspended as it is an aerosol generating procedure, unless a polymerase chain reaction (pcr) test for sars-cov- yielded negative results prior to examination. in audiology practice, contact transmission remains the most common route of covid- transmission [ ] . therefore, audiologists must understand the importance of hand hygiene, demonstrate the appropriate use of ppe for various procedures and remain alert to the cleaning and disinfection of reusable items [ ] . during this pandemic, concerns were expressed about pediatric patients, as most did not comply with the instruction to wear a facial mask. audiologists should wear appropriate ppe for self-protection in any situation. toys and reusable items handled during a play audiology assessment must be cleaned thoroughly after use. during speech therapy, the assessment and training of patients with swallowing, speech and voice pathologies may generate aerosols. this risk increased further when working with patients with tracheostomy and laryngectomy, as any training procedures might require suctioning that could induce choking, coughing, sneezing and projectile vomiting. teleconsultations through video call were used to avoid direct contact and enable the proper evaluation of patients without the need to wear facial masks. swallowing assessments were performed by video-fluoroscopy, which was a good alternative to the fiberoptic endoscopic evaluation of swallowing because it allowed speech therapists and radiologists to maintain a distance from the patients during the assessments. covid- is a common enemy worldwide, and to date, more than , people have been infected by sars-cov- . during the sars outbreak, almost % of all infected cases involved healthcare workers, which further jeopardized the existing public healthcare system [ ] . this situation may be repeated during the covid- pandemic if healthcare facilities do not increase their vigilance in terms of the protective measures used by healthcare workers. in china, nearly healthcare workers had contracted covid- and had died by early march [ ] . in italy, at least healthcare workers had contracted covid- by mid-march , and these cases accounted for . % of all cases in that country [ ] . the u.s.a. appears to be the next country at risk, with more than , confirmed covid- cases as of march , . otolaryngologists work very closely with professionals in many clinical specialties. accordingly, although healthcare personnel in the specialty of ohns are highly susceptible to the risk of sars-cov- infection, their colleagues in partnered specialties must also remain vigilant when seeing patients together with otolaryngologists in any clinical environment. having experienced the sars outbreak in , the residents of hong kong were therefore very alert of covid- and adopted escalated personal hygiene habits, including facial mask and hand sanitizer use and avoidance of social gatherings, at an early stage. accordingly, the number of suspected covid- cases in hong kong as of march , was approximately with only confirmed cases [ ] . as we started our contingency plan very early with zealous education of the health care personnel and public, we could attain zero infection rate in our health care workers in the hospitals and no otolaryngologists in hong kong were infected. however, the situation could be worsened if outbreaks were not under control in europe, the u.s.a., canada, australia, southeast asia and the middle east. although the duration of the covid- pandemic cannot be predicted accurately, some experts in hong kong claimed that it will not end until a sars-cov- vaccine becomes commercially available. therefore, we may need to revise our clinical practice guidelines and protocols for ohns from the perspective of infection control, as our clinical services cannot be reduced indefinitely in the face of a long pandemic. tele-consultation provided a good tool to see our patients who could not attend the clinic because of quarantine regulation of hong kong, cities lockdown in china or suspension of clinic service in our hospitals. the feedback from patients was excellent as they were very grateful to be seen by their doctors distantly from their home or office through their mobile phones while the hospitals were under intense pressure on manpower and beds in this pandemic. in future practice of ent, each consultation room would install hepa filter and electronic endoscopes for nose, throat, and ear examination in order to keep distance from the patients. negative pressure ventilation should be installed in at least one consultation room to cater for highly suspected or confirmed case of highly infectious viral diseases. finally, we hope our clinical experiences will be useful to professionals in the specialty of ohns and related multidisciplinary services during this covid- pandemic. world health organization clinical characteristics of hospitalized patients with as-cov- infection: a single arm meta-analysis emergence of sars-like coronavirus in china: an update update: severe acute respiratory syndrome -united states precautions for endoscopic transnasal skull base surgery during the covid- pandemic. american academy of otolaryngology-head and neck surgery, coronavirus disease : resources clinical features of patients infected with novel coronavirus in wuhan epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study clinical characteristics and imaging manifestations of the novel 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audiology health care workers are at high risk of catching covid- . the verge chinese healthcare workers have gotten the coronavirus, and died coronavirus is killing italy's doctors. the u.s. could be next. daily beast latest situation of novel coronavirus infection in hong kong publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors would like to thank ms. monica lee, ms. gloria wong, ms. bonnie cheng and ms. chan miu yue for their effort to convert the ent ward and clinics up to the highest requirement of infection control in the outbreak of covid- . we also thank the infection control teams in united christian hospital and tseung kwan o hospital for their effort to check the layout and safety for all facilities in the ward and clinics to meet the standard of infection control and provision of updated fit test of n respirators to all team members. we would also like to thank dr. cheng hung kai, dr. tse man li, mr. boris yip and the information technology team in hospitals for a timely setup of hospital's mobile apps, website and audiovisual support to facilitate a convenient platform to the patients for tele-medicine service in our clinic during covid- pandemic. there is no funding related to this article. data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.ethics approval and consent to participate not applicable. not applicable. the authors declare that they have no competing interests. key: cord- -n cd fc authors: wang, li; jiang, man; qu, jialin; zhou, na; zhang, xiaochun title: clinical management of lung cancer patients during the outbreak of covid- epidemic date: - - journal: infect agent cancer doi: . /s - - - sha: doc_id: cord_uid: n cd fc the rapid growth of novel coronavirus (covid- ) outbreak in wuhan, china, at the early december . covid- spread all over the word just a few months. the outbreak of covid- infection poses major threat to international health and economy. world health organization (who) announced that the new coronavirus was an international public health emergency on january , . however, with the spread of covid- , the routine medical care of lung cancer patients was affected. because lung cancer patients have low immunity after anti-tumor treatment, they should become the main targets for epidemic prevention. lung cancer patients are increasingly concerned about the prevention of covid- . it is necessary to provide individualized medical treatment and management for lung cancer patients based on patients’ conditions and regional epidemic patterns. coronaviruses (covs) are enveloped non-segmented positive sense rna viruses, belongs to the subfamily coronavirinae, the order nidovirales, and this subfamily including alpha-, beta-, gamma-, and delta-coronavirus [ ] . coronaviruses mainly cause infections in birds and mammals and, in recent decades, also have shown an ability to infecting humans [ ] . the outbreak of betacoronavirus including severe acute respiratory syndrome coronavirus (sars) in [ ] and middle east respiratory syndrome coronavirus (mers) in [ ] has confirmed that the lethality of coronaviruses when they infect humans. the mortality rates of sars and mers are and %, respectively [ , ] . at the end of , a novel influenza coronavirus (covid- ) that similar to sars and mers appeared in wuhan, hubei, china and has been confirmed that has the ability of human-to-human transmission [ ] [ ] [ ] . the genome of covid- is a single-stranded positive sense rna [ ] . the gene sequence analysis showed that covid- has a typical coronavirus genome structure and belongs to the beta-coronavirus cluster [ ] . with the rapid increase of the number of cases and increasing evidence of human-to-human transmission, the virus is more contagious than sars and mers [ ] [ ] [ ] [ ] [ ] [ ] . moreover, covid- show very different virological characteristics compare with sars. for the sars, the level of rna usually reaches a peak after - days of symptoms. however, the level of rna reaches a peak within days of the symptoms of covid- , which can be times higher than the sars [ ] . in additional, three major covid- variants have been found, which are divided into a, b and c types. among them, the a virus is the closest to the coronavirus found in bats and pangolins. it is the original virus type and the b type is derived from type a, type c are derived from type b. nearly half of the samples infected with type a are from outside east asia, mainly in the united states and australia, and two-thirds of american samples are infected with type a, and type b is the most common in east asia. type c is the main virus type spread in europe [ ] . lung cancer was the most incident and lethal malignant tumor among all human cancers, with an estimated that there are about , new cases with lung cancer in the united states in [ ] . there are a large number of lung cancer patients. with the prevalence of covid- epidemic, the routine medical care of lung cancer patients was affected. moreover, lung cancer patients are more susceptible to covid- since they are usually elderly patients and have low immunity and poor lung conditions. thus, they need to be well protected from covid- . to minimize the effect of the epidemic, providing clinical management for lung cancer patients in the global epidemic scenario is an urgent requirement. in this review, we focus on the epidemiological characteristics, early diagnosis, patient management and mental health of lung cancer patients during the covid- epidemic. the coronavirus consists of nucleocapsid protein (n protein), spike protein (s protein), small envelope glycoprotein (e protein), membrane glycoprotein (m protein), hemagglutinin-esterase dimer (he protein) and rna. the spike protein of coronaviruses facilitates viral entry into target cells. the spike protein is a type i transmembrane glycoprotein and can be divided into two functional units: the receptor binding subunit s and the membrane fusion subunit s [ ] . s including two domains: the c-terminal receptor binding domain (rbd) domain and the n-terminal domain [ ] . s facilitates virus infection by binding to host receptors. and s is responsible for the fusion of the virus and the membrane of host cell. covid- uses the serine protease tmpr ss as an initiator of spike protein [ ] . angiotensin-converting enzyme (ace ) is a type i membrane protein mainly expressed in the lung, heart, kidney and intestine [ ] [ ] [ ] . ace consists of an n-terminal peptidase domain (pd) and a c-terminal collectrin-like domain (cld) [ , ] . the pd of ace mainly interacts with the rbd domain of the s protein of the coronavirus [ ] [ ] [ ] [ ] [ ] . and the rbd domain of the s protein is recognized by the extracellular pd of ace mainly through polar residues [ ] . the structural information of ace is limited to the pd domain. so, the s protein of covid- exploit ace for host infection [ ] [ ] [ ] [ ] . covid- invade the human body by combine to ace receptor, resulting in excessive activation of t cells, and producing large amounts of pro-inflammatory cytokines and chemokines such as il- , gm-csf. it also generates a positive feedback mechanism with monocytes, further produce large amounts of il- and other cytokines, and then emerge a cytokine storm [ , ] . the cytokine storm will trigger a violent attack by the immune system to the human body, cause ards and multiple organ failure, and finally lead to death in severe cases of covid- infection. based on current epidemiological investigations, the covid- of median incubation period is . days (interquartile range: . - . ) days [ ] . the main route transmission of covid- is through respiratory droplets and close contact. a study found viruses in chairs, bed rails, glass windows, floors, light switches and toilets in patient rooms. however, the results of the air samples were negative, but the samples collected at the exhaust ports were positive, indicating that the air, surface environmental, and personal protective equipment contamination is a potential medium of transmission [ ] . common symptoms are fever, cough, and myalgia or fatigue [ ] . less common symptoms were sputum production, headache, haemoptysis, and diarrhoea. about % of patients experienced dyspnea (median time from illness onset to dyspnoea was . days [iqr · - - · ]) [ ] . even some cases show loss of taste and smell [ ] . approximately . , . , and . % of patients were diagnosed with severe pneumonia, mild pneumonia, and non-pneumonia, respectively [ ] . laboratory features of patients usually include leukopenia, lymphopenia and elevated aspartate aminotransferase. compared with icu patients, non-icu patients had lower plasma levels of il , il , il , gscf, ip , mcp , mip a, and tnfα [ ] . covid- pneumonia baseline chest ct presented with ground glass opacities ( %), consolidation ( %), crazy paving pattern ( %), interlobular thickening ( %), adjacent pleura thickening ( %), and linear opacities combined ( %) [ ] . the covid- deaths are more common in the majority of patients over years age and suffer from underlying diseases such as hypertension, cardiovascular disease and cancer [ ] . chinese center for disease control and prevention [ ] has shown that , cases of pneumonia were reported, including confirmed cases ( . %), suspected cases ( . %), clinically diagnosed cases ( . %), and asymptomatic infections ( . %). about ( . %) were cancer patients, of which deaths, and the crude mortality rate was . %, which was higher than the overall population crude mortality rate of . % [ ] . a study [ ] analyzed patients with covid- as of january , , ( %) had a history of cancer, % of cancer patient were lung cancer patients. cancer patients have a higher risk of serious events than non-cancer patients ( and %, p = . , ) , and symptoms deteriorate more rapidly. the symptoms of lung cancer patients include cough, sputum, dyspnea, and fever. after anti-tumor therapy, patients may have various treatment-related side effects. moreover, the imageology detection of lung cancer is not typical due to influence of the tumor. therefore, it is very difficult to identify and diagnose the covid- pneumonia early. it is necessary to actively improve the relevant examinations, carry out differential diagnosis, and clarify the cause. the diagnosis of covid- pneumonia needs to be combined with the epidemiological history and clinical manifestations (① fever and / or respiratory symptoms; ② with imaging features of covid- pneumonia; ③ normal or reduced white blood cell count or decreased lymphocyte count in the early stage of the disease). cell culture traditional cell isolation and culture is a process of obtaining a large number of cells by simulating the in vivo environment in vitro. this method is the gold standard for virus detection. however, the training cycle is long and the sensitivity is low, and it cannot be used for rapid diagnosis. therefore, it is not recommended as the first detection method [ ] . serological testing currently, serological tests include immunochromatographic methods, enzyme-linked immunosorbent assays, and more. detection the antigens by collecting patient specimens that specifically bind to known antibodies. the serological testing kit are easy to standardize and commercialize. it has the characteristics of convenient and fast operation, and suitable for screening of hidden infections and large-scale people. serological tests often show these symptoms including, leukopenia, absolute lymphocyte reduction, abnormal liver function, coagulation function. a study developed a rapid and simple way which can detect igm and igg antibodies simultaneously against covid- in human blood within min which can detect patients at different infection stages [ ] . nucleic acid detection the characteristics of nucleic acid detection are high sensitivity and strong specificity. it has become the mainstream method for novel coronavirus detection. compared with other methods, the nucleic acid detection requires less sample and can be used for high-quality single-cell transcriptome sequencing. real-time rt-pcr real-time rt-pcr is widely deployed in diagnostic virology. in acute respiratory infection, rt-pcr is routinely used to detect causative viruses from respiratory secretions [ ] . a study [ ] successfully detects covid- , and further discriminates covid- from sars-cov by this method. and this study gives the detection primer sequence and determination method. this provides a theoretical basis for the detection of -ncov. chest ct examination chest ct examination plays an important role in the initial diagnosis of covid- pneumonia. multiple patchy ground glass opacities in bilateral multiple lobular with periphery distribution are typical chest ct imaging features of the covid- pneumonia [ ] . for lung cancer patients, it is very important to make a differential diagnosis and fully assess whether the lung cancer patients have other possibilities of causing fever and respiratory symptoms. radiation pneumonia radiation pneumonia can occur in lung cancer patients month to months after radiotherapy, and some case occur during radiotherapy. patients may have symptoms such as fever, dry cough, etc. chest ct showed ground glass and flaky lung shadows [ ] . moreover, with the improvement of radiotherapy technology, the imaging characteristics of radiation pneumonitis have also become unspecific. this makes it difficult to distinguish radiation pneumonia from covid- pneumonia. we need a multidisciplinary team in the radiotherapy department, imaging department, oncology department, and infection department to fully analyze the radiotherapy time, radiotherapy dose, radiotherapy site, and imaging characteristics, and carefully identify the patient's specific clinical manifestations and test results. there is a risk of immune checkpoint inhibitorassociated pneumonia in patients who receiving immunotherapy. the clinical symptoms of the immune checkpoint inhibitor-associated pneumonia including fever, increased cough and sputum, and increased dyspnea. chest ct shows ground glass and flake shadows in the lungs, and some patients can simply show ground glass shadows in the lungs [ ] . this also requires multidisciplinary cooperation including oncology, imaging, and infectious diseases, comprehensive analysis and identification, and guidance for subsequent treatment. tumor progression tumor progression may lead to obstructive pneumonia, cancerous lymphadenitis, pleural effusion increased, pericardial effusion, etc., which can lead to fever and respiratory symptoms. chest and abdomen ct and tumor markers can assist in differential diagnosis. patients with regular examination after lung cancer surgery can delay the examination if the condition is stable. for advanced lung cancer patients with targeted therapy or immunotherapy, the scheduled examination can be postponed or postponed according to the cancer status. the interval between examinations can be extended to more than months for patients with symptomatic remission or stable disease. it is recommended that patients continue to take the original medication and closely monitor the signs during the postponed examination period. patients should be examined admitted to the hospital for treatment, if symptoms progressively worsen. and the examination procedures and methods should be simplified to shorten hospital stays. patients may consult oncologists online or offline to understand the condition after examination. the treatment of general patient antiviral treatments antiviral treatments have been shown by clinical observation and research to have certain effects in covid- therapy. according to china's new coronavirus pneumonia diagnosis and treatment plan (trial version ), drugs with potential antiviral effects should be used early in the course of the disease, and it is recommended to focus on patients with high risk factors for severe illness patients. lopinavir/ritonavir and ribavirin alone are not recommended for covid- patients. lopinavir and ritonavir lopinavir and ritonavir is widely used as a boosted protease inhibitor in the treatment of hiv infection [ ] . lopinavir and ritonavir can block the enzymes that required for virus replication. lopinavir is often combined with ritonavir to extend the half-life of lopinavir by the inhibition of cytochrome p [ ] . a study had found that the lopinavir and ritonavir combined with ribavirin in the treatment of sars was associated with better effect [ ] . and animal studies show that lopinavir and ritonavir can reduce levels of coronavirus that cause sars and mers [ ] . remdesivir remdesivir, a nucleotide analog gs- that produced by biotechnology company gilead, has a certain anti-coronal virus effect in animal experiments [ ] . in addition, remdesivir can improve lung function, reduce lung viral load and severe lung pathology in mice [ ] . a study reported that an american patient with covid- survived by treated with remdesivir [ ] . at the same time, a study showed that % of the patients with severe and critical new coronavirus have relieved symptoms and the mortality rate is % after the use of remdesivir [ ] . however, the study was conducted under sympathetic medication, and there was no control group, so it was not possible to evaluate the direct relationship between remdesivir and patients' symptom improvement. although the test results released a certain positive signal, the test has limitations and still needs follow-up discussion. chloroquine, a widely used antimalarial and autoimmune disease drug, has been reported may be a potential broad-spectrum antiviral drug [ , ] . chloroquine blocks viral infection by increasing endosomal ph required for virus fusion, and interfering with the glycosylation of sars-cov cellular receptor [ ] . a study showed that remdesivir and chloroquine are highly effective in the control of covid- infection in vitro [ ] . therefore, the efficacy of chloroquine needs to be clarified and applied to patients as soon as possible. hydroxychloroquine is a derivative of chloroquine. the two structures are similar and the mechanism of action is very similar, but they differ in terms of safety and tolerability in clinical use. a study showed that the temperature recovery time and cough remission time of patients were significantly shortened in hydroxychloroquine group. the proportion of patients with improved pneumonia was . %, which was higher than that of the control group ( . %) [ ] . hydroxychloroquine can significantly shorten the clinical recovery time of patients with new coronavirus and promote the improvement of pneumonia. however, hydroxychloroquine or combined azithromycin is not recommended for covid- patients base on china's new coronavirus pneumonia diagnosis and treatment plan (trial version ). passive immunization, a technique to achieve immediate short-term immunization, to against infectious agents by administering pathogen-specific antibodies [ ] . human blood was also identified as a source of antibodies [ , ] . convalescent blood products obtained by collecting whole blood or plasma from patients who has survived in previous infection and produce humoral immune against the disease [ ] . convalescent plasma is widely used after large-scale epidemics of various viruses, such as mers and ebola virus (ebov) [ , ] . the results of a phase i clinical trial showed that patients with severe covid- pneumonia had all symptoms, especially fever, cough, shortness of breath, and chest pain, improved within days after infusion of plasma from recovered patients, and laboratory tests, imaging performance and viral load have improved significantly [ ] . in addition, convalescent plasma is suitable for patients with rapid disease progression, severe and critically ill patients base on china's new coronavirus pneumonia diagnosis and treatment plan (trial version ). the infusion dose needs to be determined based on the patient's clinical condition and weight, usually the infusion dose is - ml. a prospective meta-analysis of clinical trials of critically ill patients with covid- showed that administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower -day all-cause mortality [ ] . nowadays, according to china's new coronavirus pneumonia diagnosis and treatment plan (trial version ), the patients with progressive deterioration of oxygenation indicators, rapid imaging progress, and excessive activation of the body's inflammatory response, glucocorticoids should be used in a short period of time. the recommended dose is equivalent to . ~ mg/kg/day of methylprednisolone, meantime, who also made a strong recommendation for use of corticosteroids in severe and critical covid- because there is a lower risk of death among people treated with systemic corticosteroids [ ] . lianhuaqingwen capsule is an innovative patented traditional chinese medicine for treating influenza. it has broad-spectrum antiviral, effective antibacterial, antipyretic and anti-inflammatory, cough and phlegm, and regulates immunity against viral respiratory infection equal effect [ ] . more and more studies showed that lianhuaqingwen capsule has antiviral and anti-inflammatory effects on the covid- at the cellular level, which brings hope for the treatment of patients [ ] [ ] [ ] . lianhuaqingwen capsule has been approved by most countries for the prevention and treatment of light and common novel coronavirus pneumonia. β-d-n -hydroxycytidine (nhc/ eidd- ) is an oral ribonucleoside analogue against various rna viruses (including influenza, ebola, cov and venezuelan equine encephalitis virus (veev)) has broad-spectrum antiviral activity [ ] [ ] [ ] . a study showed that the mice infected with covid- or mers-cov, prophylactic and therapeutic administration of nhc/eidd- can improve lung function and reduce viral titer and weight loss [ ] . the efficacy and oral bioavailability of nhc/eidd- against a variety of coronaviruses highlight their potential utility as effective antiviral agents against covid- and other future zoonotic coronaviruses. tocilizumab tocilizumab is an immunosuppressive drug, mainly used to treat rheumatoid arthritis and systemic juvenile idiopathic arthritis. it is a humanized monoclonal antibody against interleukin receptor (il- r). previous studies have shown that patients infected with covid- quickly activate inflammatory t cells and inflammatory monocytes / macrophages in the body, resulting in the significant increase in il- levels in the blood, and the levels of il- is associated with the mortality of patients with covid- infection pneumonia [ ] . a recent study showed that all patients experienced a recovery in body temperature after injection of tocilizumab, and % of patients experienced a reduction in pulmonary symptoms. according to china's new coronavirus pneumonia diagnosis and treatment plan (trial version ), tocilizumab can be tried for patients with extensive lung disease and elevated il- levels in the laboratory. the first dose of tocilizumab is - mg/ kg, and the recommended dose is mg. for lung cancer patients who have not yet begun to medical treatment, the treatment strategy should be comprehensively considered baseed on the tumor burden and general situation of the patient. for early-stage lung cancer patients who waiting for surgery, the operation time should be postponed appropriately, especially for patients who mainly have ground glass shadow on the lungs in imaging, it has little effect on the overall condition in the short term. the specific situation should be based on specific condition to make a reasonable decision. for patients awaiting adjuvant chemotherapy after surgery, reasonable decisions should be made based on the postoperative pathology, clinical stage and prognostic indicators. a study showed that lung cancer patients who recover slowly from lung cancer surgery may still benefit from delayed adjuvant chemotherapy started up to months after surgery [ ] . moreover, for patients with lymph node stage n after surgery with egfr gene mutations or the rearrangements of alk, oral targeted therapy drugs at home may be considered as the optional adjuvant treatment option, which may reduce side effects of chemotherapy and the cross infection caused by repeated hospital visits [ ] . lung cancer patients undergoing chemotherapy may not be able to receive timely chemotherapy during the epidemic. the main concern in these patients is the development of tumor due to ingenuity of chemotherapy. therefore, while we attach importance to the adverse effects of this epidemic on chemotherapy delays in lung cancer patients, we should also regard the adjustment of chemotherapy regimen rationally. we recommend the patients who with a low tumor burden, stable disease, and receiving postoperative adjuvant chemotherapy and maintenance treatment can appropriately postpone inpatient chemotherapy or switch to oral chemotherapy targeted at home. for patients who require further chemotherapy, it is recommended that individual treatment under the guidance of an oncologist. targeted therapies are revolutionized therapeutics which interfere with specific molecules to block cancer growth, progression, and metastasis [ ] . targeted therapy is recommended for patients with advanced lung cancer with the mutations of targeted driver egfr, braf or the rearrangements of alk or ros [ ] . however, we must be alert to the increase of adverse events that may be caused by targeted therapies in the current epidemic situation. lung cancer patients who take oral targeted therapy drugs and have stable conditions should maintain the original drug treatment during the epidemic. patients whose condition improved markedly after targeted therapy and those with stable disease can be appropriately deferred to the hospital for review during the epidemic. although patients can be treated at home with oral drugs, attention should still be paid to the side effects and adverse events of some targeted drugs. further, it is necessary to promptly consult an oncologist under proper protection under emergency symptoms or obvious disease progression. immunotherapy has become an innovative technology for lung cancer therapy with the discovery of immunological checkpoints. it has shown great potential in a variety of advanced cancer treatments [ ] . drug binds to pd- molecule and generate steric hindrance that prevents pd-l from binding to pd- molecule, activates the immune response of pd- pathway-mediated, including anti-tumor immune response [ ] . we suggest that for lung cancer patients who receiving immunotherapy during the epidemic, it is not urgent to receive immunotherapy on a set date. considering the adverse events of pulmonary event caused by immunotherapeutic drugs, immunotherapy can be suspended or postponed in patients with stable disease. some lung cancer patients who receiving antitumor treatment such as chemotherapy, targeted therapy, and immunotherapy need deal with treatment-related adverse events outside the hospital during the epidemic. the common adverse events include nausea, vomiting, and myelosuppression. in order to reduce the case of nausea and vomiting, we recommend that patients maintain a reasonable diet and a good mood before antitumor treatment. some studies showed that psychological adjustments such as listening to music, enjoying pictures, and yoga can also reduce the case of nausea and vomiting [ , ] . if vomiting presists, a lateral position is necessary to prevent choking. after vomiting, we recommend that patients rinse their mouths with warm water and take an appropriate amount of saline to maintain electrolyte balance. in addition, if symptoms continue including abnormal vomiting color, excessive vomiting and dizziness, the patient should be taken to the hospital for symptomatic treatment. routine blood examination should be continue in the management of lung cancer patients during antitumor treatment to monitor the extent of myelosuppression through the important concerns including platelets, leukocyte counts, neutrophils, and red blood cells and hemoglobin levels. mild to moderate myelosuppression can be treated with corresponding oral drugs. however, there are some conditions need to be treated under professional doctor guidance: neutrophil count < . × / l, leukocyte count < . × /l, platelet count < × /l, hemoglobin level < g/l, or infection symptoms, or the occurrence of gum/nose bleeds and skin congestion. at present, covid- has spread around the world. in deaths, the majority of patients over years age and suffer from underlying diseases such as cancer [ ] . some studies have shown that about half of the survivors of malignant tumors have moderate fear of cancer recurrence [ ] . meantime, fujita et al. found that . % of lung cancer patients suffered anxiety and requested a treatment delay during the covid- pandemic [ ] . coupled with the epidemic, lung cancer patients may more worry about the impact of covid- and the delay of anti-tumor treatmen, which makes them more susceptible to illness, anxiety, depression and insomnia. calvo et al. found that health surveillance and monitoring is an important part of maintaining wellbeing during the covid- pandemic [ ] . another study also showed that a higher frequency of receiving covid- information and news was associated with a lower risk of anxiety [ ] . it is recommended high risk patients be identified for psychological morbidities and screening be improved to provide quick, cost effective psychological interventions via online platforms to manage symptoms during the covid- pandemic [ ] . in addition, considering the lack of time and resources for personalized 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chemotherapy-induced anxiety and nausea-vomiting effects of an integrated yoga programme on chemotherapy-induced nausea and emesis in breast cancer patients online mental health services in china during the covid- outbreak impact of covid- pandemic on lung cancer treatment scheduling health surveillance during covid- pandemic epidemiology of mental health problems among patients with cancer during covid- pandemic mental health strategies to combat the psychological impact of covid- beyond paranoia and panic predictors of psychological distress and interest in mental health services in individuals with cancer publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors thank dr. tang for helpful comments, and zhixuan ren for technical assistance. all authors reviewed the literature and participated in the writing and editing the manuscript. all authors read and approved the final manuscript. this work was supported by the taishan scholar foundation (no tshw ). ethics approval and consent to participate not applicable. not applicable. the authors report no conflicts of interest in this work.received: july accepted: september key: cord- -k owyolj authors: le maréchal, m.; morand, p.; epaulard, o.; némoz, b. title: covid- in clinical practice: a narrative synthesis date: - - journal: med mal infect doi: . /j.medmal. . . sha: doc_id: cord_uid: k owyolj the coronavirus disease (covid- ) was first reported in the city of wuhan, china. the disease rapidly spread to the rest of china, to southern-east asia, then to europe, america, and on to the rest of the world. covid- is associated with a betacoronavirus named sars-cov- . the virus penetrates the organism through the respiratory tract, conveyed by contaminated droplets. the main cell receptor targeted is the surface-bound ace- . as of the th july , , , covid- cases and , deaths were reported worldwide. the mortality rate is estimated between . and . %. the reproductive rate without any public health intervention is estimated around - . in france. most hospitalized patients for covid- present respiratory symptoms, which in some cases is associated with fever. up to % of admissions to icu are related to acute respiratory failure. to date, no anti-viral therapy has proven its efficacy considering randomized trials. only immunomodulatory treatments such as corticosteroids have shown to cause significant improvement in patient outcome. a study estimated the rt in the city of wuhan, china, between the st january and the t march [ ] , during five successive time periods (corresponding to different public health interventions). rt peaked at . on the th january (with no major public health intervention), and subsequently declined, to below . on the th february (after one week of city lockdown, traffic suspension, and home quarantine) and was below . on the st march (after days of quarantine) [ ] . in south korea, reproduction number rt was estimated at . ( % confidence interval (ci) . - . ) [ ] . in france, flaxman et al. estimated rt before lockdown between - . ( %ci), and around . during lockdown [ ] . the virus penetrates the organism through the respiratory tract, conveyed by contaminated droplets. while the exact viral progression remains elusive, the virus seems to have a favorable tropism for epithelial cells within the airways, leading to viral replication both in the nasal cavities and in distal bronchioles [ ] . the main cell receptor targeted by the viral surface glycoprotein (s) is the surfacebound angiotensin-converter enzyme (ace ) [ ] , yet it is still unclear if the virus can benefit from a second receptor to achieve gain cell entry. tmprss is a cellular serine proteinase whose role has been pointed out to prime sars-cov- cellular entry [ ] . the viral s protein, also known as spike, is responsible for both cell attachment and membrane fusion. it is formed by three dimers of two non-covalently bound domains s and s . both subunits are synthetized as a protomer resulting from the expression of the s gene. s and s are efficiently cleaved by a cellular furin [ ] thanks to a polybasic motif (prra) specific of sars-cov- [ ] . because of its specificity and key role in viral cycle, the s protein constitutes the main target for vaccine candidates [ ] . diagnosis of covid- requires laboratory confirmation, usually performed by detection of viral rna by a reverse-transcription polymerase chain reaction (rt-pcr). while the first laboratory confirmed cases in wuhan early in january relied on deep sequencing techniques [ ] , highly scalable assays have since been developed after the viral sequence was published. the first rt-pcr protocol was published by drosten and colleagues [ ] from charité university in berlin, and since then adopted by the who. this approach relies on the amplification and detection of the following sequences among the sars-cov- genetic sequence: the e gene encoding the envelope protein is used as a screening assay targeting all members of the betacoronavirus genera, and both the rdrp gene or the n gene are used as confirmatory assays due to their specific sequence in the sars-cov- species. this protocol has been widely adopted in commercially available test kits and is now used in most facilities. the paris institut pasteur has developed its own assay [ ] , based on the detection of two sequences in the rdrp gene spanning nucleotides - and - . this protocol has been widely used in french laboratories to manage early covid- suspicions and cases [ ] . such assays can be performed on several samples, and the choice of sampling site has been a debated issue considering the consequences of false negative results. nasal swabs, oropharyngeal swabs, saliva, sputum and bronchoalveolar lavage fluid (bal) were mostly reported. nasal swabs have proven to be effective and provided adequate sensitivity ( %) [ , ] , if performed properly. oropharyngeal swabs tend to be less sensitive ( %) [ ] . saliva collection has been proposed as a viable alternative yielding higher sensitivity ( . %) [ ] , also addressing the availability of swabs issue as worldwide demand surge and laboratories face shortages in stocks. sputum samples, while being more sensitive than upper respiratory tract samples ( . %) [ , ] , raise security concerns for the safety of healthcare workers regarding the droplet dissemination nature of the covid- . bal and other lower respiratory tract samples are widely used in intensive care units and yield very good results ( % sensitivity) [ ] . the viral load seemed higher in early stages of the disease [ ] , with symptomatic patients exhibiting higher viral titers as assessed by the lower ct numbers [ ] . when analyzed by rt-pcr, stools are frequently positive ( %), and high viral loads have been pointed out in such samples in both asymptomatic and symptomatic patients [ ] . no relation has been established as of today between enteric viral excretion and clinical outcome and disease severity. in children, the average duration of viral rna shedding in stools are days (+/- days). the duration of viral shredding seemed to decrease with age [ ] and infectivity of stools is low to non-existent. due to feces positivity, the sampling of wastewater has been proposed to assess viral circulation [ ] . plasmatic detection of sars-cov- has been reported but only with low viral titers, and mainly in clinically severe cases [ ] ; bloodstream infectivity has yet to be demonstrated. urine has remained virus-free except in one study [ ] . most genomic testing in asymptomatic patients [ ] returned negative after - weeks, with exceptional long shedding up to days after symptom onset [ , ] , raising the question of the infectivity of such viral shedding. excretion of infectious virions is thought to span two days before onset of symptoms up to days after onset [ ] , viral excretion peaking at day post-infection [ ] , supporting the effectiveness of a -day quarantine period for case isolation. however, results do not fully correlate with infectivity: viral culture from clinical samples is usually infeasible after days after onset of symptoms [ ] . nucleic acid testing (nat) is key to patient management and surveillance of disease propagation. according to several works, incubation period has been estimated between a mean of . and . days [ ] [ ] [ ] [ ] . lauer et al. estimated that symptom onset will occur within . days for . % of patients, and that a days quarantine would be sufficient [ ] . a large work from zhou et al. described clinical timeline for an patient cohort [ ] . the mean time from illness onset to intensive care unit (icu) admission was - days [ , ] ; it was days ( - ) to dyspnea [ ] , - . days to hospital admission [ , ] , days ( - ) to sepsis, days ( - ) to respiratory failure, and - days to death, depending on studies [ , ] . time between onset of symptoms and dyspnea is - days, to ards - days [ , ] . one initially described symptom was fever; however, up to % of patients were described as nonfebrile, and up to % of patients admitted in icu were non-febrile [ ] . coughing was reported in - % of cases, asthenia in - % of cases, myalgia in - % of cases, dyspnea/shortness of breath in - % of cases, and diarrhea in - % of cases [ , [ ] [ ] [ ] . no symptoms are specific of covid- , but surprisingly, anosmia and ageusia appeared to be strongly linked with covid- infection. mechanism for these symptoms is still to be unveiled, as well as for digestive forms in elderly patients presenting with only diarrhea. a study described imaging data among asymptomatic patients [ ] . chest ct evidenced in of them ( %) focal ground glass opacities, and in / ( %) stripe shadows and/or diffuse consolidation; / ( %) had a normal ct scan. in a asymptomatic chinese cohort, / patients had abnormal ct scans; few patients ( %) had comorbidities [ ] . the most frequent presentation of hospitalized covid- is pneumonia ( - %) with dyspnea and a rarely productive cough [ , , , , ] . in case of patients diagnosed with clinical pneumonia, chest x-ray and ct-scanner found bilateral ground-glass opacity in - % of cases [ , ] . when considering all hospitalized covid- patients, ct scans evidenced ground-glass opacities in - % of patients and consolidation in % of patients [ , ] . pulmonary injury was bilateral in - % of patients [ , ] . thromboembolic complications several works have described the high incidence in covid- patients of both venous and arterial thromboembolic diseases. in klok's study of patients with proven covid- pneumonia admitted to the icu in the netherlands, and who all received at least standard dose thromboprophylaxis, the incidence of thrombotic complication was % ( %ci - %) [ ] . in an italian study of cases (in icu and on general wards), presented a thromboembolic event ( . %). the authors estimated that those events were highly underestimated due to the low number of specific imaging tests performed [ ] . known risk factors for thromboembolic events that are reported in covid- are excessive inflammation and immobilization [ ] . however, in a large multicenter international work published by freund et al among , patients who underwent a computed tomography pulmonary angiogram for a suspected pulmonary embolism, a positive covid- status was not associated with pulmonary embolism in multivariate analysis (p= . ) [ ] . cardiac injuries have been described in covid- patients. viruses are a common cause of myocarditis [ ] ; myocardial injury can be related to direct cell injury caused by the virus, to t lymphocyte mediated cytotoxicity, to hemodynamic damage induced by hypoxia or shock, or related to cytokine storm [ ] . arrhythmia has been described as a cause of transfer in icu in % of covid- patients [ ] ; in an covid- acute setting, it can result from direct cardiomyocyte injury, to an infection of the pericardium causing massive edema, or to an ischemia due to microcirculation lesions [ ] . in a cohort of patients in wuhan, china, patients with elevated levels of cardiac troponin had a higher risk of hospital death [ ] . several neurological manifestations of covid- have been reported. manifestations are very diverse: -olfactory dysfunction: generally, post-viral olfactory loss account for % of acute olfactory dysfunction [ , ] . several studies reported olfactory dysfunction among covid- patients ( - %) [ ] [ ] [ ] . this may be related to a localized olfactory cleft edema (local inflammation), or a direct neuroinvasion of the olfactory nerve [ , ] . the loss of flavor perception is also frequently reported; it is considered to be mainly due to a loss of retronasal olfaction rather than a loss of sense of taste itself [ ] , -central nervous system manifestations: confusion [ , , ] , acute cognitive disorder, acute myelitis, encephalopathy, encephalitis [ ] , intracranial hemorrhage, strokes [ , , ] , seizures, -peripheral nervous system manifestations: guillain-barré syndrome [ ] [ ] [ ] [ ] , skeletal muscle damage (hyperckemia, rhabdomyolysis, myopathy [ , ] ), dysautonomia), -neuropsychiatric symptoms [ ] : anxiety, depression, insomnia, and psychosis suggested mechanisms are the hypoxic brain injury on severe pneumonia with peripheral vasodilatation, hypoxia, hypercapnia, and anaerobic metabolism, immune mediated injury related to the cytokine storm, and sars-cov- direct neurovirulence, since it has already been described for other coronaviruses [ , ] . prevalence of reported comorbidities among patients with covid- has largely varied according to countries. the largest published cohorts are among chinese and american patients, and main comorbidities are hypertension ( - %) [ , , ] , obesity ( %) [ ] , diabetes ( - %) [ ] , and cardiovascular disease ( %) [ , ] . being a man was described as the main risk factor for covid- [ , ] . most icu admissions were related with a respiratory failure ( - %) [ , , ] , that is also the leading cause of mortality ( - %) [ , ] . patients with respiratory failure are described to present an acute respiratory distress syndrome (ards), defined as a respiratory failure not fully explained by cardiac failure or fluid overload, bilateral opacities in chest imaging, and oxygenation pao /fio < mmhg [ ] . report from critically-ill-patients series suggested that those patients presented a "cytokine storm". biological data showed a higher level of il- in critically-ill and non-surviving patients, a higher level of crp and a higher level of ferritin [ , , , ] . among severe patients, the lymphocytes count was lower than mid patients or healthy controls (respectively , mol/l, , mol/l, and , mol/l). cd + and cd + lymphocytes were also lower in the severe-patients group [ ] . necropsy of patients who died from covid- allowed histological analysis of lung tissue samples. reported patients spent between and days in icu before death. macroscopic examination found lungs which were heavy, congested and edematous with patchy involvement. histological examination found features corresponding to the exudative and early or intermediate proliferative phases of diffuse alveolar damage (capillary congestion, interstitial and intra-alveolar edema, dilated alveolar ducts, collapsed alveoli and loss of pneumocytes). authors also reported interstitial pneumonia (inflammatory lymphomonocytic infiltrate along the slightly thickened interalveolar septa), organizing pneumonia, and acute fibrinous organizing pneumonia [ ] . a review article on children presenting covid- was published by cui et al. reporting clinical, biological and imaging features on . children [ ] . among all cases . % were asymptomatic, . % were mild, . % were moderate, . % were severe, . % were critical, and . % ( ) led to death. regarding clinical characteristics, authors collected data from articles ( children): % presented with fever, % with cough, % with sore throat, % with tachycardia, % with rhinorrhea, % with nasal congestion, and % with shortness of breath. among critical cases, six had an underlying disease. pulmonary imaging in cases reported % of ground glass opacities, % of local patchy shadow, % of bilateral patchy shadow, and % of interstitial lesions. in an international study among children presenting covid- infection, reported risk factors for admission to icu or requiring mechanical ventilation were being less than -month-old (p< . ) and having an underlying disease (p< . ) [ ] . observations described a higher risk of kawasaki-like inflammatory syndrome in children infected by sars-cov- , also called by who the covid- associated pediatric multisystem inflammatory syndrome [ ] ; e.g., a % increase of children admitted for a kawasaki-like syndrome during covid- epidemic was described in a small french cohort [ ] ; igg antibodies against sars-cov- infection were detected among / of children presenting with a kawasaki-like syndrome during the epidemic in another french cohort [ ] . kawasaki disease is described as an acute febrile systemic vasculitis that affects medium and small-sized blood vessels. one suspected mechanism is a post-viral immunological reaction to several viruses (influenza [ ] , enterovirus [ ] , adenovirus [ ] , parvovirus [ ] , vzv [ ] , ebv [ ] , measles [ ] , or dengue [ ] ). upon infection, humoral antiviral immunity is triggered, owing to the development of specific antibodies. a vast majority of infected patients will generate anti-sars-cov- antibodies [ ] . antibody titers peak around day post-infection [ ] , but from this point forward only decrease.. igm and igg kinetics do not differ significantly [ ] , thus making differential isolation of these markers void. seroconversion is witnessed at a median of days after symptom onset [ ] . high antibody titers are associated with severe respiratory symptoms, asymptomatic patients having lower titers [ ] . this raises the so far unresolved question of covid- immune mechanisms and protection. it is not clear whether high antibody titers could promote severe clinical presentations by a mechanism similar to antibody dependent enhancement [ , ] . on the other hand, pauci-symptomatic forms of covid- could trigger a reduced humoral response only that could correlate with a shortened duration of protection [ ] . anti-sars-cov- antibodies are directed towards both the spike (s) protein and the nucleocapsid (np) [ ] . neutralising antibodies are observed in most patients and recognise specifically the spike (s) protein [ ] . neutralising activity appears to be correlated with the presence of antibodies binding the receptor-binding domain (rbd) in its closed conformation within the spike protein [ ] , and the detection of such antibodies could be a surrogate marker of protection. no cross-reactivity with other human coronavirus (hcov-oc , hcov-nl , hcov- e and hcov-hku ) has been evidenced to date (ref). however, cross-reactivity with sars-cov- has been shown at least in vitro [ ] . while serological assays allow large epidemiological studies and enable better evaluations of epidemic parameters (rt, for instance), individual benefit is scarce, if existent. accordingly, we believe patient management should focus on molecular based assays. to date, no anti-viral therapy has proven its efficacy and the current management of covid- remains supportive care and ventilatory support when needed. remdesivir remdesivir (gs- ) is a nucleotide analog that targets viral rna polymerases. it has an established in vitro (culture cells) and in vivo (mouse and primate models) efficiency on multiple genetically distinct coronaviruses, and on ebola virus [ , ] . its in vitro effect on sars-cov- has been reported in wang et al.'s work, with a high % effective concentration value against infection of vero e cells [ ] . williamson explored remdesivir's efficiency in rhesus macaques infected with sars-cov- infection [ ] . one over six macaques in the remdesivir group developed a respiratory disease vs / in the control group. after euthanasia and lung analysis, no virus was detected in lung tissue samples in the remdesivir group; remdesivir was detected in all six lungs of the treated animals. only / lobe lungs in the control group were virus-free. there was no difference in viral load in bal between both groups. gilead restricted access to remdesivir since the beginning of covid- pandemic to compassionate use and to clinical trials [ ] . the first clinical study on remdesivir was published by grein et al. on patients, without any control group. treatment was started days after symptom onset; % of treated patients showed an improvement regarding oxygen support, and % of patients who completed treatment died [ ] . a large international clinical trial compared patients receiving remdesivir with patients treated with placebo. a shorter time to recovery ( days vs days) was reported in the remdesivir group (p< . ). adverse events were reported ( % in the remdesivir group and % in the placebo group [ ] ). goldman et al. compared vs days of remdesivir treatment in a multicentric, international clinical trial among patients and did not observe any difference between the groups at days after treatment onset on primary outcome (clinical efficacy on a -points scale) [ ] . lopinavir is an antiviral agent developed to target hiv protease; it is generally used in association with ritonavir, a pharmacokinetic "booster" increasing lopinavir plasma concentration. it is widely used in adults living with hiv/aids [ ] . lpv/rtv is regarded as a potential anti-sars-cov- agent since several trials on sars-cov- showed a favorable effect. indeed, in a study of , patients with sars, chan et al. reported a % death rate in the lpv/rtv group vs % in the soc group (p< . ) if lpv/rtv was used as initial treatment, but with no difference as a rescue treatment [ ] . in a study exploring the efficacy of lpv/rtv in patients with sars regarding a composite primary outcome (severe hypoxemia or death at day ), chu et al observed that % in the lpv/rtv group met the primary outcome, vs % in a historic control group (p< . ) [ ] . the first large clinical trial published on lpv/rtv on sars-cov- compared patients receiving the antiviral vs receiving soc alone [ ] ; there was no difference between the groups regarding the primary end point (time to improvement) ( vs days, p= . ). noteworthily, the median time between symptom onset and treatment was days. % of patients in the lpv/rtv group vs % in the soc group who underwent an adverse event. hydroxychloroquine (hcq) is a widely used molecule in limited forms of lupus, with a low price, and it has an established clinical safety profile [ ] in vitro studies showed the effect of chloroquine [ ] and hcq in inhibiting sars-cov infection [ ] . in vitro activity of hcq and chloroquine against sars-cov- were not different in liu et. al's work [ ] , and hcq was found, in vitro, to reach three times the potent antiviral activity of chloroquine in yao et. al's work [ ] . noteworthily, hcq was four times less toxic than chloroquine in animal study [ ] . however, a recent in vitro study showed that chloroquine did not block sars-cov- infection of the tmprss -positive lung cell [ ] . another in vitro study also found that hcq did not show any antiviral activity in a model of reconstituted human airway epithelium [ ] . due to such in vitro results, several trials assessed the efficiency of hcq on viral load in respiratory samples (without clinical considerations [ ] [ ] [ ] [ ] . association of hcq and azithromycin was associated with a higher risk of ventricular tachycardia and prolonged qt. hcq alone was responsible for more conduction disorder. however, in patients receiving azithromycin alone compared with hcq alone, there was more prolonged qt and ventricular tachycardia. unchanged before and after hemodialysis [ ] . moreover, several observations reported the onset of severe covid- in patients who were already receiving hcq as a long-term treatment for an inflammatory disease [ ] . one randomized trial evaluated the outcome of hcq whether or not in association with azithromycine on mild to moderate covid- [ ] . primary endpoint (escalation in icu, mechanical ventilation or death) was reached by % of patients in the early corticosteroid group vs % in the control group (p= . ) [ ] . recovery was a randomized, controlled trial of the use of mg of dexamethasone vs soc in hospitalized patients with covid- . at days, / , ( . %) patients had died in the dexamethasone group vs , / , ( . %) in the soc group (p< . ) [ ] . tocilizumab is a monoclonal antibody against il- receptor. it is mainly prescribed in rheumatoid arthritis. an italian team reported the use of tocilizumab to the first patients presenting to the brescia university hospital with a covid- ards requiring ventilatory support. at h, % of patients showed an improvement, and at days after treatment inset, % of patients had improved and/or stabilized [ ] . anakinra is an antagonist of il- receptor. an italian team reported the use of anakinra in patients with moderate to severe covid- ards before mechanical ventilation, compared with patients not receiving anakinra. survival rate at days was % in the anakinra group vs % in the control group (p = . ). however, there was no difference regarding the mechanical ventilation-free survival ( % in the anakinra group vs % in the control group, p= . ) [ ] . a chinese team reported the use in covid- patients of convalescent plasma compared with a control group of patients. their primary endpoint was clinical improvement within a day-period (reduction of points on a -points disease severity scale). there was no difference between both groups (p = . ). in sub-group analysis among patients presenting a severe disease, % of patients met the primary endpoint in the plasma therapy group vs % in the control group (p = . ) [ ] . in another study, the outcomes of , severe or critical patients treated with soc and patients treated with convalescent plasma therapy were compared; . % of patients died in the plasma group vs . % in the soc group (no comparison). . % of patients were admitted to icu in the plasma group vs . % in the soc group (p= . ) [ ] . the effect of ace inhibitor and arb treatment on covid- severity and/or mortality has been reported in several studies but seems variable. in zhang et al's work, on , patients with hypertension and covid- , multivariate analysis found a lower all-cause mortality in the ace inhibitor/arb group, than in the other group (p = . ) [ ] . however, li et al did not found any difference in covid- severity (p= . ) or mortality (p= . ) among patients admitted for hypertension and covid- [ ] . in chu et al.'s meta-analysis, social distancing was considered as efficient with a - . % risk difference ( %ci [- . to - . %] of infection in short distance vs further distance [ ] . wearing respirators or face masks was associated with a large reduction in risk of infection (risk difference - . %, %ci [- . to - . %]) [ ] . eye protection also seemed efficient in infection reduction with a risk difference of - . % %ci [- . to . %] [ ] . however, lockdown had the larger impact on transmission with an % [ %- %] reduction [ ] . in france, the number of daily cases of covid- was growing by the end of summer , suggesting the debut of a second epidemic wave, as many other countries are facing. the first wave allowed us to develop and strengthen our laboratory tests. since then, french health authorities have implemented a systematic contact tracing (contact-covid) around each patient presenting a positive sars-cov- rt-pcr. this highlighted the high number of asymptomatic and mild cases, and made french people massively adapt their daily habits with a systematic face mask protection in all public areas, and restrictions in social events. however, none of the evaluated pharmacological treatments have showna clear efficacy on sars-cov- . one of the main limitations seem to be the long period between symptom onset and initiation of treatment. an effective vaccine against sars-cov- appears to be the only way to end this pandemic. at the end of august , trials were registered on clinicaltrial for a vaccine against covid- , thus raising hope to end this pandemic in a reasonable amount of time. promed post -promed-mail n diseases is for i. promed post -promed-mail china is consistent with substantial human-to-human transmission who coronavirus disease (covid- ) dashboard | who coronavirus disease who director-general's opening remarks at the media briefing on covid- - the species severe acute respiratory syndrome-related coronavirus: classifying -ncov and naming it sars-cov- a pneumonia outbreak associated with a new coronavirus of probable bat origin a sars-cov- protein interaction map reveals targets for drug repurposing moderate mutation rate in the sars coronavirus genome and its implications a dynamic nomenclature proposal for sars-cov- lineages to assist genomic 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sars-cov- neurologic manifestations in hospitalized patients with covid- : the albacovid registry severe neurologic syndrome associated with middle east respiratory syndrome corona virus (mers-cov) presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the new york city area comorbidity and its impact on , patients with covid- in china: a nationwide analysis clinical predictors of mortality due to covid- based on an analysis of data of patients from wuhan, china clinical characteristics of deceased patients with coronavirus disease : retrospective study acute respiratory distress syndrome: the berlin definition aberrant hyperactivation of cytotoxic t-cell as a potential determinant of covid- severity pulmonary post-mortem findings in a series of covid- cases from northern italy: a two-centre descriptive study children with coronavirus disease : a review of demographic, clinical, laboratory, and imaging features in pediatric patients covid- in children and adolescents in europe: a multinational, multicentre cohort study multisystem inflammatory syndrome in children and adolescents with covid- n emergence of kawasaki disease related to sars-cov- infection in an epicentre of the french covid- epidemic: a time-series analysis kawasaki-like multisystem inflammatory syndrome in children during the covid- pandemic influenza a (h n ) pdm virus infection in a patient with incomplete kawasaki disease: a case report enterovirus infection and subsequent risk of kawasaki disease: a population-based cohort study adenovirus, adenoassociated virus and kawasaki disease acute respiratory distress syndrome in a child with human parvovirus b infection kawasaki disease onset during concomitant infections with varicella zoster and epstein-barr virus incomplete kawasaki disease induced by measles in a -month-old male infant dengue-triggered kawasaki disease: a report of cases a peptide-based magnetic chemiluminescence enzyme immunoassay for serological diagnosis of coronavirus disease neutralizing antibodies responses to sars-cov- in covid- inpatients and convalescent patients antibody responses to sars-cov- in patients with covid- profiling early humoral response to diagnose novel coronavirus disease (covid- ) the potential danger of suboptimal antibody responses in covid- dissecting antibody-mediated protection against sars-cov- the dynamics of humoral immune responses following sars-cov- infection and the potential for reinfection comparison of the diagnostic sensitivity of sars-cov- nucleoprotein and glycoprotein-based antibody tests potent neutralizing antibodies directed to multiple epitopes on sars-cov- spike potent neutralizing monoclonal antibodies directed to multiple epitopes on the sars-cov- spike broad-spectrum antiviral gs- inhibits both epidemic and zoonotic coronaviruses therapeutic efficacy of the small molecule gs- against ebola virus in rhesus monkeys remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus ( -ncov) in vitro clinical benefit of remdesivir in rhesus macaques infected with sars-cov- emergency access to remdesivir outside of clinical trials compassionate use of remdesivir for patients with severe covid- remdesivir for the treatment of covid- -preliminary report remdesivir for or days in patients with severe covid- lopinavirritonavir: a review of its use in the management of hiv- infection treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study role of lopinavir/ritonavir in the treatment of sars: initial virological and clinical findings a trial of lopinavir-ritonavir in adults hospitalized with severe covid- a systematic review on the efficacy and safety of chloroquine for the treatment of covid- hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting sars-cov- infection in vitro in vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome main point : hydroxychloroquine was found to be more potent than chloroquine at inhibiting sars-cov- in vit animal toxicity and pharmacokinetics of hydroxychloroquine sulfate chloroquine does not inhibit infection of human lung cells with sars-cov- hydroxychloroquine use against sars-cov- infection in non-human primates hydroxychloroquine in patients with mainly mild to moderate coronavirus disease : open label, randomised controlled trial hydroxychloroquine and azithromycin as a treatment of covid- : results of an open-label non-randomized clinical trial preliminary evidence from a multicenter prospective observational study of the safety and efficacy of chloroquine for the treatment of covid- observational study of hydroxychloroquine in hospitalized patients with covid- cardiovascular toxicities associated with hydroxychloroquine and azithromycin: an analysis of the world health organization pharmacovigilance database hydroxychloroquine pharmacokinetic in covid- critically ill patients: an observational cohort study covid- infection also page of patients taking hydroxychloroquine hydroxychloroquine with or without azithromycin in mild-to-moderate covid- successful use of methylprednisolone for treating severe covid- early short course corticosteroids in hospitalized patients with covid- effect of dexamethasone in hospitalized patients with covid- : preliminary tocilizumab for the treatment of severe covid- pneumonia with hyperinflammatory syndrome and acute respiratory failure: a single center study of patients in brescia interleukin- blockade with high-dose anakinra in patients with covid- , acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study treatment of critically ill patients with covid- with convalescent plasma improved clinical symptoms and mortality on severe/critical covid- patients utilizing convalescent plasma transfusion association of inpatient use of angiotensin-converting enzyme inhibitors and angiotensin ii receptor blockers with mortality among patients with hypertension hospitalized with covid- association of renin-angiotensin system inhibitors with severity or risk of death in patients with hypertension hospitalized for coronavirus disease (covid- ) infection in wuhan, china physical distancing, face masks, and eye protection to prevent person-to-person transmission of sars-cov- and covid- : a systematic review and meta-analysis key: cord- -xt zxajf authors: shanmugam, chandrakumar; mohammed, abdul rafi; ravuri, swarupa; luthra, vishwas; rajagopal, narasimhamurthy; karre, saritha title: covid- – a comprehensive pathology insight date: - - journal: pathol res pract doi: . /j.prp. . sha: doc_id: cord_uid: xt zxajf corona virus disease- (covid- ) caused by severe acute respiratory syndrome corona virus- (sars cov- ), a highly contagious single stranded rna virus genetically related to sars cov. the lungs are the main organs affected leading to pneumonia and respiratory failure in severe cases that may need mechanical ventilation. occasionally patient may present with gastro-intestinal, cardiac and neurologic symptoms with or without lung involvement. pathologically, the lungs show either mild congestion and alveolar exudation or acute respiratory distress syndrome (ards) with hyaline membrane or histopathology of acute fibrinous organizing pneumonia (afop) that parallels disease severity. other organs like liver and kidneys may be involved secondarily. currently the treatment is principally symptomatic and prevention by proper use of personal protective equipment and other measures is crucial to limit the spread. in the midst of pandemic there is paucity of literature on pathological features including pathogenesis, hence in this review we provide the current pathology centered understanding of covid- . furthermore, the pathogenetic pathway is pivotal in the development of therapeutic targets. the current pandemic of corona virus disease- (covid- ) caused by severe acute respiratory syndrome corona virus- (sars cov- ) led to complete lockdown in many countries contributing to major socio-economic crisis and irreparable recession, globally. sars cov- , a novel β cov was first identified in adults presenting with acute lower respiratory tract infection of unexplained etiology in china. [ ] though no age group is spared, severe forms occur in patients older than years specifically with co-morbidities. the majority of the infected individuals are asymptomatic or with mild form of disease and are potential transmitters. this disease is highly contagious and mainly spread through respiratory droplets, close contact with infected cases or materials (fomites) and nosocomially to other patients and health care workers in the hospitals. [ , ] covid- has a much lower case fatality ratio and significantly greater transmission rate than sars pandemic. [ , ] currently rt-pcr of upper and lower respiratory swabs or samples is the gold standard diagnostic test. serological tests based on antibody detection, though not helpful during the early phases of disease, can be used to confirm infection in later phase. a thorough literature search (pubmed, preprint servers and google scholar) using terms covid- and pathology/pathogenesis, sars cov- and pathology/pathogenesis and -ncov and pathology/pathogenesis was done to maximize the yield of literature, which ended on may . in this review, we have comprehensively discussed all aspects of covid- with special emphasis on the pathology including pathogenesis and therapeutic targets. it forms a ready resource for clinicians, pathologists, and researchers including epidemiologists aiding them in the diagnosis and treatment of these patients, and may also pave way to further research. the earliest case of sars cov- infection currently known was reported on st december in wuhan, hubei province of china. [ ] after this it spread rapidly to other parts of china as well as internationally affecting over countries as of april , leading to the current global pandemic. [ ] the world health organization declared covid- to be a public health emergency of international concern on january , and recognized it as a pandemic on march .[ , ] as of may , globally . million cases of covid- have been reported, resulting in , deaths and , , people have recovered. [ ] j o u r n a l p r e -p r o o f the basic reproduction number (r ) of the sars cov- is estimated to be between . and . , indicating its highly contagious nature. [ , ] the r may be even higher in places of public gatherings like in cruise ships, religious/political/academic/business congregations as well as in hospitals non-compliant with personal protective measures. [ , , ] the incubation period and serial interval is estimated at - days and days, respectively, which is similar to that for sars cov and mers cov. [ , , , ] early in the pandemic, the case-fatality rate (cfr) was estimated to be between . % and %, [ , ] lower than other hcovs (sars cov ( %- %) and mers cov ( %- %)). [ , , ] however, by the th of may many countries exhibited exponential rise in cfr. [ ] (table:i) unlike sars cov, the high percentage of sars cov- infected individuals manifest as asymptomatic or pauci-symptomatic infection who escape detection and become potential transmitters. [ , ] it is important to note that, not all close contacts are infected suggesting a role for individual genetic susceptibility. [ , , ] in humans, the virus usually gains entry through upper aero-digestive tract. more recently sars cov- was isolated from the feces of patients, indicating the possibility of fecal-oral spread. [ , ] furthermore, sars cov- infection in pregnant women raised a possibility of vertical transmission. [ ] however, the vertical transmission was ruled out based on negative testing for the virus on the swabs collected from the amniotic fluid, cord blood, neonatal throat and breast milk of the six infected pregnant women. [ ] the long range airborne transmission is also speculated which depends on flow dynamics of the virus from the infected person and also on ventilation status of the area. [ ] moreover, the expansion and spread of covid- can be visualized by mapping techniques like cartograms. [ ] the understanding of modes of transmission of sars cov- will enable application of appropriate containment measures. though there is generalized susceptibility to sars cov- infection for all age groups, body defense against infection as well as their underlying age related organ system compromise. [ , , , ] similar to sars cov, a recent study reported non-o blood group specifically group a had higher infection and death rates due to covid- owing to absence of protective anti-a igm antibodies. [ , ] many uncertainities still persist in the sars cov- epidemiology especially virus-host interaction including host susceptibility and the evolution of epidemic. the corona viruses (covs) are classified into α and β (seen in mammals including humans); γ and δ (seen in avian species). [ to pangolin cov with a difference of only one amino acid. [ ] recently another study suggested pangolin involvement in sars cov- origin due to evidence of re-assortment in covs. [ ] sars cov- differs from other β covs by the presence of unique polybasic cleavage site that contributes to increased pathogenicity and transmissibility. [ ] each virion is a enveloped, non-segmented, positive sense single stranded rna virus the sars cov- because of its similarity with sars cov is presumed to infect human cells through its densely glycosylated spike (s) proteins s fraction with receptor binding domain (rbd) which binds to the angiotensin-converting enzyme receptor (ace- r) with to fold higher affinity than sars cov. [ [ , ] after the virus gets attached to this receptor, the sars cov- with its unique polybasic s /s protease cleavage site with sprr insertion on the spike protein which is recognized and cleaved by transmembrane protease serine (tmprsss) expressed on host cells to expose the fusion protein (s fraction) that enables the fusion of both viral and the host cell j o u r n a l p r e -p r o o f membrane. [ ] it has been demonstrated that ace- r and tmprsss are highly co-expressed in alveolar type pneumocytes, epithelium of upper esophagus and absorptive enterocytes, forming the basis of speculation that the sars cov- can gain access into host through esophageal and intestinal epithelium apart from alveolar epithelium. hence, the potential target tissues for sars cov- should co-express ace- r and tmprsss. the current understanding of pathology stems from few case reports and autopsy case studies. the gross features include heavy and boggy lungs, patchy consolidation along with pleural fibrinous exudate and /or fibrosis, sometimes with purulent inflammation due to secondary bacterial infection with/without evidence of pericarditis. [ ] the microscopic features depend on stage and severity of the disease. early stages (asymptomatic/mildly symptomatic patients) show non-specific changes including pulmonary j o u r n a l p r e -p r o o f edema, focal pneumocyte hyperplasia, focal chronic inflammatory infiltrate and multinucleated giant cells with absence of prominent hyaline membrane formation. [ ] as, the disease progress there is diffuse alveolar damage with transparent hyaline membrane formation and severe pulmonary edema. however, in sars cov- , there is firbomyxoid exudates with visible fibrinous cords along with mucous plugging of bronchioles which has a bearing with respect to oxygen therapy. there is also widespread interstitial inflammatory infiltrates with severe epithelial damage,diffuse type ii pneumocyte hyperplasia consistent with ards. [ , , , , ] one study reported massive pulmonary interstitial fibrosis with variable degree of hemorrhagic necrosis, chronic inflammation with multinucleate giant cells and intracytoplasmic viral inclusion bodies in severe cases. [ ] interestingly, another study showed features of lymphocytic viral pneumonia in a patient who died early in the disease ( th day after development of symptoms), whereas five other patients who succumbed later ( th day after development of symptoms) exhibited acute fibrinous and organizing pneumonia (afop) showing extensive fibrinous deposits forming balls/mounds but not hyaline membrane in their alveoli. these patients also showed prominent vascular injury evidenced by endothelial cell detachment and prominent intracytoplasmic vacuolization in small and medium-sized pulmonary blood vessels. [ ] also, severe covid- infection has been associated with a novel pulmonary-specific vasculopathy known as pulmonary intravascular coagulopathy (pic), that parallels disease severity. [ ] these findings may be considered as important indicators of disease severity and prognosis. the liver shows mild lobular lymphocytic infiltration and moderate micro-vesicular steatosis along with mild lobular activity, possibly related to the viral infection itself and ischemia. there were no obvious histological changes in heart tissue except for mild interstitial chronic mononuclear infiltrate. [ , , ] hence the changes in the liver and heart are more likely secondary or related to the underlying diseases. [ ] the pathology in other organs have not been elucidated. it is too early to determine the specificity and consistency of these histopathological findings with respect to the stage and severity of the covid- owing to the paucity of information obtained from few biopsy/autopsy case reports. in addition, the histopathological features may be modified or altered by patients' immunity, presence of co-morbidities, secondary infections and therapy given to these patients especially steroids. only few patients present with gastrointestinal symptoms like diarrhea ( . %) and nausea/vomiting ( . %). [ ] in . % of covid- patients there was at least one underlying co-morbidity(hypertension, diabetes, chronic cardiovascular/ pulmonary/ renal disease and cancer). [ ] the severe form is characterized by ards that necessitates mechanical ventilatory support in an intensive care unit (icu), and also leads to multiorgan involvement resulting in shock, septicemia, and mods with high mortality. [ , ] a substantial proportion of patients developed diarrhea during hospitalization, potentially aggravated by various drugs including antibiotics. [ ] these patients may also present with cardiac sounding chest pain due to myocarditis and myocardial infarction. children are either asymptomatic or pauci-symptomatic (fever ( %), cough ( %), fatigue, rhinorrhoea or nasal congestion) and are less likely to have severe infections. [ , ] gastrointestinal symptoms like diarrhoea, abdominal cramps and vomiting, common in children, covid- positive patients frequently exhibit hematologic abnormalities in the form of lymphopenia, leukopenia, and thrombocytopenia, along with elevated levels of liver enzymes, lactate dehydrogenase, prothrombin time and d-dimers. [ ] lymphopenia is associated with disease severity and mortality. [ ] acute phase reactants such as crp, ferritin and procalcitonin and pro-inflammatory cytokine levels were higher in covid- than healthy adults. [ ] covid- patients needing icu management when compared to non-icu patients had higher plasma levels of pro-inflammatory cytokines (il , il , il , gscf, ip , mcp , mip a, and tnfα), increased total wbc and neutrophil counts, higher levels of d-dimer, creatine kinase, and creatinine. [ , ] similar laboratory findings were seen in children with covid- . [ ] findings on chest imaging in sars cov- pneumonia seems to be similar to ordinary viral pneumonia, with some peculiarities. chest x-ray and ct changes may be seen even before the detection of the virus from swab. in contrast, the chest x-ray may be normal in % of laboratory confirmed covid- cases. [ ] the commonest feature on chest x-ray is presence of bilaterally symmetrical ground glass opacities with or without associated consolidation in the posterior and peripheral lung fields. [ ] however, the ct findings vary with the duration of symptoms. [ ] in the initial phase (days - ) basal multifocal peripheral ground-glass opacities are noted. with disease progression (mid phase (days - ) there is linear opacities developing on a background of ground-glass opacities (crazy pavement pattern). in the late phase (days - ) the central ground-glass opacities become surrounded by denser crescentic shaped consolidation (forming more than three-fourths of a circle) or form complete ring of at least mm in thicknesscalled as 'reversed halo sign' or 'atoll sign' [ ] children also exhibit similar radiologic features. [ ] chest ct suggesting covid- had % sensitivity in concordance with positive these tests are complex, time consuming, expensive and need expertise to perform as well as to interpret. [ , , ] the molecular test based on point of care testing using cartridges are rapid and needs less expertise. high throughput technologies including ngs can be used for simultaneous screening of large number of samples but its application is limited to research only due to high expenditure. [ ] the serological tests detects either the viral antigens (spike protein and nucleo-capsid being target antigens), or the antibody response to the virus by immunochromatography and elisa methods. specifically, the antibody testing is not helpful in the early phases of infection. though simple, cost effective, easy to perform and interpret, there are chances of false positives especially due to cross reactive antibodies against other hcovs. additionally, a negative antibody test does not exclude sars cov- infection. [ , ] the role of virus isolation and culture as well as detection of the virus by its cytopathic effects on cell lines is highly limited due to requirements of bio-safety level- facility. [ , ] hence it is not j o u r n a l p r e -p r o o f recommended by who for diagnostic purpose [ ] currently the diagnostic tests for detecting sars cov- infection is variable and non-uniform owing to the use of different probes, kits and reagents. though there are numerous reports claiming efficacy of various drugs and vaccine against covid- , none are effective and safe to receive approval by regulatory authorities. the management of covid- mainly relies on effective implementation of infection preventive and control measures and delivery of timely supportive care including oxygen therapy and mechanical ventilation as and when indicated. as the r value is > (range . to . ), [ , ] efficiency of intervention strategies such as screening of incoming people, wearing masks, quarantine for travellers has already been proved. [ ] specifically, reducing travel volume to and from china has had a positive impact on transmission dynamics of covid- . [ ] . though preventive vaccines against sars cov- can be developed targeting the spike (s) glycoprotein or its receptor-binding domain (rbd), these are made ineffective due to generation of altered immunogens in the target proteins owing to rapid mutations and recombinations. [ , ] in sars cov, live attenuated vaccine with the deleted structural e gene mutant was effective in producing neutralizing antibodies which lowered viral loads and reduced disease severity. [ ] the development of inactivated vaccines against sars cov was hindered due to occurrence of harmful immune and/or inflammatory responses post challenge. j o u r n a l p r e -p r o o f [ , , ] sub-unit vaccines (purified proteins combined with adjuvants) and viral vector (adeno virus) vaccines against s glycoprotein or its rbd and n protein of sars cov and mers cov elicited higher humoral response as well as enhanced mucosal immunity with intranasal administration. [ , , ] furthermore, dna based vaccine against s glycoprotein of mers cov also showed robust neutralizing antibody response and is currently under clinical trial. [ ] based on these reports vaccines for sars cov- is likely possible. however, its efficacy and safety has to be proved before approval. in the absence of specific anti-viral therapy, treatment is mainly symptomatic and supportive that includes oxygen therapy, conservative fluid management, hemodynamic support and / or mechanical ventilation. mechanical ventilatory support with low tidal volume and low inspiratory pressure is indicated when the respiratory distress is refractory to conventional oxygen therapy or niv. [ ] extracorporeal membrane oxygenation (ecmo) is indicated in patients with refractory hypoxemia despite prone position mechanical ventilation. [ ] a recent retrospective study identified older age, high sequential organ failure assessment score (sofa) score, and d-dimer greater than µg/ml as poor prognostic factors which aid the clinician early in instituting aggressive treatment and monitoring for such patients. [ ] steroids, and injudicious antibiotic use should be discouraged. some studies report effective use of rna polymerase inhibitors remdesivir and immucillin-a as prophylactic and therapeutic agents against hcovs including sars cov- . [ , ] anti-malarial drug chloroquine and its analogue may show protective effect against virus by decreasing intracellular ph but may cause cardiac arrythmias owing to prolonged qtc interval in some patients. [ ] monoclonal antibodies against interleukin- (il- ) like sarilumab, siltuximab, tocilizumab and interleukin- (il- ) inhibitor like anakinra may be useful in severe cases and may control the effects of sirs which is the main culprit in the pathogenesis of severe cases. [ ] currently, there are , studies registered in clinical trials involving various investigational drugs and vaccine apart from those mentioned above and are still at phase-i level. [ ] theoretically, molecules involved at each step of sars cov- pathogenesis may become potential therapeutic targets. (figure: to conclude, sars cov- is highly infective and its control depends on strict implementation of preventive measures. though rt-pcr is the gold standard for sars cov- diagnosis, the results are variable and there is scope of false negatives owing to either sampling errors or due to usage of different primers and reagents by different vendors. serologic estimations of antibody titres though not helpful for diagnosis, may be useful for prognostication and follow-up. though currently available pathologic data is limited, it is of prime importance to unveil the pathogenesis which will enable the development of therapeutic options. however, studies on larger cohorts are needed to validate the findings obtained for generalized application. importantly, due to limited availability of time and resources for research during the current emergency situation there is a huge lag and gap in understanding covid- ; hence the current review removes the lag and bridges the gap and provides pathology centered understanding of the disease. furthermore, the currently approved clinical trials that are in various stages of development on all aspects of covid- including vaccines and potential therapeutic targets will shed light in future. there are no conflicts of interest to disclose. a familial cluster of pneumonia associated with the novel coronavirus indicating person-to-person transmission: a study of a family cluster evaluation and treatment of corona virus (covid- ) statpearls ncbi-bookshelf likelihood of survival of corona virus disease . lancet coronavirus: covid- has killed more people than sars and mers combined, despite lower case fatality rate early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia pattern of early human-to-human transmission of wuhan covid- outbreak on the diamond princess cruise ship: estimating the epidemic potential and j o u r n a l p r e -p r o o f effectiveness of public health countermeasures does sars-cov- has 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use of chloroquine as an antiviral treatment we thank dr. vaseemuddin mohammad (consultant nephrologist, tables: table i key: cord- - ejjmab authors: wong, rebecca s. y. title: the sars-cov- outbreak: an epidemiological and clinical perspective date: - - journal: sn compr clin med doi: . /s - - -z sha: doc_id: cord_uid: ejjmab the severe acute respiratory syndrome coronavirus (sars-cov- ) outbreak started with the detection of an increasing number of pneumonia cases of unknown origin in wuhan, china, since december . the disease caused by sas-cov- was subsequently named coronavirus disease (covid- ). currently, the ongoing covid- pandemic poses a global health concern with more than . million confirmed cases, taking away the lives of more than , people worldwide. to prevent further spread of the disease, an understanding of the clinical characteristics and how the disease spread is essential, especially for an emerging disease like covid- . individuals who are infected with sars-cov- show diverse clinical features, and the disease severity can range from asymptomatic to death. the disease has been shown to affect not just the respiratory system but also other systems of the body. this review will discuss the pulmonary and extra-pulmonary clinical manifestations of covid- in general, as well as the clinical characteristics in different groups of patients such as children, the elderly, pregnant women, patients with comorbidities and those with a compromised immunity. it will also critically examine existing evidence from relevant studies and discuss the sars-cov- outbreak from an epidemiological perspective. with the easing of control measures in many countries after months of lockdown, it is important to revisit the lessons learnt from research, as the world enters a new normal with the coexistence of sars-cov- . in public health, battling life-threatening emerging diseases is always challenging as much has yet to be learnt and discovered about these diseases. the recent ongoing coronavirus (cov) outbreak is caused by a novel cov initially named -ncov, first identified in wuhan, hubei province, china, with increasing number of pneumonia cases being detected in december . the problem has escalated and drawn international attention due to the rapid spread of the disease in china and other parts of the world. as a result of the increasing magnitude of the global health threat, the world health organisation (who) has declared the -ncov as a global health emergency on january [ ] . the virus was later renamed as severe acute respiratory syndrome coronavirus (sars-cov- ) by the international committee on taxonomy of viruses (ictv) and the who announced that the disease caused by the virus is to be called coronavirus disease (covid- ) on february [ ] . the outbreak has alarmed scientists and healthcare professionals, government authorities and the world health organisation, with the burning needs to come up with plans and policies for diagnosis, case management, surveillance and risk management, as well as infection prevention and control. in response to the rapidly growing number of confirmed cases and deaths, some measures taken by the chinese authorities include the quarantine of millions of its citizens with the unprecedented lockdown of many cities, in an attempt to contain the virus and slow down the spread of the disease [ ] . on the other hand, as early as end of january or early february , some countries like australia and the usa have imposed travel bans on china, whereas some other countries have cancelled flights from china, which plunge the latter into deepening isolation as a result of the outbreak. major this article is part of the topical collection on covid- companies like google and facebook have banned travel to china while apple and starbucks have shut their stores in the country [ ] . the lockdown and travel bans have a huge impact on the global economy as such a rare, abrupt and open-ended freeze out involving a vital economic centre like china is likely to lead to detrimental economic effects that ripple across the world. on march , who declared the covid- outbreak a pandemic [ ] . as of september , there have been over . million confirmed cases and more than , deaths reported since the sars-cov- outbreak [ ] . the number of publications on various aspects of the sars-cov- outbreak is on the rise since early . new information and discoveries are being added to the published literature as there is a growing body of research in an attempt to unveil the mysteries of the novel coronavirus and to better understand the new pathogen. this review aims to discuss the clinical and epidemiological aspects as well as the transmission dynamics of the sars-cov- outbreak. thus far, the clinical features of covid- have been described by many. however, the current review will examine the clinical features observed in different categories of patients such as children, the elderly, pregnant women, the immunocompromised as well as patient with comorbidities to illustrate the diversity of the clinical presentation of covid- . success in the control of an outbreak often lies in the understanding of how the disease gets from one individual to another. interesting and valuable information can be deduced or inferred from several epidemiological parameters. this is important from a public health perspective, as knowledge on these epidemiological parameters of the disease helps provide insights concerning the appropriate control measures to be used in order to contain the disease and prevent further spread. this section will discuss the various parameters that are related to the transmission of a contagious communicable disease such as covid- . in a study analysing the first confirmed cases in wuhan by january , li et al. reported that prior to january , % of the cases were linked to the huanan seafood wholesale market in wuhan, whereas such linkage was observed in only . % of subsequent cases. among these cases, there was a mean incubation period of . days ( % confidence interval [ci], . to . ), with the th percentile of the distribution at . days. the epidemic was shown to double in size every . days in its early stages. findings of the study indicate the evidence of human-to-human transmission among close contacts since mid-december . due to its earlier link to the huanan seafood wholesale market in wuhan and high genomic similarities between sars-cov- and bat coronaviruses, it has been suggested that covid- is a disease of zoonotic origin with animals such as bats as the reservoir of sars-cov- [ ] . in another study, chen et al. investigated patients consisting of men and women with -ncov pneumonia in wuhan jinyintan hospital from january to january . it was shown that % (n = ) of the patients had an exposure history to the huanan seafood market. the average age of these patients was . years (sd . years) [ ] . laeuer et al. analysed cases occurring before february outside the province of hubei, in which were from outside china. most of these cases either had a travel history to wuhan or had contact with travellers from the region. an estimated median incubation period of . days ( % ci, . - . days) was reported. by . days ( % ci, . - . days), . % among those infected had showed symptoms of infection. the study also reported that to capture > % of symptomatic cases, a monitoring duration of > days was required [ ] . the serial interval (also known as generation time, t g ) refers to the average duration taken from the time an individual being infected to the time he/she infects others. an empirical estimate of t g can be obtained by observing the time from illness onset of a primary case (infector) to the secondary case's illness onset and is important in our understanding of case generation and disease transmissibility [ ] . linking dates of onset for the infector-infectee pairs is crucial to estimates of t g . however, these links may not be easily established. using contact tracing data from cases reported early in the outbreak in hubei province, an epidemiology study reported a mean serial interval of . days [ ] . another study reported an estimated mean serial interval at . days ( % credible interval . , . ) for infectorinfectee pairs (both certain and probable pairs). among the dataset, a subset of pairs (certain pairs) yielded an estimated median serial interval at . days ( % credible interval . , . ). the close-to or shorter-than-median incubation period serial interval suggests pre-symptomatic transmissions for a considerable proportion of secondary transmissions [ ] . on the other hand, liu et al. estimated the mean serial interval to be . days (± . ) using a total of pairs of infector-infectee that met strict inclusion criteria [ ] . other than the incubation period and serial interval, researchers are interested in the basic reproductive number (r , r naught or r zero) and effective reproductive number (r e or r t ). in order to better understand the transmissibility of sars-cov- , an understanding of the definition and indication of r is crucial. r can be defined as the average number of people who can be infected by an infectious person in a completely naïve population. if r is > , it means that the infection is likely to spread exponentially. on the contrary, if r is < , it means that the infection is spreading slowly and will eventually die off. for example, if the r is , it means one infected person has the potential of spreading the disease to two other persons [ ] . in general, r is affected by population density and the initial proportion of susceptible people, the organism's infectiousness, as well as the case disappearance rate (either by recovery or death). it is important to note that r is not a rate and, therefore, has no units of time such as in doubling time. on the other hand, r e or r t , refers to the average number of secondary cases per infectious case in a population of susceptible and non-susceptible hosts [ ] . therefore, r t is usually lower than r because as the previously infected people become immune to the disease, the number of people who can be infected and become secondary cases decreases. if r t is > , the number of cases will increase. if it is < , the number of cases will decrease. if r t = , the disease is considered endemic. liu et al. explored r of covid- by reviewing related studies. r was estimated be . - . (mean = . , median = . , interquartile range = . ), which was higher than the who estimate of . - . (mean = . ). however, it is noteworthy that estimates of r depend on the model used. it was observed that the two studies that used stochastic methods gave a r estimate of . - . (mean = . ). six studies that used mathematical methods and three studies that used statistical methods gave estimates of . - . (mean = . ) and . - . (mean = . ) respectively [ ] . using data retrieved from john hopkins university's covid- data repository, caicedo-ochoa et al. estimated the r t of sars-cov- infection in seven latin american countries (i.e. brazil, chile, colombia, ecuador, mexico, panama and peru) during the first days of the outbreak, during which the incidence was highest. they also compared the r t values with that of spain and italy for the same interval. as its name implies, the doubling time of a disease in a given period refers to the time required for the number of cases to double. a short doubling time means rapid increase in the number of cases and vice versa. therefore, the doubling time gives us useful information concerning the impact of interventions during an outbreak. many factors play a role in the doubling time of an infectious disease, e.g. r , r t , incubation period, latent period and serial interval. even if two diseases have to same r , the doubling time may differ due to a different serial interval. on the other, doubling time for a disease may differ from one place to another due to a different r or r t . an earlier study (from january to february ) in china reported that doubling times of the covid- epidemic for hunan province, hubei province and xinjiang province were . days ( % ci . - . ), . days ( % ci . - . ) and . days ( % ci . - . ) respectively [ ] . on the other hand, analysis of data obtained from several european countries in february and march indicates that the initial doubling times of covid- was approximately days or less using semiparametric and generalised linear methods, until social distancing measures were in place. the study also reported that the increase in the number of cases was slowed by these measures, and the effects were typically observed only in days (i.e. doubling times) after their implementations. the study concluded that the estimation of doubling time, which reflects that the temporal patterns are more crucial than the estimation of r for initiation of interventions, especially for low-and middle-income countries that are in their early stages of the outbreak [ ] . an infectious agent can be transmitted from its natural reservoir to hosts via different routes. many studies have looked into the modes of transmission of sars-cov- infection and both direct and indirect modes have been reported in the published literature. currently, human-to-human transmission via respiratory droplets is the primary route through which the infection spread aggressively in different parts of the world. humanto-human transmission can take place in one of the three ways: ( ) asymptomatic transmission, ( ) pre-symptomatic transmission and ( ) symptomatic transmission. of particular concern is asymptomatic transmission as carriers of sars-cov- without symptoms may not be identified unless they are tested positive by reverse-transcription polymerase chain reaction (rt-pcr) or other laboratory tests. one study in china reported a young -year-old male who spread sars-cov- infection to his contacts ( relative and classmates, all of which were youngsters from to years) just after a few-hour contact during the incubation period, when he was totally asymptomatic [ ] , suggesting that the disease is highly infectious during the incubation period. another study reported a -year-old presumed asymptomatic carrier of sars-cov- , who was believed to have spread the infection to relatives. at the time of contact with the relatives, the carrier had no symptoms and her subsequent chest computer tomography (ct) and lymphocyte count were normal. however, her relatives were tested positive for covid- later and were all symptomatic with abnormalities on chest ct [ ] . researchers have attempted to estimate the asymptomatic portion of the covid- . one study estimated asymptomatic infections on the diamond princess cruise ship hosting people. after a former passenger was tested positive for covid- , other passengers on the ship underwent quarantine for weeks. a total of passengers were subsequently tested positive, with symptomatic and asymptomatic cases. using statistical modelling, asymptomatic infections was estimated to be . % ( % credible interval . - . %) [ ] . another study conducted on japanese nationals evacuated from wuhan, china, on chartered flights gave an estimated asymptomatic ratio of . % ( % ci, . - . %) among evacuees [ ] . a systemic review conducted on newborns (in nine independent studies) born to mothers with confirmed covid- infection revealed the possibility of vertical transmission. out of the newborns, . % (n = ) were tested negative within the first few hours or days after birth. however, vertical transmission could not be excluded, as the oropharyngeal or nasopharyngeal swabs of . % (n = ) of the newborns were tested positive within days of birth. the throat swab of one newborn was tested negative. however, igm and igg testing was positive in this case, suggesting possible in utero infection and transplacental transmission. therefore, transplacental or vertical transmission could not be ruled out in ( . %) of out the newborns [ ] . other than aerosol transmission via sneezing, coughing, etc., research has implied that indirect routes such as contacting surfaces contaminated with sars-cov- are plausible routes of transmission. one study demonstrated that sars-cov- was able to remain viable in aerosols for h, and that viable virus could be detected on plastic and stainless steel for up to h. on the other hand, viable virus was less stable on surfaces like copper (not detectable after h) and cardboard (not detectable beyond h) [ ] . therefore, both aerosol and fomite transmissions play a role in the rapid spread of covid- . in another study, chin et al. reported that sars-cov- is highly stable and resistant for a long time at °c whereas at °c, the time required to inactivate the virus was decreased to min. at room temperature, the virus was also found to be extremely stable in ph ranges of - . adding various disinfectants at working concentrations to sars-cov- cultures at room temperature revealed a non-detection of virus after an incubation period of min. the virus was inoculated on various objects in the same study. no virus was detected on printing and tissue papers after h of incubation, while the virus was not found on treated wood and cloth on day . it was not detected on glass and banknotes on day and stainless steel and plastic, on day . however, it was found on a surgical mask's outer layer on day [ ] . studies have shown that various environmental factors may affect transmission of covid- . scientists are interested in the relationship between various environmental factors and the transmission of sars-cov- infection. it was initially believed that with rising temperatures, the spread of the disease will slow down and the number of cases will reduce. while some studies showed that environmental factors such as temperature and humidity are associated with the transmission rates of covid- , there is no strong evidence to suggest that the disease will eventually become dormant as summer approaches thus far. studies on the relationship between environmental factors and covid- transmission are often observational studies with various confounding factors such as population statistics and public health preventive measures (e.g. lockdowns or movement restrictions, etc.). meteorological data are often obtained through regional data extrapolation while ascertainment methods of cases may vary for different regions. bhattacharjee investigated the relationship between three environmental factors: ( ) maximum relative humidity (rhmax), ( ) maximum temperature (tmax) and ( ) highest wind speed (wsmax) and the daily number of confirmed covid- cases in four cities in china (i.e. beijing, chongqing, shanghai and wuhan) and five cities in italy (i.e. bergamo, brecia, cremona, lodi and milano). it was reported that the relationship between daily number of cases and rhmax and wsmax was mostly negligible, whereas the relationship with tmax ranged from negligible to moderate [ ] . on the other hand, luo et al. collected epidemiological data from hong kong, japan, south korea, singapore, taiwan, thailand and different regions of china to investigate the relationship between ( ) absolute humidity and ( ) temperature and local exponential growth of the outbreak. absolute humidity was positively correlated to case increase while weather temperature was weakly and negatively corrected to case increase [ ] . meteorological and epidemiological data collected from countries (other than china), suggested that daily new cases and deaths were related to relative humidity and temperature, after controlling for confounding factors such as national population median age, population density and wind seed. both relative humidity and temperature exhibited a negative relationship with the daily new cases and deaths. with every °c rise in temperature, there was a . % ( % ci . %, . %) and . % ( % ci . %, . %) decrease in daily new cases and new deaths respectively. as for every % increase in relative humidity, a . % ( % ci . %, . %) and . % ( % ci . %, . %) decrease in daily new cases and new deaths were observed respectively [ ] . sars-cov- infection mainly affects the respiratory system, although involvement of other organs/systems is not uncommon. the clinical presentation of covid- is diverse, ranging from asymptomatic to very severe illness, which can lead to death. to understand the clinical aspects of covid- , it is necessary to have an understanding of the pathogenesis of the disease. once a person is infected with sars-cov- , the inhaled virus binds to ace receptor to gain entry into host cells in the respiratory tract [ ] . during this initial stage (first or days) of the infection, the patient is asymptomatic, but the virus may be detected in the nasal swabs. as the virus propagates locally, individuals in this stage are infectious despite the low viral load with a limited immune response in the body. in the next few days, the virus continues to propagate down the conducting airways, triggering a more vigorous immune response [ ] . during this time, the patient begins to manifest the common symptoms of covid- , such as fever, sore throat and dry cough. in approximately % of the cases, the disease is mild to moderate, confining to the upper respiratory tract. however, % of the cases progress to more severe disease with pulmonary infiltrates, as the virus reaches the lower respiratory tract [ ] . it is this category of patients who present with dyspnoea and may progress to acute respiratory distress syndrome (ards) as the disease continues to worsen. some of the underlying immune responses in severe cases include lymphopenia and increased release of pro-inflammatory cytokines resulting in an ards-inducing "cytokine storm," which may be followed by multiorgan failure leading to death [ , ] . although covid- is mainly a respiratory disease characterised by pulmonary manifestations, reports on extrapulmonary manifestations are not uncommon in the published literature. some of these include gastrointestinal, cardiac, neurological and cutaneous manifestations, features of renal and liver dysfunction, as well as taste and smell disorders [ , ] . patients with gastrointestinal involvement may present with symptoms such as diarrhoea, vomiting, abdominal pain and loss of appetite [ ] whereas neurological manifestations such as encephalitis, encephalopathy, stroke and guillain barre syndrome have been reported [ ] . patients with cutaneous presentation may exhibit erythematous pustules or vesicles, maculopapular or vesicular eruptions, urticaria, liverdo and necrosis [ ] . on the other hand, acute cardiac injury and raised cardiac troponins are abnormalities observed in some patients with covid- , whereas patients with existing cardiovascular disease tend to have a worse outcome compared with those without. the underlying mechanisms of the injury are said to be related to direct injury to cardiomyocytes or indirectly due to overwhelming systemic inflammation [ ] . in one study, dong et al. investigated the clinical presentation of paediatric lab-confirmed (n = ) and suspected cases (n = ) of covid- with an interquartile age range from to years. it was found that > % of these patients demonstrated either no symptoms, or mild to moderate symptoms without showing any significant gender difference. the study concluded that children of all ages, especially infants, were susceptible and vulnerable to the infection, even though they presented with milder disease compared with adults [ ] . despite earlier studies demonstrating a milder course of the disease in children, recent studies have reported cases of paediatric patients with severe disease requiring intensive care. in one of these cases, greene et al. described toxic shock-like syndrome in an -year-old girl who was tested covid- positive. during her first visit to the emergency department (ed), the patient presented with fever, rash and pharyngitis. however, within h, she returned to the ed with multiorgan injury, systemic inflammation and circulatory shock and was admitted to the paediatrics icu due to cardiac and renal dysfunction, as well as fluid-refractory hypotension. while receiving supportive therapy in the picu, the patient was also given steroids and intravenous immunoglobulin (ivig) for possible incomplete kawasaki disease. dramatic improvement was observed < h and the patient was subsequently discharged home [ ] . in france, a study on children and adolescents aged from . - . years examined the relation between covid- and kawasaki disease. it was reported that % (n = ) of the patients had evidence of covid- infection with % (n = ) requiring treatment in the icu. all these children had clinical features of kawasaki disease with % (n = ) and % (n = ) presented with kawasaki disease shock syndrome and myocarditis respectively. all of them were treated with ivig and % (n = ) of the patients, with corticosteroids, after which all were discharged home. findings from this study suggest that kawasaki-like multisystem inflammatory syndrome might be related to sars-cov- infection [ ] . studies have investigated the clinical features and outcomes of covid- in pregnant women. cao et al. reported the clinical analysis of pregnant women in their third trimester till the postpartum period. all women was tested covid- positive and presented with mild disease. during the period of the study, none of the women developed severe disease, severe respiratory distress or needed to use mechanical ventilation. however, lung abnormalities were observed in the chest ct of all patients. two patients had vaginal delivery, had intrapartum caesarean section and had elective caesarean section a total of newborns ( singletons and pair of twins) were born during the study period. all the newborns had an apgar score of - and at min and min after birth respectively, and none of them had neonatal asphyxia or presented with fever, cough or diarrhoea. five of the newborns underwent covid- testing, and none of them were tested positive. the study concluded that covid- is not an indication for caesarean section [ ] . on the other hand, a systemic review and metanalysis on women in studies reported that fever ( . %), cough ( . %) and sore throat ( . %) were the commonest clinical features in pregnant women with covid- while dyspnoea ( . %) and diarrhoea ( . %) were less frequently reported. the common lab findings were increased c-reactive protein levels ( %) and lymphocytopenia ( %) whereas ground-glass opacity was observed in the chest ct in . % of the patients. there was a preterm birth rate of . % and % of women underwent caesarean section. one maternal death, foetal deaths (at gestational ages of , and weeks) were reported and newborns were tested covid- positive. it was concluded that the clinical presentation of pregnant women did not vary from the general population, however, compared with international averages there was an increased preterm birth rate and caesarean delivery rates [ ] . overwhelming inflammatory reactions due to a cytokine storm have been described in patients with severe covid- , which can result in organ damage and failure [ , ] . therefore, some believe that the anti-inflammatory effects of immunosuppression may be protective and helps to mitigate the cytokine storm associated with poor outcomes. however, findings on the outcomes of immunocompromised individuals with covid- are contradicting with some studies reporting unfavourable outcomes and others suggesting otherwise. for example, one study reported that a higher risk of severe disease and death was not observed in hiv patients with covid- [ ] whereas another study reported that hiv was associated with a doubling of mortality risk in covid- patients [ ] . one study investigated covid- mortality in cancer patients and demonstrated that those who were on various anti-cancer treatments did not have a significant higher risk of mortality. out of the cancer patients, more than half ( %, n = ) had mild disease. out of the % (n = ) patients who died, a significant association between the risk of death and ( ) when these factors were adjusted, chemotherapy, hormonal therapy, targeted therapy, immunotherapy and radiotherapy use had no significant effect on mortality from covid- when comparing patients who received these therapies versus those who did not [ ] . on the contrary, another study conducted on cancer patients with confirmed covid- reported contradicting findings. in the study, % (n = ) of the patients had solid tumours while % (n = ) had haematological malignancies. out of the patients, % (n = ) had anti-cancer therapies within weeks prior to symptom onset. a total of ( %) patients died during their hospital stay. patients with haematological malignancies had a poorer prognosis than those with solid tumours whereas a higher percentage of deaths ( %) was observed among patients with haematological malignancies compared with those with solid tumours ( %) (hazard ratio for death . [ % ci . - . ]; log rank p = · ). the risk factors of death were chemotherapy within weeks prior to symptom onset (odds ratio [or] . [ % ci . - . ]; p = · ) and male gender (or . [ % ci . - . ]; p = . ). therefore, the study concluded that hospitalised cancer patients with covid- had a high case fatality rate while being male and receiving chemotherapy prior to symptom onset were unfavourable prognostic factors among this group of high-risk patients [ ] . studies have shown that old age and comorbidities are related to the severity of covid- and death. in general, covid- is more lethal among the elderly. this can be illustrated by comparing the case fatality rates of countries with a high proportion of elderly in their population. for example, % of italy's population consisting of people > years in , and the country was hard-hit by the outbreak. deaths in the country were mainly among elderly males with multiple comorbidities. it was reported that italy had a considerable higher overall case fatality rate (cfr) than that of china ( . % vs . %). for the to years age groups, the cfr is similar for both countries. however, the cfr in individuals > years was shown to be higher in italy. the higher overall cfr in italy can be partly explained by a difference in the case distribution in the two countries; in italy . % of cases were > years, whereas in china only . % of the cases were > % [ ] . on the other hand, a study in the usa consisting of patients admitted to hospitals reported the commonest comorbidities being hypertension ( . %, n = ), obesity ( . %, n = ) and diabetes mellitus ( . %, n = ). the median age of these patient was years [interquartile range (iqr), - ].the percentage of patients admitted to the intensive care unit was . % (n = ) with a median age of years (iqr, - ). of those who received mechanical ventilation (n = ), older patients (> years) had a higher mortality rate ( . %) than patients in the to -year group. however, there was no death among those < years of age. among the patients who died ( . %, n = ), diabetic patients were more likely to be treated with invasive mechanical ventilation or given icu care compared with non-diabetic patients [ ] . some findings of the study are in tandem with those of another study conducted on hospitalised patients from hospitals in china, who had laboratory-confirmed covid- the current covid- pandemic is a global health threat, impacting the lives of people in many aspects worldwide. from this review, it can be deduced that sars-cov- has a serial interval close-to or shorter than the incubation period. the fact that sars-cov- is highly stable under various conditions at room temperature and lingers on different surfaces up to hours or days makes it highly infectious. the high proportion of asymptomatic cases and the short doubling time all contribute to the exponential growth of the pandemic. despite some studies showing an association between an increased weather temperature and reduction in the number of cases, there is no sign that the pandemic will melt away as summer approaches. worldwide, unprecedented drastic measures such as movement restrictions, lockdown, airport closures, quarantine and social distancing have been taken to combat the disease. however, despite these vigorous measures, the global number of confirmed cases and deaths is on the rise on a daily basis. many countries have suffered financially due to months of lockdown and are in a process of unlocking and opening their borders to savage the hard-hit economy. it is important to remember the epidemiological lessons learnt from research as the world embarks on a new normal with the coexistence of sars-cov- . unless and until a cure or vaccine is established, countries must be constantly on the guard to prevent a second or even third wave of the disease, which is already emerging in some places. on the other hand, an understanding of the clinical presentation of covid- is important as patients with different presenting complaints and varying degrees of severity require different management strategies. from this review, it can be concluded that the clinical manifestations of sars-cov- infection are very diverse ranging from no symptoms, to severe disease that requires intensive care and mechanical ventilation, while the most severe cases can lead to death. in the published literature, both pulmonary and extra-pulmonary clinical features have been described, suggesting that the disease can affect nearly any system in the body. infected individuals who cannot conquer the disease eventually give their lives to covid- . however, a majority of people who are infected with sars-cov- eventually recover from the disease. research has also shown that people from all ages can contract sars-cov- infection. elderly patients and those with comorbidities are highly susceptible and vulnerable. earlier studies have claimed that children tend to have milder disease. however, there is evidence that severe and lifethreatening disease can develop in children and that covid- is associated with multisystem inflammatory syndrome and kawasaki disease in some cases. on the other hand, the clinical presentation in pregnant women is similar to that of the general population, whereas there are contradicting findings on immunocompromised individuals with covid- . therefore, it is important that physicians identify the high-risk patients with adverse outcomes and manage them accordingly. author contributions the author contributed solely to the writing and submission of this article. no author who meets the criteria of authorship has been omitted from this submission. submission declaration this work has not been published previously and is not under consideration for publication elsewhere. coronavirus declared global health emergency by who who director-general's remarks at the media briefing on -ncov on wuhan, china, and at least other cities have been quarantined as china attempts to halt the spread of the coronavirus. that's about million people on lockdown travel bans plunge china into deepening isolation over coronavirus who director-general's opening remarks 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mortality in patients with cancer and covid- in hubei, china: a multicentre, retrospective, cohort study case-fatality rate and characteristics of patients dying in relation to covid- in italy presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the new york city area comorbidity and its impact on patients with covid- in china: a nationwide analysis publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the author declares that she has no conflict of interest. key: cord- -jkmjiika authors: liu, qin; xu, kaiyuan; wang, xiang; wang, wenmei title: from sars to covid- : what lessons have we learned? date: - - journal: j infect public health doi: . /j.jiph. . . sha: doc_id: cord_uid: jkmjiika abstract after the outbreak of severe acute respiratory syndrome (sars) in november , coronaviruses (covs) received worldwide attention. on december , , the first case of coronavirus disease (covid- ), caused by a novel coronavirus (sars-cov- ), was reported in wuhan, china, and covs returned to public view. on december , , the world health organization (who) declared that the covid- epidemic is a public health emergency of international concern (pheic), and on march , , the who classified covid- as a pandemic disease. as of july , , covid- has affected countries and regions, with , , confirmed cases and , deaths, and the number of new cases has been increasing daily. additionally, on march , , there were no new confirmed cases in china, providing hope and valuable experience for the international community. in this review, we systematically compare covid- and sars in terms of epidemiology, pathogenesis and clinical characteristics and discuss the current treatment approaches, scientific advancements and chinese experience in fighting the epidemic to combat the novel coronavirus pandemic. we also discuss the lessons that we have learned from covid- and sars. december , [ ] , pneumonia caused by a new coronavirus began spreading rapidly in china, with a similar trend globally. as the virus continued to spread, on march , , the who declared that covid- is a pandemic disease, making this the first time that a coronavirus infection has been regarded as a global pandemic, in contrast to sars in , which did not reach this level. as of july , , countries have been affected, with a global total of , , confirmed cases and , deaths (who real-time statistics). the main timeline of the covid- pandemic is shown in figure . the outbreak has caused widespread fear and concern and threatens global health security. the virus that causes covid- named sars-cov- [ ] , sars-cov- and sars-cov have highly similar gene sequences and behavior patterns. this paper summarizes the differences in the epidemiology, clinical manifestations, and treatment of sars and covid- during the two outbreaks, summarizes the lessons learned, and provides a comprehensive reference for the global epidemic prevention and treatment of reported in china and resulted in a large number of infections. however, the covid- has been more widespread and has spread faster than sars, affecting populations around the globe [ ] . there has been considerable discussion on the origin of the causative virus sars-cov- after the first reports of covid- in wuhan [ , ] . rapid sequencing of the nearly , -nucleotide sars-cov- genome was accomplished and announced worldwide on january , , by zhang's group and several others in china. cov is an enveloped rna virus that primarily causes respiratory and gastrointestinal infections [ ] . studies have shown that the nucleotide sequences of the sars-cov- and sars-cov genes are less than % identical [ ] . however, the amino acid sequences of the seven conserved replicase domains in orf ab that are used for cov species classification are . % identical between sars-cov- and sars-cov, suggesting that the two viruses belong to the same species. notably, studies have confirmed that sars-cov- uses the same cell entry receptor-angiotensin converting enzyme ii (ace ) -as sars-cov [ , ] . wrapp et al. found that the binding affinity of sars-cov- to ace was approximately [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] times that of sars-cov [ ] , which can provide one explanation for why sars-cov- has more human-to-human transmission than sars-cov. however, there is no clear evidence suggesting that sars-cov- has evolved from sars-cov. to date, there is no evidence showing that sars-cov- originated in the seafood market. recently, an article published in nature medicine on march j o u r n a l p r e -p r o o f clearly showed that sars-cov- is not a laboratory construct or a purposefully manipulated virus. several studies have shown that bats may be a potential reservoir for sars-cov- [ ] . sequencing of the viral genome showed . % consistency across the whole genome sequences of bat cov from rhinolophus affinis and human sars-cov- [ ] , indicating that they may belong to the same ancestor; however, no bats were sold in the wuhan seafood market [ ] . in addition, protein sequence alignment and phylogenetic analysis showed that similar receptor residues were found in many species, which provided more possibilities for alternative intermediate hosts, such as pangolins or mink [ ] . according to the research by the team of academician zhong nanshan, the incubation period of covid- ranges from to days, with a median incubation period of days. the population is generally susceptible to infection or infectious during the incubation period [ ] . covid- is highly contagious among humans, and older individuals and people with underlying diseases are especially affected. based on the published data, the median patient age was - years in covid- (similar to sars and mers), and . - . % of patients were male in covid- (the male-to-female ratio of : . in sars, and . : in mers) [ , , , ] . some studies have reported that . - % of covid- patients were children ( % in sars and % in mers) [ ] [ ] [ ] [ ] . according to the available data, children appear to be at lower risk for covid- than adults and children are less symptomatic with less fatality, which is concordant to earlier epidemic outbreaks of sars-cov respectively j o u r n a l p r e -p r o o f [ , ] . on march , , the national health commission issued the diagnosis and treatment program of covid- pneumonia (trial seventh edition) [ ] , which indicated that transmission through respiratory droplets and close contact was the main transmission route of sars-cov- . the virus can be spread by aerosol when an individual is exposed to a high concentration of aerosolized virus for a long time in a relatively closed environment. since sars-cov- can be isolated from feces and urine, attention should be paid to aerosol or contact transmission from feces, urine or environmental pollution; other avenues of spread are not entirely clear [ ] . a paper published in the lancet argues that transmission through the conjunctiva of the eye cannot be ignored [ ] . other studies have suggested that there may be mother-to-child transmission (vertical transmission) [ ] . in summary, to date, the transmission route of sars-cov- has not been completely clarified, and relevant protective measures and attention should not be reduced [ ] . regardless of the exact mechanisms by which sars-cov- was naturally selected, the ongoing surveillance of pneumonia in humans and other animals is clearly of utmost importance. according to a report published in nature on march , , %- % of newly infected people have no symptoms or mild symptoms; however, their ability to spread the virus is not low, and covert coronavirus infections could be seeding new outbreaks. there is growing evidence that some infected people are highly contagious when their symptoms are mild or asymptomatic [ ] . understanding the proportion of cases of asymptomatic or mild illness is important for us to understand the cause of this j o u r n a l p r e -p r o o f particular pandemic, as indicated by michael osterholm, director of the center for infectious disease research and policy at the university of minnesota [ ] . sars patients mainly present with fever and chills, accompanied by systemic and respiratory symptoms including mild fever and muscle pain. severe respiratory failure and other organ dysfunction can occur during the incubation period from to days, commonly from to days. the onset is rapid, and the infectivity is strong, with fever as the first symptom. the course of the disease is - weeks. the prognosis of patients with headache, muscle soreness, general fatigue and diarrhea is related to the characteristics of the host (including age and sex) [ ] . during hospitalization, the mean time from onset to severe respiratory distress was . to . days in . % of sars patients. chest computed tomography (ct) shows ground-glass opacities with smooth interlobular septal thickening, sometimes with consolidation in a subpleural location [ , ] . sars-cov- infections generally exhibit milder symptoms than sars-related infections. zhong nanshan's team and a number of studies [ , ] have shown that the main symptoms of covid- patients are fever, cough and fatigue, and the infrequency of symptoms of the upper respiratory and gastrointestinal tracts suggests that the viral tropism of sars-cov- is different from that of sars-cov [ ] . a study published in the new england journal of medicine (nejm) on march found j o u r n a l p r e -p r o o f that among covid- patients, children have milder symptoms than adults, and it is not uncommon to see asymptomatic children [ ] . the disease can be classified as mild, moderate, severe or critical according to whether there are clinical symptoms, whether there is pneumonia, the severity of the pneumonia, the presence of respiratory failure or shock, and whether there is other organ failure. the beijing center for disease control and prevention suggests that the typical covid- case exhibits a progressive disease course, and current clinical data show that most deaths occur among older patients. however, severe cases have been documented among young people with specific factors, especially those with chronic diseases, such as hypertension, diabetes, and cardiovascular disease; additionally, young people who have been using hormones or immunosuppressants for a long time and whose immune function is impaired are likely to have severe disease. laboratory examination showed that the white blood cell count in peripheral blood was normal or decreased, that the lymphocyte count was decreased, and that the degree of lymphocyte decline was correlated with disease severity [ ] . in most patients, crp and blood sedimentation were increased, and in some patients, liver enzymes, myoglobin, ldh, and d-dimer were increased. sars-cov- nucleic acids can be detected in a variety of specimens, including pharyngeal swabs, sputum, lower respiratory tract secretions, blood and feces [ ] . rt-pcr and/or ngs methods have been used to detect sars-cov- nucleic acids in lower respiratory tract specimens (sputum or airway extracts) more accurately. by serological monitoring, positivity for j o u r n a l p r e -p r o o f the new coronavirus-specific igm antibody is evident in most cases from - days after onset, and the titer of igg antibody in the recovery stage is times higher than that in the acute stage. regarding pathological changes, the mucus and mucus accumulation in the airway are mainly caused by damage to the lungs and immune system. other organs show mostly secondary damage due to different underlying diseases. data from zhong nanshan's team showed that on admission, a ground-glass shadow was the most common radiological manifestation on chest ct ( . %). lymphocytopenia at admission affected for . % of cases [ ] . radiological diagnostic sensitivity is limited, so findings should be verified by combining clinical symptoms and viral rna detection. the first autopsy report of the covid- in china indicated that the gross view of the lung had large amounts of airway viscous secretions, mainly caused by distal alveolar injury. findings from a local histological study of covid- cadaver biopsy samples published in lancet respiratory medicine showed that the pathological features of covid- were similar to those of sars and mers [ ] . more systematic autopsy data and histopathological verification are needed for further study. at present, effective antiviral drugs against the pathogen are lacking, and the main treatments are isolation and symptomatic supportive treatment. j o u r n a l p r e -p r o o f in general, the following strategies should be applied: bedrest and intense supportive treatment to ensure adequate heat; attention to water/electrolyte balance and maintenance of stability of the internal environment; and close monitoring of vital signs, namely, oxygen saturation. for patients with anoxic dyspnea in the acute phase, oxygen therapy should be given in time, and noninvasive or invasive ventilator support, which can best restore the patient's lung function, should be given when necessary. on the basis of symptomatic treatment, we should also actively prevent and treat complications, treat basic diseases, prevent secondary infection and provide timely organ function support for severe and critical cases. regarding circulation support, on the basis of full fluid resuscitation, we should also improve microcirculation, use vasoactive drugs, and perform hemodynamic monitoring if necessary. in addition, intravenous infusion of gamma globulin may be considered for severe and critical pediatric cases. severe or critical pregnancy cases should undergo termination of pregnancy, and cesarean section is the preferred delivery method. patients often have anxiety and fear and should therefore undergo psychological counseling. recently, based on the experiences of china and other countries worldwide in the fight against covid- , the who summarized and launched the four most promising covid- treatment regimens: ( ) remdesivir ( ) chloroquine phosphate and hydroxychloroquine ( ) lopinavir + ritonavir ( ) lopinavir + ritonavir + interferon. the four treatment regimens will be widely and randomly tested in a number of countries and regions, and we hope to find an effective and safe treatment for covid- as soon as possible. covid- is highly infectious and belongs to the category of traditional chinese medicine (tcm) "epidemic" diseases, and "dampness, poison, stasis, closure and deficiency" are the characteristics of its pathogenesis [ ] . tcm formulates treatment based on a symptom-based diagnosis, an approach that is increasingly emphasized in other disciplines [ ] . according to the latest research by zhong nanshan's team, lh significantly inhibits sars-cov- replication, affects viral morphology and has anti-inflammatory activity in vitro [ ] . these findings indicate that lh protects against viral attack, j o u r n a l p r e -p r o o f making lh treatment a novel strategy for controlling covid- . the differences and similarities between sars and covid- are summarized in table . on march , the who declared the outbreak of covid- to be a "pandemic" and on july , , the global epidemic had spread to countries and regions. among these countries, the united states has confirmed a total of , , cases, both brazil and india had more than , , confirmed patients and the epidemic is in a period of rapid growth. additionally, on march , the chinese mainland, including hubei province, reported zero new confirmed or suspected cases, and the new confirmed cases was lower than everyday now. during the outbreak, china acted quickly; an epidemiological investigation was carried out on december . on january , the south china seafood market in wuhan was closed. on january , the wuhan lockdown was implemented. on january , the cpc central committee set up a leading group to address the epidemic. digital media was used to monitor and report the epidemic situation in real time [ ] . the government formulated epidemic prevention policies (strict restrictions on travel and public gatherings; closure of public places; implementation of strict temperature monitoring across the country; correct use of masks; suspension of work and school; personal monitoring at home, etc.), and people throughout the country actively cooperated. in an interview on march , the who representative in china, dr. colliers, said that china has shown the world that the trajectory of the epidemic can be changed. typically, an epidemic grows exponentially, peaks, and then gradually begins to decline after all susceptible people have been infected or become ill. but that has not occurred in china. the epidemiological curve in china is irregular, the epidemic has been snuffed out in its growth phase, and the transmission of the virus has been blocked, as is clearly shown by both the collected data and the observed social reality. the national emergency response appears to have delayed the growth and limited the size of the covid- epidemic in china, averting hundreds of thousands of cases by february (day ) [ ] . chinese experience shows that not all infectious diseases need to manifest as large outbreaks that overwhelm health systems. every country can learn from this experience and apply the obtained knowledge on its own terms. ( ) early detection: viral detection reagents play an important role in this process. early in the outbreak, a community in the heart of the italian epidemic conducted an experiment in controlling the epidemic and was able to stop the rise in cases (all residents were tested repeatedly for the virus, regardless of whether they had symptoms). after the infection is confirmed, strict quarantine measures are imposed on contacts. this highlights the importance of detecting and isolating carriers of the virus. various measures should be taken to strengthen the effective control of the source of infection. ( ) early diagnosis: integrated medical thinking is required because viruses involve the respiratory system, oral cavity, digestive tract, eyes, skin, genital tract, and central nervous system. ( ) early quarantine: the population is generally susceptible, regardless of race, with slightly more males than females affected, with more older patients and fewer pediatric cases. the authors declare no conflicts of interest. the authors declare no conflicts of interest. we declare no competing interests. j o u r n a l p r e -p r o o f shaping a protocol to use a batch of effective tcm formulas. there is no fda-approved vaccine for sars. accelerating the development of vaccines. epidemiology and cause of severe acute respiratory syndrome (sars) in guangdong, people's republic of china clinical features of patients infected with novel coronavirus in wuhan labs scramble to produce new coronavirus diagnostics covid- , sars and mers: are they closely related? a pneumonia outbreak associated with a new coronavirus of probable bat origin a new coronavirus associated with human respiratory disease in china genome composition and divergence of the novel coronavirus ( -ncov) originating in 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seventh edition) -ncov transmission through the ocular surface must not be ignored the epidemiology and pathogenesis of coronavirus disease (covid- ) outbreak clinical characteristics and intrauterine vertical transmission potential of covid- infection in nine pregnant women: a retrospective review of medical records covert coronavirus infections could be seeding new outbreaks estimating the asymptomatic proportion of coronavirus disease (covid- ) cases on board the diamond princess cruise ship clinical manifestations, laboratory findings, and treatment outcomes of sars patients severe acute respiratory syndrome (sars): imaging findings during the acute and recovery phases of disease clinical features of patients infected with novel coronavirus in wuhan, china epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study a major outbreak of severe acute respiratory syndrome in hong kong sars-cov- infection in children pathological findings of covid- associated with acute respiratory distress syndrome thoughts on the etiology and pathogenesis of covid- in traditional chinese medicine symptom-based stratification of autoimmune diseases lianhuaqingwen exerts anti-viral and anti-inflammatory activity against novel coronavirus (sars-cov- ) retrospective analysis of the possibility of predicting the covid- outbreak from internet searches and social media data an investigation of transmission control measures during the first days of the covid- epidemic in china history in a crisis -lessons for covid- current status of epidemiology, diagnosis, therapeutics, and vaccines for novel coronavirus disease (covid- ) this work was supported by the national natural scientific foundation of china key: cord- -kjx z hc authors: rubio-pérez, inés; badía, josep m.; mora-rillo, marta; quirós, alejandro martín; rodríguez, julio garcía; balibrea, jose m. title: covid- : key concepts for the surgeon date: - - journal: nan doi: . /j.cireng. . . sha: doc_id: cord_uid: kjx z hc abstract in view of the current pandemic by sars-cov- it deems essential to understand the key concepts about the infection: its epidemiological origin, presentation, clinical course, diagnosis and treatment (still experimental in many cases). the knowledge about the virus is still limited, but as the pandemic progresses and the physiopathology of the disease is understood, new evidence is being massively published. surgical specialists are facing an unprecedented situation: they must collaborate in the er or medical wards attending these patients, while still needing to make decisions about surgical patients with probable covid- . the present narrative review aims to summarize the most relevant aspects and synthetize concepts on covid- for surgeons. the current pandemic of severe acute respiratory syndrome coronavirus (sars-cov- ) is an unprecedented situation for healthcare systems. the high incidence of cases has saturated these systems, leading to the reorganization of hospitals and the availability of all resources for the treatment of patients with covid- . this has had a significant impact in the field of surgery, as many elective surgical procedures have been suspended, operating rooms closed for the use of the ventilators in intensive care units, and surgical staff redistributed to other medical services. both the spanish ministry of health and numerous scientific societies have published guidelines and recommendations for medical professionals. the surgical infection division of the spanish association of surgeons (asociación española de cirujanos, or aec) and the specific surgery-aec-covid- workgroup have reviewed the scientific evidence and available guidelines, synthesizing key concepts about covid- in order to facilitate the transfer of this knowledge to surgeons. methods a review of the literature has been conducted using pubmed and platforms with specific covid- resources: litcovid, cochrane library, lancet resource center, springernature, biomed central and jama network. likewise, for other specific aspects, we have consulted updated information and documents from the spanish ministry of health, the world health organization (who), centers for disease control (cdc), as well as the recommendations of surgical societies including: aec, american college of surgeons, society of american gastrointestinal and endoscopic surgeons, european cancer organization and the association of surgeons of great britain and ireland. the co-authors conducted the bibliographic search, reviewed the selected articles, and adapted the content for synthesis. the most relevant topics were grouped in an orderly manner to facilitate accessibility and consultation of this document. the authors have provided a narrative review of the literature available for certain key aspects of covid- epidemiology, clinical presentation, diagnosis and treatment, which are of special interest to the readers of the journal. specific concepts related to surgery have also been included, based on available evidence. the new coronavirus responsible for severe acute respiratory syndrome (sars-cov- ) was first detected in december in the city of wuhan (hubei province, china). several cases of atypical pneumonia of unclear origin were detected. as the first infected patients had been to the huanan market (wuhan), this site was the suspected ground zero of the epidemic and was closed on january , . the disease is considered a zoonosis, although it still has not been determined in which animal the disease originated. based on the genetic sequencing of the virus, either bats or the pangolin would be the most probable animal of origin. the virus was sequenced in early january , which identified it as a new type of coronavirus. on january , , china openly shared the gene sequencing of the new coronavirus on the gisaid.org platform. on january , the first case outside china was detected in thailand, which was an individual who had traveled to wuhan. in the following days, cases were detected in japan, korea and other asian countries. on january , the usa reported the first positive case, a traveler who arrived in washington state that had also come from wuhan. the first case in europe was reported by the french ministry of health on january th . on january , , the who declared a public health emergency of international concern (pheic), and the number of cases continued to rise in several countries, including iran, italy and spain. on march , , the who declared covid- had progressed to pandemic status. s i t u a t i o n i n s p a i n table shows the chronology of the most relevant events in spain in terms of the start and evolution of the epidemic. by april , , a total of cases had been registered in spain, with deaths and cured patients (currently, these numbers are still rising). however, the estimates of undiagnosed cases are much higher. the community of madrid has been one of the most affected, with the highest number of confirmed cases (> on april , ). c h a r a c t e r i s t i c s o f t h e v i r u s coronaviruses are a broad family of viruses first described in the s. they are spherical, encapsulated viruses that contain single-stranded rna surrounded by a protein coat. protein s 'spikes' cause the characteristic structures giving it its crown-like appearance, and they are what determine the tropism of the virus and its fusion with host cells. there are several known coronaviruses circulating in animals and humans. an interspecies 'jump' can sometimes occur, as in the case of sars in (which originated in civets) or mers in (originating in dromedaries), causing serious novel respiratory diseases in humans. the main difference between these and the current sars-cov- is the transmissibility between humans that the latter has shown. on february , , the official nomenclature was established for the virus as sars-cov- , and the disease it causes as covid- . it is a highly transmissible virus. the main form of transmission is droplets (large particles > m, moving - m) that are produced when an infected person sneezes or coughs. transmission by contact with surfaces or fomites contaminated by these droplets is also relevant, with subsequent entry of the infection by touching the nose, eyes or mouth. transmission by aerosols (small particles < m, moving more than m) is also possible and has stirred up controversy. this factor is especially relevant in the healthcare setting. in the operating room, the possibility of aerosolization when performing intubation or any airwayrelated maneuver is of concern. aerosolization also seems possible when using electrocoagulation or laparoscopy (if the patient is infected) when performing these techniques on infected tissue, mainly the respiratory tree. in vitro studies have shown that the virus can survive on multiple types of surfaces (metal, plastic or glass), where it can remain for up to days. disinfection of surfaces is therefore essential to minimize the contagion risk. thorough hand washing (with soap and water) is recommended as a preventive measure, using either soap (due to the ability of the soap to disintegrate the viral lipid capsule) or hydroalcoholic gels. likewise, solutions of %- % alcohol (ethanol), . % hydrogen peroxide and . % sodium hypochlorite are highly virucidal (time of around one minute), which should be used in surface disinfection. other biocides such as . % chlorhexidine gluconate or . %- % benzalkonium chloride are less effective. , the who has made available formulations to for individual/institutional/local production of alcoholic solutions in case of shortages or distribution problems. p r e v e n t i o n o f t r a n s m i s s i o n a n d i n f e c t i o n as the specific mechanism of transmission of the virus is known, it is essential to establish preventive measures. in the case of transmission by droplets, the basic measures are: -cover mouth/nose when sneezing, or use a disposable tissue and throw this away immediately. -symptomatic patients should cover their nose and mouth with a mask, one without a valve to avoid the dispersion of droplets. -wash hands with soap and water or hydroalcoholic solution. -maintain interpersonal distance (some studies even recommend . - meters). -avoid touching your face (eyes, nose and mouth). -follow pertinent recommendations made by health authorities (local/national/international). in the situation of an epidemic, it is essential to adopt a series of public health measures for the population, which will depend on the evolution of the epidemic and the local context: -vigilance: rapid detection of cases in order to establish pertinent isolation measures as early as possible during the containment phase. -screening at entry points: detection of imported cases and adequate information to persons coming from affected areas. -contact studies of confirmed cases to quickly identify infected individuals, and isolation (at home) of positive patients to avoid new contacts for weeks (in the containment phase). -social distancing measures: these may include avoiding crowds or large gatherings or public events, and even mandatory quarantine of the population (mitigation phase). -healthcare authorities should inform the public about the measures implemented, number of cases and status of the epidemic; health education measures are also necessary. the clinical presentation is highly variable, and different conditions have been observed, from mild (catarrhal symptoms) to very severe (adult respiratory distress syndrome). there are asymptomatic patients who pose an epidemiological problem due to their ability to transmit the virus unnoticed. the average incubation period is about days (ranging from to days), and . % of patients develop the disease in the first . days of incubation. the most frequently described clinical symptoms have been fever, cough (with/without expectoration) and general malaise. other symptoms have been described with varying frequencies, including dyspnea, headache, asthenia, myalgia, odynophagia, nasal congestion/discharge, anosmia, ageusia, syncope, confusion, neurological symptoms, ophthalmological symptoms (conjunctivitis and dry eye) and cutaneous (rash skin eruptions). a percentage of patients report the presence of diarrhea, vomiting and abdominal pain as relevant symptoms. sars-cov- rna has been identified in stool samples from infected patients, and the viral receptor ace has been found with high expression in gastrointestinal epithelial cells, indicating that the virus could easily infect and replicate in the gastrointestinal tract. it has also been observed that the virus continues to be eliminated in the feces after the initial symptoms have passed. however, fecal-oral transmission has not been confirmed at this time. preliminary data obtained mainly from studies carried out in the chinese population seem to indicate that elderly patients with associated comorbidities (htn, cardiopathy, diabetes, cancer, obesity, etc.) are at increased risk of serious presentations. it is estimated that more than % of total cases are mild/moderate, but % are severe and % critical. patients with the highest mortality in the chinese retrospective studies were males with a mean age years older than survivors ( vs. years) who had some type of underlying pathological process (htn, diabetes, cardiovascular disease or copd). furthermore, the presence of various associated comorbidities also increased the risk of poor progress. table shows some serious risk factors and laboratory abnormalities that have been associated with poor clinical outcomes. it has been observed that cases with poor present sudden worsening (usually in the second week of illness), with the appearance of dyspnea and respiratory failure that usually lead to the need for oxygen therapy and occasionally intubation and icu care around days to . , the usual cause of death is uncontrolled sepsis and respiratory failure. this poor evolution seems to correlate with the development of a 'cytokine storm' on the th day, which occurs as a result of the virus's interaction with the patient's immune system. the molecular diagnosis is based on rt-pcr techniques that study specific sequences of the virus genome. when the sars-cov- genome was openly shared, several groups began working to develop diagnostic rt-pcr tests based on genomic regions. in general, it is recommended to detect a less specific area for screening (the envelope gene or e gene) and another more specific one for confirmation (rna-dependent rna polymerase, or rdrp). there are different combinations of sequences according to the protocol developed by several laboratories. despite having high sensitivity and specificity, these tests can present false negatives. generally, these are due to the sample being insufficient or unrepresentative, taken too early or too late in the course of the disease, or degraded during transport or handling. in negative cases where suspicion or symptoms persist, it is recommended to repeat the rt-pcr in a few days. although nasopharyngeal or oropharyngeal samples are the easiest to obtain, bronchial samples (for example, bronchoalveolar lavage) are more effective for diagnosis yet more complex to obtain and require a higher level of biosecurity for personnel during extraction. the virus has also been detected in other biological samples (blood, feces, and saliva). serological techniques are able to detect igm and igg antibodies. there is evidence that these techniques begin to detect antibodies from day after the onset of symptoms, and they can be useful for population-based seroprevalence studies. there are already commercially available serological tests (immunochromatography) performed with whole blood that may be useful in diagnosis. cell culture is used for research. it takes several days, so it is not useful for clinical diagnosis, but it enables us to study the cytopathic effect of the virus on cell lines and to obtain virions. in this instance, biosecurity facilities (minimum bsl iii) are necessary. in the initial stages of the disease, changes may not be observed on plain radiography, or even on ct scan if performed during the first days of symptoms. however, as the condition progresses, the sensitivity of ct increases, especially after the th day, when almost all patients with covid- will present some type of alteration. when the radiological image is abnormal, certain common patterns are seen. asymmetrical areas of alveolar or interstitial opacity (patches or diffuse) are identified on simple chest radiograph. the most common pattern is bilateral pneumonia, with subpleural ground glass opacities, poorly defined margins and a slight predilection for the right lower lobe (figure ) . the most characteristic findings on thoracic ct are multiple ground glass opacities with peripheral lung consolidations. if these atypical findings are identified (even in asymptomatic patients), the diagnosis of covid- should be considered. ct stratification has been used to assess severity and is the most sensitive diagnostic test, detecting lesions that are sometimes not identified on plain chest radiography. this may be especially relevant in the early identification of cases, for example preoperatively in patients with suspected disease requiring surgery. regarding lab results, increased c-reactive protein (crp) levels with normal procalcitonin and lymphopenia (< cells/l) are characteristic. it should be noted that severe cases (compared to moderate ones) more frequently presented intense lymphopenia, hypoalbuminemia and higher levels of alt, ldh, pcr, ferritin and ddimer, as well as il- r, il- , il- and tnf-. current evidence suggests that the exaggerated immune response mediated by the cytokine storm leads to acute lung injury and acute respiratory distress, which, without treatment and support, lead to death in a large proportion of patients. in severe cases, it is recommended to rule out coinfections with other respiratory pathogens (influenza a and b, pneumococcus and legionella) and to extract blood for cultures. in the first series published in china, % of the deceased presented a second infection during hospitalization. t r e a t m e n t to date, there is no known effective treatment for covid- . however, several molecules have demonstrated in vitro activity against sars-cov and they are being investigated and used off-label. there are currently various clinical trials underway from different initiatives, public and private, national and international, to try to establish which treatment may be effective for covid- . the who has proposed an international clinical trial (solidarity trial) to evaluate the efficacy of the different therapeutic modalities proposed in affected countries, which have been used empirically or based on limited evidence. it is an adaptive, open, randomized trial that allows the study branches to be modified as more data become available. currently, the molecules under evaluation are: j o u r n a l p r e -p r o o f ) remdesivir (initially developed and previously evaluated for the ebola virus) ) lopinavir/ritonavir (enhanced antiretroviral therapy used for hiv) ) lopinavir/ritonavir in combination with interferon  ) chloroquine or hydroxychloroquine (cq/hcq) (antimalarial drugs that have been used successfully in china) ) all of them will be compared with standard support treatment without any molecule with potential antisars-cov action the spanish ministry of health frequently updates the drugs proposed for treatment as data and new therapeutic options are registered. currently some of the drugs being considered in the protocol are: cq/hcq, lopinavir/ritonavir, remdesivir, tocilizumab, sarilumab, interferon beta- b and interferon alfa- b. cq/hcq has demonstrated an antiviral effect in vitro, and it therefore has been considered a possible candidate for treatment and has been widely used empirically. when administering any of these off-label treatments, it is essential to evaluate the pharmacological interactions with the patient's current medication and potential toxicity. serious interactions can occur (such as qt prolongation with cq/hcq) and occasionally there are relevant contraindications (in cardiac or hiv-positive patients, etc.). web portals such as www.hiv-druginteractions.org provide for quick consultation of interactions. the utility of plasma from convalescent patients is being tested for the treatment of critically ill patients with covid- , and several laboratories around the world are investigating the development of a possible vaccine. the aec, as well as other national and international scientific societies, have issued clinical guidelines and recommendations to try to standardize practices at this critical moment, aimed at protecting both patients and healthcare professionals. [ ] [ ] [ ] around the world, the available evidence has been used to dynamically update treatment guidelines in moderately and critically ill patients, diagnostic testing, tracing contacts, as well as the necessary protective measures for healthcare workers depending on the type of care or procedure to be carried out. any procedure with increased exposure to respiratory secretions (intubation, tracheostomy, ent examination, etc.) is considered high risk. other body fluids that may present viral load, such as saliva, feces and blood, in which viral load has been detected to a greater or lesser extent, are also considered a risk. regarding the possibility of aerosolization in surgical procedures (electric scalpel and other electronic devices, laparoscopic smoke, etc.), various studies have been carried out by surgical teams, and specific proposals have been made to reduce this aerosolization (smoke filtration with a water seal and bleach, suction of smoke from the electric scalpel, etc.). in any case, and given the possibility of this infection route, it is essential that all operating room personnel have adequate and complete personal protective equipment, especially face protection (ffp /ffp /n masks, closed goggles and shields when needed). after the experience in china and italy, some important measures have been proposed for laparoscopy: minimize the dispersion of aerosols, avoiding uncontrolled leakage of gas/fluids through trocars or incisions; use closed filtration and evacuation systems for smoke; use the lowest possible gas pressure and the lowest intensity programs for electrocoagulation. it is also essential to adequately train and instruct operating room staff in this regard. under the circumstances of a pandemic, the high number of patients affected simultaneously saturates healthcare services. in the case of covid- (due to its ability to produce severe respiratory symptoms), there is an increased demand for ventilators and hospital or icu beds for these patients. therefore, in anticipation of the need for these resources, it has been proposed to delay all elective surgical procedures when possible, always considering the local epidemiological situation and the resources of each hospital. patients with a benign pathological process and/or with a low risk of complications may be postponed without a problem. in other elective cases in which there is some risk of complication due to not performing the intervention, the urgency of each case will be assessed individually (considering the benefit/risk), but postponing is recommended as long as possible until the current epidemiological situation is normalized. , o n c o l o g y p a t i e n t s oncology patients can be especially affected during the pandemic period for several reasons: -greater susceptibility to infection due to the baseline disease or secondary to immunosuppression of adjuvant treatments (chemotherapy). -alteration of their treatment regimens (chemotherapy and radiotherapy) or inability to conduct scheduled surgical procedures, which may affect the course of their disease and/or prognosis. -complications of oncological disease that require urgent treatment or hospitalization and increase the risk of sars-cov- infection (bleeding, perforation or obstruction due to untreated stenosing tumors, thrombosis, other infections, etc.). in case of suspicion and symptoms compatible with covid- , multiple international societies, such as the european cancer organization, advocate the prioritization of sars-cov- detection tests in these patients. decisions on whether or not to proceed with elective surgery in cancer patients currently depend on the local epidemiological situation, availability of operating rooms j o u r n a l p r e -p r o o f and icu at the corresponding hospital, disease status and the risk of progression or complications (individualized), assessment of surgical risk and potential complications of the procedure. in addition, specific assessment is necessary of possible pre/postoperative covid- infection as well as the individual risk in terms of the comorbidities of the patient, who must also be informed. individualized decisionmaking is promoted by multidisciplinary committees, and the creation of 'clean' hospitals where cancer patients can be referred has been proposed in high-incidence areas. in some cases, and depending on the type of tumor, even alternative treatments (such as extra cycles of chemotherapy) are proposed to control progression and/or delay surgery. u r g e n t s u r g e r y disease requiring urgent surgical management cannot be delayed or canceled despite the pandemic situation. in cases of pathological processes requiring surgery that cannot be postponed (appendicitis, peritonitis, etc.), several aspects must be evaluated when making decisions: -patient covid- status: does the patient present a concomitant viral infection in addition to the surgical disease? this determination is essential for the patient's prognosis and surgical risk as well as for the surgical team, who must be adequately protected. -is there sufficient protective material (personal protective equipment [ppe])? are the facilities satisfactory to operate safely? -are there any alternative treatments other than surgery that would be safe for the patient? for this reason, medical societies like the aec and the american college of surgeons suggest determining the patient's covid- status before proceeding with the surgical intervention in order to act in the safest way. all available means will be used to make this determination, ideally including rt-pcr and chest radiology (preferably ct scan). when it is not possible to determine covid- status, or in uncertain cases, proceed with surgery under the assumption that the patient is positive, providing adequate protection for operating room personnel with complete ppe. some extra measures have also been suggested, such as delaying the entry of staff into the operating room as much as possible, that the procedure be carried out by the most experienced surgeon available and that all non-essential personnel leave the operating room before extubation. as already mentioned, the use of the laparoscopic approach has generated great controversy because of possible aerosolization with the use of pneumoperitoneum. h e a l t h p e r s o n n e l a n d i n d i v i d u a l p r o t e c t i o n the availability of adequate material and sufficient ppe has been one of the most relevant issues since the start of the pandemic because of the global shortage and the many infections (and deaths) occurring among front-line healthcare workers. the experience in italy has been especially important in this regard, since a much higher number of infections was detected among healthcare personnel than in china, even leading to the closure of hospitals due to lack of personnel and the death of doctors. , unfortunately, the situation in spain has developed in a way similar to italy, and we are currently the country with the most infected health personnel (around %), which in many cases is secondary to the lack of adequate protection. it is essential for any surgeon working with covid- to have sufficient, quality ppe available. the current sars-cov- coronavirus pandemic is the greatest challenge that contemporary medicine has ever experienced. it directly affects all surgeons, requiring their role within health institutions to be redefined and their usual therapeutic strategies to be rethought, while having to adapt to unfavorable working conditions in which surgeons may be seriously affected. the very high incidence of sars-cov- infection requires surgeons to have an indepth understanding of the disease, including daily tasks and medical treatments with which they are not familiar. likewise, they need to adapt their practice to a critical situation, prioritizing safety in the work environment and care for the most serious patients, while considering options they usually do not consider, especially in emergencies. the need to know and implement strategies aimed at patients whose surgeries cannot be delayed, especially cancer patients, is essential to avoid what are called secondary and tertiary victims of the pandemic: infected healthcare workers and, above all, patients who ultimately receive suboptimal treatment. it is essential to highlight that the current situation has made decision-making necessary in a scenario full of uncertainties, where the scientific evidence to support these decisions is scarce. thus, although the effort of the health community continues to be intense, it is essential to constantly reevaluate each of the measures adopted. being a surgeon in the era of covid- requires maximum versatility, which means accepting that today's decisions may not be tomorrow's. again, this is an opportunity to renew deaver's aphorism that a surgeon is always more than just a doctor, yet never anything less. the authors have no conflict of interests to declare. the novel coronavirus resource. yi chuan identifying sars-cov- related coronaviruses in malayan pangolins aerosol and surface stability of sars-cov- as compared with sars-cov- pubmed central pmcid: pmc . -world health organization. guide to local production: who-recommended handrub formulations the incubation period of coronavirus disease (covid- ) from publicly reported confirmed cases: estimation and application covid- and the digestive system characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention china medical treatment expert group for covid- . clinical characteristics of coronavirus disease in china an update on covid- for the radiologist -a british society of thoracic imaging statement thailand joins the who "solidarity trial": global testing of effective treatments of covid- across countries -an aggressive effort to save lives from the pandemic (press release) could chloroquine /hydroxychloroquine be harmful in coronavirus disease (covid- ) treatment? covid- : fda approves use of convalescent plasma to treat critically ill patients management of critically ill adults with covid- -rosenbaum l. facing covid- in italy-ethics, logistics, and therapeutics on the epidemic's front line key: cord- -yfj kkj authors: nan title: sars-cov- infektion bei kindern und jugendlichen: ein literaturüberblick der ag infektiologie der Ögkj date: - - journal: padiatr padol doi: . /s - - - sha: doc_id: cord_uid: yfj kkj nan aktuell infektiologie sars-cov- infektion bei kindern und jugendlichen ein literaturüberblick der ag infektiologie der Ögkj f im dezember kam es in der chinesischen region hubei zum gehäuften auftreten von pneumoniefällen unbekannter Ätiologie [ ] . als ursache konnte rasch ein betacoronavirus, welches im weiteren verlauf die bezeichnung sars-cov- erhielt, identifiziert werden. aufgrund der zunehmenden weltweiten verbreitung rief die who schließlich am . . die laufende pandemie aus [ ] . mittlerweile gibt es weltweit mehr als , millionen positiv getestete personen und mehr als . bestätigte todesfälle [ ] . umfassende informationen zu covid- bei kindern werden erst langsam verfügbar. kinder erkranken wesentlich seltener als erwachsene. eine auswertung der ersten knapp . labor-bestätigten covid-fälle in china zeigt, dass kinder unter jahren nur , % ( kinder) und kinder zwischen und jahren nur , % ( kinder) der fälle ausgemacht haben [ ] . diese auswertung bezieht sich nur auf fälle, welche in der regel aufgrund von (relevanter) symptomatik getestet wurden. wie viele patienten (inkl. kindern) erkrankt sind, aber aufgrund einer milden symptomatik nicht getestet wurden, ist naturgemäß unbekannt. todesfälle im kindesalter sind grundsätzlich selten, beispielsweise sind bis ende april in den schwer betroffenen ländern spanien und italien vier kinder unter jahren und kinder zwischen - jahren verstorben [ , ] . bisherige daten zu intensivpflichtigen, pädiatrischen pa-tienten sind kaum vorhanden, daher sind daten zu grund-bzw. begleiterkrankungen, alter, schwere oder organmanifestationen bisher nicht ausreichend beschrieben [ , ] . in einer größeren pädiatrischen arbeit mit über kindern, welche auch verdachtsfälle inkludiert, waren kinder aller altersstufen betroffen. ein signifikanter geschlechterunterschied zeigte sich nicht. zirka % der inkludierten fälle verliefen asymptomatisch, und fast % zeigten einen milden oder moderaten verlauf. schwere verläufe waren insgesamt selten ( %), jedoch waren kinder unter jahr am häufigsten von einem schweren verlauf betroffen. allerdings waren in dieser altersgruppe knapp % der fälle lediglich verdachtsfälle (ohne sars-cov- -laborbestätigung), sodass die autoren davon ausgehen, dass ein nicht unbeträchtlicher teil dieser schweren verläufe durch andere viren (v. a. rsv) und nicht durch sars-cov- verursacht gewesen sein könnte [ ] . bisher gibt es keine ausreichenden hinweise, dass sars-cov- vertikal übertragen wird. in zwei kleinen fallkohorten mit je neun an covid- erkrankten mütter, wurden die neugeborenen allesamt negativ getestet [ , ] . ebenso war die testung von amnionflüssigkeit, nabelschnurblut und muttermilch negativ [ ] . jedoch zeigten sich in einer diesen kohorten vermehrte fetale komplikationen wie frühgeburtlichkeit oder respiratorischer stress, wobei der direkte zusammenhang mit sars-cov- nicht geklärt ist. ebenso könnten diese komplikationen eher indirekt durch die erkrankung der mutter (z. b. wegen frühzeitiger sectio) als durch eine infektion des kindes erklärt werden [ ] . so muss natürlich auf neonatalen intensivstationen damit gerechnet werden, dass aufgrund einer sars-cov- -erkrankung der mutter eine prämature entbindung indiziert wird und die frühgeborenen behandelt werden müssen. in einem fallbericht aus china wurde ein neugeborenes einer sars-cov- positiven mutter stunden nach der geburt positiv auf sars-cov- getestet. die testung von nabelschnurblut, plazentagewebe und muttermilch waren negativ. es ist daher unklar, ob es sich um eine vertikale oder postpartale Übertragung handelt. der klinische verlauf des säuglings war mild [ ] . in einer arbeit erfolgte bei sechs müttern und neugeborenen die testung auf igm und igg antikörper, wobei zwei säuglinge erhöhte igm werte zeigten, welche in der regel nicht diaplazentar auf das kind übertragen werden. [ ] . in der muttermilch sars-cov- positiver mütter wurde bisher keine virus-rna nachgewiesen [ ] . von den meisten fachgesellschaften wird das stillen durch sars-cov- positive mütter (bzw. füttern abgepumpter mutter-milch) empfohlen. dabei sollte aber in jedem fall das Übertragungsrisiko durch tröpfcheninfektion berücksichtigt werden (mundschutz und händehygiene). der großteil der erkrankungen verläuft mild. asymptomatische verläufe sind beschrieben, wobei die häufigkeit dieser noch unklar ist. nach chine-sischen daten entwickelten % der initial asymptomatischen patienten im verlauf symptome, sodass durchwegs asymptomatische verläufe derzeit als eher selten angesehen werden (geschätzte - %) [ ] . bei kindern sind asymptomatische verläufe in bis zu % der gesamtkohorte [ ] und in einzelnen altersgruppen sogar in über % beschrieben [ ] , wobei hier teilweise unklar ist, ob es im weiteren verlauf zu symptomen gekommen ist. bei den wenigen detaillierten berichten über spezifische symptome bei kindern mit covid- wird fieber in - % und husten in - % der symptomatischen fälle beschrieben [ , , [ ] [ ] [ ] [ ] [ ] . weitere beschriebene symptome sind pharyngitis ( - %), rhinitis ( - %) und diarrhoe ( - %). eine arbeit berichtet über drei neonatale fälle in china. bei diesen zeigte sich kurzatmigkeit, husten, fieber und gastroösophagealer reflux [ ] . bei erwachsenen sind weiters berichte über neurologische auffälligkeiten bekannt [ ] . ebenso kann es auch im rahmen der infektion zum auftreten von hautveränderungen kommen [ ] . bei erwachsenen beträgt die zeit bis zur genesung für leichte fälle ca. wochen, während sie für schwerwiegende fälle mit - wochen angegeben wird. inwieweit sich inkubationszeit und erkrankungsdauer bei kindern von denjenigen bei erwachsenen unterscheiden, ist noch nicht ausreichend untersucht [ ] . in einer arbeit mit kindern wird die mediane fieberdauer mit tagen und die maximale dauer mit tagen angegeben [ ] . in einer kleinen fallkohorte mit sieben kindern in der frühen phase der epidemie in wuhan zeigten sich fieberverläufe zwischen und tagen [ ] . ende april wurde in england eine warnmeldung aufgrund vermehrter fälle von kindern mit einem ungewöhnlichen inflammationssyndrom veröffentlicht. die symptomatik sei ähnlich einem atypischen kawasaki oder toxic shock syndrom. im vordergrund stehen oft bauchschmerzen und andere gastrointestinale symptome. die sars-cov- pcr war bei diesen kindern teilweise negativ bei jedoch positiver sars-cov- serologie oder kontakt zu sars-cov- infizierten personen [ ] . inzwischen sind solche fälle auch in anderen europäischen ländern (inklusive Österreich) und den usa beobachtet worden. die pathophysiologie und die rolle von sars-cov- sind bisher unklar. laboruntersuchungen bei kindern zeigten neben normalen oder erniedrigten gesamt-leukozyten auch eine lymphopenie oder neutropenie. in schweren fällen kann es zu erhöhten ldh-werten oder leberwerten kommen. crp und pct sind häufig normal [ ] , bei hyperinflammationssyndrom aber stark erhöht [ ] . in den durchgeführten ct untersuchungen zeigen sich bei kindern -ähnlich wie bei erwachsenen -vorzugsweise fleckförmige, milchglasartige trübungen [ ] . bei erwachsenen sind als risikofaktoren für einen schweren verlauf u. a. kardiovaskuläre grunderkrankungen, diabetes mellitus, chronische respiratorische erkrankungen, arterielle hypertonie und maligne erkrankungen (bzw. deren therapie) genannt [ , ] . daten zu kindern mit risikofaktoren und grunderkrankungen (primäre und sekundäre immundefizienz, maligne grunderkrankung, chronische respiratorische erkrankungen wie cystische fibrose, kardiale erkrankungen, etc.) werden in den bisherigen pädiatrischen analysen kaum erwähnt [ , ] . in einer arbeit mit kindern mussten drei kinder intensivmedizinisch behandelt werden, welche unterschiedliche vorerkrankungen hatten (nicht nähere definierte hydronephrose, leukämie in erhaltungstherapie, invagination) [ ] . ob sich aus der tatsache, dass so wenige erkrankungsfälle bei kindern mit grunderkrankungen berichtet werden, ableiten lässt, dass diese weniger gefährdet sind als erwachsene mit risikofaktoren, ist in diskussion. auch italienische kollegen berichten lediglich von einzelfällen von sars-cov- -erkrankten kindern mit aktuell oben genannten risikofaktoren (persönliche kommunikation). in einem bericht aus den usa hatten von kindern zumindest eine grunderkrankung, wobei die meisten kinder chronische lungenerkrankungen wie asthma (n = ) oder kardiovaskuläre erkrankungen (n = ) hatten oder immunsupprimiert waren (n = ) [ ] . der nachweis von sars-cov- erfolgt mittels rt-pcr. als material kann neben einem naso-oder oropharyngealen abstrich auch sputum, bal oder trachealsekret herangezogen werden. ein negatives ergebnis schließt eine infektion nicht mit sicherheit aus und sollte bei anhaltendem verdacht wiederholt werden [ ] . eine testung vor symptombeginn kann trotz vorliegender infektion negativ sein, da es erst ca. - tage vor symptombeginn zur virus-ausscheidung kommt [ ] . bei einem großteil der patienten ist virus-rna mindestens tage lang im nasopharynx nachweisbar [ ] jedoch gibt es auch berichte, dass virus-rna nur intermittierend im nasopharynx nachweisbar ist. es wurde gezeigt, dass die viruslast zu symptombeginn im nasopharynx hoch ist, dann aber rasch abnimmt und eine weitere virusreplikation im unteren respirationstrakt stattfindet und dort auch länger nachweisbar ist [ ] . somit gibt es durch den probenentnahmeort und den zeitpunkt des probengewinnes schwankungen in der sensitivität. die spezifität hingegen ist hoch, da nur sars-cov eine kreuzreaktion zeigt [ ] . bei kindern wurde auch eine virusausscheidung im stuhl beobachtet, wobei bisher keine hinweise für eine infektiosität gefunden wurden [ ] . derzeit verfügbare antikörpertests sind klinisch nur unzureichend validiert, sodass keine robusten daten zur sensitivität und spezifität vorhanden sind [ ] . wichtiger bestandteil des managements von bestätigten covid- patientinnen und patienten ist die frühzeitige isolierung zur verhinderung der weiteren transmission. bei stationärer aufnahme sollte neben strengsten isolationsmaßnahmen eine regelmäßige Überwachung hinsichtlich des klinischen zustands und der vitalparameter (insbesondere der oxygenierung) erfolgen, um frühzeitig -die bei erwachsenen oft als plötzlich einsetzend beschriebene -verschlechterung des krankheitsverlaufes zu erkennen [ ] . die datenlage zu spezifischen therapeutischen maßnahmen insbesondere bei kindern ist noch sehr schwach. bisher gibt es keine zugelassenen medikamente zur therapie von covid- bei erwachsenen und kindern [ ] . eine publizierte arbeit aus china empfiehlt bei kindern inhalativ interferon-alpha- sowie lopinavir/ ritonavir [ ] . in einer randomisiertkontrollierten studie mit erwachsenen mit schwerem verlauf zeigte lopinavir/ritonavir jedoch keinen signifikanten vorteil [ ] . der einsatz von kortikosteroiden sollte vermieden werden und nur in speziellen intensivmedizinischen indikationen in betracht gezogen werden [ , ] . remdesivir, welches ursprünglich zur therapie von ebola entwickelt wurde, zeigt in vitro eine hemmung von sars-cov- [ ] und wurde bei erwachsenen bereits in einzelnen fallserien eingesetzt und wird derzeit in klinischen studien geprüft. erste daten aus einer randomisiert-kontrollierten multicenter-studie zeigten keinen statistisch signifikanten Überlebens-vorteil durch remdesivir, auch wenn patienten unter remdesivir tendenziell eine kürzere genesungszeit hatten [ ] . daten zum einsatz bei kindern sind jedoch bisher nicht bekannt. (hydroxy-)chloroquin zeigt ebenso eine in vitro aktivität [ , ] , jedoch sind auch hier bisher nur wenige daten und ausschließlich bei erwachsenen bekannt. ein kind erhielt auf einer intensivstation intravenöse immunglobuline [ ] . allerdings ist nicht anzunehmen, dass in handelsüblichen, gepoolten immunglobulin-präparaten spezifische antikörper gegen dieses neuartige virus enthalten sind, eine immunmodulatorische wirkung aber nicht ausgeschlossen ist. eine entlassung bzw. entisolierung sollte erst nach genesung und dem nachweis von zwei negativen pcr tests im abstand von mindestens stunden erfolgen [ ] . aufgrund von daten bei anderen respiratorischen infektionen (z. b. influenza) und der milden und eventuell auch asymptomatischen verläufe bei kindern, wurde über deren bedeutung für die transmission spekuliert. kinder scheinen aber nicht nur seltener symptome zu entwickeln, sondern sich möglicherweise auch seltener zu infizieren. eine studie zur transmission innerhalb von haushalten von indexpatienten hat gezeigt, dass sich erwachsene fünfmal häufiger infiziert haben als kinder [ ] . eine andere, ähnliche studie konnte diesen unterschied jedoch nicht zeigen [ ] . in einer isländischen studie zur rate an asymptomatisch infizierten waren erwachsenen doppelt so oft virusträger ( %) als kinder, jugendliche und erwachsene zwischen und jahren ( , %). von über untersuchten kindern unter jahren war kein einziges positiv, obwohl die grundschulen und kinderbetreuungseinrichtungen während des untersuchungszeitraumes geöffnet waren [ ] . ein australischer bericht zeigt, dass von sars-cov- infizierten ( schüler und angestellte) in a novel coronavirus from patients with pneumonia in china who declares covid- a pandemic university jh ( ) covid- dashboard by the center for systems science and engi-hier steht eine anzeige. aktuell neering (csse) at johns hopkins university (jhu) characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: 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cord- -ew wcr authors: jasti, madhu; nalleballe, krishna; dandu, vasuki; onteddu, sanjeeva title: a review of pathophysiology and neuropsychiatric manifestations of covid- date: - - journal: j neurol doi: . /s - - -w sha: doc_id: cord_uid: ew wcr introduction: the outbreak of coronavirus disease (covid- ) has become one of the most serious pandemics of the recent times. since this pandemic began, there have been numerous reports about the covid- involvement of the nervous system. there have been reports of both direct and indirect involvement of the central and peripheral nervous system by the virus. objective: to review the neuropsychiatric manifestations along with corresponding pathophysiologic mechanisms of nervous system involvement by the covid- . background: since the beginning of the disease in humans in the later part of , the coronavirus disease (covid- ) pandemic has rapidly spread across the world with over , , reported cases in over countries [world health organization. coronavirus disease (covid- ) situation report- .,]. while patients typically present with fever, shortness of breath, sore throat, and cough, neurologic manifestations have been reported, as well. these include the ones with both direct and indirect involvement of the nervous system. the reported manifestations include anosmia, ageusia, central respiratory failure, stroke, acute inflammatory demyelinating polyneuropathy (aidp), acute necrotizing hemorrhagic encephalopathy, toxic–metabolic encephalopathy, headache, myalgia, myelitis, ataxia, and various neuropsychiatric manifestations. these data were derived from the published clinical data in various journals and case reports. conclusion: the neurological manifestations of the covid- are varied and the data about this continue to evolve as the pandemic continues to progress. at the end of , many unexplained pneumonia cases occurred in wuhan, china, and rapidly spread to other parts of china, then to other parts of asia, europe, and recently to north america. eventually, this outbreak was confirmed to be caused by a novel coronavirus [ ] . this novel coronavirus reportedly had symptoms resembling that of severe acute respiratory syndrome corona virus (sars-cov) seen in the year [ ] . both these viruses share almost % of the amino acid sequences and use the same receptor-which is angiotensin-converting enzyme (ace ) [ ] to gain entry into the cells. hence, this virus was named sars-cov- . in february , the world health organization named the disease as coronavirus disease . coronaviruses cause multiple systemic infections affecting various organ systems, but primarily affect the respiratory system. they tend to mutate and adapt quickly to cross the species barrier, which occurred with sars-cov and middle east respiratory syndrome coronavirus (mers-cov), causing epidemics and pandemics. infection with these viruses in humans often leads to severe clinical symptoms with high mortality [ ] . all three of these novel viruses (sars-cov, sars-cov- /covid- , and mers-cov) originate from zoonotic transmission. these are enveloped, positive-stranded rna corona viruses in the betacoronoviride family. studies had demonstrated that the clinical course of sars and mers was highly similar and sars and mers may have similar pathogenesis [ ] . the genome sequence of sars-cov- also shows some similarities to that of mers-cov. the postulated common pathophysiologic mechanisms include dysregulation of cytokines/ chemokines, deficiencies in the innate immune response, direct infection of immune cells, direct viral cytopathic effects, and autoimmunity [ ] . mers-cov infects cells by binding to the dipeptidyl peptidase receptor, and sars-cov acts via the angiotensin-converting enzyme receptor [ ] . as for covid- , numerous studies have described typical clinical manifestations including fever, cough, sore throat, shortness of breath, diarrhea, and fatigue. covid- also has characteristic laboratory findings and lung computed tomography abnormalities [ ] . however, there is growing literature that patients with covid- have cardiac [ ] and neuropsychiatric manifestations, as well. a recently published study that looked at cases of severe coronavirus illness treated in wuhan during the early phase of the global pandemic reported that about % of patients displayed neurological symptoms [ ] . this study reports that strokes, altered consciousness, and other neurological issues are relatively common in serious cases of covid- . these include both direct and indirect involvement of the nervous system. following this study, there have been several case reports of various neurologic diagnoses. the reported manifestations include anosmia, ageusia, stroke, aidp, acute necrotizing hemorrhagic encephalopathy, toxic-metabolic encephalopathy, headache, myalgia, central respiratory failure, myelitis, ataxia, and various neuropsychiatric manifestations. in this section, we will discuss the neuropsychiatric presentations and the possible associated pathophysiology. losses of smell and taste have been strongly linked to covid- infections [ ] . so far, there have been numerous publications about the association of loss of smell and taste with covid- infection. post-viral anosmia is one of the leading causes of loss of sense of smell in adults. this post-viral loss of smell is thought to be secondary to initial congestion of the nose, which leads to loss of fine hair like endings of the olfactory receptor cells causing them to be ineffective in picking up odor molecules from the nose. sars-cov- also appears to be highly concentrated in the nostrils of affected patients causing inflammation of the olfactory nerves and structural damage to the receptors and thereby causing anosmia [ ] . studies have shown that the tongue has a very high expression of ace receptors compared to buccal and gingival tissues, thereby posing a high risk of viral binding and ageusia from taste receptor damage [ ] . there have been a fair number of reports suggesting sars-cov- infecting the neurons, raising questions about the direct effects of the virus on the brain that play a role in patients' deaths. some of the respiratory symptoms due to the disease might actually be secondary to respiratory center involvement controlled by the nervous system. according to yan-chao li, et al. [ ] , sars-cov- infects nerve cells, particularly the neurons in the medulla oblongata, which serves as the control center for the heart and the lungs. the damage to this area could contribute to the acute respiratory failure of patients with covid- . autopsy results of patients with covid- showed that the brain tissue near brainstem was hyperemic and edematous with neuronal degeneration [ ] . by contrast, there have been a few case reports which mention no penetrance of virus into the central nervous system as evidenced by the absence of sars-cov- in csf and that the cns effects are secondary to elevated inflammatory markers as csf analyses during the acute stage showed pleocytosis with increased il- and tnf-α concentrations [ ] . researchers have reported that many human cell types express ace , including lung, heart, kidney, intestine, and brain tissue [ ] . there are at least a couple of ways that the virus could invade the central nervous system-it might circulate through the blood and then attack ace receptors in the endothelia that line blood capillaries in the brain, breaching the blood-brain barrier and invading neurons through that route (fig. ) . a breached blood-brain barrier could also cause brain swelling, compressing the brain stem there by affecting respiration. apart from these two mechanisms, it has also been demonstrated that some coronaviruses can spread by synaptic transfer from chemoreceptors and mechanoreceptors in lung to the medullary cardiorespiratory center [ ] . this process could be an implicating factor in acute onset respiratory failure in some of the covid- patients [ ] . researchers in china published the first presumptive case of acute inflammatory demyelinating polyneuropathy (aidp)/ guillain-barre syndrome (gbs) associated with covid- on apr , [ ] . reportedly, the patient initially presented with signs of the autoimmune neuropathy after returning from wuhan, china and later tested positive for the covid- . considering the temporal association, it was speculated that sars-cov- infection might have been responsible for the development of aidp. following this, a case series from italy, published by toscano et al., reported five cases of aidp that started after the onset of covid- disease [ ] . around the same time, two case reports were published from spain reporting the occurrence of miller fisher syndrome and polyneuritis cranialis in patients diagnosed with covid- [ ] . all these studies showed that aidp occurs early in the course of the disease and followed the pattern of a para-infectious profile, instead of the classic post-infectious profile. the underlying pathophysiologic mechanisms might be secondary to the neuroinvasive nature of the virus precipitating demyelination [ ] versus viral infection creating an inflammatory environment triggering an aberrant immune response (secondary to molecular mimicry) leading to peripheral demyelination [ ] . poyiadji et al. reported the first presumptive case of covid- -associated acute necrotizing hemorrhagic encephalopathy [ ] . acute necrotizing encephalopathy is a rare encephalopathy and one of the remote complications of influenza and other viral infections. this has been presumed to be due to intracranial cytokine storm, which results in the blood-brain barrier breakdown, without direct viral invasion or para-infectious demyelination [ ] . accumulating [ ] . a cytokine profile resembling secondary hemophagocytic lymphohistiocytosis (a hyperinflammatory syndrome that leads to fulminant and fatal hypercytokinaemia with multiorgan failure which is commonly triggered by viral infections [ ] ) is associated with severe covid- , characterized by increased interleukin's-il- , il- , granulocyte-colony stimulating factor, interferon-alpha, monocyte chemoattractant protein , macrophage inflammatory protein -alpha, and tumor necrosis factor-alpha [ ] . predictors of fatality from a recent retrospective, multicenter study of confirmed covid- cases in wuhan, china, included elevated ferritin and il- [ ] , suggesting that hyper inflammation might be contributing to mortality. patients with severe infection were more likely to develop neurologic manifestations, especially acute cerebrovascular disease. patients with severe infection had higher d-dimer levels than that of patients with the non-severe infection, which may be the reason why patients with severe infection are more likely to develop the cerebrovascular disease. apart from the elevated d-dimer causing a state of altered coagulation cascade, there is also a theory that there is a vasculitis type of picture created secondary to intracranial cytokine storm versus the infection by the virus itself which are believed to be the possible pathophysiologic mechanisms behind stroke/cerebrovascular accident [ ] . the virus can get access to cerebral circulation from systemic circulation, attach to endothelium ace receptors, and cause endothelial ruptures and thrombus [ ] . slow cerebral circulation compared to systemic circulation pose an increased risk of replication and rupture. also, the virus can get into brain tissue from capillary endothelium by brain-blood barrier disruption and cause neuronal damage without much inflammation (fig. ) . past studies on viral pandemics, especially involving respiratory viruses, suggest that diverse types of neuropsychiatric symptoms can arise with acute infection as well as in the post-viral infectious period [ ] . one study reported persistent neurocognitive deficits up to months post-discharge [ ] . in the acute phase, apart from being the psychosocial stressor, covid- has been reported to cause neuropsychiatric manifestations, like encephalopathy, psychosis, insomnia, and mood changes. post-traumatic stress disorder, panic attacks, anxiety are mostly seen in health care workers and survivors of sars cov infection [ ] . this is largely secondary to the mental trauma and not as a direct consequence of infection. in addition, over-reactive behavior due to fear is usually noted in the public during the pandemics [ ] . aggression, frustration, can worsen with quarantine and lockout procedures [ ] . these neuropsychiatric manifestations have been attributed to viral infection per se and also secondary to the host immune response [ ] . direct viral infiltration of the central nervous system can trigger a neuro-inflammatory reaction leading to microglial activation [ ] , which in turn triggering demyelinating processes is one of the primary etiologies for encephalopathy. in the absence of direct viral infiltration, peripheral hypercytokinaemia causing an imbalance of neurotransmitters within the central nervous system has been implicated in neuropsychiatric manifestations. the state of hypercytokinaemia triggers a neuro-inflammatory response causing disruption of the blood-brain barrier, leading to peripheral immune cell transmigration into the central nervous system and, in turn, causing imbalances in neurotransmission [ ] . ace was identified as the functional receptor to enter into a cell for sars-cov- , which is present in multiple human organs, including the nervous system and skeletal muscles. patients with severe covid- disease had muscle breakdown causing muscle weakness and this manifested as elevated creatine kinase and lactate dehydrogenase levels than those without muscle symptoms. apart from the direct tissue injury by the virus, cytokine storm damage [ ] might also be the other reason for muscle involvement with covid- . this has been commonly reported in patients with moderately severe disease. the pathophysiologic mechanisms are unclear, but could be secondary to breached blood-brain barrier and involvement of the brain stem versus elevated inflammatory markers. patients with severe disease had a prolonged icu course and were noted to be encephalopathic for more than the usually expected duration. this is most likely secondary to the use of multiple and high doses of anesthetics and sedatives as a part of the symptomatic management of severe respiratory disease. hypoxia and viremia itself are also the possible factors behind encephalopathy [ ] . headache was commonly seen in patients with mild-tomoderate disease severity. these were partly believed to be secondary to raised inflammatory mediators in the body and decreased cerebral blood flow from hypoxia and endothelial changes from viremia. seizures were also randomly reported. these have been hypothesized to be secondary to decreased seizure threshold secondary to an innate immune response from cytokine surge [ ] rather than viruses primarily causing the seizures. dense parenchyma and imperviousness of brain tissues not only protects the brain from infectious processes, but also poses a challenge to eliminate them once brain involvement occurs [ ] . cytotoxic t cells are the mainstay for the elimination of viruses from brain tissue because of the lack of major histogen compatibility antigens in neurons . therefore, more research about covid- neurogenic involvement is necessary to identify and treat the neurological disease early, rather than at an advanced stage at which it will be more challenging. patients with covid- commonly have neurologic manifestations. the data/literature on this continues to evolve. on one hand, there are very commonly reported neurologic diagnoses of anosmia, encephalopathy, and stroke, and at the same time, there have been only a few isolated case reports of acute necrotizing encephalopathy and aidp. we have to keep in mind that the current information that we have about the neurologic manifestations of covid- is in the context of purposefully avoiding advanced neurodiagnostic procedures like magnetic resonance imaging, lumbar puncture, electromyography, and nerve conduction studies to reduce the risk of crossinfection within the hospital. a prospective, observational study with a larger number of patients that includes more specific neuro-imaging 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virus outbreak is urgently needed are we facing a crashing wave of neuropsychiatric sequelae of covid- ? neuropsychiatric symptoms and potential immunologic mechanisms monocyte trafficking to the brain with stress and inflammation: a novel axis of immune-to-brain communication that influences mood and behavior neuroimmune interactions: from the brain to the immune system and vice versa rhabdomyolysis secondary to influenza a infection: a case report and review of the literature nervous system involvement after infection with covid- and other coronaviruses interleukin- , produced by resident cells of the central nervous system and infiltrating cells, contributes to the development of seizures following viral infection barrier function in the peripheral and central nervous system-a review lack of major histocompatibility complex class i upregulation and restrictive infection by jc virus hamper detection of neurons by t lymphocytes in the central nervous system key: cord- -jj anf g authors: shang, you; pan, chun; yang, xianghong; zhong, ming; shang, xiuling; wu, zhixiong; yu, zhui; zhang, wei; zhong, qiang; zheng, xia; sang, ling; jiang, li; zhang, jiancheng; xiong, wei; liu, jiao; chen, dechang title: management of critically ill patients with covid- in icu: statement from front-line intensive care experts in wuhan, china date: - - journal: ann intensive care doi: . /s - - - sha: doc_id: cord_uid: jj anf g background: the ongoing coronavirus disease (covid- ) pandemic has swept all over the world, posing a great pressure on critical care resources due to large number of patients needing critical care. statements from front-line experts in the field of intensive care are urgently needed. methods: sixteen front-line experts in china fighting against the covid- epidemic in wuhan were organized to develop an expert statement after rounds of expert seminars and discussions to provide trustworthy recommendation on the management of critically ill covid- patients. each expert was assigned tasks within their field of expertise to provide draft statements and rationale. parts of the expert statement are based on epidemiological and clinical evidence, without available scientific evidences. results: a comprehensive document with statements are presented, including protection of medical personnel, etiological treatment, diagnosis and treatment of tissue and organ functional impairment, psychological interventions, immunity therapy, nutritional support, and transportation of critically ill covid- patients. among them, recommendations were strong (grade ), were weak (grade ), and were experts’ opinions. a strong agreement from voting participants was obtained for all recommendations. conclusion: there are still no targeted therapies for covid- patients. dynamic monitoring and supportive treatment for the restoration of tissue vascularization and organ function are particularly important. the outbreak of novel coronavirus pneumonia that was first detected in wuhan in december resulted in a worldwide pandemic. on february , , the world health organization (who) formally named it coronavirus disease . a person with laboratory confirmation of virus causing covid- infection, irrespective of clinical signs and symptoms, is considered as a confirmed case [ ] . globally, more than , , confirmed individuals and over , deaths, across more than countries, territories or areas have been reported [ ] . approximately % of confirmed cases developed severe disease [ ] , while the grand fatality rate was . % [ ] . as the virus continues to spread at an alarming rate, healthcare workers are seeking effective and actionable management for affected patients. in china, physicians have been coping with covid- for over months. most of the people who contracted covid- presented with mild symptoms ( . %), then severe ( . %), and finally critical ( . %) ( table ) [ ] . most of the confirmed cases were between the ages of and ( . %), diagnosed in hubei ( . %), with the overall fatality rate of . %, and . % in health workers [ ] . the case fatality rate for critical cases was . % [ ] . patients with underlying diseases had much higher fatality rates than patients with no underlying diseases ( . % for cardiovascular disease, . % for diabetes, . % for chronic respiratory disease, . % for hypertension, . % for cancer, and . % for none) [ ] . the epidemic outbreak curve peaked around january - , , after which the decline ensued. a recent single-center study found that most critical patients developed organ dysfunction, where % were found to have acute respiratory distress syndrome (ards), % with acute kidney injury (aki), % with cardiac injury, % with liver dysfunction, and % with pneumothorax [ ] . besides these epidemiological findings, chinese experts have gained valuable experience in the management and pathology of this disease. we consider it our responsibility to share these experiences through the expert consensus. chinese specialists in critical care medicine were organized and worked together to develop an expert statement after five rounds of expert seminars and discussions. this statement represents a synthesis of evidence and experts' consensus on critical care, despite the lack of clinical trials. critical cases are characterized by exhibited respiratory failure, septic shock, and/ or multiple organ dysfunction/failure [ ] . in experts' opinion, the patients should also be considered as critical cases if they are suffering from high respiratory frequency (rr ≥ bpm) and low oxygen index (arterial partial pressure of oxygen (pao )/fraction of inspired oxygen (fio ) ≤ mmhg) under high-flow nasal cannula oxygen therapy (hfnc). the experts drew up sections on the management of covid- disease, mostly based on the experience in wuhan. the statements were drawn up by a group of front-line intensive care experts in china who fought against the covid- epidemic in wuhan. the group's agenda was predefined. the expert group first defined clinical questions to be addressed and then designated the experts in charge of each question after a first meeting. all the questions were formulated according to the population, intervention, control, and outcome (pico) format, which helps defining inclusion and exclusion criteria for the literature searches and identifying relevant studies. the quality of evidence was assessed using the methodology described in grades of recommendation, assessment, development, and evaluation (grade). the quality of evidence can be high, moderate, low, or very low. because of the sudden outbreak of a covid- , the proposed question could be the subject of a recommendation as an expert opinion due to inexistent or insufficient literature. in addition, the published data on severe acute respiratory syndrome (sars), middle east respiratory syndrome (mers) and other coronaviruses infections, as well as data on supportive care in the icu from studies on influenza and other respiratory viral infections, ards and sepsis was used as indirect evidence. a total of rounds of expert seminars and discussions were organized to provide trustworthy recommendation on the management of critically ill covid- patients (table ) . we use the wording "we recommend", "recommended", "should" or "should not" for strong recommendations, "should probably", "should probably not" or "should probably be considered" for weak recommendations, and "the experts suggest", "the experts suggest against", "suggested" or "not suggested" for expert opinion. the implications of the recommendation strength are presented in table . the proposed recommendations were discussed one by one. at least % of experts agree to approve a proposal for criteria, and at least % of experts must agree to reach a strong agreement. in the absence of strong agreement, choose to reformulate the proposal and re-rating, in order to reach consensus. only the expert opinions that give strong agreement are retained. the prevention and control of infections, diagnostic strategy, therapeutic management, and transportation of patients were defined. literatures were searched via pubmed and the cochrane library databases. only articles published in english or with an english abstract were included in the analysis focused on recent data according to an order of appraisal ranging from meta-analyses to randomized trials to observational research studies. the study population size and research relevance were considered for each study. according to the grade method and summary of the results, experts drew up statements. of these guidelines, had a high level of evidence (grade ±), had a low level of evidence (grade ±), and were expert opinions. a strong agreement was reached for all statements after two rounds of scoring. as the front-line of the covid- outbreak response, health care workers are exposed to a huge risk of infection. therefore, health care workers must follow the standard precautionary principles and try their best to ensure the personal protection, hand hygiene, ward management, environmental ventilation, and sanitization of the object surface, so as to avoid nosocomial cross-infection. statement implementation of standard precautions, strengthening ward management, and self-management are suggested safety measures for health care workers (expert opinion). rationale averted by the current epidemic situation of covid- , taking proper precautions is essential for avoiding the spread of infection among health care workers. thus, the following points need to be considered. as a high-risk environment, tertiary class protection is suggested for health care workers in intensive care unit (icu). personal protective equipment (ppe) includes disposable surgical cap, n mask, work uniform, disposable medical uniforms, disposable latex gloves, goggles, and full-face shields. full-face respiratory protective devices or powered air-purifying respirators are required when performing aerosol-generating procedures. destroying and disposing of masks properly, putting on and removing ppe, and practicing hand hygiene are necessary to avoid self-contamination. special attention should be paid to details such as the side exposure of the eyes and wrists with glove slippage, as well as the risks of infection while removing some disposable shoe covers [ ] . the hand hygiene system should be strictly implemented table statement timeline march , designating the experts in charge of each addressed question each expert made a detailed outline of their respective question march , discussing and resolving the problems encountered by the experts in the process of making the statements april , ( ) discussing the experts' respective statement and rational after revision; ( ) first round of scoring april , guideline finalization meeting for the second round of scoring table recommendations according to the grade methodology grade + strong recommendation "…we recommend…", "…recommended…" or "…should…" high level of evidence grade + weak recommendation "…should probably…" or "…should probably be considered…" low level of evidence expert opinion recommendation in the form of an expert opinion "…the experts suggest…", "…suggested…", "…the experts suggest against…", or "…not suggested…" [ ] . clinical triage system needs to be established to assess all patients at admission, allow for early recognition of possible covid- cases and immediate isolation of patients with suspected disease in an area separate from other patients (source control). the number of family members and visitors who are in contact with suspected or confirmed covid- patients should be limited or visiting should be prohibited altogether. the proper disposal of clinical waste should be ensured [ ] . health care workers need to self-monitor for signs of illness and self-isolate. if illness occurs, they should report it to managers and stay at home. a sensible diet, proper rest, and adequate exercise are advised to maintain physical and psychological health. health care workers should familiarize themselves with related working procedures so as to avoid mistakes [ ] . proper icu ward setting, necessary equipment and facilities, and strict icu environmental disinfection, are suggested (expert opinion). rationale it is suggested to adjust measures according to the differing conditions so as to set the icu ward rationally. contaminated areas, potentially contaminated area and clean areas need to be strictly divided. the buffer zone should be set between every two areas. posting eye-catching logos on each area is required to prevent straying into the wrong place. different points of access should be set for medical staff and patients, making sure they do not get crossed. for icu, tertiary class protection should be correctly performed in each area, which is of great importance for precaution of covid- [ ] . the use of negative pressure rooms with natural ventilation is recommended by the who guidance to prevent the spread of airborne pathogens among rooms [ , ] . first-aid materials and medicine such as oxygen tank, electrocardiogram (ecg) monitor, defibrillator, injection pump, infusion pump, endotracheal intubation supplies, portable vacuum extractor, noninvasive ventilator, invasive ventilator, hemofiltration equipment, extracorporeal membrane oxygenation (ecmo) equipment and so on should be prepared. other equipment, including air disinfecting machine and air cleaner, as well as medical gas systems including oxygen, compressed air, special gas, and vacuum suction systems, need to be assured too. it is of particular importance to implement effective measures to prevent the spread of covid- in icu. disinfection includes concomitant disinfection and terminal disinfection. concomitant disinfection must be conducted immediately for the materials and environment contaminated by the excretion of the suspected and confirmed patients. following the end of day's work in icu, or the patients' recovery or death in the isolation ward, terminal disinfection needs to be done carefully. key disinfection objects include patients' living supplies such as clothes and quilt, medical supplies, ground and wall space of icu wards, the surface of desks and bed tables, as well as air [ , ] . current evidence indicates that covid- is mainly transmitted from person to person through droplets, contact, and even high concentrations of aerosols [ ] . large amounts of droplets and aerosol are generated by sputum suction in the airway, specimen collection, tracheal intubation, fiber bronchoscopy, tracheotomy, etc. accordingly, surgeons are at a great risk of contamination. in order to avoid occupational exposure, recommendations during the aerosol-generating procedures in covid- patients are the following: statement if possible, covid- patients should probably be admitted to negative pressure rooms (grade +, weak recommendation). rationale negative pressure rooms are aimed to decrease the concentration of severe acute respiratory syndrome coronavirus (sars-cov- ) pathogens. in view of that, the risk of contamination would be decreased during the aerosol-generating procedures in such a setting. during the severe acute respiratory syndrome (sars) epidemic, it was reported that negative pressure settings were effective in preventing cross-contamination and protecting the staff and patients inside the room [ ] . according to who recommendations for covid- patients, such locations should be with a minimum of air changes per hour or at least l/ second/patient with natural ventilation [ ] . the experts suggest that operators wear a portable air-purifying respirator with level iii biosafety protection (expert opinion). rationale an observational study reported that among hospitalized patients diagnosed with confirmed covid- in zhongnan hospital in wuhan in january, , were healthcare workers [ ] . till march , , it has been reported that over health workers were confirmed with covid- , among whom died. the memory of what has happened during the sars outbreak is still fresh. a systematic review showed that the healthcare workers who performed aerosol-generating procedures, including endotracheal intubation (odds ratio, . ), noninvasive ventilation (odds ratio, . ), tracheotomy (odds ratio, . ), and manual ventilation before intubation (odds ratio, . ) were at higher risk of suffering from sars infection compared with the non-performers [ ] . most of the infections among healthcare workers occurred at the early stage of this outbreak when the self-protective directive has not yet been established and reinforced. after confirmation of human to human transmission of sars-cov- , the self-protection for healthcare workers was subsequently established and reinforced from the end of january . level iii biosafety protection is mandatory for intubation according to the guidance of the general office of the national health committee [ ] . ppe donning process should be strictly followed during high-risk operation: disposable hair cover, fit-tested n respirator or equivalent, fluid-resistant gown, two layers of gloves, goggle and face shield, and fluid-resistant shoe covers. the main operator should use portable airpurifying respirator. all the donning processes should be supervised by a professional nurse or assistant. doffing process of ppe after high-risk exposure should also be followed: hand hygiene, face shield and goggle removal, fluid-resistant gown removal, outer glove removal, shoe cover removal, inner glove removal, hand hygiene, n respirator or equivalent removal, and hair cover removal. the doffing process seems to be of greater importance. all the processes should also be supervised so as to reduce the risk of contamination [ ] . the aerosol-generating operations such as tracheal intubation and tracheotomy are suggested to be performed by senior physicians or specialists in the field. an electronic laryngoscope with light emitting diode is suggested during endotracheal intubation. if possible, disposable equipment is suggested to be used. b) fiber bronchoscopy is not suggested for patients without an artificial airway. the operation is suggested to be performed by senior physicians or professionally trained respiratory therapists. a bronchoscope with an external display is suggested for facilitating operations. if possible, the use of a disposable bronchoscope is suggested (expert opinion). rationale large amounts of aerosols generated by incubation can increase the risk of transmission and nosocomial infection [ ] . thus, visual devices are recommended to facilitate the procedure, limit operation time [ ] and ensure the distance between operator and patient. routine fiber bronchoscopy operations are not suggested for covid- patients. meanwhile, most covid- patients have few airway secretions [ ] so that the indication of bronchoscopy should be strictly minimized. according to the recommendations by the centers for disease control and prevention (cdc) [ ] and who [ ] , disposable medical equipment should be used for patient care if possible. statement (a) deep sedation (richmond agitation-sedation scale (rass): - ) is suggested for patients during the procedure of fiber bronchoscopy. (b) the artificial airway is suggested to be connected with a threeway connector allowing access to get into the airway to perform a bronchoscopy. (c) the use of a closed airway suction device is suggested (expert opinion). rationale severe covid- patients with artificial airway tend to suffer from severe hypoxemia [ ] . the patient's secretions, droplets, and aerosols can be widely spread during the operation. patients should be intubated within s [ ] . the procedure of fiber bronchoscopy should be performed gently with great caution in severe covid- patients. during bronchoscopy, following procedures should be followed to avoid aerosols spreading: artificial airway should be connected with a disposable three-way connector to a ventilator, then (a) ventilator needs to be set to standby mode, (b) the artificial airway needs to be briefly clamped, (c) the bronchoscopy should be quickly inserted into the connector, (d) the clamp should be opened, (e) ventilation should be restored [ ] . for the patients requiring mechanical ventilation, it is not advisable to disconnect patients from the ventilator. even though some clinical experts insisted that antiviral therapy is unnecessary for seriously ill patients with covid- since the course of disease in severe types is longer than weeks, multiple virus particles have been found at the lung lesions following histopathological examination. up to date, there is no specific antiviral drug that has been testified and globally recognized effective for treating covid- . in china, several antiviral drugs such as ribavirin, ganciclovir, oseltamivir, arbidol, alpha-interferon, chloroquine, lopinavir-ritonavir, and remdesivir have been used in clinical settings for the treatment of covid- . among them, oseltamivir and arbidol hydrochloride are the most commonly utilized; however, these antiviral drugs were originally designed for influenza, and their efficacy and safety for covid- need to be further investigated. no antiviral drugs are proven effective and should probably be considered for sars-cov- treatment (grade +, weak recommendation). rationale ribavirin is a broad-spectrum antiviral drug. clinical observations have suggested that early use of this drug is efficacious in containing covid- . to avoid possible aerosol transmission, we do not recommend alpha-interferon nebulization for covid- infected patients. according to a very recently published clinical study from france, hydroxychloroquine can significantly reduce viral load in covid- patients, and azithromycin can further enhance this effect [ ] . in this study, combination use of hydroxychloroquine (hcq) and azithromycin for at least days at an early stage could rapidly reduce the nasopharyngeal viral load and decrease the length of hospital stay for infected patients. it should be noted that treatment with higher chloroquine diphosphate (cq) dosage ( mg cq twice daily) is not recommended for severe covid- due to its potential safety hazards, especially when taken concurrently with azithromycin and oseltamivir [ ] . nonetheless, a randomized controlled trial (rct) trial conducted by cao et al. suggested monotherapy of lopinavir-ritonavir did not bring about any clinical benefits for severe covid- patients compared with standard supportive care, which may be partly caused by the higher throat viral loads in lopinavir-ritonavir group, delayed treatment initiation [ ] . of note, these clinical studies were limited by relatively small sample sizes. more large-scale and well-designed clinical trials are needed to confirm their potential therapeutic effects. arbidol monotherapy might be better than lopinavir-ritonavir in reducing viral load in covid- patients [ ] . a clinical study from gilead sciences showed that remdesivir could improve clinical conditions in critically ill patients with covid- , and stop patient from receiving invasive mechanical ventilation or ecmo [ ] . however, a recent multicentre study published in the lancet found no benefit of remdesivir in improvement of clinical outcomes for severe covid- [ ] . one recent study published in n engl j med showed that compassionate use of remdesivir improved clinical outcomes in a subset of severe covid- patients [ ] . however, the absence of control groups precludes a final conclusion. the definite therapeutic effectiveness of remdesivir in the treatment of severe covid- needs to be further verified. remdesivir has been approved as a potential treatment for severe covid- patients by the japanese ministry of health, labour and welfare (mhlw) on may , due to the covid- pandemic [ ] . the main side-effects of these antivirals include qt interval elongation, bradycardia, hepatic injury, and obvious gastrointestinal reactions such as serious diarrhea and vomiting which may contributed to disease deterioration. clinical trials testing remdisivir for the treatment of severe covid- patients are underway (nct , nct ). convalescent plasma therapy belongs to passive immunization, which is used for the treatment of virus infections when specific drugs and vaccines are unavailable. convalescent plasma, which has been used for more than one hundred years, can provide specific antibodies to neutralize and eradicate the viruses from the blood circulation. up to date, there is no particular treatment for covid- . in , the who recommended the use of convalescent plasma collected from patients who recovered from the ebola virus infection as an empirical treatment during the outbreak [ ] . during the covid- epidemic period, this method was also recommended by the national health commission of china for the treatment of severe and critical patients [ ] . statement convalescent plasma therapy should probably be used for severe and critically ill patients with covid- (grade +, weak recommendation). rationale convalescent plasma has been testified to suppress viremia, shorten the hospital stay, and reduce mortality during several virus epidemics. in during a spanish influenza pandemic, convalescent plasma reduced the mortality rate by > % in severe patients [ ] . since then, it was also used for prophylaxis or as a treatment for several virus infections such as measles, argentine hemorrhagic fever, influenza, chickenpox, and infection by cytomegalovirus. over the past two decades, its efficacy and safety were confirmed during pandemics of sars, mers, h n and h n avian flu. during the sars pandemic in , eighty patients received convalescent plasma at prince of wales hospital, hong kong. by the nd day, a higher discharge rate was observed in patients (n = ) given convalescent plasma before day than that given plasma after day ( . % vs. . %; p < . ) [ ] . a prospective cohort study conducted by hung et al. showed that convalescent plasma therapy (n = ) significantly reduced mortality compared to the control group (n = ) ( . % vs. . %; p < . ). meanwhile, plasma treatment lowered the upper respiratory tract virus load and decreased serum cytokines levels in patients with severe pandemic (h n ) virus infection [ ] . these studies verified the efficacy of convalescent plasma in patients with virus infections. it has been reported that among three severe mers patients who received convalescent plasma infusion, just two showed neutralizing activity [ ] . among five critically ill patients with covid- receiving mechanical ventilation convalescent plasma infusion, patients were discharged, while clinically ill patients improved and maintained the stable condition till the day after transfusion [ ] . a study performed in severe covid- patients found that convalescent plasma treatment could improve clinical outcomes, improve immune function, and promote absorption of lung lesions [ ] . nonetheless, just like any other treatment, convalescent plasma has its limitations. the main limitation refers to the reported studies, which are not randomized trials, but just prospective cohort studies or case series studies. therefore, it was not possible to eliminate the influence of baseline severity and other treatments when evaluating the effects of convalescent plasma therapy. other limitations include the risk of transmitting infections to transfusion service personnel, the need for adequate selection of donors with high neutralizing antibody titers, and the risk of other transfusion-transmitted infections [ ] . however, regardless of these limitations, since there are still no specific etiological treatments for covid- , and convalescent plasma is available, it is reasonable to use it in the treatment of covid- patients. respiratory failure is the primary organ dysfunction, which worsens the prognosis of covid- patients. oxygen therapy and respiratory support are the key treatments for covid- -induced ards. due to inflammatory and necrosis-induced small airway occlusion, which was confirmed by autopsy of covid- -induced ards, positive pressure ventilation is vital to restore the collapsed airway and improve gas exchanges. however, high end-inspiratory pressure increases stress and strain to normal alveoli and increases the risk of lung injury. oxygen therapy and respiratory support for covid- -induced ards should balance airway recruitment and risk of lung injury (fig. ). indication for hfnc and niv. statement niv and hfnc should probably be used for covid- -induced ards with pao / fio > mmhg (grade +, weak recommendation). rationale noninvasive ventilation support (niv) and hfnc are important treatments for covid- -induced mild and moderate ards. the mechanisms of the two treatments are positive end-expiratory pressure, decreased respiratory workload, decreased incidence of intubation, ease of use, and higher comfort. in a randomized trial of adult patients admitted to the icu for acute hypoxemic, nonhypercapnic respiratory insufficiency, continuous positive airway pressure (cpap) delivered by face mask was associated with an early improvement in oxygenation; however, it was not associated with a reduced need for intubation or with improved outcomes [ ] . a trial that compared hfnc oxygen, standard oxygen via face mask and face mask niv in patients with acute hypoxemic respiratory failure, reported that the intubation rate was significantly lower with hfnc oxygen than with standard oxygen or niv among patients with pao /fio ≤ mmhg at enrollment and, for the whole group (patients with pao / fio ≤ mmhg), patients managed with hfnc had improved survival. there were no differences in outcomes between niv and standard oxygen [ ] . a substudy examined the practice of niv use in ards of lungsafe study reporting that niv was associated with higher icu mortality in patients with a pao / fio < mmhg [ ] . for covid- , there is no sufficient evidence to prove that hfnc is superior to niv. statement when using niv and hfnc, oxygenation and breathing patterns are suggested to be closely monitored, and intubation delays is suggested to be avoided (expert opinion). rationale for all cases with noninvasive support, patients should be closely monitored, as deterioration can abruptly occur [ ] . in china, some patients presented with hypoxemia, later named "silence hypoxemia", since these patients were without corresponding clinical manifestations, e.g., no high respiratory rates, high heart rate, respiratory distress, and other hypoxia symptoms. these patients have a high risk of sudden death and should be closely monitored and timely provided with oxygen therapy. positive responses are usually evident soon after the initiation of niv and hfnc. if there is no substantial improvement in gas exchange and respiratory rate within a few hours, invasive mechanical ventilation should be started without delay. failure to recognize a lack of improvement during noninvasive support may result in further respiratory deterioration and/or cardiac arrest, often with devastating consequences. delayed intubation increases ards mortality; therefore, early recognition of ards severity could avoid delayed intubation. if the use of hfnc fails, endotracheal intubation is unavoidable even with the use of rescue niv [ ] . the indications for hfnc and niv intubation are a higher level of severity (saps ii score > ), hypoxemia (pao /fio ≤ mmhg), hypoxemia that is not improved following niv treatment for h, and strong spontaneous breathing (tidal volume with niv > ml/ kg pbw) [ ] . rox index can be used to predict hfnc failure and intubation for patients with respiratory failure; > . , suggests a high chance of success, < . suggests a high risk of failure, and intubating the patient should be discussed; index between . and . , suggests the patient should be monitored very closely and intubation delays should be avoided [ ] . [ , ] . another trial that employed a multilevel mediation analysis to analyze individual data from patients with ards, who were also included in nine previously reported randomized trials, identified driving pressure as the ventilation variable that best-stratified risk. decreases in driving pressure owing to changes in ventilator settings were strongly associated with increased survival [ ] . low tidal volume ( - ml/kg pbw), limited plateau pressure (< cmh o), and driving pressure (< cm h o) could decrease ards mortality. bedside measurements should probably be used for the evaluation of lung recruitability (grade +, weak recommendation). rationale alveolar collapse is mainly generated by inflammatory lung edema, impairment of chest wall movement, and surfactant deficiency. some reports have shown different effects of recruitment maneuvers in ards patients due to lung recruitability [ ] . from our experience in wuhan, most of the covid- patients had low lung recruitability [ ] . due to the infectiousness of covid- , ct, and the other necessary equipment cannot always be used to evaluate lung recruitability. however, some bedside measurements, such as the pressure-volume curve, recruitment to inflation ratio, and clinical parameters, can be measured by a ventilator and used to evaluate lung recruitability [ ] . based on low lung recruitability in covid- -induced ards, high peep should probably not be used, and peep setting should probably be based on various factors, including gas exchange, hemodynamics, lung recruitability, and driving pressure (grade +, weak recommendation). rationale use of positive end-expiratory pressure (peep) usually improves gas exchange and helps reduce the need for high fio . in addition, appropriate levels may limit vili by maintaining lung recruitment and improving lung homogeneity [ ] . when applied with a constant pplat, peep reduces the driving pressure and keeps the lung recruited. because of the lack of resources, peep selection criteria may include lung recruitability, peep/fio table, respiratory system compliance, optimal oxygenation, and driving pressure [ , , ] . based on the available data, all peep values represent a compromise between the extent of recruitment and overdistension, and hemodynamics. the experts suggest optimizing ventilator settings to improve hypercapnia (expert opinion). rationale in china, hypercapnia has been commonly found in covid- -induced ards. the mechanisms are related to lung injury inhomogeneity and an increase in dead space. firstly, optimization of ventilator setting is important; secondly, the prone position could decrease dead space and improve hypercapnia [ ] ; thirdly, tracheal gas inflation (tgi), which influences sputum drainage, could increase alveolar ventilation and co removal [ ] ; fourthly, extracorporeal life support or co removal equipment could improve hypercapnia. statement we recommend using prone positioning in severe covid- patients to prevent the deterioration of patients' condition (grade +, strong recommendation). rationale prone positioning has a beneficial effect on oxygenation, lung recruitment, and stress distribution. the physiological effects of prone positioning include redistribution of lung densities, often with the recruitment of well-perfused dorsal regions. although prone positioning increases chest wall elastance, this change is usually accompanied by improved lung recruitment, a reduction in alveolar shunt and improved ventilation/ perfusion ratio, subsequent improvement in oxygenation and co clearance, a more homogeneous distribution of ventilation and a reduced vili risk [ , ] . indications for prone positioning include moderateto-severe ards (pao /fio < mmhg), and/or hypercapnia. duration of prone positioning should be more than h, and the termination of prone positioning should be based on the response of oxygenation, lung mechanics, and hemodynamics. because prone positioning could improve lung inhomogeneity, early prone positioning should be provided for covid- infected patients with/without respiratory failure [ , ] since it could prevent respiratory failure. since covid- is highly infectious, implementation of the prone positioning might require more manpower, thus further increasing the workload of medical personnel. pressure injury of the skin and mucous, facial edema, corneal edema, displacement of the catheter, and airway obstruction must be avoided when placing patients in the prone position. most of the covid- patients presented with mild symptoms; however, about % of patients developed into severe cases, % of them were critically ill with mortality estimates of . − . % [ ] [ ] [ ] . mechanical ventilation alone may not be enough to resolve refractory hypoxemia and hypercapnia in these patients. ecmo could be initiated to maintain oxygenation and avoid ventilator-induced lung injury. a cross-sectional study found that ( . %) patients treated with ecmo [ ] . we recommend an early use of ecmo in covid- patients with refractory hypoxemia or hypercapnia who have received invasive mechanical ventilation and prone positioning (grade +, strong recommendation). rationale the appropriate timing of ecmo in covid- patients might be challenging due to enormous demand and uncertainty related to the reversibility of impaired lungs. to guarantee the reversibility of compromised lungs, ecmo should be launched before injurious mechanical ventilation, which is common in critically ill patients with covid- [ , ] . the primary purpose of ecmo is the maintenance of sufficient oxygenation, removal of co , avoidance of high respiratory drive, and sequencing of ventilator-induced lung injury. the following traditional indications for ecmo may be suitable for covid- patients: pao /fio < for over h; pao / fio < for over h; irreversible ph < . for over h. the experts suggest using the traditional indications for ecmo in hospitals with sufficient medical resources. however, for areas with poor medical resources, the indications for ecmo are suggested to be balanced between the available resources and expected outcomes (expert opinion). the who guidance released a statement, in which they suggest referring patients with refractory hypoxemia despite lung-protective ventilation to those settings with expertise in ecmo [ ] . the latest guidance document issued by elso also suggested that ecmo should be considered according to the standard management algorithm for ards in patients with viral lower respiratory tract infections [ ] . however, in reality, numerous patients who met the criteria for ecmo were admitted over a short period, which was beyond the capacity of the medical resource, including workforce and equipment. in this context, the priority of the ecmo supply should be balanced between the available medical resources and disease reversibility. younger patients with minor or no comorbidities should be given the highest priority when resources are limited. despite standard contradictions, patients who fit the criteria below may be excluded: ( ) patients with significant comorbidities; ( ) elderly patients with worsening prognosis; ( ) patients on mechanical ventilation for more than days. prone position, as well as other adjunct therapies should probably be used for critically ill patients even during ecmo (grade +, weak recommendation). rationale ventilation with the prone position, which is currently recommended by the guidelines, can improve lung heterogeneity as well as oxygenation [ ] . it should be considered in the early stages of the disease rather than as a delayed attempt [ ] . prone position ventilation is currently widely applied for severe covid- patients in china [ ] . even if an ultraprotective ventilation strategy is implemented with the aid of ecmo, prone ventilation is considered to benefit the recovery of the lung. elevated myocardial enzymes, such as cardiac troponin t (ctnt), creatine kinase (ck), creatine kinase-mb isoenzyme (ck-mb), have been widely observed in critically ill patients with the covid- , indicating potential myocardial injury. a significant elevation of myocardial enzymes often indicates a poor prognosis. most patients with elevated myocardial enzymes do not present compromised left ventricular systolic function (reduced ejection fraction) or abnormal electrocardiogram. left ventricular diastolic dysfunction or mild-to-moderate pulmonary arterial hypertension is common in some covid- patients. intensive hemodynamic monitoring should probably be considered for patients with hemodynamic instability. ecmo should probably be used for salvage therapy for patients with severe cardiac dysfunction (grade +, weak recommendation). rationale while sars-cov- and mers-cov share similar pathogenicity, it has been shown that mers-cov can induce acute myocarditis and heart failure [ ] . elevation of biomarkers of cardiac injury is common among critically ill patients with covid- and associated with a higher risk of in-hospital mortality [ , ] . reversible subclinical diastolic dysfunction without systolic impairment was observed in sars [ ] . comparable to sars, most covid- patients with elevated myocardial enzymes do not present compromised left ventricular systolic function. left ventricular diastolic dysfunction or mild-to-moderate pulmonary arterial hypertension have been commonly found in covid- patients. from our experience, tachycardia such as sinus tachycardia and atrial fibrillation were also common, while compensatory tachycardia was absent, even in patients with severe hypoxia or hemodynamic collapse. the exact mechanism of myocardial injury in covid- remains unknown. it has been suggested that direct myocardial injury is mediated via angiotensin converting enzyme (ace ). ace -dependent myocardial infection was observed in the murine model infected with sars-cov [ ] . one study published in n engl j med provides evidence that angiotensin-converting enzyme inhibitors (acei)/angiotensin receptor blockers (arb) medications in covid- patients did not show any association with increasing susceptibility to sars-cov- [ ] . in patients with hemodynamic instability, non-invasive or invasive monitoring, such as echocardiography or thermodilution methods, should probably be used to guide fluid therapy or administration of vasoactive agents. in patients with life-threatening cardiac dysfunction, extracorporeal life support might be salvage therapy. statement hypovolemia is common in critical covid- patients, easy-to-implement parameters should probably be considered for the assessment of the patient's volumetric status (grade +, weak recommendation). rationale the use of vasoactive drugs revealed that the incidence of shock in critically covid- patients was %, and % in non-survivor population [ ] . the shock could be the result of hypovolemia, cardiac injury, and sepsis. fever and mouth breathing could cause large amounts of fluid loss in critical covid- patients, while decreased water intake, acute gastrointestinal injury, depression, intubation, and sedation could exacerbate hypovolemia. previous studies reported on the relationship between dehydration and mortality in severe h n patients [ ] . moreover, older age, comorbidities (especially diabetes and cardiovascular disease), lower lymphocyte count, and higher d-dimer levels were identified as risk factors associated with shock [ , ] . cardiac injury was found in % critical covid- patients [ ] , which meant poor fluid responsiveness and the risk of pulmonary edema. for these reasons, the patients' volumetric status, as well as the fluid responsiveness, should be dynamically assessed. one meta-analysis of rcts showed that dynamic assessment of fluid responsiveness could improve the clinically relevant outcomes in icu, such as mortality reduction, reduced duration of icu length of stay, and mechanical ventilation [ ] . considering the limited clinical resources in the covid- pandemic, we recommend using simple bedside assessments, such as passive leg raising (plr), lactate clearance, pulse pressure variation (ppv), and inferior vena cava (ivc) collapsibility or distensibility. a recent meta-analysis determined that the plr induced changes in cardiac output, with a pooled sensitivity of . and a pooled specificity of . [ ] . ppv also accurately predicted fluid responsiveness in critical patients. in a meta-analysis including studies and patients, ppv predicted fluid responsiveness with the pooled sensitivity of . and a pooled specificity of . [ ] . ivc collapsibility resulted as a simple, non-invasive bedside predictor of fluid responsiveness with a sensitivity of . and a specificity of . [ ] . early lactate clearance-directed therapy was associated with reduced in-hospital mortality, shorter duration of mechanical ventilation, and shorter icu-stay [ ] . a recent observational study showed higher serum lactate levels in covid- non-survivors ( . vs. . mm/l) [ ] . besides, additional attention should also be paid to mental states, degree of thirst, oliguria, skin temperature, and prolonged capillary refilling time as well. conservative fluid strategy should probably be considered for covid- patients with ards while ensuring tissue perfusion (grade +, weak recommendation). rationale even though fluid management in covid- remains unknown, it could be assumed that these patients would respond to fluid therapy in the same way as other ards patients. previous studies have shown that higher cumulative fluid balance is related to the higher mortality of critically ill patients, especially in cases of ards [ ] and/or septic shock [ ] . due to pulmonary edema in critical covid- patients [ ] , excessive fluid therapy could increase extravascular lung water and affect gas exchange, resulting in a poor prognosis. one clinical trial found that the conservative fluid strategy improved lung function, shortened the icu-stay length and duration of mechanical ventilation compared with a liberal strategy in patients with acute lung injury [ ] . another study reported that more than half of critically covid- patients were older than years [ ] . when older patients develop cardiac injury and pulmonary edema, they tend to be less responsive to fluid intake [ ] . conservative fluid strategies could reduce the occurrence of positive fluid balance while ensuring tissue perfusion [ ] . although it has been reported that conservative fluid strategy and liberal strategy have a similar incidence of aki and the requirement for renal replacement therapy (rrt) [ ] , it is still necessary to closely monitor the renal function of patients. at the same time, attention should be paid to maintaining electrolyte balance and acid-base balance. rationale to date, there are still no studies on fluid types in covid- patients; thus, our observations are based on relevant studies of critically ill patients in general. a systematic review of studies that included , participants revealed that using colloids (such as starches, dextrans, albumin or fresh frozen plasma, or gelatins) had no difference in mortality in critically ill patients compared to crystalloids [ ] . considering the price and accessibility, fluid resuscitation with crystalloids should probably be used for critically ill patients. one single-center research reported that low serum albumin ( . ± . g/l) was associated with the progression of covid- pneumonia [ ] , while another study found no significant differences between the nonaggravation and aggravation patients in the early stage of the disease [ ] . serum albumin level < g/l was identified as an independent risk factor for the -day mortality in patients with community-onset pneumonia [ ] . based on the previous evidence and our clinical observations, hypoproteinemia is present in most covid- patients; thus, albumin supplement should probably be used for patients with serum albumin levels below g/l. statement psychological and humanistic care should probably be considered for conscious patients with covid- (grade +, weak recommendation). rationale besides experiencing physical impairment and stressful treatments, covid- patients are being subjected to closing monitoring, and are also witnessing various events in the ward such as sudden deterioration of illness, emergency resuscitation procedures and death, all of which could lead to posttraumatic stress disorder, anxiety, and depression according to previous studies [ , ] . it was reported that % to % of sars survivors had symptoms related to posttraumatic stress disorder, anxiety, and depression and that emotional support, such as communication with others and sharing worries could reduce symptom severity [ ] . accordingly, psychological implications should not be ignored in coronavirus patients. psychological health services and humanistic care could have an important role in rehabilitation. the previous study confirmed that citalopram could improve reappraisal ability and anxiety symptoms in children and adolescents [ ] and that olanzapine could improve psychotic symptoms [ ] . therefore, citalopram or olanzapine should probably be used to improve the psychological symptoms in patients or intervention of the psychologists in the isolation ward who would perform psychological assessment and psychotherapy for patients with new coronary pneumonia. the experts suggest assessing patients' sleep quality, implementing comprehensive measures to improve sleep and reduce the incidence of delirium, thus promoting recovery (expert opinion). nonpharmacological strategies and pharmacotherapy, including dexmedetomidine and melatonin, should probably be considered to decrease the incidence of delirium (grade +, weak recommendation). rationale sleep abnormalities, including abnormal sleep architecture, sleep deprivation, and disruption, frequently occur in the icu. numerous factors can affect sleep in covid- patients, such as stress, anxiety, pain, respiratory distress, tachypnea from the underlying hypoxemia, noise levels, stage lighting in the isolation ward, implementation of healthcare, procedures of healthcare workers, and the pathophysiology of the acute illness. sleep abnormalities may not only lead to mental disorders, but could also damage tissue repair, immune regulation mechanisms and cause delirium, all of which are associated with patient's poor prognosis [ , ] . nonpharmacological strategies for preventing sleep disturbances and treating delirium, such as keeping noise levels within and db range (a) during the day, and less than db (a) at night [ , ] , and providing critical patients admitted to the icu with earplugs can significantly improve patient's sleep and reduce the risk of delirium [ ] . however, in patients with sleep disturbances and delirium, pharmacotherapy care may be necessary. medications such as dexmedetomidine [ ] and melatonin [ , ] may promote sleep and decrease the incidence of delirium, although only limited data are available in support of their use [ ] . assessing pain and preferential use of analgesia over sedation should probably be considered for covid- patients (grade +, weak recommendation). rationale pain is defined as an uncomfortable physical and mental experience caused by physical injury, inflammation, or emotional stimuli. covid- patients tend to experience pain due to hypoxia, long-term immobility, inflammatory storm, impairment of heart, liver, kidney, and other organ functions, procedures, and mental stress. opioids, such as remifentanil and sufentanil, are the firstline options for analgesia in icu according to the pain, agitation/sedation, delirium, immobility, and sleep disruption (padis) guidelines [ ] . sufentanil can be used for covid- patients receiving invasive mechanical ventilation during the early stage of severe ards because of its stronger and faster onset of analgesia, and small accumulation [ ] . remifentanil is suitable for covid- patients receiving invasive mechanical ventilation, especially during person-ventilator confrontation [ ] due to stronger respiratory depression. previous research has confirmed that music or relaxation may diminish anxiety and discomfort in some patients [ , ] . therefore, nonpharmacological pain management strategy can be used for conscious patients with covid- or for patients who do not tolerate opioid therapy, such as covid- patients receiving hfnc oxygen therapy or non-invasive mechanical ventilation. assessment of the patient's pain is the foundation of pain management. accordingly, a numeric rating scale (nrs) should probably be used for evaluation of pain in all covid- patients able to self-report their pain. behavioral pain scale (bps) and critical-care pain observation tool (cpot) should be used to evaluate pain in critically ill patients unable to express the pain for themselves. the ideal target values are: nrs < points, bps < points and cpot < points. deep sedation should be performed for patients with severe ards, especially those receiving invasive mechanical ventilation, prone position, neuromuscular blockade, or ecmo treatment (grade +, strong recommendation). rationale it is well known that analgesia and sedation can eliminate pain and discomfort, reduce sympathetic nerve excitement, patient's metabolic rate, oxygen consumption, the metabolic burden of various organs, stress, and inflammation. however, plenty of evidence suggests that deep sedation is associated with adverse outcomes, including prolonged mechanical ventilation and icu-stay, higher mortality, lower rates of in-hospital, and -year follow-up survival [ ] [ ] [ ] [ ] [ ] . under 'real-life' conditions in wuhan, deep sedation was extremely important for reducing oxygen consumption and developing tolerance to mechanical ventilation by new coronavirus patients with severe ards who suffered from respiratory distress, tachypnea and respiratory overdrive even after receiving invasive mechanical ventilation. accordingly, deep sedation should be an important part of lung-protective ventilation strategy, especially during the early stage of severe ards. previous studies have confirmed that daily spontaneous awakening trials (interruption of sedatives) lead to better outcomes in patients receiving mechanical ventilation [ ] . however, critically ill patients with covid- have a longer mechanical ventilation time, and daily sedatives interruption is not suggested for patients receiving deep sedation in order to reduce lung damage during early stage of severe ards. midazolam and propofol are the primary medications used for icu deep sedation. the sedation-agitation scale (sas) and rass are the reliable and valid sedation assessment tools used for assessing the depth and quality of sedation in covid- patients. the sas and rass should be used to measure the depth after administering sedatives. the target value is rass - - points, sas points for deep sedation, and sas point. the target value of very deep sedation is rass - point for patients receiving neuromuscular blocking agents [ ] , prone position, or ecmo treatment. we suggest a bispectral index monitoring for patients undergoing very deep sedation, if available. light sedation is suggested for severe covid- patients receiving hfnc oxygen therapy and non-invasive mechanical ventilation, and also for critically ill patients in the recovering stage (expert opinion). rationale agitation and anxiety, which frequently occur in covid- patients, may be associated with adverse outcomes. appropriate sedation can reduce anxiety and agitation while preserving patients' comfort. light sedation can maintain frequent redirection, and increase the physiologic stress response, but not increase the incidence of myocardial ischemia. we suggest the use of light sedation for covid- patients receiving hfnc oxygen therapy or non-invasive mechanical ventilation. in addition, light sedation should be given to recovering patients in order to reduce the time of mechanical ventilation and the time of stay in icu [ ] when pao / fio ≥ - mmhg. dexmedetomidine can be used for patients receiving light sedation due to the small respiratory depression. the target value of light sedation is sas - points and rass − to + points. there is some evidence that immunotherapy may be effective against novel coronavirus infection. an article [ ] published on the medrixv website stated that the mortality of covid- patients might be negatively related to the number of lymphocytes in patients. patients tend to be below normal levels and lower level of helper t cells in the severe group. the percentage of naïve helper t cells increased, and memory helper t cells decreased in severe cases. this suggested that novel coronavirus might fight the immune system; thus, early lymphocytes and t lymphoid subgroups testing are required for early intervention, which may help to avoid lymphocyte depletion. currently, there are several available immunomodulatory drugs, including glucocorticoid, thymosin, and immunoglobulin. statement systemic corticosteroids should probably not be used for the treatment of covid- . for critically ill patients with ards at an early stage, corticosteroids should probably be prudently used at a low or moderate dose over the short course if there are no contraindications (grade -, weak recommendation). rationale glucocorticoid use in ards remains a controversial topic. it is well known that corticoids are beneficial in the treatment of ards since they can alleviate inflammatory response and delay fibrosis [ ] . a retrospective study conducted in guangzhou revealed that proper use of corticosteroids in confirmed critical sars patients led to lower mortality and shorter hospitalization stay and was not associated with significant secondary lower respiratory infections or any other complications [ ] . however, there are some inconsistencies in the existing studies. a study involving patients with ards, showed improved oxygenation and lung injury score in less than h but no change in -day mortality [ ] . another study found no differences in overall mortality, while mortality was increased when steroids were started after day [ ] . as for viral pneumonia, a few studies have found that the administration of corticosteroids in patients with influenza pneumonia is associated with increased icu mortality [ , ] . who does not recommend routine use of corticoids in the treatment of covid- , while treatment with methylprednisolone may be beneficial for patients who develop ards, as was shown by a retrospective cohort study of patients with confirmed covid- pneumonia admitted to wuhan jinyintan hospital in china [ ] . given the inconclusive evidence and urgent clinical demand, the guidance published by china national health commission on march , , suggested the use of glucocorticoids over the short time period ( to days) for patients with progressive deterioration of oxygenation indicators, rapid imaging progress, and excessive activation of inflammatory response. the dosage of methylprednisolone should not exceed - mg/kg/day. it should be noted that large doses of glucocorticoid might delay the removal of coronavirus due to immunosuppressive effects. thymosin is a peptide originally isolated from thymic tissue, which was initially selected for its ability to restore immune function to thymectomized mice. thymosin may act on precursor t cells to increase the number of activated t helper cells and expression of th -type cytokines such as interleukin- and interferon-alpha. the activated dcs and th cells then kill bacterial, fungal, or viral infections and lead to the stimulation of differentiation of specific b cells to antibody-producing plasma cells and an improvement in response to vaccines by stimulation of antibody production [ ] . the use of thymosin alpha therapy in combination with conventional medical therapies may be effective in improving clinical outcomes in a targeted population of severe sepsis [ ] . also, it has been observed that lower lymphocytes in covid- patients indicate worse prognosis [ ] . thus, thymosin may theoretically have an effect on covid- , which needs to be further investigated. immunoglobulin may regulate the host's immune response in a variety of ways, but it had no effect on mortality in previous sepsis studies. at present, it is not recommended in the treatment of covid- . a study performed in severe or critical covid- patients showed that tocilizumab treatment could improve clinical outcomes, promote absorption of lung lesions, improve immune function, and reduce inflammatory response [ ] . however, il- inhibitor sarilumab was shown to be ineffective in the treatment of severe covid- , leading to early termination of this clinical trial [ ] . large sample size studies using prospective cohort designs are required to verify the therapeutic effect of il- inhibitors for severe covid- . great attention should be paid to secondary infection since it may worsen the patient's prognosis. however, since the data on the epidemiology of secondary infection in covid- patients are lacking, we can only make some suggestions according to our own experience and some previous studies focused on h n . the experts suggest against using prophylactic antibiotics for covid- patients (expert opinion). rationale due to the nature of virus infection, it is not logical to use prophylactic antibiotics, and there is no evidence that this strategy could reduce the incidence of the secondary infection. on the other hand, according to the management guidelines of covid- from who and china [ , ] , empiric antibiotic treatment should only be used based on the clinical diagnosis (communityacquired pneumonia, healthcare-associated pneumonia or sepsis), local epidemiology and susceptibility data, and treatment guidelines. based on our observations from wuhan, many severe and critical covid- patients did not show any signs of bacterial infection (such as elevated wbc, pct and similar); thus, we do not suggest the routine use of prophylactic antibiotics in covid- patients, especially at the early stage or for non-intubated patients. the experts suggest closely monitoring the signs of secondary infection, especially in critically ill patients with covid- who have been admitted to icu > h (expert opinion). rationale both long course of the disease and immunosuppressive state place the severe and critical covid- patients at a high risk of secondary infection (including bacteria and fungus). unfortunately, the data on the epidemiology of secondary infection in covid- patients are lacking. however, based on the evidence from h n , secondary infection is very common in patients admitted to icu > h [ , ] . although a complete nosocomial infection prevention and control system was set up in wuhan according to the guidelines [ , ] , ventilator-associated pneumonia and hospital acquired pneumonia were very common occurrences in the icu. we suspect this is mainly because the medical staff is wearing heavy personal protective equipment, and heavy workload adhered to the incomplete implementation of these measures. consequently, the strategies for nosocomial infection prevention should be effectively implemented, and multiple site samples (blood, sputum, etc.) should be routinely collected to monitor the signs of secondary infection. in clinical practice, coagulation dysfunction is commonly found in covid- patients, and the symptoms range from mild disorders of coagulation indicators to disseminated intravascular coagulation (dic). the exact etiology of covid- -associated coagulopathy is unclear, diverse and multifactorial, and may include direct attack by the sars-cov- on vascular endothelial cells, cytokine storm-mediated inflammation-coagulation cascades, hypoxia, and complication with sepsis. coagulation dysfunction or thrombocytopenia is closely associated with the severity and poor prognosis in covid- patients [ ] . clinicians should increase awareness of covid- -associated coagulopathy, which in covid- patients is accompanied with the following abnormal coagulation indexes: platelet-lymphocyte ratio < × , the reduction of prothrombin time (pt) and activated partial thromboplastin time (aptt) by more than the lower limit of th percentile or the increase of pt by more than s or aptt by more than s, or the increase of fibrinogen, fibrin degradation product (fdp) and d-dimer by more than the lower limit of th percentile without clinical evidence of primary blood system diseases or chronic liver diseases. routinely assessing the coagulation dysfunction on admission and dynamically monitored thereafter should probably be performed to identify covid- -associated coagulopathy as early as possible (grade +, weak recommendation). rationale according to the available literature, the condition of covid- patients is commonly complicated with coagulopathy, where the symptoms range from mild disorders of coagulation indicators to dic. the increase of d-dimer in covid- patients is very common, accounting for % to . % of all cases [ , , , , ] . the degree of elevation and persistent elevation are indicators of poor prognosis. the nanshan zhong team has reported that among covid- patients in hospitals from provinces ( mild cases and severe cases), the proportion of severely ill patients with d- dimer higher than . mg/l was up to . %, and the proportion for the mild patients was . % [ ] . zhou et al. have demonstrated that among confirmed covid- patients ( deaths, survival), d-dimer > . g/l was an independent risk factor for clinicians to identify patients with poor prognosis at the early stage [ ] . the coagulation parameters (pt and aptt) in covid- patients vary with different severity and the different courses of the disease. covid- patients in the early stage show the activation of the exogenous coagulation system, manifested as decreased pt and hypercoagulable state. along with the progression of the disease, especially when patients develop dic, pt and aptt significantly increase, which is associated with the poor prognosis of patients. tang has reported increased fibrinogen ( . g/l vs. . g/l, p = . ) and fdp values ( . µg/ml vs. µg/ml, p < . ) in covid- patients [ ] , which indicated that instead of hyperfibrinolysis observed in the late stage of dic, fibrinolysis inhibition is the main feature accompanying the progression of covid- . the autopsies of covid- patients have revealed abundant transparent thrombus in the pulmonary alveoli, myocardium, portal area, and renal tubular epithelial cells, thus indicating that fibrinolysis inhibition may have a decisive role in covid- -associated coagulation dysfunction. the incidence of dic is low in covid- patients. it has been reported that among the covid- patients, only patient ( . %) was diagnosed as dic [ ] . however, tang's report has shown that the overall incidence of dic is . %. the existence of dic was more common in fatal cases, where . % met the isth diagnostic criteria for dic; the median time for dic diagnosis after admission was days, whereas among the patients who survived, only patient ( . %) met this criterion [ ] . medical institutes should dynamically detect the pt, international normalized ratio (inr), aptt, d-dimer, fibrinogen, and fdp to identify covid- -associated coagulation disorders, which might be helpful for making timely treatment decisions. it is also suggested to use the isth score system to diagnose covid- -associated dic [ ] ; if possible, sf and pai- should be used to detect the pre-dic status in the shortest possible time. routinely evaluating the risk of venous thromboembolism (vte) and hemorrhage should probably be performed in covid- patients. for critically ill covid- patients with low hemorrhage risk, subcutaneous injection of low molecular weight heparin (lmwh) should probably be used for preventing vte (grade +, weak recommendation). rationale the most common clinical features of coagulopathy in covid- patients are thrombosis in the deep vein or intermuscular vein of the lower extremity, which can be identified by the coagulation parameters and ultrasonic monitoring. it has been reported that the incidence of vte or thrombotic complications in patients with severe covid- admitted in the icu was - % [ , ] . it is necessary to pay attention to the clinical observation of patients with bed rest lasting for more than days and observe whether these patients are experiencing asymmetric pain, swelling or discomfort in unilateral lower limbs or bilateral lower limbs, or local swelling or superficial vein filling in the lateral limbs. especially when patients show chest pain, hemoptysis, dyspnea, or hypoxemia, which cannot be explained by ncp or other basal diseases, we should be alert to the occurrence of pulmonary thromboembolism. for critically ill covid- patients with low hemorrhage risk, a subcutaneous injection of lmwh should probably be used for the prevention of vte. for patients with severe renal dysfunction (creatinine clearance rate < ml/min), unfractionated heparin is recommended. for critically ill patients whose condition is complicated with high hemorrhage risk, intermittent pneumatic compression is recommended for mechanical prevention. mild or moderate covid- patients should probably avoid sedentary lifestyle or dehydration and are encouraged to engage in active activities and to drink more water appropriately. for mild or moderate covid- patients with a high or moderately high risk of vte according to the padua or caprini evaluation model, it should probably be considered to use lmwh for to days until the elimination of risk factors. anticoagulation therapy should probably be used for patients with hypercoagulant state without bleeding risk. lmwh or unfractionated heparin should probably be considered to be the first choice (grade +, weak recommendation). rationale hypercoagulant state is common in covid- patients. meantime, cytokine storm-mediated inflammation-coagulation cascades may have an essential role in covid- -associated coagulopathy. studies have found that in addition to the anticoagulant effect, heparin also has a certain anti-inflammatory effect [ ] . therefore, lmwh or unfractionated heparin is the first choice for anticoagulation: tang et al. have reported that lmwh or unfractionated heparin anticoagulation was associated with improved survival in the patients with a sepsis-induced coagulopathy (sic) score ≥ and in those with d-dimer levels more than times of the upper limit of normal(≥ mg/l) [ ] . it is suggested that lmwh u/kg or unfractionated heparin units subcutaneously twice daily could be given to patients without contraindication once d-dimer ≥ mg/l or sic ≥ . heparin-induced thrombocytopenia (hit) should be prevented during heparin treatment, and platelet counting should be monitored daily. for patients with hit, other anticoagulants, such as agatraban, bevaludine, fondaparinux, and rivaroxaban, could be used. for patients at high risk of bleeding, anticoagulants are not recommend, and chinese traditional medicine could be used to improve blood circulation and dispersing stasis. although diffuse alveolar damage and ards are the main features of covid- , the involvement of the kidney and other organs needs to be considered. aki was associated with a higher risk of in-hospital mortality. clinicians should increase awareness of aki in hospitalized covid- patients. kidney disease: improving global outcomes (kdigo) criteria should probably be used for the diagnosis of aki in covid- patients. measuring serum creatinine every days should probably be performed to avoid a missed diagnosis of aki (grade +, weak recommendation). rationale the incidence of aki in covid- patients varies with different severity of illness: mild cases have an aki incidence of . - %, severe cases have an aki incidence of - . %, and the aki incidence for those critical cases that require to be admitted in icu is up to . - % [ , , , , ] . according to kdigo aki diagnostic criteria, certifying aki is mainly based on changes in scr, and the frequency of scr tests has a substantial impact on the detection rate of aki. in a nationwide cross-sectional survey of hospitalized adult patients in china, the detection rate of aki was only . % by kdigo criteria [ ] . after adjusting for the frequency of scr, the incidence of aki in chinese hospitalized adults rose to . % [ ] . thus, in order to improve early recognition of aki, scr measurements should be performed more frequently throughout the course of the disease. it is necessary to measure scr every days throughout the course of the disease to avoid a missed diagnosis of aki. the experts suggest using standard aki care bundle ( r principle) for covid- -associated aki (expert opinion). rationale the exact pathogenesis of covid- associated aki is unclear. the etiology of kidney impairment in covid- patients, which is likely to be diverse and multifactorial, may include direct attack by the sars-cov- on target cells in the kidney, immune systemmediated damage, disease-related prerenal factors, a complication with sepsis and nephrotoxic drug-related factors [ , ] . covid- associated aki is an independent risk factor for poor prognosis in patients. clinicians should address standard aki following r principle (risk screen, recognition in the early phase, response in time, renal replacement therapy, and rehabilitation of the kidney). aki is significantly more likely to develop in severe covid- patients than in nonsevere patients [ , , , , ] . meanwhile, studies have shown that patients with elevated baseline scr are more likely to develop aki and develop more severe aki [ ] . therefore, we should routinely screen the risk of aki in covid - patients, particularly for severe cases, patients with elevated baseline scr or those having proteinuria and hematuria at admission. optimizing the volume status and oxygenation, maintaining hemodynamic stability, making sure the mean blood pressure above mmhg are the important measures for prevention and treatment of aki. the experts suggest using crrt for the critical cases accompanied by kidgo aki - stages, or cytokine storm syndrome (expert opinion). rationale according to the available literature [ , , , , ] , the percentage of covid- patients who require continuous renal replacement therapy (crrt) is . - %, and particularly the percentage of critical patients admitted in icu that requires crrt is . - . %. indications of the crrt in covid- patients include renal indications and non-renal indications. renal indications include severe aki (kidgo aki - stages) with hemodynamic instability. non-renal indications include complications with severe ards and persistent inflammatory fever, which cannot be controlled not even with glucocorticoid corticosteroid therapy, hypernatremia refractory to conservative medical treatment, volume overload or urine output, which cannot meet the needs of drug infusion and energy supply and diuretic resistance. multiple rct research has indicated that the application of crrt in critical patients in an early phase cannot effectively decrease the mortality rates [ , ] . however, considering the suggestion that restrictive fluid volume management strategy should be adopted for covid- patients complicated by ards based on the premise of sufficient tissue perfusion, we suggest crrt initiation in severe patients within h when they show rank aki under kdigo criteria or accompanied with cytokine storm syndrome. in clinical practice, the doctors in charge should comprehensively evaluate conditions including the covid- patient's level of systemic inflammation, severity and progress of illness, severity, and progress of aki, local medical resources, and the qualification of blood purification operators to give a reasonable choice of crrt application. statement crrt prescription is suggested to be target-oriented based on the patient's condition (expert opinion). rational crrt prescription should be prescribed before the application of crrt on patients, and the prescription must be target-oriented. continuous venovenous hemofiltration (cvvh) global surveillance for human infection with coronavirus disease (covid- ) world health organization. coronavirus disease (covid- ) situation reports clinical management of severe acute respiratory infection when novel coronavirus (ncov) infection is suspected the novel coronavirus pneumonia emergency response epidemiology team. the epidemiological characteristics of an outbreak of novel coronavirus diseases (covid- )-china clinical 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espen guideline on clinical nutrition in the intensive care unit calorie intake of enteral nutrition and clinical outcomes in acutely critically ill patients: a meta-analysis of randomized controlled trial gudielines for the provision and assessment of nutrition support therapy in the adult critically ill patient: society of critical care medicine (sccm) and american society for parenteral and enteral nutrition clinical nutrition in critical care medicine-guideline of the german society for nutrition medicine(dgem) recommendations for nutrition therapy in critically ill covid- patients safe patient transport for covid- publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none. all the authors have participated in literature retrieval, viewpoint discussion, and writing the manuscript. all authors read and approved the final manuscript. none. not applicable. not applicable. not applicable. the authors declare that they have no competing interests. key: cord- -t bq yqw authors: brand, samuel p c; aziza, rabia; kombe, ivy k; agoti, charles n; hilton, joe; rock, kat s; parisi, andrea; nokes, d james; keeling, matt; barasa, edwine title: forecasting the scale of the covid- epidemic in kenya date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: t bq yqw background the first covid- case in kenya was confirmed on march th, . here, we provide forecasts for the potential incidence rate, and magnitude, of a covid- epidemic in kenya based on the observed growth rate and age distribution of confirmed covid- cases observed in china, whilst accounting for the demographic and geographic dissimilarities between china and kenya. methods we developed a modelling framework to simulate sars-cov- transmission in kenya, kenyacov. kenyacov was used to simulate sars-cov- transmission both within, and between, different kenyan regions and age groups. kenyacov was parameterized using a combination of human mobility data between the defined regions, the recent kenyan census, and estimates of age group social interaction rates specific to kenya. key epidemiological characteristics such as the basic reproductive number and the age-specific rate of developing covid- symptoms after infection with sars-cov- , were adapted for the kenyan setting from a combination of published estimates and analysis of the age distribution of cases observed in the chinese outbreak. results we find that if person-to-person transmission becomes established within kenya, identifying the role of subclinical, and therefore largely undetected, infected individuals is critical to predicting and containing a very significant epidemic. depending on the transmission scenario our reproductive number estimates for kenya range from . ( % ci . - . ) to . ( % ci . - . ). in scenarios where asymptomatic infected individuals are transmitting significantly, we expect a rapidly growing epidemic which cannot be contained only by case isolation. in these scenarios, there is potential for a very high percentage of the population becoming infected (median estimates: > % over six months), and a significant epidemic of symptomatic covid- cases. exceptional social distancing measures can slow transmission, flattening the epidemic curve, but the risk of epidemic rebound after lifting restrictions is predicted to be high. first identified in hubei province, china, capital wuhan, there has been since december an ongoing epidemic of atypical pneumonia caused by the zoonotic novel coronavirus (sars-cov- ) (li, q et al. ) . as of th april there have been over . million clinically and/or laboratory confirmed cases of covid- with over , deaths worldwide. this is the first coronavirus pandemic. a number of sub-saharan african countries, including kenya, were at moderate to high risk of novel coronavirus importation, measured by volume of air travel arriving from infected chinese provinces (gilbert et al. ) . as of th march th april , no east african country has had more than confirmed cases of covid- , and there are few confirmed instances of local transmission in the region (world health organization ). however, the likelihood of a significant outbreak remains high, with potentially severe consequences for fragile regional health systems (makoni ) . the potentially high negative impact of a novel coronavirus outbreak in kenya provides a strong motivation for forecasting studies of covid- epidemic magnitude ahead of a serious outbreak under a number of plausible scenarios. this modeling study provides a baseline for continuous updating as improved data become available, e.g. time course of covid- cases, updated mobility estimates, and the proportion and infectivity of asymptomatic infections, and new intervention strategies are proposed or implemented. it also provides the basis for studies of health service capacity; see accompanying article (barasa et al, ) . sars-cov- is the third novel betacoronavirus to pose a global health threat since , the other two being: (i) severe acute respiratory syndrome coronavirus (sars-cov; in ) , and (ii) middle east respiratory syndrome coronavirus (mers-cov; in ) . both previous novel coronaviruses (ncovs) were zoonotic, and clinically similar in their disease presentation, however they differed in their subclinical manifestation. there was virtually no evidence of asymptomatic infections of sars-cov, or of "hidden" person-to-person transmission caused by asymptomatic/subclinical or preclinical cases (anderson et al. ) . in contrast, mers-cov behaved more like other commonly circulating human covs, with a substantial proportion of asymptomatic or preclinical infections (cauchemez et al. ). the role of asymptomatic infected individuals (in this study we abbreviate to "asymptomatics") in the transmission of sars-cov- remains unclear. a significant majority of detections of sars-cov- infection have occurred after infected individuals have presented clinically with covid- . clinical cases of covid- have presented mostly among older age groups (cpere ) . this could be due to a stronger resistance among younger age groups to contracting sars-cov- (zhang et al. ; hilton & keeling ) , or due to younger people developing covid- symptoms at a lower rate after contracting sars-cov- , leading to under-ascertainment amongst those age groups. one epidemiological study of confirmed cases and their , close contacts in shenzen found that children were as likely to be infected as adults (bi et al. ) , despite presenting with symptoms less frequently. another modelling study emphasizes the role of undetected subclinical transmission in explaining the observed epidemic dynamics in china (li, r. et al. ) . these findings informed a central assumption of our modelling: that all age-groups are equally susceptible to sars-cov- infection but that the symptomatic rate is different across age groups. in a recent novel coronavirus transmission modelling study by wu et al (wu et al. ) a clinical sars-cov- case was defined essentially tautologically: a clinical case is one that has sufficiently severe symptoms that the individual is detected by the health authorities. however, this presents a difficulty in translating symptomatic rates derived from chinese confirmed covid- clinical case data into a prediction of incidence in the kenyan setting. mildly symptomatic cases, defined as non-pneumonia and mild pneumonia cases by china cdc (cpere, ) , that presented to the health system in china might not present to the health system in kenya. in this study, we provide forecasts of the possible epidemic course of covid- infections, focussing on symptomatic infection, following initial invasion of sars-cov- into kenya. we recognize the limitations of using clinically detected cases from another setting (china) to infer a symptomatic rate in this setting (kenya). this reflects the difficulty in ascertaining covid- disease with an unclear available testing capacity and coverage. this limitation highlights the importance of the sensitivity analysis in this modelling study. we treated all sub-clinical undetected infected individuals in china as asymptomatic. however, the threshold for being a sub-clinical infected individual will be different in kenya and might miss significantly infectious, or even diseased, individuals. this observation led us to consider a range of infectiousness scenarios for asymptomatic cases, each scenario being capable of explaining the agedistribution of cases observed in china. characteristics as china, the reproductive number for kenya will not be the same as that estimated for the early stages of the pandemic in china for two main reasons: . the age-profile of the kenyan population is significantly different to that of china; kenya having a far younger populace. therefore, the symptomatic rate of a "typical" infected individual will be different in kenya compared to china. . the typical mixing patterns between different age groups differ between the two countries. therefore, the transmission rate will differ even if the per-contact transmission probability is the same. our central assumption is that all age groups are equally susceptible to sars-cov- infection and that differing rates of becoming symptomatic are responsible for the age distribution of confirmed covid- cases. the age-dependent symptomatic rate could not be identified independently from an assumption about the infectiousness of undetected asymptomatics relative to detected symptomatic cases. therefore, we inferred agedependent symptomatic rates, using the age distribution of confirmed covid- symptomatic cases in china, for a range of values of the relative infectiousness of asymptomatics to symptomatic infected individuals. the range of relative infectiousness scenarios considered in this study was %, %, %, %, and %. each of these scenarios is capable of explaining the age-distribution of cases observed in china, but with a different set of fitted symptomatic rates in each scenario ( figure ). it is also possible to explain the age distribution of cases observed in china by assuming a biological mechanism exists which reduces the susceptibility of contracting sars-cov- for some age groups compared to others. in the early stages of an epidemic, it is not possible to distinguish between age-differing susceptibility and age-differing symptomatic rate if asymptomatics are not infectious ( % relative infectiousness). we find that our estimates of the kenyan reproductive number (r ), without interventions, depend strongly on the relative infectiousness of the asymptomatic cases. as a baseline, if the symptomatic rate was age-independent, so that age-structured mixing was the only driver of age heterogeneity, then we would expect the reproductive number in kenya to be . % higher than in china, because of the typically higher mixing rates estimated within the kenyan population compared to the chinese population (prem et al. ) . in a scenario where younger age groups are developing covid- symptoms at a lower rate after infection compared to older age groups and their infectiousness is negligible ( %) then the r we predict for kenya is substantially lower than the r for china ( . % lower). this is also true if younger age groups are more resistant to contracting sars-cov- (table ) . however, in scenarios where asymptomatic infected are transmitting sars-cov- within the community the predicted r for kenya is higher than the estimates for china, and this prediction holds even if the relative infectiousness of asymptomatic cases in kenya is % that of symptomatic cases (table ) . in this modelling study, we are investigating the course of a potential epidemic of covid- cases in kenya. we are focused on medium-to-long term predictions, assuming that detection at port-of-entry and within-kenya contact tracing fails to suppress transmission immediately after introduction. the experience of countries which have experienced a substantial epidemic of covid- cases has been that the onset of rapid growth in clinical cases, without any obvious transmission pathway between cases (grasselli et al. ), was preceded by a period of largely undetected transmission in the community identified subsequently via genetic analysis of sequenced strains (bedford et al. ) . we recreate this "invisible" period of spread by assuming that there have been five generations of undetected transmission in nairobi before the first set of kenyan symptomatic cases are determined. in each of the scenarios presented below we present results starting from the exponential growth phase of the epidemic. the underlying transmission scenario cannot be disentangled from the symptomatic rate estimate. we estimate that if the relative infectiousness rate of asymptomatics is higher, then their symptomatic rate must be lower to account for the observed case distribution in china ( figure ) . consequently, the level of asymptomatic infectiousness in our model influences our expectation of the epidemic's progress after five generations of unobserved transmission. in all scenarios, there were a small ( - ) number of initially symptomatic cases. in scenarios where the relative infectiousness of asymptomatics is higher, we are therefore also initializing with more asymptomatics to match the expected growth of the outbreak before detection. in line with our reproductive ratio analysis, if asymptomatics were contributing a negligible amount of transmission ( % relative infectiousness) then in the absence of interventions we predict a comparatively long epidemic (median estimate being months until new symptomatic incidence ceases, but with a high degree of uncertainty; figure ) with a slow growth rate of daily incidence, and the median estimate of daily symptomatic cases goes above per day about three months after the detection of the first cases ( figure ). left unchecked we would expect an epidemic with % asymptomatic infectiousness to result in . million symptomatic cases of covid- in kenya among a . % overall population infection rate, but with an exceptionally high level of prediction uncertainty ( % pi - . m symptomatic cases - . % population symptomatic infection rate; table ). if asymptomatics are contributing to the epidemic, then we predict a substantially faster spread than in the % relative infectiousness scenario. transmission amongst the younger age groups, who are expected to be largely asymptomatic, substantially boosts the early transmission rate within the kenyan population, leading to a rapidly arriving peak (median estimates: < months to peak, and months until end of epidemic, after beginning of exponential growth in symptomatic infections) and a high probability of more than , daily symptomatic infections around the peak ( figure ). in these scenarios, where asymptomatic infected individuals are contributing to transmission, and in the absence of effective intervention, we made a median estimate that novel coronavirus would spread first from nairobi into the lake victoria regions and central regions. this spread is then closely followed by spread to mombasa and throughout the coastal region. however, the uncertainty intervals on this prediction are substantial ( figure ). our median prediction is that, if unchecked, by days after the establishment of sars-cov- circulating in the kenyan population there will be more than symptomatic cases of covid- daily in every region of kenya, but that this depends on essentially chance events early in the . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . epidemic ( figure ). for unchecked epidemics with asymptomatic transmission our estimates of total numbers of symptomatic infections over the course of the epidemic range from . million symptomatic infections, . % population infection rate ( % pis . m - . m, . - . %) in the % relative infectiousness scenario to . million symptomatic infections, . % total population infection rate ( % pis . m - . m, . - . %) in the % relative infectiousness scenario (table ) . public compliance with government advice on self-isolation following the development of covid- symptoms ( % reduction in the infectiousness of symptomatic cases) and rapid isolation of the first symptomatic cases (isolation achieved on average by . days post incubation) would be sufficient to contain a major outbreak in the scenario where undetected cases do not transmit ( % infectiousness), reducing the median predicted symptomatic infections from over million to effectively zero if implemented immediately after first detection (table ). however, case isolation and reduction in infectiousness of the detected/clinical cases alone was insufficient to stop a major outbreak in any forecast simulation with asymptomatic transmission, or even achieve substantial delay in arrival of the peak or reduction in total cases ( table ). the essential difference in our predictions for the scenario with % relative infectiousness of asymptomatics and scenarios where asymptomatics are at least % as infectious as symptomatic infecteds could be seen in the different predicted age distributions of symptomatic cases. in the scenario with no transmission from asymptomatics the observed epidemic was dominated by cases among the working-age population (figure ), who we estimated as having high rates of assortative (i.e. within same age-group) mixing ( figure ) and a small but not negligible risk of developing symptoms of covid- after infection. in scenarios with at least % relative infectiousness of asymptomatics then the high rates of disassortative mixing between the elderly ( + year olds) and children ( figure ), who we expected to have a high rate of asymptomatic infection, led to the majority of observed cases occurring in the elderly population despite their relatively small proportion of the kenyan population ( figure ). in scenarios where asymptomatics are transmitting within the population without being detected, and person-to-person transmission has become established in kenya, it is unlikely that case isolation alone will be sufficient to contain a kenyan outbreak. therefore, we also estimated the impact of wide-ranging social distancing (sd) measures and movement restrictions (mr) on the epidemic progression, in conjunction with case isolation (ci). in reality, an implementation of these measures would include school closures, a ban on mass gatherings, a sharp reduction in non-essential social contacts, and a sharp decrease in the amount of time individuals spend away from home. the estimated effect of social distancing was to reduce assortative social mixing among both children and working-age adults (figure ), thereby reducing transmission overall. however, we expected social contacts to be increased within the household as individuals spend more time at home. this had the effect of increasing the contact rate for + year old individuals compared to before sd measures were implemented, because there is believed to be frequent within-household mixing between the elderly and children/young adults in kenya (figure ). . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . this combination of interventions (sd+mr+ci) was predicted to be sufficient to slow down transmission and flatten the epidemic curve of covid- in the scenarios where asymptomatics transmit sars-cov- ; that is, to eventually push the kenyan reproductive number below . however, maintaining sd measures for the entire course of the epidemic is extremely challenging socially and economically. therefore, we investigated the effect of implementing the full set of interventions for days after the detection of established transmission within the country followed by a relaxation. we found that despite reducing transmission over the days of implementation (median estimate symptomatic cases after days in all scenarios), there was a high probability of a rebound epidemic rapidly after relaxation of intervention measures. in the absence of a return to strict interventions if incidence rates are observed to increase, or novel effective vaccines/antivirals becoming available, the rebound epidemic was predicted to be similar in magnitude to the avoided epidemic ( figure ). in this modelling study we have integrated existing data on the social structure, and mobility, of the kenyan population with rapidly evolving estimates of the fundamental epidemiology of sars-cov- so as to make the best possible prediction of the scale of the epidemic risk that kenya faces from the first coronavirus pandemic. we predict that the impact of an epidemic of covid- cases in kenya could be severe, with a high probability of observing more than thousand infections with sufficient symptoms that they would have become clinical cases in the chinese setting, if the epidemic was left unchecked. we predict that in the more pessimistic scenarios, and in the absence of an effective vaccine and/or anti-viral treatments, substantial restrictions on the social mixing and movement of the kenyan people, either lasting for longer than three months, or reimplemented if incidence rebounds, would be required to control a covid- epidemic in kenya. in this study we do not attempt to estimate the proportion requiring hospitalization, i.e. those having most impact on the health services, and most at risk of dying -nor estimate deaths. estimating the true impact of the covid- epidemic in kenya requires an estimate of the clinical fraction of infecteds, the likelihood of clinical cases being severely ill and a detailed, and spatially explicit, understanding of the capacity of the kenyan health service. early work to assess kenya's health system capacity to absorb likely covid- cases, using the predictions from this model on the likely scale of the pandemic, reveal that kenya's health system is likely to be overwhelmed because of limited availability oxygen and other essential devices to facilitate oxygen therapy (such as pulse oximeters), and critical shortages of intensive care beds (icu) and ventilators (barasa ) . the analysis reports variation in kenya's surge capacity for hospital beds, with the county with the least surge capacity likely to need % of its available hospital beds to accommodate covid- cases if the pandemic lasts for months (barasa ) . the analysis shows that only out of the counties have at least one icu unit and that the country will need an . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint additional , icu beds and , ventilators if the epidemic will last for months. the authors indicate the need to strengthen lower cost essential services such as oxygen availability before focusing on these higher cost investments. the extrapolation of the symptomatic rate from chinese clinical observations to the kenyan setting is likely to be imprecise, and should be replaced by symptomatic rates estimated from kenyan case data as this becomes available. the chinese epidemiological reports include a substantial proportion ( . %) of mildly diseased cases (cpere ); it is possible that a proportion of mildly diseased individuals in the kenyan setting would not seek medical attention, and therefore would remain invisible to kenyan surveillance. this observation suggests that the symptomatic rate estimated here could be an overestimate of the clinical incidence that will be seen in kenya. on the other hand, it should be noted that our estimate for the symptomatic rate is somewhat lower in some age groups than other estimates in the literature. for example, davies et al (davies et al. ) make a consensus estimate of the clinical fraction of - year old infecteds as %, whereas we find the symptomatic rate for that age group is likely to be less than %. as with all modelling studies, there are limitations in our modelling structure that go beyond uncertainty in parameterization. in particular, it is possible that controlling a covid- epidemic in kenya will require measures which can break transmission from household to household. however, an explicit household structure is not part of the kenyacov modelling framework. we replicate the effect of household structure in our modelling of social distancing using a combination of social context dependent agestructured mixing matrices and an effective decline in contact rate as individuals reduce contacts among the general population in favour of repeated contacts with a relatively small group of people within their own household. whilst this is less realistic than a full, individual-based stochastic model, see for example ferguson et al (ferguson et al. ) , the benefit of using kenyacov is that, in the event of a substantial covid- epidemic in kenya, the model is sufficiently performant that incorporating new information into forecasting could occur in near real-time. as mentioned above, it is critical that estimates of the symptomatic rate, clinical fraction, and rate of severe disease are derived from kenyan case data rather than simply extrapolated from other settings. such kenyanspecific estimates of covid- , augmented by more recent data on kenyan mobility, will allow us to better understand the link between transmission predictions (as given by kenyacov), and the observed clinical burden of covid- in kenya. without understanding the link between transmission and clinical burden the design of public health interventions is done blind, and it is impossible to evaluate intervention success. there remains a very high degree of uncertainty surrounding the underlying epidemiology of sars-cov- infection, which inevitably degrades our certainty in the predictive modelling of transmission in kenya. we have attempted to partially account for these underlying uncertainties by drawing some parameters from a plausible range rather than simply using point estimates. however, some of the epidemiological uncertainties are fundamental to the structure of the kenyacov model. first, we treat the rate of developing symptoms as the detection rate in the model, following that the substantial majority of confirmed cases in the china were initially syndromic detections before test confirmation (cpere ). however, since the symptomatic rates used in kenyacov were inferred . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . from the age distribution of chinese confirmed cases, this means that our model is predicting the incidence rate of cases that would have been clinical in the chinese epidemic. it could be that the syndromic threshold for detection is different in kenya, which would alter the effective transmission rate of the undetected cases by changing the definition of detected and undetected cases so that infectious and diseased individuals might be missed in the kenyan context who would have been identified in the chinese context. second, and following from the previous comment, the rate of subclinical undetected transmission is critical to the expected outcome of an epidemic in kenya. this reflects the fact that covid- disease has been predominantly observed amongst older age groups, and therefore two major possibilities for a country with a younger demography arise. in the first possibility, the relatively large proportion of younger people effectively protect the elderly at-risk groups from transmission. in the second possibility, high rates of unobserved transmission within the young population cause significant numbers of clinical cases among the elderly. we don't know which outcome will occur until a substantial number of cases are observed, and so far, no major covid- epidemic has occurred in sub-saharan africa. if there exists climatic incompatibility for this strain of coronavirus and/or inherent resistance in the population then all modelling estimates derived from the chinese experience should be revised downwards. finally, our model presents a partial picture of the likely effects of government interventions to slow the transmission of covid- . government interventions such as social distancing and movement restrictions have secondary health, social and economic effects that should be considered when making decisions about how to intervene (dahab et al. ; barasa ) . for instance, these interventions could disrupt routine health service delivery and access (such as vaccinations, and maternal and child health services), cause income and job losses in ways that could push households into poverty, and lead to a shrinking of country economies. incorporating these dimensions in models, and ascertaining net health and non-health benefits of interventions would provide a fuller picture and improve the quality of decision making. we parameterized our sars-cov- transmission model from a range of data sources. epidemiological parameters for sars-cov- were collected from estimates that have been reported in the literature (table ) . we followed wesolowski et al (wesolowski et al. ) in dividing kenya into regions corresponding to population density concentrations. these regions overlap the counties of kenya, and results for the counties were created from simulations on regions by apportioning infections pro-rata according to the proportion of the region population from each county. we subdivided the population by their home region, and their age category. in this study we consider age categories: - years old, - years old, … , - years old, + years old. the modelled population size in each region/age category was chosen to match the recent kenyan census findings (denoted !,# for the number of individuals in . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint region and age group ) (knbs, ). we estimated the human mobility flux using mobile phone data on number and duration of trips from home regions to alternate regions (wesolowski et al. ) , rescaled to number of journeys per person per day. this allowed us to estimate both: (i) the proportion of time typical individuals in each region spent away from their home region (denoted ! ∈ [ , ] for each region ), and (ii) a probability distribution for where typical individuals travel to when they leave their home region (denoted !$ for probability of a person living in region travelling to region ). the central mobility estimates depended on a reported median nights duration per journey, which is likely to be an overestimate for short-distance journeys and an underestimate for long journeys. if the short-distance journeys are typically shorter than nights, and the long-distance journeys are typically longer then the serial interval of sars-cov- then this central mobility estimate will overestimate the rate at which sars-cov- spreads spatially in kenya. the rate of contact between individuals currently in the same region, including visitors to the region, was determined by their age group using an estimated age-mixing contact matrix for kenya from the study by prem et al (prem et al. ). prem et al give estimated contact rates between age groups for countries broken down by contact setting: at home, at work, at school, and other contacts amongst the population. the epidemiological characteristics of sars-cov- were drawn from the literature and summarized into a belief distribution for key uncertain parameters (table ). the age-profile of cases used to infer the age-dependent symptomatic rates were from the first , confirmed cases as published by china cdc on th february (cpere ). we used a variant of the susceptible-exposed-infectious-recovered (seir) metapopulation model (keeling & rohani ) , dubbed kenyacov, to simulate transmission of sars-cov- in kenya. the code and open source data for kenyacov can be found at https://github.com/samuelbrand /kenyacov. individuals divided their time between their home region and other regions according to their age and the region-specific travelling patterns described above. for simplicity, we assumed that age groups of individuals younger than and older than didn't move around the country, therefore we defined the transport matrix, !$;# , as !";$ = !" , if was an immobile age category, !";$ = !" ( − ! ) + ( − !" ) ! !" , if was a mobile age category. ( ) where !$ = if = and otherwise. the transport matrix defined the proportion of time spent in each region. the force of infection (the rate at which each susceptible becomes infected) on individuals in region i and age group a depended on their movements and age-dependent social contact rates. the force of infection on each susceptible individual currently in region and age group was, . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https: //doi.org/ . //doi.org/ . / ( ) where was the sars-cov- transmission rate, was the kenyan age-mixing matrix, and $,& and $,& were, respectively, the effective number of infected individuals in, and the effective population size of, age group currently in region . using effective numbers accounted for mobility of individuals and differential transmissibility between clinical cases and asymptomatics, where ' is the infectiousness of a asymptomatic infected relative to a clinical case, and ( was the reduction in infectiousness of clinical cases after they developed symptoms. when individuals are infected with sars-cov- , and have finished their incubation period, then they either develop sufficient symptoms to eventually become a clinical case (with age-dependent probability # ) or they are sufficiently asymptomatic to remain subclinical and remains undetected (with probability − # ). the model treats population groups as discrete, and follows stochastic dynamics, however, the overall kenyacov dynamical structure is most compactly represented using notation for an ordinary differential equation (ode), the transition rates given in equation ( ) should be interpreted as stochastic rates for each event, where !,# , !,# , !,# , !,# , !,# , and !,# were the number of susceptible, latent, infectious with sufficient symptoms to become clinical cases, infectious but subclinical, isolated and removed individuals whose home was region and age group . , , , were, respectively, the per-contact transmission probability, the incubation, recovery rate and exit rate from isolation. note that the transmission structure included both the possibility that infection is spread around the country by the movements of infected individuals, and, . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https: //doi.org/ . //doi.org/ . / by susceptible individuals who contract sars-cov- elsewhere and return to their home region. we inferred age-dependent symptomatic rates for each age group by matching the age distribution of clinical cases expected from combining the next-generation matrix for sars-cov- with symptomatic rates to the observed age distribution of clinical cases in china on th february. we denote the mixing rate at which individuals in age group contact individuals in age group , estimated for china, ( )*!+# ) #& , as estimated by prem et al (prem et al. ) . we use two versions of the age mixing matrix for china in this analysis: )*!+# , which denotes the age mixing matrix including contacts in all social settings, and, )*!+#,*,-. , which denotes the age mixing matrix including contacts only at home. for fitting age specific symptomatic rates we used )*!+#,/ . our reasoning was that the majority of cases reported in china occurred during severe lockdown restrictions on social contact outside of the household. the next-generation matrix across age groups (expected number of infections generated amongst age group b per infected in age group a) for china during lockdown was: we denote the leading eigenvector of ( *+!,$,+-./ ) $& , as # , normalized so that ∑ # # = . # is the expected proportion of infections amongst age group a, during the early stages of an outbreak but after a few generations of transmission (diekmann & heesterbeek ) . the probability that amongst a collection of confirmed cases any given case is in age group a . this allowed us to infer a posterior distribution (we assumed flat priors) for the values of # using hamiltonian mcmc with a standard multinomial likelihood of recreating the observed case data in china. this was implementing using the dynamichmc package for the julia programming language. note that # depends on # and ' , but not the per-contact transmission probability or the recovery rate. similarly, # does not change is is scaled by a constant. therefore, we fixed = . , that is we assumed a true symptomatic rate amongst + year olds of %. for inferring the per-contact transmission probability, , we matched to r estimates in china using the full chinese contact matrix )*!+# by considering the leading eigenvalue of the pre-lockdown next generation matrix. this was chosen to reflect that we are using early estimates of r before lockdowns were fully achieved. our estimated r for kenya, without interventions, was the leading eigenvalue of kenyan next-generation matrix using the kenyan age-mixing matrix #& . we consider three types of interventions aimed at restricting sars-cov- transmission in kenya: . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . • case isolation and reduction in transmission of clinical cases pre-isolation (ci). clinical individuals are isolated from the rest of the population at an isolation/treatment rate ( ), which represented the active intervention of the kenyan health system and has an initial rate ( ) = . we assumed that if the cumulative number of detected cases reaches , individuals (~ . % of the kenya population) then the health system has reached its capacity threshold and active isolation ceases ( ( ) = after capacity is reached). both before and after capacity is reached, the infectiousness of the clinical cases was reduced by a factor ( ≤ which reflected passive intervention, e.g. public campaigns to raise awareness of sars-cov- risk, encourage self-isolation and social distancing of symptomatic individuals, and increased hygiene. • wide-spread social distancing (sd). the whole kenya population is required to minimize unnecessary social contacts, along with closing schools and colleges. we modelled this as decreasing work contacts by %, decreasing other contacts by %, offset by an increase in home contacts by %. we modelled the action of sd on the contact structure of the population by replacing the agemixing matrix by a sd-mixing matrix, ( ( ) = ( )( . +-./ + . - ' + . - +/ ). where the three matrices *,-. , , , , *. are the estimated age-structured contact rates in, respectively, the home, work, and other settings (prem et al. ) . we followed tang et al (tang et al. ) in including a decreasing rate of contacts over time. the decreasing rate of contacts was combined with the change in age structured mixing, and attempted to account for increasing population compliance, a staggered step of extra interventions (e.g. closing nonessential shops and instigating a curfew), and the effective decrease in contacts across the population due to redirecting social contacts towards repeated contacts within the home. specifically, we use the down-ramp function to represent a decrease in contacts by % over days after the social distancing intervention: ( ) = − . ( − )/ for times between the intervention time and days after sd intervention • movement restrictions (mr). the whole kenyan population is required to reduce movement around the country, with waivers only for specific reasons e.g. movement of vital supplies, movement of medical professionals. we model this by replacing the transport matrix with a post-movement restriction transport matrix, : , constructed by assuming that during movement restrictions . % of the time of typical individuals was spent in their home region. we consider a range of possible levels of infectiousness of asymptomatics relative to individuals with severe symptoms who become clinical cases ( = , . , . , . , .). for each relative infectiousness scenario, detection rate, we ran simulations. we aimed to estimate the distribution of sars-cov- epidemic outcomes in kenya over uncertainty in the fundamental epidemiological parameters. we achieved this by, prior to each simulation, drawing mean incubation period and reproductive ratio for china from a belief distribution of the parameter value that encompassed published literature estimates (table ) . the chinese ; ∼ ( = , = . / ), which corresponded to a median belief that the sars-cov- ; for china is equally likely to be above . as below ( . - . percentiles of belief ; = . − . ). the mean incubation period / ∼ ( = ( ), = . ); median belief / = days ( . - . days). we fixed the mean infectious duration as / = . days, corresponding to the difference in the median serial interval less our median belief of the mean incubation period (table ) . a key point is that our belief distribution ; is based on estimates derived from data of chinese cases. therefore, the transmission rate used in each simulation, and which corresponds to some ; drawn from our belief distribution, is derived using chinese agemixing data. symptomatic rate constant over ages. susceptibility constant over ages. . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https: //doi.org/ . //doi.org/ . / table : predictions for final numbers of symptomatic cases and peak timing in two scenarios: unchecked epidemic and rapid isolation of first cases with % reduction in infectiousness of clinical cases throughout epidemic. . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . basic reproductive ratio ( ; ) ! = . ( . - . ) from early identified cases in wuhan (read et al. ). ! = . ( . - . ) from the first confirmed patients (q. ). ! = . ( . - . ); from internationally exported cases until jan th . ! = . ( . - . ); based on cases in wuhan by th jan (imperial group report). . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint figure : estimates of symptomatic rates per age group relative to symptomatic rate for + year olds. - - - - - - - - - - - - - - - . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint figure : baseline estimates of incidence rates and early spatial distribution of incidence. (top) daily incidence of symptomatic infections (median) estimates across kenya for an uncontrolled epidemic and five different rates of subclinical transmission. ribbon plot give median estimates with % prediction intervals. (bottom) as top but incidence is given for each county using the % relative subclinical transmission scenario as representative. legend is organized by median incidence rate at days. . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . age distribution of cases: uncontrolled epidemic number of symptomatic infections (thousands) % rel. infectiousness % rel. infectiousness % rel. infectiousness % rel. infectiousness % rel. infectiousness . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint figure : days of social distancing, movement restrictions and case isolation of first clinical cases. the daily incidence across kenya by transmission scenario (as above ribbon plots give median and % pi). full restrictions are assumed to apply from time zero until days (black dotted line). the median predictions of daily incidence with only case isolation (ci), but no other intervention, are shown as dashed lines. daily incidence before and after days restrictions (sd+mr+ci) days after established sars-cov- transmission daily new sympomatic infections rel. infect. of subclinical: % rel. infect. of subclinical: % rel. infect. of subclinical: % rel. infect. of subclinical: % rel. infect. of subclinical: % . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . / . . . doi: medrxiv preprint . cc-by-nc . international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/ . epidemiology, transmission dynamics and control of sars: the - epidemic assessing the hospital surge capacity of the kenyan health system in the face of the covid- pandemic genomic analysis of covid- spread epidemiology and transmission of covid- in shenzhen china: analysis of cases and , of their close contacts the epidemiological characteristics of an outbreak of novel coronavirus diseases (covid- ) in china middle east respiratory syndrome coronavirus: quantification of the extent of the epidemic, surveillance biases, and transmissibility. the lancet. infectious diseases covid- control in low-income settings and displaced populations: what can realistically be done? london school of hygiene and tropical medicine pre-print available at age-dependent effects in the transmission and control of covid- epidemics. medrxiv mathematical epidemiology of infectious diseases preparedness and vulnerability of african countries against importations of covid- : a modelling study estimation of country-level basic reproductive ratios for novel coronavirus (covid- ) using synthetic contact matrices modeling infectious diseases in humans and animals kenya population and housing census volume iii: distribution of population by age, sex and administrative units -kenya national bureau of statistics early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (sars-cov- ) time-varying transmission dynamics of novel coronavirus pneumonia in china. biorxiv, africa prepares for coronavirus. the lancet projecting social contact matrices in countries using contact surveys and demographic data b. halloran novel coronavirus -ncov: early estimation of epidemiological parameters and epidemic predictions. medrxiv an updated estimation of the risk of transmission of the novel coronavirus ( -ncov) quantifying the impact of human mobility on malaria world health organization nowcasting and forecasting the potential domestic and international spread of the -ncov outbreak originating in wuhan, china: a modelling study age profile of susceptibility, mixing, and social distancing shape the dynamics of the novel coronavirus disease outbreak in china key: cord- -gj mfzxz authors: de sanctis, vincenzo; ruggiero, leopoldo; soliman, ashraf t; daar, shahina; di maio, salvatore; kattamis, christos title: coronavirus disease (covid- ) in adolescents: an update on current clinical and diagnostic characteristics date: - - journal: acta biomed doi: . /abm.v i . sha: doc_id: cord_uid: gj mfzxz the current outbreak of infections with sars-cov- is defined as coronavirus disease (covid- ). the clinical symptoms of covid- include fever, fatigue, cough, breathing difficulty that may lead to respiratory distress; a small population of patients may have diarrhea, nausea or vomiting. the highest infection rate occurs in adults; however, neonates, children, and adolescents can also be infected. as the outbreak continues to spread worldwide, attention has switched toward determinants of clinical manifestations and disease severity. the situation surrounding the outbreak is rapidly evolving and the information and recommendations are changing as new information becomes available. this paper summarises the current findings (april , ) from a systematic literature review on the current knowledge of covid- in adolescents ( - years according to the who definition) and reports the preliminary epidemiological data stated by the italian national institute of health. (www.actabiomedica.it) the coronaviruses (covs) belong to a family of viruses that may cause various symptoms, such as cough, fever, breathing difficulty, and lung infection, mainly pneumonia ( ) . these viruses are common in animals worldwide, but, in a few instances, are known to infect humans ( ) . human coronaviruses (hcovs) were first described in the s in patients with common cold. since then, a number of hcovs have been discovered ( e, oc , nl , and hku ), including sars-cov causing the severe acute respiratory syndrome and mers-cov, the middle east respiratory syndrome; both are highly transmissible and pathogenic viruses that emerged in humans at the beginning of the st century ( ) . these hcovs are associated with lower respiratory tract syndromes, spread from personto-person via close contact; they have high morbidity and mortality caused by the progression to acute respiratory distress syndrome (ards). it was recently discovered that dromedary camels in saudi arabia harbor three different hcov species, including a dominant mers hcov lineage that was responsible for outbreaks in the middle east and south korea during ( ) . on january , a novel coronavirus, -ncov, was officially identified as the cause of an outbreak of diffuse pneumonitis in the city of wuhan in hubei province, china. the epidemic has progressed very quickly in the following weeks, and an increasing number of cases have occurred daily in many countries ( ) . the disease was named covid- by the world health organization (who) on february ( ) , and the virus, sars-cov- by the international committee on virus taxonomy on the same day. on march , who classified the outbreak as a pandemic ( ) . currently sars-cov- has now spread to all continents excluding antarctica. on april , over million patients with covid- have been reported globally, with approximately , cases having recovered and over , deaths, according to the data compiled by the center for systems science and engineering at johns hopkins university. the us has the highest reported number of patients with covid - worldwide, accounting for approximately one quarter of all global cases. after the us, italy, spain, germany, china, france, iran, and the uk have the higher number of patients. italy still has the largest number of deaths globally, accounting for nearly one third of all global fatalities (tables and ) , but it appears that the rate of new infections has slowed in the last few days. according to the who, case and contact definitions are based on the current available information and are revised daily as new information accumulates. countries may need to adapt case definitions depending on their local epidemiological situation and other factors. all countries are encouraged to publish definitions used online and in regular situation reports, and to document periodic updates to definitions which may affect the interpretation of surveillance data. as the outbreak continues to spread worldwide, attention has switched toward determinants of clinical manifestation and disease severity. this paper summarises the findings of a systematic literature review on the current knowledge of covid- in adolescents ( - years, according to the who definition) and reports the preliminary epidemiological data on adolescents in italy. literature was identified by searching the following online databases: pubmed, google scholar, me-drxiv, biorxiv, who, centres for disease prevention and control (cdc), european centre for disease prevention and control, italian national institute of health (iss), centre for evidence-based medicine (cebm), worldometer, and health authorities. the searches concluded on april . the following search terms were used: " novel coronavirus, -ncov, wuhan coronavirus, wuhan pneumonia, covid- in children and adolescents". articles were screened by title, abstract, and full text. google searches were also used to provide access to government and international institutes. in our review we preferentially included the relevant peer-reviewed scientific publications written in english. the mean incubation period is brief, reported as . days, with the th percentile of the distribution at . days ( % confidence interval: . - ) ( ) . overall, these estimates will be refined as more data become available. available evidence indicates that human transmission of sars-cov- occurs via close contact with respiratory droplets produced when a person exhales, sneezes, or coughs, or via contact with fomites. the virus has been detected in blood, saliva, tears, and conjunctival secretions ( ) ( ) ( ) ( ) . sars-cov- rna was also detected in stool specimens but according to who-china report, fecal-oral transmission did not appear to be a significant factor in the spread of infection (report of the who-china joint mission on coronavirus disease ,covid- . february [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] ) . all ages are susceptible to this viral infection ( , ) . high viral loads have been detected in nasal and throat swabs soon after symptoms onset; it is thought that the viral shedding pattern may be similar to that of patients with influenza. pharyngeal viral shedding is high during the first week when symptoms are mild or prodromal, peaking on day , suggesting an active virus replication in the upper respiratory tract tissues. other studies have also shown a higher viral load in the nasal cavity as compared to the throat, with no difference in viral burden between symptomatic and asymptomatic people. patients can be infectious for as long as the symptoms last and even after clinical recovery ( , ) . up to now, no cases of transmission via the faecal-oral route have been reported for sars-cov- , which might suggest that infection via this route is unlikely. detailed epidemiological information based on a larger sample of covid- patients is needed to determine the infectious period of sars-cov- , as well as whether transmission can occur from asymptomatic individuals during the incubation period ("pre-symptomatic" period). however, such sources of infection cannot be effectively identified due to the absence of symptoms. so far, research evidence is lacking, although there are a few studies suggesting that pre-symptomatic or asymptomatic carriers may cause viral transmission ( , ) . asymptomatic carriers can also be a source to propagate the outbreak ( ) . a study in singapore identified . % of patients among seven clusters of cases in which presymptomatic transmission was likely to have occurred to days before symptom onset ( ) . these patients are not easy to detect when initially infected but might have abnormal symptoms later. in a small number of case reports and studies, a familial cluster of infection associated with sars-cov- has been reported, indicating possible personto-person transmission during the incubation period ( , ) . the best evidence so far comes from the diamond princess cruise ship, which was quarantined with all passengers and crew members repeatedly tested and closely monitored. a modelling study found that approximately people with confirmed infection ( %) were asymptomatic ( ) . pregnant women and their fetuses represent a high-risk population during disease outbreaks. until march , the outcomes of pregnant women infected with sars-cov- and neonates have been reported with no definite evidence of vertical transmission ( ) . prenatal complications may include premature labor and fetal distress. however, vertical transmission cannot be ruled out. there have been reports of infection in neonates born to mothers with covid- ( ) , and virusspecific antibodies have also been detected in neonatal serum samples ( ) .therefore, it is crucial to screen pregnant women and implement strict infection control measures, quarantine of infected mothers, and close monitoring of neonates at risk of covid- . in conclusion, several properties of this virus make prevention difficult namely: the non-specific features of the disease, the infectivity before onset of symptoms during the incubation period, the transmission from asymptomatic people, the long incubation period, the tropism for mucosal surfaces such as the conjunctiva, the prolonged duration of the illness and the transmission after clinical recovery. many reports provide descriptions of the clinical signs associated with covid- in wuhan and other cities in china. the clinical symptoms range from mild cough and fatigue to severe acute respiratory distress and respiratory failure. in adults, the main prevalent clinical manifestations include: sore throat, cough, high fever, tachypnea/dyspnea, and chest tightness/ pain. the presence of fever is significantly higher in adults compared to children. in adults and adolescents with severe pneumonia the respiratory rate is > breaths/minute and the spo is ≤ % on room air. the leading cause of death in patients with covid- is respiratory failure from acute respiratory distress syndrome ( , , , ) . a wide range of diagnostic tests are commercially available for sars-cov- , some of which have received authorization for use by various national regulatory agencies. countries have implemented different testing strategies, reflecting the availability of equipments, diagnostic reagents, and capability of their national health system. the cdc recommends collection of a nasopharyngeal swab specimen to test for sars-cov- ( ). a positive test generally confirms the diagnosis of covid- , although false-positive results may occur. negative rt-pcr tests on nasopharyngeal specimen swabs despite ct findings suggestive of viral pneumonia have been reported in some patients who ultimately tested positive for sars-cov- ( ) . based on the findings of chest radiographs in , respiratory distress syndrome (ards) in cov-id- patients, only . % had abnormal findings ( ) . in contrast, ( . %) had abnormal and diverse chest ct images, in which ground-glass opacity (ggo) was the most common abnormality ( . %), followed by local patchy shadowing ( . %), and interstitial abnormalities ( . %). in addition, . % patients had bilateral patchy shadowing ( ) . as the disease progress, follow-up ct scans may show enlargement and consolidation of single ggo, an enlarged fibrous stripe, and solid nodules. generally, two types of abnormal radiographic presentations are seen in children and adolescents: multiple opacities and patchy opacities ( ) . in the liao et al study ( ) , only ( . %) adolescent patients showed ground-glass opacity at chest ct scanning, compared with ( . %) young adults. rodriguez-morales et al ( ) performed a systematic literature review with meta-analysis, using three databases to assess clinical, laboratory, imaging features, and outcomes of covid- confirmed cases. articles were retrieved for the time frame ( / / - / / ). after screening, articles were selected for full-text assessment, being finally included for qualitative and quantitative analyses. decreased albumin ( . %), high c-reactive protein ( . %), high lactate dehydrogenase (ldh) ( . %), lymphopenia ( . %), and high erythrocyte sedimentation rate (esr) ( . %), were the most prevalent laboratory findings. in short, confirmation of infection requires nucleic acid testing of respiratory tract samples (e.g., throat swabs). however, nasopharyngeal specimens may miss some infections and a deeper specimen may need. alternatively, repeated testing can be used because, over time, the likelihood of the sars-cov- present in the nasopharynx increases. serologic tests, once generally available, should be able to identify patients who have either current or previous infection but a negative pcr test. clinical diagnosis may be made based on symptoms, exposure, and chest imaging. chest ct may plays a key role in detection or diagnosis of cov-id- infection with some typical ct features while the initial rt-pcr result is negative. consequently, at present, exposure history, clinical manifestations, chest ct features and laboratory results, should be taken in consideration to diagnose covid- infection. at present, information regarding the epidemiology and clinical features caused by covid- in adolescents are scarce in the literature. as a first step, we reviewed the epidemiological characteristics of -ncov. from february-april , the reported prevalence of infection in adolescents in china ( ), korea ( , ) , usa (children and adolescents < years) ( ) , and italy ( ) was equal to %, %, . %, and . %, respectively. tables and , and figure illustrate the available data in adolescents compared to children ( - years) in china ( ) and italy (ruggiero l, data calculated from ref ) . notably, a higher number of positive cases were reported in the north of italy ( ) . in the chinese report, the time period from the peak of the symptom-onset-based epidemic curve (around january ) to the peak of the diagnosis-based epidemic curve (february ) was about days ( ). the proportion of chinese children who developed severe or critical covid- illness with breathlessness, acute respiratory distress syndrome (ards), and shock was much lower ( %) than among chinese adults ( %). in the united states, among , covid- cases in children aged < years, nearly one third, cases ( %) occurred in children, aged - years, and ( %) in children aged - years ( ) . no admissions in intensive care units or deaths were reported in patients younger than years up to april . compared to the adult population, cai et al. ( ) observed a longer period of incubation in adolescents with a mean of . days (range - days) from the time of exposure to symptoms. ludvigsson ( ) , in a systematic literature review, reported that the transmission could emerge rapidly between younger patients and their family members or close contacts. a detailed study on epidemiology, transmission patterns, and clinical characteristics in adolescents and young adults with covid- has been recently published ( ) ( ) ( ) . in general, common symptoms on admission were similar to those in adults, namely: dry cough ( . %), fever ( . %), and expectoration ( . %). lung auscultation may reveal rales and crackles. the less common symptoms included headache, fatigue, sore throat, chest pain, anorexia, myalgia, dizziness, diarrhoea, nausea, and shortness of breath ( ) ( ) ( ) . as far as we know, anosmia/hyposmia or ageusia/ dysgeusia has not been reported in adolescents. the american academy of otolaryngology -head and neck surgery (march , internet publication) has proposed adding anosmia and dysgeusia to the list of screening items for potential infection in adults and recommends that clinicians consider testing and self-isolation of these patients in the absence of other respiratory diseases such as rhino sinusitis or allergic rhinitis. over % of patients were asymptomatic, or with mild, or moderate clinical symptoms ( ) . however, whether the limited number of covid- in children is due to lower susceptibility or milder presentation leading to missed detection remains unknown ( ) . the mild nature of covid- in pediatric cases is likely to be multifactorial. cai et al. ( ) reported that while covid- viral shedding in respiratory specimens lasts longer in children than adults, and was also observed in the stool specimens, the virus was not detected in serum samples. the absence of viremia has likely contributed to the lack of severe illness in children cases ( ) . severe or critical illness was reported in . % of children aged to years, . % in children aged to , . % in the to age group, and . % in adolescents years and older. one -year-old child in this cohort died ( ) . compared with young adults, no severe cases and higher odds of asymptomatic cases ( . % vs . %) were observed in adolescent patients ( ) . patients with chronic diseases are at greater risk of infection. data on the management of comorbidities in patients with covid- is limited ( ) and should be tailored to the patient's chronic disease ( , ) . there are no vaccines available and there is little evidence to date on the effectiveness of potential therapeutic agents. management strategies for children and adolescents are absent because of the limited number of patients in this age group with covid- . therefore, treatment has been focused on symptomatic and respiratory support (oxygen inhalation, fluid management, and the use of broad-spectrum antibiotics to cover secondary bacterial infection). apart from the above, the use of interferon-a nebulization, anti-viral drugs (such as, remdesivir lopinavir/ritonavir), and chloroquine have been reported ( ) ( ) ( ) . in summary, compared with elderly patients, adolescent and young adult covid- patients have a longer incubation period, a shorter serial interval, higher odds of being asymptomatic and a lower mortality rate. larger epidemiologic studies are needed to confirm the lower susceptibility and milder clinical presentation of covid- in adolescents. the commonest clinical and laboratory findings in adolescents with covid- are summarized in table . the who, on january , declared that the new coronavirus sars-cov- outbreak is a public health emergency of international concern. pediatric covid- cases, including adolescents, are rapidly increasing around the world. early recognition and rapid diagnosis are essential to prevent transmission and provide supportive care in a timely manner. the cdc is working closely with state and local health partners to develop and disseminate information to the pub lic on general prevention of respiratory illness, including the -ncov. this includes everyday preventive actions such as: washing hands, cover- table . summary of the commonest clinical and laboratory findings in adolescents with covid- infection (from references: - ). young adults is longer than in older patients. . compared to young adults, adolescents were less likely to be overweight/obesity, to smoke and drink alcohol. . no severe cases and higher odds of asymptomatic cases ( . % vs . %) were observed in adolescent patients . the adolescent and young adult patients with covid- have different patterns of symptoms and lower incidence of abnormal laboratory findings. the inflammatory markers of c-reactive protein (crp) and procalcitonin (pct) were elevated in . % and . % of cases, respectively. . ground-glass opacity at chest ct scanning was found in % of adolescents compared with . % of young adults. . compared to young adults, adolescent patients received less oxygen inhalation therapy and had lower number of days with persistent fever. . lower number of adolescents developed severe complications. extended follow-up is needed to provide more detailed information on the potential risk factors interfering with clinical outcomes. ing the mouth and nose when coughing or sneezing, and staying home when ill. thus, everybody should follow the national guidelines around screening, testing, containment, care and practice social distancing. additional information and resources for this outbreak are available on the cdc website (https://www.cdc. gov/coronavirus/ -ncov/ index.html). considering that all age groups are susceptible to sars-cov- infection, it is of critical importance also, that the youngest subjects, who may be asymptomatic or have milder symptoms, should comply with the self-isolation procedures in order to prevent virus diffusion. additionally, personal protective equipment (ppe) is crucial when care providers look after an infected person. as more is learned about this novel virus and outbreak, more data will emerge to facilitate the diagnostic and preventive measures for containing and minimizing the covid- infection. at present, we suggest that in the presence of active community transmission, subjects presenting with a fever of unknown aetiology or with a fever in the presence of common cold or pneumonia symptoms should be tested for covid- , and influenza a and b viruses to rule out possible co-infection considering the seasonal overlap between influenza and covid- . in helping to prevent influenza, all persons aged ≥ months should receive influenza vaccine annually ( ) . according to the united nations educational, social and cultural organization (unesco), countries have implemented nationwide school closures, impacting over , million children and youths. at this moment, we do not have strong evidence to guide decisions on duration of school closures and how duration may affect public health. extending school closure will support the overall effectiveness of social distancing and thus aid in lowering the peak of the epidemic curve. however, prolonged periods of school closures and movement restriction may lead to additional emotional unrest and anxieties ( ) . education, social support mechanisms and access to health services need to be maintained, with parents and/or guardians playing a key role ( , ) . further relevant aspects should be also taken in consideration (table ) . this review has numerous limitations; few articles are focusing on the clinical features of covid- in adolescents. some clinical and epidemiologic risk factor data might be incomplete, as they were collected by multiple teams under protocols that, by necessity, changed as the situation progressed. data on outcomes, including hospitalization, were missing and this likely resulted in an underestimation of outcomes. no comprehensive data are available on the impact of covid- on adolescents with an underlying condition, especially those with respiratory system morbidity, but it is reasonable to consider that they might be at increased risk for severe disease. in conclusion, all clinicians should keep themselves updated about recent developments including global spread of the disease. we encourage coordinated efforts between national and international health agencies to develop effective surveys in this age group. we express our sincere condolences to the patients and their families who had covid- around the world. we greatly respect the efforts of all the hospital employees and their families, who are working tirelessly during this outbreak, and the collaborative partnership at all levels of individuals in the table . the united nations population fund recommendations (unfpa: www.unfpa.org/ sites/default/files/resource; modified) . many vulnerable young people are at greater risk of contracting covid- , such as young migrants, young refugees, homeless young people, those in detention, and young people living in crowded areas and in poverty. . if caregivers are infected, quarantined, or die, protection and psychosocial issues for adolescents need to be addressed. . with prolonged stress on the health system to address covid- , a disruption of the normal delivery of sexual and reproductive health services and information to young people will need to be addressed. . the need for mental health services and counselling is paramount, as many people, including young people, who are facing high levels of anxiety and stress related to cov-id- . . adolescents and youths, especially adolescent girls and young women, who already tend to face very high levels of domestic and intimate partner violence, may experience even higher levels of violence driven by quarantine and isolation. public and private sectors of the nations for their care, support, and love to the patients. up to april, , many doctors and nurses have been died after caring for patients with covid- infection, and of those doctors and nurses were in italy. their dedication and example will remain forever in our memory. china novel coronavirus investigating and research team epidemiology, genetic recombination, and pathogenesis of coronaviruses origin and evolution of pathogenic coronaviruses director-general's remarks at the media briefing on -ncov on world health organization. coronavirus disease (covid- ) situation report- early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia the digestive system is a potential route of -ncov infection: a bioinformatics analysis based on single-cell 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bulletin data the early phase of the covid- outbreak in cdc covid- response team. coronavirus disease in children -united states a case series of children with novel coronavirus infection: clinical and epidemiological features systematic review of covid- in children show milder cases and a better prognosis than adults epidemiological characteristics of pediatric patients with coronavirus disease in china preliminary epidemiological analysis on children and adolescents with novel coronavirus disease outside hubei province, china: an observational study utilizing crowdsourced data medrxiv epidemiological and clinical characteristics of covid- in adolescents and young adults covid- and long term conditions: what if you have cancer, diabetes, or chronic kidney disease? clinical management of severe acute respiratory infection (sari) when covid- disease is suspected inhaled steroids in asthma during the covid- outbreak clinical and epidemiological features of children with coronavirus disease (covid- ) in zhejiang, china: an observational cohort study drug treatment options for the -new coronavirus ( -ncov) remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus ( -ncov) in vitro prevention and control of seasonal influenza with vaccines: recommendations of the advisory committee on immunization practices-united states, - influenza season are we ready for coronavirus disease arriving at schools? each author declares that he or she has no commercial associations (e.g. consultancies, stock ownership, equity interest, patent/licensing arrangement etc.) that might pose a conflict of interest in connection with the submitted article key: cord- - kax m authors: song, yang; zhang, min; yin, ling; wang, kunkun; zhou, yiyi; zhou, mi; lu, yun title: covid- treatment: close to a cure? – a rapid review of pharmacotherapies for the novel coronavirus date: - - journal: int j antimicrob agents doi: . /j.ijantimicag. . sha: doc_id: cord_uid: kax m currently, there is no approved therapy for covid- . the world health organization therefore endorse supportive care only. however, frontline clinicians and researchers have been experimenting with several virus-based and host-based therapeutics since the outbreak in china. china's national health commission has issued the first covid- treatment guideline with therapy suggestions ( (th) edition attached) which inspired following clinical studies worldwide. major therapeutics are evaluated in this review. key evidence from in vitro researches, animal models and clinical researches in emerging coronaviruses are examined. antiviral therapies remdesivir, lopinavir/ritonavir and umifenovir, if considered, could be initiated before the peak of viral replication for optimal outcomes. ribavirin may be beneficial as an add-on therapy and is ineffective as a monotherapy. corticosteroids use should be limited to indicating comorbidities. ivig is not recommended due to lack of data in covid- . xuebijing may benefit patients with complications of bacterial pneumonia or sepsis. the efficacy of interferon is unclear due to conflicting outcomes in coronavirus studies. chloroquine and hydroxychloroquine have shown in vitro inhibition of sars-cov- , and the studies on clinical efficacy and whether the benefits outweigh the risk of dysrhythmias remain inconclusive. for patients who developed cytokine release syndrome, interleukin- inhibitors may be beneficial. on december st, , several pneumonia cases linked to a seafood market in wuhan, china were reported to the world health organization (who). the fast-spreading infection, now known as coronavirus disease , is caused by a novel coronavirus (sars-cov- ) [ ] . on march th, , who declared covid- outbreak a pandemic * +. according to johns hopkins' covid- global case dashboard, by june th , june th, , there were , , confirmed cases and , total deaths worldwide [ ] . at present, there is no treatment specific for sars-cov- with efficacy proven by randomized controlled trials (rct). however, given the scale and rapid spread of this infectious disease, it is obligatory to take a deeper look at medication therapies that have been experimented by frontline clinicians and examine the clinical and laboratory evidence behind them. the selection of medications in this review is based the th edition of covid- diagnosis and treatment guideline issued by the national health commission (nhc) of the people's republic of china ( table ) and relevant clinical studies. although there are few published rcts on sars-cov- , the novel virus is found to share % genome sequence with severe acute respiratory syndrome coronavirus (sars-cov) and about % with middle east respiratory syndrome coronavirus (mers-cov) while manifesting overlapping pathogenesis [ , ] . relevant in vitro researches, animal models and clinical evidence in all coronaviruses and reviewed by june th june th, , in order to gain insights on the potential role of these medication therapies in combating covid- . data for this review were identified by searches of pubmed and references from relevant articles using the search terms "*medication name+" and "sars-cov- ", "coronavirus", "covid- ". only articles published in english and chinese (speaking languages of the authors) were included. patients-based clinical data, when available, were given priority over in vitro and in vivo data. randomized controlled trials, when available, were given priority over other studies. remdesivir (gs- ) is an investigational drug first developed for the treatment of ebola [ , ] . as an adenosine analogue prodrug, it putatively disrupts viral rna transcription and is viewed as a broadspectrum antiviral agent [ , , , ] . profoundly, remdesivir has exhibited mechanisms to overcome drug resistance and genetic mutations in coronavirus [ ] . patients with severe renal impairment (egfr< ml/min/ . ) or severe liver disease are excluded from receiving remdesivir [ , , ] . remdesivir is generally well tolerated with possible adverse effects of nausea, liver enzyme elevation, hypotension and respiratory failure [ , , , ] . in a mouse sars-cov model, remdesivir reduced viral burden and lung pathology efficiently. notably, when remdesivir was given after the peak of viral replication and airway epithelium damage, it no longer increased survival or reserved pulmonary function significantly [ ] . in february , results of remdesivir in the first nonhuman primate model of mers became available, revealing successful reduction of clinical signs, lung lesions, and viral replication [ ] . the regimen was started hours postinoculation, again signaling the importance of early initiation of therapy [ ] . in february , remdesivir produced high efficacy against sars-cov- in vitro (half maximal effective concentration ec = . μm; the % cytotoxic concentration cc > μm; the selectivity index si > . ) * +. the first covid- case in the united states was treated with remdesivir intravenously (iv) [ ] . within hours of remdesivir initiation, the patient became afebrile, off nasal cannulae, with chest rales resolved. however, the viral loads had been downward trending even before remdesivir treatment. it therefore cannot be determined if further viral load decrease and clinical improvement were a direct result of remdesivir. a case series of remdesivir compassionate use (n= ) reported % improved oxygenation, % discharge and % death. the study was weakened by many factors, including most significantly the lack of a paired control group [ ] . a double-blinded rct in china (n= ) revealed no superiority of remdesivir over placebo in time to clinical recovery, -day mortality and viral clearance [ ] . on average, remdesivir was initiated days post symptom onset, likely past the peak of viral replication. as covid- surge passed in china, the trial only recruited % of target sample size, reducing statistical power. simple, a phase open-label rct, revealed that remdesivir -day vs. -day regimens of mg once followed by mg iv daily produced similar outcomes. the group that started remdesivir early (< days of symptoms onset) had a higher discharge rate on day ( % vs %). the national institutes of health (nih) recently released preliminary result analysis of the adaptive covid- treatment trial (actt, n= ) [ ] . in this rct, remdesivir arm had % faster time to recovery than the placebo group (p< . ). mortality rate was also reduced in remdesivir group but not statistically significant ( % vs. . %, p= . ). the forthcoming full publication might reveal whether the promising outcomes were associated with early administration of remdesivir, as suggested by previous studies. by far, remdesivir has not shown significant mortality benefit. when initiated early, remdesivir appears to expedite recovery. as an investigative drug on incomplete trials, remdesivir is neither recommended nor disapproved by china's nhc and who [ , ] . currently, remdesivir is recommended by the nih for hospitalized severe covid- cases as defined by oxygenation needs [ ] . lopinavir/ritonavir (lpv/r) is a combination protease inhibitor approved for the treatment of human immunodeficiency virus (hiv) infection [ ] . lopinavir binds to viral protease and prevents cleavage of the gag-pol polyprotein, resulting in the production of immature, non-infectious viral particles. ritonavir increases the plasma concentration of lopinavir by inhibiting cytochrome p a (cyp a) metabolism. short-term side effects of lpv/r include nausea, diarrhea, abdominal pain, elevation of liver enzyme and prolongation of qt and pr interval [ ] . lopinavir showed in vitro cytopathic effect against sars-cov at μg/ml * +. although the trough ( . μg/ml) concentration of lopinavir was above μg/ml, the free drug concentration would likely be below the inhibitory threshold in the setting of high protein binding ( - %). the unfavorable pharmacodynamics are likely to limit the efficacy of lpv/r in covid- as well. during the severe acute respiratory syndrome (sars) outbreak, it appeared that lpv/r conferred clinical benefit in an early phase of the disease to reduce peak viral load before progression to acute respiratory distress syndrome (ards). when lpv/r was added to ribavirin and corticosteroids as initial treatment, the mortality and intubation rates were lower than among those who received it as rescue therapy ( . % vs. . %, % vs. % respectively, p< . ) in a multicenter retrospective cohort study [ ] . a hong kong study retrospectively evaluated the efficacy of lpv/r in patients with sars. patients from the historical control arm received ribavirin while those in the second arm received lpv/r in addition to ribavirin. the second group showed lower rates of days adverse outcomes (ards or death) when compared to the historical controls ( . % vs. . %, p< . ) [ ] . in a cohort study describing patients with covid- in singapore, five of patients with hypoxemia started lopinavir/ritonavir ( mg/ mg bid). two patients deteriorated and required admission to intensive care units (icu). both patients had persistent nasopharyngeal viral loads during their icu stay. limitations of the study include statistical underpowering, suboptimal dose of lopinavir/ritonavir, and delay on initiation of therapy or absence of combination therapy with ribavirin [ ] . the elacoi trial, a single-blind rct (preprint), included patients with mild to moderate covid- symptoms. there were no differences in the primary outcome of time to negative pharyngeal pcr test between the lpv/r, umifenovir and control groups ( . , and days, respectively). there were no differences in pyrexia, cough or lung ct findings at day and . five patients in the lpv/r group experienced adverse events including gastrointestinal symptoms and worsening liver function [ ] . on march th, the results of the first covid- clinical trial of lpv/r were published. unfortunately, lpv/r did not show superiority over standard care for time to achieve clinical improvement, -day mortality and viral clearance [ ] . in the trial, lpv/r shortened icu stay by a median of days ( % ci, − to ). the authors made valuable points that the study size is small and the antiviral medication might have been initiated too late in the course of infection. recommended against by the nih due to unfavorable pharmacodynamics and lack of proven clinical efficacy [ ] . ribavirin is a nucleoside analog which has antiviral activity against multiple rna viruses, including respiratory syncytial virus, sars-cov and mers-cov by interfering with rna polymerase and viral protein synthesis [ , ] . the most severe adverse effects are hemolytic anemia and leukopenia. other adverse effects include fatigue, pruritus, rash, and gout. ribavirin is a notorious teratogenic drug and is contraindicated in pregnancy [ , ] . ribavirin, with or without the concomitant use of steroids, was used extensively during the sars outbreak. in vitro tests showed that ribavirin inhibited a β coronavirus at relatively high concentration [ ] . however, when using ribavirin with interferon-α b combined, lower concentrations of ribavirin inhibited viral replication in vero cell lines [ ] . a prospective, uncontrolled study evaluated clinical outcomes of ribavirin and corticosteroids in patients with suspected sars when fever was not resolved after hours of hospital admission. twentyfive patients ( . %) responded to ribavirin and corticosteroids and two of those patients received ribavirin iv [ ] . approximately % to % of patients treated with ribavirin had a reduction in hemoglobin of more than g/dl from baseline, % to % had evidence of hemolytic anemia and % experienced elevation of transaminases [ , ] . in a phase open-label covid- trial, which enrolled patients from hong kong hospitals, hung and his colleagues compared triple therapy (lopinavir/ritonavir / mg po every hours, ribavirin mg po every hours, and interferon β- b million iu sq on alternative days) with a control group of lpv/r [ ] . median time from symptom onset to start of treatment was days. in an intent-to-treat analysis, the triple therapy group had a significantly shorter median time to negative pcr test (hr . , % ci . - . , p= . ), shorter clinical improvement and time to complete symptoms ( days vs. days, respectively) and shorter median hospital stay ( days vs. . days). there was no difference in the incidence of adverse events, serious adverse events or duration of nausea/vomiting. limitations of study include the open-label study design, absence of critically ill patients, and the confounding factor of a subgroup omitting concurrent interferon β - b if time of symptom onset was days or more. ribavirin iv is suggested by china's nhc for covid- as only an add-on therapy to lopinavir/ritonavir or interferon (table ) [ ]. it is not evaluated by the nih [ ] . interferon (ifn) induces several parallel antiviral pathways by triggering viral rna degradation, rna transcription alteration, protein synthesis inhibition, and apoptosis [ ] . the common side effects include flu-like symptoms and mood changes [ ] . it is contraindicated in patients with decompensated liver disease, severe autoimmune disease, worsening psychiatric conditions, cytopenia and uncontrolled seizures [ ] . during the sars and mers outbreaks, interferon was widely used for its antiviral effects after showing in vitro efficacy [ , ] . an open-label uncontrolled retrospective study on sars showed that the addition of alfacon- ® (ifn-α) to corticosteroids was associated with faster lung recovery and shorter intubation time compared to corticosteroids alone [ ] . similarly, a randomized, -arm, openlabel, retrospective study on sars in guangzhou, china demonstrated that ifn plus high dose steroid therapy achieved respiratory improvement, faster resolution of pulmonary infiltrates, and less need for mv [ ] . moreover, ifn combined with ribavirin was correlated with neither a faster viral clearance, nor an improved survival rate in older (> years old) critically-ill patients with comorbidities [ , , ] . in vitro data of interferon activity against sars-cov- suggested that the ec in vero cells of [ ] . corticosteroids are a type of anti-inflammatory medication that is effective in treatment of a variety of conditions such as asthma, allergic conditions, autoimmune diseases, septic shock, and cancers [ ] . corticosteroids are a double-edged sword since while these agents inhibit inflammation, they also impair immune response and increase the risk of infection. the adverse effects vary depending on the dosage and duration of therapy. these side effects include hyperglycemia, abdominal obesity, infection, mood swing, osteoporosis, growth retardation, glaucoma and hypertension [ ] . a systematic review of steroids administered to patients with sars reported no survival benefit and possible harm including avascular necrosis, psychosis, diabetes, and delayed viral clearance [ ] . another study of patients receiving corticosteroids for mers found no benefit in mortality but delayed lower respiratory tract clearance of the virus [ ] . since the outbreak of covid- , corticosteroid treatment has been used in up to % of infected patients in china [ , ] . one retrospective observational study showed % of the icu patients with covid- received glucocorticoid therapy [ ] . in covid- patients with ards, treatment with steroids is associated with decreased risk of death compared to the patients who did not receive steroids ( % vs . %) [ ] . however, the existing evidence regarding the use of steroids in this specific patient population remains inconclusive due to methodological limitations. [ ] . as of now, the use of corticosteroids to reduce cytokine-related pulmonary damage in patients with covid- pneumonia is controversial. robust evidence from well-designed clinical trials is needed for the recommendation of corticosteroid treatment in covid- patients who developed different complications. intravenous immunoglobulin (ivig) is a product of human immunoglobulins derived from plasma, indicated for various immunodeficiencies, autoimmune and inflammatory disorders [ , ] . ivig has potent immune replacement and immune modulating effects via complex pathways [ ] . in addition, ivig has anti-inflammatory properties and can neutralize bacterial toxins [ ] . the most common adverse reactions of ivig are headache, fever and tachycardia [ ] . currently, there is no solid clinical evidence to support the use of ivig in coronaviruses. several animal studies found that equine and bovine-produced human immune antibodies can reduce viral titers and accelerate viral clearance of mers-cov in mouse models [ ] . during the sars epidemic, observational studies and case reports described ivig for the treatment of critically ill patients in combination with antiviral therapies. in a clinical review on sars, ivig was used with interferon in all critically ill patients (n= ). the authors concluded that there was no significant benefit [ ] . in another prospective observational study, ivig was used in sars patients with severe leukopenia or thrombocytopenia, and it appeared to be effective for controlling cytopenia by increasing leukocyte and platelet counts. however, without a control group, ivig's role in sars treatment remains undetermined [ ] . since the outbreak of covid- in china, clinicians have used ivig in patients infected with sars-cov- based on extrapolated ivig data from sars and mers. in a descriptive study of covid- , % of patients received ivig, but the efficacy and safety of ivig in was not addressed in this study [ ] . several observational case reports suggest that high dose ivig at the early stage of clinical deterioration may improve clinical outcomes in patients with severe symptoms [ , ] . xuebijing (xbj) is a widely used traditional herbal medicine in china for its anti-inflammatory and antiendotoxin effects [ , ] . it is a five-herbal combination (carthamus tinctorius, radix paeoniae rubra, ligusticum wallichii, salvia miltirrhiza and angelica sinensis). the common side effects include infusion reactions of rash, tachycardia, hypotension and gi discomforts including nausea, vomiting, abdominal pain and/or diarrhea [ , ] . in a meta-analysis of case-control studies on sepsis, xbj significantly reduced -day mortality and improved clinical parameters including the acute physiology and chronic health evaluation ii score (apache ii), wbc, c-reactive protein (crp), procalcitonin and body temperature [ ] . that being said, the efficacy of xbj in sepsis needs to be confirmed in a rct. the current clinical data on xbj in ards are inconsistent. one rct showed reduction in duration of mv, icu stay and murray score, while the other rct revealed no difference in these clinical outcomes [ , ] . however, neither of the ards studies proved significant -day mortality benefit. further well-designed rct with larger sample size is warranted to conclude on xbj in ards. in a multicenter rct on critically-ill patients with severe community-acquired pneumonia (cap), xbj significantly improved pneumonia severity index, -day mortality, duration of mv, and icu stay [ ] . umifenovir is a synthetic antiviral drug marketed in russia and china for treating seasonal influenza. it has shown broad-spectrum antiviral activity against other viruses including sars-cov [ ] . it is generally well tolerated. umifenovir is used alone or in combination with other antiviral treatment in a few clinical studies. in one trial, a total of covid- non-icu patients were assigned to either umifenovir group or control group. the median times from onset of symptoms to sars-cov- rt-pcr negative were similar. no clinical differences were reported and the umifenovir group had slightly longer hospital stay ( d vs. d) [ ] . in a covid- case series study, the combination of umifenovir, lopinavir/ritonavir and traditional chinese medicine alleviated pneumonia symptoms in all four patients and decreased viral load to undetectable in two [ ] . a retrospective cohort study on non-ventilated covid- patients (n= ) compared lpv/r plus umifenovir and lpv/r monotherapy over treatment of - days [ ] . the lpv/r plus umifenovir combination group had a higher negative viral detection rate on day and day , with significantly improved chest ct scans on day . however, inflammation markers were not compared at baseline. the lpv/r monotherapy group had significantly higher corticosteroids usage, which could delay viral clearance. all available clinical studies on umifenovir are with significant limitations in study designs and sample sizes. it appears that umifenovir monotherapy is ineffective. the combination of umifenovir with other antivirals might benefit viral clearance and chest ct improvement. whether the positive outcome is achieved by using antiviral combination strategy or by adding umifenovir remains to be studied. all these studies should be treated as hypothesis generating and should be interpreted with great caution. umifenovir is a newly added antiviral option in china's nhc guide on covid- ( chloroquine (cq) is a classic antimalarial drug. its well-known effect of neutralizing acidic endosomal ph supports broad-spectrum antiviral usage by blocking endosome-mediated viral entry [ ] . it also exhibits anti-inflammatory and immunomodulatory benefits in viral infections. hcq is a less toxic metabolite of cq. both could be toxic and even fatal if overdosed [ , ] . the adverse effects include retinopathy, liver enzyme elevation, blood counts change and mood change. it is important to monitor drug interactions with other qtc-prolonging agents [ , ] . since the covid- outbreak, cq showed antiviral effect on sars-cov- in vitro, with the % effective concentration (ec ) of . μm, which is clinically achievable * +. hcq is even more potent in vitro (ec = . μm) against sars-cov- and a pharmacokinetic model found that a regimen of mg twice a day orally followed by mg twice a day orally for four days would achieve therapeutic level [ ] . an open-label non-randomized clinical trial in france studied hcq regimen of mg three times a day orally with and without azithromycin. the study reported % viral clearance on day in hcq plus azithromycin group vs. . % in hcq monotherapy group vs. . % in control group [ ] . however, the small-size trial (n= ) was not randomized. the hcq group had higher viral load at baseline. the control group had younger patients. six patients were excluded in results reporting. clinical outcomes were not studied. the first published rct assessing hcq in covid- was conducted in china (n= ) [ ] . clearance is expected to happen much sooner. it is worth noting that the soc arm is not a placebo. more than % patients in both arms received other antivirals. this introduces a great confounder, especially when there are no conclusions on the effect of antivirals in covid- yet. another small-size hcq trial in shanghai with similar outcomes had the same issue [ ] . the rct also reports higher adverse effect in hcq plus soc group ( % vs. %). this could be due to the high-dose regimen of hcq - mg daily. in june, a retrospective multicenter study (n= ) in american veterans with covid- showed hcq as ineffective and potentially harmful [ ] . hcq with or without azm did not decrease mortality, mv rate or length of hospitalization. the hcq group, but not hcq + azm group, even had higher risk of death. however, the study subjects were not randomized. naturally, patients with severe disease were more likely to start hcq treatment. in fact, both hcq and hcq + azm groups had more patients with elevated liver enzymes and inflammation markers, which are confounders that could affect study outcomes [ ] . a new york hospital reported qtc prolongation associated with hcq + azm (n= ) [ ] . qtc increased from a baseline of ± ms to a maximal value of ± ms (p < . ) on day . ± daily for days in all settings due to potential toxicity [ ] . tocilizumab (actemra®), known as a humanized interleukin- (il- ) receptor antagonist, is currently approved for rheumatoid arthritis, and cytokine release syndrome (crs) due to chimeric antigen receptor t cell (cart) therapy [ ] . the common side effects of tocilizumab include hypersensitivity reaction and infection [ ] . in covid- patients with crs, patients were found to have elevated levels of cytokines such as il- receptor (il- r), il- , , and tnfα that indicate inflammation and immunological diseases. in addition, crs was revealed to be associated with the severity of covid- [ , ] . these data suggest that the il- pathway may play an important role in the overactive inflammatory response in the lungs of covid- patients. therefore, it could be a potential target for immunotherapy of covid- . a recent one single-group, multicenter study showed that within a few days of administration of tocilizumab, fever was reduced to normal temperatures and oxygen intake was lowered in % of patients with severe or critical covid- . they also observed a significant improvement in ct imaging, abnormally elevated crp and lymphopenia. no obvious adverse reactions were identified in this study [ ] . it suggests that tocilizumab may be a new therapeutic strategy for treatment of severe or critical covid- patients, however, further data from large rcts are required to justify the efficacy and safety of tocilizumab. sarilumab (kevzara®) is another fully-human monoclonal antibody that inhibits the il- pathway by binding and blocking the il- receptor. it has been approved for the treatment of rheumatoid arthritis [ ] . the common toxicities include neutropenia, thrombocytopenia, infusion reaction and infection [ ] . the global clinical trials of sarilumab in covid- treatment have been initiated to evaluate the clinical outcomes such as fever, the need for supplemental oxygen, mortality, mv, icu stay and hospitalization [ ] . siltuximab (sylvant®) approved in the us to treat patients with multicentric castleman disease is the third potential il- targeted therapy for covid- trials [ ] . similar to other il- antagonists, the common adverse effects of siltuximab are cytopenia, infection and hypersensitivity reaction [ ] . ▪ based on respiratory distress and chest imaging, may consider glucocorticoid that is equivalent to methylprednisolone - mg/kg/day for - days or less. note that large-dose glucocorticoid suppresses immune system and could delay clearance of sars-cov- . ▪ may consider xuebijing ml iv twice a day. ▪ may use microecological preparation to maintain intestinal flora balance and prevent secondary infection. ▪ provide psychotherapy for patients who develop high level of anxiety. i. practice syndrome differentiation and dialectics-based medicine. general recommendations of traditional therapies are made for each stage of clinical course from initial, severe, critical to recovery stage. (note: please refer to the original guide for details.) severe case: respiratory rate ≥ per minutes, oxygen saturation ≤ %, pao /fio ≤ mmhg, or significant disease progression in - hours per chest imaging critical case: ards requiring mechanical ventilation, shock, or organ failure requiring icu care currently the guidance from who focuses on supportive care and the management of complications per general guidelines [ ] . remdesivir is moderately recommended by the nih for hospitalized severe cases [ ] . the covid- diagnosis and treatment guideline issued by china's nhc provides several medication therapy recommendations (table ) [ ]. all these therapeutics are discussed in this review. this review does not include darunavir/cobicistat, nitazoxanide, angiotensin ii receptor blockers and other medications that have been suggested for sars-cov- , awaiting evidence. this review does not discuss any oral-route traditional chinese medications, the prescribing of which follows dialecticsbased medicine. in conclusion, supportive care remains the cornerstone of covid- management. complications should be managed according to general guidelines. when safety is ensured, remdesivir might be considered early in the course of illness promptly prior to disease progression for potential clinical recovery. for the other medication agents discussed in the review, outcomes from case reports and case series cannot be generalized for a larger population. more well-designed rcts in covid- therapies are warranted before final conclusions on efficacy can be made. funding: this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. world health organization. pneumonia of unknown cause announcement world health organization. who announces covid- outbreak a pandemic the center for systems science and engineering at johns hopkins. covid- global case dashboard genomic characterisation and epidemiology of novel 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the use of siltuximab in ards patients diagnosed with covid- infection (sisco) use of siltuximab in patients with covid- pneumonia requiring ventilatory support ethical approval: not applicable for this review article key: cord- -xbpb nfi authors: ge, huipeng; wang, xiufen; yuan, xiangning; xiao, gong; wang, chengzhi; deng, tianci; yuan, qiongjing; xiao, xiangcheng title: the epidemiology and clinical information about covid- date: - - journal: eur j clin microbiol infect dis doi: . /s - - -z sha: doc_id: cord_uid: xbpb nfi in december , pneumonia of unknown cause occurred in wuhan, hubei province, china. on january , a novel coronavirus, named as severe acute respiratory syndrome coronavirus- (sars-cov- ), was identified in the throat swab sample of one patient. the world health organization (who) announced the epidemic disease caused by sars-cov- as coronavirus disease (covid- ). currently, covid- has spread widely around the world, affecting more than seventy countries. china, with a huge burden of this disease, has taken strong measures to control the spread and improve the curative rate of covid- . in this review, we summarized the epidemiological characteristics, clinical features, diagnosis, treatment, and prognosis of covid- . a comprehensive understanding will help to control the disease. at the end of , several cases of pneumonia with unknown etiology emerged in wuhan, hubei province, china [ ] [ ] [ ] . the pneumonia spread quickly to other provinces of china and overseas. at early stage, it was reported that most patients had the contact history with huanan seafood market [ ] [ ] [ ] . after that, more and more patients had fever and cough symptoms. on january , a novel coronavirus was identified in the throat swab sample of one patient by the chinese center for disease control and prevention (cdc), and was subsequently named as ncov by world health organization (who) [ , ] . as the situation got worse, the who declared the outbreak as the public health emergency of international concern (pheic) [ ] . on february , the international committee on taxonomy of viruses renamed the virus as severe acute respiratory syndrome coronaviruse- (sars-cov- ) [ ] . and who announced the epidemic disease caused by sars-cov- as coronavirus disease (covid- ) [ ] . this is the third coronavirus pneumonia in the past years around the world. in november , a novel betacoronavirus called severe acute respiratory syndrome coronavirus (sars-cov) emerged in guangdong, china, and resulted in more than infections and deaths in countries. in , middle east respiratory syndrome coronavirus (mers-cov), which was first detected in saudi arabia, affected individuals and caused fatalities [ , ] . after the outbreak of covid- , the chinese government has initiated a level- public health response to prevent the spread of the disease on january [ ] . as of : on march (beijing time), the sars-cov- has resulted in , laboratory and clinical confirmed cases in the mainland of china, and patient deaths [ ] . currently, there are many studies of sars-cov- and covid- . this review makes a comprehensive introduction about this disease, including the genome structure and receptor of sars-cov- , epidemiology, clinical features, diagnosis, treatment, and prognosis of covid- . we hope our work can provide more information in understanding this disease, and more research findings are needed to help to limit spread of the disease and to invent vaccine and specific drugs. huipeng ge and xiufen wang contributed equally to this work. about two thirds of the overall genome, encoding nonstructural proteins (nsps), while the remaining one-third encodes accessory proteins and structural proteins [ , ] . as shown in fig. , there are some slight differences in the reported genome structure, mainly in accessory proteins [ , , , [ ] [ ] [ ] . for example, the significant difference of two accessory proteins (orf b and orf ) on the gene sequence between sars-cov- and sars-cov was reported by several studies [ , ] . using the different genome sequences as comparison can partly account for the results. as for the novel proteins of sars-cov- , whether involving in pathogenesis of the virus or not is unclear. inspired by the pathogenesis of sars-cov, the sars-cov- was presumed to infect the human cells by spike glycoprotein binding to its cellular receptor, angiotensinconverting enzyme (ace ). in fact, current evidence supports this idea. as for the spike protein of sars-cov- , it contains two regions, s subunit and s subunit, which consists of amino acids [ ] . the amino acid identity of spike protein between sars-cov- and sars-cov was about % [ , ] . generally, s domain is linked to receptor binding; s domain is linked to cell membrane fusion. similar to sars-cov, s contains the n-terminal domain (ntd) and a receptor-binding domain (rbd) which contains core domain and external subdomain (esd). s contains three functional domains, fusion peptide (fp), and heptad repeat (hr) and (fig. ) . whether sars-cov- can combine with host cells or not is determined by the affinity between the viral rbd and ace of human cells [ ] . once rbd binds to the receptor, the s changes conformation to facilitate the membrane fusion by three functional domains. although sars-cov is not the closest to sars-cov- at the wholegenome level, the rbd of sars-cov- is closer to that of [ , , , [ ] [ ] [ ] . orf = open reading frame (orange). structural proteins including s, e, m, n (blue) (s = spike, e = envelope, m = membrane, n = nucleocapsid). accessory proteins including , a, b, , , , a, b, b, , (purple). sp = signal peptide. s = subunit . s = subunit . ntd = n-terminal domain. rbd = receptor binding domain. esd = external subdomain. fp = fusion peptide. hr = heptad repeat . hr = heptad repeat . tm = transmembrane domain. cp = cytoplasmic domain. the length of genes is not drawn in scale sars-cov, and - . % amino acid sequences of rbd in both are identical [ , , ] . several critical residues in sars-cov- rbd have good interactions with human ace . most residues of rbd interacting with ace are fully conserved [ , ] . as for function domains of s , there is no difference between sars-cov- and sars-cov except some non-critical amino acids in hr region [ ] . another strong piece of evidence supporting ace as a receptor of cells is that hr and hr domain of sars-cov- can fuse with each other to form -hb following sars-cov's fusion mechanism [ ] . despite this, several studies speculated sars-cov- has less affinity with ace than sars-cov [ , , ] . on the contrary, chen et al. [ ] reported sars-cov- provided a stronger interaction with ace than sars-cov by structure analysis of the receptor binding of sars-cov- . by elucidating cryo-em structure of sars-cov- spike protein, wrapp et al. [ ] also found that compared with sars-cov, sars-cov- bound to ace with -to fold higher affinity. in order to identify the suppose of entering cellular by ace , peng et al. [ ] found that sars-cov- was able to use ace protein of many kinds of cells, including human cells, as an entry receptor in the ace -expressing cells, but not cells without ace . it also could not use aminopeptidase n and dipeptidyl peptidase which are other coronaviruses' receptors. in most recent studies, the results provided direct evidence to support ace as the receptor. yan et al. [ ] reported the ace -b at (a neutral amino acid transporter) complex can combine with two spike proteins by structural modeling in a structure analysis of fulllength human ace , and the extracellular peptidase domain (pd) of ace has the direct interaction with polar residues of rbd [ , ] . overall, there is sufficient evidence to support that sars-cov- infects cells by using the human ace . as the cryo-em structure of spike protein and human ace were revealed successfully, we have more opportunity to clarify the detailed process of entering cells [ , , ] . in early studies, - % patients had the contact history of huanan seafood market, where various kinds of living wild animals were on sale, including poultry, bats, and marmots [ , , ] . it is currently speculated that the outbreak of covid- in wuhan is associated with wild animals. according to who, the environmental samples taken from huanan seafood market were tested positive for sars-cov- [ ] , but the specific animals associated with the virus have not been identified. based on previous evidence, the bats, the host of more than coronaviruses [ ] , may be the origin of covid- . the bats are the natural reservoir of sars-cov and mers-cov, and spread to human through the palm civets and dromedary camels, respectively [ ] . the ratg , which is a short rna-dependent rna polymerase (rdrp) region from a bat coronavirus, was closest to sars-cov- with . - . % identity in whole-genome sequence [ , , , ] . the other two bat-derived sars-like coronaviruses, bat-sl-covzxc and bat-sl-covzc , were closer to sars-cov- than sars-covand mers-cov, which have approximately % nucleotide identity [ , [ ] [ ] [ ] [ ] . as for the intermediate hosts of sars-cov- , recent studies suggested pangolins were the most probable animal. two sub-lineages of sars-cov- were found in organs of pangolins obtained from anti-smuggling activities in guangdong and guangxi province of china by metagenomic sequence [ ] . xiao et al. [ ] reported the sars-cov- was derived from the reorganization of pangolin-cov-like virus and a bat-cov-ratg -like virus. however, the pangolin may not be the only intermediate reservoir, because sars-cov- was not originated from pangolin-cov-like virus directly, which was demonstrated by the molecular and phylogenetic analyses in liu's study [ ] . to sum up, the bats are the most probable original reservoir based on the current evidence. however, it is notable that wuhan huanan seafood market may not be the only source of sars-cov- spreading globally. cohen pointed out wuhan huanan seafood market was not the only origin of sars-cov- by analyzing the epidemiology of cases in the earliest study [ ] . pangolins may act as one of intermediate hosts. more work is needed to provide more precise information about original reservoir and intermediate hosts of sars-cov- . table lists some information of studies about the genome sequence identity with sars-cov- . transmissibility is an important factor of an epidemic [ ] . data as reported by am cet on march , sars-cov- has been responsible for , confirmed cases with ( . %) deaths around the world [ ] . the reported median age of patients was ranged from to years [ , , ] . male made up the majority of patients with the proportion of - % [ ] [ ] [ ] ] . due to different data sources, the infection rate of medical staff has a huge difference, with . - % [ , ] . approximately . - . % sars-cov- infected patients had one or more underlying diseases (table ) , including hypertension, diabetes, chronic obstructive pulmonary disease, cardiovascular disease, and malignancy [ - , , ] . the covid- 's median incubation period from exposure to illness onset was . days in a -case cohort and . days in a -case cohort [ , ] . it was also reported the longest incubation period was days [ ] . the percentage of patients exposed to huanan seafood market varies between . % and % [ ] [ ] [ ] ] . patients with no contact history of huanan seafood market and medical staff infection [ , , ] indicated human-to-human transmission mainly via droplets from coughing or sneezing or direct contact [ , [ ] [ ] [ ] [ ] . in addition, several studies reported fecal-mouth pathway may also be a potential way for the transmission of sars-cov- [ , ] , and the sars-cov- was also isolated from urine of a patient in a recent new [ ] . but it is unclear whether humanto-human transmission can be implemented by the above routes. the basic reproduction number r , the important property of transmission, is commonly used to estimate the average number of secondary cases generated by an infectious case in a fully susceptible population during the early phase of the outbreak [ , ] . if the r is more than , human-tohuman transmission may persist. a range from . to . of r was estimated by various methods [ , [ ] [ ] [ ] . the different values of estimated r can attribute to different data and different modeling methods [ ] . liu et al. [ ] came to conclusion that the average of estimate r was . with a median of . by an analysis of studies. so, around - is indeed a reliable range, suggesting the potential of sustained human-to-human transmission [ , ] . additionally, so many factors can affect the value of r , including estimation period, utilized models, and datasets [ ] . as various aspects of measures have taken effect, the estimated r is mutable. as david said, it is impossible to know what will happen so early in this sars-cov- epidemic [ ] . the initial r estimation for sars-cov was more than . , but the predicted large outbreak did not occur [ , ] . it is also notable that asymptomatic patients can also be a source of infection [ , ] . the super communicator is worthy of notice, who can infect more than individuals [ ] . the immediate priority is to clarify all potential routes of transmission. after all, superspreading has a huge impact on the epidemic. anyway, it is necessary for us to take effective measures and keep alert to control the epidemic. fortunately, the number of confirmed cases maintains at a lower level in mainland of china with confirmed cases on march [ ] . at this critical period, it is apparently wise to continue taking steps to control the outbreak. the clinical manifestations of sars-cov- -infected patients ranged from mild non-specific symptoms to severe pneumonia with organ function damage. the common symptoms were fever ( . - . %), cough ( . - . %), fatigue ( . - . %), dyspnea ( . - . %), myalgia ( . - . %), sputum production ( . - . %), and headache ( . - . %) [ - , , ] (table ). sore throat, rhinorrhea, chest pain, hemoptysis, conjunctival congestion, diarrhea, nausea, and vomiting were less common [ - , , ] . but one study showed . % of confirmed covid- patients had gastrointestinal symptoms [ ] , and . % patients presented with gastrointestinal discomfort at onset in wang's study [ ] . patients did not necessarily have fever at onset, some patients developed after hospitalization [ ] , and some severe patients even did not have fever. sars-cov- , sars-cov, and mers-cov infections share many similar clinical symptoms [ ] , including fever, cough, myalgia, and dyspnea. however, patients with sars and mers have more gastrointestinal involvement (about one-third) than covid- patients [ ] . and mers has a high incidence of renal failure, which is a typical characteristic not often found in other human coronavirus infections [ , ] . of confirmed patients, . - . %, . - . %, and . - . % had lymphopenia, thrombocytopenia, and leukopenia, respectively [ - , , ] ( table ) . c-reactive protein (crp), erythrocyte sedimentation rate (esr), serum ferritin, and interleukin- (il ) elevated prominently in chen's research [ ] . many patients also had increased levels of d-dimer, lactate dehydrogenase (ldh), creatine kinase (ck), prolonged prothrombin time, alanine aminotransferase (alt), and aspartate aminotransferase (ast) [ - , , , ] . however, elevated levels of procalcitonin, troponin i, and creatinine were uncommon [ , , ] . the typical imaging features of chest computed tomography (ct) for novel coronavirus pneumonia (ncp) included ground-glass opacity, bilateral patchy shadows, and subsegmental areas of consolidation, sometimes with a rounded morphology and a peripheral lung distribution [ - , , , ] . changes in the disease were accompanied by changes in ct imaging, reflecting the severity of the disease [ ] . pan et al. [ ] analyzed ncp patients from initial diagnosis until recovery (without severe respiratory distress during a hospital stay), and they found chest ct scan showed that the lung abnormalities were the most severe about days after the initial symptoms onset. overall, the ct manifestations of ncp were diverse and fast-changing [ ] . however, a normal chest ct image cannot exclude the diagnosis of sars-cov- infection [ ] . by obtaining biopsy samples at autopsy of one covid- patient [ ] , the lung biopsy specimens showed bilateral diffuse alveolar damage with cellular fibromyxoid exudates. bilateral lung tissue indicated pulmonary edema with hyaline membrane formation, reflecting ards. meanwhile, flow cytometric analysis of peripheral blood suggested the reduced counts of peripheral cd and cd t cells but a hyperactivated status. a report on systemic anatomy at autopsy from the other patient [ ] indicated gray white patchy lesions in lungs, gray white viscous fluid overflow in the lung section, and pulmonary fiber bands, reflecting that covid- caused an inflammatory response characterized by deep airway and alveolar damage. the pathological results of the first one resembled those seen in sars-cov and mers-cov infection [ ] . however, the latter found pulmonary fibrosis and consolidation were less severe than sars, but exudation was more obvious [ ] . these findings, with more pathological ards, acute respiratory distress syndrome; crp, c-reactive protein; ldh, lactose dehydrogenase; ck, creatinine kinase; alt, alanine aminotransferase; ast, aspartate aminotransferase; esr, erythrocyte sedimentation rate research, will make a great importance in understanding the pathogenesis and making therapeutic strategy for covid- . the covid- patients around the world were diagnosed based on world health organization interim guidance [ ] , and china updated the novel coronavirus pneumonia diagnosis and treatment program (trial version) (in chinese) according to epidemic situation and improved awareness of disease. a laboratory confirmed case with sars-cov- infection was defined as a positive result to high-throughput sequencing or real-time reverse-transcriptase polymerase-chain-reaction (rt-pcr) assay for sars-cov- [ , ] . chest ct, as a diagnostic method for covid- with a high sensitivity, is being given more important value for diagnosis [ ] . in the fifth trial version of novel coronavirus pneumonia diagnosis and treatment program (in chinese) [ ] , clinical diagnosis was proposed for cases in hubei province, who had epidemiology history, the above clinical features along with typical chest ct imaging. and more than , patients for clinical diagnosis got early treatment [ ] . the sixth trial version (in chinese) removed the clinical diagnosis, for reduced suspected cases and improved nucleic acid detection capability [ ] . in several clinical studies of confirmed cases, strategies for covid- patients included antiviral treatment, empirical antibiotic treatment, corticosteroid, intravenous immunoglobulin therapy, oxygen support (nasal cannula, mask oxygen inhalation, non-invasive ventilation, invasive mechanical ventilation), continuous renal replacement therapy (crrt), and extracorporeal membrane oxygenation (ecmo) [ - , , ] . due to the absence of clinical evidence, there were no approved drugs for antiviral therapy against sars-cov- . of three clinical cohort studies, oseltamivir was used for antiviral therapy in . % ( / ) patients, . % ( / ) patients, and . % ( / ) patients, respectively [ , , ] . another research [ ] included covid- patients, in which . % patients received antiviral treatment, including oseltamivir, ganciclovir, and lopinavir and ritonavir tablets, and the duration of antiviral treatment was - days. though oseltamivir had high application rate in the early cohort studies, its drug efficacy on covid- was not obvious, and the sixth trial version of novel coronavirus pneumonia diagnosis and treatment program (in chinese) did not recommend it [ ] . case report implied that lopinavir and ritonavir therapy may be beneficial for covid- cases [ , ] . remdesivir, a nucleotide analogue rna polymerase inhibitor with broad-spectrum antiviral activity, was demonstrated that it could be against ebola virus in rhesus monkeys [ ] . wang et al. [ ] found that remdesivir and chloroquine were highly effective in the control of sars-cov- infection in vitro. what's more, the first reported covid- case of the usa was cured by intravenous remdesivir [ ] and other supportive care. more researches from cells, animals, and clinical need to explore the effect of remdesivir on sars-cov- . other methods of antiviral drug administration may also have some certain function. it was reported that different combinations of interferon alpha inhalation, lopinavir/ritonavir, and arbidol may have some effects [ ] . furthermore, combined chinese and western medicine treatment, including lopinavir/ ritonavir, arbidol, and shufeng jiedu capsule (a traditional chinese medicine) may also be beneficial to treatment which deserved further study [ ] . as for the corticosteroid therapy for sars-cov- , current interim guidance from who on clinical management of severe acute respiratory infection, when sars-cov- infection is suspected (released jan , ), suggests not routinely using systemic corticosteroids unless indicated for another reason [ ] , and there were contradictory opinions from professors [ , ] . corticosteroid therapy was used in approximately - . % covid- patients [ - , , ] . compared with non-severe patients, severe patients got more corticosteroid therapy ( . % vs. . %) with the median of maximal daily dose up to . ( . - . ) (mg/kg) [ ] . according to pathological findings of one covid- patient, proper use of corticosteroid together with other support care should be considered for the severe patients to prevent ards development [ ] . there are more than running or pending clinical trials on potential treatments for covid- in china [ ] . studies of recombinant human angiotensin-converting enzyme (rhace ), mesenchymal stem cell, pd- blocking antibody, bevacizumab injection, and immunoglobulin of cured patients are registered in the website of clinical trial [ ] , and some are recruiting patients. safe and effective clinical trials will find more therapeutic possibilities for covid- patients. many patients infected withsars-cov- , especially for severe patients, had complications (table ) , including ards, shock, acute renal injury, acute cardiac injury, and secondary infection [ ] [ ] [ ] ] . the mortality rate of covid- ranged from to . % [ - , , , ] . however, yang et al. [ ] reported of ( . %) critically ill adult icu patients had died at days. it is not hard to know the disease severity is an independent predictor of poor prognosis [ , ] . compared with non-icu patients, the icu patients were older with a greater number of comorbid conditions and had more common symptoms of dyspnea, abdominal pain, and anorexia [ ] . meanwhile, it was reported that icu patients had higher plasma cytokine and chemokine levels of il , il , il , gscf, ip , mcp , mip a, and tnfα [ ] . non-survivors had more severe lymphopenia and higher blood cell counts, neutrophil counts, d-dimer and fibrin degradation product than survivors [ , ] . wang et al. [ ] analyzed the first deaths up to january , announced by the china national health commission found that the median days from first symptom to death were . (range - ) days, and seemed to be shorter among old people [ ] . in yang's study [ ] , the survival time of the non-survivors is likely to be within - weeks after icu admission. in summary, severe patients or icu patients have a relatively higher mortality [ , ] . age, comorbidity, some symptoms (dyspnea, abdominal pain, etc.), and more prominent laboratory abnormalities (lymphopenia, elevated d-dimer, etc.) may be risk factors for poor outcome [ , , , ] . according to the latest data released at : on march (beijing time), the fatality is . % and . % for the mainland of china and wuhan, hubei province, respectively [ ] . overall, sars-cov- has a relatively lower mortality rate than sars-cov and mers-cov ( . % and . %, respectively) [ ] . covid- has spread to countries, territories, or areas around the world, and is responsible for , patients as of am cet on march . the virus may be related to bats, but wuhan huanan seafood market may not be its sole origin. whatever the case, banning of wildlife sales and removing them from wet markets are beneficial to control the epidemic. except several genes of accessory proteins, sars-cov- is almost identical to sars-cov in genome organization. hence, we obtain the fact that ace is the receptor of sars-cov- entering cells. human to human transmission can be realized mainly by droplets from coughing or sneezing or direct contact. fever and cough are the main symptoms. chest ct examination is an important tool for diagnosis, and confirmed cases are diagnosed by detecting sars-cov- of specimens taken from the upper respiratory tract and lower respiratory tract. as for the treatment, there are no specific drugs for the infection, and many therapies, with preliminary good clinical response, are being tested in clinical trials. we hope that increased awareness of the virus and ongoing clinical trials can help to find effective treatment against sars-cov- . though the fatality of sars-cov- is lower than sars-cov and mers-cov, the overall mortality of sars-cov- remains to be established in the future, because a large number of confirmed and suspected cases are still in hospital; even worse, the confirmed cases are increasing in other countries, like korea and japan. further study is necessary for us to control this epidemic disease. authors' contribution huipeng ge, xiufen wang: manuscript writing, bibliographic retrieval, making tables and figure. xiangning yuan, gong xiao, chengzhi wang, tianci deng: manuscript writing. qiongjing yuan, xiangcheng xiao: manuscript editing and critical review. conflict of interest all authors declared that they had no conflicts of interest. clinical features of patients infected with novel coronavirus in wuhan epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan what next for the coronavirus response notice of 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mani title: the covid- : current understanding date: - - journal: vet world doi: . /vetworld. . - sha: doc_id: cord_uid: e f sfl in december , china reported several cases of a new coronavirus disease (covid- ). the covid- outbreak, which was initially limited to wuhan, china, has rapidly spread worldwide. infection of the disease occurs through exposure to the virus through inhalation of respiratory droplets or if a person touches a mucosal surface after touching an object with the virus on it. the common symptoms of covid- are fever, dry cough, dyspnea (difficult or labored breathing), fatigue, chest pain, and myalgia (muscle pain), etc. real-time polymerase chain reaction is used to detect the virus in sputum, throat, nasal swabs, and secretion of lower respiratory samples. early diagnosis, isolation, and supportive care are necessary for the treatment of the patients. the present review aims to provide recent information on covid- related to its epidemiology, clinical symptoms, and management. this article also summarizes the current understanding of severe acute respiratory syndrome coronavirus- and its history of origin. on december , , the municipal health authority of wuhan in the hubei province of china reported several cases of pneumonia of an unknown etiology. all the patients had a common exposure to the hunan seafood market [ ] [ ] [ ] . on january , , the chinese center for disease control and prevention discovered a novel coronavirus from a throat swab sample of one of those patients. initially, the world health organization named it ncov [ , ] , but later on february , , it was renamed as severe acute respiratory syndrome coronavirus- (sars-cov- ) by icvt, and who designated the disease as coronavirus disease [ , ] . before the covid- , the two outbreaks of coronavirus are middle east respiratory syndrome coronavirus (mers-cov) and sars-cov. both occurred over the past years, mers was first detected in saudi arabia in and affected people with mortalities [ ] , and sars was originated from guangdong (china) in and resulted in more than infections and deaths in countries [ ] . the covid- outbreak, which was initially limited to wuhan, has rapidly spread worldwide. as of now, august , , , , cases, and , deaths have been reported globally [ ] . covid- made its entry into india through various international travels. the first laboratory-confirmed case of covid- was reported from kerala on january , [ ] . now, it has spread in almost every part of india. according to the ministry of health and family welfare, currently, there are , active cases of covid- in india [ ] . researchers from all over the world are working very closely and efficiently on this pandemic [ , ] . as several studies are currently in progress, new revelations are emerging every day. therefore, this article aims to provide recent information about the covid- and the relation to its epidemiology, clinical symptoms, and treatments. this article also summarizes the current understanding of sars-cov- and its history of origin. covid- causing virus (sars-cov- ) belongs to the coronaviridae family under nidovirales order [ ] . further, this family consists of two subfamilies; coronavirinae and torovirinae, and within the coronavirinae, there are four genera: (a) alphacoronavirus; this includes the human coronavirus human coronavirus (hcov)- e and hcov-nl , (b) beta-coronavirus; this contains sars-hcov, hcov-hkv , and mers-cov, (c) gamma-coronavirus; this covers the viruses of whales and birds, and (d) delta-coronavirus; this includes viruses from pigs and birds [ ] . sars-cov- comes within the beta-coronavirus genus, which also contains two deadly viruses: sars-cov and mers-cov. betacoronavirus genus consists of many subgroups. the sars-cov- , sars-cov, and bat sars-like cov belong to sarbecovirus, whereas the mers-cov belongs to merbecovirus [ , ] . sars-cov- is an enveloped, single-stranded, and positive-sense rna copyright: tripathi and tripathi. open access. this article is distributed under the terms of the creative commons attribution . international license (http://creativecommons.org/licenses/ by/ . /), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the creative commons license, and indicate if changes were made. the creative commons public domain dedication waiver (http:// creativecommons.org/publicdomain/zero/ . /) applies to the data made available in this article, unless otherwise stated. virus [ ] . the size of this virus ranges from to nm in diameter, and the size of single-stranded rna varies from to kbs [ ] . the crown-like spikes on the outer surface of the virus give it the name of corona [ ] . spikes are glycoprotein in nature and responsible for host attachment [ ] . other proteins of coronaviruses include nucleoprotein, membrane proteins, and accessory proteins [ , ] . beta-coronavirus found in pangolins and bat coronavirus (ratg ) isolated from rhinolophus affinis might be the parental viruses responsible for the origin of sars-cov- [ , ] . bat coronavirus (ratg ) shares . % genome sequence identity with sars-cov- [ ] . despite the genomic similarity, ratg might not be the immediate ancestor of sars-cov- because of disparity in receptor binding protein domain (unlike the sars-cov- , it does not use the ace receptor of the host cell for entrance). whereas, virus from pangolins uses the same receptor (ace ) but differs in the overall genome sequence, thus, ruling out its possibility of being an immediate ancestor of sars-cov- too. however, the virus isolated from pangolins is closely related to both; sars-cov- and ratg . therefore, bats might be the original host of sars-cov- [ ] . in late december , several residents of wuhan, the capital of the hubei province of china, visited the hospital with complaints of fever, dry cough, fatigue, and infrequent gastrointestinal symptoms [ ] . all the cases had a common exposure to a seafood wholesale wet market, the hunan wholesale seafood markets [ ] . however, the first laboratory-confirmed case of covid- was on december , [ ] . on december , , china issued an epidemiologic alert and notified who about this mysterious disease. on january , , authorities shut down the hunan seafood market, assuming it the source of this virus, as several environmental samples of this market had tested positive for sars-cov- [ ] . however, based on a genomic study, research suggested that the virus came into the market from an unknown location [ ] . in china, patients were increasing rapidly, and soon after, a large number of patients started coming into the hospital with no history of exposure to the live market. reported cases of clusters of families suggested human to human transmission of this virus [ ] . due to heavy transportation load and the massive migration of the chinese population, during the chinese new year festival, several new cases were being reported in many cities and provinces of china. as several tourists had also visited china during this period, they returned to their home country with this deadly virus. thailand recorded the first exported case of covid- on january , [ ] . soon after, several other countries reported its first confirmed cases. on january , , india started thermal screening of passengers arriving from china at seven airports (delhi, mumbai, kolkata, chennai, bangalore, hyderabad, and cochin) to fight covid- . later, the government extended thermal screening to up to airports [ ] . these efforts did not work as effectively as hoped, and india recorded its first case of covid- of a student from kerala on january , ; she had just returned from wuhan [ ] . soon after, other states reported its first confirmed cases of covid- . as numbers of cases were increasing daily, the govt. of india imposed a nationwide lockdown on march , , to control the spread of this disease [ ] . till the date of writing this article (august , ), a total number of + laboratory-confirmed cases of covid- from states and union territories, out of which , , ( . %) recovered, while , ( . %) deaths are reported in india [ , ] . maharashtra is the worst affected state with a total number of confirmed cases of , (https://arogya. maharashtra.gov.in/ /novel--corona-virus seen on august , ). the frequency of confirmed cases has been increasing rapidly, and india is on the rd position in a tally of worst-affected countries globally [ ] . genome analysis of sars-cov- revealed that the ' end of the sars-cov- genome contains orf ab, and this orf ab occupies the majority of the genome. orf ab encodes for polyprotein pp ab and which comprises nonstructural proteins. the '-end of the genome contains four structural proteins and eight accessory proteins such as a, , , , and [ ] . viruses can undergo mutation, and the genome of rna viruses can mutate million times higher than the host genome. these mutations can be either harmful or beneficial to the virus [ ] . phylogenetic analysis of indian sars-cov- isolates suggests that these are strongly related to isolates reported from other parts of the world. most orfs are highly conserved, whereas mutations were also identified in some orfs. the study further revealed that most isolates from india have key mutations at th position of the s protein and th position of the orf , which has been reported to be associated with high virulence and high transmission rate [ ] . soon, it was clear that the infection of covid- occurs through exposure to the virus through inhalation of respiratory droplets or if a person touches a mucosal surface after touching an object with the virus on it [ ] . a study reported the presence of sars-cov- in stools suggesting the possibility of fecal-oral route transmission [ ] . infection through conjunctiva is also possible [ ] . initially, scientists believed that newborns could get an infection from covid- positive mothers. however, a researcher ruled out the intrauterine transmission in its study, where nine newborns did not contract the disease from their mothers [ ] . although all age groups and genders are susceptible to the attack of this virus, mostly male patients of the - age group have been reported [ , ] . elderly and people with weak immune function and hepatic dysfunction are more at risk [ ] . available at www.veterinaryworld.org/vol. /september- / .pdf sars-cov- is highly infectious, with an effective reproductive number of . (higher than sars-cov- . ) [ , ] . the mortality rate of covid- is . % globally and . % in india [ ] . the lower mortality rate in india might be due to its demographic constitution. however, due to lack of testing and surveillance, there is a possibility that the number of deaths related to covid- could not be differentiated hence not reported. india reported a . % recovery rate for covid- [ ] . according to the world health organization, covid- affects different people in different ways. on average, it takes - days from when someone is infected with the virus for symptoms to show; however, it could also possibly take up to days [ ] . most infected people will develop mild-to-moderate illness symptoms and recover without hospitalization. the most common symptoms include fever, dry cough, and tiredness, and less common symptoms are aches and pains, sore throat, diarrhea, conjunctivitis, headache, loss of taste or smell, and a rash on the skin, or discoloration of fingers or toes [ ] . severe symptoms such as difficulty in breathing or shortness of breath, chest pain or pressure, and loss of speech or movement, require immediate medical attention [ ] . according to the ministry of family and health welfare of india; a suspected case is defined as a patient with acute respiratory illness (fever and at least one sign/symptom of respiratory disease, e.g., cough, and shortness of breath) and a history of travel to or residence in a location reporting community transmission of covid- , days prior of the beginning of symptoms. it is also defined as a patient with an acute respiratory illness and has been in contact with a confirmed or probable covid- case in the past days before symptom onset; ora patient with severe acute respiratory illness (fever and at least one sign/ symptom of respiratory disease, e.g., cough, shortness of breath; and requiring hospitalization). in the absence of an alternative diagnosis that thoroughly explains the clinical presentation, a probable case is a suspect case for whom testing for the covid- virus is inconclusive or a suspect case for whom testing could not be performed for any reason, and, a confirmed case is a person with laboratory confirmation of covid- infection, irrespective of clinical signs and symptoms [ ] . the definition of a confirmed or suspected case differs from country to country. the testing strategy in india used for covid- is discussed below [ ] ; real-time polymerase chain reaction (rt-pcr) is the gold standard test for detecting cases of covid- . the average time taken is around - h from receipt of a sample to getting the result. the advantage of this platform lies in its accuracy of detection as well as the ability to run up to samples in a single run. whenever possible, it is advised to use rt-pcr as the frontline test for the diagnosis of sars-cov- . the truenat and cbnaat systems have also been deployed for the diagnosis of covid- given the availability of customized cartridges. these platforms have a quick turnaround time ( - min), but only - samples can be tested in one run, limiting the maximum numbers that can be tested to - samples/day only. rapid point-of-care antigen detection test (for diagnosis along with rt-pcr): this test is a promising tool for quick diagnosis of sars-cov- in field settings. the assay is known as standard q covid- ag kit and has been developed by sd biosensor with a manufacturing unit at manesar, gurugram. on validation, the test has been found to have a very high specificity with moderate sensitivity. igg antibody test for covid- (only for surveillance and not diagnosis): igg antibodies generally start appearing after weeks of the onset of infection, once the individual has recovered after infection, and last for several months. to ramp up testing capacity, icmr has approved a total of covid- testing labs in both public ( ) and private sector ( ). this includes rt-pcr labs ( ); truenat labs ( ); and cbnaat labs ( ) [ ] . at present, there is no specific treatment available for covid- [ ] . isolation is the first step in managing the virus. symptomatic supportive care such as oxygen therapy, fluid management, maintenance of vital signs and blood pressure, and treatment of secondary bacterial infection with the antibiotic is recommended [ ] . some victims of covid- developed ards and septic shock very rapidly, eventually leading to multiple organ failure [ , ] . therefore, early recognition of the suspected case and immediate isolation for the containment of disease is necessary [ ] . national institute of health (nih), usa, recommended the following guidelines to treat covid- and severe conditions caused by covid- [ ] . it is an old anti-malarial drug, which has shown an in vitro inhibitory effect on the growth of sars-cov- [ ] . recent studies from china and france observed that the administration of this drug in covid- patients produced significant results in both clinical outcomes as well as in viral clearance [ , ] . chloroquine/hydroxychloroquine, when given with azithromycin, yielded better results [ ] . the govt. of india has also recommended the same combination of these drugs for the management of covid- [ ] . however, the usa food and drug administration (fda) only allows this drug for the treatment of particular adolescent and adult patients hospitalized for covid- . recently, the world health organization suspended all its clinical trials as few studies suggested a high mortality risk of this drug. therefore, more researches are needed to establish the safety and efficacy of this drug. this therapy utilizes plasma of covid- recovered patients to treat other patients. several studies reported a shorter hospital stay and lower mortality rate in sars patients treated with convalescent plasma than those who were not treated with it [ ] [ ] [ ] . recently a medical practitioner from shanghai used plasma therapy to treat covid- patients and yielded positive results with rapid recovery, suggesting it could be a potential treatment for covid- patients. however, more clinical trials are needed to prove the safety and effectiveness of convalescent plasma transfusion in sars-cov- infected patients [ ] . researchers developed this antiviral drug to treat ebola, mers, and sars-cov. it is a monophosphide prodrug that acts as a nucleotide inhibitor and causes premature termination of viral rna replication [ ] . it has also shown interference with the nsp polymerase of sars-cov- in the in vitro study [ ] . some studies also reported that remdesivir alone and in combination with chloroquine and beta interferon blocked the sars-cov- [ , , ] . patients with severe covid- can develop a systemic inflammatory response that can lead to lung injury and multisystem organ dysfunction. it has been suggested that the anti-inflammatory effects of corticosteroids might prevent or mitigate these deleterious effects [ ] . therefore, the covid- treatment guidelines panel of the nih recommends using dexamethasone mg/day for up to days for the treatment of covid- in mechanically ventilated (ai) patients and in those patients who require supplemental oxygen but not the mechanical ventilation (bi) [ ] . apart from these therapies, researches on antiviral drugs and vaccines are in progress which includes: lopinavir and ritonavir are the two most critical potential candidates against sars-cov- . the combination of these two drugs (usually a component of haart regiment to treat aids) has shown an in vitro antiviral activity against sars-cov- . however, more randomized trials are mandatory to prove its effectiveness against this novel coronavirus [ ] . mscs are multipotent adult stem cells that are present in most human tissues, including in the umbilical cord. mscs can self-renew by dividing and can differentiate into multiple types of tissues, including osteoblasts, chondroblasts, adipocytes, hepatocytes, and others, which has led to a robust clinical research agenda in regenerative medicine [ ] it is hypothesized that mscs could reduce the acute lung injury and inhibit the cell-mediated inflammatory response induced by sars-cov- [ ] . mscs are investigational products that have been studied extensively for broad clinical applications in regenerative medicine [ ] and their immunomodulatory properties [ ] . no mscs are approved by the fda for the treatment of covid- . there are insufficient data to assess the use of mscs for the treatment of covid- . the fda has recently issued several warnings about patients becoming potentially vulnerable to stem cell treatments that are illegal and potentially harmful [ ] . tocilizumab, a recombinant monoclonal antibody against the interleukin- receptor, has been used to mitigate the cytokine release syndrome associated with chimeric antigen receptor t-cell therapy and has been proposed as a potential therapy for the cytokine storm syndrome associated with severe covid- pneumonia based on small phase two studies [ ] [ ] [ ] [ ] [ ] [ ] [ ] . an observational study reported reduced mortality in icu requiring covid- patients who had received tocilizumab [ ] . the indian council of medical research has recommended the use of tocilizumab in mechanically ventilated patients not improving despite the use of steroids [ ] . however, more trials are needed before its efficacy can be established. at present, no vaccine is available for the treatment of covid- . however, much research is in progress to develop an effective vaccine against this virus. according to the world health organization, candidate vaccines are in clinical evaluation, and are in preclinical evaluation. india is developing three vaccines that are under clinical trial and listed in table- , along with other clinical candidate vaccines [ ] . the sars-cov- has existed in the world for over months. during this short duration, it has spread across countries/territories/areas of the world. even developed countries could not prevent themselves from the damages caused by this virus. several measures, such as lockdown, random testing, and various researches related to therapies, have been taken to contain the spread of this disease. some drugs have shown promising results to fight against the sars-cov- , which results in a higher recovery rate. as there are no specific drugs or vaccines are available, it is impossible to predict the end of this pandemic. however, several vaccines are under clinical trials, but it will take a minimum of - months before it reaches the general population. moreover, viruses tend to mutate, so we can never be confident that vaccines will work. therefore, we will have to rely on preventive measures such as frequent hand washing, use of masks, restricted traveling, personal hygiene, and healthy eating to keep ourselves covid- free until the proper and specific treatment is available. st drafted and revised the manuscript. mmt read, edited and approved the final manuscript. both authors read and approved the 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( ) clinical management of covid- protocol newer additional strategies for covid- testing emergence of a novel coronavirus causing respiratory illness from wuhan the novel coronavirus: a bird's eye view global surveillance for covid- caused by human infection with covid- global-surveillance-for-covid- -caused-by-humaninfection-with-covid- -virus-interim-guidance coronavirus disease (covid- ) treatment guidelines remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus ( -ncov) in vitro breakthrough: chloroquine phosphate has shown apparent efficacy in treatment of covid- associated pneumonia in clinical studies hydroxychloroquine and azithromycin as a treatment of covid- : preliminary results of an open-label non-randomized clinical trial treatment of severe acute respiratory syndrome retrospective comparison of convalescent plasma with continuing high-dose clinical microbiology and infection use of convalescent plasma therapy in sars patients in hong kong anca-associated vasculitis-refining therapy with plasma exchange and glucocorticoids a comprehensive literature review on the clinical presentation and management of the pandemic coronavirus disease (covid- ) perinatally administered losartan augments renal ace expression but not cardiac or renal mas receptor in spontaneously hypertensive rats comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon-beta against mers-cov first case of novel coronavirus in the united states the national heart, lung, and blood institute acute respiratory distress syndrome (ards) clinical trials network remdesivir, lopinavir, emetine, and homoharringtonine inhibit sars-cov- replication in vitro concise review: multifaceted characterization of human mesenchymal stem cells for use in regenerative medicine hypothesis for the management and treatment of the covid- -induced acute respiratory distress syndrome and lung injury using mesenchymal stem cell-derived exosomes interactions between mesenchymal stem cells and the immune system fda warns about stem cell therapies fda approval summary: tocilizumab for treatment of chimeric antigen receptor t cell-induced severe or life-threatening cytokine release syndrome ) pathological findings of covid- associated with acute respiratory distress syndrome effective treatment of severe covid- patients with tocilizumab tocilizumab treatment in covid- : a single center experience efficacy and safety of tocilizumab in severe covid- patients: a single-centre retrospective cohort study off-label use of tocilizumab for the treatment of sars-cov- pneumonia in tocilizumab for the treatment of severe covid- pneumonia with hyperinflammatory syndrome tocilizumab among patients with covid- in the intensive care unit: a multicentre observational study draft landscape of covid- candidate vaccines the authors did not receive any funds for this study. the authors declare that they have no competing interests.veterinary world remains neutral with regard to jurisdictional claims in published institutional affiliation. key: cord- -ry boej authors: chauhan, shaylika title: comprehensive review of coronavirus disease (covid- ) date: - - journal: biomed j doi: . /j.bj. . . sha: doc_id: cord_uid: ry boej coronavirus disease (covid- ) caused by severe acute respiratory syndrome coronavirus (sars-cov- ) was first identified in december in wuhan, the capital of china's hubei province and has rapidly spread all over the world. the world health organization (who) declared the outbreak to be a public health emergency of international concern on january and recognized it as a pandemic on march . the number of people diagnosed with covid- worldwide crossed the one million mark on april , ; two million mark on april , ; three million mark on april , and the four million mark on may , . despite containment efforts, more than countries have been affected with more than , , cases in the world with maximum being in usa ( , , ) followed by , in spain and , in united kingdom as of may, . covid- is the latest threat to face mankind cutting across geographical barriers in a rapidly changing landscape. this review provides an update on a rapidly evolving global pandemic. as we face the threat of emerging and re-emerging infectious diseases, this is a stark reminder to invest in population health, climate change countermeasures, a global health surveillance system and effective research into identifying pathogens, their treatment and prevention and effective health delivery systems. coronavirus disease (covid- ) is an infectious disease caused by severe acute respiratory syndrome coronavirus (sars-cov- ). the disease was first identified in december in wuhan, the capital of china's hubei province, and has since spread globally, resulting in the ongoing e coronavirus pandemic. there was an epidemiological association with a seafood market in wuhan where there was also a sale of wild animals, which was closed on st january . cases were first reported to who on st dec of unknown pneumonia with the wuhan municipal health commission saying they were monitoring the situation closely. subsequent information was provided on th and th of january. the genetic sequence of the -ncov was reported to the who on jan and noted to be a b cov of group b with at least % similarity in genetic sequence to sars-cov and has been named -ncov by the who [ ]. subsequently, five additional -ncov sequences were deposited on the gsaid database on th january from institutes across china (chinese cdc, wuhan institute of virology and chinese academy of medical sciences & peking union medical college) and allowed researchers around the world to begin analyzing the new cov. by th january, there were confirmed cases in china and importantly, three exported cases of infected travelers who were diagnosed in thailand ( ) and japan ( ) within month, this virus spread quickly throughout china during the chinese new year e a period when there is a high level of human mobility among chinese people [ ] . the world health organization (who) declared the outbreak to be a public health emergency of international concern on january and recognized it as a pandemic on march [ ] . the number of people diagnosed with covid- worldwide crossed the one million mark on april , ; the case fatality rate across countries and territories was $ %. by comparison, the sars epidemic infected people in countries from november, , to july, , and had a case fatality rate of $ %, whereas the mers outbreak infected people in countries from april, , to november, , and had a case fatality rate of $ % [ , ] . as of may , , as shown in fig. , this has evolved into a pandemic affecting countries/regions with , , cases in the world with maximum being in usa( , , ) followed by , in spain and , in united kingdom at the time of writing . it is an un-precedented global health crisis with , deaths since the virus was first reported. u.s.a has been particularly hard hit with , deaths reported followed by united kingdom with , deaths and italy with , deaths. in usa, new york city has emerged a center of this global crisis with , deaths reported in new york city alone. there are , cases in new york followed by , in new jersey. the first case of covid- in us was reported on / / [ ] . (see fig. ). the number of people diagnosed with covid- worldwide crossed the one million mark on april , : two million mark on april , ; three million mark on april , and the four million mark on may , . it took days to reach the first million cases worldwide and just days for the second and third million subsequently [ ] . these numbers change rapidly as this is an evolving pandemic. mortality from one country to the other has differed depending on multiple parameters like the number of people tested, healthcare delivery, population demographics and factual reporting. italy has a case fatality ratio of . % (number of deaths per confirmed cases) and . deaths per , population. corresponding numbers in united kingdom are . % and . deaths per million. in usa these numbers stand at . % and . deaths per million respectively as of may , [ ] . as of april, nearly million people, or about % of the population, are under some form of lockdown in the united states. on march, . billion people worldwide were under some form of lockdown which increased to . billion people two days laterdaround a third of the world's population [ ] . as of april , over million learners were out of school due to school closures in response to covid- . according to unesco monitoring, over countries have implemented nationwide closures, impacting about % of the world's student population [ ] . earlier cdc reports have indicated that % of cases, % of hospitalizations, % of icu admissions, and % of deaths occurred among adults aged years with the highest percentage of severe outcomes among persons aged years. severe illness leading to hospitalization, including icu admission and death, can occur in adults of any age with covid- . however, individuals aged < appear to have milder covid- illness [ ] . coronavirus has an extensive history going back to the 's. avian coronavirus, initially called infectious bronchitis virus of chickens, mainly infecting domesticated chickens was first isolated in the 's followed by two more animal coronaviruses, mouse hepatitis virus (mhv) and transmissible gastroenteritis virus (tgev) in the 's [ ] . human coronavirus (hcov) was historically known to cause a large proportion of minor upper respiratory tract infections. tyrrell and bynoe [ ] , first found in , that a virus named b caused common cold in adults. hamre and procknow [ ] , first grew a virus they called e, in tissue cultures from samples obtained from medical students with colds. almeida and tyrrell performed electron microscopy on fluids from organ cultures infected with b and found particles that resembled the infectious bronchitis virus of chickens. tyyrell et al., in the late 's, demonstrated above zoonotic viruses and human strains, to be morphologically same and a new genus of viruses of coronavirus was coined [ ] . in late , sars (severe acute respiratory syndrome) epidemic appears to have started in guangdong province, china. in , chinese scientists led by shi zheng-li and cui jie of the wuhan institute of virology, china traced the source of the outbreak to horseshoe bats with civets acting as an intermediary. sars was a relatively rare disease; at the end of the epidemic in june , the incidence was , cases with a case fatality rate (cfr) ranging from from % to % depending on the age group of the patient. overall case fatality rate was . %. in the united states, only people had laboratory evidence of sars-cov infection during the outbreak. the world health organization declared severe acute respiratory syndrome contained on july [ ] . in september another novel coronavirus emerged in saudi arabia, first identified as novel coronavirus and subsequently human coronavirusderasmus medical centre (hcov-emc) after the dutch erasmus medical centre which had sequenced the virus. in may , the coronavirus study group of the international committee on taxonomy of viruses adopted the official designation, the middle east respiratory syndrome coronavirus (mers-cov), which was further adopted by who [ ] . mers-cov, also called camel flu, is believed to be derived from bats with camels being involved in spread to humans. at the end of , just under cases were reported with a case fatality rate of %. most cases have occurred in the arabian peninsula with a subsequent outbreak in in south korea with confirmed cases of infection and deaths. only two people in the u.s. have ever tested positive for mers-cov infection, both in . potential for periodic outbreaks remains, particularly in the arabian peninsula. testing includes rrt-pcr testing of respiratory and serum specimens [ ] . coronaviruses (covs), are enveloped, non-segmented, positive-sense rna viruses. they are characterized by club-like spikes that project from their surface and the largest identified rna genomes, containing approximately kilobase (kb) genome and a unique replication strategy. the strategy of replication of coronaviruses involves a nested set of messenger rnas with common polyadenylated -ends. only the unique portion of the -end is translated. mutations are common in nature. in addition, coronaviruses are capable of genetic recombination if viruses infect the same cell at the same time [ ] . the name coronavirus is derived from latin, corona, meaning crown or wreath. due to characteristic appearance of virions by electron microscopy on the surface of the virus [ fig. ], creating an image reminiscent of a crown or of a solar corona, coronavirus has acquired its name. tang et al. investigated the patterns of molecular divergence between sars-cov- and other related coronaviruses by studying the population genetic analyses of genomes of sars-cov- . they showed that sars-cov- viruses evolved into two major types (l and s types) with the s type being the more ancient version of sars-cov- . l type was shown to be more aggressive than the s type and more prevalent in the early stages of the outbreak in wuhan, the frequency of the l type decreased after early january possibly due to human intervention [ ] . sars-cov- is genetically similar to other coronaviruses in the subgenus sarbecovirus, a clade of betacoronaviruses formed by the coronavirus that causes sars (sars-cov) and other sars-cov-like coronaviruses found in bats. recombination between coronaviruses are common, and sars-cov is believed to be a recombinant between bat sarbecorviruses. interestingly, the whole genome of sars-cov- is highly similar to that of a bat coronavirus detected in (> % sequence identity), which suggests that the immediate ancestor of sars-cov- has been circulating in bats for at least several years [ ] . ace has been identified as a functional receptor for coronaviruses, including sars-cov and sars-cov- . sars-cov- infection is triggered by binding of the spike protein of the virus to ace , which is highly expressed in the heart and lungs. binding of the s unit of the viral s protein to the host ace cellular receptor facilitates viral attachment to the surface of target host cells. viral s protein priming then requires s protein cleavage of s from s (and at another s ' site) by the host cell serine protease tmprss . the viral s subunit then drives fusion of the viral and host cell membranes [ ] . additionally, cytokine storm triggered by an imbalanced response by type and type t helper cells and respiratory dysfunction and hypoxemia caused by covid- can result in damage to myocardial cells [ ] . pangolins, protected animals that are traded illegally in asia and elsewhere, have been proposed as a potential amplifying host by some studies (lam et al., ) [ ] . the reproductive number is the number of cases, on average, an infected person will cause during their infectious period. the actual r for sars-cov- remains to be determined with other estimates generally ranging between . and . . in contrast, r for measles is e making it highly infectious and for influenza it is e . for the sars pandemic in , scientists estimated the original to be around . [ ] . however, a super-spreader is an individual who is more likely to infect others, compared with a typical infected person. super-spreaders continue to be of particular concern in epidemiology and they have been identified in the ongoing covid- pandemic. the who says it is primarily spread during close contact and by small droplets produced when people cough, sneeze or talk. early on, many of the patients at the epicenter of the outbreak in wuhan, hubei province, china had some link to a large seafood and live animal market, suggesting animal-toperson spread. later, a growing number of patients reportedly did not have exposure to animal markets, indicating person-to-person spread. currently the virus seems to be spreading via community spread with individuals getting infected without a definite exposure [ ] . sars-cov- can remain viable and infectious in aerosols for hours, and on surfaces up to days; the median half-life of sars-cov- was approximately . h in aerosols, . h on stainless steel and . h on plastic; no viable virus was measured on cardboard after h, but virus was still detectable (depending on the inoculum shed) on plastic and stainless steel after h aerosol and fomite transmission of sars-cov- is plausible, since the virus can remain viable and infectious in aerosols for hours and on surfaces up to days (depending on the inoculum shed) [ ] . xiao et al. demonstrated sars-cov- rna detection and intracellular staining of viral nucleocapsid protein in gastric, duodenal, and rectal epithelia demonstrate that sars-cov- infects these gastrointestinal glandular epithelial cells. in their study they noted that more than % of patients with sars-cov- , were observed to have viral rna positive in feces, even after test results for viral rna in the respiratory tract converted to negative, indicating that the viral gastrointestinal infection and potential fecal-oral transmission can last even after viral clearance in the respiratory tract. this has strong implications in preventing further transmission via the feco-oral route if rrt-pcr result of a fecal sample remains positive [ ] . possible intrauterine transfer has been reported, with reports of abnormal igm and igg and abnormal cytokine test results in an infant born via caesarean section to a covid þ mother. the elevated igm antibody level suggests that the neonate was infected in utero. as igm antibodies are not transferred to the fetus via the placenta [ ] . the median incubation period of covid- has been estimated to be . days, and estimated that nearly all infected persons who have symptoms will do so within days of infection. clinical descriptions of asymptomatic phases after possible exposure range from to days. a -day period for monitoring after potential exposure is generally recommended, and modeling predicts that out of every , cases ( th percentile) will develop symptoms after days of active monitoring or quarantine [ ] . patients' clinical manifestations include fever, nonproductive cough, dyspnea, myalgia, fatigue, normal or decreased leukocyte counts, and radiographic evidence of pneumonia. organ dysfunction (e.g., shock, acute respiratory distress syndrome [ards], acute cardiac injury, and acute kidney injury) and death can occur in severe cases [ ] . the median time from symptom onset to the development of pneumonia is approximately days, and the median time from symptom onset to severe hypoxemia and icu admission is approximately e days. critically ill patients with covid- are older and have more comorbidities, including hypertension and diabetes, than do non-critically ill patients. acute hypoxemic respiratory failuredsometimes with severe hypercapniadfrom acute respiratory distress syndrome (ards) is the most common complication (in e % of patients admitted to the icu), followed by shock ( %), myocardial dysfunction ( e %), and acute kidney injury ( e %) [ ] . common ct findings are ground glass opacities and consolidation. ct chest can be normal in patients with nonsevere or severe covid and should not be relied upon for ruling out covid- . also, abnormal finding noted on ct might not be specific for covid- . hematological findings include lymphocytopenia, thrombocytopenia and leukopenia. most of the patients had elevated levels of c-reactive protein; less common were elevated levels of alanine aminotransferase, aspartate aminotransferase, creatine kinase, and d-dimer. patients with severe disease had more prominent laboratory abnormalities (including lymphocytopenia and leukopenia) than those with non-severe disease [ ] . mortality has been found to be markedly higher in patients with elevated troponin t levels (tnt) levels than in patients with normal tnt levels ( . % vs . %). exuberant elevation of ip- , mcp- and il- ra during sars-cov- infection is associated with disease severity and fatal outcome [ ] . diagnosis cdc recommends following revised guidelines for testing [ ] . priorities for covid- testing. to test for sars-cov- , specimen testing (nasopharyngeal or oropharyngeal aspirates or washes, nasopharyngeal or oropharyngeal swabs, bronchoalveolar lavage, tracheal aspirates, sputum, and serum) is performed using a real time reverse transcription pcr (rrt-pcr) assay for sars-cov- . sars-cov- is not detected by standard respiratory viral panels, including those that test for the previously identified beta coronaviruses. repeated sampling might be required when initial tests are negative despite suspicious clinical features [ ] . non-invasive ventilation (niv) and high flow nasal canula (hfnc) should be reserved for patients with mild ards with adequate precautions [ ] , use of personal protective equipment and use of negative pressure rooms due to concern of aerosolization from these procedures. a conservative or deresuscitative fluid strategy with early detection of myocardial involvement through the measurement of troponin and beta-natriuretic peptide concentrations and echocardiography and early use of vasopressors and inotropes are recommended. studies carried out in previous sars epidemics have shown that corticosteroids had no impact on mortality but possible harms, including avascular necrosis, psychosis, diabetes, and delayed viral clearance [ ] . at this time routine use of corticosteroids is not recommended. currently there are no proven therapies for treatment of covid- . there are ongoing trials on remdesivir, lopinavireritonavir, chloroquine, hydroxychloroquine, intravenous immunoglobulin, convalescent plasma, tocilizumab, favipiravir, and traditional chinese medicines. no peer- hospitalized patients with symptoms healthcare facility workers, workers in congregate living settings, and first responders with symptoms residents in long-term care facilities or other congregate living settings, including prisons and shelters, with symptoms persons with symptoms of potential covid- infection, including: fever, cough, shortness of breath, chills, muscle pain, new loss of taste or smell, vomiting or diarrhea, and/or sore throat. persons without symptoms who are prioritized by health departments or clinicians, for any reason, including but not limited to: public health monitoring, sentinel surveillance, or screening of other asymptomatic individuals according to state and local plans. reviewed, published safety data is available for sars-cov- on hcq though it continues to be widely used [ ] . prone ventilation is suggested for patients with refractory hypoxemia due to progressive covid- pneumonia (i.e., ards). ecmo is suggested for patients with refractory hypoxemia due to progressive covid- pneumonia (i.e., ards), if prone ventilation fails [ ] . kai duan et al. showed that administration of convalescent plasma (cp) obtained from recovered covid- patients who had established humoral immunity against the virus led to covid- patients achieving serum sars-cov- rna negativity after cp transfusion, accompanied by an increase of oxygen saturation and lymphocyte counts, and the improvement of liver function and crp. key factors in administering convalescent plasma include concerns that donor plasma must contain an adequate titre of neutralizing antibodies, be administered at the right treatment time point and risk of transmitting potential pathogens must be considered. mass testing of recovered patients who meet above criteria can provide an efficacious treatment source for covid- patients [ ] . adequate measures to prevent transmission like hand washing, proper ppe, social distancing and use of negative pressure isolation rooms are the backbone in this pandemic and must stay in place. there are currently no approved human coronavirus vaccines. future considerations in development of a vaccine pose a conundrum. previous novel vaccines towards disease such as dengue, sars, respiratory syncytial virus have led to a counterproductive and potentially severe reaction known as immune enhancement [ ] .neutralizing antibodies have been considered as an effective drug to treat or prevent virus infection, however a recent study has shown that about % of patients failed to develop high titers of nabs after covid- infection, the disease duration of these patients was similar to other patients however it is unclear whether these patients are at a higher risk of rebound or reinfection. elderly patients were noted to have a higher titre of nabs with a stronger innate immunity response-clinical co-relation with disease recovery and severity needs to be further explored [ ] . coronavirus makes clear what has been true all along. your health is as safe as that of the worst-insured, worst-cared-for person in your society. it will be decided by the height of the floor, not the ceiling. anand giridharadas @anandwrites. on march , dozens of un human rights experts emphasized respecting the rights of every individual during the covid- pandemic including rights to health care and government's responsibility to provide lifesaving interventions [ ] . the organization for economic co-operation and development has launched a platform to provide timely and comprehensive information on policy responses in countries around the world, as well as viewpoints and advice [ ] . solidarity trial is an initiative started in march by the world health organization to test drugs and drug combinations including remdesivir, chloroquine and hydroxychloroquine combination, ritonavir/lopinavir and ritonavir/ lopinavir & interferon-beta against sars cov- . according to the who director general, the aim of the trial is to "dramatically cut down the time needed to generate robust evidence about what drugs work". the first patient for this trial was one from oslo university hospital, norway [ ] . going forward there must be greater investments in public health and emergency preparedness. usa spends approximately $ per person per year ( . percent of all health care spending) inspite of spending about twice as much per capita on health care as the average among other oecd (organization for economic and cooperation development) nations. universal health coverage, bi-directional sharing of data between low income and high-income countries, greater investment in healthcare by governments all around the world are measures that should be learnt and implemented after this pandemic [ ] . yes. none. gisaid database. coronavirus statement on the second meeting of the international health regulations. emergency committee regarding the outbreak of novel coronavirus ( -ncov). world health organization who summary of probable sars cases with onset of illness from middle east respiratory syndrome coronavirus (mers-cov) mapping -ncov how to lock down . billion people without killing the economy covid- educational disruption and response severe outcomes among patients with coronavirus disease (covid- ) d united states coronaviruses: a comparative review". current topics in microbiology and immunology/ ergebnisse der mikrobiologie und immunit€ atsforschung cultivation of viruses from a high proportion of patients with colds a new virus isolated from the human respiratory tract history and recent advances in coronavirus discovery scientists trace sars virus to colony of cave-dwelling bats in china novel coronavirus update e new virus to be called mers-cov. who middle east respiratory syndrome coronavirus: another zoonotic beta coronavirus causing sars-like disease coronaviridae: the viruses and their replication on the origin and continuing evolution of sars-cov- genomic characterization and epidemiology of novel coronavirus: implications for virus origins and receptor binding covid- and the cardiovascular system clinical features of patients infected with novel coronavirus in wuhan, china identification of -ncov related coronaviruses in malayan pangolins in southern china how scientists quantify the intensity of an outbreak like covid- q&a on coronaviruses" . world health organization aerosol and surface stability of sars-cov- as compared with sars-cov- . new england evidence for gastrointestinal infection of sars-cov- possible vertical transmission of sars-cov- from an infected mother to her newborn the incubation period of coronavirus disease (covid- ) from publicly reported confirmed cases: estimation and application clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china intensive care management of coronavirus disease (covid- ): challenges and recommendations clinical characteristics of coronavirus disease in china neutralizing antibody responses to sars-cov- in a covid- recovered patient cohort and their implications evaluating and testing persons for coronavirus disease (covid- ). accessed at: www epidemiologic features and clinical course of patients infected with sars-cov- in singapore intensive care management of coronavirus disease (covid- ): challenges and recommendations sars: systematic review of treatment effects effectiveness of convalescent plasma therapy in severe covid- patients antibody-dependent enhancement of virus infection and disease neutralizing antibody responses to sars-cov- in a covid- recovered q patient cohort and their implications. ssrn elect j no exceptions with covid- nations human rights office of the high commissioner solidarity" clinical trial for covid- treatments. who doctors are being forced to ration care. don't blame them. blame decades of poor u.s. policy jopinion key: cord- -x svp y authors: bearden, donna m.; aiken, patricia b.; cheng, yu hsin; mai, emily; peters, timothy m. title: covid- : a primer for healthcare providers date: - - journal: wien klin wochenschr doi: . /s - - -x sha: doc_id: cord_uid: x svp y according to the world health organization (who) the china office was first notified of cases of atypical pneumonia in wuhan city on december . a viral genome sequence of a novel coronavirus, currently termed sars-cov‑ , with a disease process called covid- was released week later via online resources to obtain public health support in control of spread. since then, the virus rapidly evolved into a global pandemic. therefore, healthcare providers need to be familiar with the clinical presentation of infected patients and measures to quickly isolate them. the prevention of nosocomial spread is paramount to proper control of covid- and is reviewed. currently, treatment is supportive. researchers are working to develop vaccines and identify effective antiviral interventions. those recently discussed in the literature are briefly reviewed. coronaviruses include a large number of viruses found in animals. human coronaviruses were first identified in the s, isolated from patients with mild upper respiratory infections [ ] . since then, additional human coronaviruses have been discovered, including the causative agents of severe acute respiratory syndrome (sars) and middle east respiratory syndrome (mers). the first human coronaviruses upper respiratory infections in humans. in immunocompromised hosts and children, however, they can result in severe pneumonia and bronchiolitis [ ] . the sars represented the first pandemic of a coronavirus. it started in guangdong province in china in [ ] . severe atypical cases of pneumonia emerged and quickly spread worldwide. investigation by epidemiologists suggested that animal to human transmission occurred at live game markets in guangdong. small mammals such as racoon dogs and palm civets likely transmitted the disease to humans. the natural hosts are bats [ ] . eventually, public health systems and governments were able to contain the outbreak and bring it to a close. the world health organization (who) reported cases of sars worldwide, spread out among countries. they reported deaths from the virus, with a fatality rate of - % [ ] . a recent report in jama also suggested a % fatality rate and estimated that - % of infected patients required mechanical ventilation [ ] . as expected, the fatality rate was higher among the aged and those with comorbidities. perhaps most importantly, the sars outbreak showed that animal coronaviruses could spread to humans. the coronavirus has also demonstrated the ability to emerge into new hosts and then cause novel severe disease. in , the mers coronavirus was discovered in saudi arabia, isolated from the sputum of a man who died from a severe respiratory syndrome. the illness was subsequently termed mers and since then cases have been reported, resulting in deaths. this yields a higher case fatality rate than sars, at %, with mechanical ventilation needed in - % of patients [ ] . the mers is en-demic in camels, and in the middle east and east africa it continues to cause human infections [ ] . to date, mers has spread to countries by air travel [ ] . in , a single patient caused an outbreak of cases in south korea, while a more recent case identified in an emergency department patient, was contained due to rapid implementation of public health interventions [ , ] . at outbreak onset, the chinese government rapidly initiated broad isolation measures in an attempt to contain the virus. first the city of wuhan was quarantined, then the entire hubei province, stranding million residents [ ] . currently, however, the disease continues to spread. a retrospective study suggested travelling by train in china yielded the highest proportion of imported cases to new provinces ( %), followed by flying ( %) and car ( %) [ ] . several factors contribute to continued spread. qun et al. reported that delays between onset of illness and seeking medical attention are usually short, with % seeking attention within days of onset; however, delays to hospitalization were longer, with % of patients not hospitalized until at least days of illness, during which time multiple other persons are exposed to the virus [ ] . they suggest "committing considerable resources to testing in outpatient clinics and emergency departments for proactive case finding, both as part of the containment strategy" [ ] . qun et al.'s preliminary estimate of the incubation period supported a -day quarantine for exposed persons, but was based on only cases [ ] . subsequent reports on quarantined patients have demonstrated the disease can occasionally manifest past the observed -day isolation period. furthermore, it has been demonstrated that the virus can spread during the incubation period, when patients are asymptomatic [ ] . it has also been detected in patients during the convalescent period. additionally, the first person in the usa with coronavirus infection shed the virus in loose stool specimens, yielding concerns for fecal-oral transmission [ ] . to clean public surface areas after potential contamination, one group of researchers in china reported that previous research on sars and mers suggested that liquid solvents, such % ethanol, disinfectants containing chlorine , peroxyacetic acid and chloroform have the potential to inactivate sars-cov- . they also reported ultraviolet radiation and heating to °c for min may inactivate the virus. chlorhexidine is not recommended as a disinfectant [ ] . human to human transmission was realized early in the sars pandemic. primary symptoms included fever, cough and dyspnea [ ] . outbreaks were reported in hotel and housing complexes. healthcare facilities served as a reservoir for the virus, with many healthcare workers sustaining infections. it is theorized that nosocomial spread occurred because the human receptor for the sars spike glycoprotein occurs in the lower respiratory tract. hence, most patients present with pneumonia rather than upper respiratory tract symptoms. viral shedding occurs about days after initial infection, when most patients were already hospitalized. then, interventions such as nebulizer treatments, oxygen, intubation and mechanical ventilation contributed to aerosolization of the virus, with increased risk of iatrogenic infection [ ] . the mers also causes a severe atypical pneumonia, but patients frequently have accompanying gastrointestinal symptoms and acute renal failure. like sars, the human receptors for the mers virus are located in the lower respiratory tract, but additional receptors are found in the gastrointestinal tract and kidneys [ ] . it is most important, however, to glean data from patients infected with sars-cov- . several papers have reported on clinical presentation and characteristics of early cases in china and of the latest publications studied the first confirmed cases in wuhan. their median age was years and % were male. none of the cases reported were in children below the age of years [ ] ; however, an increasing number of pediatric cases are now being reported from china [ ] . the adult patients in the wuhan study had a mean incubation period of . days, with the th percentile of the distribution at . days. at onset, the epidemic grew exponentially, doubling in size every . days. the basic reproductive number was estimated to be . , meaning "that on average, each patient has been spreading infection to . other people" [ ] . the authors report that as long as the basic reproductive number is greater than , the epidemic will continue to spread. control measures are designed to decrease the reproductive number to less than . perhaps the most detailed study to date, shedding light on how patients may present and progress, is an analysis of the first cases of confirmed novel corona pneumonia in wuhan [ ] . infections were confirmed by obtaining throat swab specimens from all patients on admission and testing for the virus using real-time polymerase chain reaction protocols previously described [ ] . of the cases studied, % were men and % were women, with a mean age of . years. only a slight majority of patients ( %) had chronic diseases, the majority being cardiovascular or cerebrovascular diseases [ ] . covid- : a primer for healthcare providers k main topic presenting symptoms were fever in % of patients and cough in %. shortness of breath on admission was present in %. other presenting symptoms in % or more of admitted patients included: myalgia, headache, confusion, sore throat and rhinorrhea. only - % of patients reported nausea and vomiting, or chest pain or diarrhea and % of patients had more than one sign or symptom present on admittance [ ] . an analysis of laboratory values of infected patients showed the erythrocyte sedimentation rate was elevated in % of patients on admittance and the c-reactive protein was elevated in %. surprisingly, the procalcitonin level was only increased in % of patients with confirmed covid- pneumonia. a low albumin was identified in % of patients admitted, an elevated lactate dehydrogenase in % of patients and % had a decreased hemoglobin [ ] . based on chest x-ray and computed tomography (ct) results, % of patients had bilateral pneumonia at presentation, and % had unilateral pneumonia. during hospitalization, % of patients required oxygen therapy, % required noninvasive mechanical ventilation and % required invasive mechanical ventilation. at the time the study was released, % of patients had been discharged, and % had died. all other patients were still hospitalized [ ] . discharge criteria suggested by pediatricians in china include children with a normal body temperature for at least days, significant improvement in respiratory symptoms and completion of two consecutive negative tests of respiratory respiratory pathogenic ribonucleic acid. they suggested sampling intervals of at least day. if patients meet these criteria, they are considered safe for discharge. if needed, home isolation for days can be advised [ ] . a retrospective study from china analyzed chest ct scans from symptomatic patients with confirmed covid- [ ] . consistent with clinical findings among infected a patients, radiographic finding demonstrated most patients ( %) had bilateral involvement on ct and in % more than lung lobes were involved. the most frequent ct findings included bilateral pulmonary parenchymal groundglass and consolidative pulmonary opacities ( %). lung consolidation was observed in %. lung cavitation, discrete pulmonary nodules, pleural effusions and lymphadenopathy were absent in all of the scans. follow-up imaging in eight patients during the study period demonstrated mild or moderate progression of disease [ ] . other clinicians in china also studied chest ct scans and confirmed typical multilobar involvement on presentation, but summarized "when one or two lobes are involved, the effect on lung function is not serious, and the symptoms of shortness of breath and dyspnea are not severe" [ ] . if the disease progresses, however, the patient will develop a "white lung" with diffuse alveolar damage involving multiple lobes [ ] . the clinical characteristics associated with the development of acute respiratory distress syndrome (ards) and death after admission for covid- were recently described in a retrospective cohort study [ ] . older age, hypertension and development of fever greater than °c was associated with ards, but higher fever was also associated with better outcomes. increasingly, it is recognized that other organ systems, besides the pulmonary system, can be adversely affected by infection with sars-cov- . a retrospective, observational analysis of confirmed cases of covid- , specifically studied those with severe pneumonia, using criteria established by the american thoracic society [ ] . of those patients with severe pneumonia, . % had neurological manifestations of disease, such as acute cerebrovascular disease ( . %), impaired consciousness ( . %) and skeletal muscle injury ( . %). coagulation disorders and cardiac manifestations of covid- infection have also been reported [ , ] . a recent manuscript out of canada provided an extensive review of measures designed to prevent the nosocomial spread of the disease [ ] . they stressed the importance of identifying and isolating patients infected with sars-cov- early. currently, suspicion requires fever and symptoms of respiratory illness. with recent community spread, identifiable links to the virus may be difficult to discern and a high index of suspicion should be maintained. failure to identify infected patients has led to preventable dissemination in prior pandemics [ ] . the primary method of transmission for sars-cov- is via contact/droplet spread, related to respiratory conditions; however, as with sars, airborne transmission can occur. there are at least two reports of sars-cov- being isolated from stool specimens, so fecal-oral transmission is considered possible as well [ , ] . currently, the canadian public health agency advises placing patients with confirmed covid- or patients with suspected infection who are ill, in airborne isolation. anterooms with space to put on and remove personal protective equipment should be adjacent to these rooms. if an airborne isolation room is not available, the patient should be placed in a single room with closed doors [ ] . in the care of critically ill patients, where airborne transmission is possible, recommended personable protective gear includes fluid-resistant gowns, gloves, eye protection, full face shield and fit-tested n- respirators. hair covers or hoods should also be worn. longer sleeved gloves are preferred to prevent wrist exposure in the case of glove slippage. if necessary, vertical tape strips can be applied to keep gloves in place. circumferential taping is not advised as it may make glove and gown removal more difficult. full face protection with a shield is preferred. if not available, goggles or side shields are needed. scrubs or full coveralls should be worn under the personal protective gear. shoes worn should be impermeable to fluids and capable of being decontaminated. shoe covers can increase the risk of self-contamination during removal. strict hand hygiene must be performed after removal of protective equipment. wax and christian advised that infection control coaches should be used in some circumstances of equipment removal, such as after a "code blue." the coaches go through a checklist as the equipment is removed, to reduce the risk of self-contamination [ ] . in fact, during the sars outbreak the "protected code blue" was developed and published to guide healthcare workers in proper resuscitation techniques for infected patients. online demonstrations of the procedure have been cited by candadian researchers [ ] . it is advised that team members entering an infected patient's room be restricted to four, with team members bringing the defibrillator, medications and equipment needed in modular packs, rather than an entire cart [ ] . healthcare personnel arriving at the patient's room prior to the specialized response team can assist the patient with resuscitation interventions that have a low risk of viral transmission, such as placing an oral airway, placing an oxygen mask with an exhalation filter, chest compressions, defibrillation and cardioversion, obtaining intravenous or intraosseous access and administering drugs. higher risk interventions which may generate aerosol and increase risk for infection to staff and nosocomial spread include high flow nasal cannula, bag-mask ventilation, cpap/bipap (continuous positive airway pressure/ bilevel positive airway pressure), and endotracheal intubation [ ] . the authors also note that during the sars outbreak, there were "case reports of considerable sars transmission risk with the use of bipap to many patients over extended periods" [ ] . they concluded, in general cpap/bipap should be avoided in patients with covid- and should never be used outside of airborne/droplet isolation [ ] . they also note that high flow nasal cannula delivery systems may cause an increased risk of viral spread and practitioners should consider avoidance of humidified oxygen in covid- patients as well. bronchodilators should preferably be administered by metered dose inhalers [ ] . pediatricians in china have also provided recommendations for personal protective gear [ ] . they stated: . all medical personnel are required to wear surgical masks during medical activities. . those in triage areas wear medical overalls, caps and surgical masks. . in the emergency department and clinics where exposure is likely: medical overalls, caps, disposable clothing, surgical masks and goggles or face shields for daily rounding. when collecting body fluid samples, latex gloves, impermeable clothing and respiratory hood should be used when needed to prevent contamination by aerosolization or splash. . all personal protective equipment should be worn and removed with a strict on-off procedure, and personnel should not leave the ward with contaminated equipment. . patients and their accompanying family members are required to wear surgical masks [ ] . currently, no effective vaccines or drugs have been approved for clinical use, although inhibitors designed to treat infections in vivo are being developed. in order to increase the speed of development of potential treatments available, two approaches are generally employed. firstly, testing of current antiviral drugs and medications used to treat other infections or other disease states. the second approach is to develop novel agents based on current information and understanding of the particular coronavirus targeted [ ] . several publications have recently identified associations with decreased in vitro activity against sars and mers viruses. neurotransmitter inhibitors, such as promethazine were among such agents [ ] . pillaiyar et al. list additional compounds with antiviral activity in their extensive review [ ] . nowak and walkowiak, in a recently released review of five in vitro studies reporting on the effect of lithium in coronavirus infections, concluded that the drug does have antiviral activity and should be explored as a potential treatment or prophylaxis for covid- [ ] . currently, the most widely studied antiviral agents against coronaviruses are remdesivir, ribavirin, lopinavir, ritonavir, and interferon beta. ribavirin, used alone, has had no demonstrated effect against sars. when combined with lopinavir, plus rotinavir and a corticosteroid and given to patients infected with sars, those treated were less likely to develop ards, and death rates were lower than those treated with ribavirin and a corticosteroid [ ] . most studies published have not shown a benefit when corticosteroids are used in coronavirus infections. in fact, the use of methylprednisolone as an intervention for sars patients was associated with a higher -day mortality rate [ ] . a randomized, placebo-controlled study of sars patients suggested that those given steroids early in the infection developed prolonged viremia. finally, patients with mers who were treated with methylprednisolone, with or without antiviral agents or interferons, showed no improved outcomes [ ] . covid- : a primer for healthcare providers perhaps remdesivir, a broad-spectrum antiviral drug, shows the most promise for human coronavirus infections. it has superior activity against mers-cov in vitro, when tested against existing antivirals. in mouse models, when used for prophylaxis and treatment, it showed improved pulmonary lung function values, reduced lung viral loads and lung pathology findings on post-mortem examination [ ] . the authors concluded "our work suggests that remdesivir may improve disease outcomes in coronavirus patients, serve to protect health care workers in area with endemic mers-cov and prove valuable in preventing future epidemics " [ ] . another recent report, by a different group of researchers, also supported the use of remdesivir against coronaviruses. this group showed that remdesivir inhibited virus infection efficiently in a human cell line sensitive to sars-cov- [ ] . the same authors tested chloroquine and concluded "remdesivir and chloroquine are highly effective in the control of covid- infection in vitro." they further suggested both should be assessed in human patients with covid- [ ] . finally, neuraminidase inhibitors, such as oral oseltamivir, inhaled zanamivir and intravenous peramivir are approved antiviral treatments for influenza and mers infections; however, oral oseltamivir has been used in patients with covid- infections in china, but to date, there is no convincing evidence of its' effectiveness [ ] . interferon has been studied in vitro against coronaviruses, but there is no evidence it will be effective against covid- . pediatricians in china have suggested nebulized interferon be considered in infected children [ ] ; however, they reported there is no data to support its' use and publications from canada advise against routine nebulizer use, noting the potential for spreading of the virus by aerosolization [ ] . vaccines against covid- are being pursued. researchers report that the timeline has been compressed to . months for a phase i trial, using messenger rna technologies [ ] . other groups are attempting to construct vaccines using viral vectors and vaccines directed at subunits [ ] . despite worldwide efforts to identify methods to prevent and treat covid- , a recent comprehensive review concluded "no therapies have been shown effective to date" [ ] . currently, covid- continues to spread. latest estimates of the replication number remain well above two, so proliferation will continue. healthcare providers will play a major role in the early identification and isolation of infected patients, important measures to prevent dissemination. measures to prevent nosocomial spread are also paramount to control. finally, while treatment is largely supportive, the scientific community is working ceaselessly to de-velop interventions and vaccines to end this outbreak. health professionals need to stay abreast of all these developments. 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treatment options for the -new coronavirus ( -ncov) pharmacologic treatments for coronavirus disease (covid- ) a review key: cord- -ea a xfl authors: dhama, kuldeep; patel, shailesh kumar; sharun, khan; pathak, mamta; tiwari, ruchi; yatoo, mohd iqbal; malik, yashpal singh; sah, ranjit; rabaan, ali a.; panwar, parmod kumar; singh, karam pal; michalak, izabela; chaicumpa, wanpen; martinez-pulgarin, dayron f.; bonilla-aldana, d. katterine; rodriguez-morales, alfonso j. title: sars-cov- jumping the species barrier: zoonotic lessons from sars, mers and recent advances to combat this pandemic virus date: - - journal: travel med infect dis doi: . /j.tmaid. . sha: doc_id: cord_uid: ea a xfl coronavirus disease (covid- ), caused by sars-cov- (severe acute respiratory syndrome - coronavirus- ) of the family coronaviridae, appeared in china in december . this disease was declared as posing public health international emergency by world health organization on january , , attained the status of a very high-risk category on february , and now having a pandemic status (march ). covid- has presently spread to more than countries/territories while killing nearly . million humans out of cumulative confirmed infected asymptomatic or symptomatic cases accounting to almost million as of july , , within a short period of just a few months. researchers worldwide are pacing with high efforts to counter the spread of this virus and to design effective vaccines and therapeutics/drugs. few of the studies have shown the potential of the animal-human interface and zoonotic links in the origin of sars-cov- . exploring the possible zoonosis and revealing the factors responsible for its initial transmission from animals to humans will pave ways to design and implement effective preventive and control strategies to counter the covid- . the present review presents a comprehensive overview of covid- and sars-cov- , with emphasis on the role of animals and their jumping the cross-species barriers, experiences learned from sars- and mers-covs, zoonotic links, and spillover events, transmission to humans and rapid spread, and highlights the new advances in diagnosis, vaccine and therapies, preventive and control measures, one health concept along with recent research developments to counter this pandemic disease. in the st century, we have faced a few deadly disease outbreaks caused by pathogenic viruses such as bird flu caused by avian influenza virus h n , swine flu caused by reassorted influenza virus h n pandemic (h n pdm ), severe acute respiratory syndrome (sars) caused by sars-cov (coronavirus), the middle east respiratory syndrome (mers) caused by mers-cov [ ] [ ] [ ] , ebola [ ] , zika [ , ] , nipah virus infections, and the most recent threat [ ] , coronavirus disease (covid- ) that has been posed by severe acute respiratory syndrome coronavirus (sars-cov- ) of the family coronaviridae, genus betacoronavirus [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the sars-cov- virus emerged from the city of wuhan, hubei province, china, during december , was declared as public health international emergency by the world health organization (who) on january , . consequently, it was categorized in a high-risk category on february , , and gained the pandemic status on march , . the disease emerged from wuhan, china, as its epicentre, which moved later to italy, then the usa, and brazil. subsequently, within a short time interval of six months, it has affected nearly countries/territories and claimed near to . million human deaths out of cumulative confirmed infected asymptomatic or symptomatic cases accounting to almost million. sars-cov- has very adversely affected the usa, brazil, india, russia, south africa, peru, mexico, chile, spain, the united kingdom (uk), iran, pakistan, saudi arabia, italy and other countries. the disease incidences are lower in children than adults but exhibit all symptoms of a disease like adults [ ] . the lessons learned from earlier threats of sars, mers and the present covid- pandemic situations warrants designing and implementing some modified plans and strategies to combat emerging and zoonotic pathogens that could pose pandemic threats/risks while taking away many human lives [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] . researchers and health agencies across the world are putting high efforts to contain/restrain the spread of this deadly disease. they are pacing to develop potential vaccines and therapeutics/drugs [ , ] . evidence from the initial outbreak indicates earlier cases had links to huanan wholesale seafood market in china [ ] and further isolation of sars-cov- from different samples of the area (people, animals, birds, discharges, soil, structures) suggests the involvement of intermediate hosts [ ] . recently, a literature of review has pointed out the possible potential role of the animal-human interface, zoonotic links and spillover events towards the origin of sars-cov- / covid- [ , , [ ] [ ] [ ] [ ] [ ] . in the past couple of decade's animal origin viral diseases, especially bats-linked, have increased many folds in humans with noted cross-species transmissions. although many of the illnesses are linked with bats still information on their ecological behaviour, molecular aspects are limited, which could lead to more viral outbreaks shortly [ ] . the ongoing covid- pandemic has emphasized the importance of understanding the evolution of natural hosts in response to viral pathogens. in a recent study on ace receptors, the gene was found under intense selection pressure in bats and positive selection in other selected mammalian hosts [ ] . the sars-cov- is also thought to have originated from bats, just like sars-cov and mers-cov. civets and dromedary camels are considered as the intermediate host of sars-and mers-cov, respectively, from where they were transmitted to humans [ ] . the understanding of genomic signatures of sars-cov- with other covs is must for strategic planning through identifying natural or intermediate hosts. using genomic and protein data in a natural vector method (alignment-free approach), phylogenetic analysis revealed the possible transmission path originates from bats to pangolins to humans [ ] . however, the likely source of virus origin and the intermediate host of sars-cov- are yet to be identified. initially, when the novel virus emerged in china, a hypothesis was put forward, claiming the recent recombination event as the cause of the sars-cov- emergence . nevertheless, the phylogenetic and recombination analysis performed within the subgenus of sarbecovirus demonstrated that the novel virus shows discordant clustering with bat-sars-like coronavirus (ratg ) sequences thus rejecting the possibility of a recent recombination event [ ] . previously, it was found that the continuous passaging of mers-cov in non-susceptible cells that express viral receptors led to the accumulation of mutations in the spike protein gene. this paid attention to the potential of coronaviruses like mers-cov to undergo mutations that enhance viral entry into novel animal species, thus resulting in cross-species transmission [ ] . the covid- outbreak is still associated with several unanswered questions like the possibility of shedding of the virus before the onset of clinical signs, whether the transmission is limited to only through respiratory droplets, the possibility of an intermediate host that is responsible for zoonotic spillover, and the possible transmission characteristics [ , ] . hitherto studies report that the spillover risk remains high from zoonotic viruses and on the same lines a study from north america proposed a hypothesized conceptual model demonstrating sars-cov- spillover from humans to naive wildlife host species through the gastrointestinal route where stool from covid- infected patient contaminates water bodies and reaches to wildlife hosts [ ] . besides, the pandemic imposed a massive blow on the chinese economy, which is not going to heal soon [ ] . instead of the current situation, singapore's prime minister lee hsien loong rightly said that the virus might have started in china. however, it does not respect nationality or race. it does not check your passport before it goes into your body, and anybody can be infected. hence, all suspected people need to be tested and quarantined [ ] . further research exploring the sars-cov- associated zoonosis and mechanisms accounting for its initial transmission from animals to humans, will lead to sort out the spread of this virus as well as design and develop appropriate prevention and control strategies to counter covid- . the present comprehensive manuscript presents an overview on covid- , an emerging sars-cov- infectious disease while focusing mainly on the events and circumstantial evidences with regards to this virus jumping the species barriers, sharing a few lessons learned from sars-and mers-covs, zoonotic spillover events (zoonosis), acquiring transmission ability to infect humans, and adopting appropriate preventive and control measures [ ] . it also highlights the recent advances in sars-cov- diagnosis (see supplement material s ), vaccine, drugs and therapies (see supplement material s ), which could aid to counter and restrain this emerging virus at the face of pandemic situations, as well as prevention and control (see supplement material s ). sars-cov- is an enveloped virus measuring approximately - nm in diameter with a single strand positive-sense rna genome ranging from to kilobases in length [ , ] . it has club-shaped glycoprotein spikes in the envelope, giving it a crown-like or coronal appearance [ ] . the genome sars-cov- is comprised of ′ untranslated region ( ′ utr) that includes ′ leader sequence, open reading frame (orf) a/b (replicase genes), spike (s) protein, envelop (e) protein, membrane/matrix (m) protein, and accessory proteins (orf , , a, b, and b), nucleoprotein (n), and ′ untranslated region ( ′ utr) in their sequence [ ] . it has a % genetic identity to mers-cov and % to sars-cov [ , ] . the receptor-binding domain (rbd) of virus spikes helps in binding to cellular receptor angiotensin-converting enzyme (ace- ) [ , ] . orf and rbd of sars-cov- may have a role in elucidating cellular interactions and cross-species transmission mechanisms [ ] . receptor binding motifs (rbm) have a role in interaction with human receptors, human to human transmission, and cross-species transmission as gln provides favourable interaction, and asn shows compatibility with human ace- [ ] . besides, sars-cov- has superior transmission competence in comparison to the sars-cov, leading to a continuously increasing number of confirmed cases [ ] . sars-cov- has the potential to survive in the environment for several days [ ] . though believed to be sensitive to environmental factors and alcohol-based sanitizers, bleach, and chloroform, the sars-cov- can survive in wet surroundings for days and in closed air conditions up to hours [ , ] . survival of sars-cov- varies with the nature of the surface (glass, fabric, metal, plastic, or paper), environment, and virus load. it can survive on surfaces for hours to several days. it can survive in aerosols for up to hours and on plastic for up to hours [ , ] . the initial clinical picture of the covid- was pneumonia of unknown origin as the first clinical cases were presented with signs of pneumonia [ ] . later it was diagnosed as sars-cov- infection that was associated with severe pneumonia. hence, initially named as novel coronavirus pneumonia (ncp) [ ] . as the outbreak proceeded, a series of cases were produced, developing a wide range of clinical signs with few remaining asymptomatic being in the early incubation stage of the disease. thus covid- is characterized by three major patterns of the clinical course of infection, including mild illness producing upper respiratory signs, non-life-threatening pneumonia, and severe pneumonia with acute respiratory distress syndrome (ards) [ , ] . initially, mild signs appear for - days, followed by rapid deterioration and ards. it can be mild to moderate in % of affected cases, including pneumonia and non-pneumonia cases. in comparison, . % are severe cases, including dyspnea, respiratory distress, hemoptysis, gastrointestinal infection, liver, central nervous system, and lung damage cases [ , ] . critical cases account for . % and include respiratory failure, septic shock, and multiple organ failure/dysfunction cases. few cases remain asymptomatic and include cases that can become any of the above during infection [ ] . thus, the symptoms can be nonspecific and can range from no symptoms (asymptomatic) to severe pneumonia [ ] . in this context, a study concluded that the covid- is probably overestimated, as around . million people succumb to respiratory diseases every year in comparison to approximately , deaths due to the sars-cov- infection [ ] . the typical clinical signs of covid- are fever, chills, cough, fatigue, and chest distress [ , ] . fever and cough are considered as the most common symptoms in covid- patients [ ] , followed by headache, dyspnea, sore throat, hemoptysis, myalgia, diarrhoea, nausea, and vomiting are also observed [ , ] . some patients have shown rhinorrhea, chest pain [ ] , nasal congestion [ ] , anorexia, pharyngalgia, and abdominal pain [ ] . furthermore, neurological symptoms like anosmia and ageusia are also reported as significant clinical symptoms of covid- [ ] . the characteristic of covid- is attacking the lower respiratory tract and producing signs of upper respiratory distress, including rhinorrhea, sneezing, and sore throat [ ] . the clinical presentation of individuals infected with sars-cov- revealed upper respiratory tract infection, viremia, viral shedding from the nasopharynx, and stool along with the development of nausea, vomiting or diarrhoea after antiviral treatment [ ] . on diagnostic imaging using computed tomography (ct scan) and radiography (x-ray) bilateral pneumonia, ground-glass opacity, multiple mottling, pneumothorax, infiltration, consolidation or bronchoinflation sign has been noted in many cases of covid- [ , , ] . previously, sars-cov was found to infect the brainstem heavily [ ] . even though fever is considered as the most common symptom associated with covid- infection, a large proportion of the patients do not express fever during the initial hospital admission [ ] . the different transmission routes of sars-cov- infections have not yet been entirely ascertained, and are still under investigation. both direct and indirect pathways of transmission are being explored [ ] . similar to sars and mers, sars-cov- is predominantly spread via the respiratory route [ ] . person to person transmission is the main reason for community and global spread. the initial estimated reproduction number (rovalue) of covid- was assessed to be from . to . in december , which later has been increased to a mean value of . (range . - . ) [ ] . human-to-human transmission is by face-to-face contact with a sneeze or cough, or from contact with secretions of infected people [ , ] . nevertheless, the infectivity of other secretions and excretions are not fully understood and may require further study [ ] . aerosol and plastic surfaces can sustain virus for hours to days [ ] . travelling of infected people is considered as the main reason for the global spread of covid- [ , ] . although the asymptomatic and mild cases are the major hurdle in the evaluation of the real number of infected people, the genuine data on travellers returning from affected countries or areas may prove crucial in estimating the disease incidence [ ] . the possible occurrence of super-spreading events is very high at large gatherings, and suspension of gathering during a pandemic may prove crucial in reducing the overall transmission [ ] . close contact with any person within feet of the covid- patient or anyone having direct contact with secretions of covid- patients [ ] may set up the infection. unlike sars-cov, most transmissions in covid- are during the prodromal period when the infected individuals produce large quantities of virus in the upper respiratory tract, move/travel, and usually work thus spreading virus before illness develops [ ] . the rapid spread of covid- among the susceptible population can be due to the wide variation in illness degrees that results in a missed diagnosis. heavy viral load in asymptomatic cases and nosocomial transmission is spreading covid- unknowingly [ ] . recently, high viral load was detected in the sputum of convalescent patients, pointing out the possibility of prolonged shedding of sars-cov- even after recovery. this finding, along with the fact that asymptomatic persons can also act as the potential source of infection, may warrant a reassessment in the transmission dynamics of the covid- outbreak [ ] . the presence of viral nucleic acids in faeces is an important finding, thereby increasing the possibility of faecal-oral transmission. however, symptoms may or may not be manifested [ ] . this was found to be the unique feature of covid- and was lacking in the previous sars and mers outbreaks. in a study conducted by the chinese cdc, it was found that the majority of patients ( . %) infected with covid- infection were either asymptomatic or had mild pneumonia [ , ] . furthermore, all forms of sexual contacts have been reported to pose a significantly high risk of disease transmission through respiratory aerosols and fomites. however, to date, no evidence of sexual transmission is available, and further investigation is required in this direction [ ] . disease severity is higher in older individuals, especially males with immunocompromised conditions and comorbidities like diabetes, asthma, or cardiovascular diseases [ , ] . these are considered to be vulnerable to the sars-cov- infection. predisposition increases under risk environments where transmission of the virus from affected persons or contaminated fomites to unaffected ones becomes feasible. it was earlier noted that covs are not common to affect immunocompromised patients like other some viral infections (influenza, rhinovirus, adenoviruses, to name a few). the current pandemic has shown sars-cov- to affect more lethally than young patients, mainly destroying the lung tissues [ ] . till now, evidence regarding the higher susceptibility of pregnant women in comparison to non-pregnant women lacks in covid- . also, there is no evidence of vertical transmission (mother to fetus/baby transmission) of covid- infection [ ] . a case study reporting the birth of a healthy infant by a sars-cov- infected woman suggests that mother-to-child transmission is unlikely in the case of covid- . the study also pointed out that on the delivery day, all the samples tested negative except for sputum, which proved positive [ ] . however, as per one most recent report, neonates have been found positive for sars-cov- , indicating the possibility of vertical transmission from infected mothers to their progeny, thus rendering newborns into a high-risk group owing to their immature immune system [ ] . individuals harbouring sars-cov- may remain asymptomatic for the incubation period [ ] . different from sars-cov and mers-cov infection, the median incubation period of covid- was found to be four days [ ] . the median period from the development of signs to death was days [ ] . the case fatality rate (cfr) of covid- was found to be lower than mers and sars [ ] . however, current disease dynamics with the involvement of many more countries or areas may change the future mortality rate. the recent analysis suggests that the total fatality rate of covid- is calculated at . % [ ] . however, italy experienced the worst cfr of more than % with older people and males suffering from multiple comorbidities as primary victims [ ] . sars-cov- has shown characteristics of efficient replication in the upper respiratory tract, causing the less abrupt onset of clinical signs just like the common cold and unlike sars-cov [ ] . it can also replicate in the lower respiratory tract as has been noted in cases without pneumonia but having lesions in the lungs on radiological examination [ ] . the pathogenesis mechanisms of covid- are yet to be fully elucidated. however, both cellular and humoral immune responses against sars-cov- or its antigenic structures like spike protein (s) are believed to be of importance [ , ] with disturbed levels of inflammatory mediators playing a mediating role [ ] . following receptor binding with angiotensin-converting enzyme (ace ) through receptor binding motif (rbm) of the receptor-binding domain (rbd) of s subunit of the sars-cov- spike glycoprotein (s), virus gains entry in host cells [ , , ] . s subunit helps in the fusion of viral and hosts cell membranes [ , ] . sars-cov- produces cytopathic effects in respiratory and gastrointestinal surface epithelial cells [ ] . these include multinucleated syncytial cells, abnormally enlarged pulmonary cells, infiltration with mononuclear cells, lymphocytes infiltration in pulmonary organs, fibrinous exudation, and hyaline deposition [ ] . cytokine storm is believed to be involved in this inflammatory pathophysiology of the covid- patients producing lung lesions and systemic symptoms [ ] . elevated levels of tnf-α, il b, ifnγ, ip , gcsf, mip a, and mcp , may have stimulated t-helper- (th ) cells leading to this inflammatory cascade [ ] . however, levels of anti-inflammatory mediators (il , il ) were also increased, indicating t-helper- (th ) stimulation, which suppresses inflammation, unlike what happens in sars [ ] . a study documented that the nucleic acid of sars-cov- detected in the faecal samples was as accurate as of that of pharyngeal samples obtained from infected patients. moreover, the patients tested positive for sars-cov- in stool showed no gastrointestinal symptoms and had no relation to the severity of lung infections [ ] . one of the significant clinical signs of covid- patients during the initial presentations was gastrointestinal symptoms. hence, the involvement of git in pathogenesis needs to be explored. the significant laboratory findings include lymphopenia, increased values of erythrocyte sedimentation rate, c-reactive protein, lactate dehydrogenase, and decreased oxygenation index [ ] . an increase in proinflammatory cytokine and a decrease in antiinflammatory cytokines have also been noted [ ] . viral isolation has been achieved from bronchoalveolar lavage of affected persons; however, in the case of pregnant women, serum, faeces, urine, breast milk, umbilical cord blood, placenta, and amniotic fluid were found to be negative for sars-cov- [ ] . at the same time, the sputum was tested positive [ ] . the presence of abnormal coagulation parameters in patients with severe novel coronavirus pneumonia was associated with poor prognosis. the non-survivor patients had higher levels of d-dimer, and fibrin degradation product (fdp) along with longer activated partial thromboplastin time and prothrombin time compared to survivors at the time of admission [ ] . though clinical manifestations, pathological changes, and diagnostic laboratory findings can unravel the disease nature helping in devising therapeutic modalities, however, for epidemiological aspects and future prevention and control, simultaneous tracing of the origin and explaining the spillover events can prove beneficial. the sars-cov- has first been reported from the pneumonia patients of the wuhan city in hubei province of china. these patients were involved in trading at a wet animal market in the huanan area. it is believed that sars-cov- is introduced from the animal kingdom to human populations during november or december , as revealed from the phylogeny of the genomic sequences from the initially reported cases [ ] . the spillover of sars-cov- from animals to humans took place at the beginning of december [ ] , and the clinical cases appeared around ending december [ , ] . genetic analysis showed that this novel virus is closely related to bat covs and is similar but distinct from the sars virus [ ] . several evidences based on genome sequences, the homology of the ace receptor, and the presence of single intact orf on gene indicate bats as a natural reservoir of these viruses. however, an unknown animal is yet to be unravelled as an intermediate host [ , , , , ] . initial investigations on animal source origin of sars-cov- have inconclusively revealed snakes [ ] , pangolins, and turtles [ ] . the rapid spread of covid- followed the initial animal to human spillover through human-to-human transmission. genetic epidemiology had revealed that the spread from the beginning of december when the first cases were retrospectively traced in wuhan was mainly by a human-to-human transmission and not due to continued spillover [ ] . these species cross jumping, spillover, and rapid transmission events are linked to viral characteristics, host diversity, and environmental feasibility. coronaviruses being rna viruses have high mutation rates that, besides creating new strains, enable them to adapt to a wide range of hosts. hence, based on genome sequences, all known human covs have emerged from animal sources [ ] . this seventh member of the human cov has also been isolated initially from the pneumonia patients who were having direct or indirect links to the huanan seafood market in wuhan china, wherein other animals were also being sold [ ] . these include a -year-old lady retailer in this wet animal market, a -year-old frequent visitor to this market, and a -year-old man [ , ] . further, isolation of the sars-cov- from the environmental samples around this market, including people, animals, soil, discharges, or structures, strengthens the claims of involvement of hosts either as a reservoir or intermediate [ , , ] . recently, a pomeranian dog as a probable intermediate host was identified; however, such reports are yet to be validated, and research is underway to explore the emergence of this infectious disease at the animal-human interface [ , ] . multiple substitutions were observed in ace receptors of a dog [ ] . in this context, the pomeranian dog of the infected owner found positive for covid- suggest the permissiveness of the species for sars-cov- as a result of species jumping [ , ] . among the fifteen dogs tested from different households with confirmed human covid- cases in hong kong sar, two dogs were found to be infected with sars-cov- . the diagnosis was made using quantitative rt-pcr, serology, and viral genome sequencing. virus isolation was also done from the samples obtained from one dog. the genetic sequences of viruses obtained from the two dogs were identical to the ones that were detected from their human cases indicating human-to-dog transmission [ ] . moreover, a study reported that the sars-cov- might infect the cats and further transmitted by the infected cat to other cats [ ] . one cat was tested positive for sars-cov- in france that showed mild respiratory and digestive signs. the cat was tested positive by rt-qpcr on the rectal swab, and serological analysis identified the presence of antibodies against sars-cov- . genome analysis further confirmed that the sars-cov- isolated from the cat belongs to the phylogenetic clade a a seen in french human indicating humanto-animal transmission [ ] . this is not the first time that a domestic cat has been found susceptible to zoonotic coronavirus. during the sars-cov outbreak, domestic cats were tested positive for sars-cov that were living near sars infected humans [ , ] . even though experimental evidence indicates the possibility of sars-cov- transmission from infected to a susceptible cat close, sars-cov- transmission between cats or cat-tohumans are not reported under natural conditions [ ] . furthermore, along with dogs and cats, the zoo animals like tigers and lions were also reported to get the sars-cov- infection and exhibit clinical signs such as vomiting, diarrhoea, dry cough, breathing difficulty and wheezing [ , ] . spillover of sars-cov- was also reported in mink farms of netherlands, further increasing the concern of transmission to humans. outbreaks of sars-cov- were reported in two mink farms holding , and animals. the virus is suspected to be introduced by a farmworker having covid- [ , ] . host-pathogen interactions and pathogenesis determine the severity and expression of disease [ , [ ] [ ] [ ] . adaptation over time reduces the severity of infection as happened with hcovs; however, the emergence of novel viruses or strains due to genetic alterations or recombinations can enhance hardness producing novel diseases like covid- [ , ] . evolutionarily, the balance of viral-human interaction and immune response against virus enables adaptation, thereby persistence in a host without severe or symptomatic disease when the aggravated pathogenesis results in mortality. hence, loss of sustainable hosts and transmission to novel hosts becomes inevitable for future sustainability [ , ] . a pathogen cannot kill all its hosts, and for future sustainability, it adapts to some suitable host or spills over to a new host. sars-cov- has been implicated to be originated from animals, and associated with animal linkages, spillover events, cross-species barrier jumping and zoonosis [ , , , [ ] [ ] [ ] ] . since the beginning of till the end of , three coronaviruses viz. sars-cov, mers-cov, and sars-cov- have caused havoc in the human population globally and will continue to do so. earlier identified betacoronaviruses (sars-cov and mers-cov) were reported in guangdong province of china in november and saudi arabia in , respectively [ ] . sars-cov- is the third zoonotic betacoronaviruses recognized in this century. however, the cfr of the sars-cov- is lower to date when compared with sars and mers. it should not be overlooked as many asymptomatic cases may remain undiagnosed due to the unavailability of diagnostic kits in china. with nearly . million deaths till the preparation of the manuscript, sars-cov- is proven to be deadliest as far as the number of deaths is concerned in comparison with sars-cov and mers-cov with and associated deaths, respectively [ , ] . earlier, covid- was linked with the exposure to the huanan seafood market. however, individuals with no history of exposure above were also diagnosed with the illness, further supporting the human to human spread through droplets produced by cough and sneeze [ ] . the spread of covid- that occurred with a high pace and lack of transparency in reporting the disease by the chinese health ministry and failure in the timely implementation of preventive measures has been considered as the primary contributor as stated earlier in sars [ , ] . both sars-cov and sars-cov- showed prominent similarities in their pathogenesis and epidemics. in both cases, bats were considered as the natural host, and the cold temperature and low humidity in cold, dry winter provided conducive environmental conditions that promoted the survival of the virus in the environment [ ] . further, moriyama et al. [ ] assessed the significance of the environmental factor on host immune system targeting innate and adaptive both responses in the respiratory tract. zoonotic spillover is the transmission of pathogens to humans from vertebrate animals [ ] . at present, these spillovers are of significant concern as in the past, many spillovers in the form of nipah, hendra, ebola, sars, mers, and ongoing covid- involving many animal species like pigs, horses, monkeys, camels, civets, among others, were documented. bovine covs have been reported to infect children and thus possess zoonotic potential [ , , , ] . spillover is governed by the interaction of viral-specific proteins like s protein and host ace receptor [ , , , ] . these s proteins have rbd in covs, which contain receptor binding motifs (rbm) that help in specific binding to host ace receptors [ , ] . mutations in amino acid sequences of rbds results in a change in specificity of a receptor, interaction and binding, hence alteration in transmissibility, pathogenicity and cross-species jumping with a predisposition to novel and more severe diseases [ , ] . in the case of sars-cov- , rbd of s protein has - times affinity ace r [ , ] . it has furin recognition sequence "rrar" at the s -s cleaving site that represents a functional site for the cellular serine protease tmprss thus increasing the efficiency of transmission and contagiousness [ , , ] . in addition to enhanced binding affinity, electrostatic complementarity and hydrophobic interactions are critical to enhancing receptor binding and escaping antibody recognition by the rbd of sars-cov- , thereby further increasing transmission capability and contagiousness [ ] . a detailed investigation regarding the emergence of new coronavirus, host range, and transmissibility is crucial to understand such pandemics shortly. the literature revealed that before the appearance of sars-cov and mers-cov, human coronavirus (hcov) strains like hcov-nl , hcov- e, hcov-oc , and hcov-hku were the covs strains producing mild infections in humans. however, their natural ancestral hosts were of animal origin, like bats for hcov-nl , and hcov- e and rodents were natural hosts for hcov-oc and hku . these four hcovs were initially of low pathogenicity. to enhance the pathogenicity, they used intermediate hosts such as cattle for hcov-oc (natural host was rodent), and alpacas for hcov- e (bats were natural host) and this way acquired the ability to infect human beings with serious health hazards [ ] . added to the involvement of bats and pangolins, the recent reports revealing sars-cov- infection in cats, dogs, tigers, lions and minks have raised concerns over this virus affecting multiple animal species, and also points out towards the incidences of reverse zoonosis [ , , , , , ] . the ferrets, cats, and primates are suggested to be good candidates for susceptibility to sars-cov- [ , ] . covid- research and surveillance in companion and pet animals, livestock animals, zoo animal species, wildlife animal species as well as their handlers, veterinarians, and owners need to be enhanced during the pandemic, which would help to follow better integrated one health strategies [ ] and appropriate preventive and mitigation to counter sars-cov- effectively [ , , [ ] [ ] [ ] [ ] [ ] . significance of covid- monitoring and implementation of suitable public health measures among workers involved in meat and poultry processing facilities/industries has been emphasized, which would protect them as well as aid in preserving the critical meat and poultry production infrastructure and the meat products [ ] . the involvement of intermediate hosts in maintaining and transmitting the virus to susceptible host predisposes humans to novel covs leading to the emergence of new diseases in humans. the currently ongoing sars-cov- / covid- pandemic has put on hold the entire world [ , ] . the covs have frequently been associated with animal and human diseases and have a zoonotic interface [ , ] . usually, one or more types of animal hosts are involved in the transmission cycle of covs to humans [ , ] . that can be natural host, reservoir host, intermediate host or definitive host [ ] . bats have been the natural hosts for human covs of alphacoronavirus (hcov-nl , hcov- e) and betacoronavirus (sars-cov, mers-cov, sars-cov- ) genera whereas for betacoronavirus members hcov-oc and hcov-hku , rodents are the natural hosts. genome sequence analysis has revealed bats as a natural host for sars-cov- [ , ] . in natural or reservoir hosts, covs adapts well, however, being unstable rna viruses, they keep multiplying continuously without producing disease thereby enabling persistence or survivability and accumulation of mutations over the time resulting in the emergence of newer and novel strains of viruses [ , , ] . these unique strains or viruses occasionally spill over to other species including animals or humans, adapting to their body systems and hence broaden the biological host range for evolutionary sustainability; however, results in epidemiological widening of disease sphere as well [ , ] . this transmission and adaptation scenario initiates a host-pathogen response resulting in the novel usually severe diseases that can at times be fatal in initial stages or over extended periods until virus pathogen adapts to host or the host develops sufficient immune defence [ , ] . it has been reported that almost all hcovs have originated from animals like bats (sars-cov, mers-cov, hcov-nl , and hcov- e) and rodents (hcov-oc and hku ) [ , ] . additionally, covs have been reported to infect several species of domestic and wild animals either clinically or subclinically [ , , , ] . cattle, horses, camels, swine, dogs, cats, birds, rabbits, rodents, ferrets, mink, bats, snakes, frogs, marmots, hedgehogs, malayan pangolin along with other wild animals may serve as a reservoir host of coronavirus [ , , , , [ ] [ ] [ ] [ ] [ ] [ ] . in the context of sars-cov- , snakes, pangolins and bats have been suspected as intermediate hosts since the first cases of covid- had links to huanan sea food market where different animals, birds, and wild animals were being sold along with seafood items [ , , , , , ] . coronaviruses have been reported to cause salivary, enteric and respiratory infections in laboratory animals (mice, rat, guinea pig, and rabbit) and urinary tract infection, respiratory illness and reproductive disorder in poultry [ , ] . in bovine, canine, feline and swine covs infections have resulted in diarrhoea, enteritis, respiratory illness, gastro-intestinal affections and nervous symptoms [ , , [ ] [ ] [ ] . coronavirus, namely-sw , has been reported in captive beluga whale using a panviral microarray method [ ] . among all the assumptions on animal hosts as the intermediate host, genomic and evolutionary information from pangolins reveals the highest closeness to the sars-cov- than any other host covs isolates [ ] . the spike protein, the main target of many studies searching for a cure of covid- , has been found highly similar to sars-cov- and, thus, could serve as a surrogate system for further evaluations [ ] . bats are the natural reservoir host of many covs. as reported earlier, out of alphacoronaviruses and out of betacoronaviruses as per the international committee on taxonomy of viruses (ictv) classification were solely originated from bats [ , ] . according to the literature, bats have been regarded as a potential wildlife reservoir whereas civets and dromedary camels as intermediate hosts of sars-cov and mers-cov, respectively [ , ] . the bat coronavirus, batcov ratg , has shown higher relatedness to sars-cov- at the whole genome level and spike gene in particular [ ] . coexistence and frequent recombination between highly diversified and prevalent bat sars-related coronaviruses (sarsr-cov) and coronaviruses may suggest the probable emergence of novel viruses shortly [ , ] . benvenuto et al. [ ] analyzed the whole genome sequences of different covs using fast unconstrained bayesian approximation (fubar) to understand the evolutionary and molecular epidemiology of sars-cov- . the authors concluded that sars-cov- clustered with sequences of bat sars-like covs with a few mutations in nucleocapsid and spike glycoprotein, suggesting its probable transmission from the bats [ ] . bats, especially horseshoe bats (rhinolophus spp.), are considered to be the known reservoirs of sars-related covs. since the bat origin, covs have always caused outbreaks in humans, studying the diversity and distribution of coronavirus populations in the bats will help to mitigate future outbreaks in humans and animals [ ] . interestingly, bats play a crucial role in all the spillovers mentioned above, indicating their importance in the emergence of new viruses. the reason behind the emergence and broad host range of covs in the past and present might be due to unstable rna-dependent rna polymerase (rdrp), lack of proof-reading ability, high frequency of mutations in the receptor-binding domain of spike gene and genetic recombination [ , , ] . bat covs have high diversity and great potential of spillover in different animal species, as reported earlier in civet cat and dromedary camel, leading to well-known pandemics sars and mers, respectively along with the recent spillover in pigs resulted in swine acute diarrhoea syndrome (sads). however, spillover resulted in the emergence of sads-cov, which showed a % genomic identity with bat coronavirus, which led to severe mortality with , deaths in neonatal piglets [ ] . fortunately, it did not excel in the form of the third pandemic, and no human cases were reported till date. the spillover responsible for ongoing covid- is still under investigation and a matter of great concern for the researchers all around the globe. based on resampling similarity codon usage (rscu), snakes (bungarus multicinctus and naja atra) were suggested as wildlife reservoirs of sars-cov- and reported to be associated with the cross-species transmission [ ] and later it was disapproved by other researchers [ , ] . unfortunately, to date, the intermediate host of the sars-cov- is abstruse what results in its escalation in the human population around the globe. in this context, analyzing the interaction between the asn site in rbd of spike glycoprotein of sars-cov- and the residue at sites of ace receptor of different hosts (pangolins, turtle, mouse, dog, cat, hamster and bat) revealed that tyrosine has higher receptor binding affinity than histidine suggesting pangolins and turtle be closer than bats to humans and maybe the probable intermediate hosts of sars-cov- [ ] . however, this hypothesis was also contradicted by li et al. [ ] based on an insertion of the unique peptide (prra) in the sars-cov- virus, which was lacking in covs from pangolins. moreover, sars-cov- showed higher similarity to the betacov/bat/yunnan/ratg / compared to the ones that were isolated from the pangolins, thereby denied the direct link of the virus from pangolins. however, further studies are required to confirm the role of pangolins in sars-cov- spread to humans. the receptor-binding domain of the spike protein of sars-cov interacts with the host receptor ace facilitating its potential of cross-species, as well as human-to-human transmission [ ] . similarly, the spike protein of sars-cov- was reported to recognize ace receptors expressed in fish, amphibians, reptiles, birds, and mammals and has a more robust binding capacity (affinity) in comparison to sars-cov [ ] . this suggests their involvement as probable natural and intermediate hosts [ ] , which may further help in the selection of animal models for epidemic investigation and preventing its spread [ ] . bat origin covs have been found to cross the species barrier that favoured their transmission via recombination/mutations in the rbd. the evidence of a virus outbreak that occurred in chinese pig farms suggests its possible cross-species [ , ] . also, murine cells were found permissive for sars-cov after substitution of his with lys in the ace receptor of a mouse, which suggests the role of residue changes in the cross-species and human-to-human transmission [ ] . mutation in residues at position and of receptor binding motif (rbm) of sars-cov was reported to play a role in civet-to-human and human-to-human transmission, respectively [ , ] . the covs are more prone to recombination and mutations leading to variable host range, and resemblance of receptors in various hosts results in cross-species jumping [ , , ] . genetic divergence due to these genetic alterations results in the evolution of newer viral strains having altered virulence, tissue tropism, and host range [ , ] . moreover, the presence of threonine at position was reported to enhance the binding affinity of rbm for the ace receptor of civet and humans [ ] . however, many sarsrelated coronaviruses (sarsr-cov) have been reported in bats and used ace receptors for entry into a host cell, which showed its potential to infect humans directly without any intermediate host [ ] . in addition to this, no direct transmission of sarsr-cov is reported from bats to humans to date. however, seropositivity on a serological investigation of individuals without prior exposure to sars-cov residing near bat caves in china revealed likely infection of humans by bat sarsr-cov and related viruses [ ] . besides, the interspecies transmission potential of sarsr-covs is due to the orf gene [ ] . as per reports, the sars-cov emerged via recombination of bat sarsr-covs, was transmitted to farmed civets along with other mammals, and these infected civets spread the virus to market civets. the virus was reported to undergo mutations in infected market civets before its spillover to humans. similarly, the mers-cov circulated for years in camels before the pandemic [ , ] supporting the hypothesis that after species jumping the exogenous viruses opted for adaptation to the environment and host before spillover to humans [ ] . moreover, the possible spillover of other circulating bat sarsr-covs to humans from mammalian hosts soon is highly anticipated. the cross-species jumping and adaptation are determined by the presence of specific receptors on host tissues (like ace receptor for hcov-nl , sars-cov and sars-cov- , dipeptidyl peptidase- for mers-cov, human aminopeptidase n for hcov- e, -oacetylsialic acids for hcov-oc , hcov-hku ) which help in binding and entry of the virus into host cells [ , ] . these receptors are present in various body systems in animals and humans, including respiratory and gastrointestinal systems [ ] . reservoir host animals including bats and rodents possess these receptors which are similar to those present in camels, masked palm civets (paguma larvata), or bovines, that act as an intermediate host for different covs [ , , ] . presence of some of these receptors in humans like ace or dpp makes them vulnerable to cov infection like sars-cov and mers-cov causing sars and mers infections, respectively [ , ] . the mers-cov spike was found to possess the capacity for adapting to species variation in the host receptor dpp [ ] . the mechanism expressed by mers-cov in adapting to infect cells of new species might be present in the other coronaviruses. ace has also been found as a binding receptor for sars-cov- [ ] . the species-specific variations in the host receptors limit the interaction with cov spike protein, and this is responsible for the development of the species barrier that prevents spillover infection. snakes, civets, and pangolins are considered as the potential intermediate hosts of covid- . however, further confirmation is required by tracking the origin of the virus. this is critical for preventing additional exposure to this fatal virus [ ] . the probability of the sars-cov- spread during incubation and convalescent period has been suggested [ ] . as per reports, presence of covs has been observed in respiratory droplets, body fluids and inanimate objects with the ability to remain infectious for nine days on contaminated surfaces resulting in its risk of self-inoculation via mucous membranes of the eyes, mouth or nose [ ] [ ] [ ] . nosocomial, as well as human-to-human transmission, have been reported to occur via virus-laden aerosols, contaminated hands or surfaces, and close community contact with an infected person [ , , ] . the ocular route has been reported in the human-to-human transmission of sars-cov- , as observed in sars-cov, suggesting the involvement of different ways other than the respiratory tract [ , ] . later on, the probability of the faecal-oral route for potential transmission of the virus was also suggested [ ] . the metatranscriptome sequencing of sars-cov- in the bronchoalveolar lavage fluid (balf) of infected individuals resulted in polymorphism in few intra-hosts variants, suggesting the in vivo evolution of the virus thereby affecting its virulence, transmissibility, and infectivity [ ] . an overview of coronaviruses jumping the cross-species barriers, zoonotic covs transmitted from bats to animals before spillover to humans, and possible prospects for further transmission to mammalian hosts is depicted in figure . the first two decades ( - ) of st century have proven a nightmare for the countries around the globe considering the coronavirus zoonosis, including the ongoing crisis of covid- which has involved entire fields of global [ , ] . the countries affected severely by previous covs were even not evolved entirely from the effects of sars and mers when the covid- struck almost the entire world. novel coronavirus sars-cov- has shaken all the sectors of the countries irrespective of being developed or underdeveloped including healthcare system, economics, trade, infrastructure, service and production sectors [ , ] . being a zoonotic disease with still unknown intermediate host, undisclosed features of a novel viral pathogen, unclear modes of transmission and ecological aspects, less explored pathogenesis and substantial morbidity and considerable mortality, the safety of all is a matter of great concern, and thus the involvement of various authorities was sought since the inception of disease [ , , , ] . the first time the need for one health concept has risen to a level that authorities in various countries implemented coordinated approaches between medical, veterinary, public health, wildlife, food safety, environmental departments and so on [ ] [ ] [ ] . that involved acquiring suggestions, diagnosis and prevention and treatment measures and their implementation in collaboration. non-medical staff in association with the medical staff was employed for initial screening, quarantine, contact tracing when the expertise of molecular biologists or technicians from various disciplines was used in the laboratory diagnosis. medical staff provided the cure and management of the patients when the public health departments, including public health engineering, municipality, food and supplies ensured sanitation, hygiene, food supply and safety. imposing of lockdown was provided by security personnel's and the transport department facilitated the movement of stranded people. thus, this crises management strategy involved various agencies directly or indirectly. however, as the animal, human and environmental health is linked to one another, the prime and future efforts should primarily focus on all these aspects. in addition to regular hand hygiene, respiratory etiquette, social/physical distancing, use of personnel protective equipment (ppe) and food safety recommendations, one health approach encompasses the role of veterinary, medical and environmental specialists for the prevention and control of current covid- crises and investigating the animal origin of covid- , regulating and limiting the sale and farming of wildlife species for food and taking a one health approach to food systems feeding the world for the prevention of future pandemics [ , , ] . considering the contagiousness of the virus, discouraging the working of affected individuals, public health hygiene strategies, and social distancing has been recommended as preventive measures [ , ] . food hygiene and safety, as recommended by oie [ ] and usda [ ] , should be followed. as the viral survivability has been demonstrated on various surfaces [ ] hence disinfection by using recommended disinfectants is necessary [ ] . environmental hygiene and cleanliness are also essential [ ] . interaction with animals and improper utilization of animal products during an outbreak should be avoided [ ] . though the one health involves mainly public health, animal health and environmental experts, however, for the successful management of current crises and future prevention and control requires the participation of all concerned sectors having a role in public health measures, identifying clinical cases, diagnosis, contact tracing, proper infection control in various settings, isolation, quarantine, cure and management, public awareness, facilitation of infrastructure and other facilities through local administrations [ , ] . as the human covid- cases are on the rise due to efficient human-to-human transmission, there is a subsequent rise in the natural infections of covid- among the companion and wild animal species owing to the spillover. this is mainly because of the specific biological and virological characteristics of coronaviruses that gives them the ability to easily cross-species barriers [ ] . even though animal-to-human transmission is not reported in covid- , 'one health' approach is necessary to control this pandemic virus a schematic illustration of covid- clinical signs, modes of transmission, important diagnostic methods, and advances in vaccine development along with salient prevention and control strategies are presented in figure . with the rising number and worldwide spread of covid- , the need for global efforts rely heavily on the investigations carried out at infection sites to trace different aspects of this novel coronavirus outbreak. one of the critical facets and the earliest research must involve determining the root cause, origin, and source of this emerging infectious disease. shreds of evidence have revealed various cross-species jumping or spillover from animals to humans of these zoonotic coronaviruses. detailed serological investigation of all domestic and wild animals residing in the proximity to humans is of utmost necessity to know and prevent likely spillover of many other bat-related covs in the future. rapid detection of spillovers above will only be possible by the implementation of an effective and robust surveillance system for circulating viruses with high zoonotic potential in animals. besides, detection of a pathogen while crossing the species barrier to start circulation among humans and prevention of human-to-human transmission in early-stage may prove crucial in termination of a probable epidemic or pandemic. application of 'one health' concept involving medical, veterinary, wildlife, public health, and other related professionals may help in infection tracing, exploring risk factors and predisposition, minimizing risk to susceptible ones, and finally devising better prevention and control strategies. in the initial stages of the covid- outbreak, the steps taken for implementing stringent control and preventive measures have bought us some time. this time has to be efficiently utilized for developing sars-cov-specific therapeutic drugs and vaccines that can prevent the further spread of this fatal pathogen. for the time being early 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to help prevent another animal-to-human virus pandemic prevention cfdca. covid- and animals usda ensures food safety during covid- outbreak disinfectants for use against sars-cov none. key: cord- -kx hihnr authors: ludwig, stephan; zarbock, alexander title: coronaviruses and sars-cov- : a brief overview date: - - journal: anesth analg doi: . /ane. sha: doc_id: cord_uid: kx hihnr in late december , several cases of pneumonia of unknown origin were reported from china, which in early january were announced to be caused by a novel coronavirus. the virus was later denominated severe acute respiratory syndrome coronavirus (sars-cov- ) and defined as the causal agent of coronavirus disease (covid- ). despite massive attempts to contain the disease in china, the virus has spread globally, and covid- was declared a pandemic by the world health organization (who) in march . here we provide a short background on coronaviruses, and describe in more detail the novel sars-cov- and attempts to identify effective therapies against covid- . i n late december , several cases of pneumonia of unknown origin were reported from china, which in early january were announced to be caused by a novel coronavirus. the virus was later denominated severe acute respiratory syndrome coronavirus (sars-cov- ) and defined as the causal agent of coronavirus disease . despite intensive, wide-scale attempts to contain the disease in china, the virus has spread around the world in record time, and covid- was thus declared to be a pandemic by the world health organization (who) in march . here we provide a short background on coronaviruses and their origin, and we describe in more detail the novel sars-cov- and the efforts thus far to identify effective therapies against covid- . because they provide care for covid- patients and frequently perform procedures that generate aerosol (eg, endotracheal intubation, open suctioning, nebulized treatments), anesthesiologists and intensivists are especially at risk to be exposed to the novel coronavirus, putting them at a very high risk for infection. this is demonstrated by a recent publication showing that health care workers have a higher infection rate compared to the normal population. in addition, given that anesthesiologists and intensivists care for these patients, they should have basic knowledge of sars-cov- and the course of covid- to effectively treat these patients and to optimally protect themselves. what are coronaviruses and where do they come from? cov are found globally in humans and many different animal species. they are classified in the orthocoronaviridae subfamily (order: nidovirales, subordination: cornidovirineae, family: coronaviridae). cov can be grouped into genera, including α-/β-/γ-/δ-cov and αand β-cov can infect mammals, while γand δ-cov primarily infect birds. cov are enveloped viruses with a lipid membrane derived from the host cell, in which viral surface proteins are embedded. the proteins protruding from the viral membrane (especially the spike [s] protein) give these pathogens their characteristic halo-like appearance under the electron microscope, which has led to the name corona (latin: garland, crown). all cov have in common that their genome is in the form of a single-stranded ribonucleic acid (rna) with positive polarity, meaning that the base sequence of the rna is in the ′→ ′ orientation and corresponds to the later messenger rna (mrna). with a length of . - . kilobases, the genome of cov is the largest rna genome of all known rna viruses. besides a number of nonstructural proteins including the rna-dependent rna polymerase (rdrp), the viral rna encodes essential structural proteins, namely the nucleocapsid (n) protein surrounding the rna genome and membrane proteins: the sglycoprotein, the matrix (m) protein, and the envelope (e) protein. the s-glycoprotein on the surface of cov can attach to the cellular receptor, angiotensinconverting enzyme (ace ) on the surface of human cells. ace is found in the lower respiratory tract in late december , several cases of pneumonia of unknown origin were reported from china, which in early january were announced to be caused by a novel coronavirus. the virus was later denominated severe acute respiratory syndrome coronavirus (sars-cov- ) and defined as the causal agent of coronavirus disease (covid- ). despite massive attempts to contain the disease in china, the virus has spread globally, and covid- was declared a pandemic by the world health organization (who) in march . here we provide a short background on coronaviruses, and describe in more detail the novel sars-cov- and attempts to identify effective therapies against covid- . (anesth analg xxx;xxx: - ) coronaviruses and sars-cov- : a brief overview of humans and regulates both the cross-species and human-to-human transmission. cov have a high mutation rate due to their errorprone rdrp, which is responsible for the duplication of genetic information. in addition, homologous recombinations often occur in cov. these properties have contributed to a great diversity of cov in nature, which enables these viruses to infect numerous species. the first coronavirus described was isolated from chicken embryos in , the infectious bronchitis virus (ibv). since then, numerous cov have been detected in a wide variety of animals, including wild animals, farm animals, and pets. they are divided into the genera of the mammalian-associated αand β-cov and the bird-associated γand δ-cov. various cov are important in veterinary medicine such as transmissible gastroenteritis coronavirus (tgev) or porcine epidemic diarrhea virus (pedv) that can cause severe diarrhea in pigs. the spectrum of coronavirus diseases in animals ranges from mild to severe intestinal, respiratory, or systemic diseases. however, there are also many coronavirus infections in animals that do not appear to cause any symptoms. the presence of cov in a wide variety of animal species strongly suggested that these pathogens are of zoonotic origin and are transmitted from wild animals to humans. in particular, the sars pandemic, in - , has led to an increasing number of studies in wild animals on all continents. the greatest diversity of cov has so far been detected in bats. this has led to the hypothesis that at least the more recent cov introductions to humans were originally bat viruses that spread to an intermediate animal (eg, the himalayan palm civet for sars-cov and the dromedary camel for the middle east respiratory syndrome [mers]-cov), which then exposed humans to the viruses. however, it can be assumed that there are still some gaps in the detection of zoonotic cov in wild animal populations. in particular, the data situation for economically and/or politically unstable regions of the world is still incomplete. the first human coronaviruses (hcov) were described in the s and were designated hcov- e and hcov-oc . , there are now endemic hcov known (hcov- e, hcov-oc , hcov-nl , hcov-hku ) that circulate worldwide in the human population. in most cases, these endemic hcov cause relatively mild diseases of the upper and lower respiratory tract and are estimated to account for about a third of all "common colds" in humans. asymptomatic infections have also been described. in some cases, especially in immunosuppressed individuals, children, or persons with existing pulmonary diseases, progression to acute respiratory failure can also occur. the situation completely changed with the appearance of the sars-cov. this virus caused serious human respiratory diseases in china in - . approximately people were affected by the disease at that time, with case fatality rate (mortality rate) of around . %. sars-cov spread could be stopped by the rapid development of a detection method and extensive measures to isolate infected individuals. subsequent studies in wild animals showed that sars-related cov are found in bats and civet cats, hence it was assumed that the virus spread from the civet cat to humans, followed by human-to-human spread. while no human infections with the original sars virus have been reported since , another cov dangerous for humans emerged in . the mers-cov was isolated for the first time from a patient who was hospitalized with acute pneumonia in saudi arabia. by , around mers-cov infections have been reported in humans, with about a % case fatality rate. the main risk area for mers-cov infections is the arabian peninsula. infections were reported to be both through human-to-human transmission and through contact with dromedaries (camels). these animals appear to represent a reservoir for mers-cov. severe acute respiratory syndrome coronavirus at the end of december , china reported the increasing occurrence of pneumonia in the city of wuhan, hubei province. in january , a novel β-cov was identified as the cause. when the virus was first isolated from pneumonia cases in wuhan, china, in december , it was named novel coronavirus ( -ncov). as more information and genetic analyses became available, the virus was given the official name of sars-cov- by the international committee for taxonomy of viruses, while the who named the disease caused by the virus, covid- . the genome of the new coronavirus shows similarities to other β-cov found in bats. sars-cov- is . % identical to a bat cov ratg , whereas it shares . % identity to sars-cov. it can therefore be assumed that the virus originally came from bats and has been transmitted over time to other animal hosts and ultimately to humans. although the degree of diversification of sars-cov- is lower than that of, for example, influenza viruses, the divergence of prevalent evolvement types of sars-cov- , l type (≈ %) and s type (≈ %), was reported. according to this study, strains in l type, derived from s type, are evolutionarily more aggressive and contagious. it is clear now that sars-cov- also uses ace as a cellular receptor to infect humans. sars-cov- is efficiently transmitted from personto-person and has thus able to spread rapidly across all continents in our globalized world. in the resulting covid- pandemic, , people have been infected and , patients have died so far (as of march , , source: johns hopkins university). as an emerging acute respiratory infectious disease, covid- primarily spreads through the respiratory tract, by droplets, respiratory secretions, and direct contact. in addition, it has been reported that sars-cov- was isolated from fecal swabs and blood, indicating the possibility of multiple routes of transmission. however, this needs further clarification. the current data suggest an incubation period of - days, in most cases - days. the virus is highly transmissible in humans and causes severe problems especially in the elderly and people with underlying chronic diseases. covid- patients typically present with specific, similar symptoms, such as fever, malaise, and cough. , most adults or children infected with sars-cov- have presented with mild flu-like symptoms, but a few patients are in critical condition and rapidly develop acute respiratory distress syndrome (ards), respiratory failure, multiple organ failure, and even death. according to a recent report, the common clinical manifestations of covid- included fever ( . %), cough ( . %), fatigue ( . %), sputum production ( . %), shortness of breath ( . %), sore throat ( . %), and headache ( . %). a minor number of patients manifested gastrointestinal symptoms, with diarrhea ( . %) and vomiting ( . %). fever and cough were the dominant symptoms, whereas upper respiratory symptoms and gastrointestinal symptoms were rare. the case fatality rate increases with the severity of illness and can reach up to % in critically ill patients. unfortunately, no specific therapeutic options are currently available. only supportive measures can be applied at the moment. there is no specific antiviral treatment recommended for covid- , and no vaccine is currently available. there are several worldwide efforts at developing vaccines against sars-cov- . however, it is already clear that these vaccination strategies will not be available until at the earliest and will thus not be of any help for immediate countermeasures. thus, antiviral drugs are urgently needed. new drug licensing as well as repurposing the indications for drugs that are already in clinical use for other diseases would be the most promising options in the short term. several of these drug candidates have been proposed and tested, including the human immunodeficiency virus (hiv) drug lopinavir/ritonavir, the antimalarial drugs chloroquine and hydroxychloroquine, and remdesivir, an inhibitor of rna polymerase with in vitro activity against multiple rna viruses, including ebola. however, the results of many of these initial trials suffer from small sample sizes and/or nonrigorous study design. when lopinavir/ritonavir was tested in a rigorous randomized, controlled, open-label trial involving hospitalized adult patients with confirmed sars-cov- infection, no benefit was observed beyond standard care. while a recent trial using hydroxychloroquine was more promising and showed that treatment is significantly associated with viral load reduction/disappearance in covid- patients, this study included only a small number of individuals and therefore considered to have very limited validity. preclinical studies suggested that remdesivir (gs ) could be effective for both prophylaxis and therapy of hcovs infections. this drug was positively tested in a rhesus macaque model of mers-cov infection and has been reported to treat the first case in the united states of covid- successfully. accordingly, large clinical trials, nct for mild/moderate covid- and nct for severe covid- , were initiated in china, with an estimated end date in early april . similarly, the current lack of valid, rigorous clinical studies has prompted many clinical trials around the world. as one example, europe has begun large joint clinical studies of experimental drugs to treat covid- . the trials will include patients in the netherlands, belgium, luxembourg, the united kingdom, france, and spain, to test the clinical efficacy of the antiviral drugs remdesivir, lopinavir/ ritonavir (+/− interferon), and hydroxychloroquine (nct ). e characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention available at: https:// talk.ictvonline.org/taxonomy severe acute respiratory syndrome: identification of the etiological agent coronavirus diversity, phylogeny and interspecies jumping coronaviruses: an overview of their replication and pathogenesis structural insights into coronavirus entry ace receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia rates of evolutionary change in viruses: patterns and determinants rna recombination in animal and plant viruses cultivation of the virus of infectious bronchitis animal coronaviruses: what can they teach us about the severe acute respiratory syndrome? ecology, evolution and classification of bat coronaviruses in the aftermath of sars a new virus isolated from the human respiratory tract recovery in tracheal organ cultures of novel viruses from patients with respiratory disease coronaviruses as the cause of respiratory infections identification of a novel coronavirus in patients with severe acute respiratory syndrome hosts and sources of endemic human coronaviruses isolation of a novel coronavirus from a man with pneumonia in saudi arabia mers coronavirus: diagnostics, epidemiology and transmission china novel coronavirus investigating and research team. a novel coronavirus from patients with pneumonia in china on the origin and continuing evolution of sars-cov- a pneumonia outbreak associated with a new coronavirus of probable bat origin early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia molecular and serological investigation of -ncov infected patients: implication of multiple shedding routes clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan national microbiology laboratory, canada; canadian severe acute respiratory syndrome study team. identification of severe acute respiratory syndrome in canada clinical features of patients infected with novel coronavirus in wuhan clinical characteristics of coronavirus disease in china management of critically ill adults with covid- a trial of lopinavir-ritonavir in adults hospitalized with severe covid- hydroxychloroquine and azithromycin as a treatment of covid- : results of an open-label non-randomized clinical trial the antiviral compound remdesivir potently inhibits rnadependent rna polymerase from middle east respiratory syndrome coronavirus prophylactic and therapeutic remdesivir (gs- ) treatment in the rhesus macaque model of mers-cov infection washington state -ncov case investigation team. first case of novel coronavirus in the united states key: cord- -fpz jfuj authors: abdihamid, omar; cai, changjing; kapesa, linda; zeng, shan title: the landscape of covid- in cancer patients: prevalence, impacts, and recommendations date: - - journal: cancer manag res doi: . /cmar.s sha: doc_id: cord_uid: fpz jfuj cancer patients are susceptible groups to covid- , and risk-adjusted models show that most cancer patients have a – % mortality risk if infected with covid- . the infection rate of sars-cov- in cancer patients in china was . % ( of patients; % ci, . . %). the case fatality rate of covid- in the overall population ranges from . to . %; among these, the case fatality rate for cancer patients is at . %. in a retrospective cohort study of covid- -infected cancer patients, a total of ( . %) patients had severe outcomes with a mortality rate of . %. in a pooled analysis by aakash et al, a % cancer prevalence was found among admitted patients with covid- . in italy, a report shows that among the patients who died of sars-cov- , . % were patients with cancer. in new york, ( %) cancer patients succumbed to covid- with a case fatality rate of % ( / ) and % ( / ) for hematologic and solid malignancies, respectively. impacts of covid- in cancer care include interruptions of life-saving therapies, distraction effects, and diagnostic overshadowing that involve diverting attention to the pandemic rather than to cancer patients and disruptions of primary palliative care to patients due to forced quarantine. herein, we review the landscape of covid- in cancer care. we also briefly share our experience and the measures in place to protect cancer patients against covid- in our center. as of december , the world has grappled with a novel strain of virus caused by severe acute respiratory syndrome coronavirus (sars-cov- ) that causes the disease covid- . the first case was identified in the city of wuhan, hubei province, china, and rapidly spread globally. the origin of the virus is believed to be from bats and later transmitted to humans through an unknown intermediary in wuhan wet market, hubei province, china, in december . similar incidents of transmission happened in the past two decades, where animals to human crossover were witnessed. the first instance of such was in - , when a crossover transmission of a new coronavirus was identified in guangdong province of china. , the case fatality rate of covid- is estimated to range from to %. this novel virus is more virulent but genetically different from sars-cov and middle east respiratory syndrome coronavirus (mers-cov), albeit with lower fatality. , the universal impact of this new pandemic is exponential with countries like the usa, italy, spain, and the uk reporting staggering numbers of cases and deaths. following the outbreak in wuhan on st december , china officially notified the world health organization, and on st january , the epicenter market was closed. as of august , worldwide confirmed cases stand at . million, with over , deaths according to the latest world health organization (w.h.o) situation reports. coronaviruses are a type of enveloped rna viruses with a size of nm to nm in diameter with crownlike projections when viewed microscopically; hence the name coronavirus. on th january , the genome sequence of virus was identified by the chinese scientists to be coronavirus, which showed a striking similarity of > % with the bat coronavirus and > % with the sars-cov. samples from the wet market tested positive, confirming the epicenter of the virus and patient zero. based on this, there was clear evidence that human-tohuman transmission was happening among close contacts of patient zero since the middle of december . concerted efforts by the chinese authorities leading up to the total shutdown of wuhan city lead to excellent control of transmission in china, albeit with over deaths. the decline in the number of cases in china depicts, strict public health measures can be successful in containing epidemics. cancer patients are caught on the crossfire of this pandemic as a unique group with increased risks of contracting covid- . their weakened immunity is resulting from a myriad of factors including underlying malignancy burden and active cancer treatments like cytotoxic chemotherapy, radiotherapy, or even due to patients undergoing transplant and use of immunosuppressants to avoid rejection. however, recent evidence shows that mortality in cancer patients from covid- is mainly driven by old age and comorbidities and less likely by the use of cytotoxic drugs. risk-adjusted models show that most cancer patients have a % percent mortality risk if infected with covid- . also, most cancer patients are frail and of older age with comorbidities compared to the healthy population; hence they tend to have poor outcomes. this pandemic has caused a huge, unprecedented impact on cancer patients' care continuum in terms of diagnosis, treatment schedules, and follow up visits. new and old patients are losing valuable clinic visits due to quarantine. likewise, new patients could potentially miss early diagnosis opportunities and patients with advanced cancer experience delays or interruptions of their routine treatment leading to risks of disease progression. additionally, patients who develop adverse side-effects from cancer treatments could lose valuable time to come in for an intervention. these include; immunotherapy related adverse effects, tumor lysis syndromes, differentiation syndromes, and other severe treatment-related events. also critical is oncological emergencies commonly seen, such as; spinal cord compression, need for acute pain relief, electrolyte imbalances, need for blood transfusions, febrile neutropenia, among other sudden detrimental events. moreover, distraction effects that involve diverting attention to the pandemic as compared to cancer patients cause collateral loss and unfavorable outcomes in oncology care. instances, where even oncology care clinicians are in the frontlines to care for covid − patients, are reported in many institutions due to shortages of staff. in the middle-and low-income countries with the ailing healthcare system and sub-optimal oncology care, these distraction effects are far worse. the inability to deliver palliative care or primary palliative care to patients is another significant concern due to forced quarantine. there could be a double wave of cancer patients' deaths: a surge in immunocompromised patients who contract covid- or those whose treatments were deescalated, canceled, or delayed. as one medical oncologist described in a perspective article: "to survive sars-cov - only to then succumb to an undertreated cancer would be a pyrrhic victory". this article gives an overview of the prevalence and impacts of covid- in cancer patients and institutional recommendations put in place to mitigate the virus in this patient population. we also briefly share our proposed organizational model in our institution on the measures taken to protect cancer patients. the spread of the disease is exponential in immunocompromised populations like cancer patients during outbreaks, and eventually, immunity limits transmission. similar to cases seen during the mers-outbreak where having cancer was identified as a risk factor for mers-cov mortality, the covid- pandemic also poses threats to cancer patients. the burden and risk of developing covid- in cancer patients are compounded by their age and litany of other comorbidities. a systematic review that looked at the prevalence of underlining conditions of already hospitalized covid- patients showed cardiovascular diseases and malignancy to be among the most prevalent conditions. as the world population continues to live longer, age becomes an overall risk factor for cancer. in alone, . million cancer cases were diagnosed globally in persons aged ≥ . many of the latest covid- studies also show advanced age and comorbidities to be associated with poor outcomes. therefore, age-stratified data in the continuum of cancer care during this pandemic and beyond is paramount. in one of the early data by yu et al published in jama oncology, the infection rate of sars-cov- in cancer patients from wuhan, china, was at . % ( of patients; % ci, . . %). and in their subgroup analysis, they found that the prevalence was higher in lung cancer patients older than age compared to those younger than years ( . % vs . %). liang et al, also looked at the prevalence of cancer in covid- cases in a nationwide analysis. they analyzed a total of cases and found a prevalence of % ( % ci, . % to . %), which was higher than the overall cancer risks in the chinese population. lung cancer was similarly the most common type of disease from this cohort, accounting for %. their subgroup analysis also reported lung cancer patients with covid- to be at a higher risk of pulmonary complications and poor outcomes from the use of chemotherapy. in a retrospective cohort study of covid- infected cancer patients with laboratory-confirmed covid- from three hospitals in china, a total of ( . %) patients had severe outcomes with a mortality rate of . %. also, tumor treatment within last days seemed to significantly increase the risk of severe outcome [hazard ratio (hr) = . , % confidence interval (ci) . - . , p = . . however, according to the data from the chinese center for disease control and prevention, case fatality was higher in patients with comorbidities compared to those without. among these, the case fatality rate for cancer patients was at . %. a review of covid- patients who died in italy showed old age (mean . yrs) and comorbidities as the main contributing factors. among these, patients ( %) had active cancer. in a multicenter study, patients with hematological and metastatic cancer were found to carry a high risk for sars-cov- , which was similar to those who recently received surgery. receiving radiotherapy was not found to have any significant differences in severe outcomes when compared to non-cancer patients. in a retrospective analysis of the perioperative outcomes of six lung cancer patients with covid- , cai et al, found that three patients died from covid- pneumonia, indicating surgery might be a risk factor for death in these patients. similarly, cancer patients with covid- were found to have a higher risk of severe events (for example, need for intensive care unit and invasive ventilation, or even death) compared with patients without cancer. quantifying the risks of covid- for cancer patients hinges on; the absolute risk of covid- during anticancer therapy and the additional risk of mortality should the patient become infected. because of resulting neutropenia and lymphopenia and interference with both innate and adaptive immunity from cancer drugs, cancer patients can have a worse disease course. in a pooled analysis by aakash et al, a % cancer prevalence was found among admitted patients with covid- . alarmingly, even a past medical history of cancer in the setting of cancer survivors seemed to increase the risk for poor outcomes due to possible immune status. however, this could be a confounding factor related to old age. a case report from wenzhou, china of a -year-old gentleman previously treated for non-hodgkin lymphoma and chronic lymphocytic leukemia (cll), was found to have covid- , after presenting with atypical symptoms. the authors conclude that the patient's compromised weak immune system and cll masked the infection. another case report from wuhan of a multiple myeloma patient who presented with solitary chest tightness was diagnosed with covid and successfully treated with tocilizumab. a lung cancer case on long-term nivolumab therapy, a sudden severe interstitial pneumonitis during treatment was noticed, and the patient later tested positive for sars-cov- . immunotherapy related pneumonitis usually occurs during the first months of therapy, and the sudden onset could be attributed to the negative synergy of the a pan-cancer analysis by cai et al that looked at cancer types with the highest risk for covid- found that endometrial carcinoma expressed both transmembrane protease serine (tmprss ) and angiotensin-converting enzyme (ace ) receptors which are launching pads for sars-cov- . therefore, these subgroups of cancer patients could be at higher risk. in new york, a total of cancer patients succumbed to covid- with a case fatality rate of % ( / ) and % ( / ) for hematologic and solid malignancies, respectively. using multivariate analysis, older age, comorbidities, increased levels of lactate, and need for intensive care were associated with worse outcomes. report from the superior institute of health in italy shows that patients who died of sars-cov- , . % were patients with cancer. the report further indicates, old age and other comorbidities to have contributed to these adverse outcomes. therefore, a risk-benefit analysis of systemic treatment should be considered in this patient group, and factors like age > , comorbidities and the number of treatment visits required should inform decisions. immunotherapy, as one of the armamentariums of cancer treatments, usually comes with immune-related adverse events in a subset of patients. immune checkpoint inhibitors (ici) are commonly used to treat solid tumors such as melanoma, lung cancer, renal carcinoma, urothelial cancers, and head and neck tumors. however, the susceptibility of this subset of patients to contract covid- or other bacterial, viral infections has not been well studied. granted that immunotherapy restores the cellular immunocompetence of these patients, there could be a plausible theory that they are maybe more immunocompetent as compared with patients undergoing radiotherapy or chemotherapy. in an analysis that sort to look for the correlation between the history of immunotherapy drugs in lung cancer patients, the authors did not find any evidence even when adjusted for smoking history status which is common in these patient group. a new hypothesis on the role of androgen hormone in covid- , data from italy shows prostate cancer patients receiving androgen deprivation therapy had a significant fourfold reduced risk of covid- infections compared to their counterparts. currently, through the cyclic media news, all cancer and potential cancer patients are more oriented toward covid- symptoms and could potentially ignore any ominous symptoms like breast lump or rectal bleeding that would normally lead them to see a doctor. the differential diagnosis of covid- , especially in cancer patients, includes all types of respiratory viral infections and bacterial infections, which often present atypically. therefore, travel history is essential, and oncologists should have a high index of suspicion. above all, there is the possibility of an actual higher prevalence of sars-cov- in cancer patients than it is reported. this is further confirmed by the higher number of young and healthy young population who are probably carriers of covid- with mild or no symptoms and who do not require hospital admission, thus escaping the rapid laboratory testing. in addition, sars-cov- could as well present with genetic drift and mutation; hence should be closely monitored to avoid a second wave which will further the current effects on cancer care. more data from covid- studies on the clinical characteristics and outcomes showed cancer to be a common comorbidity with varying types, as shown in table below. taken all together, cancer patients are at higher chances to contract and die from covid- compared to the general population, and proper measures to address this should be adopted by hospitals and treatment centers. the covid- pandemic presents unprecedented challenges and learning opportunities for many cancer care providers. even though many patients will not contract the virus due to heightened precautions, people with compromised immune systems, including cancer patients and cancer survivors are at increased risk for covid- and other infections. the highest risk group in covid- transmission are the healthcare workers. in , healthcare workers accounted for % of those affected by the severe acute respiratory syndrome (sars) outbreak. as of february , . % of the reported cases in china were health care workers, and by april , a total of health care professionals were among the deaths from covid- . a study by yu et al ( ) risk of covid- in comparison to the general population. they linked hospital visits to be a contributing factor to this increased incidence. also, there is no current clear guideline on the care of cancer patients concerning their cancer types, therapy types, or subpopulation of cancer patients (eg, children, elderly). due to the looming shortage of health care resources, together with the increased risk of cancer treatment during this pandemic, informed decisions about how and when to provide cancer treatment, is paramount. the american college of surgeons recommends a delay of life-saving cancer surgeries and the cancellation of elective surgeries to cushion and shift resources to covid- patients. this hugely affects patients and could lead to loss of vital opportunities in many resectable cancers. a survey by the american cancer society cancer action network shows % of cancer patients reported delayed treatments, and % were worried about the uncertainty of future therapies. in the uk, urgent cancer referrals that are usually eligible for a two-week wait target are now subject to prioritization rules that will cause delays. also, cancer screening programs have been halted and is only offered to symptomatic patients. a similar modeling study from the uk looking at the impacts of an average -weeks delay in cancer patients' referrals shows % reductions as a result of a backlog of referrals of about % resulting from the lockdown. therefore, prompt prioritization of patients for whom referral delays would lead in most life-years lost should be considered. in the netherlands, a country of million people, the overall cancer diagnosis for all cancer sites excluding skin cancer dropped by % from january to april . furthermore, skin cancer, excluding basal cell carcinoma, decreased by % in the same time frame. the pandemic also poses significant risks to specific cancer patients, such as leukemia patients. approximately % of patients with acute leukemia present with fever and are at risk of misdiagnosis. similarly, other cancers (mediastinal tumors or lung cancer, for example) who present with respiratory symptoms like cough and are likely to be dismissed after testing negative for covid- . also, stem cell transplantation services are affected in terms of risks of transplantation, the number of procedures done, and the availability of a matched donor. such situations could have a negative impact on survival. most of the cancer clinical research programs including, clinical trials, have experienced operational changes, including delays in accruals during the covid- pandemic, according to a report by an international collaborative group that looked at the impacts of covid- on cancer care. , training and education in the oncology department have been equally affected. medical students' training programs are not ongoing. hospital morning rounds, meetings and journal clubs have been suspended, and are only accessible via teleconference. cancer care providers are at increased risk for coronavirus infection. many healthcare workers succumbed to coronavirus, representing . % of italy cases by th march . working under pressure and burn out are likely to be experienced by cancer care providers during this pandemic. mental health and psychological stress, especially vicarious traumatization in caregivers, can be caused by the covid- pandemic. in a recent study from china that enrolled front-line nurses to evaluate vicarious traumatization scores via a mobile app-based questionnaire showed significant prevalence. [ ] [ ] [ ] recommendations currently, there are no harmonized guidelines on the management of cancer patients with covid- . institutionbased guidelines are followed, and this varies from center to center. this has posed significant challenges, especially for integrative cancer treatments. , american society of clinical oncology (asco) recently released a covid- related frequently asked questions document addressing the recommendations on screening of cancer patients, in-patients and outpatients visits, collection of laboratory samples, home drug infusion options and engaging in telehealth. multiple registries of covid- in cancer patients have been launched in order to characterize the severity and clinical outcomes of cancer patients. a new registry of such is teravolt (thoracic cancers international covid collaboration) that collect lung cancer tailored risk-assessment data across multiple international centers. in ten-point recommendations for oncology practices on the safety of cancer patients and their caregivers, pelin et al, suggest prescreening, telemedicine, switch therapy, among others during this pandemic. the world health organization has given several general recommendations, which include; adopting isolate, test, treat and trace policy, hand washing after visiting every patient, screening, and isolation of suspected covid- cancer patients in different wards. additionally, care providers are advised to limit the use of aerosol-generating procedures like intubations in cancer patients. the center for disease control (cdc) recommends high-risk individuals like cancer patients to stay home and should avoid cruise ship and nonessential air travel. however, they should be provided access to several weeks of medication. during the middle east respiratory syndrome coronavirus (mers-cov), leaders in oncology care instituted a plan to manage the crisis in cancer patients. the main components of this plan include; leadership and communication, staff management, infection control, patient management, and recovery plan. such a plan presents a template for the covid- epidemic and should be adopted for the benefit of immunosuppressed groups like cancer patients. a recently published experience from china on the countermeasures against covid- in cancer recommends postponing elective surgery or adjuvant chemotherapy for stable patients and those with advanced cancer in endemic areas. strict and thorough surveillance should be considered if cancer patients are infected with sars-cov - , especially elderly patients and those with other comorbidities. , the italian authors recommend the importance of prioritizing urgent cancer treatment, especially in the setting of colorectal surgery. minimally invasive procedures should be preferred and done only on highly selected patients. radiotherapy, as an essential treatment modality, can be used as an alternative to surgery where feasible, especially by the use of hypofractionated regimens, as this will minimize the number of visits. delaying radiotherapy poses detrimental effects, especially in patients who need palliative radiotherapy. similarly, according to the early breast cancer trialists' collaborative group, radiotherapy delays obviate survival benefits associated with the adjuvant treatments of breast cancer. european/american society for radiation oncology (estro-astro) issued a consensus statement on lung cancer radiotherapy during the covid- pandemic. this practice recommendation addresses six different lung cancer cases and the prioritization of hypofractionation in the setting of risk mitigation and reduced resources. in a special issue about their experience from the covid- epicenter in the united states, masumi et al recommend the continuation of therapy in patients with curative intent. hematologic malignancy like acute leukemias needs greater urgency; hence should be handled as such. and finally, cellular immunotherapies and hematopoietic stem cell transplantation are invaluable curative interventions for most patients with aggressive disease; therefore should not be delayed if possible. patients on immunotherapy with underlying lung diseases like interstitial pneumopathy are considered a highrisk group for immunotherapy related pneumonitis. as mentioned above, there are controversies about covid- and anticancer treatment with ici. however, patients should not be denied the crucial benefits of ici treatment, especially in highly responsive diseases. a panel made up of experts in the uk has recently published updated recommendations during the ongoing covid- pandemic in the radiotherapy setting recommending hypofractionation for bowel cancer to minimize visits while maintaining the efficacy of treatment. the panel also recommends delaying any therapy in elderly patients and patients with poor performance status or those who are unfit for chemotherapy. , canadian guidelines on prioritizing systemic therapies for genitourinary malignancies during this pandemic recommend the use of radium , especially in patients with bone-only lesions and androgen-receptor -axis targeted therapies in metastatic prostate cancer while also carefully weighing the risk of taxanes related neutropenias. they also recommend the use of virtual care of cancer patients at this time to minimize visits. the national institute for health and care excellence (nice) and the european society of medical oncology (esmo) issued tiered approach guidelines in delivering cancer care during the covid- pandemic. it's designed on three levels: high, medium, and low priority using the criteria of the cancer care ontario and magnitude of clinical benefit scale (mcbs), as described in table . patients with a terminal disease or with comorbid health who contract covid- and require mechanical ventilation could have a dismal prognosis. a retrospective study from wuhan reported the survival of only one patient among the covid- patients who were severely ill and required mechanical ventilation. therefore, oncologists need to have advance care planning and discussions with cancer patients and their families on such possible outcomes. similarly, the national comprehensive cancer network (nccn), underscores the importance of supportive care discussions with cancer patients should they become infected with covid- . with scarce resources, oncologists should prioritize what treatments are most likely to be successful, symptom-relieving, and which patients are likely to benefit from such treatments. finally, oncologists should always be compassionate and do no harm-primum non nocere. fortunately, there have been no cases of covid- in our oncology department, but that is not without contingency measures put in place. first, all medical staff is trained on the latest information on covid- and how to carry out case-finding in their respective departments. secondly, a covid- ad hoc expert committee comprising of high priority: patient condition is immediately life threatening, clinically unstable, and/or the magnitude of benefit qualifies the intervention as high priority (eg significant overall survival gain and/or substantial improvement in quality of life). medium priority: patient situation is non-critical but delay beyond weeks could potentially impact overall outcome and/or the magnitude of benefit qualifies for intermediate priority. low priority: patient's condition is stable enough that services can be delayed for the duration of the covid- pandemic and/or the intervention is non-priority based on the magnitude of benefit (eg no survival gain with no change nor reduced qol) abdihamid et al dovepress infectious disease experts, hematologists and oncologists, pharmacists and radiologists has been set up and institutional guidelines put in place. thirdly, to minimize crossinfection, staff should not enter other departments other than their own without permission. fourthly, the zoning of the institution into four special categories was used to screen for incoming patients. zone (screening and surveillance zone) is for patients who need surveillance as directed by the committee of experts in-order to rule out potential infection. each patient must be isolated in a single room. zone (quarantine zone) is for suspected cases, and therefore each patient must be quarantined in a single room. zone (confirmed quarantine zone) is a treatment zone for patients with confirmed covid- . zone (oncology ward) is used as the treatment zone for cancer patients who do not have covid- . the full protocol is shown in figure even though cases in china have exponentially dropped and the curve flattened, continuous screening of cancer patients for covid- before admission or before therapy is still strictly followed in our institution. covid- has changed the world order and, more so, the order of cancer care. cancer patients and cancer survivors are at high risk for contracting and dying from covid- . the incidence data of covid- in the cancer patient population is still emerging and could be higher than it is reported. the symptomology of covid- in cancer patients is atypical and masked; hence misdiagnosis is possible, so oncologists should have a high index of suspicion. early screening, diagnosis, isolation, treatment, and education of cancer patients are of utmost importance. social distancing, handwashing should be observed by cancer patients. similarly, hospital visits should be avoided, and clinicians should engage in virtual care. patients' age, tumor type, underlying comorbidities, stage of the disease, and treatment type all affect the risk and outcomes of contracting sars-cov- in cancer patients. however, recent evidence shows that mortality in cancer patients from covid- is mainly driven by old age and comorbidities and less likely by the use of cytotoxic drugs. impacts of this pandemic in cancer care include; increased risk of mortality, missed early cancer diagnosis opportunities, cancelation, or interruptions of life-saving therapies, distraction effects and diagnostic overshadowing. also, important clinical trials, research, and academic programs and have all been severely affected. as more data emerges, the landscape of covid- will be understood, but as of now, the guidelines issued by the relevant cancer organizations should be strictly followed to protect cancer patients. preventative measures remain the only effective arsenal against this invisible pathogen. early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia who. novel coronavirus ( -ncov) situation report - january . situation report - covid- infection: origin, transmission, and characteristics of human coronaviruses insight into novel coronavirus -an updated interim review and lessons from sars-cov and mers-cov chinese clinical guidance for covid- pneumonia diagnosis and treatment world health organization declares global emergency: a review of the novel coronavirus 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a transversal challenge. the invidia study impact of pd- blockade on severity of covid- in patients with lung cancers androgen-deprivation therapies for prostate cancer and risk of infection by sars-cov- : a population-based study (n= ) cancer and coronavirus disease ; how do we manage cancer optimally through a public health crisis? review of coronavirus disease- (covid- ) presumed asymptomatic carrier transmission of covid- managing cancer care during the covid- pandemic: agility and collaboration toward a common goal protecting health-care workers from subclinical coronavirus infection death from covid- of health care workers in china cancer care delivery challenges amidst coronavirus disease - (covid- ) outbreak: specific precautions for cancer patients and cancer care providers to prevent spread covid- : recommendations for management of elective surgical procedures covid- pandemic impact on cancer patients and survivors survey findings summary. am cancer society the lancet o. 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hci. pandemic planning clinical guideline for patients with cancer clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study the importance of addressing advance care planning and decisions about do-not-resuscitate orders during novel coronavirus (covid- ) covid- in patients with thoracic malignancies (teravolt): first results of an international, registry-based, cohort study clinical characteristics, outcomes, and risk factors for mortality in patients with cancer and covid- in hubei, china: a multicentre, retrospective, cohort study clinical characteristics of deceased patients with coronavirus disease : retrospective study clinical features of sequential hospitalised patients with novel coronavirus disease (covid- ), the first uk cohort coronavirus disease infection does not result in acute kidney injury: an analysis of hospitalized patients from wuhan, china clinical characteristics of covid- patients with digestive symptoms in hubei, china cancer in intensive care unit patients with covid- covid- with different severities: a multicenter study of clinical features the authors received no funding for this work and report no financial or non-financial conflicts of interest. cancer management and research is an international, peer-reviewed open access journal focusing on cancer research and the optimal use of preventative and integrated treatment interventions to achieve improved outcomes, enhanced survival and quality of life for the cancer patient. the manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use. visit http://www.dovepress.com/testimonials.php to read real quotes from published authors. key: cord- -nmx h a authors: müller, olaf; neuhann, florian; razum, oliver title: epidemiologie und kontrollmaßnahmen bei covid- date: - - journal: dtsch med wochenschr doi: . /a- - sha: doc_id: cord_uid: nmx h a the coronavirus disease pandemic (covid- ), caused by the severe acute respiratory syndrome-related coronavirus (sars-cov- ), started in december in china. sars-cov- is easily transmitted by droplet infection. after an incubation period of – days, covid- shows a mild course in % of observed cases and a severe course in %, with a lethality rate of . – . %. elderly people and people with underlying diseases have a higher risk of severe courses with mandatory ventilation. so far there are neither effective drugs nor vaccinations available, so only public health interventions such as physical distancing and hygiene measures on the one hand and targeted testing followed by isolation and quarantine measures on the other hand are available. china has shown that maximum use of these measures can control the epidemic. the further course and also the consequences for the global economy cannot be clearly predicted at present. übertragbar. nach einer inkubationszeit von - tagen zeigt covid- in % der beobachteten fälle einen leichten und in % einen schweren verlauf, bei , - , % letalität. Ältere menschen und menschen mit grunderkrankungen haben ein höheres risiko für schwere verläufe mit beatmungspflicht. es gibt bisher weder wirksame medikamente noch eine impfung, somit stehen nur public-health-interventionen wie einerseits physisches abstandhalten und hygienemaßnahmen sowie andererseits gezieltes testen gefolgt von isolations-und quarantänemaßnahmen zur verfügung. china hat gezeigt, dass ein maximaler einsatz der maßnahmen die epidemie kontrollieren kann. der weitere verlauf und auch die konsequenzen für die weltwirtschaft sind zurzeit noch nicht klar vorhersehbar. the coronavirus disease pandemic , caused by the severe acute respiratory syndrome-related coronavirus (sars-cov- ), started in december in china. sars-cov- is easily transmitted by droplet infection. after an incubation period of - days, covid- shows a mild course in % of observed cases and a severe course in %, with a lethality rate of . - . %. elderly people and people with underlying diseases have a higher risk of severe courses with mandatory ventilation. so far there are neither effective drugs nor vaccinations available, so only public health interventions such as physical distancing and hygiene measures on the one hand and targeted testing followed by isolation and quarantine measures on the other hand are available. china has shown that maximum use of these measures can control the epidemic. the further course and also the consequences for the global economy cannot be clearly predicted at present. der erreger des coronavirus disease (covid- ) , das severe acute respiratory syndrome-related coronavirus (sars-cov- ), gehört zu einer rna-virusfamilie, die sowohl bei tieren als auch beim menschen erkrankungen hervorrufen kann. humane coronaviren (hcov) infizieren primär den respirationstrakt [ ] . sie schließen die weltweit verbreiteten, hauptsächlich ambulant erworbenen und bevorzugt in der kalten jahreszeit auftretenden erkältungsviren-typen hcov e, oc , nl und hku ein. diese sind für einen signifikanten anteil der oberen atemwegser-krankungen verantwortlich, können gelegentlich aber auch pneumonien verursachen [ ] . coronaviren sind genetisch hochvariabel [ ] . bisher unbekannte typen haben zu beginn des . jahrhunderts bereits -mal die barriere [ ] . bei kindern unter jahren traten nur wenige und hauptsächlich mild verlaufende fälle auf, während ältere menschen ab jahren sowie patienten mit chronischen erkrankungen (hypertonie, diabetes, herz-kreislauf-erkrankungen, lungen-und krebserkrankungen) das höchste risiko für schwere verläufe aufwiesen [ , ] . die letalität (anteil der verstorbenen an allen erkrankten) war bei männern höher als bei frauen ( , % vs. , %) und war bei erkrankten über jahren mit % am höchsten [ ] . für die auffallenden geografischen unterschiede in der letalität ( , % in wuhan, , % für die provinz hubei und , % in den anderen chinesischen provinzen) wird primär die unterschiedliche auslastung der jeweiligen gesundheitsdienste verantwortlich gemacht [ , , ] . ab januar reagierte die chinesische regierung sehr intensiv auf die epidemie [ ] . zunächst wurden die verdächtigen märkte in wuhan geschlossen und ein multi-sektorales kontrollprogramm entwickelt; es folgten die systematische isolierung von infizierten in krankenhäusern und quarantäne von kontaktpersonen, maßnahmen zur sicherstellung der klinischen versorgung (reorganisation in krankenhäusern, bau zusätzlicher krankenhäuser in wuhan) sowie zur verhinderung der weiteren verbreitung (strikte reisebeschränkungen ab dem . januar, schließung aller öffentlichen einrichtungen und nicht systemrelevanten produktionsstätten, verbot von versammlungen, weitgehende soziale distanzierungsmaßnahmen wie beschränkter ausgang nur mit mundschutz sowie fieber-kontrollpunkte und hygienemaßnahmen) [ , ] . in der dritten phase wurde die qualität der präventiven und therapeutischen maßnahmen verbessert, z. b. durch intensivierte kontaktverfolgung sowie über umfangreiche materielle und personelle unterstützung der hauptbetroffenen provinz hubei [ ] . nachdem die fallzahlen im märz im ganzen land auf sehr niedrige werte gefallen waren, wurden die maßnahmen schrittweise gelockert, um die wirtschaft wieder in gang zu bringen und wieder gesellschaftliche normalität zu etablieren [ , ] . die chinesischen maßnahmen werden als das weltweit bisher intensivste jemals durchgeführte programm zur eingrenzung einer epidemie angesehen. die erfolge stützen die vermutung, dass insbesondere social-distancing-maßnahmen die zahl der neuinfektionen verringern können. so wurde auch der internationalen gemeinschaft zeit geschaffen, sich auf den weiteren verlauf der pandemie vorzubereiten [ , ] . der verlauf nationaler epidemien sowie der pandemie wird von faktoren bestimmt, die bisher für covid- noch nicht vollständig verstanden sind. die basisreproduktionszahl (r ) ist entscheidend für den verlauf einer epidemie; sie ist definiert als die anzahl von menschen, die von einem infizierten in einer empfänglichen (nicht immunen) population ohne kontrollmaßnahmen angesteckt werden [ ] . liegt die reproduktionszahl im verlauf der epidemie (rt) über , steigt die zahl der infizierten, bei einem wert unter sinkt die zahl der infizierten und der ausbruch kommt zum stillstand. r wurde in china auf , geschätzt und läge damit höher als die r -werte vieler zoonotischer ausbrüche und bisheriger saisonaler influenza-epidemien sowie auch der influenza-pandemien der vergangenen jahre (zoonotisch: < ; saisonal: , ; : , ; : , ; : , ; : , ) [ , ] . ohne berücksichtigung noch unbekannter epidemiologischer faktoren und ohne kontrollmaßnahmen würde ein r -wert von , zu einer ansteckung von etwa % der bevölkerung führen (berechnet als - /r ). bei erfolgreichen kontrollmaßnahmen oder einer steigenden zahl von immunen (herden-immunität) sinkt rt bis auf einen wert unter [ ] . r -werte können aber unter besonderen epidemiologischen bedingungen auch deutlich höhere werte erreichen; so lag r für covid- z. b. auf dem kreuzfahrtschiff diamond princess bei [ ] . bei sars-cov- handelt es sich um ein virus, das sich in seinen charakteristiken wesentlich von sars-cov- und mers-cov, aber auch von influenza-viren unterscheidet [ , ] . die Übertragung erfolgt primär über tröpfcheninfektion, möglicherweise auch über schmierinfektion, und eventuell auch fäkal-oral [ , ] . der erreger bleibt in abhängigkeit vom material und den jeweiligen umweltbedingungen (z. b. temperatur, luftfeuchtigkeit) für stunden bis tage auf oberflächen potenziell infektiös, ohne dass der anteil der schmierinfektion an den Übertragungen bisher geklärt ist [ ] . im gegensatz zu sars-cov- erfolgt die virus-replikation nicht nur in der lunge, sondern bereits frühzeitig in den zellen des mund-und nasenraums [ , ] . hieraus resultiert, dass covid- -infizierte bereits - tage vor symptombeginn infektiös sind. zudem sind möglicherweise auch erkrankungsverläufe mit nur milden symptomen epidemiologisch relevant [ ] . die Übertragung von sars-cov- von asymptomatischen personen bei normalen gesellschaftlichen kontakten wurde bereits durch fallstudien dokumentiert [ , ] ; bei einer fachtagung wurde eine Ärztin während eines gesprächs beim essen infiziert [müller et al., noch unveröffentlicht]. andererseits zeigten studien mit nachverfolgung von kontaktpersonen, dass für eine Übertragung ein enger kontakt erforderlich ist [ , ] . während bei der influenza Übertragungen durch kinder eine wichtige rolle spielen, ist deren einfluss bei covid- noch nicht geklärt [ , ] . die letalität ist am anfang einer epidemie nicht genau zu bestimmen, da asymptomatische und leichte erkrankungen nicht vollständig erfasst werden (führt zu Überschätzung) und die berechnung meist auf unvollständigen follow-up-daten basiert (führt aufgrund zeitlich verzögert eintretender todesfälle zu unterschätzung). vergleiche zwischen ländern sind anfangs aufgrund von unterschieden in den initial betroffenen populationen ebenfalls schwierig, da z. b. in italien zunächst ältere menschen als in deutschland erkrankten [ , ] . berechnungen zur letalität von covid- variieren bisher im bereich von , % bis , %, liegen damit aber deutlich höher als die letalität von , % der saisonalen influenza [ , , ] . die letalität in bisher verfügbaren, aber nicht repräsentativen kohorten wie z. b. der passagiere des kreuzfahrtschiffs diamond princess ( , %), aus wuhan evakuierten japaner ( , - , %) oder des positiv getesteten gesundheitspersonals in china ( , %) bestätigen die validität dieser frühen schätzungen der sterblichkeit [ , ] . eine sehr hohe letalität ist in den populationen von alters-und pflegeheimen zu erwarten; bei einem gut dokumentierten ausbruch in einem pflegeheim in den usa lag sie bei % [ ] . der anteil asymptomatischer und mild verlaufender covid- -fälle lässt sich noch nicht sicher einschätzen. in china wird der anteil asymptomatischer fälle als sehr gering eingeschätzt, andere schätzungen gehen von bis zu % vollständig asymptomatischer und somit normalerweise nicht getesteter (aber vermutlich infektiöser) fälle aus [ ] . in der diamond-princess-kohorte blieben % der infizierten asymptomatisch, in der kohorte aus wuhan evakuierter japaner lag dieser anteil bei % [ , ] . eine belast-bare abschätzung des anteils asymptomatischer verläufe wird erst nach verfügbarkeit validierter antikörpertests und repräsentativer sero-epidemiologischer studien möglich sein. auch zur dauer der infektiosität, einem wesentlichen epidemiologischen faktor, gibt es bisher wenig belastbare daten. in einer retrospektiven multizentrischen kohortenstudie mit patienten in china betrug der median des virus-nachweises tage, und die längste nachweisbare infektiosität lag bei tagen [ ] . merke covid- breitet sich weltweit aus. % der fälle erkranken schwer, mit signifikanter letalität in abhängigkeit von der kapazität und qualität der jeweiligen gesundheitssysteme. effektive biomedizinische interventionsmöglichkeiten sind bisher nur sehr begrenzt verfügbar. potenziell wirksame medikamente, die bereits in der therapie von malaria, hiv/aids und ebola eingesetzt bzw. getestet wurden (z. b. chloroquin, lopinavir-ritonavir, remdesivir), werden momentan in großen klinischen studien weltweit getestet und könntenbeim nachweis ihrer wirksamkeitbereits in sommer zur verfügung stehen [ , ] . allerdings war lopinavir-ritonavir in einer ersten großen studie nicht wirksam [ ] . ein breit verfügbarer impfstoff gegen sars-cov- wäre die ideale intervention zur eindämmung der pandemie und es gibt zahlreiche intensiv verfolgte ansätze der entwicklung; er würde aber frühestens im jahr verfügbar sein [ ] . momentan und bis auf weiteres stehen also nur public-health-interventionen zur kontrolle der pandemie zur verfügung. prinzipiell unterscheidet man hierbei isolationsmaßnahmen (sars-cov- -infizierte und covid- -patienten) und quarantänemaßnahmen (kontaktpersonen von infizierten und erkrankten, stark betroffene gemeinden); diese maßnahmen sind besonders wirksam zum beginn einer epidemie, wenn infektionsketten noch nachvollziehbar sind [ ] . sobald sich der erreger ausgebreitet hat, bedarf es zusätzlicher maßnahmen zur verringerung der transmission; diese variieren von einfachen abstands-und hygieneregeln über verbote von versammlungen und verlängerung von schul-und universitätsferien bis hin zur schließung aller nicht systemrelevanten einrichtungen eines landes in verbindung mit reglementierung der individuellen bewegungsfreiheit (lockdown) [ ] . ob eine pflicht zum tragen von schutzmasken für die allgemeinbevölkerung zusätzliche positive effekte hätte, wird momentan noch kontrovers diskutiert. breite bevölkerungsbezogene maßnahmen haben den vorteil, dass sie sowohl die transmission durch asymptomatisch wie auch symptomatisch infizierte verringern [ ] . neben dem schutz vor infektionen sollte vor allem die zahl der todesfälle möglichst niedrig gehalten werden. als wichtigste maßnahme dazu gilt neben intensivierten interventionen zur prävention in den risikogruppen (z. b. einschränkungen und verbote von besuchen in pflegeheimen und kritischen bereichen von krankenhäusern) die sicherstellung einer ausreichenden kapazität von intensivbetten und beatmungsgeräten in krankenhäusern [ , ] . da diese kapazitäten nur langsam erhöht werden können, darf die zahl der schweren fälle auch nur langsam zunehmen. es besteht weitgehend Übereinstimmung, dass die dafür erforderliche abflachung der epidemiologischen kurve nur mit intensiven public-health-maßnahmen erreicht werden kann. weniger einigkeit besteht darüber, wie radikal eingriffe ins wirtschafts-und gesellschaftsleben eingreifen dürfen und vor allem für welchen zeitraum sie gesellschaftlich akzeptabel sind [ , , ] . der allerdings noch immer wieder diskutierte alternative vorschlag umfangreicher präventionsmaßnahmen nur für alte menschen und risikopatienten (umkehr-isolation) ist u. a. aufgrund des nicht zu vernachlässigenden anteils schwerer oder sogar tödlicher verläufe von covid- bei erwachsenen im mittleren alter und der insgesamt fehlenden praktikabilität eher keine lösung [ , ] . china hat gezeigt, dass rt mit intensiven public-health-maßnahmen innerhalb von - monaten auf unter gesenkt werden kann [ ] . das land steht aber nun vor der herausforderung, die momentan sehr niedrigen zahlen von neuinfektionen aufrecht zu erhalten, ohne die wirtschaft weiterhin massiv zu beeinträchtigen [ ] . in mehreren ländern europas (italien, spanien, frankreich, uk) und den usa wurde die dynamik der epidemie anfangs unterschätzt, mit dem resultat einer sichtbaren Überlastung der krankenhäuser [ , ] . die hohe morbidität und mortalität belasten das gesellschaftliche leben in ganzen städten und regionen [ , ] . Ärztinnen und Ärzte sowie krankenpflegepersonal sind als risikogruppen einzuschätzen. durch gute versorgung mit schutzmaterialiendie z. zt. aufgrund weltweiter lieferengpässe allerdings nicht voll gewährleistet istlässt sich dieses risiko deutlich senken [ , ] . in deutschland wurden personen aus risikogebieten und patienten mit schwerer respiratorischer symptomatik früher und intensiver als in anderen ländern europas getestet. unklar ist, ob dies allein zu einer langsameren verbreitung des virus und bisher weniger hohen todeszahlen als derzeit in italien und spanien geführt hat. auch andere faktoren könnten eine rolle gespielt haben, z. b. das niedrigere alter der anfangs hauptsächlich beim karneval und beim skiurlaub infizierten in deutschland. wie effektiv die seit mitte märz eingeleiteten maßnahmen des social distancing sind, werden die nächsten wochen zeigen [ , ] . aktuell legen die daten des robert-koch-instituts nahe, dass die zahl der täglichen neuerkrankungen rückläufig und rt auf oder darunter gesunken ist (stand . . ). es ist allerdings unklar, in welchem umfang und für welche dauer die begonnenen public-health-interventionen weitergeführt werden müssen, um einen erneuten anstieg der täglichen neuerkrankungen oder weitere ausbrüche zu vermeiden. es ist zu vermuten, dass nur eine beibehaltung von umfangreichen social-distancing-maßnahmen in kombination mit systematischem testen aller verdachtsfälle einschließlich konsequenter in-quarantäne-stellung aller kontakte einen wiederanstieg der fallzahlen vermeiden kann [ ] . da viele dieser maßnahmen auf freiwilligkeit basieren, bedarf es auch weiterhin intensiver information der bevölkerung über den sinn und die notwendigkeit langanhaltender und belastender kontrollmaßnahmen. die pandemie wird vielerorts durch lockdowns eingedämmt. social distancing mit intensivem testen gefolgt von isolations-und quarantänemaßnahmen sind momentan standard. die effektivität dieser maßnahmen über längere zeiträume ist ungeklärt. die covid- -pandemie befindet sich in deutschland im vergleich zu italien und spanien, aber auch weltweit, immer noch in einem frühen stadium. es ist offensichtlich, dass die Übertragung von sars-cov- nicht wie bei sars-cov- erfolgreich unterbrochen werden konnte. es ist momentan auch noch offen, welche ausmaße die pandemie in den industrieländern erlangen wird; dies hängt primär von der intensität und dauer der durchgeführten public-health-maßnahmen ab. in deutschland sollten die vergleichsweise günstige ausgangslage und die starke infrastruktur zur bereitstellung ausreichender behandlungskapazitäten zu einer weiteren optimierung der abstimmung zwischen Öffentlichem gesundheitsdienst und allen klinischen einrichtungen (krankenhäusern, arztpraxen, pflegeheimen) genutzt werden. global besteht die befürchtung, dass sich die pandemie insbesondere in den bevölkerungsreichen entwicklungsländern asiens und afrikas weitgehend ungebremst ausbreitet und dort mit einer sehr hohen morbidität und mortalität einhergehen wird [ ] . diese länder bedürfen daher dringend einer finanziellen und technischen unterstützung. darüber hinaus bedarf es dringender Überlegungen, welche public-health-maßnahmen unter den lebensbedingungen der menschen in armen ländern wirksam und umsetzbar sind. sehr deutlich wird momentan auch, dass die pandemie starke auswirkungen auf nationale Ökonomien und die gesamte weltwirtschaft entfaltet, woraus sich zusätzliche negative folgen für die gesundheit von bereits jetzt sozioökonomisch benachteiligten bevölkerungen und bevölkerungsgruppen entwickeln werden. mandell, douglas, bennett (herausgeber) principles and practices of infectious diseases severe acute respiratory syndrome coronavirus (sars-cov- ) and coronavirus disease- (covid- ): the epidemic and the challenges sars and mers: recent insights into emerging coronaviruses middle east respiratory syndrome a novel coronavirus from patients with pneumonia in china genomic characterisation and epidemiology of novel coronavirus: implications for virus origins and receptor binding report of the who-china joint mission on coronavirus disease (covid- ) a familial cluster of pneumonia associated with the novel coronavirus indicating person-to-person transmission: a study of a family cluster clinical characteristics of coronavirus disease in china potential association between covid- mortality and health-care resource availability characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of , cases from the chinese center for disease control and prevention covid- control in china during mass population movements at new year as normalcy returns, can china keep covid- at bay? schätzung der aktuellen entwicklung der sars-cov- -epidemie in deutschland-nowcasting how will country-based mitigation measures influence the course of the covid- epidemic? estimates of the reproduction number for seasonal, pandemic, and zoonotic influenza: a systematic review of the literature covid- outbreak on the diamond princess cruise ship: estimating the epidemic potential and effectiveness of public health countermeasures viral load of sars-cov- in clinical samples covid- : towards controlling of a pandemic sars-cov- viral load in upper respiratory specimens of infected patients presumed asymptomatic carrier transmission of covid- transmission of -ncov infection from an asymptomatic contact in germany clinical course and mortality risk of severe covid- covid- in europe: the italian lesson heterogeneity in estimates of the impact of influenza on population mortality: a systematic review the rate of underascertainment of novel coronavirus ( -ncov) infection: estimation using japanese passengers data on evacuation flights epidemiology of covid- in a long-term care facility in king county, washington estimating the asymptomatic proportion of coronavirus disease (covid- ) cases on board the diamond princess cruise ship clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study covid- -therapie: erkenntnisse und hypothesen race to find covid- treatments accelerates a trial of lopinavir-ritonavir in adults hospitalized with severe covid- sars-cov- -impfstoff: forschung mit geeinten kräften isolation, quarantine, social distancing and community containment: pivotal role for old-style public health measures in the novel coronavirus ( -ncov) outbreak the covid- pandemic in the usa: what might we expect? covid- and italy: what next? universal masking in hospitals in the covid- era the lockdowns worked-but what comes next? africa in the path of covid- key: cord- -y iewi authors: gavriatopoulou, maria; korompoki, eleni; fotiou, despina; ntanasis-stathopoulos, ioannis; psaltopoulou, theodora; kastritis, efstathios; terpos, evangelos; dimopoulos, meletios a. title: organ-specific manifestations of covid- infection date: - - journal: clin exp med doi: . /s - - -x sha: doc_id: cord_uid: y iewi although covid- presents primarily as a lower respiratory tract infection transmitted via air droplets, increasing data suggest multiorgan involvement in patients that are infected. this systemic involvement is postulated to be mainly related to the sars-cov- virus binding on angiotensin-converting enzyme (ace ) receptors located on several different human cells. lung involvement is the most common serious manifestation of the disease, ranging from asymptomatic disease or mild pneumonia, to severe disease associated with hypoxia, critical disease associated with shock, respiratory failure and multiorgan failure or death. among patients with covid- , underlying cardiovascular comorbidities including hypertension, diabetes and especially cardiovascular disease, has been associated with adverse outcomes, whereas the emergence of cardiovascular complications, including myocardial injury, heart failure and arrhythmias, has been associated with poor survival. gastrointestinal symptoms are also frequently encountered and may persist for several days. haematological complications are frequent as well and have been associated with poor prognosis. furthermore, recent studies have reported that over a third of infected patients develop a broad spectrum of neurological symptoms affecting the central nervous system, peripheral nervous system and skeletal muscles, including anosmia and ageusia. the skin, the kidneys, the liver, the endocrine organs and the eyes are also affected by the systemic covid- disease. herein, we provide a comprehensive overview of the organ-specific systemic manifestations of covid- . the sars-cov- virus has caused a worldwide pandemic in the past few months with a major impact on health care systems and economies. since december when the first diagnosed case was identified in wuhan, china, the highly contagious virus has spread throughout the world with detrimental consequences. sars-cov- belongs to the coronaviruses family of enveloped, single-stranded rna viruses [ ] . notably, the main hosts of these viruses are animals. to date, different species of the viruses have been identified, including two highly contagious and pathogenic species that led to two different outbreaks the past decades [severe acute respiratory syndrome coronavirus (sars-cov) in and middle east respiratory syndrome coronavirus (mers-cov) in ] [ ] . patients infected with this new coronavirus present with a variety of symptoms, which range from asymptomatic disease to mild and moderate symptoms (mild pneumonia), severe symptoms (dyspnoea, hypoxia, or > % lung involvement on imaging) and symptoms of critical illness (acute respiratory distress syndrome, respiratory failure, shock or multiorgan system dysfunction). the disease affects mainly elderly adults; however, younger patients without comorbidities can also be diagnosed with severe disease. the virus presents primarily as a lower tract respiratory infection transmitted via air droplets, but the multisystemic nature of the disease is becoming increasingly apparent as more data are emerging. it is postulated that it is related to the tropism of the virus for the ace- receptors located on several different human cells. the occurrence of other symptoms can not only coexist, but may also precede the typical phenotype of covid- . in a recent study, sars-cov- viral load was quantified in post-mortem autopsy tissue samples [ ] ; patients ( %) had more than two coexisting conditions. the number of coexisting conditions was strongly associated with sars-cov- affinity to the kidneys, including patients without history of chronic kidney disease. the highest levels of sars-cov- copies were detected in the respiratory tract, while the levels detected in kidneys, liver, heart, brain and blood were lower. these findings indicate a possible organ tropism of sars-cov- that might influence the course of the disease leading potentially to underlying conditions aggravation. as our knowledge on the virus mechanisms increases, our understanding on the various complications will continue to evolve. this manuscript aims to review the available literature and provide further insight on multiorgan involvement of the disease (fig. ). the severity of lung involvement associated with sars-cov- infection ranges from lack of symptoms or mild pneumonia (in %) to severe disease-associated hypoxia (seen in %), critical disease associated with shock, respiratory failure and multiorgan failure (in %) or death ( . %) [ ] . it is the most common serious disease manifestation. patients may present with dry cough, fever, sputum production, fatigue and dyspnea, and the reported frequency varies based on the cohort studied [ ] [ ] [ ] . among hospitalized patients, - % will develop acute respiratory distress . what is becoming increasingly apparent as our understanding of the mechanisms of covid- induced lung injury expands, are the distinct or "atypical" features of covid- -associated ards [ , ] . based on sars-cov virus data, the genome of which is highly homologous to the sars-cov- genome, it is hypothesized that the human angiotensin-converting enzyme (ace ) receptor is the main functional receptor for the sars-cov- virus. the ace receptor is expressed on the apical side of type ii alveolar epithelial cells in the alveolar space, and the large surface area of the lung serves as a reservoir for viral binding and replication, providing an explanation for the tropism of the sars-cov- virus and the lung vulnerability observed [ , ] . sars-cov- infection induces alveolar injury and interstitial inflammation. dendritic cells (dcs) and alveolar macrophages phagocytose the virus-infected apoptosed epithelial cells, and t cell responses are initiated activating innate and adaptive immune mechanisms [ ] . levels of proinflammatory cytokines and chemokines, such as tumour necrosis factor (tnf)-α, interleukin β (il- β), il- , and more, are increased in patients with covid- infection [ ] . the cytokine storm is hypothesized to play a central role in the immunopathology of covid- , but the primary source or the exact virological mechanisms behind it have not been identified yet. there is extensive hemophagocytosis which shares features but is distinct from the well-described macrophage activation syndrome (mas) [ , ] . in addition to the proinflammatory stage and immune system activation, an immune suppression stage follows which is characterized by lymphopenia, low cd and cd t cell counts, increasing the risk of bacterial infection [ , ] . emerging data from covid- pneumonia autopsy studies demonstrate acute interstitial pneumonia and diffuse alveolar damage (dad) with macrophage infiltration, formation of hyaline membranes and alveolar wall oedema and thickening. there is also microvasculature involvement with pulmonary vessel (intra and extra) hyaline thrombosis, haemorrhage, vessel wall oedema, intravascular neutrophil trapping and immune cell infiltration. in one series, in out of patients, major pulmonary vessel thromboemboli and/or haemorrhage were reported [ , , ] . mcgonagle et al. use the term diffuse pulmonary intravascular coagulopathy (pic) to describe this lungrestricted vascular immunopathology [ ] driven probably by the close anatomical positioning of type ii pneumocytes and the pulmonary vasculature. at early stages of this process, there is no systemic coagulopathy (dic) which is seen, however, at later disease stages coupled with the presence of ards. extensive microthrombi formation within the vascular bed causes pulmonary infarction, haemorrhage, pulmonary hypertension and secondary ventricular stress [ ] . hypoxemia and mechanical ventilation which forces immunostimulatory molecules in the microvasculature also seem to contribute to the development of pic. findings on chest radiograph imaging are not diseasespecific and usually include ground glass opacities with bilateral, peripheral or lower lung zone distribution with or without consolidation [ ] [ ] [ ] . chest ct is more sensitive, but no finding can % establish or rule out the diagnosis [ ] . according to the radiological society of north america, ct findings are categorized into typical, indeterminate or atypical for covid- demonstrating that specificity is low even for ct [ ] . in one study using rt-pcr as a reference, sensitivity was % but specificity very low at % [ ] . radiological abnormalities increase over the disease course, and the typical peak is at - days post-symptom initiation. at early stages or in mild disease, imaging may not reveal any pathology, but interestingly abnormal findings on imaging can be identified in some cases prior to symptom development or even prior to pcr rna detection [ ] . using ct as a screening tool is not, however, recommended. improvement of the findings lags behind symptom or hypoxia improvement [ ] . hypoxia is frequently a presenting feature of covid- pneumonia, but interestingly, it is often insidious and paradoxically well tolerated by the patients. this unusual clinical presentation, seen at early disease stages, is referred to as "silent hypoxia" and is linked to the "atypical" features of the ards syndrome associated with covid- pneumonia [ ] . contrary to the typical ards, lung compliance is preserved and the hypoxia-driven tachypnea allows high volumes and hypocapnia which fails to stimulate the sensation of dyspnea. a similar pathophysiological mechanism is seen in hypobaric hypoxia at high altitude [ ] . a model has been recently proposed which includes two timeassociated phenotypes. the severity of infection, patient comorbidities and physiological reserve, the time elapsed between disease onset and presentation to hospital and the host immune response all contribute. the l-phenotype is seen at early disease stages; there is high lung compliance, and the ventilation-to-perfusion ratio (va/q ratio) is low, but there is dysfunctional regulation of perfusion with hypoxic vasoconstriction. at this stage, the lung weight is low and lung recruitability is low with minimal amount of non-aerated lung tissue. this develops into the h-phenotype with decreased lung compliance due to oedema, increased fraction of cardiac output perfusing the non-aerated tissue and therefore a right-to-left shunt, increased lung volume due to oedema and consolidation and therefore high recruitability. type l patients usually remain stable for some time and can then either improve or worsen and transition into type h, secondary to evolution of the covid- pneumonia but also injury induced by high-stress ventilation [ ] . management should be adapted based on the type of phenotype and timing/stage of lung injury. a high positive end-expiratory pressure (peep) on the ventilator, at early stages of poor lung recruitability, is not very effective, but in combination with gravitational forces (using prone positioning), it may allow for perfusion redistribution and increased oxygenation [ , ] . the initial practice of early intubation was not supported by emerging data. l-phenotype patients should receive high-flow nasal cannula fio , continuous positive airway pressure or non-invasive ventilation with close monitoring. awake or self-proning has been incorporated in many hospital protocols in an attempt to prevent intubation and reverse hypoxemia [ ] . type h patients should be treated as severe ards with higher peep volumes, prone positioning and extracorporeal support. another factor that may predispose for severe and potentially fatal ards in patients with covid- is the excessive increase in circulating proinflammatory cytokines including interleukins (il- , il- ), interferon and tnf-α. this "cytokine storm" results from an inflammatory over-reaction as a response to sars-cov- infection that ultimately leads to endothelial cell dysfunction, damage of the vascular barrier, capillary leak and diffuse alveolar damage [ ] . in this context, anti-il- inhibitors, such as the monoclonal antibody tocilizumab, inhibitors of jak kinases, such as baricitinib, and corticosteroids, especially dexamethasone, have been evaluated in patients with severe covid- and have shown promising preliminary results [ ] [ ] [ ] [ ] . among patients with covid- , underlying cardiovascular comorbidities including hypertension, diabetes, and especially cardiovascular disease, have been associated with adverse outcomes [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] , whereas the emergence of cardiovascular complications, including myocardial injury, heart failure and arrhythmias, has been associated with poor survival [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the presence of obesity is also associated with adverse cardiovascular outcomes [ ] . evidence of myocardial injury in patients with covid- has been a remarkable finding [ - , , - ] . ace expression is significantly elevated in cardiac tissue [ ] and may potentially facilitate direct myocardial damage induced by viral infection. there have been also reported isolated cases of covid- -induced myocarditis, which support the hypothesis of direct myocardial injury by sars-cov- [ ] [ ] [ ] [ ] . furthermore, ace plays an important role in the renin-angiotensin system by catalysing the conversion of angiotensin ii to angiotensin - , which exerts a protective effect on the cardiovascular system [ , ] . importantly, the binding of sars-cov- to ace is anticipated to result in loss of the external ace catalytic effect [ , ] . subsequently, the theoretical downregulation of ace and the decrease in angiotensin - levels in patients with covid- may also compromise heart function [ ] . in addition to the above, a non-negligible proportion of patients with covid- seem to experience a hyperinflammatory state, in which inflammatory cytokines and other markers of systemic inflammation are markedly increased [ ] [ ] [ ] ] . the circulating cytokines can stimulate macrophages and leucocyte adhesion molecule expression on the endothelial cells of underlying atherosclerotic lesions, rendering them more vulnerable for disruption and increasing the possibility of a clinically evident acute coronary syndrome [ , ] . systemic cytokines may also activate the microvascular endothelium and induce a dysfunction of the coronary microvasculature, which may result in myocardial ischaemia and myocardial injury [ ] . inflammation and subsequent dysfunction of the endothelium in several organs are the result of both the direct effect of sars-cov- infection of endothelial cells and the indirect effects of the host inflammatory response [ ] . myocardial injury can also result secondary to a mismatch between myocardial oxygen supply and demand, known as type myocardial infarction. sars-cov- infection may be associated with myocardial damage through increased myocardial oxygen demand along with reduced myocardial oxygen supply. severe respiratory complications and associated hypoxia have been common findings in patients with covid- [ , , , , ] . moreover, hypotension, which is a common clinical feature both in sepsis and during the cytokine storm syndrome, can also reduce myocardial oxygen supply [ ] . furthermore, systemic infection and fever increase the metabolic needs of peripheral tissues and end-organs, which elevates the metabolic demands of the myocardial cells [ ] . fulminant myocarditis may be a clinical manifestation of covid- [ , ] and may result in left ventricular systolic dysfunction or even cardiogenic shock [ , ] . among chinese patients with covid- , chen et al. reported heart failure as a complication in . % (n = ), using age-related amino-terminal pro-brain natriuretic peptide (ntprobnp) cut-points [ ] . interestingly, there was a significant difference in the prevalence of heart failure between covid- survivors and non-survivors ( . % vs. . %) [ ] . another study encompassing data from patients reported a % (n = ) incidence of heart failure, . % (n = ) of which was fatal [ ] . a meta-analysis of studies involving patients reported a prevalence of heart failure as a covid- complication of . % ( %, ci . - . ) among critically ill patients compared to . % ( % ci . - . ) among non-critically ill patients [ ] . guo et al. reported sustained ventricular tachycardia or ventricular fibrillation in . % (n = ) of patients treated in a covid- specialized centre in china [ ] . another retrospective study including data from the consecutive patients with covid- in two hospitals in new york city showed that patients who received mechanical ventilation were more likely to have atrial arrhythmias ( . % versus . %) [ ] . it has to be noted that sustained ventricular arrhythmias have been reported as a frequent clinical feature of acute myocarditis [ ] , which may be the case in patients with covid- complicated by myocarditis. importantly, arrhythmias may be also induced by medical treatment for covid- , such as chloroquine phosphate, hydroxychloroquine sulphate and azithromycin [ ] . these agents and their combinations may prolong the qtc interval and predispose for torsades de pointes or other ventricular arrhythmias [ ] . another characteristic manifestation of covid- in the cardiovascular system that has been recently reported is a kawasaki-like syndrome, which is characterized by circulatory dysfunction and macrophage activation syndrome [ ] . a single-centre study conducted in bergamo, italy, reported a -fold increase in the incidence of kawasaki-like disease during the covid- pandemic, as compared with the previous year [ ] . the cytokine storm associated with infection by sars-cov- may be the predisposing mechanism for the kawasaki-like clinical phenotype, but further insight has to be shed by future preclinical studies. the underlying pathophysiologic mechanism for the occurrence of digestive symptoms is also thought to be related to the virus's affinity for ace receptors located in specific enterocytes in the ileum and colon [ , , ] . ace receptors are involved partially in inflammation mechanisms and therefore could provide an explanation for the occurrence of diarrhoea in infected patients. importantly, the binding efficiency is stronger for sars-cov- than the sars-cov- , and this might be one of the reasons of high rate of transmission [ ] . binding to primary intestinal epithelial cells also raises the question on whether the virus can be transmitted through the faecal-oral route, which currently remains unconfirmed [ , ] . the largest study evaluating digestive involvement in patients with covid- was performed in wuhan, china. the investigators evaluated retrospective cases admitted to one single hospital over a period of weeks [ ] . % ( ) of patients presented only with gastrointestinal symptoms. the most common symptom reported was loss of appetite. vomiting and nausea occurred in approximately two-third of the patients, while diarrhoea and abdominal pain were present in % and %, respectively. the main study limitations were its retrospective design along with the relatively small sample size. another cross-sectional study from hubei province reported results on digestive symptoms from patients being admitted to one of three different hospitals during january and february . in total, patients ( . %) had gastrointestinal symptoms. the symptoms included anorexia ( . %), diarrhoea ( . %), vomiting ( . %) and abdominal pain ( . %), while some patients reported symptoms combinations. notably, patients presented only with digestive symptoms with no evidence of respiratory involvement. in this case, the diagnosis was delayed due to the non-specific symptoms they experienced [ ] . another study in china included patients and demonstrated that the most common symptoms on admission were fever ( . %) and cough ( . %) [ ] . gastrointestinal symptoms were less common-nausea or vomiting % and diarrhoea . %, respectively. in a single-centre case series of hospitalized patients with covid- , . % reported diarrhoea and/or nausea, but the proportion of patients only with digestive symptoms was not outlined [ ] . in another recent study performed in china, gastrointestinal symptoms were reported in of ( . %) patients [ ] . nausea, vomiting and diarrhoea were the most common. importantly, it was demonstrated that gi symptoms were more common in patients with severe covid- disease ( % vs. . %). further data are required to understand better the role of the gastrointestinal involvement of covid- and clarify whether it is correlated with worse outcomes. the abovementioned studies did not test for virus rna in the stool, so there is no proof that active viral rna replication can be found in the digestive tract. a recent report of a -year-old female who presented with respiratory symptoms and fever indicates that the virus might be excreted in faeces [ ] . ten days after admission, she underwent real-time pcr of a pharyngeal sample that was negative for sars-cov- . a separate faecal sample was tested and found positive. the next days additional samples from the respiratory tract were tested and were all negative. this suggests that the gastrointestinal tract was the only documented source of the virus infection. in a recent singaporean study, % of patients had sars-cov- detected in their stool samples, but detection did not correlate with the presence of digestive symptoms [ ] . in another study, the duration of viral rna detection after recovery was examined [ ] . the median time from symptoms onset to first negative rt-pcr test from oropharyngeal swab was . days, but . % of the patients tested positive for viral rna from stool specimens for a median of days. this observation indicates that there might be a potential faecal-oral transmission risk many days after symptoms resolution. regarding the liver-related complications of covid- , liver test abnormalities have been described in infected patients. in one study, it was demonstrated that total bilirubin, ast and alt were elevated in %, % and % of patients, respectively [ ] . other case series have reported alt abnormalities in - % [ , , [ ] [ ] [ ] [ ] . to date, cases of acute liver failure have not been reported. liver dysfunction is mainly described in patients with severe disease upon presentation. however, it is difficult to discriminate the independent effect of the infection from other treatment modalities, such as antibiotics and antiviral drugs administered to these patients. additionally, these abnormalities could be attributed to the infection itself, the induced sepsis or the concurrence of hypoxia. one patient underwent liver autopsy which revealed microvesicular steatosis, mild lobular and portal inflammation [ ] . ace receptors are located in hepatocytes and cholangiocytes; therefore, it was anticipated that the liver would also be involved. however, cholestatic abnormalities have rarely been described. underlying pre-existing liver diseases could have contributed to liver enzyme abnormalities. the exact pattern of liver injury as well as its role in mortality needs to be further investigated. finally, very recently a systemic review and meta-analyses were published in lancet gastroenterology and hepatology in order to identify the prognosis and prevalence of digestive tract involvement and liver abnormalities in patients diagnosed with covid- . in total, studies with patients were included in the analyses. the study demonstrated that gastrointestinal symptoms and hepatic toxicity are not uncommon among patients with covid- disease [ ] . covid- is a systemic infection with a significant impact on the haematopoietic system and homeostasis [ ] . lymphopenia may be considered as a cardinal laboratory finding, with prognostic potential. approximately, - days from the onset of the initial symptoms, there is a surge in the clinical manifestations of the covid- disease with a pronounced systemic increase in inflammatory mediators and cytokines, which may even be characterized as a "cytokine storm" [ ] . in this context, significant lymphopenia becomes evident. neutrophil/lymphocyte ratio and peak platelet/lymphocyte ratio may also have prognostic value in determining severe cases. lymphocytes express the ace receptor on their surface [ ] ; thus, sars-cov- may directly infect those cells, whereas the cytokine surge may promote lymphocyte apoptosis [ ] [ ] [ ] . substantial cytokine activation may be also associated with atrophy of lymphoid organs, including the spleen, and further impairs lymphocyte turnover [ ] . abnormalities in haematological parameters have been more prominent among severe versus non-severe cases ( . % versus . % for lymphocytopenia, . % versus . % for thrombocytopenia and . % versus . % for leukopenia). these results were consistent in four other descriptive studies that were conducted during the same period in china and included , , and confirmed cases with covid- , respectively [ , , , ] . a meta-analysis of nine studies suggested that thrombocytopenia is significantly associated with the severity of the covid- disease, with very high between-studies heterogeneity, though a more sizeable drop in platelet counts was noted especially in non-survivors [ ] . during the disease course, longitudinal evaluation of lymphocyte count dynamics and inflammatory indices, including ldh, crp and il- , may help to identify cases with dismal prognosis and prompt intervention in order to improve outcomes [ ] . biomarkers such as high serum procalcitonin, crp and ferritin have also emerged as poor prognostic factors [ , , ] . more recently, high cortisol levels at presentation may reflect disease severity and have been recognized as an adverse prognostic factor associated with poor survival among patients with severe covid- [ ] . furthermore, blood hypercoagulability is common among hospitalized covid- patients, especially among those with severe disease [ , , ] . elevated d-dimer levels are consistently reported, whereas their gradual increase during disease course is associated with clinical deterioration [ , , , , ] . other coagulation abnormalities such as pt and aptt prolongation, increasing fibrin degradation products, with severe thrombocytopenia lead to life-threatening disseminated intravascular coagulation (dic) which necessitates continuous vigilance and prompt intervention [ , , , [ ] [ ] [ ] [ ] . endothelial dysfunction and immune deregulation may be implicated in the underlying pathophysiology [ ] . covid- infected patients are at high risk of venous thromboembolism (vte) (up to % for acutely ill hospitalized patients [ ] ). comorbidities, along with the possibility of endothelial cell activation/damage due to the virus binding to ace receptor, collectively increase the risk of vte. prompt pharmacological thromboprophylaxis with low molecular weight heparin is highly recommended [ , , ] . although coronaviruses mainly cause respiratory symptoms, they have been reported to be involved in direct cns infection as well as para-infectious complications [ ] . recent studies reported that over a third of infected patients developed a broad spectrum of neurological symptoms affecting central nervous system (cns), peripheral nervous system (pns) and skeletal muscles [ , ] . in each case, it has to be noted that the challenge lies in discriminating between causal relationship and incidental comorbidity [ ] . a large retrospective observational study from china showed that among hospitalized patients with confirmed sars-cov- infection, . % had neurological manifestations [ ] . most neurological symptoms occurred early during the first days after hospital admission. with regard to symptom category, . % of infected patients presented symptoms from cns, . % from pns and . % developed skeletal muscle injury. the most common cns symptoms were dizziness ( . %) and headache ( . %), and the most commonly reported symptoms involving pns were taste impairment ( . %) and anosmia ( . %). other less frequent symptoms included impaired consciousness ( . %), acute cerebrovascular disease ( . %), ataxia ( . %), seizure ( . %), vision impairment ( . %) and nerve pain ( . %). notably among severely infected patients the prevalence of neurological manifestation was even higher, up to % compared to patients with less severe disease ( . %). the correlation of disease severity with neurological symptoms was confirmed by another retrospective study from france, reporting a prevalence of % of neurological manifestations in hospitalized patients with acute respiratory distress syndrome (ards) due to covid- [ ] . of note, some of the reported symptoms such as inattention, disorientation and movement disorders persisted even after discharge. several mechanisms that may overlap have been proposed to explain the link between sars-cov- infection and nervous system injury [ ] . clinical manifestations of covid- might be a consequence of the viral infection per se and/ or the adverse insult of the hyperinflammatory status and dysregulated metabolic function, in combination with the multiple organ damage observed in patients after covid- infection [ , ] . direct viral damage of nervous tissue might be possible in different ways. as with sars and mers viruses, sars-cov- may enter the cns through the hematogenous or retrograde neuronal route. infection of olfactory neurons in the nose may enable the virus to enter the brain transneuronally and spread directly from the respiratory tract to the brain [ ] . ace receptors are also found in the nervous system and skeletal muscles [ , ] . the expression and distribution of ace in brain and endothelial cells may explain how sars-cov- may cause direct neurological symptoms and skeletal muscle damage. direct viral damage of nervous tissue resembling in some ways herpes simplex encephalitis might be also possible, although there is no definite evidence of direct injury of cns by sars-cov- virus. the excessive immune response which results in a hyperinflammatory status and cytokine storm may represent another alternative mechanism. cytokines can directly pass through the blood-brain barrier causing considerable damage such as acute necrotizing encephalopathy [ ] . an indirect injury related to host immune response effects after acute coronavirus infection could also be possible, explaining to some extent the occurrence of guillain-barré syndrome (gbs) cases, transverse myelitis or acute disseminated encephalomyelitis in patients with covid- and other virus epidemics [ , , ] . neurological symptoms caused by systemic illness especially in severely ill patients could also justify neurological manifestations of covid- infection [ ] . patients admitted to intensive care unit (icu) often develop encephalopathy, myopathy, autonomic neuropathy and polyneuromyopathy related to critical illness [ ] . cerebrovascular disease represents another mechanism explaining neurological signs and symptoms in covid- patients, although the rate of acute stroke admissions has been significantly reduced over the covid- pandemic [ ] . a large retrospective study from china reported a rate of . % for both haemorrhagic and ischaemic strokes among critically ill patients [ ] . a recent study reported a rate of . % imaging proven ischaemic stroke among hospitalized patients [ ] , stressing that cerebrovascular events may have been underestimated in intubated and sedated patients with severe covid- . in a recent study based on data from the global covid- stroke registry, it was shown that patients with stroke and concurrent covid- infection had a higher risk of severe disability (p < . ) and death (odds ratio . , % ci . - . ) compared with patients without covid- [ ] . severe sars-cov- infection is a hypercoagulable state and may predispose to both venous and arterial thromboembolic events. systemic inflammatory response triggers autoimmune mechanisms, leading to dysregulation of the coagulation cascade as reflected by elevated d-dimers, prolonged prothrombin time, high fibrinogen levels, low anti-thrombin levels, thrombocytopenia and diffuse intravascular coagulation in severely ill patients with covid- [ , , ] . imbalance between procoagulant and anticoagulant homeostatic mechanisms may result in endothelial damage, microvascular thrombosis and vessel occlusion. in addition, cardiac dysregulation and cardiac arrhythmias/dysrhythmias attributed to excessive inflammation and to respiratory failure, may lead to cardiac strain and myocardial injury/dysfunction facilitating cardioembolism. among covid- patients who suffered a stroke, the rate of cryptogenic and embolic strokes was higher, and events were more severe and affected younger patients [ , ] . finally, blood pressure alterations, hypotension or hypertension, may lead to impaired cerebral perfusion and cerebrovascular events. although not highlighted in the initial cohort studies, olfactory (od) and gustatory (gd) sense dysfunctions have been reported as common symptoms of covid- from several centres worldwide. prevalence of smell and taste disturbances varies considerably depending mainly on the assessment criteria and tools used and on the degree of sense dysfunction. in a recent multicentre european study [ ] , it was shown that patients with mild-to-moderate forms of covid present commonly with od (anosmia or hyposmia) and gd (hypogeusia or ageusia), ( % and %, respectively), even without nasal symptoms. women were more likely to be affected, and there was an early olfactory recovery rate of %, while symptoms could last even days after the resolution of symptoms. another study reported a high prevalence of od ( %) in covid- patients, with an early and severe occurrence and a high correlation with loss of taste. od was still found more prevalent in women, but also in younger patients, while there was an association with shortness of breath [ ] . a pilot quantitative study has also shown that a moderate olfactory dysfunction is present in approximately threequarters of hospitalized covid- patients using an objective smelling identification test [ ] . a multicentre prospective study demonstrated an under-reporting of od and gd manifestations in patients with more severe covid disease neglecting their symptomatology. these findings confirm that od and gd are not predictors of a milder disease but are also markedly present in covid severe infection [ ] . the american academy of otolaryngology-head and neck surgery and the british association of otorhinolaryngology suggested that anosmia-hyposmia and hypogeusia-ageusia should be considered as "significant symptoms" even in the absence of other nasal manifestations (rhinorrhea or nasal congestion), which should be used as potential markers of otherwise asymptomatic carriers of covid- infection (i.e. as a screening tool). in particular, the sudden onset of olfactory dysfunction could represent an early indicator of covid- infection [ ] . these findings make clear that clinicians should take into account self-reporting od and gd symptomatology and incorporate in their assessment, the evaluation of the olfactory nerve function [ ] . despite the lack of a clear pathogenetic mechanism explaining od and gd manifestations in covid patients, it seems that there is a specific viral neuroinvasivity and neutropism via the olfactory nerves spreading rapidly to other brain structures such as the thalamus and the brainstem, but also possibly to the temporal lobe, the amygdala, insula, limbic lobe (psycho sensorial syndrome) [ ] . neurotropism may also occur via circulation and/or an upper transnasal route covid- to reach the brain tissue, where covid- spike protein binds angiotensin-converting enzyme (ace ) receptors [ ] . interestingly, the presence of ace- , in host olfactory and gustatory pathways, might provide a potential explanatory mechanism for the smell and taste disorders in covid- patients. the expression level of ace in different tissues and in particular neural cells might be also important in viral neurotropism differences between patients from different geographic regions. thus, the differential ace expression could give an explanation of the higher prevalence of od and gd observed in european compared to asian population [ ] ; however, more studies are needed to confirm such hypothesis. in the kidney, ace is present in several cells such as podocytes, mesangial cells, epithelium of the bowman's capsule, proximal cells brush border and collecting ducts [ ] . the most frequent abnormality in patients with covid- is mild-to-moderate proteinuria which is mediated via several mechanisms [ ] . it has been reported that patients in the icu have higher levels of il- β, il- , ifn-γ and tnf-α [ ] . this suggests a potential role of cytokine release syndrome (crs), also known as "cytokine storm" comparable with sepsis-associated aki (sa-aki), where the uncontrolled systemic inflammatory response leads to kidney injury [ ] . other studies have confirmed tropism to monocytes as well as lymphocytes, where the virus induces proinflammatory responses and cell death [ ] . in addition, alterations in renal haemodynamics can induce further dysfunction [ ] . acute kidney injury (aki) is infrequent in patients with mildto-moderate disease ( %). in this patient subgroup, the abnormalities are mainly subclinical. a recent prospective study, which included patients with moderate or severe disease, demonstrated that . % presented with proteinuria and . % with haematuria at hospital admission. thirteen percentage revealed elevated levels of either serum creatinine (scr), blood urea nitrogen (bun) or both. aki occurred in . % of hospitalized patients. all these abnormalities conferred for higher death risk [ ] . another recent report showed that aki was more common in critically ill patients. in critically ill patients who were admitted to an intensive care unit (icu) in wuhan, aki was the most common extra-pulmonary complication, occurring in patients ( %). eight patients ( %) required continuous renal replacement therapy, and ( %) died with a median duration from admission to icu until death of days [ ] . in another study previously described, a in silico analysis of publicly available data sets of single-cell rna sequencing was performed. this analysis showed that rna for angiotensin-converting enzyme (ace ), transmembrane serine protease (tmprss ) and cathepsin l (ctsl) is enriched in several kidney cells. this enrichment may explain the relevant affinity that induces sars-cov- kidney injury [ ] . following that, tissue microdissection was applied on kidneys biopsied to define sars-cov- viral load in exact kidney compartments. three patients revealed detectable sars-cov- viral load in all compartments examined, mainly at the glomerular cells. these extremely interesting findings indicate that renal tropism is the obvious reason leading to kidney injury, even in the absence of severe disease. these data indicate that kidney abnormalities are common and are associated with worse clinical outcomes. kidney autopsies of sars-cov patients have also demonstrated that the virus was present in tubular epithelial cells [ ] . a number of case reports on skin complications observed in patients with covid- have been published. skin abnormalities are seen in up to % of covid- patients in some series and are very heterogenous ranging from urticarial, vesicular, purpuric to papulosquamous lesions. it is, however, not clear currently whether these skin manifestations are caused directly by the virus invasion or secondary to host immune response or treatment administration. purpuric eruptions, livedo reticularis or retiform purpura could be part of the manifestations of the vasculopathy associated with covid- infection [ ] . the nature of the association between covid- and skin lesions and the systemic implications of their presence remains to be determined and requires active input and effort from dermatologists [ ] [ ] [ ] [ ] . knocking down the host's response to cortisol stress is a strategy employed by many viruses, including sars-cov to evade the host immune system. sars-cov expresses key amino acids that act as molecular mimics to the host adrenocorticotropic hormone (acth) directing antibodies to these acth residues implying a relative cortisol insufficiency. data on serum cortisol levels in sars-cov- patients are scarce to date. a recent study among patients with no signs of adrenal insufficiency showed that high cortisol levels at presentation may reflect systemic disease severity and have associated with dismal survival among patients with severe covid- [ ] . autopsy studies from sars-cov viral infection have demonstrated degeneration and necrosis of the adrenal gland, and the virus has been identified in the glands themselves pointing to the likelihood that cortisol dynamics are altered in sars patients. the hypothalamic-pituitary-adrenal (hpa) axis might also be affected by sars viruses on the ground of a reversible hypophysitis or direct hypothalamic damage. ace is expressed on both hypothalamic and pituitary tissues explaining a possible viral tropism. a prospective study (chictr ) is currently evaluating serum cortisol and acth levels in covid- patients [ ] [ ] [ ] . in animals, coronaviruses have been known to cause ocular manifestations including conjunctivitis, uveitis, retinitis and even optic neuritis [ ] . in humans, the eye conjunctiva is considered to be a potential site for sars-cov- transmission [ ] , but currently there is no direct evidence to support that viral replication can cause injury and inflammation of the conjunctiva or other eye parts. among covid- infected patients, in the hubei province case report series, had ocular manifestations ( . %). these were more common among patients with more severe systemic disease presentation (respiratory mostly) and blood test abnormalities. they included conjunctival congestion, chemosis or epiphora [ ] . a recent protocol used optical coherence tomography to evaluate the retina of patients with covid- infection in adults. hyper-reflective lesions of the inner plexiform layers and the ganglion cells were seen in all patients, and cotton wool spots and microhemorrhages in the retinal arcade of patients with no effect on visual acuity or pupillary reflexes [ ] . increasingly emerging data will allow better understanding of the nature and the mechanisms underlying the ocular manifestations associated with sars-cov- . covid- probably represents the greatest pandemic event in modern human history. the disease presents with a broad spectrum of clinical signs and symptoms with involvement of vital organs such as the lungs, the heart, the gastrointestinal tract, the liver, the central nervous system, the blood and the kidneys. commonly, multisystemic involvement is associated with severe disease and might predict worse clinical outcomes and increased mortality. the main mechanism described is the high binding affinity of the virus with the ace receptors that are widely expressed in most human cells. the exact role of ace receptors in covid- pathophysiology is part of ongoing investigations. furthermore, the role of the infection on dysregulation of ace receptors expression, whether treatment with arbs and aces modifies this expression and whether patients with comorbidities and chronic illnesses have higher expression of ace receptors and are therefore more vulnerable to infection are also questions that need to be addressed in the near future. the sars-cov- virus enters the body through the respiratory tract and infects the epithelial cells of the trachea, bronchi, bronchioles and finally the lungs. it then infects the host, and infiltrating and circulating immune cells transfer the virus to other organs. moreover, the blood-borne sars virus infects other organs as well. immunosuppressed patients, including the elderly and patients with chronic disease, experience more severe disease with increased mortality rates. the extent of immune cell damage, represented by the lymphocyte count, is considered a strong predictor of outcome and reflects the immune status of the patient. this multisystemic disease is associated with high mortality rates; mechanical ventilation, extracorporeal membrane oxygenation, antivirals and plasma infusion are currently being applied to reduce mortality, but none is a curative intervention. although systematic treatments are currently at the forefront of clinical research, organ-specific treatment strategies should be also evaluated in order to optimize the management of patients with severe organ dysfunction. several clinical trials are ongoing to evaluate the safety and effectiveness of both novel and pre-existing antiviral drugs, but the ability to vaccinate people 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x. title: aging in covid- : vulnerability, immunity and intervention date: - - journal: ageing res rev doi: . /j.arr. . sha: doc_id: cord_uid: mg wiihj the severe acute respiratory syndrome coronavirus- (sars-cov- ) pandemic was first reported in wuhan, china in december , moved across the globe at an unprecedented speed, and has caused a profound and yet still unfolding health and socioeconomic impacts. sars-cov- , a β-coronavirus, is a highly contagious respiratory pathogen that causes a disease that has been termed the coronavirus disease (covid- ). clinical experience thus far indicates that covid- is highly heterogeneous, ranging from being asymptomatic and mild to severe and causing death. host factors including age, sex, and comorbid conditions are key determinants of disease severity and progression. aging itself is a prominent risk factor for severe disease and death from covid- . we hypothesize that age-related decline and dysregulation of immune function, i.e., immunosenescence and inflammaging play a major role in contributing to heightened vulnerability to severe covid- outcomes in older adults. much remains to be learned about the immune responses to sars-cov- infection. we need to begin partitioning all immunological outcome data by age to better understand disease heterogeneity and aging. such knowledge is critical not only for understanding of covid- pathogenesis but also for covid- vaccine development. in december , a cluster of novel infectious respiratory syndrome of unknown cause was observed in wuhan, china. thanks to the still fairly recent experience gained from the outbreak of severe acute respiratory syndrome (sars) in , chinese scientists and clinicians worked together and quickly identified a novel coronavirus, sars coronavirus (sars-cov- ) as the pathogen . a complete lock-down and other quarantine measures (e.g., staying at home, social distancing, wearing mask and gloves, hand washing, etc.) were implemented initially in wuhan city and then across much of china in the midst of its busy chinese new year holiday season. while the outbreak was brought under control in china quite promptly, the virus has quickly spread across the globe, causing significant morbidity and mortality initially in italy, then other european countries, united states (us), brazil and the rest of the world. on march , , the world health organization (who) declared covid- a global pandemic. on march th , the us government declared a national emergency. in the us, the new york city-new jersey area was the epicenter from march to may. by the end of june, covid- resurgence occurred in its sun belt states including arizona, texas, and florida, which became the new epicenter. on july , the us set a new record of over , new cases and the world saw over , new cases in a single day. as of cause pneumonia (cui et al., ; de wit et al., ) and, in severe cases, acute respiratory distress syndrome (ards). angiotensin-converting enzyme (ace ) serves as the functional cellular receptor for both sars-cov and sars-cov- (bourgonje et al., ; hoffmann et al., ) . recent mechanistic and structural analyses indicate that the viral spike (s) protein of sars-cov- binds to ace in concert with s-protein priming by the host cell transmembrane serine protease tmprss , mediating host cell entry of the virus mittal et al., ) . this binding of sars-cov- is shown to be at -to -fold higher affinity than that of sar-cov , accounting at least partially for the greater pathogenicity of sars-cov- . in addition to mediating viral entry, binding of sars-cov- to ace and subsequent endocytosis dysregulate angiotensin system, leading to the loss of ace -mediated health protection and adverse systemic effects (gheblawi et al., ) . moreover, these molecular events upregulate proteolytic cleavage mediated by a disintegrin and metalloproteinase (adam ) of not only ace itself, which further dysregulates the angiotensin system, but also its primary substrate releasing tumor necrosis factor (tnf)-along with interleukin (il)- and other cytokine mediators, leading to cytokine storm in covid- described below [fig. , (gheblawi et al., ) ]. taken together, ace is the key human cellular receptor and plays a critical role in the pathogenesis of covid- through complex molecular mechanisms against which therapeutic agents can potentially be developed, such as recombinant human ace (rhace ) and inhibitors against tmprss and possibly adam (bourgonje et al., ; gheblawi et al., ; hoffmann et al., ) . influenza, another zoonotic virus which has a segmented negative-sense rna genome and is also a significant respiratory pathogen, is well known for its genetic instability, likely due to the lack of proofreading function of its rna polymerase complex (te velthuis and fodor, ) . point mutations j o u r n a l p r e -p r o o f or small deletions in individual rna segments cause relatively minor antigenic changes, termed antigenic drift, leading to new strains each winter season responsible for seasonal influenza. for this reason, annual updates of influenza vaccines are required. exchange or re-assortment of the viral genome rna segments between strains from humans and animals (e.g., birds or swine) can lead to major antigenic alterations, termed antigenic shift, so that the novel viruses can escape from existing herd immunity and cause influenza pandemics (kim et al., ; lyons and lauring, ) . coronaviruses, on the other hand, are not known for their major genomic re-assortment capacity. why the aforementioned three virulent novel coronaviruses have emerged in less than years of this young century remains a mystery. among them, sars-cov- is the most contagious and sars-cov has not recurred since , reasons for which also remain to be determined. specific mutations are being identified in the sars-cov- genome during this ongoing pandemic. for example, a mutation that changed the amino acid at position of the spike protein from an aspartic acid to a glycine, known as g , may increase infectivity of sars-cov- (korber et al., ; kupferschmidt, ) . unlike influenza and other common coronaviruses, it is now apparent that sars-cov- spread is not impeded by warm weather despite an early study suggesting distribution of covid- outbreaks along restricted latitudes, temperatures, and humidity (sajadi et al., ) ; increased international travel by air or cruise may also contribute to the spread of sars-cov- (gupta et al., ; tabari et al., ) . the mechanism for this unique and worrisome feature remains to be elucidated as well. addressing the challenges of these unknown aspects of sars-cov- biology is critically important, particularly in considering the current resurgence of new cases and the prospect of ongoing covid- for years to come. j o u r n a l p r e -p r o o f in their s, % in their s, to . % in their s or older; the overall cfr is . % . in comparison, the overall cfr was approximately . % worldwide and . % in the us as of october , (fig. ) . the rapid growth of the number of older adults in the world's largest population, the so-called aging tsunami by some, coupled with the unique socioeconomic context, ongoing healthcare reform, and nascent development of geriatrics, creates significant challenges for china to fight againstcovid- , particularly during the early days of the pandemic (fang et al., ; li et al., ; yip et al., ) . a more profound effect of aging is shown by covid- cfr data from italy, the first country affected by the pandemic after china. again, cfrs are from less than . % or lower in patients aged in the s or younger, % among those in their s, . % in their s, . % in their s, to . % in their s and above; the overall cfr is . % (onder et al., ) . of note, the overall cfr is higher in italy than that in china ( . % vs . %, respectively). this is likely because italy not only has a higher cfr than china among adults over years of age, but also has a higher proportion of older adults than china ( . % vs . %, respectively). the us: the first covid- outbreak reported in the us was at a long-term care facility in washington state (arons et al., ; mcmichael et al., ) . the first covid- death reported in new york city was an -year-old person in brooklyn. data from a large case series of covid- patients who were admitted to hospitals in new york city have shown a strikingly similar j o u r n a l p r e -p r o o f trend of age-related increases in covid- deaths. that is, deaths among patients in hospital at the study end point were . % or lower in patients aged in the s or younger, . % among those in their s, . % in their s, . % in their s, to . % in their s and above (richardson et al., ) . as shown in fig. , data reported by the us center for disease control and prevention (cdc) also demonstrate significantly higher rates of hospitalizations, icu admissions, and deaths secondary to covid- among older adults (> years) than any younger age groups. [(cdc, ) , https://www.cdc.gov/mmwr/volumes/ /wr/mm e .htm]. perhaps, the most striking evidence is the data on covid- cases and death in nursing homes across the us from a comprehensive analysis updated by the new york times on september th [(new york times, ) , https://www.nytimes.com/interactive/ /us/coronavirus-nursing-homes.html]. currently, there are up to . million nursing home residents in the us, less than . % of its population. however, about % of confirmed covid- cases were among these vulnerable elderly individuals. moreover, they suffered % of covid deaths in the us. taken together, it is unmistakable that aging is an important risk factor for severe covid- disease and its adverse health outcomes including hospitalization, icu admission, and death. j o u r n a l p r e -p r o o f immunity is a cornerstone of host-pathogen interaction in any infectious disease. it involves three distinct but interrelated key aspects: vulnerability, immune response and protection, and potential immune pathology (fig. ) . in most cases, immune response from prior exposure to the same pathogen or through vaccination with the same dominant antigen can provide at least partial immune protection (i.e., reduction of incidence of infection and/or its severity) via immune memory. the level of vulnerability also involves innate immunity independent of antigen-specific immune responses and other physiological protective mechanisms. if the immune response to the current infection is dysregulated, however, it may cause immune pathology and contribute to the pathogenesis of the disease. since sars-cov- is a novel coronavirus with no prior immune response, the entire population is susceptible with essentially no herd immunity. as discussed earlier, this was also the case in influenza pandemics, such as the pandemics in , , , and more recently the swine flu pandemic in (petersen et al., ) . nonetheless, under certain circumstances, older adults may enjoy better protection than the young against strains that were circulating when they were young, by virtue of immunological memory and/or cross-reactivity. a considerable fraction of healthy individuals not infected with sars-cov- possess t cells reactive to sars-cov- antigens, perhaps because of cross-reactivity with other coronaviruses. it remains to be seen whether this provides any protection against covid- grifoni et al., ; mateus et al., ; sette and crotty, ) . in covid- , a number of immunological studies were initially reported from clinical observations of covid- patients in wuhan, china. while more studies are being published almost every day, they often lack breadth and depth in interrogation of the immune system. we will first review some of the published data currently available, and then propose an immune hypothesis for age-related j o u r n a l p r e -p r o o f vulnerability to severe covid- and adverse health outcomes. instead of proposing age-related chronic inflammation (akbar and gilroy, ) or immunosenescence secondary to cytomegalovirus infection (kadambari et al., ; moss, ) individually as mechanisms underlying this vulnerability, this immune hypothesis integrates immunopathology secondary to cytokine storm and inflammaging and immunosenescence as complex immune mechanisms that could provide a basis for interventional strategies, such as anti-il- therapy and immunization with covid- vaccines ( fig. ). we will also point out challenges in conducting comprehensive and in-depth immune studies and in interpretation of existing data and their implications for vaccine development. "cytokine storm" and immunopathology: severe covid- patients typically develop acute respiratory distress syndrome (ards) requiring intubation and ventilator support as well as significant involvement of other organ systems. for example, neurological manifestations, termed as "neuro-covid" by some, occur in over one-third of covid- patients (chiappelli, ; ferrarese et al., ; frontera et al., ; leonardi et al., ; wang et al., b) . while sars-cov- has been shown for its neurotrophic and neuroinvasive properties (baig et al., ; puelles et al., ) , inflammatory cytokine release and immunopathology caused by sars-cov- infection may also play an important role in contributing to neuro-covid and other systemic manifestations (jose and manuel, ; wu and mcgoogan, ) . in fact, earlier clinical observations from wuhan, china indicated patients with covid- manifest an acute increase of serum levels of inflammatory mediators, such as il- and c-reactive protein (crp) . levels of other inflammatory mediators including interferon (ifn)- induced protein (ip- , or cxcl- ) and monocyte chemotactic protein- (mcp- ) are also acutely elevated in covid- patients, and such elevation is associated with disease severity and progression (lagunas-rangel and chavez-valencia, j o u r n a l p r e -p r o o f ; lin et al., ; yang et al., ) . cytokine storm, or cytokine release syndrome (moore and june, ) , has also been observed in sars and mers and is believed to play an important role in their development and progression (de wit et al., ) . although the sources and regulation of this cytokine storm remain to be elucidated, it is likely derived from dysregulated immune responses to these virulent coronaviruses, leading to immunopathology and severe disease. these observations have led to the ongoing therapeutic development targeting il- , a cytokine mediator that is considered as a hallmark of inflammaging (franceschi et al., ; franceschi et al., ; maggio et al., ) . monoclonal antibodies (mab) targeting il- receptor (il- r, tocilizumab and sarilumab) or il- itself (siltuximab) are now available. while in-depth discussion of differences in mechanisms regulating il- signaling between these mabs and implication in their efficacy and/or side effects is beyond the scope of this article, it is worthwhile noting that anti-il- and anti-il- r mabs can all antagonize il- cis signaling (via canonical membrane-bound il- r and gp ) and trans signaling (via soluble il- r), but only anti-il- r mabs can antagonize il- trans presentation, a newly described mode of il- signaling that involves membrane-bound il- r of dendritic cells (dcs) to generate pathogenic th cells (heink et al., ; kang et al., ) . the immediate goal of such therapeutic intervention is to block the dysregulated cascade of immune activation and inflammation downstream to the cytokine storm to ameliorate severe covid- and its further progression. preliminary results available thus far did not show significant mortality benefit of sarilumab treatment (della-torre et al., ), further analyses of subgroup patients and studies of other mabs are needed. ultimately, effective vaccine and antivirals will be needed to prevent or ameliorate sars-cov- infection and its induced cytokine storm or immunopathology (tay et al., ) . ni et al., ; zhao et al., ) . one study also reported correlative igg, igm, and iga titers between serum and saliva (randad et al., ) . it is not currently known if asymptomatic infection induces detectable antibody responses or whether viral load determines antibody response. in addition, the titer threshold of anti-sars-cov- antibodies that correlates with clinical protection against covid- has yet to be determined. studies have shown higher anti-sars-cov- antibody titers in icu patients compared to mild patients and prolonged presence of neutralizing antibodies with viral shedding in covid- patients, raising questions about the protective efficiency of such antibody responses zhao et al., ) . moreover, a phenomenon called antibody-dependent enhancement (ade) was unexpectedly reported in covid- (arvin et al., ; wan et al., ) , further suggesting the complexity of the effects of such antibody responses. therapeutic use of convalescent plasma collected from recovered covid- patients is a promising passive immune therapy currently in clinical trials. observational findings suggest improved clinical outcomes in those who are transfused with covid- convalescent plasma (ccp), including radiological resolution, reduction in viral loads, and improved survival (duan et al., ; harvala et al., ; hegerova et al., ; joyner et al., ; zhang et al., a) . while two randomized trials assessing ccp china and europe were terminated early and underpowered, they did not find clinically significant differences between the study arms ; gharbharan, et al). studies aimed at defining factors that impact the quality and titer of antibody, including sars-cov- neutralization reveal that older age, male sex, and hospitalization with severe covid- are all factors that contribute to greater antiviral antibody responses against sars-cov- . cell-mediated immune response: clinical observations have revealed significant lymphopenia and increased neutrophil counts in severe covid- disease and, therefore, lymphopenia and high neutrophil-lymphocyte ratio (nlr) are considered as useful predictors for covid- death whereas high lymphocyte counts predict better clinical outcomes (chen et al., c; lagunas-rangel and chavez-valencia, ; qin et al., ; wang et al., a; zhou et al., a) . while neutrophil increases may reflect an acute inflammatory response related to the cytokine storm described above, lymphopenia indicates major impacts on cell-mediate immunity in the early stage of covid- . lymphopenia consists of depletion of both cd + and cd + t cells . the reason for such depletion is not well understood at the present time. one may speculate that t cells are redistributed from the circulation to the site of the infection in the lungs. sánchez-cerrillo et al observed redistribution of activated monocytes and dendritic cells to the lungs in severe covid- patients (sanchez-cerrillo et al., ) . alternatively, as described in more detail below, viral proteins from sars-cov also shared by sars-cov- can suppress type ifns leading to a poor cd + t cell response (fung et al., ; welsh et al., ) . whether the observed lymphopenia is a general phenomenon of acute viral infections versus unique or more profound in covid- remains to be determined. regardless, a retrospective study of covid- patients showed that restored lymphocyte counts predicted recovery during hospitalization while lymphopenia persisted in j o u r n a l p r e -p r o o f non-survivors (chen et al., c) . this further emphasizes the importance of cell-mediated immunity and its impact on clinical outcomes. t lymphocytes are a key cellular basis of adaptive immune protection and vaccination and play a critical role in assisting production of neutralizing antibodies and direct virus clearance. a number of studies have shown sars-cov- -specific cd + and cd + t cell responses in covid- patients meckiff et al., ; neidleman et al., ; ni et al., ; weiskopf et al., ) . in the setting of sars, antigen-specific memory t cells to sars-cov have been shown to persist in convalescent sars patients at low frequency for up to six years and their responses to ex vivo stimulation with sars-cov persist up to years (ng et al., ; oh et al., ) . the duration that sars-cov- -specific memory t cells persist is yet to be established. not all t cell responses are beneficial. for example, kang et al observed hyperactivation of cytotoxic t cell responses as a determinant of covid- severity (kang et al., ) . zhang and colleagues suggest aberrant cd t cell activation as a potential mechanism for cardiac injury in severe covid- (zhang et al., c) . th activation is also believed to play a role in contributing to cytokine storm in severe covid- , suppression of which is proposed to be a mechanism underlying anti-il- r therapy (lagunas-rangel and chavez-valencia, ) and other immunotherapies . comprehensive studies of cell-mediated immune responses are few and far between at the present time. peng et al observed broad and strong memory cd + and cd + t cells induced by sars-cov- in uk convalescent covid- patients, significantly more so in severe compared to mild covid- j o u r n a l p r e -p r o o f cases . a deep immune profiling of covid- patients conducted by matthew and colleagues, however, revealed great heterogeneity (mathew et al., ) . immune hypothesis for age-related vulnerability in older adults: given the disproportionate burden of severe covid- disease and death in older adults, it is important to understand mechanisms that underlie this age-related vulnerability. age-related immune system remodeling, or immunosenescence, is considered to be the major reason for increased susceptibility to infection, particularly respiratory infections such as influenza, as well as impaired immune responses to vaccination pawelec, ) . here we propose an immune hypothesis for covid- vulnerability of older adults. it involves age-related impairment of immune defense against sars-cov- infection, or immunosenescence, and increased risk for immunopathology (fig. ) . although age-related change in innate and adaptive immunity against sars-cov- infection are yet to be investigated in detail, its impairment and dysregulation in older adults can be inferred. for example, senescence-related impairment of type ifn response is responsible for enhanced influenza viral replication in cell culture (kim et al., ) and older adults manifest impaired type ifn response to influenza vaccination (thakar et al., ) . in addition, several sars-cov non-structural proteins that are shared by sars-cov- suppress type ifn response and such suppression is shown to lead to poor cd + t cell response to viral infection (fung et al., ; manners et al., ; welsh et al., ) . therefore, age-associated reduction in type ifn response coupled with direct viral suppression could serve as a critical innate immune mechanism that leads to poor cell mediated immunity and increased vulnerability of older adults against sars-cov- infection with therapeutic implication (sallard et al., ) . little data is currently available about the j o u r n a l p r e -p r o o f impact of aging on cd + and cd + t cell responses in covid- . it is postulated that age-related decline of de novo t cell responsiveness and/or impact from comorbid conditions, particularly persistent viral infections such as chronic cytomegalovirus (cmv) infection could serve as potential causes of covid- vulnerability in older adults (kadambari et al., ; moss, ; nicoli et al., ) . available data on humoral immunity are fascinating and counter-intuitive. among covid- convalescent plasma donors, klein et al observed higher sars-cov- -specific neutralizing and igg antibody titers in older donors compared with their young counterparts . in a study cited above, zhang et al also described the correlation between greater anti-sars-cov- igg titers and older age . the reason for these observations is unknown at the present time and deserves further investigation. substantial evidence supports the role of immunopathology in the pathogenesis of covid- overall as described above. based on their review of data on immune changes published during the early stage of this pandemic, lin and colleagues proposed a hypothesis for the role of immune and inflammatory factors in contributing to dysregulation of the coagulation system in the pathogenesis of covid- and suggested intravenous immune globulin (ivig) and low molecular weight heparin (lmwh) anticoagulant therapy . studies also suggested a link between complement activation and endothelial dysfunction, likely the key to microvascular thrombosis and multi-organ failure in severe covid- (mackman et al., ; magro et al., ; noris et al., ) . however, few studies are available with a focus on aging. inflammaging is well documented and can be derived from senescence-associated secretory phenotype (sasp), persistent viral infection such as cmv, and other potential sources franceschi et al., ; franceschi and campisi, ) . such an unbalanced pro-inflammatory environment could potentiate further inflammatory response j o u r n a l p r e -p r o o f upon sars-cov- infection, leading to the development of an exacerbated cytokine storm in older adults. it may also influence ace expression and facilitate viral entry (radzikowska et al., ) . further studies are urgently needed to address this important mechanism with a focus on aging. children are overwhelmingly spared from severe covid- disease except for the extremely rare occurrence of multisystem inflammatory syndrome in children (mis-c), also called kawasaki disease-like syndrome (lingappan et al., ; viner and whittaker, ) . insights into children's defense mechanisms against sars-cov- infection may shed light on age-related vulnerability in older adults from a different perspective. for example, chen et al observed significantly higher counts of total as well as both cd + and cd + t cells in pediatric covid- cases compared to their adult counterparts . on the other hand, children with covid- manifested lower levels of t cell activation than adult covid- patients (moratto et al., ) , suggesting better immune system control and regulation in response to sars-cov- infection in children. thymic function likely plays an important role in preserving t cells in covid- (rehman et al., ) . in fact, liu et al showed that thymosin  reversed lymphopenia, reversed exhausted t cells and reduced mortality of severe covid- in adults . in addition, children demonstrate strong innate immunity despite the fact that the immune system as a whole is yet to be fully developed. one possibility is "trained immunity" through scheduled immunization with many doses of pediatric vaccines (netea et al., ) . whether this can be applicable in older adults (i.e., potential protective effect from immunization with other unrelated vaccines such as influenza vaccine) remain to be investigated. challenges: despite the large number of research papers including preprints that are published almost every day, it remains a difficult task to obtain reliable knowledge of covid- that is accurate and precise. conflicting data and results that are not reproducible are not uncommon. here we discuss a few inherent difficulties that present themselves as great challenges for immune studies of covid- , reminding readers of critically evaluating the literature and putting published results in appropriate context. this is especially true for assessing covid- information in social media, particularly in the current environment of rapid dissemination of misinformation and disinformation. first, sars-cov- infection is highly heterogeneous, from asymptomatic infection to mild, moderate, or severe covid- . in addition, the infection can evolve through different stages and progress in either direction (improving and recovery versus worsening and death). most published immunological studies are cross-sectional and at one time point with a relatively small sample size. although immunological analysis itself can be cutting edge and in-depth, the results from these studies are only valid in the context of the study with limited generalizability. asymptomatic sars-cov- infection can be a challenge in selecting "healthy controls" as well. due to lack of universal covid- testing, it is difficult to know whether people are truly "healthy" (uninfected) or asymptomatic. secondly, complex impact of aging on the immune system and influences from comorbid conditions and concomitant use of medications may all contribute to the heterogeneity of the data on t-cell immune responses to sars-cov- (mathew et al., ) . finally, there is a high-sequence similarity in viral proteins (e.g., nuclear protein) between sars-cov- and other  coronaviruses (e.g. e strain) . as such, prior coronavirus infections may induce heterotypic cellular immunity against covid- . this heterotypic cellular immune response may further complicate covid- immunological studies and interpretation of their results. therefore, it j o u r n a l p r e -p r o o f is important to take these challenges into consideration in interpretation of published data as well as in design and implementation of immunological and interventional studies including covid- vaccine development. effective and safe vaccination against sars-cov- is the best strategy to stop viral spread and control the pandemic. intense worldwide efforts for covid- vaccine development began after the genetic sequence of sars-cov- was published on january th , and has since advanced at previously unimaginable speed with the first vaccine candidate entering human clinical trials on sequence became available and demonstrated promising preliminary results (jackson et al., ) . two phase / clinical trials of two different adenovirus-vectored covid- vaccines have reported robust antibody and t-cell responses to the vaccines with acceptable side effects in healthy adults (folegatti et al., ; zhu et al., a) . however, the chadox ncov- vaccine trial was conducted among adults of - years of age with no enrollment of older adults (folegatti et al., ) . despite progress that has been made thus far, significant challenges lie ahead. for example, while focusing on the vaccine itself is important, attention must also be directed to the host. because of the lack of in-depth knowledge about the immune responses to sars-cov- infection, no specific immune parameter(s) of vaccine potency, or correlates of protection, are currently available. the phenomenon of ade discussed above (arvin et al., ) , also deserves careful consideration (lambert et al., ) . aging is a critical host factor to consider in the context of vaccination responses (pawelec and weng, ) . it may be necessary to develop different vaccines on specific vaccine platforms for older adults versus those for children and young adults. in the case of influenza vaccination, the standard dose of trivalent inactivated influenza vaccine (iiv ), the only influenza vaccine available for older adults for many years before the approval of high-dose and adjuvanted influenza vaccines, showed questionable effectiveness, if at all, for the elderly, particularly those who are frail and need vaccine protection the most (yao et al., ) . over a century after the spanish flu pandemic, the worst pandemic in human history, we are still in search of a universal influenza vaccine (paules et al., ) . the ongoing pandemic poses special challenges (diamond and pierson, ) . for vaccine trials, levels of pandemic activity as well as various quarantine measures and their implementation significantly impact study enrollment, protection of both research staff and participants, and other trial logistics. because of the low level of pandemic activity in china, covid- vaccine trials are not feasible at the present time, even for vaccines that were developed in china. when a safe and efficacious covid- vaccine becomes available, the demand of the ongoing pandemic can post huge challenges on large-scale production and distribution of the vaccine. addressing these and other challenges requires global corporation and coordination among governments, academia, and industry. with rapid progress in covid- vaccine development, it is promising and hopeful that there will be one or several safe and effective covid- vaccines in the near future. but the public should be fully educated about the alternative reality, that is, we may not have such a vaccine for a long time, if ever. to that end, authorities have begun to develop protective programs against covid- outbreaks at nursing homes, the setting with arguably highest risk for older adults as j o u r n a l p r e -p r o o f described above. for example, pennsylvania state has established a statewide regional response health collaborative program (rrhcp, https://www.media.pa.gov/pages/dhs_details.aspx?newsid= ) with nearly $ million awarded to pennsylvania state university to support nursing homes in the southcentral region of pennsylvania against covid- outbreaks and mitigation should covid- be present at these facilities. rrhcp provides a wide range of covid- related clinical and public health supportive services, such as testing performance and laboratory capacity, personal protective equipment (ppe) supplies, infection prevention training and advising, rapid response teams for sites with an active covid- outbreak, staffing support, alternate care settings, mental and behavioral health support for residents and staff, clinical support via telehealth and geriatrician site visits, contact tracing, and education through a statewide learning network [https://news.psu.edu/story/ / / / /penn-state-health-receives-grant-mitigate-covid- -care-facilities]. as to the public, every one of us should adhere to social distancing and other quarantine measures that are known to be effective to prevent virus spread. a historical lesson from the spanish flu pandemic is that compared to philadelphia, st. louis was able to minimize flu pandemic deaths and flatten the curve through its prompt and strictly enforced quarantine measures (fig. a) (hatchett et al., ) . the contemporary one is that europe flattened the curve during the summer, , while the us suffers ongoing covid- resurgence (fig. b) j o u r n a l p r e -p r o o f fig. . ace as the key human cellular receptor for sars-cov- , its role and underlying molecular mechanisms in the pathogenesis of covid- . in addition to viral entry, binding to ace of sars-cov- in concert with s-protein priming by tmprss and subsequent endocytosis result in dysregulation of the angiotensin system, leading to the loss of ace -mediated systemic health protection. these molecular events also upregulate adam -mediated proteolytic cleavage of not only ace itself, which further dysregulates the angiotensin system, but also its primary substrate releasing tnf- along with il- and other cytokine mediators, leading to cytokine storm. tmprss : transmembrane serine protease ; immune response and protection against sars-cov- and immunopathology. immune response includes humoral immunity (i.e., antibody response) and cell-mediated immunity (cmi) (right). while age-related immunosenescence is believed to weaken immune protection, vaccination enhances it. inflammaging and cytokine storm may lead to immunopathology (left). not all immune responses are protective as antibody-dependent enhancement (ade) in humoral immunity may promote sars-cov- infection while th response in cmi may contribute to cytokine storm. anti-il- therapy with monoclonal antibodies against either il- or il- receptor currently in clinical trials can block cytokine storm and its downstream event and/or suppress th response. age-related decrease of physiological reserve in respiratory and other organ systems may also contribute to vulnerability. together, they lead to disproportionately severe covid- and high mortality in older adults. all the authors have seen and approved the final version of the manuscript being submitted. all the authors warrant that the article is the authors' original work, hasn't received prior publication and isn't under consideration for publication elsewhere. this study was supported in part by funding from national institutes of health (nih) (r ai and r ag ) and funding from irma and paul milstein program for senior health, milstein medical asian american partnership (mmaap) foundation of usa (www.mmaapf.org) to sxl, nih r ag to sxl and jbm, nih u ag and department of defense for covid- : w qy- - - to slk, and pennsylvania state regional response health collaborative program (rrhcp) 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cardiac injury in severe cases of covid- ? antibody responses to sars-cov- in patients of novel coronavirus disease epidemiology and cause of severe acute respiratory syndrome (sars) in guangdong, people's republic of china clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study immunogenicity and safety of a recombinant adenovirus type- -vectored covid- vaccine in healthy adults aged years or older: a randomised china novel coronavirus, i., research, t., b. a novel coronavirus from patients with pneumonia in china key: cord- -hnm k r authors: liu, jie; ouyang, liu; guo, pi; wu, hai sheng; fu, peng; chen, yu liang; yang, dan; han, xiao yu; cao, yu kun; alwalid, osamah; tao, juan; peng, shu yi; shi, he shui; yang, fan; zheng, chuan sheng title: epidemiological, clinical characteristics and outcome of medical staff infected with covid- in wuhan, china: a retrospective case series analysis date: - - journal: nan doi: . / . . . sha: doc_id: cord_uid: hnm k r backgrounds since december , a novel coronavirus epidemic has emerged in wuhan city, china and then rapidly spread to other areas. as of feb , a total of , medical staff confirmed with coronavirus disease (covid- ) caused by sars-cov- in china had been reported. we sought to explore the epidemiological, clinical characteristics and prognosis of novel coronavirus-infected medical staff. methods in this retrospective study, confirmed cases of novel coronavirus-infected medical staff admitted to union hospital, wuhan between jan, to feb, were included. two groups concerned were extracted from the subjects based on duration of symptoms: group (<= days) and group (> days). epidemiological and clinical data were analyzed and compared across groups. the kaplan-meier plot was used to inspect the change in hospital discharge rate. the cox regression model was utilized to identify factors associated with hospital discharge. findings the median age of medical staff included was years old. % were female and % were nurses. none had an exposure to huanan seafood wholesale market or wildlife. a small proportion of the cohort had contact with specimens ( %) as well as patients in fever clinics ( %) and isolation wards ( %). fever ( %) was the most common symptom, followed by cough ( %) and fatigue ( %). the median time interval between symptoms onset and admission was . days. on admission, % of medical staff showed abnormal il- levels and % had lymphocytopenia. chest ct mainly manifested as bilateral ( %), subpleural ( %) and ground-glass ( %) opacities. during the study period, no patients was transferred to intensive care unit or died, and ( %) had been discharged. higher body mass index (bmi) (hr . ; % ci . - . ), fever (hr . ; % ci . - . ) and higher levels of il- on admission (hr . ; % ci . - . ) were unfavorable factors for discharge. interpretation in this study, medical staff infected with covid- have relatively milder symptoms and favorable clinical course, which may be partly due to their medical expertise, younger age and less underlying diseases. smaller bmi, absence of fever symptoms and normal il- levels on admission are favorable for discharge for medical staff. further studies should be devoted to identifying the exact patterns of sars-cov- infection among medical staff. in december, , a group of novel atypical pneumonia patients with uncertain etiology but mostly linked to the huanan seafood wholesale market emerged in wuhan, china [ ] . a later confirmed pathogen of this previously unknown pneumonia was described as a novel coronavirus, currently named as severe acute respiratory syndrome coronavirus (sars-cov- ; previously known as ncov), was ascertained by unbiased sequencing analysis of lower respiratory tract samples from early cases on jan , following which the protocol of real-time reverse-transcriptase polymerase chain reaction (rt-pcr) assay for this novel coronavirus had also been developed [ ] [ ] [ ] [ ] [ ] [ ] . in fact, the epidemics of the two other novel coronaviruses, namely severe acute respiratory syndrome coronavirus (sars-cov) and middle east respiratory syndrome coronavirus (mers-cov), have posed a huge threat to public health in the past two decades [ , ] . sars-cov- in this outbreak, like the previous two viruses, is also categorized within the same genus of the subfamily orthocoronavirinae within the family coronaviridae, but shows a strong affinity for human respiratory receptors [ , ] . by feb , coronavirus disease (covid- ) due to the sars-cov- has caused more than , laboratory confirmed cases and , deaths among them in china [ ] . sufficient evidence indicated that the covid- clustered within close-contact human groups, such as family and hospital settings [ ] [ ] [ ] [ ] [ ] . the sars-cov- epidemic has transmitted throughout china and to other countries due to massive population movements before the lunar new year [ ] , and consequently escalated as a public health emergency of international concern declared by world health organization (who) [ ] . as of mar , more than , confirmed cases infected with sars-cov- have been identified globally [ ] . information pointing to the epidemiology and clinical features of general confirmed cases has been accumulating. the previous studies enrolling , and confirmed cases admitted to wuhan, respectively, provided an insight into epidemiological characteristics, clinical manifestations, treatment measures and clinical outcomes of these patients [ , , ] . in particular, a recent study in zhejiang province, china indicated that the symptoms of patients outside of wuhan perhaps are relatively mild versus symptoms of initial cases in wuhan [ ] . meanwhile, a new finding from a national wide descriptive report drew a huge amount of attention, which declared that the total number of confirmed novel coronavirus-infected medical staff was as high , as of february , with a peak incidence occurring on january [ ] . hospital-related transmission are one of the causes for infection of health-care workers [ ] , especially in the early stages of covid- epidemic when there was a lack of knowledge about transmission approaches of sars-cov- , as well as in the period when facing a shortage of protective materials. nonetheless, the predominant cause of the infection and the failure of protection among health workers remains to be investigated [ ] . despite the increased attention towards protecting medical staff from infection, information regarding the epidemiology and clinical features of medical staff confirmed with covid- is scarce. this single-centered, retrospective study aimed to describe epidemiological, clinical, laboratory and radiographic features, treatment, and prognosis of a group of medical staff confirmed with covid- who were admitted to union hospital, wuhan. we hope the findings in the present study will provide an insight into the prevention and treatment of this novel coronavirus for the global community. we performed a single-centered, retrospective study on a group of novel coronavirus-infected medical staff at wuhan union hospital, one of the hospitals treating patients confirmed with covid- at the earliest time. diagnosis of . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted march , . . https://doi.org/ . / . . . doi: medrxiv preprint cases with sars-cov- infection conforms to the who interim guidance [ ] . details regarding laboratory confirmation protocol for sars-cov- were described by previous studies [ , ] . throat-swab specimens were screened for sars-cov- and other respiratory viruses (influenza, respiratory syncytial virus, etc.) by real-time rt-pcr assays. a total medical staff, who were confirmed by sars-cov- real-time rt-pcr test on respiratory secretions collected by throat swab and undergone serial chest ct scans following their admission to isolation wards of union hospital between jan and feb, , were enrolled. this retrospective study was approved by the ethics of committees of union hospital, tongji medical college, huazhong university of science and technology. written informed consent was waived due to the rapid emergence of this infectious disease. the epidemiological data, medical and nursing records, laboratory examinations, chest computed tomography (ct) of all patients were reviewed and abstracted with concerted efforts of experienced clinicians. data were collected at the time of symptoms onset, presentation for medical advice and in-patient admission. the clinicians who had experience of treating patients with confirmed sars-cov- infection reviewed and collected the medical records of patients, and preliminarily collated the data. the clinical data were extracted through a standardized form for case report as previously described [ ] . epidemiological data, including exposure histories before symptoms onset (whether there is a history of exposure to the huanan seafood wholesale market, or wildlife), and close contact with laboratory-confirmed or suspected cases of covid- in a work environment (fever clinics, or isolation wards), specimens (pharyngeal swab, blood, sputum specimens, etc.) or family members with covid- were collected. in addition, information about preventive medication among medical staff was also collected. we have also collected the data on demographics, clinical manifestations, laboratory . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted march , . . examinations and radiological studies. these included age, sex, occupation (doctor, or nurse), body mass index (bmi ≥ , or < kg/m ), current smoking status (yes, or no), disease severity (non-severe, or severe), date of symptom onset, symptoms before hospital admission (fever, cough, fatigue, sore throat, myalgia, sputum production, difficulty breathing or chest tightness, chill, loss of appetite, diarrhea, and chest pain), coexisting conditions (e.g. hypertension, diabetes, etc.), laboratory testing indicators on admission (leucocyte count, lymphocyte count, platelet count, d-dimer, creatinine, creatine kinase, lactose dehydrogenase, alanine aminotransferase, aspartate aminotransferase, hemoglobin, ferritin, c-reactive protein, amyloid a, total bilirubin, procalcitonin, erythrocyte sedimentation rate, interleukin- (il- ) and lymphocyte subsets, etc.), radiologic assessments of chest ct (lung involvement, lung lobe involvement, predominant ct changes, predominant distribution of opacities, etc.), treatment measures (antibiotics agents, antiviral agents, traditional chinese medicine, immune globulin, thymosin, corticosteroids and oxygen therapy), and complications (e.g. pneumonia, acute respiratory distress syndrome, acute cardiac injury, acute kidney injury, shock, etc.). all ct images were analyzed by two radiologists (j.l. and f.y., who had and years of experience in thoracic radiology, respectively) utilizing the institutional digital database system without access to clinical and laboratory findings. images were reviewed independently, and final decisions were reached by discussion and consensus. we estimated the time interval from symptom onset to admission with maximum information available -that is, all the exact date of initial symptoms provided by the patients. then the aggregated data was sent to data analysis group. prior to statistical analysis, the aggregated data were cross -checked by group members to guarantee the correctness and completeness of data. the clinical outcomes and prognosis were continuously observed up to feb . we defined the primary outcomes as discharge. the discharge criteria of inpatients included all the following three conditions [ ] : ( ) body temperature return to normal for more than days and respiratory symptoms improvement; ( ) resolution of lung . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted march , . . https://doi.org/ . / . . . doi: medrxiv preprint involvement demonstrated by chest ct; ( ) two consecutive rt-rcr tests, with sampling interval of more than day, showing a negative result. secondary outcomes consisted of hospital discharge rate and length of hospital stay. given that treatment and monitoring of some patients in our study were still ongoing, a fixed time-interval of observation was not applied to these clinical outcomes. this study devoted to report the epidemiological, clinical characteristics and prognosis of medical staff confirmed with covid- . continuous variables were checked for distribution normality by means of the kolmogorov-smirnov test, following which they were summarized as either means with standard deviations (sd) or medians with interquartile ranges (iqr) as appropriate. counts and percentages were utilized to describe categorical variables. given the cut-off point at th day of symptoms onset proposed by previous studies [ , ] , we assigned the patients into either one of two groups based on duration of symptoms: group (≤ days) and group (> days). we applied a kaplan-meier plot to inspect the change of hospital discharge rate. the proportional hazard cox regression model was utilized to ascertain factors associated with hospital discharge. univariate models with a single variable once at a time were first fitted. the statistically significant risk factors as well as age and sex were, then, included into a final multivariate cox regression model. the hazards ratios (hrs) along with the % confidence intervals ( % cis) were calculated. statistical tests were two-sided with significance set at α less than . . we performed all data analyses by r software version . . (r foundation for statistical computing). . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted march , . . during the study period, epidemiological and clinical data were collected on medical staff with laboratory-confirmed sars-cov- infection from wuhan union hospital, of whom ( %) provided an exact date of symptom onset and only case ( %) was severe. the patients aged between and years old, and median age was years (iqr - years). the median age in group was years (iqr - years), and in group it was years (iqr - years). more than half of the cohort were female ( %) and nurse ( %). there were ( %) overweight cases (bmi ≥ kg/m ) and only was current smoker. among the medical staff recruited, no one had an exposure to huanan seafood wholesale market or wildlife, while ( %) medical staff had family members confirmed with sars-cov- infection. during patient care, ( %) and ( %) cases had contact with patients in fever clinics and isolation wards, respectively, and ( %) had direct contact with specimens collected from confirmed patients. ( %) of medical staff have used preventive medications (table ) . the median duration between symptoms onset and admission was . days in group . there were ( %) cases, most of whom were assigned to group , with one or more co-morbidities: ( %) had hypertension, ( %) had uterine fibroids, and one ( %) each had diabetes, depressive disorder, thyroid nodules or abdominal lymphatic tuberculosis. the three most common symptoms were fever ( %), cough ( %) and fatigue ( %). the relatively less common symptoms were sore throat, myalgia, difficulty breathing or chest tightness, sputum production, headache, chill, loss of appetite, diarrhea, and chest pain (table ) . table shows the laboratory and radiographic findings of medical staff with confirmed covid- . on admission, the blood counts of ( %) cases showed leukocytopenia and only one ( %) showed leukocytosis. ( %) presented with . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted march , . . https://doi.org/ . / . . . doi: medrxiv preprint lymphocytopenia and ( %) presented thrombocytopenia. most cases demonstrated normal levels of d-dimer, creatinine, and creatine kinase, but elevated c-reactive protein and amyloid a levels were presented in % and % of cases, respectively. elevated levels of alanine aminotransferase ( %) and aspartate aminotransferase ( %) were less common. a small proportion ( %) of cases had abnormal procalcitonin serum level (> . ug/l). notably, ( %) of cases had high levels of il- (> . pg/ml). medical staff of group had more prominent laboratory abnormalities (i.e., leukocytes, lymphocytes, platelet, alanine aminotransferase, amyloid a and il- ) as compared with those in group . as evidenced by table of the study participants, no person was transferred to an intensive care unit for mechanical ventilation due to acute respiratory distress syndrome. ( %) patients needed an electrocardiograph monitoring, among whom were in group . empirical intravenous antibiotic treatment was administered in ( %) patients. all the patients were given empirical antiviral therapy. meanwhile, ( %) were offered traditional chinese medicine, ( %) patients were given immune globulin, ( %) were given thymosin, and ( %) received corticosteroids. as for oxygen therapy, ( %) used nasal cannula and only ( %) used face mask, while no one . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted march , . . needed invasive mechanical or ventilation extracorporeal membrane oxygenation. as a whole, despite the negligible difference of antiviral treatment between two groups, most of the cases who received electrocardiogram monitoring, antibiotics, immune globulin, thymosin and oxygen therapy belonged to group , whereas the proportion given traditional chinese medicine was higher in group (table ) . by feb, , ( %) of the cases have been discharged and none had died, the remaining cases were still in hospital to receive supportive therapy. the median length of hospital stay was . (iqr . - . ) days in total, . (iqr . - . ) days in group and . (iqr . - . ) days in group ( table ). the overall median discharge time (i.e. equal to the time that half of the patients left the hospital) was days (figure a ). it should be noted that the endpoint of cox model was discharge, and patients who continued to be hospitalized as of feb would be regarded as censored data. the hr metric derived from multivariate cox regression model was utilized to ascertain factors significantly associated with the endpoint of patients infected with sars-cov- . results of the final multivariate cox regression model showed that larger bmi (≥ kg/m ) (hr . ; % ci . - . ), fever symptoms (hr . ; % ci . - . ) and increased il- levels (> . pg/ml) on admission (hr . ; % ci . - . ) were unfavorable factors for hospital discharge (all hrs < and all p-values < . ) according to cox regression mode ( figure b ). by feb, , hospitals across china had reported, in total, , laboratory-confirmed cases of medical staff with sars-cov- infection, of which the majority ( %) were from hubei province [ ] . according to china-who joint investigation report, most of the infections among medical staff occurred in the early stages of the covid- outbreak in wuhan, when there was a lack of knowledge . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted march , . . https://doi.org/ . / . . . doi: medrxiv preprint about transmission approaches and experience to fight with the sars-cov- [ ] . despite the outbreak of covid- occurring in few scattered hospitals (e.g. medical staff were infected at one hospital in wuhan), hospital-related transmission is not the main transmission feature of covid- in china [ ] . our findings advocate this viewpoint. according to our data, a small proportion of novel coronavirus-infected medical staff had a direct contact with specimens of patients ( %) as well as patients in fever clinics ( %) and isolation wards ( %) during patient care. in addition, none of the medical staff had an exposure to huanan seafood market or wildlife, and ( %) had family members with confirmed covid- . the exact mode of medical staff infection remains unclear. the findings are consistent with previous reports [ , ] . the demographic characteristics and clinical manifestations of medical staff with confirmed covid- in wuhan were not exactly the same as general confirmed patients included in recent studies [ , , ] . in our study, most of the novel coronavirus-infected medical staff analyzed were females and nurses, and had a smaller median and range of age. the medical staff infected with sars-cov- have similar signs and symptoms with general confirmed infection patients [ , ] . the infected medical staff tended to manifest on chest ct with bilateral, subpleural ground-glass opacities, which is consistent with the recent radiological reports on covid- pneumonia [ ] [ ] [ ] [ ] . furthermore, abnormal d-dimer levels as well as abnormal functions of kidney, heart and liver was relatively rare among medical staff with sars-cov- infection. in our study, only one of medical staff with sars-cov- infection was severe case, none developed acute respiratory distress syndrome or transferred to intensive care unit. more than half of the cases were discharged by feb, . previous studies suggested that . % of the general confirmed patients were severe cases, among whom older age, male sex, chronic diseases are more common [ , , , ] . contrarily, our study revealed that medical staff have relatively milder symptoms, . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted march , . . https://doi.org/ . / . . . doi: medrxiv preprint which may be partly due to their medical expertise, younger age and less underlying diseases. medical staff with symptoms onset for less than days by the time of admission were compared with those with symptoms of more than days. we found that medical staff with symptoms for less than days had more prominent laboratory abnormalities on admission, and they also experienced relatively worse clinical course and longer hospital stay. furthermore, the median time between symptoms onset and admission of infected medical staff in this study was . days, longer than general population as described in recent publications [ , ] . we believe that mild cases of infected medical staff without an early hospitalization was mainly because they made admirable concessions to provide the limited-number of isolation wards for infected patients with worse conditions during the peak time of covid- epidemic in wuhan. predictors of hospital discharge among infected medical staff were identified by cox model. smaller bmi, absence of fever and normal levels of il- on initial stage were favorable factors for recovery and discharge. a recent study revealed that fever was identified in only half of the patients on presentation but increased to nearly % after hospitalization [ ] . elevated il- levels were observed in % of infected medical staff on admission, which is associated with inflammatory response [ , ] . to explore how absence of fever and il- levels on initial stage affect the length of hospital stay and discharge of medical staff with sars-cov- infection, further studies are needed. given that epidemiology and clinical features of medical staff infected with sars-cov- is unclear, our study provides an insight to prevention and treatment of medical staff at risk of covid- infection. so far, more than , medical personnel outside hubei province gathered in wuhan for the battle against the epidemic, and china has attached great importance to infection prevention among . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted march , . . https://doi.org/ . / . . . doi: medrxiv preprint medical staff [ ] . although some safeguards have been introduced in the aspects including salary, injury suffered on the job, rest, and psychological adjustment for medical staff, the next step will continue to strengthen the promotion of these measures. meanwhile, some potential problems remain to be solved, such as unclear patterns of infection, mental health care for medical staff [ ] , and the possibility of airborne transmission from aerosol production by medical practices in health care facilities [ ] . a recent study from singapore found that surface environmental and personal protective equipment contamination caused by respiratory droplets and fecal shedding from patients infected with sars-cov- , suggesting that the environment is a potential viral vector [ ] . further investigations should be devoted to identifying the exact patterns of sars-cov- infection among medical staff. we acknowledge some limitations of this study. first, only for medical staff with confirmed covid- from a single hospital in wuhan were included. however, the population from which they were sampled was large and we did not include all of the cases during the study period. in fact, there are , laboratory-confirmed cases of covid- in medical staff as of feb [ ] . this limitation in our study may result in deviations in epidemiological and clinical observation characteristics. we hope that the findings presented here will encourage a more comprehensive assessment of sars-cov- infection in for medical staff. second, more detailed information, particularly regarding specific causes of sars-cov- infection among for medical staff, was unavailable at the time of analysis; however, this is a retrospective, observational study and the data used in this study only provide a preliminary insight into epidemiological features and clinical outcomes of a group of for medical staff confirmed with covid- . further research on this regard is needed. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted march , . . the study medical staff have relatively milder symptoms and favorable clinical course, which may be partly due to their medical expertise, younger age and less underlying diseases. smaller bmi, absence of fever symptoms and normal il- levels on admission are favorable for recovery and hospital discharge for medical staff infected all authors declare no competing interests. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted march , . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted march , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted march , . . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted march , . there were of novel coronavirus-infected medical staff provided an exact date of onset, of which were assigned to group and to group . the remaining patients without an exact date of onset were not grouped. data are presented as medians (interquartile ranges, iqr) and n (%). for each item, the effective sample size of total population, group and group is , and unless stated otherwise. * the group of patents with symptoms onset for or less days by the time of admission. † the group of patents with symptoms onset for more than days by the time of admission. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted march , . there were of novel coronavirus-infected medical staff provided an exact date of onset, of which were assigned to group and to group . the remaining patients without an exact date of onset were not grouped. data are presented as medians (interquartile ranges, iqr) and n (%). * the group of patents with symptoms onset for or less days by the time of first admission. † the group of patents with symptoms onset for more than days by the time of first admission. . cc-by-nc-nd . international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. 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nationwide analysis in china characteristics of and important lessons from the coronavirus disease (covid- ) outbreak in china: summary of a report of cases from the chinese center for disease control and prevention into the eye of the cytokine storm. microbiol il- induces an anti-inflammatory response in the absence of socs in macrophages mental health care for medical staff in china during the covid- outbreak surface environmental, and personal protective equipment contamination by severe acute respiratory syndrome coronavirus (sars-cov- ) from a symptomatic patient creatine kinase alanine aminotransferase we would like to thank all colleagues for helping us during the current study. the authors would like to express their appreciation for all of the emergency services, nurses, doctors, and other hospital staff for their efforts to combat the covid- outbreak. key: cord- -ifoe x authors: rabi, firas a.; al zoubi, mazhar s.; kasasbeh, ghena a.; salameh, dunia m.; al-nasser, amjad d. title: sars-cov- and coronavirus disease : what we know so far date: - - journal: pathogens doi: . /pathogens sha: doc_id: cord_uid: ifoe x in december , a cluster of fatal pneumonia cases presented in wuhan, china. they were caused by a previously unknown coronavirus. all patients had been associated with the wuhan wholefood market, where seafood and live animals are sold. the virus spread rapidly and public health authorities in china initiated a containment effort. however, by that time, travelers had carried the virus to many countries, sparking memories of the previous coronavirus epidemics, severe acute respiratory syndrome (sars) and middle east respiratory syndrome (mers), and causing widespread media attention and panic. based on clinical criteria and available serological and molecular information, the new disease was called coronavirus disease of (covid- ), and the novel coronavirus was called sars coronavirus- (sars-cov- ), emphasizing its close relationship to the sars virus (sars-cov). the scientific community raced to uncover the origin of the virus, understand the pathogenesis of the disease, develop treatment options, define the risk factors, and work on vaccine development. here we present a summary of current knowledge regarding the novel coronavirus and the disease it causes. coronaviruses, named for the crown-like spikes on their surface (latin: corona = crown), are positive-sense rna viruses that belong to the coronvirinae subfamily, in the coronaviridae family of the nidovirales order [ ] . they have four main subgroups-alpha, beta, gamma, and delta-based on their genomic structure. alpha-and betacoronaviruses infect only mammals, usually causing respiratory symptoms in humans and gastroenteritis in other animals [ , ] . until december of , only six different coronaviruses were known to infect humans. four of these (hcov-nl , hcov- e, hcov-oc and hku ) usually caused mild common cold-type symptoms in immunocompetent people and the other two have caused pandemics in the past two decades. in - , the severe acute respiratory syndrome coronavirus (sars-cov) caused a sars epidemic that resulted in a % mortality. similarly, the middle east respiratory syndrome coronavirus (mers-cov) caused a devastating pandemic in with a % mortality rate. in late , a cluster of pneumonia cases in wuhan city, hubei province, china were identified as with a novel betacoronavirus, first called the novel coronavirus ( -ncov) and often referred to as the wuhan coronavirus. when the genomics of the -ncov was sequenced, it shared . % of the genetic sequence of the sars-cov that caused the - pandemic [ ] and the international committee on taxonomy of viruses renamed the -ncov as sars-cov- [ ] . patients began to present in november and december with various degrees of respiratory distress of unknown etiology and treated at the time as possible influenza infections. as it became apparent that most cases had a shared history of exposure to the huanan seafood wholesale market (the so-called "wet market"), the wuhan local health authority issued an epidemiologic alert on december and the wet market was closed. about a week later, on january , chinese researchers shared the full genetic sequence of the novel coronavirus, now called sars-cov- [ ] . since the novel coronavirus was recognized, the disease it caused was termed coronavirus disease (covid- ) , and several reports on the clinical presentation, epidemiology, and treatment strategies have been published [ ] [ ] [ ] [ ] . in addition, several websites have been setup to track the epidemic and the case detection rate, which are being updated as often as hourly [ ] [ ] [ ] [ ] . on january , the world health organization (who) declared the covid- outbreak to be a global public health emergency, sixth after h n ( ), polio ( ), ebola in west africa ( ), zika ( ) and ebola in the democratic republic of congo ( ), and on march , the who characterized covid- as a pandemic [ ] . the timeline of events is summarized in figure . all coronaviruses that have caused diseases to humans have had animal origins-generally either in bats or rodents [ ] . previous outbreaks of betacoronaviruses in humans involved direct exposure to animals other than bats. in the case of sars-cov and mers-cov, they were transmitted directly to humans from civet cats and dromedary camels respectively ( figure ). animal origins of human coronaviruses. severe acute respiratory syndrome coronavirus (sars-cov) and middle east respiratory syndrome coronavirus (mers-cov) and were transmitted to humans from bats by civet cats and dromedary camels, respectively. the sars-cov- was likely transmitted to humans through pangolins that are illegally sold in chinese markets [ , ] . the sars-related coronaviruses are covered by spike proteins that contain a variable receptor-binding domain (rbd). this rbd binds to angiotensin-converting enzyme- (ace- ) receptor found in the heart, lungs, kidneys, and gastrointestinal tract [ ] thus facilitating viral entry into target cells. based on genomic sequencing, the rbd of sars-cov- appears to be a mutated version of its most closely related virus, ratg , sampled from bats (rhinolophus affinis) [ ] . it is, therefore, believed that the sars-cov- also originated from bats and, after mutating, was able to infect other animals. the mutation increased the rbd affinity to ace- in humans, but also other animals such as ferrets and malayan pangolins (manis javanica; a long-snouted, ant-eating mammal sold illegally for use in traditional chinese medicine), but also decreased the rbd affinity to ace- found in rodents and civets. the pangolin is believed to be the intermediate host of sars-cov- [ ] . there was some early speculation that sars-cov- emerged from a manmade manipulation of an existing coronavirus, but there is no evidence to support such a theory. in fact, anderson et al. suggest that the particular mutation that was found in the rbd of sars-cov- is different to what would have been predicted based on previously used genetic systems. the authors, however, stated that "it is currently impossible to prove or disprove the other theories of [the sars-cov- ] origin [ ] ". since sars-cov and sars-cov- are so similar, the biochemical interactions and the pathogenesis are likely similar. binding of the sars-cov to the angiotensin-converting enzyme (ace- ) receptors in the type ii pneumocytes in the lungs triggers a cascade of inflammation in the lower respiratory tract [ ] . it has been demonstrated that when the sars spike protein binds to the ace- receptor ( figure a ), the complex is proteolytically processed by type transmembrane protease tmprss leading to cleavage of ace- and activation of the spike protein ( figure b ) [ , ] , similar to the mechanism employed by influenza and human metapneumovirus, thus facilitating viral entry into the target cell ( figure c ). it has been suggested that cells in which ace- and tmprss are simultaneously present are most susceptible to entry by sars-cov [ ] . early indications are that sars-cov- virus also requires ace- and tmprss to enter cells [ ] . in the first published review of the clinical presentation of patients admitted to hospital with covid- [ ] , % of patients had a fever, % had a cough, and % had shortness of breath on admission. however, those admitted may have had less severe symptoms for to days prior to presentation, during which they were likely contagious. by the time patients developed shortness of breath, they had been sick for an average of eight days. once admitted to the hospital, all patients developed clinical pneumonia supported by chest ct findings, and of the patients ( %) developed hypoxic respiratory failure necessitating icu admission. four patients ( %) required mechanical ventilation, two of which received extracorporeal membrane oxygenation due to refractory hypoxia. in total, six patients died, giving a case fatality rate (cfr) of % and triggering panic that quickly spread worldwide. while early media reports suggested that deaths were more likely in patients with comorbid conditions, of the patients described in the chinese review, only % had comorbid conditions and the average age was . as of march , gmt, there were , confirmed cases, about half of which ( , cases, . %) were within mainland china. about % of ill people had severe disease, and . % had mild disease and a total of tested-positive cases were asymptomatic [ , ] . while initially confined to china among those who visited the wuhan wet market, over the course of about months the sars-cov- has to date been confirmed in countries and one cruise ship [ ] . the chinese cdc published the epidemiologic characteristics of the covid- outbreak as of february (table ) [ ] . initial data suggests that the majority of patients ( %) were over age years, and that the risk of death increases with age. no deaths were reported in patients younger than years old, and only . % of the total fatalities were in patients younger than years of age. [ ] . [ , ] . due to aggressive containment strategies in china, including a mass quarantine of the entire million population of wuhan, the acceleration of new cases in china has slowed whereas that outside of china has increased. as of march nd, the number of daily new cases outside of china was nine times higher than those within china. many countries have instituted travel bans and/or quarantine procedures for incoming travelers. closures of public schools and social gatherings have been instituted in many countries in an effort to contain the spread of covid- and decrease the public health burden [ , ] and the cdc has released recommendations on school closure criteria [ ] . in comparison, the sars pandemic, which also originated in china, resulted in people infected and deaths ( . %). on the other hand, the mers pandemic infected people causing deaths ( . %). therefore, although mers and sars had higher mortality, the much larger number of people infected with sars-cov- , and the rate at which the number is increasing, raises red epidemiologic flags. to assess the magnitude of the risk posed by the sars-cov- , we review four parameters that we believe important: the transmission rate, the incubation period, the case fatality rate (cfr), and the determination of whether asymptomatic transmission can occur. the reproduction number, or "r naught" (r ), is a mathematical term that defines contagiousness [ ] . specifically, it is the number of people that one sick host can infect. if the r is less than one the disease will disappear. if the r ≥ then the disease will spread between people. estimates of the r of sars-cov- have ranged from . to as high as . [ ] although the world health organization estimates it is between . and . [ ] . for the purposes of comparison, the mean r for seasonal influenza is between . and . (variable by region and immunization rates), whereas for sars was between and . . the slightly higher r for sars-cov- may be because it has a longer prodromal period, increasing the period during which the infected host is contagious. coronaviruses are generally thought to be spread most often by respiratory droplets, not to be confused with airborne transmission [ ] . droplets are larger and tend to fall to the ground close to the infected host and only infect others if the droplet is intercepted by a susceptible host prior to landing. droplet transmission is typically limited to short distances, generally less than m. however, the airborne route involves much smaller droplets that can float and move longer distances with air currents. under certain humidity and temperature environments, airborne droplets can remain in flight for hours. generally, pathogens that are transmissible via the airborne route have higher r , because infected particles can remain in the air long after the infected individual has left the premises. this airborne route occurs, for example, in measles (r between and [ ] ) and chicken pox (r s between . and . [ ] ). once infected droplets have landed on surfaces, their survivability on those surfaces determines if contact transmission is possible. based on our current understanding from other betacoronaviruses, including sars and mers, coronaviruses can survive, and remain infectious, from h up to days on inanimate surfaces such as metal, glass, or plastic, with increased survival in colder and dryer environments [ ] [ ] [ ] . for this reason, the chinese government has been reported to be disinfecting and even destroying cash in an effort to contain the virus [ ] . reassuringly, cleansing of surfaces with common biocidals such as ethanol and sodium hypochlorite is very effective at inactivation of the coronaviruses within min of exposure [ ] . the timing of maximum infectivity is currently being assessed. a small study of patients showed that nasal viral load peaks within days of symptom onset, suggesting that transmission of disease is more likely to occur early in the course of infection [ ] . understanding incubation periods is very important as it allows health authorities to introduce more effective quarantine systems for suspected cases. the best current estimates of the sars-cov- infection range from to days. analysis of the first cases of covid- in wuhan a mean incubation period of . days [ ] . a later report, based on cases, reported a mean incubation period of . days [ ] . yet another report, on cases who traveled to wuhan between and january, had incubation period ranges from . to . days, with a mean of . days [ ] . to calculate the case fatality rate (cfr) of an infection, one must divide the mortality number (m) by all those who were infected. the total number of those infected includes those who were infected and recovered without presentation (i r ), infected and presented to a health care facility (i p ), and infected and died (i d ). the cfr would be m/(i r + i p + i d ). clearly, one must have an accurate estimation of each of these parameters to accurately determine the cfr of covid- . while the (m) is generally easier to count, and a focus of media, the denominator can take much longer to calculate. during the early phases of a deadly epidemic, the number of those who were infected and recovered (i r ) is not yet known, since only those who were infected and became seriously ill are recognized and tested. in addition, because this is a novel virus, there were no existing detection methods, so early deaths due to clinical entities such as influenza, for example, may have been mis-attributed to covid- . the viral genome was published about weeks after the start of the outbreak, and pcr analysis was quickly used to diagnose suspected cases [ ] . public health officials can now test suspected cases, especially close contacts of known cases, and others with mild symptoms, but the testing capabilities can become saturated, potentially limiting the ability to get an accurate estimation of i p . for example, the initial ability of the wuhan health authority was limited to tests per day, but that number has grown to tests per day [ ] . the combination of these factors leads to a gross underestimation of the denominator of the cfr calculation, and thus an exaggeration of the mortality. until we are able to accurately represent i r and i p , it is currently impossible to precisely estimate the cfr of sars-cov- . however, during the course of a potentially fatal pandemic, an accurate estimation of cfr is important. while it is tempting to estimate the cfr by dividing the number of known deaths by the total number of confirmed cases, the resulting number may be off by orders of magnitude, especially since infected individuals at one point in time may die x days later. using the lag period approach and dividing the current number of deaths to the number of cases x days ago may be a more acute estimator of cfr. nucleuswealth.com applied this method by using the number of deaths at any particular day and dividing by number of cases , , or days prior. as seen in figure , as time progresses, whether whichever number of days is used for x, the cfr seems to converge at just under % for cases within hubei, and about . % for cases outside of hubei [ ] . the higher mortality in wuhan may be overestimated because early in the course of this epidemic, viral testing was limited to only the severe cases. however, the china national health commission admits that wuhan has a relative lack of medical resources, which may have contributed to the higher mortality rate. pathogens , , x for peer review of and dividing the current number of deaths to the number of cases x days ago may be a more acute estimator of cfr. nucleuswealth.com applied this method by using the number of deaths at any particular day and dividing by number of cases , , or days prior. as seen in figure , as time progresses, whether whichever number of days is used for x, the cfr seems to converge at just under % for cases within hubei, and about . % for cases outside of hubei [ ] . the higher mortality in wuhan may be overestimated because early in the course of this epidemic, viral testing was limited to only the severe cases. however, the china national health commission admits that wuhan has a relative lack of medical resources, which may have contributed to the higher mortality rate. infection transmission by asymptomatic individuals can make control of disease spread challenging. since late january, sars-cov- transmission from infected but still asymptomatic individuals has been increasingly reported [ , ] . assessment of the viral loads in symptomatic individuals not only showed that the viral loads peak within the first few days of symptoms, but also that asymptomatic patients can have a similarly high viral load without showing symptoms [ ] . it was suggested that viral testing should no longer be limited to symptomatic individuals, but also include those who have traveled to affected areas [ ] . at such an early phase of the covid- pandemic, it is difficult to accurately describe the populations most at risk, especially when teasing out risk factors for infection from risk factors for death from disease. early on, it became clear that those who have visited the wuhan wet market were most at risk of infection, but the population visiting the market is not an accurate reflection of the general population. the chinese cdc published the epidemiologic characteristics of the covid- outbreak along with associated risk factors for death [ ] . the largest risk factor for death is age. other risk factors include male sex and the presence of comorbid conditions (table ). however, in addition to real age-specific mortality, the age-based risk could reflect underlying comorbidities among the elderly and the distribution of the underlying population in wuhan, where the outbreak initiated. infection transmission by asymptomatic individuals can make control of disease spread challenging. since late january, sars-cov- transmission from infected but still asymptomatic individuals has been increasingly reported [ , ] . assessment of the viral loads in symptomatic individuals not only showed that the viral loads peak within the first few days of symptoms, but also that asymptomatic patients can have a similarly high viral load without showing symptoms [ ] . it was suggested that viral testing should no longer be limited to symptomatic individuals, but also include those who have traveled to affected areas [ ] . at such an early phase of the covid- pandemic, it is difficult to accurately describe the populations most at risk, especially when teasing out risk factors for infection from risk factors for death from disease. early on, it became clear that those who have visited the wuhan wet market were most at risk of infection, but the population visiting the market is not an accurate reflection of the general population. the chinese cdc published the epidemiologic characteristics of the covid- outbreak along with associated risk factors for death [ ] . the largest risk factor for death is age. other risk factors include male sex and the presence of comorbid conditions (table ) . however, in addition to real age-specific mortality, the age-based risk could reflect underlying comorbidities among the elderly and the distribution of the underlying population in wuhan, where the outbreak initiated. table . fatality rate by age, sex, and pre-existing medical conditions. the death rate represents the probability (%) of the corresponding group of dying from sars-cov- [ ] . with what we know about the pathogenesis of the sars-cov virus, it seems reasonable to assume that those with higher levels of ace- receptors may be at greatest risk. there was some speculation that the expression of ace- receptors may be linked to race, specifically after an early report suggested that asian males had higher ace- -expressing cell ratios than white and african americans [ ] . however, the sample size contained only eight different individuals (five african americans, two whites, and one asian) and extrapolating those findings to a whole race is impractical. yet, in another study assessing ace- receptor expression in tissues of patients with lung cancer, there were no significant disparities in ace- gene expression between racial groups (asian vs. caucasian), age groups (older or younger than years old), or gender groups (male vs. females) [ ] . ace- gene expression was, however, significantly elevated in smokers suggesting that smoking history should be considered in identifying susceptible populations. since smoking in china is predominantly a male attribute ( % of men, . % of women) [ ] , this may help to explain the gender difference seen in the hospitals in china. early in the covid- epidemic, it appeared that children were a protected group, but this may have been because they were less likely to have frequented the wuhan wet market, or because they were more likely to have asymptomatic or mild disease and thus less likely to have been tested. covid- has affected infants as young as month of age [ ] , most with mild or asymptomatic disease. there have been no reported cases of adverse infant outcomes for mothers who developed covid- during pregnancy. second to the hubei population, the other population at increasing risk is healthcare workers. as of february , , total of healthcare workers in china have been infected, five of whom fatally [ ] . the current best strategy of treatment of patients with covid- is purely supportive. clinicians and intensive care specialists are applying much of what they have learned during the sars epidemic to guide current therapy of covid- . recommendations for admission to critical care units, guidelines for infection control, and procedures to minimize nosocomial transmission are being established [ ] . however, there are several fronts that are being studied to develop targeted treatments. the most efficient approach to the treatment of covid- is to test whether existing antiviral drugs are effective. in previous betacoronavirus epidemics, several antiviral drugs, such as ribavirin, interferon, lopinavir-ritonavir, and darunavir/cobicistat (prezcobix) were tested, with some showing promising in vitro results [ ] . remdesivir, an adenosine analog used against rna viruses (including sars and mers-cov), was a candidate ebola treatment with promising in vitro results but disappointing in vivo effects against ebola [ , ] . there is currently in vitro evidence that remdesivir may be effective in controlling sars-cov- infection [ ] . in fact, compassionate use of remdesivir was employed in the treatment of the first covid- case in the united states, during a period of rapid clinical deterioration, and within one day there was dramatic improvement of the clinical condition [ ] . randomized double-blinded, placebo-controlled clinical trials are currently underway in china and usa to evaluate the efficacy of remdesivir and initial results are expected by the end of april [ , ] . other existing drug candidates include chloroquine and camostat mesylate. chloroquine is a widely used anti-malarial drug that is known to block virus-cell fusion and has been shown to interfere with the glycosylation of sars-cov and ace- cellular receptors, rendering the ace- -sars-cov interaction less efficient [ ] . there is also in vitro evidence that chloroquine may be effective in preventing sars-cov- cellular entry [ ] . camostat mesylate, also known as foy [ ] , was initially developed and currently approved for the treatment of chronic pancreatitis in japan [ , ] . camostat mesylate targets the tmprss protease, theoretically preventing viral entry. researchers in germany showed that camostat mesylate reduced the amount of sars-cov- viral replication [ ] . a simple but very effective treatment modality is the use of convalescent plasma, or serum from patients who have recovered from the virus, to treat patients. patients with resolved viral infection will have developed a specific antibody response which may be helpful in neutralizing viruses in newly infected individuals. this modality was successfully employed during the - ebola outbreak [ , ] . however, the use of convalescent sera is of limited benefit in an outbreak situation since the exponential growth of infected patients exceeds the ability of previous patients to provide donor plasma. the recent finding that sars-cov- binds to the same ace- receptors targeted by the sars-cov [ ] opens up the possibility of using the previous research on the sars epidemic and applying it to covid- . the first strategy would be to employ either a small receptor-binding domain (rbd) or a neutralizing antibody targeting the ace- receptor, thus blocking the binding of s protein and preventing virus entry into cells. initial in vitro results have shown promising results [ , ] and specific monoclonal antibodies are being contemplated as candidates for treatment [ , ] . the main limitation of using rbds or antibodies is that the treatment must be given within a specific time window, before the initiation of viral replication [ ] . in addition, the side effects of ace- blockade, especially since ace- is also present in non-pulmonary tissue, must be understood and minimized before implementation. in addition, finally, the turnover of ace- receptors would influence how often the therapeutic rbd or antibody would have to be administered. a second strategy is to create an ace- -like molecule that would bind to the s protein of the coronavirus itself. again, research in to the sars virus demonstrated that soluble ace- proteins blocked the sars virus from infecting cells in vitro [ , ] . the additional benefit to using this strategy lies in the possible prevention of s protein-mediated ace- shedding that has been shown to induce the pulmonary edema characteristic of sars [ , ] . a phase ii clinical trial of recombinant ace- in ards reported significant modulation of inflammatory proteins, but no significant differences in respiratory parameters [ ] . further research is necessary to assess if the animal studies will translate to clinical benefit. there are currently more than clinical trials to test a variety of potential sars-cov- treatments [ ] . the long-term goal of sars-cov- research is developing an effective vaccine to yield neutralizing antibodies. the national institutes of health in the us, and baylor university in waco, texas, are working on a vaccine based on what they know about the coronavirus in general, using information from the sars outbreak. in addition, the recent mapping of the sars-cov- spike protein may pave the way for more rapid development of a specific vaccine [ ] . of interest is the use of a relatively new vaccine technology, rna vaccines that have the ability to elicit potent immune responses against infectious diseases and certain cancers [ , ] . traditional vaccines 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coronavirus treatments cryo-em structure of the -ncov spike in the prefusion conformation direct gene transfer into mouse muscle in vivo mrna-based therapeutics-developing a new class of drugs personalized rna mutanome vaccines mobilize poly-specific therapeutic immunity against cancer a phase i/iia study of the mrna-based cancer immunotherapy cv in patients with stage iiib/iv non-small cell lung cancer mrna: a versatile molecule for cancer vaccines safety and immunogenicity study of -ncov vaccine (mrna- ) to treat novel coronavirus-full text view-clinicaltrials.gov this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license funding: this research received no external funding. the authors declare no conflict of interest. pathogens , , key: cord- -gbmnoo authors: callender, lauren a.; curran, michelle; bates, stephanie m.; mairesse, maelle; weigandt, julia; betts, catherine j. title: the impact of pre-existing comorbidities and therapeutic interventions on covid- date: - - journal: front immunol doi: . /fimmu. . sha: doc_id: cord_uid: gbmnoo evidence from the global outbreak of sars-cov- has clearly demonstrated that individuals with pre-existing comorbidities are at a much greater risk of dying from covid- . this is of great concern for individuals living with these conditions, and a major challenge for global healthcare systems and biomedical research. not all comorbidities confer the same risk, however, many affect the function of the immune system, which in turn directly impacts the response to covid- . furthermore, the myriad of drugs prescribed for these comorbidities can also influence the progression of covid- and limit additional treatment options available for covid- . here, we review immune dysfunction in response to sars-cov- infection and the impact of pre-existing comorbidities on the development of covid- . we explore how underlying disease etiologies and common therapies used to treat these conditions exacerbate covid- progression. moreover, we discuss the long-term challenges associated with the use of both novel and repurposed therapies for the treatment of covid- in patients with pre-existing comorbidities. the novel severe acute respiratory syndrome coronavirus (sars-cov- ), and subsequent sars-cov- induced coronavirus disease has spread on an unprecedented scale. according to the world health organization (who), as of the th july , there have been , , cases and , covid- related deaths worldwide. evidence from the global outbreak has clearly demonstrated that individuals with pre-existing comorbidities such as hypertension, cardiovascular disease, and diabetes are at a much greater risk of dying from covid- ( , ) . this is of great concern for individuals living with these conditions, and a major challenge for global healthcare systems and biomedical research. given that comorbidities are associated with high mortality among covid- patients, a better understanding of the biological mechanisms that underpin this risk are needed to enable development of appropriate preventative and therapeutic strategies. the immune system plays a vital role during covid- , and the degree of immune dysfunction correlates with disease severity ( , ) . severe covid- cases are associated with significant lymphopenia and an overactivated innate immune response resulting in hyperinflammation ( ) . many covid- associated comorbidities affect the function of the immune system, which in turn directly impacts the response to covid- . furthermore, the myriad of drugs prescribed for these comorbidities will also influence the progression of covid- and limit additional treatment options available for covid- . here, we review the current sars-cov- literature and explore how preexisting comorbidities adversely affect covid- outcome. furthermore, we discuss the long-term challenges associated with the use of both novel and repurposed therapies for the treatment of covid- in patients with pre-existing comorbidities. in december , several cases of an infectious pneumonia with an unknown etiology emerged in wuhan province, china. by january , a novel coronavirus termed sars-cov- was identified as the cause. the virus spread rapidly and was classified as a pandemic by the who on the th march . however, this is not the first pathogenic human coronavirus to emerge in the last decade. in , a severe acute respiratory syndrome (sars) coronavirus (sars-cov) with animal to human transmission was reported in guangdong province, china ( , ) . prior to sars-cov, four human coronaviruses belonging to the alpha and beta genera of the coronaviridae family had been identified: hcov- e, hcov-oc , hcov-nl , and hcov-hku ( ) . however, unlike the previously identified coronaviruses, sars-cov was phylogenetically distinct ( ) . furthermore, rather than causing upper respiratory tract infections with mild common cold symptoms, sars-cov caused severe lower respiratory tract infections, resulting in viral pneumonia and risk of developing acute respiratory distress syndrome (ards). the sars-cov outbreak lasted months, and infected , individuals across different countries, with a mortality rate of ∼ % ( ) . in , a second novel human coronavirus emerged in saudi-arabia and was termed middle east respiratory syndrome (mers) coronavirus (mers-cov). similar to sars-cov, infection with mers-cov can cause fatal pneumonia. to date, the who has reported , mers-cov cases, with a mortality rate of ∼ % ( ) . while the previous two coronavirus outbreaks were relatively well-contained, the unprecedented spread of the current pandemic has demonstrated increased infectivity of sars-cov- . early genome sequencing from china revealed that the k base-pair viral genome of sars-cov- shared . % sequence identity with sars-cov, whereas a bat coronavirus previously detected in rhinolophus affinis shared % sequence identity ( , ) . whilst mers-cov utilizes dipeptidyl peptidase- (ddp ) for cell entry, sars-cov, and sars-cov- share the same cell entry receptor; angiotensin converting enzyme ii (ace ) ( , ) . ace is recognized by the s -subunit of the spike protein and is ubiquitously expressed in the epithelia of the nasal cavity, airway tract and the alveolar space. notably, reports have shown that the receptor binding domain of sars-cov- s has a higher affinity for ace , which may be one contributing factor to the increased viral pathogenesis of sars-cov- ( , ) . the scale of the ongoing pandemic demonstrates the need for a more comprehensive understanding of the disease, and of the contributing factors such as pre-existing comorbidities, which are proving detrimental for disease severity and outcome. clinical presentation of covid- varies greatly. a metaanalysis of studies from countries ( , patients) reported . % of cases as mild, . % as severe and . % as critical ( ) . most healthy individuals are asymptomatic or present with mild/moderate respiratory illness ( ) . the majority of critical cases occur in older (≥ years) or comorbid individuals ( , , ) . covid- symptoms are typical of pathogenic human coronaviruses (figure ) ( ) , with fever and cough reported most commonly, however other common symptoms include dyspnoea, sore throat, sputum production, fatiguem and headache ( , , ) . more recently, olfactory dysfunction such as anosmia has been described in covid- patients ( , ( ) ( ) ( ) ( ) . furthermore, rare gastrointestinal symptoms such as nausea, diarrhea and vomiting have also been described ( , , ) . patients with severe covid- can develop serious and potentially fatal complications such as ards, thromboembolic events, septic shock and multiple organ failure (figure ) . due to the severity of these complications, many are associated with critical covid- patients who require intensive care ( , ) . due to underreporting and large inter-country variation, the fatality rate remains unclear. for instance, in italy the overall case-fatality rate has been reported as . % compared to . % in china ( ) . however, despite the variation, the evidence clearly demonstrates a higher fatality rate among those who develop severe covid- ( ) . the immune system plays a vital role during covid- , and the degree of immune dysfunction correlates with disease severity (figure ) ( , ) . during sars-cov- infection the immune system becomes activated, resulting in local inflammation, the recruitment of monocytes, dendritic cells (dcs), natural killer (nk), t and b cells. this response may manifest as mild/moderate disease resulting in a fever, cough and fatigue, however this will be followed by resolution of both the infection and inflammation. in severe covid- cases, severe lymphopenia and the accumulation of functionally exhausted t and nk cells result in an inability to mount an effective antiviral immune response to clear sars-cov- ( , ) . furthermore, interleukin (il- ) levels remain elevated over time, and are accompanied by high levels of il- , il- , il- , tumor necrosis factor-α (tnf-α), c-x-c motif chemokine (cxcl- ), monocyte chemoattractant protein- (mcp- ), and macrophage inflammatory protein- α (mip- α) resulting in systemic cytokine storm ( ) . this uncontrolled systemic hyperinflammation can cause the development of critical and potentially life-threatening complications such as severe pneumonia, ards, septic shock and multiple organ failure ( , , ) . both lymphopenia and hyperinflammation figure | prevalence of covid- symptoms and complications. data obtained from a quantitative meta-analysis of studies ( ) . it's important to note that % of all cases analyzed in the meta-analysis were hospitalized cases. therefore, the proportion of symptoms and complications are representative of this and the overall proportions with regards to all covid- cases will be much lower. the prevalence of anosmia ( ) and thromboembolic events ( ) were obtained independently from smaller cohorts and may therefore change as more data is published. figure | immune response in mild/moderate and severe covid- cases. mild/moderate covid- is characterized by local inflammation, the recruitment of monocytes, dcs, nk cells, t and b cells, followed by resolution of the infection and inflammation. severe covid- is characterized by severe lymphopenia, t cell exhaustion, and systemic hyperinflammation that can cause the development of critical and potentially life-threatening complication such as severe pneumonia, ards, septic shock, and multiple organ failure ( , , ) . are being reported in the majority of covid- cases admitted to hospital and is associated with a poor prognosis ( , , ) . more detailed examination has demonstrated negative effects on all lymphocyte subpopulations including cd + and cd + t cells, b cells, and nk cells ( ) . high-dimensional analysis of circulatory immune profiles in mild, moderate and severe covid- patients by mass cytometry revealed that proportions of naïve cd + t cells, tgfβ + cd − naïve cd + t cells, dcs, and macrophages are associated with mild cases, whereas a sharp decline in the proportion of cd + t cells and nk cells was observed in severe cases ( ) . interestingly, single-cell rna sequencing of pbmcs isolated from hospitalized covid- patients revealed a novel population of developing neutrophils, which appeared to be closely related to plasmablasts, in patients that had developed ards ( ) . as this was a small cohort of patients, further studies are needed to assess whether this novel subset of neutrophils plays a role in the development of ards and other covid- complications. functionally, cd + t cells and nk cells in severe covid- patients exhibited more signs of exhaustion than mild/moderate patients ( , ) . for example, elevated programmed cell death protein- (pd- ), cytotoxic t-lymphocyte-associated protein- (ctla- ) and t cell ig and itm domain (tigit) on cd + t cells and increased nkg a on nk cells ( , ) . as exhausted t and nk cells are less able to mount an effective antiviral immune response, it is unsurprising that these subsets are unable to eradicate sars-cov- and correlate with severe covid- cases. in addition to t cell changes, humoral immunity against sars-cov- is starting to come to light. evidence of sars-cov- specific antibodies was demonstrated in a study of hospitalized patients. igg and igm sars-cov antibodies were present in % of patients within week of onset and % by day ( ) . in another study, most patients developed robust antibody responses between and days, and although delayed, a stronger antibody response was observed in critical patients ( ) . these findings were also mirrored in a study of covid- patients, who all showed a positive igg response by day , followed by seroconversion to igm ( ) . interestingly, antibody titers were found to be higher among severe covid- patients ( ) , however the authors acknowledge that interpreting an association between antibody response and disease severity is difficult due to the small sample size of severe and critical patients in their study. a recent study reported low variable plasma antibody titers in convalescent individuals, however they found binding domain specific antibodies with potent anti-viral activity in all individuals ( ) . older individuals (≥ years) are more prone to severe covid- and have a higher mortality rate ( , , , ) . clinically, older patients have more pronounced immune dysfunction compared to younger patients, as lymphocyte counts are lower and pro-inflammatory cytokine levels higher ( ) . this is not surprising as aged immune systems are associated with immunosenescence and chronic low-grade inflammation, termed inflammaging ( ) . although immunosenescence affects all aspects of the immune system, much of the deterioration in protective viral immunity can be attributed to defective t cell immunity ( ) . the decline of naïve t cell output due to thymic involution ( ) and the accumulation of senescent t cells leads to reduced viral host immunity ( ) . in mice, cd + t cells were shown to be crucial against sars due to their important role in sars-cov clearance. this protection was lost in aged mice as senescent cd + t cells responded poorly to antigen ( , ) . moreover, in addition to inflammaging, the accumulation of senescent cd + t cells and b cells with distinct senescenceassociated secretory phenotypes ( , ) in older individuals results in elevated baseline inflammation, further increasing susceptibility to hyperinflammation and cytokine storm upon sars-cov- infection. in addition to age, biological sex and ethnicity have also been implicated in covid- outcomes. although no major sex differences exist when examining absolute number of covid- cases, disease incidence is higher in males when comparing older individuals (≥ years). furthermore, initial reports from china suggested a male bias in mortality ( , ) , which has now been reported in out of countries that have reported sex-disaggregated data, revealing a global male case fatality rate of . % compared to . % in females ( , ) . this finding is consistent with data obtained from the previous sars and mers epidemic ( ) ( ) ( ) . the predominant hypothesis to explain these biological sex differences is that estrogen plays a protective role against covid- . following the sars epidemic, studies in mice demonstrated that ovariectomy or pharmaceutical blocking of estrogen in female mice resulted in elevated immune cell infiltration in the lung and consequently a more severe disease outcome ( ) . in support of this, researchers in china reported that lower levels of estrogen were associated with more severe covid- cases in women ( ) . although the exact molecular mechanisms underpinning how estrogen protects against covid- are yet to be confirmed, the influence of estrogen on aging and immunity, ace levels, and sex-related risk factors for comorbidities have all been suggested ( , , ) . due to these benefits, researchers in the uk have commenced investigations into the effects of hormonal therapies such as the contraceptive pill and hormone replacement therapy, however no data has been published yet. more recently, data has emerged suggesting that black, asian and minority ethnic (bame) individuals are at a greater risk of acquiring sars-cov- and have worse clinical outcomes ( ) . for instance, in the uk two thirds of covid- fatalities among healthcare workers were bame individuals ( , ) . underlying comorbidities, which are more prevalent in bame individuals, in addition to cultural, behavioral and socio-economic differences have been proposed as possible causes ( ) . however, more data is needed in order to truly establish whether a relationship between covid- and ethnicity exists. evidence from the global outbreak has demonstrated that individuals with pre-existing comorbidities are at a much greater risk of dying from covid- ( , ) . however, a greater understanding of the biological mechanisms that underpin this risk is needed to develop appropriate preventative and therapeutic strategies. here we review the major comorbidities identified in a number of meta-analyses ( figure ) ( , ). after identification, independent searches were conducted in order to comprehensively assess the impact of each comorbidity and its associated therapies on sars-cov- risk, covid- progression and outcome, and future covid- therapy options. hypertension has been repeatedly reported as the highest pre-existing comorbidity in covid- patients ( , , , - ). retrospective analysis revealed that patients with hypertension have an increased risk for severe infection and mortality ( , ) . however, whether hypertension itself or the use of hypertensive therapies are responsible for these statistics is currently unknown. hypertensive patients are commonly treated with renin angiotensin system inhibitors, such as ace inhibitors (acei) and angiotensin-receptor blockers (arb). as acei and arb can significantly increase ace expression ( ), many speculate they are responsible for the increased risk to hypertensive patients ( ) . conversely, a retrospective review of hospitalized covid- patients, of which . % had underlying hypertensions, indicated that acei and arb may be protective effect against covid- , as the percentage of severe cases were lower in patients treated with acei/arb ( . %) when compared to those treated with other anti-hypertensive treatments such as calcium channel blockers, β-blockers, and diuretics ( %) ( ) . however, patients treated with non-aci/arb were also found to have a higher incidence of additional comorbidities ( ), which may have been responsible for the development of severe disease. due to the conflicting evidence and opinions among the scientific community, it remains unclear whether treatment with acei/arb has a positive or negative impact on covid- progression, however many are continuing to examine this. ( ). hypertension ( %), cardiovascular disease ( . %), and diabetes ( . %) were the most prevalent pre-existing co-morbidities. as this data is representative of hospitalized patients, the prevalence of these among mild/moderate cases may be different, and as more data is analyzed these may change. frontiers in immunology | www.frontiersin.org cardiovascular disease has also been highly reported among covid- patients and is associated with an increased mortality rate ( , , ) . furthermore, cardiovascular complications such as thromboembolic events, myocarditis, acute coronary syndrome, arrythmia, cardiogenic shock and heat failure, have been documented in covid- patients without prior cardiovascular disease ( ), demonstrating a significant impact of sars-cov- infection on the heart. in a case series of covid- patients, those with underlying cardiovascular disease had a mortality rate of . %, which was further increased to . % in a subset of patients who had both underlying cardiovascular disease and elevated troponin t levels, indicative of myocardial injury ( ) . two possible explanations for the increased prevalence and mortality among patients with comorbid cardiovascular disease have been proposed. firstly, cardiovascular disease is commonly treated with renin angiotensin system inhibitors as described above ( , ) , and secondly, ace is highly expressed in the heart ( ) . a recent study analyzing the cellular distribution of ace in human heart tissue obtained from covid- patients identified that ace was highly expressed in pericytes, cardiomyocytes and fibroblasts ( ) . furthermore, cd , an additional binding receptor for sars-cov, was specifically expressed in macrophages ( ) . due to the increased presence of macrophages in cardiovascular disease, the authors speculate that cd + macrophages may enhance viral entry into the human heart. collectively, this study indicated an intrinsic susceptibility to sars-cov- infection in the heart, which could explain the high susceptibility to covid- among cardiovascular disease patients and the higher incidence of acute cardiac injury in non-cardiovascular disease patients. according to numerous reports severe covid- patients are at heightened risk of thromboembolic events, with - % of critically ill covid- patients reported to have developed thromboembolic complications ( , ( ) ( ) ( ) ( ) . systemic inflammation and subsequent activation of coagulation are both contributing factors to this increased risk ( , ) . coagulation abnormalities have been reported throughout the covid- pandemic and the term covid- -associated coagulopathy (cac) has been used to describe patients displaying coagulation changes ( ) . elevated levels of prothrombin, fibrinogen and ddimer, in addition to elevated inflammatory markers such as c-reactive protein (crp) and il- , are markers of cac ( ) . in particular, increased d-dimer levels highly correlate with disease severity, as elevated d-dimer presenting at admission or over time are associated with increase mortality in covid- patients ( ) . due to the high incidence of thromboembolic events, the use of thromboprophylaxis for patients admitted to hospital with severe covid- has been suggested ( , ) , and cac should be monitored carefully in all hospitalized covid- patient, particularly those with pre-existing risk of thromboembolic events. diabetes is the third most prevalent underlying comorbidity in covid- patients ( , , , , ) . type diabetes is a multifactorial disease characterized by chronic inflammation and impaired metabolism and has become an increasing risk to human health. diabetic individuals have an increased susceptibility to infection ( ) , and are at a high risk of developing multiple comorbidities such as cardiovascular disease ( ) . one study on covid- found that diabetic patients were more likely to develop pneumonia and were responsible for . % of severe cases, but only % of mild/moderate cases ( ) . there are a number of reasons as to why people with diabetes are more likely to develop severe covid- . firstly, chronic inflammation in diabetic patients increases their susceptibility to hyperinflammation and the development of cytokine storm. this has been already reported in covid- patients, as il- and crp levels were found to be significantly higher in diabetic patients ( ) . secondly, it is well-documented that hyperglycaemia can impair the immune response, increase oxidative stress and is associated with the onset of premature senescence ( , ) . consequently, diabetic patients that are unable to control their blood glucose levels may have an even greater vulnerability to severe disease. finally, in addition to disease etiology, the treatment of diabetes may also impact covid- development. as previously discussed for hypertension and cardiovascular disease, the use of renin angiotensin system inhibitors may increase susceptibility to sars-cov- infection ( , ) . furthermore, dpp inhibitors commonly used to treat diabetes have an anti-inflammatory effect, resulting in reduced macrophage infiltration, which could impair the innate immune response during covid- ( ) . obesity is associated with most of the common covid- comorbidities such as hypertension, cardiovascular disease and diabetes ( , ) . the global prevalence of obesity varies greatly, for example obesity is more common in the united states and europe than it is in asian countries ( ) . consequently, covid- severity and mortality rates may also vary as a result of this. one study reported a higher bmi in patients with severe infection, and when comparing survivors vs. nonsurvivors, it was reported that . % of non-survivors had a bmi above kg/m , which was a significantly higher proportion than survivors ( ) . however, the cohort for this study was small (n = ) and further retrospective analysis of existing studies is needed to clarify the impact of obesity on covid- . following the previous h n pandemic, retrospective analyses reported that obesity was associated with increased risk of severe infection and mortality ( ) , which is in line with the increased risk of infection in obese individuals ( ) . in addition to increased risk of comorbidities, obesity is also linked to an impaired immune response ( ) , with evidence of impaired antibody ( ) and t cell ( ) responses. furthermore, expression of ace is upregulated in adipocytes of obese individuals and therefore may act as a potential target for sars-cov- ( ). the incidence of cancer as a covid- comorbidity has been low. in an extensive meta-analysis of , patients, malignancy accounted for just . % of comorbidities reported ( ). however, a nationwide analysis in china reported that . % of covid- cases had active cancer, and these patients had a higher proportion of serious events in comparison to individuals without cancer ( ) . at this current time, it is unclear whether cancer patients are at high risk of covid- due to an immunocompromised state linked to certain cancer therapies. in one particular study, patients that underwent recent chemotherapy or surgery had a higher risk of clinically severe events than those who did not. however, a limited number of just patients were included in this analysis ( ) , demonstrating the need for more thorough research. furthermore, not all cancer patients should be considered equally immunocompromised. cancer patients treated with immuno-oncology therapies such as immune checkpoint inhibitors (ici) could be more immunocompetent than patients undergoing chemotherapy ( ) . nonetheless, there are two major concern associated with the use of immuno-oncology therapies during covid- . firstly, there is potential overlap between covid- interstitial pneumonia and possible pneumological toxicity from anti-pd- /pdl- agents, which can be fatal. although this is a rare immune-related adverse event, it has been reported in . - % of patients treated with anti-pd- /pdl- monotherapy, and - % of patients treated with anti-pd- /anti-ctla- combination therapy ( , ) . secondly, there is a risk of cytokine release syndrome associated with t cell-engaging immunotherapy, such as chimeric antigen receptor (car) t cells. given that cytokine storm has been linked to a negative outcome in covid- due to the development of ards and multiple organ failure, ici and car-t cell therapies may exacerbate this hyperinflammatory state and increase mortality in these patients ( ) . overall, despite the lower incidence of cancer among covid- patients, those being treated with immunocompromising therapies such as chemotherapy, and those susceptible to immune-related adverse events in response to immuno-oncology therapies should be monitored carefully. as infection with sars-cov- results in an acute respiratory disease that can progress to ards, respiratory failure and potentially even death, it is reasonable to speculate that patients with pre-existing respiratory disease would be at increased risk of severe covid- . surprisingly, this risk is not as striking as one might anticipate, as the prevalence of asthma was just . % in a study of covid- patients in china ( ) . furthermore, the incidence of chronic obstructive pulmonary disease (copd) among hospitalized covid- patients was reported to be just . % in a meta-analysis of , patients ( ). conversely, the center for disease control and prevention (cdc) recently released data of us hospitalizations indicating that copd is present in . % of patients ( ) . a possible explanation for this global variation could be due to differences in therapeutics agents and disease management. for instance, a global survey assessing the severity and control of , asthmatic adults worldwide published that individuals in japan and asia-pacific regions reported less severe disease than those in europe and the united states ( ). the prevalence of chronic liver disease in covid- patients is estimated to be % ( , ) . however, liver damage has been repeatedly reported as a common complication in response to covid- ( , , ) . in a study of , patients in china, elevated levels of the liver enzyme aspartate aminotransferase (ast) were reported in % of mild/moderate covid- patients, and % of severe covid- patients ( ) . the same study also reported elevated levels of alanine aminotransferase (alt) in % of mild/moderate covid- patients and % of severe covid- patients ( ) . consequently, it has been proposed that liver damage associated with severe covid- patients is due to dysregulated innate immunity against sars-cov- , or hepatoxicity in response to treatments, rather than pre-existing liver disease. chronic kidney disease is associated with an increased risk of pneumonia, and elevated mortality from infectious diseases has been reported in patients with end stage renal disease ( ) . in an extensive meta-analysis, chronic kidney disease accounted for . % of comorbidities in covid- patients ( ). while the prevalence of chronic kidney disease among covid- patients is low, those with pre-existing kidney disease have been associated with severe disease and increased mortalities ( ) . ace expression in the kidney is elevated in chronic kidney disease ( ) . however, elevated ace expression in the kidney does not appear to correlate with increased susceptibility to sars-cov- in the same way as it does in the heart. nonetheless, chronic kidney disease is associated with persistent, low-grade inflammation which could exacerbate covid- symptoms. several factors contribute to this inflammation such as elevated cytokines including il- and crp, oxidative stress and impaired metabolism ( ) . therefore, the underlying pathogenesis of chronic kidney disease may increase vulnerability to hyperinflammation and cytokine storm upon sars-cov- infection, resulting in severe covid- . autoimmune diseases are conditions characterized by inappropriate immune activation and destruction of healthy cells. lymphopenia is common among autoimmune diseases such as type diabetes, rheumatoid arthritis and systemic erythematosus lupus ( ) , and since lymphopenia is regarded as a major risk factor for developing severe covid- , individuals living with an autoimmune condition may be perceived as high risk. however, unlike other comorbidities mentioned above, autoimmune diseases have not been reported as a risk factor in the current meta-analyses. one possible explanation could be that autoimmune diseases are often treated with drugs designed to restrict immune activation, many of which are now being repurposed for covid- and will be discussed below. furthermore, potential alterations in patient behaviors in order to shield themselves from infection could influence reporting of autoimmunity as a risk factor. as the pandemic continues to accelerate globally, so does the race to develop an effective therapy to protect against and treat covid- (figure ) . however, robust efficacy and safety assessments are needed, particularly with regards to their use in comorbid patients, as reviewed below. the sars-cov- genome and spike protein structure was discovered very rapidly ( ) , enabling focussed development of both rna-and protein-based vaccines. however, vaccine development is a challenging and time-consuming process. following the sars-cov epidemic, several vaccines were developed and assessed using animal models. vaccination with live virus was shown to cause complications in mice such as lung damage ( , ) , and although recombinant spike protein based vaccines were able to protect animals from sars-cov challenge, they were ineffective at inducing sterilizing immunity ( ) . other vaccines with inactivated sars-cov and mers-cov have demonstrated reduced viral titers, reduced morbidity and greater survival in animal models ( , ) . however, the rapid eradication of sars-cov reduced demand for development. some mers-cov vaccines are currently in pre-clinical and clinical development ( ) , however as mers-cov is less closely related, it is unlikely that these will cross-protect against sars-cov- . learnings from previous coronavirus outbreaks indicate that antibody responses are not particularly long-lived, with sars-cov antibodies lasting on average just years ( ) . this apparent lack of long-term protection exacerbates the need for an effective vaccine or vaccine programme to protect against potential recurrent seasonal sars-cov- infections. on the th july , the who reported candidate sars-cov- vaccines under development worldwide ( ) . some of the most promising include an mrna vaccine; mrna- ( ), a dna plasmid vaccine ( ) , and an adenovirus vaccine; chadox ncov- ( ) . although clinical evaluation is underway, outcomes are not available yet. furthermore, frontiers in immunology | www.frontiersin.org vaccine efficacy depends upon an individual's ability to mount a strong immune response against it. consequently, vaccine regimens that grant protection in healthy individuals may not be adequate for older individuals and those with comorbid conditions who have increased immunosenescence ( ) . for influenza, the use of adjuvant ( ) and high dose vaccines ( , ) have been developed and implemented to increase vaccine immunogenicity for older and high-risk comorbid adults. therefore, similar measures are likely to be needed to fine tune a sars-cov- vaccine once it becomes available. in the interim, rolling out a sars-cov- vaccine with proven efficacy in healthy individuals could result in herd immunity, preventing transmission to those more vulnerable and offer indirect protection. another therapeutic approach intended to prevent covid- is convalescent plasma therapy. previous use during the sars ( ) and mers ( ) epidemics, and h n pandemic ( ), demonstrated reasonable efficacy and safety. evidence from those outbreaks revealed that convalescent plasma contained neutralizing antibodies ( ) , and a meta-analysis from sars-cov and influenza studies, reported a significant reduction in mortality following convalescent plasma therapy ( ) . several convalescent plasma studies for sars-cov- have been reported. in china, a small pilot study was conducted to test convalescent plasma collected from recently recovered patients on severe covid- patients, four of which had underlying conditions including hypertension and cardiovascular disease ( ) . from the patients, had high neutralizing antibody titers of ≥ : . no serious adverse events were reported following transfusion, and all patients experienced improved symptoms within to days post-transfusion. however, there are many caveats to this study, the very small sample size and the use of concomitant treatments mean it is not possible to ascertain if clinical improvements were due to convalescent plasma. consequently, additional large scale, controlled, randomized trials are needed and are currently underway. despite no adverse events being reported in the small sample sizes currently being tested for covid- , plasma transfusions are not without risk. as with any transfusion, there is a risk of transfusion transmitted infections, albeit small ( ) . perhaps of more concern are the non-infectious risks such as allergic reactions, transfusion related acute lung injury characterized by acute hypoxemia and pulmonary oedema, and transfusion associated circulatory overload, characterized by hypertension, tachycardia, tachypnoea and dyspnea ( ). these are of particular concern for severe covid- patients with extensive lung damage, and for those with pre-existing hypertension, cardiovascular disease or renal failure ( , ). due to the increased prevalence of comorbidities among covid- patients, those predisposed to transfusion-related adverse events will need to be carefully evaluated. as transfusion volume and rate have both been identified as risk factors for transfusion associated circulatory overload ( ) , covid- trials should examine these parameters to ensure safety in comorbid patients. while many scientists attempt to develop novel therapies to prevent covid- , others are focusing their attention on repurposing drugs that are already on the market (figure ) . at present, the most contested repurposed drug is chloroquine and its analog hydroxychloroquine. following the sars-cov epidemic, researchers found that in vitro treatment of chloroquine could increase endosomal ph and impair terminal glycosylation of ace receptors on the cell surface, therefore inhibiting sars-cov-ace interactions and preventing virus entry ( , ) . similarly, after the mers-cov epidemic, researchers demonstrated that chloroquine could inhibit in vitro replication of mers-cov in well-established cell lines ( ) and primary mature antigen presenting cells ( ) . however, as sars-cov and mers-cov resolved relatively quickly, continued assessment of chloroquine remained limited. furthermore, although in vitro treatment can inhibit sars-cov- ( ), the use of chloroquine and hydroxychloroquine for covid- in the clinic is highly controversial. a series of early clinical trials conducted in china reported apparent efficacy of chloroquine phosphate in treating covid- ( ) . this was followed by a small, non-randomized study of just patients from france, which demonstrated a clinical benefit from the use of hydroxychloroquine, but lacked an appropriate control group and a long-term follow-up ( ) . however, an observational study of , patients treated with hydroxychloroquine report no sign of efficacy for covid- ( ) . this was further confirmed by results from the large randomized evaluation of covid- therapy (recovery) trial that examined , hospitalized covid- patients treated with hydroxychloroquine and reported no significant difference in mortality when compared to , standard of care patients ( , ) . lopinavir is a protease inhibitor often formulated with lowdose ritonavir and traditionally used to treat hiv patients ( ) . lopinavir/ritonavir was previously assessed in a small, nonrandomized study conducted in hong kong during the sars-cov epidemic. this study demonstrated that lopinavir/ritonavir treatment resulted in reduced viral load and milder disease, with less recurrence of fever, diarrhea, and improved chest radiographs when compared with those treated with ribavirin, an alternative antiviral ( ) . during the current outbreak, two independent case studies of covid- patients hospitalized in south korea, reported a reduction in viral load and subsequent recovery of patients following the administration of lopinavir/ritonavir ( , ) . however, a randomized control study in china of severe covid- patients demonstrated no difference in mortality, or in the amount of viral rna detected ( ) . furthermore, recent findings from the recovery trial comparing , patients randomized to lopinavir/ritonavir to , standard of care patients concluded no clinical benefit from the use of lopinavir/ritonavir ( , ) . moreover, protease inhibitors such as lopinavir/ritonavir have been associated with hepatotoxicity during hiv treatment ( , ) , and drugto-drug interaction (ddi) with certain statins, for example rosuvastatin, can increase the risk of myopathy ( , ) . therefore, administration to covid- patients with preexisting liver disease and those being treated with statins could prove detrimental. like other members of the protease inhibitor class, lopinavir/ritonavir has also been associated with metabolic changes that can result in hyperglycaemia ( ) , hyperlipidaemia ( ) , and insulin resistance ( ) . due to the lack of efficacy and increased risk of toxicity to certain covid- patients lopinavir/ritonavir could be prove more harmful to patients and should therefore be avoided. oseltamivir and favipiravir, two antiviral treatments traditionally used to treat influenza, have also been examined for use in covid- . oseltamivir is a neuraminidase inhibitor, which has been extensively used as a prophylactic against influenza. in a small, single-center study of patients with sars-cov- pneumonia in china, . % of patients received oseltamivir alongside anti-bacterial drugs such as moxifloxacin, ceftriaxone, azithromycin, and glucocorticoid therapy ( ) . the study concluded no effective outcomes based on oseltamivir ( ) . however, the small study size, lack of appropriate control and the fact that many patients remained hospitalized at the time of publications limits full interpretations. favipiravir is an antiviral with potent inhibitory activity against viral rna-dependent rna polymerase. experimentally, favipiravir demonstrated effective sars-cov- inhibition in vero e cells ( ) . furthermore, a small, open-label, non-randomized comparative study of patients in china, compared clinical outcomes of patients treated with favipiravir and lopinavir/ritonavir ( ) . the median time until viral clearance was days with favipiravir compared to days with lopinavir/ritonavir. at day , ct scans of the chest from patients treated with favipiravir demonstrated significant improvements. adverse events occurred in % of favipiravir treated patients compared to % of lopinavir/ritonavir treated patients ( ) . however, despite initial promise more robust clinical data is needed in order to establish the efficacy and safety of favipiravir as a treatment of covid- . another antiviral agent being examined for use in covid- is remdesivir. when metabolized into its active form, remdesivir inhibits viral rna polymerases, causing a decrease in viral rna production. remdesivir has been shown to inhibit sars-cov and mers-cov in human airway epithelial in vitro models ( , ) , and in combination with interferon beta, remdesivir has been shown to be superior to lopinavir/ritonavir in a mers-cov mouse model ( ) . despite some initial controversial findings ( ) , results from more robust clinical trials have demonstrated reasonable efficacy. for instance, preliminary results from the national institute of allergy and infectious diseases adaptive covid- treatment trial involving , patients, demonstrated that remdesivir accelerated recovered by % compared to placebo ( ) . furthermore, recent results from the phase simple trial investigating the use of remdesivir in patients with moderate covid- showed that patients receiving remdesivir treatment were % more likely to have improved clinically by day than standard of care patients ( , ). due to the success of these two trials, the use of remdesivir has been approved by the fda, ema, uk, and japan as a treatment for covid- . despite proven efficacy, adverse events in response to remdesivir have been reported in % of patients of which % were severe ( ) . these included septic shock, multiple organ dysfunction syndrome, acute kidney injury and hypotension. therefore, the use of remdesivir in comorbid patients with increased susceptible to these adverse events requires further evaluation. as severe covid- cases are characterized by hyperinflammation, the use of immune modulating and anti-inflammatory treatments to prevent severe lung injury and disease progression are being explored. due to their immunomodulatory properties, mscs are being clinically assessed to treat inflammatory conditions such as systemic lupus erythematosus ( ) and graft vs. host disease following allogeneic haemopoietic stem-cell transplantation ( ) . consequently, a pilot study was initiated to investigate the potential therapeutic benefit of mscs for covid- infected patients in china. the study involved just covid- patients who were monitored for days post-msc injection ( ) . msc treatment was well-tolerated and no adverse events occurred during treatment. furthermore, virtually all clinical symptoms subsided, with patients being discharged days post-msc injection ( ) . mass cytometry of pbmcs revealed that peripheral lymphocytes, regulatory cd + cd c + cd b mid dcs and il- increased. whereas, crp, tnf-α and overactivated cxcr + cd + /cd + /nk cells decreased to days following injection compared to placebo group. mscs were shown to be ace negative, meaning they were immune to sars-cov- infection ( ) . although this pilot study shows promise, more robust clinical data is required to validate therapeutic benefit and safety. moreover, the use of mscs would require clinical grade msc production and may not be a plausible solution for many healthcare systems. il- is considered the key cytokine responsible for the induction of cytokine storm during sars-cov, mers-cov and sars-cov- infections ( , , ) . consequently, the recombinant humanized anti-human il- receptor monoclonal antibody tocilizumab, currently used to treat rheumatoid arthritis (ra), has been examined for use during covid- . tocilizumab first demonstrated effectiveness in a small retrospective study of patients with severe covid- pneumonia in china ( ) . oxygen intake was reduced, and improved symptoms occurred in % of patients. lymphocyte levels returned to normal in % of patients and crp levels reduced significantly in . % of patients ( ) . several case studies have also demonstrated rapid clinical improvements following tocilizumab ( ) ( ) ( ) . although these initial studies are promising, the full clinical trial data is still unavailable. furthermore, although safety profiles for tocilizumab are well-established for intermittent use in ra, the safety of tocilizumab when used in combination with antiviral agents and other comorbid therapies has not been established. other anti-inflammatory treatments now being tested clinically for their use against covid- are janus kinase (jak) and bruton's tyrosine kinase (btk) inhibitors. the jak-signal transducer and activator of transcription (jak/stat) pathway mediates the signal transduction of numerous cytokines in a number of immune cells such as t cell, nk cells, and dcs ( ) . consequently, jak inhibitors have emerged as effective treatments for many autoimmune and immunemediated disease. at present, a number of jak inhibitors such as ruxolitinib ( ), baricitinib ( ) , and fedratinib ( ), are being assessed as a potential treatment for covid- . preliminary results from a pilot study evaluating hospitalized patients, of which were treated with baricitinib, demonstrated significant reductions in serum il- , il- β, and tnf-α, as well as a rapid recovery of circulatory t and b cell frequencies following baricitinib treatment ( ) . consequently, a phase adaptive covid- treatment trial (attc- ) has now been established in order to evaluation the use of baricitinib in combination with remdesivir compared to remdesivir alone ( ) . however, despite promising initial findings, as jak inhibitors block a wide range of cytokines including ifn-α, which is crucial during early innate immunity in response to viral infections, the impact of this on viral clearance needs to be evaluated. furthermore, ruxolitinib and baricitinib have both been associated with increased weight gain, cholesterol and albumin levels ( , ) . although no causal association has been reported yet, the issue should not be dismissed and covid- patients with metabolic and cardiovascular comorbidities should be carefully considered before use. bruton's tyrosine kinase (btk) is a key regulator of cell surface receptors expressed primarily in b cells, but also in monocytes/macrophages and neutrophils ( ) . currently, btk inhibitors are used to treat various b cell malignancies and chronic graft vs. host diseases ( ) . as btk can regulate il- , tnf-α, and mcp- , btk inhibitors are being tested in combination with car-t cells ( ) , to alleviate cytokine release syndrome. furthermore, in chronic lymphocytic leukemia, btk inhibitors have been shown to increase cd + and cd + t cell, and significantly downregulate pd- and ctla- ( ) , highlighting a potential reversal of t cell exhaustion, which could be beneficial in covid- . consequently, clinical trials to assess the use of btk inhibitors against covid- are underway. the use of corticosteroids to treat covid- remained largely uncertain until recently. although individuals being treated with long term corticosteroid were instructed to continue with their medication, the use of corticosteroids specifically to treat covid- was not recommended ( ) . this was largely due to the unknown impact of immune suppression on viral clearance and potential adverse outcomes. however, preliminary data from the recovery trial evaluating , patients randomly allocated to receive dexamethasone has proven significant clinical improvements ( ) . dexamethasone is a steroid used to reduce inflammation in a myriad of inflammatory conditions and now reported to reduce covid- related deaths among patients receiving respiratory support by one-third ( ) . in response to these findings the demand for dexamethasone to treat the most critical covid- patients has surged globally ( ) . whilst these findings are exciting, safety data detailing potential adverse events and the impact of co-medications, such as nonsteroidal anti-inflammatory drugs, has not yet been reported and thus dexamethasone should still be considered carefully prior to administration. patients with pre-existing comorbidities are at a greater risk of dying from covid- . however, not all comorbidities confer the same risk. by exploring the underlying disease etiologies and common therapies used to treat these conditions, we have discussed their impact on covid- . comorbidities closely associated with age, chronic inflammation and dysregulated metabolism such as hypertension, cardiovascular disease, and diabetes are the most prevalent comorbidities. however, many of these comorbidities are strongly associated with each other. consequently, many patients will have multiple comorbidities and therefore while we have discussed these individually, the reality is that a combination of factors will be at play. furthermore, as multiple drug use is inevitable for patients with pre-existing comorbidities, the impact of overlaying 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madhav title: covid- , modern pandemic: a systematic review from front-line health care providers’ perspective date: - - journal: j clin med res doi: . /jocmr sha: doc_id: cord_uid: y a g km coronavirus disease (covid- ) caused infection in , cases worldwide in about countries and killed more than , people around the world as of march , , as per the world health organization (who). compared to severe acute respiratory syndrome and middle east respiratory syndrome, there is the rapid transmission, long incubation period, and disease containment is becoming extremely difficult. the main aim of this systematic review is to provide a comprehensive clinical summary of all the available data from high-quality research articles relevant to the epidemiology, demographics, trends in hospitalization and outcomes, clinical signs and symptoms, diagnostic methods and treatment methods of covid- , thus increasing awareness in health care providers. we also discussed various preventive measures to combat covid- effectively. a systematic and protocol-driven approach is needed to contain this disease, which was declared as a global pandemic on march , , by the who. coronavirus disease (covid- ) infection, which is a global pandemic declared on march , , by world health organization (who), was reported to have infected , cases worldwide in about countries and territories and killed more than , people around the world as of march , [ ]. there is a rapid transmission, long incubation period, and the containment of the disease is extremely difficult compared to prior epidemics of severe acute respiratory syndrome (sars) and middle east respiratory syndrome (mers) [ ] . there is a paucity of literature on this pandemic as it is novel. we aimed to provide a concise clinical summary of all the quality data relevant to the epidemiology, trends in hospitalization and outcomes, clinical signs and symptoms, diagnostic and treatment methods of covid- , thus increasing awareness in health care providers at the front-line. we also discussed various preventive measures to combat and contain covid- effectively. we conducted a systematic search of published articles from pubmed, google scholar databases and in-press literature from google search engine through snowballing. there were two independent reviewers, each focusing on covid- , novel coronavirus (ncov), sars and mers, and third independent reviewer to resolve any conflicting article of interest. we used the keywords as mentioned above and after stringent exclusion criteria, a total of articles, including reports from the trusted newspapers and websites. most of the articles were single case reports, multiple case studies and systematic reviews ( retrospective studies, one meta-analysis, three systematic reviews, six case series, five case reports, five newspapers, science research articles, and rest reference's from official websites). slcovzc and bat-sl-covzxc , % identity with the sars coronavirus and % identity with mers coronavirus [ , ] . according to chan et al, sars-cov- is thought to be transmitted via contaminated hands, surfaces and aerosolized droplets, and extensive human-to-human transmission is evident [ ] . according to li et al, the average incubation period is days but is highly variable and can last up to weeks [ ] . sars-cov- is thought to have originated from bats and transmitted to humans from an intermediate host, civets and dromedary camels, respectively. still, no source or intermediate host has been confirmed yet via genome sequencing and phylogenetic analysis [ ] . this hypothesis was made because previous coronavirus strains have originated from the rhinolophus affinis bat [ ] . however, xiao et al reported the isolation and characterization of a -ncov-like coronavirus from pangolins (manis javanica) [ ] . similarly, in october , a viral metagenomic study of pangolins identified severe acute respiratory syndrome-coronavirus (sars-cov)-related sequences [ , ] . according to the study by xu et al, % of people diagnosed with covid- had traveled to wuhan or nearby regions ( %), % had close contact with novel coronavirus pneumonia (ncp) patients and % had no definite exposure [ ] . according to the study by tian et al, . % of people diagnosed with covid- had traveled to wuhan or nearby regions [ ] . beijing is the fourth mostaffected city in china [ ] . according to xu et al, their patients with mild, common and severe covid- were of mean ages of years, years and years, respectively [ ] . the age distribution of cov-id- diagnosed patients in the study by tian et al included ages < ( %), - ( %), - ( %), - ( %) and > ( %) [ ] . liu et al described covid- in children. they analyzed a total of hospitalized patients, and % (six patients) of them were positive for covid- . according to huang et al and chen et al, sars-cov- seems to have a predilection for the elderly male population and patients with comorbidities [ , ] . according to the study published in osong public health and research perspectives, % of the population were greater than years of age, and % were less than years of age [ ] . these findings are summarized in figure . males are experiencing a higher rate of incidence and case fatality compared to females [ ] . in a study reported from south korea, % were females and % were males [ ] . these results for multiple studies are summarized in figure . xu et al analyzed patients with covid- confirmed cases and symptoms included fever ( %), cough ( %), expectoration ( %), fatigue ( %), headache ( %), gastrointestinal discomfort ( %), shortness of breath (sob) ( %) and muscle ache ( %) [ ] . fever is the most common symptom [ ] . in china and symptoms included fever ( %), cough ( %), fatigue ( %), sob ( %) and headache ( %) [ ] . in severe cases, sob was present in . % of the patients. tian et al reported that the median time of incubation was approximately days [ ] . the median time from onset of illness to a hospital visit and hospital visit to the defined confirmed case were . and . days, respectively [ ] . yang et al analyzed cases of rt-pcr confirmed covid- in china and symptoms included fever ( %), cough ( %), expectoration ( %) and sob ( %) [ ] . however, a significant number of patients do present with atypical symptoms [ ] , including nausea, vomiting ( - %) and diarrhea ( - %) [ , ] . chen et al analyzed patients in a retrospective single-center study in wuhan, and patients presented with fever ( %), cough ( %), sob ( %), muscle aches ( %), confusion ( %), headache ( %), sore throat ( %), rhinorrhea ( %), chest pain %, diarrhea ( %), nausea and vomiting ( %) [ ] . according to wang et al, even though fever is the most common symptom of covid- , the absence of fever in covid- cases is more frequent than in sars-cov and mers-cov infection [ ] . lillie et al presented a case where symptom onset started with fever, which then progressed to sore throat and dry cough followed by diffuse myalgia [ ] . according to the study published in osong public health and research perspectives, they analyzed the first cases reported in south korea. out of patients, % reported fever and sore throat, % cough with or without sputum, % chills, % muscle aches, % generalized weakness and % headache at the time of presentation. moreover, % developed pneumonia. the incubation period was . days [ ] . luo et al analyzed patients confirmed with covid- infection in anqing, china; of these, eight patients were asymptomatic at confirmation, one of whom did not develop any signs or symptoms during the entire -day hospitalization. this patient was a -year-old female with no comorbidities. despite her negative labs and radiological tests, her throat swabs and anal swabs were positive of virus nucleic acid for at least days, indicating that healthy carriers are very likely a possibility [ ] . hu et al [ ] described clinical characteristics in asymptomatic patients after screening among close contacts in nanjing, china. out of patients, seven patients did have a normal computed tomography (ct) and had no symptoms during their entire hospitalization. the median age of these seven patients was years younger than the rest of the patients. the median communicable period is defined as the first day of a positive nucleic acid test to the first day of the negative nucleic acid test. it can be up to days in asymptomatic patients [ ] . a case report describing the first case of canada showed that the patient had symptoms of hemoptysis on days through along with fever and non-productive cough on presentation [ ] . lillie et al presented a case where symptom onset started with fever, which then progressed to sore throat and dry cough followed by diffuse myalgia. this seems to be the most consistent pathway of symptom onset [ ] . the most common symptoms include fever ( %), cough ( %) and breathlessness ( %) [ ] . according to the chinese centers for disease control and prevention (cdc), % of infections were considered mild and only . % asymptomatic [ ] . according to huang et al, the current published data indicate a long mild incubation period followed by rapid progression of the disease with days being the median time from initial symptoms to the onset of breathlessness, days to acute respiratory distress syndrome (ards) and days to admission to the intensive care [ ] . the clinical signs and symptoms from different studies covid- is diagnosed via rt-pcr [ , , ] . multiple sources found that a normal to slightly reduced leukocyte count occurred in patients with covid- ( %) [ , ] . xu et al reported a decreased lymphocyte count in % of their patients [ ] , while yang et al reported leukopenia and lymphopenia in % and % of their patient population respectively [ ] . an elevated c-reactive protein (crp) was reported in - % of the patients [ , ] . thrombocytopenia was seen in % of patients. acute kidney injury was present likely due to dehydration, not from the virus directly [ ] . according to the meta-analysis done by lippi et al, elevated procalcitonin levels were associated with almost five-fold increased risk of severe covid- infection (odds ratio (or): . ; % confidence interval (ci): . - . ). they advised that serial measurements of procalcitonin may play a pivotal role in analyzing the worsening of the disease to more severe form [ ] . according to the case report by ruan et al, they found a patient with a negative nucleic acid test, tested twice days apart. as the patient was showing typical ct imaging patterns suspicious for covid- and deterioration of symptoms, repeat testing on day was positive. as exact biological characteristics of covid- are still not defined well, multiple sampling from multi-sites for the highly suspected population can be useful for covid- detection at a much earlier stage [ ] . specimens should be tested for routine bacterial and viral infections, as well as using both upper and lower respiratory tract samples to test for sars-cov- [ ] . serological tests are in development, and they can be used if rt-pcr is not available [ ] . as per the case reported by chen et al, the oropharyngeal swab test of covid- rna turned positive even during the convalescence period in a confirmed case; it emphasizes the significance of active surveillance of covid- rna for inactivity assessment [ ] . the laboratory results from different studies are summa-rized in figure . according to zhang et al, in a month, out of , suspected patients suspected of coronavirus pneumonia, patients ( %) had typical imaging findings or positive nucleic acid tests [ ] . chest ct is an important tool for diagnostic for lung diseases. combining imaging with clinical and laboratory findings could facilitate early diagnosis of covid- pneumonia. because the time of onset of symptoms to ards can be as short as days, early recognition of the disease is therefore essential for management. in a retrospective study done in wuhan on patients from december , to january , , they were able to describe the characteristics of the chest ct at specified time points during the disease course. they have divided the patients into four different groups, as shown in table [ ] . based on the review, covid- pneumonia is described radiographically as bilateral, subpleural ground-glass opacities with air bronchograms, ill-defined margins and slight predominance on the right lower lobe. it was also noted that the radiological evolution of covid- pneumonia is consistent with the clinical course of the disease. therefore, serial ct could help monitor disease progression. the study also pointed out that patients with old age, male and with underlying comorbidities as well as progressive radiographic deterioration on follow-up are the risks for poor prognosis [ ] . according to chen et al, the majority ( %) of patients had bilateral pneumonic changes on ct imaging [ ] . guan et al reported out of , ( %) cases [ ] , and chung et al reported three out of ( %) have normal ct scans for patients diagnosed with symptoms along with confirmation of infection with rt-pcr [ ] . according to a single-center study done by chen et al in patients, % of patients showed bilateral pneumonia, ards developed in % and % of them died with multi-organ failure [ ] . as per the review of literature, the ct scans of the chest showed lesions or abnormalities more commonly found in bilateral lower lobes with the right middle lobe least affected. multilobar involvement was seen in - % of the patients [ , , ] . the lesions are mostly located in the peripheral area under the pleura with possible extension into the pulmonary hilum ( % in the periphery and % in the center of the lung) [ , , ] . these lesions sometimes were accompanied by air bronchograms but rarely pleural effusions [ , ] . regarding lobar involvement, right lower lobe is most commonly involved in approximately % of cases followed by left lower lobe ( %), left upper lobe ( %) and right upper lobe ( %) [ ] . pneumothorax, as well as bilateral pleural effusions, was identified only in % of the patients [ , ] . approximately % of the patient had normal ct findings. ct findings based on the stage of the disease are as follows [ ] : ) mild novel coronavirus pneumonia patients have no abnormalities seen on a ct scan. ) the early-stage infection which is more common has ground-glass opacities identified in the periphery and about % of the patients, mixed groundglass opacity along with consolidation in approximately % of the patients, nonuniform density with air bronchograms in about % and thickened interlobular/intralobular septa in % of the patients. ) patients who are severe or critically ill have multiple patches of ground-glass opacities as well as consolidation in approximately % of the patients and mixed findings in about % of the patients in bilateral lungs. almost all patients have thickened interlobular septa. the patients generally have multilobar involvement bilaterally more commonly in lower and upper lobes. approximately - days after infection, most lesions were absorbed with a reduced extent and decreased density with the formation of fibrotic stripes. lesions can also become worse starting with ground-glass opacities and areas of consolidation in the center of opacities on day progressing to multiple lungs on day with thickened interlobular septa by day . the lesions can get worse before getting better. ct scan of the chest shows the greatest severity approximately - days after the onset of initial symptoms [ ] . the bilateral patchy shadows or ground-glass opacities from various studies are summarized in figure . patients infected with covid- and had multiple medical comorbidities were reported to have higher morbidity and mortality. as per the analysis by wang et al involving cases of covid- , approximately % of them have comorbidities, and more importantly, patients admitted to the intensive care unit had a higher number of comorbidities ( %) compared to who did not ( %) [ ] . as per the meta-analysis of yang et al involving , covid- infected patients, the most prevalent comorbidity was hypertension with a range of - %, diabetes mellitus with a range of - %, cardiovascular diseases with a range of % and respiratory diseases around %. as per the final analysis, underlying hypertension, cardiovascular disease and respiratory system disease might be risk factors in patients with severe infection compared to patients with known severe infection [ ] . other studies discussing about comorbidities are summarized in table . in a case study with patients performed by chen et al, % of diagnosed patients developed ards, % required non-invasive respiratory support, % needed invasive ventilation and % needed extracorporeal membrane oxygenation (ecmo) [ ] . in a review by tian et al, approximately % of patients died from covid- out of patients, all of whom had respiratory failure and were above the age of [ ] . yang et al described that . % of , in the hubei province in china died from coronavirus vs. % of patients diagnosed in wenzhou city up until february , [ ] . these numbers show that there is a regional difference in mortality of covid- as the wenzhou province has more resources than the former. yang et al estimated the overall adjusted case fatality rate (cfr) among confirmed patients to be % with a sample size of , [ ] . the course of hospitalization, morbidity and mortality are summarized in figure . tients who are elderly with several comorbidities. mulbsta score is an early warning model for predicting morbidity in viral pneumonia in days as summarized in table . it has a sensitivity of . % and specificity of . %. it has better predictive ability than curb- (confusion, blood urea nitrogen, respiratory rate, blood pressure and age greater than years) [ ] . xu et al performed high-resolution ct scan on patients admitted with sars-cov- . it was classified into four types, as summarized in an outbreak of a novel coronavirus (covid- or -cov) infection causes significant morbidity and mortality. coronavirus-specific treatments and antiviral treatments were very useful for the treatment of sars and mers and should be considered as potential treatments for covid- [ ] . there is an emergent need for other treatment options and a review of the literature for alternate treatment to control the disease mentioned below. multiple vitamin supplements and antioxidants can be considered to reduce the risk of infection. vitamins a, b, thymosin alpha- , thymopentin can be promising options for the adjunctive treatment of coronavirus and the prevention of lung infection [ ] . vitamin c supplementation might decrease the susceptibility to respiratory infections, as three human controlled clinical trials showed a lower incidence of pneumonia in supplemented groups [ ] . decreased vitamin d and e in calves had been reported to cause the infection of bovine coronavirus [ ] . it could be another therapeutic option for this virus. selenium with ginseng stem-leaf saponins could induce an immune response to a live bivalent infectious bronchitis coronavirus vaccine in chickens. selenium supplementation could be a possible choice for the treatment [ ] . zinc and pyrithione combination at low concentrations can inhibit the replication of sars coronavirus (sars-cov) [ ] . type i ifns, including ifn-b, could inhibit the replication of sars-cov and can be potent inhibitors of mers-cov replication in vitro. still, no in vivo experiments have been performed [ ] . ifn treatment was used in % of patients [ ] . ifn-α vapor inhalation was administered at a dose of million units for adults, two times/day for no longer days [ ] . glycyrrhizin, baicalin and ginseng are all chinese medicinal treatments that can help enhance host immunity against cov-id- infection. they have been found to inhibit sars-cov in vitro [ ] . covid s-protein uses ace- as a sole receptor for entry into human cells. monoclonal antibody neutralizes sars-cov and inhibits syncytia formation between cells expressing the s-protein and ace- receptor [ ] . chloroquine is a potent sars-cov inhibitor through interfacing with ace- [ ] . chloroquine is a potent sars-cov inhibitor through interfacing with ace- [ ] . gao et al described chloroquine as a cheap and safe drug available for more than years, which has been shown to have apparent efficacy and decent safety against pneumonia associated with covid- in multicenter trials performed in china. as per the review of results from hospitals and more than patients, they showed that chloroquine phosphate is superior to control in decreasing the exacerbation of covid- pneumonia. the anti-inflammatory and antiviral property of chloroquine may be responsible for its potent efficacy against covid- pneumonia [ ] . chloroquine phosphate is orally administered at a dose of mg for adults, two times/day. chloroquine was found to block sars-cov- infection at low micromolar concentration, with a half-maximal effective concentration (ec ) of . µm and a half-cytotoxic concentration (cc ) greater than µm [ ] . emodin or promazine blocks interaction between s-protein and ace- , therefore, it could abolish sars-cov infection by being a competitive inhibitor [ ] . nation has shown to synergistically inhibit the replication of sars-cov in animal and human cell lines [ ] . kim et al have reported a case of mers-cov successfully treated with triple combination therapy with lopinavir/ritonavir, ribavirin and ifn-alpha a therapy in south korea [ ] . remdesivir has been reported to inhibit human and zoonotic coronavirus in vitro and restrains sars-cov in vivo [ ] . remdesivir + ifn-b was found to be superior to lopinavir/ritonavir + ifn-b therapy against mers-cov in vitro and in vivo. yamamoto et al have found that nelfinavir could strongly inhibit the replication of sars-cov [ ] . akerstrom et al have reported that organic nitric oxide could significantly inhibit the replication cycle of sars-cov in a concentration-dependent manner and could be taken via inhalation [ ] . favipiravir is a drug currently undergoing testing to combat covid- . it was approved for the treatment of novel influenza in china. favipiravir is an rna-dependent rna polymerase (rdrp) inhibitor. it inhibits the replication of rna viruses like noro, arena, flavi, alpha, bunya, filo groups. therefore, favipiravir may have potential antiviral action on sars-cov- , which is an rna virus. a clinical trial involving patients has shown that favipiravir had more potent antiviral action than that of lopinavir/ritonavir. it had significantly fewer adverse events than the lopinavir/ritonavir group [ ] . remdesivir is a drug currently undergoing testing to combat covid- . remdesivir is a nucleoside analog and a broad-spectrum antiviral [ , ] . animal experiments indicated that remdesivir could effectively reduce the viral load in lung tissue of mice infected with mers-cov, improve lung function and alleviate pathological damage to lung tissue [ ] . wang et al found that remdesivir potently blocks sars-cov- infection at low-micromolar concentrations and has a high selectivity index (ec : . µm; cc > µm; si > . ) and had in vitro activity against sars-cov- [ ] . holshue et al reported that remdesivir yielded promising results in the treatment of a patient with covid- in the united states. a recent randomized controlled trial (rct) is being performed [ ] . it may also be possible to enhance the protective host immune response to infection [ ] . darunavir is a second-generation hiv- protease inhibitor. on february , , researchers in china announced that darunavir inhibited sars-cov- infection in vitro [ ] . sars-cov- uses the cellular protease tmprss receptor, sars-cov receptor and ace- for entry into target cells as mentioned by hoffmann et al. a tmprss inhibitor would block entry and thus constitute a treatment option [ ] . imatinib has anti-coronal activity primarily because it inhibits the fusion of virions with the endosomal membrane [ ] . arbidol is orally administered at a dose of mg three times a day in adults and able to inhibit sars-cov- infection in vitro in a clinical study. lopinavir/ritonavir is administered mg/ mg for adults, two times a day for no longer than days. stockman et al reported to inhibit sars-cov reproduction in vitro [ , ] . ribavirin is administered intravenously at a dose of mg for adults, to times daily, in combination with ifn-α or lopinavir/ritonavir. chu et al suggested that patients treated with the combined therapy had a lower risk of ards and death in patients with sars [ ] . steroids increase viral shedding in patients with mers-cov, so who advised against their use in covid- other than patients with ards [ ] . according to current who guidelines, they do not recommend corticosteroid use as it did not reduce mortality and potentially delayed viral clearance [ ] . patients who have respiratory tract infections can have coexisting gut dysfunction. with more severe infections, there is a lung-gut cross-connection. this mechanism might also happen with covid- infection, hence identifying and targeting gastrointestinal microbes can be a new treatment option or at least adjuvant treatment choice [ ] . it has profound antiviral activity, and there have been previous reports on its inhibitory effect on both sars-cov and previous strains of coronaviruses. it can inhibit -ncovr at a low concentration. compared to regular infections without drug treatment, the viral rna yields were significantly lower in vitro when using cep; thus, our data suggest that cep can potently inhibit coronavirus infection at viral entry and postentry phases [ ] . cep has low toxicity in animals and has no significant side effects in humans [ ] . mefloquine is an antimalarial drug found to have antiviral activity against both mers-cov and sars-cov in vitro [ ] . no in vivo trials have been performed. selamectin is a topical broad-spectrum anti-parasitic in cats and dogs to control fleas, heartworms, hookworms, roundworms, etc. the antiviral mechanism is unknown, but selamectin could be a -ncovr specific inhibitor [ ] . no in vivo trials have been performed. mechanism of action of cep, mefloquine and selamectin is unknown. all possible therapeutic options are summarized in table . the primary mode of transmission is via respiratory droplets with the most significant risks of transmission within feet but up to feet [ ] . portable radiography should be used to limit covid- , modern pandemic j clin med res. ; ( ): - patient transportation [ ] . hospital care workers are recommended to wear full isolation gown with n mask or higher, disposable gloves, eye protection with goggles, with a face mask in front of goggles when caring for patients [ ] . surfaces of ct, mri machines, ultrasound probes, blood pressure cuffs and mouse/keyboards of radiologic equipment should be disinfected with soap or alcoholic-based disinfectant [ ] . zhang et al stated that viral nucleic acid was found in stool samples from the patients who are suffering from covid- pneumonia. so fecal-oral transmission is also possible. hence, more consideration is given to hand hygiene, disinfection of contaminated surfaces as well as patient's stools and vomitus [ ] . close contact tracing and longitudinal surveillance through serial nucleic acid tests are essential in combating disease as asymptomatic carriers play a significant role in spreading the disease [ ] . effective management and treatment play a very crucial role, starting from identifying appropriate treatment and curing patients. covid- imposes a significant public health concern as it became "once in a century pandemic" [ ] due to its severe contagious transmission. effectively identifying and treating one patient can help in preventing the development of several patients in the community. an action plan needs to be implemented in every organization to combat the disease at an early stage. patients should be offered to wear a nasal mask irrespective of symptoms when they visit the hospital. it is essential to take travel history for every individual regardless of whether they are having symptoms suspicious for covid- either to a different state or a different country. the second question is if they have any symptoms of cough either dry or with expectoration, increasing shortness of breath, con- gestion, fever, chest pain, headaches, generalized body aches and pains. the third question is contact with a patient with a confirmed coronavirus infection. drills and emergency preparedness about covid- should be performed in all health care facilities involving providers who will be in touch with covid- suspected patients. as escalating infection control in a health care setting can effectively prevent health care providers in contracting virus. according to cheng et al, , a bundled approach involving active and enhanced laboratory surveillance, early airborne isolation, contact tracing with unprotected exposure, rapid testing completely prevented nosocomial transmission of covid- [ ] . if the patient responds yes to the above questions, health care personal entering the room should be appropriately wearing personal protective equipment to encounter a patient suspected covid- . it is crucial as the disease spread among healthcare providers will result in the rapid spread of the virus, thus increasing the morbidity and mortality. once the patient is identified as a suspect of covid- with presenting symptoms of fever, cough, congestion, chest pain, nausea and generalized body aches, they should be placed in a negative pressure isolation unit. the emergency room physician should order basic labs, including complete blood count (cbc), including a differential (cbc), complete metabolic panel (cmp), respiratory viral panel and a portable chest x-ray to rule out other etiologies. if other etiologies are ruled out and the patient is suspected of having covid- , the local health department should be notified, and pcr testing is recommended. the patient should be transported to a negative pressure isolation room in the hospital. all isolation rooms should have negative air pressure and specially filtered air, containing and eliminating the circulation of the virus in the air. all staff should be well educated on the use of cleaning supplies and appropriate cleaning methods. all team members involved in patient care should receive regular education on the use of personal protective equipment. we should continuously monitor the united states centers for disease control and prevention (cdc) guidelines and adopt best practices as sooner they become available if possible health care professionals should be able to use a robotic mode of delivering medication and checking vitals to prevent the spread of the disease. this method helped in containing the disease in patients treated at china, in washington dc. an emergency covid- response team should be prepared in every hospital comprising of a hospitalist, infectious disease specialist and pulmonary/critical care physician to help with managing patients daily. all the essential up-to-date changes in treatment and management should be delivered to all the health care professionals daily in that hospital and to the community to help in treating other patients. the mode of transmission is when a patient with covid- coughs or exhales, they release droplets of fluid, which is infected, and most of these droplets fall nearby objects such as telephones tables and desks as well as other equipment. the public can catch the disease by touching these contaminated objects, and later touching the nose eyes or mouth. notably, this is called transmission through fomites [ ] . patients can catch it by breathing in droplets if they are standing within m of covid- patients. they should be visited restrictions at all facilities encouraging people to visit patients by a telephone or electronically. we should also encourage people coming to the health care facilities for testing/treatment to limit the number of people who accompanied them. since the virus causes significant mortality in older adults with significant comorbidities, they should be more restrictions placed on nursing homes such as no visitor policies in a high-risk environment. we should encourage social distancing, which means avoiding crowds and staying feet away from other people as much as possible. we should also cancel or postpone all nonessential community events. all travel should be avoided unless absolutely necessary particularly to highly endemic zones of covid- . according to wang et al, those having had close contacts with infections are currently being asked to receive medical observation and quarantine for days [ ] . influenza and covid- differ by multiple means. the first, only % of reported cases are asymptomatic and most patients develop symptoms within days from covid- . with influenza, people who are infected might not get sick be due to herd immunity developed over the years [ ] . the second difference is that covid- causes more severe illness than influenza as it is a new virus and community have not developed any immunity, which makes more people susceptible to severe infection [ ] . globally, covid- mortality is . % compared to influenza with mortality of less than % [ ] . third, no vaccines are there for covid- at present, unlike seasonal flu which has a vaccine. currently, more than vaccines are in the clinical trial stage. fourth, contact tracing and containment will possibly help for covid- compared to influenza [ ] . these are the reasons why who recommends "everything we can do to contain the virus" suggests a comprehensive approach to treat covid- . screening should start in the outpatient setting with patients who should undergo infrared temperature detection before en- [ ] . contact tracing and testing all the suspected contacts at an early level and isolating them in isolation wards will help in halting disease at the early stages. identifying and treating the entire community plays a pivotal role than detecting and single patients in this epidemic. testing and identifying individuals even if they have an uncomplicated upper respiratory tract should be advised [ ] . medical professionals treating these patients should take the following precautions including: ) wearing disposable work caps; ) wearing protective glasses or face masks (antifog type); ) wearing medical protective masks (n ); ) wearing protective clothing or isolation clothing; ) wearing disposable latex gloves (double layered); ) wearing disposable shoe covers; and ) strictly implementing good hand hygiene. in everyday clinical practice, the most common phrase heard is covid- , also called as novel coronavirus. as of march , , a total of , confirmed cases in countries were reported. among , more than , deaths of covid- have been reported to who outside of china, and it exceeded china's death rate [ ]. while cases from china have been decreasing according to the recent available data, the reported cases from outside of china have been increasing at an alarming rate. the number of cases reported were nine times more in the rest of the world compared to china since january , [ ] . reviewing the history of the disease, as of december , a total of cases of pneumonia of unknown origin have been confirmed in the city of wuhan. most of them visited local fish and wild animal market within days of infection in wuhan, hubei province, china [ ] . it was first identified and announced as a new coronavirus ( ncov) by a scientific team lead by dr. jianguo xu, an academician of the chinese academy of engineering [ ] . in human coronaviruses, there is a spectrum of the viruses, which can cause infections ranging from the common cold to fatal diseases including, sars and mers, which are zoonotic. the unique pathogenesis of covid- compared to sars and mers is, it mainly affects the lower respiratory tract as well as the involvement of the gastrointestinal system causing diarrhea, compared to few patients with mers and sars having diarrhea [ ] . it was estimated that covid- has a reproductive rate ranging from . ( % ci: . - . ) to . ( % ci: . - . ), which is correlated to eight-fold to two-fold rise in reporting rate [ ] . imai et al provided the first estimation of the reproduction factor, using r of . and based on the number of cases in china and those detected in other countries [ ] . other authors estimated r to be . , . , . and . [ ] . according to wang et al, the model used to calculate r was assumed of the model from wuhan, china, as summarized in table . the model used to calculate r assumed that there were no new transmissions from animals, no differences in individual immunity, the time-scale of the epidemic is much faster than specific times for demographic processes (natural birth and death), and there are no differences in natural births and deaths [ ] . assuming the epidemic continues to develop with r = . , . and . from december , , the number of infections will continue to rise. by the end of february , covid- cases would be , , , and , in wuhan, china with r = . , . and . , respectively [ ] . according to read's research, r for covid- outbreak is much higher compared with other emergent coronaviruses [ ] . we see a decreased trend in r t as discussed in table with effective implementation of public health measures to control the spread of the disease. after reviewing cases from hubei province, severe cov-id- cases occur mostly in men, and many of them do have comorbid conditions, including cerebrovascular, cardiovascular and diabetes. several sequelae were seen including, coagulation activation, cellular immune deficiency, hepatic and kidney injury, secondary bacterial infection and myocardial injury. lymphopenia and sustained inflammation seen in patients with severe disease and death are most likely secondary to antibody-dependent enhancement (ade) of covid- due to previous exposure to other coronaviruses [ ] . especially this kind of pattern is also seen in patients who had sars during an epidemic in [ ] . covid- is a significant clinical threat to the general popula- phase an early phase of the epidemic when few prevention and control measures were implemented. r was . . phase public transportation to and from wuhan, as well as public transportation within wuhan, were stopped. while gathering events inside wuhan was banned, quarantine and isolation were gradually established in wuhan. r t was . . phase new infectious disease hospitals and mobile cabin hospitals came into service, and many medical and public health teams from other provinces and cities in china arrived in wuhan. the quarantine and isolation at the community level were further enhanced. r t decreased to . . phase the peak of public health restrictions in wuhan, china. r t became . . tion and health care workers worldwide. unfortunately, knowledge about the novel virus is limited, causing lots of concern and panic. to decrease morbidity and mortality associated with covid- , public health and infection control measures are urgently required to limit the global spread of the virus. all efforts should be made to slow the spread of the illness in order to provide time for health care systems and the general public to prepare and to develop timely diagnostics, therapeutics and vaccines. finally, although the improvement of internet communication enhances information dissemination, it also has the potential to spread misinformation. hence, we need to educate the public to follow information from a reliable website such as the cdc in the us. there are several unanswered questions at present in the management of covid- . even though several case studies, rcts and systemic reviews were done, there is no clarity regarding the exact pathogenesis of the disease, duration of shedding of virus and the possibility of other contaminant viral infections including influenza as well as secondary bacterial infections. the pandemics like covid- put stress on every part of society, posing significant treat to international health and the economy. several vaccines and promising treatments are being tested on clinical trials. however, the rising number of infected people, as well as mortality from it and the highly contagious nature of covid- with a prolonged incubation period and asymptomatic carriers shredding the virus, makes it challenging to contain the spread. at present, handwashing, isolating and quarantine patients who are exposed or infected with the virus, disinfecting the contaminated surfaces as well as extensive public health measures such as avoiding large group meetings, closure of schools, restricting travel are being implemented by different countries to curb the spread of this virus. hopefully, we develop an effective vaccine and treatment as soon as possible. continued clinical trials are required to understand the pathogenesis of covid- to tackle the disease better and to decrease morbidity and mortality. accessed on the sars, mers and novel coronavirus (covid- ) epidemics, the newest and biggest global health threats: what lessons have we learned? genomic characterisation and epidemiology of novel coronavirus: implications for virus origins and receptor binding coronavirus disease : coronaviruses and blood safety a familial cluster of pneumonia associated with the novel coronavirus indicating person-to-person transmission: a study of a 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cell lines combination therapy with lopinavir/ritonavir, ribavirin and interferon-balla et al alpha for middle east respiratory syndrome hiv protease inhibitor nelfinavir inhibits replication of sars-associated coronavirus nitric oxide inhibits the replication cycle of severe acute respiratory syndrome coronavirus remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus ( -ncov) in vitro first case of novel coronavirus in the united states the novel coronavirus ( -ncov) uses the sars-coronavirus receptor ace and the cellular protease tmprss for entry into target cells sars: systematic review of treatment effects role of lopinavir/ritonavir in the treatment of sars: initial virological and clinical findings covid- : a puzzle with many missing pieces repurposing of clinically approved drugs for treatment of coronavirus disease in a -novel coronavirus ( -ncov) related coronavirus model researchers at shenzhen third people's hospital. fecalto-mouth transmission risk of new coronavirus escalating infection control response to the rapidly evolving epidemiology of the coronavirus disease (covid- ) due to sars-cov- in hong kong who director-general's opening remarks at the media briefing on covid- - preliminary estimation of the basic reproduction number of novel coronavirus ( -ncov) in china, from to : a data-driven analysis in the early phase of the outbreak report : transmissibility of -ncov. reference source novel coronavirus -ncov: early estimation of epidemiological parameters and epidemic predictions i thank all the authors who contributed in carrying out research. none to declare. none to declare. mb, gpm, mp, vg and sa were involved in data collection, review and preparation of the manuscript. mb and mp created figures/bar graphs. mb, sn, nmk and vmk involved in the analysis of data and final review the manuscript, preparation of tables. all of the authors reviewed the manuscript and agreed with the findings and interpretation. pubmed, google scholar databases and in-press literature from google search. the authors declare that data supporting the findings of this study are available within the article. key: cord- - gupfqnl authors: martinez-perez, clara; alvarez-peregrina, cristina; villa-collar, cesar; sánchez-tena, miguel Ángel title: citation network analysis of the novel coronavirus disease (covid- ) date: - - journal: int j environ res public health doi: . /ijerph sha: doc_id: cord_uid: gupfqnl background: the first outbreaks of the new coronavirus disease, named covid- , occurred at the end of december . this disease spread quickly around the world, with the united states, brazil and mexico being the countries the most severely affected. this study aims to analyze the relationship between different publications and their authors through citation networks, as well as to identify the research areas and determine which publication has been the most cited. methods: the search for publications was carried out through the web of science database using terms such as “covid- ” and “sars-cov- ” for the period between january and july . the citation network explorer software was used for publication analysis. results: a total of , publications were found with , citations generated in the network, with june being the month with the largest number of publications. the most cited publication was “clinical characteristics of coronavirus disease in china” by guan et al., published in april . nine groups comprising different research areas in this field, including clinical course, psychology, treatment and epidemiology, were found using the clustering functionality. conclusions: the citation network offers an objective and comprehensive analysis of the main papers on covid- and sars-cov- . coronaviruses (coronaviridae) are a family of viruses that cause infections in humans and animals. it is a zoonotic disease, i.e., it can be transmitted from animals to humans through direct contact with infected animals or their secretions [ , ] . in , sars-cov- caused almost cases in countries and had a % mortality rate. between that year and december , no further cases were detected in humans [ ] . then, a group of pneumonia cases with an unknown origin was reported in wuhan, in the chinese province of hubei, on december [ ] . on january , the chinese authorities identified a new outbreak of the coronaviridae family after analyzing several samples from the respiratory tract, which was subsequently named sars-cov- [ , ] . on february, the general director of the who (world health organization) announced "covid- " as the name of the disease caused by sars-cov- . a month later, the who declared the pandemic status following an increase in the number of cases, which had reached , infections and more than deaths in countries [ ] . in europe, the first case was detected in france on january, and the virus then spread to nine other countries in just one month (belgium, finland, france, germany, italy, russia, spain, sweden and the united kingdom). by march, the number of positive cases in europe had increased to , [ ] . meanwhile, between january and february, positive cases were reported in the americas in the search of publications was carried out using the web of science (wos) database with the following search terms: "covid- ", "sars-cov- ", "the coronavirus disease " and "corona virus disease ". these terms were selected bearing in mind the study objective; additionally, these are the most common terms in all research fields. since the results of the search comprised some articles shared by several fields, the boolean operator not was used in the second search ("sars-cov- " not "covid- "), the third search ("the coronavirus disease " not "sars-cov- " not "covid- ") and the fourth search ("corona virus disease " not "the coronavirus disease " not "sars-cov- " not "covid- "). additionally, the search was carried out by selecting "subject" as the search field, and it was limited by abstract, title and keywords. in this way, we covered all articles that included other terms, such as " novel coronavirus", " novel coronavirus diseases" or " -ncov". the period selected was from january to july . furthermore, web of science makes it possible for users to add references to their library when conducting bibliographic searches directly in external databases or library' catalogs. with regards to the citation indexes, social sciences citation index, science citation index expanded and emerging sources citation index were used. on the other hand, given that the way in which authors and institutions cite works may vary, the citespace software was used to standardize the data. the date on which the publications were searched and downloaded was july . the publications were analyzed using the citation network explorer software, which allows the researcher to analyze and visualize citation networks of scientific publications. furthermore, it is possible to download citation networks directly from web of science and manage citation networks that include millions of publications and related citations. therefore, a citation network composed of several millions of publications can be the starting point from where a deeper analysis can be conducted to obtain a small subnetwork with publications on the same subject. a quantitative analysis of the most mentioned publications in a period was carried out using the attribute citation score. therefore, not only the internal connections within the web of science database but also any external connections were quantified, meaning that other databases were considered [ ] . citnetexplorer provides several techniques for the analysis of publication citation networks. the clustering functionality is achieved using the formula developed by van eck in (equation ( )) [ ] . then, to assign a group to each publication, the clustering functionality was applied. as a result, the most related publications are usually found in the same group based on citation networks [ ] . finally, the core publications were analyzed using the identifying core publications functionality, which consists of identifying the publications that are considered the core of a citation network; that is, they have a minimum number of connections with other core publications, so those that are irrelevant may be eliminated. the number of connections is established by the researchers, so the higher the value of this parameter, the lower the number of core publications [ ] . in this study, the publications that have four or more citations in the citation network were considered. additionally, the drilling down functionality, which allows for a deeper analysis of each of the groups at different levels, was also used. the vosviewer software (centre for science and technology studies (cwts), leiden, the netherlands) was used to create and visualize bibliometric networks (journals, researchers, individual publications, bibliographic relationships, etc.) through graphs. the first articles on covid- were published at the beginning of , so the period of time selected was from january to july . a total of , publications and , citation networks were found in the search in wos. among all the publications, . % were articles, . % were editorial material, . % were letters, . % were reviews, . % were news items and . % were edits, book reviews, retractions or meeting abstracts. figure shows the publications with greater weights and the group to which they belong. the color of an article represents its group, and the lines that connect the elements represent links. the number of publications on covid- has increased since april (january-march : . % of the publications; april-december : . % of the publications). june was the month with the largest number of publications, with publications and citation networks ( figure ). table shows the most cited publications in this citation network. the most cited article is that of guan et al. [ ] , published in april , with a citation index of . in this publication, patients were included from december (when the disease first broke out) to january . the patients were from hospitals in different regions of mainland china, out of which were excluded because they had been admitted to the icu (intensive care unit), were on invasive mechanical ventilation or had died. the most common symptoms were fever ( . % when admitted to hospital and . % during hospital stay), cough ( . %) and diarrhea ( . %). in addition, ground-glass opacity of the lung was the most common radiological finding in thorax computed tomography (ct) scans ( . %), and . % of patients presented lymphocytopenia upon admission. the average hospitalization time was days. during the first two months of the outbreak, covid- spread quickly throughout china. the disease often presented with different degrees of severity, as patients frequently showed no signs of fever or unusual radiological findings. when analyzing the most cited articles, can be found on the symptoms, viral transmission and experimental treatment methods [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . there are two that address unusual clinical symptoms and findings [ , ] , and there is one that compares how covid- affects patients with cancer and those without cancer [ ] . the research on covid- is multidisciplinary. the fields of internal medicine ( . %) and public environmental occupational health ( . %) are worth mentioning ( figure ). medicine is the main area of publication in the field of health, as it is one of the oldest research fields [ ] . similarly, public environmental occupational health has been studied for centuries. however, this research field has significantly increased in the past few years [ ] . the quartile according to the scimago journal rank (sjr) is included in the table to show the importance and relevance of the main journals that have published the most articles, a dimension selected based on its quality and the fact that its use is widespread among the international scientific community. quartiles are based on the rank of each journal within its topic and are measured by assessing the distribution of the impact factor of a given journal for that topic category. scimago journal rank is a website of scientometric and informetric values, which allow researchers to monitor the behavior and impact of their contributions on an international scale; that is, it measures the scientific influence of the journals according to the number of citations. the citations are weighted depending on their field and prestige [ ] . table shows the journals with the largest number of publications. after comparing our results with the first bibliometric publications on covid- , we could observe that the journals with the largest number of publications were as follows: journal of medical virology, which has the most publications (n = ), followed by chinese journal of tuberculosis and respiratory diseases (n = ), journal of travel medicine (n = ), journal of clinical medicine (n = ), lancet (n = ), radiology (n = ) and jama (n = ) [ ] . as shown in table , the authors with the largest number of publications on covid- were wang y ( . %), mahase e ( . %) and li y ( . %). the united states ( . %), china ( . %) and italy ( . %) were the countries with the highest publication rates (figure ) . similarly, the study by fan et al. [ ] analyzed the countries with the highest rates of publication and found that the authors with a large number of publications on covid- in english-language journals were as follows: li y had the highest number of published papers ( , . %), followed by benvenuto d, eurosurveillance editorial team and leung gm ( , . %) and angeletti s, gao gf, ran j, wei y, wu jt and yang g ( , . %). as regards chinese journals, the authors with the largest numbers of publications were as follows: wang yg and yang fw published the highest number of papers ( , . %), followed by wang yj ( , . %). similarly, the study by belli et al. [ ] analyzed the first weeks after the outbreak and found that china represented . % of the publications, followed by the us with . %. the most frequently used keywords were "covid- " ( publications), "coronavirus" ( publications) and "sars-cov- " ( publications). figure shows the most used keywords from the most relevant publications. this is consistent with the study conducted by fan et al. [ ] , in which the most common keywords in english-language publications were "sars-cov- ", "covid- ", "china", "sars", "epidemic", "adult", "psychological", "nucleic acids", "plague" and "infection". moreover, the most common keywords used in chinese journals were "covid- ", "sars-cov- ", "prevention and control", "traditional chinese medicine", "computed tomography", "epidemic", "public health", "mers", "pneumonia" and "male". by using the clustering function, each publication in the citation network is assigned to a group, which means that publications that are close in the citation network must belong to the same group. consequently, each of these groups consists of publications that are strongly connected through their citations. in this way, it could be interpreted that every group represents a different topic in the scientific literature. in order to differentiate the groups, each of them has been assigned a specific color. additionally, the links between groups have been marked using colored lines. the clustering function identified groups, of which have a significant number of articles; however, the remaining groups only account for . % ( figure ). table shows the information of the citation networks for the nine main groups, listed from the largest to the smallest according to their size. in group , publications and citations were found throughout the network. the most cited publication is that of guan et al. [ ] , published in april in the new england journal of medicine, which is also at the top of the most cited publications. in this group, the different articles analyze the viral transmission of sars-cov- , the most frequent symptoms (fever, cough, diarrhea, etc.) and experimental treatment methods such as chloroquine phosphate (figure ). for group , publications and citations were found throughout the network. the most cited publication is that of liang et al. [ ] , published in march in lancet oncology. in this paper, the authors discuss how cancer patients are more vulnerable to covid- than people without cancer. this is due to their immunosuppressive status resulting from malignant neoplasm or cancer treatments such as chemotherapy. furthermore, these patients have a worse prognosis. therefore, three control strategies were established for cancer patients during the covid- crisis: • postpone surgery and chemotherapy treatment in patients diagnosed with cancer in a stable state. • improve staff protection. increase surveillance or provide more intensive treatment when cancer patients are infected with sars-cov- , especially in elderly patients or those with comorbidities. by analyzing the articles belonging to group , it can be noticed that they address how covid- can affect patients with cancer and how they should be treated. additionally, they discuss the different methods of transmission, namely, through droplets, aerosols or contact with elements such as metal. consequently, an analysis of protection methods against covid- is offered, both for health professionals and other members of staff, with the final recommendation being to opt for telemedicine. additionally, the procedure for performing tracheotomies in the icu and in the operating room is also explained (figure ). in group , publications and citations were found throughout the network. the most cited publication is that of chen et al. [ ] , published in april in lancet psychiatry. this article analyzed the physical and psychological pressures to which health professionals were exposed. to this end, a psychological response plan was developed, covering three main areas: • development of a medical/psychological intervention team, which provided online courses in order to guide medical staff to deal with common psychological issues. • a psychological hotline team, which provided guidance and supervision on solving psychological issues. psychological interventions, providing group activities aimed at relieving stress. moreover, health professionals presented diverse concerns, namely, infecting their relatives, poor knowledge of the disease, lack of protective equipment, inability to treat patients and poor rest. therefore, hospitals were forced to improve their resting areas, food supply and safety measures. they concluded in this study that preserving the mental health of employees is essential to improving the management of infectious diseases; however, it is still uncertain which approach would be the best. therefore, the articles belonging to group address the psychological problems of health professionals, medical students and patients (anxiety, stress or depression). furthermore, they show methods of treatment aimed at reducing mental health issues, such as support supervisors or online mental health services (questionnaires, books, communication programs, psychological guidance or cognitive therapy) (figure ). in group , publications and citations were found throughout the network. the most cited publication is that of shi et al. [ ] , published in april in lancet infectious diseases. the authors described findings from thorax computed tomography (ct) scans over the course of the disease. patients were grouped depending on the onset of the symptoms and the results of their first ct scan. as a result, the authors found that covid- pneumonia causes abnormalities that can be found in ct images of the thorax, even in asymptomatic patients, as well as the quick development of ground-glass focal opacities, which evolve from unilateral to bilateral diffuse lesions and advance or coexist with pulmonary consolidations over - weeks. therefore, they concluded that combining ct assessment and clinical and laboratory findings could help in providing an early diagnosis of covid- pneumonia. articles from this group focus on clinical findings in computerized tomography images from the lungs due to covid- pneumonia ( figure ) . in group , publications and citations were found throughout the network. the most cited publication is that of mao et al. [ ] , published in april in jama neurology. in this article, the authors analyze neurological disturbances in patients infected with covid- . they examined hospitalized patients, and the neurological disturbances were categorized as follows: • central nervous system manifestations: dizziness, headache, altered states of consciousness, acute cerebrovascular disease, ataxia and seizures. • peripheral nervous system manifestations: taste, sight, smell and nervous alterations. manifestations of muscular-skeletal lesions. the study showed that . % of the patients presented neurological alterations. they advised that, upon detecting any neurological disturbance, doctors should consider covid- as a differential diagnosis in order to avoid late or erroneous diagnosis. when analyzing the total number of articles in this group, it is clear that their main aim is to analyze neurological alterations related to covid- ( figure ). in group , publications and citations were found throughout the network. the most cited publication is that of emanuel et al. [ ] , published in may in the new england journal of medicine. this article analyzes the lack of healthcare resources in us hospitals during the covid- crisis, namely, icu beds, respiratory ventilators, qualified healthcare personnel for critical care units, personal protective equipment and medication. in this sense, they presented recommendations to maximize the benefits (saving the largest number of lives or saving the largest number of years of life by giving priority to patients who will survive longer after treatment), to treat all patients in an equal manner, to encourage and reward instrumental value (the instrumental value could be fostered by giving priority to those who can save others, or rewarding those who have saved others in the past) and to give priority to the most disadvantaged (those who are sick or the youngest people). articles in this group analyzed how to take advantage of and distribute limited critical care resources during a pandemic. furthermore, in order to avoid further outbreaks, these authors determined that social distancing could be necessary until and that continuous surveillance of covid- should be conducted, given that a resurgence of contagion could be possible until (figure ). in group , publications and citations were found throughout the network. the most cited publication is that of dong et al. [ ] , published in march in jama: journal of the american medical association. this article analyzed whether sars-cov- could be transmitted in the uterus from the infected mother to her baby before birth. to this end, both the mother and baby underwent a thorax ct scan; furthermore, rt-pcr (reverse transcription-polymerase chain reaction) was conducted for sars-cov- nucleic acid through a nasopharyngeal swab, and igm (immunoglobulin m) and igg (immunoglobulin g) antibodies, cytokines and other biochemical markers in the blood were analyzed. additionally, vaginal secretions of the mother during labor were tested with rt-pcr. the results of the analysis showed that newborns born from a mother with covid- had high antibody levels and unusual cytosine test results two hours after birth. high igm antibody levels suggest that the newborn was infected in the uterus since these antibodies are not transferred to the fetus from the mother. although the possibility of infection at birth cannot be dismissed, igm antibodies do not usually appear until - days after the infection. conversely, igg antibodies may be transmitted to the fetus through the placenta and may appear at a later time than igm antibodies, so high igg levels could be a symptom of maternal or infant infection. the articles in this group address coronavirus infection in children and babies ( figure ). in group , publications and citations were found throughout the network. the most cited publication is that of luo et al. [ ] , published in february in the chinese journal of integrative medicine. this study consisted of an analysis of chinese medicine and its potential use for preventing covid- . to this end, provinces in china were treated with "chinese medicine" to strengthen qi and protect it from external pathogens by dispersing wind, dissipating heat and reducing humidity. they found that the chinese herbal formula could be an alternative treatment approach to prevent covid- in a population at high risk. nevertheless, further studies are necessary to confirm this theory. in this group, the articles analyze the use of traditional medicine to protect patients from covid- . in addition, they also establish that environmental pollution can be a trigger for enhanced transmission of covid- ( figure ) . in group , publications and citations were found throughout the network. the most cited publication is that of fang et al. [ ] , published in april in lancet respiratory medicine. this article shows the importance of half-face masks for preventing the spread of respiratory infections. evidence shows that covid- can be transmitted even before the carrier shows any symptoms, and, thus, the transmission rate could be reduced if everyone, including those who are already infected but asymptomatic and yet contagious, wore masks. these articles emphasize that authorities should optimize the distribution of masks, prioritizing frontline health workers and the needs of the most vulnerable population, as the latter is more susceptible to infection and mortality, including older adults and people with other underlying medical conditions. this group analyzes the different methods for individual protection, such as half masks, safety spectacles, gloves, facial shields, respirators, air purifiers and robes ( figure ). after analyzing the relationships among the nine main groups using the drilling down functionality, a connection between groups and ( figure ) was found. furthermore, it was found that publications by the authors an p, baud d and chen cj appear in both groups. thirteen sub-clusters were found (figure ) , five of which have a significant number of publications ( table ). the rest of the groups are relatively small, with fewer than publications and citation networks. sixteen sub-clusters were found (figure ), only four of which have a significant number of publications ( table ). the rest of the groups are relatively small, with fewer than publications and citation networks. alterations in the digestive system as a result of covid- blood clotting alterations in covid- patients. clinical findings can help not only to identify the cause of death but also to provide new ideas on the pneumonia's pathogenesis related to sars-cov- . this may help doctors to give an appropriate response or to provide a therapeutic strategy for critical patients and thus reduce the mortality rate. sars-cov- uses sars-cov's ace receptor for the input and the tmprss serine protease for the priming of protein s. treatment using cytokines and/or tocilizumab is likely to become one of the effective approaches for critically ill covid- patients. it has been shown that digestive symptoms are common in covid- patients. furthermore, these patients showed longer blood clotting time and increased hepatic enzyme levels. however, more sample studies are needed to confirm these findings. covid- patients show signs of venous thromboembolism. it has been proven that an anticoagulant therapy, mainly low molecular weight heparin, seems effective. however, more studies are necessary to establish the type of medication, the dose and the optimal duration of the prophylaxis. evaluate the incubation period of covid- and its effects on public health. evaluate the efficiency of the contention methods for reducing covid- outbreaks. the presence of sars-cov- on different surfaces is very similar to that of sars-cov- . the epidemiological differences between these viruses may be due to the high viral loads in the respiratory tract and the possibility that sars-cov- -infected people could transmit the virus while being asymptomatic. the mean period of incubation is of days, and in most of the people, the symptoms appear within days. however, these numbers vary between mild cases and severe cases. containment methods, such as social distancing or the use of masks, have proven to be effective in limiting virus transmission. therefore, the general public must be aware of the recommendations regarding covid- contention. public health authorities must keep tracking the situation to obtain new information about the virus and its outbreaks in order to estimate the risk of further outbreaks with greater precision. the main databases, such as web of science or scopus, make it possible to create citation networks. however, their usefulness is limited when conducting a systematic review of all of the existing literature on a subject, as they do not offer a general overview of the connections among the citations of a group of publications. for this reason, the citnetexplorer software was selected, as it allows the researcher to visualize, analyze and explore citation networks of scientific publications. hence, citnetexplorer offers a more detailed analysis through the creation of citation networks when compared to other databases, such as web of science or scopus [ ] . the main goal of this study was to analyze the existing literature on covid- . it should be taken into consideration that the search was carried out before the existence of an effective vaccine against sars-cov- in humans. in order to identify relevant publications, the web of science database was used, which is one of the most comprehensive databases, as its searching range goes back to the year . nevertheless, it must be taken into consideration that web of science only accepts international journals once they have undergone a rigorous selection process. thus, once the existing bibliography had been downloaded from wos, the citnetexplorer software allowed us to collect and analyze every available piece of literature on covid- to date. furthermore, the connections between fields of study and the different research groups were obtained through the analysis of citation networks. the function called "clustering" was used to collect the results, and the publications were then grouped according to the relationships among the citations. the drilling down function was used to examine the existing bibliography for each group, and the core publication function was used to show the main publications, that is, to show the publications with a minimum number of citations. therefore, these functions make it possible to conduct a complete study and analysis of the research on the field of study. the first publication on covid- was published by bogoch et al. [ ] on january in the travel medicine journal. when this article was published, there was news about a pneumonia outbreak in wuhan, china. consequently, the authors analyzed the potential for the international dissemination of this disease through air travel. subsequently, numerous research pieces followed the same idea, including studies on epidemic processes, as well as measures and strategies for prevention and control. in doing so, they analyzed the source of infection, mode of transmission, the population's susceptibility and other influencing factors. when comparing these articles to previous studies on other viruses, such as sars-cov or mers cov, they found that the most frequent transmission routes, like respiratory droplets and direct contact, were the same as those for covid- [ , ] . furthermore, it was found that, even though covid- does not seem as severe as sars-cov and mers-cov, the sudden increase in the number of cases and growing evidence of human transmission suggest that this virus is more infectious [ , ] . the countries with the largest number of publications are china, the us and italy. at the beginning of the pandemic, as expected, most of the research works published in international journals were written by chinese researchers. however, this has been a cause of major concern among frontline health workers and politicians due to the language barrier. currently, publications mainly cover the symptomatology and focus on finding an effective vaccine against covid- . this explains why research is being carried out in this field in countries with higher income and thus better infrastructures, which leads to an increasing number of publications. we suppose that countries with lower income focus on other research fields, such as transmission or epidemiology, although with fewer publications [ , ] . similarly, the upward trend in numbers of publications in countries such as the us or the uk has been linked to a combination of factors, such as the fact that they are english-speaking countries or the possible connections between different research groups within the scientific community [ , ] . other bibliometric studies on covid- and sars-cov- , such as those conducted by lou et al. [ ] and tran et al. [ ] , have found a significant increase in the number of publications over the last few months. comparing our bibliographical research to theirs, we found that june was the month in which the number of publications was significantly larger when compared to other months. as more publications become available in the upcoming months, we foresee that these numbers will grow significantly. the reason for this might be that our research scope was wider and comprised more types of documents and a longer period. furthermore, of the studies in june, the research by mcgonagle et al. [ ] should be highlighted, as they found that patients with severe pneumonia related to covid- might show signs of systemic hyperinflammation (macrophage activation syndrome) or cytokine storm (secondary hemophagocytic lymphohistiocytosis). in this sense, the clinical features of covid- are diverse, from the asymptomatic state to acute respiratory distress syndrome and multiple organ dysfunction. the study conducted by chen et al. [ ] showed that the progression of the disease was linked to increased inflammatory cytokines, namely, il , il , il , gcsf, ip , mcp , mip a and tnfα. additionally, the study conducted by casey et al. [ ] found that, in some patients, covid- was related to a hypercoagulable state and to an increased risk of venous thromboembolism. in addition, they found that, unlike patients with pulmonary embolism, positive covid- cases rarely showed hemoptysis. on the other hand, the study conducted by yang et al. [ ] suggested that the gastrointestinal tract and the liver could also be infected by the sars-cov- . this is due to the gastrointestinal epithelial cells and hepatic cells expressing ace enzymes (main receptor of sars-cov- ). these findings prove that, even when sars-cov- has been eliminated from the respiratory tract in some patients, the virus continues replicating through the gastrointestinal tract and could be excreted in the feces. the study by xu et al. [ ] analyzed the characteristics of pediatric patients with covid- and found that % of them recurrently tested positive in rectal swabs, even after the nasopharyngeal tests had come back negative. in turn, the study by ellul et al. [ ] showed a broad range of neurological manifestations in covid- patients. sixteen out of the patients in chinese hospitals and out of the patients in french hospitals showed signs of encephalopathy. moreover, guillain-barré syndrome was found in of the patients. on the other hand, anosmia and ageusia were frequent and could occur in the absence of other clinical features, while - % of hospitalized patients showed apoplexy. regarding the treatment, various antiviral medications have been tested, such as ribavirin and lopinavir/ritonavir, which are commonly used in the treatment and prevention of aids. thus, the study showed that a patient treated with lopinavir/ritonavir together with ribavirin had better results when compared to those to whom only ribavirin was administered [ ] . chloroquine has also been used as a form of treatment and has shown antiviral effects on the cells of primates infected by sars-cov. similarly, in the research by vincent et al. [ ] , a favorable inhibition of the virus spread was observed when the cells were treated with chloroquine before or after sars-cov infection. it should be noted that the use of remdesivir was authorized on july as the first conditionally marketable treatment. this facilitates early access to medication in emergency public health situations. this antiviral is a treatment against covid- for adults and teenagers aged or over who suffer from pneumonia and who require supplementary oxygen [ ] . on the other hand, there are currently possible vaccines from different laboratories, of which are in a preclinical phase and are in the clinical phase [ ] . research conducted by gao et al. [ ] was published recently, and it reports a pilot-scale production of picovacc, a possible vaccine that would inactivate the sars-cov- virus. this vaccine has created antibodies in mice, rats and non-human primates. they also neutralized strains representative of sars-cov- , which might suggest a greater possible neutralizing capacity against other strains. this leads us to believe that there is a strong probability of developing an effective vaccine for humans shortly. additionally, upon development/availability and approval of a vaccine or a new effective treatment against sars-cov- , we believe it necessary to carry out a new search and citation analysis. the future of covid- is still uncertain. this is due to the lack of knowledge of the clinical progression of this illness. in particular, many patients experience a recurrence of symptoms after periods of showing no signs, or they show symptoms such as febricula, asthenia or headaches for a longer period. moreover, some patients test positive again in the pcr test after testing negative. this might be due to the sensitivity of this test, especially when the viral charge is lower and/or when the viral rna is on the threshold of the detection rate of the test [ ] . on the other hand, whether covid- can also have after-effects is still to be determined. the research by zhang et al. [ ] found that . % of survivors showed signs of pulmonary fibrosis. we recognize that there is still further research to be conducted in order to confirm whether covid- can have after-effects or whether it varies depending on the severity of the condition. consequently, the number of studies on covid- is constantly on the increase since more research is needed in order to fight this illness. citation network studies are becoming more numerous, as this is the only analysis method that provides a global overview of the different research fields within a specific topic. furthermore, citnetexplorer software facilitates the analysis of all existing research on a specific topic through detailed studies. this could change how studies in different research areas are conducted. in conclusion, this research offers a specific and objective analysis of the main articles on covid- and sars-cov- . in addition, it was possible to visualize, analyze and explore the most cited articles and citation networks existing to date using the web of science database and the citation network explorer database. by doing so, we have obtained information regarding the epidemiology, clinical features, diagnosis and treatment of covid- . the importance of neurological and gastrointestinal alterations in a high percentage of positive cases of covid- is also worth mentioning. in addition to the great progress made towards effective treatment, the research conducted by gao et al. must be highlighted, as it shows the first results regarding the creation of the first vaccine for humans. therefore, covid- disease is a relevant field for researchers, with the number of publications continuously on the increase. consequently, the clinical progression of the disease will be understood in the upcoming months, and a new vaccine and an effective treatment will be discovered soon. in this way, this paper contributes to a better understanding of the information structure by identifying, in chronological 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coronavirus disease patients with coagulopathy the incubation period of coronavirus disease (covid- ) from publicly reported confirmed cases: estimation and application pneumonia of unknown etiology in wuhan, china: potential for international spread via commercial air travel routes of transmission of influenza a h n , sars cov, and norovirus in air cabin: comparative analyses transmission of sars and mers coronaviruses and influenza virus in healthcare settings: the possible role of dry surface contamination preliminary estimation of the basic reproduction number of novel coronavirus ( -ncov) in china, from to : a data-driven analysis in the early phase of the outbreak estimating the unreported number of novel coronavirus ( -ncov) cases in china in the first half of january : a data-driven modelling analysis of the early outbreak timely research papers about covid- in china countries are hoarding medical supplies-here's why it damages the global response to covid- research trends in science education from to : a content analysis of publications in selected journals a bibliometric analysis of the health field regarding social networks and young people coronavirus disease : a bibliometric analysis and review studies of novel coronavirus disease (covid- ) pandemic: a global analysis of literature the role of cytokines including interleukin- in covid- induced pneumonia and macrophage activation syndrome-like disease epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study covid- pneumonia with hemoptysis: acute segmental pulmonary emboli associated with novel coronavirus infection implications of gastrointestinal manifestations of covid- characteristics of pediatric sars-cov- infection and potential evidence for persistent fecal viral shedding neurological associations of covid- chloroquine is a potent inhibitor of sars coronavirus infection and spread european commission secures eu access to remdesivir for treatment of covid- rapid development of an inactivated vaccine candidate for sars-cov- epidemiologic features and clinical course of patients infected with sars-cov- in singapore long-term bone and lung consequences associated with hospital-acquired severe acute respiratory syndrome: a -year follow-up from a prospective cohort study key: cord- - fdcu f authors: wu, renyi; wang, lujing; kuo, hsiao-chen dina; shannar, ahmad; peter, rebecca; chou, pochung jordan; li, shanyi; hudlikar, rasika; liu, xia; liu, zhigang; poiani, george j.; amorosa, louis; brunetti, luigi; kong, ah-ng title: an update on current therapeutic drugs treating covid- date: - - journal: curr pharmacol rep doi: . /s - - - sha: doc_id: cord_uid: fdcu f the current pandemic of coronavirus disease (covid- ) caused by severe acute respiratory syndrome coronavirus (sars-cov- ) has presented unprecedented challenges to the healthcare systems in almost every country around the world. currently, there are no proven effective vaccines or therapeutic agents against the virus. current clinical management includes infection prevention and control measures and supportive care including supplemental oxygen and mechanical ventilatory support. evolving research and clinical data regarding the virologic sars-cov- suggest a potential list of repurposed drugs with appropriate pharmacological effects and therapeutic efficacies in treating covid- patients. in this review, we will update and summarize the most common and plausible drugs for the treatment of covid- patients. these drugs and therapeutic agents include antiviral agents (remdesivir, hydroxychloroquine, chloroquine, lopinavir, umifenovir, favipiravir, and oseltamivir), and supporting agents (ascorbic acid, azithromycin, corticosteroids, nitric oxide, il- antagonists), among others. we hope that this review will provide useful and most updated therapeutic drugs to prevent, control, and treat covid- patients until the approval of vaccines and specific drugs targeting sars-cov- . coronavirus disease sars-cov- severe acute respiratory syndrome coronavirus the horrific pandemic outbreak of covid- (coronavirus disease ) around the world caught the health care systems in every country by storm, most if not all were caught off guard without proper defense mechanisms to cope with and to control such a pandemic. covid- , caused by a new and novel coronavirus (severe acute respiratory syndrome coronavirus , sars-cov- ), has recently been identified and characterized [ ••] . coronaviruses are named for their crown-like spikes on their surface and there are four main sub-groupings of coronaviruses, known as alpha, beta, gamma, and delta [ , ] . sars-cov- belongs to the beta sub-grouping, and is one of the seventh coronavirus to date infecting humans [ ••] . some coronaviruses such as e alpha coronavirus [ ] , oc beta coronavirus [ ] , nl alpha coronavirus [ ] , and hku beta coronavirus [ ] were associated with mild clinical symptoms, whereas sars-cov beta coronavirus [ ] , middle east respiratory syndrome coronavirus (mers-cov) beta coronavirus [ ] , and sars-cov- caused severe diseases [ ] . sars-cov- is a positive-sense single-stranded rna virus with , bases, % identical at the whole-genome level to a bat coronavirus, and shares . % sequence identity to sars-cov [ ••] . sars-cov- encodes spike s protein containing receptor binding domain (rbd) that binds to the human angiotensin-converting enzyme (ace ), and promotes membrane fusion and uptakes of the virus into human cells such as the lung by endocytosis [ , [ ] [ ] [ ] . upon entering the human cells, sars-cov- , like other coronaviruses, will takeover or hijack the human cells' protein synthesis machinery to synthesize the viral proteins and assemble the proteins and subsequent viral replication [ •] . once inside the human body, viruses in general will trigger a series of good versus bad host responses including autophagy, apoptosis, stress response, and innate immunity [ ] . fortunately, majority (more than %) of sars-cov- infected individuals are asymptomatic or have mild symptoms, most likely due to the activation of the good response. these good responders would likely activate the body's innate immune system by activating the body's antiviral defense mechanisms including natural killer cells and antiviral t cells, and induction of interferon (ifn) [ ] [ ] [ ] [ ] . unfortunately, in about % of sars-cov- -infected individuals including the immune compromised, elderly, patients with underlying health conditions such as cardiovascular and pulmonary problems, diabetics, hypertension, obesity, chronic obstructive pulmonary disease (or copd, such as emphysema), pulmonary fibrosis, asthma, and interstitial lung disease [ , ] would encounter more severe disease characterized by significant respiratory symptoms leading to acute respiratory distress syndrome (ards) and even death. an important consideration to note is that ards occurs later in disease progression and is preceded by acute lung injury (ali) [ ] . this distinction may inform treatment strategy in terms of drugs directed towards cytokine storm and thrombosis which is described in this manuscript. a study on sars-cov and mers-cov has found that these two coronaviruses appear to have evolved mechanisms to attenuate or delay ifn production, resulting in enhanced inflammatory host responses and severe lung injury [ , , [ ] [ ] [ ] . this aberrant host immune response with the production of powerful inflammatory cytokines, known as "cytokine storm" found in sars-cov-and mers-covinfected patients, would correlate with disease severity and poor prognosis [ , , [ ] [ ] [ ] [ ] . severe covid- patients exhibit profound inflammatory response [ , ] . transcriptomic rna-seq analysis of covid- patients has revealed that several immune pathways and pro-inflammatory cytokines cxcl, ccl , cxcl , ccl , il , and ccl l in bronchoalveolar lavage fluid (balf) and tnfsf , cxcl , il , timp , c , il , areg, and nrg in peripheral blood mononuclear cells (pbmc) were induced by sars-cov- infection, suggesting a sustained inflammation and cytokine storm [ ] . importantly, sars-cov- infection-induced excessive cytokine release correlates with lung tissue injury and covid- pathogenesis [ ] . this estimated % of patients developing more severe disease with sars-cov- infection are most likely due to genetics, epigenetics, and or other factors, with dampened innate immune response to fight the virus coupled with enhanced viral load leading to cytokine storm, severe inflammatory/oxidative stress response, and severe lung injury secondary to ards. while there is clear understanding that the respiratory system is dramatically impacted in covid- patients, evidence suggests that other organ systems are also affected. emerging data show that sars-cov- may lead to damage to other organs including the heart and brain. nearly % of hospitalized patients with covid- have indication of cardiac damage [ ] . furthermore, neurologic symptoms have been reported in patients and infection of sars-cov- has been found in the brainstem of both humans and experimental animals [ , ] . currently, there is no vaccine and/or specific therapeutic drugs targeting the sars-cov- . hence, it remains a major challenge to decide what potential therapeutic regimens to prevent and treat the severely sick covid- patients. effective vaccines are essential to combat against the extremely contagious sars-cov- . at present, a lot of research efforts have been invested to develop vaccines around the world. until we have specific vaccines or therapeutic drugs targeting sars-cov- , "repurposed" drugs that have been approved by the fda in the usa for other indications have been used to treat covid- patients. this review will summarize the most current pharmacotherapeutics prescribed in the treatment of severe cases of covid- patients. these include antiviral therapy, antibiotics, systemic corticosteroids and anti-inflammatory drugs (including anti-arthritis drugs), neuraminidase inhibitors, rna synthesis inhibitors, convalescent plasma, and traditional herbal medicines. in the absence of definitive and specific treatment regimens, strategies including early diagnosis, timely reporting, isolation, and supportive treatments are important line of actions against covid- infections. current social practices including timely release of epidemic information and maintenance of social orders and personal practices such as improving personal hygiene, wearing facial coverings or masks, adequate rest, and keeping rooms well ventilated remain some of first line of actions against covid- pandemic. at present, the treatments of patients with sars-cov- infection are mainly repurposing the available therapeutic drugs and based on symptomatic conditions. considering ards, followed by secondary infections, antibiotics, antiviral therapy, systemic corticosteroids, and anti-inflammatory drugs (including anti-arthritis drugs) are often used in the treatment regimens. in addition to antiviral interferers and antibiotics, neuraminidase inhibitors, rna synthesis inhibitors, convalescent plasma, and traditional herbal medicines have also been utilized in the treatment of covid- [ ] . nevertheless, the efficacy of these treatment regimens remains to be verified by appropriately designed clinical trials. remdesivir is a potential drug for treatment of covid- . it is a phosphoramidate prodrug of an adenosine c-nucleoside and a broad-spectrum antiviral agent synthesized and developed by gilead sciences in as a treatment for ebola virus infection [ ] . remdesivir is metabolized into its active form, gs- , that obscures viral rna polymerase and evades proofreading by viral exonuclease, causing a decrease in viral rna production. the antiviral mechanism of remdesivir is a delayed chain cessation of nascent viral rna. animal experiments indicate that remdesivir can effectively reduce the viral load in lung tissue of mice infected with mers-cov, improve lung function, and alleviate pathological damage to lung tissue [ ] . wang [ ] . in order to evaluate the efficacy and safety of the drug in patients with covid- , a randomized, placebo-controlled, double-blind, multicenter, phase iii clinical trial was launched on february , in china. patients in the experimental group received an initial dose of mg of remdesivir and a subsequent dose of mg for consecutive days via intravenous infusion in addition to routine treatment. patients in the control group received same dose of placebo treatment. the trial is expected to conclude by the end of april . the number of cases planned to be enrolled is and , respectively [ , ]. current recommendation for remdesivir includes a -day regimen of remdesivir treatment: mg loading dose on day , followed by mg once-daily maintenance doses for days in both studies. this regimen of remdesivir therapy is similar to that of former randomized clinical trial against the ebola virus [ , ]. in a summary of subjects receiving remdesivir via compassionate use in the usa, nearly % of patients had improvement in terms of oxygen requirements and many patients that were mechanically ventilated were extubated. this report did not include a control group; therefore, extrapolating these results is difficult. it is too early to conclude the direct antiviral effect of remdesivir on the enhanced clearing of viral loads in the respiratory tract, but it indeed suggests a promising therapeutic effect of remdesivir [ ] . chloroquine and hydroxychloroquine are drugs with a long history of clinical use with similar chemical structures often used in the treatment of lupus erythematosus, rheumatoid arthritis, and malaria [ ] . compared with chloroquine, hydroxychloroquine has a hydroxyl group, which makes it less toxic while maintaining similar activity. one mechanism of action of chloroquine and hydroxychloroquine is targeting lysosome which may be useful to control graft-versus-host disease in humans [ ] . with the accumulation of chloroquine in lysosomes, the ph of lysosomes is significantly changed and the activity of proteases in lysosomes is directly affected, thus affecting the degradation of proteins and glycosaminoglycan [ , ] . chloroquine can inhibit the entry of sars-cov- and prevent virus-cell fusion by interfering with glycosylation of ace receptor and its binding with spike protein, suggesting that chloroquine treatment might be more effective in the early stage of infection, before covid- reduces ace expression and activity [ , , ] . hydroxychloroquine possesses anti-inflammatory effect on th -related cytokines (il- , il- , and il- ) in healthy individuals, and systemic lupus erythematosus (sle) and rheumatoid arthritis (ra) patients [ ] . there is some evidence that chloroquine and hydroxychloroquine can reduce cytokine storm. according to one analysis, the main cause of death of covid- patients is related to the triggering of the cytokine storm, which contributed to acute respiratory distress [ ] . it has been reported that hydroxychloroquine is effective in inhibiting sars-cov- infection in vitro [ , , ] . zinc inhibits sars-covand retrovirus rna polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture [ ] . there is also evidence that zinc enhances chloroquine intracellular uptake [ ] . as such, combining zinc with chloroquine or hydroxychloroquine is intriguing and is currently under investigation. overall, more clinical trials are underway to evaluate the safety and efficacy of hydroxychloroquine as a prophylactic and treatment for covid- . the us fda has issued emergency authorization for the use of chloroquine and hydroxychloroquine for the treatment of covid- . a recent study by tang et al. reported that hydroxychloroquine did not lead to higher negative conversion rates, but had reduced clinical symptoms through the anti-inflammatory properties and recovery of lymphopenia [ •] . it has also been reported that high doses of chloroquine ( mg twice daily for days or total dose of g) may be associated with significant cardiac risks and should not be recommended for treating covid- [ • ]. there is still a lack of evidence regarding the safety and effectiveness of these agents in treating covid- . in this regard, clinicians and patients should be made aware of the risk versus benefit profile of these medications [ ] . lopinavir is a protease inhibitor with high specificity for hiv- protease. lopinavir is marketed and administered exclusively in combination with ritonavir. this combination was first marketed by abbott under the brand name kaletra in [ ] . due to lopinavir's poor oral bioavailability and extensive biotransformation, it is co-formulated with ritonavir to enhance its exposure. ritonavir is a potent inhibitor of the enzymes that are responsible for lopinavir metabolism, and its co-administration "boosts" lopinavir exposure and improves antiviral activity [ ] . lopinavir is a peptidomimetic molecule, containing a hydroxyethylene scaffold that mimics the peptide linkage typically targeted by the hiv- protease enzyme but which by itself cannot be cleaved, thus preventing the activity of the hiv- protease [ ] . lopinavir-ritonavir was investigated in an open-label, individually randomized, controlled trial, where patients with covid- received either lopinavir-ritonavir mg/ mg, orally twice daily plus standard of care, or standard of care alone. no benefit was observed with lopinavirritonavir treatment beyond standard care. diarrhea, nausea, and asthenia were the most frequently reported adverse effects in patients receiving lopinavir-ritonavir-based regimen [ ] . interestingly, in a report from korea, lopinavir-ritonavir administration significantly decreased coronavirus titers with no or little coronavirus titers were observed in the follow-up study. however, the analysis included a single patient in the initial phase of outbreak in korea [ ] . umifenovir (branded as arbidol), a derivative of indole carboxylic acids, was first developed in in russia and has since been approved in russia and china for treating prophylaxis and infections associated with influenza a and b, and other arbovirus [ ] . later on, umifenovir demonstrated in vitro antiviral efficacy in widely spreading virus strains such as the ebola virus, human herpesvirus (hhv- ), hepatitis c virus (hcv), and tacaribe arenavirus [ ] . its major mechanism of action is to block the virus-cell membrane fusion as well as virus-endosome fusion through incorporation into cell membranes and interference with the hydrogen bonding network of phospholipids [ ] . in influenza virus, it has been shown to directly interact with virus particles to stabilize hemagglutinin (ha), reducing the likelihood of reaching the low ph threshold required for conformational transition into functional fusogenic ha [ ] . blaising et al. reported the in vitro activity of umifenovir against sars-cov- and sars-cov- [ , ] . a retrospective cohort study has reported that compared with lopinavir-ritonavir (lpv-rtv) only group, combination of umifenovir and lpv-rtv has shown increased negative conversion rate of sars-cov- and improved chest ct scan results [ ] . however, another prospective study (chictr ) has shown that compared with favipiravir, umifenovir has inferior outcome in clinical recovery rate and relief of fever and cough [ ] . there are two randomized and open-label trials ongoing in china, investigating the efficacy and safety of umifenovir against covid- . the effect of umifenovir plus standard treatment versus lpv-rtv plus standard treatment will be evaluated in nct , and the effect of umifenovir plus standard treatment versus standard treatment will be tested in nct . favipiravir (branded as avigan) has been developed by fujifilm toyama chemical in in japan for the treatment of avian influenza or novel influenza resistant to neuraminid a s e i n h i b i t o r s . i t i s a g u a n i n e a n a l o g u e w i t h pyrazinecarboxamide structure, and its antiviral activity is decreased at the presence of purine nucleosides due to the competition [ ] . the prodrug favipiravir first enters the infected cells through endocytosis and is then transformed into active f a v i p i r a v i r r i b o f u r a n o s y l p h o s p h a t e s t h r o u g h phosphoribosylation and phosphorylation [ , ] . the antiviral activity is exhibited through selectively targeting conservative catalytic domain of rna-dependent rna polymerase (rdrp), interrupting the nucleotide incorporation process during viral rna replication [ ] . the dysregulation in viral rna replication results in increased number and frequency of transition mutations including replacement of guanine (g) by adenine (a) and cytosine (c) by thymine (t) or c by uracil (u) which induces destructive mutagenesis in rna viruses [ ] . favipiravir has been used in the treatment of infectious diseases caused by rna viruses such as influenza, ebola, and norovirus [ ] . recent in vitro and human studies have repurposed favipiravir as an experimental agent against enveloped, positive-sense, single-strand rna virus sars-cov- . an in vitro research has investigated seven potential anti-sars-cov- medicines including ribavirin, penciclovir, favipiravir, nafamostat, nitazoxanide, remdesivir, and chloroquine, showing that remdesivir and chloroquine have favorable selectivity index [ ] . in addition, the study showed favipiravir has exerted efficacy in vero e cells infected with sars-cov- with half-maximal effective concentration (ec ) of . μm and half-cytotoxic concentration (cc ) at over μm, implying the high concentration is needed for safe and effective treatment [ ] . clinical trials testing favipiravir against covid- have been carried out vigorously in various countries including china and japan. a randomized control trial (chictr ) has shown that covid- patients treated with favipiravir have superior recovery rate ( . %) than that treated with umifenovir ( . %), and the duration of fever and cough relief time are significantly shorter in favipiravir group than in umifenovir group [ ] . up to mid-april , there are eight undergoing clinical trials in china and two in japan examining the anti-sars-cov- potential of favipiravir. these trials include non-randomized and randomized controlled trials evaluating t h e e f f i c a c y a n d s a f e t y o f f a v i p i r a v i r a l o n e (chictr , jprn-jrcts , jprn-jrcts ) or in conjunction with interferon-α ( c h i c t r ) , b a l o x a v i r m a r b o x i l (chictr , chictr ), tocilizumab (chictr , nct ), or chloroquine phosphate (chictr , nct ). oseltamivir(branded as tamiflu) is a drug approved for treatment of influenza a and b. oseltamivir targets the neuraminidase distributed on the surface of the influenza virus to inhibit the spread of the influenza virus in the human body [ , ] . a study in wuhan reported that no positive outcomes were observed after receiving antiviral treatment with oseltamivir [ ] . several clinical trials are still evaluating the effectiveness of oseltamivir in treating sars-cov- infection. oseltamivir is also used in clinical trials in several combinations, such as with chloroquine and favipiravir [ ] . in the absence of vaccine or specific antiviral drugs been proven against sars-cov- , many adjunctive therapies are used as supportive care for covid- patients. the adjunctive therapies including azithromycin, ascorbic acid, corticosteroids, epoprostenol, sirolimus, tocilizumab, sarilumab, and anakinra are highlighted below. several of these therapies (i.e., tocilizumab and other interleukin-directed therapies) are administered in an effort to blunt the cytokine storm often seen in progressing disease. the optimal timing of administration is yet to be identified. conceptually, blocking cytokine production before it progresses to an exaggerated level would seem to be the most mechanistically idea. elevated serum concentration of il- is associated with worse outcome in covid- and blocking the activity of this pro-inflammatory mediator with directed therapies may be a key target [ ] . other adjuncts are directed at viral replication, viral entry, or through some other alternative mechanisms. azithromycin is an antibiotic that can be used to fight many different types of infections caused by susceptible bacteria, such as respiratory infections, skin infections, and sexually transmitted diseases [ ] . moreover, it has been proven to be active in vitro against zika and ebola viruses and to prevent severe respiratory tract infections when treated to patients suffering viral infection [ ] [ ] [ ] . for the mechanism of action, azithromycin prevents bacteria from growing by interfering with their protein synthesis. it binds to the s subunit of the bacterial ribosome, thus inhibiting translation of mrna [ ] . previously, azithromycin has been used as adjunctive therapy to provide antibacterial coverage and potential immunomodulatory and anti-inflammatory effects in the treatment of some viral respiratory tract infections (e.g., influenza) [ , ] . currently, many trials are testing the effect of azithromycin conjunction with hydroxychloroquine on the course of disease in people with sars-cov- . for example, pfizer has announced positive data for the use of its a z i t h r o m y c i n ( z i t h r o m a x ) d r u g , a l o n g w i t h hydroxychloroquine, in a covid- clinical trial that was performed in france. in brief, the clinical trial was conducted to assess hydroxychloroquine in patients, of which were co-administered with azithromycin. compared with controls and hydroxychloroquine alone group, the patients treated with hydroxychloroquine + azithromycin presented with highest virologic cure rate following -day treatment [ ] . three other clinical studies used azithromycin ( mg on day , then mg daily on days - ) co-treated with day regimen of hydroxychloroquine ( mg daily) in an open-label non-randomized study in france ( pts) [ ] , open-label uncontrolled study in france ( pts) [ ] , and uncontrolled observational study in france ( pts) [ ] . specifically, gautret et al. reported a % viral clearance in nasopharyngeal swabs in their patients after co-treated of hydroxychloroquine and azithromycin [ ] . but the findings reported by molina et al. stand in contrast with those reported by gautret. molina et al. repeated the experiments, thought the rapid and full viral clearance was quite unexpected and found of patients had significant comorbidities [ ] . .based on those results, data presented to date are insufficient to evaluate possible clinical benefits of azithromycin in patients with covid- [ ] . furthermore, one must consider the additive cardiac toxicity of hydroxychloroquine and azithromycin. both agents are known to prolong the qt interval and may potentiate the risk for cardiac events in a population known to have cardiac-related comorbidities. vitamin c is an essential nutrient and plays significant roles within the human body. it can neutralize free radicals and assist to prevent or reverse cellular damage as a potent antioxidant agent. it is also involved in some biological processes, many of which are associated with immune health [ ] . moreover, vitamin c appears to be effective as an antiviral agent, especially against influenza viruses [ ] . many studies showed that vitamin c positively affects the development and maturation of t lymphocytes and nk (natural killer) cells involved in the immune response to viral agents. it also contributes to the inhibition of reactive oxygen species (ros) production and to the remodulation of the cytokine network typical of systemic inflammatory syndrome [ ] . given this background, a phase ii clinical trial (nct ) is initiated in china to evaluate high-dose iv vitamin c in icu patients with severe covid- -associated pneumonia [ ] . some hospitals have reported giving infected patients mg of vitamin c as supportive treatment. high-dose iv vitamin c has been given in the treatment of moderate to severe covid- patients in china [ ] . the doses varied between and g per day, given over a period of -- -h iv infusion. the oxygenation index was improved in real time and all the patients eventually recovered and were discharged [ ] . moreover, high-dose ( . mg/kg body weight) vitamin c has been used for several decades clinically and an nih panel also documented clearly that this dose regimen is safe and has no major side effects [ , ] . as a potent anti-inflammatory and anti-fibrotic drug, low doses of methylprednisolone (depo-medrol or solu-medrol) have the potential to prevent an extended cytokine response and may accelerate resolution of pulmonary and systemic inflammation in pneumonia [ , ] . recently, many medical researchers believe that corticosteroids, especially methylprednisolone, may improve dysregulated immune response caused by sepsis (possible complication of infection with covid- ) and increase blood pressure when it is low [ ] . specifically, in a retrospective cohort study, patients with confirmed covid- who developed ards were treated with methylprednisolone ( - mg/kg daily iv for - days) and the results showed that treatment with methylprednisolone may be beneficial for patients who develop ards in the reduction of the risk of death. briefly, of those patients with ards who received methylprednisolone treatment, of ( %) patients died, while those who did not receive methylprednisolone, of ( . %) died [ ] . in another study, patients with severe covid- that progressed to acute respiratory failure, use of methylprednisolone was associated with improvement in clinical symptoms (i.e., fever, hypoxia) and a shortened disease course in patients who received the drug compared with those who did not [ ] . moreover, according to expert consensus statement from chinese thoracic society, dosage regimen of methylprednisolone should be low to moderate (i.e., ≤ . to mg/kg daily or equivalent) [ ] and the most common regimens of methylprednisolone applied in china were typically - mg iv daily for a course of - days [ ] . the appropriate dosage (low dose versus high dose), place in therapy (early versus late), and role for corticosteroids (cytokine storm or comorbidity management) require additional clarity. there is concern that the use of corticosteroids may have deleterious effects (i.e., inhibition of immune response and pathogen clearance) in patients with covid- [ ] . one study reported no effect on mortality and decreased viral clearance with the use of corticosteroids [ ] . furthermore, the infectious diseases society of american recommends against the routine use of corticosteroids in covid- . however, they do recommend the use of corticosteroids in the setting of ards in the context of a clinical trial [ ] . similarly, the surviving sepsis campaign recommends against corticosteroids in mechanically ventilated patients with acute lung injury in the absence of ards [ ] . however, they provide a recommendation for the use of corticosteroids in patients with ards acknowledging the weak level of evidence. dexamethasone has demonstrated utility on ards by decreasing ventilator days and mortality on severe ards in patients without covid- [ ] . whether the use of corticosteroids provides similar benefit in patients with covid- and ards remains to be seen. ultimately, the clinical utilization of corticosteroids still needs to be established and should be considered on a case by case basis. since patients with pre-existing pulmonary conditions are at higher risk of covid- and should be closely monitored and cared, pulmonary vasodilator agents have been used in some patients for hypoxemia refractory to conventional treatments, but no study has been performed specifically on covid- patients. the surviving sepsis campaign suggested a trial of inhaled pulmonary vasodilator method as rescue therapy in mechanically ventilated adults with covid- , severe ards, and hypoxemia despite optimized ventilation and other rescue strategies. inhaled nitric oxide (ino) and inhaled epoprostenol (iepo, a naturally occurring prostaglandin) are two common pulmonary vasodilators that have been widely studied [ ] [ ] [ ] . experience in patients with ards indicates that ino can substantially reduce mean pulmonary artery pressure and improve oxygenation in such patients. furthermore, in vitro evidence of direct antiviral activity against sars-cov was studied and the genetic similarity between sars-cov and sars-cov- suggests their potential effectiveness against sars-cov- [ ] . for iepo, dosages up to ng/kg per minute have been used [ , , , ] . previous studies reported that to provide a clinically important increase in pao and reduction in pulmonary artery pressure, the most effective and safe dosage appears to be - ng/kg per minute in adults and ng/kg per minute in pediatric patients [ ] . for ino, therapy was given for ≥ days ( ppm on day , followed by and ppm on days and , respectively, then weaned on day ) in a pilot study on sars-cov [ ] . additionally, clinical trials evaluating ino for treatment or prevention of covid- are planned or underway (nct , nct , nct ) [ , ] . and on march , , fda granted emergency expanded access allowing its ino delivery system (inopulse®) to be immediately used for the treatment of covid- . finally, additional studies are needed to evaluate the potential role of iepo and ino in the treatment of covid- patients. sirolimus, also known as rapamycin, is an immunosuppressant that is used to prevent organ transplant rejection and to treat lymphangioleiomyomatosis (lam) by inhibiting mammalian target of rapamycin (mtor) kinase. it was originally isolated from the bacterium streptomyces hygroscopicus found on easter island (rapa nui) [ ] and is commercially available as rapamune (pfizer). mtor, and more specifically a protein complex mtorc formed by mtor, plays a key role in viral replication. in an in vitro experiment, sirolimus has been shown to affect pi k/akt/mtor pathway which inhibited mers-cov activity [ ] . a new randomized double-blind placebo-controlled clinical trial (scope) by university of cincinnati is planned to be conducted between april and september to test the effect of sirolimus on progression of patients hospitalized with covid- to advanced respiratory support [ ] . studies of patients hospitalized with influenza can further shed light on the antiviral effect of sirolimus. in a randomized clinical trial conducted on patients with confirmed h n pneumonia and on mechanical ventilator support, a group treated with corticosteroids and mg/day of sirolimus for days (n = ) showed significantly better clinical outcomes compared with the group treated with corticosteroids only, including shorter median duration of ventilator used [ ] . delayed oseltamivir plus sirolimus treatment in ph n -infected mouse model further suggested a significant association between the sirolimus treatment and improved outcomes [ ] . additionally, a new trial by the chinese university of hong kong is planned to begin in august to investigate the effect of sirolimus and oseltamivir on normalization of respiratory status and changes in biomarkers (viral rna concentration, cytokines/ chemokines and pro-inflammatory mediators) and several other clinical endpoints in influenza patients [ ] . at least one in silico study identified sirolimus as one of the potential candidates for treating covid- patients based on data from other human coronavirus infections using network-based drug repurposing model [ ] . tocilizumab (branded as actemra) is a humanized mab developed by roche and chugai pharmaceutical for treating ra and systemic juvenile idiopathic arthritis patients. at the time of publishing this article, clinicaltrials.gov listed planned studies that included tocilizumab treatment arm, all of them at the recruiting stage or earlier. a study published in april reported that severe or critical covid- patients in china were treated with the compound, with of them recovered at the time of publication and on the way to recovery (but still in icu). encouraged by these results, a larger multicenter clinical trial was launched (chictr ) and had about patients treated with tocilizumab already enrolled [ , ] . sarilumab, (branded as kefraza), a humanized mab, was developed by regeneron pharmaceuticals and sanofi for treatment of rheumatoid arthritis (ra). a phase / randomized double-blind placebo-controlled clinical trial was planned by regeneron pharmaceuticals and sanofi (and in partnership with northwell health's feinstein institutes for medical research) for march targeting to enroll covid- patients, measuring percent change in c-protein (phase only) and time to improvement on a -point scale (based on death and type of hospitalization) in patients with serum il- level above a threshold as primary endpoints. as of the time of this publication, the results of this study have not been made public [ ] . anakinra (branded as kineret by swedish orphan biovitrum) is a modified human il- receptor antagonist (il- ra) approved in in the usa and in in europe for use in ra patients. il- family of receptors triggers innate immune response and was associated with damaging inflammation [ ] . out of approved clinical trials involving anakinra treatment, also have tocilizumab as a comparison: one multicenter open-label non-randomized trial in greece with estimated enrollment of patients [ ] , and another multicenter randomized open-label trial in belgium with estimated patients has been enrolled to date [ ] . angiotensin-converting enzyme (ace ) receptor is regarded as an important target in the pathogenesis of covid- . studies reveal that frequently observed comorbidities, including hypertension and diabetes in patients infected with sars-cov- , are under medication with angiotensin-converting enzyme (ace) inhibitors or angiotensin receptor blocker (arb) [ ] [ ] [ ] [ ] that result in overexpression of ace . it is speculated that sars-covand sars-cov- bind to human cells via interaction with ace receptors [ , ] . the opposing physiological actions of ace and ace in the renin-angiotensin system are reviewed to determine the therapeutic efficacy of ace inhibitors or arbs [ , ] . in hypertensive patients, chronic treatment with angiotensin ii type receptor (at r) antagonists like losartan, lisinopril, or olmesartan facilitates cardiac and renal ace overexpression according to some in vivo studies [ , ] . in contrast, sar viral rna following entry into respiratory epithelial cells downregulates the activity of ace , thereby increasing the levels of angiotensin . this may potentially cause severe lung damage [ , ] . continued treatment with these drugs may be essential for the survival to attenuate the cardiac stress of advancing covid- infection and limit the vasoconstriction and profibrotic effects of angiotensin in alveolar capillaries. some of the anti-inflammatory drugs such as ibuprofen, a nonsteroidal anti-inflammatory drug (nsaid), are activators of ace receptors, same as ace inhibitors or arbs. their usage can lead to increased risk of contracting covid- [ ] . since fatal lung failure induced by sars-cov infections may be controlled by blocking renin-angiotensin pathway [ ] , ibuprofen may not be harmful. however, there is no strong evidence, suggesting a link between intake of an nsaid and worsening symptoms due to infection caused by sars-cov- . the fda considers ibuprofen and the likes as a potentially promising therapeutic agent against covid- [ ] . studies have demonstrated that thiazolidinedione and its derivatives, which are type diabetes mellitus drugs, show efficacious effect against pulmonary disease induced by respiratory syncytial virus (rsv) or h n influenza infection [ , ] . but their role as a therapeutic drug against coronavirus is not yet explored. interestingly, it is known that thiazolidinediones may have the potential to upregulate ace receptor, which is identified as a binding target for sars-cov- in host cells [ ] . however, lack of clinical evidence makes it uncertain to determine its therapeutic efficacy against coronavirus infections. amici et al. have demonstrated that indomethacin, a wellknown nsaid and a potential cyclooxygenase (cox) inhibitor, exhibits antiviral activity against sars-cov and canine coronavirus (ccov). in vitro studies suggest that indomethacin exhibits dose-dependent response in canine a cell monolayers infected with ccov with an ic of um after h of exposure. also, remarkable inhibition against sars-cov-infected vero cells by more than % at concentrations that were non-toxic for uninfected cells is also observed. in addition, indomethacin significantly blocks viral rna synthesis in dogs infected with ccov following oral administration of the drug ( mg/kg) [ ] . this suggests probable efficacy of indomethacin against sars-cov- [ ] . colchicine is an anti-inflammatory drug commonly used for gout management and a variety of other conditions sharing similar pathophysiology. its mechanisms of action are related to interfering with migration of neutrophils to sites of inflammation and blocking the inflammasome complex in both neutrophils and monocytes, thus reducing il- beta activation [ ] . colchicine also has inhibitory effects on macrophages via the inhibition of the nacht-lrrpyd-containing protein (nalp ) inflammasome and pore formation activated by purinergic receptors p x and p x . there may also be beneficial effects on endothelial function due to colchicine's antifibrotic activities. some patients with covid- present with myopathies and colchicine has been shown to reduce inflammation in the cardiac myocytes [ ] . there are several ongoing studies investigating colchicine for cytokine storm (nct , nct , nct ). niclosamide, an anthelmintic drug, has been shown to be an effective sars-cov virus replication inhibitor at dose concentration of . um or higher in vero e cells without interfering with binding of corona virus onto the cells [ ] . another study reveals the efficacy of niclosamide in inhibiting mers-cov replication in verob cells via reduction of skp regulated becn ubiquitination and enhancement of autophagic flux and its ic value is determined to be . um [ ] . thus, the possibility of niclosamide to inhibit sars-cov- cannot be neglected. ivermectin, a potent anthelmintic drug, was first discovered to inhibit interaction between integrase (in) molecule of human immunodeficiency virus (hiv)- and its nuclear transport receptor importin α/β [ ] . further studies exhibit its potential to prevent viral replication of a broad spectrum of viruses, including dengue virus, flavivirus, and influenza [ ] [ ] [ ] .very recently, ivermectin has shown inhibition against sars-cov- up to -fold at h in vitro. inhibition of impα/β -mediated nuclear import of viral proteins is suggested as the probable cause of its antiviral activity [ ] . it will be interesting to know its inhibition effect against sars-cov- in vivo. both nitazoxanide and its metabolite and tizoxanide have shown inhibitory effects against mers-cov in llc-mk cells. besides, inhibition of other corona virus strains, including murine corona virus, mouse hepatitis virus strain a (mhv-a ), bovine corona virus strain l (bcov-l ), and human enteric corona virus (hecov- ) by nitazoxanide is reported via suppression of viral n protein [ ] . nitazoxanide is found to suppress pro-inflammatory cytokines in peripheral blood mononuclear cells (pbmcs) and il- in vivo. however, the relevance of this information is currently unknown [ ] . this treatment option refers to transfusion of plasma loaded with antibodies from individuals after resolution from a specific pathogen. this technique has been used for decades [ ] . transfusion can offer a short-term, immediate immunity for individuals. convalescent plasma can be used prophylactically and for already infected patients to attenuate clinical severity [ , ] . mechanism of action is through binding of the transfused antibodies to the pathogen, resulting in cellular cytotoxicity, phagocytosis, or direct neutralization of the pathogen [ , ] . previously, convalescent plasma was used for two coronaviruses, sars-cov and mers [ ] . one large study in hong kong involving patients with sars-cov supported early administration of antibodies for optimal clinical effect compared to later administration [ ] . limited data from taiwan and south korea showed clinical benefits in severe cases of sars-cov and mers [ , ] . reported dosage varied widely in terms of the amount of plasma transfused and antibody titer [ ] . limited data on covid- patients from china illustrated clinical benefits [ , ] . pilot study reported clinical improvement in terms of fever, cough, tightness of breath, and chest pain while no serious side effects were reported [ ] . there has been considerable attention placed on the role of hypercoagulable state leading to micro-and macro-vascular thrombosis in covid- . disseminated intravascular coagulation and elevated d-dimer level were identified as predictors of worse outcomes in a cohort study of patients with covid- [ ] . patients receiving anticoagulants had a decreased mortality [ ] . heparin has anti-inflammatory properties and may also inhibit viral attachment via conformational changes to the sars-cov- surface receptor (spike) s [ ] . low molecular weight heparin in patients hospitalized with covid- was associated with lower serum il- concentrations, suggesting that there may be an added mechanism besides prevention/treatment of thrombosis [ ] . based on available evidence, it is reasonable to administer venous thromboembolism prophylaxis with either a low molecular weight or unfractionated heparin in hospitalized patients. in patients with rapidly progressing respiratory deterioration or where clinical judgment suggests thrombosis, treatment doses of anticoagulants may be considered. historically, traditional herbal medicines have been used in the past to control and to treat epidemic outbreaks [ ] including the past epidemic outbreaks, such as sars and h n influenza [ , ] . to date, china and south korea have issued traditional medicinal treatment guidelines on the prevention and treatment of covid- [ ] . it is reported that greater than % of sars-cov- -infected patients in china had received some forms of traditional chinese medicine (tcm) treatments [ ] . similar to sars-cov, sars-cov- uses host receptor ace for the cellular entrance; it appears that some traditional medicines may have the capacity to target ace and these show some promises to prevent the infection of sars-cov- [ , ] . due to the high similarity in epidemiologic, genomics, and pathogenesis between sars-cov- and sars-cov, some herbal medicinal products were used for the treatment of patients with infection of sars-cov- in china and korea [ , ] . the top most commonly used tcm herbal medicinal products in china to treat covid- patients include astragalus membranaceus, glycyrrhiza uralensis, saposhnikoviae divaricata, rhizoma atractylodis macrocephalae, lonicerae japonicae flos, fructus forsythia, atractylodis rhizoma, radix platycodonis, agastache rugosa, and cyrtomium fortunei j. sm [ ] . in addition, some tcm herbal products, such as shen fu injection and re du ning injection, could manifest potential immunosuppressive effects and thereby decrease the level of tnf-α, il- β, il- , il- , il- , and other cytokines, resulting in inhibition of lung inflammation or acute lung injury [ , [ ] [ ] [ ] . as discussed above, cytokine storm/inflammatory responses may contribute to the deaths of many covid- patients. thus, anti-inflammatory agents presumably could reduce the severity and mortality rate [ , , ] . it is reported that qingfei paidu decoction could inhibit and alleviate excessive immune response and eliminate inflammation by regulating immune-related pathway and cytokine actionrelated pathway. the herbal formula qingfei paidu decoction was recommended by both chinese and korean guidelines. according to a recent publication, this herbal formula increases immunity and reduces inflammation by targeting the lung and spleen in covid- patients [ ] . li et al. reported that lianhuaqingwen (lh), a tcm formula, significantly inhibited sars-cov- replication in vero e cells and markedly reduced pro-inflammatory cytokine (tnf-α, il- , ccl- /mcp- , and cxcl- /ip- ) production at the mrna levels [ ] . sangju yin and yinqiao san are commonly used in clinical treatment to clear "lung heat," expel phlegm, relieve cough, regulate the patient's lungs, and restore normal lung function [ ] . similarly, yinqiao san may have antibacterial and antiviral functions [ ] . several clinical studies showed that tcm may bring new hope for the prevention and control of covid- [ ] [ ] [ ] . in general, it appears that tcm products were commonly used in covid- patients with mild symptoms to severe symptoms and could prevent or block the diseases progression. although the precise molecular mechanisms currently are unknown, the potential role of anti-inflammatory/antioxidative stress, improving hypoxemia/hypoxia and antiviral activities, among others, could be some of the major drivers. further investigations in the future are needed to uncover the molecular mechanisms. conclusion the covid- pandemic represents the greatest global public health crisis in the past years. hopefully vaccines and or specific therapeutic drugs targeting sars-cov- will be made available in the next few months or years. with the speed and volume of basic and clinical covid- / sars-cov- research to develop potential drugs and therapies for this disease, our hope will be on the horizon. particular interest, published recently, have been highlighted as: • of importance •• of major importance a pneumonia outbreak associated with a new coronavirus of probable bat origin the proximal origin of sars-cov- growth and intracellular development of a new respiratory virus the adaptation of two human coronavirus strains (oc and oc ) to growth in cell monolayers identification of a new human coronavirus characterization and complete genome sequence of a novel coronavirus, coronavirus hku , from patients with pneumonia sars-cov infection in a restaurant from palm civet isolation of a novel coronavirus from a man with pneumonia in saudi arabia bad news wrapped in protein: inside the coronavirus genome structural basis for the recognition of sars-cov- by full-length human ace characterization of spike glycoprotein of sars-cov- on virus entry and its immune cross-reactivity with sars-cov emerging coronaviruses: genome structure, replication, and pathogenesis human coronavirus: host-pathogen interaction t cell-mediated immune response to respiratory coronaviruses viral innate immune evasion and the pathogenesis of emerging rna virus infections the host immune response in respiratory virus infection: balancing virus clearance and immunopathology groups at higher risk for severe illness coronavirus and covid- : who is at higher risk? covid- does not lead to a "typical" acute respiratory distress syndrome middle east respiratory syndrome: emergence of a pathogenic human coronavirus sars-cov and ifn: too little, too late dysregulated type i interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in sars-cov-infected mice sars and mers: recent insights into emerging coronaviruses clinical features of patients infected with novel coronavirus in wuhan, china epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in covid- patients drug treatment options for the -new coronavirus ( -ncov) discovery and synthesis of a phosphoramidate prodrug of a pyrrolo[ , -f][triazin- -amino] adenine c-nucleoside (gs- ) for the treatment of ebola and emerging viruses comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against mers-cov remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus ( -ncov) in vitro first case of novel coronavirus in the united states compassionate use of remdesivir for patients with severe covid- antimalarial drugs in the treatment of rheumatological diseases the lysosomotropic amines, chloroquine and hydroxychloroquine: a potentially novel therapy for graftversus-host disease chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion new insights into the antiviral effects of 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pharmacology lianhuaqingwen exerts anti-viral and anti-inflammatory activity against novel coronavirus (sars-cov- ) the effects and mechanism of yinqiao powder on upper respiratory tract infection traditional chinese medicine treatment of covid- traditional chinese medicine for covid- treatment network pharmacology-based analysis of the role of traditional chinese herbal medicines in the treatment of covid- publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations funding information this work was financially supported in part by institutional funds, by r ca , from the national cancer institute (nci), r at and r at from the national center for complementary, and integrative health (nccih) of the national institute of health (nih) awarded to dr. ah-ng tony kong. key: cord- -v z jq authors: rajagopal, keshava; keller, steven p.; akkanti, bindu; bime, christian; loyalka, pranav; cheema, faisal h.; zwischenberger, joseph b.; el banayosy, aly; pappalardo, federico; slaughter, mark s.; slepian, marvin j. title: advanced pulmonary and cardiac support of covid- patients: emerging recommendations from asaio—a “living working document” date: - - journal: asaio j doi: . /mat. sha: doc_id: cord_uid: v z jq the severe acute respiratory syndrome (sars)-cov- is an emerging viral pathogen responsible for the global coronavirus disease (covid)- pandemic resulting in significant human morbidity and mortality. based on preliminary clinical reports, hypoxic respiratory failure complicated by acute respiratory distress syndrome is the leading cause of death. further, septic shock, late-onset cardiac dysfunction, and multiorgan system failure are also described as contributors to overall mortality. although extracorporeal membrane oxygenation and other modalities of mechanical cardiopulmonary support are increasingly being utilized in the treatment of respiratory and circulatory failure refractory to conventional management, their role and efficacy as support modalities in the present pandemic are unclear. we review the rapidly changing epidemiology, pathophysiology, emerging therapy, and clinical outcomes of covid- ; and based on these data and previous experience with artificial cardiopulmonary support strategies, particularly in the setting of infectious diseases, provide consensus recommendations from asaio. of note, this is a “living document,” which will be updated periodically, as additional information and understanding emerges. the human environment is surrounded by a myriad of viruses, the number, and type increasingly being defined. many viral species result in serious, if not fatal infections, e.g., marburg, hanta, ebola, although typically remaining contained to specific hosts, circumstances of infections, or geographies, limiting modes, and extent of spread. [ ] [ ] [ ] of viral species, respiratory viruses, in particular, have periodically presented with widespread distribution of virus resulting in pandemics, with often overwhelming morbidity and mortality. , we presently face such a situation with the emergence of the severe acute respiratory syndrome (sars)-cov- virus. [ ] [ ] [ ] the major viral pandemics of the last century, including those involving h n and h n influenza and sars-cov and middle east respiratory syndrome (mers)-cov coronavirus, predominantly manifested as respiratory system illnesses with possible secondary cardiovascular and other end-organ system effects. although many patients develop a mild to moderate illness, a significant subset of patients develop severe progressive respiratory and occasionally cardiac failure, refractory to conventional therapies, including advanced ventilator management strategies. for these patients, the only plausible treatment strategy is artificial lung or circulatory support. from the initial clinical experience in china and in italy, it is clear that sars-cov- infection, also termed coronavirus disease , that is covid- , has a disease natural history that results in severe respiratory and circulatory compromise for a significant portion of those infected. it is the specific goal of the present paper to provide a resource document to the clinical community regarding evolving best practice strategies for advanced pulmonary and cardiac support in patients with severe progressive covid- . overall, the philosophy of the present paper is to be a living document-one gathering best practice information of the moment, which will be rapidly and continuously updated as improved strategies emerge. we first provide a brief background on the biology and pathophysiology of covid- infection, evolving modes of diagnosis, and valuable laboratory parameters to follow. we provide evolving information on medical therapies. we then focus on management of the severely compromised patient warranting artificial lung or circulatory support. recommendations are offered for patient selection and details of appropriate therapeutic pulmonary or cardiac support. covid- is the result of infection with sars-cov- , a novel coronavirus, causing severe acute respiratory syndrome. , , covid- is considered a zoonotic infection, with a natural reservoir most likely in bats, and with a potential intermediate species before the onset of human infection. , at the time of this writing, it is unclear how human transfer occurred. moreover, if or when mutations have occurred in sars-cov- , it is unknown whether these may have occurred within nonhuman animal reservoirs, or following human transfer. recent studies, however, now point to pangolin species as a natural reservoir of sars-cov- -like covs. sars-cov- is a single (+) stranded rna virus whose replication is catalyzed by an rna-dependent rna polymerase. however, genomic single-stranded rna also has messenger rna function, such that it may be translated on ribosomes into a peptide sequence. similar to the original sars virus, also a coronavirus, sars-cov- is capable of binding cell surfacebound angiotensin-converting enzyme (ace ), which is richly expressed on pneumocytes, as well as endothelial cells. , this interaction facilitates viral intracellular entry. in addition, the viral spike protein has a polybasic cleavage site at a location between the spike subunits, which may be proteolytically cleaved; this is thought to enhance viral entry and infectivity. , infection with sars-cov- results in the development of acute pneumonia, with patchy ground-glass opacities. the distribution of this infiltrate appears to be more dominant in lung bases, and is eccentric, with an emerging pattern. this pattern may be appreciated via direct example shared on line. this is a near-universal (> %) finding in hospitalized patients with covid- , based upon data from the original patient cohorts in wuhan, china. however, clinical manifestations may be quite variable. fever is a near-universal finding. however, although dyspnea is a common finding both in intensive care unit (icu)-hospitalized as well as non-icuhospitalized patients, it is unsurprisingly significantly and substantially more common in icu patients. in addition, constitutional symptoms such as anorexia are more common in icu patients. acute hypoxemic respiratory failure of varying severity is the norm in icu patients. a median p a o /f i o ratio of < was identified in icu-hospitalized patients, and ratios were worse in non-survivors in comparison to survivors. the documented incidence of acute respiratory distress syndrome (ards) was ≈ %. biochemical evidence of myocardial injury was present in ≈ % of patients; further, overt shock was evident in < % of patients. as expected, ards and shock were more common in icu-hospitalized patients. systemic arterial blood pressure did not appear to relate to survival; however, inotrope/vasoconstrictor usage was substantially higher in icu-hospitalized and non-survivor patients. moreover, the hemodynamic profiles of shock in these patients are unclear. finally, as is common in other etiologies of shock and respiratory failure, dysfunction of other end-organs, such as the kidney and the liver, was found to be more common and more severe in icu-hospitalized and non-survivor patient groups. in particular, acute kidney injury and its severity were highly correlated with poorer outcomes. laboratory data consistent with higher-risk covid- subgroups were identified as well. icu-hospitalized patients and non-survivors tended to have overall leukocytosis yet with lymphopenia, coagulation profiles consistent with disseminated intravascular coagulation (elevated prothrombin time and d-dimer), elevated blood urea nitrogen and creatinine, elevated serum transaminase levels, and elevated procalcitonin. , these findings are broadly consistent with those of high-risk subsets of sepsis. many fail to appreciate the degree of isolation and care that chinese medical institutions provided their early patients. they were experienced with the sars epidemic and applied that experience early in the spread of the disease. likewise, the medical sophistication of italy appears underappreciated in the lay press. the italian setup mostly focused on large hospitals with icu preparedness, lacking a comprehensive plan on community medicine and small healthcare institutions. indeed, the first patient was diagnosed in a small city, codogno. following this, a "red zone," with total limitation of social mobility, was instituted for containment of infectious spread. the case was particularly challenging since this patient was a young healthy athlete without any medical or epidemiological (travel to china or contact) risk factors. the first case immediately prompted the development of a task force for managing and limiting the outbreak on a regional level. the united states is early in its experience with covid- , but has per capita fatality rates that are, along with germany, the lowest of those countries afflicted with a large burden of infected patients. the early german public health experience with covid- is particularly noteworthy for the lowest mortality outcomes within the group of infected patients, but the reasons for this are unclear at this time. unpublished communications suggest that this may be due, at least in part, to a younger covid- -infected population. covid- infection manifests with symptoms typically associated with other respiratory infections, that is, fever, cough, and shortness of breath, which are sensitive but highly non specific. to this end, a basic diagnostic algorithm for "fever clinics," given the high sensitivity of fever as a sign of covid- , has been developed. high-fidelity, sensitive, specific, and predictive diagnostic strategies are needed. it should be noted that current center for disease control (cdc) recommendations reiterate that "clinicians are strongly encouraged to test for other causes of respiratory illness" as appropriate. conversely, covid testing should be employed for those with a high index of suspicion and for those at increased risk. a hierarchy of "priorities of testing" is provided by the cdc. current diagnostic strategies include obtaining samples for viral testing from the upper (nasopharyngeal or oropharyngeal swab or wash) or lower (induced sputum, endotracheal aspirates, bronchoalveolar lavage) respiratory tract samples for via nucleic acid amplification tests, such as reverse transcriptase-polymerase chain reaction; as well as for bacterial or fungal cultures as is appropriate. , confirmation of sars-cov- may be made via follow on nucleic acid sequencing, via detection of the specific n, e, s, and rdrp viral genes. for in-hospital patients, we recommend sending two specimens on two different days to ensure adequate specimen collection. a computed tomography scan of the chest revealing ground-glass opacities or consolidation consistent with the disease increases the clinical suspicion of disease. , basic monitoring includes pulse oximetry and telemetry for stable patients outside the intensive care unit, and more invasive monitoring with systemic arterial and central venous/pulmonary arterial (pa) catheters in the intensive care unit. of note, for inpatients, continued viral detection and shedding has been reported which may also be monitored via blood and stool sampling. , a baseline transthoracic echocardiogram (see following) can be performed if the patient presents with systemic arterial hypotension or overt shock. pa catheter placement may be useful in patients with shock as well (see following). we do not recommend routine endomyocardial biopsies, due to risks of cardiac structural injury (iatrogenic ventricular septal defect, right ventricular [rv] free wall rupture and cardiac tamponade, and tricuspid valve injury with regurgitation). in patients who have evidence of focal/regional cardiac injury, via electrocardiography or echocardiography, diagnostic left-sided cardiac catheterization with coronary angiography is reasonable. ultimately it will be important to monitor if a given patient mounts an immune response and develops protective immunity. while the covid pandemic is just evolving, it is important to mention this here as well. as such, with an eye to the future, early reports examining the serologic response of patients in china reveal that covid patients generally mount a typical serologic response to viral infection. specifically, utilizing elisa, igm has been detected by day with igg levels rising subsequently as igm begins to decline. there are currently no specific therapeutics approved by the food and drug administration to treat this patient population. the only randomized-controlled trial done to date was an open-label trial comparing rotinavir/lotanavir combination therapy to standard of care in patients with confirmed covid- illness. this study included hospitalized patients with treatment with the study drug failing to show difference in time to clinical improvement or mortality. there was a trend towards better outcomes in patients started on the study drug less than days after symptom-onset and met the study's secondary outcome. the number of severely ill patients needing invasive mechanical ventilation was low in this particular trial. further studies are required to determine if this drug is efficacious in patients with severe hypoxemic respiratory failure. remdesivir, an inhibitor of rna synthesis, developed by gilead sciences inc., is currently enrolling patients for three clinical trials on the basis of their previous data which showed promise in animal models for treating mers and sars which are also caused by coronaviruses. favipiravir is a similar antiviral agent under investigation in asia. hydroxychloroquine/chloroquine, reported to inhibit sars-cov- in vitro, is postulated to help with inhibition of viral entry and reduce viral infectivity. although this has been currently universally recommended given absence of strong data for any other drugs, there is currently no randomized-controlled trial that has proven its efficacy. with respect to therapies that are not directly antiviral, corticosteroids have been studied in a subset of patients from wuhan with positive results (hr . , ci, . - ), in a retrospective study cohort of patients. further prospective randomizedcontrolled trials are needed to study this further. tocilizumab, an anti-interleukin (il)- receptor blocking monoclonal antibody, is being studied for patients with cytokine release syndrome. there is limited evidence at present time for this drug. similarly, other anti-inflammatory agents inhibiting il- receptor signaling, such as anakinra (soluble il- receptor antagonist) and canakinumab (anti-il- β monoclonal antibody), are under evaluation. adoptive transfer of sera from recovered covid- patients also is being undertaken in covid- . , this approach was utilized with some success in ebola, sars, and mers, with enhanced efficacy if utilized early in the disease natural history. , conceptually, this technique is logically predicated upon ( ) adequate anti-coronavirus antibody titers and ( ) that these antibodies are disproportionately neutralizing in character. from an immunological perspective, solid organ transplant recipients are a group warranting particular attention and careful therapeutic consideration. consensus presently does not exist as to how to best manage immunosuppressive regimens in the setting of covid- infection. it may be reasonable to use lower levels of immunosuppression in the setting of covid- infection, as is often employed when transplant recipients develop other infections, waged from the perspective of favoring innate immune augmentation. however, as some mortality and morbidity in covid- -infected patients may be due to hyperactivation of adaptive or innate components of the immune system, it may be reasonably hypothesized that maintained or even increased levels of immunosuppression may be beneficial in the setting of covid- infection. as such, we urge caution and careful consideration on an individual patient in addressing this issue. clarity for this issue will emerge as we progress further in the covid pandemic. pharmacotherapies for the cardiopulmonary physiologic effects of covid- are under investigation. anticoagulation is strongly recommended in patients with persistent d-dimer elevation, due to suspicions of an as-yet-to-be-defined prothrombotic milieu in these patients. the role of inhaled pulmonary vasodilators is unclear in the setting of covid- with refractory acute hypoxemic respiratory failure but is being studied. there is no current available guidance regarding the merits of utilizing inhaled nitric oxide, although it could be postulated that this could be helpful in normal compliance ards by reducing hypoxic pulmonary vasoconstriction and improving ventilation-perfusion (v/q) matching, reducing rv afterload. last, with respect to prophylaxis and protection, anti-covid- vaccines are under development by several groups. these include standard peptide/protein-based strategies, as well as rna-based strategies. plans for rapid testing are underway. the need for pulmonary or cardiac support strategies, and the extent of support required, is inversely proportional to the quality of native pulmonary or cardiac function. in addition, the availability of particular types of support equipment is inversely proportional to their invasiveness, complexity, and extent of support required. the broad recommendations below are in line with these concepts. what is proposed as first-line therapeutic strategies generally provide lesser degrees of gas exchange or hemodynamic function support, but are clearly more widely available, and are less complex and less invasive (and thus, less dependent upon operator expertise). however, escalation to second-or third-line therapeutic strategies should not be delayed in favor of prolonged trials of first-line support. decisive determination of whether a strategy is succeeding or failing is essential to achieving optimal outcomes. tables and provide a simple reference guide. covid- results in acute hypoxemic respiratory failure, with severe v/q mismatch and overt intrapulmonary shunting. , the recommendations below are based on previous experience with the management of ards, especially the h n influenza pandemic experience. [ ] [ ] [ ] mechanical ventilation: noninvasive and invasive. noninvasive mechanical ventilation (mv) strategies, such as continuous positive airway pressure (cpap) and bilevel positive airway pressure (bipap), may be appropriate for short durations in patients with hypoxemia suboptimally treated by high-flow supplemental o systems alone. as either a noninvasive or invasive mode of mv, cpap increases basal (throughout the respiratory cycle, and thus evident even at end-expiration, the invasive analog being positive end-expiratory pressure [peep]) intra-alveolar pressure, and thus, lung volume. globally, this may manifest as an improvement from lower-normal to higher lung volumes in the setting of normal overall lung compliance, or in the setting of low overall lung compliance, from lower-to normal-higher lung volumes. mv recruits under-or non-ventilated alveoli that are otherwise yet perfused, and thus improves o transfer of blood flowing past these alveoli, and the overall v/q ratio. bipap, which is analogous to pressure-support invasive mv, provides cpap plus additional input airway pressure during inspiration. this not only increases mean alveolar pressure and volume, but does so by augmenting the inspiratory flow rate, and for a fixed inspiratory time, the tidal volume. noninvasive ventilation (niv) is a reasonable initial strategy in patients with covid- -related respiratory failure, provided that hypoxemia is not profound, and the anticipated duration of niv support is not long. the issue with niv is the need for patient cooperation. there is current concern that cpap and bipap modes may potentiate aerosolization of the respiratory viral particles. some institutional guidelines limit high-flow nasal cannula to < l/min, and avoid niv, due to risk of staff infection, and further suggest that early intubation should be attempted. the timing of such transition from niv to invasive mv presently remains patient specific. a variety of invasive mv modes are available to treat acute hypoxemic respiratory failure. volume-controlled, pressurecontrolled, pressure-support, and mixed invasive mv modes may be best suited for individual patients. based upon data principally best expressed in the ardsnet studies, it is well established that excess pressure and volume each may contribute to pulmonary injury (barotrauma and "volu"-trauma, respectively). , consequently, whether either volume-controlled or pressure-controlled modes of invasive mv are chosen, lungprotective mechanical ventilation should be used in patients with covid- -related acute hypoxemic respiratory failure. this consists in: tidal volumes of < ml/kg ideal body weight, plateau airway pressures of < cm h o, and f i o titrated in order to achieve adequate systemic arterial o saturations. in some patients, paralytic agents may be required. , importantly, individual centers, depending upon availability of invasive and even noninvasive mv, need to make often difficult decisions about resource utilization in the context of potentially more than one individual patient condition. factors in these considerations include severity of gas exchange derangement, individual patient comorbidities, anticipated survivability of the covid- infection, and availability of resources, all must be considered in determination of mv allocation to an individual patient. these issues are even more acute with respect to advanced lung support strategies, as are discussed below. prone position mechanical ventilation. prone positioning is now the standard of care in ards and should be considered in patients with covid- as this would potentially improve lung aeration at the bases of the lung. a prospective multicenter randomized control trial has shown that in patients with p a o / f i o ratio less than mmhg, with an f i o ≥ . , and a peep ≥ cm h o, early application of prolonged prone positioning sessions significantly decreased the -day and -day mortality ( % vs. . %, -day mortality; . % vs. %, -day mortality). we recommend that whenever feasible, all patients with severe hypoxemic respiratory failure with covid- ards should undergo either manual or artificial prone positioning, depending upon the resources available. there is a concern that the man-power needed to prone these patients could potentially expose a large majority of staff members to the virus, and this should be taken into consideration before proning. other observations and unique considerations with respect to conventional management. regarding the preliminary experience with covid- which highlighted the discrepancy between gas exchange and lung mechanics (severe hypoxemia with normal compliance) some relevant physiologic and clinical points are noteworthy. first, several groups have (unpublished data) suggested that covid- is associated with microvascular thrombosis in several tissue beds: pulmonary, coronary, and renal. indeed, high d-dimer is associated with increased severity and mortality of covid- , which is indicative of microthrombosis in these arterial/arteriolar/capillary beds. this may a contributory mechanism with respect to why severe hypoxemia is observed in the setting of normal or high lung compliance, since capillary endothelium and alveolar epithelium both may be involved. in addition to hypoxemia, pulmonary vascular microthrombi, when severe, may also contribute to shock. second, because of refractory hypoxemia, most clinicians increase peep. however, high peep may result in alveolar overdistension in the setting of normal or high compliance. high peep also can augment pulmonary vascular impedance (creation of west zone lung; although if this incidentally happened to occur in unventilated lung zones and pulmonary blood flow were better redistributed to betterventilated lung zones, this might ameliorate hypoxemia), and reduce systemic venous return, both of which reduce rv stroke volume and cardiac output (co). conversely, decreased oscillatory lung loading via low tidal volume and distending pressure "lung-protective" ventilation may cause or exacerbate hypercapnia, permissive or otherwise. extracorporeal gas exchange: extracorporeal membrane oxygenation. if invasive mv fails, a decision needs to be made quickly as to whether extracorporeal gas exchange is appropriate. since covid- -associated respiratory failure is hypoxemic in nature, extracorporeal membrane oxygenation (ecmo) is almost certainly the most appropriate extracorporeal strategy (in contrast to extracorporeal carbon dioxide removal). the decision to utilize ecmo, similar to that for mv above, relates to ( ) anticipated benefit (failure of mv to achieve adequate oxygenation, or requirement of traumatic mv settings in order to achieve adequate oxygenation) in the background of organ systems not directly supported or treated by ecmo, ( ) risks (most notably, local cannulation-related complications, and active or biochemical coagulopathy), and ( ) ecmo supply availability and other institutional infrastructure, and ( ) practitioner expertise. in the case of covid- , in particular, but in ecmo deployment in general as well, dysfunction of organ systems other than those that are ecmo-supported (e.g., hematological/immune, renal, hepatic) decreases the anticipated benefit and may even increase the risks of therapy. , ecmo support has well-recognized local cannulation site vascular risks-that is, both ischemic and bleeding. preexisting coagulopathy increases the risks of local bleeding complications but also increases systemic bleeding complications-most ominously, intracranial hemorrhage. additionally, practical considerations, while non-ideal, are real factors that influence the decision to implement ecmo. with respect to recently published literature, ecmo utilization in the setting of covid- respiratory failure has been associated with poor outcomes (hospital survival well below %), although the number of cases has been too small to draw definitive conclusions. most patients reported in the population from china died. more recent data available to us, as yet unpublished, seem more encouraging, although we do not have data on survival to hospital discharge. overall, we believe that in a high mortality scenario such covid- , ecmo would not significantly impact on the global outcome figures, rather should be discussed on a patient-specific individual basis. our suggestion is that the decision to implement ecmo should follow a clear failure of invasive mv, paralytic agents, and prone positioning; however, this assessment should be rapid. the latter of these is to avoid dysfunction or failure of other organ systems, and we further recommend that in light of the pandemic status of covid- and the generalized poorer outcomes of ecmo support when other organ system dysfunction occurs, that ecmo implementation generally should be restricted to those with isolated single organ system (pulmonary) dysfunction who are invasively mechanically ventilated ≤ days. each institution's experience and resources differ, as do the local and regional epidemiology of covid- ; consequently, ecmo implementation in the setting of renal or hepatic failure must be assessed on a case-by-case basis (further discussion regarding institution in the setting of cardiac failure follows later in this document). we also mention emerging early experience to combine ecmo with means of modulating or removing cytokines, as yet a further extension of modalities for the sickest of patients with cytokine storm and severe cardiopulmonary compromise. we now turn to the specific "tactical" aspects of ecmo, focusing on cannulation approaches, since the cannulation approach is one of the few important variables that can be not only controlled, but altered to optimize gas exchange. we initially focus on "right-sided" ecmo used for pulmonary support, that is, ecmo in which the right side of the circulation is exclusively accessed (the most common form of which is veno-venous [v-v] ecmo). tables and provide a summary. central versus peripheral. central cannulation, that is, of the great vessels and generally via an open surgical approach, has the advantage of providing large cannula, with low resistance and high maximal volumetric flow rates. however, it is invasive and has greater periprocedural (not necessarily longer-term, though) bleeding risks. moreover, central cannulation requires cardiothoracic surgeons to perform it. peripheral cannulation generally cannot achieve the fluid mechanics of central cannulation. however, peripheral cannulation is most commonly percutaneous and has lower periprocedural bleeding risks. finally, practitioners of a variety of specialties can be trained to perform peripheral cannulation procedures-i.e. cardiothoracic surgeons, interventional cardiologists, critical care anesthesiologists, and icu physicians. although central cannulation is hemodynamically advantageous (with respect to higher flow rates; hemodynamic support is not relevant in pure v-v ecmo), in light of its invasiveness, bleeding risks, and specialized training required, it is more reasonable to propose peripheral cannulation as the initial approach of choice for covid- -related respiratory failure. percutaneous: single versus two cannula. for right-sided ecmo, either single cannula (dual-lumen) or dual cannula approaches exist. advantages of the single cannula approach include reduced risks of local bleeding complications and the potential to ambulate. in the case of right atrial/ventricular inflow and pulmonary arterial outflow, lesser degrees of recirculation are present. this latter single cannula approach also provides rv mechanical circulatory support (mcs) (see below). however, overall volumetric flow rates may be lower, and image guidance during cannulation is necessary. in contrast, the two-cannula approach requires two venous cannulation sites and typically precludes the ability to ambulate. moreover, recirculation is common, although it may occur with the single cannula approach if both inflow and outflow are in the systemic venous compartment. however, higher flow rates are achievable with the two-cannula approach, and image guidance-which often is not present under emergent circumstances-usually is not needed. the lack of need for image guidance means that unlike the single cannula approach, cannulation using the two-cannula technique does not require operating room or catheterization laboratory environments, and potential covid- exposure of these vital spaces and their ancillary staff. thus, we suggest that the two-cannula technique should be preferred for most institutions and circumstances. bi-femoral approaches are particularly advantageous in terms of rapidity of deployment, avoidance of cannulating surgeons and physicians being positioned near the patient's oropharynx and endotracheal tube, and ease of subsequent prone positioning. however, under the current circumstances, we recommend each team use whatever cannulation technique is most familiar and comfortable, to minimize complications. some patients with covid- develop shock. , the hemodynamic profile of shock (cardiogenic versus distributive versus hypovolemic), and its coexistence or lack of coexistence with respiratory failure is unclear based upon the available published literature. it is possible that, in highly selected and limited cases, mcs with or without pulmonary support may be appropriate. [ ] [ ] [ ] in particular, decision-making regarding implementation of left ventricular (lv) support is complex (see below). these strategic and tactical issues related to mcs in covid- -infected patients are reviewed. when (if at all) should mcs be used in the setting of shock in covid- . based upon the existing data, it is unclear whether shock occurs in a subset of hospitalized covid- infected patients with respiratory failure, or whether it may occur independent of respiratory failure. unpublished communications to us suggest that shock occurs in a small but noteworthy (due to their dire clinical status) subset of covid- patients with respiratory failure requiring at least mechanical ventilation. because outcomes are clearly poorer when more organ systems are dysfunctional, we suggest that mcs ought to be highly selectively implemented in covid- -infected patients. yet, some patients, particularly those who are relatively younger, with fewer underlying comorbid conditions and good overall short-and long-term life expectancy, may be appropriate candidates for mcs. given the range of clinical profiles in patients with covid- , we recommend early adoption of an interdisciplinary approach, incorporating advanced heart failure specialists, a lesson learned from ongoing efforts in the arena of complex cardiogenic shock. , the immediate discussion is restricted to the left-sided circulation because decision-making here is even more complex. it is first important to determine whether left-sided cardiac dysfunction is present. in patients with shock, echocardiography (see following discussion) is particularly useful, and pulmonary arterial catheters are helpful as well, both for blood flow measurements as well blood gas measurements from different circulatory compartments. underlying congenital or acquired structural or coronary arterial disease is assumed to be absent for the purposes of this discussion. if the systemic arterial blood pressure (mean arterial pressure [map] < mmhg) is decreased, or high doses of inotropic and vasoactive agents are required to achieve a normal-range systemic arterial blood pressure, then echocardiography should be undertaken. if the lv ejection fraction (lvef) is at least moderately reduced (lvef < %), this is clearly abnormal, and in the acute setting, with a non-dilated lv and normal-range lv end-diastolic volume (lvedv), stroke volume would be substantially reduced. in addition, invasive hemodynamic monitoring assessments, such as those provided by pulmonary arterial catheters, often are helpful in discerning whether intrinsic lv dysfunction is present (lv stroke work may be calculated; see discussion below). however, it is important to note that the lvef is not a good index of intrinsic lv systolic function or true lv contractility because it is inversely proportional to afterload; indices such as prsw are superior, but generally are not feasible to obtain in the clinical setting. the lvef may be reduced if the impedance of the systemic circulation is increased, without decreased lv contractility; however, the systemic arterial blood pressure most commonly is normal-range or increased in such patients (calculations of lv stroke work or power would be required in order to formally assess this), which is not the case in shock. regardless of whether systemic arterial hypotension is thought to be cardiogenic with lv failure, distributive, or mixed, the lvef generally is a useful index to use in order to determine whether mcs is reasonable. if lvef is high or even normal in the setting of systemic arterial hypotension, and the lvedv and heart rate are normal, then the co is normal or elevated, and mcs would have to be able (with native output) exceed that in order to have a hemodynamic benefit. in contrast, if the lvef is low, then for a normal lvedv and heart rate, the co is reduced despite optimal lv preload, and mcs may be reasonable. if the lvef is reduced, and high doses of inotropes are required to treat systemic arterial hypotension, mcs for the lv may be appropriate in highly selected covid- patients. however, with rare exception, shock with a normal lvef (predominantly distributive) should not be treated with mcs, unless volumetric flow rates well in excess of the native co can be achieved. as discussed, although invasive hemodynamic assessment may not be feasible in a timely fashion in patients with covid- whose clinical status is rapidly deteriorating, invasive assessment is the gold standard. if pa catheters can be placed expeditiously in patients with shock, they are recommended for the purposes of definitive diagnostics; from pa catheters, the co and index, lv power/cardiac power output (cpo), as well as pa pulsatility index, may be obtained. as stated earlier, prsw or stroke work index is the gold-standard index for the assessment of lv systolic function, being superior to systolic ventricular elastance measures. , determination of prsw requires a range of lvedvs to be studied, but for a given lvedv, a particular sw may be used as an isolated data point. lv power (cpo) is the closest clinical correlate to sw (being lv work per unit time) and is clinically calculated as map multiplied by co. this is analogous to electrical power, which for a simple circuit with a single battery and resistor is equal to current (flow) multiplied by voltage (pressure difference), or the square of the current (flow) multiplied by resistance (systemic vascular resistance). an important caveat in using cpo is that it is not a per beat assessment, in that heart rate is incorporated. tachycardia commonly observed in the majority of shock may limit decreases in cpo, even when per lv dysfunction is evident on a per beat basis. modalities for support: veno-arterial ecmo, short-term ventricular assist devices. v-a ecmo: central or peripheral. the relative advantages of central versus peripheral cannulation have been discussed above. however, unlike right-sided ecmo, systemic arterial cannulation is employed. ischemic extremity complications are far more common with peripheral arterial cannulation than central cannulation, which reduces the relative advantages of central cannulation. perhaps more importantly, lower extremity arterial cannulation may result in differential hypoxemia when hypoxemic respiratory failure is present, wherein the lv ejects hypoxemic pulmonary venous return into the aortic root/coronary arteries/proximal aortic arch, whereas the lower body is perfused with normoxemic or hyperoxemic postgas exchanger blood flow. consequently, decision-making with respect to central versus peripheral cannulation for v-a ecmo is more complex than for v-v ecmo alone. hybrid v-v/v-a ecmo approaches may be reasonable under such circumstances. however, hybrid configurations are more complex and resource-intensive, typically requiring continuous bedside attendance by a perfusionist or ecmo specialist. short-term paracorporeal left ventricular assist devices with either central or peripheral cannulation; short-term cathetermounted left ventricular assist devices (impella). the principal advantages of left ventricular assist devices (lvads) over v-a ecmo in shock are direct lv unloading, and more homogeneous distribution of blood flow through the systemic arterial circulation. direct (inflow cannula within the left side of the heart, and particularly the lv) lv unloading is more effective in reduction of lvedv, and consequently, lv diastolic and systolic pressures (reduction of systolic pressures being a manifestation of the frank-starling mechanism); this may be advantageous relative to indirect (inflow cannula proximal to/ upstream of the left side of the heart) unloading (e.g., via v-a ecmo) vis-à-vis greater reduction of pathologic load-induced signals and resultant mechanotransduction. it should be noted that the effectiveness of v-a ecmo in unloading the left side of the heart is an area of some controversy. modeling studies suggest that v-a ecmo should consistently result in augmentation of the lvedv and lvedp. however, this is demonstrably not so based upon clinical experience in which lv distension and even subclinical lv volume overload only occur in a minority of cases , as well as recent and even classical controlled animal model studies of v-a ecmo support in acute lv systolic dysfunction. [ ] [ ] [ ] even when lv distension does occur, drainage through a rightsided pa vent catheter can decompress the lv, which runs counter to the aforementioned modeling studies. what is less controversial and clearer, based upon a review of physiologic concepts and the literature regarding lv distension in v-a ecmo, is that mcs approaches which employ left-sided circuit inflow ("direct" unloading) generally are more effective in achieving lv unloading than those which employ right-sided circuit inflow. consequently, in some patients, lvad-based approaches may be superior to v-a ecmo. in addition, when gas exchangers are used in concert, this "modular" approach permits isolated treatment (as well as de-escalation) of cardiac and pulmonary failure. however, these approaches are more technically demanding and require a high level of practitioner and institutional expertise. as is the case for v-a ecmo, we recommend that only highly selected patients with covid- be considered for short-term lvad support. because the impella catheter-mounted micro-axial vads are substantially different from other pump mechanisms insofar as the pump mechanisms themselves are intracorporeal and miniaturized, we briefly mention two salient features. first, percutaneous transfemoral placement may be performed at the bedside under echocardiographic guidance, rather in than in a cardiac catheterization laboratory. in pandemic conditions, this may be useful. second, placement via an axillary artery approach, using the newest iteration of introducer sheaths and securing devices, results in secure pump position, which may facilitate safer prone positioning. with further reference to the range of impella devices, a wide range of delivered volumetric flow rates may be achieved. the original impella . device generally may not provide adequate flow for the severely compromised shock patient for which robust lv mcs is required. the impella cp device is better with a peak flow of . l/m. the impella . and . devices, each of which may be introduced via side-grafts on the axillary artery, are capable of providing flows of . and . l/m, respectively, that is, levels of flow close to those achievable with surgically implanted lvads, all via a minimally invasive platform. finally, secure pump positioning achieved with devices inserted via axillary artery side-grafts has the advantage of longer-term mcs, in patients with slow recovery of lv function. experience with impella in combination with ecmo, that is, "ecpella," to enhance unloading and boost support is just beginning to emerge in severly compromised covid patients. right ventricular support. respiratory failure commonly causes an increase in the pulmonary vascular impedance, increasing rv afterload. in some cases, this can occur to such an extent ("afterload mismatch") that even in the setting of normal intrinsic rv contractility, the rvef and output may decrease substantially (cor pulmonale). in such patients in the acute setting, attempting to treat the underlying etiology of impaired gas exchange using v-v ecmo alone may not be sufficient. this is because v-v ecmo recirculation is exacerbated by reduced rvef and tricuspid regurgitation. in cases of cor pulmonale with covid- -related respiratory failure, we suggest that strategies to support the rv are appropriate. for patients who may require proning, percutaneous rvads using femoro-femoral approaches, can be used with an oxygenator. the single cannula (e.g., protek duo) approach to this offers the advantages of peripheral cannulation via one site, and with minimal recirculation. central approaches may be reasonable in patients in whom high-flow rates cannot be achieved. if high-flow rates are thought not to be achievable with a single cannula approach, then v-v ecmo plus a device such as the impella rp may be reasonable. our asaio recommendations are meant to complement those of the extracorporeal life support organization (elso). the potential role of ecmo, in particular, in covid- is discussed in an overview in lancet respiratory medicine. the elso guidance document: "ecmo for covid- patients with severe cardiopulmonary failure" describes usage of ecmo in covid- patients intended for experienced ecmo centers. although the published small number of patients from china who underwent ecmo had poor outcomes, currently unpublished data from japan and south korea, with ecmo support in + covid- cases, is communicated at ≈ % recovery and survival; however, other locations have communicated equivalent or worse outcomes. accepted ecmo indications, access, and management, are described in the elso guidance for adult respiratory and cardiac failure on the elso web site (elso.org). in general, ecmo is warranted when metrics indicate a high ( %) risk of mortality with conventional management. these notably include p a o /f i o ratio below , despite available optimal care. ecmo used at the time when patients meet indications (not days later) has better outcomes. as mentioned in a recent article by elso leaders in jama, for inexperienced centers, "ecmo is not a therapy to be rushed to the front lines when all resources are stretched during a pandemic." to supplement general ecmo guidelines a covid-specific elso ecmo guidance document has just been published online. a list of experienced ecmo centers is provided on the elso web site. the recommendations below are summarized from the elso report. during the covid- surge, we propose concentrating the sickest young patients in hospitals where experienced ecmo teams are available. because the use of ecmo for covid- is occurring in the midst of a pandemic which can overwhelm hospital resources, important unique strategic issues/questions/considerations for ecmo resource allocation in covid- patients are as follows: should ecmo be considered for covid- patients? this is largely a local (hospital and regional) decision based on overall patient load, other events, and policies in the hospital. if the hospital must commit all resources to other patients, then ecmo should not be considered until the resources stabilize. if the hospital feels that ecmo can be safely provided, then it should be offered to patients based on risk/benefit analyses. understanding hospital resource limitations as above, standard ecmo should continue when that is possible related to overall hospital resources. patients without comorbid conditions under age are the highest priority while resources are limited. health care workers are high priority. standard contraindications apply: terminal disease or otherwise highly limited life expectancy at baseline, active biochemical or clinical coagulopathy (particularly that which is unable to be treated or has failed treatment), major cns damage, do not resuscitate (dnr status), and the absence of consent. exclusions for covid- during limited resources are hospital-specific. because prognosis is worse, patients with major comorbid conditions (of particular note is immunosuppressioneither due to disease or iatrogenically), age > , and mechanical ventilation greater than days, could be reasonably excluded. anecdotally, renal failure is not an exclusion; however, general outcomes with covid- patients with renal failure is exceedingly poor in the published chinese experience. should ecmo during cpr (e-cpr) be considered for covid- patients? due to the complexity and extensive team training associated with doing e-cpr, centers who do not currently provide these services, should not initiate programs during times of limited resources. in ecmo centers, consideration should be given to whether to continue developmental programs such as out of hospital e-cpr or off-site cannulation during resource-limited times. if an e-cpr program is also structured for organ donation and shares these personnel, strict cooperation with the transplant allocation system should be maintained, as covid- status has eventually to be thoroughly assessed and evaluated. what protective measures for the team should be used? standard covid- precautions as recommended by who and national health organizations (e.g., centers for disease control) should be used. there are not special precautions for blood contact. eventually, health care workers who are immune to covid- (post-convalescent, or vaccinated) may not need protection for themselves (although they could be carriers). it has come to our attention that some groups are considering early adoption of ecmo as a potential alternative to mechanical ventilation. we emphasize that v-v ecmo is not an alternative to mechanical ventilation or proning. on a physiologic level utilizing active, appropriate pressure and volume lung inflation, avoiding barotrauma, with low-level peep, is vital to maintain pulmonary alveolar inflation, reduce fluid transudation and attempt to maintain a modicum of innate lung physiology, with an aim towards recovery. v-v ecmo should only be considered when mechanical ventilation is failing. further, from a resource utilization and relative risk perspective, moving to ecmo is a resource-intensive and resource-consuming procedure that should be utilized with careful consideration. to date, survival on ecmo for cardiorespiratory failure is highly variable in covid patients and significantly less than the previously reported % at most centers. how to approach therapeutic futility for termination? during times of limited resources observing no lung or cardiac recovery after days on ecmo can largely be considered futile, and the patient can be returned to conventional management. of course, individual patient decisions must be guided by the overall consensus related to a given patient, in a given clinical context, by the treatment team involved. of note, the "save"-survival after veno-arterial ecmo, scoring system has been developed by elso and the department of intensive care at the alfred hospital in melbourne, to provide estimates of survival for adults undergoing v-a ecmo. however, we caution that this was developed based solely on consideration of patients with refractory cardiogenic shock. as of this writing, no data exists as to its translatable utility in compromised covid patients on ecmo. further, the bulk of compromised patients with covid in need ecmo, with pulmonary dominant needs, will require vv, rather than v-a ecmo, to which save does not apply. the covid- pandemic poses major and possibly unique challenges to physicians and medical institutions. although a limited number of patients may need artificial lung and/ or heart support, these patients are among the most complex and resource-intensive. consequently, it is important to develop pathways for their optimal care. this document is offered by asaio as a starting point of guidance in order to help our community approach these critically ill patients. this document will evolve as our collective experience grows, and as treatment approaches reveal efficacy versus limited success. we refer all readers to the asaio website "covid- active portal" (in red), to the input tab of "therapeutic and diagnostic suggestion/comments" to provide in the field practical feedback and insight. as our collective experience of what is working vs. what is not evolves, this living document will be rapidly updated. thank you for your participation to improve care for covid- patients, over the spectrum of illness, including the most gravely ill. the global virome project the pathogenesis of ebola virus disease marburg virus infection detected in a common african bat a global perspective on hantavirus ecology, epidemiology, and disease mutation and epistasis in influenza virus evolution a novel coronavirus emerging in china -key questions for impact assessment emerging viruses without borders: the wuhan coronavirus real-time tentative assessment of the epidemiological characteristics of novel coronavirus infections in wuhan, china, as at epidemiology and cause of severe acute 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mendoza, jose luis accini; estrada, victor hugo nieto; lópez, nelly beltrán; bolaños, elisabeth ramos; franco, daniel molano; castell, carmelo dueñas; moreno, albert alexander valencia; amaya, iván camilo alarcón; flórez, john serna; valencia, bladimir alejandro gil; camilo pizarro, g; polo, yulieth maría zabaleta; meza, carmen lucia chica title: actualizacion de la declaraciÓn de consenso en medicina critica para la atenciÓn multidisciplinaria del paciente con sospecha o confirmaciÓn diagnÓstica de covid- date: - - journal: nan doi: . /j.acci. . . sha: doc_id: cord_uid: qwh inx antecedentes y objetivos: la enfermedad por coronavirus de (covid- ) es una enfermedad ocasionada por el nuevo coronavirus del síndrome respiratorio agudo grave (sars-cov- ). se identificó por primera vez en diciembre de en la ciudad de wuhan, en los meses siguientes se expandió rápidamente a todos los continentes y la organización mundial de la salud (oms), la reconoció como una pandemia global el de marzo de . la mayoría de los individuos son asintomáticos pero una baja proporción ingresan a cuidados intensivos con una alta morbilidad y mortalidad. este consenso tiene como objetivo actualizar la declaratoria inicial emitida por la asociación colombiana de medicina crítica (amci) para el manejo del paciente críticamente enfermo con covid- dentro de las áreas críticas de las instituciones de salud. métodos: este estudio utilizó dos técnicas de consenso formal para construir las recomendaciones finales: delphi modificada y grupos nominales. se construyeron preguntas por la estrategia pico. grupos nominales desarrollaron recomendaciones para cada unidad temática. el producto del consenso fue evaluado y calificado en una ronda delphi y se discutió de forma virtual por los relatores de cada núcleo y los representantes de sociedades médicas científicas afines al manejo del paciente con coid- . resultados: expertos nacionales participaron en la actualización del consenso amci, especialistas en medicina critica y cuidados intensivos, nefrología, neurología, neumología, bioeticistas, medicina interna, anestesia, cirugía general, cirugía de cabeza y cuello, cuidados paliativos, enfermeras especialistas en medicina crítica, terapeutas respiratorias especialistas en medicina crítica y fisioterapia, con experiencia clínica en la atención del paciente críticamente enfermo. la declaratoria emite recomendaciones en los ámbitos más relevantes para la atención en salud de los casos de covid- al interior de las unidades de cuidados intensivos en el contexto nacional de colombia. conclusiones: un grupo significativo multidisciplinario de profesionales expertos en medicina crítica emiten mediante técnicas de consenso formal recomendaciones sobre la mejor práctica para la atención del paciente críticamente enfermo con covid- . las recomendaciones deben ser adaptadas a las condiciones específicas, administrativas y estructurales de las distintas unidades de cuidados intensivos del país. background and objectives: the coronavirus disease (covid- ) is caused by the new severe acute respiratory syndrome coronavirus (sars-cov- ). it was first identified in december in wuhan, china. in the following months it spread quickly to all continents and was recognised as a global pandemic by the world health organization (who) on march th, . most cases of infection remain asymptomatic, while a low proportion require intensive care, experiencing high morbidity and mortality. this consensus aims to update the initial statement issued by the colombian association of critical medicine (amci) for the management of the critically ill patient with covid- within the critical areas of health institutions. methods: this study used two formal consensus techniques to construct the final recommendations: modified delphi and nominal groups. questions were constructed using the pico strategy. recommendations for each thematic unit were developed by nominal groups. the consensus product was evaluated and qualified in a delphi round, and was discussed virtually by the speaker of each nucleus, as well as the representatives of scientific medical societies related to the management of the patient with covid- . results: a total of national experts participated in the update of the amci consensus, all specialists in critical and intensive care medicine, nephrologists, neurologists, chest physician, bioethicists, internal medicine specialists, anaesthetists, general surgeons, head and neck surgery, palliative care, nurses specialised in critical medicine, respiratory therapists specialised in critical medicine and physiotherapy, with clinical experience in the care of critically ill patients. this update issues recommendations in the most relevant areas for health care of covid- patients within the intensive care units, contextualised for colombia. conclusions: a significant multidisciplinary group of professionals, who are experts in critical medicine, reviewed and issued recommendations on best practice for the care of critically ill patients with covid- through formal consensus techniques. recommendations must be adapted to the specific, administrative, and structural conditions of the different intensive care units in the country. para la actualización de la declaratoria se utilizaron dos técnicas para el desarrollo de consensos de tipo formal, técnica delphi modificada y grupos nominales. un consenso formal permite integrar las opiniones de un colectivo de expertos que están expuestos a un tema específico (experto afectado) con la mejor evidencia científica disponible, utilizando técnicas que permitan reducir los sesgos de subjetividad. la técnica delphi es una metodología que plantea enviar cuestionarios a un grupo de expertos, para que califiquen una serie de recomendaciones en rondas reiteradas con retroalimentación de los resultados y respuestas anónimas, la técnica delphi empleada fue modificada, variante a la versión original propuesta por la corporación rand en , pero se mantuvo las ventajas de la técnica, la iteración y retroalimentación para reflexión de las propias opiniones. los grupos nominales es una técnica que reúne a un grupo de expertos bajo la coordinación de un facilitador para evaluar y calificar información o preguntas ( , ) . para la actualización se convocó grupos nominales con expertos multidisciplinarios cada uno con un líder o jefe de núcleo. los grupos construyeron las preguntas por metodología pico y desarrollaron progresivamente las recomendaciones hasta las versiones finales. el proyecto se desarrolló en fases, fase : formulación del problema y socialización; fase : elaboración de las preguntas, fase : formulación de las recomendaciones y ronda de calificación. las estrategias de búsqueda se desarrollaron en bases de datos especializadas (medline, embase, lilacs, central), en las circunstancias donde no se encontró evidencia directa, se utilizó y se adaptó evidencia indirecta del tópico relevante en el paciente críticamente enfermo general. expertos con un promedio de años de experiencia en la atención del paciente crítico evaluaron y calificación las recomendaciones en la metodología delphi mediante un cuestionario distribuido por medio de correo electrónico, respetando la política de privacidad de datos vigente. recomendaciÓn se recomienda que los prestadores de servicios de acuerdo con su infraestructura física y la disponibilidad de recursos (tecnológico, humano, de interdependencia y apoyo) definan su modelo de atención para pacientes con covid- en estado crítico basado en principios de factibilidad, efectividad, seguridad y la relación entre la demanda (momento epidemiológico) y capacidad/capacidades de respuesta:  modelo . atención de pacientes con sospecha o confirmación diagnóstica covid- . este enfoque permite concentrar, optimizar y racionalizar recursos y reducir el riesgo potencial de contagio al equipo de atención, de apoyo y de pacientes.  modelo . atención mixta, de pacientes con y sin diagnóstico de covid- , en escenarios que cuentan con unidades de aislamiento normatizados (presión negativa y > -renovaciones completas de aire por hora) soportado en el documento institucional de gestión organizacional y operativo del servicio de cuidados intensivos, descrito en los procesos prioritarios. amci ® menos accidentalidad y violencia). la reducción de procedimientos quirúrgicos complejos electivos es una opción razonable condicionado a las posibilidades del paciente. sin embargo, situaciones como la progresión y descompensación de las patologías crónicas asociadas a las medidas de restricción social puede plantear un efecto bumerang con mayor demanda de camas de uci. con base en las predicciones simuladas de las tasas esperadas de ingreso a uci de pacientes con covid- contrastado con el déficit de servicios y camas de cuidados críticos en el país a partir de la capacidad instalada se han planteado fases de desarrollo cuyas características en términos de servicios, recursos y cronología se aprecian en la ilustración y .  fase (para el gobierno nacional: ampliación de la capacidad instalada*). parte de la liberación de camas de cuidados intensivos destinadas para atención covid- bajo el modelo y/o . la liberación de camas y servicios con mínima adaptación es la fase más inmediata y resolutiva que debe acogerse a la exigencia normativa (resolución de ), en la que se espera menos mortalidad, morbilidad y tasa de complicaciones asociados con la atención de pacientes con covid- en estado crítico.  fase (optimización para el gobierno nacional*) representan el reordenamiento de las camas de cuidados intermedios adultos en camas de cuidados intensivos y de hospitalización en intermedio. de adultos. el gobierno nacional toma en cuenta la ampliación de la capacidad instalada hospitalaria descrita en el plan territorial. para esta fase se necesitan equipos de ventilación mecánica (excluidos por la norma de estos servicios), monitoreo básico y avanzado y un número mayor de talento humano multidisciplinario competente. amci ® acuerdo con las etapas ( - ) y los perfiles requeridos priorizados como primera, segunda y tercera línea de respuesta*. en la ilustración podemos observar que avanzar de las fases a se va a necesitar mayor intervención en términos de organización, planeación operativa, formación por competencias y apoyo por telesalud (teleapoyo o teleexperticia). el personal no especializado o especializado de servicios hospitalarios diferente a urgencia, quirófano o uci pueden constituir grupos de apoyo para la gestión administrativa y de índole humanitaria (líneas de respuesta) la integración de estos requerimientos adaptativos se ha puesto de manifiesto en la experiencia del centro médico new york -presbyterian weill en la ciudad de nueva york, en donde la demanda de camas de unidades de cuidados intensivos (uci) y ventilación mecánica excedió su capacidad.( ) se recurrió a los quirófanos y de recuperación las cuales no estaban en uso porque los procedimientos electivos habían sido pospuestos. se hicieron adecuaciones físicas para garantizar la vigilancia continua de los pacientes y la seguridad del equipo de atención. se capacito a todo el personal de cuidado perioperatorio disponible y fueron distribuidos en las áreas recién configuradas. las enfermeras familiarizadas con las máquinas de anestesia asumieron como terapeutas respiratorios y los intensivistas de anestesia supervisaban estas unidades. recomendaciÓn se recomienda la adopción de un modelo simulado de predicción (basado en el cociente de fatalidad, tasa de ingreso a uci y el número de reproducción ro) para proyectar, de manera anticipada las necesidades de recurso físico, tecnológico y humano de cuidados críticos en fase de preparación de la pandemia por covid- . las tomas de decisiones relacionadas con el fortalecimiento de la capacidad/capacidades de la oferta de cuidados críticos (habilitadas o adaptadas) pueden deducirse mediante la aplicación de modelos matemáticos que intentan, desde la dinámica epidemiológica, establecer el efecto simulado de las medidas de mitigación o supresión adoptadas sobre la tasa de contagio a través del tiempo. con ello se busca planear el uso de recursos e implementar acciones de prevención y de distanciamiento social más eficientes, así como establecer las necesidades en materia de cama de cuidados críticos (intensivos e intermedios) habilitadas o adaptadas en áreas de expansión y con ello los recursos resolutivos como tecnologías, interdependencias y talento humano capacitado. la capacidad predictiva del modelo resulta de establecer: la información en términos de casos proyectados (población susceptible), el modelo de transmisión, el impacto de las amci ® intervenciones no farmacológicas (mitigación y supresión) para lograr disminuir el número de reproducción r (tasa de contagio), la distribución de la gravedad de la enfermedad y con ello el porcentaje esperado de casos críticos el decreto del . . ( ) , por el cual se declara un estado de emergencia económica, social y ecológica en todo el territorio nacional proyectó para una tasa de contagio de . y cerca de millones de casos, la ocurrencia de mil casos de pacientes con covid- en estado crítico ( . %) y la necesidad de incrementar las camas de cuidados intensivos en un % que con una estancia promedio de días tendría un costo de mil millones de pesos. colombia cuenta con cerca de camas de cuidados intensivos ( / parte son intermedio) de las cuales el % podría ser utilizada para la atención de pacientes covid- ( ). con base en el modelo matemático ha proyectado la necesidad de camas de uci indicando por deducción la necesidad de camas a partir de un plan adaptativo de expansión y extensión. colombia reporta a la fecha actual , casos confirmados y nuevos casos de covid- confirmados y cerca del % ocupan una cama de cuidados intensivos (esta cifra es mayor si se tomaran en cuenta los casos sospechosos). de este modo, los modelos matemáticos permiten predecir el comportamiento epidemiológico de la enfermedad y con esto anticiparse a proyectar el plan de fortalecimiento hospitalario (incluyendo camas, tecnologías, talento humano) y los recursos financieros para respaldar la expansión del cuidado críticos. estos modelos deben ser predictivos y no reactivos al comportamiento epidemiológico de la enfermedad y solo debe des escalarse hasta después de reducirse a menos de . el índice ro. ( - ) recomendaciÓn se sugiere la implementación de una estrategia de telesalud (teleapoyo o teleexperticia) en el marco de la pandemia covid- , cuando no se cuente con un intensivista presencial, que, mediante una tecnología adecuada complemente la atención en las áreas de cuidados críticos realizado por personal capacitado. aún cuando es considerada ventajosa sus implicaciones en términos de resultados clínicos, económicos y de riesgos legales no se ha demostrado. en situaciones donde se declara una pandemia los sistemas de salud pueden tener dificultades para hacer frente a una demanda exponencial y fuera de control. esto puede ser así en el marco pandemia covid- que prevé un % de pacientes en condición crítica y que amerita reorganización y/o adaptación de su capacidad de respuesta. incrementar la disponibilidad de camas y servicios de cuidados críticos mediante una estrategia de expansión supone retos asociados a la insuficiencia que se puede presentar en talento humano especializado específicamente de especialistas en medicina crítica y cuidado amci ® intensivo, escenario que se puede complicar en la medida que intensivistas sean separados o aislados en el curso de la epidemia. en este contexto se hace necesaria la implementación de modelos ágiles de telesalud (ts) para el acompañamiento de las unidades de cuidado crítico en expansión y de instituciones prestadoras de servicios de salud de baja y mediana complejidad para la regulación con los equipos de referencia y contrarreferencia de pacientes que pueden necesitar atención en cuidados intensivos. ( ) ( ) ( ) ( ) ( ) ( ) el decreto ley de ( ) plantea la adopción de medidas en el sector salud para garantizar la prestación de los servicios de salud y para facilitar la implementación de modelos de atención que incluyan la telesalud y la prestación de los servicios en la modalidad de telemedicina se determinan algunas medidas temporales para: i) adecuar temporalmente un lugar no destinado a la prestación de servicios de salud, intra o extra mural. ii) prestar servicios en modalidades o complejidades diferentes a las habilitadas dentro de las cuales puede estar la telemedicina iii) prestar servicios de salud no habilitados. en este decreto también se establecen condiciones temporales para la implementación de plataformas tecnológicas para la telesalud. en complemento, la resolución de ( ) (estándares de habilitación) plantea la modalidad de la telemedicina (prestador remisor-prestador de referencia) para las unidades de cuidado intermedio e intensivo. la telesalud se puede prestar de dos maneras: teleapoyo y teleexperticia. tabla . teleapoyo (ta) soporte solicitado por un profesional de la salud a otro profesional de la salud a través de tic siendo responsable de la conducta quién solicita el apoyo. no requiere habilitación y por tanto no requiere autorización transitoria relación a distancia con comunicación sincrónica o asincrónica utilizando tic entre dos profesionales de la salud, uno de los cuales atiende presencialmente al usuario y otro atiende a distancia. el primero es responsable de las decisiones/recomendaciones entregadas al paciente y el segundo es responsable de la calidad de la opinión que entrega y debe especificar las condiciones en las que se da dicha opinión, lo cual debe consignarse en la historia clínica. requiere autorización transitoria (decreto ) ( ) la telesalud y la prestación de servicios de salud en esta modalidad son estrategias seguras y efectivas para guiar, a distancia, el diagnóstico y el tratamiento del paciente hospitalizado y en estado crítico. sus ventajas generales se presentan en la tabla . asociaciÓn colombiana de medicina crÍtica y cuidados intensivos. amci ® tabla . ventajas generales de la telesalud decreto legislativo de .  facilita la viabilidad de aplicación modelos organizativos que favorecen la continuidad y la integridad asistencial y la atención centrada al entorno del paciente, aplicando conceptos de globalidad e interoperabilidad a las organizaciones sanitarias, dando lugar a nuevas formas de organización y trabajo en red.  mejora de la calidad asistencial, ya que facilitan el acceso y la disponibilidad de servicios asistenciales en condiciones de calidad.  mejora calidad de vida del paciente por la disminución de desplazamientos para la atención ya que permite la atención o monitorización remota con tic en su domicilio.  mejora la oportunidad y la resolutividad de la atención.  facilita la equidad en el acceso a los servicios de salud independientemente de la localización geográfica (acerca la atención especializada a toda la población).  mejora la atención integral y seguimiento tanto de los pacientes crónicos, como los de las enfermedades de baja prevalencia.  reduce los tiempos de espera (tanto en la realización del diagnóstico como en el tratamiento), evitando complicaciones por no atención oportuna.  posibilita realizar atención remota de mediana y alta complejidad en la baja complejidad, reduciendo el número de remisiones.  disminuye la posibilidad de infección cruzada entre usuarios de los servicios de salud y el personal de salud.  incide en la formación y competencia del talento humano en salud.  facilita la educación de pacientes en medicina preventiva y salud pública.  descongestiona servicios de urgencias y consulta externa.  contribuye a la reducción de movilidad de personas en la ciudad.  responde a las necesidades inmediatas en salud de la comunidad.  es un medio de racionalización de costos en salud. puede abarcar otros servicios de gestión administrativa como entrega de fórmulas o facturación. amci ® se recomienda la implementación de un modelo de cuidados críticos covid- liderado por intensivistas, en áreas habilitadas o adaptadas, con el beneficio preponderante de disminuir la mortalidad, tiempo de estancia y optimización de recursos. se recomienda una cobertura por intensivistas de al menos horas diarias y un cociente intensivista/paciente cercano a intensivista por cada - pacientes, basado en la alta complejidad de la enfermedad critica covid- con un alto porcentaje de pacientes en ventilación mecánica, largos tiempos de estancia y alto riesgo de mortalidad. fuerte a favor fundamento un intensivista es un profesional médico capacitado en medicina crítica y de cuidados intensivos conforme a los estándares establecidos por una institución de educación superior debidamente reconocida ante el ministerio de salud. este especialista debe liderar y tomar todas las decisiones con respecto al cuidado de los pacientes críticos, incluyendo admisiones y egresos, qué médicos consultar, estándares de atención, gestión de la calidad y seguridad, gestión humana y ética, interacción con la familia e implementación de un programa de investigación y de formación continua para mejorar capacidades y competencias del equipo de atención, control de conflictos, entre otras.( ) existe una enorme validez conceptual y una preponderancia de evidencia que sugiere que ser atendido por un especialista en cuidados críticos (intensivista) es "bueno" para los pacientes de la uci. la mayoría de los estudios demuestran el impacto positivo de un uci dirigida por intensivistas los modelos de personal médico de la uci más ampliamente estudiados difieren en el nivel al cual los intensivistas están involucrados en el manejo de los pacientes. las uci de alta intensidad son aquellas donde un intensivista de tiempo completo u obligatorio maneja a la mayoría de los pacientes diariamente. las uci de baja intensidad no tienen participación intensivista u ofrecen consultas intensivistas electivas. un metaanálisis mostró que un modelo de alta intensidad en comparación con uno de baja intensidad estuvo asociado con una menor mortalidad en la uci, menor mortalidad hospitalaria, y una reducción significativa en la duración de la estancia hospitalaria. un modelo de alta intensidad por la noche se asoció con menor mortalidad solo cuando durante el día era de baja intensidad. ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) asociaciÓn amci ® forzosa" por condición de riesgo siempre en consonancia con los términos establecidos en el decreto ley de ( ). según la normatividad vigente todo miembro del equipo de atención, especialista no intensivista o no especialista (enfermeras, fisioterapeutas/terapeutas respiratorias) y auxiliares de enfermería deben tener constancia de asistencia a acciones de formación continua y/o capacitación en atención covid- en cuidados críticos las cual puede ser parte de un programa institucional de capacitación liderado por el intensivista coordinador o titular del servicio o a partir de cursos respaldados por instituciones académicas acreditadas o los ofrecidos por la asociación colombiana de medicina crítica y cuidados intensivos (amci). las tablas y nos muestra como dentro de este proceso adaptativo por estado de emergencia y atribuido a un desequilibrio entre la oferta y la demanda, otras especialidades, profesionales de la salud y personal en formación pueden hacer parte de los equipos de atención bajo las siguientes premisas: . la supervisión, coordinación y liderazgo del intensivista es necesaria y . el intensivista establece los roles y competencias del th no intensivista y no normatizado, de acuerdo a sus perfiles, y delegada acciones asistenciales (vía aérea, accesos vasculares, reanimación cardiopulmonar, pronación), administrativas (ordenes médicas, notas clínicas) o de naturaleza humanitaria (comunicación con la familia, apoyo emocional al th, etc.). es necesario considerar los roles de las especialidades que formarán parte de la gestión asistencial y/o administrativa de pacientes con covid- en áreas críticas habilitadas o adaptadas de manera transitoria en colombia tabla . integridad de interdependencia (norma / ) integralidad e interdependencia (adaptiva) gfa integridad de interdependencia (norma / ) integralidad e interdependencia (norma / ) integridad de interdependencia (norma / ) obligatorio en gestión asistencial integralidad e interdependencia(norma / ) obligatorio gestión asistencial apoyo a tomas de decisiones(gfa) apoyo a tomas de decisiones (gfa) a:formacion continua + covid- (curso virtual); b: requiere capacitación covid- (curso virtual); c: gfa: grupo focal asistencial, sistema alerta-acción, rcp, pronación, accesos vasculares, ingreso a uci. d: gfad: grupo focal administrativo: consentimiento, notas de evolución. ts: telesalud. se recomienda la aplicación de la escala news- por parte de un equipo de respuesta rápida, para establecer el lugar de atención de pacientes con diagnóstico definitivo o sospecha de infección por covid- que encuentran en los servicios de urgencias o de hospitalización. se recomiendan escalas como el qsofa y el curb- para apoyar la decisión tomada con base en la escala news- . sin embargo, un qsofa mayor o igual a puntos (mínimo / ) y un crb- mayor o igual puntos tienen baja sensibilidad (alta incidencia de falsos negativos) para identificar pacientes que puedan requerir ingreso a uci. se recomienda el score de riesgo covid- -gram para identificar el riesgo de desarrollar un estado de la enfermedad crítico en pacientes con covid- y como herramienta complementaria a la escala news- en escenarios de alta demanda y escasez de recursos, de manera que la decisión de ingreso a uci se haga sobre aquellos pacientes que realmente se beneficiarán de la misma en términos de vidas salvadas y número de años salvados. la escala news fue construida y validada en paciente con infección por el virus de la influenza a/h n y se recomienda como una herramienta objetiva para decidir nivel de atención, incluyendo ingreso a uci o situaciones terminales que requieren acompañamiento familiar y medidas de cuidado paliativo. esta escala incluye variables fisiológicas que son: frecuencia respiratoria, saturación arterial de oxígeno (spo ), uso de oxígeno suplementario, presión arterial sistólica, frecuencia cardiaca (pulso), temperatura y nivel de conciencia. es de mencionar que esta escala no contempla la edad del paciente. en un reporte del acute medicine task force of the royal college, london, uk, recomendó la utilización de la escala news en los servicios de urgencias ( ) . un estudio que evaluó una base de datos con . signos vitales obtenidos de . pacientes demostró que esta escala tiene una buena capacidad para discriminar pacientes en riesgo para un desenlace combinado de paro cardiaco, ingreso no anticipado a uci o muerte dentro de las primeras horas de atención; de esta manera genera una gran oportunidad para el establecimiento temprano de una intervención clínica que cambie el pronóstico del paciente ( ) . la escala news- tampoco contempla la edad, pero sí incluye la presencia de hipercapnia bajo diferentes niveles de spo y oxígeno suplementario. esta escala es la que ha sido estudiada como herramienta para identificar pacientes en riesgo de desarrollar un estado de enfermedad crítica por covid- con un valor ≥ puntos ( / ) ( ) . con base en la escala news- se establece el grado de riesgo, el tipo de alerta, y la intensidad de monitoreo requerido; y de acuerdo con el puntaje arrojado, se define claramente el nivel de atención que requiere el paciente con diagnóstico de infección por covid- , incluso ingreso a uci (tabla ). esto se establece a través de una escala de puntuación así: -score puntos: manejo domiciliario bajo aislamiento y signos de alarma. -score punto: manejo domiciliario y seguimiento clínico en casa. -score - puntos: manejo en salas de hospitalización. -score - puntos: manejo en uci, área covid- . -score ≥ puntos sin condición extremadamente grave o irreversible y con alta posibilidad de recuperación: traslado a uci, área covid- . amci ® -score ≥ puntos con condición extremadamente grave y con datos de irreversibilidad o enfermedad terminal: no ingresa a uci y se traslada a salas de hospitalización con acompañamiento familiar y consulta a experto en bioética y cuidados paliativos. la ilustración establece un flujograma de conductas basado en el puntaje del news- . tabla . news- score. el qsofa con un valor ≥ puntos es otra herramienta recomendada para decidir qué pacientes que ingresan a uci. esta herramienta fue recomendada por la tercera definición de consenso (sepsis- ) para identificar pacientes con alto riesgo de muerte o estadía prolongada en uci entre aquellos con sospecha de infección ( ) . en este score, un punto es asignado para variables así: frecuencia respiratoria ≥ /min, presión arterial sistólica ≤ mmhg y escala de coma de glasgow (ecg) < . el score curb- y su versión simplificada, el crb- se utilizan para evaluar la severidad de enfermedad en personas hospitalizadas con neumonía adquirida en comunidad (nac). ambos scores han sido adoptados por la sociedad británica de tórax para predecir la necesidad de soporte respiratorio o vasopresor intensivo (srvi) en pacientes con covid- ( ) . el score crb- asigna un punto para variables así: confusión de reciente inicio, frecuencia respiratoria ≥ /min, presión arterial sistólica < mmhg o presión arterial diastólica ≤ mmhg y edad ≥ años. pacientes con un score ≥ puntos necesitan hospitalización ( ) . en un estudio clínico observacional realizado sobre los primeros pacientes ingresados en un hospital de noruega con diagnóstico confirmado de covid- , se evaluó la utilización de sistemas de score clínicos al momento del ingreso: news- , qsofa, crb- y sirs, con los puntos de corte previamente mencionados ( ) . la enfermedad se clasificó como enfermedad severa y enfermedad crítica. solo pacientes ( %) se clasificaron como enfermedad crítica. al evaluar los scores con sus puntos de corte, pacientes presentaron un qsofa ≥ [ con enfermedad severa ( %) y con enfermedad crítica ( %)], solo pacientes presentaron un crb- ≥ [ con enfermedad severa ( %) y con enfermedad crítica ( %)] y pacientes presentaron un news- ≥ [( con enfermedad severa ( %) y con enfermedad crítica ( %)]. la mediana del score news- para pacientes con enfermedad severa fue de . [riq: - ] vs . [riq: . - ] para pacientes con enfermedad crítica. los autores concluyen que el qsofa y el crb- se comportan similar y con una baja capacidad para la identificación de enfermedad crónica en pacientes con covid- ; por otro lado, los datos indican que el news- podría ser una herramienta más útil para identificar pacientes con riesgo de un curso más agresivo de la enfermedad ( % vs. %) ( ) . amci ® un estudio de cohorte retrospectivo realizado en un hospital en liverpool (uk), el puntaje qsofa se comportó como el más específico ( %; % ic: % - %) pero el menos sensible ( %; % ic: % - %) en comparación al puntaje sirs y la escala news como predictor de mortalidad hospitalaria en un grupo de paciente admitidos por sepsis al servicio de emergencias ( ) . otro estudio retrospectivo de un único centro comparó el rendimiento de sistemas de score, qsofa, curb- y crb- para predecir la necesidad de soporte vasopresor o respiratorio intensivo (svri) en pacientes ingresados con diagnóstico confirmado de covid- a un hospital de wuhan (china) ( ) . un total de pacientes ( . %) necesitaron svri durante su estadía en el hospital. la tasa de mortalidad hospitalaria en esta cohorte fue de pacientes ( . %). se evalúo el rendimiento de las escalas con análisis de curva roc (auc), puntos de corte óptimo, sensibilidad, especificidad y valores predictivos. el punto de corte óptimo del crb- para predicción de srvi fue de puntos, con una sensibilidad del % y una especificidad del . %. el valor auc del score crb- para predecir la necesidad de svri fue significativamente más alto que el del qsofa ( . ± . vs. . ± . , p= . ). los valores de auc fueron similares entre crb- y curb- para predecir svri ( . ± . vs. . ± . , p= . ). los autores concluyen que el crb- podría ser mejor que el qsofa para identificar paciente con covid- en riesgo de necesitar svri. su et al consideran que fue la inclusión de la edad ≥ años dentro del score crb- lo que le dio un mayor grado de superioridad sobre el qsofa ( ) . el crb- puede ser una herramienta de puntuación útil para covid- debido a su simplicidad en la aplicación, especialmente en emergencias y condiciones de escasez de recursos. finalmente, el score de riesgo covid- -gram fue descrito por un grupo de investigadores en covid- quienes reunieron datos de pacientes en hospitales en china ( ) . esta fue una cohorte retrospectiva multicéntrico en la que se recogieron un total de variables entre demográficas, médicas, clínicas (signos y síntomas), imagenológicas y de resultados de laboratorios. utilizando la metodología de regresión lasso (least absolute shrinkage and selection operator) construyen un modelo de regresión multivariable resultando en un score de riesgo predictivo para desarrollar enfermedad critica en pacientes con covid- confirmado al momento de la admisión. de las variables iniciales fueron predictores independientes estadísticamente significativos para el desarrollo de enfermedad crítica. estas variables fueron: anormalidad en los rx tx (or: . ; %ic: . - . recomendaciÓn se recomienda la aplicación de un algoritmo basado en una evaluación dinámica del score news que involucre una escala de evaluación funcional, para priorizar el ingreso a uci con transparencia científica y ética con equidad social, y de ser posible respaldado por un comité de priorización clínica (cpc) integrado por expertos de cuidado intensivo y un representante del comité de ética hospitalaria durante la pandemia por covid- . se recomienda un modelo determinado por prioridades para definir criterios de ingreso a uci, permite establecer rápidamente qué pacientes se benefician de ingreso uci y qué pacientes deben permanecer en servicios de hospitalización, o con acompañamiento familiar y cuales con medidas de cuidado paliativo. fuerte a favor page amci ® fundamento la pandemia covid- nos ha enseñado que la disponibilidad de camas de uci puede ser insuficiente y el plan estratégico diseñado para ampliar la capacidad de respuesta debe ir de la mano con la implementación rigurosa de un protocolo de triaje y de priorización de ingreso a cuidados intensivos, como medida extraordinaria para optimizar los recursos, mitigar y controlar los efectos de la pandemia sobre el balance oferta (efectiva y resolutiva) y la demanda. los protocolos de triaje y priorización están diseñados para asignar los limitados recursos de una manera justa y transparente donde, por definición, algunas personas serán excluidas del acceso a la atención orientado a aumentar la disponibilidad de camas de cuidados intensivos. sin embargo, es necesario enfatizar que la disponibilidad de camas no es un fin en sí mismo. la intención implícita y explícita de los protocolos de clasificación debiera ser el «bien público» de maximizar la supervivencia de la población. pero es incorrecto suponer que este bien público se logra al maximizar la supervivencia entre los que reciben cuidados intensivos. si bien muchos protocolos de triaje reconocen esto al tratar de excluir a los pacientes que no lo necesitan absolutamente (el «demasiado sanos») y los que tienen menos probabilidades de beneficiarse (él «demasiado enfermo»), no prestan suficiente atención a las diferencias entre grupos en términos de la duración de los cuidados intensivos necesarios para lograr resultados. si el objetivo del triage es mejorar la supervivencia de la población con un recurso escaso, entonces el recurso escaso no son camas, sino días de cama; no son ventiladores, sino tiempo de ventilación. de ello se deduce que el triaje no será efectivo si en la valoración, no se discrimina adecuadamente y se considera de manera equívoca que la gran mayoría de las personas que requieren cuidados intensivos tienen una probabilidad similar de supervivencia y una duración de estadía anticipada similar. ( ) de este modo, el ingreso a uci debe acogerse a los criterios habituales, científicos y éticos, bajo el rigor de "idoneidad clínica" tomando en cuenta parámetros como la gravedad de la enfermedad, la presencia de comorbilidades (severidad, clase funcional), potencial de recuperabilidad, deseo del paciente (o la familia), de equidad distributiva y el uso de las escalas validadas de severidad y de predicción de ingreso a cuidados intensivos. los pacientes con covid- tienden a progresar después del inicio de los síntomas dentro de los a días a una forma grave con síndrome de dificultad respiratoria aguda (sdra) o falla multiorgánica órgano. la identificación temprana y simple de pacientes que requieren respiración intensiva o el soporte vasopresor sería de gran valor durante el brote covid- . ( ) ( ) ( ) ( ) la implementación de un algoritmo "dinámico" que vincule uno o más de las escalas fisiológicas (news con o sin qsofa y/o crb- ≥ ), una escala de predicción de ingreso a uci (covid- -gram) y un puntaje de fragilidad (vipi) puede informarnos sobre el estado actual y evolutivo de la enfermedad y a priorizar el ingreso de pacientes a uci permitiendo un uso óptimo de los recursos y tomar decisiones éticas, transparentes y centradas en la dignidad de los pacientes y el bien público ilustración - . se recomienda no usar escalas de severidad de enfermedad (criterios objetivos) para definir el traslado de pacientes de uci hacia un nivel de menos complejidad de atención, ya que estas escalas no han sido validadas para este uso. se recomienda en la atención por covid- en cuidados intensivos utilizar los mismos criterios de egreso que se emplean para el traslado desde uci hacia una unidad de menor complejidad de pacientes sin infección por covid- . se recomienda contar con áreas de bajo nivel de complejidad asignadas solo a la atención de paciente con infección por covid- , las cuales serán las áreas hacia donde se realiza el de-escalamiento gradual de los pacientes basado en su evolución clínica. cuando se habla de criterios objetivos, se hace referencia a escalas de severidad de enfermedad que ayuden a tomar decisiones más racionales y no basadas en consideraciones tradicionales de resolución de cuadros clínicos. no hay una recomendación definida sobre el uso de escalas de severidad de enfermedad para definir el de-escalamiento de la atención para pacientes críticos. los sistemas de evaluación de severidad de enfermedad generales y específicos pueden identificar una población específica de pacientes en alto riesgo de deterioro clínico luego del traslado fuera de la uci( ); sin embargo, su valor para evaluar que tan preparado está un paciente individual para ser trasladado a un nivel inferior de cuidado no ha sido evaluado( ). los criterios que recomienda el colegio americano de cuidado intensivo( ) para definir el traslado desde uci a un nivel de menor complejidad (unidad de cuidados intermedios o sala de hospitalización) se basan en principios:  cuando el estado fisiológico del paciente se ha estabilizado y ya no es necesario monitoreo y tratamiento en uci.  cuando el paciente cumpla con los criterios de admisión del nivel de menor complejidad, teniendo en cuenta la disponibilidad actual del recurso, el pronóstico del paciente y la presencia de intervenciones activas en curso. específicamente para los pacientes con alto riesgo de muerte y reingreso a uci en quienes se decide no hacer intervenciones adicionales (alta severidad de enfermedad, inestabilidad fisiológica, soporte orgánico), el colegio americano de cuidado intensivo( ) siguiere pasarlos a una unidad de menor nivel de atención o a un hospital de cuidado agudo de largo plazo; siempre con un formato escrito donde se deje claro la decisión para reducir la tasa de reingreso a uci( ). específicamente en situaciones de pandemia y escasez de recursos, la sociedad española de medicina intensiva, crítica y unidades coronarias (semicyuc) recomienda la realización de la escala sofa al menos cada horas para identificar pacientes con evolución tórpida y progresiva a un fallo multiorgánico luego de la iniciación de tratamientos de soporte vital. esto permitirá la adecuación y reorientación de medidas terapéuticas a un objetivo más paliativo, incluyendo la transferencia del paciente a un nivel más bajo de complejidad y la consulta al servicio de cuidado paliativo para que brinde la atención respectiva( ). finalmente, se debe mencionar que no se ha establecido una diferencia en los criterios de egreso de pacientes con covid- para su traslado desde uci hacia una unidad de menos complejidad, con respecto a los utilizados para pacientes sin infección por covid- ( ). todo paciente hospitalizado en uci sea covid- o no, debe ser valorado diariamente para establecer en qué momento su condición clínica permite que sea trasladado fuera de la uci hacia una unidad de menor complejidad. en caso de tratarse de pacientes con sospecha o diagnóstico de covid- , este traslado puede hacerse a una unidad de cuidados intermedios dispuesta como área covid- o una sala de hospitalización con igual asignación( ); esto es lo que se conoce como de-escalamiento gradual de la atención hasta el final egreso del paciente a casa. se recomienda para pacientes con covid- que evolucionan hacia la mejoría, utilizar los criterios clásicos de de-escalamiento del nivel de atención (unidad de cuidados intermedios o sala de hospitalización) que propone el colegio americano de cuidado intensivo( ) . se recomienda aplicar la escala sofa al menos cada horas sumado al criterio de fragilidad y años de vida saludables salvados estos criterios podrían ser válidos en pacientes con fallo terapéutico a las medidas óptimas y orientar decisiones de deescalamiento de medidas y de nivel de complejidad de atención cuando la demanda potencial supera la oferta (capacidad y capacidades), estas decisiones deben ser tomadas idealmente en junta médica. amci ® se recomienda generar procesos administrativos más eficientes para el traslado de pacientes fuera de la uci hacia niveles de menor complejidad, estos ayudarán a liberar recursos para otros pacientes. se recomienda no utilizar el resultado de la rt-pcr positiva para decidir el egreso de la unidad de cuidados intensivos. la literatura no ha definido unos criterios de flexibilidad en uci para el traslado de pacientes con sospecha o diagnóstico confirmado de covid- ; y los criterios que definen la posibilidad de egreso de uci y que aplican a todos los pacientes, incluso aquellos ingresados por una condición crítica en relación con infección por covid- , están claramente definidos por el colegio americano de cuidado intensivo en su documento-guía del .( ). los principios fundamentales han sido revisados en los fundamentos de la pregunta . es importante implementar una estrategia de identificación temprana para aquellos pacientes con soporte vital avanzado que evolucionan progresivamente a fallo multiorgánico y pocas probabilidades de recuperación; el de-escalamiento de medidas y su posterior traslado fuera de la uci, liberará espacio para otros pacientes en situaciones de desborde de la demanda. la sociedad española de medicina intensiva, crítica y unidades coronarias (semicyuc) recomienda que en caso de complicaciones o que se prevea una mala evolución tanto clínica como funcional, se plantee el retiro terapéutico por futilidad y se inicie un manejo con medidas de soporte paliativo, tal como ha sido considerado en los fundamentos de la pregunta ( ) . para el grupo español es claro que, adecuar procesos administrativos más eficientes para traslado de pacientes fuera de la uci a los usualmente utilizados en condiciones normales de práctica clínica, ayudaría a ser más eficientes en la gestión de la demanda ( ) . finalmente, la persistencia de una rt-pcr positiva no es una contraindicación para el traslado del paciente fuera de la uci siempre y cuando se aseguren condiciones de aislamiento por contacto y aerosol en aquellas áreas de menor complejidad de atención; estas incluyen zonas de expansión o área del hospital específicamente acondicionadas para el manejo de pacientes estables o pacientes con limitación de esfuerzo y manejo paliativo de su condición ( ). recomendaciÓn se recomienda que la disposición final de cadáveres de personas con sospecha o diagnóstico de covid- se haga preferiblemente por cremación. en tal caso, las cenizas pueden ser objeto de manipulación sin que suponga ningún riesgo. amci ® se recomienda que la disposición final del cadáver se haga por inhumación en sepultura o bóveda individualizada cuando no se cuente con instalaciones para cremación en el territorio donde ocurrió el deceso o la disponibilidad de esta tecnología desborda la capacidad económica de las personas. se recomienda realizar siempre el aislamiento del cadáver en el lugar del deceso, siguiendo las recomendaciones del ministerio de salud y la protección social (msps). se recomienda que en los casos que se requiera necropsia médico legal y estuviese indicada la cremación, esta deberá contar con la orden del fiscal del caso. se recomienda que la institución establezca en sus procesos prioritarios un protocolo humanizado de despedida bajo estrictos criterios de bioseguridad. no existe una evidencia fuerte que recomiende hacer una disposición de cadáveres de pacientes fallecidos con sospecha o diagnóstico confirmado de covid- con un acto de cremación o con inhumación y sepultura en féretro; sin embargo, siempre y cuando la manipulación y manejo del cadáver hasta su disposición final se haga manteniendo todas las medidas de precaución para evitar la diseminación del virus y siguiendo la normatividad legal vigente, ambas formas son aceptadas. la infección por covid- es una enfermedad con gran variabilidad en presentación clínica, alta tasa de contagio y para la cual no existe en el momento un tratamiento definido. el riesgo de contagio al personal que ejecuta autopsias o procedimientos de tanatopraxia y la probabilidad de diseminación de la enfermedad por la manipulación de cadáveres no se conoce, pero se considera que puede ser alto, teniendo en cuenta que, en ausencia de la aplicación de un método de diagnóstico masivo, todo caso debe considerarse potencialmente positivo. por tanto, el manejo de cuerpos de personas fallecidas con diagnóstico confirmado, sospechoso o probable de sars-cov- (covid- ), debe realizarse con la mínima manipulación posible( ). el cadáver debe ser transferido lo antes posible al depósito y entregado al servicio funerario antes de horas luego del fallecimiento( ). el transporte, la cremación o inhumación, según sea el caso, se efectuará en el menor tiempo posible, con el fin de prevenir la exposición de los trabajadores y comunidad general al virus sars-cov- (covid- ). se debe evitar la realización de rituales fúnebres que conlleven reuniones o aglomeraciones de personas( ). el alistamiento del cadáver será realizado en el ámbito hospitalario del mismo sitio del deceso. las personas que accedan a la habitación donde se encuentre el cadáver, deben tomar las precauciones de transmisión por contacto y gotas, y para ello deben contar con todos los elementos de protección personal (epp) y seguir los procedimientos de amci ® bioseguridad de acuerdo con lo establecido en el protocolo del msps.( ) para hacer el alistamiento del cadáver, se debe cubrir todos los orificios naturales con algodón impregnado de solución desinfectante y se deberá envolver en su totalidad sin retirar catéteres, sondas o tubos que puedan contener los fluidos del cadáver, en tela antifluido o sábana; luego se deberá envolver en dos bolsas plásticas biodegradables que cumplan con las características técnico-sanitarias de impermeabilidad y resistencia a la presión de gases en su interior( ). se debe rociar el interior y el exterior de ambas bolsas con solución desinfectante de hipoclorito sódico que contenga . ppm de cloro activo( ) (exceptuando los casos asociados de covid- y muerte violenta). una vez el cadáver esté adecuadamente dispuesto en las bolsas, se podrá movilizar sin riesgo hacia el depósito de cadáveres siguiendo la ruta intrahospitalaria dispuesta para este traslado. luego el cadáver podrá será entregado al personal del servicio funerario para su depósito en ataúd o contenedor de cremación o inhumación y posterior traslado al sitio de destino final (horno crematorio y/o cementerio), luego de completar toda la documentación necesaria. cuando deba practicarse necropsia médico legal, el cuerpo será entregado a los servidores del sistema judicial quienes asumirán la custodia( ). si se han seguido correctamente todas estas indicaciones, se asume que no hay ninguna diferencia entre disponer del cuerpo enviándolo al crematorio o colocarlo en ataúd para llevarlo al tanatorio y realizar el entierro. si se opta por lo primero, las cenizas pueden ser objeto de manipulación sin que supongan ningún riesgo.( ) se recomienda que el trabajador de la salud conozca a través de la institución donde labora, los riesgos éticos, de salud y seguridad a que se expone por la atención en el paciente covid- , evitando así conflictos e incertidumbres que afecten la atención. se recomienda que las instituciones prestadoras de salud a través de los líderes de atención médica, guíen y orienten a los trabajadores, para ofrecer una mejor atención médica y menor daño emocional durante la pandemia. se recomienda dar a conocer las directrices institucionales sobre el nivel de atención (uci vs. sala médica); inicio del tratamiento de soporte vital (incluyendo rcp y soporte de ventilación); retirada del tratamiento de soporte vital; y derivación a cuidados paliativos (centrados en la comodidad) en la atención médica de los pacientes durante la pandemia, esto genera una atención caracterizada por alivio del sufrimiento, no abandono, respeto a amci ® los derechos y preferencias de los pacientes, igualdad moral de las personas y la equidad en la distribución de riesgos y beneficios en la sociedad. el apoyo de la práctica ética es necesario integrarlo al cuidado de la salud y al bienestar de la fuerza laboral del cuidado en salud. reconociendo los desafíos especiales a que se enfrentan al responder al covid- . esto forma parte del liderazgo en la atención médica y del servicio del deber cívico. berlinger n. el de abril del . en su artículo "respondiendo a covid- como un desafío regional de salud pública pautas preliminares para la colaboración regional que involucra hospitales". refiere que los trabajadores del equipo médico tienen el deber de conocer la gestión asistencial de los "desafíos éticos" previsibles durante la emergencia de salud pública (pandemia covid- ). que los desafíos éticos surgen cuando existe incertidumbre acerca de cómo "hacer lo correcto" es cuando los deberes o valores en los trabajadores entran en conflicto. estos desafíos afectan a la fuerza laboral (carga moral y emocional ante una decisión no prevista) en la atención médica. así como la operatividad en la atención médica (falta de epp y recursos que pueden limitar el buen desempeño por temor a infectarse).( ) los líderes de atención médica tienen el deber de guiar a los trabajadores de atención médica que experimentan condiciones laborales exigentes, mayor riesgo de daños ocupacionales, incertidumbre ética y angustia moral durante una emergencia de salud pública.( ) chih chen a, t. el de abril del . en su editorial ¿cómo deben prepararse los sistemas de salud para la evolución de la pandemia de covid- ? sugiere un apoyo emocional adecuado para el personal y horas razonables de exposición al riesgo para evitar el agotamiento, ya que los profesionales de la salud luchan por cuidar a los pacientes y proteger sus vidas y sus familias. se refiere que a medida que aumenta el número de casos, los médicos y los trabajadores de la salud en la primera línea deben reducir al mínimo su carga de trabajo clínico. las instituciones de atención médica deben reasignar al personal realizar tareas no clínicas, incluidos el papeleo y la recopilación de datos, tanto como sea posible. los hospitales deben tomarse su tiempo para capacitar al personal para implementar eficazmente las precauciones de contacto y los procesos de flujo. ( ) jick j.l. el de marzo del . en relación con la obligación de planificar la atención médica, considera que: los líderes de atención médica tienen el deber de planificar la gestión de los desafíos éticos previsibles durante una emergencia de salud pública. la planificación de los desafíos éticos previsibles incluye la identificación de posibles decisiones de triage, herramientas y procesos. en una emergencia de salud pública que presenta una enfermedad respiratoria grave, es posible que se deban tomar decisiones de clasificación sobre el nivel de atención (uci vs. sala médica); inicio del tratamiento de soporte vital (incluyendo rcp y soporte de ventilación); retirada del tratamiento de soporte vital; y derivación a cuidados paliativos (centrados en la comodidad) si el tratamiento de soporte vital no se iniciará o se suspenderá. es posible que también se deban tomar decisiones de clasificación en relación con la escasez de personal, espacio y suministros. el deber de cuidado fundamental requiere fidelidad al paciente (no abandono como una obligación ética y legal), alivio del sufrimiento y respeto a los derechos y preferencias de los amci ® pacientes. el deber de cuidado y sus ramificaciones son el enfoque principal de la ética clínica, a través de los servicios de consulta de ética clínica a pie de cama, el desarrollo de políticas institucionales y la educación y capacitación en ética para los médicos. deberes de promover la igualdad moral de las personas y la equidad (justicia en relación con la necesidad) en la distribución de riesgos y beneficios en la sociedad. estos deberes generan deberes subsidiarios para promover la seguridad pública, proteger la salud de la comunidad y asignar de manera justa recursos limitados, entre otras actividades. estos deberes y sus ramificaciones son el foco principal de la ética de la salud pública. no se puede emitir una recomendación a favor o en contra acerca del uso de los medicamentos y dispositivos "prototipos" utilizados en el manejo del covid- denominados de uso compasivo o fuera de etiqueta, se considera sin embargo que no pueden ser utilizados por fuera de ensayos clínicos o protocolos institucionales estandarizados de evaluación del perfil de riesgo/beneficio y bajo la aplicación de consentimiento informado. se entiende como uso compasivo la utilización, en pacientes aislados y al margen de un ensayo clínico. dichos medicamentos experimentales no han sido aprobados aún por la fda, ( ) y no se ha demostrado su seguridad y eficacia. es importante recordar que el medicamento médico puede tener efectos secundarios inesperados y graves, y que los pacientes deben considerar los posibles riesgos cuando procuran acceder a un producto médico experimental. hay que tener en cuenta que, para utilizar un medicamento bajo las condiciones de uso compasivo, se requerirá el consentimiento informado por escrito del paciente o de su representante legal, un informe clínico en el que el médico justifique la necesidad de dicho tratamiento. la regulación de la utilización de medicamentos por la vía del uso compasivo se ha realizado dentro de un texto legal sobre la realización de ensayos clínicos. una interpretación común del uso no indicado en la etiqueta y el uso compasivo de medicamentos es que, si el paciente murió, murió de la enfermedad, pero si el paciente sobrevivió, sobrevivió debido al medicamento administrado. recomendaciÓn se recomienda en la comunicación inicial con los familiares del paciente adulto con sospecha o diagnóstico de covid- críticamente enfermo incluir de forma clara y transparente los aspectos relacionados con el derecho al final de la vida que incluye: proporcionalidad en el tratamiento, adecuación del esfuerzo terapéutico, documento de voluntad anticipada, adecuación del esfuerzo terapéutico y la atención paliativa. situaciones estas que se pueden presentar durante la evolución hospitalaria y que requieren de una decisión conjunta entre el médico y el familiar del paciente. se recomienda dar una información específica, y adecuada a los familiares del paciente con sospecha o diagnóstico de covid- , para que firmen el consentimiento informado, generando esta información confianza y comprensión en el familiar. la información del consentimiento que recibe el familiar debe constar dentro de la historia clínica. fundamento el ministerio de salud y protección social del de marzo del a través del documento de "recomendaciones generales para la toma de decisiones éticas en los servicios de salud durante la pandemia covid- ". ante la posible circunstancia de pacientes sin capacidad para la toma de decisiones, por deterioro del estado general o requerimiento de aislamiento, en el cual no se puede contactar a su representante, conduzca la toma de decisiones teniendo en cuenta la prioridad de no hacer daño y la modificación en las condiciones de disponibilidad de los recursos en caso de presentarse deterioro. recuerde que esta situación debe preverse y debe ser informada a los representantes desde la admisión del paciente". durante toda la atención debe darse información sobre la posibilidad de que se presenten limitaciones de acceso a los soportes necesarios incluido al personal de salud , lo anterior puede limitar los derechos individuales o preferencias, esto debe ser informado al paciente y su familia, para que les permita entender que bajo la emergencia, puede presentarse una circunstancia que en condiciones habituales pudiera ser reversible de ser tratada pero en el contexto actual los recursos pueden verse trágicamente limitados, sin que esto implique abandono en el cuidado. el documento se refiere a la información que debe recibir el paciente o su familiar sustituto durante su evolución o fallecimiento. ( )la información durante la evolución también debe incluir: la información sobre el ejercicio de derechos al final de la vida incluyendo la adecuación de los esfuerzos terapéuticos y la suscripción de documentos de voluntad anticipada la consulta y revisión de existencia de este en todos los casos. se recomienda tener un consentimiento informado al ingreso hospitalario del paciente covid- , se deben tener en cuenta las circunstancias del paciente al ingreso hospitalario, si la capacidad para la toma de decisiones está limitada por su estado clínico o incapacidad mental. de ser estas las circunstancias se dará la información al familiar en primera línea de consanguinidad quien asume por el paciente el consentimiento de la información (consentimiento sustituto). se recomienda tener el consentimiento informado en situaciones de excepción o urgencia ante la pandemia por covid- , debe ser universal, en el que se informe el ingreso a la uci, o a cualquier otra área hospitalaria, realización de procedimientos, administración de tratamientos, posibles riesgos, beneficios durante su hospitalización. con esto se respeta el derecho a la autonomía personal en el paciente competente. en caso contrario el familiar tomará la información y asume el consentimiento a la información dada. es importante que el familiar esté informado de las decisiones que se vayan tomando durante la evolución hospitalaria (realización de procedimientos, inicios o cambios de tratamientos, movilización dentro del área hospitalaria. etc.) fuerte a favor fundamento el ministerio de salud y protección social, el de marzo del ha elaborado un formato de "consentimiento informado para acompañante de casos probable/confirmado de covid- ". en que se expresa: "que de manera detallada se me ha suministrado información completa, suficiente, con un lenguaje sencillo y claro. el profesional de la salud me ha explicado la naturaleza de la enfermedad, acerca del significado de caso sospechoso o confirmado del coronavirus covid- en cuanto a su presentación clínica, modo de contagio, medidas para contenerla, posibilidad de sufrir la enfermedad, complicaciones o muerte, mientras permanezca como acompañante del paciente". este documento se firma al ingreso por el acompañante o familiar quien asume las decisiones durante su estancia hospitalaria. ( ) el consentimiento informado en los pacientes covid- será un consentimiento sustituto para su ingreso a la uci y para los procedimientos que en la uci se realicen (colocación de tubo orotraqueal, diálisis, colocación de catéteres, reanimación cardiopulmonar, ecmo, etc.). previa información y autorización del familiar. en circunstancias normales el consentimiento debe ser firmado por el paciente quien en su autonomía acepta la información sobre su manejo y tratamiento. feld ad. recomendaciÓn se sugiere ante la pandemia del covid- , si es posible, que el grupo de expertos en bioética y/o comité de ética institucional sean consultados y estén informados por el médico responsable para la orientación o consejo en la toma de directrices ante decisiones difíciles. se sugiere en lo posible que el médico tratante no asuma solo la responsabilidad moral de la decisión y que la decisión sea institucional y documentada en la historia clínica e informada a los familiares. en caso de no contar con un comité de bioética y/o ética hospitalaria el médico responsable podrá tomar la decisión fundamentada en principios éticos y derechos del paciente o convocar a una junta médica u otro comité relacionado con su dilema o consultar un apoyo externo en bioética. débil a favor fundamento el ministerio de salud y protección social. ( ) el de marzo del en el documento "recomendaciones generales para la toma de decisiones éticas en los servicios de salud durante la pandemia covid- establece: "que en caso de que la institución cuente con un comité de bioética y/o Ética, con el servicio de bioética o Ética clínica, o consultoría clínico-ética, se debe definir una ruta de consulta para los casos que de forma concreta puedan superar las recomendaciones generales. de igual forma establece que en las circunstancias actuales que se viven el actuar ético es parte integral del profesionalismo del cuidado. teniendo en cuenta que los profesionales de la medicina serán los llamados a tomar decisiones de alto estrés moral, al tener que adherirse y promover conductas concretas basados en las circunstancias que les rodean para dar o retirar tratamientos de las personas infectadas, quienes esperan confirmación del diagnóstico y de las personas que acuden a la atención en salud por razones diferentes a la infección por covid- . partiendo de lo antes referenciado, se recomienda que las acciones emprendidas, busquen siempre poder responder a: a. no hacer daño b. beneficiar c. actuar con justicia sobre la persona en el contexto de la emergencia frente a la justicia sanitaria de la población d. mantener la integridad profesional" el comité de bioética y/o comité de ética institucional en tiempos normales o en tiempos de pandemia deberá mantener actualizadas las directrices de toma de decisiones. que apoyaran al médico responsable en la decisión. de no contar el médico con dicho comité o directrices institucionales y deba tomar una decisión que no permite interconsultar, deberá justificar en la historia clínica fundamentado en los principios éticos y derechos del paciente las razones que lo llevaron a tomar la decisión e informar y dialogar con los familiares del hecho. esto es importante que siempre quede documentado en la historia clínica la acción moral y ética de la decisión y el diálogo con la familia. en caso de que el médico responsable no cuente con un comité de bioética y/o comité de ética institucional, ni con el apoyo externo de expertos en bioética. y no quiera tomar la amci ® decisión a título personal podrá consultar a otro médico de la institución su decisión y entre ambos definir la acción a seguir. esta decisión conjunta debe ser documentada en la historia clínica e informada al grupo de trabajo y a los familiares como junta médica. si los familiares después de recibir la información no quedan satisfechos ellos tienen el derecho a la segunda opinión. los comités de bioética y/o comités de ética hospitalaria son entes administrativos, consultores, orientadores, asesores y consejeros de las situaciones que tienen que ver con el respeto y cumplimiento de los principios éticos, deberes y derechos de los pacientes, sus recomendaciones no son vinculantes, apoyan y orientan la decisión médica. aconsejando la mejor decisión ante una situación que genera un dilema moral o ético en el médico responsable. las decisiones médicas son tomadas por el consultor en bioética, quien es médico. los comités institucionales fuera de un comité de bioética y/o ética que podría dar apoyo al médico responsable y que serían otras instancias consultivas serian el comité de humanización, comité de historias clínicas, comité de bioseguridad, comité de infectología, comité de mortalidad hospitalaria, comité de paliativos o un comité de gerencia. pues todos los mencionados tiene que ver con el bienestar del paciente y la seguridad del médico ante una decisión. las decisiones especiales deben ser tomadas inicialmente a través de la realización de un comité (pueden ser los mencionados), en su defecto una junta médica. una vez se tenga la decisión esta debe ser consultada a la familia como una decisión institucional respaldada por el comité o junta médica realizada. se recomienda que todo ensayo clínico que se realice en la institución debe ser presentado, revisado y aceptado por un comité de investigación local o un comité de investigación externo nacional o internacional. se recomienda que todo paciente que se incluya en un ensayo clínico debe contar con un consentimiento informado el cual garantiza la aceptación voluntaria a participar y la comprensión de los objetivos, riesgos, beneficios, derechos y responsabilidades que tiene dentro de la investigación. se recomienda el consentimiento informado en todo ensayo clínico, el cual debe ser debe ser individual en tiempos de normalidad como en tiempos de pandemia por covid- . solo el comité de ética en investigación podrá establecer en tiempos de normalidad o de pandemia las condiciones de dispensa o excepción al requisito de obtener el consentimiento informado. refiere que el consentimiento informado tiene sus raíces en el código de núremberg de y la declaración de helsinki de y ahora es un principio rector para la conducta en la investigación médica. en el consentimiento informado para investigaciones clínicas es claro que los participantes deben entender ampliamente los componentes del consentimiento. ( ) thanh tam, n. et al. el de enero . mediante una revisión sistemática de pubmed, scopus y google scholar y revisando manualmente las listas de referencias para publicaciones hasta octubre de . realizó un metaanálisis de los resultados del estudio utilizando un modelo de efectos aleatorios para tener en cuenta la heterogeneidad. evaluó la proporción de participantes en ensayos clínicos que entienden los diferentes componentes del consentimiento informado. encontrando que los participantes en ensayos clínicos deben comprender los componentes fundamentales del consentimiento informado como: la naturaleza y los beneficios del estudio, la libertad de retirarse en cualquier momento y la naturaleza voluntaria de la participación, así como la comprensión de otros componentes, como la aleatorización y el placebo. la proporción de participantes en ensayos clínicos que comprendieron diferentes componentes del consentimiento informado varió de . % a . %. esto asegura que la toma de decisiones de los participantes es significativa y que sus intereses están protegidos. ( ) la red de américa latina y el caribe de cnb-unesco, ( de marzo de ) que agrupa a las comisiones y consejos nacionales de bioética cuya finalidad es la de asesorar sobre los problemas éticos relativos a las ciencias de la vida y la salud humana expresa su preocupación ante la realización de investigaciones biomédicas en relación con la pandemia de enfermedad infecciosa por coronavirus covid- . reconociendo lo siguiente en relación con el consentimiento informado: que la investigación con seres humanos durante las emergencias debe contar con garantías éticas mayores, no menores, que en las situaciones ordinarias. que en situación de excepción o emergencia los participantes deben seleccionarse en forma justa y proporcionar una justificación adecuada cuando se escogen o excluyen determinadas poblaciones, distribuyendo en forma equitativa las posibles cargas y beneficios de participar en esa investigación. "que se debe obtener el consentimiento informado individual de los participantes incluso en una situación de excepción o alarma, a menos que se cumplan las condiciones para la dispensa del consentimiento informado. las cuales el comité de revisión ética solo puede decidir dar la dispensa al requisito de obtener consentimiento informado: a) si no es factible obtenerlo; y si además los estudios: b) tienen un importante valor social y científico, c) solo suponen riesgos mínimos para los participantes, d) no implican agravio comparativo con otros grupos en situación o no de vulnerabilidad; y si e) se garantiza que no se privará a la población investigada de acceder en forma preferencial al beneficio derivado. de otorgarse un consentimiento informado amplio, éste debería ser única y exclusivamente para los procesos asociados con covid- ".( ) amci ® se recomienda considerar la transición del cuidado intensivo al cuidado paliativo en todo paciente con sospecha o diagnóstico de covid- sin mejoría a pesar de las intervenciones óptimas, con empeoramiento progresivo de su pronóstico vital y ante un evidente deterioro; aplicando medidas generales en control de síntomas ( manejo de secreciones -tratamiento del dolor -tratamiento de la disnea -sedación paliativa), así como apoyo espiritual, siempre acompañando al paciente y nunca abandonarlo en el final de la vida. fuerte a favor fundamento la sociedad española de anestesiología, reanimación y terapéutica del dolor en su documento: "marco Ético pandemia covid- " madrid, de marzo de refiere: la sedación paliativa en pacientes hipóxicos con progresión de la enfermedad no subsidiaria de tratamiento debe considerarse como una expresión de buena práctica clínica y debe seguir las recomendaciones existentes. si se prevé un período agónico no corto, se debe proporcionar una transferencia a un entorno no intensivo.( ) se recomienda la utilización de guías establecidas previamente a la pandemia por el ministerio de salud y sociedades científicas para orientar las decisiones que se tomen al final de la vida en pacientes con sospecha o diagnóstico de covid- . estas guías deben ser divulgadas al equipo de atención y aplicadas en los pacientes en casos de: adecuación del esfuerzo terapéutico (aet), orden de no reanimar (onr), consentimiento sustituto, voluntades anticipadas, cuidados paliativos. se recomienda fundamentar las decisiones del final de la vida individualizadas a cada paciente y a cada situación sin llegar a tomar decisiones apresuradas sin fundamento científico o ético, solicitando de ser posible una valoración por medicina paliativa para el manejo de síntomas. se recomienda indagar durante la hospitalización de todo paciente con sospecha o diagnóstico de covid- , si en tiempos de salud hizo válida su autonomía y realizó un documento de voluntad anticipada, teniendo en cuenta que esta será equivalente al consentimiento informado. amci ® terapéuticos y la suscripción de documentos de voluntad anticipada.( ) el inicio de sedación paliativa con reubicación del pacientede ser necesario el des escalonamiento por deterioro clínico. en situación de pandemia covid- cuando se refiere a situaciones del final de la vida se relaciona a la adecuación del esfuerzo terapéutico, la sedación paliativa la cual será la maniobra terapéutica que se utilizará en pacientes no recuperables y que no son candidatos a cuidados intensivos por covid- ,( ) que evolucionan desfavorablemente y tienen mal pronóstico a corto plazo, así como la disnea refractaria y la limitación del esfuerzo terapéutico. el delirium o síndrome confusional por fallo cerebral agudo, es un problema habitual en situaciones de alteración orgánica severa, y ha sido descrito como uno de los síntomas neurológicos presente en los pacientes que sufren infección por el covid- ( ). wilson c. de abril del . en su artículo "la crisis golpea al final de la vida" se refiere a que el brote de coronavirus está obligando a las personas a enfrentar dilemas en torno a la cantidad de atención médica que se debe brindar al final de la vida y apresurar decisiones controvertidas sobre rechazar ciertos tratamientos. dicen los expertos que esto ha alentado a más personas a tomar decisiones de tratamiento anticipadas relacionadas con la rcp y la ventilación,( ) haesen s. el de mayo de . en su artículo "dirigir a los ciudadanos a crear directivas anticipadas" las voluntades o directrices anticipadas son para las personas que quieran asumir plenamente su papel de ciudadanos responsables tomando decisiones proactivas. la decisión de redactar directivas anticipadas marca un cambio del enfoque actual de "aceptación" a un escenario de "exclusión voluntaria".( )al emitir una directiva de tratamiento anticipado, una persona autónoma puede expresar formalmente qué tipo de tratamiento desea y no desea recibir en caso de que se enferme o se lastime y no pueda decidir de manera autónoma sobre su tratamiento. ( ) ministerio de salud y protección social en su documento de voluntades anticipadas que es el documento en el que toda persona capaz, sana o en estado de enfermedad, en pleno uso de sus facultades legales y mentales y como previsión de no poder tomar decisiones en el futuro, declara, de forma libre, consciente e informada su voluntad sobre las preferencias al final de la vida que sean relevantes para su marco de valores personales.( ) se recomienda que el paciente crítico con covid- que no es candidato para ingresar o continuar recibiendo cuidados intensivos y que presente deterioro rápido con mal pronóstico a corto plazo, se le brinde una adecuación del esfuerzo terapéutico orientada a acompañamiento al final de la vida, alivio del sufrimiento y control de síntomas. dependiendo de la disponibilidad de recursos se sugiere dentro del plan de atención hospitalaria contar con un área destinada a la atención del final de vida con el recurso físico, humano y de procesos necesario. marzo del . refiere: en situación de adecuación terapéutica, retirada de medidas y/o mala evolución es adecuado derivar al paciente a un área de menor complejidad para establecer el plan de cuidados paliativos. consultar al servicio de cuidados paliativos para procurar la continuidad de cuidados de los pacientes en los que se haya acordado la limitación de tratamientos y aliviar su sufrimiento, incluyendo la sedación paliativa en los casos en los que sea precisa.( ) schmidhauser tf. el de abril . considera en su publicación que: los cuidados paliativos durante la pandemia de covid- deben adaptarse a un estilo de" cuidados paliativos de emergencia" ya que los pacientes pueden deteriorarse rápidamente y requieren decisiones rápidas y planes de tratamiento claros. estos deben ser seguidos fácilmente por los miembros del personal de salud que atienden a estos pacientes. además, los cuidados paliativos deben estar a la vanguardia para ayudar a tomar las mejores decisiones, atender a las familias y ofrecer apoyo espiritual.( ) se recomienda como estrategia de protección personal en las unidades de cuidado intensivo sin presión negativa y cubículos abiertos utilizar de forma continua el respirador n o fpp , adicional a otros elementos de protección para prevención del contagio por covid- . la atención segura en áreas crítica para todas las modalidades de atención se fortalece a través de las medidas de precauciones estándar en el manejo de todos los pacientes, establecidos en el "manual de medidas básicas para control de infecciones en prestador servicios de salud" ley de , por la cual se dictan medidas sanitarias. resolución de , numeral y numeral . epp. el respirador, n o fpp , puede utilizarse de manera continua por a horas, o desecharlo antes si está visiblemente contaminada o si está húmeda. luego de colocar la n se debe verificar prueba de ajuste antes de ingresar a la unidad para atención de pacientes con covid- de la siguiente manera: mascarillas sin válvula de exhalación: cubra la totalidad de la mascarilla con ambas manos y exhale con fuerza. si nota fugas de aire por sus bordes, reajuste la posición del respirador. mascarillas con válvula de exhalación: cubra el respirador con ambas manos e inhale con energía. deberá sentir una presión negativa dentro de la mascarilla. si detecta alguna pérdida de presión o entrada de aire, reajuste la posición del respirador. no se puede emitir una recomendación a favor o en contra acerca de la efectividad de bioseguridad del uso extendido, continuo o intermitente de los respiradores n ó ffp . sin embargo, se considera que puede ser una alternativa, bajo la adopción de un protocolo riguroso, cuando se debe optimizar el uso de los epp en el contexto de un acceso limitado. el reúso no está permitido en colombia. la duración máxima del uso continuo de la n es de a horas, siguiendo las recomendaciones del manual de medidas básicas para control de infecciones en ips de minsalud. pero en la vida real, ningún trabajador tolera a horas continuas con un respirador. por esto, su uso continuo en el sitio de trabajo dependerá de la necesidad de pausar para comer, para ir al baño, etc. en este caso, se guardará en una bolsa de papel para su nueva colocación, si tiene menos de horas, o desechará si está visiblemente contaminada o se torna húmeda. el reúso de la n dependerá de la casa del fabricante, de si contiene o no celulosa en su estructura del respirador. por ejemplo, la recomendación de desinfección para los respiradores sin celulosa es con peróxido de hidrógeno vaporizado al % por minutos (tabla y ). los respiradores n de uso industrial tienen mayor contenido de celulosa que los de uso médico por lo tanto para procesos de esterilización, solo los n de uso médico podrán ser esterilizados mediante de peróxido de hidrógeno vaporizado (sterrad®) ( - ) . ¿existe superioridad en términos de protección personal para el personal sanitario y de apoyo dentro de las unidades de cuidados intensivos con la utilización del overol frente a la bata manga larga con antifluido durante la atención del paciente con covid- ? no se puede emitir una recomendación a favor o en contra si los overoles ofrecen mayor protección por cobertura corporal frente a otros elementos como vestidos largos, batas y delantales. resulta intuitivo que su uso genera una mayor protección en especial en servicios cohortizados. sin embargo, su uso está asociado con una mayor dificultad para su colocación y retiro, lo que puede potencializar el contagio del usuario, la utilización debe hacerse bajo un protocolo supervisado y chequeado. las batas modificadas para ajustarse firmemente en el cuello pueden reducir la contaminación. en estudios ya descritos el uso de un respirador eléctrico purificador de aire con overol puede proteger contra el riesgo de contaminación mejor que una máscara n y una bata con un rr: . , intervalo de confianza (ic) del %: . a . pero fue más difícil su retiro con rr . , ic del % . a . . en un eca ( participantes), las personas con una bata larga tenían menos contaminación que aquellas con un overol. las batas pueden proteger mejor contra la contaminación que los delantales.( - ) los epp como batas y overoles deberían estar hechos de un material que cumpla con los requisitos mínimos de la asociación americana de químicos textiles:  tipo a: buena repelencia al agua, resistente a la penetración, pero mala permeabilidad al aire.  tipo b: buena repelencia al agua, buena permeabilidad al aire, pero poca resistencia a la penetración del agua.  tipo c: bata quirúrgica que tiene poca repelencia al agua y resistencia a la penetración de agua.  tipo d: hecho de fibras de polietileno de alta densidad, tela no tejida (tyvek®), tiene buena repelencia y resistencia al agua, mala permeabilidad al aire. no se puede emitir una recomendación a favor o en contra para el uso de respiradores elastoméricos como elementos de protección personal dentro de las unidades de cuidados amci ® intensivos. no hay evidencia que soporte la superioridad de los respiradores elastoméricos frente a los n , son más costosos, difíciles de utilizar y pueden implicar algún riesgo para el paciente. por tanto, su uso sólo debería considerarse frente a un desabastecimiento de los n y bajo la adopción de un protocolo institucional riguroso y bajo chequeo. los respiradores elastoméricos son respiradores ajustados a media cara o cara completa, esta última otorga protección ocular. su filtración está determinada por el filtro que se utilice, estos van desde partículas de nivel n a p . están hechos de material sintético o de goma que les permite desinfectarse, limpiarse y reutilizarse repetidamente. están equipados con cartuchos de filtro reemplazables. al igual que los respiradores n , los respiradores elastoméricos requiere entrenamiento adecuado para su correcta colocación y retiro. por eso es muy importante revisar el manual del usuario antes de su uso. los respiradores elastoméricos no deberían utilizarse en entornos quirúrgicos, debido al riesgo potencial de contaminación del campo quirúrgico, con el aire que sale de la válvula de exhalación. como recomendación de buena práctica, aprobado por la fda, debe colocarse una máscara quirúrgica encima de la válvula de exhalación para evitar este riesgo. solo se debe permitir el uso del respirador elastoméricos por clínica para evitar infecciones cruzadas, esto permitirá una protección esencial contra agentes infecciosos y la auto contaminación. aunque los cartuchos de filtro son finalmente desechables, están destinados a ser reutilizados hasta que ya no se puede respirar o se vuelven visiblemente sucio. generalmente se recomienda, en la mayoría de los casos, hacer recambios cada días. deben tener procedimientos de limpieza/desinfección actualizados y aprobados por su manufacturador.( , - ) recomendaciÓn se recomienda realizar la limpieza y desinfección de equipos biomédicos y de superficies las veces que sean necesarias y en el momento de egreso del paciente siguiendo los protocolos de cada institución. el desinfectante para este proceso debe ser de nivel intermedio o alto para superficies y equipos biomédicos y cumplir con las recomendaciones del fabricante según lo aprobado en el registro sanitario. fuerte a favor fundamento para la desinfección de las superficies ambientales hospitalarias y domiciliarias, la oms recomienda emplear un desinfectante que sea efectivo contra virus cubiertos (el coronavirus pertenece a esta categoría), específicamente, recomienda emplear alcohol etílico para la desinfección de algunos equipos biomédicos reusables (p. ej.: termómetros) y para las superficies, el hipoclorito de sodio o precursores de sodio como el dicloroisocianurato de sodio (nadcc) que tiene la ventaja de la estabilidad, la facilidad en la dilución y que no es corrosivo.( ) (tabla ). page se recomienda que el ingreso de un paciente a uci debe hacerse bajo un procedimiento estandarizado que incluya la coordinación y comunicación de los servicios vinculados, adecuación de la unidad de atención a las necesidades del paciente y la garantía de la bioseguridad del equipo multidisciplinario. se recomienda que cada institución establezca en sus procesos prioritarios el circuito del traslado que incluye el itinerario del traslado, el uso de ascensor, el número y la organización de los intervinientes sanitarios y no sanitarios (celadores, seguridad, limpieza), las medidas de protección empleadas por los mismos (epp, limpieza) y los recursos materiales necesarios durante el traslado. el traslado de pacientes con casos sospechosos o confirmados de covid- se puede presentar entre servicios a nivel hospitalario o entre instituciones con diferentes niveles de atención y deben tenerse las precauciones universales de un traslado seguro. una posición responsable es evitar el traslado de estos pacientes el máximo posible, a menos que sea imprescindible, teniendo en cuenta el riesgo/beneficio. considerar evitar traslados interinstitucionales solo por temas administrativos. el personal sanitario que realice el traslado debe contar con todos los epp, considerando este traslado como de alto riesgo de transmisión vírica. se debe utilizar mascarilla quirúrgica o n- , de acuerdo con el riesgo amci ® de aerosolización. hasta que la rt-pcr para sars-cov- este negativo se podrían retomar las prácticas habituales de traslado de los pacientes . ( ) ( ) ( ) capítulo . abordaje diagnóstico y covid- se recomienda en pacientes con diagnóstico o sospecha de infección por sars-cov- clasificar la enfermedad en leve, severo o paciente crítico, teniendo en cuenta los criterios de la clasificación por las fases y estadios de la enfermedad. se recomienda en pacientes con diagnóstico o sospecha de infección por sars-cov- , clasificados como críticos y que requieren de intubación orotraqueal realizar la clasificación por fenotipos ( o ), con el fin de proyectar una estrategia de ventilación mecánica. el covid- , es una enfermedad con una presentación clínica diversa, desde formas leves hasta presentaciones graves que incluyen el sdra, la mediana del período de incubación desde la exposición hasta el inicio de los síntomas es de aproximadamente a días, y el . % de los pacientes sintomáticos tendrán síntomas dentro de los . días después de la infección ( ) , que incluye fiebre, tos, disfagia, malestar general, mialgias, anorexia, náuseas, diarrea, anosmia y ageusia; la disnea se presentó entre los y días ( ) y puede representar progresión a covid- severo, que se manifiesta con hipoxemia, disfunción orgánica múltiple, documentación de arritmias cardíacas, rabdomiólisis, coagulopatía y choque ( ) . dentro del espectro de enfermedad, siddiki et al, proponen un enfoque estructurado por fases expresados en tres estadios (historia natural de la enfermedad), siendo el primero donde la patogenicidad viral es dominante, se incluye el periodo de incubación, síntomas leves, con multiplicación del sars-cov- centrándose principalmente en el sistema respiratorio gracias a la unión del virus con el receptor de la enzima convertidora de angiotensina (ace ), el hemograma puede revelar linfopenia y neutrofilia sin otras anormalidades significativas. el estadio es la enfermedad pulmonar establecida, neumonía viral, tos, fiebre con progresión en algunos casos a hipoxia con trastorno de los índices de oxigenación (pao /fio menor mmhg), hallazgos en imágenes de tórax (radiografía y/o tomografía) de infiltrados alveolares o vidrio esmerilado, mayor linfopenia y elevación de transaminasas ( a: sin hipoxemia, b: con hipoxemia). el estadio o fase de híper inflamación sistémica extrapulmonar se caracteriza por elevación de biomarcadores inflamatorios y estado protrombótico (il - , il- , il- , ftn -α, proteína c reactiva, ferritina y el dímero d), con presencia en las formas más graves de disfunción orgánica múltiple, lesión miocárdica (troponina y péptido natriurético de tipo b elevados), con fenómenos trombóticos, progresión a sdra y choque ( ) . amci ® la neumonía por sars-cov- , se característica por disociación entre la severidad de la hipoxemia y el mantenimiento relativamente bueno de la mecánica respiratoria, con compliance del sistema respiratorio en promedio de ml / cmh o; gattinoni, marini et al, proponen dos fenotipos de presentación de la insuficiencia respiratoria; el primero (tipo ) con una mecánica pulmonar adecuada, con baja probabilidad de reclutabilidad y con hipoxemia, relacionado al desbalance entre la perfusión y la ventilación; el segundo (tipo ) más acorde a las definiciones de sdra (csdra "covid- patient with sdra"), con una compliance pulmonar baja y reclutabilidad potencial( , ) ( ). se propone la siguiente clasificación clínica del covid- . ( , , y pacientes críticos de %, con tasa global de mortalidad de , %, siendo mayor entre los pacientes de a años con % y entre los mayores de años con . %, dentro del grupo de pacientes clasificado como crítico la mortalidad descrita fue del %( ). recomendaciÓn se recomienda en cuidado intensivo, realizar el diagnóstico de covid- del paciente sospechoso por medio de rt-pcr conociendo su alta especificidad, su variabilidad en relación con el tiempo y pérdida de rendimiento diagnóstico luego de la primera semana de inicio de los síntomas. se recomienda tomar la primera muestra para rt-pcr de hisopo nasofaríngeo o de cornete medio sobre hisopado oro faríngeo o de saliva, de ser negativo se puede repetir la prueba de a horas preferiblemente de tracto respiratorio inferior, esputo no inducido o en aspirado traqueal en paciente intubado. se recomienda el uso conjunto de rt-pcr e igm por elisa en pacientes con sospecha de covid- , primera rt-pcr negativa, que se encuentren entre la segunda y tercera semana desde el inicio de los síntomas, con el objetivo de mejorar la sensibilidad en la identificación de infección por sars-cov- . en cuidado intensivo, el diagnóstico de covid- se fundamenta con base en la presentación clínica compatible y factores epidemiológicos asociados con probabilidad de infección; el diagnóstico definitivo se realiza con pruebas de amplificación de ácido nucleico del virus (naat), la detección del genoma viral del sars-cov- se realiza por medio de reacción en cadena de la polimerasa por transcriptasa reversa (rt-pcr) dado a su especificidad del % ( , ) ; por lo cual todo paciente que cumple con la definición de caso sospechoso se le debe realizar rt-pcr, sars-cov- independientemente de si se encuentra otro patógeno respiratorio ( ) . las muestras para el diagnóstico por rt pcr se recolecta de las vías respiratorias superiores, nasofaringe, cornete medio u orofaringe; todos con alta especificidad. sin embargo, se sugiere recolectar los hisopos nasofaríngeos o de cornete medio por tener mayor sensibilidad ( ( / ) . en pacientes con neumonía severa a quienes se le realizó lavado broncoalveolar (bal) y rt-pcr entre los días y el % de las muestras fueron positivos, en pacientes no intubados con esputo no inducido el % de las muestras fueron positivas ( , ). wang et al, en un estudio de pacientes con covid- , las rt-pcr con tasas positivas más altas fue en muestras extraídas por bal ( %; de muestras) y esputo % ( de muestras) ( ) . para la detección del sars-cov- por rt-pcr en pacientes en cuidado intensivo, teniendo en cuenta la rigurosidad de aspectos de bioseguridad y aerosolización, se debe tomar la primera muestras en nasofaringe o cornete medio, si esta prueba es negativa se puede repetir en a horas, si este es el caso o existe más de días desde el inicio de los síntomas se prefiere una muestra del tracto respiratorio inferior, por esputo no inducido por personal de salud o por aspirado traqueal en pacientes intubados ( , ), aunque el rendimiento diagnóstico del bal es alto por lo general, se debe evitar la broncoscopia para minimizar la exposición de los trabajadores de la salud ( ) . la probabilidad de detección del arn de sars-cov- puede variar según la fase de la enfermedad, si bien una rt-pcr positiva confirma el diagnóstico de covid- , los reportes falsos negativos y la sensibilidad se ve influenciado por el tiempo desde la exposición e inicio de síntomas. kucirka et al, en un análisis de siete estudios evaluaron el rendimiento diagnóstico de la rt-pcr en relación con el tiempo desde el inicio de los síntomas o la exposición, con resultados expresados en tasa estimada de falsos negativos, siendo del % el día de la exposición, del % el día (estimado como primer día de síntomas, ic: % a %), % en el día (día desde el inicio de síntomas, ic: % a %) luego comenzó a aumentar nuevamente de % en el día (ic: a %) a % en el día (ic: a %) ( ) . la precisión y los valores predictivos de rt-pcr para sars-cov- no se han evaluado sistemáticamente, la sensibilidad de las pruebas moleculares está influenciada por múltiples factores como sitio y calidad de la muestra, técnica de procesamiento; probablemente las menores tasas de falsos negativos (sensibilidad entre y %) está entre el día y luego de inicio de los síntomas ( ) . a partir de aquí el rendimiento diagnóstico disminuye, por lo tanto, es importante que el intensivista valore estas consideraciones en el momento de tomar conductas, en cuanto tipo de aislamiento, tratamiento y pronóstico. amci ® las pruebas serológicas detectan anticuerpos contra el sars-cov- y ayudan a identificar pacientes que han tenido la enfermedad y algunos con la enfermedad activa, la seroconversión se ha descrito entre el día y , sin embargo, hay incertidumbre en la incidencia de la seroconversión ( ) . estas pruebas se usan principalmente en tamizaje poblacional y estudios de seroprevalencia; en cuidado intensivo el análisis de la igm por elisa contribuye a la detección de pacientes con infección reciente, además con el análisis conjunto con la igg se clasifica el estado de infección en agudo o convaleciente. las pruebas serológicas se realizan por diferentes técnicas como la inmunocromatográfica de flujo lateral, la inmunofluorescencia indirecta (ifi) y el ensayo de inmunoadsorción ligado a enzima (elisa) ( , ) . las pruebas serológicas no deben usarse como la única prueba para diagnosticar o excluir la infección activa por sars-cov- . la sensibilidad y la especificidad de muchas de estas pruebas serológicas son inciertas, así como su valor predictivo positivo. los anticuerpos detectables generalmente tardan varios días en desarrollarse. guo et al, documenta niveles de anticuerpos por elisa, con una mediana de detección de anticuerpos igm e iga de días (iqr, - ) y de igg de días (iqr, - ) después del inicio de los síntomas, con una probabilidad de resultados positivos de . %, . % y . % respectivamente; es probable que el rendimiento diagnóstico de igm por elisa sea mayor que la de rt-pcr después del quinto día luego de inicio de síntomas; cuando se combinan estas técnicas (elisa igm con rt-pcr) la tasa de detección positiva es del . % ( ) . zaho et al, en un estudio de pacientes con covid- , donde el , % estaba en condición crítica, la mediana del tiempo desde el inicio de los síntomas hasta la detección de anticuerpos (técnica elisa) fue de días para igm y días para igg; dentro de los primeros días desde el inicio de los síntomas solo el . % tenía anticuerpos detectables, entre los días a la sensibilidad de igm fue . % e igg de . %, luego de los días la sensibilidad igm e igg fue de . % y . % respectivamente; el uso combinado de rt-pcr y elisa igm presentó una sensibilidad del % entre los días a y del % entre los días a . ( ) la rt-pcr tiene especificidad del %, con adecuado rendimiento diagnóstico entre los días y luego del inicio de los síntomas con sensibilidad que varía entre el y %, con presencia ascendente de falsos negativos luego del día , por lo cual el diagnóstico debe tener consistencias epidemiológicas y clínicas (síntomas y hallazgos radiológicos compatibles con covid- ) donde una rt pcr negativa no excluye la enfermedad; la precisión y el tiempo para la detección de anticuerpos varían con la técnica utilizada, su uso es limitado en cuidado intensivo, sin embargo su identificación por técnica elisa en conjunto con rt-pcr mejora la sensibilidad y la probabilidad de falsos negativos, especialmente entre los días y desde el inicio de síntomas. faltan estudios que evalúen el rendimiento diagnóstico de las diferentes pruebas. amci ® se recomienda la medición de marcadores de severidad al ingreso a uci del paciente críticamente enfermo por covid- (hemograma, transaminasas, ldh, ferritina, troponina, dímero d y pcr) los cuales se han asociado con peor pronóstico en la enfermedad por covid- , logrando ofrecer intervenciones más tempranas. se recomienda no utilizar una periodicidad de rutina para la medición de seguimiento de biomarcadores de severidad en el paciente con sospecha o diagnóstico de covid- . en un estudio cohorte retrospectivo que evaluó pacientes diagnosticados con covid- desde el de enero de hasta el de marzo de , fang liu y colaboradores encontraron correlación en la elevación de il- y pcr con la gravedad clínica, lo que sugiere podrían usarse como factores independientes para predecir la severidad del cuadro, los pacientes con il- > . pg./ml o pcr> . mg/l tenían más probabilidades de tener complicaciones graves ( ) , así mismo en otro estudio multicéntrico retrospectivo de pacientes infectados se identificó resultados de laboratorio con diferencias significativas con elevación de glóbulos blancos, valores absolutos de linfocitos, plaquetas, albúmina, bilirrubinas, función renal, transaminasas, troponina, proteína c reactiva e interleucina (il ) en el grupo con desenlace de mortalidad contra los dados de alta ( ) . entre otros marcadores la troponina como lesión cardiaca (elevación de troponina por encima del percentil límite de referencia superior) se ha reportado en % a % de los pacientes con covid- en wuhan, china, en dos estudios retrospectivos por xiabo yang y colaboradores ( , ) . en una revisión sistemática de mayo , kermali m. y colaboradores exponen que existe evidencia a favor de los valores bajos de linfocitos y plaquetas y valores elevados de los biomarcadores il- , pcr, troponina, ldh, ferritina, proteína amiloidea a y dímero d, pueden relacionarse con la gravedad de la infección por covid- y su fuerte asociación con la mortalidad ( ) . estos resultados pueden usarse como un complemento en la práctica clínica para guiar a los médicos a identificar pacientes con mal pronóstico y la rápida implementación de medidas de soporte, monitorización y reanimación en la evolución de los pacientes críticos en la unidad de cuidados intensivos. solo en estudio, karmali et al, en , determinan en promedio entre a horas, la periodicidad en el seguimiento de estos, sin embargo, no se discrimina entre pacientes críticos y no críticos. consideramos que el seguimiento de estas pruebas debe estar ajustado al juicio clínico del médico intensivista tratante, según la evolución de los pacientes. se muestran el comportamiento de los biomarcadores mas frecuentes en la tabla . tabla . biomarcadores en pacientes críticos con sospecha o diagnóstico de covid- . tendencia de biomarcador en relación con la gravedad covid- pcr aumentada recomendaciÓn se recomienda la no medición de marcadores de inflamación o de severidad de forma rutinaria solo con el objetivo de iniciar un tratamiento específico o algoritmos terapéuticos en la enfermedad por covid- en pacientes críticos. el síndrome de liberación de citocinas o denominado "tormenta de citocinas" parece asociarse en pacientes con afecciones graves por covid- . la citocina proinflamatoria il- es la citocina mejor documentada en covid- correlacionada con la gravedad, el estado crítico del paciente, la carga viral y el pronóstico ( , , ) . se han descrito mayores niveles de citoquinas proinflamatorias (il- , il- , il- , factor estimulante de colonias de granulocitos, factor de necrosis tumoral e interferón gamma) asociadas a compromiso pulmonar severo en pacientes con infección por coronavirus, determinado por la rápida replicación del virus, infiltración masiva de células inflamatorias y trastorno severo de la inflamación ( , ) . igualmente, está asociada la presencia de linfopenia como biomarcador de mal pronóstico para covid- ( ) . hallazgos similares se encontraron en la pandemia de influenza a (h n ) de sin ser especificó su valor ( ) . las manifestaciones clínicas de la tormenta de citocinas incluyen síndrome de respuesta inflamatoria sistémica, hipotensión, síndrome de fuga capilar, insuficiencia renal, sdra, miocarditis, entre otras ( ) , algunos autores han determinado este cuadro como un síndrome de linfohistiocitosis hemofagocitica secundaria. es razonable pensar que, en pacientes con sospecha de tormenta de citocinas basado en los hallazgos de laboratorio, el manejo con inmunomoduladores puede resultar beneficioso, sin embargo, los resultados del manejo de la hiperinflación basado en pruebas diagnósticas han tenido resultados encontrados en pacientes con covid- . el uso de esteroides, inmunoglobulina endovenosa, inhibidores del receptor de citoquinas (tocilizumab) o inhibidores de janus kinasa, han disminuido los valores de los biomarcadores, días de hospitalización ( ) o necesidad de fracciones elevadas de oxígeno ( ) , sin embargo no han demostrado beneficio sobre la mortalidad y en algunos casos, si un aumento en la incidencia de infecciones bacterianas o fúngicas sobreagregadas ( ) . se recomienda realizar radiografía simple de tórax para todos los pacientes con sospecha o diagnóstico de covid- en uci. se recomienda realizar tac de tórax según disponibilidad de tecnología institucional, ante la incertidumbre diagnostica, teniendo en cuenta las condiciones clínicas, la tolerancia del paciente al traslado y los protocolos administrativos de seguridad. fuerte a favor fundamento se reconoce como el gold estándar diagnóstico de infección pulmonar por covid- a los estudios moleculares, sin embargo, estos presentan limitaciones: a) contaminación de las muestras b) errores en la técnica de la toma, c) muestra insuficiente para ampliación genética favoreciendo falsos negativos d) demora de reporte de los resultados. por lo anterior, se recomienda imágenes diagnósticas en la aproximación de paciente con sospechas de infección pulmonar por covid- ( , ) .  radiografía simple de tórax: ventajas: mayor accesibilidad que la tac de tórax y realización de la prueba a la cabecera del enfermo desventaja: baja sensibilidad en estadio temprano, después del día de inicio de los síntomas presenta aumento en el rendimiento diagnóstico  tac de tórax: ventaja: es ampliamente recomendada. alta sensibilidad en estadios tempranos. permite describir extensión, distribución, localización, densidades parenquimatosas, aplicables en clasificaciones y puntajes diagnósticos, pronósticos y de seguimiento en permanente evolución y mejoría. algunas asociaciones referentes como asociación china de radiología, en su recomendación de expertos propone clasificación tomografía en estadios temprana avanzada severo disipación desventaja: traslado del paciente hasta el tomógrafo (no todos los enfermos toleran el transporte) y tecnología no disponible en todos los niveles de atención page no se puede emitir una recomendación a favor o en contra para el uso de ecografía pulmonar a la cabecera del paciente crítico como herramienta diagnóstica o de pronóstico en con covid- . se puede considerar como una alternativa para la valoración imagenológica pulmonar en el paciente crítico con covid- cuando las condiciones del paciente no permitan su traslado. no se sugiere la utilización de la ecografía pulmonar para el seguimiento de lesiones pulmonares agudas en el enfoque del paciente crítico con covid- . puede utilizarse para determinar complicaciones asociadas a la enfermedad o en la inserción de dispositivos invasivos. en general los estudios de imágenes no representan un papel concluyente para el diagnóstico de covid- . la ultrasonografía en específico requiere estudios de validación, un programa de entrenamiento es operador dependiente, y se le atribuido limitaciones en la capacidad de discriminación en la cronicidad de las lesiones pulmonares. la ultrasonografía pulmonar puede servir como herramienta a la cabecera del paciente para mejorar la evaluación del compromiso pulmonar y reducir el uso de radiografías de tórax y tomografía computarizada ( ) , sin embargo no debe usarse para el diagnóstico inicial, pues éste se compone de criterios clínicos, radiográficos y microbiológicos que actualmente son el estándar de oro; la ecografía no los reemplaza debido a la baja especificidad en relación con el virus, se sugiere su uso como complemento en la valoración diaria del paciente, ojalá realizada por el mismo observador. la ecografía pulmonar es altamente sensible y puede revisar de forma rápida y precisa la condición pulmonar, creando un potencial para evaluar los cambios o la resolución con el tiempo, especialmente en la uci, escenario en el que cada vez se usa más para la detección de múltiples patologías pulmonares que se pueden demostrar junto con covid- , sin embargo, hasta la fecha no hay hallazgos específicos, ni patognomónicos que se relacionen con covid- en el examen ecográfico del paciente ( ) . la adopción de ultrasonido pulmonar puede reducir la necesidad de exposición a la radiación ionizante y, a su vez, reducir la cantidad de radiografías necesarias para la evaluación rutinaria del paciente, disminuyendo también la exposición de personal asistencial adicional como el uso de elementos de protección personal ( ) . es bien conocido el beneficio de la ecografía durante y después de la colocación de accesos venosos centrales para establecer la presencia o no de complicaciones inmediatas como neumotórax. a la fecha no hay publicaciones acerca de la utilidad del ultrasonido como herramienta para establecer pronóstico. se necesitan más estudios para evaluar la utilidad de la ecografía pulmonar en el diagnóstico y manejo de covid- ( ) . se recomienda no establecer un punto de corte en el valor de dímero d para el inicio rutinario de anticoagulación plena en el contexto de infección por covid- . se recomienda la administración de profilaxis antitrombótica según protocolo institucional independiente de niveles de dímero d en el paciente críticamente enfermo por covid- . los fenómenos inflamatorios inherentes a procesos infecciosos son considerados desde décadas previas, factores protrombóticos, no siendo una excepción la infección por covid- . en algunas publicaciones se hallan asociaciones con desenlaces cardiovasculares negativos ( ) y sugieren asociación entre niveles elevados de dímero d ( marcador de estado de trombosis ) y riesgo de embolismo pulmonar con or crecientes or de . a los días hasta . a los días de seguimiento ( ) . de igual manera, zhou et al, reportan asociación de dímero d mayor a mcg/ml y mortalidad ( ) sin embargo los estudios presentan limitaciones en su diseño, a pesar de ello algunos autores proponen anticoagulación como factor de protección en mortalidad sin precisar precisión en la dosis, tipo de heparina y selección de enfermos ( ) . finalmente la european heart journal en su entrega de farmacología cardiovascular desarrolla una propuesta en la cual combina un puntaje previo de riesgo de cid en uci a niveles de fibrinógeno; esta pudiera ser una herramienta para selección de pacientes a recibir anticoagulación sin embargo aún está en proceso de validación ( ) . por estos motivos, hasta el momento, no se tiene suficiente cuerpo de evidencia que permita hacer una recomendación basado en los niveles de dímero d como variable aislada para administración de anticoagulación terapéutica. se recomienda no utilizar de rutina la procalcitonina en un algoritmo diagnóstico, para diferenciar entre neumonía viral vs bacteriana o confirmar la presencia de una sobreinfección bacteriana en el paciente con sospecha o diagnóstico de covid- . se recomienda no medir de forma rutinaria la procalcitonina en pacientes con sospecha o diagnóstico de covid- como factor pronóstico. la procalcitonina es un biomarcador que ha sido incluido en algoritmos de diagnóstico y pronóstico durante los últimos años. schuetz et al, en , concluyen en una revisión sistemática de estudios, que la procalcitonina es segura dentro de un algoritmo, para guiar a los médicos tratantes entre iniciar o suspender antibióticos en neumonía adquirida en la comunidad; sin embargo en una revisión sistemática más reciente, kamat et al, reportaron una sensibilidad % [ic % %- %; i = . %], especificidad % [ % ic, %- %; i = , %]) para el inicio de tratamiento antibiótico para neumonía bacteriana, lo cual nos determina que la prueba es inespecífica para diferenciar entre infecciones virales vs bacterianas. en neumonía por sars-cov- , se han publicado algunos artículos evaluando el uso de la procalcitonina como prueba asociada al pronóstico de los pacientes. liu et al encontraron que la procalcitonina se asoció a mayor severidad de los cuadros de neumonía. hr, . ; % ci, . - . ; p= . . en este estudio también se tuvo un resultado similar con la proteína c reactiva y la il- . plebani et al, publican un metaanálisis, donde sugiere que los niveles elevados de procalcitonina se asocian a mayor severidad de la infección. (or, . ; % ci, . - . ). es importante mencionar, que en estos estudios se evaluaron otros biomarcadores de inflamación como interleucina , proteína c reactiva y ferritina; presentando todos ellos, aumento en sus valores y asociándose a severidad de la enfermedad; por tanto, se considera que, en particular, la procalcitonina elevada, no representa una diferencia en el pronóstico, comparado con otros biomarcadores de inflamación. hasta el momento no se han publicado estudios en infección por sars-cov- donde se evalué el papel de prueba diagnóstica para confirmar sobreinfección bacteriana o diferenciar entre neumonía viral vs bacteriana. ( , ( ) ( ) ( ) se recomienda no usar de forma rutinaria el uso de pruebas clínicas de laboratorios clínicos para determinar la resolución de la enfermedad crítica por covid- . se recomienda considerar la ausencia de dificultad respiratoria y fiebre por más de horas, requerimiento de oxígeno a baja concentración y bajo flujo, como indicadores clínicos de resolución de la fase crítica de la enfermedad por covid- . se recomienda no utilizar de forma rutinaria el uso de pruebas microbiológicas de erradicación viral, para determinar la resolución de la enfermedad en pacientes en uci con covid- . amci ® enfermedad está asociado tanto a la carga viral como a la respuesta hiperinflamatoria del huésped a la infección viral. en cuanto a la carga viral, en pacientes que tienen un curso leve de infección, el pico de la carga viral en muestras nasales y orofaríngeas ocurre durante los primeros - días tras el inicio de síntomas y prácticamente desaparece al día , mientras que en los que cursan con neumonía severa en uci, la carga viral es veces mayor y puede persistir la excreción viral hasta el día a ( ) . por esta razón, consideramos que en los pacientes en uci no es necesario confirmar la erradicación del virus o su negativización en muestra respiratorias, orina o heces, para determinar la mejoría clínica, curación o para el egreso del paciente crítico ( ) . en el contexto clínico, el pronóstico se ha asociado a la presencia de marcadores bioquímicos elevados, sin embargo, no existe evidencia que el seguimiento con estos marcadores iniciales de inflamación determine el momento exacto de la resolución de la enfermedad. varias organizaciones internacionales como el cdc de usa y el european centre for disease prevention and control ( mar ) ( , ), national centre for infectious diseases (ncid) singapore ( ), world health organization ( de marzo de )( ), han establecido criterios para resolución clínica y egreso hospitalario de los pacientes. estos criterios incluyen: ausencia de fiebre mayor a horas sin antipiréticos, mejoría de los síntomas respiratorios, ausencia de requerimiento de hospitalización por otras patologías, el resultado de dos ( ) rt-pcr para sars-cov- negativas, con intervalo de muestra mayor a horas. la utilidad de dichos criterios no ha sido evaluada en pacientes en cuidado intensivo. en uci, huang et al ( ) , describieron en pacientes a quienes se dio egreso, la ausencia de fiebre por días, mejoría radiológica y evidencia de erradicación viral, como criterios de alta. sin embargo, consideramos que deben primar los criterios clínicos sobre los paraclínicos, en el momento de definir el egreso de un paciente de cuidado intensivo, teniendo como principal indicador la ausencia de dificultad respiratoria y la mejoría en los índices de oxigenación, con requerimiento de oxígeno suplementario a bajos flujos y concentración ( ) . se recomienda la cánula de alto flujo, donde esté disponible, en pacientes con covid- a nivel del mar con hipoxemia leve (pao /fio < y > o sao /fio < y> ). en alturas superiores a los mts por encima del nivel del mar esta terapia se puede considerar en pacientes que no tengan hipoxemia severa (pafi< ). amci ® se recomienda en pacientes críticos por covid- el uso de la cánula de alto flujo en salas de presión negativa, donde estén disponibles, que garanticen la seguridad del recurso humano. si no se dispone de habitación con presión negativa se puede optar por habitación individual cerrada. se debe contar con todo el equipo de protección personal necesario para el personal sanitario y de apoyo. se recomienda colocar mascarilla quirúrgica por encima de la cánula nasal en el paciente con sospecha o diagnóstico de covid- y mantener una distancia mínima de metros con otros pacientes. se recomienda la intubación inmediata en pacientes críticamente enfermos con sospecha o diagnóstico covid- con índice de rox ([spo /fio ] / frecuencia respiratoria) < a las horas de iniciada la oxigenación con cánula de alto flujo teniendo en cuenta que el retraso en la intubación aumenta la mortalidad. se recomienda considerar la cánula de alto flujo en caso de agotamiento de ventiladores mecánicos. la cánula de alto flujo ofrece flujos de hasta litros/minuto, que aportan una fracción inspirada de oxígeno (fio ) constante que reduce el espacio muerto y produce una presión positiva que genera reclutamiento alveolar y puede redistribuir el líquido alveolar ( ) ( ) ( ) . se ha reportado que al generar aerosoles, aumenta el riesgo de contagio para el personal de salud ( , ( ) ( ) ( ) . hasta el punto de que se ha recomendado su uso en salas con presión negativa ( ) . recientes publicaciones han establecido que la cánula de alto flujo genera una corta distancia de dispersión de aerosoles con lo cual las medidas de distanciamiento, un adecuado equipo de protección personal y donde estén disponibles, realizarla en salas de presión negativa darían seguridad al uso de la cánula de alto flujo ( , ) . a pesar de que la experiencia en la actual pandemia ha sido escasa, basada en series de casos, estudios retrospectivos y de metodología limitada, ha resultado ser promisoria en cuanto a la mejoría en la oxigenación y la tolerancia por el paciente ( , , , , , ( ) ( ) ( ) ( ) ( ) . sin embargo, hasta el momento no se ha establecido que la cánula de alto flujo evite la intubación. la caf podría convertirse en un alto riesgo de mortalidad al prolongar la decisión de intubación y al favorecer la lesión pulmonar autoinducida (p-sili) por aumento del esfuerzo inspiratorio. por todo ello es necesario un estricto y estrecho monitoreo del paciente durante una o dos horas para definir si ha habido mejoría o no mientras se realizan estudios que demuestren que evita la intubación y genera desenlaces clínicos importantes como menor estancia en uci, menor estancia hospitalaria y menos días de ventilación mecánica. la terapia de oxígeno de caf podría ser considerada para pacientes atendidos en altitudes mayor a mts, que no tienen hipoxemia severa (pafi < ), la respuesta debe evaluar dentro de los a minutos posteriores a su inicio y los pacientes que no mejoran amci ® significativamente y progresa la dificultad respiratoria no deben mantenerse con esta terapia. el monitoreo del paciente con caf para la toma de decisión de éxito o fracaso de esta estrategia y considerar la posibilidad de intubación incluye la evaluación gasométrica, la oximetría de pulso, así como considerar los criterios para intubación: frecuencia respiratoria > por minuto, deterioro de conciencia, inestabilidad hemodinámica, pao /fio < (a nivel del mar), sao /fio < , índice de rox< , , spo < % ( , - , - , , ) . se recomienda crear o ajustar protocolos institucionales de sedoanalgesia basado en objetivos con escalas validadas. se recomienda el uso de analgesia multimodal que incluya analgésicos opioides, no opioides y bloqueos regionales en el paciente crítico por sospecha o diagnóstico de covid- . se recomienda sedación profunda con agentes como midazolam o propofol para mantener rass entre - y - en pacientes covid- con sdra severo, necesidad de uso de relajantes neuromusculares o posición prona. se puede considerar en planos de sedación superficial agentes como propofol o dexmedetomidina (coadyuvante) para mantener rass entre y - en pacientes seleccionados con sospecha o diagnóstico de covid- con sdra no severo. en la actualidad no se encuentra evidencia de alta calidad proveniente de ensayos clínicos, sino editoriales, series, reportes de casos y artículos de revisión de expertos ( ) ( ) ( ) . la creación y aplicación de protocolos de sedoanalgesia adaptados a cada institución ha mostrado disminución del tiempo en la uci y menores complicaciones ( , ) . es importante definir objetivos guiados por escalas, recomendándose sedación profunda o completa en situaciones especiales como ventilación mecánica invasiva por sdra severo, disincronía ventilatoria persistente, posición prona y bloqueo neuromuscular (bnm), como puede observarse en pacientes covid- con compromiso pulmonar severo. mientras que se debe procurar sedación ligera, cooperativa o no sedación en pacientes en ventilación mecánica invasiva en pacientes con sdra no severo, ventilación no invasiva y en el retiro de la ventilación ( , ) . los opioides han sido el pilar de la analgesia en dolor moderado a severo. el fentanilo es actualmente el más usado; el remifentanilo reduce el tiempo en ventilación en pacientes amci ® renales, hepáticos, ancianos y neurológicos; la hidromorfona se prefiere en el retiro de la ventilación y en pacientes extubados; y la metadona ha mostrado disminuir la tolerancia a opioides ( ) . se propone el uso de estrategias de analgesia multimodal asociando medicamentos no opioides como el paracetamol, ketamina a dosis analgésicas (< , mg/kg) en dolor somático, lidocaína en dolor visceral, y pregabalina en dolor neuropático ( ) . la sedación ligera o cooperativa son mejores con propofol en cuanto a tiempo de despertar y con dexmedetomidina para preservar funciones cognitivas y el impulso respiratorio, con menor desacondicionamiento ( ) . en sedación profunda, el propofol ha mostrado más fácil titulación y menos acumulación que el midazolam; sin embargo, su uso se ve limitado hasta horas y a dosis < , mg/kg/h, ante el riesgo de pris (síndrome relacionado con la infusión de propofol). el midazolam, sin dosis techo ni tiempo límite y de bajo costo, ha sido el más utilizado de los sedantes, disminuyendo su uso por su asociación con delirium y de retraso en los tiempos en ventilación; sin embargo, la pandemia covid- ha vuelto a aumentar su uso. la dexmedetomidina ha sido utilizada como adyuvante en sedación profunda, disminuyendo el consumo de sedantes, con menos efectos secundarios ( , ) . se muestran los medicamentos para sedoanalgesia y relajación neuromuscular que se pueden utilizar en los pacientes con covid- en la tabla . se recomienda iniciar una estrategia individualizada de ventilación mecánica ajustadas a las condiciones específicas de severidad en el paciente crítico con covid- . amci ® se recomienda la ventilación protectora en modos controlados por volumen o por presión que garanticen un volumen corriente < cc/kg de peso predicho teniendo como metas una presión meseta < cm h o y una presión de conducción < cm h o. se recomienda emplear fracciones inspiradas de oxígeno para lograr metas de saturación de acuerdo con la pao /fio entre y % en el paciente con sospecha o diagnóstico de covid- . en la paciente embarazada entre y %. se recomienda en el paciente crítico por covid- iniciar con peep individualizado a la severidad del compromiso pulmonar y ajustar el nivel de peep de acuerdo con la tabla de fio /peep. el estudio arma ( ) demostró que la ventilación con bajos volúmenes corrientes (vt) se asocia con reducción de: mortalidad (p= . ), en días libres de ventilación mecánica (p= . ) y días libres de falla orgánica (p= . ). una revisión sistemática posterior confirmó que el uso de bajos volúmenes se asocia con menor progresión a sdra ( ) . un metaanálisis que revisó estudios y meta-análisis en uci confirmó que la ventilación protectora era una de las tres intervenciones que mejora la sobrevida en pacientes con sdra ( ) . esto fue confirmado por landoni en un análisis de estudios multicéntricos con impacto en mortalidad en uci ( ) . recientes publicaciones han sugerido que en covid- puede haber dos fenotipos que se diferencian en la distensibilidad ( , ) . sin embargo, el mismo estudio arma demostró que "el beneficio de ventilación con vt más bajo fue independiente de la distensibilidad de las vías respiratorias, lo que sugiere que el vt más bajo fue ventajoso independientemente de la distensibilidad pulmonar". más aún, el uso de bajos vt se asoció con una reducción en las concentraciones de interleuquina lo cual explicaría el mayor número de días sin falla orgánica múltiple y sugeriría una reducida respuesta inflamatoria asociada a la ventilación protectora ( ) . con el tiempo la evidencia ha demostrado que la ventilación protectora, además de vt y presión meseta bajos, debe incluir presiones de conducción menores de cm h o ( ) ( ) ( ) . existe suficiente evidencia que demuestra que fio y pao altas se asocian con aumento en la morbimortalidad ( ) ( ) ( ) . en sdra el estudio arma y una más reciente publicación demostraron que el tener metas conservadoras de pao se asocia con mayor sobrevida ( , ) . hasta el momento, la literatura en ventilación mecánica ha demostrado que la mejor estrategia para ajustar el nivel de peep en sdra es la tabla de fio /peep ( , ) . amci ® se recomienda la ventilación mecánica protectora en sdra por covid- independiente del fenotipo de presentación. se recomienda la clasificación de fenotipos en sdra para pacientes con covid- para ajustar la toma de decisiones de manera individualizada en ventilación mecánica. el manejo ventilatorio en covid- tiene los mismos principios generales de los pacientes con sdra ( ) . sin embargo, la identificación de fenotipos podría impactar en la evolución y pronóstico ( ) . gattinoni ha postulado el desarrollo de un sdra típico (fenotipo h: con alta elastancia, alto cortocircuito, alto peso pulmonar) o una presentación atípica (fenotipo l: caracterizado por baja elastancia, bajo shunt, bajo peso pulmonar). ( ) . pelosi et al sugiere clasificar los pacientes con tres fenotipos similares ( ) . con base en tales fenotipos se han propuesto estrategias ventilatorias diferenciales para minimizar el daño inducido por el ventilador (vili) ( ): . el primer paso, en el fenotipo l, es revertir la hipoxemia aumentando la fio . . en el tipo l, hay varias opciones no invasivas: cánula nasal de flujo alto, presión positiva continua en la vía aérea (cpap) o ventilación no invasiva (niv). se debe evaluar el esfuerzo inspiratorio y, de estar disponible, medir la presión esofágica. la peep alta puede disminuir los cambios de presión pleural y detener el ciclo vicioso que exacerba la lesión pulmonar. sin embargo, la peep alta, en pacientes con distensibilidad normal, puede tener efectos hemodinámicos perjudiciales. en cualquier caso, las opciones no invasivas son cuestionables, ya que pueden asociarse con altas tasas de fracaso y retraso de la intubación. . la magnitud de las presiones pleurales inspiratorias puede determinar la transición del tipo l al h. la presión esofágica > cmh o aumenta el riesgo de vili y, por lo tanto, la intubación debe realizarse lo antes posible. los tipo l, si son hipercápnicos, pueden ser ventilados con volúmenes > ml / kg (hasta ml / kg). la posición prona debe ser usada solo en último caso, ya que las condiciones pulmonares son buenas. la peep debe reducirse a - cm h o, dado que la capacidad de reclutamiento es baja y el riesgo de falla hemodinámica aumenta. la intubación puede evitar la transición al fenotipo tipo h. . los pacientes tipo h deben ser tratados como sdra grave, incluyendo mayor peep, si es compatible con la hemodinamia, posición en pronación y soporte extracorpóreo. en el fenotipo se deben aplicar las estrategias de ventilación protectora convencional ( , ) . amci ® se recomienda en paciente con covid- considerar hipoxemia refractaria cuando no se obtienen las metas de oxígeno propuestas, a pesar de las maniobras ventilatorias recomendadas y cumple con los siguientes parámetros: pafi < , fio > , y peep apropiado, considerando la altitud. se recomienda considerar la utilización de ecmo, en sitios donde esté disponible y con alta experiencia para obtener resultados aceptables, en pacientes con hipoxemia refractaria luego de haber implementado ventilación protectora, relajación neuromuscular y posición prona. se recomienda administrar tromboprofilaxis en todos los pacientes con covid- con hipoxemia refractaria que no presenten contraindicaciones. la hipoxemia refractaria no es un concepto estático y absoluto, según la definición de berlÍn del sdra, se clasifica el sdra en leve, moderado y severo de acuerdo con la relación pao y fracción inspirada de oxígeno, con peep mayor de cms de h o. la hipoxemia severa es aquella que cuenta con una pafi menor de ( ) ( ) ( ) . la hipoxemia refractaria hace referencia a un estado de hipoxemia severa que a pesar de las diferentes estrategias ventilatorias no aumenta la pafi y tiene consecuencias en el estado ácido básico y metabolismo celular permitiendo una anaerobiosis ( , ) . para definir la hipoxemia refractaria deben coincidir varios escenarios , una pafi menor de , una fracción inspirada de oxígeno mayor de . , a pesar de un peep apropiado no se tiene en cuenta en la definición el ph ni la paco ni el tiempo transcurrido ( ) . algunas de las medidas terapéuticas no ventilatorias que se han empleado en sdra y covid- con hipoxemia refractarias son la oxigenación con membrana extracorpórea (ecmo) y la tromboprofilaxis o anticoagulación de rutina. la oxigenación extracorpórea a través de una membrana ha sido una estrategia controvertida en pacientes con hipoxemia refractaria de diferentes orígenes, en la epidemia de la influenza por el virus h n fue usada en pacientes con hipoxemia refractaria teniendo resultados aceptables ( ) . en el estudio eolia los resultados no mostraron mejoría en la supervivencia, aunque hay diferentes posiciones y estudios post hoc de este ensayo clínico con beneficios, su uso se limita a casos muy restringidos y en sitios de alta experiencia para obtener resultados aceptables ( ) . en sdra por covid- el ecmo se ha usado en hipoxemia refractaria entre un a . % en diferentes series con resultados variables ( , , ) . un tipo de pacientes hipoxémicos y con ventilación mecánica han presentado cuadros tromboembólicos pulmonares en estos casos la trombólisis de rescate con activador de plasminógeno tisular rtpa (alteplase) se ha recomendado con resultados alentadores en serie de casos, pero su evidencia es muy débil para ser recomendada( - ). dada la alta frecuencia de enfermedad tromboembólica reportada en covid- se ha reportado la utilidad de la tromboprofilaxis, especialmente en casos de dímero d o índice de sic elevado ( ) . amci ® se recomienda monitorizar sistemáticamente la oxigenación con los índices: pao /fio y sao /fio , y en donde esté disponible el monitoreo continuo con capnografía. se recomienda monitorizar de forma rutinaria la presión meseta y la presión de conducción como estrategia al pie de la cama para verificar la ventilación protectora. el sdra y covid- , es una condición dinámica que apenas se está caracterizando, hay varias presentaciones que no cumplen con todos los criterios de berlÍn ( , ) . gattinoni ha caracterizado en dos presentaciones el sdra en los pacientes con neumonía por coronavirus sars-cov- , una con alta compliance, mínima reclutabilidad; la otra con baja compliance, pulmones pesados y reclutabilidad, tal vez esta presentación sea el verdadero sdra ( , , ) . los pacientes que requieren ventilación mecánica por falla ventilatoria en covid- , son los que mayor mortalidad tienen al parecer por la lesión pulmonar inducida por la intubación tardía y el gran esfuerzo respiratorio con presiones transpulmonares oscilantes y muy negativas ( , , ) . la monitoria de estos pacientes soportados con ventilación mecánica tiene dos objetivos: el primero detectar el deterioro clínico para sugerir estrategias más avanzadas como el ecmo, y el segundo es evitar el daño pulmonar inducido por la ventilación mecánica. se debe tener presente la mayor posibilidad de contagio con el número de manipulaciones en el paciente, por esto nunca olvidar el perfecto uso de los elementos de protección personal y disminuir el número de contacto con el paciente. las metas que se buscan con la ventilación mecánica en el paciente con sdra por covid- son mantener una oxigenación adecuada teniendo en cuenta la altura sobre el nivel del mar con pao entre y mmh y metas de saturaciones reportadas entre y % a y % , mantener una ventilación adecuada evitando el espacio muerto , disminuir el trabajo respiratorio y protegiendo el pulmón del daño ocasionado por la ventilación mecánica y las repercusiones hemodinámicas ( ) .  el confort de los pacientes en ventilación mecánica es la principal señal de un uso adecuado del modo ventilatorio y los parámetros ventilatorios apropiados para la patología y demanda del paciente ( ) .  las curvas y bucles son herramientas indispensables para valorar la mecánica respiratoria del paciente soportado con ventilación mecánica, se puede diagnosticar amci ® las asincronías del paciente y el ventilador, el origen, tipo y frecuencia además de la respuesta al manejo. también se evalúa la resistencia de la vía aérea ( ) . variables fisiológicas:  es importante valorar la oxigenación del paciente, la literatura actual sugiere el monitoreo de la pafi es el más representativo y sencillo test para valorar la oxigenación y representa el shunt pulmonar, se debe hacer mínimo diariamente, o cuando se haga una intervención en el ventilador o paciente; en sdra por covid- la hipoxemia se relaciona directamente con mortalidad, debe mejorar con la ventilación mecánica ( , ) .  la medición de la paco indica la de la ventilación, la hipercapnia tiene relación directa con el espacio muerto en el paciente con sdra, y varios estudios la relacionan con la mortalidad. puede evaluarse directamente en los gases arteriales o relacionarla con el pco expirado por medios de la capnografía, gattinoni propone una forma de evaluarla al lado de la cama del paciente relacionando el etco /paco , cuando es < de sugiere un shunt elevado y mayor espacio muerto; áreas de pulmón ventiladas y no aireadas. otras tecnologías incluidas en el ventilador moderno como la capnografía volumétrica se está validando para evaluar el espacio muerto, la reclutabilidad y la titulación de peep ( , ) .  la saturación venosa mixta svo , refleja de manera subrogada la función ventricular, no todos los pacientes tienen catéter de arteria pulmonar para su medición por lo que se está reemplazando con el ultrasonido en la cabecera del paciente; recordar que el % de los pacientes con sdra cursan con falla ventricular derecha ( ) . monitoria de mecánica ventilatoria y protección pulmonar:  para evitar el daño pulmonar debe propender por un volumen corriente bajo ( - ml/kg de peso predicho) y presión plateau menor de cms h , para garantizar la ventilación con protección pulmonar ( , ) .  driving pressure ( presión cambiante de la vía aérea, presión diferencial o presión de conducción) es la presión plateau (presión pico en ventilación controlada por presión) menos peep, debe ser menor de cm h , está relacionado con aumento en la mortalidad en pacientes ventilados por que representa una medición indirecta del strain pulmonar porque relaciona el volumen corriente con la compliance del sistema respiratorio y este a su vez se relaciona con el volumen espiratorio pulmonar final ( ) .  la medición de la compliance del sistema respiratorio es necesaria y nos clasifica el paciente de acuerdo con su fenotipo para trazar el plan de manejo ventilatorio, cuando la compliance es baja, esto se puede hacer al lado de la cama del paciente con los ventiladores modernos ( , ) .  la construcción de la curva presión/volumen aún es una herramienta útil para ubicar el área de ventilación segura del paciente, evitando el atelectrauma y la sobredistensión pulmonar(estrés) , el peep se calcula dos puntos por encima del punto de inflexión inferior y el punto de inflexión superior nos indica hasta dónde podemos aumentar el volumen corriente este punto debe estar por debajo de cms h para evitar la sobre distensión, con los ventiladores modernos se puede construir esta curva ( , ) . amci ®  las curvas presión tiempo en pacientes ventilados con modos volumétricos pueden monitorizar la resistencia de la vía aérea, la compliance pulmonar, el trabajo respiratorio, las curvas de flujo puede también indicar si se presenta autopeep, resistencia aumentada de la vía aérea entre otras ( ) .  presión transpulmonar, en casos más complicados donde es más difícil obtener la meta de oxigenación a pesar del peep en aumento una opción es el catéter esofágico, para medir la presión transpulmonar en la inspiración y espiración y calcular así el stress pulmonar y evitar las presiones oscilatorias y sobre todo negativas para evitar el daño pulmonar. esta herramienta también ayuda a evaluar el trabajo respiratorio, y el diagnóstico de las asincronías que se presenten en el paciente ventilado ( , ) . se recomienda no utilizar de forma rutinaria la relajación neuromuscular en el paciente crítico con covid- con sdra. se recomienda utilizar la relajación neuromuscular en pacientes en posición supino o prono, que están fuera de parámetros de protección pulmonar (presión de conducción mayor y presión plateau mayor a ) con pafi menor y cuando ya no es posible limitar el volumen corriente. se debe considerar la utilización de protocolos estandarizados con el fin de disminuir la variabilidad, y según disponibilidad seleccionar el cisatracurio como primera opción, en caso de escasez se pueden utilizar otras opciones teniendo en cuenta su farmacodinamia y farmacocinética. el de marzo de , la organización mundial de la salud emite una serie de orientaciones para el manejo de la infección respiratoria aguda grave (irag) en pacientes con sospecha o diagnóstico de covid- . en el paciente críticamente enfermo con sdra moderado o grave (pao /fio < ) por covid- no está indicado de forma sistemática el bloqueo neuromuscular mediante infusión continua debido a que no se cuenta con evidencia suficiente que sustente mejoría en la supervivencia con respecto a una estrategia de sedación ligera sin bloqueo neuromuscular, se debe considerar su uso cuando se evidencia asincronía paciente-ventilador a pesar de la sedación, hasta el punto de que no se pueda limitar el volumen corriente de forma fiable, hipoxemia o hipercapnia que no mejoran con el tratamiento ( ) . recomendaciÓn se recomienda no utilizar de forma rutinaria oni en pacientes adultos que presenten sdra e infección por sars-cov- . fuerte en contra fundamento a la fecha (mayo de ) no contamos con estudios sobre el uso de óxido nítrico inhalado (oni) como tratamiento de pacientes con infección covid- . existe evidencia indirecta sobre el uso de oni en el síndrome de dificultad respiratoria aguda (sars-cov), y la infección por coronavirus en el síndrome respiratorio de oriente medio (mers-cov) ( ) . en cochrane realizó una revisión sistemática que incluyó ensayos de calidad moderada con pacientes adultos con sdra tratados con óxido nítrico inhalado. los resultados no mostraron ningún efecto estadísticamente significativo sobre la mortalidad (rr . , % ci . - . ). se mostró mejora transitoria en el índice de oxigenación a las horas (md (diferencia media) - , , ic del % - , a - , ) y mejoría en pao /fio a las horas (md , , ic del % , a , ). no se identificó diferencia significativa en los días libres de ventilación y finalmente se presentó aumento estadísticamente significativo en la incidencia de insuficiencia renal en pacientes con óxido nítrico inhalado (rr , , ic del % , )( ). amci ® en se realizó un estudio observacional que incluyó pacientes tratados de dos hospitales de beijing con oni como tratamiento para sars ( ) . en comparación con ningún tratamiento, oni mejoró la saturación arterial de oxígeno (spo ) de % a % (p< . ); se asoció a menor necesidad de oxígeno suplementario (p< . ) y menor necesidad y retiro de cpap y bial (p < . ). los cambios en radiografía de tórax mejoraron en de los pacientes que recibieron oni. sin embargo, debido a problemas graves de validez por pequeño tamaño de la muestra (n= , oni= , control= ), no aleatorización y no enmascaramiento en la asignación, se considera que este estudio cuenta con baja calidad metodológica, lo cual limita la interpretación de los resultados. en un estudio retrospectivo multicéntrico que incluyó pacientes con mers-cov en condición crítica en arabia saudita, se mostró que el manejo con ventilación no invasiva (niv) tenía mayor probabilidad de requerir óxido nítrico en comparación con los pacientes con ventilación mecánica invasiva ( , % vs , %, p a , ) ( ) . en una serie de casos en la que participaron pacientes con infección por mers-cov confirmada o probable, pacientes recibieron oni debido a hipoxemia refractaria. en el seguimiento a días, cinco de los pacientes continuaron vivos ( ) . los estudios sobre mers-cov se limitaron a una serie de casos y una cohorte retrospectiva con baja calidad de evidencia. en ambos estudios, los pacientes recibieron otras terapias de rescate (relajación neuromuscular, ventilación oscilatoria de alta frecuencia, ecmo y posición en prono), por lo tanto, se desconoce el efecto terapéutico clínico del oni en el tratamiento de la infección por mers-cov. a la fecha ( de mayo de ) tres ensayos clínicos evalúan el papel del óxido nítrico inhalado en pacientes con covid- y sdra leve/moderado, y como profilaxis para los trabajadores de la salud covid- (tabla ). tabla . comparación de ensayos clínicos que evalúan el papel del óxido nítrico inhalado en pacientes con covid- y sdra leve/moderado, y como profilaxis para los trabajadores de la salud covid- . no se cuenta con evidencia por el momento que respalde el uso de óxido nítrico inhalado en pacientes con covid- . los resultados de los ensayos en curso, así como ensayos clínicos de alta calidad son necesarios para apoyar su uso. sólo evidencia indirecta metodológicamente limitada de óxido nítrico en pacientes con sras mostró una mejor oxigenación, una menor necesidad de oxígeno suplementario y mejoría en la radiografía de tórax. en pacientes con sdra y mers-cov, no mostró un beneficio claro e incluso mostró un mayor riesgo de insuficiencia renal ( ) . otros estudios han evaluado el efecto tóxico asociado a su uso documentando metahemoglobinemia( ), inhibición de la agregación plaquetaria y formación de dióxido de nitrógeno ( ) . razones por la cuales guías recientemente publicada no recomienda su uso de forma rutinaria( ). recomendaciÓn se recomienda el uso temprano de la ventilación en posición prona, por al menos horas continuas, en pacientes con sdra por covid- con pao /fio < mmhg. la ventilación en posición prono como estrategia ventilatoria propuesta desde los años ( ), cuenta con evidencia que demuestra resultados positivos en cuanto a mejoría de mortalidad, mejoría en el trastorno de oxigenación y el reclutamiento alveolar en pacientes con sdra. los mecanismos por los cuales la posición prona conduce a la mejoría en el trastorno de oxigenación y del reclutamiento alveolar en los pacientes con sdra, incluyen ( ) ( ) ( ) ( ) : amci ®  mejoría de la relación ventilación/perfusión y mayor homogeneidad en la distribución de aire en los pulmones.  aumento del volumen de fin de espiración.  disminución del efecto compresivo del corazón en los pulmones.  mejoría del drenaje de las secreciones.  optimización del reclutamiento alveolar, con mejoría de la distribución del volumen corriente, a su vez, limita el desarrollo del daño alveolar pulmonar. los estudios coinciden en el efecto benéfico que esta terapia tiene en la mejoría de la oxigenación, el objetivo se centrará en evaluar las recomendaciones con respecto a:  beneficio de la terapia con respecto a la mortalidad al día , al día y a los meses.  beneficio de la terapia según el grado de severidad de sdra con respecto la relación pao /fio .  tiempo de terapia en posición prono con mayor beneficio.  número de sesiones de la terapia en posición prono.  recomendaciones según balance riesgo/beneficio en lo que respecta a los efectos adversos: retiro o desplazamiento no planeado de catéteres, obstrucción de tubo endotraqueal, neumonía asociada a ventilador, lesiones de presión. se eligieron artículos que con las características metodológicas consistentes ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . de estos ocho artículos se excluyó uno por corresponder a pacientes pediátricos ( ) . al evaluar los escritos de forma cronológica, se puede apreciar en los primeros artículos ( , ) , la dificultad para lograr enrolar (reclutar) el suficiente número de pacientes, de tal manera que algunos estudios fueron detenidos de forma prematura ( , , , ) . era entonces esperable que los resultados no fueran concluyentes, y que no lograran ser robustos, al no alcanzar el tamaño de muestra deseado, comprometiéndose la confiabilidad, el poder y corriendo el riesgo de obtener resultados falsamente negativos. sin embargo, se podía percibir en los diferentes estudios, una notoria mejoría en la oxigenación, sin repercusión en la mortalidad ( ) ( ) ( ) ( ) ( ) ( ) . por otro lado, es necesario tener en cuenta que los estudios iniciales ( ) ( ) ( ) ( ) no se realizaron con el uso de ventilación protectora asociada a la pronación. esto es un elemento pertinente, pues la ventilación protectora puede per se, brindar un efecto adicional en la mejoría de la oxigenación. otro efecto importante que debe analizarse es el bloqueo neuromuscular, cuya evidencia hoy sugiere su uso en criterios ya mencionados ( ) . con el tiempo y según la experiencia de cada centro, se fue utilizando con menor dificultad ( ) . sin embargo, no se tenía aún claro qué tipo de pacientes obtenían el mayor beneficio de la terapia, además que el tiempo de la terapia en posición prona, seguía siendo una incógnita. la evidencia reflejaba hasta el momento que los pacientes con sdra más severos y la terapia aplicada por más tiempo se asociaban con una tendencia a la reducción en mortalidad. para dirimir qué tipo de pacientes se beneficiarían más de la terapia, se tomó como base, la severidad del sdra según la relación pao /fio ( ) . a pesar de que los estudios iniciales( - ) enfrentaban el reducido tamaño de muestra, algunos análisis identifican beneficio de la mortalidad ( ) en pacientes con sdra más severo, constituyendo un probable umbral de beneficio cercano y por debajo de - mmhg ( ) . amci ® antes del estudio proseva ( ) en totalidad estudios reportan mortalidad al día ( , ) , un estudio mortalidad al día ( ) , uno estudio mortalidad al día ( )y uno mortalidad al día ( ) . sin embargo, al tomar todos los estudios, aún no se alcanzaba suficiente significancia estadística para reducir la mortalidad a los días y meses. con el estudio proseva -guerin et als -en el año ( ) , se alcanza más poder estadístico, demostrando un beneficio importante en pacientes con pao /fio menor de mmhg, ventilados con bloqueo neuromuscular y ventilación protectora en su totalidad, y logrando una reducción de la mortalidad al día y mantenida hasta el día con respecto al grupo control ( . % ( de participantes) versus . % ( de ) (p< . ). de tal manera que, según la evidencia disponible, en lo que al trastorno de oxigenación se refiere (según la relación pao /fio ), sugiere que el mejor candidato para esta estrategia ventilatoria es el paciente con sdra severo con una pao /fio menor de mmhg. es de primordial importancia detenerse a considerar por otra parte, el número de horas que se implementaría la terapia. el estudio inicial realizado por gattinoni et al. ( ) , llevó a los pacientes a un período corto de horas, sin encontrar resultados positivos en mortalidad. (resultados que no se pueden solamente atribuir a la calidad del estudio, sino también, al reducido número de horas de la ventilación en posición prono). mancebo et als (la abreviación latina para "otros "es et al.), y fernández et al. ( , ) por su parte, optan por ventilar un mayor número de horas ( - horas) obteniendo resultados (que sugieren una reducción en mortalidad) con tendencia a disminuir mortalidad. si bien diferentes metaanálisis sugieren no (la ausencia de beneficio) beneficio de la ventilación en prono ( , ) , los resultados son diferentes cuando se aborda la terapia con períodos mayores a horas ( ) . teniendo en cuenta, que el estudio con más poder estadístico ( ) postula horas de terapia en posición prono, la recomendación es la pronación por un tiempo mayor a horas, contemplando hasta las horas por sesión. otra pregunta que surge con frecuencia es el número de veces que se puede implementar la terapia. existen diferentes estudios en los cuales se indica el número de veces en promedio en que se llevó el paciente a posición prono ( , ) , otro protocolo en donde se estipula un número límite de días en los que se llevó a cabo la terapia( ), y otro estudios en los cuales no se precisó el número de sesiones de la terapia ( , ) . se podría entonces recomendar con respecto a la mayor evidencia disponible ( ) , pronar a los pacientes en varias sesiones ( en promedio) (depende de los criterios para continuar o suspender el prono que deben ser individualizados para cada paciente, en cada zona geográfica y en cada unidad de cuidados intensivos, es difícil saber si es el promedio para todos), y considerarla más veces si es necesario. en lo que respecta a los efectos adversos, tres estudios reportaron barotrauma y neumonía asociada a ventilador ( , , ) ; dos estudios desplazamiento de catéter central ( , ) y siete estudios reportaron extubación ( ) ( ) ( ) ( ) ( ) ( ) ( ) . sin embargo, los efectos adversos no alcanzaron significancia estadística para proscribir la terapia ( ) . recientemente fue publicado el consenso colombiano de sdra( ) en el cual se hace referencia a las recomendaciones para realización de ventilación prono. se presenta la lista de chequeo, y medidas que deben ser realizadas en la maniobra para lo cual se cuenta con la participación de terapia respiratoria, enfermería y médico. se recomienda implementar un protocolo de retiro de ventilación mecánica basado en la prueba de respiración espontánea y articulado con un protocolo de sedación y analgesia en el paciente críticamente enfermo por sospecha o diagnóstico de covid- . desde diciembre de , un número de casos de neumonía por síndrome respiratorio agudo severo sars-cov /covid- en wuhan china se identificaron, como causa de insuficiencia respiratoria aguda( ). el síndrome de dificultad respiratoria aguda (sdra) ocurre en el % de los pacientes hospitalizados y en el % de los pacientes admitidos a la unidad de cuidados intensivos (uci) en wuhan ( ) . mientras la ventilación mecánica es una intervención que potencialmente salva la vida, esta puede llevar a múltiples complicaciones y contribuir a la lesión pulmonar ( ) . es por todo esto que el retraso en el retiro de la ventilación mecánica puede aumentar el riesgo de amci ® infecciones, aumenta la sedación innecesaria, el trauma de la vía aérea y aumento en el costo de la atención de estos pacientes ( ) . el retiro de la ventilación mecánica es un proceso de tres pasos, el primero es conocido como preparación la cual depende de variables fisiológicas, criterios clínicos y predictores de weaning (destete), el segundo paso es el propio weaning, el cual consiste en la disminución del soporte ventilatorio entregado al paciente, con el objetivo de llevar al último paso que es la extubación( ), ilustración . por todo lo anterior, se recomienda realizar un proceso de retiro de ventilación mecánica invasiva adoptando un protocolo, seleccionando adecuadamente a los pacientes, ya que evidencia sugiere que la adecuada selección de los pacientes disminuye los días de ventilación mecánica, disminuye la estancia hospitalaria y la estancia en uci ( ) . se recomienda realizar el retiro de la ventilación mecánica siguiendo los pasos antes mencionados, iniciando con la preparación, la cual consiste en: preparación . asegurarse que la lesión pulmonar que llevó a la falla respiratoria esté resuelta. . adecuado intercambio de gas, definido como adecuados índices de oxigenación con peep (presión positiva al final de la expiración) a cmh o, y fio (fracción inspirada de oxígeno) < . . al igual que el proceso de intubación, es un proceso que genera aerosoles por lo cual se recomienda la aplicación de lidocaína dosis de , a , mg por kilogramo de peso, a minutos antes la extubación con el objetivo de disminuir el reflejo de tos ( ) y la exposición del personal de salud. se recomienda en el paciente con sospecha o diagnóstico de covid- a quien se considera realizar vmni, utilizarla en salas de presión negativa, donde estén disponibles, que garanticen la seguridad del recurso humano, con todo el equipo de protección personal necesario. se recomienda considerar la vmni en pacientes con covid- con hipoxemia leve (pao /fio < y > o sao /fio < y> ) en salas de presión negativas, donde estén disponibles que garanticen la seguridad del recurso humano, con todo el equipo de protección personal necesario. fuerte a favor se recomienda considerar la vmni en pacientes con covid- con hipoxemia leve (pao /fio < y > o sao /fio < y> ) y con historia de epoc o cuadro de edema pulmonar agudo asociado en salas de presión negativas, donde estén disponibles que garanticen la seguridad del recurso humano, con todo el equipo de protección personal necesario. se recomienda colocar doble filtro en el circuito del ventilador para reducir el riesgo de generación de aerosoles en vmni del paciente crítico con sospecha o diagnóstico de covid- . se recomienda la intubación inmediata en pacientes críticamente enfermos por covid- si se evidencia respiración toraco-abdominal, uso de músculos accesorios, frecuencia respiratoria > , hipoxemia (pao /fio < o sao /fio < ), fracaso ventilatorio (ph< . con paco > mmhg), hacor> . existe suficiente evidencia que demuestra que la vmni es una estrategia que reduce la mortalidad en pacientes críticos ( , , ) . además, reduce la necesidad de intubación. los números de casos necesarios a tratar (nnt) son: ocho para salvar una vida y para evitar una intubación ( ) . estos desenlaces son fundamentalmente en pacientes con epoc y edema pulmonar agudo ( ) ( ) ( ) ; también hay evidencia a favor, aunque menos fuerte, en pacientes inmunosuprimidos ( , ) . se ha planteado mayores tasas de éxito con interfaces faciales totales o con helmet ( , ( ) ( ) ( ) ( ) ( ) . por el contrario, en falla respiratoria hipoxémica hay evidencia en contra del uso de vmni ( ) . la experiencia previa con h n , sars y mers no apoya el uso de la vmni en falla respiratoria hipoxémica de origen viral ( ) ( ) ( ) ( ) ( ) ( ) . además, se ha cuestionado el uso de vmni en covid- por el riesgo de contagio al generar aerosoles ( ) . recientemente se demostró que la distancia de dispersión de aerosoles era menor de un metro ( ) . por otro lado, el fracaso de la vmni se ha asociado con alta morbimortalidad ( ) ( ) ( ) . ello obliga a evaluar estrictamente la posibilidad de éxito o fracaso. así, en falla respiratoria amci ® hipoxémica la escala hacor ha sido validada para este fin y un puntaje> contraindicaría la vmni ( ) . adicionalmente si se emplea la vmni el prolongar la decisión de intubación puede aumentar la mortalidad y es por ello necesario monitorizar estrictamente al paciente y evaluarlo para establecer, ojalá antes de dos horas, si el paciente responde a la vmni ( , , ) . las indicaciones para intubación en este caso son respiración toracoabdominal, uso de músculos accesorios, frecuencia respiratoria mayor de , hipoxemia (pao /fio < o sao /fio < ), fracaso ventilatorio (ph< . con paco > mmhg), hacor> o índice de rox (spo /fio )/frecuencia respiratoria) < ( , , , , , ) . recomendaciÓn se sugiere el uso de posición prono en pacientes no ventilados críticamente enfermos por covid- que no responden a la oxigenoterapia convencional de acuerdo con los protocolos institucionales, las condiciones de cada servicio y la tolerancia individual de cada paciente. débil a favor fundamento los pacientes con enfermedad por coronavirus (covid- ) están en riesgo de desarrollar un síndrome de dificultad respiratoria aguda (sdra) ( ) . en pacientes intubados con síndrome de dificultad respiratoria aguda grave, la posición prona (pp) temprana y prolongada (al menos horas diarias) mejora la oxigenación y disminuye la mortalidad ( , ) .debido a que las unidades de cuidados intensivos (uci) están sobrecargadas con pacientes con covid- , la pp en paciente despierto con respiración espontánea puede ser útil para mejorar la oxigenación y prevenir las transferencias hacia uci. un estudio describió la viabilidad del uso de la ventilación no invasiva y la cánula de alto flujo asociado a la pp estableciendo su tolerancia y su seguridad en pacientes con sdra moderado y severo( ); la pronación puede reclutar todas las regiones pulmonares y favorecer el drenaje de secreciones de la vía respiratoria, mejorando el intercambio gaseoso y la supervivencia en el síndrome de dificultad respiratoria (sdra) ( ) . en una comunicación corta proveniente de italia en el cual se incluyeron pacientes que son sometidos al pp asociada con el uso de ventilación no invasiva, se concluye que proporcionar niv en la posición prona a los pacientes con covid- y sdra en salas generales en un hospital en italia era factible. la frecuencia respiratoria disminuyó durante su implementación y la oxigenación mejoró durante una pronación posterior a su línea de base. si la intubación se evitó o se retrasó, queda por determinar ( ) . en otro reporte de caso, publicado recientemente por un grupo francés( ) de pacientes con covid- e insuficiencia respiratoria hipoxémica manejados fuera de la uci, el % amci ® fue capaz de tolerar pp durante más de horas. sin embargo, la oxigenación aumentó durante el pp solo un % y no se mantuvo en la mitad de los pacientes después del regreso a la posición supina. estos resultados son consistentes con los hallazgos de pequeños estudios previos de pp en pacientes no intubados ( ) . un ensayo clínico controlado que evalúe el uso del pp en pacientes no intubados puede ser un mecanismo para seleccionar pacientes que bien puedan beneficiarse de esta estrategia terapéutica. dada la evidencia débil que soporta el uso del pp en pacientes no intubados en términos de la disminución de la necesidad de entubación o ingreso a cuidados intensivos y la duda razonable de aumentar desenlaces deletéreos en aquellos pacientes en los cuales se retarde el tiempo de intubación, no se emite recomendación, a favor o en contra, del empleo de esta estrategia de manera rutinaria. en situaciones en las cuales hay limitación de recursos y de disponibilidad de camas en cuidados intensivos el uso de la pp asociada a vni o cánula de alto flujo podría ser una estrategia útil para mejorar la oxigenación en pacientes infectados con covid- e hipoxemia. se recomienda considerar la elevación de biomarcadores como la troponina i o t y el nt-pro-bnp en el paciente con covid- como indicadores de injuria miocárdica aguda, sin embargo, no reemplazan la ecocardiografía en el enfoque del paciente con sospecha de disfunción miocárdica. fuerte a favor fundamento la injuria miocárdica aguda asociada a covid- se reporta con frecuencia teniendo en cuenta los cambios en biomarcadores como la troponina y cambios electrocardiográficos, pero su impacto en la función cardíaca se desconoce y mucho menos su correlación con los cambios ecocardiográficos. los pacientes con covid- pueden desarrollar una serie de complicaciones cardiacas desde injuria miocárdica, arritmias, infarto, hasta miocarditis fulminante con falla cardiaca aguda y shock cardiogénico ( ) . la troponina i, se ha encontrado más elevada en pacientes con curso fatal por covid- ( ) . los niveles de nt-pro-bnp han sido reportados con elevación severa en pacientes con miocarditis y disfunción sistólica, con una disminución progresiva en relación a la mejoría de los pacientes, pero no parece tener un correlación significativa con el cambio de la fracción de eyección (fevi) ( ) . la evidencia clínica sugiere que la elevación de los biomarcadores es más relacionada al compromiso sistémico que el daño miocárdico directo, q. deng y colaboradores en un análisis retrospectivo de pacientes, reportaron niveles iniciales de troponinas normales casi en la mayoría, en el , % de los casos los niveles incrementaron significativamente, principalmente en los que fallecieron y solo pacientes tenían fevi menor al % y ninguno inferior al %, lo cual no sugiere una asociación entre las dos amci ® pruebas ( ) . en una publicación donde se compara el fenotipo de pacientes con covid- con un histórico de pacientes con sdra por influenza ( ) , se encontró que los primeros tenían mayor elevación de troponinas % vs %, pero en los parámetros ecocardiográficos contrario a lo que se esperaría los índices de rendimiento ventricular fueron mayores para el grupo de covid- : Índice cardiaco . vs . l/m/m ; fevi vs %; tapse vs mm, nuevamente aunque no fue uno de los objetivos del estudio, parece no encontrarse correlación entre los biomarcadores que sugieren injuria miocárdica y los parámetros ecocardiográficos, el cual constituye uno de los pilares de la exploración cardiaca. se recomienda considerar como marcadores iniciales de mal pronóstico en el paciente crítico con covid- con sospecha de disfunción miocárdica aguda la elevación persistente de troponina i, mioglobina o creatin kinasa; independiente de la fracción de eyección del ventrículo izquierdo evaluada mediante ecocardiografía. fundamento los pacientes con covid- admitidos a la unidad de cuidados intensivos presentan con frecuencia disfunción cardiaca primaria, que puede corresponder a cardiomiopatía por estrés o miocarditis viral, pero también pueden ser consecuencia del compromiso sistémico ( , ) . aunque parece que en los fenotipos cardiovasculares estudiados, el compromiso hemodinámico severo de la función sistólica izquierda y derecha es menor ( ) . en el estudio de deng y colaboradores con pacientes con covid- , la fiebre, la disnea, hipoxemia, la obesidad y niveles elevados de cpk, troponina y nt-pro-bnp se relacionaron significativamente con mayor severidad ( ) . en el subgrupo de pacientes con miocarditis frente a controles, el perfil clínico se describe con mayor edad, niveles de temperatura más elevados ( . ± . vs . ± . ; p: . ), mayor proporción de disnea ( , vs %), y de dolor torácico ( , vs , %). en los pacientes fallecidos el % tuvieron picos de elevación de troponina i y de nt-pro-bnp dentro la semana que precedió la muerte, el % presentaron alteraciones electrocardiográficas y solo el % presentaron fracción de eyección menor o igual al % ( ) . shi y colaboradores, enrolaron pacientes para describir el significado clínico del compromiso miocardio de pacientes con covid- en wuhan, pacientes fallecieron, de los cuales el % presentaron injuria miocárdica aguda ( ) . el área bajo la curva (auc) de la troponina i inicial para predecir muerte intrahospitalaria fue de , (ic %, de , - , ) con una sensibilidad y especificidad del %, el auc para mioglobina fue de . y para cpk-mb fue de , ( ). un punto de corte para el pico más alto de troponina i de . , tuvo un hazard ratio para mortalidad de . (ic %, . - . ; p= . ). en un análisis multivariado la edad avanzada, la respuesta inflamatoria y las enfermedades cardiovasculares subyacentes se asociaron con mayor riesgo de lesión miocárdica en pacientes con covid- . con la información disponible parece que los biomarcadores de lesión miocárdica aguda elevados amci ® al ingreso y de forma persistente pueden predecir el riesgo de mortalidad intrahospitalaria en los pacientes con sospecha o diagnóstico de covid- con afectación cardiovascular. se recomienda no realizar de forma rutinaria ecocardiografía en pacientes críticos con covid- . se debe practicar ecocardiografía en pacientes con sospecha o diagnóstico de covid- si presenta alguna de las siguientes condiciones: . síntomas y signos de insuficiencia cardíaca aguda de novo. . shock o deterioro súbito hemodinámico refractario a líquidos y/o vasoactivos con sospecha de origen cardiogénico. . sospecha de infarto agudo de miocardio o embolismo pulmonar para determinar intervenciones terapéuticas con un beneficio clínico. . cambios en el electrocardiograma, arritmias ventriculares o paro cardiorrespiratorio no explicados por otra causa. para nuestro conocimiento, en el momento no existe estudios clínicos que evalúen los criterios para realización de ecocardiograma en el paciente con covid- . las sociedades de ecocardiografía han recomendado realizar el ecocardiograma en el contexto clínico en el cual, la información obtenida proporcione un cambio en la conducta o se espere un beneficio clínico al realizar este procedimiento ( ) ( ) ( ) ( ) . igualmente, se recomienda realizar el examen a la cabecera del paciente y el escaneo debe ser dirigido a contestar preguntas específicas según el contexto clínico del paciente ( ) ( ) ( ) ( ) ( ) . ward et al, en su publicación describe cómo el uso del ecocardiograma limitado (dirigido) en la university of chicago medicine (ucm), aumentó significativamente durante la pandemia ( % frente a %, p < . ), posterior a la implementación de recomendaciones sobre el uso apropiado de la ecocardiografía en tiempos de pandemia ( ) . los pacientes con infección por sars -cov- pueden presentarse con comorbilidades cardiovasculares que potencialmente estén descompensadas y/o compromiso cardiovascular por covid- . en este último, podemos encontrar alguno de los siguientes fenotipos: falla cardiaca aguda en el marco de compromiso directo viral o secundario al estrés metabólico y liberación de citoquinas, síndrome coronario agudo, cor-pulmonar secundario a tep o por compromiso secundario al sdra ( , , , ) . las manifestaciones cardiovascular puede sospecharse en el marco de choque que no esté explicado por causas extracardiacas evidentes que no responde a líquidos, dolor torácico con clínica de síndrome coronario agudo, cambios electrocardiográficos y elevación de biomarcadores de lesión miocárdica, signos de falla cardiaca descompensada, deterioro súbito de la oxigenación, arritmias o paro cardiorrespiratorio ( , , ) . ante estas manifestaciones, el ecocardiograma podría ser útil para entender el origen de la descompensación aguda, al estar enfocado a amci ® responder preguntas acerca de la función ventricular global y segmentaria (en el abordaje de síndrome coronario agudo), compromiso del ventrículo derecho, alteraciones valvulares, derrame pericárdico, si existe una contribución cardiovascular al compromiso pulmonar, si en el marco del choque existe evidencia de componente cardiogénico y cómo podría guiarse/optimizarse el soporte hemodinámico de estos pacientes( - ). se sugiere en pacientes críticamente enfermos con covid- que cursan con shock y sdom, ajustar la monitoria a las condiciones clínicas del paciente y recursos disponibles. se puede considerar el cap para el monitoreo del gasto cardiaco, la valoración de la perfusión y orientar los elementos hemodinámicos del tipo de shock, el cap de gasto cardiaco continuo puede disminuir la exposición del personal de salud frente al catéter de medición convencional. se sugiere la utilización de la tdtp dependiendo de la disponibilidad del recurso para orientar el diagnóstico diferencial del sdra versus edema pulmonar cardiogénico en los pacientes con covid- . fundamento los pacientes con infección severa por sars-cov- , cursan con alto riesgo de falla renal y cardiovascular, con necesidad de un manejo restrictivo de líquidos, lo que justifica la monitoria estricta en uci ( , ) . el catéter venoso central es útil para la monitoria inicial de estos pacientes, sin embargo, su predicción a respuesta a volumen está limitada ( ) ( ) ( ) . la monitoría no invasiva tiene limitaciones en casos severos de inestabilidad hemodinámica, ventilación espontánea y en presencia de peep alto, lo que limita su uso para el cálculo de gasto cardiaco y la predicción de respuesta a líquidos ( , ) . la monitoria con cap puede ser considerada en pacientes con covid- que cursan con choque y doms, con el objetivo de realizar un diagnóstico definitivo de los componentes del choque, valorar la hipoperfusión, la función cardiaca y el estado de volemia ( , ) . igualmente, los pacientes con sospecha tep o compromiso del ventrículo derecho pueden beneficiarse de esta monitoria( ). richard et al, en su estudio determinaron los desenlaces asociados al uso de cap vs cvc en pacientes con shock, sdra, o ambos, sin evidenciar diferencias en mortalidad ( . % vs . % p =. ) o estancia hospitalaria. el uso de cap no garantiza la mejoría de desenlaces en pacientes con covid- , sin embargo, la presencia de una monitoria continua ayudaría a optimizar los recursos y disminuiría la interacción con el paciente, con menor exposición del equipo médico ( ) . la monitoria por tdtp puede utilizarse en pacientes con covid- que cursan con choque, buscando optimizar el manejo hídrico, valorar el agua extravascular pulmonar (evlw) y el índice de permeabilidad vascular pulmonar (pvpi) con el fin de establecer el diagnóstico amci ® definitivo del edema pulmonar: sdra vs cardiogénico ( ) ( ) ( ) . hu et al, en su estudio evaluaron los desenlaces del uso de evlw y la presión de cuña de la arteria pulmonar (pawp) como estrategias para el manejo de líquidos en pacientes sdra, no encontraron diferencias significativas en las tasas de supervivencia (p = , ). no obstante, en el grupo de evlw la duración de la ventilación mecánica y la estancia en la uci fueron significativamente menor (p < , ), al igual que el balance hídrico (p < . ), con mejoría significativa en los índices de oxigenación (p = . )( ). no se puede emitir una recomendación a favor o en contra para la utilización de un protocolo de ultrasonido rutinario a la cabecera del paciente (pocus). sin embargo, se podría considerar el uso en pacientes seleccionados, con los adecuados epp y desinfección de los equipos; donde el pocus pueda tener ventajas sobre otras modalidades de monitoria o en pacientes con limitaciones para monitoria invasiva que requieren evaluación del estado hemodinámico o determinación de severidad del compromiso pulmonar. las recomendaciones sobre la utilidad de pocus en pacientes con covid- están enfocadas principalmente en la evaluación de la severidad/progresión de la lesión pulmonar, diagnóstico de manifestaciones cardiovasculares, monitoria hemodinámica y en la guía de fluidoterapia ( , ( ) ( ) ( ) . en la valoración del compromiso pulmonar por covid- , el pocus ofrece una ventaja sobre otras modalidades de monitoreo, debido a la capacidad de enmarcar el compromiso pulmonar en una línea de tiempo según sus hallazgos: desde la aparición de un patrón de "líneas b", consolidaciones subpleurales con evolución a consolidaciones multilobares, irregularidades en el artefacto de la línea pleural y finalmente aparición de patrón de "líneas a" una vez inicie la recuperación, con adecuada correlación tomográfica ( ) ( ) ( ) ( ) . en la diferenciación del origen del choque, el pocus ha demostrado superioridad versus el concepto clínico al evaluar: función ventricular (incluyendo ventrículo derecho), vena cava inferior, líquido libre abdominal, lesiones aórticas, compromiso pulmonar y búsqueda de trombosis venosa profunda identificando tep ( , ) . en cuanto a la monitoria hemodinámica de pacientes con covid- , adicional a la función y gasto cardíacos, se recomienda variables dinámicas de respuesta a líquidos y ultrasonido pulmonar en el diagnóstico de sobrecarga hídrica ( ) . la variabilidad de gasto cardiaco calculado por pocus durante la elevación pasiva de miembros inferiores, identifica los respondedores a líquidos con sensibilidad del % y un lr (-): . [ %ci, . - . ]) ( ) . la variabilidad de la vena cava inferior muestra limitaciones en pacientes con aumento de presiones de cavidades derechas y respiración espontánea ( ) . en cuanto a otras modalidades de monitoría no invasiva, es importante conocer las limitaciones en el marco de compromiso hemodinámico severo, ventilación espontánea, alteraciones valvulares aórticas, entre otras ( ) . marik ( ) . el ultrasonido tiene limitaciones específicas como la necesidad de un operador experimentado y la adecuada calidad de las imágenes. adicionalmente, en los pacientes con covid- , esta modalidad de monitoreo requiere una mayor interacción con el paciente, mayor uso de epp en comparación con otras modalidades el pac( ). se recomienda perseguir al inicio de la reanimación del paciente críticamente enfermo con covid- , metas clínicas de fácil medición, como la presión arterial media (entre y mmhg) o el gasto urinario (mayor a , cc/k/h) y metas de perfusión como el lactato en sangre arterial (menor a mmol), la saturación venosa central de oxígeno (entre y %) y la diferencia veno arterial de co (menor a mmhg). se han reportado casos de disfunción ventricular como causa de choque asociado a covid- , sin embargo, no se ha descrito un manejo específico o cambios en las metas de reanimación para estos pacientes, las manifestaciones de hipoperfusión tisular son: alteración de la conciencia, oliguria, piel fría y moteada y pulso débil. a nivel de gases sanguíneos las metas de reanimación pueden ser globales como el lactato (en sangre arterial vn< mmol) y la diferencia veno arterial de co (pv-aco vn < mmhg) o regionales como la saturación venosa central de oxígeno medida en la sangre venosa tomada de un catéter central (vn: - %). se puede optimizar la perfusión, interviniendo los principales determinantes: fluidos para aumentar el volumen intravascular, inotrópicos para aumentar la fuerza de contractilidad, vasopresores para recuperar la presión de perfusión y transfusión de glóbulos rojos para aumentar la hemoglobina como transportador de oxígeno ( ) , las recomendaciones dadas en el documento anterior siguen siendo válidas e incluyen entre otras que todo paciente con covid- en estado de shock debe ser ingresado de forma inmediata a la unidad de cuidados intensivos, garantizando el aislamiento indicado, procurando recuperar la presión arterial media a valores > mmhg, para ello la utilización de un catéter venoso central en los pacientes que no responden al manejo inicial y el procedimiento debe ser realizado por el médico con mayor entrenamiento, idealmente guiado por ecografía si hay disponibilidad y las competencias, así mismo las estrategia de control estricto de fluidos para no generar efectos deletéreos relacionados a la sobrecarga de volumen, es lo más indicado. se recomienda en la reanimación inicial de pacientes en estado de shock con sospecha o amci ® diagnóstico de covid- , guiar la fluidoterapia con el uso de índices clínicos como el tiempo de llenado capilar, temperatura de la piel y depuración de lactato; en fases avanzadas donde el monitoreo clínico es insuficiente utilizar medidas dinámicas como la variabilidad de presión de pulso (vpp), la variabilidad de volumen sistólico (vvs), la respuesta a la maniobra de elevación pasiva de piernas o la prueba de oclusión teleespiratoria de acuerdo a los recursos disponibles y la experiencia. fuerte a favor fundamento sobre los objetivos de intervención y el tipo de agente vasoactivo a utilizar en pacientes con covid- y shock no existe una evidencia directa y las recomendaciones se basarán en evidencia indirecta de pacientes críticos con diversos tipos de shock en especial el séptico y vasopléjico. la falla circulatoria aguda asociado a sdra en covid- se presenta con una frecuencia del - % y en la admisión a urgencias la hipotensión y un lactato ≥ es infrecuente( , ). la baja sensibilidad del qsofa y crb- para predecir la severidad del covid- y la necesidad de intervenciones de terapia intensiva refleja lo infrecuente del shock en esta condición. factores como la vasoplejia, fuga capilar asociada al estado hiperinflamatorio, altos requerimientos de peep y disfunción cardiaca pueden ser generadores o contribuyentes del shock y deben ser considerados en el abordaje diagnóstico, en su interpretación para lograr tomas de decisiones adecuadas. en pacientes con sdra, una reanimación óptima de líquidos debe tomar en cuenta aspectos como tiempo (oportunidad), tipo (cristaloides balanceados y/o no balanceados o coloides) y volumen (ni mucho, ni poco) con el objetivo de disminuir la mortalidad, el tiempo de vm y de cuidados intensivos, sin que ello afecte los índices de oxigenación, de perfusión tisular y la morbilidad asociada con su uso inadecuado. la administración agresiva de líquidos puede empeorar la oxigenación y la disfunción ventricular, lo que potencializa un mayor tiempo de ventilación mecánica e incluso la mortalidad. la evidencia ha demostrado que una estrategia conservadora de fluidos (balance - +/- amci ® en una revisión sistemática y un metaanálisis de rct (n = . ) una terapia dirigida al aclaramiento temprano de lactato frente a una terapia guiada por la saturación venosa central de oxígeno (svo ), se asoció con una reducción significativa de la mortalidad (rr , ), menor estadía en la uci (dm , días), y menor duración de la ventilación mecánica (dm - , horas). pero se debe resaltar que un nivel alto de lactato no siempre indica hipovolemia; también puede ser causada por uso de adrenalina, agonistas beta o por disfunción mitocondrial, insuficiencia hepática e isquemia mesentérica ( ) . por otra parte, el llenado capilar (crt), una prueba técnicamente fácil y accesible, realizada cada minutos se asoció con una reducción no significativa de la mortalidad (hr , ) en comparación con la medición de lactato sérico cada horas. dado el potencial beneficio sobre mortalidad, duración de estancia en uci y la duración de la ventilación mecánica, así como su accesibilidad, sugerimos utilizar parámetros dinámicos de temperatura de la piel, tiempo de llenado capilar y / o medición de lactato sobre parámetros estáticos para evaluar la capacidad de respuesta a la fluidoterapia en pacientes con covid- y shock( ). se recomienda en pacientes adultos con covid- y estado de shock, escoger la norepinefrina como el vasopresor de primera línea y a la vasopresina el de segunda. si no se cuenta con norepinefrina el uso de vasopresina o epinefrina serían la primera elección; la dopamina no se recomienda por el mayor riesgo de arritmias. se recomienda iniciar dobutamina frente al aumento de la dosis de norepinefrina en pacientes en estado de shock con evidencia de disfunción cardíaca e hipoperfusión persistente a pesar de la reanimación inicial. fuerte a favor fundamento sobre los objetivos de intervención y el tipo de agente vasoactivo a utilizar en pacientes con covid- y shock no existe una evidencia directa y las recomendaciones solo pueden basarse en evidencia indirecta de pacientes críticos con sepsis y sdra. en pacientes en shock séptico los agentes vasoactivos para alcanzar una pam de - es un objetivo razonable. una presión media más alta puede incrementar . veces el riesgo de arritmias cardiacas y no está exento de riesgo de isquemia en las extremidades ( ) . para aproximarnos a la escogencia de los vasoactivos en shock séptico, basados en su perfil de riesgo/beneficio, la guía scandinavian society of anaesthesiology and intensive care medicine (ssai ) task force for acute circulatory failure( ), la revisión sistemática de cochrane database con rct con un n: ( ) y el ensayo clínico controlado de honarmand k et al con un n: , ( ) amci ®  la noradrenalina es el agente vasoactivo más ampliamente estudiado con el menor riesgo a priori de efectos no deseados, razón por la cual se sugiere usar como el agente vasoactivo de primera línea en pacientes con covid- y shock.  si la noradrenalina no está disponible la vasopresina o epinefrina se muestran como la mejor alternativa. los factores que determinan la elección entre vasopresina y epinefrina pueden incluir disponibilidad y el perfil de seguridad de estos agentes. con la vasopresina, la isquemia digital puede ser una preocupación y con epinefrina, la taquicardia, la isquemia miocárdica y el exceso de producción de lactato.  el uso de dopamina se ha asociado un . veces mayor de riesgo de aparición de arritmias frente a la norepinefrina y un posible aumento del riesgo de mortalidad. por ello la dopamina no debe utilizarse en pacientes con covid- y shock donde haya disponible de norepinefrina o las alternativas señaladas  en shock distributivo la adición de vasopresina a las catecolaminas evidenció baja certeza de reducción de la mortalidad (rr , ; ic del %: , a , ), alta certeza de una reducción de la fibrilación auricular (rr , ; ic del %: , a , ) y certeza moderada de un mayor riesgo de isquemia digital (rr , ; ic del %: , a , ). en vista de estos hallazgos se plantea la vasopresina como un agente vasoactivo de segunda línea a ser utilizado si la pam objetivo no se ha alcanzado con norepinefrina en pacientes con covid- y shock. no existe evidencia directa en pacientes con covid- y shock, para establecer una recomendación sobre cuál es el agente inotrópico óptimo. en una guía de práctica clínica de que evalúa el agente inotrópico óptimo en pacientes con insuficiencia circulatoria aguda (shock), no se identificaron rct que comparen dobutamina versus placebo o ningún tratamiento. con base en una justificación fisiopatológica, sugerimos agregar dobutamina, más que no suministrar ningún tratamiento, en pacientes con covid- y shock con evidencia de disfunción cardíaca e hipoperfusión persistente a pesar de la reanimación con líquidos y altas dosis de norepinefrina. el uso de dobutamina en estado de shock, incluso en pacientes con covid- con shock, debe ser investigado. recomendaciÓn se recomienda no suspender la medicación estándar para falla cardiaca en pacientes con sospecha o diagnóstico de covid- , especialmente los iecas, ara-ii, y b-bloqueadores, si la condición clínica permite continuar el uso de esta medicación, ya que no se ha podido confirmar una asociación nociva. amci ® previos alrededor de la relación independiente de la edad avanzada, enfermedad cardiovascular subyacente (enfermedad coronaria, insuficiencia cardíaca y arritmias), tabaquismo activo y epoc con muerte por covid- ( ) ( ) ( ) ; esos mismos reportes sugieren que las mujeres son proporcionalmente más propensas a sobrevivir a la infección por covid- que los hombre; existen además consideraciones especiales desde el punto de vista cardiovascular, que se deben tener en cuenta al decidir cualquier terapia en paciente afectados por covid- y existe la hipótesis de un efecto nocivo de la terapia estándar para falla cardiaca en estos pacientes ( ) . en un estudio observacional que incluye paciente con infección por covid- , se evaluó la relación entre la enfermedad cardiovascular subyacente, y la asociación entre la terapia farmacológica cardiovascular y la mortalidad ( ); respecto a los factores de riesgo cardiovascular, el . % de los pacientes tenían hiperlipidemia, el . % tenía hipertensión, el . % tenía diabetes mellitus, y en relación a los medicamentos, los sobrevivientes usaron más comúnmente ieca y las estatinas que los no sobrevivientes, mientras que no se encontró asociación entre la supervivencia y el uso de ara ii; respecto a los otros medicamentos incluidos b-bloqueadores, antiplaquetarios e insulina no se encontraron diferencias significativas; sin embargo, y teniendo en cuenta el impacto sobre mortalidad del uso de betabloqueadores en la falla cardiaca, consideremos que la decisión de continuar su uso debe basarse en el análisis clínico de cada paciente y su estabilidad clínica. se recomienda establecer un protocolo de reanimación ajustado al contexto del paciente con covid- con una organización administrativa ajustada a la pandemia que incluya las siguientes estrategias:  desarrollar una estrategia de prevención del paro cardiorrespiratorio en el paciente con sospecha o diagnóstico de covid- basada en la detección oportuna.  formar un equipo multidisciplinar formado en rcp con líderes médicos, de en enfermería y en terapia respiratoria, los cuales deben educar a todo el equipo de trabajo en la identificación de signos de alerta temprana, cambios abruptos de variables clínicas, técnicas de monitoreo, interpretación de paraclínicos y de alarmas de monitoreo.  entrenamiento del personal sanitario a través del uso de la simulación clínica en manejo de crisis, epp, y procesos de atención fundamentales en la atención del paro cardiaco en el paciente con sospecha o diagnóstico de covid-  promover la comunicación asertiva, planeación y retroalimentación de las intervenciones realizadas antes y después de un evento de paro cardiaco (briefing y debriefing), con el fin de establecer modificaciones que conllevarán a mejoras en la atención de futuros eventos. amci ® el pronóstico y sobrevida de un paciente con sospecha o diagnóstico de covid- que presenta paro cardiaco depende de la prevención a través del reconocimiento oportuno de las causas reversibles de éste, la no presencialidad y un ritmo de paro no desfibrilable lo hacen de mal pronóstico. la prevención va a depender del nivel de entrenamiento del equipo previamente, y en época de pico de pandemia cuando el talento humano especializado disminuya, se hace necesario que en los equipos de trabajo estén liderados por especialistas en la disciplina para que puedan guiar al equipo. los nuevos procesos de atención del paciente, la alta contagiosidad del virus, y el uso de nuevos medicamentos hacen que se requiera un entrenamiento del personal para estandarizar los procesos y disminuir el error médico. la crisis de covid- está ejerciendo una presión sin precedentes sobre las personas, los equipos y los sistemas organizacionales, conllevando a errores médicos que van desde la infección cruzada por el personal sanitario con la posibilidad de cometer errores en la atención. cada día trae nuevos desafíos: picos en volumen y gravedad, escasez de equipos y estrés en los médicos sobrecargados, que se manifiesta según la experiencia de wuhan en insomnio y depresión. se propone implementar una estrategia antes, durante y después del trabajo clínico, denominada circle up covid- desarrollada por center of medical simulation dirigida a convertir equipos de trabajo muchas veces insustituibles , en eficientes , seguros, fuertes y que se apoyan mutuamente incluyendo en mejora de la salud psicológica . impactando en el rendimiento del equipo , y promoviendo el bienestar y la resiliencia( - ) se recomienda establecer un protocolo de reanimación ajustado al contexto clínico del paciente con covid- que incluya las siguientes modificaciones:  implementar criterios de selección e inicio de maniobras de rcp en la atención del paro cardíaco basados en la bioética y en el pronóstico de supervivencia a corto y largo plazo de los pacientes.  promover la prevención del paro cardiaco mediante la detección oportuna del riesgo y definir intubaciones programadas.  asegurar la correcta protección con los epp necesarios al abordar el paro cardiaco y la intubación que son procedimientos generadores de aerosoles.  priorizar el manejo de la vía aérea antes del inicio de las compresiones torácicas, haciendo énfasis en la reducción de la exposición de aerosoles (código azul protegido).  utilizar filtro de alta eficiencia contra virus para todas las estrategias de ventilación (bolsa mascarilla con cierre hermético y en el circuito del ventilador).  promover la realización de la intubación por el operador de mayor experticia con uso de videolaringoscopio si está disponible y considerar el acceso supraglótico solo si el intento de intubación es fallido. amci ®  en caso de parada cardiaca en ventilación mecánica iniciar el masaje cardiaco evitando las desconexiones del circuito del respirador.  en caso de paro en posición prono si el paciente se encuentra vigil retornar rápidamente a la posición supino y si está en ventilación mecánica es razonable realizar compresiones en la espalda. fuerte a favor fundamento se hace necesario el entrenamiento en el manejo de los procedimientos generadores de aerosoles y se sugiere que el que realiza la intubación orotraqueal debe ser el más experto. el riesgo de aerosolización es de . en el proceso de intubación orotraqueal, el de compresiones torácicas es de , , ventilación mecánica no invasiva de , , ventilación manual pre-intubación de , , succión después de intubación , . se ha descrito que si no se ha capacitado previamente en el retiro de los epp existe más riesgo de auto contaminación y aumenta ésta sin un líder supervisor al retirarlo. según revisión de cochrane sobre ropa y equipo de protección para los trabajadores sanitarios para evitar que se contagien con el coronavirus y otras enfermedades altamente infecciosas da a conocer que la capacitación presencial, la simulación por ordenador y la capacitación por vídeo dieron lugar a menos errores a la hora de quitarse el epp que la capacitación impartida solo como material escrito o una conferencia tradicional ( ) ( ) ( ) ( ) ( ) ( ) . se recomienda no considerar la existencia de manifestaciones neurológicas específicas o típicas atribuidas a la infección por sars-cov- . se recomienda realizar la valoración neurológica integral del paciente con diagnóstico o sospecha de sars-cov- teniendo en cuenta manifestaciones frecuentes relacionadas a covid- : disgeusia, anosmia, cefalea, vértigo, confusión, delirium, alteración de estado de consciencia, eventos cerebrovasculares, ataxia, polineuropatías inflamatorias y convulsiones. una revisión sistemática realizada por asadi-pooya et al. entre diciembre y marzo de mostró que el % de los pacientes con covid- presentaron sintomatología neurológica. analizaron cinco artículos (n= ) donde eran retrospectivos, y era prospectivo, encontrando cefalea entre el y el %, vértigo entre el y el %, confusión en el %, alteración del estado de consciencia en el %, eventos cerebrovasculares en un %, ataxia en un , % y convulsiones en un , % ( ) . amci ® menor a participantes donde recolectarán información sobre el compromiso neurológico en pacientes con covid- con un seguimiento hasta febrero de ( ) . la hiposmia y la disgeusia de aparición súbita son manifestaciones clínicas muy prevalentes en pacientes con covid- evidentes aun en ausencia de sintomatología respiratoria alta. lechien et al publicaron un estudio multicéntrico que incluyeron hospitales europeos reclutando pacientes infectados con covid- levemoderado donde , % presentaron alteraciones relacionadas con el olfato y , % presentaron alteraciones relacionadas con el gusto, donde la anosmia se presentaba antes que cualquier otro síntoma en el , % de los casos y el , % de los casos no presentaba rinorrea u obstrucción nasal, la recuperación del olfato fue presente en el % de los pacientes y las mujeres fue el grupo poblacional más afectado (p= , ) ( ) . otras manifestaciones clínicas son las alteraciones de la agudeza visual, y dolor tipo neuralgia ( ) . respecto a las patologías psiquiátricas; la serie de mao comenta que el , % de los pacientes tiene clínica de alteración del estado de consciencia, concepto que se aproxima a la defunción de delirium. severance et al. encontraron que pacientes con sintomatología psicótica aguda presentaron niveles elevados de inmunoglobulina g para coronavirus del tipo hku , nl y oc con diferencias estadísticamente significativas respecto a los individuos controles (n= ) (p< , ). donde la respuesta inmune para nl fue asociado con el espectro-esquizofrenia (or: . , ci . - . , p= . ) pero no se correlaciona con desórdenes afectivos ( ) . aún no se ha descrito una correlación directa de este trastorno psicótico con covid- . los síntomas musculares se han observado en pacientes infectados por covid- incluyendo la miopatía del paciente en estado crítico (miopatía difusa no necrotizante con degeneración grasa de fibras musculares), la miopatía necrotizante (ligada a falla orgánica múltiple) y la miopatía de filamentos gruesos( ). se recomienda considerar como predictores clínicos neurológicos de alerta para sospechar covid- : anosmia, disgeusia, delirium y alteraciones neuromusculares inespecíficas sin otra causa aparente de explicación. se recomienda no establecer de rutina predictores neurológicos específicos de mal pronóstico en el paciente críticamente enfermo con covid- . se deben tener en cuenta los factores de riesgos generales de mal pronóstico para la población general como la edad avanzada, las comorbilidades cardiovasculares y el tabaquismo. page la proteína spike (s) del covid- es reconocida por la enzima convertidora de antígenos (eca ) de la célula huésped cuyo papel es el punto de entrada molecular a tejidos pulmonares, gastrointestinales y neuronales ( ) . la forma como el covid- ingresa al sistema nervioso central es desconocido, pero se especula que inicialmente invade terminales nerviosas periféricas y después llega al sistema nervioso central a través de una ruta guiada por sinapsis nerviosas con un patrón ascendente (ruta dada por el coronavirus hev y el oc- ) ( , ) . en modelos de roedores el covid- ingresaría al cerebro a través del nervio olfatorio, atravesando la lámina cribiforme propagándose por el tálamo y el tallo cerebral; explicándose por la expresión de los receptores de la enzima convertidora de antígenos (eca ) en la superficie de las mucosas nasales, las neuronas y la glía ( , , ) . una segunda forma de ingreso es a través de la vía hematológica mediante arterias cerebrales atravesando la barrera hemato-encefálica utilizando las células inflamatorias como un modelo similar al del caballo de troya ( , , ) logrando una ubicación definitiva en células neuronales y endoteliales del lóbulo frontal como lo demostraron en estudios post-mortem descritos por paniz -mondolfi et al, lo que explicaría los cambios comportamentales de paciente ( ) . la tercera forma de acceso al sistema nervioso central es mediante el drenaje del sistema linfático cerebral invadiendo ganglios linfáticos hiliares y mesentéricos con sintomatología gastrointestinal asociada ( ) . una vez ha logrado ingresar tiene la capacidad de infectar macrófagos, microglía, y astroglía los cuales secretan factores proinflamatorios como interleuquina , interleuquina , y factor de necrosis tumoral alfa ( ) . esta condición se exacerba con el desencadenamiento de la tormenta de citoquinas liderada por la interleuquina , interleuquina , interleuquina e interferón gamma ( ) . de esta forma los coronavirus siendo neurotrópicos ocasionan múltiples manifestaciones clínicas ya mencionadas, así como encefalitis, parálisis flácida, incluyendo la asociación con guillain-barré ( ) . los síntomas que harían sospechar la presencia de neurocovid- son la náusea, el vómito y la anorexia, estos síntomas pueden ser el reflejo del compromiso del virus en el área postrema del piso del cuarto ventrículo que hace parte del complejo vagal dorsal de la médula oblonga. sin embargo, estos síntomas pueden enmascararse como una respuesta inespecífica relacionada con un compromiso gastrointestinal ( ) . como se mencionó previamente la anosmia y la disgeusia son síntomas significativos para sospechar en covid- ( ) ; esto es debido a una lesión directa sobre el nervio olfatorio (i par craneal), y la lesión de alguno de los tres nervios encargados de registrar el sentido del gusto como lo son el vii, ix y x pares craneales, así como el compromiso del núcleo solitario y del tálamo como zona de relevo; de hecho el núcleo del tracto solitario es muy cercano al centro respiratorio que podría ocasionar disnea de origen central ( ) , otros núcleos como el núcleo dorsal motor del vago y el núcleo ambiguo están relacionados con funciones cardiovasculares a tener en cuenta ( ) . respecto a los factores de riesgo destaca el tabaquismo el cual aumenta la posibilidad de neuroinfección debido a interacciones funcionales entre el receptor nicotínico de acetilcolina y el receptor eca el cual está sobreexpresado en pacientes fumadores ( ) . amci ® en pacientes con infecciones severas vs infecciones no severas ( . % vs . %, p = . ), incluyendo eventos cerebrovasculares ( , % vs , % p= , ), alteración del estado de consciencia ( . % vs . %; p< . ) y lesiones musculoesqueléticas ( , % vs , % p< ) ( ) . la encefalopatía que se manifiesta como una alteración aguda o subaguda del estado de consciencia presentándose en pacientes con comorbilidades, factores de riesgo cardiovasculares, edad avanzada y deterioro cognitivo previo ( , , ) . así como aquellos individuos con hipoxemia la cual induce metabolitos anaerobios en el sistema nervioso central, edema celular, intersticial e isquemia ( ) . los eventos cerebrovasculares pueden ser desencadenados por cuadros de hipoxia, inmovilización, un incremento de la respuesta proinflamatoria o por predisposición a la hipercoagulabilidad ( ) . respecto a este último rubro tanto la edad (hazard ratio , /por año % ic , - , ) y la coagulopatía definida como como un tiempo de protrombina mayor a segundos, o tiempo de tromboplastina mayor a segundos (hr , % ic , - , ) fueron considerados predictores independientes de complicaciones trombóticas ( ) ; otros trabajos reportan incremento del conteo plaquetario y niveles elevados de dímero d ( ) . de hecho, un scoping review realizado por wilson y jack muestra que la presencia de eventos cerebro vasculares es un factor de riesgo de mal pronóstico para pacientes infectados por covid- ( ) . mao et al. reportaron eventos cerebro vasculares en pacientes con covid- , los factores de riesgo más relevantes fueron los clásicos factores de riesgo cardiovasculares (diabetes, hipertensión y edad avanzada), así como una presentación sistémica severa, teniendo como un denominador común el compromiso estructural de grandes vasos ( ) . la presencia de convulsiones (clínicas o subclínicas) puede ser una manifestación de eventos cerebro vasculares, meningoencefalitis o hipoxia cerebral. siendo los factores de riesgo más importantes en su exacerbación las alteraciones electrolíticas como hipocalcemia, las reacciones adversas a medicamentos y la epilepsia como comorbilidad de base ( , ) . otros tipos de coronavirus como lo son el e, , y oc se han aislado de líquido cefalorraquídeo (lcr) de pacientes con esclerosis múltiple sugiriendo posiblemente sean agentes etiológicos en la exacerbación de brotes de esta patología sin embargo aún no se ha documentado la asociación entre covid- y ésta condición ( ) . otras patologías en las cuales se ha asociado la presencia de esta familia de microorganismos es la enfermedad de parkinson, la esclerosis lateral amiotrofia, la neuritis óptica y la encefalitis aguda diseminada ( , ) . múltiples trabajos han documentado la asociación entre polineuropatía y coronavirus. la mayoría de ellos consideran que existe una estrecha relación entre una polineuropatía autoinmune exacerbada por la infección por coronavirus o bien un compromiso nervioso periférico inducido por bloqueo neuromuscular, alteraciones hidroelectrolíticas o disvitaminosis( ). amci ® se recomienda que todo paciente con acv isquémico se considere sospechoso de infección por covid- si presenta: sintomatología asociada sospechosa de infección por covid- , contacto cercano con individuos con sintomatología infecciosa, allegados con viajes recientes, si la historia clínica es atípica, si la información suministrada no es clara, si presenta deterioro del estado de alerta inexplicable, y si al examen físico presenta hallazgos compatibles con una infección por covid- . se recomienda que todo paciente con acv isquémico de quien no se pueda recibir información se considere sospechoso de covid- ya que el evento cerebro vascular es una complicación que se ha reportado en pacientes con infección por covid- . hay una gran evidencia que correlaciona la presencia de infección por covid- con factores de riesgo cardiovasculares. esto se demostró en un metaanálisis que incluyó estudios de china (n= ) donde las comorbilidades más frecuentes fueron hipertensión ( , %, % ic: - , %), diabetes ( , %, % ic , - , %), enfermedad cardiovascular ( . %, % ic: . - . ) y patologías respiratorias ( . %, % ic: . - . %). al comparar severidad vs no severidad la presencia de hipertensión tuvo un or de . ( % ci: . - . ), y la enfermedad cardiovascular un or de . ( % ci: . - . ) respectivamente ( ) . existieron pocos casos de hipercoagulabilidad en pacientes sin factores de riesgo cardiovasculares ( ) . la cohorte de wuhan (n= ) publicada por wang et al. mostró otros factores de riesgo que podrían eventualmente estar asociados a estado de embolia y trombosis como shock en , %, arritmias , % y miocarditis en un , %. situaciones que conllevarían a hipercoagulabilidad, lesión endotelial y eventualmente la aparición de acv. ( ) . en este orden de ideas existe una estrecha correlación entre la presencia de factores de riesgo cardiovasculares que ocasionarían acv y que podrían eventualmente estar relacionados con la patogenia de covid- . ante esta inquietud khosravani et al. publicaron en stroke un informe especial donde realizan ciertas recomendaciones para el abordaje de los pacientes con acv en el contexto de la pandemia por covid- de una forma rápida, eficaz y segura para los diferentes profesionales de la salud. surge así el código stroke protegido el cual consiste en:  usar elementos de protección personal y una mascarilla al paciente  ejecutar protocolo de aislamiento de contacto y gotas  ejecutar protocolo de aerosoles si el paciente está sometido a ventilación mecánica no invasiva, manejo de aspiración de secreciones o maniobras de reanimación cardiopulmonar básica y avanzada  si el paciente presenta deterioro del estado de alerta con necesidad de soporte ventilatorio alto con fracción inspirada de o mayor a % se recomienda intubar temprano y proceder con el transporte. se debe proceder con el código stroke protegido si el paciente presenta alguna de las siguientes condiciones:  si el paciente presenta sintomatología sospechosa de covid- (fiebre, tos, dolor torácico, disnea, cefalea, mialgias, emesis)  si existe algún contacto cercano con sintomatología infecciosa  si el paciente o alguno de sus allegados ha presentado viajes recientes amci ®  si el paciente es covid- positivo  si refiere al interrogatorio una historia clínica atípica o poco clara  si el paciente o alguno de sus acudientes es incapaz de suministrar información  si el paciente presenta deterioro del estado de alerta  si al examen físico se encuentran signos compatibles con patologías diferentes a covid- por último, estas son las recomendaciones en el momento de realizar el traslado a saber:  no apresurarse dentro de la sala de reanimación o dentro de la unidad de cuidados intensivos y mantener la calma  designar un líder para el traslado del paciente y para supervisar el uso adecuado de los elementos de protección personal  limitar el número de personas encargadas del transporte  evitar la contaminación con otras áreas del hospital( ). se recomienda no realizar neuroimagen de rutina en pacientes críticos por covid- con cefalea y anosmia, dado que no existe una evidencia concluyente que demuestre una estrecha correlación entre estos síntomas y hallazgos imagenológicos. fuerte en contra fundamento en la mayoría de los casos la cefalea es un síntoma no específico que no es característico de irritación meníngea la ocurrencia de cefaleas aisladas en ausencia de otros síntomas sugiere un mecanismo benigno más que un compromiso de sistema nervioso central ( ) . sin embargo, el covid- al tener una capacidad neuroinvasiva, se han reportado casos de encefalitis virales con o sin necrosis hemorrágicas de compromiso temporal mesial y talámico que ameritarían estudio de imagen diagnóstica ( ) . un estudio retrospectivo publicado por kandenmirli et al. evaluó pacientes en hospitales infectados con covid- de los cuales requirieron manejo en uci donde el % de ellos (n= ) presentaron sintomatología neurológica. la resonancia magnética cerebral fue realizada en % (n= ) de estos pacientes. el % tuvieron hallazgos agudos, el % tuvieron alteraciones corticales de la captación de señal en el modo flair, pacientes tuvieron anormalidades en la señal flair en la sustancia blanca profunda y subcortical, pacientes con lesiones en el lóbulo frontal, en el lóbulo parietal, en el lóbulo occipital, en el lóbulo temporal, en la corteza de la ínsula, y en el giro cingular ( ) . amci ® un paciente presentó trombosis de seno venoso y otro presentó un infarto en el tercio medio del territorio de la arteria cerebral media. en % de los pacientes no se encontraron hallazgos que sugieran compromiso intracraneal de covid- . una correspondencia escrita por helms et al. reportaron pacientes con sdra y covid- en dos unidades de cuidados intensivos en francia entre marzo y abril del , el % presentaron signos neurológicos como delirium evaluados mediante cam-icu ( %), agitación ( %), signos del tracto cortico espinal ( %), síndrome disejecutivo ( %). de ellos se realiza resonancia magnética en pacientes encontrando alteraciones en la perfusión en un %, un realce de leptomeninges en un %, y un acv isquémico en un %; dos pacientes asintomáticos presentaron áreas isquémicas con hiperintensidad focal ( ) . ante estos hallazgos los principales diagnósticos diferenciales son las patologías autoinmunes, encefalitis, convulsiones e hipoglucemia. los pacientes con compromiso frontal bilateral poseen hipoxemia que ocasionan hipoperfusión fronto temporal. las microhemorragias corticales (y no) son consecuentes de la ruptura de la membrana hematoencefálica resultando en este patrón mencionado. el estado postictal muestra un compromiso simétrico de la sustancia blanca. de esta forma hay que considerar otras condiciones como las comorbilidades cardiovasculares, las reacciones adversas a los medicamentos, e hipoxia inducida por sdra que ocasionarían patrones imagenológicos de confusión, que ponen en duda la estrecha relación entre covid- y hallazgos de resonancia magnética ( ) . en este orden de ideas necesitamos más datos para determinar cuáles son los hallazgos imagenológicos relacionados con neurotropismo y qué patrones pueden encontrarse directamente relacionados con la presencia de convulsiones, hipoxia o el desencadenamiento de una tormenta de citoquinas( , , ). se recomienda la valoración neurológica completa en los pacientes con sospecha o infección por covid- . se recomienda la monitorización electroencefalográfica continua por al menos h o según la consideración del especialista en neurociencias en el paciente en estado crítico con sospecha o infección por covid- en quien se sospeche crisis epilépticas o estatus no convulsivo. las manifestaciones neurológicas en pacientes con infección por covid- pueden estar presentes en el % de los casos ( , , ) . en el paciente en estado crítico con infección por covid- se han observado complicaciones vasculares que puede causar ataque cerebrovascular agudo isquémico o hemorrágico con tazas de entre el al % por lo que el examen neurológico debe realizarse para documentar la presencia de déficit amci ® neurológico focal que haga sospechar esta patología ( , , ) . es conocido que los pacientes en unidades de cuidado crítico tienen patologías que aumenta el riesgo de crisis o estado epiléptico, entre las cuales se encuentran ( ) ( ) ( ) ( ) :  pacientes sin patologías neurológicas hospitalizados en unidad de cuidado intensivo  hemorragia subaracnoidea  hemorragia intracraneal  trauma cráneo encefálico moderado a severo  infección del sistema nervioso central  tumor cerebral  encefalopatía hipóxico-isquémica algunas de estas patologías se presentan más frecuentemente en pacientes por covid- por lo que la monitorización electroencefalográfica continuar es requerida en este grupo de pacientes. el virus puede producir descompensación de paciente con epilepsia conocida, crisis por fiebre, crisis producidas por el estado crítico del paciente o las patologías subsecuentes que se han observado en esta infección ( ) . el tiempo de monitorización requerido debe ser entre a horas para lograr una sensibilidad de a %( , ). se recomienda realizar tomografía cerebral simple ante las manifestaciones neurológicas focales que nos hagan sospechar ataque cerebrovascular isquémico o hemorrágico. la resonancia cerebral puede ser necesaria como estudio complementario para determinar otros diagnósticos diferenciales en los pacientes con sospecha o infección por covid- . las manifestaciones neurológicas en pacientes con infección por covid- pueden estar presentes en el % de los casos ( , , ) . en el paciente en estado crítico con infección por covid- se han observado complicaciones vasculares que puede causar ataque cerebrovascular agudo isquémico o hemorrágico con tazas de entre el al % por lo que el examen neurológico debe realizarse para documentar la presencia de déficit neurológico focal que haga sospechar esta patología ( , , ) . la tomografía cerebral hace parte de la valoración inicial del ataque cerebrovascular isquémico y del estudio para determinar la presencia de otros diagnósticos diferenciales como ataque cerebro vascular hemorrágico en paciente con dicha patología puede ser necesario realizar angiotac con extensión a tórax en caso de sospecha de oclusión proximal o estudios endovasculares en pacientes que sea indicado ( ) . la realización de resonancia cerebral usualmente documenta alteraciones en los pacientes con covid- en el - % de los casos evaluados no relacionada con el acv. se recomienda la realización de punción lumbar en el paciente con sospecha o diagnóstico de covid- con base en los reportes de casos disponibles:  paciente con crisis epilépticas de novo.  paciente con alteración del estado de conciencia persistente a pesar de encontrarse metabólicamente compensado, descartado ataque cerebrovascular u otra causa de encefalopatía.  paciente con manifestaciones como mielitis, neuropatía craneal múltiple o sospecha de polineuropatía desmielinizante aguda. las capacidades neurotrópicas de los coronavirus en general han sido expuestas desde la infección por sarscov. en cuanto al sars-cov- , asadi-pooya y colaboradores( ), han descrito, la posibilidad de ingreso al sistema nervioso central tras el ingreso por la mucosa nasal o por una gran viremia en el torrente sanguíneo. se han descrito procesos inflamatorios asociados (encefalitis) y en previamente con el sars y el mers hasta lesiones desmielinizantes (encefalomielitis aguda diseminada). estas primeras manifestaciones en con el sars fueron presencia de crisis epilépticas de novo, en quienes excluyendo otras causas tanto por neuroimagen además de pruebas microbiológicas en lcr, les fue descubierto el sars cov mediante pcr rt. en la presente pandemia, takeshi moriguchi y colaboradores ( ) describieron el primer caso de encefalitis asociado a sars-cov- , en un hombre joven en japón, que, tras días de clínica respiratoria, desarrollo crisis epilépticas y alteración del estado de conciencia, sin antecedente conocido de epilepsia. se realizo imagen por resonancia cerebral, demostrando hiperintensidades a nivel temporal y lcr que mostró pleocitosis linfocitaria, se descartaron otros virus ( herpes, herpes zoster) y se le realizó pcr rt para sars-cov- siendo positiva. inclusive en este paciente los primeros hisopados faríngeos fueron negativos, pero los hallazgos en tomografía de tórax hicieron sospechar la infección por sars-cov- . otro caso descrito de encefalitis hemorrágica aguda, fue también descrito en la revisión de ahmad y colaboradores ( ) . donde una mujer joven presentó cuadro respiratorio de fiebre de días de evolución y compromiso del estado de conciencia. en esta paciente se aisló el sars-cov- en hisopado faríngeo y ante el compromiso severo del estado de conciencia, se realizó resonancia que mostró compromiso hemorrágico bitalámico, en regiones temporales e ínsula, apoyando que se tratara de una diseminación tras neuronal probablemente con puerta de entrada mucosa olfatoria y siguiendo la diseminación por el los tractos del primer nervio hasta la corteza entorrinal, que es la vía propuesta de infección descrita inclusive por grupos como el de montalvan ( ) y natoli ( ) . amci ® precisamente, en la revisión sistemática de montalvan ( ) se describen caso de mielitis en contexto de paciente con infección por sars-cov- , en quien se documentó la infección en lcr. se recomienda la medición de ácidos nucleicos por rt-pcr para sars-cov- en líquido cefalorraquídeo en los pacientes con sospecha o confirmación de infección por sars-cov- que realice crisis epilépticas de novo, en quien se descarte otras causas de estructuralidad (acv, tumores) o causas metabólicas (alteraciones hidroelectrolíticas, hipoglicemia, uremia etc.). se recomienda la medición de ácidos nucleicos por rt-pcr para sars-cov- en líquido cefalorraquídeo en pacientes con sospecha o confirmación de infección por sars-cov- con alteración franca del estado de conciencia, en quien se haya descartado como causante hipoxia, ataque cerebrovascular, alteración hidroelectrolítica o estatus no convulsivo mediante imágenes y electroencefalograma. se recomienda la medición de ácidos nucleicos por rt-pcr para sars-cov- en líquido cefalorraquídeo en pacientes con sospecha de encefalitis, mielitis o síndrome de guillain barré. en pacientes críticos, se ha recomendado búsqueda activa de compromiso del snc por sars-cov- , sobre todo en pacientes con crisis epilépticas que no sean sintomáticas a trastornos metabólicos, además de hallazgos imagenológicos y curso clínico. las descripciones hechas por asadi y takeshi ( , ) , muestran pacientes con cursos tórpidos, en los que el común denominador es una alteración del estado de conciencia persistente a pesar que otras variables (metabólicas, vasculares e infecciosas diferentes al sars-cov- ). de igual forma pacientes que realicen en contexto de la enfermedad, un cuadro de debilidad generalizada aguda, con arreflexia e incluso compromiso de nervios craneales como los descritos por zahra sedaghat( ). page amci ® se recomienda en los pacientes críticos con compromiso pulmonar por covid- , un manejo orientado de fluidos frente a una estrategia liberal, ajustando el balance de fluidos de acuerdo con la evaluación clínica y/o a la capacidad de respuesta a volumen para garantizar la perfusión renal. se recomienda ajustar la intensidad de la monitoria en el paciente crítico con covid- al grado de severidad de la enfermedad para alcanzar tempranamente metas de reanimación que se reflejen en menor riesgo de lesión renal aguda. se recomienda evitar el uso de medicamentos nefrotóxicos teniendo en cuenta la farmacocinética y farmacodinamia individual, así como las interacciones farmacológicas en el paciente crítico con covid- . el manejo de la volemia en los pacientes críticos ha cambiado considerablemente en las últimas décadas orientándose a un manejo titulado, evitando la administración empírica de altos volúmenes de líquidos durante la fase de reanimación de los pacientes siendo el flujo sanguíneo el determinante primordial del aporte tisular de oxígeno; los principales componentes de este deben optimizarse y balancearse para evitar la disoxia tisular. en estados de bajo flujo, los mecanismos compensadores neurohumorales producen una redistribución del flujo a lechos no esplácnicos y a nivel renal una redistribución corticomedular convirtiendo el tejido medular renal en una zona vulnerable a la lesión. de igual forma, el flujo sanguíneo renal se ve reducido de forma refleja en presencia de hipoxemia y/o hipercapnia. diversas fuentes de información nos han indicado cómo orientar adecuadamente el manejo del estado de perfusión tisular en los pacientes críticos con o sin una condición de shock, siendo la estimación aproximada del estado de volumen del paciente el pilar fundamental sobre el cual se basará toda la estrategia de restablecimiento o mantenimiento de la volemia del paciente con el fin de mantener la perfusión adecuada. aunque históricamente se prioriza la normalización del volumen en la reanimación de un paciente inestable, hemos comprendido la importancia que tiene el tiempo para lograr las metas en el pronóstico general del paciente y evidencias como el trabajo de ospina y cols. soportan el uso temprano de vasopresores para lograr de forma temprana metas de perfusión mientras buscamos la normovolemia. los pacientes con enfermedad pulmonar asociada a covid- deben mantenerse normovolémicos para preservar el flujo sanguíneo renal siendo la evaluación del estado de volumen un verdadero reto clínico. la fiebre, el aumento de pérdidas insensibles, la baja ingesta o las pérdidas por el tracto digestivo, pueden hacer que un paciente con covid- tenga hipovolemia, situación que puede desencadenar daño renal de no ser revertida apropiadamente y a tiempo. del otro lado del espectro, la administración liberal de líquidos además del potencial de empeorar la lesión pulmonar en presencia de una membrana alveolo capilar seguramente alterada, puede producir por sí misma un incremento en el riesgo de desarrollar lesión renal como lo demostró el estudio de grissom. desde el punto de vista de las metas amci ® hemodinámicas que se deben tener con un paciente con covid- , se recomienda seguir los lineamientos de la campaña sobreviviendo a la sepsis, orientadas a mantener un óptimo estado de volumen, unas presiones de perfusión en un rango que permita la regulación de los flujos regionales en los distintos órganos y un gasto cardíaco dentro de unos rangos establecidos para una perfusión sistémica óptima. el examen clínico sigue teniendo vigencia absoluta para una adecuada aproximación al paciente, por ello debemos buscar los indicadores clínicos tradicionales de hidratación (piel, mucosas, enoftalmos, edema, etc.), el llenado capilar como lo describe hernández y cols en el estudio andrómeda-shock, el estado de alerta, las funciones cognitivas y la rata urinaria son entre otros unos marcadores aceptables para hacernos una idea del estado de adecuación de la perfusión periférica. la oliguria como marcador de perfusión renal está presente en / parte de los pacientes al ingreso a uci sin tener en sí sola una implicación pronóstica, sin embargo, la persistencia de esta en el tiempo es un indicador de alerta y obliga a una evaluación más detallada de las diversas variables que pudieran ocasionarla. debemos recordar que la administración de cargas de líquidos solamente está justificada cuando hay una respuesta cardiovascular a dicha administración, situación que se puede prever con una prueba de elevación pasiva de las piernas o con métodos más invasivos como la variabilidad de la onda de pulso, del volumen sistólico y/o del gasto cardíaco, entre otros. el esfuerzo respiratorio del paciente, los volúmenes utilizados en las estrategias de ventilación protectora y las arritmias frecuentemente presentes en los pacientes con compromiso pulmonar limitan el rendimiento diagnóstico de diversos dispositivos utilizados para la evaluación del estado de volumen y el gasto cardíaco, situación que debemos conocer y manejar( , - ). se recomienda no utilizar de forma rutinaria la administración de tratamientos específicos antivirales para el paciente crítico con covid- , con lesión renal aguda o crónica se recomienda no utilizar de rutina remdesivir en los pacientes con falla renal crónica y debe suspenderse en los pacientes que desarrollan lesión renal aguda con tfg < ml/min. las intervenciones farmacológicas en los ensayos clínicos deben ajustarse a la farmacocinética y farmacodinamia específicas de cada molécula. la incidencia de falla renal reportada por criterios de kdigo, en los estudios chinos fue de . % de los pacientes críticamente enfermos y de . % en los pacientes con covid- y amci ® sdra. sin embargo, otros estudios han demostrado que hasta un %de pacientes con covid- que ingresan a la uci pueden presentar falla renal aguda. la falla renal en los pacientes con covid- es multifactorial como se ha descrito en preguntas anteriores por lo que se recomienda la toma diaria de creatinina sérica y el seguimiento continuo del gasto urinario y otros parámetros de la función renal como hematuria, proteinuria, tasa de filtrado glomerular, nitrógeno ureico en sangre, dímero d. los medicamentos que se emplean en el manejo de la infección covid- que actualmente incluyen oseltamivir, lopinavir/ritonavir, ribavirina, y la cloroquina o hidroxicloroquina son metabolizados principalmente en el hígado, aunque en la orina se encuentran metabolitos derivados de oseltamivir, ribavirina y de la hidroxicloroquina. por esto en ninguno de los estudios realizados en torno a la infección por sars-cov- se ha realizado ninguna recomendación en cuanto a la modificación de su dosis. la hidroxicloroquina por su parte se metaboliza a cloroquina, que a su vez se metaboliza a monodesetilcloroquina y a bisdesetilcloroquina. este medicamento no es dializable en las diálisis intermitentes y la única recomendación en los pacientes con falla renal, es hacer seguimiento electrocardiográfico estrecho para vigilar la prolongación del qtc. el favipiravir es un inhibidor de la polimerasa dependiente de rna que se encuentra en fase experimental para el tratamiento de la infección por sars-cov- . la eliminación de este medicamento se realiza por vía renal y en los pacientes con falla renal en estadios leves a moderados se ha encontrado una concentración dos veces mayor en el riñón que sus niveles en sangre; sin embargo, esto no se ha asociado con ningún evento adverso por lo que la recomendación actual es no disminuir la dosis en pacientes con falla renal. el remdesivir se elimina por vía renal por lo cual no se recomienda administrar en pacientes con falla renal y los pacientes que desarrollan falla renal con el medicamento durante los estudios han sido retirados de los ensayos clínicos. no se cuenta con estudios que evalúen el remdesivir en una tfg < ml/min. en la tabla se describen algunas intervenciones farmacológicas propuestas en medio de la pandemia para el manejo del covid- y su relación con la tasa de filtración según tfg. recientemente , izzedine et al publicaron una carta editorial en el kidney international may , donde alertan sobre el posible efecto nocivo de la hidroxicloroquina en la aparición de falla renal aguda al inhibir la autofagia celular que es un proceso importante en la remodelación de los túbulos renales, siendo estas células de alto recambio, pudiendo todo esto contribuir a la aparición de falla renal aguda( , , - ) se recomienda aplicar las indicaciones tradicionales de terapia de soporte renal en pacientes críticamente enfermos con covid- . se recomienda el inicio de terapia de soporte renal en pacientes críticos con covid- con hipercalemia severa o acidosis metabólica severa, refractarias a pesar del manejo médico óptimo o cuando el balance positivo de fluidos es deletéreo, con mayor requerimiento de oxígeno suplementario y que no responde a diuréticos. se recomienda el inicio temprano de terapia de soporte renal dentro de las primeras horas de una indicación absoluta, asegurando previamente una adecuada reanimación de la perfusión tisular. en ausencia de trastornos hidro-electrolíticos y severa sobrecarga de volumen, el tiempo de inicio de diálisis es controversial. amci ® se recomienda en pacientes críticos con covid- que requieren soporte renal, las modalidades de terapia continua o extendida si cursa con inestabilidad cardiovascular, de acuerdo con la disponibilidad institucional. se debe considerar en pacientes críticos con covid- , que requieren inicio de soporte renal preferir la vía femoral para inicio de la terapia para disminuir el riesgo de contaminación por proximidad, la siguiente vía se establecerá de acuerdo con la evolución y condiciones del paciente. en pacientes diagnosticados con covid- se puede presentar la insuficiencia renal aguda como parte de su enfermedad. en estudios observacionales de usa y china la ira se reportó entre un y % de los pacientes. la enfermedad renal en pacientes con covid- se puede manifestar como ira, hematuria o proteinuria, y conllevan un mayor riesgo de mortalidad. la ira se asocia con cambios hemodinámicos y liberación de citocinas, pero no se descarta citotoxicidad directa por el virus. en un estudio realizado en nueva york con pacientes covid- positivos se diagnosticó lesión renal aguda en % de ellos, siendo leve con aumento de creatinina dos veces por encima del nivel basal en % de los pacientes, moderada en % de los pacientes, y severa con más del triple de la creatinina basal en %. hubo hematuria en el % de los pacientes y proteinuria en el %. se requirió terapia dialítica en el % de todos los pacientes con diagnóstico de ira, y el % de los pacientes que requirieron diálisis estaban en ventilación mecánica. la ira fue notada dentro de las primeras horas de admisión a uci en el % de los pacientes y se relaciona con la severidad de la enfermedad. existen además predictores independientes: edad, raza negra, diabetes, hipertensión, enfermedad cardiovascular, ventilación mecánica, y uso de vasopresores. la terapia dialítica debe instaurarse precozmente una vez realizado el diagnóstico, idealmente dentro de las primeras horas, después de asegurado que se ha completado el proceso de reanimación correspondiente. las indicaciones te trr en pacientes críticos con ira en covid- no difieren del paciente crítico general y se debe considerar ante: manifestaciones severas de uremia, sobrecarga de volumen, trastornos ácidos básico, refractarios, hipercalemia severa con manifestaciones cardiovasculares. pero no hay datos clínicos que respalden el inicio temprano vs tardío en esta población particular. pero un planteamiento válido es que la sobrecarga de volumen en pacientes que desarrollan sdra es perjudicial, dificultando el soporte ventilatorio óptimo, por lo cual se puede considerar un umbral más bajo para el inicio de trr con esta indicación específica: sdra + sobrecarga de volumen + infección covid- ( ) . amci ® el paciente debe ser dializado en el cubículo de cuidado intensivo o en la habitación de aislamiento en los casos en que esté disponible y siempre evitar traslado a unidades con otros pacientes. la crrt es la modalidad preferida para este tipo de pacientes, pero debe quedar claro que esto depende de las facilidades de la institución que albergue al paciente y de la experticia de los profesionales. el acceso vascular en el paciente crítico general debe ser en su orden: vena yugular interna derecha, venas femorales comunes, vena yugular interna izquierda, y debe ser colocado por el médico encargado del paciente si está capacitado para ello, para evitar exposiciones innecesarias del personal de la salud. sin embargo, por precaución por el riesgo de contaminación, recomendaciones de expertos basadas en seguridad sugieren la utilización el catéter femoral. el tipo de catéter recomendado es un catéter doble lumen transitorio. sería ideal el monitoreo a través de cámaras del procedimiento para evitar el contacto prolongado del personal de enfermería durante el procedimiento de diálisis. en algunos casos específicos y de acuerdo con la disponibilidad, la diálisis peritoneal puede ser una alternativa. en los casos de crrt el líquido efluente no es contaminante para el personal de la salud. para terminar, es importante hacer énfasis en que en algunos hospitales ha habido escasez de insumos y esto puede llegar a convertirse en un serio problema. se recomienda para casos de fuerza mayor:  un litro de solución salina al . % con cloruro de potasio a necesidad  un litro de dextrosa al % en agua con meq de bicarbonato de sodio  un litro de solución salina al . % con gr de cloruro de magnesio  un litro de solución salina al . % con gr de cloruro de calcio esto nos da una solución de cuatro litros que contienen: meq/l de sodio, . meq/l de bicarbonato, . mmol/l de magnesio y . mmol/l de calcio, más una cantidad variable de potasio. esta solución se puede usar como líquido dializante en pacientes en terapias de reemplazo renal continuo. especial cuidado se debe tener en el proceso de anticoagulación, pudiéndose usar heparina no fraccionada, hbpm, y citrato en los centros donde se tenga experiencia ( , , ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . se sugiere no utilizar de rutina la trrc más hemoperfusión en el paciente crítico con covid- . débil en contra page amci ® se puede considerar en el paciente crítico con covid- con lesión renal aguda en quien se considere inicio de trrc, considerar la utilización de filtros de fibra hueca con propiedades adsortivas o asociado con cartuchos para hemoperfusión directa. el síndrome de liberación de citocinas (tormenta de citocinas) es un importante determinante en la transformación de infección por covid- de leve a moderado y progresión de la lesión de un órgano como el pulmón con neumonía y sdra a compromiso sistémico con inestabilidad hemodinámica, cid y fom. los pacientes afectados de tormenta de citocinas se encuentran con niveles altos de il- especialmente, además de il- , tnf, que se relacionan con pobres pronósticos y mayor mortalidad. la asociación entre la lesión alveolar y renal (eje pulmón-riñón) es evidenciada en estudio del por panitchote y cols con pacientes con sdra secundaria a neumonía y sin enfermedad renal preexistente que desarrollaron lesión renal aguda en el % con aki en el % de ellos. recientemente en estudio en china zhou, con pacientes afectados de covid- se encontraron como indicadores de mal pronóstico pacientes con altos niveles de dímero d, il- , troponina i, dhl, ferritina y choque séptico. las terapias de depuración extracorpórea han sido utilizadas como tratamiento en pacientes con lesión severa por covid- ; dentro de estas se cuentan la crrt, hemoperfusión aislada, intercambio plasmático (tpe), plasmafiltración y adsorción (cpfa) y crrt + hemoperfusión. dentro de los beneficios de la crrt se cuentan la estabilidad hemodinámica, estabilidad del medio interno, depuración de toxinas pequeñas y medianas, incluidos mediadores inflamatorios, cuando se utiliza terapia convectiva, además de permitir soporte nutricional. la asociación de este procedimiento con membranas especiales (an + metilsulfonato y polietilamina oxiris) permiten hacer adsorción de citocinas (il- ) y endotoxinas, por periodos de h por días consecutivos para manejo de tormenta de citocinas. la hemoperfusión aislada o asociada a crrt, también permite la remoción de il- , utilizando cartuchos ha , con procedimientos de a horas de duración por días consecutivos ( , ( ) ( ) ( ) ( ) ( ) ( ) . no se puede emitir una recomendación a favor o en contra sobre el uso rutinario de la plasmaféresis como opción terapéutica en la fase de inflamación del paciente con covid- . amci ® el coronavirus covid- puede inducir el síndrome respiratorio agudo severo (sars), que conduce a la disfunción inmune, la liberación excesiva de citoquinas inflamatorias, y a una serie de reacciones en cascada de activación de citoquinas, que resultan en lesiones alveolares difusas, formación de membrana hialina, exudación de fibrina y otras manifestaciones de lesión del pulmón. en casos severos, la tormenta de citoquinas sistémicas invade el sistema circulatorio, lo que lleva a una inestabilidad hemodinámica, shock y mods ( ) . los niveles de il- , il- , tnf-a y otras citoquinas inflamatorias en pacientes con covid- grave son significativamente más altos, lo que puede estar relacionado con un mal pronóstico ( ) . por lo tanto, la plasmaféresis se puede usar con seguridad y efectividad en pacientes con covid- grave, para eliminar mediadores inflamatorios de gran peso molecular. la seguridad depende como todas las terapias extracorpóreas de un personal de la uci entrenado, preparado y capacitado para aplicar las intervenciones en forma óptimas ( ) . las terapias extracorpóreas de soporte de órganos pueden representar una parte importante de la respuesta y los médicos y otros profesionales de la salud deben estar familiarizados con estas terapias sofisticadas. se debe hacer un llamado a la acción, para crear conciencia sobre las diferentes técnicas extracorpóreas, cada una con criterios específicos y modalidades de prescripción, entrega y monitoreo( , ). se recomienda no utilizar de forma rutinaria el uso de un tratamiento específico dirigido a pacientes con infección por sars-cov- /covid- comparado con el manejo estándar para mejorar desenlaces clínicos fuertes. actualmente no existe una terapia dirigida que se a efectiva para el manejo del virus; un número alto de estudios han surgido en los últimos dos meses, la mayoría sin el rigor metodológico suficiente para tomar decisiones adecuadas con respecto al manejo del amci ® paciente con infección por sars-cov- . el conocimiento en la estructura del virus y el mejor entendimiento en la fisiopatología de la enfermedad genera un sinnúmero de potenciales fármacos que han sido ensayados para el manejo de la enfermedad. en tiempos de pandemia, con una patología catastrófica en términos de vidas humanas y costos hospitalarios; es importante encontrar soluciones a desenlaces importantes como mortalidad, días de estancia en uci y en el hospital, aumento en los días libres del ventilador, disminución de complicaciones mayores debido a la enfermedad entre otros. hasta el momento no se ha documentado ninguna terapia específica que pueda impactar sobre estos desenlaces; pero la calidad de los trabajos, tampoco dejan claro sin él no usar ningún tratamiento específico mejora los desenlaces al menos al disminuir el número de complicaciones. este nuevo beta-coronavirus es similar al coronavirus del síndrome respiratorio agudo severa (sars-cov) y del síndrome respiratorio del medio este (mers-cov); por lo tanto, varias moléculas que habían sido evaluadas en este tipo de enfermedad rápidamente se abrieron paso a ensayos clínicos en paciente con covid- . estos ensayos principalmente observacionales, aleatorios pero abiertos con un número pequeño de pacientes no han permitido sacar adecuadas conclusiones y es frecuente como ver las diferentes guías de las principales sociedades del mundo cambiar de forma frecuente sus recomendaciones; no existes evidencia de estudios clínicos aleatorios y controlados que midan desenlaces fuertes, la premura de un tratamiento efectivo ha sacrificado el rigor metodológico que una investigación requiere. una estructura viral y replicación conocidas generan posibles dianas para que diferentes fármacos puedan ser investigados, antivirales tipo arbidol el cual inhibe la fusión de la membrana en la envoltura viral a algunos receptores; antimaláricos como la hidroxicloroquina y la cloroquina, las cuales inhiben la entrada viral y endocitosis por múltiples mecanismos, así como los efectos inmunomoduladores demostrados en el huésped; antivirales que impiden la replicación como el lopinavir o darunavir inhibiendo las proteasas o la ribavirina, el remdesivir o el favipiravir que actúan como análogos de nucleótidos o fármacos que actúan modulando la respuesta específica del huésped como el tocilizumab el cual se une al receptor de la il- inhibiendo el punto de acción de esta; los corticosteroides con múltiples efectos en la modulación del sistema inmunológico del paciente o los fármacos para evitar la respuesta secundaria a esta cascada inflamatoria como son los anticoagulantes. por último, se han buscado estrategias con el fin de mejorar la inmunización pasiva del huésped en el uso del plasma de pacientes convalecientes o el uso de inmunoglobulinas enriquecidas entre otros tratamientos propuestos para esta enfermedad. como vamos a ver más adelante, actualmente no existe un tratamiento específico con el nivel de evidencia suficiente para recomendar de manera generalizada; tampoco existe suficiente evidencia del manejo del soporte básico sin el uso de fármacos dirigidos, que demuestre que esta estrategia se deba implementar de manera sistemática en todos los pacientes; por lo tanto, a continuación trataremos de resolver las inquietudes con respecto a los diferentes medicamentos que han sido usados en la pandemia del sars-cov- /covid- . se recomienda no utilizar antimaláricos tipo hidroxicloroquina (hcq) o cloroquina (cq) para el manejo de pacientes con infección por sars-cov- /covid- . para la fecha no hay un adecuado sustento bibliográfico que soporte el uso de antimaláricos en la prevención o manejo de pacientes con infección por sars-cov- tanto leve, moderada como severa. los mayores estudios no muestran utilidad clínica y tendencia a mayores eventos cardiovasculares con el uso de antimaláricos en pacientes con infección por covid- comparado con no darlo. su utilidad se deriva principalmente de resultados en estudios preclínicos e in vitro; como los presentados por wang y cols donde evaluaron medicamentos de manera in vitro contra el covid- , siendo el remdesivir y la cq efectivos de manera in vitro contra el nuevo coronavirus( ); liu y cols, donde la hcq fue efectiva en inhibir la infección por sars-cov- in vitro que junto con su potencial antiinflamatorio tenía potencial para el uso clínico ( ) y yao y cols, donde la hcq fue más potente que la cq para inhibir el sars-cov- in vitro y fue recomendado para el uso en humanos en dosis de mg dos veces al día por el primer día, seguido de mg dos veces al día por días más mantendría la concentración efectiva del fármaco en el tejido pulmonar ( ) . los pocos estudios clínicos, son de baja calidad y no han mostrado mejoría ni eficacia en el uso de antimaláricos para el manejo de paciente adultos con covid- , algunos estudios iniciales con pocos pacientes con resultados favorables ( ) e incluso con recomendaciones para uso en las primeras versiones de guías internacionales para la amci ® hcq y cq, encontrando superioridad en estudios observacionales, de pocos pacientes, sin comparadores para inhibir la exacerbación de la neumonía, hallazgos de las imágenes pulmonares, promover una conversión negativa al virus y acortar el curso de la enfermedad; la cq tuvo un efecto notable tanto en términos de resultado clínico como de eliminación viral ( ) ; considerando la hcq y la cq como un tratamiento costo efectivo ( ) . estudios posteriores con un mayor número de pacientes no han logrado reproducir los estudios preclínicos iniciales; mahévas y cols, evaluaron la efectividad de la hcq en pacientes admitidos a cuatro hospitales en francia, con neumonía por covid- quienes requieren oxígeno, pero no se encontraban en uci, comparado con una población con manejo estándar; la hcq se usó a dosis de mg día en las primeras horas a la admisión, este estudio no soporte el uso de la hcq en pacientes admitidos al hospital con covid- que requieren oxígeno al no reducir de forma significativa la admisión a la uci, el sdra o muerte en el día después del ingreso ( ) ; por el contrario, se han reportado efectos secundarios frecuentes (prolongación del intervalo qt, hipoglucemia, cambios en el estado mental, alteraciones gastrointestinales y retinopatía); silvia borda y cols, evaluó la seguridad y eficacia de dos dosis de cq en pacientes con covid- severo en un estudio aleatorizado, doble ciego fase iib en pacientes adultos hospitalizados con infección por sars-cov- , los pacientes fueron expuestos a dosis altas de cq ( mg dos veces al día por días) o dosis bajas ( mg dos veces al día en el día y una vez al día por días), los hallazgos preliminares de este estudio sugieren que la dosis más alta de cq no debe recomendarse para pacientes críticos con covid- debido a sus posibles riesgos de seguridad, especialmente cuando se toman simultáneamente con azitromicina y oseltamivir; estos hallazgos no pueden extrapolarse a pacientes con covid- no severo ( ); tang y cols, evaluaron la eficacia y seguridad de la hcq con el manejo estándar en un estudio multicéntrico, abierto, aleatorio y controlado en china, pacientes con covid- positivo se incluyeron en el análisis de intención a tratar ( en el grupo de hcq y en el grupo estándar), la hcq fue administrada a dosis de mg día por tres días y mantenimiento con dosis de mg día (duración del tratamiento: dos a tres semanas en pacientes con enfermedad leve a moderada o enfermedad severa respectivamente); la administración de hcq no resultó en una significativa mayor probabilidad de conversión negativa comparado con el tratamiento estándar, los efectos adversos fueron mayores en el grupo de hcq ( ) . con todo esto la hcq y la cq, si se usan deberá ser bajo estudios experimentales aprobados con una estricta monitorización y vigilancia clínica de la frecuencia cardíaca y el intervalo qt, los niveles de glucosa, la función hepática y renal, y el cribado clínico de trastornos mentales y visuales en pacientes que reciben estos fármacos. debe evitarse hcq/cq en pacientes con enfermedades cardiovasculares subyacentes. nuevas evidencias con un mayor número de pacientes podrían sacar la hcq y la cq inclusive de estudios clínicos; barbosa y cols, evaluaron en un estudio cuasialeatorio comparativo el uso fuera de registro de la hcq en pacientes positivos por el sars-cov- , el pronóstico primario fue la necesidad de escalar el soporte ventilatorio, cambio en el conteo de linfocitos o cambio en el índice de neutrófilos/linfocitos, un total de pacientes fueron incluidos, en el brazo de hcq. la administración de hcq fue asociada con la necesidad de aumentar el nivel del soporte ventilatorio comparado con aquellos que no recibieron hcq al día del estudio, no hubo beneficios en la mortalidad, reconstitución inmunológica y riesgo de intubación ( ) . el estudio con un mayor número de pacientes proviene de la ciudad de new york; geleris y cols, examinaron la asociación entre el uso hcq y la intubación o muerte en un centro médico de ny, se analizaron . amci ® estaban más enfermos en términos de oxigenación, en este estudio observacional la administración de hcq no fue asociada con una disminución en el riesgo compuesto de intubación o muerte ( ) . se recomienda no utilizar antimaláricos tipo hidroxicloroquina (hcq) o cloroquina (cq) en combinación con azitromicina (az) para el manejo de pacientes con infección por sars -cov- /covid- . fundamento para la fecha la evidencia no favorece el uso combinado de los antimaláricos en combinación con la azitromicina; por el contrario, la combinación de estos dos medicamentos puede ser deletérea, inclusive con un aumento reportado en la mortalidad y la aparición de arritmias ventriculares de novo; estudios iniciales fueron promisorios, gautret y cols, evaluaron inicialmente el efecto de la hcq en la carga viral respiratoria en conjunto con el uso de azitromicina, la presencia del virus al día fue el pronóstico primario; pacientes con tratamiento mostraron una significativa reducción en la carga viral al día de la inclusión comparado con los controles; la azitromicina adicionada a la hcq fue significativamente más eficiente en la eliminación viral ( ) ; nuevamente gautret y cols, realizaron un estudio observacional, no controlado, no comparativo de pacientes tratados con la combinación de hcq más azitromicina, presentando una mejoría significativa en disminución de la carga nasofaríngea del virus y una menor tiempo de enfermedad ( ) ; luego million y cols, evaluaron la combinación de hcq y az en un estudio retrospectivo de . pacientes con sars-cov- tratados con hcq ( mg tres veces al día por días) + az ( mg en el día , seguido de mg al día por los próximos días), el pronóstico fue mortalidad, empeoramiento clínico (ingreso a uci) o persistencia viral; la administración de hcq+az en combinación antes de que aparecieran las complicaciones del covid- es segura y asociada a una baja mortalidad en los pacientes ( ) ; soportado además por estudios in vitro que demuestran que la combinación de hcq y az tienen efectos sinérgicos para el sars-cov- a concentraciones compatibles con las que se obtienen en pulmones humanos ( ) . otros estudios por el contrario no han encontrado resultados positivos, es así como, magagnoli y cols, en un análisis retrospectivo de pacientes confirmados con infección por sars-cov- en centros de veteranos de los eeuu, un total de pacientes fueron evaluados (hcq, n= ; hcq+az, n= ; no hcq, n= ), en este estudio no hubo evidencia que el uso de la hcq tanto sola o en combinación con la az, redujo el riesgo de ventilación mecánica en pacientes hospitalizados con covid- ; una asociación con un aumento en la mortalidad fue identificada en pacientes tratados con hcq sola ( ) . nuevamente los estudios con un mayor número de pacientes se encuentran en la ciudad de new york; rosenberg y col, describieron la asociación entre hcq, con o sin az en el pronóstico de pacientes hospitalizados con covid- ; un estudio de cohorte multicéntrico retrospectivo en pacientes hospitalizados con covid- en hospitales de ny, los pacientes recibieron ; en pacientes hospitalizados en el área metropolitana de ny con covid- , el tratamiento con hcq, az o ambos, comparado con ningún tratamiento, fue no significativamente asociado con diferencias en la mortalidad hospitalaria ( ) . recomendaciÓn se recomienda no utilizar de forma rutinaria el uso rutinario del lopinavir/ritonavir para el manejo de pacientes con infección por sars-cov- /covid- . en la actualidad no existe evidencia a favor o en contra en el uso del tratamiento con antirretrovirales con lopinavir/ritonavir en el manejo de pacientes adultos hospitalizados con covid- ; no se observó ningún beneficio con lopinavir/ritonavir más allá de la atención estándar. se está en espera de cierre de diferentes ensayos futuros que confirme o excluyan el uso de lopinavir/ritonavir en el paciente covid- . en diciembre de , un nuevo coronavirus, designado sars-cov- , ha causado una pandemia ( , , , ) ; cuando hablamos de enfermedad producida por covid- hablamos de enfermedades que van desde las enfermedades leves autolimitantes del tracto respiratorio hasta neumonía rápidamente progresiva, neumonía grave, falla multiorgánica y muerte. hasta este momento no existen agentes terapéuticos específicos para las infecciones por coronavirus. después de la aparición del síndrome respiratorio agudo grave (sars) en , entre los fármacos aprobados se identificó lopinavir, un inhibidor del aspartato proteasa tipo del virus de inmunodeficiencia humana (vih), que tiene actividad inhibitoria in vitro contra el sras-cov, el virus que causa el sars en los seres humanos y el ritonavir combinado con lopinavir para aumentar su vida media plasmática a través de la inhibición del citocromo p ( ) . se comenzaron estudios evaluando la respuesta antiviral in vitro de la combinación de lopinavir/ritonavir y ribavirina en pacientes con sars; comparados con pacientes tratados con ribavirina sola, que sirvieron como controles históricos; el pronóstico adverso (sdra o muerte) fue significativamente más bajo en el grupo de tratamiento comparado con los controles históricos ( . % vs . %, p = . ) al día del inicio de los síntomas; una reducción adicional en el uso de esteroides y de infecciones nosocomiales fue vista en el grupo de tratamiento con una disminución en la carga viral y aumento en el conteo de linfocitos ( ) ; del mismo modo, el lopinavir tiene actividad, tanto in vitro como en modelo animal, contra el coronavirus del síndrome respiratorio de oriente medio (mers-cov) ( ) . estos estudios previos son el soporte inicial para el uso del lopinavir/ritonavir en la epidemia del covid- ; cao y cols, en mayo de publicaron en china, un estudio controlado, aleatorizado en pacientes hospitalizados con prueba ; los efectos adversos gastrointestinales fueron más comunes con el lopinavir-ritonavir, pero los eventos adversos serios fueron más común con el grupo control; el tratamiento con lopinavir-ritonavir fue suspendido en pacientes ( . %) secundario a los eventos adversos ( ) . otro estudio hung y cols, en hong kong, evaluaron en un trabajo multicéntrico, prospectivo, aleatorizado, fase la eficacia y seguridad de la terapia combinada por días de lopinavir mg y ritonavir mg cada h, ribavirina mg cada h y tres dosis de millones de ui de interferón beta- b en días alternos en pacientes con covid- comparado con lopinavir/ritonavir cada h (grupo control); el resultado primario fue tiempo en la negativización de la pcr viral en el hisopado nasofaríngeo en paciente con covid- ; pacientes fueron ingresados, en el grupo de combinación y en el grupo control; en el grupo de intervención de forma significativa se negativizo la prueba de pcr de forma más rápida ( días [iqr - ]) que el grupo control ( días [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] ; hr . [ic % . - . ], p = . ); los eventos adversos fueron similares entre los grupos; ningún paciente murió durante el estudio ( ) . por último, un pequeño estudio de zhu y cols en china, con pacientes con sars-cov- ; evaluaron de forma retrospectiva los efectos antivirales y seguridad del lopinavir/ritonavir y el arbidol (antiviral aprobado en china y rusia para el sasr y la influenza), pacientes en el grupo de lopinavir/ritonavir y en el grupo de arbidol; los pacientes lopinavir/ritonavir presentaron un mayor tiempo para la negativización de la prueba de pcr viral (p < . )( ). se recomienda no utilizar de forma rutinaria remdesivir como antiviral para el manejo de pacientes con infección por sars-cov- /covid- . se debe considerar su uso en escenarios de estudios de investigación clínica aprobados. actualmente no hay disponibilidad del medicamento en el país (colombia) por lo cual no se incluye en los protocolos de manejo de paciente con covid- . en estados unidos el primer paciente con covid- mostró una mejoría significativa de sus síntomas con horas de tratamiento con remdesivir ( ) , lo que abrió la puerta a un nuevo tratamiento para el sars-cov- ; el remdesivir (gs- ) es un análogo de los nucleótidos que inhibe la rna polimerasa; con un amplio espectro antiviral, puede inhibir la replicación de múltiples coronavirus en las células epiteliales del sistema respiratorio ( ) ; estudiado ( ) . por último, un estudio publicado por antinori y cols, en milán, italia; de manera prospectiva (compasional) incluyó pacientes con neumonía por sars-cov- mayores a años bajo ventilación mecánica o con una saturación de oxígeno ≤ % al aire ambiente o un puntaje del national early warning score ≥ ; el pronóstico primario en cambio en el estado clínico en una escala ordinal de categorías ( = no hospitalizado de regreso a sus actividades diarias normales; = muerte); de los paciente ingresados, se encontraban en uci y en un piso de hospitalización de enfermedades infecciosas; un curso de días de remdesivir fue completado por pacientes ( %) y suspendido en , de os cuales ( . %) se descontinuo por eventos adversos; a los días, ( . %) pacientes de piso fueron egresados, permanecían hospitalizados y uno murió ( . %), en la icu ( . %) fueron egresados, ( . %) pacientes murieron, ( . %) aún se encontraban en ventilación mecánica y ( . %) estaba con mejoría pero aún hospitalizado; la hipertransaminasemia y la injuria renal aguda fueron los eventos adversos más frecuentes reportados ( . % y . %, respectivamente); los datos sugieren que el remdesivir puede beneficiar a pacientes con neumonía por sars-cov- hospitalizados por fuera de la unidad de cuidado intensivo ( ). page se recomienda no utilizar de rutina la ivermectina para el manejo de pacientes con infección por sars-cov- /covid- . para la fecha no se cuenta con la suficiente evidencia para emitir una recomendación para el uso de la ivermectina en pacientes con covid- , en estudios iniciales in vitro, caly y cols, demostró como la ivermectina, una droga autorizada por la fda como antiparasitario tiene un efecto antiviral de amplio espectro de manera in vitro, con una reducción significativa de la replicación viral en modelos experimentales ( ) , un estudio aún sin publicar, observacional multicéntrico de casos y controles (n: casos y n: controles), realizado entre el de enero y de marzo de , incluyó pacientes diagnosticados con covid- confirmados por laboratorio, la dosis fue de mcg/kg de ivermectina más la terapia médica de soporte en comparación con terapia médica sin ivermectina, el resultado principal fue la medición de supervivencia; en pacientes que requirieron ventilación mecánica, la mortalidad fue menor en el grupo de ivermectina ( , % y , % respectivamente) y las tasas de mortalidad global fueron más bajas con ivermectina ( no se puede emitir una recomendación a favor o en contra sobre el uso compasivo o rutinario de tocilizumab en pacientes con infección por sars-cov- /covid- . en pacientes individualizados se ha reportado desenlaces clínicos favorables. se puede considerar su uso en pacientes que cumplan con todos los siguientes criterios: ver tabla . el tocilizumab (tcz) un anticuerpo monoclonal humanizado igg k, el cual se puede unir de manera específica a los receptores solubles de membrana para la il- (sil- r and mil- r) y ha sido ampliamente usado en el tratamiento de enfermedades autoinmunes, tales como la artritis reumatoide, la enfermedad de still del adulto o vasculitis de grandes vasos ( ) . un primer estudio de xiaoling xu y cols, describió en china, pacientes tratados con tocilizumab, se documentó una mejoría en los síntomas, en los requerimientos de oxígeno y en los hallazgos imagenológicos de la tomografía de tórax; los niveles promedio de il- antes de la terapia fueron de . pg./ml; todos los pacientes recibieron lopinavir y metilprednisolona antes de la terapia. se trata de una serie con una muestra pequeña de pacientes en donde solo ( %) pacientes estaban en condición crítica ( ) . posteriormente luo y cols, en china, reportan el uso de tocilizumab en pacientes, con mejoría en el aumento de la pcr en todos los pacientes, excepto uno, y una disminución de la il . el nivel sérico de il- tendió a aumentar inicialmente y luego disminuyó en pacientes. los niveles medios de il- antes de la terapia fueron de . pg./ml; % de los pacientes recibieron metilprednisolona; el % fallecieron. es otra serie pequeña, con pacientes ( , %) en condición crítica ( ) . roumier y cols, en francia, estudiaron pacientes que recibieron tcz, observando que se redujo la necesidad de ventilación mecánica en comparación con los controles ( amci ® . ); en este estudio, no hubo diferencias en la reducción de la mortalidad y pacientes ( %) se encontraban en uci ( ) . klopfenstein y cols, también en francia, en un estudio retrospectivo de casos y controles, encontraron que pacientes que recibieron tcz (n= ), a pesar de tener más requerimiento de oxígeno, con resultados biológicos más pobres (mayor linfopenia y un nivel de pcr superior) al inicio del estudio que los pacientes sin tcz (n = ), presentaron el objetivo combinado (ingreso a uci y mortalidad) menor que los pacientes sin la terapia ( % vs %, p = . ); es otra serie, que disminuye la necesidad de ventilación mecánica ( % vs %, p = . ) de manera significativa ( ) . luego rimland ca y cols informan los primeros datos de pacientes con covid- tratados con tcz en los estados unidos, de ellos en ventilación mecánica; la pcr y el fibrinógeno mejoraron rápidamente, pero no hubo mejoría en otros marcadores o resultados clínicos. sólo a seis pacientes les tomaron niveles previos de il y de ellos dos tenían niveles bajos ( ) . en otro estudio mikulska y cols, próximo a salir en jama, en pacientes con sdra moderado a severo, hay mayor disminución de la mortalidad con el tratamiento combinado de tocilizumab y esteroides, en relación con cada una de estas terapias. por último, no todos los estudios han mostrado resultados positivos; kimmig y cols, de chicago (eeuu), en de los pacientes críticos con covid- , que recibieron tcz, se asoció con una mayor incidencia de infecciones bacterianas secundarias, incluida la neumonía asociada al ventilador ( . % vs. . % p = . ) ( ) . posterior a la recomendación hay nueva evidencia publicada y estudios aún sin publicar que puede soportar el uso de los inhibidores de la il- en pacientes con sars-cov- /covid- ; morena y col, en un estudio de tocilizumab como uso "off-label" en el tratamiento de neumonía por sars-cov- en milán, italia, este estudio abierto, prospectivo, describe las características clínicas y el pronóstico de pacientes con covid- confirmado y severo tratados con tcz iv, todos los pacientes, presentan niveles plasmáticos elevados de il- (> pg/ml) y saturación de oxígeno < % al aire ambiente, pacientes ( %) se encontraban con sistema de alto flujo de oxígeno y en ventilación invasiva, a los días luego del tratamiento se observa una caída dramática en la temperatura corporal y la pcr, con un incremento significativo en el conteo de linfocitos (p < . ); a los días del tratamiento, pacientes ( %) mostraron una mejoría en la severidad del cuadro; fueron dados de alta; ( %) mostraron empeoramiento de su cuadro clínico y de estos, murieron ( %). la mortalidad fue significativamente asociada con el uso de ventilación mecánica al inicio ( . % vs % de los pacientes en soporte de oxígeno no invasivo, p = . ), el efecto adverso más frecuente reportado fue la elevación de las enzimas hepáticas ( %), trombocitopenia ( %) e infecciones bacterianas serias e infecciones fúngicas en un ( %); los autores concluyen que el tcz ejerce un rápido beneficio sobre los marcadores inflamatorios y la fiebre, aunque no se consiguió un impacto clínico sobre el pronóstico, el riesgo aumentado de infecciones severas no es despreciable ( ) . capra y col, describieron pacientes en un hospital de italia con neumonía por covid- y falla respiratoria sin soporte ventilatorio y al menos uno de los siguientes: frecuencia respiratoria ≥ respiraciones/min, saturación ≤ % o pao /fio <= mmhg, los pacientes recibieron la terapia estándar para el momento (hidroxicloroquina, lopinavir y ritonavir) y fueron considerados el control; pacientes recibieron tzc con días de la admisión más el manejo estándar, los pacientes en el grupo de tratamiento mostraron de manera significativa una mayor sobrevida comparado con los pacientes control (hr para muerte, . ; % ic], . a . ; p = . ), ajustado para las características clínicas de base; de pacientes en el grupo de tcz y de en el grupo control murieron; % y . % de los pacientes que se dieron de alta en el grupo de tcz y en el control se recuperaron; la función respiratoria mejoró en el . % de los amci ® pacientes con tcz que aún se mantenía hospitalizados, donde el % de los controles empeoro y requirieron ventilación mecánica, dando al tcz un espectro positivo en términos de curso clínico y sobrevida en pacientes con covid ( ). guaraldi y col; evaluaron el papel del tcz en reducir el riesgo de ventilación mecánica invasiva en pacientes con neumonía severa por covid- quienes recibían tratamiento estándar para el momento (hidroxicloroquina, azitromicina, antirretrovirales y heparinas de bajo peso molecular) en un estudio retrospectivo, observacional en bologna, reggio emilia y módena, italia; el tcz fue dado a dosis de mg/kg de peso corporal de forma iv (con un máximo de mg) en dos infusiones separadas h o mg sc administradas en dos dosis simultáneas, una en cada muslo ( mg en total), cuando la formulación iv no se encontraba disponible; el pronóstico primario fue la combinación de ventilación mecánica invasiva o muerte; de pacientes ingresados, ( %) tenían neumonía severa por covid- y fueron incluidos, ( %) de pacientes en el grupo estándar requirieron ventilación mecánica, comparados con ( %) de pacientes tratados con tcz (p = · ; [ %] de pacientes tratados iv y [ %] de pacientes tratados sc); ( %) pacientes en el grupo estándar murieron, comparado con ( %; p < . ) pacientes con tcz ( [ %] del grupo iv y [ %] sc); luego de ajustar para sexo, edad, centro de reclutamiento, duración de los síntomas y puntaje de sofa, el tratamiento con tcz fue asociado con una reducción en el riesgo de ventilación mecánica invasiva o muerte (hr . , % ic . - . ; p = . ); ( %) de pacientes tratados con tcz fueron diagnosticados con nuevas infecciones en comparación con ( %) de pacientes en el grupo estándar (p < . ) ( ) . campochiaro y col, en un solo centro evaluó la eficacia y seguridad del tcz en pacientes con covid- severo, se diseñó un estudio retrospectivo en pacientes con características de hiper-inflamación (definida como una elevación tanto en la pcr, ≥ mg/l, normal < mg/l o ferritina ≥ ng/ml, normal < ng/ml en presencia de un incremento en la dhl > u/l), acompañado de un compromiso respiratorio severo, definido como hallazgos típicos en la radiografía y/o tomografía, la presencia de una saturación de oxígeno ≤ % al aire ambiente o una pao :fio ≤ mmhg ingresados a la uci, comparando pacientes con tcz iv al manejo estándar, pacientes fueron incluidos de los cuales fueron tratados con tcz; los pacientes se encontraban con alto flujo o ventilación mecánica no invasiva, a días de seguimiento, % de los pacientes con tcz experimentaron mejoría clínica comparado con un %del tratamiento estándar (p = . ); la mortalidad fue % en el grupo de tcz y % en el grupo estándar (p = . ); la incidencia de infección y trombosis pulmonar fue similar en ambos grupos ( ); somers y col, evaluaron un estudio observacional en pacientes con neumonía por covid- severo que se encontraban en ventilación mecánica, evaluando como pronóstico la probabilidad de sobrevida posterior a la extubación; pacientes fueron incluidos, recibieron tcz y no; en los modelos ajustados, el tcz, fue asociado con una reducción del % en el riesgo de muerte [hr . % ic . a . ]; aunque el tcz, fue asociado con un incremento en la proporción de pacientes con superinfecciones ( % vs. %; p < . ), no hubo diferencias en la mortalidad a días entre los pacientes tratados con tcz con o sin superinfecciones [ % vs. %; p= . ] ( ). price y col, también publicaron un estudio observacional de pacientes hospitalizados con covid- , los pacientes recibieron tcz si cumplían criterios del síndrome de liberación de citoquinas, se evaluaron pacientes; de los cuales ( %) recibieron tcz, estos pacientes que recibieron ventilación mecánica la sobrevida fue del % ( % ic, - ), luego del tcz pocos eventos adversos fueron reportados y tanto la oxigenación como los biomarcadores de inflamación mejoraron ( ) y por último, en un estudio preliminar con datos aún sin publicar perrone y col, evaluaron la eficacia del tcz en pacientes con neumonía por covid- , en un estudio amci ® multicéntrico fase en italia; se utilizó tcz, a dosis de mg/kg iv, una o dos administraciones con horas de diferencia; y casos fueron disponibles para un análisis de intención a tratar, pacientes murieron; las tasas de letalidad fueron de . % ( . % ic, . - . , p = . ) y . % ( . % ic, . - . , p < . ) a y días; el tcz redujo la tasa de letalidad a días pero no a días comparado con las esperadas sin presentar una toxicidad significativa; la eficacia fue más evidente en los paciente que no requerían ventilación mecánica ( ). recomendaciÓn se recomienda no utilizar de rutina bloqueadores de interleuquina- (anakinra) en pacientes con infección por sars-cov- /covid- . aunque su ventaja está en el perfil de seguridad, su vida media corta ( horas) y porque las infecciones oportunistas son raras ,no hay suficiente evidencia para emitir una recomendación sobre el uso de este medicamento; cavalli y cols, de milán, italia, realizaron un estudio de cohorte retrospectivo en pacientes con sdra moderado a severo con hiperinflamación (pcr ≥ mg/dl, ferritina ≥ ng/ml o ambos), manejados con ventilación mecánica no invasiva fuera de la uci y que recibieron tratamiento con hidroxicloroquina y lopinavir, los pacientes que recibieron anakinra, mg/kg dos veces al día intravenosa (n= , dosis alta) o mg dos veces al día subcutánea (n= pacientes, dosis baja) fueron comparados con una cohorte retrospectiva que no recibió anakinra (tratamiento estándar); la duración del tratamiento se prolongó hasta el beneficio clínico sostenido (reducción del % en la pcr, y una pafi > , durante al menos días consecutivos) o hasta la muerte, bacteriemia, o efectos secundarios (alt > veces valores de referencia); el tratamiento con anakinra a bajas dosis se interrumpió después de días debido a la escasez de efectos sobre la pcr y el estado clínico. a los días, el tratamiento con dosis altas de anakinra se asoció con una reducción en la pcr y mejoría en la función respiratoria en de pacientes ( %); en el grupo estándar, ocho de pacientes ( %) mostraron mejoría respiratoria a los días. en días de seguimiento, la sobrevida fue del % en el grupo de dosis altas de anakinra y del % en el grupo estándar (p = . ). se trata del primer estudio que demuestra seguridad y mejoría en los pacientes covid- , pero en el contexto fuera de la uci ( ) . huet y cols, de parís, francia, realizaron el estudio llamado ana-covid- en el que compararon pacientes tratados con anakinra subcutánea mg dos veces al día durante h, luego mg diarios durante días, con pacientes históricos; su criterio de inclusión fue tener una saturación de oxígeno del % o menos con un soporte de mínimo de l / min de oxígeno. la admisión a la uci por ventilación mecánica invasiva o muerte se produjo en ( %) pacientes en el grupo de anakinra y ( %) pacientes en el grupo histórico (hr . amci ® pacientes en el grupo histórico tuvieron un aumento en las aminotransferasas hepáticas ( ). recomendaciÓn se sugiere que la terapia con interferón sólo sea considerada en pacientes con formas graves de infección por covid- en el marco de un estudio clínico. estudios preliminares muestran que el virus del covid- induce una expresión muy débil de interferones en las células infectadas, lo que obstaculiza la respuesta inmune innata temprana a la infección y sugiere que el uso de interferón (ifn) exógeno para estimular la inmunidad antiviral ( ) . zhou q y col, en china, en un estudio observacional de pacientes con covid- con gravedad mixta proporcionó evidencia de muy baja calidad que la adición de interferón-α a la terapia con umifenovir no afecta el tiempo de eliminación viral o la duración en la estancia hospitalaria cuando se comparó con el umifenovir solo ( ) . hung if y cols, de hong kong, realizaron un ensayo multicéntrico, en adultos con covid- , en los que pacientes recibieron una combinación de lopinavir/ritonavir y tres dosis de millones de unidades internacionales ( · mg) de interferón beta- b en días alternos (grupo de combinación) y pacientes recibieron lopinavir/ritonavir (grupo control); la terapia de combinación fue segura y superior al control, para aliviar los síntomas y acortar la duración de la eliminación del virus y la estancia hospitalaria; se trata de un estudio fase , en pacientes con covid- leve a moderado (ningún paciente con ventilación en el grupo de combinación), en el que el ifn se administró en los primeros días de inicio de los síntomas y con el uso de un análogo de nucleósido oral (ribavirina), que no está en nuestras guías ( ) . se necesitan estudios de ifn solo o combinado en pacientes críticos con covid- . los efectos adversos de los ifn tipo i pueden limitar su uso para una intervención generalizada, como se propone en el brazo ifn-β con lopinavir/ritonavir del ensayo solidaridad de la oms. la administración por inhalación de vapor que se realiza actualmente en china ofrece la ventaja de acceso rápido al tracto respiratorio; sin embargo, la farmacodinamia y la farmacocinética de este modo de administración nunca se han evaluado. se sugiere no utilizar de rutina corticoides en el tratamiento de pacientes con sospecha o diagnóstico de covid- . no se puede considerar su uso profiláctico ni en pacientes con enfermedad leve sin requerimiento de oxígeno. débil en contra page en diciembre de , una serie de casos de neumonía de causa desconocida surgió en wuhan, hubei, china, con presentaciones clínicas muy parecidas a una neumonía viral; los análisis de secuenciación profunda de muestras del tracto respiratorio inferior indicaron un nuevo coronavirus, que se denominó novel coronavirus (covid- - ) ( ) . en la actualidad, en ausencia de terapia preventiva para sars-cov- , la piedra angular de atención para pacientes con covid- sigue siendo el manejo de apoyo, que va desde el tratamiento ambulatorio sintomático hasta el tratamiento intensivo completo con medidas de soporte en cuidados intensivos ( ) . dentro del manejo farmacológico se ha planteado la opción del uso de corticoides, la justificación estaría basada en la disminución de la respuesta inflamatoria del huésped a nivel pulmonar; es decir, un efecto inmunomodulador, ya que esta infección puede conducir a un síndrome de distrés respiratorio agudo (sdra); sin embargo, el beneficio puede verse superado por los efectos adversos, incluido el retraso en el aclaramiento viral y mayor riesgo de infección secundaria. a pesar de que la evidencia directa de corticoides en covid- es limitada, revisiones de los resultados en otras neumonías virales nos podrían orientar en principio en esta actual situación ( ) . teniendo en cuenta lo anterior; stockman y cols, en el . , realizaron una revisión sistemática sobre ensayos en pacientes con sars; quince ensayos examinan el uso de corticoides con diez o más pacientes en tratamiento; ensayos también recibían ribavirina; trece de estos estudios no fueron concluyentes; dos estudios describen un daño potencial con el uso de esteroides; en la literatura china estos autores encontraron catorce estudios con uso de esteroides en sars; doce fueron suspendidos por posible daño, la mayoría de estos ensayos se realizaron con muestras pequeñas de pacientes y de manera retrospectiva ( ) . arabi y cols, en noviembre de . , realizaron un estudio multicéntrico de cohorte retrospectivo en hospitales de atención terciaria de arabia saudita, donde se incluyeron pacientes; el uso de corticoides en pacientes con mers no se asoció con un cambio significativo a los días en la mortalidad y se documentó un retraso en la eliminación del arn de mers-cov ( ) . en cuanto hace referencia a la situación actual de pandemia por sars-cov- y compromiso pulmonar; wu y cols, en marzo de . realizaron un estudio retrospectivo de pacientes con covid- en china; para aquellos pacientes que desarrollaron sdra, el tratamiento con metilprednisolona estuvo asociado con una disminución del riesgo de muerte ( / [ %] con esteroides vs / [ %] sin esteroides; hr, . [ic %, . - . ]), con las limitaciones de los estudios retrospectivo, de un solo centro, con un limitado número de pacientes ( ). zha y cols, en marzo de . , describen el uso de corticosteroides en el tratamiento de pacientes con covid- ; no hallaron asociación entre la terapia con esteroides y el pronóstico de los pacientes sin sdra, siendo un estudio con una serie muy pequeña de pacientes ( ) . yang y cols, en marzo de . , en una revisión sistemática y meta-análisis que incluyó . pacientes de estudios, describen como el tratamiento con corticoides estuvo asociado con una mayor mortalidad (rr = . , ic % = . - . , p = , ), mayor estancia (wmd = . , ic % . - . , p = < , ) y una mayor tasa de infección bacteriana (rr = . , ic % . - . , p = < . ); con algunas limitaciones en este metaanálisis, la mayoría de los estudios incluidos son estudios de cohorte retrospectivos, controles históricos, con un bajo nivel de evidencia y una falta de ensayos controlados aleatorizados con buen diseño, sin un estándar uniforme para el tiempo y la dosis de los corticoides utilizado en los estudios; los efectos de los corticosteroides pueden ser influenciado también por otras opciones terapéuticas, como los medicamentos antivirales ( ) . por último, li y cols, en mayo de . , en otra revisión sistemática y metaanálisis, con respecto al uso de corticosteroides en sujetos con amci ® infecciones por sars-cov- , sars cov y mers-cov, se determinó que hubo retraso en la eliminación del virus sin mejoría en la supervivencia, reducción en la duración de la hospitalización o tasa de admisión en la uci y/o uso de ventilación mecánica; presentándose varios efectos adversos. debido a la preponderancia de los estudios observacionales en el conjunto de datos y los sesgos de selección y publicación, se concluye especialmente con respecto al sars-cov- , que se necesita mayor investigación con ensayos clínicos aleatorizados. internamente en este meta-análisis sugiere precaución al usar esteroides en pacientes con covid- ( ). horby y col en una rama del ensayo de evaluación aleatorizada de la terapia covid- (recovery), estudio aleatorizado, controlado, abierto que compara una gama de posibles tratamientos con la atención habitual en pacientes hospitalizados con covid- , compararon el uso de la dexametasona a dosis de mg día (oral o intravenosa) una vez al día por días o el alta según lo que ocurriera primero contra el manejo habitual; en pacientes aleatorizados que recibieron dexametasona se compararon con pacientes en manejo estándar; ( . %) pacientes en el grupo de dexametasona y ( . %) pacientes en el grupo control murieron a los días, con un riesgo relativo ajustado para la edad (rr . ; % ic . a . ; p < . ). la mortalidad relativa y absoluta variaron significativamente en relación al soporte ventilatorio al momento de la aleatorización; la dexametasona redujo las muertes en una tercera parte de los pacientes que recibieron ventilación mecánica invasiva ( . % vs. . %, rr . , % ic . a . ; p < . ), y una quinta parte en los pacientes que reciben oxígeno sin ventilación mecánica invasiva ( . % vs. . %, rr . , % ic . a . ; p = . ), pero sin reducir la mortalidad en paciente que no recibieron soporte respiratorio al momento de la aleatorización ( . % vs. . %, rr . , % ic . a . ]; p = . ) ( ). se recomienda no utilizar plasma convaleciente como tratamiento de rutina en paciente con sars-cov -covid- . se debe considerar su uso en el marco de un ensayo clínico y con alguno de los dos escenarios siguientes: escenario a (enfermedad severa), definida como uno o más de los siguientes: disnea, frecuencia respiratoria > /min, spo < %, pao /fio < o empeoramiento radiológico con aumento > % de los infiltrados pulmonares en - horas. escenario b (enfermedad que amenaza la vida), definida como uno o más de los siguientes: falla respiratoria, choque séptico, o disfunción multiorgánica. se recomienda no utilizar plasma convaleciente para profilaxis clínica de rutina contra la infección por sars-cov- , solo se debe considerar en el marco de un ensayo clínico. ( ) . una revisión sistemática y meta-análisis exploratorio realizado en identificó estudios de infección por coronavirus sars e influenza severa, el estudio reveló una reducción de la mortalidad, especialmente si el plasma convaleciente se emplea en la fase temprana de la enfermedad cuando se comparó con placebo o no tratamiento (or . ; ic del % . - . ); sin embargo, hay que tener presente que los estudios son de baja calidad, carecen de grupos control y puede tener riesgo moderado a alto de sesgo ( ) . se ha sugerido que el plasma convaleciente de pacientes que se han recuperado de covid- puede ser una terapia potencial, proporcionando inmunidad pasiva de los anticuerpos específicos contra sars-cov- y podría servir para prevenir y tratar la enfermedad ( ) . las personas que se han recuperado de la infección por sars-cov- pueden generar anticuerpos neutralizantes ( , ) que podrían tener aplicación en la prevención de infección en ciertos escenarios, como las personas con comorbilidades subyacentes que predisponen a enfermedad grave y aquellas con exposición de alto riesgo como los trabajadores de la salud y los expuestos a casos confirmados de covid- . existen algunos riesgos asociados con el uso de plasma convaleciente, unos conocidos y otros teóricos; los riesgos conocidos son aquellos asociados con la transfusión de hemocomponentes, incluida la transmisión de virus (ej. vih, vhb, vhc, entre otros) ( ); riesgo muy bajo, con los estándares de calidad actuales de los bancos de sangre; también se pueden presentar complicaciones no infecciosas, como las reacciones alérgicas, anafilaxia, reacción febril a la transfusión, lesión pulmonar aguda relacionada con la transfusión (trali), sobrecarga cardiaca asociada a transfusión (taco) y hemólisis si se administra plasma abo incompatible ( ) . los riesgos teóricos incluyen el empeoramiento de la infección dependiente de anticuerpos (antibody-dependent enhancement of infection -ade); el ade puede ocurrir en varias enfermedades virales e implica una respuesta inflamatoria exagerada ante la presencia de ciertos anticuerpos ( ) . otro riesgo teórico es que la administración de anticuerpos a las personas expuestas al sars-cov- puede evitar la enfermedad, pero modifica la respuesta inmune de tal manera que esos individuos monten respuestas inmunes atenuadas, lo que los haría vulnerables a la reinfección posterior, si se comprueba que este riesgo es real estos individuos podrían ser vacunados contra covid- cuando exista una vacuna disponible ( ) . durante el brote actual en china, se utilizó plasma convaleciente en algunos pacientes con covid- ( ), desde esta publicación se identificaron publicaciones relacionadas con el tema, entre todos los estudios fueron tratados con plasma convaleciente un total de pacientes( - ) (tabla ). shen y cols en marzo describieron en china el primer reporte en el cual el plasma convaleciente puede ser una opción de tratamiento en pacientes con covid- ; reportaron una serie de casos de pacientes críticamente enfermos con covid- y síndrome de dificultad respiratoria aguda (sdra), todos en ventilación mecánica, a quienes se les administró plasma convaleciente con anticuerpos neutralizantes [ a días después del inicio de la enfermedad (ddie)], todos ellos posteriormente mostraron mejoría clínica, la carga viral de los pacientes disminuyó y fueron negativas en los días posteriores a la intervención ( ) . de forma similar, duan y cols en mazo en china reportaron mejoría clínica en una serie prospectiva de casos de paciente severamente enfermos con covid- , que recibieron plasma convaleciente con un tiempo medio de . ddie ( a días) después del inicio de los síntomas, e hicieron amci ® una comparación con un grupo control histórico comparables en edad, género y severidad de la enfermedad ( ) . zhang y cols en mazo , en china reportaron una serie de casos de pacientes con covid- críticamente enfermos, en falla respiratoria con ventilación mecánica y dos de ellos con ecmo (membrana de oxigenación extracorpórea), a quienes se les dio tratamiento con plasma convaleciente en un tiempo medio . ddie, posteriormente todos tuvieron mejoría clínica ( ) . posteriormente ahn y cols en abril en corea, describieron una serie de dos casos de paciente con covid- severamente enfermos, en falla respiratoria y con ventilación mecánica, quienes además de recibir hidroxicloroquina, lopinavir/ritonavir y metilprednisolona, fueron tratados con plasma convaleciente entre - ddie, ambos pacientes se recuperaron y fueron liberados de la ventilación mecánica, uno fue dado de alta al momento del reporte ( ) . ye y cols en abril en china, describieron una serie de pacientes con covid- con anormalidades imagenológicas y deterioro clínico a pesar del tratamiento estándar y con pcr para sars -cov- persistentemente positiva, aunque no estuvieron en falla respiratoria o con ventilación mecánica, de hecho, una de las pacientes era portadora asintomática; todos recibieron plasma convaleciente entre a ddie, en todos los pacientes, excepto , hubo resolución de los cambios de vidrio esmerilado y consolidación, todos mejoraron y fueron dados de alta ( ) . zeng y cols en abril en china, reportaron una serie de casos con covid- en falla respiratoria y se compararon con controles que no recibieron plasma convaleciente por limitación en la disponibilidad y compatibilidad abo; a este grupo de paciente, se les administró plasma convaleciente en promedio . ddie, en todos los casos se negativizó la pcr para sars-cov- a los días después del tratamiento; sin embargo, contrario a los reportes de los estudios previos, en este grupo se murieron pacientes ( % vs %, p = . ), pero tuvieron mayor porcentaje de aclaramiento del virus (pcr sars-cov- negativa % vs . %, p = . ) antes de la muerte e incluso el tiempo de sobrevida fue mayor en el grupo de tratamiento (p = . ) ( ) . salazar y cols en mayo , en houston, texas, reportaron una serie de pacientes con covid- severa o amenazante para la vida, el desenlace primario fue seguridad y el secundario fue el estado clínico de los pacientes al día luego de la transfusión; al día posttransfusión, pacientes ( %) mejoraron con relación a su estado clínico basal, ( %) no tuvieron cambios y pacientes tuvieron deterioro clínico. siete de los nueve pacientes que mejoraron ( %) habían sido dados de alta; para el día post-transfusión, ( %) de los pacientes presentaron mejoría y pacientes más, habían sido dados de alta; tres pacientes permanecían sin cambios, pacientes se deterioraron y uno murió por una condición no relacionada con el plasma; el promedio de estancia hospitalaria fue de . días y la estancia hospitalaria luego de la transfusión fue en promedio días; hubo una disminución de los valores promedio de pcr desde . mg/dl el día , a , mg/dl y . mg/dl los días y respectivamente; al momento de la publicación del artículo, solo permanecían intubados pacientes; todos los pacientes que requirieron ecmo ya se habían liberado y ( %) fueron dados de alta ( ) . también en texas, estados unidos, ramachandruni y col en mayo , reportaron una serie de casos con covid- severa, falla respiratoria y en ventilación mecánica o pao /fio < , todos con comorbilidades; a los cuales les administraron metilprednisolona y posteriormente plasma convaleciente; compararon los valores basales de pao /fio y posterior a la intervención; encontrando, mejoría de la pao /fio en % luego del tratamiento con esteroides y en % luego de la administración de plasma convaleciente ( ) . finalmente, en respuesta al brote de covid- en los eeuu y las tasas de mortalidad reportadas, la fda en colaboración con la mayo clinic y la comunidad nacional de bancos de sangre desarrollaron un programa nacional de acceso ampliado para recolectar y distribuir plasma convaleciente donado por amci ® individuos que se han recuperado de covid- ; entre abril y mayo , ; fueron incluidos . pacientes con covid- severa o potencialmente mortal o con riesgo alto de progresión a covid- severa o potencialmente mortal en el programa nacional de acceso ampliado; en ese tiempo, un total de . pacientes inscritos recibieron transfusión de plasma convaleciente covid- . en una publicación reciente, joyner y cols en mayo , en estados unidos, hicieron un análisis de seguridad después de la transfusión de plasma convaleciente covid- humano con compatibilidad abo en . adultos hospitalizados con covid- grave o potencialmente mortal, % de los cuales se encontraban en uci; la incidencia de eventos adversos serios (eas) durante las horas siguientes a la transfusión de plasma convaleciente fue < %, incluyendo mortalidad ( . %); de los eas reportados, hubo incidentes reportados como eas relacionados, incluyendo muertes, eventos de taco, trali y reacciones alérgicas graves asociadas a la transfusión; sin embargo, solo (de ) eas fueron considerados definitivamente relacionados con la transfusión de plasma convaleciente por el médico tratante; en este grupo de pacientes, la tasa de mortalidad a los siete días luego de la administración del plasma convaleciente, fue del , % ( ) . a pesar que la tasa general de letalidad para la covid- parece ser aproximadamente . % ( ), la tasa de mortalidad reportada parece no ser excesiva si la comparamos con los informes de wuhan que sugieren tasas de letalidad del % para los pacientes hospitalizados ( ) y % entre los pacientes en unidad de cuidados intensivos ( ) . los nueve estudios mostraron mejoría en muchos aspectos, incluyendo el aclaramiento del virus, la disminución del suplemento de oxígeno y la ventilación mecánica, la normalización de los valores de laboratorio, y la recuperación en los hallazgos pulmonares radiológicos. todos los estudios, reportaron que no se presentaron eventos de seguridad o reacciones adversas serias relacionadas con la administración de plasma convaleciente en pacientes con covid- , excepto en casos relacionados, según criterio de los médicos tratantes, en el estudio publicado por joyner y cols ( ) . esta serie de estudios son alentadores; sin embargo, la mayoría de los reportes de casos tienen limitaciones significativas: carecen de los ajustes para factores de confusión críticos, incluidos los co-tratamientos, las características basales, la gravedad de la enfermedad y el momento de administración del plasma y deben ser seguidas de investigaciones adicionales. para establecer mejor el papel del plasma convaleciente es necesario realizar estudios dirigidos a los siguientes escenarios: . el uso como profilaxis post-exposición . evaluar si el plasma convaleciente es útil en paciente con enfermedad leve . el efecto del plasma convaleciente en pacientes con enfermedad moderada . el tratamiento de rescate con plasma convaleciente en pacientes que requieren ventilación mecánica debido a covid- . finalmente, trabajos que evalúen la seguridad y farmacocinética del plasma convaleciente en los pacientes pediátricos con alto riesgo. actualmente están en curso varios estudios para evaluar el tratamiento de pacientes infectados con sars-cov- con plasma convaleciente. una búsqueda realizada el de mayo de en clinicaltrials.gov con los términos "plasma convaleciente y covid- " mostró ensayos en curso sobre el uso de plasma convaleciente en pacientes con amci ® covid- , que nos ayudarán a resolver las inquietudes relacionadas con esta intervención ( ) . page se recomienda no utilizar de rutina las las inmunoglobulinas hiperinmunes en pacientes con infección por sars-cov- /covid- . la inmunoglobulina hiperinmune (h-igiv) se deriva de individuos con altos títulos de anticuerpos contra patógenos específicos y se ha utilizado con éxito en el tratamiento de infecciones, como el citomegalovirus y la gripe h n ( ) . se propone que la inmunoglobulina hiperinmune combinada con medicamentos antivirales puede ser efectiva en el tratamiento de pacientes con covid- , estos anticuerpos (ac) recogidos de los pacientes recuperados serán específicos contra covid- al aumentar la respuesta inmune en pacientes recién infectados ( ) . existe evidencia más sólida para el uso de h-igiv en el tratamiento de enfermedades virales. cheng y cols en enero de , realizaron una revisión retrospectiva en hong kong, que reveló que el plasma convaleciente de los sobrevivientes de sars-cov administrados a pacientes con sars-cov que tenían enfermedad progresiva resultó en tasas de alta significativamente más altas en el día y tasas de mortalidad más bajas, en comparación con los controles históricos ( ) . hung y cols en febrero de , realizaron un estudio de cohorte prospectivo sobre la efectividad del plasma convaleciente de los sobrevivientes de h n con un título de ≥ : ofrecido a pacientes de la uci con infección grave por h n ; los pacientes que rechazaron las infusiones de plasma convalecientes fueron controles; veinte de los pacientes recibieron sueros convalecientes, el tratamiento con plasma convaleciente condujo a una reducción significativa de la carga viral respiratoria, los niveles séricos de citocinas (il- , il- , tnfα) y la mortalidad ( ) . posteriormente hung y cols en agosto de , publicaron un estudio multicéntrico prospectivo, doble ciego, aleatorizado y controlado en el que compararon la efectividad de la inmunoglobulina hiperinmune (h-igiv) del plasma convaleciente de los sobrevivientes de h n versus la inmunoglobulina iv (igiv) normal, en pacientes con h n en uci con soporte respiratorio y recibiendo oseltamivir; este estudio mostró, una reducción de la carga viral y una mayor supervivencia en el grupo que recibió h-igiv dentro de los días posteriores al inicio de los síntomas, demostrando la superioridad de la inmunoglobulina hiperinmune sobre la igiv en el tratamiento de la infección grave por h n ( ). el uso de inmunoglobulina hiperinmune ha demostrado una clara efectividad en el tratamiento de la gripe y el sars-cov; sin embargo, el plasma se debe recolectar y procesar de pacientes convalecientes y verificar que tenga títulos adecuados. según la experiencia con el sars-cov, lo ideal es recolectar plasma de pacientes con un curso de enfermedad más leve ( ) . poco se sabe sobre la seguridad de la inmunoglobulina hiperinmune cuando se usa para el tratamiento de infecciones por coronavirus, los riesgos incluyen la exacerbación de la infección dependiente de anticuerpos (antibody-dependent enhancement of infection -ade)( ); el ade puede ocurrir en varias enfermedades virales, e implica una respuesta inflamatoria exagerada ante la presencia de ciertos anticuerpos; sin embargo, los estudios en sars y mers no proveen información suficiente para extrapolarse a la infección por sars-cov- . no se encontraron estudios con inmunoglobulina hiperinmune en el tratamiento de pacientes con covid- . no se puede emitir una recomendación a favor o en contra para el uso de la inmunoglobulina intravenosa como tratamiento adyuvante en pacientes con covid- severo. se debe considerar la inmunoglobulina intravenosa como tratamiento adyuvante en pacientes con covid- severo, en el contexto de estudios clínicos en los siguientes escenarios. escenario a (enfermedad severa), definida como uno o más de los siguientes: disnea, frecuencia respiratoria > /min, spo < %, pao /fio < o empeoramiento radiológico con aumento > % de los infiltrados pulmonares en - horas. escenario b (enfermedad que amenaza la vida), definida como uno o más de los siguientes: falla respiratoria, choque séptico, o disfunción multiorgánica. en las enfermedades virales, los anticuerpos ejercen su efecto por neutralización viral (bloqueo de la entrada de células virales y, por lo tanto, replicación), activación del complemento, opsonización y mediación de citotoxicidad celular dependiente de anticuerpos. la neutralización viral es específica de antígeno; otras actividades antivirales son antígeno-inespecíficas y se realizan en parte a través de interacciones fc: fc receptor. en la infección por sars-cov- , el principal antígeno objetivo asociado con la neutralización es la proteína spike, que es responsable de la unión del sars-cov- a las células epiteliales, incluidos los neumocitos; los anticuerpos en las inmunoterapias pasivas covid- son de naturaleza policlonal, con múltiples epítopos contra los paratopes de sars-cov- , incluido el dominio de unión al receptor en la proteína spike ( ) . la inmunoglobulina intravenosa (igiv) es un producto derivado del plasma de miles de donantes utilizados para el tratamiento de inmunodeficiencias primarias y secundarias, afecciones autoinmunes/inflamatorias, trastornos neuroinmunológicos y secuelas relacionadas con infecciones; la igiv proporciona protección inmune pasiva contra una amplia gama de patógenos; actualmente, la experiencia con el uso de igiv en el tratamiento de la infección por sars-cov- es muy limitada; sin embargo, la justificación del uso de ivig en la infección por sars-cov- es la modulación de la inflamación ( ) . la igiv se ha usado en el tratamiento de otros coronavirus, incluido el sars cov. stockam y cols, en septiembre de , en respuesta a una petición de "the world health organization -who", realizaron una revisión sistemática de los efectos del tratamiento en los pacientes con síndrome respiratorio agudo, incluida la igiv o el plasma convaleciente; se evaluaron cinco estudios sobre el uso de igiv o plasma convaleciente administrado además de corticosteroides y ribavirina, se consideró que estos estudios no fueron concluyentes ya que los efectos de la igiv o el plasma convaleciente no podían distinguirse de otros factores que incluían comorbilidades, estadio de la enfermedad o el efecto de otros tratamientos ( ) . wnag y cols, en mayo , hicieron un estudio prospectivo, en un solo centro, de infección por sars en taiwán, se administró igiv si el paciente tenía leucopenia amci ® o trombocitopenia, o si había progresión rápida de la enfermedad en la radiografía; un total de pacientes recibieron igiv, de los cuales tenían citopenias graves, uno de ellos tenía evidencia de síndrome hemofagocítico y paciente tuvieron progresión radiológica de la enfermedad; el estudio sugiere que la igiv condujo a una mejora significativa en el recuento de leucocitos y plaquetas, pero reconoce que no había un grupo de control para evaluar objetivamente las respuestas ( ) . lew y cols, en julio , reportaron un estudio retrospectivo de un solo centro en singapur, se encontró que los pacientes adultos con sars tratados con un régimen de pulso de metilprednisolona ( mg) e igiv ( . mg/kg) diariamente durante tres días consecutivos tuvieron una hazard ratio ajustada de . para mortalidad en comparación con el grupo no tratado, con una tendencia hacia una recuperación más temprana; sin embargo, este hallazgo no fue estadísticamente significativo (ic del %: . a . ; p = . ); además, este resultado tuvo como factor de confusión el uso concurrente de esteroides ( ) . aunque algunas de las preparaciones de igiv comercializadas actualmente (gamunex-c y flebogamma) contienen anticuerpos que reaccionan de forma cruzada contra el sars-cov- y otros antígenos de virus, in vitro( ), hasta la fecha, ningún ensayo clínico de alta calidad ha demostrado eficacia y seguridad convincentes de igiv en epidemias de coronavirus. a pesar de que los datos para el uso de igiv en la infección por sars y mers son débiles, la dosis alta de ivig puede ser útil en la infección grave por sars-cov- a través de la modulación inmune, saturando fcγr y reduciendo ade ( ) . en general, la inmunoglobulina intravenosa es bien tolerada y el perfil de seguridad es bien conocido. las reacciones adversas comunes son leves y autolimitadas, pero se sabe que en pacientes de alto riesgo se producen efectos adversos graves, como trombosis, disfunción renal y muerte. en cuanto la evidencia (tabla ); xie y cols en abril, en wuhan, china, realizaron un estudio retrospectivo, revisando casos de covid- severa (disnea, fr > /min, spo < % en reposo, pao /fio < , progresión imagenológica > % en - horas) o críticamente enfermos (falla respiratoria con ventilación mecánica, choque, disfunción orgánica múltiple) en el cual evaluaron la mortalidad a días como desenlace primario y como desenlace secundario evaluaron la mortalidad a días, días de estancia hospitalaria, de uci y la necesidad de ventilación mecánica; reportaron que el tratamiento con igiv dentro de las horas posteriores al ingreso no sólo redujo el uso de la ventilación mecánica comparado con el tratamiento luego de horas del ingreso ( . % vs . %, p = . ), sino que también redujo la duración de la estancia en el hospital ( . ± . vs . ± . días, p = . ) y la uci ( . ± . vs . ± . días, p = . ); mejorando en última instancia la mortalidad a los días (p = . ); concluyen, que el estudio demostró que el tratamiento con igiv en pacientes con covid- con neumonía grave puede mejorar los indicadores en poco tiempo y mejorar la eficiencia del tratamiento de los pacientes con alta efectividad ( ) . el tratamiento con dosis altas de igiv ( g/día durante días) al inicio del distrés respiratorio, sumado al tratamiento de soporte y en un caso combinados con antivirales (lopinavir/ritonavir) y metilprednisolona en covid- grave publicado por cao y cols en marzo, en wuhan, china ( ), demostró la elevación de los recuentos de linfocitos, disminución de los marcadores inflamatorios, recuperación de la oxigenación, resolución parcial/completa de las alteraciones radiológicas pulmonares y las pruebas de hisopos nasales y orofaríngeos negativos dentro de unos pocos días después del inicio tratamiento (< días). lanza y cols en mayo , reportaron en nápoles, italia, el caso de una mujer de años que tenía covid- severa y que venía con deterioro clínico a la cual se le venía dando tratamiento con hidroxicloroquina más azitromicina, no se le administraron amci ® esteroides por el riesgo de disminuir la depuración de la viremia, a quién se le administró igiv el día después de iniciados los síntomas con mejoría clínica rápida, normalización de los gases arteriales y disminución marcada de los infiltrados pulmonares al día y respectivamente; como evento adverso, reportaron hipotensión durante el inicio de la infusión que se mejoró al disminuir la velocidad de infusión. la paciente finalmente se recuperó, negativizó rt-pcr sars-cov- y fue dada de alta ( ) . se recomienda la tromboprofilaxis farmacológica en todos los pacientes confirmados o sospechosos de covid- severo, a menos que está contraindicada, en cuyo caso es razonable la implementación de profilaxis no farmacológica. en términos generales se reconoce que los pacientes hospitalizados con enfermedad médica aguda, incluidas infecciones como la neumonía, tienen un mayor riesgo de eventos tromboembólicos ( ) . tang y cols, en china describieron múltiples trastornos de la coagulación en pacientes con covid- , aquellos pacientes que no sobrevivieron tenían significativamente mayores niveles de dímero-d y productos de degradación de la fibrina y con tiempos de coagulación convencionales más alargados al ingreso (p < . ); . % de los no sobrevivientes y . % de los sobrevivientes cumplían criterios para coagulación intravascular diseminada( ); este mismo grupo realizó un estudio con pacientes con covid- severo, pacientes con coagulopatía asociada a covid- (cac), definida por un sic score ≥ la utilización de tromboprofilaxis redujo de manera significativa la mortalidad a días ( . % vs . %, p = . ) así como también en aquellos con un se recomienda no utilizar de rutina antiagregación en pacientes con covid- severo con el fin de prevenir desenlaces neurológicos adversos. no se encuentran estudios en la literatura para el uso de antiagregantes para el manejo específico del covid- ; el manejo de los eventos cardiovasculares en pacientes covid- no difiere de la población general sin la enfermedad. no se establecen diferencias en los estudios descritos, ni en las publicaciones hasta la fecha de la revisión ( ) . no se puede emitir una recomendación a favor o en contra sobre el uso de la anticoagulación terapéutica de rutina con heparinas de bajo peso molecular o heparina no fraccionada en pacientes con bajo riesgo de sangrado y con un curso clínico grave o crítico, que además tengan elevación del dímero d mayor a mcg/ml ( ng/ml) y/o fibrinógeno mayor a mg/dl. diferentes publicaciones describen como una estrategia de tratamiento basada en profilaxis con heparina de bajo peso molecular (hbpm) para tratar la coagulopatía grave por covid- podría no ser suficiente. especialmente porque estos pacientes tienen dentro de su coagulopatía, una predisposición mayor a la presencia de trombosis que al sangrado. además, los bajos niveles de antitrombina que se han descrito en estos pacientes, los hace más resistentes a la heparina, lo que sugiere que las dosis profilácticas ya sea de heparina no fraccionada o hbpm pueden ser inadecuadas( - ). asociaciÓn colombiana de medicina crÍtica y cuidados intensivos. amci ® no se puede emitir una recomendación a favor o en contra sobre la anticoagulación terapéutica de rutina con heparinas de bajo peso molecular en pacientes con covid- en estado crítico, que presenten elevación del dímero d mayor a mcg/ml ( ng/ml). tang y cols, en china con un estudio retrospectivo donde se incluyeron pacientes con covid- severo, se evaluó la presencia de trombosis como desenlace asociado. este estudio describe como niveles de dímero d por encima de ng/ml estaban asociados a una mayor probabilidad de muerte y en estos pacientes el tratamiento anticoagulante reduce de manera significativa la mortalidad ( . , ic % . - . ) ( , ) . no se puede emitir una recomendación a favor o en contra para la medición rutinaria de niveles de anti xa en pacientes con covid- en los que se decide hacer anticoagulación terapéutica con hbpm. se puede considerar la medición de niveles anti xa si se cuenta con la disponibilidad del recurso. harr y cols, en un estudio en donde se incluyeron pacientes con hiperfibrinogenemia relacionada a trauma, se evidenció como los niveles de fibrinógeno se correlacionaron significativamente con la consistencia del coágulo y adicionalmente como se genera una relación inversa entre los niveles de fibrinógeno y la actividad de las hbpm, lo que sugeriría una potencial resistencia a la heparina. basados en que los pacientes covid- presentan niveles de fibrinógeno en muchas ocasiones con niveles > mg/dl e incluso > mg/dl lo que hace razonable considerar que aquellos pacientes covid- que requieren dosis terapéuticas de hbpm y es posible evaluar los niveles de anti xa, hacer ajustes y monitoreo del nivel de anticoagulación sería una opción razonable ( ) . se recomienda el uso de hbpm o hnf para la anticoagulación terapéutica en pacientes con una indicación específica con diagnóstico de covid- . amci ® como previamente se describió, una revisión sistemática comparó las dosis fijas de hbpm subcutánea con dosis ajustadas de hnf intravenosa o subcutánea en personas con clínica sugestiva de tep, esta revisión demostró que la incidencia de tep recurrente fue menor con hbpm que en los participantes con hnf (or . , ic % . a , ), también se asoció con una reducción en el tamaño del trombo (or . , ic % . a . ), evidencia de baja calidad. sin embargo, no hubo diferencias en la mortalidad general entre los participantes tratados con hbpm y los tratados con ufh (or . , ic % . a . ). por otra parte, los protocolos de manejo en escenarios de coagulación intravascular diseminada (cid), proponen el uso de hnf por encima de la hbpm en pacientes en los que se indica la anticoagulación. más aún, la presencia de falla renal aguda es común en los pacientes con covid- , por lo que la opción de tratamiento con hnf tiene también escenarios en donde podrían ser de elección ( , ) . capítulo . procedimientos y covid- recomendaciÓn se recomienda realizar la preoxigenación en pacientes con sospecha o diagnóstico de covid- , cuando estén disponibles, en áreas de presión negativa con mínimo recambios de aire por hora o en instalaciones con ventilación natural o que tengan un recambio de aire de mínimo l/seg si están disponibles. se recomienda como complemento opcional durante la preoxigenación en el paciente crítico con diagnóstico o sospecha de covid- la caja de acrílico para protección durante la intubación, la caja no protege contra la generación de aerosoles fuera de esta y requiere para su uso, entrenamiento previo. si es difícil su uso retírela inmediatamente. se recomienda utilizar en la mascarilla quirúrgica sobre la mascarilla de oxigenación en el paciente crítico con sospecha o diagnóstico de covid- . se recomienda utilizar filtros hpfa entre la máscara y el dispositivo disponible para la preoxigenación en el paciente crítico con sospecha o diagnóstico de covid- . se recomienda en el paciente con sospecha o diagnóstico de covid- preoxigenación por a min, si el paciente luego de minutos no tiene incremento en la mejoría inicie la administración de medicamentos. se recomienda en caso de compromiso hemodinámico considerar ventilación a dos manos con cierre hermético de la máscara sobre la cara del paciente con frecuencias altas (> por minuto y baja presión). amci ® fundamento el manejo de la vía aérea es un procedimiento considerado generador de aerosoles, la enfermedad covid- tiene una alta tasa de transmisión y el personal de salud requiere el uso estricto del epp ( , ) , revise el enunciado para epp recomendado en esta guía. la posibilidad de permanencia del virus en algunos ambientes puede durar hasta horas, por esto una estrategia para proteger al equipo de salud y otros pacientes podrías ser estar en áreas con presión negativa, lo cual no es fácil de encontrar en nuestro contexto o que tenga un adecuado recambio de aire( ). como medidas complementarias se pueden utilizar opciones como las cajas acrílicas para intubación, esta disminuye el riesgo de contaminación por gotas, pero no elimina los aerosoles, es necesario previo entrenamiento. en caso de que la caja sea una limitante retírela inmediatamente ( ) . los pacientes covid- , clásicamente se presentan con tos, esto es un factor de riesgo para quienes manipulan la vía aérea, la utilización de mascarilla por parte del paciente debajo del dispositivo bolsa mascarilla , la cual también deberá tener un filtro de alta eficiencia para disminuir el número de partículas que pueden estar en el ambiente durante la preoxigenación y posible ventilación, ésta última la cual será evitada al máximo ( , , ) . la preoxigenación es una técnica que pretende barrer el nitrógeno y aumentar la disponibilidad de oxígeno para que cuando el paciente presente apnea por los medicamentos para la intubación o por su condición clínica, se disponga de un tiempo mayor sin desaturación crítica y riesgo de colapso cardio-respiratorio. considere que los pacientes con formas moderadas y severas de covid- , pueden tener más comprometida esta reserva respiratoria y puede no ser efectiva la preoxigenación y cuando inicia la apnea, la desaturación será más precoz. si después de minutos de preoxigenación no hay mejoría de la saturación arterial, considere fallida esta maniobra y considere mayor riesgo de hipoxemia severa con probabilidad de bradicardia extrema y paro cardiorrespiratorio. en caso de requerir ventilación por disminución rápida de la saturación de oxígeno arterial y considere necesario ventilación manual bolsa mascarilla a dos manos no debe ser vigorosa y debe utilizar filtros hpfa, estos reducirán los aerosoles en el ambiente( , ). se recomienda la utilización de cajas de acrílico para intubación del paciente con sospecha o diagnóstico de covid- como complemento durante la intubación para disminuir el riesgo de contaminación por gotas, sin embargo, no protege % la generación de aerosoles y si ésta hace más difícil la intubación retírela inmediatamente. amci ® se recomienda minimizar los intentos de intubación orotraqueal en el paciente con sospecha o diagnóstico de covid- , el primer intento debe procurar ser realizado por el más experimentado en el manejo de la vía aérea. se recomienda la intubación con videolaringoscopio en pacientes con covid- teniendo en cuenta disponibilidad y entrenamiento); esta alternativa puede ofrecer ventajas frente a la laringoscopia tradicional. se recomienda administrar medicamentos para asegurar la vía aérea en secuencia de inducción rápida, para obtener en el menor tiempo posible condiciones para la intubación ( a s). se recomienda en caso de intubación fallida por personal experto, considerar dispositivos supraglóticos como las máscaras laríngeas como medida de rescate con el riesgo de generación de aerosoles. se recomienda contar con disponibilidad de vasopresor y atropina en el sitio donde se realizará la intubación. en caso de contar con lidocaína se recomienda utilizar a dosis de mg/kg sin epinefrina. administrada minutos antes de la intubación. como se describió en el aparte de preoxigenación, se deben garantizar todas las medidas basadas en bioseguridad y protección adecuada para el personal de la salud, ubicación en áreas que cuenten con presión negativa o salas con un óptimo recambio de aire pueden ayudar a disminuir el riesgo de contagio. las medidas complementarias como la caja de taiwán o caja de intubación puede complementar de forma opcional estas medidas durante el proceso de aseguramiento definitivo de la vía aérea pero no garantiza % la eliminación de aerosoles, pudiendo ser un obstáculo para quien realiza la intubación, de ser así, se deberá retirar inmediatamente, por eso sólo es un complemento al epp, que es la verdadera protección en estos escenarios (se debe incluir máscaras n o ffp fpp ) ( , ) . el paciente críticamente enfermo puede tener comprometida de forma significativa su reserva respiratoria y hemodinámica por su cuadro clínico y puede empeorar por los medicamentos utilizados durante la intubación orotraqueal. las complicaciones en el manejo de la vía aérea se presentan cuando se realiza más de un intento dentro de los cuales están el traumatismo, desaturación e hipoxemia ( ) . es por esto por lo que se debe procurar que el primer intento sea realizado por el más experimentado en el manejo de la vía aérea e idealmente se logre la intubación en el primer intento con la menor hipoxemia secundaria ( , , ( ) ( ) ( ) . basado en el planteamiento anterior y considerando la ventaja de intubar pacientes críticamente enfermos en el primer intento dadas sus condiciones clínicas, la revisión de amci ® demandas asociadas a manejo de vía aérea en los estados unidos sigue siendo preocupante al considerar posibles causas la falta de entrenamiento y falta de aplicación de las guías y recomendaciones de manejo así como en la utilización de equipos adecuados para pacientes específicos ( ) ; se ha planteado especialmente en los pacientes covid- los cuales tienen un importante compromiso pulmonar y alto riesgo de desaturación, la posibilidad de encontrar una vía aérea difícil no predicha y dificultades en su manejo( , ). es por esto que se requiere del mejor dispositivo para manejo de vía aérea invasiva disponible, siempre y cuando se cuente con el adecuado entrenamiento previo en su uso, la ventaja de los videolaringoscopio se debe a la superioridad al compararla con la laringoscopia convencional, siendo en algunos grupos la primera opción para intubaciones electivas ( , ) . como se ha mencionado, el riesgo de una rápida desaturación en pacientes con enfermedad pulmonar, así como en pacientes con covid- , se debe utilizar la inducción de secuencia rápida la cual se utiliza para pacientes con estómago lleno en los cuales se quiere lograr condiciones de inconciencia y de intubación óptimas en el menor tiempo posible para disminuir el riesgo de broncoaspiración. en estos casos de falla respiratoria con tan mala reserva se quiere aprovechar la ventaja que ofrece esa técnica para tener en poco tiempo al paciente intubado con menor riesgo de desaturación. es así como los medicamentos en una inducción de secuencia rápida incluyen el opioide, hipnótico y relajante, estos dos últimos administrados simultáneamente y lavados con un bolo de cc. la opción del opioide en nuestro contexto suele ser fentanilo a dosis de a mcg / kg iv, dando a minutos de latencia para su efecto, luego el hipnótico que puede ser propofol entre y , mg / kg si la estabilidad hemodinámica lo permite o considera usar vasopresor simultáneo. en caso de preferir evitar la hipotensión la ketamina a dosis de a , mg / kg es una opción más estable hemodinámicamente. con relación al relajante neuromuscular la succinilcolina es la clásicamente utilizada dosis de a , mg/kg pero debido a sus efectos secundarios como hiperpotasemia, fasciculaciones, mialgias y un importante riesgo de hipertermia maligna algunos grupos no lo consideran, el rocuronio a dosis de , mg/kg ha demostrado lograr tiempos y condiciones de intubación similar a la succinilcolina sin los efectos secundarios de esta ( , ) algunos grupos han considerado no utilizarlos si la condición clínica del paciente es crítica pues éste período de latencia puede ser acompañado de una hipoxemia severa y paro cardíaco, por lo tanto sólo usan hipnótico y relajante neuromuscular. ante una vía aérea difícil no predicha en la cual no se logre la intubación, considere los dispositivos supraglóticos como las máscaras laríngeas los cuales son más fáciles de insertar en comparación con la técnica de intubación orotraqueal, y deben estar dentro del planeamiento y organización de elementos para manejo de la vía aérea invasiva. al lograr ventilar con este dispositivo se logrará una recuperación del paciente, pero se pueden generar aerosoles pues este mecanismo de cierre puede permitir escape de aire y macropartículas durante el ciclo respiratorio ya sea manual o mecánico ( , ) . el cuadro clínico de pacientes críticos y particularmente covid- , puede asociarse a inestabilidad hemodinámica y requerimiento de soporte vasopresor. la adición de medicamentos como los opioides o hipnóticos pueden asociarse a hipotensión la cual puede no responder a volumen, es necesario evitar episodios de hipotensión en especial en pacientes ancianos, con enfermedades cardiovasculares de base las cuales pueden tolerar menos estos cuadros de hipotensión, así como también pueden favorecer amci ® desbalance en la relación ventilación/perfusión a nivel pulmonar empeorando los cuadros de hipoxemia. la hipoxemia puede acompañarse de bradicardia y si no se corrige la ventilación o la bradicardia es muy probable que el paciente presente paro cardiorrespiratorio, por lo cual se recomienda utilizar una dosis de atropina para corregir la bradicardia, no mejorará la oxigenación, pero tendrá un tiempo adicional para recuperar la oxigenación y ventilación del paciente. en estos casos debe tener disponibles vasopresores y atropina desde el planeamiento de los medicamentos necesarios para el manejo de la vía aérea ( ) . se recomienda la intubación orotraqueal oportuna y no retrasar el inicio de la ventilación mecánica invasiva en los pacientes con sdra severo por covid- debido a mayor riesgo de desenlaces adversos. fundamento definir el momento de la intubación en esta población es un reto. la mayoría de los autores recomiendan el inicio "temprano" de la ventilación mecánica, sin embargo, la definición de cuando es temprano no es clara. este punto es motivo de análisis dado que a la luz de la evidencia actual la utilización de métodos no invasivos como la ventilación no invasiva y la cánula de alto flujo, para manejo inicial de pacientes con algún grado de hipoxemia es controvertido entre otras por el riesgo que supone al personal sanitario al ser un procedimiento generador de aerosoles. en el un estudio mostró que la intubación retrasada después de la falla al utilizar cánula de alto flujo o la ventilación no invasiva para pacientes con insuficiencia respiratoria moderada y grave se asoció con una mayor mortalidad. publicaciones recientes muestran que solo la quinta parte de los pacientes que murieron por covid- recibieron ventilación mecánica invasiva y soporte respiratorio más agresivo antes de la muerte, lo que indica que en muchos pacientes se habría retrasado la intubación. de los pacientes fallecidos solo el % recibieron tratamiento de oxígeno nasal o con mascarilla facial antes de su muerte. esta baja proporción puede tener varias explicaciones. primero, algunos pacientes con hipoxemia severa no tenían otros síntomas, como dificultad para respirar o disnea, es decir, desarrollaron una especie de hipoxemia silenciosa. en segundo lugar, la falta de suficientes ventiladores mecánicos invasivos es una razón importante que evitaría que los pacientes reciban intubación. tercero, el manejo de estos pacientes por un equipo de médicos no intensivistas; por lo tanto, pueden no estar seguros del momento en que un paciente requiere intubación. la serie de casos de la epidemia de covid- en wuhan mostró que la intubación tardía era común en la etapa inicial de la epidemia, mostrando que una de esas posibles razones del retraso incluía falta de ventiladores mecánicos invasivos y falta de capacitación clínica específica para el soporte respiratorio. recomendaciÓn se recomienda tomar la decisión de intubación orotraqueal en el paciente crítico con sospecha o diagnóstico de covid- utilizando una combinación de variables clínicas, gasométricas y hemodinámicas. tabla la intubación orotraqueal (iot) efectiva y segura, programada debe prevenir el colapso respiratorio y hemodinámico. siempre es necesario asegurar la escena del procedimiento de intubación con las consideraciones técnicas y de protección personal adecuadas. conocer los pasos para la realización del procedimiento de intubación orotraqueal (iot) contextualizados al paciente covid- , reduce los riesgos innecesarios. la iot es un procedimiento generador de aerosoles por lo tanto lo ideal es realizarlo en una habitación con presión negativa, sin embargo, la baja disponibilidad en el país obliga a utilizar otras alternativas de seguridad. una habitación de presión negativa es un cuarto que tiene una presión más baja que las áreas adyacentes, lo que mantiene el flujo de aire fuera de la habitación y hacía habitaciones o áreas contiguas. las puertas de la sala deben mantenerse cerradas, excepto al entrar o salir de la sala, y la entrada y la salida deben minimizarse. la intubación en el paciente crítico con covid- es de los procedimientos que mayor riesgo de aerosolización tiene, por lo tanto, se debe adoptar una posición de intervención oportuna, pero también segura, para evitar desenlaces desfavorables en el paciente y disminuir el riesgo de contaminación en el personal de salud, se recomienda individualizar cada caso mediante la combinación y análisis de los criterios clínicos, gasométricos y hemodinámicos de cada paciente. ( , ( ) ( ) ( ) se recomienda no realizar de rutina broncoscopia en los pacientes con sospecha o diagnóstico de covid- , debido al riesgo de generación de aerosoles. se puede considerar en atelectasias masivas con compromiso significativo de la oxigenación adicional a la lesión pulmonar per sé y la hemorragia alveolar para control local directo. en general la realización de broncoscopia en pacientes con sospecha o confirmación de covid- debe ser evitada y realizarse sólo con indicación de emergencia como cuerpo extraño en la vía aérea, hemoptisis masiva, obstrucción grave de la vía aérea central o atelectasia lobar o pulmonar completa( ). esto debido a la alta carga viral en la mucosa nasal y faríngea de los pacientes con infección por sars-cov- ( ) y la alta producción de aerosoles infecciosos que se generan durante este procedimiento. en caso de ser necesaria su realización, deberá ser llevada a cabo por el operador con mayor experiencia amci ® minimizando el tiempo de exploración y el personal expuesto en la sala. es mandatorio utilizar epp completo que incluya respirador fpp o fpp , bajo protocolo supervisado de donning y doffing ( ) . son de elección los broncoscopios desechables de un solo uso, pero de no ser posible se prefiere el uso de un broncoscopio flexible por encima de uno rígido por la más fácil manipulación de este. idealmente el procedimiento se llevará a cabo en el mismo cubículo del paciente que deberá contar con presión negativa y recambio de aire de a veces por hora. recomendaciÓn se recomienda no realizar de rutina la broncoscopia para la recolección de muestras para el diagnóstico de covid- en el paciente críticamente enfermo. la broncoscopia es una prueba de segunda elección para la toma de muestras respiratorias en los pacientes con sospecha o confirmación de covid- ( ) . la toma de muestras del tracto respiratorio superior por hisopado nasofaríngeo u orofaríngeo es el método primario y de elección para determinar la infección por sars-cov- . solo si resultaran dos pruebas negativas y persistiera una alta sospecha diagnóstica estaría indicado tomar muestras del tracto respiratorio inferior por broncoscopia, ya sea aspirado endotraqueal (bas) o lavado bronco alveolar (bal) ( ), prefiriendo la realización de minibal para la recolección de muestras ( ). las muestras deberán ser recogidas en un recipiente estéril, e introducidas en una bolsa con autocierre. deben manejarse con cuidado extremo evitando manipulaciones innecesarias y bajo protocolos de protección para el personal que las maneja, y trasladarse al laboratorio para su análisis. pueden almacenarse a - ºc las primeras h de su recolección; si se demorara más el análisis, precisa almacenarse a temperatura de - ºc ( ) . en una serie china la sensibilidad del bal fue de % frente a % en muestra de esputo (no recomendada) y % en hisopado nasofaríngeo ( ) por lo que el especialista que realiza el procedimiento deberá sopesar el riesgo de este procedimiento en cada caso, valorando que se beneficiarán aquellos pacientes que tengan una indicación adicional para su realización. se recomienda la realización de la traqueostomía cuando está indicada, en los pacientes covid- sospechosos y confirmados con pronóstico razonable de vida, después del o día de ventilación , previa valoración y consenso por el equipo quirúrgico y de cuidado intensivo, asegurando que las condiciones clínicas, ventilatorias y hemodinámicas se encuentran controlada. en el contexto de pacientes hospitalizados en cuidado intensivo, la traqueostomía se realiza para facilitar el destete de la ventilación mecánica, mejorar la limpieza de la vía aérea y el manejo de las secreciones, aumentar la comodidad de los pacientes y la movilización y disminuir la probabilidad de complicaciones como la estenosis traqueal; sin embargo no hay una clara disminución en la mortalidad ( ) ( ) ( ) . la infección actual por sars-cov , tiene diferentes estadios de gravedad, uno de ellos es el compromiso pulmonar el cual se caracteriza por un síndrome de dificultad respiratorio agudo (sdra). de acuerdo con el comportamiento de la covid- , entre un % a un % de los pacientes requieren ventilación mecánica ( , ) , este grupo de pacientes con manifestación grave del compromiso pulmonar requiere estrategias de protección pulmonar en la ventilación mecánica, sedación profunda y posiblemente parálisis muscular y puede tener una mortalidad entre el % y el % ( , ) . una de las principales características en éste grupo de pacientes es la mortalidad temprana, definida ésta como aquella que se produce en menos de días; de acuerdo a la experiencia en wuhan, china; leung ( ), reporta que la mortalidad se presenta en los primeros cinco días luego de la admisión hospitalaria y de acuerdo a lo referido por graselli et al ( ) , en la región de lombardía, italia, la mediana de mortalidad se presenta al día siete después del ingreso. con estas consideraciones, al principio de la pandemia y en las aproximaciones iniciales no se recomendaba realizar la traqueostomía en los primeros días posteriores a la intubación orotraqueal. sin embargo, con el conocimiento de la fisiopatología y las experiencias en otras series, como medida para facilitar la liberación de la ventilación mecánica, se ha podido realizar el procedimiento después de la primera semana de inicio de la ventilación. de acuerdo con el curso natural de la enfermedad, el paciente en promedio se intuba al día a de iniciado los síntomas, una semana posterior a la intubación para la traqueostomía, estaríamos alrededor del día de la enfermedad, donde los pacientes ya tendrán una disminución de la carga viral. esto sin embargo no evita la utilización de los epp necesarios. esta medida en específico fue discutida y consensuada entre la sociedad de medicina critica amci y la asociación colombiana de cirugía. no existe evidencia que permita evaluar el riesgo real de infección del personal asistencial de los pacientes con sospecha o diagnóstico de covid- en la realización de traqueostomías. se debe considerar en la traqueostomía y la realización de ésta como un procedimiento generador de aerosoles (organización mundial de la salud). se recomienda que los epp requeridos para la realización del procedimiento, deben incluir máscaras ffp o n , protección ocular, vestido antifluido idealmente desechable y amci ® guantes; este nivel de protección representa el mayor nivel de seguridad para realizar el procedimiento en el paciente con sospecha o diagnóstico de covid- . no existe actualmente artículos que permitan evaluar cual es el riesgo real de infección del personal asistencial en la realización de traqueostomías en pacientes con covid- ; quizás el ejemplo más cercano, es una serie de casos, reportada durante la epidemia del síndrome respiratorio agudo grave en el ( ), en el cual se realizaron traqueostomías sin ninguna infección del personal, en este reporte se aseguró un adecuado uso del equipo de protección personal (epp), el cual incluía las medidas de barrera, máscaras ffp y cuando existía la disponibilidad, respiradores con suministro de aire purificado. la traqueostomía y la realización de ésta es considerada por la organización mundial de la salud (oms) un procedimiento generador de aerosoles, bajo esta perspectiva, el epp requerido para la realización del procedimiento, debe incluir máscaras ffp o n , protección ocular, vestido antifluido idealmente desechable y guantes; este nivel de protección representa el mayor nivel de seguridad para realizar el procedimiento mencionado. es obligatorio, que todo el personal reciba el entrenamiento para la postura, el uso y el retiro de los epp, si estos pasos no se realizan de la forma adecuada, representan una fuente de contaminación( ). se recomiendan no esperar la negativización de la pcr para sars-cov para realizar la traqueostomía en el paciente con diagnóstico de covid- . fuerte en contra fundamento los estudios de zou et al y lescure et al ( , ) , muestran que la carga viral de los hisopados nasales y faríngeos es elevada en la primera fase de la enfermedad, con una disminución entre el día nueve al quince, pero esta puede permanecer detectable hasta por tres semanas ( ) . existen recomendaciones acerca de la necesidad de realizar la traqueostomía una vez la pcr para sars-cov sea negativa ( , ) ;aunque este esquema suena lógico, es importante tener presentes las siguientes consideraciones. la sensibilidad de una sola muestra para ruta-pcr puede ser sólo del %( ) y es posible que sea necesario realizar una segunda prueba para minimizar el riesgo para quien realiza el procedimiento, aunque esta aproximación no siempre puede ser viable desde el punto de vista clínico, epidemiológico y administrativo. amci ® recomendamos que la mejor estrategia es diferir la realización de la traqueostomía hasta días luego de la intubación cuando esta indicada, con el conocimiento acerca de la evolución natural de la enfermedad, en ese momento en la mayoría de los pacientes, lo más probable es que la condición ya se encuentre en la tercera semana desde el inicio de los síntomas, en cuyo caso lo más probable es que ya exista una disminución de la carga viral; este hecho no evita que se deba utilizar de la forma correcta los epp. recomendaciÓn se recomienda escoger la técnica teniendo en cuenta la experticia que tenga en el grupo tratante y la anatomía del paciente para la decisión de la técnica. se recomienda la guía ecográfica para disminuir la probabilidad de complicaciones del procedimiento si la anatomía es desfavorable para la realización de traqueostomía percutánea. se recomienda la traqueostomía quirúrgica en pacientes de riesgo elevado de complicaciones donde se requiere un control más rápido y seguro de la vía aérea. se recomienda no utilizar de forma rutinaria la utilización de broncoscopia para la realización de traqueostomía por vía percutánea. no hay evidencia directa hasta la fecha de publicación del consenso si existe superioridad entre las dos técnicas en el paciente con sospecha o diagnóstico covid- . en pacientes críticos no existen diferencia en los desenlaces cuando se evalúa el rendimiento de la técnica percutánea y la técnica quirúrgica, la elección de uno u otro método está dado por la anatomía del paciente, el entrenamiento de los profesionales y la disponibilidad de los diferentes insumos y técnicas. tampoco se ha logrado hasta la fecha evaluar durante la pandemia de covid- si existe una diferencia entre las dos técnicas y por lo tanto no es posible acercarse a una recomendación basada en la literatura. sin embargo, es importante que para la decisión de la técnica a utilizar se considere la anatomía del paciente y los siguientes aspectos:  no se recomienda la utilización de broncoscopia para la realización de traqueostomía por vía percutánea, ésta aumenta la generación de aerosoles y el número de personas expuestas a estos ( , ) . amci ®  si la anatomía es desfavorable para la realización de traqueostomía percutánea, la guía ecográfica puede disminuir la probabilidad de complicaciones del procedimiento ( ) .  la traqueostomía quirúrgica es una alternativa para la realización del procedimiento en las unidades de cuidado intensivo en momentos de sobrecarga laboral y adicionalmente puede tener un mejor y más rápido control de la vía aérea, especialmente en pacientes con riesgo elevado de complicaciones ( ) . recomendaciÓn se recomienda el uso de la terapia ecmo en sdra severo refractario por covid- (pao /fio < , posición prona, requerimiento de relajantes neuromusculares en algunos casos vasodilatadores pulmonares y maniobras de reclutamientos) sin respuesta clínica manifestado por:  pao /fio < mmhg por mas de horas  pao /fio < mmhg por mas de horas  ph < . + paco > mmhg por mas de horas además del criterio anterior, se recomienda tener en cuenta la edad, las comorbilidades y la expectativa de sobrevida del paciente con buena calidad de vida y en circunstancias donde no exista limitación de recursos. no hay estudios clínicos aleatorizados sobre el uso del ecmo en pacientes con covid- ( , ) . existe el estudio eolia ( ) , el cual fue detenido durante su realización, y de acuerdo a un análisis bayesiano posterior puede interpretarse como una disminución de la mortalidad en los pacientes en ecmo con sdra severo ( , , ( ) ( ) ( ) ( ) . de igual manera debe considerarse la racionalización de los recursos y el estado de prevalencia de la pandemia en un lugar determinado. el inicio de la terapia puede evaluarse en función de la cantidad de pacientes en falla respiratoria y la disponibilidad de personal y otros recursos; si el hospital debe comprometer todos los recursos en proveer medidas básicas de cuidado intensivo no debe utilizar el ecmo ( , ) . los pacientes jóvenes sin comorbilidades son considerados de alta prioridad al igual que los trabajadores de la salud ( , ) . amci ® se recomienda no desarrollar nuevos centros de ecmo en época de pandemia, sobre todo en situaciones con limitación de recursos. fuerte en contra fundamento actualmente se recomienda el uso del ecmo con las mismas indicaciones para sdra basado en la capacidad de las instituciones de salud para iniciar éste tipo de terapias ( ) . en épocas de crisis la capacidad de los hospitales está saturada y obliga a la reubicación y optimización de los recursos ( , ) . los centros que ofrecen la terapia en ecmo deben ser centros con resultados favorables y tiempos de soporte de pacientes relativamente cortos ( ) . cuando estamos en tiempos de capacidad hospitalaria convencional y existe disponibilidad de camas de cuidado intensivo se pueden ofrecer los servicios de ecmo vv, va, e-cpr inclusive a pacientes no covid- , cuando estamos en contingencia y capacidad nivel se debe hacer un triage respecto a pacientes jóvenes y ofrecer ecmo vv, va, escoger muy bien los casos para pacientes no covid- y no ofrecer e-cpr, cuando estamos en contingencia y capacidad nivel es porque ya se están usando sitios de expansión y están casi saturados se restringe el ecmo a todas las indicaciones y se prioriza a pacientes con indicaciones no covid- con mayor riesgo de sobrevida, el ecmo vv queda para pacientes jóvenes, con disfunción de órgano y covid- positivo, no se ofrecerá ecmo va o e-cpr y cuando estamos en capacidad de crisis es porque la capacidad total hospitalaria está sobresaturada y no es posible realizar ecmo tanto en pacientes covid- como en los no covid- ( , ) . se recomienda practicar e implementar medidas de capacitación y vigilancia continua para mejorar la higiene de manos, evaluando la adherencia a protocolos establecidos en los trabajadores de la salud mediante listas de chequeo y supervisión para evitar infecciones cruzadas en el entorno del paciente con sospecha o diagnóstico de covid- . se recomienda establecer protocolos específicos para reducir el riesgo de infecciones que se deriven de la interacción y el cuidado del paciente crítico con sospecha o diagnóstico de covid- . amci ® se recomienda implementar prácticas de cuidado para la prevención de contagio de covid- . se debe utilizar el equipo de protección personal (epp) para la prevención de enfermedades de componente infeccioso asociado a exposición con fluidos corporales derivados del paciente crítico con sospecha o diagnóstico de covid- . las infecciones relacionadas con la atención sanitaria (iras) son definidas por la organización mundial de la salud como aquellas "infecciones que se presentan en un paciente durante el proceso de atención en un hospital u otro centro sanitario que no estaban presentes o no se estaban incubando en el momento del ingreso; se incluyen las infecciones contraídas en el hospital pero que se manifiestan tras el alta hospitalaria y también las infecciones profesionales entre el personal del centro sanitario". las iras representan una importante carga de enfermedad que se asocia a un impacto negativo en la economía del paciente y del sistema sanitario. la organización mundial de la salud plantea la higiene de manos como la principal medida necesaria para reducir y prevenir las iras; por esta razón establece directrices sobre la higiene de manos en la atención sanitaria y basada en esta propone la estrategia multimodal para la mejora de higiene de manos. las estrategias mencionadas anteriormente han demostrado el incremento en el cumplimiento de higiene de manos y disminución en las infecciones relacionadas con la atención en salud. la estrategia multimodal se articula a través de cinco componentes: cambio del sistema, formación, evaluación/ retroalimentación, recordatorios en el lugar de trabajo clima institucional. a través de estos componentes, se garantiza que el centro sanitario cuenta con la infraestructura necesaria para practicar adecuadamente el lavado de manos incluyendo dentro de este el acceso a un suministro seguro continuo de agua, jabón, preparado alcohólico y toallas; a su vez se proporciona educación, evaluación y retroalimentación con regularidad a todos los profesionales sanitarios ( se recomienda realizar un plan de cuidados organizado y específico en paciente crítico con sospecha o diagnóstico de covid- , ofreciendo el uso óptimo de recursos e intervenciones. se recomienda evitar el uso de excesivo de papelería relacionada con los registros usados para gestión de insumos y atención de los pacientes. se recomienda realizar intervenciones educativas enfocadas a mejorar la adherencia y adecuado uso de los epp. se debe procurar el cuidado de los elementos de protección personal bajo un protocolo que conserve las condiciones de integridad de estos. la actual reserva de elementos de protección personal (epp) es insuficiente debido al aumento de la demanda global, por el incremento de casos de covid- y por la información errónea que ha conllevado a compras de pánico y almacenamiento. por esta razón la organización mundial de la salud a través de su guía: uso racional del equipo de protección personal para la enfermedad por covid- ha implementado las siguientes estrategias para optimizar la disponibilidad de (epp): usar los (epp) adecuadamente, minimizar la necesidad de (epp) y coordinar el suministro adecuado de (epp). ( ) la duración máxima del uso continuo de la n es de a horas, siguiendo las recomendaciones del manual de medidas básicas para control de infecciones en ips de minsalud. pero en lo cotidiano, ningún trabajador tolera a horas continuas con un respirador. por esto, su uso continuo en el sitio de trabajo dependerá de la necesidad de pausar para comer, para ir al baño, etc. en este caso, se guardará en una bolsa de papel para su nueva colocación, si tiene menos de horas, se desechará si está visiblemente contaminada o se torna húmeda. el reusó de la n dependerá de la casa del fabricante, de si contiene o no celulosa en su estructura del respirador. por ejemplo, la recomendación del consenso colombiano acin sobre la desinfección para los respiradores sin celulosa es con peróxido de hidrógeno vaporizado al % por minutos. los respiradores n de uso industrial tienen mayor contenido de celulosa que los de uso médico por lo tanto para procesos de esterilización, solo los n de uso médico podrán ser esterilizados mediante de peróxido de hidrógeno vaporizado (sterrad®)( - ). amci ® se recomienda elaborar el protocolo de pronación del paciente críticamente enfermo por covid- , garantizando el entrenamiento al personal de salud, organizando el recurso humano, dispositivos de apoyo y tiempo establecido para cambios de posición para prevenir las lesiones por presión en el paciente. fuerte a favor fundamento la estrategia de pronación es una alternativa eficiente en el manejo del síndrome de dificultad respiratoria en pacientes críticos y es fundamental la gestión del profesional de enfermería en la prevención de complicaciones y eventos adversos, lo cual aportará significativamente a la calidad del cuidado ofrecido favoreciendo las mejoras en la oxigenación. es importante optimizar los cuidados de enfermería en torno de los cuidados de piel en los pacientes en ventilación mecánica en decúbito prono, los estudios han demostrado como principal complicación las lesiones de presión con una incidencia hasta de . %, siendo las más frecuentes las grado y ( ). una lesión se puede producir si se supera una presión en el tejido capilar arterial de mmhg denominándose interfaz de presión. basándose en lo anteriormente mencionado, el cambio de posición es un componente integral de la prevención y el tratamiento de las upp, con una justificación sólida y de amplia recomendación en la práctica de enfermería ( ) . el uso de superficies especiales para el manejo de la presión (semp) a partir del estudio de defloor ( ), se determinó un antes y un después en el uso de las semp en conjunción de los cambios posturales. este realizo un importante aporte para reducir la incidencia de lesiones por presión comparado con los colchones de estándar. se recomienda promover actividades para controlar el nivel de estrés en el personal durante las jornadas de trabajo: identificar y reconocer los propios límites, buscar o proponer ayuda psicológica profesional cuando sea requerido, promover estilos de vida saludables, y organizar los turnos de trabajo asegurando periodos de descanso. se recomienda compartir las emociones con pares y superiores, analizar objetivamente las situaciones adversas, manejar fuentes de información objetivas y científicas, realizar pausas activas durante el turno y brindar espacios grupales para expresar emociones, miedos e incentivar al equipo de trabajo reconociendo su labor. amci ® se recomienda utilizar recursos de salud mental ocupacional, apoyo por enfermedad y licencia familiar, además de garantizar una adecuada dotación de personal. los estilos de superación personal y el crecimiento psicológico desempeñan un papel importante en el mantenimiento de la salud mental de las enfermeras. es razonable suponer que los niveles de ansiedad y estrés entre los profesionales de la salud son proporcionalmente más altos que los de la población general debido al contacto directo con pacientes infectados. esto puede explicar por qué las enfermeras de primera línea son excepcionalmente vulnerables a la fatiga y al agotamiento (wang, okoli, et al. ) , agotamiento mental, falta de moral del personal, control / autonomía de decisión, menor calidad de vida y baja satisfacción laboral (cheung y yip, ). ( ) . una investigación reciente realizada en china continental menciona el impacto negativo de la pandemia de covid- en los trabajadores de atención médica de primera línea, incluidos los mayores niveles de ansiedad (shanafelt, ripp y trockel, ), depresión (xiang et al. ), estrés postraumático síntomas, soledad e impotencia (xiang et al. ) ( , ) . los aspectos traumáticos y estresantes de la participación en una pandemia también ponen en riesgo el daño psicológico a los médicos ( ) . la experiencia psicológica de las enfermeras que atienden a pacientes con covid- se puede resumir en temas: primero, las emociones negativas presentes en la etapa inicial consisten en fatiga, incomodidad e impotencia que fue causado por el trabajo de alta intensidad, el miedo y la ansiedad, y la preocupación por los pacientes y sus familiares. segundo, los estilos de auto afrontamiento incluyeron ajustes psicológicos y de vida, actos altruistas, apoyo de equipo y coordinación racional. tercero, encontramos crecimiento bajo presión, que incluía un mayor afecto y agradecimiento, desarrollo de posición de responsabilidad profesional y autorreflexión. finalmente, encontraron que las emociones positivas ocurrieron simultáneamente con emociones negativas( ). se recomienda ofrecer mecanismos de apoyo para amortiguar el estrés relacionado con la pandemia por covid- . esto incluye intervenciones para pacientes y familias ofreciendo recursos de salud mental y educación al egreso, previo a este reforzar visitas virtuales. se recomienda anticipar las necesidades de salud mental de los pacientes, el personal y las familias para ofrecer una respuesta integral de salud pública. se debe incluir atención psicológica en la hospitalización para pacientes, familiares y personal afectado por covid- . se recomienda proporcionar atención de salud mental en las comunidades, mientras que se requiere distanciamiento social y los recursos del sistema de salud son limitados. amci ® se recomienda mantener una estrategia de comunicación asertiva con la familia, teniendo en cuenta la formación del personal sobre las estrategias para comunicar malas noticias. ser solidarios con el duelo de las familias y acompañar el proceso de afrontamiento aún en la distancia, identificando factores de riesgo para patología mental o duelo complicado, utilizando los recursos institucionales de salud mental para mejorar las intervenciones. la pandemia tiene el potencial de crear una crisis secundaria de angustia psicológica y desbordamiento del sistema de salud mental. los miembros de la familia pueden experimentar angustia, miedo o ansiedad por la hospitalización de un ser querido, particularmente cuando las medidas de control de infecciones restringen las visitas. la telesalud (incluida la cobertura de seguro para la telesalud), el suministro extendido de medicamentos, el aumento de la capacitación en salud mental del proveedor, el apoyo virtual de pares y los grupos virtuales de apoyo al uso de sustancias pueden ayudar a garantizar que se satisfagan las necesidades de salud mental de la comunidad ( ). el sistema de salud y los líderes de enfermería deben asegurarse de que su personal de enfermería clínica esté protegido y respaldado para que puedan proporcionar esta dimensión crucial de la atención de covid- . se recomienda crear grupos centralizados y definidos para atención de pacientes con sospecha o diagnóstico de covid- que se encarguen de elaboración, socialización e implementación de protocolos. estos deben incluir los aspectos de infraestructura, áreas delimitadas, utilización de epp, listas de chequeo, observadores, insumos y recursos que permitan atención integral. se recomienda organizar el plan de atención del paciente con sospecha o diagnóstico de covid- de enfermería con la asignación de actividades, número de personas según escalas que midan escalas de carga laboral para definir el número adecuado de los miembros del equipo de trabajo, tiempo de atención, gestión de recursos, gestión de riesgo y un líder por turno que garantice el cumplimiento fuerte a favor fundamento la implementación de estrategias de gestión en contingencias genera un trabajo organizado, enfocado en la prevención y tratamiento centralizado, elaboración y socialización de protocolos claros, áreas específicas, delimitadas y asignadas, con un uso racional del recurso humano que se despliega en fases, desde el inicio de la emergencia considerado como detección temprana hasta la atención directa de pacientes con sospecha amci ® o confirmación de sars-cov- . dentro de las fases tempranas, se busca la gestión de los recursos necesarios para la atención de estos pacientes, con una asignación de zonas o servicios y unas condiciones particulares, tratamientos específicos y actividades de atención especiales para las cuales se discriminan medicamentos, dispositivos e insumos necesarios para el cuidado de enfermería. los grupos de atención deben contar con capacitación, gestión y supervisión, apoyo logístico, apoyo psicológico y retroalimentación ( , ) . el plan de atención de enfermería debe tener presente la minimización de exposición, la prevención de infecciones en el personal y cuidados especiales derivados de la condición clínica de los pacientes con esta infección, altamente contagiosa y con síntomas o necesidades que rompe el modo operacional convencional y que requiere implementación basada en la práctica clínica. por lo tanto, el plan debe ser centralizado oportuno, ordenado, seguro y eficiente e incluye: relación enfermería/paciente de acuerdo a criticidad, capacitaciones y entrenamiento al personal de enfermería de línea de frente en el área crítica de aislamiento mediante videos, infografías y procesos prácticos (el contenido de capacitación incluye el uso de elementos de protección personal, higiene de manos, desinfección de áreas, manejo de residuos y esterilización de dispositivos de atención al paciente y manejo de exposición ocupacional), asignación de actividades clínicas (atención directa) y administrativas (supervisión, observador, líderes, gestión de recurso humano y medicamentos), soporte y contratación de personal adicional ante la contingencia con preparación académica o inducción, asignación de turnos razonables con períodos de descanso (alimentación, eliminación), coordinación con otros departamentos y optimización de flujos de trabajo, estrategias de control de infecciones y trabajo en equipo ( , ) . se recomienda que las muestras clínicas tomadas para el diagnóstico de covid- deben conservarse a temperatura entre - a °c, y luego de las horas deben permanecer congeladas a una temperatura de - °c. se recomienda que se realice el envío al laboratorio de salud pública de referencia dentro de las horas posteriores a la toma de la muestra del paciente. se recomienda que el transporte de las muestras debe realizarse con geles o pilas congeladas. se recomienda considerar que las muestras del tracto respiratorio bajo presentan la mejor certeza diagnóstica en pacientes con neumonía para adultos intubados y ventilados mecánicamente con sospecha de covid- . se recomienda contar con elementos de protección personal de acuerdo con las precauciones establecidas para el paciente con sospecha o diagnóstico por covid- para evitar la transmisión a profesionales de la salud. se debe evitar perder el circuito cerrado en los pacientes ventilados mecánicamente y valorar el riesgo de las acciones en pacientes con peep alta. se recomienda realizar la toma de muestra post mortem no invasiva por hisopado nasofaríngeo dentro de las primeras seis ( ) horas posteriores al fallecimiento, para que esta sea útil para su análisis. las muestras clínicas tomadas para el diagnóstico de coronavirus deben conservarse a temperatura entre - a °c, y luego de las horas deben permanecer congeladas a una temperatura de - °c. sin embargo, la muestra puede conservarse en un tiempo máximo de refrigeración por horas. no obstante, se sugiere que se realice el envío al laboratorio de salud pública de referencia dentro de las horas posteriores a la toma. si no se conserva la cadena de frío adecuada, la muestra puede ser inviable. el transporte de las muestras debe realizarse con geles o pilas congeladas ( , , ) .se debe tener en cuenta que no conservar la cadena de frío durante el transporte de la muestra, degradan la partícula viral, obteniéndose falsos negativos ( ) . las muestras del tracto respiratorio bajo presentan la mejor certeza diagnóstica en pacientes con neumonía. para adultos intubados y ventilados mecánicamente con sospecha de covid- en comparación al tracto respiratorio superior (nasofaríngeo u orofaríngeo). en el caso de aspirado traqueal, es importante considerar que para la obtención de las muestras para el diagnóstico de covid- se deben contar con elementos de protección personal de acuerdo a las precauciones estándar para evitar la transmisión a profesionales de la salud, circuito cerrado y valorar su realización en aquellos pacientes con peep alta ( ) . la toma de muestra post mortem no invasiva por hisopado nasofaríngeo se debe hacer antes de seis ( ) horas post mortem, para que esta sea útil para su análisis( , - ). se recomienda en los pacientes con diagnóstico covid- , monitorizar continuamente la oxigenación mediante saturación arterial de oxígeno con pulso oxímetro y la aparición temprana de signos clínicos de dificultad respiratoria durante la monitorización (aleteo nasal, cianosis, tirajes intercostales). se recomienda no suministrar de forma rutinaria suministrar oxígeno si la saturación de oxígeno (spo ) está por encima de %, y no se evidencian signos clínicos de dificultad respiratoria durante la monitorización continua del patrón respiratorio. se recomienda como parámetro importante para evaluar la oxigenación y guiar el suministro de oxígeno mediante los diferentes dispositivos la transferencia de oxígeno, medida por la pao / fio o sao /fio . se propone iniciar la oxigenoterapia por cánulas de bajo flujo y ajustar el flujo (máximo l) hasta alcanzar la spo objetivo ≥ %; si el paciente se encuentra en estado crítico iniciar con mascarilla con bolsa de reserva (a - l / min). una vez que el paciente esté estable, el objetivo de oxigenación es mantener niveles de spo entre y % en pacientes no embarazadas y entre - % en pacientes embarazadas. se recomienda no utilizar de forma rutinaria el uso de dispositivos que generan aerosoles durante la administración de oxígeno (dispositivos venturi o nebulizador de alto flujo o jet) en pacientes con sospecha o diagnóstico covid- . en las diferentes guías publicadas para manejo de pacientes positivos para covid- las metas de oxigenación durante la terapia de oxígeno en adultos recomiendan iniciar la oxigenoterapia a l / min y ajustar el flujo hasta alcanzar la spo objetivo ≥ % durante la reanimación; o use mascarilla con bolsa de reserva (a - l / min) si el paciente está en estado crítico. una vez que el paciente esté estable, el objetivo de oxigenación es > % de spo en pacientes, no embarazadas y ≥ - % en pacientes embarazadas( ). los dispositivos para la oxigenoterapia se pueden dividir en dos grupos, dependiendo de si cubren la totalidad o una parte de los requerimientos respiratorios del paciente. unos son de bajo flujo o para esfuerzos mínimos del paciente, estos dispositivos completan su ventilación con aire ambiente y los sistemas de alto flujo cubren la totalidad de los requerimientos inspiratorios del paciente. escalones terapéuticos: oxigenoterapia convencional a diferentes concentraciones de bajo flujo (son las cánulas nasales, las mascarillas simples y las mascarillas con reservorio), es el primer escalón terapéutico ante cualquier paciente que presente una situación de hipoxemia (spo ) < % respirando aire ambiente. el objetivo debe ser ajustar la fio (hasta . ) para mantener un nivel de oxigenación adecuado, considerado este como una spo > %. la administración de oxígeno se considera un procedimiento generador de aerosoles de riesgo bajo y por lo tanto es adecuado para pacientes covid- positivos( ). b. en adultos con signos de emergencia (respiración obstruida o ausente, dificultad respiratoria severa, cianosis central, shock, coma y / o convulsiones) deben recibir vía aérea amci ® de emergencia manejo y oxigenoterapia durante la reanimación para apuntar a spo ≥ %. una vez el paciente está estable, objetivo> % de spo en adultos no embarazadas y ≥ - % en mujeres embarazadas. c. para el manejo del paciente con covid- la máscara de no re inhalación se considera como la opción de preferencia para escalar el paciente antes de la intubación y considerar la transferencia a uci; esto se debe a que puede proporcionar altas fracciones inspiradas de oxígeno ( ) . d. los dispositivos que generan aerosoles durante la administración de oxígeno (dispositivos venturi o nebulizador de alto flujo o jet), no están indicados para manejo de covid- ( ). se recomienda aplicar las estrategias de retiro de la ventilación mecánica habituales para pacientes adultos críticos en general, hasta el momento no se ha construido una evidencia contundente para el destete en covid- . se recomienda en el paciente críticamente enfermo por covid- un descenso de la presión de soporte (psv) según tolerancia clínica, de esta forma el paciente podrá ser sometido a la realización de prueba de respiración espontánea con una presión de soporte de entre - cm h o. se recomienda que el destete automatizado puede ser considerado como una herramienta útil según disponibilidad de equipos para realizarlo. se recomienda no utilizar las maniobras que incrementan la aerosolización como la prueba de respiración espontánea en pieza en t o el cuff-leak test en el momento de realizar la medición de los predictores de éxito en el destete. fuerte en contra fundamento la realización de las pruebas de respiración espontánea sigue siendo un factor predictor importante en el éxito en el retiro del soporte ventilatorio mecánico y la indicación de tiempo de duración sigue siendo de a minutos debido a que las intubaciones realizadas en el mismo periodo de tiempo no han tenido diferencias significativas en el éxito del destete ( , ) . en los pacientes que han sido ventilados por más de horas y que el motivo por el cual fueron llevados a ventilación mecánica ya ha sido superado se debe establecer un protocolo de destete que debe incluir una prueba diaria de respiración espontánea y la minimización o retiro de la sedación (si no existe alguna contraindicación)( , ). la movilización temprana como factor coadyuvante en el éxito de la liberación mecánica ya se ha documentado en otros escenarios similares, razón por la cual la implementación amci ® temprana de este tipo de estrategias será un punto de vital importancia para recuperar la funcionalidad de los pacientes con covid- ( ) . se recomienda que la extubación de los pacientes críticamente enfermos por covid- se debe realizar con los elementos de protección personal requeridos para el riesgo de aerosoles. se recomienda no estimular la tos y el esputo inducido en los pacientes con sospecha o diagnóstico de covid- posterior a la extubación inmediata. se recomienda no utilizar de forma rutinaria la vmni en la falla respiratoria post extubación en pacientes críticos que no tengan una enfermedad concomitante que sea respondedora a la vmni como el epoc o edema pulmonar de origen cardiogénico en pacientes con sospecha o diagnóstico de covid- . fuerte en contra se recomienda mantener un umbral bajo para decidir intubación en caso de sospecha de fallo en la extubación en el paciente con sospecha o diagnóstico de covid- . la estricta monitoria y manejo del paciente posterior a la extubación surgen como un reto insoslayable para el personal de cuidado intensivo, enfocando todos sus esfuerzos en evitar la re-intubación, lo que se traducirá en un descenso significativo de la morbilidad y la mortalidad que supone una re-intubación ( ), la cual se puede definir como el no requerimiento de re intubación en las primeras horas post extubación ( , ) . en los últimos años la cánula nasal de alto flujo (caf) se ha convertido en una herramienta útil en el soporte de oxigenoterapia en los pacientes extubados que presenten riesgo de reintubación ( , ), y a la vez no presenten hipercapnia ( ) . la utilización de ventilación mecánica no invasiva de manera profiláctica en la falla respiratoria post extubación no ha demostrado tener éxito evitando la re-intubación en las primeras horas ( , ) excepto en las situaciones donde el paciente presente una enfermedad pulmonar o alteración cardiaca concomitante que sea respondedora a el manejo con vmni como lo son la enfermedad pulmonar obstructiva crónica (epoc) y el edema pulmonar de origen cardiogénico ( , ) . los pacientes extubados en los que se halla documentado epoc, se sugiere posterior a la extubación la implementación de una estrategia de niv de manera protocolaria ( , ), con una intensidad de hora cada horas durante un período mínimo de horas ( ). se recomienda utilizar en los pacientes con extubación reciente que no expresen predictores de riesgo de fracaso, sistemas de oxigenoterapia convencionales de bajo flujo que generen menos riesgo de aerosolización, fuerte a favor se podría considerar cánulas de alto flujo de oxígeno y/o la ventilación mecánica no invasiva (con una máscara facial adecuadamente ajustada y ramas inspiratorias y espiratorias separadas) como terapia de puente después de la extubación, pero se deben brindar las condiciones estructurales necesarias (habitaciones de presión negativa o habitaciones aisladas de puertas cerradas) y con epp estrictos para el personal sanitario. fuerte a favor fundamento las pautas de anzics establecen que la caf y/o la ventilación no invasiva (con una máscara facial bien ajustada y ramas inspiratorias y espiratorias separadas) pueden considerarse como terapia de puente después de la extubación, pero deben proporcionarse epp estricto en el aire. la terapia cpap o bipap (con alta presión espiratoria final) podría ser útil para prevenir la eliminación del reclutamiento en estos pacientes. en el momento de la extubación, los pacientes a menudo han estado enfermos durante más de una semana. es probable que su carga viral disminuya en ese punto, por lo que el riesgo de transmisión del virus puede ser menor (en comparación con la intubación inicial) ( ) . de no contar con predictores de que nos indiquen que podría fracasar la extubación se deben utilizar entonces sistemas de oxigenoterapia convencionales de bajo flujo que generen menos riesgo de aerosolización( ). se recomienda limpiar y desinfectar con frecuencia el área de retiro de epp, incluso después de que se haya completado cada procedimiento de eliminación. se debe limpiar esta zona, pasando de las áreas más limpias a las más sucias, antes de ingresar a la habitación del paciente y realizar el manejo y disposición final de residuos. se recomienda realizar la limpieza de superficies con un desinfectante adecuado o con una solución de hipoclorito sódico que contenga ppm de cloro activo (por ejemplo, un producto con hipoclorito en una concentración de - gr/litro, se hará una dilución : en el momento de su utilización). amci ® se recomienda que los recipientes que contengan los residuos deberán quedar en el lugar designado a tal efecto, que permanecerá cerrado hasta que, según el procedimiento de gestión de residuos de la institución sean retirados. los circuitos, filtros, succión cerrada y tot deben ser dispuestos en bolsas de color rojo las cuales deben ser de polietileno de alta densidad de . milésimas de pulgada y deben contar con un rótulo donde se indiquen: el nombre del generador, las palabras residuos biolÓgicos (covid- ) . una vez dispuesto, apretar y asegurar con nudo la bolsa de residuos y remover la bolsa de residuos del recipiente de residuos. posteriormente, desinfectar el exterior de la bolsa con solución desinfectante. luego colocar la bolsa de residuos en otra bolsa adicional de residuos y apretar y asegurar con nudo la bolsa de residuo. finalmente desinfectar la exterior bolsa de residuos con solución desinfectante. una vez terminada la disposición de los residuos de extubación, desinfectar los guantes con que manipuló los residuos con solución desinfectante y ubicar la bolsa de residuos dentro del vehículo de recolección interna de residuos. finalmente desinfectar el exterior de la bolsa de residuos con solución desinfectante. una vez terminada la disposición de los residuos de extubación, desinfectar los guantes con que manipuló los residuos con solución desinfectante y ubicar la bolsa dentro del vehículo de recolección interna. acogerse a la ruta sanitaria que asegure el menor riesgo de contaminación en el traslado interno de los residuos en la habitación del paciente (zona limpia) y zona sucia, se debe garantizar la ubicación de recipiente plástico de color rojo, liviano, resistente a los golpes, en material rígido impermeable, de fácil limpieza, y resistentes a la corrosión. los recipientes deberán ser lavados y desinfectados de acuerdo con los procedimientos establecidos por el prestador de servicios de salud( - ). se recomienda utilizar un ajuste de peep del paciente crítico por covid- , basado adicional a la tabla de peep, en las condiciones clínicas del paciente, en los índices de oxigenación, en la mecánica respiratoria del paciente y en los métodos de monitoreo disponibles. se recomienda titular la peep más alta que mantenga o mejore la relación safi y permita una presión plateau ≤ cmh o. se recomienda utilizar otras estrategias de titulación de peep probadas y con las cuales el equipo de trabajo esté familiarizado, dependiendo de la disponibilidad del recurso: ensayo peep decremental precedido por una maniobra de reclutamiento; titulación mediante la amci ® estimación de la presión transpulmonar con catéter esofágico o tomografía de impedancia eléctrica. fuerte a favor fundamento la titulación de la peep debe hacerse en función de la distensibilidad, oxigenación, espacio muerto y estado hemodinámico. puede titularse la peep mediante la estimación de la presión transpulmonar con catéter esofágico o tomografía de impedancia eléctrica. podría también titularse a partir de la fórmula (dp=plateau-peep) teniendo en cuenta que sea lógico el acoplamiento matemático fisiológico (lo que resultaría en una peep de cmh o si la presión plateau es de cmh o). la titulación de la peep requiere consideración de los beneficios (reducción de atelectrauma y mejora del reclutamiento alveolar) frente a los riesgos (sobre distensión inspiratoria final que conduce a lesión pulmonar y mayor resistencia vascular pulmonar)( , , ). se recomienda aplicar los protocolos de rehabilitación física como estrategia beneficiosa en el tratamiento respiratorio y físico de pacientes críticamente enfermos por covid- . se recomienda realizar la movilización precoz del paciente críticamente enfermo por covid- durante el curso de la enfermedad siempre que sea posible hacerlo de forma segura, asegurando la protección personal del personal sanitario. derivado del tratamiento médico intensivo para algunos pacientes con covid- , incluida la ventilación pulmonar protectora prolongada, la sedación y el uso de agentes bloqueantes neuromusculares, los pacientes con covid- que ingresan en la uci pueden presentar un elevado riesgo de desarrollar debilidad adquirida en la uci empeorando su morbilidad y mortalidad. por lo tanto, es esencial la rehabilitación temprana después de la fase aguda del síndrome de distrés respiratorio agudo (sdra) para limitar la gravedad de la debilidad adquirida en uci y promover la recuperación funcional. según la guía de la oms y la ops, enfatizan extremar el uso de los elementos de protección personal (epp) durante las intervenciones de rehabilitación física. la rehabilitación física proporciona intervenciones a través de movilizaciones, ejercicio terapéutico y programas individualizados a las personas que superan la enfermedad crítica asociada con covid- durante la ventilación mecánica y luego de esta, con el fin de permitir un retorno al hogar con funcionalidad. la prescripción de la movilización y ejercicio terapéutico debe de ser considera cuidadosamente en función del estado del paciente teniendo en cuenta, la estabilidad hemodinámica y clínica de la función respiratoria. cuando las movilizaciones, ejercicio terapéutico o programas de rehabilitación están indicados, debe realizarse una correcta planeación teniendo en cuenta amci ® la identificación/uso del personal mínimo necesario para realizar la actividad de manera segura. y el aseguramiento de todo el material que requerido esté a la mano y funcione correctamente y esté perfectamente limpio y desinfectado. si el material/equipo tiene que ser compartido con otros pacientes, límpielo y desinféctelo después de cada uso, entre paciente y paciente. se requiere personal entrenado específicamente para la limpieza y desinfección de los equipos, en una habitación aislada. y siempre que sea posible, evitar el traslado del material entre las áreas infectadas y no infectadas del hospital, manteniendo el equipamiento en las zonas aisladas ( ) ( ) ( ) ( ) ( ) . ( basados en un estudio preliminar aún sin publicar, se podría sugerir el uso de dexametasona a dosis de mg (oral o venosos) por días o hasta el alta si ocurre primero en pacientes hospitalizados con sospecha o diagnóstico de covid- que requieren suplencia de oxígeno, incluyendo aquellos con ventilación mecánica, que sean menores de años y con más de días de síntomas. amci ® actualmente no existe una terapia dirigida que se a efectiva para el manejo del virus; un número alto de estudios han surgido en los últimos dos meses, la mayoría sin el rigor metodológico suficiente para tomar decisiones adecuadas con respecto al manejo del paciente con infección por sars-cov- . el conocimiento en la estructura del virus y el mejor entendimiento en la fisiopatología de la enfermedad genera un sinnúmero de potenciales fármacos que han sido ensayados para el manejo de la enfermedad. en tiempos de pandemia, con una patología catastrófica en términos de vidas humanas y costos hospitalarios; es importante encontrar soluciones a desenlaces importantes como mortalidad, días de estancia en uci y en el hospital, aumento en los días libres del ventilador, disminución de complicaciones mayores debido a la enfermedad entre otros. hasta el momento no se ha documentado ninguna terapia específica que pueda impactar sobre estos desenlaces; pero la calidad de los trabajos, tampoco dejan claro sin él no usar ningún tratamiento específico mejora los desenlaces al menos al disminuir el número de complicaciones. este nuevo beta-coronavirus es similar al coronavirus del síndrome respiratorio agudo severa (sars-cov) y del síndrome respiratorio del medio este (mers-cov); por lo tanto, varias moléculas que habían sido evaluadas en este tipo de enfermedad rápidamente se abrieron paso a ensayos clínicos en paciente con covid- . estos ensayos principalmente observacionales, aleatorios pero abiertos con un número pequeño de pacientes no han permitido sacar adecuadas conclusiones y es frecuente como ver las diferentes guías de las principales sociedades del mundo cambiar de forma frecuente sus recomendaciones; no existes evidencia de estudios clínicos aleatorios y controlados que midan desenlaces fuertes, la premura de un tratamiento efectivo ha sacrificado el rigor metodológico que una investigación requiere. una estructura viral y replicación conocidas generan posibles dianas para que diferentes fármacos puedan ser investigados, antivirales tipo arbidol el cual inhibe la fusión de la membrana en la envoltura viral a algunos receptores; antimaláricos como la hidroxicloroquina y la cloroquina, las cuales inhiben la entrada viral y endocitosis por múltiples mecanismos, así como los efectos inmunomoduladores demostrados en el huésped; antivirales que impiden la replicación como el lopinavir o darunavir inhibiendo las proteasas o la ribavirina, el remdesivir o el favipiravir que actúan como análogos de nucleótidos o fármacos que actúan modulando la respuesta específica del huésped como el tocilizumab el cual se une al receptor de la il- inhibiendo el punto de acción de esta; los corticosteroides con múltiples efectos en la modulación del sistema inmunológico del paciente o los fármacos para evitar la respuesta secundaria a esta cascada inflamatoria como son los anticoagulantes. por último, se han buscado estrategias con el fin de mejorar la inmunización pasiva del huésped en el uso del plasma de pacientes convalecientes o el uso de inmunoglobulinas enriquecidas entre otros tratamientos propuestos para esta enfermedad. amci ® a los diferentes medicamentos que han sido usados en la pandemia del sars-cov- /covid- . de manera reciente en datos preliminares aún sin publicar horby y col en una rama del ensayo de evaluación aleatorizada de la terapia covid- (recovery), estudio aleatorizado, controlado, abierto que compara una gama de posibles tratamientos con la atención habitual en pacientes hospitalizados con covid- , compararon el uso de la dexametasona a dosis de mg día (oral o intravenosa) una vez al día por días o el alta según lo que ocurriera primero contra el manejo habitual; en pacientes aleatorizados que recibieron dexametasona se compararon con pacientes en manejo estándar; ( . %) pacientes en el grupo de dexametasona y ( . %) pacientes en el grupo control murieron a los días, con un riesgo relativo ajustado para la edad (rr . ; % ic . a . ; p < . ). la mortalidad relativa y absoluta variaron significativamente en relación al soporte ventilatorio al momento de la aleatorización; la dexametasona redujo las muertes en una tercera parte de los pacientes que recibieron ventilación mecánica invasiva ( . % vs. . %, rr . , % ic . a . ; p < . ), y una quinta parte en los pacientes que reciben oxígeno sin ventilación mecánica invasiva ( . % vs. . %, rr . , % ic . a . ; p = . ), pero sin reducir la mortalidad en paciente que no recibieron soporte respiratorio al momento de la aleatorización ( . % vs. . %, rr . , % ic . a . ]; p = . ) ( ) . no se emite recomendación a favor ni en contra para el inhibidor de la janus quinasa (baricitinib) en los pacientes con sospecha clínica o diagnóstico de covid- severo. uno de los reguladores conocidos de la endocitosis es la proteína quinasa asociada a ap (aak ); la interrupción de aak podría, a su vez, interrumpir el paso del virus a las células y también el ensamblaje intracelular de partículas del virus. uno de los seis fármacos de unión a aak de alta afinidad es el inhibidor de la janus quinasa (jak y jak ), llamado baricitinib, que también se une a la quinasa asociada a la ciclina g, otro regulador de la endocitosis ( ) . el baricitinib alcanza concentraciones plasmáticas suficientes para inhibir aak con mg o mg una vez al día; por su baja unión a proteínas plasmáticas y a su mínima interacción con las enzimas cyp, permite combinarlo con los antivirales. sin embargo, algunos piensan que el bloqueo de la señal jak-stat por baricitinib puede producir un deterioro de la respuesta antiviral mediada por interferón, con un posible efecto facilitador sobre la evolución de la infección por sars-cov- ; otras limitantes son la linfopenia (no dar si < cel./ mm ) y el aumento de la cpk. ( , ) . cantini y cols, en abril , en italia, administraron baricitinib a mg/día vía oral por semanas a pacientes con covid- moderado y los compararon con un grupo control; la terapia mejoró significativamente los parámetros clínicos, respiratorios y de laboratorio (pcr); ninguno de los pacientes requirió uci vs % del grupo control, sin eventos adversos. se amci ® trata de un estudio piloto de seguridad e impacto clínico en pacientes que no estaban en uci ( ) . ¿en pacientes hospitalizados con sospecha o diagnóstico de covid- el uso de n-acetil cisteína modifica el curso clínico de la enfermedad o genera beneficios en desenlaces clínicos de interés? basados en evidencia indirecta para el manejo del sdra y resultados observaciones en covid- , se podría utilizar el uso de n-acetil cisteina a dosis de mg/kg/día durante los primeros cinco días del sdra, aunque no se ha demostrado impacto en la mortalidad, su utilización parece relacionarse con una disminución significativa en la estancia en la unidad de cuidados intensivos y con disminución de los marcadores inflamatorios en pacientes con covid- . la severidad de la infección en covid- , en gran parte depende de la respuesta inmunológica de cada persona, sin embargo, se encuentran mecanismos fisiopatológicos de relevancia. sobreproducción de moco en vía aérea superior e inferior, que en parte explica la dificultad en la mecánica ventilatoria y los retos de ventilación en estos pacientes, la descarga desmedida de citoquinas proinflamatorias que se asocian a la falla multiorgánica y la coagulopatía asociada a la disfunción endotelial. esto mecanismos fisiopatológicos son comunes en el sdra, incluido los casos asociados a covid- ( ). amci ® enfermo con falla respiratoria aguda, la cual engloba falla respiratoria hipóxica (tipo ), falla respiratoria hipercápnica aguda (tipo ), sdra y lesión pulmonar aguda, se revisaron ensayos clínicos, más de pacientes. el análisis del grupo de n acetilcisteína intravenoso mostró una reducción de estancia en uci, de . días, con una heterogeneidad muy baja del %, con valoración de la evidencia calificada como de alta calidad y baja probabilidad de sesgo ( ) . en covid- , fue utilizada con recuperación completa en un caso severo de un paciente con déficit de glucosa fosfato deshidrogenasa (g pd), con control de la hemolisis y resolución del compromiso pulmonar. en pacientes sin déficit de g pd, también ha sido asociada a mejoría clínica y disminución significativa de los niveles de pcr y ferritina ( ) . en una revisión de costo efectividad nacional, se identificaron referencias, de ellos era revisiones sistemáticas de la literatura, dos de las cuales incluían metaanálisis (lu y zhang ), y fueron incluidos en la evaluación. estos estudios incluyeron información de ensayos clínicos que comparaban la aplicación de nac intravenosa frente a placebo o cuidado usual en pacientes con sdra. los tres estudios reportan como resultado de mortalidad rr de . con ic al % de . a . (lu ), rr de . con ic al % de . a . (lewis ) y rr de . con ic al % de . a . (zhang ) . para el tiempo de estancia en uci solo las revisiones con metaanálisis reportaron resultados, encontrando una diferencia de promedio de días de estancia de - . días con ic al % de - . a - . (lu ) y de - . días con ic al % de - . a - . (zhang ). una de las revisiones reportó que en ninguno de los estudios analizados se presentaron eventos adversos. no se encontraron resultados para los desenlaces de infección, sobreinfección, ni uso y tipo de antibiótico utilizado. en el análisis se encontró una reducción estadísticamente significativa de los días de estancia en uci de los pacientes que recibieron tratamiento con n-acetilcisteína intravenosa con dosis entre y mg/kg/día durante los primeros cinco días del sdra, en comparación con los pacientes que recibieron placebo o manejo usual. no se reportó diferencia estadísticamente significativa en la reducción de la mortalidad de los pacientes que recibieron nac. ( ) calidad de vida . ¿cómo podemos medir la calidad de vida, en los pacientes con covid- que egresan de la uci? se recomienda utilizar los marcadores disponibles de severidad y del riesgo de mortalidad por covid- en los pacientes internados en la uci. amci ® las secuelas inmediatas en los pacientes víctimas del devastador ataque sistémico del covid- durante su estancia en la uci son valorables, pero no se dispone de herramientas que permita medir el grado de afectación de la calidad de vida de estos pacientes posterior al egreso de la uci o de alta hospitalaria, por lo tanto, se sugiere realizar estudios de creación, validación y utilización de instrumentos de valoración de la calidad de vida en pacientes con covid- posteriores al alta hospitalaria. parte importante de los pacientes con diagnóstico de covid- que ingresan a la uci, evolucionan tórpidamente presentando deterioro progresivo de los diferentes órganos llegando en pocos días a una falla multiorgánica ( ) , estos pacientes presentan características clínicas y de laboratorio que se relacionan de manera significativa con mayor severidad y riesgo de mortalidad ( , ) . a pesar de conocer con alguna precisión el riesgo de severidad y mortalidad de los pacientes que ingresan a la uci, no disponemos de un score que nos permita evaluar y predecir el grado de afectación en la calidad de vida de los pacientes que logran sobrevivir. aproximadamente un , % del total de pacientes con enfermedad por covid- ingresan a uci, y de estos , % sometidos a ventilación mecánica ( ); lamentablemente los pacientes con enfermedad severa que logran sobrevivir y recuperarse han sido sometidos a una larga estancia en la uci y a ventilación mecánica invasiva con una intubación prolongada, que puede producir disfunción en la deglución impidiendo a la persona alimentarse de forma correcta y segura. es importante diagnosticar esta disfagia en los pacientes que se están recuperando del covid- y tratarla correctamente desde el principio para evitar complicaciones importantes como la malnutrición y la deshidratación, así como el riesgo de neumonía aspirativa. además de la disfagia, la fibrosis pulmonar y el riesgo de trombos son los problemas más frecuentes, pero no los únicos. una de las características de la enfermedad severa por covid- es que el virus provoca una enfermedad multiorgánica, con un amplio y heterogéneo abanico de secuelas cuyo alcance todavía se desconoce y aunque el órgano más afectado es el pulmón, puede afectar también otros órganos o sistemas incluido el snc, que en los casos más graves puede presentar encefalitis, delirios, desorientación y confusión, síntomas que pueden persistir tras el alta de la uci. otra secuela frecuente son las polineuropatías, esta afectación suele comenzar con una sensación de hormigueo en las extremidades y en los pacientes con covid- se presenta además con un cuadro de miositis que provoca debilidad y cansancio al caminar, a veces incluso en reposo; en algunos pacientes se presenta tal debilidad que dificulta llevar el alimento a la boca e incluso deglutirlo. sin embargo, la primera y más frecuente de las manifestaciones neurológicas del covid- es la pérdida del olfato, que a veces perdura como secuela tiempo después del alta. un estudio en pacientes ingresados en el hospital clínico san carlos de madrid revela que el % había sufrido anosmia en mayor o menor grado. la importancia de este síntoma radica en que las fosas nasales pueden ser la vía de acceso del virus al sistema nervioso central. amci ® otras posibles secuelas neurológicas asociadas a la infección por covid- son la ageusia, la cefalea y amnesia a corto y mediano plazo. también son importantes las secuelas que afectan al sistema cardiovascular. un estudio publicado en la journal o the american medical association advierte que un % de los pacientes presenta una elevación de las enzimas que indican daño en el miocardio. la inflamación que provoca el virus puede provocar directamente ese daño y también puede agravar el estado de pacientes que ya tengan una patología cardiovascular de base, muchas miocarditis son reversibles, pero hay una parte importante que deja como secuela una pérdida de la función contráctil. todavía se desconoce el alcance y es difícil medir el impacto de la enfermedad sobre el corazón porque en algunos casos, los síntomas de insuficiencia cardíaca se confunden con los de la neumonía. otra de las complicaciones más frecuentes, y potencialmente más grave, afecta al mecanismo de coagulación de la sangre. durante el ingreso hospitalario se han visto numerosos casos de ictus. la secuela más importante es el riesgo de que se formen trombos, que pueden ir al pulmón o al cerebro, y si se producen en las arterias, pueden dar lugar a un infarto, aunque este efecto es mucho menos frecuente. eso explica que algunos pacientes de covid- dados de alta hayan tenido que volver a ingresar por trombosis. finalmente es importante tener presente que a las afectaciones que haya podido producir el virus, hay que sumar las secuelas neurológicas propias de una estancia prolongada en una unidad de cuidados intensivos que también pueden ser graves y a veces no se distinguen bien unas de otras. debilidad muscular, desorientación, depresión y problemas psicológicos son secuelas muy habituales entre los pacientes que salen de la uci por enfermedades diferentes. por la anterior razón es difícil, por ahora, saber qué es efecto directo del virus y que puede derivarse del proceso de hospitalización. aún es difícil decir si los daños a largo plazo dependen del propio virus o de los efectos adversos del proceso tratante. sin embargo, este análisis de las posibles secuelas del covid- en el cuerpo, se presenta con más dudas que certezas. como es habitual en medicina, las causas pueden ser múltiples y muchas veces reflejan la participación de varias complicaciones que se han podido dar durante el proceso infeccioso directo o por la hospitalización, la información sobre los mecanismos de invasión del sars-cov- en todos los órganos sigue siendo, por ahora, escasa. y también lo es nuestro conocimiento sobre los efectos adversos de los medicamentos, muchos de ellos experimentales, que se han utilizado durante esta crisis. gran parte de lo que conocemos actualmente sobre los efectos de este virus proviene de la experiencia clínica de otros colegas y de las historias de pacientes que han sufrido la enfermedad, quedando todavía mucho por descubrir. dado el actual panorama, diferentes hospitales e instituciones de salud se preparan en torno a la rehabilitación, habilitando ya unidades multidisciplinares poscovid- para el seguimiento de estos pacientes y algunos centros están contactando con los pacientes dados de alta para evaluar su estado y hacer un seguimiento a su salud. también están en marcha varios estudios multicéntricos para evaluar el alcance de las secuelas, prácticamente todos los centros sanitarios deberán tener pautas de seguimiento y control para los pacientes ya dados de alta, creándose necesario la utilización simultánea de amci ® instrumentos de medición de calidad de vida, que en nuestro país colombia, ya se han utilizado previamente con este fin ( , ) . con este instrumento de medición de la calidad de vida se realizaron algunos estudios piloto tanto en pacientes crónicos como en la población general con el fin de determinar la comprensión del instrumento y factibilidad de aplicación del mismo en cuanto a la consistencia interna, la revisión realizada por vilagut y cols demostró que la aplicación de la escala arrojó en diversos estudios un alfa de cronbach igual o superior a . en todas las escalas excepto en función social ( ) . y aunque un número cada vez mayor de estudios mide los resultados físicos, cognitivos, de salud mental y de calidad de vida relacionada con la salud (cvrs) en los sobrevivientes adultos de la uci, los datos sobre las propiedades de medición de tales instrumentos son escasos y, en general, de calidad deficiente a justa. se necesitan análisis empíricos que evalúen el rendimiento de los instrumentos en adultos sobrevivientes de la uci para avanzar en la investigación en este campo ( ) . finalmente, el conocimiento de las secuelas y complicaciones dejadas por la infección del covid- , permitirá identificar importantes variables clínicas que acompañan a esta enfermedad y que afectan de manera importante la calidad de vida de los pacientes que padecen la enfermedad severa en la unidad de cuidados intensivos. en la actualidad no existen estudios para evaluar el riesgo de malnutrición aguda en pacientes hospitalizados por sars-cov- . experiencias con otras infecciones virales por influenza, se han identificado como factores asociados con mortalidad, la presencia de malnutrición, la adquisición de infección intrahospitalarias, la falla respiratoria y la presencia de infiltrados en la radiografía de tórax ( ) . las guías espen recomiendan utilizar el must o el nrs- ( ), para la tamización del riesgo nutricional, estos puntajes de tamización previamente han sido validados en múltiples patologías y contextos clínicos; sin embargo, existen otros puntajes útiles desde la perspectiva clínica como la valoración global subjetiva, mini-nutritional asessment( ), puntaje nutric ( ) y la global leadership initiative on malnutrition (glim) ( ) . el proceso de diagnóstico nutricional debe involucrar, dos componentes: la identificación del riesgo con la utilización de alguno de los puntajes previamente validados en otros contextos y posteriormente el diagnóstico de los pacientes con malnutrición y la valoración de la gravedad de ésta; en este último paso es importante la valoración del índice de masa corporal, los hábitos de consumo calórico y proteico, la presencia de inflamación, los trastornos gastrointestinales, las enfermedades de base y siempre que sea factible el cálculo de la masa muscular. tabla . en vista del riesgo de infección al personal de salud, no siempre será necesario la visita nutricional al paciente, ésta podría ayudarse con entrevista al familiar, interrogatorio vía amci ® telefónica y sólo en caso necesario el examen del paciente para lo cual se requiere el uso de equipo de protección personal completo. esta estrategia de interrogatorio al familiar o al paciente por vía remota o telefónica puede ayudar a identificar los patrones de consumo y los hábitos nutricionales de riesgo y en caso de ser necesario la valoración nutricional disminuye el tiempo de exposición a un ambiente contaminado. para la atención presencial de pacientes en el ámbito de cuidado intensivo, es necesario definir cuál es el riesgo que existe de infección para el personal de salud, para aclarar esta pregunta se debe definir si hay un riesgo de generación de aerosoles( ). aunque no existen pautas específicas para la nutrición en pacientes con covid- , las diferentes sociedades científicas han desarrollado guías de pauta clínica para la nutrición de pacientes con esta enfermedad ( , ) . idealmente la nutrición debe ser iniciada de forma temprana, esto se refiere al inicio en las primeras a horas del ingreso a cuidado intensivo o en las primeras horas luego de la intubación y el inicio de la ventilación mecánica( ) y se prefiere la vía enteral. aunque no existen estudios para evaluar el momento del inicio de la nutrición en pacientes con infección por sars-cov , el inicio temprano de la nutrición ha mostrado beneficios en términos de mortalidad y reducción de infecciones con dicha estrategia ( , ) . adicionalmente es importante, evaluar el riesgo de morbilidad y mortalidad asociado a la malnutrición aguda en el ámbito del paciente crítico, en los pacientes que no se alcance la meta de aporte calórico y proteico por vía enteral o que exista contraindicación para ésta, se debe considerar el inicio de nutrición por vía parenteral, especialmente cuando su riesgo nutricional agudo sea elevado (puntaje nutric ≥ , nrs ≥ ) ( ) ( ) . el choque no es una contraindicación para la utilización de nutrición enteral ( ) y no es una indicación para el uso de nutrición parenteral, quizás la mejor estrategia, es vigilar la presencia de disfunción gastrointestinal, en combinación con la presencia de intolerancia a la nutrición enteral, especialmente en pacientes con acidosis láctica en progreso y cuando sea necesario escalar la dosis de vasopresores o exista incapacidad para la reducción de éstos. no es necesario medir el residuo gástrico de rutina, es preferible iniciar procinéticos de forma rutinaria. la sonda debe colocarse con cuidado de evitar riesgo de contaminación, preferiblemente al entubar al paciente. algunos pacientes pueden presentar diarrea, ya que se ha descubierto la presencia de la proteína ace (receptor del virus sars-cov- ) en células del esófago, estómago, duodeno y recto. no existe evidencia que indique que la nutrición enteral durante la posición prono aumente el riesgo de complicaciones. sugerimos no suspender nutrición enteral al durante la pronación, se debe iniciar con dosis trófica de ml/h. amci ® se recomienda una estrecha monitorización de la tolerancia a la nutrición enteral para pacientes en posición prono. se recomienda para aumentar la tolerancia de la ne a los pacientes en posición prona, una elevación del tórax entre - º (posición de trendelenburg inversa) no realizar endoscopias digestivas para ubicación de sondas avanzadas recomendaciones de nutrición parenteral los pacientes con covid- pueden requerir niveles significativos de sedación y bloqueo neuromuscular, lo que puede aumentar la incidencia de intolerancia gastrointestinal. la nutrición parenteral (np) debe utilizarse donde la alimentación enteral no está disponible o no logra completar el % de los requerimientos. si existen limitaciones para la ruta enteral, se podría recomendar nutrición parenteral periférica (npp) en la población que no alcanza el objetivo proteico energético por nutrición oral o enteral. la np temprana debe 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