key: cord- - um w dx authors: brunker, lucille; hirst, priscilla; schlesinger, joseph j. title: new-onset refractory status epilepticus with underlying autoimmune etiology: a case report date: - - journal: sn compr clin med doi: . /s - - -z sha: doc_id: cord_uid: um w dx management of new-onset refractory status epilepticus and the approach to burst suppression variable is often challenging. we present the unusual case of a previously healthy -year-old male with new-onset status epilepticus admitted to the neurologic intensive care unit for days. despite treatment with multiple anti-epileptic drugs in addition to iv anesthetics, burst suppression was initially unsustainable and the patient remained in super-refractory status epilepticus. extensive evaluation revealed an underlying autoimmune-mediated etiology with positivity for glutamic acid decarboxylase- antibody. clinical response with a goal of – bursts per screen on eeg monitor was eventually achieved after a course of rituximab and plasma exchange therapy as well as a -day barbiturate coma with a regimen of clobazam, lacosamide, keppra, and oxcarbazepine followed by a slow taper of phenobarbital and the addition of fosphenytoin. remarkably, the patient was subsequently discharged to a rehabilitation facility with complete neurologic recovery. we discuss treatment strategies for new-onset refractory status epilepticus and highlight the role of rapid initiation of burst suppression with high-dose iv anesthetics to ensure neuroprotection while the underlying etiology is addressed with immune-modulating therapy. the management of first-episode unprovoked seizures involves an individualized approach that weighs the risk of seizure recurrence against the adverse effects of anti-epileptic drugs (aeds). while sharing a common property of suppressing seizures, aeds can be classified into different pharmacological subtypes based on the mechanism of action, tendency for drug-drug interactions, and toxicity profiles. major mechanisms of action include alteration of sodium currents, modulation of gabaergic tone, antagonism of the nmda glutamate receptor, alteration of calcium currents, and the binding of synaptic vesicle proteins. refractory status epilepticus (rse) is defined as persistent seizures despite administration of an initial benzodiazepine and a nonbenzodiazepine antiseizure drug [ ] . super refractory status epilepticus (srse) is defined as status epilepticus that continues or recurs after the onset of anesthetic therapy and that recurs on the reduction of anesthesia [ ] . although the optimal treatment of rse is unclear in the literature, primary therapies include midazolam, propofol, and phenobarbital. patients in this setting should be intubated and monitored on continuous electroencephalogram (eeg) with the goal of burst suppression. of note, prolonged use of a propofol infusion is associated with propofol infusion syndrome (pris), which involves rhabdomyolysis, severe metabolic acidosis, as well as cardiac and renal failure, and green urine [ ] . in addition, hypotension is common with many patients requiring vasopressor support in this setting [ ] . ketamine is an n-methyl-d-aspartase (nmda) antagonist that can also be used in the treatment of rse. although evidence for its use is limited, a meta-analysis suggests that ketamine contributed to seizure control in rse for approximately % of adult patients with median loading doses in the range of - mg/kg, with a continuous infusion ranging this article is part of the topical collection on medicine anywhere from to mg/kg/h, based on the cited reports [ ] . glutamate antagonists have been shown to be particularly effective in the later phases of se when gaba agonists have lost some effectiveness and glutamatergic activity may underlie ongoing seizure activity [ , ] . a previously healthy -year-old male was admitted to the hospital with new-onset seizures following episodes of staring, drooling, and unresponsiveness in addition to flu-like symptoms and fatigue on the day prior to admission. possible exposure history was notable for a recent cruise to the caribbean. en route to the hospital, the patient suffered a generalized tonic-clonic seizure witnessed by emt. on initial clinical exam, the patient appeared somnolent although neurologic exam (cranial nerves, motor strength, sensory) was without deficits. two-hour eeg monitoring revealed continuous . - -hz right frontal lateralized periodic discharges. initial imaging with ct and mri was unremarkable. inpatient treatment with an aed regimen of levetiracetam and valproic acid was initiated. given the concern for meningoencephalitis from an infectious etiology, the patient was treated with vancomycin, ceftriaxone, and acyclovir. over the next h, continuous eeg monitoring was notable for subclinical seizures and the patient was started on oxcarbazepine, lacosamide, and topiramate with as needed lorazepam. based on the results of lumbar puncture and cerebral spinal fluid analysis, acyclovir and antibiotics were discontinued. on hospital day , the patient was found to be in status epilepticus (se) on eeg and unresponsive but without convulsions on exam. he was emergently transferred to the neurologic intensive care unit (nicu) and intubated for airway protection. continuous eeg monitoring displayed se despite broad aed therapies (levetiracetam, lacosamide, topiramate, oxcarbazepine). for neurologic protection, the patient was initiated on burst suppression therapy, with a target of - epileptic bursts per screen on eeg monitor. a midazolam infusion was initiated and up-titrated to mg h − but failed to achieve burst suppression, and the patient continued to have generalized epileptic discharges on eeg. the patient was subsequently changed to a propofol infusion up to mcg kg min − with intermittent boluses to maintain burst suppression. despite the addition of phenobarbital, epileptic discharge activity remained evident on eeg, and events of facial twitching and arm convulsions were observed on exam. burst suppression was eventually achieved with the addition of a pentobarbital infusion. given the severity of ongoing epileptic activity, broad-spectrum antibiotic coverage was resumed with the addition of doxycycline to cover tick-borne illness. despite this regimen, the patient continued to have epileptic discharges evident on eeg but was not convulsive on exam. a ketamine infusion was subsequently added. empiric treatment with intravenous immunoglobulin (ivig) therapy and methylprednisolone for autoimmune and paraneoplastic causes were initiated. in the following days, the patient continued to experience breakthrough seizures evident on eeg and on exam with facial twitching and rhythmic arm movement when pentobarbital was decreased, consistent with srse. these ongoing eeg findings with evident seizures when anesthesia was decreased led to further modification of the aed regimen ( fig. , timeline of agents used) including the addition of clobazam. of note, the patient developed diabetes insipidus secondary to the pentobarbital infusion and a vasopressin infusion was administered. on hospital day , sufficient burst suppression was achieved with a regimen of pentobarbital, ketamine, clobazam, lacosamide, levetiracetam, oxcarbazepine, and valproic acid. when the pentobarbital infusion was decreased, eeg continued to be consistent with se. for this reason, the phenobarbital infusion was continued in order to maintain burst suppression. at this point, the patient underwent a tracheostomy procedure due to prolonged mechanical ventilation requirements. a ketogenic diet was initiated and continued for the duration of hospitalization [ ] . in the following days, the patient remained in srse with epileptic activity on eeg and with facial twitching on exam. felbamate was added to the aed regimen of levetiracetam, lacosamide, oxcarbazepine, and clobazam. plasma exchange (plex) therapy was initiated along with hypothermia protocol [ , ] . on day four of five of plex therapy, hospital day , laboratory results from csf paraneoplastic and autoimmune evaluation elisa returned positive for anti-glutamic acid decarboxylase- (gad ) antibody > : as represented in table . after completion of the -day course of plex therapy, rituximab was added and dosed every weeks, in addition to the existing aed regimen of oxcarbazepine, clobazam, levetiracetam, and topiramate. at this point, the patient continued to have clinical seizures with bilateral epileptic discharge on eeg. a pentobarbital -day coma for burst suppression was then initiated. the patient was loaded with fosphenytoin on hospital day . following loading and maintenance doses, blood serum levels of therapies were verified and phenytoin levels found to be subtherapeutic at . mcg ml − (goal of - mcg ml − ). phenobarbital levels were found to be supratherapeutic at . mcg ml − ( goal of - mcg ml − ). appropriate medication alterations were made to bring both drugs to appropriate therapeutic levels (phenobarbital at . mcg ml − and phenytoin at . mcg ml − ). while these agents were being titrated, perampanel was initiated on hospital day . on hospital day , when burst suppression was lifted, clinical seizures had resolved. eeg monitoring was continued and, by hospital day , focal ictal discharges had ceased. throughout the remainder of the admission, the patient was successfully weaned off of the ventilator, was able to tolerate eating meals by mouth, and worked with occupational and physical therapy to return to his baseline functional status. he was transitioned from fosphenytoin to phenytoin extended release mg by mouth twice daily, continued on phenobarbital mg by mouth four times daily, perampanel mg by mouth each evening, and topiramate mg by mouth twice daily, and ultimately discharged on this aed regimen. the patient was discharged to inpatient rehabilitation to continue recovering from prolonged hospitalization prior to returning home. here, we present a case of new-onset srse (norse) with underlying autoimmune etiology in a previously healthy young male who ultimately made complete neurological recovery after extensive treatment and nicu admission. the clinical outcome raises discussion as norse is typically considered a life-threatening condition with mortality up to % [ ] . although general expert consensus in the literature recommends approaching norse with pharmacologic-induced coma and continuous infusion of iv anesthetic agents to suppress brain activity and preserve normal brain physiology [ ] , a precise roadmap to clinical neurological recovery is not described, pointing to educational value in individually described cases. the unusual outcome demonstrated here raises a discussion of optimal approach and treatment as applied to a case of norse where complete neurological recovery was ultimately achieved. in this particular case of norse, the underlying etiology was obscure despite an exhaustive workup and was ultimately discovered to be an autoimmune-mediated epilepsy with anti-gad antibody positivity. the patient's csf was tested for a panel of other antibodies against surface antigens relevant to autoimmune etiology, all of which were found to be negative with the exception of gad . while positivity of anti-gad antibodies should not in itself be considered a cause of autoimmune encephalitis, the other clinical and laboratory findings in the case were also consistent with autoimmune etiology. these findings included a negative infectious workup, a negative paraneoplastic workup, the viral-type symptom prodrome at presentation, and the intractable resistance to aed therapy. on review of the literature, management of se in setting of known anti-gad antibody positivity is often difficult and, in some cases, irreversible [ , ] . case reports described by mäkelä and colleagues ( ) have shown moderate responses to steroids, ivig, and plex, but immunosuppression with better cns penetration has been fig. drug timeline. given the acute changes and multiple therapies constantly being titrated during a prolonged hospital course, the significant events and therapies are summarized found to be more effective. similarly, in our case, clinical response was ultimately achieved with rituximab following ineffective treatment with steroids, ivig, and plex, consistent with the aforementioned reports of autoimmune-mediated se in the literature. on initial presentation, it can be difficult to distinguish between norse of autoimmune etiology versus infectious etiology. patient prognosis remains highly dependent on the underlying etiology, and treatment regimens differ significantly, making early suspicion in either direction of great importance. it has been suggested that autoimmune etiology is associated with certain clinical features such as younger age of onset (< ), female sex, psychosis, and super-refractory se, in addition to lymphocytic predominance in csf. in contrast, other features such as high csf portal protein, pleiocytosis and reduced glucose ratio are associated with infectious etiology [ ] . raising suspicion based on these factors early on in a hospital admission can help guide rapid initiation of appropriate therapy to achieve clinical response and neuroprotection. notably, although csf analysis can be helpful in this distinction, in the case of anti-gad antibody-mediated autoimmune epilepsy, lack of response to ivig and plex has been shown to be to typical [ , ] and possibly diagnostic. given that the prevalence of autoimmune and infectious status epilepticus are similar, factors that facilitate early clinical suspicion for either process are valuable for icu physicians in the rapid initiation of appropriate empiric therapy. autoimmune etiology has recently been recognized as an important cause in epilepsy and in norse. in recent years, increasing numbers of auto-antibodies, which can be either autoimmune or paraneoplastic in nature, have been identified in patients with new-onset seizures. these auto-antibodies are involved in maintaining the balance between excitatory and inhibitory neurotransmission, underlying their role in seizure activity [ ] . antibodies associated with autoimmune epilepsy can be categorized into two groups: those against neuronal cell surface and synaptic proteins, and those against intracellular antigens. intracellular antigen-mediated autoimmune epilepsy (e.g., mediated by anti-hu/anna- , ma /ta, cv /crmp , and gad ) is frequently paraneoplastic in nature with the exception of purely gad -related epilepsy [ , ] . gad mediated epilepsy is also typically more refractory to therapy, as demonstrated in our case, and carries a poorer prognosis when compared with neuronal cell surface/synaptic autoimmune epilepsy (e.g., mediated by anti-nmdar, gabar, lgi [ ] ). these elements of gad -mediated autoimmune epilepsy are consistent with our clinical scenario in addition to the fact that our workup was negative for paraneoplastic causes. furthermore, it has been suggested in the literature that in contrast to other autoimmune-mediated epilepsies, gad antibody-mediated epilepsy is less responsive to standard aeds and to immune therapy with steroids, ivig, and plex, and that treatment with aggressive immunosuppressants such as rituximab is necessary to achieve clinical response [ , ] as is demonstrated in our patient. the pathogenic role of gad is debated in the literature. although the precise mechanism of pathogenicity remains unclear, it is suggested that intrathecal synthesis of gad antibody leads to the degeneration of gabaergic neurons that consequently release cytoplasmic proteins into the csf eliciting an immune response [ ] . as gad is expressed by gabaergic neurons and is an enzyme involved in the conversion of glutamate to gaba, the inhibition of gad via an autoimmune process could result in excessive excitatory neurotransmission, ultimately resulting in lowering of the seizure threshold [ , ] . the management of autoimmune se requires a balance of aeds and iv anesthetics for burst suppression while the immunosuppressant therapy treats the underlying cause of norse. aed selection in gad epilepsy is similar to generalized clinically acceptable principles, that is, to achieve seizure control and tolerability. the challenges of therapy for burst suppression require frequent patient monitoring in a critical care setting, continuous subjective interpretation of eeg, and the careful titration of iv anesthetics. further monitoring must be done to avoid aeds and iv anesthetics at dangerous levels or the development of adverse side effects. furthermore, there are consequences to prolonged high-dose infusion for each of these iv anesthetic agents. for example, due to high-dose propofol infusions for multiple days, the patient was screened for propofol infusion syndrome by following creatinine protein kinase (cpk) levels and lactate levels. in addition, treatment with phenobarbital requires the monitoring of a basic metabolic panel (bmp) for hypokalemia and liver function tests (lfts) for hepatic dysfunction. of note, phenobarbital is a cyp p inducer and affects the serum levels of other aeds, in this case phenytoin. it is important to monitor serum drug levels to ensure therapeutic levels of phenytoin are maintained while phenobarbital is being administered. in conclusion, this challenging case of norse in a previously healthy young adult emphasizes the importance of rapid recognition of autoimmune etiology as well the achievement of burst suppression in se refractory to multiple therapeutic approaches. despite the high-mortality prognosis, the prolonged duration of the epileptic state, and the difficulty in maintaining burst suppression, the clinical evolution resulted in complete neurological recovery. refractory status epilepticus: frequency, risk factors, and impact on outcome the pathophysiology 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conflict of interest the authors declare that they have no conflicts of interest.ethical approval a written hipaa authorization to use/disclose existing protected health information was obtained.informed consent informed consent was obtained from all individual participants included in the study. key: cord- -tzctvs q authors: martelletti, luigi; martelletti, paolo title: air pollution and the novel covid- disease: a putative disease risk factor date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: tzctvs q nan long-term care facilities, and all people with existing health conditions are those who will develop more critical illness [ ] . there is the additional environmental aspect, which could facilitate the spread of the virus, namely the high agglomeration of air pollutants. the assumption that air pollution conditions facilitate the spread of the virus was shown and supported by cui et al. [ ] during the sars outbreak in mainland china in november . this study analyzed the correlation between the increment of the api (air pollution index) and the rate of fatality due to sars across regions in china. the regions were selected according to their elevated air pollution index, taking into consideration that an api less than is thought to be healthy for the general population. according to this research, the five regions under investigation (guangdong, shanxi, hebei, beijing, and tianjin) presented a linear relationship between api, in the period april to may , and fatality rate due to sars. the lower the api, the lower the mortality rate [ ] . in , ciencewicki and jaspers conducted an epidemiological analysis regarding air pollution and respiratory viral infections which noted positive correlation between the high level of particulate matter (pm) in some urban areas and mortality due to cardiovascular and respiratory conditions. elevated exposure to common pm present in the air can alter host immunity to respiratory viral infections [ ] . a recent study from the sima (società italiana di medicina ambientale) reported that the specificity of the high spread of the contagious virus in some areas of northern italy is likely to be linked to air pollution conditions. according to the recent sima analysis of covid- diffusion in italy, the atmospheric particulate matter exercises a carrier (or boost) action along with the virus. the pm (particulate matter) is composed of solid and liquid particles which allow to float in the airflow longer and to be widespread over larger distances. atmospheric pm has a sub-layer that facilitates the virus survival in airflows for hours or days. the local atmospheric aspect is another environmental factor that must be considered in the accelerated diffusion of this virus. in fact, sars-cov- has facilitated activation rates when in presence of high local relative humidity, while it is inhibited in hot climate situations [ ] . this research shows how the italian northern regions, which have been the most affected by covid- , are also those with a high amount of atmospheric particulate matter (pm and pm . ) going above the legislative standards (limit, μg/m per day) in the month of february . this relationship can also be seen by comparing the following two images which illustrate the nitrogen dioxide emissions and the covid- case fatality in northern italy during january . the red zone in fig. indicates high pm agglomerations while the red circles in fig. designate those infected. a correlation between elevated concentration of pm and the high spread and mortality rate is visible. although the connection can be considered both a false statement as it lacks data and causality, china has faced a near identical situation with the epicenter of the covid- pandemic, where elevated concentrations of air pollutants were present in the regions mostly affected (see figs. and ) . the above studies show that air pollutants, such as particulate matter, nitrogen dioxide, and carbon monoxide, are most likely direct to facilitate the longevity of virus particles in favorable climate conditions. sars virus and other respiratory diseases such as copd (chronic obstructive pulmonary disease) find fertile "territory" in air pollutant particles and, in a linear relationship, they survive longer and become more aggressive in an immune system already aggravated by these harmful substances. this hypothesis needs to be validated by further future epidemiological studies in multiple geographic regions affected by the covid- pandemic. 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 holder. to view a copy of this licence, visit http://creativecommons.org/licenses/by/ . /. world health organization. coronavirus disease (covid- ) -events as they happen the difference in the incubation period of novel coronavirus (sars-cov- ) infection between travelers to hubei and non-travelers: the need of a longer quarantine period things everyone should know about the coronavirus outbreak clinical features of patients infected with novel coronavirus in wuhan centers for disease control and prevention. coronavirus disease (covid- ). . available at air pollution and case fatality of sars in the people's republic of china: an ecologic study air pollution and respiratory viral infection position paper relazione circa l'effetto dell'inquinamento da particolato atmosferico e la diffusione di virus nella popolazione. sima -società italiana di medicina ambientale; covid- -situazione in italia air pollution over china dropped in january, rebounding in marchsatellite data coronavirus map: tracking the global outbreak key: cord- -oar pttf authors: kijima, emi; yamamura, haruka; okada, mari; nagasawa, masayuki title: kawasaki disease and invasive pneumococcal infection date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: oar pttf nan streptococcus were both negative. intravenous cefotaxime (ctx) administration was started empirically. in the morning, she developed five out of six major kd symptoms (except for lip findings), and intravenous immunoglobulin ( g/kg; ivig) and oral aspirin ( mg/kg/day) were started according to the definite diagnosis of kd with a kobayashi score of [ ] . the blood culture became positive for gpc in the evening, and intravenous ampicillin (abpc) was added to cover enterococcus infection, empirically. both spinal fluid and urine culture were negative. on the next day, fever decreased transiently. however, fever increased again to . °c on the rd day after admission and systemic rash and edema became further deteriorated. blood examination revealed wbc of , /μl, crp of . mg/dl, sodium of meq/l, albumin of . g/dl, and d-dimer aggravated to . μg/ml. gpc was determined to be streptococcus pneumoniae with penicillin susceptibility, and antibiotic treatment was switched to abpc only. considering of unresponsiveness to ivig, prednisolone ( mg/kg/day; psl) was added. the follow-up blood culture performed on the same day was found to be negative later. fever decreased to normal level, and a rash and edema improved dramatically on the th day. the pneumococcal serotype was determined as b (nonvaccine strain) later. the patient was discharged on oral aspirin after days antibiotic treatment. during the course, the coronary lesion was absent. in our case, kd was unresponsive to ivig in spite of proper antibiotic treatment for ipd, and kd was well responsive to psl instead. it is considered that ipd might be a triggering factor of kd and highly elevated d-dimer is a significant risk factor of ivig unresponsiveness in kd as we have previously reported [ ] . concerning the preceding febrile episode which occurred days before the admission, the likelihood of exanthem subitum was speculated, although it was not confirmed serologically. it is very interesting to speculate that the preceding viral infection might be a prerequisite background of kd which was later triggered by ipd, when considering the unknown immunological pathology of kd [ , ] . furthermore, when once induced, kd requires specific treatment for itself, even if the triggering infection such as ipd as in our case is controlled by proper antibiotic therapy. kawasaki disease associated with pneumococcal infection. sn comprehensive clinical medicine evaluation of kawasaki disease risk scoring system in a single center experience from japan impact of d-dimer on the resistance to intravenous immunoglobulin therapy in kawasaki disease gsl circulating cd + hla-dr+ extracellular vesicles are not increased in the acute phase of kawasaki disease soluble sortilin in elevated in the acute phase of kawasaki disease an outbreak of severe kawasaki-like disease at the italian epicentre of the sars-cov- epidemic: an observational cohort study erythema multiforme and kawasaki disease associated with covid- infection in children publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. sn compr key: cord- -zfcz hpd authors: chow, lai chee; chew, lee ping; leong, tze shin; mohamad tazuddin, estrellita elena; chua, hock hin title: thrombosis and bleeding as presentation of covid- infection with polycythemia vera. a case report date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: zfcz hpd coronavirus disease (covid- ) has a wide spectrum of clinical manifestations. in this case report, we describe our first case of covid- pneumonia that was complicated by cerebral venous thrombosis and bleeding in a patient with polycythemia vera. madam a, a -year-old lady with polycythemia vera, ischemic stroke, hemorrhoids, diabetes mellitus, hypertension, and dyslipidemia was admitted to the hospital for covid- pneumonia. she was treated with hydroxychloroquine and lopinavir/ritonavir as per hospital protocol. she continued taking hydroxyurea and aspirin for her treatment of polycythemia vera. subsequently, she developed rectal bleeding when her platelet count was × ( )/μl, even though she was not on an anticoagulant. her aspirin was withheld. one week later, she was readmitted to the hospital for cerebral venous thrombosis and her d-dimer was . μg/ml. she was commenced on a therapeutic dose of low molecular weight heparin. following that, her d-dimer level showed a decreasing trend and normalized upon her discharge. patients with polycythemia vera are prone to develop thrombotic and bleeding complications. management of this group of patients has become more complex with covid- infection. it is crucial for us to decide when to start an anticoagulant especially when there is a history of recent bleeding. we need to balance the risks of further bleeding versus potentially fatal thrombotic events. studies have shown that d-dimer can be used as a clinical marker to predict thrombotic events in covid- infection. patients with covid- infection and polycythemia vera will benefit from both pharmacological thromboprophylaxis and close monitoring for bleeding. coronavirus disease was first detected at wuhan, china, in december . this ongoing global pandemic has caused millions of confirmed cases and thousands of deaths [ ] . this disease has a wide spectrum of clinical manifestations, ranging from mild upper respiratory tract infection symptoms to severe pneumonia that require ventilation support, shock, and multi-organ failure [ ] . covid- is considered as multi-organ disease as it involves different organs and even systemic complications [ ] . we report a case of an elderly patient with underlying polycythemia vera, diagnosed this with covid- pneumonia which was complicated by cerebral venous thrombosis. we obtained the written informed consent from her next of kin. madam a, a -year-old lady, was diagnosed with jak v f mutation polycythemia vera in and was treated with tablet hydroxyurea mg daily and oral aspirin mg daily. she required therapeutic phlebotomy once a week for the first month as her hematocrit level was persistently more than %. prior to her diagnosis of polycythemia vera, she had a history of ischemic stroke in with residual left-sided hemiparesis, hemorrhoids with banding done twice, diabetes mellitus, hypertension, and dyslipidemia. in early march , during the covid- outbreak in malaysia, most of her family members whom she was staying with were infected with covid- . therefore, she was screened for being a close contact and was tested positive for sars-cov- by qualitative real-time reverse-transcriptase-polymerase-chain-reaction (qrt-pcr) assay. she was admitted to the isolation ward for close observation as per local covid- protocol. her treatment of aspirin and hydroxyurea for her underlying polycythemia vera was continued. while under observation, she developed a worsening cough with chest radiograph showed worsening bilateral lower zone opacities. however, her oxygen saturation remained stable at to % under room air. due to the severity of her covid- infection, she was commenced on oral hydroxychloroquine for days and oral lopinavir/ritonavir for weeks. her clinical condition improved with treatment. however, she developed per rectal bleeding which was attributed to her hemorrhoids. her hemoglobin was . g/dl, total white cell count was × /μl, and platelet count was × /μl at the time the bleeding occurred ( table ) . as a result, her hydroxyurea dosage was increased to mg twice daily but her aspirin was withheld. her rectal bleeding resolved after that. she was hospitalized for days and was discharged following a negative covid- swab. she was not commenced on any anticoagulant in view of the history of rectal bleeding. one week post discharge, she was readmitted with sudden onset of altered consciousness associated with right-sided body weakness. her glasgow coma scale (gcs) was / , e v m on presentation. computed tomography (ct) brain was performed and revealed cerebral venous thrombosis of the straight sinus, vein of galen, and bilateral internal cerebral veins with venous infarcts (fig. ) . she was commenced on subcutaneous (s/c) enoxaparin mg twice a day (weight kg). on day of admission, she had a repeat ct brain and cerebral venography for fluctuating gcs level. the repeat brain scan showed evidence of thrombosis involving the superior sagittal and right sigmoid sinus as well, bilateral vasogenic edema, swollen left basal ganglia, and left thalamic region. she was started on intravenous dexamethasone for days to reduce cerebral edema and oral levetiracetam for seizure prophylaxis. her gcs started to improve days after the commencement of the above treatment. she had a repeat non-contrasted ct brain a week after her nd ct brain and showed unchanged multifocal infarcts, no intracranial hemorrhage, and less swollen left basal ganglia region. at the time of her discharge, her gcs was / and she was on nasogastric tube feeding and wheel-chaired bound due to incomplete recovery of her motor function. on her clinic follow-up a month later, her d-dimer was normal at . μg/ml, and her s/c enoxaparin mg bd was converted to oral warfarin. she is clinically stable on her last review months later. patients with polycythemia vera are deemed high-risk group if aged more than years old with or without history of thrombosis [ ] . these patients with polycythemia vera are prone to develop thrombotic and sometimes bleeding complications. this is certainly the case for madam a as she was years old. hence, she was treated with cytoreductive agent, hydroxyurea, and aspirin to achieve good disease control as per management of polycythemia vera in various guidelines [ ] [ ] [ ] . however, management of this group of patients becomes more complicated with coronavirus infection. coronavirus infection is a respiratory illness that was caused by sars-cov- . it releases pro-inflammatory cytokines such as il- , il- , and tnf-alpha which leads to systemic inflammatory response [ ] . patients with covid- infection are postulated to be in a hypercoagulable state and prone to develop micro-and macrothromboses [ ] . several studies have shown an increase prevalence of thromboembolism in covid- infection. in a series of patients hospitalized with covid- infection in china, . % of them developed deep vein thrombosis [ ] . in another study of covid- icu patients in the netherlands, % of them had thrombotic complications despite receiving standard doses thromboprophylaxis [ ] . we describe a case of cerebral venous thrombosis in covid- infection with underlying polycythemia vera a b fig. a axial non-contrast-enhanced ct showed ill-defined hypodensities at both basal ganglia and thalami, predominantly on the left, suggestive of the venous infarct. hyperdense thrombus was seen in both internal cerebral veins ( ) vein of galen ( ) and straight sinus ( ). b sagittal contrast-enhanced ct showed filling defect within the internal cerebral veins, vein of galen, straight sinus, torcula herophili extending to the superior sagittal sinus that happened in sarawak general hospital, malaysia during the early stage of the pandemic. to date, there is scarce data on patient with myeloproliferative neoplasm such as polycythemia vera, especially in the geriatric population, who has covid- infection [ ] . the complexity in the management of patient with polycythemia vera and coronavirus was demonstrated in the treatment of madam a. retrospectively, the patient should have been started on low molecular weight heparin while she was hospitalized based on prothrombotic tendencies of both coronavirus infection and polycythemia vera [ ] . however, this was not implemented as there was no clear guideline during the early stage of a pandemic where the knowledge of coronavirus management was still limited. furthermore, during madam a's first admission, her platelet counts gradually increased to more than × /μl and she developed lower gastrointestinal bleed. we need to balance the risks of further bleeding versus potentially fatal thrombotic event. to our knowledge, hypercoagulability in covid- infection can manifest as an elevated d-dimer level. there are few studies that have shown patients with venous thromboembolism in covid- infection have higher d-dimer [ , ] . in this case, we did not have her baseline d-dimer level at the time of admission. madam a's d-dimer level was . μg/ml (< . μg/ml) when she had per rectal bleeding. her d-dimer level was elevated from . to . μg/ml when she was diagnosed to have cerebral venous thrombosis during her second admission to the hospital (graph ). her d-dimer level subsequently decreased after she was started on therapeutic dose of low molecular weight heparin and normalized upon her discharge and follow-up. this showed that d-dimer can be used to guide us in predicting thrombotic complication in covid- infection. however, there is a limitation of d-dimer usage as a clinical marker to predict thromboembolic events. ddimer has high sensitivity but low specificity. it can be a b graph d-dimer level throughout the hospital stay and follow-up elevated in other medical conditions that increase fibrin production or breakdown. this includes malignancy, pregnancy, sepsis, myocardial infarction, stroke, liver disease, and postoperative state [ ] . covid- infection in a patient with polycythemia vera may present with bleeding and thrombotic manifestations. however, we should not treat this group of patients differently in the setting of coronavirus infection. patients should be assessed accordingly. if they are deemed high risk of thrombosis when considering underlying diseases such as polycythemia vera, they should be started on pharmacological thromboprophylaxis with close monitoring of bleeding tendencies. this anecdotal experience could also lead us to consider using d-dimer as a surrogate clinical marker for the risk of developing thrombotic event. it can also be used to monitor response to treatment of thrombosis in polycythemia vera patients in the context of covid- infection. however, this requires further validation via prospective studies. acknowledgments the authors would like to thank the director general of health malaysia for the permission to publish this paper. we would like to thank our colleagues from covid and infectious disease teams for their contributions and hard works during the covid- pandemic. conflict of interest the authors declare that they have no conflict of interest. the study was carried out in accordance with the declaration of helsinki and subsequent amendments or comparable ethical standards. informed consent written informed consent was obtained from the patient's next of kin. world health organization (who) coronavirus disease (covid- ) situation report- 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- : is it just a lung disease? a case-based review thromboembolic events in polycythemia vera how i treat polycythemia vera a guideline for the diagnosis and management of polycythaemia vera. a british society for haematology guideline understanding pathophysiology of hemostasis disorders in critically ill patients with covid- deep vein thrombosis in hospitalized patients with covid- in wuhan, china: prevalence, risk factors, and outcome incidence of thrombotic complications in critically ill icu patients with covid- extremely severe case of covid- pneumonia recovered despite bad prognostic indicators: a didactic report clinical management of adult coronavirus infection disease (covid- ) positive in the setting of low and medium intensity of care: a short practical review incidence of asymptomatic deep vein thrombosis in patients with covid- pneumonia and elevated d-dimer levels covid- and coagulation: bleeding and thrombotic manifestations of sars-cov- infection ddimer: simple test publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- - kr y authors: goletti, orlando; nessi, chiara; testa, amidio; albano, giovanni; torri, valter; beretta, giordano domenico; castoldi, massimo; bombardieri, emilio title: factors affecting mortality in covid- patients referred to an emergency department in bergamo during the peak of the pandemic date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: kr y the unexpected outbreak of covid- in the area of bergamo and the general crisis of personnel and devices has been managed as well as possible during the maximum peak of epidemic; humanitas gavazzeni hospital implemented its facilities and organization in order to optimize the treatment of patients. the number of beds in the intensive care unit (icu) was doubled (from to ), and more than beds were dedicated to the covid- patients. this paper analyzes the factors affecting mortality in covid- patients who referred to humanitas gavazzeni between february and march , . a total of ( . %) fatal events were registered: among those admitted to the intensive care unit (icu) and covid department and among those treated in acute admission unit level ii (aaul- ) who died before hospital admission. this paper studies dead cases by analyzing patient’s characteristics, physiological and laboratory parameters, symptoms, and the scores of severity of the disease. patients who had fatal events in the aaul- showed the worst parameters of risk. the most important differences regarded the apache ii score, glasgow coma score (gcs), crp (c-reactive protein), ph, creatinine, rr (respiratory rate), and asthenia. the outbreak of covid- in italy has recently become a public health emergency of international concern. northern regions were the most affected with , positive cases and , deaths in lombardy [ , ] . the province of bergamo was one of the most damaged, with a rapid increase of positive cases in a very short period [ ] . bergamo's hospitals had to face a tremendous overload of patients in the emergency department. the unpredictable influx of patients determined a deep crisis in personnel, beds, and devices. the facilities were not prepared for such a dramatic event. humanitas gavazzeni gave its maximum effort in order to assure the best assistance by implementing the icu beds, by transforming the normal wards in covid structures, and by organizing new protocols according to the international who recommendations for the pandemic management considering of a lack of validated protocols of specific treatment. it should also be considered that it was not possible to transfer any acute patients to other hospitals due to the spread of the same crises in the other structures of the healthcare system. a total of covid positive patients referred to the emergency department: were admitted into the hospital (covid department and icu) with respiratory disease and a wide spectrum of clinical manifestations, were discharged at home with therapy prescriptions and daily follow-up, and were observed and treated in a section of the emergency department (acute admission unit level ii, aaul- ) and died before admission. within the period of the maximum peak of endemic, fatal cases were registered: hospitalized patients and patients accepted in aaul- . this paper analyzes retrospectively the characteristics of deceased patients and describes the different distributions of parameters of severity of disease between two groups (those dead inside the hospital and those in aaul- ). we retrospectively evaluated the records of all patients referred to humanitas gavazzeni between february and march , , during the peak of pandemic. in that period, overall patients referred to the emergency department with different diseases, including covid pathology. a team of experienced intensivists and anesthesiologists detected covid- positive patients. their clinical status was evaluated according to the severity of disease, oxygen desaturation, fever, respiratory symptoms, radiologic imaging and paying attention to several indices of risk [ ] [ ] [ ] [ ] . the admitted cases with clinical diagnosis of covid- were confirmed by radiology and/or laboratory tests (nasopharyngeal swab). all patients showed severe disease, mainly characterized by persistent fever (> °c), recent worsening dyspnea, cough, and various flu-like symptoms. the aim of this study was the evaluation of fatal events registered within the considered period. overall patients died: patients into the covid- department and icu and in aaul- . we analyzed the data registered at patient presentation: age and sex, physiological and laboratory parameters, symptoms, and presence of comorbidities (cardiovascular diseases, respiratory diseases, arterial hypertension, diabetes, oncological diseases, chronic renal failure, neurological diseases, smoking, and others). we calculated also the chronic health evaluation ii (apache ii) [ ] score and the glasgow coma score (gcs), as indicators of risk of death, considering the measures obtained within h from the patients' admission. the informed consent for the scientific utilization and publications of data related to the disease was obtained by the patients at their admission according to the rules of humanitas gavazzeni covid- emergency department. this retrospective study was notified to the ich ethical committee (rozzano-milano). basic demographic characteristics were described by common statistical summary measures (frequencies and proportion for categorical data, mean and standard deviation for continuous variables). the association between these characteristics and the site of hospitalization, assessed by univariate and multivariate logistic model, were measured with the odds ratio (or) and % ci for each factor. the reported analysis did not consider the type of treatments administered to the patients, because of the various changes that occurred over the time. in fact, the therapy of covid patients has undergone revisions in a very short time, due to the subsequent indications and experiences in the national and international centers. all patients who died ( ) in aaul- received oxygen therapy and current supportive care, while hospitalized patients ( ) received different combinations of treatments according to the protocols discussed within the internal steering committee for covid- . in fig. the graph shows covid positive patients admitted to the emergency department during the peak of the pandemic ( february to march ), divided into those who were hospitalized in the covid department and icu (green), those who were discharged with home treatment and daily follow-ups (orange), and those who died in aaul- before the hospitalization (light blue) addition, patients were discharged with oxygen desaturation of ≥ % and treated at home with daily follow-up (fig. ) . we analyzed the distribution of the most important physiological and laboratory parameters in the dead patients ( ), split into those who died in aaul- ( ) and those who died inside the hospital ( ). mean, ci ( %), and p value have been reported (table , fig. ). the majority of cases was represented by males ( . %), while only ( . %) were females. the distribution of males and females was not different between groups; males represented % in both. the distribution of comorbidities (cardiovascular diseases, respiratory diseases, arterial hypertension, diabetes, oncological diseases, chronic renal failure, neurological disease, smoking history) was very similar between the two groups of patients. we were not able to collect information about comorbidities in all patients. in the group with fatal events in aaul- was registered a higher percentage of patients with > comorbidities ( patients, . %) than in the group admitted to the covid department and icu ( patients, . %) ( table ). there is evidence that there is a clear difference between the two groups of patients died in aaul- and in the covid department. a great statistical difference was observed in nearly all physiological and laboratory parameters. the age that is known as an important prognostic factor was considered in the evaluation of the apache ii score. a high difference for apache ii score and gcs that are currently used as index of severity of disease was observed between the two groups. patients who were treated in aaul- had a fatal event within h (median day, range - ), while patients admitted in the covid department or in icu died within days (median days, range - ). the multivariate analysis applied to the physiological and laboratory parameters, the symptoms, and the scores of severity of the disease was able to differentiate patients who died in aaul- and those in the covid department or in the icu for the following indicators: asthenia, smoking history, apache score, gcs, mean arterial pressure, ph, and crp (table ). this retrospective study reports the experience of the emergency department of humanitas gavazzeni in bergamo during the peak of the covid- pandemic. the epidemiological and clinical characteristics of covid patients, with the pronominal symptoms and the main comorbidities, were described in the recent paper by kaur et al [ ] . given the mortality rate of covid- , physicians should be aware of the potential risk factors associated with fatal outcome [ - ]. these have been described in the recent literature, however, due to the high rate of mortality observed in our emergency department, which is out of ( . %); we wanted to focus our attention on our deceased patients in that period ( february to march ). this high rate of death is based both on the severity of this viralinduced disease that progresses rapidly into severe acute respiratory failure and on the tremendous unexpected overload of patients referring to ed. of course, our structure made its maximum effort to face the situation. facilities, devices, and personnel were implemented in order to guarantee patients the best assistance as possible. in spite of the lack of validated protocols able to cure these unknown viral infections, fig. the graph shows ( %) covid positive patients admitted during the peak of the pandemic ( february to march ), divided into those who died in the covid department and icu (red), those who died in aaul- (light blue), and those who survived (orange) physicians optimized the patient's management in order to provide rational treatments able to control their symptoms. in fact, some of them, in spite of extremely severe conditions, were successfully discharged thanks to the intensive care received [ ] . this was done according to the who recommendation for endemic, the international literature on covid- , and the current indications of the scientific societies [ ] [ ] [ ] [ ] . we analyzed the most important risk factors able to characterize the dead population, and we observed that some of them resulted very important such as age, oxygen desaturation, ph, crp, and comorbidities as it was reported by the recent literature [ ] . we found also significant differences between patients deceased in covid department (including icu) and patients who died in the acute admission unit level ii (aaul- ). factors that were able to characterize the difference between these two groups were asthenia, smoking history, apache score, gcs, mean arterial pressure, ph, and crp. in particular, the apache ii score (including age for its calculation) was higher in the group died in aaul- , while gcs was lower. patients deceased in aaul- resulted in the worst conditions in comparison with patients who died in the icu and in covid- department, and their prognostic parameters reflect the situation. all patients received the correct therapy with respect to their clinical status and according to the internal protocols. patients who were critically ill received palliation and oxygen therapy. in conclusion this paper reports the most important factors of mortality risk, retrospectively calculated in patients treated at the ed of humanitas gavazzeni bergamo, in the period february to march corresponding to the peak of the covid- pandemic in our region. these results were obtained from our experience in a critical situation of emergency and through a monocentric study. they represent a further contribution to the knowledge on the factors that affect the risk of mortality from covid- , and in general, they do not differ from the experiences described in similar situations in other parts of the world. severe acute respiratory syndrome coronavirus (sars-cov- ) and coronavirus disease- (covid- ): the epidemic and the challenges clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study risk factors for severity and mortality in adult covid- inpatients in wuhan clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single-centered, retrospective, observational study epidemiological and clinical characteristics of covid- patients: a pooled analysis coronavirus covid- global cases by the center for systems science and engineering (csse real estimates of mortality following covid- infection clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study clinical features of cases with coronavirus disease clinical predictors of mortality due to covid- based on an analysis of data of patients from wuhan, china [published correction appears in intensive care med extremely severe case of covid- pneumonia recovered despite bad prognostic indicators: a didactic report clinical management of severe acute respiratory infection (sari) when covid- disease is suspected: interim guidance national health commission of the people's republic of china. chinese management guideline for covid- (version . ) apache-acute physiology and chronic health evaluation: a physiologically based classification system clinical features of patients infected with novel coronavirus in wuhan comorbidity and its impact on patients with covid- publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations acknowledgments the authors are grateful to dr. christine sangalli and dr. giada esposito for their kind support in the editorial assistance.funding information this paper was partially supported by the "fondazione humanitas per la ricerca" and by the private donation from ms. antonella manera in memory of her parents. conflict of interest the authors declare that have no conflict of interest.ethical approval all procedures in this study were in accordance with the ethical standards as laid down in the declaration of helsinki and its later amendments.informed consent the patients gave their informed consent to the anonymous publication of data for scientific purposes. this study has been notified to the local ethics committee.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 holder. to view a copy of this licence, visit http://creativecommons.org/licenses/by/ . /. key: cord- -l omunq authors: schönegger, carmen maria; gietl, sarah; heinzle, bernhard; freudenschuss, kurt; walder, gernot title: smell and taste disorders in covid- patients: objective testing and magnetic resonance imaging in five cases date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: l omunq smell and taste disorders are acknowledged as characteristic symptoms for sars-cov- infection by now. these symptoms have been linked to a neuroinvasive course of disease. in this study, we investigated five consecutive covid- patients with a prolonged course of dysosmia and dysgeusia. those with objectifiable alteration in taste or smell were subjected to mri with contrast agent to investigate possible involvement of the central nervous system. we found dysosmia and dysgeusia to be mostly objectifiable, but no evidence for neuroinvasiveness could be detected by mri in the late stage of the disease. alterations in taste and smell could be objectified in most patients. nevertheless, no evidence for a neuroinvasive potential could be identified by mri, at least in the late stage of disease. we encourage medical professionals to conduct specialized examinations and mris in the acute stage of disease, which guarantees an optimum patient care. although a lot of effort has been made in order to investigate this novel coronavirus, our knowledge about many pathogenic aspects of covid- is still limited. clinical and experimental studies proved that several coronaviruses have neuroinvasive capacities, since they show the ability to spread from the respiratory tract to the central nervous system [ ] . hypothesis of neurotropism of sars-cov- is based on covid- patients with neurological manifestations. furthermore, neurological complications up to actual damage hint neurovirulence [ ] . actual case reports substantiate this assumption. covid- can cause meningitis with a fatal outcome, which was evidenced by the case of a -year-old man in japan, who succumbed to the disease [ ] . brain mri demonstrated hemorrhagic lesions that were consistent with acute necrotizing hemorrhagic encephalopathy [ ] . another manifestation of nervous system involvement is the appearance of alterations of taste and smell [ ] . anosmia and dysgeusia are by now acknowledged as significant symptoms in association with covid- by the american academy of otolaryngology-head and neck surgery (aao-hns) and other researches [ , ] . case series show a high frequency of chemosensitive disorders in patients, ranging between . and % [ , ] . according to vaira et al., the presence of olfactory and gustatory dysfunction may predict a milder course of disease. on the other hand, the neglect of such symptoms suggests a more severe course of disease [ ] . some patients reported isolated olfactory or taste disorders, but more complained about a combined dysfunction. even though a complete recovery could be noted in regard to most patients, evidence has been found about persisting alterations in chemosensory function for a prolonged period [ ] . at the shahid beheshti university of medical sciences in tehran/iran, possible olfactory bulb alterations were investigated by olfactory bulb magnetic resonance imaging. in spite of isolated sudden onset anosmia and positive sars-cov- polymerase chain reaction during the acute phase of the carmen maria schönegger and sarah gietl contributed equally to this work. this article is part of the topical collection on covid- disease, the mri demonstrated normal volume and signal intensity of olfactory bulb with no sign of nasal congestion [ ] . the study was conducted on five patients reporting impairment of taste and smell with confirmed sars-cov- infection in east tyrol. written informed consent was obtained from all participants. age ranged between and years, and all the participants were female. clinical data and history of symptoms were assessed anamnestically. olfactory and gustatory testing was conducted between and days after disease onset, which was defined as the commencement of symptoms. in case objective testing revealed alterations in taste or smell, patients were subjected to mri in a timely manner. a follow-up examination was conducted in three of the patients whose mri raised suspicion of alterations in the first run. olfactory and gustatory function assessment was carried out by means of burghart screening test with taste strips in accordance with the manufacturer's instructions [ , ] . in order to evaluate olfactory function, an identification test, called sniffin' sticks, was performed [ ] . twelve common odorants were consecutively presented to the patient close to both nostrils. out of four options the participant was requested to identify the presented smell. results were interpreted according to a scoring system considering patients age. a score above ten was determined as normal, between six and ten a hyposmia was diagnosed and a score below six was reported as anosmia. gustatory testing was performed by taste strips covering the four basic gustatory qualities sweet, salty, sour, and bitter [ ] . taste strips were applied on patient's tongue. for each stripe, the test person had to choose the corresponding odor from four answers. according to the count of correct answers, four categories of classification were established: normal (score ), mild hypogeusia (score ), moderate hypogeusia (score ), severe hypogeusia (score ), and ageusia (score ). a standard brain mri protocol was used involving axial t tse, axial flair, axial dwi (b and b ), dadc, axial t w ffe, and isotropic t w d ir tfe with a -mm slice thickness without contrast media and cet w d mprage, on a . t prodiva philips mri machine. the d t sequences with and without contrast were reconstructed in coronal, axial, and sagittal projection for the radiologic evaluation. a short-term follow-up examination days later was performed with the same axial flair and dwi/dadc. sequences were used as well as isotropic d t and d flair sequences (appendix). olfactory and gustatory testing was conducted between and days after onset of disease, which was defined as the commencement of symptoms. out of the five patients three showed a manifest anosmia, one result was rated as a hyposmia and one as normosmia. gustatory testing revealed two normal scores ( / ), one moderate hypogeusia ( / ), one severe hypogeusia ( / ), and one ageusia ( / ). detailed results are summarized in table . three weeks after the first olfactory and gustatory examination, a follow-up testing was conducted with the three patients who also had a second mri. this investigation revealed one persistent anosmia ( / ), one persistent hyposmia ( / ), and one patient's condition improved from anosmia to hyposmia ( / ). gustatory testing showed an enhancement in two patients ( / ; / ); one patient had the same score ( / ). detailed results are summarized in table . none of the patients showed any changes in the paranasal sinuses, not even small fluid collections or mucosal swelling. the cribriform plate was normal in all cases, and the olfactory nerve was normal in size and signal, without any side differences and there was no neuronal or perineural enhancement. the meninges showed no enhancement or thickening. the gyrus rectus was normal in size and signal intensity in all patients and showed no swelling. no signal changes in the medial temporal lobes or the thalami could be found and no hemorrhagic microbleeding in t * sequences were observed. even though ischemic events and leptomeningeal enhancement have already been reported, there were no signs for an acute or chronic ischemic event [ ] . in the first examination, one patient showed a symmetric, slightly hyperintense signal in the head of the caudate nucleus, parahippocampal gyrus, and the uncus, predominantly on the left side. in t , the area appeared thicker and swollen with a higher si, but all the other sequences including dwi were normal. also, si measurements were slightly elevated with values of compared to on average in primarily healthy individuals. in the follow-up examination, there was a slight drop to , but the additional high-resolution d flair and t images showed no anomalies, so probably this finding lies within the normal range. all the other patients had a normal brain mri (images , , and ). in contrast to galougahi et al., we evaluated symptom status in the late stage of covid- [ ] . the smell and taste disorders could mostly be objectified, although not in regard to all patients, which underlines the necessity of objective testing. compared to dell'era et al., who reported a median recovery time of days, our findings show that olfactory impairment is a long-lasting sequela of covid- [ ] . even after to days, patients still suffered from objectifiable smell and taste disorders. in order to rule out permanent damage, further surveillance is necessary. however, it should be notified that a loss of smell and taste is not pathognomonic for covid- , as it appears as well in the course of other respiratory infections. nevertheless, controlled studies indicate that anosmia is more common in covid- patients than in patients suffering from other viral infections or controls [ ] . in contrast to other infectious smell impairments, a loss of smell and taste in covid- seems to be rarely accompanied by a severely blocked nose [ ] . the first mri images showed slight alterations in one patient, which could be associated with a sars-cov- infection. however, the follow-up examination contradicted this assumption. image mri cor t the mri investigation in our patients taught us two things: first, at least in chronic stages of the illness, we did not gain any evidence of prolonged neuroinvasive association. up to now, mri investigations have focused on the acute stage of illness and are very rare. in our case, the organization was hindered by the concern that such investigations might be an incalculable risk for the staff involved. according to politi et al., conducting an mri examination in a patient suffering from persistent severe anosmia and dysgeusia, cortical hyperintensity in the right gyrus rectus could be detected days after symptom onset. consistent with our results, a complete resolution of the previously seen signal alterations could be observed in a follow-up imaging days after symptom onset [ ] . contrary to assumptions of other researchers, no evidence of a general neuroinvasiveness could be given, at least in the chronic stage of disease [ ] . more extensive studies in the acute stage of illness followed by long-term follow-ups are desirable. contrary to other evaluations, our study population is rather small which is a limiting factor to the informative value. as hygiene measures proved to be sufficient avoiding contagion, we encourage medical professionals to conduct specialized examinations and mris in the acute stage of disease, which guarantees an optimum patient care. authorship contribution sg and cms wrote the manuscript and were responsible for the organization. bh was responsible for magnetic resonance imaging, kf for the objective olfactory and gustatory testing. gw supervised and reviewed the manuscript. conflict of interest the authors declare that they have no conflict of interest. consent for publication written informed consent was obtained from all participants. ethics approval ethical approval was not necessary as the evaluation was performed in the course of patient care and clinical monitoring. human coronaviruses and other respiratory viruses: underestimated opportunistic pathogens of the central nervous system? viruses neurological complications of coronavirus and covid- a first case of meningitis/ encephalitis associated with sars-coronavirus- covid- -associated acute hemorrhagic necrotizing encephalopathy: ct and mri features evidence of the covid- virus targeting the cns: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms covid- anosmia reporting tool, american academy of otolaryngology-head and neck surgery self-reported loss of smell and taste in sars-cov- patients: primary care data to guide future early detection strategies isolated sudden onset anosmia in covid- infection. a novel syndrome? olfactory and gustatory dysfunctions as a clinical presentation of mild-tomoderate forms of the coronavirus disease (covid- ): a multicenter european study olfactory and gustatory function impairment in covid- patients: italian objective multicenter-study objective evaluation of anosmia and ageusia in covid- patients: single-center experience on cases olfactory bulb magnetic resonance imaging in sarscov- -induced anosmia: the first report normative data for the "sniffin' sticks" including tests of odor identification, odor discrimination, and olfactory thresholds: an upgrade based on a group of more than , subjects taste strips" -a rapid, lateralized, gustatory bedside identification test based on impregnated filter papers neurologic features in severe sars-cov- infection smell and taste disorders during covid- outbreak: cross-sectional study on patients the role of self-reported smell and taste disorders in suspected covid- predictive value of sudden olfactory loss in the diagnosis of covid- magnetic resonance imaging alteration of the brain in a patient with coronavirus disease (covid- ) and anosmia sars-cov- : olfaction, brain infection, and the urgent need for clinical samples allowing earlier virus detection publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- -yt bgc authors: ferrara, francesco; de rosa, francesco; vitiello, antonio title: worldwide recommendations and therapies for multiple sclerosis: are they safe in the covid- pandemic period? date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: yt bgc nan dear editor, sars-cov- infection has spread rapidly throughout the world causing a global pandemic and a health emergency with a few precedents in the human history. some categories of people such as those with pre-existing comorbidities, the elderly, or people with chronic therapeutic treatments are at greater risk of infection and complications and can rapidly develop serious respiratory tract injuries. the host immune system is very important in the early stages of sars-cov- infection to combat viral replication. patients with multiple sclerosis (ms) treated with immunomodulating pharmacological agents may have a higher risk of becoming infected with sars-cov- and associated complications. proper management of the clinical pharmacological aspects of the ms patient is of paramount importance especially in this period of the covid- pandemic. the data show that the ms patient has a higher risk of infection (about + %) than the general population and the most frequent hospitalizations are caused by respiratory and urinary tract infections. this is why it can be said that the patient with ms is a fragile patient, and in this pandemic period, he or she needs to be closely monitored. treatments for ms are immunomodulatory and include first-line drugs such as interferon beta (ifn-β), glatiramer, dimethylfumarate, and teriflunomide and second-line drugs such as fingolimod, natalizumab, ocrelizumab, alemtuzumab, and cladribine. thanks to these treatments, it is possible to control the disease for many years, but these therapeutic agents can also lead to adverse reactions with serious effects and an increased risk of viral, bacterial, and fungal infections [ ] [ ] [ ] [ ] . the safety profile of ifn-β and glatiramer has been evaluated in numerous studies; the most frequent adverse reactions recorded are flu-like syndrome symptoms and injection site reaction. at the moment, they seem to be the safest drugs to avoid the risk of infection. fingolimod can lead to serious adverse reactions, and the most common are urinary and lower respiratory tract infections. these reactions have been shown to be due to the reduction of lymphocytes in the blood. the use of teriflunomide and dimethylfumarate shows that these drugs lead to a slight reduction in white blood cell counts that could expose the patient to serious infectious risks. adverse events of ocrelizumab concern allergic reactions due to infusion, itching, rash, hives, hypoglobulinemia, and lymphocytopenia associated with secondary infections. based on the current literature, patients with ms being treated with these drugs should be closely monitored for any increased risk of infection associated with the drugs and the disease. medications such as ifn-β and glatiramer seem to be safer in this respect; ocrelizumab or cladribine seems to lead to a higher risk of infection than other drugs. at the moment, the guidelines of the various countries and scientific societies have not always coinciding positions on this delicate issue [ , ] . in general, no country recommends stopping ms treatment. all countries agree that ifn-β is the safest drug and can also protect against covid- infection due to its antiviral properties. treatment with glatiramer is also considered to be very safe. the usa offers the doctor greater freedom of choice as to whether or not to continue with ongoing therapy. the food and drug administration simply divided the drugs according to risk. in general all recommendations consider that first-line drugs (teriflunomide and dimethylfumarate) should be continued and suspended in case of covid- infection; in germany and canada, suspension is also recommended in case of severe lymphopenia. in italy the position is more cautious with regard to teriflunomide, and the possible shift towards interferon therapy should be evaluated. secondline therapy with fingolimod does not have a common point of view among the various countries; in germany and canada, it is recommended to continue the therapy by carefully assessing the risk; in italy the suspension or switch to ifn-β is assessed. impoverished drugs (cladribine, ocrelizumab, and alemtuzumab) should be carefully evaluated. treatment with natalizumab is considered safe in this pandemic period; in italy there is more caution with immediate suspension in case of covid- positive patients [ ] . sars-cov- has highlighted even more the issue of drug safety for ms, especially for new immunomodulatory drugs with higher potential risks of infection. is it safe to continue therapy during the pandemic? based on the evidence in the literature, the position of agencies in different countries, and the complexity of ms treatment, it is not recommended to discontinue ms therapy but to carefully assess the risk of infection. the manuscript was written entirely by the authors, and all authors made an equal contribution in the development of the paper. compliance with ethical standards there are no sensitive data and no patients were recruited for this study. the document does not conflict with ethical legislation. ms society medical advisors. ms treatments and covid- coronavirus clinical characteristics of coronavirus disease in china liver injury in covid- : management and challenges clinical features of patients infected with novel coronavirus in wuhan, china oral drugs in multiple sclerosis therapy: an overview and a critical appraisal publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. sn compr the authors declare that they have no conflict of interest. key: cord- - tdrd w authors: siordia, juan a.; bernaba, michael; yoshino, kenji; ulhaque, abid; kumar, sooraj; bernaba, mario; bergin, edward title: systematic and statistical review of coronavirus disease treatment trials date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: tdrd w the following systematic review and meta-analysis compile the current data regarding human controlled covid- treatment trials. an electronic search of the literature compiled studies pertaining to human controlled treatment trials with covid- . medications assessed included lopinavir/ritonavir, arbidol, hydroxychloroquine, tocilizumab, favipiravir, heparin, and dexamethasone. statistical analyses were performed for common viral clearance endpoints whenever possible. lopinavir/ritonavir showed no significant effect on viral clearance for covid- cases (or . [ % ci . – . ]). hydroxychloroquine also showed no significant effect on covid- viral clearance rates (or . [ % ci . – . ]). arbidol showed no -day (or . [ % ci . – . ]) or -day viral (or . [ % ci . – . ]) clearance difference compared to lopinavir/ritonavir. review of literature showed no significant clinical improvement with lopinavir/ritonavir, arbidol, hydroxychloroquine, or remdesivir. tocilizumab showed mixed results regarding survival. favipiravir showed quicker symptom improvement compared to lopinavir/ritonavir and arbidol. heparin and dexamethasone showed improvement with severe covid- cases requiring supplemental oxygenation. current medications do not show significant effect on covid- viral clearance rates. tocilizumab showed mixed results regarding survival. favipiravir shows favorable results compared to other tested medications. heparin and dexamethasone show benefit especially for severe covid- cases. severe acute respiratory syndrome-coronavirus (sars-cov ) is a novel coronavirus responsible for causing coronavirus disease . it quickly became a pandemic in the beginning of . originating in wuhan, china, the virus rapidly spread to other countries of the world [ ] . on january , , the world health organization (who) declared sars-cov a public health emergency of international concern (pheic) [ ] . medications are quickly being tested to assess for a suitable treatment regimen for the novel virus. the following systematic and statistical review assesses the current evidence regarding human controlled covid- treatment trials. an electronic search compiled human controlled studies analyzing treatments for covid- . medical therapies investigated included lopinavir/ritonavir, arbidol, hydroxychloroquine, remdesivir, favipiravir, heparin, glucocorticoids, interferon, ivermectin, and convalescent plasma. inclusion criteria included needing a control (whether standard therapy, placebo, or another medication) and testing among human subjects with covid- . in vitro and animal studies plus those without controls were not included in the review. databases included google scholar and pubmed. key words included covid- , sars-cov , randomized, this article is part of the topical collection on covid- controlled, human, retrospective, prospective, trial, chloroquine, hydroxychloroquine, lopinavir, ritonavir, arbidol, umifenovir, tocilizumab, favipiravir, steroids, dexamethasone, glucocorticoids, interferon, ivermectin, remdesivir, azithromycin, heparin, and low-molecular weight heparin. abstracts and titles were reviewed for relevancy. studies that had human subjects and a control arm were included in the study; otherwise, they were excluded. duplicated studies were removed. the studies were organized based on the study medication; some studies presented more than one study medication and were included in more than one group. statistical analysis was performed if there were two or more studies showing information regarding positive-to-negative conversion rates; number of days varied based on reported similarities among chosen studies. if there were any common endpoints among the trials collected, a meta-analysis would then be performed. endpoints were related to viral clearance. statistical analyses used the review manager version . (the cochrane collaboration, copenhagen, denmark) software program. a forest plot was created using the program with the dersimonian and laird fixed-effects model to reduce heterogeneity. the mean difference with a confidence interval (ci) of % was reported with the inverse variance method. due to using a scale, the value marking no significance via confidence interval was zero. an i greater than % suggests significant heterogeneity. if there was significant heterogeneity, a random-effects model would be used instead. a total of articles were found with the keywords selected. a total of studies were included initially based on title and abstract review. a total of studies were included in the systematic review: four studies elaborated about lopinavir/ r i t o n av i r ; f o u r s t u di e s s t u d i e d a r bi d o l , s i x f o r hydroxychloroquine, one for remdesivir, six for tocilizumab, two for favipiravir, two for heparin, and one for dexamethasone. statistical analyses regarding positive-to-negative conversion rates were possible for lopinavir/ritonavir, arbidol, and hydroxychloroquine. no human controlled trials were found for glucocorticoids, interferons, ivermectin, or convalescent plasma. statistical analysis regarding positive-to-negative conversion rates was possible for lopinavir/ritonavir (two studies), arbidol (two studies), and hydroxychloroquine (four studies) (fig. ). treatment four controlled trials exist regarding the treatment for covid- (table ) . two studies are randomized controlled trials and two are retrospective controlled studies [ ] [ ] [ ] [ ] . the most recognized is the randomized, controlled, openlabel trial by cao et al. [ ] the study showed no significant difference in terms of -day mortality or time of positive-tonegative reverse transcriptase-polymerase chain reaction (rt-pcr) conversion. lopinavir-ritonavir did reduce the time to clinical improvement by day but was considered marginally non-statistically significant. this study had many limitations. the study was organized as an open label and with lack of placebo. about % of trial recipients could not complete a full -day treatment course due to adverse medication effects including nausea, vomiting, and diarrhea. however, the incidence of respiratory failure, acute kidney injury, and secondary infection was higher in the standard-care group. positive-to-negative rt-pcr conversion was not significant with lopinavir-ritonavir ( fig. ) [ , ] . there was no significant difference between the study and control group at days (or . [ % ci . - . ]). other retrospective studies suggest earlier clearance with lopinavir-ritonavir but did not report the results at days [ , ] . furthermore, the two studies that did suggest clearance are retrospective studies while the other two are randomized controlled trials. the most significant lopinavir/ritonavir side effects include loss of appetite, nausea, vomiting, and diarrhea [ , ] . diarrhea can possibly become severe [ ] . apart from elevated transaminase levels, other laboratory markers do not significantly differ from the control group [ , ] . there are currently four controlled trials discussing the use of arbidol for the treatment of covid- patients (table ) [ , [ ] [ ] [ ] . two of the trials are randomized while the other two are retrospective studies. only li et al. includes a comparison between arbidol and standard supportive therapy [ ] . the two retrospective studies include a comparison with lopinavir/ritonavir [ , ] . chen et al. compare arbidol with favipiravir [ ] . arbidol was commonly compared with lopinavir/ritonavir [ , ] while there is no difference in positive-to-negative conversion rates between the two medications at the seventh (or . no significant difference in positive-to-negative rt-pcr conversion or time to clinical improvement t = c = ye et al. [ ] retrospective (t = ; c = ) symptoms and labs improved earlier for lopinavir/ritonavir group. positive-to-negative rt-pcr conversion also decreased with lopinavir/ritonavir. yan et al. [ ] retrospective symptoms improved earlier for lopinavir/ritonavir group. positive-to-negative rt-pcr conversion also decreased with lopinavir/ritonavir. t, treatment group (lopinavir/ritonavir); c, control group employed to counter the heterogeneity, resulting in a nonsignificant difference between the two medications. adding arbidol with lopinavir/ritonavir did show significant conversion rates and ct scan improvements compared to lopinavir/ritonavir by itself [ ] . while favipiravir did not show any difference compared to arbidol regarding -day recovery rate, it did show faster recovery from fever and cough. there was no difference regarding oxygen and non-invasive positive pressure ventilation use between arbidol and favipiravir [ ] . arbidol side effects include nausea and diarrhea [ ] . arbidol demonstrated less hyperuricemia compared to favipiravir (p = . ). both favipiravir and arbidol did not show any significant difference in abnormal liver function tests, psychiatric symptom reaction, or digestive tract reactions [ ] . six controlled trials exist comparing hydroxychloroquine versus standard therapy (table ) [ ] [ ] [ ] [ ] [ ] [ ] . three studies were randomized, one was prospective, and two were retrospective studies. the data regarding hydroxychloroquine remains equivocal. the three randomized controlled trials present conflicting information regarding significance in clinical improvement and positive-to-negative conversion [ , , ] . chen z et al. observed conversion based on ct scan results, but ct scans have a high negative predictive value for covid- during the pandemic [ ] [ ] [ ] [ ] . the prospective trial by gautret et al. showed earlier conversion with hydroxychloroquine [ ] . they included patients that took azithromycin with hydroxychloroquine in their study, but that was not included in this analysis. they have yet to present clinical status changes from their study. a retrospective controlled study among veterans showed increased mortality with hydroxychloroquine use. mechanical ventilation rates were similar among the two study arms [ ] . another retrospective review showed no difference in inhospital mortality [ ] . the positive-to-negative conversion analysis (fig. ) was performed at - days to include all the studies. rt-pcr or ct scans were used to monitor time to covid- resolution. hydroxychloroquine did not show significant effects on positive-to-negative conversion time compared to standard therapy (or . [ % ci . - . ]). with significant heterogeneity (i = %), a random-effects model was used. deng l et al. [ ] retrospective lpv/r lpv/r + arbidol dual therapy with lpv/r and arbidol showed better -and -day negative conversion rates and more -day chest ct scan improvements compared to lpv/r alone [ ] retrospective lpv/r arbidol arbidol had shorter duration of positive rna tests compared to lpv/r [ ] randomized no anti-viral therapy arbidol positive-to-negative conversion rates and ct scan clearance rates were similar between arbidol and the control group at and days. t, testing group; c, control group; lpv/r, lopinavir/ritonavir analyzing the three randomized controlled trials only showed no significant difference between hydroxychloroquine and standard therapy (or . [ % ci . - . ]) (fig. ) [ , , ] . this was with nonsignificant heterogeneity (i = %), and therefore a fixed-effects model was kept. cardiac complications, including cardiac arrest, were more common with hydroxychloroquine use especially when combined with azithromycin [ ] . gastrointestinal symptoms, including diarrhea and elevated transaminase levels, were mentioned with hydroxychloroquine, but they were not statistically significant compared to the control groups [ , , ] . currently there is only one published controlled trial with remdesivir (table ) [ ] . the randomized, double-blind, placebo-controlled trial showed no difference in time to clinical improvement compared to the control arm (hazard ratio . [ % ci . - . ]) [ ] . a limitation of the study however was that patients in both groups were permitted concomitant use of lopinavir-ritonavir, interferons, and/or corticosteroids. about % who received remdesivir reported an adverse side effect. the most common side effects were constipation, hypoalbuminemia, hypokalemia, anemia, thrombocytopenia, and increased bilirubin [ ] . six studies assessed the benefits of tocilizumab (table ) . tocilizumab presents with mixed results. half of the studies report no significant benefit compared to standard therapy [ ] [ ] [ ] , while the other half report improvement for severe cases or improved hospital stay, survival, and freedom from ventilation [ ] [ ] [ ] . no studies assessed the duration of positive-to-negative sars-cov conversion. the following studies did not report any associated side effects with tocilizumab compared to standard therapy. there are two controlled trials regarding the use of favipiravir (table ) [ , ] . the first is a randomized controlled trial comparing favipiravir to arbidol for covid- patients [ ] . arbidol effects are similar to standard therapy [ ] . the other is an open-label, non-randomized, prospective trial comparing favipiravir versus lopinavir/ritonavir [ ] . lopinavir/ ritonavir is also similar to standard therapy [ , ] (table ) . chen et al. showed no significant -day recovery rate with favipiravir compared to arbidol. the secondary endpoints of fever and cough relief did resolve significantly sooner with favipiravir compared to arbidol, with fever resolving for all patients at day (versus days - ) and cough improving at day (versus day +). there was no difference regarding oxygen and non-invasive positive pressure ventilation use [ ] . favipiravir shows a similar side-effect profile as to lopinavir/ritonavir, including nausea, vomiting, diarrhea, rash, and elevated transaminase levels [ , ] . compared to arbidol, it increases uric acid levels more. while the side effect profile is similar to lopinavir/ritonavir, the frequency of adverse effects is less with favipiravir [ ] . treatment two retrospective controlled studies included data regarding heparin use (table ) [ , ] . these studies involved deep vein thrombosis prophylaxis dosing of unfractionated ( , iu/day) and low-molecular weight ( - mg/day) heparin (table ) . tang et al. showed no difference in -day mortality rates. most patients received low-molecular weight heparin. they note significant improvement in heparin users among those with severe sepsis-induced intravascular coagulopathy. this was determined by a scoring system utilizing platelet count, prothrombin time, and sequential organ failure assessment (sofa) scoring [ ] . shi et al. showed no difference in outcomes including clinical improvement and positive-to-negative conversion rate. all patients in the study improved [ ] . the studies included in the review did not report adverse effects. however, all heparin medications have welldocumented side-effects including hemorrhage, osteoporosis, renal tubular acidosis type with hyperkalemia, and heparininduced thrombocytopenia [ ] [ ] [ ] . adverse effects of low- molecular weight heparin are more common in patients with kidney injury [ ] . deep vein thrombosis prophylaxis presents with a lower rate of side-effects [ ] . one large randomized controlled trial, the recovery trial, found an overall benefit when assessing all covid cases together (table ) [ ] . while there was no benefit for those without oxygen needs, dexamethasone reduced mortality by one-fifth in patients requiring noninvasive oxygen therapy, and by one-third in those requiring mechanical ventilation. dexamethasone also reduced hospital length of stay and progression to needing invasive mechanical ventilation. while the recovery trial does not report any adverse reactions compared to the standard therapy, glucocorticoids have multiple side-effects. adverse reactions from acute use include altered mental status, hyperglycemia, increased risk for infection, hypertension, arrhythmias, and myopathy [ , ] . lopinavir/ritonavir, arbidol, hydroxychloroquine, favipiravir, remdesivir, and heparin are medications that have been tested in human controlled trials for covid- treatment. for the meta-analyses, neither lopinavir/ritonavir nor hydroxychloroquine showed significant positive-to-negative conversion rates. the systematic review revealed inconclusive or negative results for all medications regarding clinical improvement. favipiravir showed significant improvement compared to its competitor medications, but there were no supportive therapy or placebocontrolled trials. heparin showed significant clinical improvement only with those with severe covid- . apart from heparin, the adverse effects of the medications mainly include gastrointestinal symptoms. lopinavir, a hiv protease inhibitor, inhibits the major protease involved in covid- replication and development of functional viral proteins. ritonavir acts to increase the levels of lopinavir and improve bioavailability [ ] [ ] [ ] . lopinavir/ ritonavir along with ribavirin were previously used to treat sars in non-randomized clinical trials to prevent development of ards [ ] . in vitro studies show an antiviral effect of lopinavir on covid- [ ] . however, human trials show no significant difference in clinical improvement and viral shedding. furthermore, a comparison trial shows inferiority to arbidol regarding viral clearance [ ] . while arbidol has displayed antiviral effects with previous coronaviruses [ ] [ ] [ ] , the mechanism of action on covid- is currently unknown. in human trials, arbidol shows no significant positive-negative conversion rate or recovery time compared to standard therapy or lopinavir/ritonavir [ , ] . the meta-analysis comparing -and -day viral clearance between arbidol and lopinavir/ritonavir possibly favored arbidol significantly. employing a random-effects model to account for large heterogeneity removed the statistical significance. it does show promise for post-exposure prophylaxis [ ] . hydroxychloroquine, a member of the -aminoquinolines, works by neutralizing the acidic potential of lysosomes resulting in an inhibition of cell chemotaxis, phagocytosis, antigen presentation, and interferon release [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . in vitro studies have shown its anti-viral effects on covid- , specifically by preventing viral infusion by altering the ph of cell membranes and impairing ace receptor-mediated entry. it further disrupts viral activity inside the cell [ ] . combining t, treatment group (remdesivir); c, control group all the hydroxychloroquine human trials showed no benefit with reducing covid- viral shedding time. most of these studies included azithromycin. one retrospective trial suggests increase mortality with hydroxychloroquine use [ ] . the ineffectiveness, high side-effect profile, and increased mortality caused researchers from the solidarity trial-a trial comparing the effects of hydroxychloroquine, remdesivir, lopinavir-ritonavir, and interferon-beta-to cancel their hydroxychloroquine study arm [ , ] . there are no human trials showing the efficacy of hydroxychloroquine for covid- prophylaxis. side-effects include visual abnormalities, gastrointestinal issues, cardiac arrhythmias with qt interval prolongation, drug-induced psychosis, and leukopenia. it also interacts with various other medications, including heparin to increase the risk of the bleeding and lopinavir/ ritonavir to further prolong the qt interval [ ] . remdesivir is a prodrug that is metabolized into an analogue of adenosine triphosphate, allowing it to inhibit viral rna polymerases [ ] . in vitro studies exhibit its potential in combating sars-cov [ , ] . a cohort study suggested potential benefit as compassionate use for severe covid- [ ] . however, the randomized, double-blinded, placebocontrolled trial included in the review showed no statistical effect with remdesivir regarding clinical improvement, mortality, and viral load change [ ] . adverse effects were not significant among the groups. limitations to the study included both study groups allowing for other therapies (i.e., glucocorticoids and lopinavir/ritonavir), although their use was not colaneri et al. [ ] prospective tocilizumab did not reduce -day mortality rates. t = c = (hydroxychloroquine, azithromycin, heparin dvt prophylaxis) martinez-sanz et al. [ ] retrospective tocilizumab had no difference in death or icu admissions compared to the control. t = c = ip et al. [ ] retrospective tocilizumab had no statistically significant benefit in icu survival. t = c = wadud et al. [ ] retrospective tocilizumab was associated with increased survival for patients requiring mechanical ventilation t = c = capra et al. [ ] prospective tocilizumab was associated with improved in-hospital survival t = c = (hydroxychloroquine and lopinavir/ritonavir) rossi et al. [ ] retrospective tocilizumab was associated with improved survival and freedom from ventilation t = c = t, treatment group (tocilizumab); c, control group [ ] prospective lopinavir/ritonavir favipiravir showed more -day chest ct scan improvement and sooner viral clearance compared to lopinavir/ritonavir t = c = t, treatment group (favipiravir); c, control group significantly different among the groups. remdesivir was also started late in some of the study patients. the study was also considered underpowered [ ] . tocilizumab is an il- antibody that suppresses acute phase reactants [ ] . it shows a possible benefit for patients with covid . few studies showed survival benefit plus decreased risk of ventilation and disease progression. however, other studies showed no significant benefit. more studies are required to establish the true benefit of tocilizumab. favipiravir is a broad spectrum antiviral against rna viruses. inside infected host cells, it becomes phosphorylated into favipiravir-rtp and inhibits viral rna-dependent rna polymerase [ , ] . favipiravir also suppresses tumor necrosis factor-alpha (tnf-a) production [ , ] . the human covid- trials with favipiravir are compared with two specific controls. compared to arbidol, favipiravir reduces symptom duration [ ] . compared to lopinavir/ritonavir, favipiravir reduces viral shedding time and hastens chest ct scan improvement while having fewer side effects [ ] . favipiravir adverse effects include gastrointestinal symptoms and elevated uric acid levels [ , ] its safe profile has made it a preferred medical therapy for those with cardiovascular and renal disease [ , ] . heparin has various non-anticoagulant properties including reducing il- -associated inflammation [ ] [ ] [ ] . il- causes hypercoagulation [ ] . levels are significantly higher in severe covid- patients [ , , ] . heparin binds to il- , reducing the interaction between il- , sil- r, and sgp [ ] . this benefit may explain the meta-analysis findings showing ards-associated mortality benefit with early low-molecular weight heparin initiation [ ] . heparin also binds to various viral entry proteins, including herpes simplex, zika, and sars [ ] [ ] [ ] . similarly, it attaches to the s spike protein of covid- and causes a conformational change, inhibiting viral membrane fusion with the cell wall [ ] . the current studies suggest benefit mainly with severe covid- cases [ , ] . dexamethasone shows promise with decreased mortality in overall covid- cases. the benefit is particularly seen with patients requiring supplemental oxygenation or mechanical ventilation. there was no benefit for mild cases. this may be due to dexamethasone suppressing the cytokine storm [ ] . while only one study showed results regarding dexamethasone, it was a large, randomized controlled trial. the meta-analysis portion of the study has some limitations. the first limitation is the small number of patients in the trials and therefore the overall analysis. another limitation is the use of surrogate endpoints to complete the meta-analysis. this is regarding the use of ct scan resolution for viral clearance in the hydroxychloroquine analysis. chest ct scans have significant negative predictive value, but is not directly comparable to rt-pcr [ ] [ ] [ ] [ ] . the endpoints were not well-established among all reviewed medications, making it difficult to compare them between studies. regarding the systematic review, publication bias influences the information presented. favipiravir trials on covid- only involve those compared with other no difference in positive-to-negative clearance rate or duration of hospital stay t = c = t treatment group (heparin); c control group horby et al. [ ] randomized dexamethasone reduced -day mortality, especially in those requiring any form of oxygenation. t = c = t, treatment group (dexamethasone); c, control group medications and not with a placebo or supportive therapy control arm. the heparin and dexamethasone studies mainly involved the level of severity of covid- rather than having the infection itself. current investigated medications do not hasten viral clearance time. clinical improvement is equivocal with lopinavir/ritonavir, arbidol, hydroxychloroquine, and remdesivir. favipiravir shows faster viral clearance and clinical improvement compared to lopinavir/ritonavir and arbidol. heparin shows benefit in patients with severe covid- infections. conflict of interest the authors declare that they have no conflict of interest. ethical approval all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 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induced-cytopathic effects in human neural progenitor cells coronaviridae and sars-associated coronavirus strain hsr the coronavirus (sars-cov- ) surface protein (spike) s receptor binding domain undergoes conformational change upon heparin binding covid- : consider cytokine storm syndromes and immunosuppression publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- -osgi o authors: panoutsopoulos, alexios a. title: conjunctivitis as a sentinel of sars-cov- infection: a need of revision for mild symptoms date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: osgi o covid- has been declared a pandemic by the world health organization on march , and since then, more than million cases and a quarter million deaths have occurred due to it. lately, there is a growing evidence for an ophthalmologic symptom (conjunctivitis) to be connected with the disease. this seems to happen in early stages of the infection by sars-cov- , and thus, it is of major importance to understand the mechanism through which the virus can facilitate such a symptom. here, we are proposing a molecular mechanism through which the novel coronavirus could act in order to affect the eye and use it as another, secondary but alternative, point of entry to the host organism. the sars-cov- virus, a novel coronavirus, emerged in december in china, and then japan, south korea, europe, and north america. on march , , the world health organization declared the spreading novel coronavirus outbreak as a pandemic, thus showing the possibility that the virus spread to all countries worldwide [ ] . as of may , , about . million confirmed cases of coronavirus disease and almost , deaths have been reported, with one third of the cases and more than % of the deaths to have occurred in the usa (john hopkins coronavirus resource center statistics). in response to the most serious global health threat in a century, researchers from all biomedical fields worldwide have participated in an unprecedented response to the covid- pandemic, with rapidly increasing resources aimed at finding safe and effective treatments for the disease (comprehensively reviewed in [ ] ). research for treatments has emerged from different backgrounds, pharmacologically with the use of well-known drugs for other diseases [ ] [ ] [ ] [ ] [ ] , with corticosteroids [ ] , immunologically from the serum of antibodies against former coronaviruses or from patients that have recovered from covid- [ ] [ ] [ ] or even with the use of revolutionary ideas such as cripr-cas [ ] [ ] [ ] . another tremendous effort from nih (clinicaltrials.gov identifier: nct ) and all countries around the globe focuses on the successful development of a vaccine that would prevent the emergence of covid- through the years and create a repeating cycle of spreading, like the influenza virus [ , ] . while up to mid-april , the only symptoms that were officially recognized as linked with covid- were fever, cough, shortness of breath, or difficulty breathing, the cdc (centers for disease control and prevention) have lately updated the symptom list based on changes in the disease's definition adopted by the council of state and territorial epidemiologists (cste). chills, rigors, myalgia, headache, sore throat, and new olfactory and taste disorder(s) have been officially added in cdc's website as symptoms connected with sars-cov- infection. moreover, gastrointestinal symptoms like nausea, vomiting, and diarrhea are stated as reported symptoms for the same disease in cdc's official website (cdc.gov). importantly, it is already known that a substantial percentage of patients do not exhibit any symptom while infected with sars-cov- [ , ] . in this review, we will focus on another symptom that has not been officially recognized, yet is arguably found in a small percentage of covid- patients [ ] , and is of a major concern for ophthalmologists, i.e., conjunctivitis or pink eye. we will summarize all the cases reported in other publications, and through basic molecular biology mechanisms, we will propose a possible explanation of the etiology of this symptom. the molecular biology of coronaviruses and sars-cov- coronaviruses (covs) are rna viruses with the largest rna in base length identified so far and belong to the coronaviridae family. they are divided into groups: α-, β-, γ-, and δ-cov [ ] . sars-cov and sars-cov- have . % sequence identity in their spike (s) protein s subunits, which mediate the membrane fusion process, and both of their s subunits utilize human angiotensin-converting enzyme (hace ) as the receptor to infect human cells [ ] . most importantly, the ace -binding affinity of the s protein of sars-cov- is -to -fold higher than that of sars-cov [ ] , which contributes to the higher infectivity of sars-cov- as compared with sars-cov [ ] . after binding of the s protein of the virion to the ace receptor on the target cell, the heptad repeat (hr ) and (hr ) domains in its s subunit of the s protein interact with each other to form a six-helix bundle ( -hb) fusion core [ ] , bringing viral and cellular membranes into close proximity for fusion and infection [ ] . therefore, the specificity of the virus is determined through the s-protein-receptor interaction to a host cell receptor. cathepsin protease action is the first step for the virus in order to access the host cell's cytosol by proteolytic cleavage of the s protein, followed by fusion of the virus and the host's membranes. fusion occurs within the endosomes and the formation of the bundle after fusion mixes viral and cellular membranes. as a result, the viral genome is released into the cytoplasm [ ] . coronavirus lifecycle proceeds with the translation of the replicase gene from their genomic rna, where the polyproteins pp a and pp ab encoded from two large orfs [ , ] . polyproteins of coronaviruses are further cleaved by a group of proteases [ , ] . importantly, many non-structural proteins (nsps) are assembling the replicase-transcriptase complex (rtc) needed for rna synthesis, while specifically nsp encodes the rna-dependent rna polymerase (rdrp) domain, arguably the most important enzyme for the replication of the virus. this is the enzyme that will elongate new positive sense rna molecules from the original rna of the virion [ ] . subgenomic rnas (sgrnas) are abundantly produced by the virus. sgrnas serve as mrnas mainly for the structure of the virus. importantly, homologous and nonhomologous recombination can happen in the virus genome at this stage [ , ] . after replication and sgrna synthesis, s, e, and m structural proteins are translated and transferred into the endoplasmic reticulum (er). these proteins move to the endoplasmic reticulum-golgi intermediate compartment (ergic) [ , ] and are encapsulated into membranes to form mature virions [ ] . the m protein is responsible for most protein-protein interactions required for assembly of coronaviruses, while the e protein functions as a chaperone to the m protein [ ] . lastly, the s (spike) protein that is not required for assembly is transferred to virions by interacting with the m protein. as already stated, the trimeric s protein is the spike-like protein on the surface of the virus [ , ] and acts as a class i fusion protein [ ] that ensures attachment to the host receptor. following assembly, newly made viruses transport to the cell surface and are released to the environment by exocytosis [ ] . conjunctivitis, or pink eye, is an irritation or inflammation of the conjunctiva, which covers the white part of the eyeball [ ] . it can be caused by bacteria, viruses, or allergies. it can be contagious as it is spread by contact with eye secretions. symptoms include itching, redness, and tearing of the eyes. it can also lead to discharge or crusting around the eyes [ ] . it is important to stop wearing contact lenses while affected by conjunctivitis. while allergic conjunctivitis can be treated with antihistamines and bacterial conjunctivitis can be treated with antibiotic eye drops to speed up the recovery process, the only way to recover from viral conjunctivitis is to let it resolve on its own while taking care of the overall good health of the patient [ ] . adenovirus is the most common cause of viral conjunctivitis. viruses of the adenoviridae family consist of nonenveloped, double-stranded dna. the most frequent infections caused by the adenovirus are eye infections, upper respiratory tract infections, and diarrhea in children [ ] . except for adenovirus derived, herpes conjunctivitis is also common in children [ ] . except for dna viruses though, rna viruses are often associated with conjunctivitis. picornaviruses can cause acute hemorrhagic conjunctivitis and are highly infectious, and hiv can also cause conjunctivitis producing redness, irritation, and tearing [ ] . cell infection of picornaviruses starts with its attachment to cell receptors. these receptors are subdivided into two major groups, i.e., canyon and non-canyon binders, which refers to different structures of the virus' surface [ , ] . canyon receptors like icam- , pv receptor, or α v β and α v β integrin receptors bind into the canyon of the viral surface, triggering conformational changes of the virus essential for infection, while non-canyon binders such as the ldl receptor, pselectin glycoprotein ligand- (psgl- ), and heparan sulfate proteoglycan (hspg) receptors attach to the virus surface elsewhere except for the canyon, guiding the virus to the host cell surface and as a result signal for virus endocytosis [ ] [ ] [ ] [ ] . the hspgs are continuously reported as providers of an increased efficiency of viral attachment to host cells, thus allowing the binding of the virus to another receptor [ ] [ ] [ ] . it is not uncommon for coronaviruses to be found in tears through the years. sars-cov, hcov-nl , and sars-cov- coronaviruses have been detected active through rt-pcr in tears in previous coronavirus outbreaks [ ] [ ] [ ] [ ] [ ] . on the other hand, other studies have shown no evidence of live viruses in tears of patients infected with several different strains of coronaviruses [ , ] . given the uprising number of publications and case reports of covid- patients showing conjunctivitis [ , ] and the history of other coronaviruses that are found in tears, we have to consider the possibility of a separate, alternative viral mechanism through which the virus can enter the patient's organism through epithelial cells of the eye [ ] . the growing evidence on covid- and its ocular implications and manifestations, in both animals and humans, is covered by many interesting reviews, all published to months after the novel coronavirus' outbreak [ ] [ ] [ ] [ ] [ ] , something that reveals the need to understand the virus from different perspectiveswhich at first may have seemed secondary in priority-in order to be able to reach a treatment. as not much has been yet published about the sars-cov- pathogenic mechanism, from genomic and structural analyses, it is known that the sars-cov- has a similar receptor binding mechanism as sars-cov. the angiotensin-converting enzyme- (ace ) receptor is so far the best candidate for the main entry mechanism of sars-cov- [ ] . the ocular surface is comprised by the conjunctival and corneal epithelia which are connected to the upper respiratory system [ ] . liquid from the eye is absorbed by the conjunctiva and cornea epithelium and drained into the nasal cavity through the nasolacrimal duct to the respiratory tract through the trachea [ ] . as a result, pathogens from the eye can be transported to the respiratory system. interestingly, the human eye has its own intraocular angiotensin system (ras), which has been popular as a way of antiglaucoma drug development. as secondary evidence, ace , the main entry receptor of hcov-nl , sars-cov, and sars-cov- , has been found in the aqueous humor [ ] and at the conjunctival epithelial cells of the ocular surface [ ] . however, ace expression in human ocular surface is much lower than in other tissues [ ] . besides the immune conditions of the host, the efficiency of a virus infection depends on the infection rate of the virus and the viral receptors on the host cell membrane. as with picornavirus and other viruses, hspg receptors are known to create a first attachment of the virus close to an epithelium that consists of cells with a low number of the ace receptors. the entry of the virus inside these cells is facilitated through the ace receptors, but hspgs provide an environment of enrichment of the virus load close to the host cells through low affinity interactions [ ] . while the exact mechanism still remains unclear, many investigations point to the fact that the infection of sars-cov and hcov-nl into human cells is mediated by more receptors other than ace on host cell membrane. among other factors, hspgs can clearly also serve as first attachment receptors [ ] . first, the virus is docked to the host cells with a first link between the s protein on viral surface and the heparan sulfate chains of hspgs on the host cell membrane [ , ] . this binding event acts as an anchor for the more stable binding of the s protein to ace receptor of the host cell membrane, followed by endocytosis of the viral particles [ , ] . as shown in fig. , this is very likely to be the mechanism of the invasion of sars-cov- in the epithelial cell of the cornea and conjunctiva as well. by better understanding the mechanism discussed here with more clinical and experimental trials, ophthalmologists can play a major role on tracking early symptoms of covid- and helping in the better treatment of the disease. compliance with ethical standards there was no research involving human participants or animals for the preparation of this review. the author declares 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key: cord- -qioy eso authors: pourahmad, ramtin; moazzami, bobak; rezaei, nima title: efficacy of plasmapheresis and immunoglobulin replacement therapy (ivig) on patients with covid- date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: qioy eso since the rapidly evolving outbreak of covid- , several empirical therapeutic options have been recommended including the use of antivirals, steroids, and vaccines. according to recent observations about different modalities in treatment of patients infected with covid- , plasmapheresis and intravenous immunoglobulin (ivig) have been reported to be an effective empirical therapeutic option to control the infection. in this review, we aimed to provide an overview on the possible application of plasmapheresis and intravenous immunoglobulin in patients with covid- . in december , a new member of the coronaviruses emerged in wuhan, china. the world health organization (who) declared this novel coronavirus as a "public health emergency of international concern (pheic)" in january , . the who officially named the -ncov as coronavirus disease in geneva, switzerland. according to the who reports, the clinical spectrum of sars-cov- is wide and can be classified in groups: patients with asymptomatic infection (mild type) with upper respiratory tract distress, patients with pulmonary infiltration (common type), and patients with severe signs that need intubation and intensive care (severe type). to date, several empirical therapeutic options have been recommended, including generation of antivirals, steroids, and vaccines. however, the optimal and definite treatment strategy is not yet determined. according to the medical experiences in the treatment of patients infected with other members of coronavirus family such as sars-cov and mers-cov, plasmapheresis and intravenous immunoglobulin (ivig) have been reported to be an effective empirical therapeutic option to control the infection [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the aim of the present review was to evaluate the current evidence regarding the efficacy of plasmapheresis and ivig in the management of patients with covid- . coronaviruses (covs) as a member of the coronaviridae family comprised large, single, and positive-sense rna categorized into subgroups: alpha, beta, gamma, and delta covs [ , ] . among these subgroups, human covs (hcovs) have been identified that can cause infection in human: hcov- e, hcov-oc , hcov-nl , hcov-hku , severe acute respiratory syndrome (sars-cov), and middle east respiratory syndrome coronavirus (mers-cov) [ ] . in addition, sars-cov and mers-cov belong to the beta covs [ ] . the first emergence of sars-cov was observed in in china, guangdong province, and later spread in countries with a case fatality rate of % [ ] . the novel coronavirus ( -ncov) that was first reported in wuhan, china, also belongs to the beta covs based on viral genome assessment by the phylogenetic analysis [ , ] . the genome sequence shared many identical sequences to sars-cov with almost . % similarity. also it has been revealed that covid- is % identical at whole genome level to bat coronavirus [ ] . plasmapheresis involves separating the liquid part of the blood or plasma from the blood cells. there are fundamentally two different ways for plasmapheresis: centrifugation or membrane filtration. with centrifugation apheresis, the major blood components get separated into layers. the major advantage of this method is that there is no limit in the size of the molecules being removed. on the other hand, membrane filtration plasmapheresis is an another option where its major disadvantage is the size of the molecules removed that has been limited by the size of the pore of the filter. this feature could be problematic as seen with the ultra-large von willebrand factor multimers that can measure up to million daltons [ ] . moreover, another potential disadvantage is the activation of the complement and leukocytes by the artificial membrane and the need for a central large-bore catheter to obtain the adequate blood flow [ ] . the first reports of bloodletting began around b.c. in egypt. since antiquity, mankind believes in a bad component in sick patient's blood, called "humor." they believed that the removal of these humors that accumulate in blood makes patients feel better [ ] . nowadays, plasmapheresis is a great therapeutic way in such diseases such as myasthenia gravis, guillain-barre syndrome, and thrombotic microangiopathy. moreover, plasmapheresis plays a major role in renal diseases. the pathologic factors that may be removed with plasmapheresis are including autoantibodies, complement products, lipoprotein, immune complexes, cryoglobulin, myeloma protein, adamts- , protein-bound toxins, cell platelets, and wbc [ ] . it has been well-described that the "cytokine storm" plays an important role in the pathophysiology of the covid- in critically ill patients [ ] . patients' condition may become deteriorated and require icu admission along with mechanical ventilation support. reports have shown that icu patients have significant higher levels of cytokines and chemokine in their blood [ ] [ ] [ ] [ ] [ ] . the first signs of the cytokine storm (define as decrease in blood oxygenation, declined lymphocyte count over time, serum enzymes, elevated creatinine levels, and high levels of crp) and endothelial dysfunction are trigger points in the patients' medical condition [ ] . several case reports have shown favorable results of using plasmapheresis (pe) and immunoglobulin replacement therapy (ivig) on prevention of worsening the condition and recovering the lymphocyte count [ ] [ ] [ ] ] . based on these reports, the administration of plasmapheresis and ivig should be promptly administered to covid- patients in order to have the highest efficacy in their treatment [ , , ] . a report from the people's hospital of guizhou showed that a -year-old woman with laboratory-confirmed covid- infection underwent antiviral therapy and inhaled interferon-α b followed by lopinavir and ritonavir. on the th day of admission, the patient's condition deteriorated, so pe treatment with ivig was initiated. after four times of pe, the patient made a prompt recovery (doi ) and finally discharged from hospital with obvious improvements of chest radiographic evidence [ ] . the initiation time of plasmapheresis in patients with covid- is very important in the following stages of the infection, and we can prevent the urgent need of mechanical ventilations and intensive supporting care. the benefit of plasmapheresis is that it has a very successful precedent as a treatment option for a wide range of medical conditions, including disorders associated with brain and nervous system, such as acute guillain-barré syndrome [ , ] , blood disorders, such as thrombotic thrombocytopenia, some kidney disorders, such as goodpasture syndrome, and hyperviscosity disorder, such as myeloma. there are not many reports about the risks of the plasmapheresis because frequently it has been reported as a safe treatment option in many cases. the adverse side effects of plasmapheresis include fall in arterial blood pressure, arrhythmias, sensation of cold with elevated temperature, and paresthesia. with continuous observation in healthcare faculties, these side effects could be closely monitored and ensure patients' safety [ ] . immunoglobulin replacement therapy or intravenous immunoglobulin (ivig) is a kind of a therapeutic choice for patients with antibody deficiencies. ivig is a blood product, prepared from the serum of to , donors per batch. ivig is used at a replacement dose of - mg/kg body weight, for weeks. in contrast, we have high dose ivig (hdivig), given frequently at g/kg/month. hdivig is used as an immunomodulatory agent in various immune and inflammatory disorders [ ] . as the world confronting a pandemic due to sars-cov- , immunoglobulin replacement therapy (ivig) could be an ideal option for prevention and treatment of covid- disease. with the sufficient number of patients recovered from covid- disease, they can donate their immunoglobulin-containing serum. ivig has been used in a wide range of conditions including heart failure, mycobacterial infection, adult respiratory distress syndrome, and alzheimer's disease. in the clinical specialties, neurology, nephrology, hematology, immunology, rheumatology, and dermatology are using the largest amount of ivig. intravenous immunoglobulin (ivig), in a simple explanation, consists of separate components: [ ] actions mediated by f(ab′) with anti-proliferative properties, apoptosis modulation and immunomodulation of inflmmatory responses. [ ] fc receptor (fcr), inhibition of phagocytosis, inhibition of adcc, [ ] action mediated by complement binding within the fc fragment, and [ ] substances other than antibodies in ivig preparations [ ] . in the s, before the introduction of the antimicrobial chemotherapy, serum therapy was one the treatment options for a wide range of diseases. at first, serum therapy was introduced for treatment of diphtheria, but nowadays, it has made significant progresses in curing diseases [ , ] . currently, immunoglobulin replacement therapy (ivig) is used to stem the outbreak of the viral diseases such as influenza [ ] , poliomyelitis [ ] , mumps [ ] , and measles [ , ] . in the threatening outbreak of measles in in a boy's preparatory school, convalescent measles serum was used prophylactically on uninfected boys; according to the experiments, it was expected that % of the group develop measles but only cases of measles subsequently developed in that group [ ] . eight relevant studies on patients in world pandemic of influenza h n , complicated with pneumonia, showed that patients who received influenzaconvalescent human blood product may have experienced a significant lower mortality rate [ ] . in , during the outbreak of the influenza h n , a prospective cohort study was conducted based on experiences from treatment of spanish influenza and h n influenza patients with immunoglobulin replacement therapy, by recruiting patients with severe h n infection that requires intensive care. the study showed that plasma treatment had significantly reduced mortality rate ( . % vs . %). this study showed that the convalescent plasma reduced the respiratory tract viral load, serum cytokine response, and mortality [ ] . for further examples, we can indicate the use of ivig for lassa fever [ ] , ebola virus [ ] , and junin virus (argentinian hemorrhagic fever) [ ] . however, covid- was declared as a world pandemic in . the sars epidemic was contained, although mers became endemic in the middle east and made a second major outbreak in south korea. during the sars epidemic, a study in the prince of wales hospital, hong kong, was conducted on patients to evaluate the efficacy of convalescent plasma therapy in patient with severe acute respiratory syndrome (sars); the result showed that the patients given convalescent sera before day of illness showed better results than those who received the therapy after day [ ] . another study in taiwan showed that using ivig on infected healthcare workers with coronavirus (sars) resulted in a significant reduction in viral load and anti-sars-cov igm and igg increased in a time-dependent manner [ ] . according to the reports, china has used immunoglobulin replacement therapy on several covid- patients during the outbreak of this novel coronavirus which showed promising results [ ] . risks of immunoglobulin replacement therapy fall into categories, known and theoretical. known complications are associated with other infectious diseases during transferring of blood substances or reaction to serum constituents such as serum sickness. the theoretical aspect of passive immunotherapy involves the phenomenon of antibody-dependent enhancement of infection (ade) [ ] . previous studies have shown that the antibodies target one serotype of virus but only subneutralize another, leading to ade [ ] [ ] [ ] . ade can lead to worsened symptoms in secondary viral infection, causing major concern for epidemiology. ade has been observed in coronavirus for decades, and now it is a concern that it can occur in sars-cov- [ ] . another potential risk factor for immunoglobulin replacement therapy usage in patients with covid- may be due to mitigating antibody response that could interfere with establishing efficient immune responses against viremia. so, still there are vulnerable individuals to subsequent reinfection. if this risk proved real, the individual should be vaccinated against covid- when a vaccine becomes available [ ] . covid- immunoglobulin replacement therapy can be used for both prophylactic and treatment of the disease [ , , ] . in the prophylactic way, the benefit of ivig is that it can prevent infection in the individuals such as healthcare workers or patients that are at increased risk of disseminated infection [ ] . in the therapeutic way, a controlled clinical trial should be conducted to infer the efficacy of this approach. since december , many countries have been confronting to a new member of coronaviruses that emerged in wuhan, china. according to the reports, confirmed cases of covid- rise rapidly during the last months, although there is no effective vaccine or therapeutic drug available for covid- . significant progresses have been made through finding an effective vaccine, and a number of them showed promising results. our clinical spectrum and pathophysiological changes of this virus have increased significantly; however, high rate and absence of effective therapies, as our experience in both sars epidemic in and mers in , led to using plasmapheresis and immunoglobulin replacement therapy (ivig) as a main therapeutic option after anti-viral therapy in countries such as china and iran [ , ] . as reports demonstrated, the best results of plasmapheresis and ivig therapy are highly dependent on timing. clinical observation has shown that covid- has phases in symptomatic cases: starting phase with subsequent viremia, the accelerating phase that is the vital phase of the infection, and the recovery phase with progressive lymphocytopenia and elevated inflammatory markers [ , , ] . several studies have also shown that the administration of ivig and pe before day of the illness could be associated with better outcomes [ , ] . the main reason for this observation may be partly due to the fact that viremia develops within the first week of infection. subsequently, the primary immune response first appears in the blood by day - and followed by viral clearance. 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entry extensive complement-dependent enhancement of hiv- by autologous non-neutralising antibodies at early stages of infection antibodydependent enhancement of ebola virus infection the convalescent sera option for containing covid- management of covid- virus infection by convalescent plasma immune-epidemiological parameters of the novel coronavirus -a perspective temporal dynamics in viral shedding and transmissibility of covid- publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations acknowledgments this is dedicated to honoring the memory of our brave fallen doctors and nurses who fought against covid- . conflict of interest the authors declare that they have no conflict of interest.ethical approval not applicable.informed consent not applicable. key: cord- -bntcn m authors: thangaraju, pugazhenthan; venkatesan, nanditha; sudha, t. y. sree; venkatesan, sajitha; thangaraju, eswaran title: role of dupilumab in approved indications of covid- patient: an efficacy-based nonsystematic critical analysis date: - - journal: sn compr clin med doi: . /s - - -x sha: doc_id: cord_uid: bntcn m with many drugs being tried in the management and treatment of covid- , dupilumab is one such monoclonal antibody that has come under the limelight for its possible role as an adjunct therapy in covid- position. there are isolated case reports and series that document a milder course of covid- infection in patients who have already been on dupilumab therapy for treatment of conditions such as atopic dermatitis and chronic rhino-sinusitis with nasal polyp. there is also an ongoing debate regarding the continuation of biologicals in the covid patient. in this article, a non-systematic critical analysis of dupilumab was performed to delve into this hypothesis further. dupilumab is a human monoclonal igg antibody which binds to the alpha subunit of il- , receptors and promotes signaling after binding to the il- rα subunit. while it has already been in use in dermatology clinics for the treatment of atopic dermatitis (ad), it was most recently approved for the indication of chronic rhinosinusitis with nasal polyp (crswnp) by the us food and drug association (fda) on the th of june, [ ] . the pathophysiology explored in ad and crswnp and the role of the above monoclonal antibodies in link with virus are shown in fig. . a significant anti-viral role of cells, namely, cd + t (production of essential specific antibodies) and cd + t (cytotoxic toward virus infected cells), plays a very important in balancing against the infection of sars-cov- and associated inflammation. in addition, there is major trigger for differentiation of t cells into t-helper (th ) and th in series to the massive release of pro-inflammatory cytokines, namely, tumor necrosis factor (tnf β), interleukin (il) ( , , , and ) , and monocytes chemoattractant protein- (mcp ) by the viral infection. so these lead to the cytokine storm that will prevent the activation of cd + t cells. the corona virus also seems to stimulate the secretion of il- and il- (th- cytokines). this in turn suppresses the inflammation mediated by t helper cell ( / ). but dupilumab inhibits the function of il- and il- . so whether dupilumab usage is beneficial or can lead to increased risk of contraction to sars-cov /complication is still questionable. so at the level of molecular mechanism whether it acts as adjuvant in controlling or against in increased risk should be explored [ , ] . dupilumab, in the crswnp patients, shows its clinical efficacy by minimizing nasal polyp size and increasing quality of life by reducing sinonasal symptoms, particularly in patients with comorbidities such as asthma. several case reports and letters to the editor have pointed out the safe use of dupilumab in patients in dermatology and otorhinolaryngology outpatient clinics [ ] . dupilumab has been associated with a reduced infection rate in ad patients. a pooled analysis of seven rcts this article is part of the topical collection on covid- on dupilumab-treated ad adults showed a decreased risk of serious infections, skin infections, and herpes infections (eczema herpeticum or herpes zoster) in the dupilumab groups compared with placebo [ ] . solo and solo were rcts that demonstrated that rates of upper respiratory tract infections were much the same in placebo and dupilumab [ ] . there were no reports of more serious lower respiratory infections in dupilumab. a decrease in theoretical risk for covid- in dupilumab-treated patients in addition to its ability to control viral infection-induced asthma has also been noted. the european task force on atopic dermatitis recently commented that "targeted treatment selectively interfering with type- inflammation such as dupilumab is not considered to increase the risk for viral infections and might thus be preferred …in a situation such as covid- pandemic" [ ] . however, recommendations swing both ways. the american academy of dermatology currently recommends that patients with active covid- infection should discontinue any systemic treatment under the supervision of a dermatologist. the international league of dermatological society (ilds) guidance in contrast asserts that current evidence does not justify the discontinuation of dupilumab therapy for ad in healthy subjects [ ] . the current recommendations of the german society for allergology and clinical immunology for the use of biologics in the treatment of patients with chronic rhinosinusitis and nasal polyp alongside evidence from various published literature point toward the continuation of the treatment [ ] . herein, we explore evidence from published literature and collate their findings that could throw light on the current scenario though a non-systematic critical appraisal. a search was conducted across databases that included pubmed, medrxiv, biorxiv, and ssrn. the search strategy was carried out using keywords such as "dupilumab," "covid- ," and similar such terms. we included clinical trials, research studies, case reports, and randomized control trials that employed the use of dupilumab at any point in the treatment of patients who were laboratory confirmed cases of covid . given the small number of articles that were found in our search, full-text screening of all articles were done. patients: patients, both adult and pediatric population, who are laboratory confirmed cases of covid- . dupilumab used at any point in the treatment of any disease condition (ad or crswnp). clinical trials, research studies, case reports, randomized control trials, and editorials. two reviewers independently screened the search results that were documented on google sheets. details that were extracted included author and journal details, year of publication, sample size, age, sex, indication for rational use of dupilumab, duration for treatment, adverse effects observed, and course of covid- infection. once this data was retrieved, we measured the total number of covid patients who were on dupilumab and recorded their course of disease. the data were extracted in google sheets in numbers and converted later to percentages. as of july , (fig. ) , we recorded a total of articles, in pubmed, in the medrxiv/biorxiv covid- preprint collection and relevant searches in the ssrn database. out of these articles, only met the inclusion criteria. of these articles, of them used dupilumab for the indication of atopic dermatitis while only article was a case report of a patient on dupilumab for the indication of crswnp. pooled data from these studies revealed a total of patients on dupilumab, of which developed covid- infection ( . % infection rate). all patients had a mild course of disease and recovered. no deaths were reported in this group. only out of studies from the non-systematic analysis mentioned the duration of therapy. out of the results from pubmed, studies recommended continuation of use while review inclined more toward withholding the medication in high-risk groups. our results show that the use of dupilumab in general is much lesser for crswnp as compared with ad. this could be owing to the difference in time points for when this drug fig. flow chart of collected information was approved for the two separate indications. among those patients that developed covid- infection, all of them displayed a mild disease course, tempting us to speculate the possible immune-modulating role of dupilumab. one case report highlighted the effect of dupilumab in a patient with crswnp who developed covid- infection. they hypothesized that the unexpectedly light course of disease could be attributed to ( ) reduction in local inflammation and better nasal respiration and sinonasal function, ( ) achievement of complete control of asthma in patient in study, and ( ) increased eosinophils in patient; strengthening the recently described negative association between an increased number of eosinophils and viral load [ , ] . dupilumab in crswnp treats symptoms such as anosmia, nasal congestion, and cough which are symptoms common to covid- . in this case, theoretically, patients on dupilumab might not show classic symptoms of covid- . this needs to be borne in mind while these patients are educated about symptoms of covid- . it has been cited as a safe choice of medication, which has largely been attributed to its targeted mode of action rather than widespread immunosuppression, latter being a risk factor for severe degree of covid- infection [ ] . abrupt cessation of the therapy in patients could exacerbate previously controlled symptoms, consequently leading to the progression of the inflammation causing a flare up of existing underlying comorbidities that were otherwise under control by the action of dupilumab, such as asthma. with atopic patients having a higher likelihood of developing asthma, viral infections in these patients could exacerbate the condition. in such a context, dupilumab will prove to be effective. also, it needs to be borne in mind that anti-drug antibodies or neutralizing antibodies could be generated during the period of discontinuation that could eventually render the treatment useless at a later stage [ ] . knowledge of immunological pathways also has shown that the pathways of il- and il- , which are th cytokines, have not been implicated in host defense mechanisms against viral infections. however, an excess of the th cytokines (il- , ) have been documented in fatal cases of the sars-cov infection, as compared with recovered patients [ ] . with studies showing that heightened immune response and rise in levels of il could potentially worsen the hyperinflammatory response, we speculate that immune-modulation by dupilumab in covid might prove to be beneficial. a recent article also supports on the continuation of monoclonal antibodies when there is no concrete evidence against its usage in atopic dermatitis or chronic rhinosinusitis with nasal polyp [ ] . our study has several limitations that need to be considered while interpreting the results. -this is a very preliminary collation of existing articles. very small number of studies have been published in the context of dupilumab use in covid- . more evidence in this regard, with a larger sample size, is needed. -there is lack of any mention of the duration of therapy in these patients. duration of therapy will influence the effect of the drug on the immune system. -many of these patients might have eventually gone on to develop the covid- infection, so the rate of infection is not an absolute indicator. culmination of these effects could push the patient into a more severe form of covid- . flare up for asthma and rhinosinusitis would additionally cause an increase in sputum production and cough, which could increase rates of transmission. interruption of therapy could lead to the progression of rhinosinusitis, expansion of polyp formation, worsening of comorbidities, and production of anti-drug antibodies. unlike other immune-modulatory therapies, clinical trials have shown that the full effect of dupilumab on the immune system occurs much later after initiation. this needs to be borne in mind as duration and initiation of therapy needs more synthesis of evidence. data regarding duration of therapy and its effect on the immune system also needs to be researched further. in the context of covid- , its role as an immunemodulating agent should be explored further and considered urgently. conflict of interest the authors declare that they have no conflict of interest. ethical approval this article does not contain any studies with human participants or animals performed by any of the authors. informed consent not applicable; this article does not contain any studies with human participants or animals performed by any of the authors. efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (liberty np sinus- and liberty np sinus- ): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase trials coronavirus infections and immune responses clinical features of patients infected with novel coronavirus in wuhan covid- infection in a patient with severe chronic rhinosinusitis with nasal polyps during therapy with dupilumab infections in dupilumab clinical trials in atopic dermatitis: a comprehensive pooled analysis two phase trials of dupilumab versus placebo in atopic dermatitis european task force on atopic dermatitis (etfad) statement on severe acute respiratory syndrome coronavirus (sars-cov- )-infection and atopic dermatitis guidance on the use of systemic therapy for patients with psoriasis/atopic dermatitis during the covid- (sars-cov- , coronavirus) pandemic dgaki. statement of the german society for allergology and clinical immunology (dgaki) dated march , on the active substances: omalizumab, mepolizumab, reslizumab, benralizumab and dupilumab patients of covid- may benefit from sustained lopinavir-combined regimen and the increase of eosinophil may predict the outcome of covid- progression covid- : risk for cytokine targeting in chronic inflammatory diseases? biologics for psoriasis in covid- era: what do we know? t cell responses to whole sars coronavirus in humans dupilumab and covid- : what should we expect? publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- -a wgvgz authors: Çelik, ersin; Çora, ahmet rıfkı title: treatment approach to coronavirus disease (covid- ) seen early after open heart surgery. case report date: - - journal: sn compr clin med doi: . /s - - -y sha: doc_id: cord_uid: a wgvgz sars-cov- was reported for the first time in china on december , , as the cause of some pneumonia cases characterized by fever, cough, dyspnea, myalgia, and fatigue. here, we present our approach to a -year-old male patient who had coronary artery bypass (cabg) surgery diagnosed as high probability coronavirus disease (covid- ) in early postoperative period. severe acute respiratory syndrome coronavirus (sars-cov- ) has been reported for the first time in china on december , , as the cause of some unknown pneumonia cases [ ] . within - days after exposure to the virus, some people develop coronavirus disease (covid- ), characterized by fever, cough, dyspnea, myalgia, and fatigue. high mortality rates related to pneumonia, shock, acute respiratory distress syndrome, acute cardiac injury, and acute kidney injury were observed especially in patients with chronic disease and the elderly [ ] . although it has been a short time since it was reported for the first time, covid- was declared as a pandemic by the world health organization on march , [ ] . we aimed to present our approach to high probability covid- pneumonia which developed on early postoperative period in our patient after coronary artery bypass grafting (cabg) operation, which was not reported in the literature before. the written consent form was obtained from the patient. a -year-old male patient presented as non-st elevation myocardial infarction underwent emergent coronary angiography and critical stenosis evaluated on proximal left anterior descending artery (lad) and the first diagonal branch. cabg surgery planned and taken to service follow-up. routine blood tests performed on preoperative period were normal. on echocardiography, ejection fraction was %. seventy percent stenosis on the right and % stenosis on the left internal carotid artery were detected on routine carotid color doppler ultrasonography. pulmonary function tests and chest x-ray ( fig. a) were applied. after chest physician evaluation, dual inhaler medication was started. following a week of inhaler treatment, patient's pulmonary function tests recovered and taken to the operation. median sternotomy was performed under general anesthesia. two vessel cabg were applied by using left internal mammary artery and saphenous vein under cardiopulmonary bypass (cpb). patient was taken to cardiovascular surgery intensive care unit uneventfully after the operation. patient was extubated uneventfully and continued intensive care unit follow-up without any clinical problem. there was no pathology evaluated on chest x-ray taken on second postoperative day. (fig. b) . after removing the chest tubes and arterial lines, patient was taken to service follow-up. results of the blood tests taken on the th postoperative day were white blood cell (wbc) . ( /μl), lymphocyte . ( /μl), lymphocyte count . %, eosinophil . ( /μl), c-reactive protein (crp) . mg/dl, respectively. on physical examination, body temperature was raised to . °c on the th postoperative day. oxygen saturation in room air was %, and heart rate and blood pressure were / min and / mmhg, respectively. control chest x-ray performed for evaluating the cause of this hyperthermia and infiltration areas were evaluated. thorax computed tomography (ct) was taken for further investigation. multifocal ground-glass opacities with peripheral and basal distribution, peripherally located bilateral infiltrative pneumonia, and vascular thickening were detected on thorax ct (fig. ) . co-rads was reported on thorax ct of the patient. after consultations applied by chest physicians and infectious disease departments of our hospital, covid- was evaluated as a high probability due to the laboratory tests, radiological findings, and clinical course. patient was taken to the covid- isolation service; swabs were taken from the oropharynx and nasopharynx for real-time polymerase chain reaction (rt-pcr) test. since rt-pcr analysis results within - h, the treatment of the patient was started with × mg oral oseltamivir phosphate tablet (tamiflu, f. hoffmann-la roche ltd., basel, switzerland); followed by × mg loading dose, with × mg oral hydroxychloroquine sulfate tablet (plaquenil, sanofi synthelabo limited, fawdon, england); and followed by × mg loading dose, with × mg oral azithromycin tablet (azitro, deva holding a.Ş., tekirdağ, turkey) without waiting for the results. this treatment protocol which is suggested by the turkish republic ministry of health and covid- science committee is the first treatment step for whole patients. control rt-pcr test was sent h after the first test and the first rt-pcr test was negative. the second test result was also negative. fever control was achieved on the third day of the treatment. wbc and crp values decreased. infiltration areas regressed in control thorax ct (fig. ) . on the fifth day of the therapy, treatment was completed. the patient was hemodynamically stable and had no respiratory distress. he was evaluated by the hospital pandemic team and recommended to be discharged and have isolation at home for days. the patient stated that he had no complaints in the outpatient control on the th day. although rt-pcr is accepted as the gold standard for the diagnosis of covid- , positivity is reported in - % in series depending on the lack of experience on sampling, lack of cooperation of the patient, and transfer and kit performance [ ] . and also according to reports, when disease manifests on the pulmonary area, viral load began to decrease, and for that reason, rt-pcr results could become negative. therefore, thorax ct has become a widely used diagnostic feature for covid- pneumonia. studies comparing thorax ct and rt-pcr methods have been added to literature, and the sensitivity and specificity results of the radiological diagnosis are quite satisfactory [ ] . the covid working group of the dutch radiological society has developed the co-rads fig. a preoperative lung x-ray. b chest x-ray on the nd postoperative day classification for thorax ct evaluation and taken it into clinical use [ ] . when we evaluated our case according to the co-rads classification, we determined it as co-rads (high probability covid- pneumonia). on blood tests of patients, lymphocytopenia, eosinopenia, and decreased lymphocyte count were reported with covid- [ ] . eosinopenia and low lymphocyte count were detected in our case as well. systemic inflammatory response occurs as a result of cytokine release and complement system activation caused by cpb effect [ ] . with the resultant immune system changes, these patients become more susceptible to possible infections. the patients that have undergone cabg operation are generally those who are elderly and have multiple accompanying risk factors. therefore, they are in a high-risk group in terms of morbidity and mortality that might be developed due to covid- . having considered our patient as high risk, without waiting for the rt-pcr result, we started the specific treatment for covid- immediately, by evaluating clinical, laboratory, and radiology findings. although both rt-pcr tests were negative, we continued the treatment for days. because no physical and hemodynamic impairment was evaluated in our case, response to our therapy was followed up by the means of control thorax ct. after days of the treatment, there was an obvious regression evaluated on thorax ct. we should assume and keep in mind that there are also pandemic and asymptomatic carriers, especially in elderly patients who undergo open heart surgery with many additional risk factors. we believe that, in case of doubt, early treatment should not be ignored in the presence of clinical, laboratory, and radiological findings even if rt-pcr is negative. authors' contributions all authors confirm in accordance with the committee on publication ethics (cope) guidelines and international committee of medical journal editors (icmje) criteria. each author had made a substantial contribution to the conception and design, acquisition of data, and/or analysis and interpretation of data. each author participated in the drafting of the article, revised it critically for important intellectual content, and had read before the approval of the final manuscript. conflict of interest the authors declare that they have no conflicts of interest. ethical approval all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the helsinki declaration and its later amendments or comparable ethical standards. clinical features of patients infected with novel coronavirus in wuhan rolling updates on coronavirus disease (covid- ) evaluating the accuracy of different respiratory specimens in the laboratory diagnosis and monitoring the viral shedding off -ncov infection correlation of chest ct and rt-pcr testing in coronavirus disease (covid- ) in china: a report of cases performance of radiologists in differentiating covid- from viral pneumonia on chest ct patients of covid- may benefit from sustained lopinavir-combined regimen and the increase of eosinophil may predict the outcome of covid- progression the systemic inflammatory response syndrome and cardiopulmonary bypass publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations informed consent written informed consent for the publication was obtained from the patient. key: cord- - hnh authors: leeson, cale e.; ismail, asmaa; hashad, mohamed m.; elmansy, hazem; shahrour, walid; prowse, owen; kotb, ahmed title: systematic review: safety of intravesical therapy for bladder cancer in the era of covid- date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: hnh a novel coronavirus has emerged in late capable of causing a severe respiratory disease known as covid- . its pathogenesis appears to be the initiation of an immune response and resulting cytokine storm that damages the healthy lung tissue of the host. some epidemiological studies found bacillus calmette-guérin (bcg) vaccine can help to decrease morbidity and mortality of the viral infection. we aim to review and summarize what is known about covid- and the current implications of intravesical bcg with regard to the disease. in december , a novel coronavirus, now officially known as severe acute respiratory syndrome coronavirus (sars-cov- ), emerged in china and is capable of causing the infectious disease called coronavirus disease . [ ] since then, the world health organization has declared a global pandemic, with , , global cases of covid- , resulting in , deaths as of april , . [ ] the clinical manifestations of covid- are varied, ranging from mild symptoms such as fever, dyspnea and cough to more severe complications in the case of acute respiratory distress syndrome (ards), septic shock and death. pathogenesis of the disease likely involves initiation of an immune response, resulting in the production of cytokines in a "cytokine storm" that damages healthy lung tissue of the host. [ ] future clinical trials are being arranged to determine if bacillus calmette-guérin (bcg), an attenuated version of mycobacterium bovis and vaccine against tuberculosis, has the ability to upregulate the immune system against the novel coronavirus. [ ] furthermore, bcg immunotherapy is often utilized in the field of urology for the treatment of bladder cancer. it is not yet determined if intravesical therapy will have a positive or negative effect on the immune system in bladder cancer patients with covid- . bladder cancer is a common urologic condition, with urothelial carcinoma comprising the largest proportion of cases ( %). [ ] in addition, % of new bladder cancer cases will be non-muscle invasive bladder cancer (nmibc), typically treated with a high-quality transurethral resection of the bladder tumour (turbt), followed by either intravesical chemotherapy or immunotherapy. [ ] [ ] [ ] compared with other intravesical therapies, bcg is the only agent associated with a decreased cancer progression risk compared with turbt alone but is associated with a higher risk of adverse events. [ ] the mechanism of action of bcg is still relatively unclear but may involve an upregulation of the immune system characterized by induced expression of cytokines in the urine and bladder tissue. [ ] intravesical bcg treatment in immunocompromised patients remains a relative contraindication in some guidelines , while its role in the treatment of acute immunological disorders remains uncertain. in this review, we aim to summarize what is known about the immunologic mechanisms of covid- , the current recommendations, mechanisms of action and adverse effects of intravesical bcg in bladder cancer and determine if this article is part of the topical collection on covid- * ahmed kotb drahmedfali@gmail.com intravesical bcg is safe in patients that are suspected or confirmed to have covid- . in addition, implications for bcg immunotherapy in the treatment of viruses and immunological disorders will be explored. our article followed prisma checklist. this review article is irb exempt as we did not include any data from our patients. a comprehensive search of pubmed was performed for available literature on the effect of covid- on immune response, as well as current intravesical management of bladder cancer. we reviewed relevant articles focusing on the mechanism of action of intravesical bcg and chemotherapy, including systemic outcomes and side effects from intravesical treatment, and its safety and efficacy in immunocompromised patients or those with acute immunological disorders. search terms included "sars-cov- " or "covid- " combined with "immune response", "intravesical bcg" combined with "bladder cancer", "urothelial carcinoma", "adverse events", "side effects", "mechanism of action", "immunocompromised" and "immunological disease". references from review articles and guidelines were also evaluated for articles that may have been missed. standard electronic search methods using pubmed database and google scholar were employed. there were no limits set on publication date, though literature within the last decade was prioritized to formulate a narrative review. all searches were performed using standard search techniques with the exclusion of editorials and letters. forty-five references were of relevance to our work. no study did actually look for the direct correlation between covid- and intravesical bcg but were correlating with different diseases that were of relevance. we avoided guidelines inclusion into our manuscript as guidelines during that stressful time were mainly looking at decreasing patients travel to hospital mainly to decrease their exposure to infection rather than for the actual risk benefit ratio of bcg itself. sars-cov- infection has been described in three stages: an asymptomatic incubation period up to days (stage i), a nonsevere symptomatic period with the presence of the virus (stage ii) and a severe respiratory symptomatic stage with high viral load (stage iii). [ , ] stages i and ii require a specific adaptive immune response in healthy hosts to eliminate the virus and prevent progression to stage iii; thus, strategies to boost immune responses may play a role in the early stages of covid- . [ ] when this immune response is impaired, the virus will propagate and result in massive destruction of hostaffected tissues. [ ] if the disease progresses to stage iii, the severe respiratory phase, lymphocytopenia and high levels of pro-inflammatory cytokines have been observed, suggesting a "cytokine storm" plays a major role in the pathogenesis of covid- . [ , [ ] [ ] [ ] [ ] [ ] [ ] . interestingly, a review by d'antiga [ ] of the current and past coronavirus outbreaks found that immunosuppressed patients are not at increased risk for more severe pulmonary disease compared with the general population and concluded there is no reason to postpone life-saving treatments such as transplantation or chemotherapy for cancer. this may be related to the implications of the host immune system response leading to tissue damage in healthy patients that advance to the severe stage of covid- , whereas those who are immunocompromised may have a weakened response that could be protective. therefore, the pathogenesis of covid- appears to be heavily related to a cytokine storm resulting in inflammatory damage of host lung tissue and has the potential to result in ards and death, especially in older patients with comorbidities. to help guide future implications for intravesical treatment in covid- and immunological disorders, it is crucial to review our understanding of the mechanisms of action for bcg intravesical therapy. as previously discussed, there are two branches of intravesical therapy for the treatment of bladder cancer: chemotherapy and immunotherapy. overall, immunotherapy acts with the patient's immune system to upregulate and encourage destruction of cancer cells. in general, our understanding of the mechanisms of action for intravesical immunotherapy with bcg is still unclear. it is thought that the instillation of intravesical bcg results in a large local immune response by induced expression of cytokines in the urine and bladder tissue. [ ] bcg first attaches to the urothelium via fibronectin and integrins and is then internalized by urothelial cells and captured by the initial innate immune response. [ ] it is then that antigen presentation and cytokine release results in the upregulation of major histocompatibility complex (mhc) ii, il- , il- and granulocytemacrophage colony-stimulating factor (gm-csf). [ ] this stimulates local recruitment of immune cells such as granulocytes, cd and cd t cells, natural killer (nk) cells and macrophages that produce th- cytokines. [ ] according to prescott et al., [ ] the antitumor activity of bcg in bladder cancer appears to be a local phenomenon confined to the site of administration. in another study, peripheral blood mononuclear cells (pbmc), urine and serum were obtained from patients with superficial carcinoma at various times during the course of bcg instillation, and found an increase in systemic immune activity. [ ] further research is required to determine the precise mechanisms of action of bcg and advance our current knowledge of the immunological processes involved. with knowledge of the recent sars-cov- pandemic, and the risk for severe complications such as ards, it is necessary to review the side effects of intravesical treatment in an attempt to determine its safety in covid- and immunocompromised patients. one major drawback of intravesical bcg is that it is associated with more side effects when compared with intravesical chemotherapy, though more serious adverse outcomes are encountered in less than % of patients. [ ] though still debated, pulmonary complications appear to be of two categories: hypersensitivity reactions and mycobacterial pneumonia. an interstitial pattern on chest radiography, lymphocytosis on bronchial alveolar lavage (bal) and absence of granulomas on lung biopsy, as well as negative sputum and tissue cultures, are indicative of hypersensitivity response. [ ] mycobacterial pneumonia is characterized by biopsies revealing granulomata and radiographic evidence of consolidation, although testing for acid-fast bacteria (afb) may be negative. [ ] a large analysis of patients treated with intravesical bcg revealed . % of patients developed life-threatening bcg sepsis, and . % developed granulomatous pneumonitis. [ ] with regard to other intravesical therapy, mmc has little systemic absorption due to low molecular weight, and chemical cystitis is common. [ ] intravesical bcg is generally considered to be a relative contraindication and used with caution in immunocompromised patients based on current guidelines. however, there have been few studies that have examined the use of intravesical bcg in bladder cancer patients that are concurrently immunosuppressed. in addition to concerns of disseminated infection in immunocompromised patients, bcg is dependent on an effective immune response to exert its mechanism of action in the case of bladder cancer. this has raised concerns that even if instillation is safe in the immunocompromised population, treatment may be ineffective. herr and dalbagni [ ] discovered that bcg therapy was safe in immunocompromised patients with high-risk bladder tumours and may achieve similar results to non-immunosuppressed patients. however, the sample size was small, and generalization was cautioned. a retrospective chart review of immunosuppressed patients (e.g. concurrent lymphoma, chronic lymphocytic leukemia or on corticosteroid therapy) receiving intravesical bcg concluded that the side effects profile associated with bcg therapy in these patients was comparable with those in patients with no evidence of immunosuppression. [ ] additionally, a number of studies have demonstrated safe use in transplant patients, [ , ] and in patients with concurrent human immunodeficiency virus (hiv) infection. [ ] therefore, the use of intravesical bcg may be feasible in patients that are concurrently immunocompromised, but larger trials are required for definitive answers. though immunosuppressed patients with covid- are not at increased risk for more severe pulmonary disease compared with the general population [ ] , intravesical bcg should be used on a case by case basis in this population until definitive outcomes are determined with further studies. with the possibility that bcg may exhibit a systemic immune response, future research may be warranted regarding the use of bcg in the fight against viruses such as sars-cov- and various immunological disorders. there has been promising research in recent years exploring the use of bcg against viruses and other immunological disorders with which to build from and guide future studies. additionally, new clinical trials are being planned to explore the efficacy of boosting immune responses with bcg in the fight against covid- . [ ] recently, a study published in by gofrit et al. [ ] followed patients for year after their diagnosis with bladder cancer. during follow-up, patients developed alzheimer's disease (ad), a condition in which the immune system is a major contributor to pathogenesis. of the patients who developed ad, ( . %) were treated with intravesical bcg, while ( . %) did not receive bcg therapy. it was determined that patients treated with intravesical bcg manifested more than -fold less risk for ad than those not treated with intravesical bcg. in the field of virology, bcg vaccination was shown to protect against a non-related viral infection in an experimental model of human yellow fever virus, and it was discovered that the il- pathway is essential for an efficient induction of trained immunity in humans, which may have important implications for vaccination and the pathogenesis of autoinflammatory diseases. [ ] finally, bcg vaccination impacts the immune response to subsequent infections, resulting in reduced morbidity and mortality, and may protect against various dna and rna viruses, including herpes and influenza viruses. [ ] in these unprecedented times of the sars-cov- pandemic, bcg may offer the potential to boost the immune system in the critical early stages of covid- . the recent and ongoing sars-cov- pandemic is a rapidly evolving situation, with many questions remaining unanswered. the pathophysiology of covid- -related ards and death appears to be heavily related to a cytokine storm resulting in inflammatory damage of host lung tissue. strategies to boost the immune system in the early stages of the disease may help in preventing it from progressing to a more severe respiratory stage. compared with other intravesical therapies, bcg appears to have a higher risk of severe respiratory complications such as ards, and its concurrent use in patients with covid- should be carefully monitored. additionally, these side effects are rare and preventable with proper administration. although there is no current strong evidence, intravesical bcg may be boosting the immune system and may be playing a role towards decreasing morbidity and mortality of covid- . following disease control, multicentric studies should aim to retrospectively look for the correlation between intravesical bcg and development of covid- . novel coronavirus (covid- ) outbreak: a review of the current literature world health organization coronavirus disease (covid- ): what we know can a century-old tb vaccine steel the immune system against the new coronavirus cua guidelines on the management of non-muscle invasive bladder cancer diagnosis and treatment of non-muscle invasive bladder cancer: aua/suo guideline eau guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update intravesical therapy for the treatment of nonmuscle invasive bladder cancer: a systematic review and meta-analysis immune mechanisms in bacillus calmette-guerin immunotherapy for superficial bladder cancer covid- infection: the perspectives on immune responses immune responses in covid- and potential vaccines: lessons learned from sars and mers epidemic clinical features of patients infected with novel coronavirus in wuhan risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease pneumonia in wuhan, china clinical characteristics of coronavirus disease in china di napoli r. features, evaluation and treatment coronavirus (covid- ). instatpearls [internet] coronaviruses and immunosuppressed patients. the facts during the third epidemic the use of intravesical bcg in urothelial carcinoma of the bladder. ecancermedicalscience mechanisms of action of intravesical bacille calmette-guerin: local immune mechanisms systemic immune response after intravesical instillation of bacille calmette-guerin (bcg) for superficial bladder cancer intravesical bcg therapy as cause of miliary pulmonary tuberculosis incidence and treatment of complications of bacillus calmette-guerin intravesical therapy in superficial bladder cancer complications of intravesical therapy for urothelial cancer of the bladder intravesical bacille c almette-g uérin (bcg) in immunologically compromised patients with bladder cancer safety and efficacy of intravesical bacillus calmette-guerin instillations in steroid treated and immunocompromised patients intravesical bacillus calmette-gueÈrin for the treatment of superficial bladder cancer in renal transplant patients management of bladder cancer following solid organ transplantation hiv-associated bladder cancer: a case series evaluating difficulties in diagnosis and management bacillus calmette-guérin (bcg) therapy lowers the incidence of alzheimer's disease in bladder cancer patients bcg vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity non-specific effects of bcg vaccine on viral infections publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations conflict of interest the authors declare that they have no conflicts of interest. key: cord- -cf axwcb authors: schena, daniele; marinoni, guido; galassi, luca title: re-reading the sars-cov- epidemic in bergamo date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: cf axwcb bergamo province was one of the hardest hit regions by the novel sars-cov- virus. since the beginning of the epidemic, more than , people have died as a result of the infection. although many hypotheses have been formulated to explain the rapid outbreak of covid- in lombardy, none have yet considered the specific conditions that characterized the bergamo hinterland. in this letter, we try to identify and investigate which elements could have helped the rapid spreading of the virus. in recent months, several hypotheses have been offered to explain the rapid spread of the virus in bergamo province and lombardy, but all of them are focused on what happened in the hospitals (codogno, alzano lombardo, and other emergency departments across the territory) involved in the sars-cov- epidemic. in particular, the management of two patients admitted in the alzano lombardo hospital on the rd of february was thought to be critical for the epidemic outbreak. however, we believe this conclusion to be imprecise because it does not consider at all the context outside the hospitals. new evidence shows how the virus was already in italy from mid-january [ ] . this belief is strengthened by the fact that some physicians had positive swab test results on the th of february, and it is reasonable to think that the contagion happened days before the test. moreover, it also has to be considered that covid- presented itself, at first, to be an asymptomatic virus making it extremely difficult to identify any suspect cases prior to the appearance of symptoms. during the last week of february and first week of march, many events could be implied in the spread of sars-cov- . the ongoing trade between factories around bergamo (involving workers) and different regions of china was maintained until the beginning of the province lock down on the th of march. moreover, as reported in the official communication to the government by lombardy medical council [ ] , general practitioners lack of individual protection devices during their routine activity could have further eased the sars-cov spreading in the population. an important role might also be attributed to a soccer match that took place on th of february in milan with an audience of more than , people (the majority coming from the bergamo hinterland). it is also important to point out that the criteria for oropharyngeal swab tests imposed by the italian health ministry suggested that tests should only be administered in cases of reasonable suspicion or for people coming into contact with people arriving from china. we strongly support that no actual delay has taken place during the management of the two covid- cases, but the smart intuition to test the patients, derived from government indications [ ] , could have helped to make clear the presence of an already ongoing epidemic. although no interstitial pneumonitis registry of the past years is present, more retrospective studies are needed to investigate among all the hospital facilities in bergamo and surrounding areas in order to clarify the real evolution of covid- in the province of bergamo. in conclusion, and for future reference, it is vital to organize a stronger collaboration between regional medical centers and hospitals in order to coordinate all the efforts to combat the spreading of the virus. genomic characterization and phylogenetic analysis of sars-cov- in italy misure cautelative relative all'evolversi della situazione epidemiologica da covid- aggiornamento della definizione di caso covid publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations authors' contributions all authors conceived and planned this paper, devised the project and the main conceptual ideas. moreover, all authors provided critical feedback and helped shape the research, analysis and writing of the manuscript. conflict of interest the authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge, or beliefs) in the subject matter or materials discussed in this manuscript. key: cord- -kjeqs zh authors: shen, bingzheng; chen, li; zhang, lu; zhang, mengke; li, jing; wu, jie; chen, kunlin; xiong, yuanguo; song, wei; zhou, benhong title: wuchang fangcang shelter hospital: practices, experiences, and lessons learned in controlling covid- date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: kjeqs zh in early january , the outbreak of the new corona virus pneumonia (corona virus disease , covid- ) occurred. wuhan, the capital city of hubei province, became the epicenter of the disease in china. the rapid growth of patients had exceeded the maximum affordability of local medical resources. a large comprehensive gymnasium was converted into wuchang fangcang shelter hospital in order to provide adequate medical beds and appropriate care for the confirmed patients with mild to moderate symptoms. for these hospitalized patients with covid- , medication became the mainstay of therapy. from th february to th march, a team of pharmacists successfully completed drug supplies and pharmaceutical services for patients and approximately medical staff, and, while doing so, received zero complaint, and experienced zero disputes and zero pharmacist infection. this paper summarizes the development and construction of the pharmacy, human resource allocation of pharmacists, pharmacy administration, and pharmaceutical services. it aims to review a -day period of pharmaceutical practice and serve as a reference for other health professionals working on covid- prevention and treatment in other regions. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. on th december , a confirmed case of the new coronavirus infection of pneumonia, termed corona virus disease (covid- ), was detected in wuhan city [ ] . in a short period of time, the virus spread quickly throughout the country, and the number of infected patients increased rapidly. at the beginning of february , available hospital beds soon reached full occupancy in those hospitals designated for antivirus treatment. to complicate matters further, some medical workers were infected due to occupational exposure, which forced the medical team into quarantine for medical observation. based on clinical manifestations, confirmed patients are divided into mild, moderate, severe, and critical types [ , ] . since more than % of covid- patients were mild or moderate types [ ] [ ] [ ] , a novel public health measure, fangcang shelter hospitals, was conceived [ ] . in case of emergency, these temporary hospitals have been able to provide extra beds capacity at short notice and provide classified treatments. all confirmed patients with mild and moderate symptoms could be admitted to the fangcang shelter hospital for free medical treatment. during the worst epidemic period in wuhan, a total of fangcang shelter hospital were established. wuchang fangcang shelter hospital was developed from the hongshan gymnasium and was one of the first three hospitals accepting patients and was the last one to be closed. it covered an area of , m and housed a total of beds, which were separated across three independent regions in order to optimize management and treatment efficiency. during this major public health emergency, pharmacists, as a member of the medical team, have been responsible for providing professional and superior pharmaceutical services. this paper looks back at the pharmacy construction, occupational protection, pharmacy administration, and pharmaceutical services at wuchang fangcang shelter hospital. these practices and lessons at the forefront of containing the virus may help others in their efforts around the world. the pharmacy of wuchang fangcang shelter hospital was a conversion from two referee meeting rooms in hongshan gymnasium ( fig. a and b) . the two rooms were adjacent and connected by a shuttle door. one room was used as pharmacy, the other served as a level warehouse (fig. c and d) . due to space constraints, there was no room for a level warehouse for medications requiring refrigeration. all central air conditioners were turned off to prevent the virus spreading through the ventilation systems. several household heaters, humidifiers, air purifiers, and refrigerators were used to maintain the appropriate temperature, humidity, and clean air for the storage of medicines. ten pharmacists from renmin hospital attached to wuhan university provided strong support and formed a professional pharmaceutical team ( table ). the pharmacy was open / (pharmacists working -h shifts), enabling the constant availability of pharmaceutical services at all times. considering the long hours, high-intensity, and complexity, most pharmacists working in wucang fangcang shelter hospital were young to middle-aged, well-educated with a master's degree or higher, and with at least years of pharmacy experience. the team of pharmacists was monitored regularly. body temperature was measured twice a day, and nucleic acid and specific antibodies of covid- were tested twice per month. attention was also paid to the staff's mental and emotional health. if necessary, psychological evaluations were carried out, and psychological counseling was provided. the correct use of personal protective equipment (ppe) and regular and thorough hand hygiene were key measures in the prevention and control against infection through contact transmission, droplet transmission, and airborne virus particles. according to the risk of exposure in different working areas, pharmacists took different precautions ( table ) [ ] . various protective measures were taken to ensure that pharmacists provided professional services in a responsible manner. all medications used in wucang fangcang shelter hospital were obtained from three sources: . renmin hospital of wuhan university, which acted as the national general coordinating agency for all medical teams, provided medicines for chronic diseases and firstaid. . some medicines recommended in the diagnosis and treatment guidelines were obtained from wuhan epidemic prevention and control headquarters [ ] . . medicines donated by pharmaceutical companies or charitable organization. the diverse sources of medications added to the need for efficient and accurate pharmacy work, caused many difficulties for the pharmacy administration. the corresponding work processes, including the receipt of medicines, selection, inspection, prescription-checking dispensing, and distribution were established under the unified leadership of wuchang fangcang shelter hospital (fig. ) . according to their characteristics and according to the diagnosis and treatment guidelines, other regulatory documents [ , ] , combined with expert clinical opinions, a list of medicines was determined for infected patients with mild and moderate symptoms. this involved symptomatic treatment, prevention of complications, treatment of underlying diseases, emergency rescue medications, and so on. based on the actual clinical situation, the variety and quantity of medication were regularly adjusted and supplemented. a catalog containing medications was finally revised in mar and showed in table s . the category of medicines in the pharmacy was compatible with the function of the fangcang shelter hospital, and covered antiviral, antibacterial, antipyretic, antitussive, antianxietic, expectorant, and chronic disease medications. it conformed the treatment protocols for covid- , and met the needs of some patients with underlying disease, as well as including first-aid medicines to be able to deal with any sudden incidents. to integrate traditional chinese and western medicine to treat infected patients, kinds of traditional chinese medication, including preventive and therapeutic decoctions for medical staffs and patients (fig. s ) , respectively, were also available. in addition to maintaining a constant and regular supply of drugs, the provision of pharmaceutical services was another important and indispensable duty during the pandemic [ ] [ ] [ ] . relying on the g network and medical information systems, the team of pharmacists accomplished pharmaceutical services smoothly, helping to reduce the risk of occupational exposure in the shelter hospital. pharmaceutical services focused on the following six aspects: . checking medical orders related to the drug therapy . paying attention to the prescriptions for patients with underlying diseases . the suitability of the usage and dosage of the medication . monitoring adverse drug reactions and drug-drug interactions . summarizing and sharing the latest drug information . providing medication-related consultation and education. in some cases, several patients with chronic diseases took repeated medications or overdose. they were admitted to the hospital with their own chronic disease medicines. not clearly understanding the situation, doctors prescribed the same medication or other drugs possessing the same pharmacological effect. to overcome this problem, patients taking chronic disease medicines (such as antihypertensive drugs and hypoglycemic agents) were screened out by the pharmacy information system. as a result, pharmacists could intervene in time on medical orders and prescriptions. the pharmacists also while our understanding of the virus deepens and with the constant improvement of diagnosis and treatment and strategies for prevention and control, pharmacists should continue to actively collect and improve their services based on the latest information. for instance, it has recently been discussed whether or not angiotensin-converting enzyme inhibitor (ace-i) and angiotensin receptor blockers (arbs) increased the susceptibility of covid- . in the pharmaceutical services provided at wuchang fangcang shelter hospital, ace-i and arbs were not recommended, but now, the latest joint viewpoint from three u.s. heart groups states that patients with covid- should take ace inhibitors and arbs [ ] . not to be neglected, the mental health of the pharmacist also requires close attention. having worked in this shelter hospital for days, one pharmacist felt anxious and uncomfortable. tests of viral-specific nucleic acid and antibody were negative and computed tomography reported normal results. after psychological counseling and a brief period of rest, the physical and mental states were greatly improved, and the pharmacist gradually recovered. psychology-related research shows that during the peak of the covid- epidemic in china, more than one-third of medical staffs suffer from insomnia, which may progress to depression, anxiety, and stress trauma [ ] . on march , , wucang fangcang shelter hospital was closed, thus indicating that all of these large-scale temporary hospitals had completed their missions in wuhan. the team of pharmacists has done their utmost efforts to perform their professional duties, ensuring the supply of medicines and providing high-level pharmaceutical services. currently, the covid- outbreak is spreading worldwide, and the situation awaits a vaccine. pharmacists should unite globally to contribute their expertise and strength to help prevent the spread of the virus. acknowledgments in this concerted effort against the covid- virus, thousands of medical staffs in china (doctors, pharmacists, nurses, inspection, and image technicians) put their hearts and souls into curing infected patients, subjecting themselves to huge risk of infection. we thank all pharmacists for their valuable suggestions and great contributions in fighting this epidemic disease. thanks also to all logistics support workers in delivering invaluable protection equipment and living supplies to medical staffs and patients. authors' contributions bs and bz initiated the topic. bs, bz, lc, lz, mz, jl, jw, kc, yx, and ws participated in discussions. bs wrote the first draft of the manuscript. all authors read and approved the final manuscript. conflict of interest the authors declared that they have no conflict of interest. ethics statements not applicable. this is a descriptive and retrospective study that and does not undermine the principles according to the ethical standards of the institutional and/or national research committee and/or the helsinki declaration and its later amendments or comparable ethical standards. clinical characteristics of coronavirus disease in china a familial cluster of pneumonia associated with the novel coronavirus indicating person-to-person transmission: a study of a family cluster office of state administration of traditional chinese medicine. diagnosis and treatment protocol for covid- coronavirus disease (covid- ): a perspective from china coronavirus disease (covid- ): current status and future perspectives clinical characteristics and imaging manifestations of the novel coronavirus disease (covid- ): a multi-center study in wenzhou city fangcang shelter hospitals: a novel concept for responding to public health emergencies coronavirus sars-cov- infection: expert consensus of guidance, prevention and control strategy for hospital pharmacy work (the second edition) china national health commission. diagnosis and treatment guidelines for the new coronavirus infected pneumonia international pharmaceutical federation. coronavirus -ncov outbreak: information and interim guidelines for pharmacists and the pharmacy workforce providing pharmacy services during the coronavirus pandemic providing pharmacy services at cabin hospitals at the coronavirus epicenter in china fighting against covid- : innovative strategies for clinical pharmacists covid- and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: what is sn compr survey of insomnia and related social psychological factors among medical staff involved in the novel coronavirus disease outbreak publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations electronic supplementary material the online version of this article (https://doi.org/ . /s - - - ) contains supplementary material, which is available to authorized users. key: cord- -xbomgwzx authors: singh, sandeep; desai, rupak; gandhi, zainab; fong, hee kong; doreswamy, shriya; desai, virmitra; chockalingam, anand; mehta, puja k.; sachdeva, rajesh; kumar, gautam title: takotsubo syndrome in patients with covid- : a systematic review of published cases date: - - journal: sn compr clin med doi: . /s - - -w sha: doc_id: cord_uid: xbomgwzx takotsubo syndrome (tts) is caused by catecholamine surge, which is also observed in covid- disease due to the cytokine storm. we performed a systematic literature search using pubmed/medline, scopus, web of science, and google scholar databases to identify covid- -associated tts case reports and evaluated patient-level demographics, clinical attributes, and outcomes. there are cases reported of tts associated with covid- infection with mean age of . ± . years (range – years) with elderly ( . % > years) female ( . %) majority. the time interval from the first symptom to tts was . ± . days (range – days). out of cases, reported apical ballooning, reported basal segment hypo/akinesia, and reported median tts. out of cases, during hospitalization, data on left ventricular ejection fraction (lvef) was reported in only of the cases. the mean lvef was . ± . % (male, . ± . %, and female, . ± . %). troponin was measured in all cases and was elevated in ( . %) without stenosis on coronary angiography except one. out of cases, developed cardiac complications with case each of cardiac tamponade, heart failure, myocarditis, hypertensive crisis, and cardiogenic shock in . five patients required intubation, patient required continuous positive airway pressure, and patient required venovenous extracorporeal membrane oxygenation. the outcome was reported in terms of recovery in ( . %) out of cases, and a successful recovery was noted in ( . %) cases. covid- -related tts has a higher prevalence in older women. despite a lower prevalence of cardiac comorbidities in covid- patients, direct myocardial injury, inflammation, and stress may contribute to tts with a high complication rate. takotsubo syndrome (tts, takotsubo cardiomyopathy, stress cardiomyopathy, or "broken heart syndrome") is characterized by acute left ventricular dysfunction usually in the setting of physical or emotional stress [ ] . conditions of acute stress leading to catecholamine surge have been suggested as pathophysiological mechanisms to date [ ] . according to the world health organization, the current ongoing covid- pandemic has infected over million people and has led to approximately , deaths worldwide. a high burden of acute cardiac injury ( . - . %), leading to significantly high mortality, has been reported in these patients [ , ] . covid- patients with cardiovascular injury have been reported to have a high burden of underlying cardiovascular comorbidities [ , ] . furthermore, accumulating evidence suggests a picture of severe systemic inflammation and cytokine storm in covid- patients [ ] . hyperinflammatory states could lead to acute stress and injury, evident from elevated markers of myocardial injury such as c-reactive protein, pro-calcitonin, creatine kinase, myoglobin, and n-terminal pro b-type natriuretic peptide (nt-probnp) in these patients [ ] . emerging evidence suggests a picture of cytokine storm syndrome, resembling cytokine release syndrome, in covid- patients [ ] . it has been observed that cytokine release syndrome is accompanied by catecholamine surge [ ] , which can predispose to tts in covid- patients. however, limited data on tts in covid- patients with only a handful of case reports promoted us to systematically review the published cases and pertinent outcomes. we searched pubmed/medline, web of science, scopus, and google scholar until june , for case reports and case series using these keywords: covid- , sars-cov- , takotsubo syndrome/takotsubo cardiomyopathy, stressinduced cardiomyopathy, and broken heart syndrome. all the published case reports included in the final analysis were in english except one in italian. since the number of case reports is few, we translated case report in italian [ ] using google translator. data from the article were curated and summarized in the form of country of origin, age, and gender of the patients, their presenting complaint, any coexisting comorbidities, medical interventions during hospitalization, and their outcome. continuous variables were presented as means ± standard deviations and categorical data as absolute values and percentages. all data extraction and descriptive analysis were performed using microsoft excel. our search identified articles; were excluded due to duplication, were excluded because they were review articles on covid- , and did not report any cases with tts. finally, articles describing patients for the analysis were selected [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] (tables and ). the mean age of the reported patients was . ± . years (range - years). of all the reported cases, . % (n = ) were women and mostly elderly (n = ; > years, . %) patients. most of the reported cases were from italy ( %) and the usa ( %), while belgium, spain, and switzerland contributed case each. only reports ( %) identified the triggering/stress event in these cases. among cases, only cases had positive family contact history, had no contact history, and did not report any contact history. out of cases, cardiovascular comorbidities were reported (hypertension was reported in ( . %), diabetes in ( . %), and dyslipidemia in ( . %)). the most common presenting symptoms noticed were shortness of breath/ dyspnea in ( %), fever in ( . %), and chest pain in ( . %) of the cases. the time interval within the first symptom to the development of tts was . ± . days (range - days). out of cases, chest imaging in the form of a chest x-ray or ct chest was present in cases. the most common chest imaging findings were bilateral opacities in ( . %) and ground-glass opacity in ( . %) cases. overall, of the reported cases had heart failure with reduced ejection fraction on echocardiography with myocardial injury noted by elevated troponin i but no significant stenosis on coronary angiography. only patient had angiographically significant proximal lad disease requiring two drug-eluting stents. only ( %) had abnormalities on ecg, with st segment elevation in ( %), t-wave inversion in ( %), prolonged qtinterval in cases ( %), and low voltage complex in ( . %) case. out of cases, during hospitalization, data on left ventricular ejection fraction (lvef) was reported in only of the cases. the mean lvef was . ± . % (male, . ± . %, and female, . ± . %). brain natriuretic peptide (bnp) was reported in out of cases and was found to be elevated in all the cases. out of cases, in cases, c-reactive protein was measured and found to be elevated in all the cases ( . ± . mg/l). ferritin was measured in only of the cases out of and was raised in both the cases ( ± . ng/ml). in of the cases, the interleukin- level was measured and was found to be raised ( . ± . pg/ml). troponin was measured in all the reported cases and was high in ( . %). out of cases, reported apical ballooning, reported basal segment hypo/akinesia, and reported median tts. out of cases, ( . %) cases reported at least one complication. out of cases, developed cardiac to our knowledge, this is the first systematic review of covid- patients developing tts. existing literature suggests that postmenopausal females are more prone to developing tts [ ] as was observed in our report. loss of sympatholytic effect of estrogen and increased myocardial and vascular response to beta-adrenergic receptors in postmenopausal women has been suggested as one of the several reasons for increased risk of tts [ ] . however, it remains unexplored if this mechanism also poses a greater risk of tts among elderly women with concomitant covid- infection as compared with men. in this study, only a handful of cases reported classic triggering events like the development of tts after physical stress like intubation and/or emotional stress pointing towards the physical or emotional stress towards the development of tts in this covid- patients [ , , ] . however, a large number of cases did not report any particular triggering event. in addition to the physical impact, an emotional impact in the form of social isolation leading to anxiety and stress during this pandemic could also trigger tts [ ] . we found that more than half of the patients had a current or past history of underlying cardiovascular comorbidities including nonischemic cardiomyopathy in , hypertension in , diabetes in , and dyslipidemia in case [ - , , ] . patients with these comorbidities have a high burden of pro-inflammatory cytokines like interleukin- (il- ) and tumor necrosis factor-α (tnf-α) [ ] . although the exact mechanism of tts in covid- is not fully explained, a cytokine storm syndrome-like picture has been seen in covid- patients [ ] , with a high burden of pro-inflammatory cytokines like il- , which was reported in cases [ , ] . the cytokine storm syndrome has been noted to be accompanied by a surge in catecholamines [ ] . this surge could lead to direct catecholamine toxicity and myocardial damage leading to tts [ ] . we noticed that covid- patients had raised inflammatory markers in terms of raised crp and ferritin. furthermore, a high burden of pro-inflammatory state in these patients could lead to coagulation abnormalities and related complications. bernardi et al., in their case report, descried left ventricular thrombus formation in a covid- patient with tts [ ] . more than half of the cases presented with the classical symptoms seen in covid- including chest pain and [ , , [ ] [ ] [ ] [ ] , which is also frequently seen in patients with tts [ ] . furthermore, a modest increase in cardiac troponin and ecg changes suggestive of myocardial injury was noted in all the cases, which is commonly seen in tts [ ] , and could mimic acute coronary syndrome (acs). furthermore, sars-cov- infection could lead to myocarditis which could be misdiagnosed as tts [ ] . however, the absence of any significant coronary lesions, in most the patients who underwent coronary angiography, makes acs an unlikely culprit. besides, ventriculography demonstrated the apical ballooning in most of the cases [ , , , , ] , apical hypo/ akinesia with or without basal hyperkinesia [ , , ] , basal or mid and basal segment hypo/akinesia [ , [ ] [ ] [ ] , and median tts [ ] characteristic of tts variants. even though most of the cases recovered and discharged successfully, more than % of the patients developed complications such as cardiac tamponade, heart failure, cardiogenic shock, myocarditis, hypertensive crisis, or respiratory failure. a marked decrease in the systolic left ventricular function has been reported in the acute phase of tts [ ] with a prognosis depending on the nature of triggering factors. tts secondary to emotional factors has shown a good prognosis while tts secondary to medical conditions or procedure has shown unfavorable short and long-term prognosis [ ] . all patients with qt interval prolongation except one were on hydroxychloroquine for covid- treatment. hydroxychloroquine has arrhythmogenic potential and should be used cautiously in covid- patients with a high burden of myocardial injury as it could further contribute to the risk of dysrhythmias and worse outcomes in tts. some limitations warrant attention while inferring these results: first, small sample size with the only case reports with tts triggered by covid- related stress was included. second, there is a chance for publication bias, as the more challenging cases are more likely to be reported and published; and third, the lack of generalizability as the demographics and baseline information cannot be used for outcomes of a larger population without a control group. covid- -associated direct myocardial injury, inflammation, and stress may account for tts despite low cardiac comorbidities. covid- -related tts is predominant in older women with a high complication rate with the majority of cases recovering successfully. conflict of interest the authors declare that they have no conflict of interest. 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 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vs. non-coronary disease levels of troponin release can aid in the early exclusion of stress-induced (takotsubo) cardiomyopathy long-term prognosis of patients with takotsubo syndrome publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- -vfmzk el authors: ming, yi; qiang, liu title: involvement of spike protein, furin, and ace in sars-cov- -related cardiovascular complications date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: vfmzk el the novel coronavirus disease (covid- ) is a global epidemic caused by severe acute respiratory syndrome coronavirus- (sars-cov- ). sars-cov- has a similar structure to severe acute respiratory syndrome coronavirus- (sars-cov- ). the s protein on the surface of the virus is cleaved by host proprotein convertases (pcs) to expose the active n-terminal s extracellular domain. its receptors are angiotensin-converting enzyme (ace ), and the c-terminal s membrane anchoring protein is responsible for translocating the virus into the cell. among patients with covid- , there is a higher prevalence of cardiovascular disease, and more than % of patients have suffered myocardial damage due to the infection, but the internal mechanism is still poorly understood. there is currently no specific and effective targeted treatment. reduction of the patient’s morbidity and mortality is an urgent problem that needs to be solved clinically. by exploring the theoretical analysis of pcs and ace in covid- cardiovascular susceptibility, some insights on how to prevent and alleviate adverse cardiovascular prognosis have been provided in this study. the epidemics caused by coronavirus before covid- , acute respiratory syndrome (sars) [ , ] , and middle east respiratory syndrome (mers) [ , ] outbreaks were reported to be related to cardiovascular disease. current clinical reports indicate that sars-cov- is associated with significant morbidity of cardiovascular diseases and complications, such as hypertension (htn), myocarditis, acute myocardial infarction, and increased heart failure [ , ] . researchers have extensively studied the pathophysiology of sars-cov- infection and believe that the ace receptor acts as a highaffinity receptor and co-transporter of the virus into the cell [ , ] . the widespread expression of ace in the myocardium and vascular endothelial cells might be due to the presence of sars-cov- , which could cause direct cardiovascular damage and lead to adverse consequences [ , ] . the s protein plays a vital role in the process of sars-cov- infecting the host and translocating into the cell [ , ] . coronavirus s protein is a granule-shaped structural protein with a length of about aa, which helps the virus to bind to cell receptors and participate in mediating viral infection and pathogenesis [ , ] . during viral infection, the host cell pcs cleave the s /s cleavage site of the trimer s protein dividing it into an n-terminal s extracellular domain that recognizes the relevant cell surface receptor and a c terminal s membrane anchor protein that is involved in translocation of the virus into the cells [ , ] . sars-cov-s and sars-cov-s proteins contain a conserved receptor-binding domain (rbd), which can recognize ace [ ] . therefore, pcs family, especially furin, can be considered the key medium that mediates the maturation of s protein processing and recognition of membrane proteins. furin can also be considered a critical molecule that makes sars-cov-s cause adverse cardiovascular events through the ace receptor. this yi ming and liu qiang contributed equally to this work. this article is part of the topical collection on covid- * yi ming mingming @ .com speculation is also supported by the occurrence of a high level of furin in the peripheral blood of heart failure patients. based on these theoretical assumptions, it can be concluded that the s protein/host furin/ace signal axis exists in the pathological process of sars-cov-s infection and mediates the occurrence of adverse cardiovascular prognosis events. numerous studies discussed ace before, and therefore this article has focused on the role of furin in this pathological process. furthermore, a unique furin-like cleavage site exists in the s protein of sars-cov-s [ ] ; thus, the theoretical advantage inferred from this cleavage site in disease infection models can be deduced to prevent and combat covid- caused by sars-cov- . covid- is mainly presented with respiratory symptoms. patients with severe infections usually present with acute respiratory distress syndrome (ards) and septic shock. the cardiovascular system involvement in this infection is also a significant feature. cardiovascular disease (cvd) is a common comorbidity of covid- , sars, and mers patients. in sars, the prevalence of diabetes mellitus (dm) and cvd is % and %, respectively, and their occurrence increases the risk of death [ ] . about % of mers cases are combined with dm and htn, and about % are combined with cvd [ ] . covid- also has cardiovascular comorbidities, especially in cases with more severe conditions. by april , the "analysis of new coronavirus pneumonia epidemiological characteristics," published by the chinese center for disease control and prevention, indicated that hypertension was the most common underlying disease among the patients. there were patients with hypertension, accounting for . % of the total number of patients, . % of the dead patients had hypertension, . % of patients and . % of patients with cardiovascular disease [ ] , and more than % of severe patients had myocardial damage [ ] . besides, some patients showed symptoms of palpitations. in a study of patients, . % of patients had palpitations as the initial symptom [ ] . finally, a recent meta-analysis of eight studies from china, including a total of , infected patients, showed that the most common comorbidities were htn ( ± %, % ci - %), dm ( ± %, % ci - %), and cardiovascular disease ( ± %, % ci - %) [ ] . however, the mechanism of these associations is currently unclear. the current hypotheses include the common risk factors of cvd and covid- (such as advanced age and low immunity), ace , and furin levels. the processing and activation of the coronavirus s protein are critical to the infectivity of the virus. therefore, relevant enzymes constitute potential targets for antiviral intervention. the proprotein convertase family (pcs; gene name pcsks) is composed of nine serine-secreting proteases and is widely involved in regulating various biological processes in normal and disease states. the pcs can perform multiple activation functions and are involved in many key cellular pathways. the pcs cleave precursor proteins at specific single or paired basic amino acids (aa), turning them precursor proteins into an active state. in many pcs, the processed substrate is the infectious virus cell surface glycoproteins [ ] . the relationship between pcs (especially furin) and viral infection was confirmed based on their role in the processing of many essential cell surface proteins [ ] . for human coronavirus infections, the s proteins of hcov-oc , mers-cov, and sars-cov show the catalytic motif of pcs: lys/arg-xn-lys/arg↓ (where xn is other amino acids except cysteine). of amino acids, n can be , , , or ↓ [ ] . this further confirms the role of pcs in the mechanism of coronavirus infection. the s protein acts as a key medium for sars•cov• to invade the host and cause cell damage. after entering the body, the host cell pcs cleave the trimer s protein at the s / s cleavage site, dividing it into an n-terminal extracellular domain of s , which recognizes related cell surface receptors, and a c-terminal s membrane anchoring protein, which is involved in the entry of the virus into the cells. sars-cov-s , like the s protein of sars-cov-s , contains a conserved rbd that recognizes ace [ , ] . therefore, the pcs family, especially furin, can be regarded as a key medium that mediates the processing and maturation of viral spike protein and recognizes membrane proteins and plays an important role in the treatment process of viral infection [ , ] . the biological process of furin processing and activation of coronavirus s protein to expose the reactive domain also explains partially the phenomenon of covid- with severe cardiovascular damage. furthermore, heart failure, accompanied by a marked increase in the level of furin in the peripheral blood in the course of covid- in patients [ ] , makes this conjecture more credible. therefore, inhibition of such processing enzymes could represent a potential antiviral strategy. interestingly, members of the pcs family often cause functional redundancy or complementation due to the high structural similarity [ ] . among the pcs secreted by the heart, pcsk is the most abundant [ ] and is more than % structurally similar to furin. pcsk functions as a critical protease for processing corin and is involved in the regulation of enkephalin blood pressure [ ] . it has also been shown to be involved in the pathological process of atherosclerosis and myocardial fibrosis after myocardial infarction [ ] . therefore, furin is likely to be a functional complementarity or redundancy of pcsk . blocking the activity of these enzymes can reduce viral infections and cardiovascular damage and is beneficial for the treatment of cardiovascular diseases. besides, to limit viral infection, host cells infected by the virus can cause an interferon response, which autonomously inhibits the enzyme activity of furin [ ] . these previous findings have indicated that furin inhibitors could help in suppressing the spread of sars-cov- . moreover, based on the role of furin protein in cardiovascular disease, its inhibitors might also improve cardiovascular prognosis and reduce critical deaths. therefore, furin could be a promising target for the development of new treatments. pathogens or their toxins require processing by host pcs to enter host cells and cause disease. conversely, inhibiting pcs may protect host cells from furin-dependent pathogens. the correctness of the concept of furin-dependent infection has been supported by many basic studies [ ] [ ] [ ] . various methods have been proposed that inhibit furin activity hence limiting viral and bacterial infections and tumor growth. the variant of natural serine protease inhibitor α- antitrypsin affects the replication of the hiv- virus by interfering with the differentiation and maturation of gp to gp and gp [ ] . also, the clarification of the crystal structure of furin promotes the design of , -dideoxystreptamine derivative inhibitors [ , ] . nevertheless, because furin is involved in many cellular processes, it is important to avoid this systemic inhibition as it can cause some toxicity. therefore, rapid screening of small molecule inhibitors or other more effective oral active inhibitors, such as andrographis paniculata [ ] , should be conducted to evaluate its antiviral effect on -ncov. the abnormal expression or activity of furin can cause a variety of diseases that include infectious (viral or bacterial infections) and non-infectious diseases, metabolic diseases, and even cancer [ ] . furin has also been shown to be involved in s protein cleavage and sars-cov- pathogenicity [ ] . although furin has been regarded as a potential therapeutic target for infectious diseases, the use of host protease inhibitors (especially inhibitors against furin) as a treatment strategy for covid- seems to be premature. therefore, its lysis role and pathogenesis in sars-cov- need further clarification. for coronavirus to enter the host target cell, it needs to complete two key steps. it first binds to the cell surface by attaching to the host cell receptor and then fuses its envelope to the cell membrane for the viral genome to be released into the cytoplasm of the host cell to achieve viral replication. both of these steps are controlled by the s envelope protein [ ] . s protein is a structural protein of about aa in length that constitutes the corona shape of coronavirus particles. it binds to the cell receptors and participates in mediating viral infection and pathogenesis [ ] . however, in the process of infection, the s protein plays a direct damaging role by recognizing and binding to the ace receptor and invading the host cell [ ] . studies have shown that the affinity of the s-spike protein of sars•cov• with ace is to times higher than that of sars•cov- [ ] . based on the high expression of ace in cardiomyocytes, it is theoretically speculated that many new coronaviruses could directly bind to ace and directly damage cardiomyocytes. on the other hand, s protein depletes in binding to ace , leading to myocardial damage mediated by ace/ace imbalance in vivo [ ] . ace is a homolog of ace, but their functions are entirely different [ ] . ace-mediated endocrine regulation causes vasoconstriction and increased blood pressure through the ace•angii (angiotensin ii)•at axis [ ] . the ace •ang • •mas axis mediated by ace can antagonize the above effects [ ] . angii, as an inflammatory factor regulatory protein, plays an essential regulatory role in mediating myocardial injury, and ace has a protective effect in organs such as the heart and kidney [ ] . it is theoretically speculated that sars•cov• reduces the expression of ace after infecting cardiomyocytes through s protein, causing an increase in angii level, which results in cardiomyocyte damage and apoptosis. based on these theories, it is assumed that the ace receptor plays an important role in this pathological process, and therefore by directly acting or by discontinuing acei/arb, ace has become a candidate treatment strategy [ ] . the theoretical advantages of discontinuing acei/arb from results observed in clinical cohort studies are inconsistent [ , ] . drug analysis in hypertensive-positive patients found no association between any single drug category and the increased likelihood of positive tests. at the same time, no drug is associated with a significant increase in the risk of serious diseases. the reduction of mortality caused by the use of acei/arb has been adequately studied. the current beneficial effects on patients with diabetes, chronic kidney disease, and proteinuria or proteinuria exceed the theoretical risk. in patients with chronic heart failure, the beneficial effects of acei/arb outweigh the theoretical risks. currently, covid- has reached a pandemic level and affect more patients with cardiovascular comorbidities, and the ongoing randomized clinical trials to investigate whether hospitalized covid- patients should continue to use acei/arb, will shed more light on the accuracy of the existing hypothesis (nct ). out of caution, there is currently no plan for discontinuation of acei/arb in covid- patients with heart failure, hypertension, or ischemic heart disease. faced with the dilemma of whether to discontinue acei/arb, the clinical strategy of direct injection of ace seems more promising. the bacterial-derived ace -like enzyme b -cap and human recombinant soluble angiotensinconverting enzyme (rhace ) have the same mechanism of action. the use of b -cap and rhace can eliminate the membrane-anchoring domain to inhibit angiotensin ii induction, high blood pressure, myocardial hypertrophy, and fibrosis, which in turn shows beneficial effects in disease models such as heart failure, acute lung injury, and diabetic nephropathy. the rhace is currently being tested clinically to treat patients with ards and covid- infection [ , ] . on the other hand, hrsace or b -cap can prevent sars-cov- from entering the cell and induce the virus to attach to the exogenous ace copy instead of the host cell. this destroys the ability of the virus to infect the cell to the same extent leading to reduced viral replication in the lungs and other organs. furthermore, the role of hrsace or b -cap in inhibiting covid- could be achieved by downregulating the host ace since it is the right receptor of sars-cov- . therefore, hrsace or b -cap is expected to treat sars-cov- infection, and some of the ongoing clinical trials will further corroborate these clinical advantages (nct , nct ). at present, there is still a lack of in-depth research on the complete pathophysiological process of covid- and cardiovascular disease. however, through clinical manifestations and theoretical assumptions, it is speculated that sars•cov• may affect the cardiovascular system through various mechanisms. here, the s protein/furin/ace signal axis provides a further potential explanation for the susceptibility of the heart to covid- . the sensitivity of sars-cov- infection may be due to the simultaneous upregulation of ace and furin in the diseased myocardium, and raas in this population. the lack of a specific antiviral drug means that the infected people cannot be treated and poses difficulties in controlling the spread of the virus. we mainly rely on isolation measures to prevent the spread of covid- . although clinical trials of antiviral drug candidates (hiv protease inhibitors lopinavir and ritonavir) were conducted early in the outbreak, the test results were unfortunately disappointing. chloroquine and hydroxychloroquine are not beneficial and increase the risk of arrhythmia or even death. it is still necessary to continue to test and apply the currently available and future therapies of covid- . therefore, in patients with sars-cov- infection, transient regulation of the viral binding sites on ace or furin through immunological or pharmacological methods may constitute a new therapeutic strategy to deal with this unprecedented and powerful virus threat. authors' contributions ym and lq were contributors writing the manuscript. all authors have read and approved the submitted manuscript. the work was supported partly by the shenzhen science and technology research and development fund (no jcy ). availability of data and material all available information is contained within the present manuscript. conflict of interest the authors declare that they have no conflict interest. abbreviations covid- , novel coronavirus disease; sars-cov- , severe acute respiratory syndrome coronavirus- ; sars-cov- , severe acute respiratory syndrome coronavirus- ; pcs, proprotein convertases; ace , angiotensin converting enzyme ; sars, severe acute respiratory syndrome coronavirus; mers, middle east respiratory syndrome; htn, hypertension; rbd, receptor-binding domain; ards, acute respiratory distress syndrome; cvd, cardiovascular disease; dm, diabetes mellitus; angii, angiotensin iireferences clinical progression and viral load in a community outbreak of coronavirus-associated sars pneumonia: a prospective study epidemiology and cause of severe acute respiratory syndrome (sars) in guangdong, people's republic of 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michela; vaccaro, angelina title: how covid- pandemic changed children and adolescents use of the emergency department: the experience of a secondary care pediatric unit in central italy date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: cupy gl italy was the first european country hit by sars-cov- infection, particularly northern regions. after the beginning of national lockdown (march th, ), we observed a significant decrease in pediatric emergency department consultations (daily pediatric visits; pre-lockdown, ( – ); lockdown, ( – ); phase , ( – ), p < . ). on the other hand, the percentage of children discharged right after pediatric visit significantly decreased from % in january to % in april. after march th, we registered a change in the diagnoses of emergency department visits, with an increase in the percentage of non-infectious acute conditions and a decrease in infectious diseases, with two cases of a noteworthy delayed access to hospital care. we performed a retrospective analysis of consultations requested to our pediatric unit for children and adolescents referred to the general emergency department of san luca hospital of lucca (tuscany, central italy) from january st to may st, . we split data in two different time periods according to consultations performed before (january st–march th) and after the beginning of lockdown (march th–may st). analyzing the number of children hospitalized from january to may in comparison with the same period in , a decreased hospitalization became evident after march (march − . %, april − . %, may − . %). nasopharyngeal swabs done in children showed only one case of covid- . even if covid- outbreak more seriously affected northern italy, utilization of pediatric emergency services significantly changed also in central italy with consequent reduced demand and increased appropriateness. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. coronavirus disease (covid- ), a novel disease caused by severe acute respiratory syndrome coronavirus (sars-cov- ), emerged in china in december and rapidly spread worldwide [ ] . italy was the first european country hit by sars-cov- infection. indeed, after detecting the first italian patient affected by covid- on february st, , in codogno (lombardy, northern italy), sars-cov- infection affected the entire peninsula, and on june th, the italian ministry of health reported , cases and , deaths [ ] . the first tuscan case of covid- was detected on february th. on june th, tuscany (central italy) was the fifth italian region by number of cases with , confirmed cases and deaths. lucca with cases was the second province of tuscany after florence [ , ] . available international data showed that newborns, children, and adolescents with covid- usually develop a mild disease with few symptoms and a good prognosis compared with adults [ ] [ ] [ ] . published preliminary italian data confirmed a general favorable clinical course of covid- in pediatric age [ ] . however, two italian pediatric research networks reported a not negligible rate of severe presentations in children with comorbidities [ ] ; four deaths (age ≤ years) have been reported on june th [ ] . to tackle covid- outbreak, the italian government imposed strict containment measures. since march th, , italian schools and universities were closed. during phase (national lockdown period, march th-may rd, ) the italian ministry of health recommended to avoid direct access to the emergency department (ed) in case of fever and/or cough or other respiratory symptoms, favoring home care or phone consultation for ill patients without compromised general conditions [ ] . phase started on may th, , and was characterized by progressive relaxation of containment measures allowing outdoor physical activity, opening of the public parks, and visits to relatives within the regional territory (always keeping the distance of at least m and with the mandatory use of masks) [ , ] . these strategies caused a substantial decline in ed visit and hospitalizations [ , ] . preliminary data from italian pediatric ed showed that, during lockdown (march st- th, ), ed visits were significantly decreased (up to %) as compared with the same time period in and . alarmingly, cases of severely ill children with delayed access to hospital care ( deaths) were reported [ ] . the aims of this study were to ( ) evaluate the impact of covid- pandemic on the activity of a secondary care italian pediatric unit assessing, in particular, the characteristics of pediatric ed consultations performed in before and after the beginning of lockdown; ( ) evaluate the prevalence of sars-cov- infection in children and adolescents referred to ed; and ( ) compare pediatric ed activity during the same period of and . we performed a retrospective analysis of consultations requested to our pediatric unit for children and adolescents referred to the general ed of san luca hospital of lucca (tuscany, central italy) from january st to may st, . during covid- pandemic, this hospital was qualified to admit patients with suspected or confirmed sars-cov- infection ("covid- hospital"). from the general ed management software (firstaid®, dedalus healthcare systems group, florence, italy), we extracted anonymous data such as gender, age, date (weekday or pre-holiday/holiday), and outcome (discharge after ed visit, short-stay observation ( - h), ordinary hospitalization (≥ h), or transfer to tertiary care hospital) of patients < years referred to the ed and needing pediatric visit. we split data in two different time periods according to consultations performed before (january st-march th) and after the beginning of lockdown (march th-may st). the latter was further divided in phase (march th-may rd) and phase (may th- st), as indicated by the italian government [ ] [ ] [ ] . diagnoses of pediatric visits were grouped in main categories (upper respiratory tract infections, lower respiratory tract infections, gastroenteritis/vomiting, acute abdominal pain, trauma, neurologic diseases, other acute diseases, and no urgency). we also evaluated the number of pediatric ed visits performed monthly from january st to may st, , for selected infectious and non-infectious diseases. covid- was diagnosed testing nasopharyngeal swab for sars-cov- nucleic acid using real-time reverse transcriptase polymerase chain reaction technique. swabs were collected by trained personnel, and analyses were performed in regional referral laboratories. according to local, regional, and national recommendations, pediatric covid- was initially suspected in the presence of both fever and respiratory symptoms (cough and/or dyspnea). giving the progressive increase of sars-cov- cases in tuscany, nasopharyngeal swab was subsequently performed in every child with fever and/or respiratory symptoms. since april th, , all patients possibly requiring hospitalization were tested for sars-cov- , independently of presentation at ed admission. this measure was adopted to avoid nosocomial transmission of covid- among hospitalized patients. tested children were grouped in symptomatic (in the presence of fever and/or respiratory symptoms) and asymptomatic (if apyretic and without respiratory symptoms). clinical and biochemical data were collected to compare symptomatic and asymptomatic patients. we selected five easily recognizable and well-identifiable common causes of ed access, that is, minor head trauma, earache, crying in infant < year, vomiting and/or diarrhea, and skin rash, to compare pediatric ed activity during covid- pandemic and the corresponding period in (time interval available for analysis march st-may th). finally, we retrospectively extracted anonymous data on children hospitalized from january st to may st, , in our pediatric unit, after referral to the ed, by using the dedicated management software (areas®, engineering ingegneria informatica, rome, italy) and compared them with data observed in the same months of . children hospitalized for planned surgery or diagnostic procedures requiring general anesthesia (i.e., magnetic resonance imaging or esophagogastroduodenoscopy) were excluded from analysis. the parents of the patients and the patients themselves, as appropriate, gave their informed consent to the anonymous publication of data for scientific purposes. all continuous variables were not normally distributed; thus, nonparametric mann-whitney test and kruskal-wallis test were used to compare groups. data were reported as median and interquartile range (iqr). fisher's exact test or chi-square test was used to compare categorical variables, as appropriate. all statistical analyses were carried out using the spss (statistical package of social sciences, chicago, il, usa) for windows software program version . . a p value < . was considered significant. after the beginning of national lockdown, we observed a significant, sudden decrease in pediatric ed consultations ( fig. ) , in particular during phase (phase showed a slight increase in daily pediatric access to ed). during january and february , pediatric visits peaked in pre-holidays and holidays, but after the lockdown started, this trend disappeared (before the lockdown beginning, weekdays = daily visits (iqr - , range - ) vs. pre-holidays/holidays = (iqr - , range - , p < . ); phase , weekdays = daily visits (iqr - , range - ) vs. pre-holidays/holidays = (iqr - , range - , p = . ); phase , weekdays = daily visits (iqr - , range - ) vs. pre-holidays/holidays = (iqr - , range - , p = . ). monthly comparison of pediatric ed visits performed from january to may confirmed a significant reduction in daily consultations after february, with a considerable percentage of days with ≤ visits/day (table ) . daily pediatric ed consultations significantly varied also considering pre-and post-lockdown beginning period (pre-lockdown, ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) the percentage of children discharged after ed evaluation significantly decreased from % in january and february to % in april, while children needing ordinary hospitalization increased from . % in february to . % and . % in april and in may, respectively. during may, we registered the highest percentage of seriously ill patients requiring transfer to tertiary care hospital ( . %). particularly, after the beginning of lockdown, we observed two cases of a noteworthy delayed access to hospital care: a . -year-old girl affected by brain tumor with hydrocephalus seen in april and a . -year-old girl with guillain-barré syndrome seen in may. in both, parental fear of contracting sars-cov- infection in hospital setting was the main reason of delayed ed access. by comparing pediatric visits performed before and after the beginning of lockdown, we observed that after march th, , the percentage of male subjects referred to ed, weekday visits, and patients needing hospitalization significantly increased ( table ). the age of patients did not change significantly, but newborns and infants (< years) represented . % of total consultations after the beginning of lockdown. after march th, we registered a change in the diagnoses of ed visits, with an increase in the percentage of non-infectious acute conditions (such as traumas or neurologic diseases) and a decrease in infectious diseases (upper and lower respiratory tract infections, gastroenteritis/vomiting). indeed, the decrease in ed consultations monthly requested for infectious diseases was more pronounced than that for non-infectious ones (table ) . interestingly, during may , we observed a remarkable increase (more than times) of children presenting to ed for minor head trauma or apyretic seizure in comparison with the previous month. with the exception of one case of complete kawasaki disease (a . -year-old male successfully treated with acetylsalicylic acid and intravenous immunoglobulin) in january , we did not observe any other case of the disease or of a multisystem inflammatory syndrome in the next months. despite italian ministry of health recommendations, after the beginning of lockdown, some children ( / , . %) were referred to ed for non-urgent pediatric consultation ( follow-up visits, balanoposthitis, infantile colic, dermatitis, conjunctivitis, jaundice, stipsis, and postimmunization fever). during the period march th-may st, , we performed nasopharyngeal swab to children and adolescents requiring pediatric ed visit. of them, were suspected for sars-cov- infection (fever and/or respiratory symptoms), while were asymptomatic (apyretic and without respiratory symptoms). the prevalence of fever, cough, and dyspnea in symptomatic patients was . % ( / ), . % ( / ), and . % ( / ), respectively. comparison between symptomatic and asymptomatic patients tested for sars-cov- is depicted in table . children referred to ed for suspected covid- were significantly younger than subjects without fever and respiratory symptoms. sars-cov- negative upper and lower respiratory tract infections represented the most common diagnoses between symptomatic children. after ed visit, children with fever and/or respiratory symptoms in good general conditions ( / , . %) were discharged with nasopharyngeal swab in progress (recommending home isolation until response) to avoid unnecessary hospitalization. as expected, biochemical evaluation showed that the symptomatic patients had higher markers of inflammation (white blood cell count, c-reactive protein, procalcitonin) than the asymptomatic ones. from march th to may st, we identified only a . -yearold girl positive for sars-cov- (prevalence of : ). the child was referred to ed for complex febrile seizure (first episode, no familiarity) triggered by an upper respiratory tract infection without signs of central nervous system infection. seizure, characterized by loss of consciousness and focal involvement of upper left limb, spontaneously recovered after s with postictal paresis. fever lasted days (higher reported temperature . °c) and was associated with rhinorrhea and cough. instrumental evaluation showed normal chest x-rays, pathological electroencephalogram (spikes and/or spike-andwaves in right frontotemporal and occipital derivations), and normal cerebral magnetic resonance imaging. no cases of sars-cov- were detected in asymptomatic patients. the amount of pediatric ed visits performed for selected common causes of ed access during covid- pandemic (march st-may th ) in comparison with the same time interval in was clearly lower (minor head trauma − . %, earache − . %, crying − . %, vomiting and/or diarrhea − . %, skin rash − . %) (fig. ) . table shows the number of children hospitalized from january to may in comparison with the same period in . a decreased hospitalization was appreciable at every month of becoming even more pronounced after march (january − . %, february − . %, march − . %, april − . %, may − . %). interestingly, from march , we observed a more evident reduction in children needing short-stay observation than in those with more serious diseases requiring ordinary hospitalization. during may , a significant percentage of children ( / , . %) was transferred to tertiary care hospital ( . -year-old girl with ataxia, . -year-old girl with guillain-barré syndrome, . -year-old male with testicular torsion, . -year- old male with brain tumor-induced epilepsy, -month-old male with epilepsy). to our knowledge, this is the longest retrospective italian study assessing the effect of covid- pandemic (prelockdown, phase , and phase ) on pediatric ed visits in a secondary care hospital. after the beginning of lockdown, we observed a remarkable decline in daily pediatric ed consultations; the highest reduction was registered in march (− visits, − . % vs. february) with the lowest absolute amount in april ( consultations). during march, we registered / days without any request for pediatric ed visits, an absolutely unusual picture for our unit. differently, the number of ed visits doubled during may in comparison with april, returning similar to that observed in march. particularly, phase was characterized by a moderate increase in requested pediatric ed consultations in comparison with phase , but the number of children needing hospitalization remained lower than half of those seen during the same period of . interestingly, after the beginning of lockdown, we no longer observed the increase in ed visits on pre-holidays and holidays (outside the office hours of family pediatricians). in ordinary times, indeed, in the absence of their pediatrician, parents often bring not seriously ill children to ed asking for a pediatric visit that is always available (day and night) and free of charge [ ] . exceptionally, during lockdown, tuscan family pediatricians guaranteed continuous ( days a week) daytime availability for phone consultations, helping to manage patients at home also on weekends. we speculate that this procedure, together with lockdown retractions, contributed to reduce ed overcrowding, particularly during weekends. covid- significantly influenced the causes for referral of children and adolescents to ed. after lockdown was started, we registered an absolute and percentage reduction in infectious diseases (mainly respiratory tract infections and gastroenteritis/vomiting) associated with a percentage increase of non-infectious conditions such as acute neurological diseases or traumas. acute onset conditions such as appendicitis, seizures, and syncope were diagnosed during this time, without reporting significant delay in ed accesses. considering the outcome of ed visits, we observed a clear reduction in the total amount of children needing hospitalization after the beginning of lockdown (january n = , february n = , march n = , april n = , may n = ) with a two-fold increase in the percentage of hospitalized children after ed evaluation ( vs. % pre-lockdown). particularly, after march, we registered a percentage increase of children needing ordinary hospitalization, and may was characterized by the highest percentage of patients requiring transfer to tertiary care hospital ( . %). all these data suggest that during covid- pandemic, fewer children were referred to the ed but with greater need for hospital care. similar conclusions can be inferred comparing and data. indeed, we observed a remarkable reduction in the number of hospitalized children during the period march-may in comparison with the same interval in the previous year, associated with a similar or increased percentage of children needing ordinary hospitalization (the difference in type of hospitalization reached statistical significance in may). moreover, the number of pediatric visits requested for common causes of ed access during the pandemic period of covid- was dramatically lower than that observed in the same period in . a significant reduction in pediatric ed consultations (ranging from to %) during covid- pandemic has been reported also by few other italian hospitals of northern [ ] , a finding similar to our results. furthermore, italian studies reported that pediatric patients had more appropriate accesses to ed during covid- pandemic [ , , ] . thus, available data suggest that even if covid- outbreak more seriously affected northern italy, utilization of pediatric emergency services significantly changed in the entire country with consequent reduced demand and increased appropriateness. this trend was neither confined to pediatric age or to italy. bellan and colleagues reported a reduction of . % of adult ed visits during covid- from march st to april th in novara (northern italy) [ ] . ophthalmological (− % vs. ) and otorhinolaryngoiatric (− % vs. ) ed visits also decreased during italian covid- pandemic [ , ] . interestingly, from march th to april th, , the proportion of children and adolescents presenting to ophthalmological ed halved from to . % in comparison with [ ] . similarly, del pinto and colleagues reported a significant reduction in less all-cause and cardiovascular hospitalizations occurred from january st to march st, , than in the similar period of in italian hospitals located in the province of l'aquila (southern italy) [ ] . these authors also reported a significant increase in intra-hospital deaths attributable to major cardiovascular diseases in march compared with the same month in (+ . %), possibly due to barriers to seeking emergency care during covid- pandemic [ ] . recent published morbidity and mortality weekly report described a significant impact of the covid- pandemic on ed visits also in the usa. particularly, during early american pandemic period (march th-april th, ), the total number of ed visits was % lower than the same period in . visits declined in every age group, but the largest reduction was observed in children ≤ years ( %) and in - -year-old adolescents ( %) [ ] . several reasons may explain these results. first of all, strict limitations imposed during lockdown reduced contacts between children and consequently the dissemination of all infectious diseases (not only sars-cov- ). similarly, traumas related to road accidents and outdoor activities also diminished. in addition, parental fear of contracting sars-cov- infection in hospital settings represented a significant determinant of ed accesses reduction. late diagnoses, sometimes with consequent death due to delayed access to hospital care, have been reported in march in some [ , ] but not all [ ] italian secondary and tertiary care hospitals. in our study, we described cases of delayed ed access to hospital setting ( in april and in may), as a consequence of not justified parental fear. indeed, being our hospital qualified as covid- hospital, our ed was efficiently reorganized to avoid intrahospital spread of sars-cov- , separating suspected covid- and standard care pathways. we detected only case positive to sars-cov- (a . -year-old girl admitted for complex febrile seizure) among symptomatic and asymptomatic patients tested with nasopharyngeal swab, confirming the low prevalence of covid- among children and adolescents reported by other italian records [ , , , ] . febrile seizures represent a rare presentation of covid- in pediatric age. the most recent (april th) multicenter italian study reported only / patients who presented with sars-cov- (including our own child) and a first episode of febrile seizure (without signs of encephalitis) [ ] . a recent review confirmed that sars-cov- exhibits neurotropic properties and may cause different neurological diseases (including seizures), independently of the respiratory system involvement [ ] . our study has some limitations. our analysis was limited to pediatric consultations requested for ed patients < years; thus, children exclusively managed by ed personnel or other specialists (i.e., orthopedists, dermatologists, ophthalmologists, and otolaryngologists) were not included. so, the number of pediatric consultations we reported did not reflect the entire population of pediatric patients referred to our ed. however, the indications to request specialized consultations (including pediatric visit) did not change during covid- emergency; thus, our comparison before and after the beginning of lockdown and with can be considered reliable. regarding the prevalence of sars-cov- infection, in suspected covid- patients, we performed a single nasopharyngeal swab, so we cannot absolutely exclude the occurrence of false-negative results. in conclusion, covid- emergency significantly influenced the ed utilization by children and adolescents. while the pandemic put a strain on the italy's national health service overloading intensive care units and causing a high number of deaths, children and young adolescents seemed to be spared. indeed, covid- pandemic caused a remarkable reduction of pediatric ed accesses (particularly the inappropriate ones), allowing a better organization of work. we hope that italian population can learn from covid- emergency to avoid ed overcrowding in the next future. furthermore, given the good results obtained during covid- pandemic, a closer collaboration between primary and secondary pediatric care is advisable to provide a better management of not severely ill children and reduce inappropriate ed utilization. authors' contributions all authors contributed to the study conception and design. material preparation, data collection, and analysis were performed by francesco vierucci, caterina bacci, cristina mucaria, and francesca dini. the first draft of the manuscript was written by francesco vierucci, and all authors commented on previous versions of the manuscript. all authors read and approved the final manuscript. conflict of interest francesco vierucci is a consultant for abiogen pharma and received speaker honorarium from abiogen pharma. the remaining authors declare that they have no conflict of interest. ethical approval all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the helsinki declaration and its later amendments or comparable ethical standards. informed consent the parents of the patients and the patients themselves, as appropriate, gave their informed consent to the anonymous publication of data for scientific purposes. table children hospitalized after ed visits from january st to may st in comparison with the same months in a novel coronavirus outbreak of global health concern italian ministry of health ( ) covid -ripartizione dei contagiati per provincia / / ore coronavirus disease (covid- ) in children and/or adolescents: a meta-analysis sars-cov- infection in children and newborns: a systematic review covid- in the pediatric population admitted to a tertiary referral hospital in northern italy: preliminary clinical data multicentre italian study of sars-cov- infection in children and adolescents, preliminary data as at characteristic of covid- infection in pediatric patients: early findings from two italian pediatric research networks caratteristiche dei pazienti deceduti positive all'infezione da sars-cov- in italia gazzetta ufficiale della repubblica italiana ( ) decreto legge marzo gazzetta ufficiale della repubblica italiana ( ) decreto legge changes in routine pediatric practice in light of covid- not just little adults: preparing a children's emergency department for covid- delayed access or provision of care in italy resulting from fear of covid- a covid- outbreak's lesson: best use of the paediatric emergency department impact of covid- epidemics in pediatric morbidity and utilization of hospital pediatric services in italy lockdown: more domestic accidents than covid- in children reluctance to seek pediatric care during the covid- pandemic and the risks of delayed diagnosis the impact of the covid- lockdown in italy on a pediatric emergency setting sainaghi pp ( ) pattern of emergency department referral during the covid- outbreak in italy the impact of covid- pandemic on ophthalmological emergency department visits changes in the use of otorhinolaryngology emergency department during the covid- pandemic: report from lombardy, italy increased cardiovascular death rates in a covid- low prevalence area barriers to seeking emergency care during the covid- pandemic may lead to higher morbidity and mortality -a retrospective study from a swiss university hospital impact of the covid- pandemic on emergency department visits -united states children with covid- in pediatric emergency departments in italy sars-cov- infection of the nervous system: a review of the literature on neurological involvement in novel coronavirus disease (covid- ) key: cord- -t cuop c authors: görgülü, Özkan; duyan, murat title: rrt-pcr results of a covid- diagnosed geriatric patient date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: t cuop c in this study, we aimed to present a geriatric patient with the diagnosis of covid- and with contradictory results in rrt-pcr examinations in short time intervals. a -year-old male patient was admitted to the emergency room on the th day of may , with the complaints of fever, sweating, myalgia, dry cough that continued for days, and the lack of taste that started on the day he applied to the emergency room. comorbidity factors include diabetes mellitus, bronchial asthma, and hypertension. the patient has a history of years of smoking . packs per day. high laboratory findings during hospitalization: monocytes, creatinine, crp (c-reactive protein). in the thorax ct, in the parenchyma areas of both lungs, there are increases in attenuation with multilobe distributions (more visible at the level of the upper lobes) in the form of ground-glass opacities. may , , was subjected to the rrt-pcr test, repeated twice on the th of may which also resulted in positive. despite rrt-pcr tests, which were negative on th of may and positive on th of may, the patient, whose symptoms disappeared, and general condition improved, was discharged on june , , with the recommendation for home isolation. in our case, unlike the incubation period only, we encountered a negative rrt-pcr result on the th day after diagnosis. therefore, the covid- pandemic control and filiation evaluation with the rrt-pcr test may produce false negative results. coronavirus disease (covid- ), also known as severe acute respiratory syndrome coronavirus (sars-cov- ), is a new zoonotic infectious disease which was first reported to the world health organization on december , and which was declared as a pandemic by the who on march , [ ] . covid- continues to affect elderly adults disproportionately with severe patient losses, from severe hospitalization to increased risk of mortality [ ] . advances in various diagnostic approaches such as real-time polymerase chain reaction (rrt-pcr), chest radiography and computed tomography (ct) imaging, and other modern diagnostic methods for this infection have been emphasized as the major diagnostic tools [ ] . rrt-pcr is the preferred method for measuring mrna [ ] . definite diagnosis of covid- is based on the viral isolation or positive result of polymerase chain reaction from sputum, or throat swab, or nasal swab [ ] . although rrt-pcr is often described as a "gold" standard, it is far from being a standard assay [ ] . in this study, we aimed to present a geriatric patient with the diagnosis of covid- and with contradictory results in rrt-pcr examinations in short time intervals. a -year-old male patient was admitted to the emergency room on the th day of may , with the complaints of fever, sweating, myalgia, dry cough that continued for days, and the lack of taste that started on the day he applied to the in thorax ct of the patient, in the parenchyma areas of both lungs, there are increases in attenuation with multilobe distributions (more visible at the level of the upper lobes) in the form of ground-glass opacities (fig. ) . in the covid- pandemic clinic, following the pantoprazole × mg, hydroxychloroquine sulfate ( mg) after × -mg loading dose, × -mg maintenance dose, oseltamivir × mg, vitamin c (ascorbic acid) mg/ ml, oksapar anti-xa iu/ . ml, and beklomethasone dipropionate, salbutamol mcg inhaler was administered. in the patient with palpitations days following the hospitalization, ecg: supra ventricular tachycardia ( / min), left bundle branch echocardiography: ejection fraction %, left ventricular concentric hypertrophy, diastolic dysfunction, and stage i left atrium dilatation were detected. by monitoring the patient, -mg intravenous bolus adenosine was administered. due to ongoing supraventricular tachycardia, -mg adenosine intravenous bolus was repeated min later. through the intervention, the patient returned to sinus rhythm. metoprolol × -mg, amlodipine × mg, and adenosine mg/ ml intravenous infusion were added to the patient's treatment. rt-pcr test the patient living in a low socioeconomically low area resulted as negative within the scope of filiation screening on april , . patient with positive covid- igm rapid test performed on may , , was subjected to the rrt-pcr test, repeated twice on the th of may which also resulted in positive. despite rrt-pcr tests, which were negative on th of may and positive on th of may, the patient, whose symptoms disappeared, and general condition improved, was discharged on june , , with the recommendation for home isolation. the results of the repeated rrt-pcr test on june , were also negative (fig. ) . the patient does not currently have any symptoms related to the disease. although subfebrile fever and leukocytosis can usually be seen in viral infections, it is noteworthy that our patient had normal fever and leukocyte levels. in the literature, investigating covid- pneumonia, increased crp serum level, and lymphopenia are noted [ ] . in our case, while neutrophil, lymphocyte, and platelet counts were at normal values, monocyte and crp values exhibited increases. both lung and cardiovascular injuries are common in the management of covid- infections, especially those with only cardiovascular disease symptoms [ ] . although a case of hydroxychloroquine-induced ventricular tachycardia has been reported in the literature [ ] , in our case, we could not determine the cause of supraventricular tachycardia since we also administered beta-agonist therapy together with hydroxychloroquine. since our case has cardiac comorbidities, sars-cov- infection has been complicated to include the lungs. morbidity and mortality of elderly patients with covid- are higher than young and middle-aged patients [ ] . in our case, intensive care and mechanical ventilation support were not required during the hospitalization process. rrt-pcr results are just a momentary display of information about a specific amount of transcripts in a cell or tissue [ ] . the nucleic acid test functions as the gold standard method for confirming the sars-cov- infection; however, some recent studies have detected false negative results of real-time reverse transcriptase polymerase chain reaction (rrt-pcr) [ ] . in the literature, ct sensitivity in the diagnosis of covid- was determined as . %, while the initial rrt-pcr sensitivity was only . % ( ) . however, rrt-pcr may initially give false negative results and it is suggested that rrt-pcr should be repeated for avoiding the isolation and misdiagnosis of patients with typical ct findings but negative rrt-pcr results [ ] . false negative results increase especially during the incubation period of the disease. similar to our case, there are case reports of reverse transcription-polymerase chain reaction (rt-pcr) test initially false negative and later positive in the literature [ ] . acquired immunity may protect against sars-cov- [ ] . in contrast, in the case were reported that recovered from covid- pneumonia with positive serology, negative nasopharyngeal rrt-pcr tests for month and then a second igm seroconversion and positive rrt-pcr test result after exposure to the virus [ ] . in our case, unlike the incubation period only, we encountered a negative rrt-pcr result on the th day after diagnosis. therefore, it can be argued that covid- pandemic control and filiation evaluation with the rrt-pcr test may produce false negative results. authors' contribution Özkan görgülü: manuscript writing/editing. murat duyan: data collection or management. conflict of interest the authors declare that they have no conflict of interest. financial disclosure no financial disclosure was declared by the authors. ethical approval ethics committee approval is not required; data use permission was obtained from the hospital management. informed consent informed consent and publication permission of the patient was obtained. code availability (software application or custom code) available. quarantine alone or in combination with other public health measures to control covid- : a rapid review (review) rationing limited health care resources in the covid- era and beyond: ethical considerations regarding older adults sars-cov- causing pneumonia-associated respiratory disorder (covid- ): diagnostic and proposed therapeutic options quantification of mrna using real-time rt-pcr a case report of covid- with false negative rt-pcr test: necessity of chest ct incidental diagnosis of covid- pneumonia on chest computed tomography a close-up on covid- and cardiovascular diseases chronic hydroxychloroquine use associated with qt prolongation and refractory ventricular arrhythmia clinical features of covid- in elderly patients: a comparison with young and middle-aged patients diagnosis of the coronavirus disease (covid- ): rrt-pcr or ct? a comprehensive approach is vital for diagnosing covid- : a case of false negative new igm seroconversion and positive rt-pcr test after exposure to the virus in recovered covid- patient publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- -gzqd g k authors: vitug, sarah; ravi, vikas; thangathurai, duraiyah title: sedation with ketamine and fentanyl combination improves patient outcomes in intensive care units date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: gzqd g k psychological manifestations such as depression and suicidal ideation are commonly caused by poorly controlled pain, anxiety, and sleep deprivation in intensive care unit (icu) patients. we are concerned that previous analgesic and sedative techniques administered as single-medication approaches are outdated and inadequate. it is imperative that icu practitioners are knowledgeable in multimodal approaches to pain and sedation in high acuity settings. we have shown that appropriate combinations of ketamine and fentanyl are effective, and if further supplementation is needed, we utilize additional pharmacological agents in low doses and regional techniques that ultimately lower the overall opioid consumption. we acknowledge that a variety of medication supplementations tailored to the patient’s clinical needs and nature of surgery improves a patient’s outcome in icu and overall quality of life. pain, anxiety, and sleep deprivation are commonly experienced by intensive care unit (icu) patients. often, these issues may result in psychological manifestations such as severe depression, demoralization, hopelessness, delirium, psychosis, delusions, ptsd, and, occasionally, suicidal ideations. in these scenarios, patients lose the will to live, as severe hopelessness and learned helplessness may cloud decision-making which may result in patient request for termination of care. the neuroendocrine stress responses often associated with noxious conditions can produce deleterious hemodynamic, metabolic, nutritional, and immunologic changes. prevention or timely treatment of symptoms can reduce the need for large doses of sedatives. however, irritation by the endotracheal tube may result in coughing and fighting the ventilator, which necessitates large doses of sedatives. this further complicates the management of patients on ventilatory support. asynchrony between spontaneous ventilatory efforts and machine-delivered breaths predisposes to pulmonary barotrauma, interferes with alveolar gas exchange, and increases the work of breathing [ ] . inappropriate hyperventilation is a common occurrence and may lead to hypocapnia, respiratory alkalosis, and hemodynamic disturbances. for these reasons, sedation is mandated, which also provides amnesia. neuromuscular paralysis may be used to decrease patient resistance to ventilatory support; however, side effects such as prolonged muscle weakness and myopathic changes are associated with these drugs. earlier sedation practices relied primarily on intermittent intravenous narcotics such as morphine sulfate, meperidine, or methadone [ ] . benzodiazepines such as diazepam, lorazepam, and midazolam, and barbiturates such as phenobarbital and pentobarbital were given when amnesia or hypnosis was required. these drugs are known to cause addiction, potentially leading to increased tolerance and functional changes within the brain. long-acting sedatives and narcotics often cause respiratory and circulatory depression, which may prolong the stay on respirators. opioid sedatives can also decrease gastrointestinal function and increase the risk of aspiration pneumonia, by slowing motility and prolonging ileus. for the last years, we have adopted a multimodal approach for pain and sedation, such as ketamine and fentanyl combinations for many of our postoperative icu patients. of note, the majority of our patient population have undergone major oncologic surgeries at the norris cancer institute/usc. a multimodal approach minimizes the requirement of individual medications and their potential side effects. in patients who are resistant to sedation, we add medication in addition to ketamine and fentanyl, such as low-dose propofol, midazolam, or dexmedetomidine [ ] . if analgesic requirement is high, we supplement with iv infusions of acetaminophen. ketamine, in particular, has many beneficial effects such as hemodynamic stability, bronchodilation, and minimal respiratory depression. ketamine also has many powerful analgesic and amnesic properties [ ] . ketamine is used in acute and resistant-depressive states, which is common in the icu [ ] . although the rate of hallucinations and nightmares is less than %, these psychotomimetic reactions are attenuated when ketamine is combined with a benzodiazepine or opioid. a concomitant infusion of an opioid or ketamine augments the sedation, provides analgesia, and reduces drug requirements. adding fentanyl to ketamine as an appropriate combination can provide excellent analgesia and reduce further sedative or analgesic requirements. we have been using a ketamine and fentanyl combination in surgical oncology icu for over years with excellent results, including early extubation, early return of gastrointestinal function, fewer hemodynamic/ respiratory complications, minimal psychological issues including depression and psychosis, shorter icu stays, and overall decreased morbidity and mortality. the purpose of our multimodal approach to pain and sedation in the postoperative icu setting is to improve the quality of care for our patients by minimizing undesired effects associated with analgesic agents. in standard practice, ketamine is commonly used in larger doses for induction and anesthesia maintenance. intraoperatively, higher doses of ketamine are associated with hypertension, tachycardia, and arrhythmias. postoperatively, hallucinations and psychotic states are occasionally associated with ketamine. ketamine use may result in medication-related psychotic states in patients with a history of psychoses such as schizophrenia or similar disorders, substance abuse/withdrawal, or medication-induced or metabolic-related causes. thus, we take extra precautions in patients with relevant psychiatric or medical histories. we found that by using sub-anesthetic doses of ketamine in combination with either low-dose fentanyl or midazolam, the incidence of psychotic symptoms is minimized. occasionally, we supplement ketamine with low-dose dexmedetomidine infusion or quetiapine (seroquel) in those who develop persistent psychotic symptoms. we acknowledge that even lowdose ketamine and supplementary analgesic/sedative agents can precipitate unwanted medication-induced psychotic symptoms and other side effects; thus, continued close monitoring of postoperative icu patients under this multimodal regimen is advised. authors' contributions all authors dutifully fulfill the following criteria: -substantial contributions to the conception or design of the work or the acquisition, analysis, or interpretation of data for the work -drafting the work or revising it critically for important intellectual content -final approval of the version to be published -agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved sedating patients in intensive care units analgesia and sedation in intensive care early sedation with dexmedetomidine in critically ill patients ketamine by continuous infusion for sedation in the pediatric intensive care unit ketamine and depression publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. sn compr conflict of interest the authors declare that they have no conflict of interest. key: cord- -lsvifqyo authors: kalyanasundaram, sridhar; krishnamurthy, kandamaran; sridhar, aparna; narayanan, vidya kanamkote; rajendra santosh, arvind babu; rahman, sayeeda title: novel corona virus pandemic and neonatal care: it’s too early to speculate on impact! date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: lsvifqyo the entire world is reeling under the effects of the novel corona virus pandemic. as it is a new infection, our knowledge is evolving constantly. there is limited information about impact of corona virus on neonatal care in relation to newborns with confirmed or suspected covid- . in this article, we summarize the current approach to this infection in relation to newborn babies. we discuss the basic aspects of the infection, the approach of care to novel corona virus disease (covid- ) in positive pregnant women, the likely presentation in newborns (as per current knowledge), and the approach to the management of neonates with infection or at risk of the infection. children are less susceptible to covid- infection and generally have a mild course. there is a lower risk of severe disease among pregnant women and neonates. it was recommended to follow the current protocols for management of symptomatic newborn with isolation precautions, antibiotics, and respiratory support. since december , when the novel corona virus-related infections were reported in the wuhan province in china, the world has witnessed a situation never seen before. the virus this article is part of the topical collection on covid - has now been reported in most countries around the world and since march , , has been declared a pandemic by the world health organization (who) [ ] . there has been a high case fatality rate, and as of now (mid-june ), close to million cases and nearly , deaths have been reported [ ] . as it is a new infection and disease characteristics are still being elucidated in many settings, the exact protocols that we follow in different age groups will need regular updates. the knowledge on covid- in neonates is only based on a recent experience over the past months or so. children are less susceptible to covid- infection and generally have a mild course in newborns, and children experience with significantly lower death rates [ , ] . moreover, there is limited information about the impact of corona virus on neonatal care in relation to newborns with confirmed or suspected covid- [ , ] . in this article, we discuss the basic aspects of the infection, the approach of care to novel corona virus disease in positive pregnant women, the likely presentation in newborns (as per current knowledge), and the approach to the management of neonates with infection or at risk of the infection. the novel coronavirus, named as severe acute respiratory syndrome coronavirus (sars-cov- ), belongs to the family of viruses called beta coronavirus, similar to the one causing sars- outbreak in - [ ] . it is a single-stranded rna virus with a helical capsid with radiating spikes (hence the name corona), and the disease is referred to as coronavirus disease . later on, on february , the coronavirus study group of the international committee on taxonomy of viruses issued a statement announcing an official designation for the novel virus: severe acute respiratory syndrome coronavirus (sars-cov- ) [ ] . the virus spreads by airborne (aerosol and droplet generation by atomization while coughing, sneezing, or even talking) and droplet contact spread and has a high attack rate [ , ] . although the elderly people with co-morbidities are at high risk, so far, newborns and children are relatively spared from serious complications [ ] . symptoms of covid- appear to be less severe in infants and children in comparison than that of adult patients [ , [ ] [ ] [ ] . the diagnosis is made by positive reverse transcriptase-polymerase chain reaction (rt-pcr) test result for severe acute respiratory syndrome coronavirus (sars-cov- ) usually on swabs taken from deep intranasal and oropharyngeal swabs [ , ] . the antibody testing and other tests to assess immune status are not fully developed yet. pregnant women with covid- : impact on maternal/neonatal health currently, there is no evidence of higher risk of severe disease and complications among pregnant women with covid- compared with healthy non-pregnant adults [ ] [ ] [ ] [ ] [ ] . there is only limited data on the impact of the current covid- outbreak on women affected during pregnancy and newborns. currently, no data was suggesting an increased risk of miscarriage in pregnant women with covid- infection. in women with symptomatic covid- , there may be an increased risk of fetal compromise in active labor [ ] . women have been advised to avoid water births to prevent the risk of disease transmission through feces. data from china found severe complications in % of pregnant women with covid- [ ] . however, the high rate of cesarean section deliveries (csd) in chinese reports is concerning, and subsequent reports from different countries have not confirmed any need to consider csd apart from the obstetric and maternal conditionbased decisions. martinez et al. [ ] reported delivery details of covid- positive mothers in spain, and the csd decision was based on obstetric decision (just over % csd rate). the study could not demonstrate the presence of coronavirus in placenta, amniotic fluid, or cord blood in the cases [ ] . the maternal outcome was slightly worse (in terms of needing respiratory support) for mothers undergoing csd, and the newborn outcome was not different. only of the newborns were positive on the initial test, and all of these were negative on the repeat test at h. two of the babies developed infection after days, likely acquired from the mother, but all babies were well and asymptomatic [ ] . besides, initial reports on the covid- infected pregnant women in wuhan indicated that most of them were in their third trimester, few on second trimester, and none identified at first trimester [ ] . however, the study showed that the fetus of the sars-cov infected mother in the first trimester of pregnancy would develop intrauterine growth restriction (iugr); therefore, more attention should be paid on the prevention of covid- in the first trimester of pregnancy [ ] . there is no evidence that covid- has an effect on fetal development [ ] ; however, increased potential risk of preterm delivery has been emphasized [ ] . an analysis of studies involving pregnant mothers with covid- demonstrated a preterm delivery rate of % [ ] . one of the major complications of preterm deliveries, necrotizing enterocolitis, may overburden the obstetrics and neonatal services [ ] . recent studies from the uk and other countries confirmed that vertical transmission due to covid- can occur, although the rate is low [ ] [ ] [ ] [ ] [ ] . it is encouraging that horizontally infected neonates had shown a mild clinical profile with good outcomes [ , ] . early chinese reports suggested that vertical transmission of sars-cov- does not occur, as amniotic fluid, vaginal mucus, placenta, umbilical cord, cord blood, and neonatal stool specimens tested negative for the virus [ , ] . congenital sars-cov- infection, with virus present in a neonate's nasopharynx at the time of birth, may occur, with a frequency not yet defined. there are reports of perinatal spread especially where the mother is symptomatic just prior to delivery; this could be explained by the relatively high viral load in symptomatic mothers [ , , ] . pcr is a highly sensitive test, and even vaginal secretions in the baby's nose can cause positivity. results from cord sample and liquor samples are not clear-cut. in another series of neonates born by csd in zhongnan hospital of wuhan university, newborns showed high igm levels to covid , suggesting antenatal infection (as igm does not cross placenta); however, false positive tests cannot be ruled out [ ] . recent ukoss (uk) study confirmed that vertical transmission due to covid- can occur; however, the rate is low [ ] . the study followed up pregnant women admitted to the hospital with confirmed covid- infection, and women had given birth. among the infants delivered, % (n = ) tested positive, and six infants tested positive within the first h of birth. igm antibodies were detected (cord blood serum) in infants who were tested negative and were all asymptomatic. postnatal transmission from parents or carers who have the infection (or are asymptomatic carriers) is the commonest reason a baby may get infected. the role of breast milk in spreading is also being debated, as there have been reports of breast milk being positive for the virus where the mother was symptomatic around delivery [ ] . however, the world health organization (who) as well as other bodies like the canadian pediatric society encourage breast feeding either directly or as expressed milk after parents have been explained the risk and benefits [ , ] . a recent study has reported that neonatal covid- infection is uncommon, uncommonly symptomatic, and the rate of infection is no greater when the baby is born vaginally, breastfed, or allowed contact with the mother [ ] . another recent case study published in nature communication reported transplacental transmission of covid- from a positive pregnant mother during the last trimester to her offspring which occurred due to maternal viremia, placental infection, and neonatal viremia following placental infection [ ] . during this crisis, obstetrics and neonatal departments in most hospitals need to plan major changes in their daily health professional team as there may be shortages of staff due to the infection or replacement in other positions [ ] . further, stress for being infected and possibly infecting families, overwork with long shifts, isolation, restrictions on socialization, and death of relatives or colleagues may decrease their performance [ , ] . strict precautions should be maintained by using personal protective equipments (ppe) with social distancing measures in the obstetric and neonatal wards to minimize staff exposure [ , ] . breaks should be spread out so colleagues do not eat or drink with each other without mask. if any team member has symptoms or has an infected family member, he/she should be self-isolated and tested. asymptomatic contacts of this team member should be tested as well, and self-isolation in these cases depends on exposure risk and unit policy [ ] . the ppe shortages are reported worldwide, and this should be considered in decision-making. some hospitals have devised their own policies to reuse n or equivalent masks on a rotational basis. this is an increasingly common scenario as the virus spreads in the local community and the pregnant women are likely to get infected. thankfully, thus far the disease has not been reported to be any more severe in pregnant women compared with other healthy adults, though mothers with co-morbidities will still be at high risk. routine separation of the mother and baby is not promoted, and guidance on individualized care is recommended in pregnancy and delivery [ ] . this has been well discussed in a recent article published by chandrasekharan et al. [ ] . from the obstetric and neonatal team's point of view, a clear plan has to be put in place preferably including the parents in the discussion-the following should be discussed [ , , , ] : . full ppe as per guidelines for all healthcare personnel involved in delivery process and attending the delivery (resuscitation of newborn). be careful when baby needs suction, intubation, or mask ventilation as these are aerosol generating procedures. it is recommended to move babies between areas in an incubator as far as feasible. . avoid close contact with the mother soon after birth (skin to skin care not given); delayed cord clamping should be done as per protocol. . if the mother is not symptomatic, the baby can be roomed in with the mother with a safe distance of ft ( m) between her bed and the crib. except while feeding and during cares, the baby should be in the crib. the mother should wear gloves while handling the baby (preferably) and should wear a mask while approaching or holding the baby or during feeding. . breast feeding options should be discussed. if the mother is symptomatic, we could consider giving a formula and expressing and discarding the milk during the symptomatic phase (when the likelihood of viral shedding in milk is more, and also since the mother may be on antiviral treatment some of which may be relative contraindications during breast feeding). if mother is asymptomatic, she could either breast feed directly wearing a mask or express breast milk wearing a mask and an unaffected relative/carer could feed the baby. . where the mother is symptomatic, especially if she is unwell to look after the baby, it is better to consider separation until the mother is asymptomatic. the baby can then be transferred to her and would use the approach to feeding as above. due consideration should be given for formula feeds if expressed milk is not adequate or the mother is unable to express due to her condition. depending on family circumstances and resource availability, the baby can be kept away from the mother either in a nursery setting or in a separate room and looked after by an unaffected family member, with plan to discharge home with them once stable. this option is not preferred if mother is symptomatic but can be offered in an asymptomatic mother if family prefers this option and resources permit the same. the parents should be involved in this decision, and they should be aware that despite these precautions, there is a small risk of the baby getting the infection, and this discussion should be documented. . the current recommendation is for the baby to get the test on day (preferably before any direct contact with mother), and if positive, the test could be repeated on days - and further repeat if still positive. if initial test is negative, we could consider testing again after h in case of a false negative first test. if the baby and mother are well, and the baby is negative, the baby could be discharged home. if the baby is positive for covid- , because of the unpredictable course, we could consider monitoring in the hospital until negative result is documented. as the condition evolves and we see more cases, testing to confirm in asymptomatic babies may not be needed-it should be feasible to manage asymptomatic covid- positive babies at home as well after a period of initial stability, and routine repeat tests may not be needed as long as they are isolated and monitored adequately. in some cases, the babies have presented with fever, loose stools, and respiratory distress, but majority is asymptomatic [ ] . since community spread is noted in most countries, any symptomatic baby presenting with fever, diarrhea, unexplained respiratory distress, and other manifestations should have a covid- pcr test sent. even if the baby's test is positive, management is according to current protocols for symptomatic newborn with isolation precautions, antibiotics and respiratory support as indicated. such babies should be nursed in incubators. though the clinical outcome has been good, the neonates with covid- are more likely symptomatic than older children who get the infection. babies who are asymptomatic could be managed with the parents (rooming in). babies are unlikely to be infectious unless aerosol generating events like crying or sneezing, but healthcare workers should wear full ppe while handling them. stool may be infective as well, and precautions are essential while handling stools. antipyretics like paracetamol can be used as normally indicated. if the baby is unwell with respiratory distress, antibiotic cover as per unit policy would be indicated. in babies presenting with gastrointestinal concerns, a period on intravenous (iv) fluids may be needed, but most of these symptoms appear to resolve over - days. some babies present like acute bronchiolitis and may need a period of respiratory support. as high flow nasal cannula therapy and nasal continuous positive airway pressure (cpap) are aerosol generating procedures, such babies should be in incubators, with expiratory flow tubing preferably within the incubator. the severe disease in adults is a result of an uncontrollable host inflammatory response, a cytokine storm [ ] , and luckily, this is less pronounced in children as a group including neonates and that could be a factor behind the milder manifestations in this age group. the kawasaki like inflammatory syndrome described in older children has not been noted in newborns, but we should be alerted to record and publish such presentations if we encounter them. there are no reports so far regarding experience with antivirals and use of immunomodulators like hydroxychloroquine in neonates so far. the recent recovery study [ ] in a mainly adult population (unpublished as of now) has reported improvement in patients needing oxygen or ventilatory support with the use of steroids, and if a newborn is sick with covid- -related complications, this could be a factor to consider, though not evidence based yet. all suspected or confirmed covid- neonates are required to be admitted to neonatal intensive care units (nicus) [ , ] . since community transmission places any individual at risk of being asymptomatic and carrying the virus, it is advisable to minimize visiting hours (and allow only parents to visit) [ ] . skin-to-skin care and direct breast feeding while in nicu may need to be minimized in open layout nicus [ ] . unfortunately, one of the negative effects of this practice would be exposure to bottle feeding, as cup feeding or syringe feeding needs closer contact and possible aerosol exposure. it was suggested that covid- negative results of respiratory specimens or anal swabs should be obtained at least h before discharge [ ] . general oral care recommendations such as oral hygiene care by gentle wiping of oral cavity using sterile gauze dipped in drinking water should be followed. colostrum can serve as a beneficial oral care in newborn especially for preterm infants. dental procedures are usually indicated when neonates have the presence of natal or neonatal teeth. dental extraction is indicated when natal or neonatal teeth are associated with the following conditions: (i) mobility, (ii) inconvenience during sucking/breast feeding, (iii) oral ulceration, and (iv) supernumerary teeth [ ] . during covid- pandemic, the dentist must clinically evaluate oral cavity and history associated with feeding discomfort. the dentist should prefer early appointment during the beginning of weekday. early appointment will prevent the neonate to expose to the patient crowd in the dental office and preventing cross-infection. telephone conversation and teledentistry should be preferred mode of communication with dentists. dental practices are considered the focal points for cross-infection, and dental care professionals must take precautions to minimize the risk of infection by adopting national/international infection control and prevention guidelines [ ] . since this is a novel infection, an ongoing coordinated multinational data collection [ ] the current crisis is a unique situation faced by the medical fraternity worldwide. it is very important to share clinical and research information and disseminate unique presentations, as well as contribute wholeheartedly to the data collected by registries as mentioned above. as more neonates are affected with acute disease, it is possible that we will see a broader spectrum of problems and we should be alert to new presentations. more challenges will be faced like payment systems and insurance-related issues restricting more frequent testing (when governments scale down testing), and local teams should work together to formulate guidelines suitable to their system, so they can overcome such challenges by working together in a team. authors' contributions sk: conceptualized the review, conducted literature review, extracted relevant information, and drafted the manuscript. kk: conceptualized the review, conducted literature review, extracted relevant information, and drafted the manuscript. as: conducted literature review, extracted relevant information, and reviewed and revised the manuscript. vkn: conducted literature review, extracted relevant information, and reviewed and revised the manuscript. as: conducted literature review, extracted relevant information, and reviewed and revised the manuscript. sr: conducted literature review, extracted relevant information, and critically reviewed the manuscript for important intellectual content. conflict of interest the authors declare that they have no conflict of interest. ethical approval this article does not contain any studies with human participants or animals performed by any of the authors. consent for publication all authors reviewed and approved the final version and have agreed to be accountable for all aspects of the work including any issues related to accuracy or integrity. 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perinatal transmission of covid- associated sars-cov- : should we worry? probable congenital sars-cov- infection in a neonate born to a woman with active sars-cov- infection antibodies in infants born to mothers with covid- pneumonia characteristics and outcomes of pregnant women admitted to hospital with confirmed sars-cov- infection in uk: national population based cohort study transplacental transmission of sars-cov- infection breastfeeding when mothers have suspected or proven covid- neonatal resuscitation and post-resuscitation care of infants born to mothers with suspected or confirmed sars-cov- infection maternal transmission of sars-cov- to the neonate, and possible routes for such transmission: a systematic review and critical analysis detection of sars-cov- in human breastmilk novel coronavirus disease (covid- ) in newborns and infants: what we know so far the royal college of paediatrics and child health (rcpch) covid- -guidance for neonatal settings royal college of obstetricians & gynaecologists. coronavirus (covid- ) infection in pregnancy. information for healthcare professionals. version . london: rcog analysis of clinical features of patients with novel coronavirus pneumonia national clinical research center for child health and disorders and pediatric committee of medical association of chinese people's liberation army. a contingency plan for the management of the novel coronavirus outbreak in neonatal intensive care units working group for the prevention and control of neonatal sars-cov- infection in the perinatal period of the editorial committee of chinese journal of contemporary pediatrics maternal transmission of sars-cov- to the neonate, and possible routes for such transmission: a systematic review and critical analysis coronavirus disease (covid- ): characteristics in children and considerations for dentists providing their care publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- -tv y eqc authors: ray, upasana; aziz, faisal; shankar, abhishek; biswas, aalekhya sharma; chakraborty, abhijit title: covid- : the impact in oncology care date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: tv y eqc the covid- pandemic has imposed a critical challenge to the current oncology care and practices including late diagnoses, delayed anti-cancer treatment, and static clinical trials. with the increasing risk of cancer patients acquiring infection during receiving the essential care, the debate ensues on how to balance the risk factors and benefits out of the oncologic emergencies in cancer patients. in this review article, we have focused on the current global re-organization of the integrity and effectiveness of the treatment modalities depending on the patient and cancer-specific urgencies while minimizing exposure to the infection. in this review, we addressed how the worldwide oncology community is united to share therapy schemes and the best possible guidelines to help cancer patients, and to strategize and execute therapy/trial protocols. this review provides collective knowledge on the current re-structuring of the general framework that prioritizes cancer care with the available exploitation of the reduced resources and most importantly the unparalleled levels of companionship as a large health care community towards the need to offer the best possible care to the patients. in december , a distinctive coronavirus (cov) was determined to be responsible for an outbreak of potentially fatal atypical pneumonia, ultimately defined as coronavirus disease , in wuhan, hubei province, china [ ] . early cases of severe acute respiratory syndrome coronavirus (sars-cov- ) were identified in people who visited or worked in the huanan wholesale seafood market in wuhan. from wuhan, china sars-cov- is dramatically spreading in several months all over the world. the disease related to sars-cov- is called coronavirus disease . as of oct , , a total of , , confirmed covid- cases and , , deaths have been reported worldwide (https://coronavirus.jhu.edu/). the number of patients and death are estimated to increase furthermore. according to the death rates, covid- is the worst pandemic compared with the previous cov pandemics-severe acute respiratory syndrome (sars) and the middle east respiratory syndrome (mers) [ , ] . due to low immunity after chemotherapy, many cancer patients (especially lung cancer patients) frequently have similar pulmonary symptoms as of covid- . they easily suffer from fever, either due to infection, drug-induced causes, radiation, chemotherapy-induced febrile neutropenia, or tumor fever. because of existing abnormalities, they are prone to be infected by covid- . patients who underwent chemotherapy or surgery in the past month possess a much higher risk to get infected [ ] . this crisis period raises a lot of challenging questions towards the global oncology community to prioritize the safety considerations for the cancer patients requiring essential care in the endemic areas. a set of guidelines and international recommendations are now available for managing cancer patients with special protocols [ ] . after a pandemic of severe acute respiratory syndrome (sars) in years ago and a severe outbreak of middle east respiratory syndrome (mers) in [ , ] , in december , a distinctive coronavirus (cov) was determined to be responsible for an outbreak of potentially fatal atypical pneumonia, ultimately defined as coronavirus disease , in wuhan, hubei province, china. the world health organization (who) declared the situation pandemic and the biggest threat to public health in the world. the symptoms and severity of patients from different countries were depicted in table . according to the reports the angiotensin receptor (ace ) helps the virus to enter the respiratory mucosa [ ] . using the receptor-binding domain of spike protein s , the virion attaches to the cell membrane by interacting with host ace receptor in the lower respiratory tracts of infected patients to gain entry into the lungs [ ] . this receptor binding capacity is to -fold higher than sars-cov and mers-cov virus [ ] . the receptorbinding domain (rbd) of the s subunit then determined the host membrane binding by conformational changes. figure illustrated the comparison between three different pandemic causing coronaviruses receptor binding structures. it assumes that the receptor binding capacity of sras-cov- is much higher than sars-cov and mers. cancer is a genetic disease that occurred due to genetic alteration of growth-regulatory genes [ ] . the major risk factors are lifestyle, which includes diet, age (aging), tobacco and drugs, obesity, alcohol consumption, and infectious diseases [ ] [ ] [ ] [ ] . which means the power to minimize and control of cancer is in our own hands. although some of these cannot be controlled like aging. human health becomes susceptible with age due to various anatomical, physiological and immunological changes. one of the major changes is our respiratory system, which included chest wall and thoracic spine deformities. these impair the total respiratory system compliance leading to increased work of breathing. with the increasing age, the strength of respiratory muscle decreases. for this reason, older persons are sensible for dyspnea and diminished ventilatory response to hypoxia and hypercapnia. due to this, they are more vulnerable to ventilatory failure (i.e., heart failure, pneumonia) [ ] . previous studies reported that hospitalization rates for pneumonia range from / individuals in the general population to / over age years and / for residents of chronic care facilities. [ , ] . in recent pandemic, clinical data showed that covid- and aging have positive correlation and showed a severe high number of covid- related deaths in high age people. (https://www.cdc.gov/mmwr/volumes/ /wr/mm e . htm, https://www.cdc.gov/coronavirus/ -ncov/needextra-precautions/people-at-higher-risk.html, https://www. cdc.gov/mmwr/volumes/ /wr/mm e .htm, https:// www.latimes.com/science/story/ - - /coronavirusdeath-rate-estimates-show-risk-rising-sharply-with-age, https://www.bloomberg.com/opinion/articles/ - - / comparing-coronavirus-deaths-by-age-with-flu-drivingfatalities). mainstream tobacco smoke (mts) is the major risk factor in the development and pathogenesis of several lifethreatening diseases [ ] . it is estimated that use of tobacco smoke kills around million people annually. about half of all smokers will develop a serious smoking-related illness, such as chronic obstructive pulmonary disease (copd), which is characterized by irreversible airway obstruction or cardiovascular disease. the most severe adverse effects of cigarette smoke on the immune system, which triggers pathologies such as copd, respiratory infections, increased incidence and severity of asthma, and cancer are well known nowadays. the immune defects that are caused by smoking relate to the seemingly contradictory nature of smoke as a damaging and pro-inflammatory factor, as well as an immunosuppressive factor. there is lots of evidence, which explores the role of smoking in the risk of lung cancer [ , ] . according to food and drug administration (fda) and who's statement smoking may increase both the risk of covid- as well as severity; however, no such published data available at this time to establish this correlation. zhao et al. [ ] reported a high correlation between smoking and severity of covid- and show these two are highly significant after analyzing patients from different studies. in a review with patients, emami et al. [ ] shows the prevalence of smoking of . % in the hospitalized patients with covid- . smoking is directly associated with increased risk of virtually every other respiratory infectious disease by destroying airway cilia which is a defense from infectious particles by moving it out of the airway. additionally, smoking's effect on increasing ace- receptors in the lungs, which is the entry point for the sars-cov- virus, and theoretically, an increase in receptor density give the virus more points of entry to infect and replicate. (https://www. medpagetoday.com/infectiousdisease/covid / , https:// www.ucsf.edu/news/ / / /smoking-nearlydoubles-rate-covid- -progression, https://www.newscientist. com/article/ -smoking-probably-puts-you-at-greaterrisk-of-coronavirus-not-less/#). patients with cancer are considered as the most vulnerable group in the current covid- pandemic. the increased rate of susceptibility is the cause of their severe systemic immunosuppressive state due to varied anticancer treatment modalities. the alarming widespread nature of the infection raises the concern for its influence on patients with cancer. thereby both the needs of cancer patients and the workforce caring for them are currently at the forefront of our attention and action. first information on incidence of covid- in cancer patients comes from a study in wuhan, china, where . % ( patients) of the cancer patients admitted showed infection between december to february [ ] . given the rate of contagion was high compared with the collective prevalence in the community ( . %), this report holds limitations in not addressing the covid- [ ] . some patients with cancer have known to acquire the covid- infection on getting anti-cancer treatment during hospitalization, which supports the susceptibility of cancer patients in the existing pandemic. however, the associated limitation of the study resides on the multiple factors like unavailability of proper clinical information that can correlate the infection risk to the tumor stage among patients. secondly, the retrospective and nonrandomized form of the study based on a relatively small population size attributes to its limitation. the heterogeneity of the disease among patients and the diverse treatment modalities in practice also contributes to its constraint [ ] . further the report only suggests rudimentary complication and fatality rates of covid- infection in cancer patients; however, comparisons between cancer and non-cancer patients with the infection may possibly reveal more valuable information. thereby, future studies with large population cohorts and prospective study designs are necessary to reveal the risk issues and severe events in the infected cancer patients. the outcomes of additional analysis of cancer patients hospitalized for covid- infection over a period of week from hospitals in china were compared with a control group of non-cancer patients and matched for age, hospital, and admission time [ ] . reports demonstrate lung cancer (n = ) as the most frequent cancer to be affected in the ongoing pandemic trailed by gastrointestinal (gi, n = ), thyroid or breast (n = ), and hematological (n = ) cancers. besides the cancer patients showed high death rates (or, odds ratio . ), increased rates of icu admission (or . ), higher probability of severe symptoms (or . ), and a two-fold increased susceptibility to having ventilation as compared with the matched non-cancer control patients. due to limitation of the analysis to be applied to other countries with unlike cancer epidemiology and clinical practice [ ] , a study was initiated with the investigation of the electronic medical records (emr) of mount sinai health system (mshs) in the new york city, usa, to determine whether cancer patients present poor prognosis of covid- . a total of patients ( %) were found with cancer (lung, breast, urothelial, prostate, and colon cancer) among the total patients with covid- infection [ ] . age-group-dependent stratification of patients declares a significantly increased risk of intubation in cancer patients aged to ; however, patients with cancer younger than age found to have a high mortality rate. this is the first kind of a study in the usa on the prognosis of cancer patients with covid- infection which accounts for its correlation to the patient's age, one of the strongest prognostic factors in determining risk, with a relatively large population cohort. a higher incidence of cancer in covid- infected patients has been stated from new york city, where % of the patients had cancer out of hospitalized with covid- [ ] . likewise, % of the patients with either present or past history of cancer were reported to be admitted to the intensive care unit for covid- in lombardy, italy [ ] . another study from italy reports % of the deaths from covid- contagion in patients with cancer [ ] . still there arises an urgent need to unravel the logistics behind whether covid- -infected cancer patients will have separate clinical courses and whether the patients should receive typical antitumor treatments in the epidemic areas. the current argument emphasizes on whether or not to postpone the anti-cancer treatments, which need to be prepared on a patient-to-patient basis and the associated risk. given the high susceptibility of the cancer patients in the covid- setting and the associated risk in acquiring the infection during anti-cancer treatments and/or hospitalization, a debate ensues on how to balance the risk factors and benefits out of the oncologic emergencies in cancer patients. delaying anti-cancer treatment in the ongoing pandemic cannot be recommended as a sensible choice to reduce the associated infection risk in patients. thus, the health care facilities are required to re-emphasize the integrity and effectiveness of the basic infection control measures to combat the spread of the contagion. the major question lies in how to modify the treatment modalities based on the patient and cancer-specific urgencies. care of cancer patients generally includes the following discussed forms [ ] . first form of care includes the subjects that can be evaluated remotely and are not time-sensitive, which mainly embraces patients who have completed their anti-cancer treatment and possess no acute signs of recurrence or the low-risk patients getting hormonal or oral chemotherapy. second form of care includes the patients where the treatment delayed or omitted will have a minimal effect on the quality and/or quantity of life. in cases of patients with advanced cancer at times oncology care involves systemic chemotherapy and, in cases where it can be determined that the survival benefit of the chemotherapy is limited, a decision on delay can be taken depending on the potential benefit of therapy vs the risk if the patient becomes contagious. likewise, delaying surgery and directing neoadjuvant therapy for the moment can reduce risk to the patient and reserve the health care resources. a report on the measures taken at the cancer center in new york, usa, includes a comprehensive departmental strategy to triage and shorten the radiation therapy for oncologic crises. according to the report, the oncology department has logically implemented a three-tiered system in the ongoing pandemic to characterize clinically urgent cases, where postponing therapy would result in compromised outcomes or severe morbidity [ ] . tier- care includes patients with metastatic cancer requiring palliative radiotherapy as urgent need. tier- care embraces patients with symptomatic disease lacking oncologic crises in which radiotherapy is the basic standard of care, and patients with asymptomatic disease in which radiotherapy is suggested to avert imminent functional deficits. tier- care includes patients with asymptomatic or symptomatic disease in which radiotherapy functions as one of the effective treatment strategies. management in the described manner may help the radiation oncologists to exclude, delay, or impose short-term courses to lessen the number of hospital visits in the setting of covid- pandemic. third form of care includes the patients where delay in treatment has an adverse impact on the survival or quality of life. in most cases, for several cancer types, the oncologists are advising marginally less effective drug regimens that have minor risk of causing hospitalization [ ] . current practice recommends the oncologists to reasonably use stringent neutrophil counts and the white cell growth factor before ensuing with the next therapy cycle, and restricting usage of steroids to manage nausea. whenever feasible, oral therapies are replaced with intravenous form and different other modifications are taken into account to lessen the patient visits and/or hospitalizations. to further prioritize the situation therapy schemes were modified and the treatments expected to cause immunosuppression should be avoided or low dosages to be provided, whereas patients in poor health condition will not receive such treatments. likely, at least a week ahead before anti-cancer treatment, the cancer patients should stay under observation of the consultants and in isolation. additionally, strong personal protection including their families must be prepared for the patients. fourth form of care comprises the patients where the treatment owns the potential to cure and cannot safely be postponed, which includes new diagnoses of high-grade lymphoma, acute leukemia, and the therapy-responsive cancers small cell lung, ovarian, and testicular cancers [ ] . depending on the lethality associated with these cancers, the oncologists are not modifying the therapy regimens despite the covid- risk. for most allogeneic transplants, which cannot be safely delayed, both the recipients and the donors were introduced to the covid- testing before the start of induction. ensuring the risk associated with cancer patient's care and the risk of contracting covid- infection the subsequent step is to consider the ability of the regional health care organization to meet the projected and prevailing needs. to this awareness is required to understand whether the organization is in the preparative, acute, or crisis stage of the pandemic. the preparative stage discloses the integrity of the health care workforce and ensures the availability of the necessary equipment including ventilators, intensive care units (icus), and the patient beds [ ] . the acute stage deals with when there is limited workforce in the system but still functional through strategic reformation to provide the basic cancer care to their patients. the crisis stage deals with when the system over surpluses with the covid- cases and deprived of its ability to provide cancer patient care. overall, immunosuppressive therapy in cancer was decided to be suspended in patients who test positive for the infection. a case study reports that ibrutinib (bruton's tyrosine kinase inhibitor) for chronic hematologic malignant patients might be an exception [ ] and the treatment should be considered on a particular case basis [ ] . moreover, decision-making for cancer patients getting glucocorticoids diagnosed with covid- must be personalized and put forward on a case-by-case basis. however, non-immunosuppressive oral treatments including hormonal treatments or therapies targeting the activating mutations (like egfr/mek inhibitors) must be individualized. cancer patients at an advanced stage or with comorbid health disorders affecting the lungs or the heart, if they acquire covid- infection, the diagnosis is expected to be dismal [ ] . medical decisions depend on the practical discussions of the consultants with their patients on the goals of advance care planning [ ] . several approaches were prioritized by critical oncology organizations in the ongoing pandemic setting. the american society of clinical oncology (asco) recommends that in cancer patients diagnosed with the infection, the immunosuppressive therapies should be withheld until the symptoms resolve like complete remission of fever without use of antipyretics along with a negative covid- test. furthermore, the us centers for disease control and prevention (cdc) includes more stringent guidelines on calling of a negative test result using the fda-approved molecular assay technique for covid- from at least two successive negative nasopharyngeal swab specimens that are collected h apart. likewise, the world health organization (who) suggests that the patients be tested negative using two consecutive specimens collected at -h interval before release from home quarantine. on the contrary, the uk national institute for health and care excellence (nice) declared published guidelines on initiating or resuming the anticancer therapy only after a single negative covid- test. some institutions also recommend sending the cancer patients recovered from covid- infection to resume therapy at an isolated infusion center distant from the core infusion center depending on the available resources [ ] . nevertheless, contact limitation and physical distancing guidelines continue to be an important part of the cancer treatment strategies during the pandemic in order to protect the patients, health-care personnel and non-covid- patients being treated in the same organization. the asco prioritize several guidelines provided by the cdc in the current pandemic setting. firstly, the patients should be made aware of covid- symptoms and should be trained in executing accurate hand wash, maintaining hygiene and minimizing exposure to infected contacts and huge gatherings. both patients and health workers need to follow the cdc guidelines on mask use whenever out. as already discussed, any clinic visit that can be delayed without causing any risk to the patient should be suspended. a pre-screening strategy through digital platforms or phone calls for covid- symptoms and acquaintance history preceding planned health center visits in-person is recommended [ ] . additional precautions include proper maintenance of hygiene and cleanliness of the health care centers and the workforces cleaning rooms must use full ppe if the patients were suspected or confirmed of having the contagion. besides, the pandemic demands adequate availability and use of personal protective equipment (ppe) as per the cdc (https://www.cdc.gov/coronavirus/ -ncov/healthcare-facilities/guidance-hcf.html) and the american college of surgeons (acs) (https://www.facs.org/ covid- /clinical-guidance) guidelines to protect all health workforces from being infected. further to optimize protection to the health personnel from infection, which spreads with an aerosol transmission through droplets and surfaces [ ] , planning a negative pressure operating room (or) and anteroom was recommended by the acs (https:// www.facs.org/covid- /clinical-guidance) and by liang et al. (https://www.alnap.org/help-library/handbook-of-covid- prevention-and-treatment) for covid- suspected or positive patients. for a negative pressure or, due to the low air pressure created inside than its surroundings, the air that flows into the room cannot escape, thereby protecting workforces in the same center. particularly, extubation, a risky process comprising viral spread is recommended to be executed either in the negative pressure or in a committed anesthesia recovery room [ ] . additional consideration is the course of surgical access where minimal invasive surgery with pneumoperitoneum, an aerosol generating procedure (agp) must be cautiously considered. reports suggest active replication of covid- virus in the respiratory and gi tracts [ , ] , thus during the digestive surgeries, the probable risk for aerosol transmission has been warned and a passive evacuation system to be used with electrostatic filter from ventilators has been proposed [ ] to protect health care personnel. likely, the readiness of a plethora of guidelines possibly will be helpful and approachable given the discrepancies in resources available round the world. management of cancer in recent days are subjected to clinical research trials, which are an integrated part of the routine cancer care, providing additional treatment opportunities for eligible patients. a critical barrier has been imposed to the enrollment and ongoing participation in clinical trials due to the covid- pandemic [ ] . the international bodies including the us fda and the european medicines agency have stated proper guidelines for the sponsors and study centers to warrant the safety of participation in trial studies, through reducing the risks to the study integrity and maintenance of other regulatory compliances [ ] . though the clinical trial accretion has reduced severely along with the availability of bio-specimens for various correlative analyses, the oncologists still focus on the therapeutic trial participants so that they can receive their protocol directed treatment and assessments wherever it is safe. with the continuation of the crisis period, the oncologists report unparalleled levels of companionship and cooperation to share responsibility across the world. the oncology community across the world was reported to be united to share therapy schemes, to formulate the best possible guidelines to help cancer patients, to accumulate and assemble the available data, and to strategize and execute therapy/trial protocols. several associations came up unitedly with identification of patients at the risk of being infected and determining how the anti-cancer treatment influences the existing covid- illness in them and critically analyze whether it is safe to resume the treatment in the contagious patients. the critical question remains on how to maintain the clinical standards so that the value of cancer treatments with the challenging risks during this period of declining resources will meet the expectations of humanitarian welfare. since the present situation deals with prohibition of visitors accompanying patients, the oncology clinicians and cancer patients must pay attention on clarifying progress directives, prioritize health care substitutes and end-of-life care preferences [ ] . several guidelines from a group of experts across the world were dedicated to provide care to certain cancer types that can be affected mostly by covid- infection. for breast cancer, the european society of medical oncology (esmo) and the american society of breast surgeons have issued guidelines on providing interdisciplinary care in breast cancer patients and another international group has prioritized guidance for radiation therapies in early breast cancer cases [ ] . besides the guidelines on colorectal surgery from the american college of surgeons (acs) and gi-tract cancer surgery from the esmo, guidance to minimize risk in gi malignant patients has been also developed by an american group of oncologists [ ] and the us colorectal cancer alliance. likewise the management of gynecologic cancers is further developed by the society of gynecologic oncology, the international journal of gynecologic cancer [ ] , the national college of french gynecologists and obstetricians [ ] , and from the international gynecologic cancer society, in addition to that of the acs and the esmo. an important consideration in the ongoing pandemic is the patients with lung cancer. the thoracic surgery outcomes research network has put forward the guidelines on triage for thoracic surgery in the thoracic cancer patients [ ] in addition to that of the acs. besides esmo published specific strategies on the care of different lung cancer types that should be considered with high, medium and low priority depending on the associated risk and the stage of the cancer patients with the available resources. additional to the basic guidance from the american society of transplantation and cellular therapy (astct), the american society of hematology, the esmo, and the european society for blood and marrow transplantation (ebmt) guidelines on the management of patients with hematologic malignancies was also published by the seattle cancer care alliance [ ] . further improvised radiation therapy strategies were provided by the international lymphoma radiation oncology group [ ] . besides an international group put forward the care of aged multiple myeloma patients [ ] , whereas the us cutaneous lymphoma consortium guides therapy of the cutaneous lymphoma [ ] . for the maintenance of hepatocellular cancer in addition to the esmo, guidelines were also established by the international liver cancer association, the french association for the study of the liver [ ] and the american association for the study of liver diseases (aasld) [ ] . in case of head and neck cancer the specific triage recommendations for surgery in covid- pandemic was provided by the university of texas md anderson cancer center [ ] and an expert group comprising of the french society of otolaryngology, the head and neck surgery and the french society of head and neck carcinology [ ] . care of patients with brain tumors has been established by the american association of neurological surgeons, the society for neuro-oncology, and the congress of neurological surgeons tumor section [ ] , and detailed guidelines for care of the glioma patients have been obtained from an international multidisciplinary group [ ] . beyond this, a recent article in morocco that report on the possible ways to minimize the risk of spreading infection in cancer patients in the post-covid- period explains the need to strategize and implement a national screening awareness for the infection to all the patients in order to protect them and the medical supervisors from the disease [ ] . recommendations for the management of covid- negative patients should be prioritize depending on the urgency of their health condition, while a dedicated surveillance and optimal care should be implicated for all the positive individuals where the critical management cannot be postponed in the post-covid- period. every crisis period brings with it the power to create several new opportunities in order to develop and expand our professional knowledge, available techniques, and accurate exploitation of the reduced resources and perhaps most importantly the selfurge to unite ourselves and show the unparalleled levels of companionship as a large health care community towards serving for the benefit of our patients. the outbreak of covid- has caused pandemic worldwide, which is much more effective than sars and mers, which are experienced by the world. due to lack of knowledge and work, there is no such evidence that proves the possible treatment approach of cancer patients. it is hard to make management decisions due to lack of data. at this time, the most challenging part is delaying cancer treatment, 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of , a cluster of unexplained pneumonia cases were reported in wuhan, china. in less than a year, sars-cov- has infected over million people and claimed more than , deaths worldwide. diabetes is a highly prevalent chronic metabolic disease, and recent reports have suggested a possible existence of covid- related new-onset diabetes. hyperglycemia induces an inflammatory state in the body, which coupled with coronavirus associated immune response is a possible explanation for clinical worsening of patients. we present a summary and pooled analysis of available evidence to ascertain the relationship between hyperglycemia in undiagnosed diabetics and outcomes of covid- disease. our results showed that hyperglycemia in non-diabetics was associated with higher risk of severe/critical illness (or . ( % ci . – . , p < . ) and mortality ( . , % ci . – . , p < . ) compared with those with normal values of blood glucose. the management of hyperglycemia in covid- poses significant challenges in clinical practice, and the need to develop strategies for optimal glucose control in these patients cannot be overlooked. the first case of novel coronavirus pneumonia, also known as sars-cov- (severe acute respiratory distress syndrome coronavirus- ), emerged in december in wuhan, china. designated as coronavirus disease (covid- ) , it affects the lungs primarily and has a high transmission rate [ ] . diabetes as a risk factor for severe covid- disease has already been studied and reported in detail [ ] . sars-cov- interacts with the body's glucose metabolism via a variety of pathways, the commonest being ace- expression in the pancreas [ ] . it is well established that hyperglycemia increases the risk of lower respiratory tract infections and is linked to poor outcomes [ ] . since an acute rise in blood glucose is associated with increased inflammatory mediators [ ] , it is conceivable that hyperglycemia can potentiate the harmful effects of cytokine storm in patients with covid- pneumonia. hence, there is growing concern that hyperglycemia independent of diabetes could be a factor contributing to poor prognosis in covid- illness. this study aims to shed light on the correlation between hyperglycemia in those without an established diagnosis of diabetes mellitus and covid- related clinical outcomes. a literature search was performed in august and september using databases pubmed, google scholar, and scopus to identify studies reporting an association between blood this article is part of the topical collection on covid- glucose levels and covid- disease outcomes in patients without a history of diabetes. the search strategy consisted of different combinations of the following keywords: "covid- ," "sars-cov- ," "hyperglycemia," "impaired glucose tolerance," "prediabetes," and "impaired fasting glucose." those with raised blood glucose, no prior history of diabetes, and those with prediabetes and impaired fasting glucose were placed group designated as "hyperglycemia without diabetes." on the other hand, patients found to have normal blood glucose values on admission were part of the normoglycemia group (group ); refer to table . the presence of diabetes was negated by one of the following: a negative history of diabetes as per the patient or his/her medical records, lack of ongoing treatment with glucose-lowering medications, or hbaic < . . the criteria for inclusion into these two groups for each study have been mentioned in table . whenever available, data on the following was included: clinical features, in-hospital complications, patient outcomes such as mechanical ventilation and icu admission, disease severity and mortality among laboratory-confirmed, and sars-cov- patients in the hyperglycemia and normoglycemia groups. we excluded duplicate studies, letters, case reports, abstracts, reviews, and articles not translated in english. statistical analysis was performed using openmeta[analyst ] software. odds ratio (or) with % confidence interval (ci) was determined and pooled analysis performed to determine the pooled odds ratio. heterogeneity was assessed using the i test, and i > % was considered as a moderate inter-study variation. a p < . was considered statistically significant. initial search yielded studies. after excluding irrelevant articles, reviews, and duplicate items, a total of studies were included. ten studies were included in quantitative analysis (pooled or for severe/critical covid- and death). these ten studies have been summarized in table . studies have shown that covid- patients with hyperglycemia are older compared with those with normal blood glucose levels. a retrospective study by zhang et al. included data of covid- patients and stratified them according to diabetic status into the following three groups-diabetes, impaired fasting glucose (ifg), and normal fasting glucose (nfg). those who were diagnosed as having an impaired fasting glucose were older than those with normal fasting glucose (mean age years vs years, p < . ) and had a higher burden of comorbidities ( % vs %, p < . ). men comprised a larger proportion of covid- patients presenting with impaired fasting glucose, compared with those without hyperglycemia ( % vs %). further, they also reported data on common coronavirus disease symptoms. dyspnea ( % vs %) and hypoxemia ( % vs %) were more commonly seen in the ifg cohort compared with the normal fasting glucose group (p < . ). fever ( % vs %), chest pain ( % vs %), diarrhea ( % vs %), nausea and vomiting ( % vs %), and polypnea ( % vs %) were also seen with a greater frequency in among those with ifg, compared with those with nfg, although the difference was not statistically significant (p > . ) [ ] . compared with patients with normal glucose levels, those with hyperglycemia had more abnormalities in lab markers. zhang et al. reported various irregularities in laboratory values of covid- patients who were also concurrently diagnosed as having raised blood glucose. increased neutrophils and leukocytes, decreased eosinophils, were more commonly seen in those with hyperglycemia compared with known diabetics and those with normal blood glucose levels. abnormalities in liver function test components such as hypoalbuminemia and raised alt levels were also more commonly recognized in patients belonging to the hyperglycemia group vs the normoglycemia and diabetic group. similar trend was observed in case of inflammatory markers such as lactate dehydrogenase (ldh), ferritin, and c-reactive protein (crp). interestingly, il- , an important component of inflammatory response, was also significantly higher in this group compared with the other two ( . % vs . %, p < . ) [ ] . disturbed coagulation profile is an important prognostic finding in covid- patients. significantly raised d-dimer ( % vs %) and fibrinogen levels ( % vs %) were observed in those with impaired fasting glucose compared with ones with a normal fasting glucose in the retrospective observational study by zhang et al. [ ] . they also reported higher troponin , ast, alt, cystatin c, neutrophil/lymphocyte (n/l) ratios, and decreased lymphocytes and platelets in the same subset of patients, compared with those with normal glucose tolerance (p < . ). aggravated findings on ct scan imaging of the chest were more frequently observed in those with impaired fasting glucose compared with covid- patients with normal fasting glucose [ ] . lacobellis et al. reported that admission hyperglycemia (day- average blood glucose levels) was the strongest predictor of radiographic findings of sars-cov pneumonia in patients without a known history of diabetes, even after accounting for body temperature [ ] . it would not be wrong to believe that heightened inflammation and exacerbated immune response, as a result of acute hyperglycemia, could be responsible for radiographic progression of ards in these patients. sardu et al. in a study assessing the role of insulin in controlling blood sugar levels among covid- patients also compared the risk of severe disease in patients with diabetes, hyperglycemia without diabetes, and normoglycemia. after risk-adjusted cox regression analysis, they found that patients with hyperglycemia had an increased risk of severe covid- disease [ ] . six studies reported quantitative data on severe/critical covid- illness. critical illness/severe disease was defined by the occurrence of adverse clinical outcomes such as respiratory failure requiring mechanical ventilation, icu admission for organ failure, in-hospital complications, shock, or death. some chinese studies defined disease severity as per chinese covid- management guidelines or covid- guidelines issued by chinese national health committee. one study defined severe covid- using the infectious disease society of america/american thoracic society cap severity criteria. pooled odds ratio was calculated using a random effects model. pooled or for severe/critical covid- illness among patients with hyperglycemia was . ( % ci . - . , p < . ) (fig. a) . other studies reported separately the clinical outcomes that comprise critical/severe covid- illness, as shown in table . recent evidence suggests that every mmol/l ( mg/dl) increase in fasting plasma glucose levels correlates with increasing covid- severity in both diabetics and non-diabetics, but the association was stronger among the latter [ ] . furthermore, the optimal fasting blood glucose levels for predicting critical covid- illness were reported to be ≥ . mmol/l [ ] . pao :fio ratio is the worst among those with hyperglycemia compared with diabetic individuals and those with normal blood glucose values [ ] . eight studies reported a higher mortality in patients with hyperglycemia compared with those with normal blood glucose levels. random effects model was used to compute pooled odds ratio for the same. sars-cov- infected patients who presented with raised blood glucose levels had an approximately threefold increased risk of dying when compared with those with normal glucose levels at presentation (pooled or . , % ci . - . , p < . ) (fig. b) . our pooled analysis showed an increased risk of critical illness or severe covid- , as well as mortality in patients who presented with raised glucose levels and no prior history of diabetes compared with those with normal glucose levels. diabetes is a comorbidity that negatively affects prognosis of covid- disease, but the impact of hyperglycemia in those without an established diagnosis of diabetes is a more concerning matter for clinicians. research has shown that acute hyperglycemia can cause impairment in innate immunity, leading to a heightened risk of infections [ ] . there is substantial evidence to suggest that hyperglycemia at admission is associated with worse outcomes in communityacquired pneumonia [ ] . few studies have also reported similar results with sars and mers viruses [ , ] . glucose is pro-inflammatory and causes generation of reactive oxygen species (ros), leading to acute oxidative and inflammatory stress [ ] . this milieu of heightened inflammation can possibly be a contributing factor to the cytokine storm witnessed in covid patients, resulting in more severe illness. it is wellknown that glycosylation (a consequence of sustained hyperglycemia) of the ace receptor increases the propensity of virus linkage to this cellular receptor [ ] . conceivably, this aberrantly glycosylated ace in the tissue in uncontrolled hyperglycemia not only favors the cellular intrusion of sars-cov but subsequently leads to a wide-spread organ involvement and a greater disease severity, thus translating liu et al. [ ] fasting blood glucose at admission (irrespective of diabetic status) was an independent predictor of icu admission (or . , % ci . - . , p < . ) zhang et al. [ ] patients with hyperglycemia were more likely to need mechanical ventilation ( . % vs . %), stay in the hospital for a longer duration ( . ± . vs . ± . days) smith et al. [ ] disease severity was defined in terms of the requirement for intubation. the intubation rate in non-diabetic patients was %, while that of pre-diabetics was . % wang et al. [ ] among patients without a previous diagnosis of diabetes, admission fasting plasma glucose (fbg) ≥ . mmol/l and . - . mmol/l were at a higher risk of in-hospital complications compared with those with fpb < . mmol/l (or . , % ci . - . ; or . , % ci . - . , respectively) li et al. [ ] compared with hyperglycemia, normoglycemia in covid- was associated with a higher chance of developing acute respiratory distress syndrome ( . % vs . %), acute kidney injury ( . % vs . %), shock ( . % vs . %), non-invasive ventilation ( . % vs . %), invasive ventilation ( . % vs . %), and admission to icu( . % vs . %) (p < . ) zhang et al. [ ] risk of acute respiratory distress syndrome ( % vs %), acute kidney injury ( % vs %), and septic shock ( % vs %) was higher in the impaired fasting glucose group vs normal fasting glucose (p < . ). into worse outcomes. worsening respiratory function is believed to be the major factor responsible for the detrimental effect of hyperglycemia in patients infected by sars-cov- [ ] . it has been observed that there exist varying magnitudes of association between fasting blood glucose levels and severe/critical covid- illness among patients presenting with hyperglycemia without a known diagnosis of diabetes. additionally, the shape of such an association is j-shaped as shown by zhu et al. in their study [ ] . further, it has been reported that optimal glycemic control of hyperglycemia in covid- patients leads to a reduction in the risk of severe disease and death [ ] . therefore, it is of utmost importance that plasma sugar values be strictly monitored in all covid- patients, more so in the critically-ill patients. we do acknowledge some limitations to our study. patients presenting with raised glucose levels (especially glucose levels > . mmol/l) may be cases of new-onset diabetes or may have missed being diagnosed in the past. criteria for placing patients into the normoglycemia and hyperglycemia groups was not consistent throughout all studies (refer table ). also, comorbidities such as hypertension, cardiovascular disease, chronic kidney, and liver disease were not accounted for in all included studies. hyperglycemia is a significant blood finding in patients admitted in view of covid- and can be used as a prognostic marker to stratify based on risk of severe disease and death, thus enabling early intervention resulting in improved patient outcomes. glycemic status rather than a prior diagnosis of diabetes is a predictor of adverse outcomes. the need for timely recognition and management of blood glucose levels should be emphasized in covid- disease. large-scale patient studies are warranted in order to establish appropriate treatment guidelines for hyperglycemia in covid- patients, so as to minimize worse outcomes for these patients. conflict of interest the authors declare that they have no conflict of interest. ethical approval this article does not contain any studies with human participants or animals performed by any of the authors. informed consent na early transmission dynamics in wuhan, china, of novel coronavirusinfected pneumonia diabetes mellitus is associated with increased mortality and severity of disease in covid- pneumonia-a systematic review, meta-analysis, and meta-regression binding of sars coronavirus to its receptor damages islets and causes acute diabetes serum glucose levels for predicting death in patients admitted to hospital for community acquired pneumonia: prospective cohort study lowering glucose to prevent adverse cardiovascular outcomes in a critical care setting impaired fasting glucose and diabetes are related to higher risks of complications and mortality among patients with coronavirus disease the clinical characteristics and outcomes of patients with diabetes and secondary hyperglycaemia with coronavirus disease : a single-centre, retrospective, observational study in wuhan newly-diagnosed diabetes and admission hyperglycemia predict covid- severity by aggravating respiratory deterioration fasting blood glucose predicts the occurrence of critical illness in covid- patients: a multicenter retrospective cohort study hyperglycemia at hospital admission is associated with severity of the prognosis in patients hospitalized for covid- : the pisa covid- study fasting blood glucose at admission is an independent predictor for -day mortality in patients with covid- without previous diagnosis of diabetes: a multi-centre retrospective study newly diagnosed diabetes is associated with a higher risk of mortality than known diabetes in hospitalized patients with covid- elevation of blood glucose level predicts worse outcomes in hospitalized patients with covid- : a retrospective cohort study glycemic characteristics and clinical outcomes of covid- patients hospitalized in the united states [published correction appears in impaired glucose metabolism in patients with diabetes, prediabetes, and obesity is associated with severe covid- admission hyperglycemia and radiological findings of sars-cov in patients with and without diabetes outcomes in patients with hyperglycemia affected by covid- : can we do more on glycemic control? diabetes care hyperglycemia is a strong predictor of poor prognosis in covid- the effect of short-term hyperglycemia on the innate immune system the relation between hyperglycemia and outcomes in , patients admitted to the hospital with community-acquired pneumonia plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with sars diabetes mellitus, hypertension, and death among patients with mers-cov infection, saudi arabia glucose challenge stimulates reactive oxygen species (ros) generation by leucocytes hyperglycemia, hydroxychloroquine, and the covid- pandemic j-shaped association between fasting blood glucose levels and covid- severity in patients without diabetes [published online ahead of print publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- -c jq j authors: tagliabue, fabio; galassi, luca; mariani, pierpaolo title: the “pandemic” of disinformation in covid- date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: c jq j in recent years, mass media and social networks have played an important role in disseminating information regarding public health. during the covid- epidemic, misinformation and fake news have represented an important issue generating confusion and insecurity among the population. in our analysis, we investigate the role of mass media as a critical element during the sars-cov- outbreak that has influenced the public perception of risk. the role of the mass media and social networks has always been fundamental in the management of health-related information. during this current pandemic, people have been continually searching for information regarding the coronavirus infection. in many cases, people have unfortunately found themselves overwhelmed with news containing fake reports and misinformation, which, for those without the right skills, can be complicated to digest. this situation has generated confusion within the population and has also influenced some statements by public figures and politicians, which have in turn have led to further repercussions on public opinion. the general population has, in good faith, taken the information, including fake news, most relevant to their own personal situation and has used it to formulate their own interpretation of the pandemic. at the beginning of the pandemic, the medical community also played a role in making the situation even more confusing by giving, in some cases, inaccurate and sometimes contradictory indications on covid- . there have been numerous media debates about who advocated distinct conflicting positions. two opposite positions could be recognized from the numerous interviews between members of the medical community: on the one hand those who were inclined to spread alarming news and on the other who had optimistic ideas that supported a non-hazardous nature of covid- . a few weeks after the start of the pandemic, comments from non-specialists in infectious-respiratory problems could be seen in the mainstream media. it seemed as though the entire scientific community (gastroenterologists, nephrologists, surgeons, neurologists…) were releasing statements and writing articles as if they were the main experts of covid- . people were so overwhelmed by this flood of information that they did not have time to understand it correctly. the massive presence in the mass media of doctors who expressed their opinions, sometimes not supported by scientific evidence, could be interpreted as a desire to appear rather than the need to provide the correct indications. the alarming tone of some experts has caused in some cases a rush to purchase personal protective equipment (ppe) and alcoholic detergents; this fact partially contributed to the lack of ppe in the clinical sector and to a disproportionate increase in the prices of these products. in psychologically fragile subjects, an exacerbation of psychiatric pathologies [ ] and determined headline stress disorder [ ] has been manifested. initial, and overly optimistic medical statements that judged the epidemic as a simple influenza lowered social attention on the covid- pandemic and instilled in some people conspiracy or denial ideas supported by statements by some doctors and non-medical professionals who said, "it's just a flu." [ ] the poor perception of the risks related to covid- infection also manifested itself despite the exponential growth of infections and deaths. in italy, on march , , while [ ] . in the usa, the lockdown, imposed to reduce contagion, has been strongly opposed and its purpose diminished by comments in the media from public figures who have a greater following than the scientific community in influencing public opinion. similarly, the mass media, in an attempt to gain visibility, have perhaps unwittingly misinformed the public whenever a new experimental treatment started. the beginning of an experimental treatment was reported by newspapers who reported it as the decisive discovery to combat sars-cov- , thus accentuating people's sense of security [ ] . moreover, the search for journalistic scoops has triggered a race to find responsibility for the covid- pandemic, and has thus reduced the trust of people in the national and international institutions responsible for preserving public health. social media platforms are well known for the spread of misinformation and denial of scientific literature [ ] . fake news has reduced the relevance to evidence-based precautions promoted by national health services [ ] , and perhaps, little has been done to stop this virus on social networks. the who has offered a whatsapp service to refute fake news, but unfortunately the rapid, viral spread of disinformation on social networks has been so widespread that we have in fact witnessed the appearance of attitudes harmful to health. in some cases, patients refused to take ibuprofen or other anti-inflammatory drugs because of the erroneous idea that they could increase the chances of getting infected with the coronavirus [ ] . misleading information about treatment for covid- has resulted in an increasing number of vitamin d abuse and even mass poisoning from methanol intake [ ] . after the lockdown, in countries where social distancing and the use of face masks were mandated, news of correlation between cancer and mask coverings appeared on social networks [ ] . the lockdown and consequent social distancing has resulted, especially in those residing in highly infected areas, in a posttraumatic stress syndrome (ptsd) characterized by anxiety, sleep disturbances, distress, and a drop in the tone of the mood with a decrease of positive mood such as happiness and serenity and an increase of sadness or boredom [ , ] . misinformation and fake news contributed to the onset of ptsd and headline stress disorder cases [ ] . the consequences of these disorders have not only had effect in the peak infection phase but will also have future repercussions. the historical importance of the covid- pandemic is such that, also in the future, covid- -related news will be published cyclically in the mass media and on social networks. poor quality information may in the future amplify anxiety to the state of panic especially in the event of a new wave of infections; people will relive the moments of the first phase of the peak of covid- and will return to look for information to safeguard their health and that of their loved ones. fake news also stimulated indignation with the consequent reaction of people for an alleged injustice. the incomplete or incorrect news reported by the mass media and then reworked on social networks have also focused attention on possible errors of some hospital structures. in some cases, this will mean that patients will be reluctant to go to hospitals or medical centers in the fear of becoming victims of medical errors or to be at a greater risk of contagion. healthcare workers, subject to ptsd risk, may have an additional psychological burden as they may suffer lawsuits brought by relatives of victims of covid- who will accuse them of not having undertaken for their loved one's therapies that the mass media described as effective, but which were actually experimental. even an effective vaccine against covid- could run the risk of falling victim of fake news by reducing the number of people who will join the vaccination campaigns. the rapid evolution of the covid- pandemic has not permitted immediate and certain scientific data. considering this, the need therefore arises that, especially in the event of pandemics, doctors must provide the public only with evidence-based information in a simple and shared way in order to avoid misinterpretation and misunderstanding. better coordination between the medical community, governments, and the mass media is therefore needed to avoid the spread of disinformation through different channels, limiting the dissemination of fake news and thereby better engaging the general public to adhere to correct guidelines. author contributions all authors conceived and planned this paper, devised the project and the main conceptual ideas. moreover, all authors provided critical feedback and helped shape the research, analysis, and writing the manuscript. conflict of interest the authors declare that they have no conflicts of interest. covid- effect on mental health: patients and workforce letter to the editor: headline stress disorder caused by netnews during the outbreak of covid- il coronavirus è poco più di una normale influenza italian ministry of the interior. monitoraggio dei servizi di controllo inerente le misure urgenti per il contenimento della diffusione del sn compr antimalarial drug has curative effect on coronavirus, chinese experts say the twitter pandemic: the critical role of twitter in the dissemination of medical information and misinformation during the covid- pandemic going viral: doctors must tackle fake news in the covid- pandemic headache medication and the covid- pandemic methanol mass poisoning outbreak: a consequence of covid- pandemic and misleading messages on social media le mascherine fanno venire il cancro? la teoria di montanari fa infuriare burioni covid- pandemic in the italian population: validation of a post-traumatic stress disorder questionnaire and prevalence of ptsd symptomatology the enemy which sealed the world: effects of covid- diffusion on the psychological state of the italian population publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- - wv v authors: fang, lanlan; wang, dingjian; pan, guixia title: analysis and estimation of covid- spreading in russia based on arima model date: - - journal: sn compr clin med doi: . /s - - -y sha: doc_id: cord_uid: wv v russia has been currently in the “hard-hit” area of the covid- outbreak, with more than , confirmed cases as of may . it is necessary to analyze and predict its epidemic situation to help formulate effective public health policies. autoregressive integrated moving average (arima) models were developed to predict the cumulative confirmed, dead, and recovered cases, respectively. r . . software was used to fit the data from january to may , , and predict the data for the next days. the covid- epidemic in russia was divided into two stages and reached its peak in may. the epidemic began to stabilize on may . the case fatality rate has been at an extremely low level. arima ( , , ), arima ( , , ), and arima ( , , ) were the models of cumulative confirmed, dead, and recovered cases, respectively. after testing, the mean absolute percentage error (mape) of three models were . , . , and . , respectively. this paper indicates that russia’s health system capacity can effectively respond to the covid- pandemic. three arima models have a good fitting effect and can be used for short-term prediction of the covid- trend, providing a theoretical basis for russia to formulate new intervention policies. since january , a new coronavirus from wuhan, china, has been spreading around the world and is named coronavirus disease (covid- ). since the world war ii, the covid- pandemic is the most serious global crisis, affecting almost all countries on our planet [ ] . on march , who publicly announced covid- as a "global pandemic." as of may , , it infected more than million population and killed more than , people (https://www.who.int/docs/ default-source/coronaviruse/situation-reports). the pandemic is still growing in most countries and is far from under control. russia is currently in the "hard-hit" area of the covid- outbreak, with more than , confirmed cases as of may . from may to may , more than new cases were confirmed daily (https://www.worldometers.info/ coronavirus/country/russia). it is also posing a challenge to the prevention and control of the second wave of the epidemic in china, bordering with russia. therefore, the construction of a reasonable prediction model in russia contributes to prevent and control the spread of covid- . moreover, it can provide a methodological reference for the prediction of infectious diseases in the future. in recent studies, the prediction models of covid- are mainly divided into two categories, which are infectious disease models and their modified models, and artificial intelligence algorithms based on massive data. for example, shengli et al. [ ] established an seir epidemic dynamics model that can be used to evaluate and predict the covid- epidemic in hubei province. yang et al. [ ] applied modified seir and ai to predict the trend of china's covid- under public health intervention. pereira et al. [ ] developed a modified stacked auto-encoder for modeling the transmission dynamics of the epidemics and applied this model to forecasting covid- dynamics in brazil. al-qaness et al. [ ] improved the adaptive neuro-fuzzy inference system (anfis) by applying an enhanced flower pollination algorithm using the salp swarm algorithm to estimate the number of confirmed covid- cases in china. however, they also have their disadvantages. epidemiological models require parameters and depend on many assumptions. artificial intelligence algorithm requires huge amounts of data, high complexity, and uncertainty [ ] . to overcome these limitations and help public health planning and decision-making, we try to use the autoregressive integrated moving average (arima) model, which has the advantages of simple structure, strong applicability, and strong data set interpretation ability [ ] . it has been widely used for short-term prediction of infectious diseases. for instance, earnest et al. [ ] used the arima model to predict and monitor the number of beds occupied during a sars outbreak in a tertiary hospital in singapore. wang et al. [ ] estimated the morbidity of influenza in ningbo, china, - by the arima model. singh et al. [ ] forecasted the transmission trajectory of covid- disease in the worst-hit countries in the next months based on the arima model. therefore, we respectively established the arima model based on the monitoring data of cumulative confirmed cases, cumulative death cases, and cumulative recovered cases of covid- in russia as of may , , to predict the trend in the next days. from january to may , , russia's covid- daily reported cumulative confirmed, dead, and recovered data were extracted from the john hopkins coronavirus resource center (https://coronavirus.jhu.edu/). the data from january to may is used as a training set to build arima models, and the data from may to may is used as a verification set to test the accuracy of these models. excel is used to build the russian covid- time series database, and r . . software is used to build and predict the arima model. descriptive statistics of the covid- data of russia between / / and / / are given in table . the arima model is a time series forecasting method proposed by box and jenkins in the s. the model includes ar(p), ma(q), arma (p, q), arima (p, d, q), and so on. among them, arima (p, d, q) means that the time series is differentiated d times, and each observation in the sequence is represented by a linear combination of the past p observations and q residuals [ ] . p and q are the autoregressive order and moving average order, and d is the different order. the basic idea of the model is to treat the sequence as a set of time-dependent random variables and describe it with a mathematical model, based on the previous sequence value to predict future values [ ] . the predicted value represents a linear function composed of the most recent true value and the most recent prediction error. the arima (p, d, q) model can be presented as given in the eq. ( ). the steps to build the arima model include the following: ( ) stationarity test use the augmented dickey-fuller (adf) test to detect whether the time series is stationary. the p value of the adf test is less than . , indicating that the sequence is stationary. if the original sequence is not stationary, it can be converted to a stationary sequence by differential operation [ , ] , and the value of d is determined. ( ) model identification use the autocorrelation (acf) graph and partial autocorrelation (pacf) graph to determine the values of p and q. ( ) fit and evaluation model use box. test () function to test whether the residual sequence is white noise. p > . , the residual sequence is white noise. the arima model can better fit the data. in this study, mean percentage error (mpe), mean absolute percentage error (mape), and mean absolute standardized error (mase) were applied to verify the fitting effect of the developed arima model. [ ] . it is expressed mathematically in the eq. ( ). the tendency analysis of covid- in russia as seen in fig. a , russia has , confirmed cases, deaths, , recovery cases, and , existing cases as of may , . the cumulative number of confirmed cases remained at cases from january to march and was recovered from the hospital on february . therefore, the russian epidemic was free from february to march . russia's case fatality rate has always been at a very low level of . % as of may . as seen from fig. b ( ) stationarity test judging from fig. a , the original sequence has a clear longterm trend, indicating that it is not stable. use the diff () function for the second-order difference, and then use the adf.test () function for the adf test. the results show that dickey-fuller (confirm) = . , p = . ; dickey-fuller (death) = . , p = . ; dickey-fuller (recover) = − . , p = . , so the sequence after the difference is stationary, and d = . ( ) model identification determine the value of p and q according to acf and pacf graphs of the sequence after difference. figure a shows that acf and pacf are both gradually reduced to , using the arima (p, d, q) model. take , , , respectively, and experiment from low order to high order one by one. debug one by one according to the minimum principle of akaike information criterion (aic), and finally choose arima ( , , ) as the confirmed model. figure b shows that the acf graph shows tailing, and the pacf graph decreases to after the third order, that is, the third-order truncation, p = , so the dead model is arima ( , , ) . figure c shows that the acf graph decreases to after the first order, that is, the first-order truncation, q = , and the pacf graph shows tailing, so the recovered model is arima ( , , ). it is seen from table that the residual sequences are all white noise sequences (p > . ). the values of mpe, mape, and mase are also small, and the maximum values of the three indicators are . , . , and . , respectively, indicating that the models fit well. test the accuracy of the model by comparing the difference between the predicted value and the actual value from may to may , . as seen in table , the mape of the confirmed model is . , indicating that the model has high prediction accuracy and is robust. the mapes of the death model and the recovery model were . and . , respectively, indicating that models are relatively robust. use established arima models to predict the cumulative confirmed, death, and recovered data for the next days in russia. as seen in fig. , on june , the cumulative number of confirmed, death, and recovered cases will reach , , , , . discussion covid- in russia was divided into two stages. from january to march , there was no impact on the epidemic. from march to the march , the disease broke out, spread, and grew exponentially. there were three main reasons for the russian epidemic: ( ) russia did not strictly control the entry of people in europe immediately after the outbreak in europe. according to relevant reports, more than , people entered russia from europe, and they were distributed in various places in russia. ( ) after the domestic epidemic had been controlled, russia had also relaxed its prevention and control. ( ) compared with international standards, russian selfdeveloped kits had two grades lower, so many patients with asymptomatic and mild symptoms were not diagnosed and separated in time. analyzing these reasons had a good warning meaning to the countries that had controlled the epidemic and prevent the spread of the second wave of the epidemic. the epidemic in russia peaked in may, with more than , new cases confirmed daily for consecutive days. since may , there had been a downward trend. judging from the recovery curve, the daily confirmed cases and recovered cases coincided on may , which showed that the epidemic situation in russia tended to be stable. russia's case-fatality rate had been at a very low level of . %, which might be because the cases were mostly mild, which also indirectly shown that its intervention measures are effective. although the number of confirmed cases ranked among the top in the world on may , russia's health system capacity could effectively respond to the covid- pandemic. time series data can help to predict epidemic trends and improve prevention systems. the time series forecasting models include the exponential smoothing model and artificial neural network. although these models can be used to predict the incidence of infectious diseases, they have some limitations. for exponential smoothing model, it is difficult to determine the smoothing coefficient because the weight decreases with the extension of the forecast period. for artificial neural networks, it may not well explain the nonlinear relationship in time series data. the arima model is the most popular and classic time series forecasting model because of its simplicity, system structure, and acceptable prediction performance [ ] . it obtains a smooth sequence through difference and then selects the best model for prediction. it can not only solve the problem of data autocorrelation but also analyze data with periodic effects. therefore, it can better simulate the past epidemic situation and obtain better prediction effect. in my study, arima models were developed to predict the cumulative confirmed, dead, and recovered cases of covid- in russia, respectively. taking the data from . to . as a test set to evaluate the extrapolation effect of the models with mape as the evaluation standard. the cumulative confirmed model was very robust, with the mape of . . from the mapes of . and . , the cumulative death and recovery models were relatively stable. there have been many articles using the arima model to predict the trend of covid- in different countries [ , ] . in iran, moftakhar et al. [ ] used the arima model and artificial neural network to predict the daily new covid- infections, which showed that the arima model was more accurate. ceylan [ ] estimated the prevalence of covid- in italy, spain, and france, with m a p e ( i t a l y ) = . , m a p e ( s p a i n ) = . , and mape (france) = . . therefore, the arima ( , , ), arima ( , , ), and arima ( , , ) models were considered to be reasonable for forecasting with high accuracy. according to the predicted data from . to . , although the cumulative number of confirmed cases is still on the rise, the number of daily new confirmed cases on may fell to , and then basically stabilized at about , lower than the daily new recovery cases. therefore, the russian epidemic will be further controlled. constructing the predictive model based on time series data is an important method for the prevention and control of infectious diseases. the arima model has a mature theoretical basis and clear criteria, which can effectively predict the epidemic trend of infectious diseases. this will help to effectively allocate medical resources and will have guiding significance for scientific prevention and control of covid- . russia's interventions on covid- have achieved remarkable effects. russia's health system capacity can effectively respond to the covid- pandemic. established arima models had a good fitting effect and can be used for short-term prediction of the covid- trend, providing a theoretical basis for russia to formulate new intervention policies. modeling and forecasting of epidemic spreading: the case of covid- and beyond study on the epidemic development of corona virus disease- (covid- ) in hubei province by a modified seir model modified seir and ai prediction of the epidemics trend of covid- in china under public health interventions forecasting covid- dynamics in brazil: a data driven approach optimization method for forecasting confirmed cases of covid- in china strengths, weaknesses, opportunities, and threats analysis of artificial intelligence and machine learning applications in radiology using autoregressive integrated moving average (arima) models to predict and monitor the number of beds occupied during a sars outbreak in a tertiary hospital in singapore epidemiological features and forecast model analysis for the morbidity of influenza in prediction of the covid- pandemic for the top affected countries: advanced autoregressive integrated moving average (arima) model reducing demand uncertainty in the platelet supply chain through artificial neural networks and arima models the analysis of time series: an introduction time series analysis: forecasting and control, th edition permeate flux prediction in the ultrafiltration of fruit juices by arima models application of a combined model with seasonal autoregressive integrated moving average and support vector regression in forecasting hand-footmouth disease incidence in wuhan comparison of arima and gm( , ) models for prediction of hepatitis b in china estimation of covid- prevalence in italy exponentially increasing trend of infected patients with covid- in iran: a comparison of neural network and arima forecasting models publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- - sg uvd authors: llansó, laura; urra, xabi title: posterior reversible encephalopathy syndrome in covid- disease: a case-report date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: sg uvd posterior reversible encephalopathy syndrome (pres) is a clinical syndrome that can include headache, altered consciousness, visual disturbances, and seizures, usually related to autoregulatory cerebral failure and hypertension. the neuroimaging is essential to diagnosis, showing white matter vasogenic edema in posterior areas. we present a case of a -year-old woman with severe pneumonia by sars-cov- who developed a posterior reversible encephalopathy syndrome with a typical clinical and radiological presentation, after being treated with anti-interleukin treatment (anakinra and tocilizumab) following local guidelines. we report a case of posterior reversible encephalopathy syndrome in a patient with covid- disease, possibly related to anti-il- or anti-il- , suggesting that anti-interleukin treatments may cause this syndrome, at least in patients with predisposing conditions such as infections and hydroelectrolytic disorders. a -year-old woman with covid- presented with adult respiratory distress syndrome (ards). besides bilateral pneumonia, she developed multiple complications such as cardiorespiratory arrest, bacterial superinfection, hyponatremia, massive hemoptysis requiring embolization, and acute renal injury. she was started on lopinavir/ritonavir, hydroxychloroquine, and azithromycin. after radiological pulmonary progression, anti-il- (daily anakinra) and anti-il- (single dose of tocilizumab) were started, following local and hospital guidelines. these drugs are recommended in covid- when there is clinical, blood test, or radiological progression, to avoid an excessive immunological systemic response to the virus, which is thought to worsen pulmonary infiltrates and disease prognosis. ten days after the initiation of immunodepressants, she developed altered mental status without fever, previous headache, or visual disturbances. at the examination, the patient opened eyes to painful stimuli, had no verbal response, and showed withdrawal response to pain (glasgow coma scale ). the blood tests showed stable hyponatremia ( meq/l) and leukocytosis without any other significant findings. her vitals were within normal limits, and blood pressure had been mildly increased during the previous h with a maximum systolic pressure of mmhg. electrocardiogram showed sinus rhythm and had not atrioventricular node blocks. a ct scan with angiography was performed. there was no large vessel occlusion, no perfusion alterations, and the baseline ct ( fig. ) showed temporooccipital white matter hypodensity with symmetric obliteration of the sulci in that region. considering the infectious background, the immunomodulatory treatments, modest hypertension in the hours before the symptoms, and the distribution of the lesions on the ct scan, the most likely diagnosis is posterior reversible encephalopathy syndrome (pres) [ ] [ ] [ ] [ ] [ ] . hypertension plays a vital role in this article is part of the topical collection on covid- the disease due to a failure in cerebral blood flow autoregulation, and in this case, rapid rise or fluctuations in blood pressure from baseline may have been harmful, despite not being severely high [ ] . the electroencephalogram showed focal slowing and epileptiform discharges in both occipital areas and ruled out nonconvulsive status epilepticus. the symptoms improved over the following days after tight control of blood pressure with labetalol infusion and discontinuing anakinra. after week, radiological infiltrates worsened and a blood test showed increased acute phase reactants. in this context, a diffuse alveolar hemorrhage was diagnosed by bronchoalveolar lavage, with suspicion of hemophagocytic syndrome. she required red blood cell transfusions and immunosupressants were restarted, as well as mechanical ventilation. the ct pulmonary scan showed worsening of infiltrates and presence of an intrapulmonary hematoma. finally, the patient had a torpid evolution to multiorgan failure and death. the absence of fever and radiological findings did not suggest an encephalitic cause of the symptoms. the serum sodium levels were only slightly decreased and had been stable for the previous days without intravenous infusion of sodium. thus, hyponatremia was not assumed to be the cause of the sudden loss of consciousness. the cardiorespiratory arrest happened a month before the event while intubated, and it was secondary to a mucus plug after a period of desaturation and bronchospasm. it lasted less than min and ended as the mucus plug was removed by fibrobronchoscopy. the postanoxic cerebral damage was prevented by treating fever; avoiding systemic hypotension, hypoxemia, or glycemic disbalance; and continuing renal replacement therapy with hemodiafiltration instead of hemodialysis to prevent large changes in volemia. one week later, sedation was stopped and a tracheostomy was placed, and the patient progressively awakened up to a normal state of consciousness without focal neurologic signs. the timeline and posterior complete recovery from the respiratory arrest cannot explain the current episode as hypoxic-ischemic encephalopathy. pres has been associated with immunosuppressive and cytotoxic therapies such as platinum-containing drugs, (r)-chop regimens, gemcitabine, cyclosporine, tacrolimus, sirolimus, and interferon therapies. also, agents that target angiogenesis such as bevacizumab (anti-vegf) and tyrosine kinase inhibitors (tki) against vegf receptor (pazopanib, sorafenib, sunitinib) have been described as risk factors [ , ] . prior exposure to the predisposing drug does not appear to be protective, and patients can develop pres even after several months after exposure [ ] . furthermore, the disorder has been associated with both acute and chronic renal disease, as was the case in our patient, and medical conditions such as hyponatremia or pulmonary infection could exacerbate the neurological findings. despite not being described yet, the occurrence of pres a few days after anti-interleukin (il- or il- ) treatments which were given in this patient, raises the possibility that these kinds of immunomodulatory agents may also favor pres. conflict of interest the authors declare that they have no conflict of interest. ethical approval and informed consent consent for publication was obtained from the next of kin (daughter). approval from the hospital's irb was provided for this study. posterior reversible encephalopathy syndrome: associated clinical and radiologic findings controversy of posterior reversible encephalopathy syndrome: what have we learnt in the last years? reversible posterior leukoencephalopathy syndrome after bevacizumab/folfiri regimen for metastatic colon cancer cisplatin neurotoxicity presenting as reversible posterior leukoencephalopathy syndrome hypertensive encephalopathy: findings on ct, mr imaging, and spect imaging in cases publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- -e g j authors: vitiello, antonio; pelliccia, chiara; ferrara, francesco title: covid- patients with pulmonary fibrotic tissue: clinical pharmacological rational of antifibrotic therapy date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: e g j in december , the first data emerged from wuhan, china, of a serious acute respiratory disease caused by a new coronavirus, sars-cov- (covid- ). in a short time, the health emergency became a global pandemic. to date, there are about . million infected people and about , deaths. there are currently no effective vaccines, and treatments are mostly experimental. the symptoms associated with covid- are different, ranging from mild upper respiratory tract symptoms to severe acute respiratory distress syndrome (sars). data from previous coronavirus outbreaks such as sars-cov ( outbreak) and emerging epidemiological data from the current global covid- pandemic suggest that there could be substantial tissue fibrotic consequences following sars-cov- infection, responsible for severe and in some cases fatal lung lesions. some data show that even patients cured of viral infection have lung fibrotic tissue residues responsible for incorrect respiratory function even after healing. the role of antifibrotic drug therapy in patients with ongoing sars-cov- infection or in patients cured of residual pulmonary fibrosis is still to be defined and unclear; the scientific rationale for initiating, continuing, or discontinuing therapy is poorly defined. in this article, we describe the advantages of antifibrotic therapy in patients with ongoing sars-cov- viral infection to prevent the worsening and aggravation of the clinical situation, and the advantages it could have in the role of preventing pulmonary fibrosis after sars-cov- infection, and in accelerating the complete healing process. the new coronavirus sars-cov- (covid- ) is responsible for the current global pandemic, representing a health challenge with few precedents in human history. at the time of writing this manuscript, covid- infected . million people and caused about , deaths [ ] . sars-cov- infection can have a completely asymptomatic or mildly symptomatic course, but in some cases, it can also cause systemic hyperinflammation, pulmonary fibrosis and scarring with lung collapse, multi-organ dysfunction, and patient death [ ] . to date, no effective or antiviral vaccines against sars-cov- are available, treatments are mostly experimental, so it is very important to know the advantages of current therapeutic solutions to decrease the aggressiveness of the viral infection, avoiding serious complications and consequent patient death. the most serious phases of viral infection are characterized by a sudden and excessive release of proinflammatory mediators, which leads to lung damage with extensive fibrosis and rapid onset of respiratory distress syndrome [ ] . studies have shown that bilateral interstitial pneumonia caused by covid- , so called because it attacks the tissue covering the lung alveoli, is associated with the presence of fibrotic tissue caused by excess collagen (fibrosis) in the lung crevice with associated hyperinflammation present. in this direction, the use of a pharmacological approach to reduce or prevent fibrotic status, with antifibrotic agents such as pirfenidone, used with demonstrated clinical efficacy in idiopathic pulmonary fibrosis [ ] can be a valuable aid in the prevention of serious or fatal complications from covid- in patients with ongoing infection, or in those already healed with residual fibrotic lung lesions [ ] . pulmonary fibrosis is a pathological consequence of interstitial pulmonary diseases and is characterized by the persistence of fibroblasts and excessive deposition of collagen and extracellular matrix, as well as the destruction of normal pulmonary architecture [ ] . the progression of pulmonary fibrosis leads to a loss of pulmonary function with damage to the correct exchange of oxygen capillary alveoli [ ] . causes of pulmonary inflammation include age, smoking, and viral infections [ ] . among the pathological mechanisms are altered oxidative stress and excessive production of reactive oxygen species (ros); altered tgf-b, fgf, and pdgf contribute to the development of fibrosis [ ] . a hyperactive inflammatory state such as that present in the most severe stages of covid- infection, caused by the cytokine storm, is probably the main cause of pulmonary fibrosis responsible for severe and in some cases fatal lung lesions. evidence shows that the most severe cases of covid- have an extensive presence of pulmonary fibrotic tissue, and data show that serum levels of the above-mentioned cytokines and growth factors causing pulmonary fibrosis are strongly increased in patients with covid- [ ] . mediators such as tgf-β, vegf, il- , and tnf-α vascular dysfunctions can lead to the progression of fibrosis [ , ] . the pathophysiological similarity between ipf and covid- viral infection suggests a similar pathogenetic mechanism of pulmonary fibrosis in these two diseases; therefore, it is hypothesized that drugs useful for the treatment of ipf could also be useful for patients with covid- . the reason for the use of antifibrotic therapy in covid- patients is primarily based on the following objectives: to avoid serious complications and fatal lung injury in patients with ongoing infection, to accelerate the healing process in healed patients with residual reversible fibrotic lesions [ ] . as described above, unregulated immune/inflammatory mechanisms as a result of a cytokine storm promote pulmonary fibrosis [ ] . to date, there are antifibrotic drugs such as pirfenidone and nintedanib used with proven efficacy in the treatment of ipf. specifically, pirfenidone is attributed to pleiotropic actions [ ] (fig. ) . in fact, existing data indicate that pirfenidone has both antifibrotic and anti-inflammatory properties and is able to mitigate the proliferation of fibroblasts and the production of proteins and cytokines associated with fibrosis; it also mitigates the accumulation of extracellular matrix in response to cytokine growth factors such as tgf-β and pdgf [ , ] . data suggest that pirfenidone has more anti-inflammatory and antioxidant effects than its exceptional antifibrotic capacity. indeed, the data show that with early use, its strong anti-sod activity and inhibition of the effects mediated by il- and il- , an important therapeutic scenario for the prevention of interstitial pulmonary fibrosis caused by covid- , can be opened. to date, the therapeutic efficacy of antifibrotic therapy in pulmonary fibrosis induced by sars-cov- is still being investigated in clinical trials. nevertheless, evidence has already demonstrated the efficacy of antifibrotics in diseases with profibrotic pathways activated by immune/ inflammatory dysregulation, which may have similarities with those caused by sars-cov- infection [ ] . a key aspect to consider is the timing of the onset of antifibrotic action. in some severe cases of sars-cov- , the evolution towards a severe pulmonary fibrotic lung state can be very rapid which can lead to antifibrotic therapy not acting in time; probably in these cases, a therapeutic regimen combined with immunomodulants (il- or il- inhibitors) and antifibrotics could lead to an important and more effective pharmacological synergism. synergistic therapy could more quickly counteract the anti-inflammatory and antifibrotic pathways and mitigate their consequences. although many patients who develop sars-cov- respiratory distress syndrome survive the acute phase of the fig. antifibrotic therapy, pleiotropic effects of pirfenidone disease, data have shown that some of them die from progressive pulmonary fibrosis [ ] . however, some studies indicate that pulmonary fibrosis is more prevalent in patients who have a longer duration of viral infection, suggesting that antifibrotic therapy should be administered early to be more effective clinically. it should also be added that a percentage of patients cured of covid- show radiological and physiological abnormalities consistent with fibrotic lung disease; even in this type of patients, a medium-long-term antifibrotic therapy may be necessary to accelerate the complete healing process [ ] . while pirfenidone in the acute phase of the disease can be used in combination with anti-inflammatory drugs to limit the damage produced by the cytokine storm and avoid the death of the patient, in the chronic phase, when the patient is saved and cured of the infection, pirfenidone can be used to eliminate residual complications, such as fibrotic tissue in the lungs. this can be done in monotherapy or together with other medications if there are multiple post-infection complications [ ] . several reports suggest, however, that there are differences between ipf and covid- -induced pulmonary fibrosis, diversity in the rapid evolution of the fibrotic and inflammatory state, and a highly developed procoagulant effect in sars-cov- viral infection [ , ] . all these considerations suggest that other treatments should be implemented in synergy with antifibrotic therapy. the use of steroids or inhibitors il- /il- is important to reduce inflammatory status. the use of spironolactone may be of significant importance in fibrosis prevention [ ] , the use of anticoagulants may reduce the risk of thrombosis, and the administration of antivirals is important to reduce the viral load. in addition, agents acting ras could be efficacy by increasing of ace- with a key role protective in the lungs. the global covid- pandemic seems to be continuing, and the lack of effective and antiviral vaccines directed against sars-cov- forces scientists to seek new treatment options from existing therapeutic solutions. in this article, we have described the pathophysiological similarities of sars-cov- virus infection with ipf. one of the causes of severe lung injury is pulmonary fibrosis. while waiting for antivirals directed against sars-cov- , a valid therapeutic solution to avoid the most serious complications in patients with ongoing infection or aimed at accelerating healing processes in patients after covid- infection can be represented by antifibrotic therapy, in therapeutic regimens combined with other drugs. ongoing clinical studies will provide us with the necessary evidence. conflict of interest the authors declare that they have no conflict of interest. coronavirus disease (covid- ) situation report available from the neuroinvasive potential of sars-cov may play a role in the respiratory failure of covid- patients clinical course and outcomes of critically ill patients with sars-cov- pneumonia in wuhan, china: a single centered, retrospective, observational study safety and efficacy of pirfenidone in advanced idiopathic pulmonary fibrosis: a nationwide postmarketing surveillance study in korean patients clinical characteristics of coronavirus disease in china fibrosis of the lung and other tissues: new concepts in pathogenesis and treatment viral infection and aging as cofactors for the development of pulmonary fibrosis reactive oxygen species as signaling molecules in the development of lung fibrosis covid- : pathogenesis, cytokine storm and therapeutic potential of interferons tgf-β isacriticalmediatorofacutelunginjury anti-vascular endothelial growth factor gene therapy attenuates lung injury and fibrosis in mice radiological findings from patients with covid- pneumonia in wuhan, china: a descriptive study advances in the research of mechanism of pulmonary fibrosis induced by corona virus disease and the corresponding therapeutic measures pirfenidone: a novel hypothetical treatment for covid- the added value of pirfenidone to fight inflammation and fibrotic state induced by sars-cov- : anti-inflammatory and anti-fibrotic therapy sn compr pirfenidone safety and adverse event management in idiopathic pulmonary fibrosis pirfenidone in patients with unclassifiable progressive fibrosing interstitial lung disease: a double-blind, randomised, placebo-controlled, phase trial persistent elevation of inflammatory cytokines predicts a poor outcome in ards. plasma il- β and il- levels are consistent and efficient predictors of outcome over time epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study cytokine storm and colchicine potential role in fighting sars-cov- pneumonia the procoagulant pattern of patients with covid- acute respiratory distress syndrome reduction of acute lung injury by administration of spironolactone after intestinal ischemia and reperfusion in rats correlation between renin-angiotensin system and severe acute respiratory syndrome coronavirus infection: what do we know? publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- - vpawtef authors: jakhmola, shweta; indari, omkar; chatterjee, sayantani; jha, hem chandra title: sars-cov- , an underestimated pathogen of the nervous system date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: vpawtef numerous clinical studies have reported neurological symptoms in covid- patients since the spread of severe acute respiratory syndrome coronavirus (sars-cov- ), apart from the atypical signs of pneumonia. angiotensin-converting enzyme- (ace- ), a potential receptor for sars-cov- entry, is expressed on various brain cells and cerebral parts, i.e., subfornical organ, paraventricular nucleus, nucleus of the tractus solitarius, and rostral ventrolateral medulla, as well as in non-cardiovascular areas such as the motor cortex and raphe. the resident cns cells like astrocytes and microglia also express ace- , thus highlighting the vulnerability of the nervous system to sars-cov- infection. additionally, transmembrane serine protease (tmprss ) and furin facilitate virus entry into the host. besides, the probable routes of virus entry into the nervous system include the hematogenic pathway, through the vagus, the olfactory nerve, or the enteric nervous system. however, the trajectory of sars-cov- to the brain needs investigation. furthermore, a th -mediated cytokine storm is seen in covid- cases with higher levels of il- β/ / / / / / , gm-csf, ifn-γ, tnf-α, cxcl- , mcp , and mip α/β. some cytokines can cross the blood-brain barrier and activate the brain’s immune cells to produce neural cytokines, leading to neuronal dysfunctions. nonetheless, most of the neurological conditions developed due to viral infections may not have effective and registered treatments. although, some antivirals may inhibit the virus-mediated pathogenesis and prove to be suitable in covid- treatment. therefore, clinicians’ and researchers’ collective expertise may unravel the potential of sars-cov- infection to prevent short-term and long-term cns damage. the initial cases of severe acute respiratory syndrome coronavirus (sars-cov- ) infection appeared in december in hubei province, china [ ] . since then, it has become a global threat. besides systemic and respiratory ailments, . % of coronavirus disease of (covid- ) patients developed neurological symptoms [ ] . additionally, taste, smell, and visual impairments are reported in several cases of covid- [ ] . sars-cov- , a human cov (hcov) belongs to β-coronaviruses, and various clinical and pre-clinical studies have reported potential neurovirulent properties of these viruses [ ] . furthermore, the presence of sars-cov- in cerebrospinal fluid (csf) of covid- patients is confirmed through genome sequencing [ ] ; however, experimental evidence is needed to validate virusmediated neurological damage. moreover, acute necrotizing hemorrhagic encephalopathy (ane) was observed in brain computed tomography and magnetic resonance imaging of a covid- patient [ ] . this rare complication is often associated with intracranial cytokine storms and points towards the indirect mode of sars-cov- influence on the brain [ ] . also, a detailed study of brain tissue distribution of angiotensin-converting enzyme- (ace- ), a potential receptor for sars-cov- entry [ ] , may shed light on potential sars-cov- -induced neurological alterations. elaborate ace- expression studies state that the receptor is preferentially expressed in the endothelium, vascular smooth muscle cells, and on the surface of a variety of the central nervous system (cns) and peripheral nervous system (pns) cells [ ] [ ] [ ] . additional plausible entry routes to the brain may include the hematogenic pathway, transmission through the vagus, the olfactory nerve, or the enteric neuron ( fig. a) [ ] . in brief, here we recapitulate varied aspects of covid- -related neurological manifestations. this article is part of the topical collection on clinical outcomes of virus-mediated brain dysfunction: more prevalent than acknowledged? the association of viruses with neural disorders is widely popular, although the relativity is still disputed. neurodegenerative diseases, affecting approximately million people worldwide, include degenerative ailments of the nervous system-the brain, spinal cord, and nerves [ ] . numerous genomic and proteomic studies unravel the similarities between virusmediated and classical neurodegeneration or neuropathies [ , ] . viruses introduce alterations in the functioning of neurons directly or indirectly. the neurotropic viruses afflict neurons through cell lysis, necrosis, or apoptosis [ ] . indirectly, the viruses damage the neurons by manipulating or attacking the host immune responses. in the cns, the virus can activate both the adaptive and innate immune responses [ ] . common pathways involved in the activation of the immune responses include the tlr mostly , , and mediated damage, the release of free radicals, and inflammation [ ] . although, not always does the cns immune response lead to detrimental outcomes as they usually assist in repair and regeneration [ ] . multiple studies mention the corroboration of infectious respiratory organisms as causative agents of various neurological diseases [ ] . respiratory syncytial virus (rsv) is known to infect the lower respiratory tract, cause infections in the immunocompromised patients, and target the cns [ ] . often the virus is detected in the csf samples of the patients exhibiting symptoms like seizures and convulsions, along with signs of ataxia, hormonal dysfunction, and encephalopathies [ ] . also, in vivo studies demonstrate the movement of the virus intranasally to the cns [ ] . another respiratory virus that affects the infants and has neurovirulent abilities is the human metapneumovirus (hmpv) [ ] . the virus is substantially detected in encephalopathic patients' csf samples, although studies demonstrating the virus' neuroinvasive properties are to be conducted [ ] . furthermore, hendra virus (hev) and nipah virus (niv) affect humans and cause lung damage, pneumonia, along with hemorrhagic and necrotizing alveolitis [ ] . typical signs of neurological disturbance, including convulsions, seizures with motor deficits, and febrile encephalitic syndrome, are observed due to infection caused by these zoonotic viruses [ ] . animal studies show the olfactory nerve to be the main route to the cns [ ] . also, the flu-causing influenza viruses account for numerous seasonal epidemics with a severe lethality rate, approximately a million cases per year [ ] . additionally, the viruses also affect the brain and are linked to encephalitis, febrile seizure, acute necrotizing encephalopathy, and syndromes like the reye syndrome and guillain-barré syndrome [ ] . according to some animal studies, the influenza virus can alter the brain homeostasis by traveling to the brain through the vagus nerve or the olfactory route [ , ] . intriguing, its association with parkinson's disease (pd) and multiple sclerosis (ms) is also mentioned [ ] . many encephalitis lethargica and postencephalitic parkinsonism cases followed by the "spanish" flu pandemic, caused by influenza a (h n ), make the involvement of the flu virus evident [ ] . viruses like the enteroviruses polioviruses (pv), coxsackieviruses (cv), echoviruses, and human rhinoviruses (hrv) are known to invade the cns [ ] . studies describe hrv-induced meningitis and cerebellitis [ ] . ev-a (hand-foot-mouth disease (hfmd)) and d outbreaks are associated with neurological complexities like myelitis (afm), meningitis, and encephalitis [ ] . the hcovs can aggravate various neuropathologies. hcovs are related to the neuroinvasive animal covs like porcine hemagglutinating encephalomyelitis virus, feline cov, and the mouse hepatitis virus, which is used to generate ms models [ , ] . furthermore, a study conducted to demonstrate the relation between the hcovs ( e and oc ) with ms and other neurological disorders involves identifying viral rna in human brain autopsies [ ] . importantly, cov-oc and cov- e are found in the csf of pd patients [ ] . however, detailed studies are needed to differentiate the mere presence and virus-associated disease alterations. in addition, association of sars-cov is not just limited to the virus in the bloodstream may infect the peripheral immune cells. these infected leukocytes may traverse the blood-brain barrier (bbb) composed of specialized tight junctions, endothelial cells, pericytes, and astrocytes. in addition, the virus may also cross the bbb which could be severed due to the action of the cytokines or may enter the cerebrospinal fluid (csf) by direct interaction with the brain microvascular endothelium cells. both the mechanisms result in alterations in the brain homeostasis and aggravate cytokine production within the cns (ii) several viruses like hsv and influenza viruses are known to infect the olfactory epithelial membrane. sars-cov- may also infect and damage olfactory sensory neurons (osns) in the epithelium lining. the damage may be direct or due to the production of cytokines produced by the accessory cells in the olfactory system. the virus may anterogradely reach the olfactory bulb through the cribriform plate. finally, the virus may potentially gain entry into the cns through the mitral cells along the olfactory tract. (iii) alpha herpesviruses (e.g. hsv- , prv) and polio virus (pv) along with rabies viruses (rv) may migrate to the cns through the peripheral nerves. (i) viruses may infect the mucosal epithelium following infection of the axonal termini of the peripheral nerves. the virus may spread to the spinal cord through retrograde axonal transport. (ii) viruses infect the smooth muscle cells and spread through the neuromuscular junctions (nmj) from muscles into the sensory/motor neurons of pns ganglia. (iv) the gastrointestinal epithelium expresses ace- receptors. therefore, the cells may be easily infected by the virus. the virus may directly invade the enteric nervous system or indirectly it may prime the immune cells which may result in delayed neurological impairment. b sars-cov- -mediated cytokine storm. after attachment and entry into the epithelial cells through ace- receptor, the virus may activate the pro-inflammatory pathway through tlr or nf-κb signaling followed by the formation of inflammasome. various pro-inflammatory cytokines and chemokines released due to this autonomous intrinsic defense mechanism include ccl- , ccl- , cxcl- , and il- . these proteins attract various immune cells in the circulation like the monocytes, macrophages, t cells, and neutrophils at the site of infection. additionally, the situation is worsened by production of tnf-β, il- , il- , il- , and il- by the t lymphocytes, which further accumulate the immune cells establishing a pro-inflammatory feed-back loop. these cytokines may damage the bbb and activate astrocytes and microglia, the cns resident immune cells. in response, the activated microglia and astrocytes produce il- β, il- , tnf-α, and il- . elevated levels of these inflammatory cytokines can impart neurotoxic effects leading to neuronal dysfunction and various cns disease-associated pathologies lungs; instead, it is known to infect many organs, including the cns [ , [ ] [ ] [ ] . the real-time quantitative pcr assay targeting the polymerase (orf ab) and nucleocapsid region of the sars-cov confirmed the presence of sars-cov in csf and serum of the infected patients [ , ] . a report suggests the association of status epilepticus with sars [ ] . hospitalized children with the acute encephalitis-like syndrome were positive for anti-sars-cov igm [ ] . sars-cov is associated with demyelinating pathology and found in the brain parenchyma of ms patients [ , ] . neurological symptoms are also associated with mers-cov [ ] . these examples impress on the connection of hcovs with neurological dysfunctions. therefore, the association of neurological complications with sars-cov- is not surprising. according to a case report of sars-cov- infection, virus rna was determined in the patient's csf; however, the nasopharyngeal swabs tested negative [ ] . currently, evidence to state the neuropathogenesis of the sars-cov- in covid- remains scarce. nevertheless, reports suggest that sars-cov- can cause meningitis and encephalitis [ ] . variable neurological symptoms are displayed by the covid- patients like pns symptoms, including hypogeusia, hyposmia, hypoplasia, and neuralgia vertigo, and cns dysfunctions like cephalgia, impaired consciousness, seizures, ataxia, and acute cerebrovascular disease, with headache and dizziness being the most common [ , ] . neurological manifestations are common in many covid- patients like anosmia, an early covid- symptom [ , [ ] [ ] [ ] . though seizures are seldom reported in covid- patients, and usually indicate an ischemic stroke, meningitis, or cerebral hypoxia, its association with comorbidities like hypocalcemia or drugs remains elusive [ ] . the neurological alterations caused by the virus may result from direct cns/pns attack or indirect influence on various organs that later affect the nervous system. for example, hypertension, common covid- comorbidity, results in blood-brain barrier (bbb) impairment and may enhance the risk of covid- -related cerebral complexities [ , ] . a hypothesis relates neuronal damage to the respiratory stress from deteriorated lung conditions [ ] . the oxygen deprivation may result in multiple organ failure and may affect the brain [ ] . besides, patients considered during the earlier studies of the sars-cov pandemic displayed axonal motor sensory neuropathy and myopathy [ ] . however, it remains unclear if the illness was virus-mediated or an outcome of high drug doses [ ] . nevertheless, the effect of the sars-cov- on pns is noteworthy as guillain-barre, miller-fisher syndrome, and polyneuritis cranialis are reported in covid- fig. (continued) [ ] [ ] [ ] [ ] [ ] [ ] . development of rhabdomyolysis, neuralgia, and myalgia in sars-cov- -infected patients further support the virus' ability to affect pns [ ] [ ] [ ] . a study reported elevated creatinine kinase and muscle pain in . % of patients with severe covid- [ ] . furthermore, some covid- patients with neurological symptoms might have a prior history of neurological complications or maybe treated for viral infections. hence, it is necessary to treat such cases using drugs with properties of high bioavailability in the brain. we have summarized information like the mode of action and brain or csf/plasma ratio of a few antivirals, which have shown promising outcomes in covid- treatment (table ) [ , ] . the use of efficient bbb penetrating drugs may be preferred during this pandemic to minimize the onset of neurological consequences of sars-cov- infection. indirectly the viruses may damage the neurons by manipulating or attacking the host immunity [ ] . in the cns, sars-cov- can activate both the adaptive and innate immunity [ ] . t helper cell (th )-mediated cytokine storm, evident in virus infections, is seen in covid- with neurological manifestations (fig. b) [ , ] . clinical studies report systemic inflammation involving enhanced cytokines, particularly il- β, il- , il- , granulocyte colony-stimulating factor, granulocyte-monocyte colony-stimulating factor, c-x-c motif chemokine ligand (cxcl ), mcp- , macrophage inflammatory proteins -α, and tumor necrosis factor α in covid- . additionally cd + and cd + t cell lymphopenia and decreased secretion of ifn-γ in severe cases of covid- are reported (fig. a) [ , , ] . intriguingly, a study suggests that an ms patient undergoing ocrelizumab (an immunosuppressive drug) therapy diagnosed positive for covid- does not display serious complications [ ] . the increased levels of cytokines may escalate vascular and bbb permeability and inflammation [ , ] . this information supports the hypothesis that increased bbb permeability allows virus entry into the cns, leading to covid- -related neurological complexities. some cytokines released in the circulation can cross the bbb and activate the resident brain immune cells like microglia and astrocytes to produce neural cytokines, further worsening the condition (fig. b) [ ] . astrocytes regulate a wide variety of functions, which may aggravate neuroinflammation. microglia mature into macrophages and may engulf the neighboring neurons on activation [ , ] . furthermore, microglia are the primary source of pro-inflammatory cytokines, nitric oxide, prostaglandin e , and reactive oxygen and nitrogen species [ ] . microglia express ace- , along with ace and at [ ] . these receptors play a significant role in microglia activation and balance the pro-inflammatory or antiinflammatory effects [ ] . more specifically, sars-cov- infection can hamper the ace- -mediated signaling, creating a glitch in the at receptor-mediated path, thereby inducing a pro-inflammatory response [ ] . in vivo studies suggest induction of pro-inflammatory cytokines in microglia and the mouse brain and spinal cord [ ] . the situation becomes dreadful when the pro-inflammatory substances produced by astrocytes and microglia fenestrate the bbb [ , ] . besides, sars-cov infects the myeloid cells and manipulates the innate immune system to ease its propagation to other tissues (fig. a) [ ] . these persistently infected leukocytes act as reservoirs of the neuroinvasive hcov and can be held responsible for long-term neurological sequelae [ ] . therefore, [ ] , pd [ ] *csf/serum ratio. hand hiv-associated neurocognitive disorders, pd parkinson's disease, rsv respiratory syncytial virus. the brain to plasma ratio or csf to plasma ratio has been denoted for each drug assuming that brain penetration is similar between rodents, non-human primates, and human patients the possibility of such cases of persistent sars-cov- infection may appear in the future. notably, peripheral inflammatory reactions observed in covid- may result in symptoms of neurological disorders [ ] . cytokine storms may influence the cns and enhance the severity of covid- patients to develop ane, meningitis, and hemorrhage [ , ] . therefore, it is necessary to identify the mechanism behind sars-cov- induced cytokine storms and the course of release of the cytokines during the infection. the contribution of the proinflammatory cytokines alone and the direct tissue damage caused by the virus needs to be addressed. the indirect influence of systemic inflammation on the cns by targeting the proinflammatory mediators will be worth investigating. it is found that ace- is expressed in various brain regions, like the subfornical organ, the nucleus of the tractus solitarius, and rostral ventrolateral medulla, as well as in non-cardiovascular areas such as the motor cortex and raphe [ ] . according to a spatial distribution analysis, ace- is expressed in substantia nigra and brain ventricles [ ] [ ] [ ] . the protein's cell type distribution revealed both excitatory and inhibitory neurons, pericytes and endothelial cells, and glial cells like astrocytes and oligodendrocytes in human middle temporal gyrus and posterior cingulate cortex express ace- , unlike the cells in the region of the prefrontal cortex [ ] . additionally, the hippocampus has few ace- expressing cells [ ] . studies report that angiotensin ii downregulates the expression of ace- in neonatal rat cerebellar or medullary astrocytes [ ] . therefore, the predominant expression of ace- in the brain hints towards the virus's potential to infect the cns. furthermore, brain endothelial and smooth muscle cells of the blood vessels express ace- [ ] . the virus may enter into the cns through the hematogenic pathway, subsequently crossing the bbb [ ] . a post-mortem study of the frontal lobe of a covid- patient reports virus presence in neurons and capillary endothelial cells [ ] . infection of endothelial cells may allow the virus to pass from the respiratory tract to the blood. the virus in the peripheral system can move into the cerebral circulation, where the blood's sluggish movement may facilitate the viral s protein interaction with the ace- expressed on the endothelial lining of the brain (fig. a) [ ] . another speculated entry route for sars-cov- may be through the enteric nervous system upon infection of enterocytes [ , ] . enterocytes express high magnitudes of ace- [ ] . once inside the brain, the virus can infect the neural cells, astrocytes, and microglia. these cells express ace- , thus initiating the viral budding cycle followed by neuronal damage and inflammation (fig. a) [ ] . moreover, multiple transcriptome studies show and validate ace- expression levels in various non-neuronal cells of olfactory mucosa [ ] . studies support the viral susceptibility of the mucosal cells, sustentacular cells, bowman's cells, and olfactory stem cells [ , ] . loss of smell in covid- is marked by potential deterioration of olfactory stem cells and other accessory cells [ ] . also, a high-throughput single-cell expression study mentioned no ace- expression in olfactory covering glia, microvillar cells, and immature or mature olfactory sensory neurons [ ] . it is speculated that sars-cov- on binding may stimulate olfactory receptor neurons (orns) to exert an exaggerated immune response. earlier studies with sars-cov have established infection of the brain through orns [ ] . studies describing the transneuronal/transsynaptic movement of the sars-cov already exist. rabies viruses can take over the vesicular axonal transport machinery to disseminate in the brain (fig. a) [ ] . human herpesvirus- (hhv- ) propagates in olfactory endothelial (oe) cells before invading the brain [ ] . these studies enable to predict and support the movement of sars-cov- through the vesicular axonal pathway in an anterograde fashion through the olfactory nerve and facilitate brain infection [ ] (fig. a) . also, the virus may directly reach the csf around the olfactory nerve fibers from oe cells [ ] . a probable trajectory of sars-cov- to the brain may be via high-ace- -expressing non-neuronal oe cells to low-ace- -expressing mature orns along the olfactory axons. this mechanism highlights the ace- independent process of virus spread. lastly, the expression of transmembrane serine protease (tmprss ) in human olfactory mucosa may further worsen the case of sars-cov- infection [ ] . a study demonstrates that respiratory epithelial cells express tmprss without ace- [ ] . the mosaic distribution of tmprss in mature orns is reported [ ] . therefore, the virus can preferentially gain entry into the pns through one of the two epithelial cell types in the nose, either the goblet cells or the ciliated cells. tmprss , in collaboration with furin, accelerates sars-cov- entry [ ] . furin, a host serine endoprotease, is particularly of neurological relevance. in general, furin can activate neuronal growth factors and influence cns homeostasis [ ] . however, upon attachment of sars-cov- with ace- , the enzyme generates an active s protein through irreversible cleavage of the precursor protein [ ] . the protein s /s subunits separate, which subsequently facilitate virus entry into the host [ ] . thus, exploring the possible avenues of sars-cov- entry and impact on cns is the need of the hour. various clinical reports have made the association of sars-cov- with neurological dysfunction prominent. covid- -associated neurological severity is primarily associated with cytokine storms. the earlier identified sars-cov is already known to suppress the host antiviral response and activate the pro-inflammatory pathways. briefly, it would be crucial to analyze the ifn-antagonizing and inflammasome-activating properties of sars-cov- . furthermore, the interaction of sars-cov- and ace- -expressing neuronal/glial cells may facilitate virus entry into the nervous system through different routes. thus, the nervous system's involvement in covid- may be more than the current situation apprehends, therefore referring to the virus as an underestimated pathogen. medical expert clinicians and researchers' collaboration may address the enhanced incidents of neural dysfunctions in infected individuals. after identifying initial neurological damages, careful monitoring of covid- patients in the long term is also necessary. acknowledgments we thank the ministry of human resource and development and department of biotechnology, govt. of india for fellowship to shweta jakhmola and omkar indari, respectively, in the form of a research stipend. we appreciate our lab colleagues for insightful discussions and advice. we gratefully acknowledge the indian institute of technology indore for providing facilities and support. authors' contributions conceptualization, data curation, formal analysis, investigation: sj, oi, sc. methodology, project administration, resources, 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sha: doc_id: cord_uid: us do c coronavirus disease (covid- ) not only causes pulmonary inflammation but also causes multiple organ damages, including the kidney. ace , as one of the receptors for sars-cov- intrusion, is widely distributed in kidney tissues. currently, the diagnosis and treatment of sars-cov- infection in patients with chronic kidney disease (ckd) are still unclear. here, we review the recent findings of characteristics of covid- in ckd patients and highlight the possible mechanisms of kidney injury caused by sars-cov- infection. we then discuss the emerging therapeutic approaches aimed at reducing kidney damage and protecting kidney function including virus removal, immunotherapy, supporting treatment, special blood purification therapy, etc. problems unresolved and challenges ahead are also discussed. coronavirus disease (covid- ) is the first confirmed pandemic sparked by a coronavirus in the twenty-first century. as covid- continues to spread globally, inevitably, it may trigger new challenges and issue to patients with confounding chronic diseases. many studies have confirmed that comorbidities are important risk factors for the severity and outcome of sars-cov- infection [ ] . chronic kidney disease (ckd) [ ] is not uncommon and represents one of the chronic diseases witnessed during covid- ranging from . to . % so far reported [ ] . in this article, we reviewed the impact of sars-cov- infection in disease progression and outcome in ckd patients and relevant interests or topics. it was reported that - % of hospitalized patients have one or more comorbidities. the most prevailing ones are diabetes mellitus ( . - %), hypertension ( . - . %), and other cardiovascular and cerebrovascular diseases ( . - %) [ , [ ] [ ] [ ] [ ] . the prevalence of ckd was - . %, which represents a minor proportion in covid- patients [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] (table ) . a national wide analysis demonstrated that . % ( / ) of covid- -infected patients may be confounded by at least one comorbidity, which significantly differed from patients without any, in risk of worse clinical outcomes. the hazard ratio (hr) among patients with two or more comorbidities was greater than those with one comorbidity [ . ( % ci . - . ) vs. . ( % ci . - . )] [ ] . concordantly, previous studies also demonstrated that the number of comorbidities was correlated with severity and accumulative clinical outcomes [ ] . although the primarily targeted organs of covid- include but not limited to the respiratory, immune, and coagulation systems, ckd may represent an additional risk factor for augmented impairment of these systems. the reported morbidity of ckd in severe covid- patients is even higher than non-severe patients ( . - . % vs. - . %) [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] (table ) , consistent with observed higher incidence in patients admitted to the intensive care unit (icu) comparing with non-icu patients ( / ( . %) vs. / ( . %) [ ] . a meta-analysis including covid- patients showed the yongqian cheng and wenling wang contributed equally to this work. this article is part of the topical collection on covid- table prevalence of number of main comorbidities in covid- some studies about renal function in covid- patients have shown common manifestations of kidney dysfunctions and incidental acute kidney injury [ , ] . clinically, the incidence of acute kidney injury in covid- varied from to % in different centers [ , ] . there were %, %, %, and % patients who had features of proteinuria, hematuria, and elevated blood urea nitrogen or serum creatinine, respectively. according to the recent studies, - . % of covid- patients were found with increased creatinine or urea nitrogen, . - % patients exhibited proteinuria, and . - % patients had hematuria [ ] [ ] [ ] (table ). in total, . % ( / ) patients for first time concurred with aki after infecting sars-cov- [ ] . over % of patients infected with sars-cov- had prior evidence of kidney diseases, and the presence of kidney diseases was associated with increased risk of mortality during hospitalization [ ] . risk of mortality in covid- patients with aki was . folders of that without aki. the comorbidities of aki were . % in non-survivors [ ] . the incidence of aki was % in severe patients [ ] , and it was higher in patients with elevated baseline serum creatinine compared with normal baseline serum creatinine ( . % vs. . %) ckd [ ] . it is worth notification that patients under sars-cov- infection, especially severe one, have varied degrees of kidney injury. in ckd patients, the renal impairment was further aggravated, and aki surged significantly higher than those without ckd. controversial results also exist like another study [ ] indicating that sars-cov- infection was not found significantly correlated with incremental acute renal injury or aggravate chronic kidney failure in the covid- patients. in that study, . % of patients showed mild elevation of blood urea nitrogen or creatinine, while . % with trace amount or + albuminuria. in the current study, kidney injury in patients with covid- is mainly evaluated based on serum creatinine elevation. so far, limited studies were available in prospective design by incorporating more sensitive surrogate markers of early-onset kidney injury, such as urinary β- microglobulin, microalbumin, nagl, etc. furthermore, it is also critical to understand prognosis of covid- patients with kidney injury or even aki, especially in those with predisposed ckd. in order to evaluate the risk of serious adverse outcomes in covid- patients according to the number and type of comorbidities, guan et al. [ ] have analyzed laboratoryconfirmed hospitalized patients in province/autonomous regions/provincial municipalities from mainland china. . % ( / ) was reported to have at least one comorbidity. . % ( / ) of patients reached the composite endpoints, which consisted of admission to intensive care unit, or invasive ventilation, or death, and . % ( / ) had two or more comorbidities. the hr was . ( % ci . - . ) vs. . ( % ci . - . ) among patients with at least one comorbidity or two or more comorbidities. the prevalence of ckd was . % ( / ). it is the lowest one compared with hypertension ( ; . %), diabetes ( ; . %), other cardiovascular diseases ( ; . %), cerebrovascular diseases ( ; . %), hepatitis b infections ( ; . %), or chronic obstructive pulmonary disease (copd) ( ; . %). intriguingly, significantly more patients with ckd ( . % vs. . %) reached the composite endpoints compared with those without, which ranked behind copd ( . % vs. . %), malignancy ( . % vs. . %), and cerebrovascular diseases ( . % vs. . %), albeit higher than diabetes ( . % vs. . %), cardiovascular diseases ( . % vs. . %), and hypertension ( . % vs. . %). it is herein postulated that covid- patients with underlying ckd are at higher risk of progression to severe conditions. lab test findings in the ckd patients with covid- infection showed that the leukocyte count in patients with elevated baseline serum creatinine was . ± . × /l, which was significantly higher than those with normal baseline serum creatine ( . ± . × /l). while the lymphocyte count and platelet count in the patients with elevated baseline serum creatinine was significantly lower than those in the patients with normal serum creatinine ( . ± . × /l vs. . ± . × /l, ± × /l vs. ± × /l) [ ] . radiologic finding on chest computed tomography (ct) showed that . % patients with covid- revealed abnormal results. the most common patterns on chest ct were groundglass opacity ( . %) and bilateral patchy shadowing ( . %) [ ] . in covid- patients with ckd, abnormal chest x-ray and chest ct were showed in . % and . % patients, respectively, while in non-ckd covid- patients, it was . % and . %, respectively, ct [ ] . in hd patients with covid- , % of patients showed unilateral infiltrates, % showed bilateral infiltrates, and % had multiple ground-glass opacity lesions [ ] , while in kidney transplant patients with covid- , % patients showed infiltrate chest x-ray at hospital admission. chest radiographs were repeated in / patients, and radiological findings worsened in % / patients [ ] . a recent study by li et al. showed that the median kidney ct value of patients with covid- was . hu which was significantly lower than the healthy control group who had no kidney diseases (n = , . hu) and the patients with other pneumonia (n = , . hu). it indicated that inflammation and edema of the renal parenchyma may commonly occur in covid- patients [ ] . unfortunately, there was no statistical comparison data about the imaging of the lungs or kidneys in patients with ckd or not. hemodialysis [ ] patients are another special population in ckd. in the study conducted by ma et al. [ ] , there were ( . %) hd patients diagnosed positive for covid- with among them perished. in that study, the clinical symptoms such as fever, fatigue, cough, chest pain, and nausea were not prominent in hd patients with covid- . compared with non-hd patients with covid- , the proportion of t cell counting and plasma cytokines such as il- , il- , il- , tnf-α, and inf-γ was lower in hd patients infected by sars-cov- . a case report by tang et al. [ ] also mentioned profile of one hd patient infected with sars-cov- . this patient displayed a relatively mild course despite multiple comorbid conditions including hbv infection and diabetes. wang et al. reported that up to the end of their study, none of the hd patients with covid- infection had developed acute respiratory distress syndrome, shock, or other serious complications [ ] . from evidence aforementioned, it could be stipulated that hd patients may be vulnerable to sars-cov- due to their impaired immune system, but in parallel, they may not suffer from the worst condition due to less triggered immune responsemediated pathogenesis as symbolized by low cytokines in plasma. more studies are warranted to investigate and provide solid evidences. kidney transplant recipients are being treated with long-term immunosuppression agents. the outcome of sars-cov- infection in these patients remains unclear. banerjee et al. [ ] reported on seven cases of covid- in kidney transplant recipients, all displayed respiratory symptoms and fever. dosage of immunosuppressant was modified in six of seven patients. four was transferred to the icu, and one patient died after days from symptom onset. in another recent study with kidney transplant recipients, sars-cov- -induced pneumonia was characterized by high risk of deterioration and significant mortality [ ] . in this study, twenty kidney transplant recipients with median post-transplant years were enrolled. all had immunosuppressant discontinued and were started on methylprednisolone. they experienced a rapid clinical deterioration and escalating oxygen requirement. six patients developed aki with one requiring hd, and among them five patients died after a median period of days from symptom onset. therefore, sars-cov- infection in kidney transplant patients from this study showed that such cases may be severe enough requiring intensive care admission and these patients are in high risk of disease progression and death. remains elusive. however, it has been revealed that there required one synergistic action of s protein binding to receptors on the cell surface and a series of proteolysis when virus attached to the cell surface. researchers have found that at least three proteins are indispensably required in this process, including ace , type ii transmembrane serine proteases (tmprss ), and an enzyme called furin. surprisingly, these molecules were found to be abundant in kidney tissue which indicates that kidney tissue might be target cells invaded by sars-cov- . angiotensin-converting enzyme ace belongs to the angiotensin-converting enzyme family of dipeptidyl carboxydipeptidases and is homologous to human angiotensin- -converting enzyme. it had been illustrated that ace was one of the major receptors which mediated the entry of sars-cov- into human cells. a study by fan and colleagues [ ] showed that ace mrna level and ace protein are both higher in kidney cells. the expression distribution of ace suggests that a potential mechanism of infection and direct damage of kidney may be caused by sars-cov- binding to ace . another study based on single-cell analysis by lin and colleagues [ ] also found that ace was enriched in proximal tubular cells which may indicate that the kidney is more susceptible to sars-cov- infection. previous studies have confirmed that ace exists in a variety of renal tissue cells. the expression of ace was strongly positive in the apical border of the proximal tubular cells whereas less present in cytoplasm. glomerular visceral was weak ace staining, and the mesangium and glomerular endothelium were negative [ ] . recently, caibin fan et al. searched literatures and analyzed the online datasets showing that the expression level of ace protein is significantly higher in the kidney, especially in renal tubular cells [ ] . it could be speculated that sars-cov- may directly impair the kidney via proximal renal tubular injury. previous study identified that a peculiar "rrar motif" in sars-cov- is a furin recognition site eligible to be activated by an enzyme called furin [ ] . presence of the motif containing this cleavage site between s /s proteins is one of the most critical differences between sars-cov and sars-cov- [ ] . furin is one of the proprotein convertases that can cleave viral envelope glycoproteins specifically, thereby enhancing viral fusion into host cell membranes. furin had high expression level in the salivary gland, lachrymal gland, colon, liver, and also kidney [ ] . heretofore, sars-cov- might utilize this specific feature by increasing furin-mediated cleavage site to become more infectious in the kidney and increased kidney injury. the sars-cov- gains entry to a cell by binding of the spike (s) proteins to ace and s protein priming by host cell proteases. a study by hoffmann and colleagues [ ] demonstrated that the ace receptor was the cellular receptor of sars-cov- and tmprss was cell proteases priming of s protein, and ace and tmprss are both the key point to sars-cov- infecting human cells. ace receptor and tmprss both exist in the kidney [ , ] . that means that the virus has the potential to attack the kidney by this way. therefore, a tmprss inhibitor might be useful for antiviral intervention including protecting kidney. it was reported that nucleocapsid protein of sars-cov- was detected in urine in . % of diagnosed covid- patients [ ] , and sars-cov immunohistochemistry results showed that sars-cov- np expression was typically restricted to kidney tubular cells. recently, hua su et al. [ ] reported their renal histopathological findings of postmortem covid- patients. diffuse proximal tubular injury with disarrangement of brush border was observed under light contrast microscope. clusters of coronavirus particles with distinctive spikes were detectable under electron microscopic examination in the tubular epithelium and podocytes. single-cell rna sequencing technology provided the cellular evidence that sars-cov- invaded human kidney tissue via proximal convoluted tubule, proximal tubule, proximal straight tubule cells, and glomerular parietal cells by means of ace -related pathway and used their cellular protease tmprss for priming [ ] . these findings demonstrated direct evidence of the invasion of sars-cov- into kidney tissue. it was also confirmed that the renal target cells attacked by the sars-cov- are proximal renal tubular cells, which is consistent with the distribution of ace in renal tissue [ ] . they also found an upregulation of ace expression on the surface of renal tubular cells. cytokine storm is also an important factor leading to multiple organ damage in covid- patients. high levels of proinflammatory cytokines may lead to shock and tissue damage in the heart, liver, and kidney, as well as respiratory failure or multiple organ failure [ ] . both icu patients and non-icu patients had a higher level of il b, il ra, il , il , il , il , fgf, gcsf, gmcsf, ifnγ, ip , mcp , mip a, mip b, pdgf, tnfα, and vegf than healthy adults [ ] . compared with non-icu patients, icu patients had an even higher level of il , il , il , gcsf, ip , mcp , mip a, and tnfα. most patients with severe covid- exhibited significantly elevated levels of serum proinflammatory cytokines, including il- and il- β as well as il- , il- , il- , g-csf, gm-csf, ip , mcp , mip -α (also known as ccl ), and tnf. in addition, c-reactive protein and ddimer were found to be abnormally high. acute kidney injury occurred in % of icu patients, while in non-icu patients, acute kidney injury seldom occurs [ ] . that indicated that kidney injury might be associated with cytokine storm and further studies are needed to investigate the association between inflammatory storm and kidney injury. in addition to the direct virulence of sars-cov- and cytokine storm, there are potentially other factors attributing to acute kidney injury, such as systematic hypoxia, abnormal coagulation, and possible drug-related or hyperventilationrelevant rhabdomyolysis. all these factors may lead to further impairment of renal function in ckd patients (figs. and ) . it was believed that not only the virus but also the overactive immune response made people severely ill or cause death. therefore, the treatment target is antiviral and immunosuppressive. unfortunately, there are no approved specific antiviral agents targeting the sars-cov- , although there are some promising antiviral drugs in clinical trials, including remdesivir, lopinavir/ritonavir, chloroquine, and hydroxychloroquine. there are also many therapeutic methods in the field of immune regulation for severe covid- patients, including tocilizumab, convalescent plasma (cp) and stem cell therapy, etc., but only glucocorticoid is considered in clinical practice for patients who manifested as progressive worsening or severe condition. in addition, the blood purification system is one of the important life support systems for the treatment of critically ill patients and helps to remove proteins that are typically elevated during infections, which associated with a "cytokine storm" that occurs in some covid- patients, leading to severe inflammation, rapidly progressive shock, respiratory failure, organ failure, and death. as aforementioned, covid- patients with ckd have higher risk of progression to critical illness or aki. moreover, critical condition or aki may further aggravate the renal damage to an irreversible stage. therefore, more attention should be paid to protection of renal function in the treatment of these patients to minimize drugs that may cause renal injury, such as antibiotics, contrast agents, hes, etc. if necessary, renal replacement therapy (rrt) should be initiated in a timely manner, particularly for those with strong inflammatory storm. angiotensin-converting enzyme inhibitors (aceis) and angiotensin receptor blockers (arbs) are highly recommended medications for ckd patients especially with cardiovascular disease, hypertension, or diabetes. ace served as not only the receptor for sars-cov- but also a key element in the protective arm of the renin-angiotensin system (ras) [ ] . ras plays an important role in the pathophysiology of hypertension and cardiovascular and renal diseases [ ] . recently, a hypothesis suggested that patients taking aceis/arbs may be at increased risk of severe disease outcomes during sars-cov- infection. ace has also been suggested as a potential therapeutic target for sars-cov- [ ] . to date, there is no high-quality evidence to support covid- patients to adjust or discontinue aceis/arbs treatment with exception for some special cases which concurred with complications including hyperkalemia, aki, or hypotension. therefore, many medical academic societies, including the european society of hypertension, international society of hypertension, and european society of cardiology [ ] [ ] [ ] , recommend continuing aceis/arbs due to lack of evidence that taking aceis/ arbs drugs might increase susceptibility to sars-cov- infection nor is there sufficient evidence showing that aceis/arbs may play a protective role in the treatment of covid- . while three studies recently reported the association between the use of aceis/arbs and the risk of covid- or in-hospital death [ ] [ ] [ ] , mancia et al. [ ] reported on a total of cases of patients infected with sars-cov- matched to , controls according to sex, age, and municipality of residence, and the use of aceis/arbs did not show any association with covid- . the adjusted or was . ( % ci . - . ) for aceis and . ( % ci . - . ) for arbs. another study by reynolds et al. [ ] also showed this association. in their study, in , patients who were tested for covid- , a total of ( . %) were positive, and ( . %) had severe illness, while neither aceis nor arbs increased in the likelihood of a positive test for covid- or in the risk of severe covid- among patients who tested positive. an observational study by mehra et al. [ ] on patients with covid- from hospitals in asia, europe, and north america showed that coronary artery disease [ . % vs. . % among those without disease; or . ( % ci . - . )] was independently associated with an increased risk of in-hospital death, while no increased risk of in-hospital death was found to be associated with the use of aceis [ . % vs. . %; or . ( % ci . - . )] or the use of arbs [ . % vs. . %; or . ( % ci . - . )]. the exact prevalence of ckd in covid- patients the proportion of patients with covid- combined with ckd is relatively lower ( - . %) [ , , , [ ] [ ] [ ] [ ] . but the diagnosis of comorbidities mostly depends on self-report on admission with insufficient diagnostic testing which undermined the validity and accuracy [ ] . for hypertension and diabetes, they are common comorbidities of covid- , and both diabetes and hypertension are high risk factors for [ ] . ace is mainly distributed in the glomerular visceral and parietal epithelium, in the brush border and cytoplasm of proximal tubular cells, and in the cytoplasm of distal tubules and collecting ducts [ ] . decreased pressure of the glomerular artery and direct viral damage may be associated with glomerular lesions. the main pathological findings were fibrin thrombi and ischemic glomerular contraction [ ] . b schematic diagram of pathological damage of proximal convoluted tubules and peritubular capillaries of the kidney. inflammatory cell infiltration, release of inflammatory cytokines, chemokine, and others caused renal tubular injury. erythrocyte aggregates obstructed peritubular capillaries, and debris comprised of necrotic epithelium accumulated in tubular lumens [ ] . c sars-cov- invades renal tubule-associated molecules. schematic diagram of proteins associated with sars-cov- invasion into proximal tubule cell ckd. therefore, more relevant diagnostic testing is needed to elucidate the exact prevalence of ckd in covid- patients, so as necessary renal function protection measures for potential ckd patients could be implemented. angiotensin-converting enzyme (ace ) is a key element in the protective arm of the renin-angiotensin system [ ] , and it also acts as a receptor for sars-cov- . there are circulatory and local ras systems. moreover, there was no significant correlation between local renal ras system and circulating ras system. the circulating ras system is based on angiotensinogen (agt), which is mainly synthesized in the liver. there is another independent ras system in the kidney that can self-sufficiently fulfill the biosynthetic process. agt in the kidney mainly originates from proximal renal tubules [ ] [ ] [ ] . in kidney tissues, sars-cov- infection was confirmed by immunofluorescence staining and transmission electron microscopy observations at autopsy in severe covid- patients. sars-cov- mainly distributes in proximal tubular epithelium and podocytes which triggered some interesting questions: does the use of aceis/arbs lead to increased ace expression and subsequently enhance viral entry? does the interaction between viral s protein and ace has an impact on the systematic or renal local ras system? if yes, does the treatment of ckd patients need to be adjusted? liu et al. reported that ang ii levels were higher in patients with covid- compared with healthy controls, and it is correlated with lung injury (pao /fio ). this was a small sample size study (including patients), and unfortunately the authors did not mention way of blood sample collection and processing methods which could be critical in measuring the components of the ras [ ] . further studies are still warranted for comprehensive understanding of the relationship between sars-cov- and ras systems. ckd is one of the major public health problems worldwide with a high prevalence and incidence in general population. hd patients need rrt in hospital. social distancing and restrictions during the outbreak may substantially interfere the regular treatment of these patients. monitoring of plasma concentration of immunosuppressive drugs may be inconvenient for renal transplant patients. zhang et al. [ ] reported that during the covid- outbreak period, many problems in the management of chinese children with ckd have been disclosed. in their study, they suggested that three-algorithm diagnosis and treatment system and "internet + ckd health management" are desired for children with chronic diseases such as ckd, while the circumstances in adult ckd patients are also needed to explore. kidney injury was associated with higher mortality rates in covid- patients and was an emerging concern to the clinicians [ ] , while the long-term prognosis of covid- patients with renal injury is unknown. it was reported [ ] that most covid- patients with aki will recover if their serum creatinine level is normal at admission. pei et al. reported / ( . %) patients who had abnormal urine dipstick tests or aki. patients with renal involvement had higher overall mortality compared with those without renal involvement [ / ( . %) versus / ( . %)]. the severity of pneumonia was the risk factor most commonly associated with lower odds of proteinuric or hematuric remission and recovery from aki in stepwise multivariate binary logistic regression analyses [ ] . we suggested that covid- patients with renal injury during hospitalization should be regularly tested for routine urine and renal function after discharge in order to monitor patients for the development or progression of ckd after aki [ ] . if conditions permit, more sensitive indicators of renal injury such as urinary microalbumin, β- microglobulin, kim- , ngal, timp- *igfbp , and serum cysteine c should be tested. if the above indicators persist, abnormal or serum creatinine does not return to baseline levels, and consideration should be given to possible progression to ckd. if necessary, renal biopsy should be performed in time to make a definite diagnosis. author's contributions gyc designed the study. yqc, wlw, and lw did the literature search. yqc and wlw wrote the original draft. gyc reviewed and edited it. yqc and wlw contributed equally to this work. funding this study was supported by the national key technology r&d program ( yfa ) and the science and technology project of beijing (d ). conflict of interest the authors declare that they have no conflict of interest. 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 holder. to view a copy of this licence, visit http://creativecommons.org/licenses/by/ . /. comorbidity and its impact on patients with covid- in china: a nationwide analysis management of coronary disease in patients with advanced kidney disease global, regional, and national burden of chronic kidney disease, - : a systematic analysis for the global burden of disease study 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 clinical characteristics of novel coronavirus cases in tertiary hospitals in hubei province clinical characteristics of coronavirus disease in china clinical characteristics of patients infected with sars-cov- in wuhan early antiviral treatment contributes to alleviate the severity and improve the prognosis of 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loads and lung injury the impact of the covid- outbreak on the medical treatment of chinese children with chronic kidney disease (ckd) a multicenter cross-section study in the context of a public health emergency of international concern kidney injury in covid- : an emerging concern to the clinician renal involvement and early prognosis in patients with covid- pneumonia covid- and acute kidney injury in hospital: summary of nice guidelines publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- - w b authors: ruan, pei-sen; xu, hui-qing; wu, jun-hua; song, qi-fa; qiu, hai-yan title: covid- in children: clinical characteristics and follow-up study date: - - journal: sn compr clin med doi: . /s - - -x sha: doc_id: cord_uid: w b since december , the coronavirus disease (covid- ) has spread globally. but the clinical symptoms and detailed follow-up of children with covid- infection are lacking. here, we conducted a retrospective study including children with confirmed covid- . we recorded patients’ epidemiological, clinical features, and follow-up data after discharging in order to improve the awareness and treatment of children with covid- . since december , multiple patients of pneumonia infected with the emergence of severe acute respiratory syndrome coronavirus disease (covid- ) had been detected in wuhan city, china [ ] . with the spreading of the epidemic, other more patients had also founded in china and other countries [ ] . at present, pediatric patients have been reported all over the world, mainly asymptomatic and mild infections. with the progress of the epidemic and the innovation of detection technology, it was not ruled out that pediatric patients were particularly severe, and the number of critically infected children had increased and died. as children were also susceptible to covid- infection and they need more attention. so, analysis of the clinical characteristics, epidemiological characteristics, and follow-up results after discharge of pediatric patients with confirmed covid- in this area was aimed at improving the awareness and treatment of children with covid- . we retrospectively analyzed children with covid- admitted to ningbo women and children's hospital after diagnosed on feb , , to april , . diagnosis and discharge standards were performed according to the content of the "diagnosis and treatment guidelines for novel coronavirus pneumonia (trial version ) (in chinese) [ ] ." we observed and recorded the patient's epidemiological characteristics, clinical manifestations, laboratory tests, radiography, treatment methods, and transfer return. from the beginning of hospitalization to weeks after discharge, we performed a dynamic tracking including laboratory tests, radiographic inspection, and sars-cov- rt-pct in nasopharyngeal and feces swabs. we tested the sars-cov- of feces swabs and nasopharyngeal swabs every days throughout the process. we conducted a blood laboratory and radiographic times (on the day of discharge, weeks after discharge, and weeks after discharge). between feb , , and april , , pediatric patients with covid- were reported in ningbo in china (aged - months; mean age . [sd . ] months). two ( %) of patients were female. the household registration of patients was in zhejiang province, and the other were in hubei province. all patients had no underlying disease. we found that patients were all family cluster infection ( %), and there were to confirmed infections in the family. all of the patients contacted with adult patients with novel coronavirus pneumonia (ncp). one patient had the symptoms of nasal congestion and runny nose ( %), which resolved after days. cov- detoxification time in nasopharyngeal swab was (sd . ) days. we found patients with nasopharyngeal swabs turned negative, but sars-cov- could still be detected in the feces swabs during the same period. we also found all patients underwent multiple lung radiation without significant changes. we traced treatments and primary manifestations to assess disease progression and outcome, and varieties of treatments were given such as bed rest, ensuring calorie intake, monitoring vital signs, interferon atomization inhalation, and bifidobacterium triple live bacteria powder. the mean time in hospital was (sd . ) days. by feb , , all patients were cured and quarantined for a further weeks. follow-up was continuing every days after discharging to weeks ( table ) . we found that the gastrointestinal detoxification time was mean (sd . ) days, and the younger pediatric patient had decreased the time of gastrointestinal detoxification (p = . ). we did not find respiratory and digestive symptoms, and no abnormalities in blood laboratory and radiographic in pediatric patients. we also did not find positive rt-pcr test results in recovering covid- pediatric patients. researchers had predicted that the r values of the epidemic were . [ ] , which suggested that the epidemic had a strong ability to spread from person to person. there were fewer cases of covid- infection in children than in adults, and it was more common in children with asymptomatic infection and mild and common infection, and the clinical symptoms were usually mild [ ] . familial clustering was the main way for children to be infected with covid- [ ] . early laboratory tests and radiation tests could be atypical, and fecal sars-cov- measurements suggested that children in the recovery period still had the risk of being infected by excretion of the virus through fecal-oral transmission [ ] . this means that virus-containing feces might be spread further by polluting the environment. therefore, asking in detail epidemiological history was very important. many researchers had reported that varieties of cases of recovered covid- pediatric patients had positive rt-pcr test again. this might be due to biological characteristics of sars-cov- (a recombinant viruses) and might also be related to the basic disease, weak immune function, glucocorticoid using, processing and detecting of patients, and some even related to sars-cov- mutations [ ] . at present, because the understanding of covid- infection was limited to us, further research was needed to strengthen the early identification and early diagnosis of covid- infection in children, especially in children with ncp and critically ill children with ncp. severe acute respiratory syndrome coronavirus (sars-cov- ) and coronavirus disease- (covid- ): the epidemic and the challenges potential for global spread of a novel coronavirus from china national health and health commission of the people's republic of china. diagnosis and treatment guidelines for novel coronavirus pneumonia (draft version ) estimation of the transmission risk of the -ncov and its implication for public health interventions clinical and epidemiological features of children with coronavirus disease (covid- ) in zhejiang, china: an observational cohort study a familial cluster of pneumonia associated with the novel coronavirus indicating person-to-person transmission: a study of a family cluster persistence and clearance of viral rna in novel coronavirus disease rehabilitation patients cause analysis and treatment strategies of "recurrence" with novel coronavirus pneumonia (covid- ) patients after discharge from hospital publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations acknowledgments we would like to acknowledge all of our colleagues of the ningbo women and children's hospital. ethical approval the study was approved by the institutional helsinki committee, which waived the requirement to obtain written consent from the parents of studied patients.informed consent informed consent was obtained from the patient's parents for publication of this report. authors' contributions hq designed the study and did the literature search. jw and hx were responsible for disease diagnosis and treatment and data collection. qs collected and analyzed the data. pr analyzed the data and wrote the report.funding this study was funded by ningbo clinical research center for children's health and diseases, project of ningbo reproductive medicine center (ppxk - ). key: cord- - lml t authors: karia, rutu; gupta, ishita; khandait, harshwardhan; yadav, ashima; yadav, anmol title: covid- and its modes of transmission date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: lml t the world health organization recognized sars-cov- as a public health concern and declared it as a pandemic on march , . over million people have been affected across several countries since it was first recognized. sars-cov- is thought to commonly spread via respiratory droplets formed while talking, coughing, and sneezing of an infected patient. as several cases, with an absence of travel history to the majorly affected areas were identified, a strong possibility of community transmission could have been possible. broadly, two modes of transmission of covid- exist—direct and indirect. the direct mode includes ( ) transmission via aerosols formed via surgical and dental procedures and/or in the form of respiratory droplet nuclei; ( ) other body fluids and secretions, for example, feces, saliva, urine, semen, and tears; and ( ) mother-to-child. indirect transmission may occur via ( ) fomites or surfaces (e.g., furniture and fixtures) present within the immediate environment of an infected patient and ( ) objects used on the infected person (e.g., stethoscope or thermometer). as many of these modes may be underestimated, it is necessary to emphasize and illustrate them. the goal of this paper is to briefly review how sars-cov- is shown to transmit via various modes and propose measures to reduce the risk of spread within the population and operating personnel. coronavirus disease- (covid- ) , caused by severe acute respiratory distress syndrome-coronavirus- (sars-cov- ), was initially reported in december as pneumonia with unknown etiology in wuhan city of china. the world health organization recognized sars-cov- as a public health concern and declared it as a pandemic on march , . over million people have been affected across several countries since it was first recognized [ ] . the disease, unless combined with other comorbidities or other preexisting diseases, is usually mild. approximately % of cases require acute medical aid [ ] . broadly, two modes of transmission of covid- exist-direct and indirect [ ] . the direct mode includes ( ) transmission via aerosols formed via surgical and dental procedures and/or in the form of respiratory droplet nuclei; ( ) other body fluids and secretions, for example, feces, saliva, urine, semen, and tears; and ( ) mother-to-child. sars-cov- is thought to commonly spread via respiratory droplets formed while talking, coughing, and sneezing of an infected person. the exposure and, hence, risk of transmission are increased if the infected person is present within -m length of susceptible host. less number of infected patients has shown to shed virus from sources other than the respiratory tract. though not high, the risk of transmission this article is part of the topical collection on covid- through modes other than respiratory tract can still be possible. indirect transmission may occur via ( ) fomites or surfaces (e.g., furniture and fixtures) present within the immediate environment of an infected patient and ( ) objects used on the infected person (e.g., stethoscope or thermometer) [ , ] . several of these modes may be underestimated and cause increased spread of virus. the goal of this paper is to briefly review how sars-cov- is shown to transmit via various modes and propose measures to reduce the risk of spread within the population and operating personnel. an electronic search was conducted in the months of may and june for manuscripts on possible modes of transmission of sars-cov- . primary databases that were used for the search are who, pubmed, and google scholar. the search strategy used the keywords modes, transmission, spread, coronavirus, covid- , and their combination. the final review articles fulfilled the following criteria: . reported modes of transmission in the laboratory-proven covid- patients . included patient data regardless of age, gender, or location . full text, peer-reviewed articles . articles in english articles that did not contain patient data or studies pertaining to sars-cov- and mers were excluded. each paper was reviewed by two reviewers independently, and disagreements were discussed and resolved via a consensus. data was collected in the following categories when available: we tabulated the data using microsoft excel. referencing was done according to guidelines using endnote. this study did not require ethical approval as data was obtained from already available databases, and patients were not directly involved. the outbreak of sars-cov- occurred in wuhan, china, and soon a large number of residents and the tourists visiting the city contracted the virus. however, overtime several cases with an absence of travel history to the majorly affected areas were identified, hence, raising a strong possibility of community transmission and necessitating the need to explore various ways by which the virus may be transmitted. interestingly, a number of modes were identified other than respiratory tract secretions (fig. ) . airborne transmission via aerosols formation is suspected to be the main mode of transmission. aerosols are particles under μm in diameter [ ] . thus, their minute size and suspension in the air may ease direct contraction of the virus. aerosols may be formed during various surgical and dental procedures or may be formed as droplet nuclei while talking, coughing, and sneezing by an infected patient. in a study by li et al., eight healthcare staff and five postoperational patients tested positive for covid- after being in close contact with an infected patient. this suggests that droplet formation serves as a potent mode for human-to-human transmission [ ] . in the same study, li et al. also suggested that cough training (respiratory exercise), which is done postoperatively, produces a large number of droplets and aerosols in the surrounding space. this increases the amount of exposure and, thus, the risk of virus transmission [ ] . dentists are at a higher risk of exposure as dental patients are required to spit or gargle after oral procedures like extraction, drilling, and drainage of dental abscess. thus, these aerosol-producing procedures must be performed using appropriate protective equipment. ong et al. studied several samples taken from the furniture and fixtures from an infected patient's room (before routine cleaning of the room) [ ] . interestingly, all the samples returned positive for the virus. work by doremalen et al. demonstrated that aerosolized sars-cov- remains viable in the aerosols for h and on different surfaces for - h [ ] . thus, virus may be transmitted to those touching the contaminated surfaces (fomites). fomites may be regarded as an indirect way of human-to-human transmission. measures including strict precautions and adequate protective devices and infection control training should be implemented for all hospital workers for such circumstances. gastrointestinal tract may be regarded as another potent mode of transmission. huang et al. reported a covid- positive family cluster, wherein anal swabs taken from both the cases were persistently positive sars-cov- [ ] . xing et al. studied patients for persistent fecal shedding of virus in stools. they found that viral shedding in the stools occurred despite resolution of the symptoms and radiological findings, while samples from nasopharynx and/or oropharynx were also negative for viral nucleic acid [ ] . similarly, fan et al. reported an infant with covid- who continued to test positive in the anal swabs, even after days of testing negative by the nasopharyngeal swab test [ ] . this raises the need to include testing of feces or anal swab or rectal swab samples for possible presence of virus prior to discharge. sharing of toilets may risk transmission of virus. less data is available on other body fluids and secretions (other than respiratory secretions) of infected patients testing positive for the virus. these include saliva, urine, semen, and tears. in the study by azzi et al., salivary samples of two patients proved positive, while their respiratory swabs showed negative results on the same day [ ] . virus may migrate from the nasopharynx but may be present in the oral cavity as the epithelial cells of the oral mucosa show a high expression of angiotensin-converting enzyme- (ace- ) receptors [ ] . ren et al. found that urine of an asymptomatic patient was positive for viral nucleic acid and concluded that urine may serve as a mode of virus transmission [ ] . valente et al. identified conjunctival swabs from three of the patients, with ocular manifestations, tested positive for covid- , while güemes-villahoz et al. identified only one patient with the presence of viral rna in the tears [ , ] . despite the low prevalence and rapid regression of viral presence in the conjunctiva, sars-cov- transmission through tears may be possible, even in patients without apparent ocular involvement. of note, li et al. found that semen of cases tested positive for sars-cov- [ ] . thus, the authors suggest that the presence of virus in semen may raise suspicion of sexual transmission of virus. in a study by yu et al., one of the seven neonates tested positive for sars-cov- after h of birth [ ] . on the contrary, all the neonates born to pregnant women, included in the two studies by khan et al. and li et al., tested negative for virus and, thus, could not find any evidence of vertical transmission [ , ] . authors conclude that transmission from mother-to-child may be rare, but not completely absent. further data is needed to find the details on this mode of transmission. transmission from mother-to-child can be prevented by delivering the neonates in negative pressure isolation rooms. newborns may also be infected post-delivery via breastfeeding or via inhalation of droplets produced by infected parents and/or healthcare professionals. protective measures like mothers and all healthcare staff wearing protective suits and masks at all times while being around the newborns may mitigate transmission. inculcating appropriate hygiene measures, transferring the newborns to the neonatology department after birth and avoiding prolonged exposure of the neonate to family members becomes of utmost importance. however, our review consists of several limitations. the included studies are mainly from china, italy, spain, and singapore. thus, data from other majorly affected demographic areas would contribute in a better understanding of virus transmission. number of patients in the included studies was relatively small. hence, samples from a bigger and diverse population are needed to gain adequate details on transmission as well as duration and source of viral shedding postresolution of symptoms. covid- has a very high infectivity rate. two modes of transmission exist-direct and indirect. the direct mode includes transmission via aerosols, anal (feco-oral) secretions, tears, saliva, semen, and mother-to-child. indirect modes include transmission via fomites. several of these modes may be underestimated and, thus, risk the spread of virus. to contain the spread of the virus, it is imperative to reduce human-tohuman contact, disinfection of day-to-day objects and proper self-hygiene (washing hands regularly, proper coughing and sneezing techniques, and use of face masks). social distancing plays a key role in reducing transmission. sars-cov- has impacted medical practice to a great extent. the use of personal protective equipment among health professionals is essential to reduce the risk of transmission. knowledge about sars-cov- is still rapidly evolving, and a greater number of studies are required to assess other potential modes of transmission. world health organisation: who coronavirus disease (covid- ) letter: the risk of covid- infection during neurosurgical procedures: a review of severe acute respiratory distress syndrome coronavirus (sars-cov- ) modes of transmission and proposed neurosurgery-specific measures for mitigation modes of transmission of virus causing covid- : implications for ipc precaution recommendations indirect virus transmission in cluster of covid- cases recognition of aerosol transmission of infectious agents: a commentary clinical and transmission characteristics of covid- -a retrospective study of cases from a single thoracic surgery department air, surface environmental, and personal protective equipment contamination by severe acute respiratory syndrome coronavirus (sars-cov- ) from a symptomatic patient aerosol and surface stability of sars-cov- as compared with sars-cov- a family cluster of covid- involving an asymptomatic case with persistently positive sars-cov- in anal swabs prolonged viral shedding in feces of pediatric patients with coronavirus disease anal swab findings in an infant with covid- saliva is a reliable tool to detect sars-cov- positive rt-pcr in urine from an asymptomatic patient with novel coronavirus infection: a case report ocular manifestations and viral shedding in tears of pediatric patients with coronavirus disease : a preliminary report sars-cov- rna detection in tears and conjunctival secretions of covid- patients with conjunctivitis clinical characteristics and results of semen tests among men with coronavirus disease clinical features and obstetric and neonatal outcomes of pregnant patients with covid- in wuhan, china: a retrospective, single-centre, descriptive study impact of covid- infection on pregnancy outcomes and the risk of maternal-to-neonatal intrapartum transmission of covid- during natural birth lack of vertical transmission of severe acute respiratory syndrome coronavirus , china publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations authors' contributions rk conceived the idea. rk, ig, and hk reviewed the literature and collected the data with the help of as y and an y. rk and hk designed the figure. all authors discussed the results and contributed to the final manuscript. conflict of interest the authors declare that they have no conflict of interests. the data used in this study are publicly available and de-identified database thus informed consent or irb approval was not needed for this study. key: cord- -mck cmn authors: krasnanova, veronika; kovacikova, lubica title: tigecycline therapy for multi-drug-resistant pseudomonas aeruginosa sepsis associated with multi-organ failure in an infant with persistent arterial duct. case report date: - - journal: sn compr clin med doi: . /s - - -w sha: doc_id: cord_uid: mck cmn sepsis is the leading cause of death in infants and children worldwide. the growing drug resistance in nosocomial gram-negative bacteria has resulted in treatment challenges. one of the most common multi-drug-resistant bacteria is pseudomonas aeruginosa. resistance to antibiotics used in pseudomonas aeruginosa infections limits the therapeutic options. we present a tigecycline administration in a -month-old infant with patent arterial duct, heart failure, and respiratory failure due to respiratory syncytial virus bronchiolitis with subsequent respiratory distress syndrome and severe sepsis caused by multi-drug-resistant pseudomonas aeruginosa. despite combined antibiotic therapy with meropenem, amikacin, and colistin, inflammatory markers increased. because of life-threatening condition, tigecycline was added to the therapy and was administered intravenously twice daily. within h, inflammatory markers started to decrease and tigecycline therapy continued for days without adverse effects. tigecycline used in combination with other antibiotics might be a valuable therapeutic approach in the management of multi-drug-resistant bacteria infections in pediatric patients when conventional antibiotics have failed. further studies are needed to evaluate the efficacy and safety of tigecycline administration in critically ill pediatric patients. severe sepsis in critically ill infant in the intensive care unit is a major healthcare problem associated with high morbidity and mortality. in recent years the growing drug resistance in nosocomial gram-negative bacteria has resulted in treatment challenges for physicians, mostly for pediatricians [ , ] . despite the rising relevance of pseudomonas aeruginosa infections in adults, only a few studies have evaluated this condition in pediatric population [ , ] . this case report describes the efficacy and safety of glycylcycline antibiotic tigecycline as a salvage therapy for an infant with severe sepsis caused by multi-drug-resistant pseudomonas aeruginosa. a -month-old boy with patent arterial duct, congestive heart failure, and respiratory syncytial virus infection was admitted to pediatric intensive care unit for respiratory failure. while intubated on mandatory ventilation, the patient developed sepsis and hemodynamic instability requiring inotropic support with catecholamines. empiric therapy with meropenem, gentamicin, and fluconazole was initiated. to stabilize hemodynamics, transcatheter occlusion of patent arterial duct was performed. microbial specimens from upper respiratory tract, bronchoalveolar lavage, and urine showed a presence of multi-drug-resistant pseudomonas aeruginosa. oropharyngeal swab was taken by inserting swab into the posterior pharynx and tonsillar areas and rubbed over both tonsils and posterior wall of oropharynx while avoiding contact with other areas of the oral cavity. nasopharyngeal swab was taken by inserting swab through the nares parallel to the palate until resistance was indicating contact with the nasopharynx (approximately the distance equivalent to that from the ear to the nostril of the patient). then, the swab was rubbed and left in place for several seconds to absorb secretions. blood cultures remained negative. based on minimum inhibitory this article is part of the topical collection on medicine * veronika krasnanova veronika.krasnanova@gmail.com concentration, the therapy was changed to amikacin and colistin. meropenem was discontinued due to resistance. three days later, the patient clinical conditions deteriorated. low cardiac output syndrome was treated by combination of epinephrine, norepinephrine, and terlipressin and acute respiratory distress syndrome by high frequency oscillatory ventilation, inhaled nitric oxide, and pulmonary surfactant. in case of serious sepsis and carbapenem resistance, high-dose meropenem ( mg/kg every h) was considered but could not be administered because of oligoanuria. thus, the dose of mg/kg was given on the first day followed by mg/kg for the next days. organ dysfunction involved also other systems, and the patient developed pancytopenia, hepatopathy with cholestasis, paralytic ileus, and renal failure with anuria. despite combined antibiotic therapy with meropenem, amikacin, and colistin, procalcitonin and creactive protein increased to ng/ml and mg/l, respectively ( fig. ) . because of life-threatening condition, tigecycline was added to the therapy with permission and agreement of the parents. tigecycline was administered intravenously twice daily with a loading dose of mg/kg and then mg/kg. within h, inflammatory markers started to decrease and cardiac output improved. tigecycline therapy continued for days without adverse effects. then, amikacin, colistin, and meropenem were gradually discontinued. catecholamines were reduced. renal and hepatic impairment improved. patient was successfully extubated on the th day of hospitalization. patient fully recovered and was discharged from intensive care unit after days. in the recent era, raising bacterial resistance to standard antibiotics resulted in limited options for the treatment of serious infections. one of the most common multi-drug-resistant bacteria is a gram-negative non-fermenting bacillus, pseudomonas aeruginosa, being the major infectious agent responsible for ventilator-associated pneumonia, catheter-associated urinary tract infections, surgical site infections, and intra-abdominal infections [ ] . the risk of developing infection with multidrug-resistant pathogens depends on the presence of risk factors (hospitalization longer than days, recent hospitalization within days, recent antibiotic therapy, residence in a nursing home, need for chronic care outside the hospital) [ ] . the risk of intrinsic and acquired resistance is an important factor while selecting empiric or directed therapy. common resistance to standard antibiotics in pseudomonas aeruginosa infections limits the therapeutic options. the antipseudomonal antibiotic agents include penicillin-beta-lactamase combinations (piperacillin-tazobactam), cephalosporins, monobactams, fluoroquinolones, carbapenems, aminoglycosides, and polymyxins. in severe infections, combination of antibiotics is advocated [ , ] . in some cases, antibiotic combinations may include agent, to which bacteria show microbial resistance [ ] . synergistic effects against multi-drug-resistant bacteria, including pseudomonas aeruginosa, have been revealed for double and triple antibiotic combinations including an aminoglycoside, meropenem, colistin, a fluoroquinolone, a macrolide, or rifampin [ , ] . colistin with meropenem may also be considered salvage therapy for carbapenem-resistant pseudomonas aeruginosa strains [ ] . in our patient case, we presumed that returning meropenem to the therapy would result in synergic effect with amikacin and colistin. however, despite the combination therapy, patient condition deteriorated with worsening of multi-organ failure. adding a tigecycline into the therapy resulted in inflammatory markers decline and improvement of clinical condition. in adults, there are many clinical trials with the use of tigecycline as a broad-spectrum antibiotic. in infants, only a few cases of tigecycline use have been reported because of side effects that include nausea, vomiting, diarrhea, acute pancreatitis, teeth discoloration, and neutrophil engraftment delay [ , ] . however, the recent data show that tigecycline may represent a considerable treatment option in life-threatening infectious complications in pediatric patients as a part of combination therapy. although pseudomonas aeruginosa is not reliably inhibited by tigecycline, it seems to be a highly active antimicrobial agent in critically ill and immunocompromised pediatric patients [ ] . iosifidis et al. [ ] conducted a retrospective chart review of children treated with tigecycline. the youngest child was . months old. tigecycline was used for managing bacteremia, pneumonia, and three unspecified infections. song et al. [ ] described a case series of pediatric patients suffering from serious infections after surgery with median age of . months who received an initial dose of . mg/kg and then . mg/kg of tigecycline every h. median duration of treatment was days and % of patients had positive response. emiroglu et al. [ ] described a -month-old infant with ventriculo-peritoneal shunt meningitis. tigecycline dose of . mg/kg twice a day was administered for days. in our patient, tigecycline was used as a salvage therapy in combination with other antipseudomonal antibiotics in a patient with sepsis-induced multi-organ failure. tigecycline was given for days twice daily with the initial dose of mg/kg and maintenance dose of mg/kg. we observed no adverse effects during therapy. tigecycline did not eradicate pseudomonas aeruginosa, although inflammatory markers decreased which may be raised initially because of other conditions rather than sepsis. although pseudomonas aeruginosa colonization persisted, inflammatory markers decreased and patient fully recovered. we can conclude that cardiac failure in an infant with congenital heart disease can be complicated with respiratory failure due to viral infection and, subsequently, with multi-organ failure in case of pseudomonas sepsis. based on our patient case, we suggest that tigecycline in combination with other standard antipseudomonal antibiotics may be considered in children for the management of severe multi-drugresistant bacteria infections when conventional treatment has failed. treatment option for sepsis in children in the era of antibiotic resistance tigecycline treatment of infection caused by kpc-producing escherichia coli in a pediatric patient tigecycline application in a -month-old infant with multiple drug resistant klebsiella pneumonia: a case report tigecycline salvage therapy for critically ill children with multidrug-resistant/extensively drugresistant infections after surgery nosocomial pneumonia: lessons learned in vitro and in vivo activities of tigecycline-colistin combination therapies against carbapenem-resistant enterobacteriaceae insights into newer antimicrobial agents against gram-negative bacteria synergic activity of cephalosporins plus fluoroquinolones against pseudomonas aeruginosa with resistance to one or both drugs combination antibiotic therapy for multidrug-resistant gram-negative bacteria management of ventilator-associated pneumonia (vap) caused by resistant gram-negative bacteria: which is the best strategy to treat? tigecycline use in critically ill patients: a multicentre prospective observational study in the intensive care setting is there a future for tigecycline? use of tigecycline in pediatric patients with infections predominantly due to extensively drug-resistant gramnegative bacteria tigecycline therapy in an infant for ventriculo-peritoneal shunt meningitis publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations acknowledgments the authors are thankful to the team of pediatric cardiac intensive care unit in national institute of cardiovascular diseases in bratislava.author contributions vk and lk cared for the patient, drafted the manuscripts, and carried out the literature research. both authors read and approved the final manuscript.data availability all data are included in this published article. ethics approval and consent to participate written informed consent was obtained from the parents to participate on this study. this study was approved by the institutional review board of the national institute of cardiovascular diseases in bratislava, slovakia.consent for publication formal written informed consent was obtained from the parent for the publication of this case report. the authors declare that they have no conflicts of interest. key: cord- -yrlzxtbw authors: fong, raymond; tsai, kelvin c. f.; tong, michael c. f.; lee, kathy y. s. title: management of dysphagia in nursing homes during the covid- pandemic: strategies and experiences date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: yrlzxtbw the global novel coronavirus disease (covid- ) pandemic has had devastating effects not only on healthcare systems worldwide but also on different aspects of the care provided to nursing home residents. dysphagia management is a crucial component of the care provided to many nursing home residents. this article presents the dysphagia management strategies applied in hong kong during the covid- pandemic and the related experiences. a two-tier protection system was implemented wherein residents were categorised according to their contact and hospitalisation histories. the provided swallowing management and personal protective equipment level differed between the two tiers. the article also discusses the referral and prioritisation of clinical services for residents requiring swallowing management, as well as the adaptations of swallowing assessment and management during the pandemic. the possible effects of covid- on mealtime arrangements in nursing homes, the implications of the pandemic on the use of personal protective equipment and the use of telepractice in nursing homes were also discussed. this article has summarised the actions taken in this regard and may serve as a reference to clinicians who are responsible for swallowing assessments and dysphagia management in nursing homes. the world health organization (who) declared the novel coronavirus disease to be a global pandemic in march [ ] . covid- has caused widespread devastation in communities worldwide, and even more significant increases in associated mortality in nursing homes relative to the surrounding communities [ ] . residents in nursing homes often have multiple health conditions and are therefore at a higher risk of mortality in a pandemic scenario. in the covid- pandemic, this increased risk of mortality is not only due to the pandemic disease itself but also due to pre-existing medical conditions, regardless of the residents' covid- infection status. dysphagia is a prevalent problem among nursing home residents. previous studies have reported global prevalence rates ranging from to % [ ] [ ] [ ] . if neglected or mismanaged, dysphagia can lead to serious complications such as malnutrition, dehydration, aspiration pneumonia and death [ ] . dysphagia can be assessed using either noninstrumental or instrumental assessment methods. clinicians rely largely on the former methods because the latter are rarely available in nursing homes. non-instrumental assessment methods, which are also referred to as clinical swallow evaluations (cse), include communication assessments, physical examinations and swallowing trials [ ] . the physical examination in a cse includes an assessment of the cranial nerves, voice and laryngeal function. in some protocols, the clinicians elicit a volitional cough from the patients to assess the airway protective mechanism [ , ] . the swallowing management strategies that can be applied in nursing homes are less confined to the setting. for example, exercises of the oromotor and pharyngeal muscles can be performed [ ] . additionally, clinicians can apply surface electromyography, neuromuscular electrical stimulation and expiratory muscle strength training to the residents. compensatory strategies such as dietary, environmental and utensil modifications are also commonly used [ ] . several of these procedures may induce coughing as a reflexive response to protect the airway. the cse was classified as medium risk according to stratification risk for covid- transmission. the risk of the procedure is attributed by the close proximity to the residents' upper mucosa, prolonged exposure and possibility of reflexive cough during the procedures [ ] . compared with the general community, nursing home residents are at substantially higher risk for having bacterial and viral infections [ ] . healthcare workers (hcws) have to provide care to many residents, which further increases the risk of cross-infection. nursing home residents are also more prone to hospitalisation and thus face an increased risk of hospital-acquired infections, as well as exposure to novel viral agents such as severe acute respiratory syndrome coronavirus (sars-cov- ), the causative agent of covid- . the nature of these procedures also places clinicians at a risk of infection with sars-cov- during dysphagia assessments and management [ ] . covid- advisory group of royal college of speech and language therapists also presented that dysphagia assessment should be considered as an aerosol generating procedures based on theoretical and empirical evidences [ ] . however, cses are crucial to the physical and psychological well-being of many nursing home residents, despite the risk of infection, and thus cannot be suspended. below, some practical strategies and considerations regarding dysphagia management in nursing homes are described. these strategies have been applied in hong kong, one of the first regions affected by covid- [ ] . during the peak of the pandemic, nursing home personnel only included hcws, residents and essential administrative staff. although the loosening of public health policies in late may led to the reopening of schools and public facilities [ ] , visiting policy and visitor numbers at nursing homes remained restricted. patients with covid- , individuals who had come in close contact with infected patients and patients under quarantine were not allowed to visit nursing homes. individuals presenting signs and symptoms of covid- , including a fever, runny nose, loss of smell and taste and a travel history within the past days, were also not allowed to enter nursing homes [ ] . these restrictions protected residents by allowing only minimal contact with individuals outside the nursing home. in hong kong, covid- testing efforts were restricted to approximately samples per day until june and were mainly targeted at travellers to hong kong and those admitted to hospitals [ ]. in july , there was an outbreak after relaxation of social distancing policy [ ] . to date, cluster outbreaks in nursing homes have been reported in at least local nursing homes. the re-emergence of the disease, which previously have been largely contained in the community, has affected nursing homes in this wave of outbreak and the following measures were more important to ensure the safety and well-being of nursing home residents. residents requiring dysphagia management were categorised as either 'standard' or 'at-risk'. the at-risk group included those who had been hospitalised within the past days or had been diagnosed previously with covid- and discharged. residents who had been diagnosed with covid- were assessed after discharged to the nursing home as patients with covid- were considered at high risk for oropharyngeal dysphagia [ ] , especially those who have been previously intubated [ ] . these at-risk residents were deescalated to the standard level after days of quarantine in the facility. therefore, standard and at-risk residents should be considered differently with respect to dysphagia assessments and management and personal protective equipment usage. nursing home residents were referred by the medical doctors or nurses to undergo swallowing assessments and/or management or to receive routine assessment under an annual review of the integrated care plan. two additional measures were enforced during the covid- pandemic. for all referrals, the source was asked to indicate whether the nature was urgent or non-urgent. all standard-level residents were assessed and managed, whereas only the at-risk residents whose referrals were deemed urgent underwent assessments. the at-risk residents with non-urgent referrals were assessed after they deescalated to the standard level. in the latter cases, the eating assessment tool (eat- ) [ ] was applied by interviewing residents with the ability to communicate, and the eat- score was computed. those who received an eat- score of or higher proceeded to a swallowing assessment, while those with lower scores were deemed 'not at significant risk' and were seen at a later stage. in addition to screening tools such as the eat- , clinicians also relied more heavily on the residents' medical records and histories when prioritising cases for assessment and management. dementia, a severely dependent functional status, a high nutritional risk status and an underweight status were identified as risk factors for dysphagia in nursing home residents [ , ] . consequently, the residents' medical records were searched for these factors, and the residents were prioritised accordingly for assessment and management. the use of screening tools such as the eat- and well-researched risk factors facilitated the decisions. clinicians should keep in mind that this is far from ideal, but it is a balance between risk and clinical outcome [ ] . the cse comprises several key components, including a physical examination and swallow trials. cognition and dentition have been identified as indicators of dysphagia in elderly residents of aged care facilities [ ] . therefore, these two aspects were emphasised when determining the residents at a higher risk of dysphagia. an assessment of cognition and dentition would not require the clinician to be in close proximity of the patient and would not be an aerosol-generating procedure (agp), unlike an oral motor examination and swallow trials [ ] . clinicians can reduce their risk of exposure by decreasing their involvement in the performance of agps. some clinicians include volitional or reflexive coughing as a possible indication of aspiration during the cse [ ] . some swallowing manoeuvres, such as the supraglottic swallow, also involve volitional coughing after swallowing to eliminate the aspirated bolus in the airway [ ] . these practices are not advocated and should be avoided during a pandemic to reduce the risk of infecting the clinician during the agp, as well as the risk of exposure of other residents if these manoeuvres were recommended to be performed during mealtimes. in nursing homes, cervical auscultation may be used as an adjunct during a swallowing assessment [ ] . during the covid- pandemic, the use of a stethoscope across multiple patients was limited as much as possible to avoid crossresident infection. whenever a stethoscope was applied to a resident, it was thoroughly cleaned with alcohol wipes ( % ethanol content) at least three times before it was used on another patient. similar disinfection procedures were used for pulse oximetry devices. the use of utensils of different sizes, shapes and types is another compensatory strategy implemented in cse and dysphagia management. during the covid- pandemic, utensils and containers were largely switched to disposable options to reduce the risk of infection. therefore, the use of utensils and containers as a compensatory strategy for dysphagia management may be limited in a pandemic setting. in addition to the limitations associated with utensils and manoeuvres, limitations were also placed on exercises or therapy options because of the covid- pandemic. although the use of sensory stimulation in clinical practice is not supported by solid evidence, it is nevertheless used by some clinicians [ ] . the use of a cold and sour stimulant may trigger gagging and coughing responses, and clinicians must remain in close proximity to the patient during these procedures. therefore, sensory stimulation is associated with a higher risk of infection. these practices were completely avoided in patients that were deemed at risk and generally avoided in residents at the standard level of care. expiratory muscle strength training (emst) has been advocated to improve the swallowing functions of patients with dysphagia associated with different aetiologies [ , ] . however, this procedure involves blowing air into the device, and this method and the difficulty associated with device disinfection made it necessary for clinicians to avoid prescribing emst for at-risk patients. emst was only applied to patients at a standard level of care, and they were advised to remain at a distance of at least . m from residents during the procedure. dysphagia management across the two-tiers of residents also differed; the at-risk residents were managed conservatively with diet modification and swallowing manoeuvres [ ] . direct treatments can be considered when these at-risk residents were deescalated to the standard level after the quarantine in the facility [ ] . in nursing homes, mealtimes normally involve a gathering of residents in a dining hall. each resident would receive their meal on their own tray and would eat individually. the covid- pandemic led some nursing homes to change this practice, after which residents were only allowed to eat meals in their own rooms or personal spaces. other homes segregated residents into small groups and only allowed one small group to dine at a time. the lack of olfactory and visual stimulation associated with mealtimes in dining halls may have affected some of the feeding behaviours and patterns of residents, especially those with dementia [ ] . clinicians monitored these behaviours and intake amounts more closely once these changes had been implemented and made any necessary suitable arrangements to overcome the sensory deprivation and social isolation. the recommendations for nursing homes that assessed and managed patients at the standard level of care indicated that face masks and gloves should be considered the minimal level of personal protective equipment (ppe); if available, face shields should be used when interacting with all standardlevel patients. in contrast, face shields and personal gowns should be used in addition to face masks and gloves when interacting with at-risk residents. all clinicians received proper training in infection control, which addressed the use of different forms of ppe and the standard procedures for donning and doffing these items according to training materials from the government website [ ] . hand hygiene was advocated among clinicians and was required before and after visiting the patient and touching any of his/her belongings. existing evidence supports the use of telepractice in dysphagia management. studies on this approach have advocated the use of trained assistant personnel at a remote site to provide the service and achieve valid and reliable results [ , ] . some studies have used videoconferencing software to allow the clinician and patient to interact in real-time and to facilitate the provision of clinical services. many nursing home residents do not have a sufficient cognitive level that would allow them to use electronic communication devices such as tablets independently. these residents would require assistance with device operation from another individual. consequently, a surge in the use of telepractice for dysphagia management in nursing home settings was not observed during the covid- pandemic. however, telepractice may be considered for older adults who live at home with caregivers who could provide assistance with device operation. during the covid- pandemic, nursing home residents were as vulnerable as any other population, given their already fragile state. however, members of this population still required swallowing assessments and dysphagia management, regardless of their covid- status. however, many aspects were considered to minimise the risk of infection among residents and clinicians. this commentary has summarised the actions taken in this regard and may serve as a reference to clinicians who are responsible for swallowing assessments and dysphagia management. clinicians should also remain aware of all changes to guidelines on dysphagia management [ , , ] , for nursing homes [ ] or for certain clinical populations from other specialities [ ] . conflict of interest the authors declare that they have no conflict of interest. ethical approval and informed consent this article does not contain any studies with human participants performed by any 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service-delivery during the covid- global pandemic moving forward with dysphagia care: implementing strategies during the covid- pandemic and beyond management of dysphagia in the patient with head and neck cancer during covid- pandemic: practical strategy royal college of s, language therapists c-ag. aerosol generating procedures, dysphagia assessment and covid- : a rapid review unique sars-cov- clusters causing a large covid- outbreak in hong kong shedding light on dysphagia associated with covid- : the what and why postintubation dysphagia during covid- outbreak-contemporary review validity and reliability of the eating assessment tool (eat- ) prevalence and associated factors of dysphagia in nursing home residents indicators of dysphagia in aged care facilities the long-term effects of covid- on dysphagia evaluation and treatment aerosol generating procedures, dysphagia assessment and covid- the reliability and validity of cervical auscultation in the diagnosis of dysphagia: a systematic review the effects of sensory stimulation on neurogenic oropharyngeal dysphagia impact of expiratory muscle strength training on voluntary cough and swallow function in parkinson disease expiratory muscle strength training for radiation-associated aspiration after head and neck cancer: a case series dysphagia in covid- -multilevel damage to the swallowing network? factors influencing the pace of food intake for nursing home residents with dementia: resident characteristics, staff mealtime assistance and environmental stimulation validity of conducting clinical dysphagia assessments for patients with normal to mild cognitive impairment via telerehabilitation training the allied health assistant for the telerehabilitation assessment of dysphagia centers for disease control and prevention (n.d.) preparing for covid- in nursing homes ) tracheotomy recommendations during the covid- pandemic publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- -srbualjc authors: klang, eyal; soffer, shelly; nadkarni, girish; glicksberg, ben; freeman, robert; horowitz, carol; reich, david l; levin, matthew a title: sex differences in age and comorbidities for covid- mortality in urban new york city date: - - journal: sn compr clin med doi: . /s - - -w sha: doc_id: cord_uid: srbualjc previous studies demonstrated a higher covid- fatality rate in men. the aim of this study was to compare age and comorbidities between women and men who died from covid- . we retrospectively analyzed data of covid- patients hospitalized to a large academic hospital system in new york city between march and may , . we used a multivariable logistic regression model to identify independently significant variables associated with gender in patients who died from covid- . the model was adjusted for age and comorbidities known to be associated with covid- mortality. we identified patients diagnosed with covid- . of these patients, / ( . %) were women. the mortality rate was higher for men (women . % vs. men . %, p = . ). of the patients who died, women were on average years older than men (woman . ± . vs. men . ± . , p < . ). in the multivariable model, cardiovascular comorbidities were not significantly different between women and men. chronic kidney disease (aor for women . , % ci . – . ) and smoking (aor for women . , % ci . – . ) were more common in men. age decile (aor for women . , % ci . – . ) and obesity (aor for women . , % ci . – . ) were higher in women. this study demonstrates that women who died of covid- showed a similar cardiovascular disease profile as men. yet, they are years older than men. investigating the gender impacts of covid- is an important part of understanding the disease behavior. the coronavirus disease (covid- ) is a pandemic viral disease caused by severe acute respiratory syndrome coronavirus (sars-cov- ). several studies have demonstrated that elderly patients with comorbidities are at increased risk of dying from covid- . underlying health conditions such as cardiovascular disease, hypertension, and diabetes mellitus were associated with increased risk of mortality [ ] [ ] [ ] . smoking and obesity were also found to be risk factors [ , ] . a number of studies have shown a higher fatality rate in men than in women [ ] [ ] [ ] . a research conducted in china reported that % of the mortality cases were men [ ] . it was suggested that the gender discrepancy is due to a higher smoking rate in men and subsequently a higher comorbidity rate [ ] . the present study was designed to compare age and comorbidities between women and men who died from covid- . a multicenter observational retrospective study was conducted using data of covid- patients who presented to a large we identified all patients who were positive for covid- by nasopharyngeal swab polymerase chain reaction (pcr) test and were admitted to the hospitals. demographic data, clinical information, and medical history were retrieved from the hospitals' electronic medical records. smoking was defined as past or current smoking. obesity was defined as body mass index (bmi) larger than kg/m . for . % of patients with missing bmi, obesity diagnosis was retrieved from patients' files. the analysis was performed with python (ver. . . , bits). a p value of < . was considered statistically significant. age distribution curves were plotted for women and men who died from covid- . gaussian kernel density estimates were fitted to the plots. univariate analysis compared age and comorbidities between men and women who died from covid- . categorical variables were compared using chi-square test. continuous variables were compared using student's t test. a multivariable logistic regression model was used to identify independently significant variables associated with gender. the model was adjusted for age decile and comorbidities known to be associated with covid- mortality. adjusted odds ratios (aor), % confidence intervals (ci), and p values were calculated for the variables in the models. overall, patients were diagnosed with covid- . of these patients, / ( . %) were women. of the patients, ( . %) patients died during the study's time frame: / ( . %) of the women and / ( . %) of the men died (p = . ). of the patients who died, women (mean . ± . ) were significantly older than men (mean . ± . ). figure shows the age distribution curves for women and men who died from covid- . the women's age distribution curve is shifted several years forward from the men's age distribution curve. in univariate analysis (table ) , no significant gender differences were observed for cardiovascular diseases, diabetes mellitus, and chronic obstructive pulmonary disease. hypertension (women . % vs. men . %, p = . ) and obesity (women . % vs. men . %, p < . ) were significantly more common in women. chronic kidney disease (women . % vs. . %, p = . ) and smoking (women . % vs. men . %, p = . ) were significantly more common in men. the results of the multivariable model are presented in table . after adjustment, there was still no significant gender difference in cardiovascular comorbidities. features independently significant in the multivariable analysis were similar to the univariate analysis. age decile (aor for women . , % fig. age distribution plot in patients who died from covid- , stratified by sex. the age distribution curve for women is shifted about - years ahead of the men's age distribution curve ci . - . ) and obesity (aor for women . , % ci . - . ) were higher in women. chronic kidney disease (aor for women . , % ci . - . ) and smoking (aor for women . , % ci . - . ) were higher in men. this study demonstrates that in patients who died from covid- , no significant difference was noted between cardiac morbidity and gender. yet, a difference was found for age. women who died were on average years older than men. like previous research, our data shows that mortality and hospital admission rates were higher for men. previous studies suggested that the gender disparity is a result of behaviors such as smoking and drinking that lead to underlying cardiovascular morbidity [ ] . indeed, in our study, we found that the smoking rate was higher for men. yet, this difference was not reflected in comorbidity differences between the genders. obesity was more frequent among women who died. it is worthy of note that the mortality rate in our cohort is higher than that reported from different locations [ ] . our results are in accordance with other publications from the new york city area, which demonstrated a high covid- mortality rate [ , ] . the link between gender and the severity of covid- disease is still not completely understood. this link can be related to a number of causes including physiological, biological, and sociological factors. in our cohort, there was a fiveyear discrepancy between men and women who died from covid- . one possible explanation is that the gender difference results from the association between covid- mortality and underlying health conditions, particularly cardiovascular diseases. in women, cardiovascular disease starts to develop approximately - years later due to the protective effect of estrogen [ , ] . this means that the cardiovascular injury, which may affect the course of covid- , begins to accumulate later in women. our study is limited to an assessment of gender differences among patients who have died from covid- without considering the comorbidity rate of men versus women in the general population. secondly, this is a retrospective observational study, with all the associated limitations. thirdly, due to large missing values for race, we did not include this variable in the logistic regression model. finally, the study represents the urban new york city population, and other populations may have different results. investigating the gender impacts of covid- is an important part of understanding the disease behavior. women who died of covid- showed a similar cardiovascular disease profile as men. yet, on average, they are years older than men. the mount sinai institutional review board (irb) approved this study. informed consent was waived by the irb committee. prevalence of comorbidities in the novel wuhan coronavirus (covid- ) infection: a systematic review and meta-analysis risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease pneumonia in wuhan, china clinical course and risk factors for mortality of adult inpatients with covid- in china: a retrospective cohort study presenting characteristics, comorbidities, and outcomes among patients hospitalized with covid- in the new york city area morbid obesity as an independent risk factor for covid- mortality in hospitalized patients younger than clinical characteristics of deceased patients with coronavirus disease : retrospective study coronavirus disease (covid- ) in italy covid- : the gendered impacts of the outbreak the gendered dimensions of covid- covid- patients' clinical characteristics, discharge rate, and fatality rate of meta-analysis prevalence and impact of myocardial injury in patients hospitalized with covid- infection lifelong gender gap in risk of incident myocardial infarction: the tromsø study sex differences in cardiovascular disease and cognitive impairment: another health disparity for women? the authors declare that they have no conflict of interest. key: cord- -jtvn tlm authors: cimolai, nevio title: a minimalist strategy towards temporarily defining protection for covid- date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: jtvn tlm until either efficacious therapy or vaccination for covid- is achieved, there will be a need to regain world economic stability while yet controlling the pandemic with current approaches. for those infected thus far, there is a prevailing perspective that devising recognition for protective immunity will progressively allow segments of society to return to some functionality more than is existing. at this time, the best correlates with protection from natural coronavirus infections are systemic neutralizing antibody and mucosal iga. serum neutralizing antibody more easily fulfills the latter requisite, but current live virus methods for neutralization prevent large-scale application. it is conceivable that the exposure of previously infected individuals can allow for the definition of protective thresholds of neutralizing antibody. thereafter, many other antibody assays will be able to screen for surrogate protection after correlations with protective neutralizing antibody are made. specificity of common antibody tests would benefit from confirmatory blocking systems or confirmatory immunoblotting fingerprints with well-defined antigen(s). the opportunity for the scientific community to make these assessments is evident in the current context of the covid- epidemic given the large numbers of infected individuals worldwide. such information will also be vital to guide vaccine development and/or immunotherapy. the clinical burden of covid- in the current pandemic is undoubtedly considerable, but the socioeconomic burden must equally weigh in determining how the world will move forward until either an effective chemotherapy and/or vaccine is devised [ ] . pending that such success in treatment and/or prevention are achieved, the continuous or relapsing lockdown of societies and hence economies has the potential to cause more damage than may be initially apparent [ ] . indeed, it could be prognosticated that the relative economic standstill may cause more damage to humanity than the disease itself. many countries have attempted to partially restore pre-pandemic functions only to experience yet second waves of increasing infections during july and august, . to some, the answer may be to tolerate the expectations of herd immunity with lesser in the way of resistance to infection spread [ , ] . to others at the other end of the spectrum, a more cautious approach has been to create the best environment for disease prevention while patching holes for or propping up failures in the economy as they appear [ ] . somewhere in the midst of this maelstrom, there will need to be practical strategies for achieving success with both the pandemic and the economies simultaneously. contexts of disease and economy will no doubt vary along a spectrum and may require somewhat different approaches in their detail. in this review, a minimalist strategy is proposed to in part provide some solutions towards regaining economic focus while preventing disease. these steps are a modest beginning from the perspective of devising recognition for protective immunity that will progressively allow segments of society to proceed with their lives as they once were or nearly so. such a strategy will thereafter be enhanced as treatment or vaccine developments arise. studies with passive immunity are highly suggestive that antibody has a significant role in protection of coronavirus infection [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the latter includes passive administration of anti-sars-cov- human monoclonal antibody in animal systems [ ] . these findings are critical to our theme since direct antibody in some way may be used as the correlate with neutralization if not directly then by association. therefore, the prospects of finding a serological assay based on antibody detection that defines in some way neutralization and then after disease prevention are considerable. infection with coronaviruses generally protects against reinfection [ , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . analogous to the role of passive immunity, pre-existing immunity can potentially be defined with the right measures. both parenteral neutralizing antibody and secretory iga (siga) are associated with protection in model systems [ , , [ ] [ ] [ ] [ ] [ ] . siga has logistical problems with collection and analysis, although technological advances are quite likely capable of overcoming the latter. therefore and in the interim, serum neutralizing antibody measurements will generally be applied as the standard, and other correlates of the latter could be put into common use. for mers, mild infection was associated with decreased antibody levels [ ] [ ] [ ] . severe infections are associated with long-lived neutralizing antibody. increased neutralizing antibody is associated with decreased viral shedding, but there have not been enough natural infections to allow for study and analysis of natural protection as would be desirable. likewise for sars, field studies for the practical protective effects of neutralizing antibody could not be studied due to the short-lived spread of the virus. in studies for sars-cov- , of over control sera from uninfected patients, no neutralizing antibodies were found [ ] . severe disease was associated with earlier generation of anti-sars-cov- antibody, and peak neutralizing antibody was measured at approximately ½ weeks. stereotypic antibody responses to sars-cov- led to hypotheses that there should be cross-reactivity with sars-cov in the constant rbd [ ] . in both humans and animals, such cross-reactivity was suspected to be due to non-neutralizing anti-s antibody again likely relating to a conserved region [ ] . crossneutralization was however uncommon, but conceivably there could be other reasons for any such non-specificity [ ] [ ] [ ] . among humans, s-specific antibody dominates and may correlate better with neutralization [ , , ] . furthermore, the correlation between antibodies for different antigens (e.g., s and n proteins) may not be as initially conceived [ , ] . human monoclonal antibodies that neutralize virus or pseudovirus especially recognized the rbd [ ] . collaborative groups have found a strong association between neutralizing antibodies and igg antibodies to the rbd [ , ] . others have found strong correlations between neutralizing antibodies and eia-detected antibodies to various sars-cov- antigens [ , ] .some have found diversity in immune responses contingent on the nature of presenting disease [ , ] . the latter would be consistent with the variable antibody responses now determined for the spectrum of pediatric disease [ ] . for eia-based antibody studies otherwise, we have learned so far that the type and severity of disease and age may have bearing on the quality and quantity of antibody responses [ , [ ] [ ] [ ] [ ] . gender may also possibly affect antibody responses or other relevant immune responses [ , ] . does neutralization antibody ensure protection? at this time, we can reasonably conclude that the existence of neutralizing antibody and its quantitation associate with protection against coronavirus infections. what we cannot do, however, is guarantee that the presence of all such neutralizing antibody, as measured by conventional live virus neutralization methods in vitro, will ensure protection. that is, laboratory methods measure neutralization as so defined but not protection directly. therefore, it can be held that not all neutralization methods duly measure the same effect that leads to that neutralization outcome [ ] . in essence, what creates an in vitro neutralization may or may not truly block viral entry, prevent intracellular events, or ameliorate disease. one potential and theoretical approach to vetting sera that have a higher likelihood of indication for protection is to choose those with higher neutralizing titres. there are several limitations with the application of neutralization as a surrogate for protection [ , ] . infections with coronaviruses do not always lead to a major increase in such antibody. previously acquired antibody is not always protective for subsequent infection, but low levels of antibody better correlate with susceptibility. resistance is best to the homologous coronavirus, but susceptibility can be had to heterologous strains. there is also the prospect that subsequent changes in viral genome may be accompanied by changes in epitopes that afford neutralization with an accompanying change in neutralization capacity of post-infection or post-vaccination sera [ ] . the latter could be the prelude to neutralization escape mutants should they occur [ ] . the latter may also be the prelude to emerging reports of possible sars-cov- repeat infections [ ] . the traditional approach to determining antibody responses is likely to dominate the search for protective immunity, but due consideration and open-mindedness should be maintained for measuring t cell post-infection immunity and its correlates [ ] [ ] [ ] [ ] . with the availability of viral antigen, most scientists in the know-how would be able to fashion a test for antibody determination in short order and most would likely choose an enzyme immunoassay (eia) (or nearly equivalent non-enzymebased assay) for its potential of automation and widespread use. the latter is especially likely in the current context where a majority of serodiagnostic tests are of that methodology. the expeditious derivation of an eia or equivalent is a common goal when serodiagnosis is deemed to be of potential value. whereas the creation of an eia is seemingly a relatively easy task, the application of any such is where the test of the matter lies. historically, whether for antibody or antigen detection, eia approaches had a number of pitfalls that were repetitively realized for nearly every such system that was subsequently developed [ , ] . as would naturally be desirable, an assay with very high sensitivity at the appropriate timing is one evident target. furthermore, an assay with a highly specific result is another evident target. the reality of serodiagnostic systems, however, is that there is generally a gray or indeterminate zone where sensitivity and specificity collide [ ] . there is an intersection of true positive results and false positive results more or less in almost every system with few exceptions. for whatever maneuver is conceived to diminish that overlap, eia or an equivalent for antibody detection can be modulated to enhance predictive values in one direction or another, but commonly realizing that there will be a trade-off. the application of a serodiagnostic assay for antibody postinfection or vaccine is furthermore complicated in its evaluation. typically, a standard set of known or presumed "negative" sera are tested as is a standard set of known or presumed "positive" sera. many such analyses, however, do not thereafter assess the assay in the context of the working world prospectively. the jeopardy here is that the prevalence of true disease in the population of patients from whom sera are acquired can vary considerably. there is an inherent bias in such assessments to ensure that the tested serum pool has a considerable number of true positive samples. biases in this regard can be greater than those engendered by convenience sampling [ , ] . given the functionality of these assays, the predictive values of positive or negative tests vary considerably depending on the prevalence of the infection in the population so studied [ ] . for example, even for a given high sensitivity and specificity, a reduction in prevalence from to % can lead to a situation where the false positive assays nearly equal the number of true positive assays. the latter scenario can occur when assessments are performed on preselected sera rather than on sera from patients prospectively collected in a larger population. therefore, unless there is considerably widespread infection leading to a proportionately high seroprevalence, serodiagnostic tests will likely suffer with their predictive values. how would this dilemma then be potentially overcome? one such approach to improving specificity would be to conduct blocking assays (direct or competitive) for positive sera in order to reduce the number of false positive tests [ ] . this is a time-honored approach that is often forgotten when new serodiagnostic assays are initially created. the approach was also germane to some antigen detection eia versions. effectively, the specificity is enhanced when it can be shown that the antigen of choice significantly reduces the assay quantitation after absorption. the implementation of a blocking step can be entered into an automated procedure in tandem from the start or may be performed as a confirmatory test. the latter is especially suited to a scenario where the proportion of positive tests is low. the simplicity of a blocking test mandates only a brief turnaround time if it is performed in an algorithmic second step. there may be various approaches to the definition of antigen used in the blocking test, but it would be best in the inaugural stages to choose antigen(s) that are deemed inherent to the neutralization effects seen in postinfectious sera. although it could prove that one antigen, e.g., rbd or spike protein sequence otherwise, may alone suffice, pilot studies would be better to work backwards after establishing the antigen-neutralization correlates as described above. purity of the blocking antigen is essential to avoid non-specific competition of non-viral elements if virus is acquired from tissue cultures. another approach to a blocking assay would be the competition between antibody in the human serum specimen and a known monoclonal antibody with affinity to sars-cov- . choice of a specific monoclonal antibody, or several for this purpose, requires specific characterization. there are many commercial assays for sars-cov- antibody that have emerged, but for a survey sample of several so assessed thus far, none has blocking assays as potentially part of the procedure [ ] [ ] [ ] [ ] [ ] [ ] [ ] . developmental assays also commonly do not include blocking assays [ ] [ ] [ ] . igm assays are particularly an issue with non-specificity since apparent igm rises may relate in part to solid phase (e.g., polystyrene) absorption or non-specific igm antibody (e.g., rheumatoid factor). of note, early reports have now emerged of blocking assay variations for systems relating to either mers-cov or sars-cov- [ ] [ ] [ ] . as suggested above, antigen detection can also suffer from non-specificity, and this dilemma has now been found in some systems [ ] [ ] [ ] . again, a blocking assay in any such configuration for antigen detection has potential to resolve this critical issue especially when raising the threshold for the enhancement of sensitivity is being considered. a second approach, alone or alongside an eia-blocking assay, could be immunoblotting. again, it could prove that one antigen substrate may suffice, but it would be prudent to work backwards after establishing the antigen-neutralization correlates. as experienced pointedly with lyme disease or hiv infections, the immunoblot response can be considerably variable, but a confirmatory fingerprint or several fingerprints can be defined as minimal diagnostic thresholds. a higher threshold stringency can enhance serodiagnostic specificity. guan and others provided some key insights in this regard with sars-cov immunoblotting, and it is only highly probable that similar findings will be had with sars-cov- [ ] . not all antigens identified in immunoblotting may have functions in neutralization, and likewise, there may be more antigens that are capable of inducing neutralization than are identified by resolving antigens in denaturing electrophoresis procedures [ ] . given advances as detailed by olvera et al. and several others, the fingerprint patterns could also conceivably be assessed with peptide sets rather than larger antigens which may bear non-specific epitopes [ , , ] . the protein micro-array concept bears relevance to the ingenuity of how a complex recognition pattern could occur and be thereafter automated [ , ] . furthermore, we should not restrict ourselves to common antigens that are currently thought relevant since novel key antigens may yet arise [ ] . if serological methods of choice later prove to be a surrogate for infectious virus neutralization, e.g., viral pseudoparticles, blocking test components can also be built into those processes [ ] [ ] [ ] [ ] [ ] . the latter approaches too are capable of automation design or large batch processing. if conventional neutralization assays yield titres in lower dilution than pseudotype virus neutralization assays (e.g., s protein-bearing pseudoviruses with murine leukemia virus), the latter may set higher thresholds as the correlation dictates [ ] . if neutralizing antibody correlates with protection, is there a threshold at which the prediction can be confident? whereas there are no guarantees, if the presence of neutralizing antibody correlates with protection, it can be reasonably hypothesized that more protection correlates with higher titres. such a hypothesis is easily testable in the current pandemic given preliminary consensus for the type of neutralization assay to be used. it is proposed that the : - : standard of conventional neutralizing antibody be used as the minimal threshold in inaugural studies. the threshold could be raised or lowered depending on the outcome of field assessments. prospective follow-up of study subjects with the established minimum neutralizing antibody and its potential change in titre and/or protection would be determinable over time. there is then a role for other measures of antibody thereafter. as the initial neutralizing antibody threshold for protection is established, correlates with other tests as surrogates can then begin. in the latter, it would also be best to choose higher thresholds of positivity rather than any positive test per se. such thresholds could thereafter vary pending correlations that become apparent. such an approach provides an abundance of precaution rather than the converse. the test of a minimalist strategy and thereafter its refinement is currently feasible in the milieu of the current pandemic. given the magnitude of infected individuals throughout the world, the numbers required to test for protection could be easily acquired from a multi-centered approach with highly endemic foci or with even a regional study again in a highly endemic area. there will be concern in allowing previously infected, neutralizing antibody-positive individuals to be naturally exposed once again in the community, but such an approach has little difference to the broad testing of candidate vaccines. indeed, the answers may come sooner than the answers of whether vaccine candidates will succeed. infection exposures in the community for those previously infected with or without such antibody markers will also slowly answer other questions relating to those with low level neutralizing antibody (e.g., below threshold), those that do not have any measurable antibody, anamnestic responses, and susceptibility to changing virus. furthermore, the minimalist strategy will potentially set the goal posts for vaccine evaluations. reports of repeat sars-cov- infections have already begun to emerge as the pandemic continues [ , [ ] [ ] [ ] . undoubtedly, much more similar information will be collated anecdotally or in larger series and observations. an analysis of these is relevant in considering any minimalist strategy. gousseff et al. present a case series of healthcare workers and community patients who appeared to have a relapsing pattern of covid- [ ] . the establishment of re-infection within such a short period of time is tenuous at best. early and later positive diagnostic samples could be assessed with viral sequencing. serological profiling with both igg and igm and correlation with viral neutralization are additional tools of interest. the persistence of viral genome after acute infection, and as determined with genetic amplification technology, is well-known and can be measured in weeks. accordingly, comparison of diagnostic cycle thresholds can be of value as was done. co-determination of other pathogens, especially viral for co-infection, is essential. that some patients may clinically relapse with a complicating respiratory illness after an initial non-complicated illness is in keeping with many other respiratory infections. viral culture to confirm live virus provides an additional step in confirmation but evidently is difficult to achieve without support from reference level laboratories. as the authors suggest, are these examples simply ones of persistence or re-infection? bentivegna et al. describe a -year female with possible re-infection in which repeat rt-pcr positive samples of the respiratory tract were obtained in the context of four negative samples in between over a - -week period [ ] . immunoglobulin g serology was reactive on each occasion. igm serology was reactive only late in the second putative infection. blocking assays for the second serology could have potential use if devised. neutralization tests would have been of value to correlate with putative protection. an established fingerprint of immunoblotting if devised could be sought for in both early and later blood samples to further characterize the quality of immune reactivity. this case report emphasizes the role for a better understanding of applicable diagnostic and confirmatory serology. tomassini et al. highlight a case series of six patients who were possibly re-infected [ ] . igm serology, blocking for igg serology, neutralization correlates, and comparison of diagnostic ct values all have their potential merit. to and colleagues describe a repeat infection in a -year male in which two distinct isolates were believed to have been identified by whole-genome sequencing [ ] . the episodes occurred some months apart. measurable igg was not detected within days of the first episode. igm diagnostics, blocking for igg serology, and neutralization correlates all have their potential merit. the authors initiate relevant dialog about the relevance of genetic drift and possible re-infection. van elslande et al. provide some evidence for a repeat infection after a -month interval [ ] . a comparison of diagnostic samples suggested repeat infection with phylogenetically distinct strain detections. diagnostic serology with blocking studies, neutralization correlates, and comparison of diagnostic ct value all have their potential merit. these authors repeat the theme on genetic drift and its implications. in any of the aforementioned, sample collection and recollection validation shortly after the initial diagnostic specimen test positive can also contribute to overall accuracy of determining re-infections. while such an approach to defining protective immunity in the interim reaches our goals if that is possible, the otherwise sensible approaches to disease prevention should continue to be enforced. given the current evidence on person-person direct transmission, person-person aerosol transmission, and environment-person indirect transmission, adherence to the basic principles of abrogating infection spread should be maintained as is practical. facets of physical distancing, appropriate decontamination and disinfection, and contextappropriate use of masking all have their roles in minimizing risk. it will be the study populations where some of these preventions may be less stringent in order to test the hypotheses of natural protection after infection or vaccine prevention. nevertheless, if we do define a highly probable and preventative serodiagnostic correlation, the modes of prevention may eventually be seen in alternative fashion or stringency. the overall approach to disease control will be fluid and will adapt as the potential arises. the global economic outlook during the covid- pandemic: a changed world after less than months, the simulations that drove the world to strict 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and soluble ace inhibition of a replicationcompetent vsv-sars-cov- and a clinical isolate of sars-cov- longitudinal dynamics of the neutralizing antibody response to sars-cov- infection development of a safe neutralization assay for sars-cov and characterization of s-glycoprotein clinical recurrences of covid- symptoms after recovery: viral relapse, reinfection or inflammatory rebound? new igm seroconversion and positive rt-pcr test after exposure to the virus in recovered covid- patient setting the criteria for sars-cov- reinfection-six possible cases symptomatic sars-cov- reinfection by a phylogenetically distinct strain publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations acknowledgments this review is dedicated to those healthcare workers and researchers who have had the commitment to protect the populace and energetically pursue the science. key: cord- -epsi qq authors: feng, gong; huang, wan-qiang; liu, man-ling; lin, si-ceng; zhang, xiao-zhou; zhang, yan; he, xiao-qing; liu, jun-lin; chen, zi-jun; guo, zi-kai; gao, jie; yao, cheng-zi; he, na; yan, qin-qin; mi, man title: clinical features of covid- patients in xiaogan city date: - - journal: sn compr clin med doi: . /s - - -z sha: doc_id: cord_uid: epsi qq on february , , xiaogan city became the second most seriously affected city with coronavirus disease (covid- ), outside wuhan district, hubei province, china. the objectives are to study the clinical features of covid- patients and assess the relationship between the severity of covid- , age, and c-reactive protein (crp) levels. the retrospective data of covid- patients hospitalized in hospitals of xiaogan city, between february and march , , was collected. this study documented covid- patients. clinical data in terms of body temperature, history of travel, and direct contact with covid- patients, and incubation period was collected. out of the patients, only required intensive care. moreover, patients succumbed during this period. the median age of patients was ( – ) years. the most common symptoms at the onset of disease were fever ( . %), cough ( , %), and sore throat ( . %). amongst the medicines used, antiviral agents ( . %) followed by the traditional chinese medicine ( . %) were most commonly used. in both the crude and adjusted (i to iii) models, odds ratio and its % confidence interval for both age and crp levels were > . moreover, the smooth curve fitting graph reflected that the severity of covid- was positively correlated with both age and crp levels (all p value < . ). the signs and symptoms of covid- patients were fairly moderate. the health care professionals treating the covid- patients should be aware of the increased likelihood of progression to severe covid- in elderly patients and those with high crp levels. coronavirus disease (covid- ), resulting from an infection with the severe acute respiratory syndrome coronavirus (sars-cov- ), has become a serious threat to global public health [ , ] . on february , , xiaogan city became the second most seriously affected city, outside wuhan, hubei province, china, by covid- [ ] . the sars-cov- , severe acute respiratory syndrome coronavirus (sars-cov), and middle east respiratory syndrome coronavirus (mers-cov) are responsible for severe and potentially lethal acute respiratory syndromes in humans. unfortunately, to date, there are no specific/targeted drugs, or vaccines, and the number of sars-cov- -positive patients is growing in various parts of the world. in spite of the rising number of confirmed cases, the epidemiological studies involving covid- are insufficient, especially those focusing on asymptomatic patients, patients with mild symptoms, or the areas surrounding the covid- hotspots [ ] . it is worth mentioning that around - % of covid- patients either are asymptomatic or have mild wan-qiang huang, man-ling liu, si-ceng lin, xiao-zhou zhang, yan zhang, xiao-qing he and jun-lin liu contributed equally to this work. this article is part of the topical collection on covid- * na he ylhena@ .com * qin-qin yan yanqinqin @ .com * man mi a @ .com disease, but this does not result in their decreased ability to spread the virus. thus, these patients may trigger a new wave of covid- outbreak [ ] . moreover, the attention received by the covid- hotspots often exceeds the areas around them, which may result in a surge in the number of patients. in a study by lu et al., multivariate cox regression analysis revealed that the patient's age and c reactive protein (crp) levels are independent risk factors for predicting the death [ ] . but the studies exploring the relationship between age, crp levels, and the severity of covid- , especially by the means of smooth curve fitting, are lacking. thus, we describe the clinical characteristics as well as laboratory findings of covid- patients residing in xiaogan city, so as to have an insight regarding the prevention as well as treatment of covid- , and simultaneously explore the relationship between age, crp levels, and the severity of covid- , thereby exploring the indicators for predicting the severity of covid- . this was a retrospective study involving the confirmed covid- cases, diagnosed between february and march , , and residing in xiaogan city. since the break out of covid- , stringent preventive measures were followed in hubei province, including the introduction of fever clinics that catered specifically to the suspected covid- patients, defined as the presence of fever, dry cough, or any respiratory signs, and particularly those with a history of travel to wuhan or direct exposure to confirmed covid- patients within weeks prior to the beginning of disease. a confirmed case of covid- was defined in accordance with the criteria given by the world health organization (who) [ ] . only the laboratory confirmed covid- patients were included in the study. we gathered the information of laboratory confirmed covid- patients admitted in hospitals of xiaogan city. the collected data included the dates of disease onset, visits to clinical facilities, and hospital admissions. the incubation period was defined as the duration between direct exposure and the onset of symptoms, estimated amongst the patients providing a reliable date of close contact with confirmed or suspected covid- patients from wuhan. the epidemiological information was gathered through short interviews involving each patient. the medical records of patients were fetched and sent out to the data collection center located in xiaogan. the data was gathered and evaluated by a group of physicians directly involved in the treatment of covid- patients. the data was then entered in a specifically designed case report form. however, if the available information was unclear, the working group in xiaogan contacted the doctor in-charge and a clarification was obtained. this study was approved by the ethics committee of the xiaogan central hospital in hubei province. written informed consent was obtained from each participant. at admission, sputum specimens and throat swabs were collected from all the patients. the presence of virus was confirmed by subjecting the samples to real-time polymerase chain reaction (rt-pcr) for sars-cov- rna within h. rt-pcr was repeated twice every h. other laboratory tests included a complete blood count, serum biochemistry, and recognition of other respiratory pathogens including influenza a virus (h n , h n , h n ), influenza b virus, respiratory syncytial virus, and others. the majority of the patients received antiviral treatment. similarly, many patients received probiotics. moreover, the patients with resting respiratory rate > per minute, oxygen saturation < % on room air, or > % progression of illness involving numerous pulmonary lobes on two consecutive days on chest computed tomography (ct) received corticosteroid ( - mg/day) and gamma globulin ( - g/day) for - days. antibiotics such as quinolones and ndgeneration beta-lactams were used, if the fever lasted for > days or the levels of crp were ≥ mg/l (normal range - mg/l). covid- patients were considered as cured and subsequently discharged from the hospital, if the outcomes of successive rt-pcr, performed h apart, were negative. in order to explore the association between age, crp levels, and severity of covid- , we used the methods of multiple regression equation and curve fitting. the multiple regression equation included crude and adjusted (i, ii, and iii) models and were used to remove the influence of confounding factors and find independent quantitative effect values [ ] . in order to intuitively reflect the relationship of disease severity with age and crp levels, we used the method of smooth curve fitting [ ] . on admission, based on the american thoracic society guideline, the study cohort was divided into severe and non-severe cases [ ] . the continuous variables were described as either means and standard deviations or medians with interquartile ranges, while the categorical variables were described as percentages. differences in the laboratory values were assessed by the student's t test or the mann-whitney u test (for normally or not normally distributed continuous variables, respectively). a p value of < . was considered as statistically significant and analysis was performed by spss version . (spss, chicago, il, usa) for windows and r . . (r advancement core group, http://www.r-project.org). the median age of confirmed covid- patients was ( - ) years. over half of all the patients were women ( . %). a history of contact with wildlife, recent travel to wuhan, and close contact with people from wuhan was observed in . %, . %, and . % of patients, respectively. moreover, patients were local residents of wuhan (table ) . amongst the patients, there were only ( . %) patients with severe illness, of which ( . %) received care in intensive care units (icu) and patients died. amongst the patients with coexisting conditions, ( . %) had hypertension, ( . %) had diabetes, and only ( . %) had cerebrovascular disease. the median duration from the beginning of symptoms to hospital admission was . ( . - . ) days. the most common symptoms reported at the disease onset were fever ( . %), cough ( . %), sore throat ( . %), myalgia or fatigue ( . %), shortness of breath ( . ), nausea and vomiting ( . ), diarrhea ( . ), and chest pain ( . %) ( table ) . in order to explore the relationship between the severity of covid- and crp, the laboratory data was collected in detail, and the data was then divided into severe and nonsevere group, as well as icu and non-icu groups ( table ) . compared with non-severe patients, the severe patients had significantly higher median blood levels of white blood cell (wbc) count, neutrophil count, alanine aminotransferase (alt), aspartate aminotransferase (ast), potassium, blood urea nitrogen (bun), fasting glucose, crp, and lactate dehydrogenase (ldh) and significantly lower median blood levels of lymphocyte count, albumin, and sodium (all p values < . ). similarly, compared with non-icu patients, icu patients had significantly higher median blood levels of ast, potassium, fasting glucose, crp, creatinine, and ldh and significantly lower median blood levels of lymphocyte count, sodium, and albumin (all p values < . ). amongst patients who underwent chest ct on admission, the most common patterns were ground-glass opacity ( . %) and bilateral patchy shadows ( . %). severe patients yielded more prominent radiologic abnormalities on than non-severe patients (all p values < . ). amongst all the patients with covid- , the most common complications were acute respiratory distress syndrome (ards, . %), cardiac arrhythmias ( . %), myocardial injury ( . %), ventilator-associated pneumonia (vap, . ), and acute kidney injury ( . %). overall, in terms of medication, intravenous antibiotics, antifungal agents, antiviral agents, corticosteroid, immunoglobulin, and chinese medicine were administered in . %, . %, . %, . %, . %, and . % respectively. simultaneously, oxygen inhalation, invasive, and noninvasive mechanical ventilation were initiated in . %, . %, and . % patients respectively ( table ) . the relationship between severity of covid- and age was assessed by the methods of multiple regression equation and smooth curve fitting. in the crude mode, the severity of covid- was associated with age (odds ratio (or) = . , % ci . - . ). additionally, this relationship was also evident through adjusted i model (or = . , % ci . - . ), adjusted ii model (or = . , % ci . - . ), and adjusted iii model (or = . , % ci . - . ) ( table ). the smooth curve fitting graph also reflected that the severity of covid- was positively correlated with age (fig. ) . similarly, the crude mode revealed an association between the severity of covid- and crp levels (or = . , % ci . - . ). additionally, this relationship was also evident through adjusted i model (or = . , % ci . - . ), adjusted ii model (or = . , % ci . - . ), and adjusted iii model (or = . , % ci . - . ) ( table ). the smooth curve fitting graph also reflected that the severity of covid- was positively correlated with crp levels (fig. ). compared with the initial covid- patients observed in wuhan, in terms of disease symptoms and severity, the patients from xiaogan city, in our study, were relatively moderate, but we could not neglect asymptomatic or mild patients. according to michael osterholm, director of the center for infectious disease research and policy, university of minnesota, knowing the proportion of asymptomatic or mild patients is crucial to understand the reasons behind a particular epidemic [ ] . a study investigated japanese citizens (n = ) evacuated from wuhan in early february. all these individuals were monitored for the symptoms and repeatedly tested for sars-cov- . it was reported that only of the evacuees were infected, of which ( %) never developed any symptom [ ] . a shanghai children's medical center study involving more than sars-cov- infected children across the country found that % of the children were asymptomatic or had mild form of covid- [ ] . thus, the only way to prevent the spread of these asymptomatic cases is the use of social isolation measures including closing the schools, cancelling public gatherings, and keeping people at home and away from public places. in terms of medication, following the antiviral agents, chinese herbal medicines were most widely used. amongst the confirmed covid- chinese patients, . % used chinese herbal medicine, of which . % resided in hubei province [ ] . clinical observations have revealed that the cure rate with traditional chinese medicine (tcm) has reached over % [ ] . the tcms have been found to effectively alleviate the symptoms, contain the progress of the disease, improve the cure rate, reduce the mortality rate, and promote the recovery from covid- [ , ] . as per our analysis, the severity of covid- was found to be positively correlated with the age and crp levels. firstly, the crp levels were significantly elevated amongst the severe patients and those admitted in icu (all p value < . ), as compared with non-severe and non-icu patients, respectively. secondly, in both the crude and adjusted (i to iii) models, the value of or was > (all p value < . ). finally, as per the smooth curve fitting, the severity of covid increases with increase in the age and crp levels (all p value < . ). this study has some limitations. the sample size was insufficient, especially the severe cases. when the data was collected, most of the patients were still hospitalized, so we were unable to estimate either the case fatality rate or the predictors of fatality. compared with the patients primarily infected with sars-cov- in wuhan, the signs and symptoms of patients in xiaogan city were fairly moderate. to prevent another wave of covid- outbreaks, these asymptomatic or mild patients should not be ignored. the tcms were widely used and could play a significant role in the treatment of covid- patients. the severity of covid- was positively correlated with the age and crp levels. thus, in clinical practice, to prevent worsening of the disease, the treating physicians should pay special attention to elderly covid- patients and those with high crp levels. funding information this work was supported by grants from the epidemic prevention and control project of shaanxi institute of higher education(xgh ), the social science foundation of shaanxi province ( g ), and chang'an university graduate student scientific research practice project ( ). compliance with ethical standards this study was approved by the ethics committee of the xiaogan central hospital in hubei province. written informed consent was obtained from each participant. a novel coronavirus from patients with pneumonia in china early transmission dynamics in wuhan, china, of novel coronavirusinfected pneumonia a tadiomics nomogram for the preoperative prediction of lymph node metastasis in bladder cancer clinical findings in a group of patients infected with the novel coronavirus (sars-cov- ) outside of wuhan, china: retrospective case series covert coronavirus infections could be seeding new outbreaks acp risk grade: a simple mortality index for patients with confirmed or suspected severe acute respiratory syndrome coronavirus disease (covid- ) during the early stage of outbreak in wuhan machine learning algorithms outperform conventional regression models in predicting development of hepatocellular carcinoma noninvasive central systolic blood pressure is more strongly related to kidney function decline than peripheral systolic blood pressure in a chinese community-based population association between admission temperature and mortality and major morbidity in preterm infants born at fewer than weeks' gestation diagnosis and treatment of adults with communityacquired pneumonia. an official clinical practice guideline of the estimation of the asymptomatic ratio of novel coronavirus infections (covid- ) epidemiological characteristics of pediatric patients with coronavirus disease in china prevalence and risk factors of significant fibrosis in patients with nonalcoholic fatty liver without steatohepatitis traditional chinese medicine for covid- treatment lianhuaqingwen exerts anti-viral and anti-inflammatory activity against novel coronavirus (sars-cov- ) publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors declare that they have no conflicts of interest. key: cord- - t yaoct authors: ismaili, nabil; elmajjaoui, sanaa title: covid- and gynecological cancers: a summary of international recommendations date: - - journal: sn compr clin med doi: . /s - - -x sha: doc_id: cord_uid: t yaoct morocco and the rest of the world are experiencing a pandemic of a new coronavirus known as covid- or sars-cov- (severe acute respiratory syndrome coronavirus ). on august , , the spread of the virus in morocco had caused more than , cases and deaths. cancer patients are more susceptible to develop an infection than people without cancer because of their immunosuppression caused by the disease and treatments (surgery and chemotherapy). therefore, these patients are at higher risk of infection with covid- and a much higher risk of developing more serious forms. given this epidemiological context, the establishment of guidelines for patients with gynecological cancers, requiring multidisciplinary management during the global covid- pandemic, is crucial to limit their infection while maintaining their chances for a cure. in this paper, we summarize the international covid- recommendations on the prioritization of surgical cases, the perioperative protective measures, the precautions to be taken in the brachytherapy unit, the covid- screening, and finally the therapeutic indications of gynecological cancers by tumor location. morocco and the rest of the world are experiencing a pandemic of a new coronavirus known as covid- or sars-cov- (severe acute respiratory syndrome coronavirus ) [ ] . on august , , the spread of the virus in morocco had caused more than , cases and deaths. cancer patients are more susceptible to develop an infection than people without cancer because of their immunosuppression caused by the disease and treatments, such as chemotherapy and/or surgery. therefore, these patients are at higher risk of infection with covid- and a much higher risk of developing more serious forms [ ] . given this epidemiological context, it is important to establish recommendations that may still offer these patients effective treatment while at the same time limit their exposure and infection with the virus. in fact, a recent turkish study of patients who received surgery for gynecological cancers during the covid- pandemic showed that gynecological cancer surgery can be performed safely when appropriate measures to protect patients and staff from the exposure to covid- are taken preoperatively, intraoperatively, and postoperatively. only % of cases developed symptoms of covid- after surgery, and no member of the surgical team developed symptoms related to covid- disease [ ] . two precautions seem to be important for our patients [ , ] : ) limiting the consequences of very high-risk situations such as surgery and chemotherapy; ) limiting exposure of patients to treatment stations. to protect patients and healthcare staff form covid- contamination, screening of covid- infection in cancer patients should be recommended before initial management. screening should be based on clinical evaluation of symptoms suggestive on covid- infection, systematic temperature taking at the entrance to cancer units, and, on pcr test, possibly coupled with a chest ct scan, depending on availability, in addition to blood tests to look for eosinopenia, lymphopenia, and an increase in inflammatory parameters. teleconsultation is an interesting monitoring tool that ensures continuity of care for cancer patients and thus reduces the unnecessary physical travel to care facilities, by selecting those who really need it. in this paper, we sought to report useful recommendations to reduce the impact of this pandemic in patients with gynecologic cancers. face masks can provide source control (protecting others from respiratory secretions from the mask wearer) and protection (protecting the wearer from secretions from others), but not all masks play both roles. for example, surgical masks provide source control with limited or no wearer protection, while n (or ffp mask) respirator masks provide source control and wearer protection. n respirators are also recommended for the care of covid- positive/suspected patients [ ] . access to rapid and reliable tests to detect the presence of an active infection by the virus has been a major challenge during this pandemic due to the limited capacities of testing. the cdc (https://www.cdc.gov/coronavirus/ -ncov) and many medical institutions rapidly developed pcr tests in nasopharyngeal or oropharyngeal swabs. clinical screening is based on the evaluation of symptoms of a viral infection (fever, dry cough, tiredness, etc.), systematic temperature taking at the entrance to cancer units, and research of potential contact with high-risk individuals, including those in quarantine. all patients should undergo clinical screening by teleconsultation prior to visit, before the entrance to the cancer center, and immediately prior to surgery, etc. [ ] . diagnostic testing involves identifying specific genes for sars-cov- (core or envelope) by real-time rt-pcr, with most results expected within to h. theoretically, rt-pcr assays for sars-cov- is very sensitive to detect the presence of viral rna. however, the limit of detection differs for different respiratory tract sources. the performance of rt-pcr from nasopharyngeal secretions varies depending on the time since symptom onset or exposure to covid- virus, the false-negative rate ranged from to %. routine preoperative covid- testing is recommended due to the high prevalence of asymptomatic cases. a single negative test cannot exclude the wearing of n masks, when available, during agp (aerosol-generating procedures). in surgical emergencies, surgery should be performed on the assumption that the patient is positive if test results are not available [ ] . preoperative screening by chest computed tomography (ct) may be relevant in patients at risk. indeed, nearly % of covid- pneumonia occurs in asymptomatic patients. in settings where rt-pcr testing is not available and in areas of high prevalence of covid- , chest ct may be the only option as a preoperative test. however, the cdc (https:// www.cdc.gov/coronavirus/ -ncov) and the american college of radiology do not recommend performing chest ct as a test for covid- but reserve it for diagnostic purposes in symptomatic patients [ ] . the american college of surgeons (acs) and other international societies have established recommendations to protect patients and medical staff from covid- contamination and to preserve hospital resources. patients with gynecological cancers often require surgery which is particularly disrupted during the covid- pandemic. consequently, accurate triage of urgent vs elective surgical cases is crucial in order to preserve the availability of medical resources to face a growing number of covid- -positive patients. in addition, hospitals are an important vector for the virus spread therefore guidelines should be strategic to ensure the safety of patients and staff [ , ] . most cancer-related interventions, including those for gynecologic cancers, are given a high priority level (semiurgent) [ , ] . the surgical prioritization is determined according to: the highest priority should be given to the surgical treatment of high-risk cancers, especially those candidates for minimally invasive surgery (such as robotic surgery) and short hospital stay, in addition to potentially curative procedures for early-stage cancers. in addition, women with advanced ovarian and uterine cancers, requiring cytoreductive interval surgery after neoadjuvant chemotherapy should be given priority when possible. however, in the restricted surgical areas of high covid- prevalence, cytoreduction (primary/interval) should be postponed, and chemotherapy started (or continued up to cycles) to prevent exposure of immunocompromised patients to the virus and to conserve hospital resources [ ] . according to the american society for colposcopy and cervical pathology (asccp), surgery for high-grade dysplasia may be delayed for up to months and dysplasia of lower grade surgery can be delayed for to months. in contrast, patients with invasive disease should be treated within month [ ] . during surgery, the most dangerous time in a covid- positive or unknown patient is endotracheal intubation and extubation considered as aerosol-generating procedures (agp). agps are more likely to generate higher concentrations of infectious respiratory aerosols than coughing, sneezing, speaking, or breathing. therefore, enhanced security measures are necessary [ ] . the following recommendations allow a fast and safe intubation/extubation process for all operating room staff [ ] : & only necessary personnel should be in the operating room during the intubation/extubation process. the rest of the surgical team should stay out of the room, and the time of re-entry depends on the type of mask they wear and the level of air renewal in the room. in a standard operating room, % of airborne pathogens are cleared from the room within min, after which time staff can re-enter safely with surgical masks and eye protection. the surgeon and operating room staff may also wear an n respirator with goggles if they cannot leave the room (patient not masked). & rapid sequence intubation and video laryngoscopy reduce the risk of aerosolization and promote accuracy and increase the distance between the intubator and the patient. & all surgeons should wear the usual cap, gowns, protective shoes, and double gloves. n masks and eye protection are recommended for agp procedures; a surgical mask with eye protection can be used for non-agp procedures. robotic surgery has major advantages over laparoscopic surgery. robotic surgery can be performed safely with pressures low than mmhg. this lower pressure requirement probably reduces the risk of transmission of viral particles to the medical staff. another advantage is the reduced number of healthcare professionals in an operating room and the distance between team members. in conventional laparoscopic surgery, the surgical team traditionally includes the surgeon, an assistant, a technician, and a nurse. these members are very close to each other. with robotic surgery, the surgeon's console is separated from the robot, providing more space between team members. additionally, robotic surgery may require fewer assistants, which means less overall exposure [ ] . during the covid- pandemic, precautions should be done in order to reduce the spread of the virus in brachytherapy unit: & management of cancer patients should be done in "covid- -negative" units for patients with cervical cancers, to minimize the risk of contamination, prefer the schemes with a reduced number of fractions: × gy or × gy by using an hdr icbt schedule of gy per fraction for fractions in insertions week apart. for patients over years of age or with significant comorbidities who have small tumors or responding well to external beam radiotherapy (ebrt), a more shortened schedule of gy per fraction in fractions at week apart may be considered. in stage i, low-risk endometrial cancer, it is recommended to postpone brachytherapy up to weeks. for patients with significant comorbidities, exposing them to the risk of severe complications of covid- infection, it may be judicious to delay brachytherapy for months. patients, who should start vaginal vault brachytherapy (vvb), should consider the schedule of gy for fractions, to limit the number of patient displacement. an interval spacing of days between the fractions is also acceptable. however, for high-risk patients who received adjuvant external rt, omitting bvv may be reasonable. for stage ii endometrial cancers, adjuvant vvb is delivered exclusively (if invasion < % of the myometrium, g and ) or after ebrt (if invasion > % of the myometrium, g ). in both cases, consider to postpone brachytherapy by to months. in the case of a covid- -positive patient, postpone treatment for at least days [ ] . for low-grade cervical dysplasia, the diagnostic evaluation may be postponed for to months. however, in the case of high-grade dysplasia (cin or cis), the diagnostic evaluation should be done within months [ , ] . for patients with early-stage cervical cancer (figo ia, ib , ib , and iia stages), if surgery is still allowed in the institution, consider standard treatment with surgery. however, when access to surgery is limited, the following procedures may be considered [ ] [ ] [ ] [ ] ] : & for limited disease, consider to postpone surgical treatment (trachelectomy or radical hysterectomy) for a period of weeks or until the crisis resolves; & for microscopic disease (stage ia) or low-risk disease (< cm, low-risk histology excluding adenocarcinoma and small cell carcinoma), consider conization or a simple trachelectomy + sentinel node mapping (if available) or pelvic lymphadenectomy; & for large tumor > cm (stage ib or iia), surgical staging is more accurate than clinical and radiological staging and should be discussed on a case by case basis. the primary treatment is either surgery or radiotherapy/brachytherapy. radical hysterectomy with bilateral pelvic lymph node dissection ± para-aortic lymph node dissection is the preferred surgical option. radiotherapy/brachytherapy should be considered in the case of limited access to surgery or for patients who are not eligible for hysterectomy [ ] . for locally advanced stages of the disease (figo stages ib , ib -iva), concurrent chemoradiotherapy followed by brachytherapy is recommended and should be started on time without delay [ , ] . consider hypo-fractionated radiotherapy to reduce the frequency of patient exposure to treatment stations [ ] . patient with metastatic cervical cancer should be considered for first-line chemotherapy based on paclitaxelcarboplatin ± bevacizumab (prefer carboplatin to cisplatin) [ ] . however, second-line treatment has a low benefit and limited priority. for early-stage disease (ia and ib), surgery is the primary treatment [ , ] . minimally invasive laparoscopic surgery/ robotic surgery results in lower perioperative complication and should be the preferred option if available [ ] . useful preoperative prognostic factors to guide treatment strategy are age, lympho-vascular invasion, tumor size, depth of uterine invasion, and lymph node involvement [ ] . for low-risk cancers (stage ia, grade and ), consider total hysterectomy and bilateral salpingo-oophorectomy (th/bso) with sentinel lymph node procedure (if available) or lymph node dissection. for intermediate risks (ib, grade and ), radical surgery plus vaginal brachytherapy is the preferred strategy [ , , ] . for elderly women and for patients with comorbidities, initial systemic therapy with hormone therapy (for estrogen and progesterone receptor positive), and postpone surgery until the crisis resolves [ , ] . for high-risk cancers (ib grade or high-risk histology type ), the recommended surgical procedure includes th/bso with surgical staging and lymph node dissection in a single-incision surgery [ ] . adjuvant treatment with radiotherapy without brachytherapy is recommended and should be started within months [ , , ] . systemic adjuvant therapy using carboplatin auc plus paclitaxel mg/ m for cycles is to be considered in high-risk disease. consider granulocyte colony-stimulating factors (gcsf) to limit the risk of febrile neutropenia. in stage ii endometrial cancer, proceed with radical surgery and consider adjuvant therapy for patients with high-risk factors (same as stage i). for locally advanced stages (iii and iva), surgical treatment is the treatment of choice [ , , ] . adjuvant treatment with radiotherapy ± vaginal brachytherapy is recommended. in the adjuvant setting, chemotherapy with carboplatin plus paclitaxel (plus gcsf) is the preferred regimen for cycles [ , ] . for patients who are not suited for surgery, radiotherapy/ brachytherapy is an effective treatment and may be considered with or without chemotherapy [ ] . for metastatic disease (figo ivb stage), chemotherapy based on carboplatin/ paclitaxel plus gcsf is recommended. elderly patients or pauci-symptomatic patients with low-grade histology favor mono-chemotherapy (paclitaxel, doxorubicin, carboplatin) or hormone therapy (for hormone receptor-positive cancers) [ , ] . early-stage ovarian cancer proceeds with oophorectomy on the suspect mass; then, the decision to complete surgical staging is based on final histological analysis [ , ] . consider adjuvant chemotherapy with carboplatin-paclitaxel ( cycles) for patients with high-grade serous and endometrial ovarian carcinoma. for early-stage non-serous, non-endometrioid, or low-grade histological cancers, the benefit of chemotherapy is controversial and surveillance is the preferred option. for stages ic and ii (with high-risk factors), consider adjuvant chemotherapy with paclitaxel-carboplatin plus gcsf for cycles [ ] . for patients with advanced stage (stages iii/iv) high-grade epithelial (serous or endometrioid) ovarian cancer, the standard treatment is based on primary debulking surgery and adjuvant chemotherapy (protocol based on the result of the surgery). however, during the covid- pandemic, neoadjuvant chemotherapy (nac) strategy is the preferred option even in patients who are candidates for primary surgery because of the occupancy of intensive care unit beds by covid- patients [ ] . in addition, randomized trials have reported a significant reduction in operative time and complications in favor of nac. carboplatin auc /paclitaxel mg/m every weeks for cycles is the recommended regimen, following neoadjuvant treatment, consideration of maximum debulking surgery with total hysterectomy (th), bilateral salpingo-oophorectomy (bso), omentectomy, and complete resection of all visible disease. in the case of r surgery first, adjuvant treatment based on carboplatin/paclitaxel for cycles is recommended without maintenance chemotherapy [ , ] . for patients with high-risk factors (r and r resection, and stage iv disease), maintenance treatment with bevacizumab is recommended [ ] . for patients with a germ line or somatic brca / mutation, maintenance therapy with parp inhibitor is the preferred option (if available) [ ] . for patients receiving neoadjuvant chemotherapy, consideration of extending treatment for six cycles until the crisis resolves and postpone surgery at a later date, due to the unavailability of icu beds . for patients not eligible for surgery, chemotherapy with carboplatin/paclitaxel and bevacizumab for cycles followed by maintenance bevacizumab is recommended. for patients with brca mutation, consider the early start of maintenance therapy with parp inhibitors after cycles of chemotherapy [ , ] . after disease progression, chemotherapy may be indicated for symptomatic patients [ , ] . for early-stage vulvar cancer (t or t ), primary surgery is the treatment of choice [ ] . inguino-femoral lymph node dissection is recommended for t or t stages with a depth of invasion > mm. consider adjuvant radiotherapy for high-risk disease with adverse prognostic factors in the pathology report (lymph node involvement, positive vascular emboli, marginal < mm or positive tumor margins, tumor size > cm, and or depth of invasion) [ ] . when surgical management would require very heavy surgery, consider concurrent chemoradiotherapy. for elderly women with early-stage disease, postpone treatment by - weeks. for locally advanced vulvar cancer (t -t ), standard treatment is based on concurrent chemoradiotherapy with cisplatin or -fu/cisplatin [ ] . for metastatic disease, consider radiotherapy for symptoms palliation and local control [ ] . chemotherapy and supportive care are two alternatives in the context of the covid- pandemic [ ] . for early-stage i squamous cell carcinoma of the vagina, if < mm of invasion, exclusive brachytherapy is the treatment of choice. in patients with significant comorbidities (old age, chronic respiratory pathology or cardiac, immunosuppression ...), consider to postpone brachytherapy by to months. if invasion > mm, consider radiotherapy followed by brachytherapy. for patients with stage i vaginal adenocarcinoma, consider radical vaginectomy and hysterectomy with lymph node dissection. adjuvant rt should be considered in the case of close or positive surgical margins [ ] . for patients with advanced stage vagina cancer (ii, iii, and iva), radio-chemotherapy and brachytherapy are the treatment of choice [ ] . for stage ivb vaginal cancer, palliative chemotherapy based on fluorouracil-carboplatin is the preferred option [ , ] . recognizing that the morbidity and mortality from postoperative covid- pneumonia is significant, surgery should be delayed in covid- -positive patients until they are asymptomatic for more than weeks; some teams recommend a negative control test by rt-pcr [ , ] . the largest series (n = ) analyzing patients with gynecological cancer and covid- infection is that of the new york city, an area highly exposed to the coronavirus. overall mortality among patients infected with covid- and having gynecologic cancer was %, while mortality among hospitalized patients was . %. these results show that the mortality rate among patients hospitalized in this series is lower compared with the rate reported in the general population of the new york region which is . %. this suggests that patients with gynecologic cancer and covid- infection do not have a higher risk of covid- -related mortality compared with the general population [ ] . a dedicated circuit should be implemented for covid- positive patients whose management cannot be postponed. during urgent surgery for covid- -positive patients, patient and staff safety must be the priority. each center should consider assigning a dedicated team of surgeons to provide surgical care for covid- patients. professional at high risk of developing severe forms of covid- should avoid participating in the surgical care of covid- -positive patients. according to the cdc (https://www.cdc.gov/coronavirus/ -ncov), these persons are those aged > or those with chronic lung disease, moderate/severe asthma, severe heart disease, immunosuppressive disease or therapy, cancer, etc. it is also desirable to limit the exposure of pregnant women to covid- patients [ , ] . very high priority: curative chemotherapy with high benefit (> %): chemotherapy for trophoblastic and germ cell tumors. concurrent chemoradiation in cervical, vaginal, and vulvar cancers. high priority: curative treatment with intermediate benefit ( to %) compared with local treatment alone: chemotherapy in high-grade epithelial ovarian cancer. medium priority: curative treatment with low benefit ( - %): high-grade ovarian cancer during the first platinumsensitive relapse. high-grade advanced endometrial cancer. low priority: palliative treatment with high benefit: palliative chemotherapy in the treatment of metastatic cervical, vaginal, vulvar, and endometrial. very low priority: palliative treatment with low benefit chemotherapy in platinum-resistant ovarian cancer. palliative radiotherapy for symptom control: palliative radiotherapy for metastases and symptomatic pelvic masses. authors' contributions all authors contributed to the conception and design, drafting, and critical revision of this manuscript. all authors have given final approval of this version to be published, and all authors accept responsibility for its contents. conflict of interest the authors declare that they have no conflict of interest. ethical approval this article does not contain any studies with human participants performed by any of the authors. covid- recommendations for patients with cancer: the post-covid- era performing gynecologic cancer surgery during the covid- pandemic in turkey: a multicenter retrospective observational study prise en charge chirurgicale des cancers gynécologiques en période de pandémie covid- -recommandations du groupe francogyn pour le cngof covid- global pandemic: options for management of gynecologic cancers when to operate, hesitate and reintegrate: society of gynecologic oncology surgical considerations during the covid- pandemic robotic surgery during the covid pandemic: why now and why for the future covid- , brachytherapy, and gynecologic cancers: a moroccan 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openlabel, multicentre, randomised, phase trial ottevanger pb; european organisation for research and treatment of cancer, gynaecological cancer group (eortc-gcg). systemic review: radiation therapy alone in medical non-operable endometrial carcinoma ovarian cancer, version . , nccn clinical practice guidelines in oncology nccn guidelines insights: ovarian cancer, version . . j natl compr cancer netw standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (icon ): overall survival results of a phase randomised trial covid- and gynecological cancers: a moroccan point-of-view vulvar cancer, version . , nccn clinical practice guidelines in oncology. j natl compr cancer netw pdq adult treatment editorial board. vaginal cancer treatment (pdq®): health professional version. pdq cancer information summaries bethesda (md): national cancer institute (us) covid- outcomes of patients with gynecologic cancer in new york city publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- -mkjogy h authors: trevisan, caterina; miconi, lorella; barbierato, emanuele; marinaro, giuseppe; targhetta, stefano; d’agata, mario; rinaldi, daniela title: labile pt-inr in a covid- patient under long-term vitamin k antagonist therapy: a case report date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: mkjogy h the coronavirus disease- (covid- ) has been associated with thromboembolic complications, but evidence on its impact on hemorrhagic risk are still scarce. we describe a case of covid- with hemorrhagic complication in the post-acute phase of the disease. the patient was a -year-old woman admitted to a post-acute care unit for covid- patients in northern italy. the patient’s medical history included moderate cognitive impairment, atrial fibrillation under oral anticoagulation (warfarin . mg and . mg on alternate days, showing stable pt-inr values since october ), and arterial hypertension. the patient was affected by covid- , treated with supportive therapy. in the post-acute phase of the disease, the patient presented with melena and showed a marked elevation of pt-inr of . . she was treated with venous infusion of three-factor prothrombin complex concentrate and vitamin k until pt-inr reduction. after days, blood analyses revealed normal hemoglobin, pt-inr . , and a slight alteration of liver function. this case supports a strong impact of the infection on the coagulative pattern not only pro-thrombotically but also by increasing hemorrhagic risk. special attention should therefore be paid to covid- patients under anticoagulation with vitamin k antagonist and a shift to heparin treatment until illness resolution may be a safe option in these individuals. the impact of infective diseases on coagulative pattern has been demonstrated by previous studies [ ] . this issue concerns, in particular, older individuals who, because of coexisting chronic conditions and pharmacologic treatments, nutritional disorders, and age-related changes in hemostasis, are at higher risk both of thromboembolic and hemorrhagic complications [ , ] . the coronavirus is caused by sars-cov- , and has been associated with thromboembolic complications [ , ] , such as myocardial infarction and stroke. however, evidence on its impact on hemorrhagic risk are still scarce [ ] , especially in patients who already are under anticoagulation treatment. we describe a case of covid- with hemorrhagic complication in the post-acute phase of the disease. the patient was a -year-old woman admitted to a post-acute care unit for covid- patients in camposampiero (padua, northern italy) on april , . the unit was set up by the local health and social services department to offer medium-and long-term care to covid- patients after the acute infection phase. it admits patients who usually have both medical and social needs and its purpose is to alleviate the burden of the pandemic on hospital departments providing higher intensity care. the patient was admitted to our unit in the post-acute phase of the disease because of a lack of adequate assistance at home. despite having moderate cognitive impairment (short performance mental status questionnaire score / ), the patient lived alone at home and, in the pre-covid- period, she attended a day care center for the elderly and received further assistance from her sons. in addition to cognitive impairment (for which she took trazodone mg/day), her medical history included atrial fibrillation under oral anticoagulation (warfarin . mg and . mg on alternate days), and arterial hypertension treated with two diuretics (furosemide mg/day and perindopril mg/day). the patient's pt-inr values had been regularly monitored since october (time in therapeutic range [ttr] estimated using the traditional method was . %, see fig. ). on march , the patient presented with fatigue, high fever, and cough, for which her general practitioner prescribed a nasopharyngeal swab for covid- , which was analyzed by reverse transcriptase-polymerase chain reaction (rt-pcr) assay. the test confirmed the presence of severe acute respiratory syndrome coronavirus (sars-cov- ) infection and the patient was given supportive therapy with antipyretics. her symptoms gradually improved from april , but since the patient's sons were by then also affected by covid- and were unable to give her assistance, on april , the patient was admitted to our unit for post-acute care and assistance. at admission, the patient was afebrile, her blood pressure and heart rate were within the normal range (bp / mmhg, hr bpm arrhythmic), and oxygen saturation in ambient air was %. at physical examination, breath sounds were slightly reduced at both lung bases, and there were no fine or coarse crackles. there were no substantial pathologic findings at the abdominal and neurologic examinations. given that the patient was clinically stable, biochemical analyses were arranged to be carried out a few days later. meanwhile, her home therapy was continued. on april , the patient presented with melena and bp below / mmhg, associated with an hr of bpm and an oxygen saturation in ambient air of %. she was transferred to the emergency department where recent upper gastrointestinal bleeding was confirmed at nasogastric lavage and digital rectal exam. blood examination showed mild leukocytosis (wbc . × /l, with high neutrophil [ . %] and low lymphocytes [ . %] ), normal levels of hemoglobin ( g/l) and platelets ( × /l), and slightly altered kidney function (estimated gfr ml/min). as illustrated in fig. , the coagulative pattern was markedly altered in respect to trend observed for months before infection, with a pt ratio of . , pt-inr of . , and aptt ratio of . . the patient was treated with a venous infusion of ui of three-factor prothrombin complex concentrate (factors ii, ix, x) and mg of vitamin k. pt-inr values at blood sampling . and . h after infusion were . and . , respectively. the hemoglobin concentration after . h was g/l. on april , the patient was re-admitted to our unit, anticoagulation was temporarily stopped, and a proton-pump inhibitor (pantoprazol mg) was administered twice daily via venous infusion. from april , the patient no longer exhibited signs of gastrointestinal bleeding. on april , blood analyses revealed hemoglobin g/l, pt-inr . , and a slight alteration of liver function with ast u/l (normal range: - ). the temporal relationship between covid- onset and pt-inr elevation in a patient whose pt-inr values were stable in the months before the hospitalization supports the hypothesis that this infection may impact on the coagulative pattern not only pro-thrombotically [ , ] but also by increasing hemorrhagic risk. this confirms that special attention should be paid to covid- patients under long-term anticoagulation with vitamin k antagonist and a shift to heparin treatment until illness resolution may be a safe option in these individuals [ ] . older people may be particularly vulnerable to the influence of covid- on pt-inr instability due to nutritional deficiencies, co-occurring clinical conditions, and possibly liver dysfunction, which may be exacerbated by sars-cov- infection. conflict of interest the authors declare that they have no conflict of interest. the study was carried out in accordance with the declaration of helsinki and subsequent amendments or comparable ethical standards. informed consent for reporting the patient's data in an anonymous form was obtained from her next of kin. review: viral infections and mechanisms of thrombosis and bleeding mortality rate and risk factors for gastrointestinal bleeding in elderly patients anticoagulation in older adults with multimorbidity incidence of thrombotic complications in critically ill icu patients with covid- covid- and its implications for thrombosis and anticoagulation clinical features of covid- in a young man with massive cerebral hemorrhage-case report switch from oral anticoagulants to parenteral heparin in sars-cov- hospitalized patients publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- -taaz mhs authors: fatehi, poya; hesam-shariati, negin; abouzaripour, morteza; fathi, fardin; hesam shariati, mohammad bakhtiar title: acute ischemic and hemorrhagic stroke and covid- : case series date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: taaz mhs the coronavirus covid- pandemic is the defining global health crisis of our time and the greatest challenge we have faced since the world wars; it can attack several systems in the body and has high complications and mortality. covid- can cause venous and arterial thromboembolism due to immobility, high inflammation, extensive intravascular blood coagulation, and hypoxia. in this study, we report cases of adults with covid- , hospitalized in tohid hospital, sanandaj, iran. three patients were male and two were female. the youngest patient was years old and the oldest was years old. all patients had at least one family member with coronavirus. fever, chills, muscular pain, cough, and tachypnea were present in all patients. red blood cell (rbc) was observed in all patients at a low level. computed tomography (ct) scans of all patients showed abnormal findings in different areas of the brain. these cases indicate that covid- may damage blood vessels in the brain and lead to stroke. covid- (coronavirus) is a viral respiratory disease, which has infected many people around the world in the past months. the world health organization (who) declared covid- as a global health emergency in january [ ] . dry cough and fever are two of the most common symptoms of this disease, which can cause complications such as chest pain, acute respiratory distress syndrome (ards), and vascular insufficiency [ ] . factors such as old age, hypertension, diabetes, neutrophilia, lymphocytopenia, high inflammatory indicators, and blood coagulation disorders are the key agents in causing death and respiratory distress in patients with covid- [ ] . there is ample evidence that the covid- effects are not always limited to the respiratory system but can also impair the cardiovascular, gastrointestinal, urinary, reproductive, and nervous systems [ , ] . symptoms of coronavirus affecting the nervous system can be classified into three groups: ( ) symptoms of central nervous system that include headache, vertigo, acute cerebrovascular disease, and epilepsy; ( ) symptoms of peripheral nervous system that include loss of appetite and loss of sense of smell and taste; and ( ) damage to skeletal muscles [ , ] . in addition, patients are at high risk of thrombosis due to their over-coagulation status, blood stasis, and endothelial damage [ ] . furthermore, recent studies have shown that patients with covid- usually have high concentrations of cytokines including il , il , il , gcsf, ip , mcp , mip a, and tnfα [ , ] . stroke is currently one of the most common health problems in developed countries and was the second leading cause of death worldwide according to the who latest report [ ] . recently, the importance of this issue in developing countries has become more prominent [ ] . however, no cases of acute vascular disease have been reported so far. in this article, we report several cases of patients with coronavirus with brain disorders who have been admitted to tohid hospital in sanandaj, iran. written informed consent was obtained from a legally authorized representative(s) for anonymized patient information to be published in this article which was approved by the research center of kurdistan university of medical sciences. a -year-old man was infected with the coronavirus after attending a wedding. symptoms such as fever, chills, muscular pain, weakness, cough, tachycardia, and acute respiratory syndrome have been reported. he was hospitalized in the tohid hospital, sanandaj, iran. he had no history of underlying diseases. two of his brothers were also infected with the coronavirus. all of the patient's clinical findings, including cardiovascular and abdominal examinations, were normal. the amount of oxygen measured in the blood, when referred to the corona emergency department, was reported to be %. there was no evidence of arrhythmia in the patient. the patient had a history of smoking for years. all laboratory findings of this patient are presented in table . coronavirus test results were positive. computed tomography (ct) scans of his chest were performed to confirm the presence of coronavirus, and the images showed that the patient had coronavirus (fig. ). in the next step, due to frequent headaches and decreased consciousness, the patient underwent a brain ct scan by the order of a neurologist who observed the initial images and examinations (fig. ) of the hypodense areas in the left parietal area. ischemic stroke was confirmed by a radiologist from the ct scan. supportive care, antibiotics, and other treatments were used to treat the patient. after days, the patient's general condition improved, and his respiratory and nervous symptoms gradually subsided. a -year-old woman was examined at the corona emergency department of tohid hospital in sanandaj, iran, with fever, cough, headache, myalgia, and photophobia. although she denied any close contact with others in the previous month, the information from her family confirmed that she had attended two friendly parties over the past month. during hospitalization in tohid hospital emergency department, the patient's physical examination was reported including body temperature of . °c, blood pressure of . mmhg, pulse rate of beats/min, respiration rate of breaths/min, and blood oxygen saturation of % in l/min of oxygen. mild hypoxemia was diagnosed due to low oxygen levels in the patient's blood. the most common blood and electrolyte tests were reported to be normal. testing for other viral diseases, including influenza a and b, was negative. other laboratory findings were in accordance with table . preliminary results of the coronavirus test were negative, but in the second test, she was diagnosed with coronavirus, and the ct images of lungs were a definite indication of the virus (fig. ) . due to the persistent headache during the treatment period, a brain ct scan was taken, the radiologist distinguished the hypodense lesions in the parietal lobe on the right, and an ischemic stroke was confirmed (fig. ) . supportive care, antibiotics, and antiviral treatments were performed. after a month, the general condition of the patient improved and the viral and neurological symptoms were gradually ameliorated. a -year-old woman was admitted to the icu of tohid hospital, sanandaj, iran, with symptoms of fever, tachypnea, respiratory problems, severe headache, frequent vomiting, and decreased consciousness. the initial physical and clinical examinations were normal, and the patient's history showed no underlying disease. he was not taking any special medications at the time and had no history of alcohol or tobacco use. her blood pressure was / mmhg with a regular pulse rate of beats/min, a respiratory rate of cycles/min, and a temperature of . °c. while there was no evidence of arrhythmia, the patient had mild hypoxemia with oxygen levels of - %. the patient's important laboratory findings are listed in table . this patient had normal chest radiographs despite positive reverse transcription-polymerase chain reaction (rt-pcr) test. but high-resolution ct scan of the chest revealed evidence of the coronavirus (fig. ) . she was treated in the intensive care unit and was able to breathe using a ventilator a few hours after being admitted to the icu. due to decreased level of consciousness, according to the neurologist order, a brain ct scan was taken. the non-contrast ct scan showed hyperdense areas in the left parietal lobe, which caused bleeding in the brain tissue (fig. ) . however, the brain images did not indicate any brain shift or hydrocephalus in the brain tissue. patient underwent supportive, antibiotic, and an -year-old young boy patient was admitted to the emergency department of tohid hospital, sanandaj, iran, with symptoms of quadriparesis. the patient's nervous manifestations began days before hospitalization. he experienced bilateral facial paresis accompanied by progressive weakness, but there was no urinary and fecal incontinence. there were signs of an imbalance in him. his first symptoms were cough and shortness of breath week before hospitalization when he was referred to an allergy specialist and was diagnosed with coronavirus disease after testing for rt-pcr and a confirmative ct scan of the chest. at the time, the patient was treated with hydroxychloroquine and azithromycin. there was no evidence of underlying disease in the patient's history, and physical examination showed that the patient was afebrile with blood pressure of / mm/hg, respiratory rate of /min, oxygen saturation of % on room air, and heart rate of beats/min. at the time of hospitalization, the patient was conscious but had respiratory distress. lung ct scan revealed diffused consolidations and ground-glass opacities in both lungs and bilateral pleural effusion (fig. ) . the important laboratory results of the patient are shown in table . on day of hospitalization, brain imaging was performed using ct. the non-contrast ct scan showed hypodense areas in the cerebellum, indicating an ischemic stroke (fig. ) . however, the brain images did not indicate any brain shift or hydrocephalus in the brain tissue. a -year-old male was admitted to tohid hospital in sanandaj, iran, with abdominal pain, nausea, and vomiting. he admitted that he had not complied with any of the health protocols against coronavirus. after days, the laboratory reported positive result for the patient's rt-pcr test. additionally, ct scans showed the effects of coronavirus in the patient's lungs (fig. ) . so, she was a confirmed case of fig. axial ct scan without injection brain images. cranial ct scan imaging showed the areas of the hypodermis in the left parietal region of the brain (case ). cranial ct scan imaging showed the areas of the hypodermis in the right parietal region of the brain (case ). cranial ct scan imaging showed the areas of the hyper dense in the left parietal region of the brain (case ). cranial ct scan imaging showed the areas of the hypodermis in the cerebellum region of the brain (case ). cranial ct scan imaging showed the areas of the hypodermis in the left parietal region of the brain (case ) coronavirus according to the diagnostic protocols. in the hospitalization period, the physical examinations indicated a body temperature of . °c, blood pressure of / mmhg, pulse rate of beats/min, breathing rate of breaths/min, and the blood oxygen saturation of % at l/min of oxygen. the routine blood tests, kidney function, electrolyte, and serum procalcitonin were normal. the extra laboratory results are presented in table . the patient's doctor ordered an ultrasound of the abdomen due to recurring abdominal pain and vomiting. the ultrasound showed that all abdominal and pelvic organs were normal except for both kidneys. due to decreased level of consciousness, according to the neurologist order, a brain ct scan was taken. ct scan without contrast shows excessive areas in the lobe of the left body, indicating an ischemic stroke (fig. ). some patients with coronavirus, specifically those with older age and chronic medical situations such as diabetes, hypertension, cancer, and pulmonary asthma, may be at risk for acute respiratory distress syndrome and organ dysfunction [ , ] . evidence from previous studies have indicated that patients with severe coronavirus disease might experience respiratory failure with an urgent need for artificial respiration, and other organ dysfunction [ ] . pathophysiological studies have also shown that patients with coronavirus are prone to dehydration due to fever, diarrhea, hypotension, and secondary infections, which can lead to venous thrombosis [ ] . risk classification for thrombotic and hemorrhagic strokes disease is of crucial importance for prediction of coronavirus. in addition, severe acute respiratory syndrome coronavirus (sars-cov- ) have been reported to attack the heart and some major arteries that lead to a damage to the nervous system [ , ] . according to studies, coronavirus can play a decisive role in causing strokes and vascular complications in general [ ] . another study by rothstein et al. showed that most patients with ischemic stroke have common vascular risk agents and stroke mechanisms [ ] . numerous studies have shown that angiotensin-converting enzyme (ace ) is highly expressed in human tissues such as vascular endothelial cells, heart, gastrointestinal tract, and urinary system [ , ] . furthermore, tsaytler et al. showed that ace is a major target in human sars-cov- infections. after the coronavirus infection, the level of ace decreases or may even disappear completely [ ] . therefore, they reported that all tissues and organs in which the ace is expressed may be in the conflict zone between sars-cov- and immune cells, eventually leading to organ failure and death [ , ] . thus, to reduce the side effects and death rate of coronavirus, it is necessary to assess the risks of arterial and venous thrombosis, and lesions in the central nervous system. as it is known, cerebral hemorrhage refers to spontaneous hemorrhage in cerebral parenchyma without any head injury [ ] . the most common causes of cerebral hemorrhage include high blood pressure, hardening of the cerebral arteries, intravascular and vascular anomaly, and cerebral amyloid [ ] . rupture of a small artery caused by high blood pressure can lead to death shortly due to effects of bleeding on the body's main activities, such as breathing and heart pumping. acute cerebrovascular diseases are one of the most common diseases in middle-aged and elderly people, and with its wide range of effects, it can lead to high mortality and disability [ ] . studies have also shown that in addition to a pandemic, the coronavirus will cause a widespread stroke epidemic [ ] . therefore, due to these symptoms, care measures are necessary to prevent a stroke epidemic in people with covid- disease [ ] . most patients with coronavirus can be treated, but many will not survive due to the destructive effects of the virus on vital organs. the main cause of death in patients with coronavirus is respiratory distress, followed by vital organ dysfunction, cardiovascular failure, and bleeding. studies have shown that the coronavirus mainly involves the respiratory, cardiovascular, digestive, and urinary systems. in many cases, liver and kidney functions are disrupted. a coronavirus study by zhang b et al. concluded that the sars-cov- , in addition to directly attacking the tissues and organs of the body, triggers a cytokine storm by stimulating the immune system [ ] . they reported that many patients with severe coronavirus were exposed to the cytokine storm, which is considered a reaction of the body's immune system to the virus [ ] . in this reaction, a large number of anti-inflammatory agents such as interleukin- , interleukin- , and tumor necrosis factor are released, and excessive activation of immune cells is a non-specific cause [ ] . therefore, according to these results, it is recommended that medical team members consider two goals in the treatment process of patients with coronavirus: first, the protection of organs and functioning of the body's systems against invasion and damage and, second, strengthening the immune system to control the formation of cytokine storms. in general, coronavirus is highly contagious, and although accurate information is not yet available, early detection can help treat the disease. coronavirus can damage the vascular system and cause bleeding; this damage to the nervous system can be accompanied by dysfunction of another system in the body. thus, early treatment can be very beneficial for this prognostic disease. in addition, it has been shown that the virus can weaken the immune system with secondary pathogen infections in the body, so it is necessary to strengthen the immune system. acknowledgments the authors thank all the teaching and medical staff of kurdistan university of medical sciences for their effort in eradicating this virus. author contributions mbhs supervised the study and drafted the manuscript; pf collected the clinical data; ma and ff analyzed the data and images; and nhs reviewed the manuscript. compliance with ethical standards written informed consent was obtained from a legally authorized representative(s) for anonymized patient information to be 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infarction in a japanese rural community clinical outcomes depending on acute blood pressure after cerebral hemorrhage ischemic stroke epidemiology during the covid- pandemic: navigating uncharted waters with changing tides acute stroke care in the coronavirus disease clinical characteristics of death cases with covid- : medrxiv can we use interleukin- (il- ) blockade for coronavirus disease (covid- )-induced cytokine release syndrome (crs)? conflict of interest all authors declare that they have no conflict of interest. key: cord- -u wnu authors: patrocínio de jesus, rita; silva, raquel; aliyeva, elzara; lopes, luís; portugalyan, mihran; antunes, liliana; diaz, priscila; costa, carolina; araújo, ana carolina; coelho, sílvia; mendes, joão joão; gomes, sara; serra, isabel; freitas, paulo title: reactivation of sars-cov- after asymptomatic infection while on high-dose corticosteroids. case report date: - - journal: sn compr clin med doi: . /s - - -x sha: doc_id: cord_uid: u wnu as sars-cov- and its related clinical syndrome (covid- ) became a pandemic worldwide, questions regarding its clinical presentation, infectivity, and immune response have been the subject of investigation. we present a case of a patient previously considered recovered from nosocomially transmitted asymptomatic covid- illness, who presented with new respiratory, radiological, and rt-pcr findings consistent with covid- , while on high-dose prednisolone due to a suspected secondary demyelinating disease. importantly, it led to three subsequent cases within patient’s household after discharge from the hospital. after reviewing this case in light of current evidence and debates surrounding sars-cov- rt-pcr results, we hypothesize that patients on corticosteroids may have particular viral shedding dynamics and should prompt a more conservative approach in regard to isolation discontinuation and monitoring. since the identification of the severe acute respiratory syndrome coronavirus (sars-cov- ) as the cause of the disease which was later named covid- , and as it progressed to the current worldwide pandemic, much investigation has been made regarding its clinical presentation, transmission route, and immunity. here, we present an atypical case regarding clinical evolution and sars-cov- reverse-transcription polymerase chain reaction (rt-pcr) dynamics and discuss it in light of the current published evidence. we report the case of a -year-old with no relevant underlying medical conditions who was admitted to our hospital on june due to a -day history of gait ataxia, dizziness, headache, and vomiting. on admission, he was screened for covid- as a standard procedure for hospitalized patients (bd max™ system: negative sars-cov- rt-pcr). thorough diagnostic workup raised the suspicion of a secondary demyelinating disease, and the patient was started on highdose steroids (methylprednisolone g/day for days followed by prednisolone mg/kg/day) (fig. ) . on june , a patient who had been admitted for a bilateral pneumonia (with two negative tests for sars-cov- ) and was sharing the same room was intubated as an emergency in the context of a cardiopulmonary arrest, with a subsequent post-mortem nasopharyngeal and oropharyngeal swab revealing sars-cov- rna. hence, our patient collected a swab on the rd of june as screening, which proved to be positive (quantstudio™ flex rt pcr system: n c t . , n c t . , rp c t ). he was moved to a covid- isolation area, and during his hospital stay reported no fever, respiratory, or gastrointestinal symptoms. he subsequently presented two negative sars-cov- tests on june and (aptima® sars-cov- assay, which uses target capture and this article is part of the topical collection on covid- transcription-mediated amplification), so he was considered cured from asymptomatic covid- . he was discharged on july on prednisolone mg/day. while at home (july ), he had chest computed tomography (ct), which had been ordered to exclude signs of sarcoidosis as part of the secondary demyelinating disease workup and which revealed a peripheral ground-glass opacity compatible with early covid- ( fig. ). on july , he represented with fever, headache, myalgias, and cough, and on july , he was tested as an outpatient for sars-cov- with a positive result. his family (mother, father, and wife) also developed respiratory symptoms and all tested positive for sars-cov- . importantly, they were shielding and reported no other risk contact besides the one with our patient. on july , he was admitted to our hospital, reporting worsening of the symptoms, with dyspnea and thoracalgia. on admission, he was tachypneic and presented with severe respiratory failure, rapidly requiring intubation and transfer to our intensive care unit (icu). chest ct showed diffuse bilateral ground-glass opacification and extensive subpleural consolidation of the lower lobes (fig. ) , and sars-cov- swab was positive (xpert® xpress sars-cov- : e c t . ; n c t . ; spc c t . ). serologic tests were performed on july (negative igm and igg) and on july (positive igg ( . ua/ml); positive iga ( . ico); negative igm ( . ua/ml)). the patient clinically improved on methylprednisolone mg/day (for days followed by tapering), piperacillin/tazobactam, and remdesivir and was extubated after days. at the time of the writing of this report, he has been discharged from the icu and is progressing favorably in the covid ward. we found this case remarkable for its clinical evolution, infectivity, and immune response. firstly, this patient had an initial positive sars-cov- rt-pcr test h after a risk contact, remaining asymptomatic for days after this test, which is a criteria for releasing asymptomatic patients from isolation according to the who guidance [ ] . additionally, the two negative sars-cov- tests further reinforced the criteria for cure of the (asymptomatic) disease. after days of the positive swab, he presented with his first symptoms. this could point either to a reactivation of the disease in a patient who first presented as asymptomatic or to a long incubation period ( days from risk contact until developing symptoms, with a ct performed days prior to the onset of symptoms showing an evolving disease, which is consistent with previous studies reporting typical radiological findings of covid- in asymptomatic or presymptomatic patients [ ] ). some outbreak studies have followed up patients who were asymptomatic at the time of diagnosis and concluded that some patients developed symptoms and were actually presymptomatic [ ] [ ] [ ] . in one study, the median time for developing symptoms after the initial positive rt-pcr test was days (range from to ) [ ] . interestingly, this patient seems to have transmitted the disease to his family during the presymptomatic period, since he was at home for the days prior to symptom onset and his household members reported symptoms to days after him, having no other risk contacts. there are numerous reports on transmission of sars-cov- from asymptomatic individuals or individuals who were within the incubation period [ ] [ ] [ ] . current data suggests that infectiousness peaks in the earlier stages of infection [ , ] , and one modeling study suggested individuals could be infectious to days prior to symptom onset [ ] . finally, analyzing serology markers for this patient, immune response seems to be delayed considering his first exposure to the virus (igg and iga detected days after the first positive test). however, most published seroconversion studies evaluated immunoglobulins levels according to symptom onset. our patient presented with detectable igg and iga days after symptom onset. a recent study which compared iga, igm, and igg responses in covid- patients [ ] has showed that medium seroconversion time was to days for iga and igm and to days for igg. notably, this patient's iga levels were not available on the first serology sample collected on the seventh day after symptoms onset, which is of importance since iga detection seems to show the highest sensitivity at the beginning of disease (highest positive diagnostic rate at to days after symptom onset) [ ] and to contribute to a greater extent to virus neutralization [ ] . in the same study [ ] , igm showed a lower positive diagnostic rate, which is in line with our patient's results (whose igm was negative). fluctuating shedding of sars-cov- has been described on covid- patients [ , ] and not only has asymptomatic infection been associated with a higher likelihood of sars-cov- rna clearance within the first week of diagnosis when compared with symptomatic infection [ ] but there have also been reports of covid- reactivation [ , ] . hence, a possible explanation is that this case represents a reactivation of covid- in a patient which first presented as an asymptomatic carrier. another is that the two negative sars-cov- could simply reflect the fluctuant presence of the virus. examining the timeline (fig. ) , it could also be speculated that the fact that the patient was on high-dose steroids in the early course of disease might have delayed the clinical presentation at first. since the beginning of the pandemic, the effect of steroids on viral clearance and their role in the management of covid- have been the subject of much speculation. some small retrospective studies early in the pandemic suggested that low-dose corticosteroid therapy did not delay viral clearance in patients with covid- [ , ] . there were also concerns raised around steroids being associated with higher mortality, longer length of stay, and higher rate of bacterial infection, extrapolating data from retrospective studies among patients with coronaviruses infections (including middle east respiratory syndrome coronavirus and severe acute respiratory syndrome coronavirus) [ ] . recently, the recovery trial indicated that dexamethasone reduced -day mortality among covid- pneumonia patients requiring invasive mechanical ventilation or oxygen [ ] . however, there was no benefit in patients not receiving respiratory support [ ] . this is in line with the currently known pathophysiology of covid- illness which appears to progress from an early infection stage related with a viral response phase, followed by a pulmonary phase and finally a hyperinflammation phase during which steroids are thought to have its greatest value [ ] . notably, % of the patients recruited for recovery were not considered suitable for randomization to dexamethasone, although it was not clarified the amount of them who was considered by the managing physician to have a definite contraindication and which one was it [ ] . moreover, it is unclear whether that, even in severe disease, steroids may be less beneficial for some subsets of patients, such as the elderly and those immunosuppressed. since the administration of steroids comes with risks, the risk-benefit balance should always be assessed. to the best of our knowledge, no data on the effect of steroids in asymptomatic (or presymptomatic) patients has been reported, nor on sars-cov- dynamics in patients who are chronically on steroids. in conclusion, this case highlights that the ongoing pandemic urges for a better understanding of sars-cov- replication, infectivity, and immunity. we hypothesize that patients on corticosteroids or other immunosuppressive medication may have particular viral shedding dynamics and should prompt a more conservative approach in regard to isolation discontinuation and monitoring, even with a negative nucleic acid amplification test. importantly, after having been considered cured for asymptomatic covid- illness, this case led to three subsequent cases. studies including determination of sars-cov- infectivity through viral culture, immunity assessment, and genomic comparison of viral strains can prove to be paramount in further understanding these factors and, ultimately, in improving management of cases. 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immunosuppressed states: a clinical-therapeutic staging proposal publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations authors' contributions all authors meet the icmje authorship criteria. rpj, rs, ll, mp, la, pd, cc, aca, sc, jjm, sg, is, and pf were involved in the treatment, decision-making, and clinical management of the patient. rpj wrote the manuscript. ea assisted in the review of the case report and pathological findings. all the authors critically revised the manuscript for intellectual content and approved the final version of the manuscript. conflict of interest the authors declare that they have no conflict of interest. the patient has consented this publication. key: cord- -cso l ze authors: bao, yi; lin, shu yu; cheng, zhao hui; xia, jun; sun, yan peng; zhao, qi; liu, guang jian title: clinical features of covid- in a young man with massive cerebral hemorrhage—case report date: - - journal: sn compr clin med doi: . /s - - -y sha: doc_id: cord_uid: cso l ze covid- is currently a pandemic in the world, can invade multiple systems, and has a high morbidity and mortality. so far, no cases of acute cerebrovascular disease have been reported. this article reports the clinical features of a covid- patient whose first symptom was cerebral hemorrhage. more importantly, after the craniotomy, the patient had high fever and it was difficult to retreat. after cerebrospinal fluid testing, it was determined that an intracranial infection had occurred. after anti-infection and plasma infusion of the recovered person, the patient’s symptoms gradually improved. this case suggests that covid- may infringe on cerebral blood vessels and cause cerebral hemorrhage. transfusion of plasma from rehabilitation patients is effective for critically ill patients. since december , covid- was first discovered in wuhan, china [ ] . at present, the disease has occurred in a worldwide pandemic, is highly contagious, has a high morbidity and mortality, and has been declared a public health emergency of international concern by the world health organization (who) [ ] [ ] [ ] . as of april , it has caused a total of . million patients, of which more than , died. the most typical symptom of covid- is respiratory distress. more and more evidence shows that sars-cov- is not always limited to the respiratory system, but can also violate the cardiovascular, digestive tract, kidney, nervous system, and reproductive systems [ ] [ ] [ ] ; symptoms of nervous system are divided into three categories: central nervous system (cns) symptoms (headache, dizziness, acute cerebrovascular disease, ataxia, disturbance of consciousness, epilepsy), and peripheral nervous system (pns) symptoms (hyposmia, taste loss, loss of appetite, neuralgia), skeletal muscle damage [ ] [ ] [ ] [ ] [ ] [ ] . however, no cases related to acute cerebrovascular disease have been reported so far. this article reports a case of covid- complicated with cerebral hemorrhage and summarizes the relevant treatment experience, which is now shared as follows. at : on february , , a -year-old man suffered a sudden disturbance of consciousness during dinner and fell to the ground. he could not be awakened, could not speak, accompanied by vomiting, no abnormal limb movements and convulsions, and no incontinence. after onset, the family sent him to the local town health center. after symptomatic treatment, the patient's symptoms did not get better, so the patient was transferred to the local people's hospital for emergency treatment. computed tomography (ct) examination of the brain revealed a large amount of cerebral hemorrhage, and the family was informed that the patient was in critical condition ( fig. ) . at : on february , the patient presented with difficulty breathing and poor blood oxygen saturation. after endotracheal intubation, breathing was assisted by ventilator. for further treatment, the patient was transferred to the cerebrovascular disease treatment center of our hospital at : pm. the patient's past history was obtained by asking family members: physical fitness, denying the history of hypertension, diabetes, and heart disease; denying a history of hepatitis b and tuberculosis; denying a history of food and drug allergies; and denying a history of trauma and surgery. contact history of the epidemic area and close contact history of covid- confirmed patients were denied. physical examination: t . °c, p times/min, r times/min, bp / mmhg, acute physiology and chronic health evaluation scoring systemii (apache ii) scoring points, conscious coma, endotracheal intubation, indwelling urinary catheter, examination cannot cooperate. there was no trauma or deformity in the skull, the pupil was unequal on both sides, the diameter of the left side was . mm, the diameter of the right side was mm, and the light reflection was weakened. the neck was soft, the breath sounds in both lungs were rough, moist rales could be heard at the bottom of the lungs, the heart rhythm was uniform, no obvious murmurs were heard in the auscultation area of each valve of the heart, the abdomen was soft, and the liver and spleen were not touched. there was flexion in the left limb tingling, muscle strength level , poor response in the right limb tingling, muscle strength level , increased muscle tension, and the right barbinski sign was positive. examination data showed: white blood cells (wbc) . x g/l, neutrophil absolute value (ne#) . x g/l, neutrophil percentage (ne%) . %, lymphocyte absolute value (ly#) . x g/l, lymphocyte percentage (ly%) . %, and high sensitivity c-reactive protein (hscrp) . mg/l. emergency cranial ct examination showed that there were large irregular high-density lesions in the left temporal lobe, basal ganglia, and radiating coronal area, with uniform density and clear edges, the maximum layer size was about . × . cm, there were large patches of low-density edema around, the left ventricle was compressed and deformed, and the midline structure was shifted to the right; high-density shadows were seen in the bilateral ventricles. conclusion: the left temporal lobe, basal ganglia, and radiation coronal hematomas break into the ventricles and brain hernias were formed. chest ct results showed that there were cords and strip-shaped high-density shadows on the upper and lower lobe of both lungs, and the state was blurred; no abnormal density shadows were found in the remaining lungs. endotracheal intubation, clear hilar structure, no displacement of the mediastinum, no obvious enlarged lymph nodes, no pleural effusion. conclusion: sedimentary inflammation in both lungs. at : on february , in order to remove the intracranial hematoma, after informed consent and signature by the patient's family, the operation was performed under general anesthesia: removal of left intracerebral hematoma + decompression of the left cranial flap + dura meningiotomy. during the operation, a dark red blood clot was seen in the left basal ganglia, and the clot was removed. no aneurysm and vascular malformation were seen during the operation. one drainage tube was placed in the hematoma cavity. after removing the bone flap, a second drainage tube was placed outside the dura mater, and the muscle, subcutaneous, and scalp were sutured, and the drainage tube was fixed. safe transfer to intensive care unit (icu) after surgery. continue to use ventilator to assist breathing, oxygen inhalation, electrocardiogram (ecg) monitoring, anti-infection (flucloxacillin), hemostasis (aminocaproic acid), dehydration (mannitol), brain protection, prevention of epilepsy, and other treatments, as well as symptomatic support treatment, and closely observed the changes of consciousness and pupil (fig. ) . on february , the patient had a high fever with a body temperature of . °c, re-examination of the craniocerebral ct revealed that: post craniocerebral operation, intracranial gas was accumulated, a drainage tube was placed, part of the left frontal parietal temporal bone was missing, and the left temporal lobe, basal ganglia, and radiative coronal area showed patchy high-density lesions, which were significantly reduced compared with the previous (february , ). the center line structure was less offset to the right than before; high-density shadows on both sides of the ventricle were slightly reduced compared with before. the scalp soft tissue was swollen and gas was accumulated. re-examination of the chest ct showed that there were patches and strip-like highdensity shadows on the back of both lungs, with a blurred state and partial consolidation, which was more than before (february , ). considering the aggravation of lung infection, meropenem was used to continue anti-infection treatment. on february , the patient still had high fever, excessive phlegm, and low blood oxygen saturation. rough breath sounds could be heard at auscultation, and both lung breath sounds were low. asked the family members of the patient to know that the close contact history of covid- could not be completely ruled out. covid- should be considered in combination with the patient's chest ct, which showed pulmonary interstitial inflammation, blood routine lymphocytic reduction, and poor anti-bacterial treatment effect, etc. then the patient samples (pharyngeal swabs, sputum, serum, and stool) were taken for real-time fluorescence quantitative reverse transcription-polymerase chain reaction (rrt-pcr), and sars-cov- antibody-igg and igm tests were completed; the results were negative. on the th, the patient's blood oxygen saturation could not be maintained, dyspnea was aggravated, and sputum was difficult to be sucked out. then, tracheostomy was performed under local anesthesia, and the ventilator was used to assist breathing. in order to further improve the positive rate, the reexamination of sputum results showed that the sars-cov- nucleic acid test was positive. the covid- consultation expert group considered: combining epidemiology, lymphocytic decrease, increased crp, pulmonary interstitial inflammation, and sars-cov- nucleic acid positive; covid- could be confirmed. in treatment, abidol combined with ribavirin antiviral, alpha-interferon nebulization treatment, thymosin to enhance immunity, and continued anti-infective treatment. nursing: paid attention to strengthening airway management, strengthening atomization, sucking sputum in time, and turning back and patting frequently. on february , the patient developed high fever again with a body temperature of . °c (fig. ) . the cerebrospinal fluid became turbid as before. the examination showed that the cerebrospinal fluid (csf) was dark red, no clot, protein was . g/l, sugar was . mmol/l, and white blood cells were × g/l, among which multinucleated cells accounted for % (table ) . cerebrospinal fluid test results showed intracranial infection; the first consideration was sars-cov- intracranial infection. check the cerebrospinal fluid sars-cov- nucleic acid rna, and the result was negative. continue to give antiviral and antibacterial treatment. on february , in order to alleviate the patient's condition, with the consent of the patient's family, ml plasma of type a rh positive covid- -convalved patient was given. re-examination of the brain ct showed that the scope of the patchy high-density foci in the left temporal lobe, basal ganglia, and radiating coronal region was approximately the same as before, the density was lower than before ( - - ), and the midline structure shifted to the right was less than before; the density of bilateral ventricles was slightly reduced. reexamination of the chest ct results showed that there were patches and strip-shaped high-density shadows on the back of the two lungs, with a blurred state and partial consolidation, which was reduced from the previous (february , ). on february , after the patient was infused with covid- convalescent plasma, the symptoms improved, the body temperature decreased, and the dyspnea decreased. both sars-cov- nucleic acid tests were negative ( h interval), fig. the treatment of covid- patients with intracerebral hemorrhage suggesting that antiviral treatment was effective. however, in the afternoon of the same day, the patient developed hyperthermia again, and his body temperature reached . °c; considering the central hyperthermia, the patient improved after depyrexia treatment. on february , the patient did not have high fever again, the results of the cerebrospinal fluid review showed that it was light red, no clot, protein decreased to . g/l, sugar increased to . mmol/l, and white blood cells decreased to × g/l, of which monocytes accounted for %. this indicated that the intracranial infection was better than before. on march , for several days, the patient's temperature was around . °c. a review of cranial ct showed that the range of patchy high-density lesions was narrower than before ( - - ), the left ventricle was compressed and deformed, the degree to which the centerline structure shifts to the right was lessened than before; high-density shadows in the ventricle were slightly reduced, the soft tissue swelling of the scalp was more obvious than before. re-examination of the chest ct showed that there were patches and strip-like high-density shadows on the back of both lungs, with a blurred state and partial consolidation, which was more than before (february , ). review of csf: csf was pink, no clots, protein decreased to . g/l, sugar . mmol/l, slightly lower than before, white blood cells rose to × g/l, mononuclear cells accounted for %. the patient's cerebrospinal fluid showed improvement, and since the two re-examinations of sars-cov- nucleic acid test was negative, and the antiviral treatment with abidol, ribavirin, and oseltamivir had reached the course of treatment, so it was discontinued. on march , the patient developed hyperthermia again, the body temperature reached . °c, and the cerebrospinal fluid with clots was drained from the lumbar cistern. the test results showed that the cerebrospinal fluid was light red with clots, protein significantly increased to . g/l, sugar decreased to . mmol/l, and white blood cells increased to × g/ l, among which polykaryotic cells accounted for %. the cause of fever was considered to be intracranial infection; gram-negative bacilli were more likely. continue treatment against infection. on march , the patient developed high fever, up to °c, and the body temperature was not easy to control. the cerebrospinal fluid was yellow with clots, protein . g/l, glucose . mmol/l, and white blood cells increased to × g/l, among which polykaryotic cells accounted for %. the patient had a clear history of cerebral hemorrhage, pus was drained from the lumbar cistern drainage tube, and cerebrospinal fluid analysis indicated pyogenic infection, especially the drug-resistant gram-negative bacilli. clinical pharmacists suggested meropenem combined with rifampicin to fight the infection. yeast was cultured in the patient's sputum, and the possibility of fungal infection could not be ruled out, and voriconazole antifungal treatment was added. in addition, central fever needs to be considered. on march , the culture results of cerebrospinal fluid showed acinetobacter baumannii. considering opportunistic pathogenic infections, after in-hospital consultations, tigecycline and cefoperazone and sulbactam were given intrathecally by intrathecal injection, and oral minocycline. continue to use voriconazole against fungus. on march , dark red substances were drained from the gastric canal and black stools were observed in the patient, considering gastrointestinal bleeding, hemostatic drugs were administered, low-temperature noradrenaline dilution solution and low-temperature thrombin solution were injected into the gastric canal respectively, but the effect was poor. on march , the patient still had gastrointestinal bleeding, and his body temperature was . °c. brain ct examination showed that the range of patchy high-density lesions was significantly smaller than that before (march , ), the patchy low-density shadows were increased, and the left brain tissue was significantly swollen; the left ventricle was compressed and deformed, and the scalp soft tissue was swollen. reexamination of the chest ct showed that there were patches and strip-like high-density shadows on the back of both lungs, with a blurred state and some consolidation, which was more than before (march , ). in order to alleviate the condition and supplement the patient's coagulation factors, ml of type a rh-positive plasma was given after the consent of the patient's family. the patient's gastrointestinal bleeding stopped and the temperature gradually returned to normal. the re-examination of sars-cov- nucleic acid test was still negative on march , . sars-cov- can invade the cardio-cerebrovascular system and damage the nervous system, which has been reported in several articles [ ] [ ] [ ] [ ] [ ] [ ] [ ] . angiotensin converting enzyme (ace ) is highly expressed in human tissues such as the vascular endothelial cells, heart, liver, digestive tract, and kidneys [ , ] . studies have found that ace is an important target for sars-cov- infection in humans. after infection, ace levels are reduced or even absent. therefore, it was learned that all tissues and organs expressing ace may be the battlefield between sars-cov- and immune cells, eventually leading to multi-organ failure and life-threatening [ ] . after infection with sars-cov- , this patient did not first appear classic respiratory clinical symptoms, but presented with cerebral hemorrhage. whether this is a coincidence or an inevitable correlation, the pathophysiological mechanism requires further study. as we all know, cerebral hemorrhage refers to spontaneous hemorrhage in nontraumatic brain parenchyma. common causes are hypertension, cerebral arteriosclerosis, intracranial vascular malformation, cerebral amyloid vascular disease, hematopathy, vasculitis, etc. the vast majority of cerebral hemorrhage is manifested as small artery rupture caused by hypertension, which can cause extremely serious symptoms within a short period of time, and even affect patients' basic physiological activities such as breathing and heartbeat, resulting in death. it is a common acute cerebrovascular disease in middleaged and elderly people, with a high fatality and disability rate [ ] . the patient had no history of hypertension, sudden cerebral hemorrhage, and no vascular abnormalities such as aneurysms during the operation. is the occurrence of cerebral hemorrhage in patients related to the consumption of ace by sars-cov- ? the patient had no exact close contact history, and chest ct did not have the typical covid- features, which may be related to the mask of combined hypostatic pneumonia. however, in combination with the patient's high fever, lymphocytopenia, increased neutrophils, and poor antibacterial treatment effect, the clinical manifestations conform to the covid- characteristics, and nucleic acid detection is required. as is known to all, nucleic acid detection is the gold standard for the diagnosis of sars-cov- infection, but the first test result is negative, which is related to the low positive rate of sars-cov- detection using fluorescent quantitative rt-pcr as the detection method, currently only to %, leading to an extremely high false negative rate [ ] . because the test results are affected by a variety of factors, including: in vivo viral load, whether the specimen is qualified, whether the transport conditions meet the standards, whether the specimen is contaminated by rna enzymes resulting in nucleic acid degradation, etc. the patient obtained a positive result on the second test and was eventually diagnosed with covid- . therefore, we believe that the standardized collection and transportation of specimens and repeated testing are conducive to the improvement of positive rate, early diagnosis and early treatment. studies have found that the susceptibility of sars-cov- is related to blood type. among covid- patients at wuhan jinyintan hospital, the analysis results showed that the proportion of a, b, ab, and o accounted for . %, . %, . %, and . %. compared with blood types o, b, and ab, the risk of covid- infection in blood group a was significantly increased (or was . ; % confidence interval ci was . - . , p = . ) [ ] . the patient had blood type a and was susceptible. nevertheless, are patients with type a more likely to develop cerebrovascular accidents after sars-cov- infection? this requires large sample studies. when the patient was critically ill, ml of type a rh-positive covid- convalescent plasma was injected. after treatment, the nucleic acid turned negative after multiple re-examinations, indicating that the treatment was effective. from the perspective of clinical pathology, igm antibodies produced after human infection with the virus gradually decline after reaching the peak in the acute infection period, and usually persist for - weeks or longer. most covid- patients will produce specific antibodies against sars-cov- in their bodies. after treatment and rehabilitation, igg antibodies are of therapeutic value are found in the plasma. these specific antibodies are injected into the body and neutralized with sars-cov- to achieve the purpose of virus suppression and elimination. however, in fact, in addition to the "antibody pathway", the specific immunoglobulin in the plasma of the convalescent patients can also play a therapeutic role, and even the plasma itself has a certain role [ , ] . it is important to note that the plasma composition is complex and there is uncertainty as to whether it will cause other problems. in clinical use, it is necessary to grasp the indications, contraindications, and unsuitable conditions. indications for clinical use of recovered plasma, nucleic acid test positive and rapid progression, critical covid- patients, should be used as soon as possible; in principle, the course of disease does not exceed weeks. contraindications: terminal stage of critical illness, multiple organ failure cannot be reversed; non-neutralizing treatment of sars-cov- ; comprehensive assessment by the clinician that there are other unsuitable infusion situations. after sars-cov- infection, most patients were cured, but many patients progressed to severe illness and eventually died. respiratory failure is the main cause of death, followed by sepsis (multiple organ failure), heart failure, bleeding, and kidney failure. the affected organs mainly include the respiratory system, cardiovascular system, coagulation function, and the liver and the kidney. in many cases, multiple organ functions are impaired. through the study of death cases, it was found that in addition to directly attacking human tissues and organs, sars-cov- caused a cytokine storm by stimulating the human immune system. many patients with severe covid- will develop cytokine storm, which is an over-immune response of the human body. the main reason is the over-activation of non-specific immune cells, which release a large number of pro-inflammatory factors, such as interleukin- , interleukin- , and tumor necrosis factor. [ ] . therefore, it is suggested that clinicians should take a twopronged approach to severely ill patients with covid- , in addition to paying special attention to the protection of organ function, but also need to strengthen the control of cytokine storm. the patient presented with cerebral hemorrhage at the time of onset, and soon developed high fever, dyspnea, and difficulty in maintaining blood oxygen saturation, requiring ventilator-assisted breathing. the early lung ct did not have the typical manifestations of covid- . although the symptoms did not improve after the antibacterial treatment, the lung ct gradually showed the image of covid- . the patient's cerebral hemorrhage was treated early and the hematoma was absorbed. when diagnosed, after antiviral and plasma treatment, the patient's symptoms improved, and the cerebrospinal fluid improved, but later swelling of the brain tissue and purulent cerebrospinal fluid occurred. this was considered because sars-cov- infection damaged the immune system [ ] . in the late stage, the immune system was weakened, opportunistic pathogens invaded again, and fungal infection occurred, making the infection difficult to control. in addition, the patient also developed gastrointestinal bleeding, which was difficult to control with ordinary hemostatic drugs. finally, the patient's symptoms gradually stabilized by re-infusion of plasma. through this case, we have gained experience: covid- is highly contagious, and although there is no clear history of close contact, infection is still possible. early detection of highly suspected cases helps early treatment. sars-cov- can damage the neurovascular system and cause bleeding, and it can be followed by multiple system failure. early treatment is beneficial to the prognosis. sars-cov- can lead to a weakened immune system and secondary opportunistic pathogenic infections. it is necessary to focus on improving immunity as soon as possible. the shortcomings of this article: lack of magnetic resonance data, lack of pathological tissue data, and lack of substantial evidence. a new coronavirus associated with human respiratory disease in china clinical characteristics of coronavirus disease in china clinical features of patients infected with novel coronavirus in wuhan. china the lancet 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 prevalence and impact of cardiovascular metabolic diseases on covid- in china the novel coronavirus epidemic and kidneys the neuroinvasive potential of sars-cov may be at least partially responsible for the respiratory failure of covid- patients neurological manifestations of hospitalized patients with covid- in wuhan, china: a retrospective case series study encephalitis as a clinical manifestation of covid- cov- : olfaction, brain infection, and the urgent need for clinical samples allowing earlier virus detection a first case of meningitis/ encephalitis associated with sars-coronavirus- prevalence and impact of cardiovascular metabolic diseases on covid- in china differential diagnosis of illness in patients under investigation for the novel coronavirus (sars-cov- ) ace in brain physiology and pathophysiology: evidence from transgenic animal models the association between ace gene polymorphism and the stroke recurrence in chinese population structural basis for the recognition of the sars-cov- by full-length human ace clinical outcomes depending on acute blood pressure after cerebral hemorrhage combination of rt-qpcr testing and clinical features for diagnosis of covid- facilitates management of sars-cov- outbreak relationship between the abo blood group and the covid- susceptibility sars-cov- cell entry depends on ace and tmprss and is blocked by a clinically proven protease inhibitor convalescent plasma as a potential therapy for covid- clinical characteristics of death cases with covid- . medrxiv blood single cell immune profiling reveals the interferon-mapk pathway mediated adaptive immune response for covid- . medrxiv publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations acknowledgments the authors thank all the medical staff who provided the patient with careful treatment and care. competing interests the authors declare that they have no competing interests.ethical approval all relevant ethical guidelines have been followed. sn compr. clin. med. key: cord- -wo ggmmn authors: giustiniano, enrico; fazzari, fabio; bragato, renato maria; curzi, mirko; cecconi, maurizio title: trans-thoracic echocardiography in prone positioning covid- patients: a small case series date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: wo ggmmn during sars-cov- pandemic, several subjects were treated in our intensive care unit (icu) because of acute respiratory failure following covid- pneumonia. most of them required mechanical ventilation and someone in prone position (pp) too, because of acute respiratory distress syndrome (ards). during pp, trans-esophageal echocardiography (tee) is not always easy, mainly due to the forced position of the neck of the patient. moreover, during a pandemic, given the great number of patients needing treatment, tee probes and monitoring devices are not widely available. then, trans-thoracic echocardiography (tte) plays a crucial role as it is non-invasive, repeatable, and available every time it is needed. moreover, it can be safely performed also in prone position (ttep). according to in-hospital protocol, ttep was performed using the apical-four-chamber (a- -c) view in patients. we temporarily deflated the lower thoracic section of the air-mattress to place the probe between the mattress surface and the thorax of the patient. we collected both tee and hemodynamics data. the main result of our retrospective analysis is that tte can be performed in patients in prone positioning and is reliable and repeatable; the single apical-four-chamber view provides sufficient data to evaluate the cardiac performance in case of scarce availability of hemodynamic monitoring devices, like in a pandemic setting. tte may be a helpful tool for cardiac performance evaluation and diagnosis not only in supine or anterolateral positioning like in echocardiographic lab, but also in subjects admitted to icu due to ards needing of mechanical ventilation in prone positioning. during sars-cov- pandemic, several subjects were treated in our intensive care unit (icu) because of acute respiratory failure following covid- pneumonia. most of them required mechanical ventilation (mv) and some of them in prone position (pp) too, because of acute respiratory distress syndrome (ards), trying to re-open the collapsed and wet lung parenchymal districts, particularly when severe hypoxemia occurred [ ] . after a brief period of non-invasive ventilation (niv), mechanical respiratory support was needed, since patients showed type l and/or type h of respiratory involvement. if in type l, clinical situation niv may be the initial attempt to support the respiratory function, the type h clinical scenario makes mv mandatory since higher positive end-expiratory pressure (peep) levels and prone positioning are required, like in any type of ards [ ] [ ] [ ] . during ards treatment, sedation and myorelaxation are required to make the patient be safely and efficaciously ventilated. consequently, vasopressor administration may be necessary for hemodynamic support, both to counteract the vasodilation due to sedation and to provide a sufficient blood pressure, particularly when patient lays in prone position [ , ] . such a critical illness demands a strict cardiovascular monitoring and repeated cardiac function assessment. hemodynamic monitoring can be performed by right heart catheterization, trans-pulmonary thermodilution (tpt) technique, or echocardiography. the latest offers the advantage to evaluate both cardiac function and hemodynamic status this article is part of the topical collection on covid- non-invasively and in a cost-saving way [ , ] . peng et al. reported that during the covid- pandemic in china, the main cardiocirculatory abnormal findings were as follows: ( ) hyperdynamic state; ( ) stress-induced cardiomyopathy (takotsubo); ( ) right ventricle enlargement and acute pulmonary hypertension; ( ) diffuse myocardial inhibition [ ] . during prone positioning, trans-esophageal echocardiography (tee) is not always easy, mainly due to the forced position of the neck of the patient. moreover, during a pandemic, given the great number of patients needing treatment, tee probes and monitoring devices are not widely available. then, trans-thoracic echocardiography (tte) plays a crucial role as it is non-invasive, repeatable, and available for many patients every time it is needed; moreover, it can be safely performed also in prone position (ttep), as we described in a previous report [ ] . in this small case series, we report our experience about ttep in mechanically ventilated patients admitted to covid- isolation intensive care unit (icu-covid- ). we retrospectively analyzed electronic medical records of patients admitted to our icu-covid- from march to may , , during the new coronavirus outbreak in italy. only of them received echocardiographic evaluation both in supine and in prone positions and were included in the study. patients' clinical data are summarized in table . clinical variables were as follows: age, sex, body mass index, comorbidities, mean arterial pressure (map), heart rate (hr), mechanical ventilation measurements like peep, and respiratory system compliance (c rs ). only few patients included into the study received trans-pulmonary thermo-dilution hemodynamic monitoring. none of the included cases received pulmonary artery catheter (pac) hemodynamic monitoring. according to our institutional protocol, all patients received non-invasive ventilation (niv) as first choice. when respiratory function deteriorated despite niv, patients have been intubated and admitted to our icu-covid- to receive invasive mechanical ventilation. in case of severe hypoxemia (po /fio < mmhg) despite peep ≥ cmh o, they received mechanical ventilation in prone positioning (pp-mv). before declaring the patient unresponsive to pp-mv (i.e., po /fio < mmhg with peep ≥ cmh o), the pp cycle was attempted for three times. each pp cycle included - h in prone positioning followed by - h of supine positioning (sp). protective ventilation protocol included tidal volume (vt) of - ml/kg and peep ≤ cmh o with target driving pressure (dp) ≤ cmh o and airway plateau pressure (p plat ) ≤ cmh o. the compliance of the respiratory system (c rs ) if not provided by the ventilator software was computed by the following formula: vt/dp (ml/cmh o), where dp results from the difference (p plat − peep). all the patients underwent thoracic ct scan before prone positioning when it was possible according to the logistic availability and the patient safety. the evolution from interstitial pneumonia to ards was diagnosed according the berlin definition [ ] . all the patients received invasive blood pressure monitoring by an arterial line. the first-choice drug to support hemodynamics was norepinephrine (ne), followed by dobutamine (db) when inotropic support was needed, targeting a cardiac index > l/kg/ min (measured by tpt of tte) and a mean arterial pressure (map) ≥ mmhg. trans-thoracic echocardiography was performed as stated by guidelines using the us machine ge-venue (©general electric healthcare, little chalfont, buckinghamshire, uk). according to in-hospital protocol, ttep was performed using the apical-four-chamber (a- -c) view. we temporarily deflated the lower thoracic section of the air-mattress to place the probe between the mattress surface and the thorax of the patient (fig. ) . the following echocardiographic data were collected: lv ejection fraction (lvef); the mitralic annular plane excursion (mapse); the left ventricle outflow tract velocity-time integral (lvot-vti); the ratio between the rv end-diastolic diameter and lv end-diastolic diameter (rv/lv) measured at the mid-basal level in the a- -c view; the rv systolic performance by the tricuspid annular plane excursion (tapse); tricuspid regurgitation pressure gradient to estimate the pulmonary artery systolic pressure (paps). we assumed as normal rv-edd ≤ mm, lv-edd ≤ mm, and normal ratio rv/lv edd ≤ . , [ ] [ ] [ ] . echocardiographic examinations in prone and supine positions were performed by one experienced operator, and echocardiographic recordings were post hoc analyzed by two independent readers (one anesthesiologist and one cardiologist) (fig. ) . when the patient was considered for prone positioning, he/ she received a supine tte. the ttep was performed within - min after prone positioning. the independent ethics committee of humanitas clinical and research center (irb approval n. / , on march th ) approved the study and given its retrospective and observational design waived the need for individual informed consent. we followed the strobe statement for observational study on human subjects (http://www.strobe-statement.org/). results are reported as average ± standard deviation (sd) or median and range enclosed in parentheses, or number and percentage enclosed in parentheses, as appropriate. percentage variation between sp and pp data was computed with the following formula: prone value−supine value ð Þ =supine value ½ we adopted student's t test for parametric data analysis while for non-parametric variables, we adopted fisher's exact test. level of statistical significance was p < . . analysis was performed with the prism . . software (graphpad, northside dr., suite , san diego, ca , usa). among the patients included in our analysis, none of them needed dobutamine administration. conversely, all of them received norepinephrine to sustain hemodynamics and reach a map ≥ mmhg. table reports the main results. lvef was normal in % of patients ( / had a lvef more than %), and right ventricular function expressed as tapse was under the lower reference limit in one patient ( % of cases, mean value ). rv dimension was over the upper limit in all patients with a mean value of rv/lv ratio of . . eighty-seven percent of patients showed high paps (mean value of ) and inferior vena cava was dilated in patients ( %); only one patient showed a caval index more than %. map showed a little but not significant lowering. at the same time, the other hemodynamic parameters did not change significantly. respiratory data showed not any modification, even the po /fio ratio which was expected to improve significantly. as showed in table , the majority of patients ( / , %) showed no change in lvef, while the remaining two patients showed respectively improvement and worsening of lvef. rv diameter reduced in / patients ( . %) and increased in patients. paps lowered in / patients and augmented only in one patient. the greatest negative variation of tapse observed was in case n. (− %) with a worsening of paps too (+ %), a little reduction of p/f (− %), and a great variation of respiratory compliance (c rs − %) ( table ). this patient was the only one who died after the shortest icu staying ( days). mortality rate of this small group of patients was . % (only one patient died). among survivors, the mean the main results of our retrospective analysis on a small cases series consisted of few main points: ( ) tte can be performed in patients in prone positioning and is reliable in comparison with the supine tte and repeatable, meaning that it may be used also to "monitor" the cardiac function every time it is needed, in a standardized way (i.e., without any minimal changing of the patient position, during both supine and prone positioning); the single apical-four-chamber view provides sufficient data to evaluate the cardiac performance in case of scarce availability of hemodynamic monitoring devices, like in a pandemic setting; ( ) according to recent scientific reports, prone positioning in patients suffering from ards due to covid- pneumonia is not always effective. it may depend on the phenotype of the disease and may be effective only in extremely severe cases [ ] [ ] [ ] [ ] . we observed a reduction of paps and rv-edd after prone positioning. we may speculate that paps lowering may be the effect of a supposed reduction of pulmonary resistances after prone positioning. it may be the cause of the reduction of the rv-edd. this may translate in an improved rv function as showed by the increase of s′ tdi tricuspid valve annulus (table ) . unfortunately, these variations did not reach a statistical significance, but it may be due to the small sample of the trial. in our small case series, only one patient died. this patient showed a reduction of the rv and lv performances along with an increase in paps and a worsening of respiratory compliance in prone position. we may suppose that the reduction of pulmonary compliance caused the worsening of the rv function and increase of paps. the course of this case was also more rapid compared with the others. the tte in prone positioning (tte p ) was helpful to evaluate the hemodynamic state of our patients despite they did not receive a specific monitoring methods (trans-pulmonary thermodilution, pulmonary artery catheter, or semi-invasive pulse-contour systems). despite its diagnostic primary property and because we had not a sufficient number of hemodynamic monitoring devices, tte p resulted a valid alternative to classical hemodynamic monitoring. it is safe, repeatable, and cost saving. while tee performed in the prone positioning has been reported as a safe procedure [ ] , in our opinion, one limitation may be the position of the neck and head of the patient that is laterally rotated and may make it difficult to introduce the tee probe. additionally, given the potential high number of patients requiring this type of evaluation and the number of devices available, tee is often a logistic challenge. our study has a lot of limitations. the main are as follows: ( ) the sample is too small to permit definitive conclusions which in this case could be only speculative; ( ) it is a retrospective analysis of data collected in a situation of extreme difficulty like during a pandemic; then, several further data that are helpful for a more detailed analysis are not available because our database is lacking. in conclusion, tte may be a helpful tool for cardiac performance evaluation and diagnosis not only in supine or anterolateral positioning like in echocardiographic lab, but also in subjects admitted to icu due to ards needing of mechanical ventilation in prone positioning. in particular, our "trick" (i.e., mattress deflation) permits to perform tte in prone positioning without any minimal changing of the patient position. the study was approved by the independent ethical committee of the humanitas clinical and research center on march th, (irb n. / ) prone positioning in patients with moderate and severe acute respiratory distress syndrome: a randomized controlled trial management of covid- respiratory distress covid- does not lead to a "typical" acute respiratory distress syndrome covid- pneumonia: ards or not? the right ventricle in ards predictors of mortality in acute respiratory distress syndrome. focus on the role of right heart catheterization guidelines for performing a comprehensive transthoracic echocardiographic examination in adults: recommendations from the american society of echocardiography using echocardiography to guide the treatment of novel coronavirus pneumonia echocardiography during prone-position mechanical ventilation in patients with covid- : a proposal for a new approach acute respiratory distress in adults recommendations for chamber quantification: a report from the american society of echocardiography's guidelines and standards committee and the chamber quantification writing group, developed in conjunction with the european association of echocardiography, a branch of the european society of cardiology recommendations for cardiac chamber quantification by echocardiography in adults: an update from the american society of echocardiography and the european association of cardiovascular imaging acute respiratory distress syndrome: advances in diagnosis and treatment transesophageal echocardiography in prone position during severe acute respiratory distress syndrome publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors declare that they have no conflict of interest. key: cord- -vn yd authors: sanyaolu, adekunle; okorie, chuku; marinkovic, aleksandra; patidar, risha; younis, kokab; desai, priyank; hosein, zaheeda; padda, inderbir; mangat, jasmine; altaf, mohsin title: comorbidity and its impact on patients with covid- date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: vn yd a novel human coronavirus, severe acute respiratory syndrome coronavirus (sars-cov- ), was identified in wuhan, china, in december . since then, the virus has made its way across the globe to affect over countries. sars-cov- has infected humans in all age groups, of all ethnicities, both males and females while spreading through communities at an alarming rate. given the nature of this virus, there is much still to be learned; however, we know that the clinical manifestations range from a common cold to more severe diseases such as bronchitis, pneumonia, severe acute respiratory distress syndrome (ards), multi-organ failure, and even death. it is believed that covid- , in those with underlying health conditions or comorbidities, has an increasingly rapid and severe progression, often leading to death. this paper examined the comorbid conditions, the progression of the disease, and mortality rates in patients of all ages, infected with the ongoing covid- disease. an electronic literature review search was performed, and applicable data was then collected from peer-reviewed articles published from january to april , . from what is known at the moment, patients with covid- disease who have comorbidities, such as hypertension or diabetes mellitus, are more likely to develop a more severe course and progression of the disease. furthermore, older patients, especially those years old and above who have comorbidities and are infected, have an increased admission rate into the intensive care unit (icu) and mortality from the covid- disease. patients with comorbidities should take all necessary precautions to avoid getting infected with sars cov- , as they usually have the worst prognosis. coronavirus disease caused by severe acute respiratory syndrome coronavirus (sars-cov- ) is a global pandemic that initially started in wuhan, china, and spread extremely quickly, making its way to over countries. as the novel coronavirus continues to evolve, there are still many limitations to our knowledge of who exactly this virus would impact critically. older adults and people of any age who have underlying medical conditions, such as hypertension and diabetes, have shown worse prognosis [ ] . diabetic patients have increased morbidity and mortality rates and have been linked to more hospitalization and intensive care unit (icu) admissions [ ] . people with chronic obstructive pulmonary disease (copd) or any respiratory illnesses are also at higher risk for severe illness from covid- [ ] . the risk of contracting covid- in patients with copd is found to be -fold higher than patients without copd [ ] . this article is part of the topical collection on covid- * adekunle sanyaolu sanyakunle@hotmail.com federal ministry of health, abuja, nigeria a retrospective study of middle-aged and elderly patients with covid- found that the elderly population is more susceptible to this illness and is more likely to be admitted to the icu with a higher mortality rate [ ] . the age-related changes in the geriatric population may be due to the changes in lung anatomy and muscle atrophy which results in changes in physiologic function, reduction of lung reserve, reduction of airway clearance, and reduction of the defense barrier function [ ] . the clinical outcomes and length of stay directly correlate with the underlying conditions and age of the covid- patient. researchers in china studied patients in the icu with covid- . of the subjects, patients died on the th day with a median survival of days [ ] . of these patients, there were many with different comorbidities with patients having hypertension [ ] . in survivors, the median duration of hospitalization for a negative test result was days [ ] . furthermore, another study conducted in china studied covid- patients, of whom patients had at least one comorbidity and that concluded that older individuals, greater than years, were more likely to exhibit a more severe form of covid- disease [ ] . during the study, patients with a median age of . years died giving an effective mortality rate of . % [ ] . it has been concluded that the older the patients are, the more likely they are to succumb to the covid- disease. in the usa, the centers for disease control and prevention (cdc) uses covid-net in states to monitor the demographics of covid- patients who are being hospitalized [ ] . from march through , , there were a total of patients on covid-net, of which . % of the patients had an underlying comorbidity [ ] . of the patients, . % aged years and older had at least comorbidity [ ] . the most common comorbidities found were obesity, hypertension, and diabetes mellitus [ ] . the purpose of this paper is to review these comorbidities, given that most patients with severe covid- cases had comorbidity. furthermore, we would like to examine specific comorbidities in relation to the covid- disease progression and outcomes based on the literature report since the outbreak. an electronic literature search was performed using pubmed, google scholar, ebscohost, mendeley, and medline plus. the search was limited to peer-reviewed articles published from january to april , . an article was selected if it included keywords such as coronavirus, covid- , sars-cov- , clinical features, comorbidity, diabetes, and hypertension. articles were then reviewed and included based on the applicability to the topic. confirmed and reported cases of covid- have a wide range of symptoms from mild complaints, such as fever and cough, to more critical cases associated with difficulty in breathing [ ] . some of the most common symptoms include cough, fever, chills, shortness of breath (sob), muscle aches, sore throat, unexplained loss of taste or smell, diarrhea, and headache [ ] . symptoms can start as mild and become more intense over to days, worsening if pneumonia develops in patients [ ] . approximately, out of infected individuals become seriously ill and develop difficulty in breathing, especially in the elderly with underlying health conditions [ ] . a meta-analysis study of covid- patients, as depicted in fig. , showed fever ( . %) as the most common symptom, followed by dry cough ( %) and fatigue ( %) [ ] . other symptoms noted were productive cough ( . %), sob ( %), muscle pain ( . %), sore throat ( . %), and headache ( . %) [ ] . the least common symptoms were diarrhea ( . %), nausea and vomiting ( . %), rhinorrhea ( . %), abdominal pain ( . %), and chest pain ( . %) [ ] . symptoms of covid- may appear anytime from to days after exposure; therefore, -day quarantine is recommended [ ] . the average incubation period for covid- is approximately . days [ ] . in wuhan, china, the most common symptoms observed from the onset of this outbreak include fever, cough, and fatigue, while some features that were not so prevalent were sputum production, headache, hemoptysis, and gastrointestinal (gi) symptom such as diarrhea [ , ] . another study that was conducted in beijing, china, showed that the average age of patients with covid- was . years and had a mean of . days from the onset of symptoms to admission in the hospital [ ] . the same study also showed that fever was present in . % of patients, which persisted for . days, and symptoms resolved . days after a negative test result [ ] . some individuals who are infected do not develop any symptoms at all, and about % of positive cases recover from the disease without any treatment [ ] . however, there have also been instances of transmissions of covid- from one person to another before the person became aware of being sick, or the symptoms were so mild that the person did not know he/she had the illness [ ] . it becomes essential to seek medical attention immediately if a person suspects that he/she may have been infected or is a confirmed case of covid- experiencing respiratory distress, has blue lips, is in constant pain, or has pressure in the chest [ ] . also, it is important to note that covid- is more infectious than sars-cov and mers-cov due to its numerous epidemiological and biological characteristics [ ] . due to covid- being a relatively new and understudied disease, the data available is limited. however, from the cases that emerged, it was observed that comorbidities increase the chances of infection [ ] . based on current information and clinical expertise, the elderly, especially those in long-term care facilities, and people of any age with serious underlying medical conditions are at a greater risk of getting covid- [ ] . the elderly, a vulnerable population, with chronic health conditions such as diabetes and cardiovascular or lung disease are not only at a higher risk of developing severe illness but are also at an increased risk of death if they become ill [ ] . people with underlying uncontrolled medical conditions such as diabetes; hypertension; lung, liver, and kidney disease; cancer patients on chemotherapy; smokers; transplant recipients; and patients taking steroids chronically are at increased risk of covid- infection [ ] . a meta-analysis study on covid- comorbidities, as depicted in fig. , had a total of patients, of which were male and were female with a mean age of years old [ ] . the most common comorbidities identified in these patients were hypertension ( . %), cardiovascular and cerebrovascular conditions ( . %), and diabetes ( . %) [ , ] . the less common comorbidities were coexisting infection with hiv and hepatitis b ( . %), malignancy ( . %), respiratory illnesses ( . %), renal disorders ( . %), and immunodeficiencies ( . %) [ ] . patients with moderate to severe asthma are at a disadvantage because this virus affects their respiratory tracts, leading to increased asthmatic attacks, pneumonia, and acute respiratory distress [ ] . according to the cdc's morbidity and mortality weekly report, . % of patients aged to years old have an underlying chronic lung disease, such as asthma [ ] . in iran, a case study reported that genetic predisposition to covid- can increase the probabilities of getting infected with sars-cov- and can lead to death from this virus [ ] . this genetic predisposition was seen in brothers in iran who were years apart in age ( , , and ) years who died due to covid- , despite no identified comorbidities and living separately from one another [ ] . as of january , , wuhan, china, had patients admitted to the hospital who tested positive for covid- , of which % ( / ) were men with a median age of years old, % ( / ) of these patients had been exposed to the huanan market, % ( / ) had underlying diseases such as diabetes % ( / ), hypertension % ( / ), and cardiovascular % ( / ) [ ] . patients who are hiv positive, along with a low cd count and not on antiretroviral therapy, have a higher risk and incidence of other medical issues including covid- [ ] . according to the international aids society (ias), people [ ] who are human immunodeficiency virus (hiv) positive, taking antiretroviral treatment, and do not have a low cd count will have the same risk of having covid- as one without hiv [ , ] . as depicted in fig. , a population-based surveillance report via covid- -associated hospitalization surveillance network (covid-net) reported clinical data on covid- -positive patient hospitalizations from march to march , [ ] . among the patients studied, % of adults showed clinical data of underlying medical conditions with the most prevalent being hypertension ( . %) and obesity a close second ( . %) [ ] . other medical conditions included chronic lung disease ( . %), diabetes mellitus ( . %), and cardiovascular diseases ( . %) [ ] . outcome covid- can cause severe disease leading to hospitalization in icu and potentially death, especially in the elderly with comorbidities [ ] . according to the cdc, out of deaths reported in the usa occurred in adults years old and above [ ] . roughly % of covid- -positive cases result in full recovery from the illness without any hospitalizations or interventions [ ] . there are still many facts that we do not know about covid- due to gaps in knowledge; therefore, many studies are underway to better understand this virus [ ] . wuhan, china, had patients admitted to the hospital who tested positive for covid- from december , , to january , , and the clinical outcomes are shown [ ] in fig. [ ] . of the patients with confirmed covid- in the hospital, % had pneumonia, % developed acute respiratory distress syndrome (ards), % exhibited an acute cardiac injury, and % acquired a secondary infection [ ] . the majority of these patients ( %) were discharged, % remained hospitalized, % ended up in the icu, and % ended in death [ ] . from february to march , , a study was conducted in evergreen, washington, on the characteristics and outcomes of critically ill patients with confirmed covid- diagnosis [ ] . this study showed that % of these patients required mechanical ventilation and acute respiratory arrest was seen in all of them [ ] . within h of developing ards, % of these patients showed increasing severity of respiratory problems, leading to poor short-term outcomes and a higher risk of death [ ] . as of march , , the mortality rate was % in these patients, with % critically ill and . % discharged from hospital [ ] . as shown in the cdc's mortality and morbidity weekly report in fig. , case mortality increased as the patient's age increased [ , ] . among the age group ≤ years, no icu admission or mortality was reported [ ] . covid- has also been noticed in children, but the disease took a more moderate course when compared with adults. the prognosis was also seemingly better, and deaths were infrequent [ ] . on april , , who reported over million confirmed covid- cases worldwide, with over , of these cases resulting in mortality [ ] . the majority of these [ ] deaths are within the usa with over , , followed by italy with over , and spain with over , [ ] . new york is being hit the hardest by the novel coronavirus spreading across the usa, with more cases and deaths per capita than any other state. table reports that over % of covid- deaths involved at least one comorbidity, according to the new york state department of health [ ] . multiple comorbidities are associated with the severity of covid- disease progression. many of the poorer outcomes for covid- have been related to cardiovascular comorbid conditions [ ] . however, this may be a direct result of the cardiovascular condition itself or attributed to other comorbidities along with a cardiovascular condition [ ] . patients with type diabetes were also more likely to have increased severity of covid- [ ] . in a cohort study of patients with covid- with and without type diabetes, it was shown that those with type diabetes required increased interventions for their hospital stay versus those that were nondiabetic [ ] . it was shown that those with poorer blood glucose control had an all-around increased mortality rate than those with better glucose control [ ] . the study concluded that patients with blood glucose specifically those in the range of . to . mmol/l had overall decreased composite adverse events and mortality [ ] . it was noted that poor blood glucose control resulted in a substantially increased risk of complications and death [ ] . among other comorbidities, chronic obstructive pulmonary disease (copd) has also been associated with poor disease progression. a meta-analysis of multiple studies in china found that there was a four-fold increase in mortality in patients with preexisting copd that were diagnosed with covid- [ ] . in this analysis, the smoking status of patients and severity of covid- were also studied. only one study was found to have an association with smoking and severe course of covid- [ ] . after this study was removed, there was no significant association with smoking and severe covid- disease [ ] . patients with acute respiratory distress syndrome and respiratory failure associated with the novel coronavirus may be linked to a prothrombotic coagulopathy [ ] . the autopsy of covid- -related deaths revealed dispersed microthrombi in the pulmonary vasculature, demonstrating an occlusive etiology of respiratory failure [ ] . a to % improvement was noted in three cases with covid- -related acute respiratory distress syndrome (ards) and respiratory failure, following treatment with intravenous (iv) antithrombotic alteplase [ ] . the results, although reassuring, were transient in two of the three cases with recovery succumbing posttreatment [ ] . the use of anti-thrombolytic therapy needs to be further studied to ascertain that the results are due to treatment and not chance alone [ ] . a retrospective meta-analysis including covid- patients was conducted until march , , on subjects with underlying comorbidities and the risk for acquiring covid- [ ] . common comorbidities such as hypertension, copd, diabetes, and cardiocerebrovascular disease were observed to be the more significant risk factors in subjects when compared with other underlying disease states [ ] . other than intense supportive measures, a definitive treatment has yet to be identified [ ] . authorities speculate that subjects with comorbidities were linked to a more severe disease outcome when infected with the novel coronavirus when compared with patients with no underlying disease [ ] . the study was met with barriers due to the diminutive sample size and some subjects having more than one underlying comorbidity [ ] . in literature and earlier research, underlying diseases increase the mortality rate in patients who acquired covid- with cardiac disease and diabetes being the most significant risk factors [ ] . once again, insufficient sample size and inadequate time have led to limitations in the data collected [ ] . over countries have been affected by covid- , resulting in mass death worldwide. as cases evolve globally, it has been noted that persons with underlying chronic illnesses are more likely to contract the virus and become severely ill. due to sars cov- being a relatively new virus, the data available is limited. however, patients with comorbidities have more deteriorating outcomes compared with patients without. covid- patients with history of hypertension, obesity, chronic lung disease, diabetes, and cardiovascular [ ] disease have the worst prognosis and most often end up with deteriorating outcomes such as ards and pneumonia. also, elderly patients in long-term care facilities, chronic kidney disease patients, and cancer patients are not only at risk for contracting the virus, but there is a significantly increased risk of death among these groups of patients. of the cases reported worldwide, symptoms of covid- ranged from mild respiratory disease to severe illness, which requires intubation and mechanical ventilation. since there is a period where the patient is asymptomatic, and the incubation period is between and days, it is difficult to establish an early diagnosis, much less curb the transmission of the infection if the patient is unknowingly exposed. however, within this period, if respiratory symptoms develop, it is important to seek immediate care. therefore, patients with comorbidities should take all necessary precautions to avoid getting infected with sars cov- , as 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associated acute respiratory distress syndrome (ards): a case series does comorbidity increase the risk of patients with covid- : evidence from meta-analysis prevalence and impact of cardiovascular metabolic diseases on covid- in china publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations authors' contribution a.s., conceptualization and design and approval of the final version, responsibility for the accuracy, and integrity of all aspects of research. c.o., supervision and revising the article for intellectual content and editing. a.m., drafting the article and editing and project administration. r.p., drafting the article and acquisition of data. k.y., drafting the article and acquisition of data. p.d., drafting the article and acquisition of data. z.h., drafting the article and acquisition of data. i.p., data analysis and interpretation of data. j.m., data analysis and interpretation of data. m.a., data analysis and interpretation of data. conflict of interest the authors declare that they have no conflict of interest. key: cord- -z ayolzb authors: gaur, uma; majumder, md anwarul azim; sa, bidyadhar; sarkar, sankalan; williams, arlene; singh, keerti title: challenges and opportunities of preclinical medical education: covid- crisis and beyond date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: z ayolzb covid- pandemic has disrupted face-to-face teaching in medical schools globally. the use of remote learning as an emergency measure has affected students, faculty, support staff, and administrators. the aim of this narrative review paper is to examine the challenges and opportunities faced by medical schools in implementing remote learning for basic science teaching in response to the covid- crisis. we searched relevant literature in pubmed, scopus, and google scholar using specific keywords, e.g., “covid- pandemic,” “preclinical medical education,” “online learning,” “remote learning,” “challenges,” and “opportunities.” the pandemic has posed several challenges to premedical education (e.g., suspension of face-to-face teaching, lack of cadaveric dissections, and practical/laboratory sessions) but has provided many opportunities as well, such as the incorporation of online learning in the curriculum and upskilling and reskilling in new technologies. to date, many medical schools have successfully transitioned their educational environment to emergency remote teaching and assessments. during covid- crisis, the preclinical phase of medical curricula has successfully introduced the novel culture of “online home learning” using technology-oriented innovations, which may extend to post-covid era to maintain teaching and learning in medical education. however, the lack of hands-on training in the preclinical years may have serious implications on the training of the current cohort of students, and they may struggle later in the clinical years. the use of emergent technology (e.g., artificial intelligence for adaptive learning, virtual simulation, and telehealth) for education is most likely to be indispensable components of the transformative change and post-covid medical education. the covid- pandemic required a massive and rapid change in the way we deliver medical education, particularly to the junior years of the medical program. [ ] the global covid- pandemic impacted every sphere of human life including medical education, resulting in the suspension of face-to-face teaching in medical schools across the world [ , ] . medical schools have adopted several innovative strategies in response to the crisis, with shift to online learning and assessment [ ] . however, medical schools are currently facing the biggest challenge, "training medical students within limitations of social distancing" especially in the preclinical phase due to suspension of practical/lab sessions. the british model of mbbs curriculum is spilt into preclinical and clinical phases; the initial years are preclinical years dealing with basic science subjects, i.e., anatomy, physiology, biochemistry, pharmacology, microbiology, and pathology. preclinical phase plays a very crucial role in shaping up scientifically grounded and clinically competent physicians [ , ] . before the outbreak of covid- , blended learning was highly recommended for preclinical years using active learning strategies which were found to be more effective learning this article is part of the topical collection on covid- experiences [ , , ] . online learning emerged as a sole option to continue the semester during lockdown and social distancing era. implementation of a well-structured "blended" preclinical curriculum with integration of knowledge and skills to prepare a better trained doctor is highly recommended. we searched relevant literature in pubmed, scopus, and google scholar using specific keywords, e.g., "covid- pandemic," "preclinical medical education," "online learning," "remote learning," "challenges," and "opportunities." original studies, reviews, editorials, commentaries, perspectives, short or special communications, and policy papers on covid- pandemic were reviewed. information from websites of different medical schools, universities, professional associations, and international or national organizations were extracted. reference lists from retrieved articles were also examined manually for relevant information. preclinical curriculum is considered the "foundation" and "core component" for clinical education and allows students to learn basic sciences. learn in-depth mastery of the preclinical knowledge necessary to prepare tomorrow's doctors for the scientific advances that are rapidly changing the perspective of medical practice. preclinical curriculum utilizes didactic lectures with practical-oriented, laboratory-based hands-on training [ ] [ ] [ ] . however, in recent years, preclinical faculty has been facing the reduction of contact hours with the introduction of integrated curriculum and limited resources [ ] [ ] [ ] [ ] . to accommodate the transition from regional to systemic integration in anatomy, preclinical education in the last few decades observed a slow transition from didactic, lecture-based classroom teaching to small group sessions, problem-based learning, teambased learning, and flipped lectures [ ] [ ] [ ] [ ] [ ] . introduction of these new teaching strategies makes learning more active, studentcentered, engaging, creative, effective, and enjoyable [ ] . new strategies are emerging in the preclinical phase that integrates technology to make learning effective and appealing to students, [ ] [ ] [ ] , making them more relevant and applicable for remote learning during the current covid- pandemic. these strategies proved very useful in the current covid- crisis, and medical students appreciated synchronized online learning, especially preclinical students [ ] . medical education in the last two decades has seen the extensive implementation of evidence-based teaching with the adaptation of new learning strategies supported by digital technology [ ] [ ] [ ] [ ] [ ] . technology-based medical curriculum was found to be more effective than the traditional approach and was well-received by medical fraternities [ ] [ ] [ ] [ ] [ ] [ ] . digital approaches transformed medical education to achieve higher levels of knowledge and skills through competency-based education with the application of adult learning theory [ ] [ ] [ ] ] . in this unprecedented and unforeseen circumstance raised by covid- , online learning may be the only way to continue teaching basic sciences during post-covid- . we will need to develop new and enduring ways to support medical students who may be scarred by this pandemic. [ ] the effect of current pandemic has an enduring transformation on medical education and will likely to have long-lasting repercussions on student learning. the academic leadership has been placed under tremendous pressure in terms of delivery, access, and assessment of courses; [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] while simultaneously preserving the principles of integrity, equity and inclusiveness, fairness, ethics, and safety [ ] . the unprecedented use of online pedagogy as an emergency measure during covid- period, with an adaptation to the "new normal" to deliver preclinical medical education, has brought both challenges and opportunities to medical education [ , [ ] [ ] [ ] [ ] . the main impediments to providing online learning include lack of reliable network infrastructure (hardware and software, network bandwidth) and compatible online platforms that work with existing learning management system (lms) [ , , , [ ] [ ] [ ] [ ] . other challenges included shortage of competent it personnel to extend technical support, zoombombing/cyberattacks on online platforms, increased cost (schools, students, and faculty), time constraints, poor computer technical skills of faculty and students, inadequate infrastructure and resources, and an absence of institutional policies, which will pose real challenges for low-and middleincome countries [ , , , [ ] [ ] [ ] [ ] . the transition from on-campus medical school settings to home environments results in isolation, stress, lack of concentration, reduced interaction with peers, and disturbance caused by family affairs [ , , , , ] . sudden transition from classroom to home learning affected the performance of students and faculty. adaptability to home learning would be a challenging task [ , , , ] . moreover, students would lose access to dissection rooms and practical labs, prosections, models, pathology specimens, skeletons, and other lab-or practical-based materials and equipment [ , , , [ ] [ ] [ ] . this is worrying because the medical curriculum has already shortened the basic medical sciences teaching time and limited students' exposure to anatomy and other important foundation subjects of the medical program [ ] [ ] [ ] . very short notice transitioning of the teaching community from face-to-face to online teaching with limited and in some cases no prior exposure has been a real challenge for preclinical faculty. this resulted in a struggle to find "a best-suited medium" for teaching anatomy and other basic sciences [ , , , [ ] [ ] [ ] [ ] [ ] . the current situation also raised concerns regarding unlimited amount of time spent in front of the computer screen, lack of social interaction, and lack of real-life verbal and nonverbal communication which could result in a passive form of learning [ , , , [ ] [ ] [ ] [ ] . moreover, facial expression and voice would be compromised in online teaching to some extent. online learning will minimize the chances of building a better mentoring relationship between faculty and students as well. the lack of hands-on training in the preclinical years may have serious implications on the training of the current cohort of preclinical students, and they may struggle later in the clinical years [ , [ ] [ ] [ ] [ ] . it is well establish that clerking patients cannot be replace by online learning as "clinical experience and human interaction are extremely important for the practice of medicine" and online learning cannot completely replace in-person live sessions [ ] . clinical students can be benefited when teaching is supplemented by virtual simulations and computer-based models [ , ] . to create a conducive learning environment (internet access, dedicated space) to deliver a "forced home learning" has also been a challenge for both staff and students [ , , [ ] [ ] [ ] . physical (e.g., lack of social interaction and outdoor activity) and psychological wellbeing of both students and staff is of great concern [ ] [ ] [ ] ] . the preparation of online assessments and training for various online platforms has been a struggle for faculty as well as students [ , , , ] . furthermore, unproctored online assessments may encourage students towards academic misconduct or dishonesty, i.e., plagiarism and cheating, [ , ] which may "severely affect the knowledge and conduct of future doctors and therefore the quality of healthcare" [ ] . while covid- has thrown many challenges for preclinical medical education, it has also created opportunities-academic leaders with servant leadership, distribution of leadership responsibilities, and clear lines of communication dealt with the situation aptly [ , [ ] [ ] [ ] [ ] . during this challenging time, the academic leadership presented guidelines/protocols to conduct course delivery and assessment in a remote environment which were found to be helpful for students and staff [ ] [ ] [ ] [ ] . medical schools and faculty utilized novel methods of delivering education, which need to be adopted much earlier to teach "adult learners" [ , ] . online delivery of courses has the potential to enhance student engagement, geographical accessibility, and synchronous/asynchronous learning and assessment [ , , , , ] . medical educators worldwide are trying to learn from experiences of innovative schools and developing survival packages for their medical schools. many medical schools have worked to transform pedagogy by increasing online lectures of basic medical sciences, using technology to replace and enhance basic sciences and laboratory teaching, and implementing online formative and summative assessments [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . online lectures, flipped lectures, videos, virtual simulators, webcasting, online chatrooms, and other technologies and simulation-based teaching modalities have been used to teach preclinical courses [ - , , ] . small group teaching in virtual team settings are found to be effective, even for some laboratory science and practical training contents [ , ] . for example, a recent study showed that fourteen medical schools in the uk and republic of ireland used technology to teach and assess anatomy in medical students (table ) [ ] . medical schools in australia and new zealand used diverse platforms/policies for the delivery of online lectures and active learning (asynchronous/synchronous, discussion boards, prerecorded lectures, and feedback), practical sessions (asynchronous/ synchronous), and online assessments (random q&a, modified weighting, pass/fail, and team exams) [ ] . imperial college london's first-ever online exam by open-book examination (obe) approach, for final years, has proven successful [ , ] . many medical schools have adopted similar approaches to engage students with their studies. all these positive impacts will certainly provide "an initial insight into new and innovative ways of delivering medical education," especially in preclinical phase during the post-covid era [ ] [ ] [ ] [ ] ] . the pandemic has provided opportunities for staff to acquire skills in online pedagogy and digital media production while developing alternative modes of assessments and transferring principles of learning [ - , , , ] . online learning during covid- received positive students' feedback with "an extremely high level of satisfaction and engagement with online learning activities" and brought a psychological resilience among staff and students [ , , ] . this is an opportunity for the academic sector to converge, strengthen connections across countries and continents, and collaborate. medical schools, regulatory bodies, and other stakeholders have a responsibility to ensure that tomorrow's doctors are "sufficiently trained and supported to deliver essential patient care, even in crises" [ ] . medical educators should "learn from this experience and prioritize a forward-thinking and scholarly approach" to implement best practices and flexible approaches adopted in medical education around the world for an effective transition to online learning and assessment [ ] . as pandemic exposed the "flaws" in medical education and healthcare, medical educators should review curriculum using the "bioscientific model of health" and widen the educational approach by incorporating determinants of health (behavioral, social, and environmental factors) [ ] . medical curriculum should include "surveillance for disease, investment in disease and injury prevention, and disaster planning" as core components [ ] . we must remain optimistic as the medical education fraternity has accepted that "transition is inevitable" and has already started preparing to ensure that "transition can be smooth through resilient educational systems" [ ] . we are waiting to see what ingenuities for medical education will emerge in the face of the covid- pandemic [ ] . basic or preclinical sciences are considered the foundation of medical practice. the covid- pandemic has impacted medical education globally. covid- has disrupted medical education and forced basic science teaching to rapidly adapt to changes which will pose unique challenges to the clerkship training. the preclinical medical curricula have seen the introduction of novel methods of delivering education online, and online classes received positive responses from students and faculty. the use of remote learning as an emergency measure has brought both challenges and opportunities for many medical schools worldwide affecting faculty, students, and administrative and support staff. however, the lack of hands-on training in the preclinical years may have serious implications on the training of the current cohort of students, and they may struggle later in the clinical years. medical educationists need to adopt a "forward-thinking and scholarly approach" with curricular innovations to train future medical graduates during and after the pandemic [ ] . to make an online learning package beneficial, it needs to be "suitably integrated into curriculum design" to "guide students through a learning journey, rather than simply made available as another resource" [ ] . moreover, technology-based teaching modalities must be evaluated for effectiveness and sustainability for application in the preclinical settings. appropriate attention must be paid to pedagogical requirements of online learning as well as providing face-to-face clinical training so that students can develop required competencies to practice medicine. if the higher education sector believes that digital education should replace contact teaching and learning, it runs the risk of producing highly qualified people with severely underdeveloped human or social skills. they will just be robots [ ] . (dr. sizwe mabizela, vicechancellor of rhodes university in south africa) terry hartle, vice-president of the american council on education, mentioned the pandemic as an "epochal event" which will "leave a huge impression on the education sector" [ ] . mccullough et al. [ ] also warned: "the covid- pandemic will not be the last major infectious disease that puts learners at risk." however, many medical schools have successfully transitioned their teaching and learning environment to emergency remote learning, having monitored and examined student and staff readiness, and completed online formative and summative exams both in preclinical and clinical years. while bringing closure to the turmoil academic year - , medical schools are now making final preparations for the start of the new academic year and carefully monitoring national and international covid- environments. due to the covid- pandemic, online learning has been expanding as a relatively new concept in medical education. implications for educators now include increased responsibility; a need to alter teaching style, curriculum planning, and assessment strategies; more meaningful and continuous communication; and better preparedness to not only challenge learners of the digital age [ , , , , , ] but also to obtain "deeper learning" and "apply knowledge in the clinical context" [ ] . however, due to the "immersive nature of medical education," medical educators should find innovative ways to have face-to-face teaching alongside online delivery [ ] . novel and authentic assessment strategies are required where students can develop a set of graduate attributes or "soft skills" (e.g., communication skills, reflective practice, group work, and collaboration) and demonstrate understanding and application of the relevant basic science knowledge required for clinical phase [ ] . and, further design of quality assurance strategies that will monitor the online delivery of curriculum and assessment is also crucial. during and after this pandemic, extensive research is required to examine the effectiveness of superimposed online pedagogy and indicators such as students' academic performance, their mental health, and teaching transferable graduate mcqs multiple-choice questions, emqs extending matching questions, saqs single-answer questions, sbas single-best-answers skills. the use of emergent technology for education, such as artificial intelligence for adaptive learning, virtual simulation, and telehealth, are most likely to be essential components of the transformative change and the future of medical education, including clinical training [ ] . author's contributions ug: conceptualized the review, conduct literature review, extracted relevant information, and drafted the manuscript. maam: conceptualized the review, conduct literature review, extracted relevant information, and drafted the manuscript. bs: conduct literature review, extracted relevant information, and reviewed and revised the manuscript. ss: conduct literature review, extracted relevant information, and reviewed and revised the manuscript. aw: conduct literature review, extracted relevant information, and reviewed and revised the manuscript. ks: conduct literature review, extracted relevant information, and critically reviewed the manuscript for important intellectual content. other disclosures none. ethical approval not applicable. disclaimer none. consent for publication all authors reviewed and approved the final version and have agreed to be accountable for all aspects of the work including any issues related to accuracy or integrity. abbreviations covid , coronavirus disease of ; mbbs, bachelor of medicine bachelor of surgery; lms, learning management system; it, information technology; uk, united kingdom; q&a, question and answer; mcqs, multiple-choice questions; emqs, extending matching questions; saqs, single-answer questions; sbas, single-bestanswers the impact of covid- pandemic on medical education a vision of the use of technology in medical education after the covid- pandemic we signed up for this!" student and trainee responses to the covid- pandemic pandemics and their impact on medical training: lessons from singapore medical education today: all that glitters is not gold medical education: past, present and future gamification in action: theoretical and practical considerations for medical educators teaching anatomy using an active and engaging learning strategy technology-enhanced learning in asia: new educational possibilities for the tomorrow's doctors and tomorrow's cures the sudden transition to synchronized online learning during the covid- pandemic in saudi arabia: a qualitative study exploring medical students' perspectives twelve tips for covid- friendly learning design in medical education going virtual to support anatomy education: a stopgap in the midst of the covid- pandemic covid- -the impact on our medical students will be far-reaching medical student education in the time of covid- [published online ahead of print medical education amid the covid- pandemic strength, weakness, opportunity, threat (swot) analysis of the adaptations to anatomical education in the united kingdom and republic of ireland in response to the covid- pandemic academic leadership in a time of crisis: the coronavirus and covid- guidance from the board for undergraduate studies on the waiver of faculty regulations on exams due to covid- forced disruption of anatomy education in australia and new zealand: an acute response to the covid- pandemic the impact of the covid- pandemic on current anatomy education and future careers: a student's perspective the virtual anatomy laboratory: usability testing to improve an online learning resource for anatomy education teaching anatomy at the time of covid- effective use of educational technology in medical education. in colloquium on educational technology: recommendations and guidelines for medical educators. aamc institute for improving medical education: washington covid- and online teaching in higher education: a case study of peking university medical-school-life/medical-school-assessment-during-covid- -shelf-exams-go self-reported cheating among medical students: an alarming finding in a crosssectional study from saudi lifting the carpet" on cheating in medical school exams the impact of covid- on the undergraduate medical curriculum using technology to increase student (and faculty satisfaction with) engagement in medical education medical students take final exams online for first time, despite student concern. the guardian effects of online testing on student exam performance and test anxiety institutional report for covid- impact on medical education medical and surgical education challenges and innovations in the covid- era: a systematic review medical student involvement in the covid- response covid- : lessons from the disaster that can improve health professions education covid- : the global disrupter of medical education covid- and medical education covid- : 'this is not the end of contact teaching covid- : consequences for higher education teaching professional formation in response to the covid- pandemic barriers and solutions to online learning in medical education -an integrative review publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations acknowledgments we extend our gratitude to mrs. stella williams, former lecturer in health communication, centre for medical sciences education, faculty of medical sciences, the university of the west indies, st. augustine campus, and trinidad & tobago, for her assistance in reviewing this manuscript for english language and grammar. key: cord- - im gxw authors: violetis, odyssefs a.; chasouraki, angeliki m.; giannou, alexandra m.; baraboutis, ioannis g. title: covid- infection and haematological involvement: a review of epidemiology, pathophysiology and prognosis of full blood count findings date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: im gxw the unfolding covid- pandemic began in december in wuhan, hubei province. covid- is a systemic infection affecting several systems including the haematopoietic system. surveys illustrating the laboratory findings of these patients conclude that lymphocytopenia, neutrophilia and thrombocytopenia are prominent amongst them. moreover, it has been reported a significant decrease in t lymphocyte subsets and an increase of inflammatory cytokines of hospitalized patients with covid- . generally, thrombocytopenia is commonplace in critically ill patients and usually suggests serious organ malfunction. in view of this, this review investigates the correlation between these abnormalities and the prognosis and disease course. full blood count is an easy, economic and widely available tool which may help to discriminate between patients with or without severe disease. last but not least, this review examines potential pathophysiological mechanisms by the novel coronavirus which contribute to these haematological alterations aiding the clinicians to better understand this disease and provide more clinical treatment options. severe acute respiratory syndrome (sars-cov- ) was first recognized in wuhan, china, in december causing coronavirus disease and has swiftly spread all over the world infecting approximately billion individuals until may . the world health organization has already issued a proclamation characterizing the covid- outbreak a pandemic (https://www.who.int/emergencies/diseases/novelcoronavirus- ) [ ] . coronaviruses (covs) are a large family of respiratory viruses that can cause diseases ranging from the common cold to severe acute respiratory syndrome (sars) and middle east respiratory syndrome (mers) [ , ] . sars-cov was the cause of the former infection which first appeared in china in but ultimately was first isolated in vietnam a few months later by the italian doctor carlo urbani [ ] . the outbreak of sars affected countries and provoked deaths out of laboratory-confirmed cases (https://www.who.int/ csr/sars/en/). regarding the latter infection, the responsible virus was the middle east respiratory syndrome (mers)-cov that, in , was first reported in saudi arabia [ ] . mers has been found in countries, mostly in the middle east, and occasionally reappears in human population due to the ongoing contact with dromedary camels. until november , mers has caused deaths out of laboratoryconfirmed cases (https://www.who.int/emergencies/mers-cov/ en/). covid- infection is regarded as a systemic disease due to the fact that aside from the respiratory system, it affects this article is part of the topical collection on covid- several other systems such as cardiovascular [ ] , neurological [ ] , haematopoietic [ , ] , gastrointestinal, [ ] and immune [ ] . herein, we summarize the hematologic findings on full blood count focusing on white blood cells and platelets analysing their pathophysiology and their potential use as a tool for spotting the patients who are prone to a more severe progression of the disease or even a lethal upshot. guen et al. released a grand survey examining the clinical and laboratory characteristics of . patients infected with covid- . they reported that admission lymphocytopenia, thrombocytopenia and leukopenia were quite prevalent. in detail, . % of the patients presented with lymphocytopenia, which was defined as a lymphocyte count of less than mm whereas . % of them presented with thrombocytopenia, which was defined as a platelet count of less than , mm . with regard to leukopenia (wbc less than mm ), it was apparent in . % of the patients. furthermore, the incidence of these abnormalities in the blood cell count was in line with the severity of the disease. hence, the patients, who suffered from a more severe disease, tended to have more pronounced abnormalities in comparison with those with mild disease ( . % vs . % as concerned to lymphocytopenia, . % vs . % as concerned to thrombocytopenia and . % vs . % as concerned to leukopenia respectively) [ ] . wang et al. examined the kinetics of the laboratory parameters in patients infected by covid- during their hospitalization. thirty-three patients came down with severe disease and patients eventually died. comparing the laboratory data derived from the patients who were admitted in icu to those who did not, it can be clearly seen that the data differ. with regard to white blood count and neutrophil count, higher levels were observed on the first group, notably . -fold and . -fold higher respectively. furthermore, it has been mentioned that the non-survivors were more frequently prone to develop leukocytosis [ ] . similarly, the study published by huang et al. advocates that leukocytosis ( . -fold rise) and neutrophilia ( . -fold rise) were predictors of the severity of the disease, which was confirmed by the need for admission in an icu environment, while examining patients with covid- infection [ ] . according to a meta-analysis, the patients with severe disease presented a slight increase in their white blood cells while those who did not survive presented a significant increase. thus, it is recommended that wcc should be examined on a regular basis on the grounds that the increase of the white blood cells in a patient with severe disease may indicate clinical deterioration and a grave outcome. the increase of neutrophils accounted for the surge of the white blood cells as the other bloodlines (lymphocytes, monocytes and eosinophils) dropped [ ] . the available literature advocates that neutrophilia is an expression of the cytokine storm and hyperinflammatory state which have an important pathogenetic role in covid- and related infections such as sars [ , , , ] . neutrophilia may also indicate a superimposed bacterial infection [ ] . another potential application of data derived from the fbc would be to use formulas such as neutrophil-to-lymphocyte ratio (nlr), platelet-to-lymphocyte ratio and monocyte-tolymphocyte ratio to act as surrogates to assess the extent of systemic inflammation. although an extensive study is at this point lacking, qin et al. have reported an increase in nlr in patients with severe disease compared with those without [ ] . to date, regarding eosinophil count, literature suggests that there is no link between low eosinophils and the severity of the disease [ ] . several factors might play an important role in the pathophysiology of lymphocytopenia. firstly, it has been discovered that angiotensin-converting enzyme receptors (ace receptors) are likely the cell receptor of covid- , which was also the receptor for sars-cov [ ] . therefore, cells which express ace receptors are susceptible to covid- infection. nonetheless, there had been no evidence that lymphocytes could express those receptors which could make them vulnerable to the new virus. however, a study published by xu et al. demonstrated that ace receptors were expressed in lymphocytes in oral mucosa, lungs and digestive system [ ] . hence, the direct impact of the virus on the lymphocytes, which could induce their lysis, does not seem unfounded. moreover, covid- infection causes the production of inflammatory cytokines such as il- , il- , il- , granulocyte-colony stimulating factor, interferon-γ-inducible protein , mcp- , mip -a and tnf-a, recognizable as a cytokine storm, which leads to not only lymphocytes' apoptosis but also lymphoid organs' atrophy (e.g. the spleen) [ ] . as already mentioned above, lymphocytopenia is a strong predictor of the severity of the disease. in china, patients who ultimately required icu environment during their hospitalization presented a more significant drop in lymphocyte count compared with those who did not [ , ] . these findings are consistent with studies in singapore [ ] . moreover, lymphocytopenia was highly correlated with the severity of lung injury [ ] . lymphocytopenia was also associated with survival incidence, as non-survivors presented a more considerable decrease in lymphocyte count compared with survivors [ ] . in a us study from washington dc, lymphocytopenia was prominent amongst critically ill patients [ ] . a retrospective study by bo xu et al. examined the alteration of lymphocyte subsets in patients with covid- . the findings illustrate that the patients who were categorized as severely ill and critically ill including those who passed away experienced a considerable dip of t lymphocyte subset counts. particularly, in critically ill and severely ill patients, the median counts of lymphocyte, cd + t cell, cd + t cell and cd + t cell were declined to almost a third and about two-thirds of median counts values respectively when they were compared with mildly ill patients. in patients who died during their hospital stay, the median lymphocyte, cd + t cell, cd + t cell, cd + t cell, b cell and nk-cell were observed to be lower than other critically ill patients [ ] . another study concluded that there was no difference in cd + /cd + ratio between healthy controls and patients with covid- or between those with mild disease and those with severe disease [ ] . thrombocytopenia is a well-known predictor of mortality in the icu environment and it is used in several disease severity scores. a meta-analysis conducted by lippi g. et al. included studies with a total of covid- patients examining the association between thrombocytopenia and severity of the disease. it was revealed that low platelet count was associated with a threefold enhanced risk of severe disease and with a fatal outcome. taking a closer look, the analysis showed that platelet count was significantly lower in patients with more severe covid- (wmd − × /l; % ci, from − to − × /l) while the subgroup analysis of three studies, whose primary outcome was mortality, showed a more significant drop in platelets in non-survivors (wmd, − × /l; % ci, − to − × /l; i , %; p < . ) [ ] . several hypotheses regarding the pathophysiological mechanisms, which could lead to low platelet count in patients infected with covid- , have been cited. to begin with, it is speculated that covid- has similar action with a frequent common cold's coronavirus, hcov- e. this speculation derived from the genome similarities between covid- and sars virus and sars virus and hcov- e respectively. hcov- e binds cd receptors which are expressed on the surface of haematopoietic and stromal cells in the bone marrow leading to their apoptosis and consequently to haematopoiesis inhibition. in addition, the induced cytokine storm after the covid- infection, which has similarities with secondary haemophagocytic lymphohistiocytosis (shlh), may play a role in thrombocytopenia through destruction of the haematopoietic progenitor cells. in parallel with hiv infection, covid- may produce autoantibodies and complexes specific to platelets' antigens resulting in their destruction by the reticuloendothelial system [ ] . a large number of existing studies in the broader literature have examined the platelets biogenesis in the lung circulation. experiments in mice suggest that megakaryocytes and large cytoplasmic fragments are produced in the bone marrow, then they emigrate to the pulmonary circulation and eventually are transformed into platelets under the shear stress and the turbulence into pulmonary vasculature. those findings can only indirectly be confirmed in humans [ ] . therefore, it is speculated that lung injury caused by covid- infection may limit sites with preserved endothelium that could participate in platelet production from intravascular megakaryocytes [ ] . most patients with covid- who have thrombocytopenia have elevated d-dimer levels and impaired coagulation time and the majority of the patients with lethal outcome fulfil the clinical criteria for disseminated intravascular coagulation (dic) [ ] . patients presenting with a virus infection may develop sepsis which is well established as a common cause of dic. the development of dic results when leukocytes, platelets and endothelial cells are activated to inducing dysregulation of thrombin formation that occurs both systemically and locally in the lungs of the patients with severe pneumonia. circulation of free thrombin, uncontrolled by natural anticoagulants, can activate platelets and stimulate fibrinolysis [ ] . for that reason, it is conjectured that platelet consumption during microthrombus formation in dic is one of the pathogenic mechanisms explaining the profound thrombocytopenia. in summary, findings on full blood count could indicate the patients who suffer from severe disease and could be used as a prognostic tool by the clinicians. leukocytosis, neutrophilia, lymphocytopenia and thrombocytopenia are prominent in patients with severe disease. these markers may play a role not only in a more efficient triage of those patients on admission but also during their hospitalization so that more vigorous therapeutic procedures should follow. even though corticosteroids are known to cause lymphocytopenia, recently published experience suggests that the lymphocyte count promptly recovers after an initial drop with the use of corticosteroids (namely dexamethasone) in severe covid- infection [ ] . dexamethasone seems to benefit patients with severe covid- infection, according to a recent announcement by the recovery investigators (https://www.recoverytrial.net/ news/low-cost-dexamethasone-reduces-death-by-up-to-onethird-in-hospitalised-patients-with-severe-respiratorycomplications-of-covid- ). moreover, flow cytometry is likely to be used for the same purposes and for investigating how the immune system responds to the infection by the new virus. finally, the pathophysiological mechanisms which lead to these abnormalities should be investigated thoroughly by the forthcoming studies as until now there is a lack of knowledge. the collected data were mostly based on asian population since data from other nationalities are not yet available. therefore, with the release of new publications, this information may need to be further evaluated. 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wuhan outbreak and modeling of its spike protein for risk of human transmission high expression of ace receptor of -ncov on the epithelial cells of oral mucosa hematological findings and complications of covid- hematologic parameters in patients with covid- infection clinical and biochemical indexes from -ncov infected patients linked to viral loads and lung injury characteristics and outcomes of critically ill patients with covid- in washington state suppressed t cell-mediated immunity in patients with covid- : a clinical retrospective study in wuhan characteristics of peripheral lymphocyte subset alteration in covid- pneumonia thrombocytopenia is associated with severe coronavirus disease (covid- ) infections: a meta-analysis mechanism of thrombocytopenia in covid- patients platelet biogenesis in the lung circulation abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia disseminated intravascular coagulation in patients with -ncov pneumonia initial real-life experience from a designated covid- centre in athens, greece: a proposed therapeutic algorithm publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- -eph g authors: spuntarelli, valerio; luciani, m.; bentivegna, e.; marini, v.; falangone, f.; conforti, g.; rachele, e. s.; martelletti, p. title: covid- : is it just a lung disease? a case-based review date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: eph g due to its extreme virulence, covid- virus has rapidly spread, developing a severe pandemic. sars-cov- mostly affected the respiratory tract, causing a severe acute lung failure. although the infection of airways, covid- can be associated with chronic and systemic damages still not so much known. the purpose of this research is to collect recent evidence in literature about systemic diseases caused by covid- . the format of the present article has features of a systematic case-based review (level of evidence), and it is structured as a case series report (patients of our covid- medicine ward have been selected as cases). data for this review have been selected systematically, taking evidence only from indexed journals and databases: pubmed, scopus, medline, and cochrane systems. papers chosen included systematic reviews, case series, clinical cases, meta-analysis studies, and rcts. we start collecting studies since . the main keywords used were “covid- ” “or” “sars” “or” “sars – cov ” “and” “systemic disease” / “nephropathy” / “cardiac pathology” / “central nervous system.” clinical cases belong to our covid- medicine ward. one of the most severe covid- clinical presentations includes cardiovascular problems, like myocarditis, pericarditis, and acute hearth failure. cytokine release syndrome caused by covid- develops severe acute kidney failure. it is still unknown the way coronavirus damages the liver, brain, and reproductive system. considering the majority of the new studies about this pathology, it issues that covid- is considered to be a multi-organ disease. covid- pandemic reached . million confirmed reported cases worldwide, and it is generally associated to the acronym that precedes its name: severe acute respiratory syndrome (sars). however, the bottom of the iceberg is being progressively unveiled since it is far more than simply a severe interstitial pneumonia. there is a gap in knowledge of pathophysiological process that allows covid- to be considered a multi-organ disease in all respects. we looked for main papers about sars and covid- as systemic diseases, focusing on cardiovascular, renal, liver, nervous, and reproductive systems. the sars-cov- virus not only causes viral pneumonia; however, it also has major implications for the cardiovascular system, but the extent, severity, and duration are still to be defined. in a study of patients, two patients had succumbed to acute myocardial infarction [ ] . a study from huang et al. demonstrated that myocardial injury, defined by an increase in hs-ctni levels (> pg/ml), occurred on out of covid- patients. noteworthy is the fact that % of these patients required icu management demonstrating that myocardial damage in sars-cov- infection is severe [ ] . a prospective study investigating left ventricular performance in patients with severe acute respiratory syndrome showed subclinical diastolic impairment without systolic involvement [ ] . another study in patients with sars identified cardiovascular complications including tachycardia ( %), hypotension ( %), bradycardia ( %), transient cardiomegaly ( %), and transient paroxysmal atrial fibrillation in only patient, although usually self-limiting [ ] . a study from singapore reported postmortem examinations: the presence of pulmonary embolism (pe) and deep vein thrombosis and acute myocardial infarction is of great clinical interest, but the generalizability of this limited study is not established [ ] . anyway, it is well recognized that sars-cov- infection alters coagulation pathway. zhou et al. demonstrated that nonsurvivor covid- patients show significant higher levels of plasma d-dimer, activated partial thromboplastin times, and prothrombin times compared with survivors [ ] . pathological findings of covid- associated with acute respiratory distress syndrome showed few interstitial mononuclear inflammatory infiltrates, but no other substantial damage in the heart tissue [ ] . shi s. et al [ ] reported that between out of patients, . % had coronary heart disease, . % had heart failure, and . % had cerebrovascular disease underlying the importance of cardiac injury in covid- . a case report highlights myocarditis as a complication associated with covid- , even without symptoms and signs of interstitial pneumonia in an otherwise healthy -year-old white woman [ ] . another case report [ ] of an infected year-old man, from lombardy, italy, concluded that covid- infection was the most likely cause of myocarditis since tests for common causes of myocarditis (parvovirus b , human herpes virus, epstein-barr virus, enterovirus, cytomegalovirus, adenovirus, hiv, and hepatitis c virus) were negative. hydrocortisone improved its clinical picture. also, very recently, an association between covid- and medium size vasculitis-kawasaki disease-has emerged. according to older studies, a suspected association between hcovs and kawasaki disease could not be confirmed. however, shirato k. et al [ ] postulated that hcov- e is a possible causative agent for kawasaki disease. future case control studies are needed to settle the issue. clinical case a -year-old male arrived to emergency for chest pain, tachycardia, and dyspnea. blood gas analysis showed mild respiratory failure. sars-cov- buffer was positive. blood analysis pointed out an increase of serum myoglobin, high sensitive troponine, and mb creatine kinase. electrocardiogram was typical for myocarditis ( fig. ). three potential pathogenic mechanisms of kidney injury secondary to covid- have been identified. first, cytokine release syndrome (crs)-aka cytokine storm-has been implicated in the development of intrarenal inflammation and increased vascular permeability. il- , markedly elevated in ards patients, plays a major role in the pathogenesis of the disease. in crs patients who have undergone car-t cell therapy, the cytokine is the target of the therapy with tocilizumab and, thus, is now also being used empirically in patients with covid- . second, alveolar-tubular and cardiorenal crosstalk has been implicated. acute kidney injury (aki) is the most frequent extra-pulmonary organ failure in acute respiratory distress syndrome (ards), according to a recently confirmed bidirectional organ crosstalk, possibly il- fig. moderate st depression in most precordial leads mediated. il- is not a risk factor for ards development, but high levels are associated to increased mortality rate in patients with ards. independent risk factors are older age, disease severity, diabetes mellitus, and acidosis. finally reninangiotensin-aldosterone system increases both glomerular capillary and systemic hypertension, inducing hemodynamic injury to the vascular endothelium and glomerulus. angiotensin ii and aldosterone may also promote kidney damage with direct profibrotic and proinflammatory actions. as shown in the clinical case below, the further renal impairment caused by covid, in already nephropathic patients, can be considered a mortality predictor. clinical case a -year-old woman with chronic kidney failure was hospitalized in emergency ward for metabolic acidosis. sars-cov- buffer was positive. blood exams showed an important increase of serum creatinine. during observation, patient developed an important ards with lung edema (fig. ) . she died after days of noninvasive ventilation. it is less clear whether covid- damages the liver. case reports have described increased levels of alanine aminotransferase (alt), aspartate aminotransferase (ast), and bilirubin, indicating liver involvement, in which frequency is related to the severity of covid- illness. the same was observed during previous sars and mers epidemics. on the other hand, mansoor n.b. et al [ ] reassure about the relationship, describing that the previous studies on the issue actually suggest that clinically significant liver injury is uncommon, even when data for the most severely ill patients are selected. liver injury can also alternatively due to hypoxemia, dysregulated immune response, or drug toxicity. one-third of patients affected with covid- have nervous system involvement. virus can be detected in brain specimens and in cerebrospinal fluid. acute onset smell and/or taste disorders are significantly more frequent in cases of covid- which is a common influenza and should be considered a focus for clinical suspicion and consideration to selfisolation procedures. anosmia and ageusia are frequently early manifestation of covid- . although pathogenetic mechanisms are still unclear, vaira l. a. et al [ ] proposed a potential explanation. ageusia could be related to the highly expression of ace , identified as the cellular receptor for sars-cov- , on the oral mucosa and tongue. anosmia seems not to be related to a mere local inflammatory condition fig. emergency chest x-ray with severe interstitial edema in the nasal mucosa: in the absence of rhinitis symptoms, one hypothesis could be that the alterations are due to direct damage caused by the virus to the olfactory pathway. although many other neurological symptoms, such as headache, dizziness, conjunctivitis, and trigeminal neuralgia can be recorded in these patients, recent studies identified association with many neurological diseases. guillain-barre-strohl syndrome (gbs) is an acute demyelinating polyradiculoneuropathy affecting cranial nerves, dorsal and ventral radices, spinal ganglia, and peripheral nerves. a type hypersensitivity disorder is usually preceded by a respiratory (m. pneumoniae, h. influenzae, cmv, ebv) or gastrointestinal (c. jejuni). sedaghat z. et al [ ] , on april , described the first case of gbs apparently associated with covid- infection. on the april, another italian case report [ ] speculates the association between the acute polyradiculoneuropathy and covid- . the patient tested negative the most common abovementioned infections classically related to gbs. although the study could not exclude the possibility of an autoimmune or paraneoplastic polyradiculoneuropathy mimicking gbs, the postinfectious etiology, the acute clinical course, and the typical neurophysiologic findings on electroneurography make alternative diagnosis less likely. poyiadji n. et al [ ] found out that a woman with covid- presenting with altered mental status had features on brain images consistent with acute necrotizing hemorrhagic encephalopathy (ane). the authors concluded that the presence of the characteristic features of symmetric, multifocal lesions with thalamic involvement suggests that this is a case of acute necrotizing hemorrhagic encephalopathy associated with covid- . ane is a rare complication of influenza and other viruses resulting from intracranial cytokine storm and resulting in blood-brain barrier damage, plausible with covid- pathogenetic signature. although metabolic and electrolyte derangements, especially in thalamocortical pathways, secondary to covid- are plausible causes of clinical or subclinical acute symptomatic seizures and status epilepticus [ ] , lu l. et al [ ] concluded that neither the virus nor potential risk factors for seizures increased the likelihood of acute symptomatic seizures in covid- . clinical case a -year-old male arrived to emergency ward for altered brain status. sars-cov- buffer was positive. blood exams were quite normal. chest ct scan showed fig. normal brain ct scan at the entrance interstitial pneumonia. brain ct was normal at the entrance (fig. ) . patient was treated with antiviral therapy for days. at discharge, another brain ct showed new periventricular ischemic lesions (fig. ) . subject presented a mild cognitive impairment (mini mental state examination was ). little is still known about an association with reproductive system. ace expression in testes poses patients at risk of orchitis. pathologic analyses of testes of six patients who died of sars revealed widespread germ cell destruction few or no spermatozoon in the seminiferous tubule, thickened basement membrane, and leukocyte infiltration. it further suggests that the reproductive functions should be followed and evaluated in recovered male sars patients [ ] . conclusion covid- virus still represents a health and socioeconomic problem all over the world. clinicians must consider that it is no longer just a respiratory virus, as it has got a multi-organ trophism. it is important to consider extrapulmonary symptoms immediately to allow for early diagnosis and medical treatment. conflict of interest the authors declare that they have no conflict of interest. ethical approval na. consent written informed consent was obtained by patient for publication of this case report and accompanying images. 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 holder. to view a copy of this licence, visit http://creativecommons.org/licenses/by/ . /. clinical progression and viral load in a community outbreak of coronavirusassociated sars pneumonia: a prospective study clinical features of patients infected with novel coronavirus in wuhan left ventricular performance in patients with severe acute respiratory syndrome cardiovascular complications of severe acute respiratory syndrome analysis of deaths during the severe acute respiratory syndrome (sars) epidemic in singapore: challenges in determining a sars diagnosis clinical course and risk factors for mortality of adult inpatients with covid- in wuhan china: a retrospective cohort study pathological findings of covid- associated with acute respiratory distress syndrome association of cardiac injury with mortality in hospitalized patients with covid- in wuhan cardiac involvement in a patient with coronavirus disease (covid- ) possible involvement of infection with human coronavirus e, but not nl , in kawasaki disease covid- and the liver: little cause for concern potential pathogenesis of ageusia and anosmia in covid- patients. int forum allergy rhinol guillain barre syndrome associated with covid- infection: a case report guillain-barré syndrome following covid- : new infection, old complication? covid- -associated acute hemorrhagic necrotizing encephalopathy: ct and mri features central nervous system manifestations of covid- : a systematic review new onset acute symptomatic seizure and risk factors in coronavirus disease : a retrospective multicenter study orchitis: a complication of severe acute respiratory syndrome (sars) publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- -e iyso n authors: bhattacharjee, sukrita; banerjee, mainak title: immune thrombocytopenia secondary to covid- : a systematic review date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: e iyso n immune thrombocytopenia, often known as immune thrombocytopenic purpura (itp), has emerged as an important complication of covid- . a systematic review was done to analyze the clinical profile and outcomes in a total of cases of new-onset itp in covid- patients described in literature until date. a comprehensive approach is essential for diagnosing covid- -associated itp after excluding several concomitant factors that can cause thrombocytopenia in covid- . majority of itp cases ( %) were found to be elderly (> years) and % cases had moderate-to-severe covid- . three patients ( %) were in the pediatric age group. reports of itp in asymptomatic covid- patients ( %) underscore the need for covid- testing in newly diagnosed patients with itp irrespective of covid- symptoms amid this pandemic. itp onset occurred in % cases weeks after onset of covid- symptoms, with many reports after clinical recovery. sars-cov- -mediated immune thrombocytopenia can be attributed to the underlying immune dysregulation, susceptibility mutations in socs , and other mechanisms, including molecular mimicry, cryptic antigen expression, and epitope spreading. no bleeding manifestations were reported in % cases at diagnosis. severe life-threatening bleeding was uncommon. one case of mortality was attributed to intracranial hemorrhage. secondary evans syndrome was diagnosed in one case. good initial response to short course of glucocorticoids and intravenous immunoglobulin has been found with the exception of delayed lag response in one case. thrombopoietin receptor agonist usage as a second-line agent has been noted in few cases for short duration with no adverse events. in the relatively short follow-up period, four relapses of itp were found. a novel coronavirus disease (covid- ) pandemic, caused by severe acute respiratory syndrome corona virus (sars-cov- ), has affected over million people worldwide since its inception. acute respiratory distress syndrome (ards), cardiac complications, and thromboembolic events have contributed to majority of the disease mortality. among hematological complications, a systemic hyperinflammatory s t a t e r e s e m b l i n g s e c o n d a r y h e m o p h a g o c y t i c lymphohistiocytosis (hlh) and distinct coagulopathy resembling hypercoagulable stage of disseminated intravascular coagulation (dic) have been reported [ ] . the incidence of thrombocytopenia in patients with covid- has been variable across studies. mild thrombocytopenia has been observed in up to one-third of these patients, with even higher rate in patients with severe disease ( . %) compared with nonsevere disease ( . %) [ ] . a late-onset mild thrombocytopenia (mean time for nadir count from illness onset . days) for short duration (mean . days) has also been reported [ ] . however, majority did not have any severe degree of thrombocytopenia (< × /l or a sudden drop > % over - h) as can be seen in patients with immune thrombocytopenia irrespective of inciting event [ ] . "immune thrombocytopenic purpura" (itp), defined by a platelet count < × /l, classically presents with petechiae or purpuric rashes [ ] . more recently, a change in the term i n o l o g y w a s p r o p o s e d i n f a v o r o f " i m m u n e thrombocytopenia" to recognize that many patients with itp do not have bleeding symptoms [ ] . in this review, both terms have been used interchangeably. itp has been described following several viral infections, including hepatitis b/c viruses (hbv/hcv), cytomegalovirus (cmv), varicella zoster virus (vzv), human immunodeficiency virus (hiv), and most recently, following zika viruses [ ] . multiple cases of itp secondary to covid- have hitherto been reported . diagnosis of itp in patients with moderate-to-severe covid- poses a major diagnostic as well as therapeutic challenge to clinicians owing to presence of multiple concomitant conditions including hlh, dic, sepsis, antibiotic use, heparin prophylaxis, and thromboembolic events. the aim of this systematic review was to analyze the clinical characteristics, diagnostic work-up, blood count parameters, therapeutic strategies, and outcomes of confirmed covid- patients presenting with new-onset itp. a systematic review of literature was performed across pubmed, google scholar, and embase databases until august , , using the following keywords as per the prisma guidelines: "covid- ," "immune thrombocytopenic purpura," "thrombocytopenia," "immune cytopenia," "petechiae," "hemorrhage," "bleeding," with interposition of the boolean operator "and." the search was conducted by two independent authors (sb and mb). articles hence identified were further screened. duplicate articles, articles in non-english language, reviews and comments/communications, and articles not pertaining to new-onset itp secondary to covid- were excluded. finally, a total of articles met the eligibility criteria and were included (fig. ). the included articles and the number of patients in each article have been summarized in table . the following data were extracted from the included studies: age of the patient at presentation, gender, covid- illness severity, comorbidities, medication use, nadir platelet count, onset of covid- symptoms to diagnosis of itp, bleeding manifestations of itp, time to recovery from start of treatment, and clinical outcomes. mild covid- disease was defined by presence of fever and cough only. moderate-to-severe covid- disease was defined by presence of dyspnea with pneumonia as evident by crepitations on lung auscultation or radiological evidence. outcomes to treatment were categorized into two groups: response to treatment and complete response. response to treatment was defined by documentation of platelet doubling with platelet count reaching at least > × /l. complete response was noted when platelet reached to > × /l or baseline count of that patient. statistical analysis was performed using the statistical package for social sciences (spss) . software program (spss inc., chicago, il, usa). normally distributed data were expressed as mean ± standard deviation (sd), while nonparametric data were expressed in median (interquartile range, iqr). a total of covid- patients with itp were included in the final analysis. fifty-eight percent of patients were males. itp was reported in one pregnant patient [ ] . median age of the study population was years. only patients ( %) were in the pediatric age group [ , , ] ; ( %) patients were above years of age. needless to say, majority of the study population had wide range of comorbidities. moderate-tosevere covid- illness was present in % of all patients; mild symptoms were reported in patients ( %). three patients ( %), who tested positive for covid- , did not give any history of fever or other typical flu-like symptoms and were considered to be asymptomatic [ , ] . among patients with individual data of clinical recovery of covid- symptoms (n = ), itp presented in patients ( . %) in postrecovery period [ , , , , , , ] . among these patients, one was negative for covid- at itp onset [ ] . in the french multicenter series [ ] , sars-cov- was negative at itp onset in patients. data have been presented in table . [ , , , ] . among them, only one mortality has been reported [ ] . two patients had small intraventricular hemorrhage and subarachnoid microhemorrhage in the right frontal lobe, respectively [ , ] . among symptomatic patients with available data (n = ), median day from onset of covid- symptoms to diagnosis of itp was days, with majority reported in the second and third week. median nadir platelet count was × /l; only patients ( . %) had nadir count more than × /l [ , , , , ] . secondary evans syndrome, as evident by concomitant hemolytic anemia, was diagnosed in one case [ ] . data have been summarized in table . majority ( %) of the patients were treated with intravenous immunoglobulin (ivig) only. glucocorticoids were used alone in % cases and in combination with ivig in . % cases. thrombopoietin receptor agonists (tp-ra) were used [ , ] or both ivig and glucocorticoids [ , , ] . in one patient, tp-ra was used alone when ivig was discontinued owing to the development of acute heart failure [ ] . in the study population, patients had complete response and patients showed only response to treatment according to study definition. a total of individuals expired: one was due to intracranial hemorrhage [ ] and others succumbed to severity of covid- illness after showing platelet response to treatment [ , ] . a total of patients ( %) had relapse following treatment response in the followup period [ , ] . among patients with available individual data, median days to response and complete response were and days, respectively. data have been presented in table . to the best of our knowledge, this is the first comprehensive systematic review of new-onset itp secondary to covid- , comprising cases described in literature until date. we excluded patients with covid- from analysis, who had presented with exacerbation of previously diagnosed chronic or persistent [ ] [ ] [ ] . likewise, we excluded one patient who contracted sars-cov- in post-partum period weeks after being diagnosed with evans syndrome and treated with rituximab infusion due to poor response to steroids [ ] . another patient with evans syndrome was excluded due to presence of high titer of antiphospholipid antibodies and past history of venous thrombosis in childhood [ ] . immune thrombocytopenia is often a retrospective diagnosis based on exclusion of other possible causes of thrombocytopenia and assessment of the response to treatment [ ] . diagnosing itp secondary to covid- can be a major challenge for clinicians due to various concomitant conditions or factors associated with covid- . covid- has been associated with a systemic hyperinflammatory state resembling secondary hemophagocytic lymphohistiocytosis [ ] . a distinct coagulopathy with high risk of thrombosis has also been observed, which has mandated clinicians to screen moderate-to-severe covid- patients with sepsis-induced coagulopathy (sic) score or disseminated intravascular coagulation (dic) score [ ] . both these conditions can cause thrombocytopenia. evidence of microangiopathic hemolytic anemia with thrombocytopenia must also prompt physicians to exclude thrombotic thrombocytopenic purpura (ttp). patients should be tested for adamts- (a disintegrin and metalloproteinase with a thrombospondin type motif, member ) activity and adamts- inhibitor level, an autoantibody to adamts- . to date, one patient of autoimmune ttp associated with covid- has been reported, who had low adamts- activity and very high adamts- inhibitor level [ ] . in presence of evidence of hemolytic anemia, direct antiglobulin test can clinch the diagnosis of evans syndrome (es). es has been reported following viral infections including hepatitis c, cytomegalovirus, and varicella zoster viruses [ ] . in our review, one patient out of total patients was diagnosed with es secondary to underlying immune dysregulation of covid- [ ] . this -year-old male patient had presented with evidence of immune hemolysis days after being discharged with demonstration of a complete platelet response to treatment of itp. of note, authors did not completely rule out the rare possibility of immune hemolytic anemia following ivig treatment in this case [ ] . due to high risk of thrombosis, heparin prophylaxis has been recommended for all adolescents and adults hospitalized with covid- [ ] . heparin-induced thrombocytopenia (hit), a well-known clinical entity occurring - days after heparin exposure, is an important differential for patients presenting with thrombocytopenia after hospitalization. patients with hit usually have moderate platelet count ( - × /l). they do not develop severe thrombocytopenia (< × /l) unless fulminant thrombosis or consumptive coagulopathy develops as a complication [ ] . anti-platelet factor (pf- )/heparin antibodies or functional assays (serotonin release assay) can be considered if available. however, it is pragmatic to use a clinical scoring system, namely ts score, which incorporates factors, including timing of heparin therapy, complications of thrombosis or thrombocytopenia, and exclusion of other causes [ ] . a low ts score (≤ ) can reliably exclude hit owing to its high negative predictive value [ ] . in the case of clinical suspicion, discontinuation of heparin and consideration to start alternate anti-coagulation strategy (argatroban, danaparoid) is a safe approach [ , ] . other drugs most commonly implicated to cause thrombocytopenia are quinine, penicillin, tirofiban, and abciximab [ ] . in contrast to hit, drug-induced immune thrombocytopenia (ditp) presents with severe thrombocytopenia (< × /l) and bleeding manifestations [ ] . among the patients in review with available data for prior medication use, few received cephalosporins after hospitalization [ , , ] ; however, cephalosporin-induced thrombocytopenia is relatively rare. in one patient who received interferon-α and umifenovir, the possibility of ditp could not be ruled out [ ] . management of suspected ditp would be to discontinue the offending agent, send blood for flow cytometry-based testing for drugdependent platelet-reactive antibodies (if available), and consider ivig or/and glucocorticoids along with platelet transfusions [ ] . viral serologies for hepatitis b (hbv), hepatitis c (hcv), and human immunodeficiency virus (hiv) must be included in the diagnostic work-up. other infectious agents known to cause itp are epstein-barr virus (ebv), varicella zoster virus (vzv), parvo-virus b , cytomegalovirus (cmv), and helicobacter pylori. if available, testing for these agents can also be considered, as done in few cases [ , ] . autoimmune profile, including anti-nuclear antibodies (ana), anti-neutrophil cytoplasmic antibodies (anca), rheumatoid factor, anti-cardiolipin, and anti-beta- glycoprotein antibodies, should be done. the high incidence of thrombotic events in covid- and reports of high anti-phospholipid antibodies (apla) in critically ill patients made several researchers to investigate the role of apla in this coagulopathy [ ] . antiphospholipid syndrome (apls) can often arise following infectious triggers [ ] . however, in view of transient elevation of apla in various infections or inflammatory states, it is unclear if they represent an epiphenomenon or play a role in coagulopathy in covid- . in view of no convincing data at present and unreliability of apla assay in presence of high c-reactive protein [ ] , routine apla testing must be avoided. mild elevation in ana titer with nonspecific pattern should also be interpreted cautiously [ ] . of note, positive apla, low c , negative antids dna, and diffusely homogenous high ana titer ( : ) were found in one covid- patient with evans syndrome. past history of venous thrombosis in this patient negates the possibility of secondary apls due to covid- [ ] . due to a possible association of itp with multiple myeloma (mm) [ ] , serum protein electrophoresis has been done in few studies [ , ] . it is justified to rule out mm, especially for elderly patients with high index of clinical suspicion. direct monoclonal antibody immobilization of platelet antigen assay (maipa) evaluates presence of platelet autoantibodies on glycoproteins (gp) ib/ix, iib/iiia, and v bound on the patient platelets [ ] . maipa, as used in several cases of this review [ , , ] , can be helpful to support the clinical diagnosis of itp. indirect maipa positivity at itp onset has also been associated with higher rate of bleeding episodes and development of chronic itp [ ] . however, anti-platelet autoantibodies on platelet surface can be detected in only - % of patients [ ] . hence, the diagnosis of itp should rely on excluding other causes of thrombocytopenia. bone marrow aspiration (bma) study is not essential in the diagnostic work-up for itp. increased megakaryocytes can be classically seen with no abnormalities in other cell lineages. bma should be done if abnormal cells are present in peripheral blood smear. b lymphocyte immunophenotyping is additionally useful in selected cases since lymphoproliferative disorders can often present with itp and management often involves treatment of the underlying disorder [ ] . however, in few cases of chronic lymphocytic leukemia (cll), management is similar to that of idiopathic itp [ ] . of note, one patient had a concomitant diagnosis of cll in the french s e r i e s [ itp was reported in one pregnant patient of this review [ ] . gestational thrombocytopenia, ttp, and hellp syndrome (hemolysis, elevated liver enzymes, low platelet count) are common differentials to note in this context. a systematic approach to diagnosis of itp secondary to covid- has been given in fig. . covid- -associated itp has been reported more in elderly patients with median age above years of age. majority of patients were above years of age ( %) and had moderateto-severe covid- disease ( %). nonetheless, reports of itp in asymptomatic covid- patients underscore the need for covid- testing in newly diagnosed patients with itp amid this pandemic. clinicians should also take note of several reports of itp in covid- patients in post-recovery period ( %). clinical presentation of itp is variable. in this review, ( . %) patients had severe thrombocytopenia (platelet count < × /l). itp patients with severe thrombocytopenia are more likely to have severe bleeding. however, a total of patients ( %), including patients with severe thrombocytopenia (out of ), had no signs of active bleeding manifestations. as opposed to thrombocytopenia due to other causes, for example, bone marrow suppression, the correlation between platelet count and bleeding in itp is not consistent [ ] . negative antibody results on maipa and increased concentration of circulating platelet microparticles (pmp) may partly explain this lack of bleeding in many patients of itp [ , ] . nonetheless, reports of severe bleeding also depend on study population, underlying disease, definition of severe bleeding, and methods of reporting. of note, no standardized tool for bleeding severity was used for the cases in this review. nonetheless, intracranial hemorrhage (ich) was found in patients, with one patient reportedly died of it. in two patients, the microhemorrhage in ventricles or subarachnoid space was not life-threatening. non-ich severe forms of bleeding, such as gastrointestinal bleed, metrorrhagia, and hematuria, were reported in patients [ , , , , , ] . severe forms of bleeding at itp onset were found to be rare (< %) in a large population-based study comprising incident itp patients [ ] . however, this data was not exclusive for secondary forms of itp. rapidity of platelet fall, as seen in druginduced or allo-immune thrombocytopenia, is another major determinant of bleeding risk [ ] . in addition to the dramatic platelet fall, concomitant use of anticoagulation in hospitalized covid- patients can explain the relatively high number of severe bleeding episodes reported in total patients of itp ( %). in case of platelet count < × /l, discontinuation of heparin and intermittent pneumocompression has been recommended in the interim guidance [ ] . onset of itp has been found more commonly in the second and third week after onset of covid- illness. however, many cases of itp onset within the first week may be due to the failure of patients to recognize or report onset of first covid- symptom. a considerable proportion of cases were also found to ensue after weeks ( . %). this points towards the myriad of multiple pathophysiological mechanisms by which viruses are known to cause itp [ ] . several possible mechanisms of sars-cov- -mediated thrombocytopenia have already been described [ , ] . mechanisms involve inhibition of platelet synthesis due to direct infection of the bone marrow cells or platelets by the virus (possibly via cd- receptors) and dysfunctional marrow microenvironment; virus-mediated liver damage leading to decreased thrombopoietin production; pulmonary endothelial damage followed by platelet aggregation in the lungs, subsequent formation of microthrombi, and platelet consumption; and finally, the destruction of platelets by the immune system manifested as dramatic fall from baseline as described in this review. potential immune mechanisms of thrombocytopenia have not been adequately discussed until date. viral induction of autoimmunity can be explained by various phenomena, including molecular mimicry, cryptic antigen expression, and epitope spreading. the collateral stimulation of the immune system through certain microbial antigens via "molecular mimicry" has been well described with varicella zoster viruses, hiv, hcv, and h. pylori [ ] . this can lead to generation of cross-reactive antibodies to certain glycoproteins on platelet surface. for example, hiv- gp / antigen can cross-react with the anti-platelet membrane gpiiia - igg antibodies [ ] . although anti-gp iib/iiia, gp-ib/ix, or gp-v antibodies have been identified in several cases of this review [ , , ] , sequence homology between sars-cov- and platelet components is yet to be identified. platelets are coated by these anti-platelet antibodies and immune complexes, which result in clearance of platelets by reticuloendothelial system. these antibodies can also inhibit the development of bone marrow megakaryocytes and promote their apoptosis, thus inhibiting platelet production [ ] . bone marrow study in these few selected cases of itp would reveal low number of megakaryocytes, as seen in one patient of this review, who presented with severe thrombocytopenia (count × /μl) [ ] . covid- nucleic acid test of the bone marrow aspirate was found to be negative in this case [ ] . viruses are capable of inducing expression of cryptic antigens via direct infection of cells. platelets do not have ace receptors. however, recent study suggests that platelets may take up sars-cov- mrna independent of ace [ ] . diversification of immune response induced by an antigen to new t call and/or antibody specificities targeting new target epitopes of same or different antigens is known as epitope spreading. several factors, including enhanced expression of cryptic antigens under inflammatory milieu and release of self-antigens following tissue damage and b cells, may play a role in induction of this phenomenon. not surprisingly, it is uncommon for itp patients to possess single antiplatelet antibody specificity to a particular glycoprotein [ , , , ] . cytotoxic cd + t cells can directly cause platelet lysis, induce the apoptosis of platelets, and inhibit platelet production by megakaryocyte maturation [ ] . low or dysfunctional regulatory cd + t cells can also be seen in patients with itp, pointing towards their possible role [ ] . covid- patients with immune dysregulation can have lower levels of regulatory t cells, which are more decreased in severe cases [ ] . this can explain the greater occurrence of itp in moderate-tosevere covid- cases of this review. remarkably, greater than one-third of the immunogenic proteins in sars-cov- have been found to have homology to proteins that are essential to human adaptive immune system [ ] . autoimmunity against these proteins and their interactors may impact several functions of adaptive immune system, including mhc class i and class ii antigen presentation, cross-presentation of exogenous antigens, and pd- signaling [ ] . all these may have a role to play in the development of immune cytopenias. interestingly, lee et al. have recently found heterozygous truncation variant in suppressor of cytokine signaling (socs ) in two unrelated covid- patients with autoimmune cytopenias [ ] . heterozygous socs loss of function mutations can lead to enhanced interferon signaling and increased immune cell activation, thereby predisposing to immune thrombocytopenia secondary to covid- . c-reactive protein (crp) can also bind to platelet phosphorylcholine residues, thereby facilitating iggmediated phagocytic responses against platelets [ ] . this perpetuating role of crp can be implicated in the finding of higher incidence of itp in patients with moderate-to-severe covid- . pathogenetic mechanisms for covid- associated itp have been summarized in table . five patients with platelet count > × /l had minor mucocutaneous bleeding in this review. among them, spontaneous recovery was noted in one patient on observation only [ ] , whereas others received glucocorticoids [ , ] . although observation alone is recommended as per recent management guidelines for such cases, treatment with glucocorticoids can be considered for those with comorbidities, age > years or on anticoagulation [ ] . ivig was used alone in majority of these patients in variable doses ( mg/kg/day for days or g/kg for - days). this can be attributed to the concerns of glucocorticoid use in severe acute respiratory illness in covid- patients [ ] . nonetheless, ivig is appropriate for patients at risk for severe bleeding because it can produce a platelet count rise within - h; whereas glucocorticoids usually result in platelet count improvement by - days [ ] . dexamethasone has been used in standard high doses mg/day for days in majority; mg/day dosing for days was also used in one patient [ ] . intravenous methylprednisolone ( mg/kg/ day) or oral prednisolone ( mg/kg/day) for short duration has also been used. of note, fear of precipitating ketoacidosis and increased mortality associated with it can be another barrier for its use in usual therapeutic doses in diabetic patients [ ] . the american society of hematology guideline recommends dexamethasone ( mg/day for days) or prednisolone ( mg/kg/day) with tapering (depending on response and for a maximum duration of weeks) [ ] . dexamethasone may be preferred over prednisolone due to finding of increased response rate at days from trials on adults with itp [ ] . however, duration of gc use should be kept at minimum due to concerns for delayed recovery of active covid- disease [ , ] . it is reassuring to note that low-dose dexamethasone for maximum days can significantly decrease -day mortality significantly for covid- patients requiring oxygen or ventilation support [ ] . lack of response or fall of platelets after initial response to short-course gc (without tapering) has been the indication for ivig or a second gc course in few cases [ , , ] . lack of sustained response to ivig monotherapy has also been noted [ ] . thrombopoietin receptor agonists (tp-ra), which can lead to a steady rise in platelet count - weeks after administration, can also help to avoid rapid recurrences of severe thrombocytopenia [ ] . due to increased potential for thrombotic complications and hepatotoxicity, interim guidance suggests use of tp-ra only as a second-line agent in covid- patients with no evidence of frank dic [ ] . eltrombopag ( - mg) or romiplostim has been used in total patients ( %) in the review for a duration from days to weeks; no adverse events were reported [ , , , ] . vincristine single dose along with tp-ra was used in one case due to lack of response to first-line therapies, including ivig and gc [ ] . authors suggested that high antibody load related to underlying severe covid- and increased platelet consumption or loss of ivig due to active bleeding might have led to this relative resistance to ivig treatment [ ] . platelet transfusions have also been used in few of these patients presenting with active bleed. in the french multicenter series of patients, patients experienced a relapse after a median follow-up period of days (range - days) [ ] . another patient, initially treated with doses of ivig, had relapsed at day after discharge in this review [ ] . although specific management guidelines are lacking for evans syndrome, glucocorticoids are often considered the first-line therapy, with the use of ivig in severe cases. second-line therapies include immunosuppressive agents such as rituximab, mycophenolate mofetil, cyclosporine, and cyclophosphamide [ ] . this study has certain limitations. first, bias of reporting cases with only very low nadir platelet count cannot be ruled out. hence, itp patients with moderate thrombocytopenia may be underrepresented. second, severity of bleeding could not be graded by a standardized tool. third, follow-up period of all cases was not adequate to comment on durability of treatment response. hence, recurrence/relapse data may not be truly reflective of actual data. immune thrombocytopenic purpura (itp) can occur secondary to covid- infections. a systematic approach is essential to diagnose new-onset itp after excluding several concomitant factors or conditions that can cause thrombocytopenia in covid- . itp has been found to be more common in elderly and moderate-to-severe covid- patients. several reports of itp in asymptomatic covid- patients underscore the need for covid- testing in newly diagnosed patients with itp amid this pandemic. clinicians should also take note of several reports of itp in covid- patients in post-recovery period. sars-cov- -mediated immune thrombocytopenia can be attributed to the underlying immune dysregulation, socs mutations, and several other mechanisms, including molecular mimicry, cryptic antigen expression, and epitope spreading. no bleeding was reported in almost one-third of the patients at diagnosis. severe lifethreatening bleeding has been reported to be uncommon. good initial response to short course of glucocorticoids and intravenous immunoglobulin has been found with relative resistance in one case. thrombopoietin receptor agonist usage as a second-line agent has been noted for short duration in few cases with no adverse thrombotic events. in the relatively short follow-up period, four relapses of itp have been reported. covid- -associated hemophagocytic lymphohistiocytosis and coagulopathy: targeting the duumvirate clinical characteristics of coronavirus disease 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thrombocytopenia during the covid- pandemic platelets and infection -an emerging role of platelets in viral infection mechanism of thrombocytopenia in covid- patients mechanisms involved in the development of thrombocytopenia in patients with covid- crosstalk between platelets and microbial pathogens platelet gene expression and function in covid- patients dysregulation of immune response in patients with coronavirus (covid- ) in wuhan, china pathogenic priming likely contributes to serious and critical illness and mortality in covid- via autoimmunity immune dysregulation and multisystem inflammatory syndrome in children (mis-c) in individuals with haploinsufficiency of socs clinical profile and outcomes in covid- patients with diabetic ketoacidosis: a systematic review of literature dexamethasone in hospitalized patients with covid- -preliminary report publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- -kci uw u authors: majid, sabhiya; farooq, rabia; khan, mosin s.; rashid, samia; bhat, showkat a.; wani, hilal a.; qureshi, waseem title: managing the covid- pandemic: research strategies based on the evolutionary and molecular characteristics of coronaviruses date: - - journal: sn compr clin med doi: . /s - - -z sha: doc_id: cord_uid: kci uw u coronavirus disease (covid- ), an ongoing global health emergency, is a highly transmittable and pathogenic viral infection caused by severe acute respiratory syndrome coronavirus (sars-cov- ). emerging in wuhan, china, in december , it spread widely across the world causing panic—worst ever economic depression is visibly predictable. coronaviruses (covs) have emerged as a major public health concern having caused three zoonotic outbreaks; severe acute respiratory syndrome-cov (sars-cov) in – , middle east respiratory syndrome-cov (mers-cov) in , and currently this devastating covid- . research strategies focused on understanding the evolutionary origin, transmission, and molecular basis of sars-cov- and its pathogenesis need to be urgently formulated to manage the current and possible future coronaviral outbreaks. current response to the covid- outbreak has been largely limited to monitoring/containment. although frantic global efforts for developing safe and effective prophylactic and therapeutic agents are on, no licensed antiviral treatment or vaccine exists till date. in this review, research strategies for coping with covid- based on evolutionary and molecular aspects of coronaviruses have been proposed. coronaviruses (covs) are spherical rna viruses, deriving name from latin word "corona" or crown as they appear like a royal crown under the electron microscope due to characteristic spike projections on their spherical surface. covs belong to family coronaviridae within order nidovirales, which further has two subfamilies: orthocoronavirinae and torovirinae. subfamily orthocoronavirinae encompasses four genera: alpha coronavirus, beta coronavirus, gamma coronavirus, and delta coronavirus [ ] . beta coronaviruses are a subgroup of the coronavirus family, large enveloped positive-sense singlestranded rna (+ssrna) viruses able to infect a wide variety of mammals and avian species, causing mainly respiratory or enteric diseases [ ] . discovered long back in s, hcov- e and hcov-oc were known to cause common cold in humans. to date, seven beta coronaviruses are known to cause human disease-the prevalent strains, hcov e, hku , nl , and oc , typically cause mild infections of the upper respiratory tract in humans [ ] [ ] [ ] . however, scenario has altered in the past two decades with covs becoming a major public health concern as three strains, sars-cov [ , ] , mers-cov [ , ] , and the newly identified sars-cov- , are associated with serious respiratory diseases and have led to severe zoonotic outbreaks [ ] [ ] [ ] . the sars-cov pandemic initiated in guangdong province, china, in . the rabia farooq and mosin s. khan have contributed equally as second authors infected patients exhibited pneumonia symptoms with a diffused alveolar injury which lead to acute respiratory distress syndrome (ards); the disease quickly spread worldwide causing serious illnesses and nearly deaths in - [ , ] . mers-cov epidemic took place in [ , ] . in both cases, the infected patients manifested severe acute pneumonia, but while sars-cov infected mainly the lower respiratory tract, mers-cov caused more pronounced gastrointestinal symptoms, often associated with kidney failure [ , ] . the world health organization (who) has reported a total number of mers-cov cases with associated deaths from to january [ ] . sars-cov- and the covid- pandemic currently, the novel coronavirus, sars-cov- alternatively termed ncov, has caused panic with who declaring it as a global health emergency on january [ ] . it was initially identified in the city of wuhan, china, in december ; patients presented with severe viral pneumonia and respiratory illness. the number of cases has been mounting since then to whopping figure of around six and half million globally [ ] [ ] [ ] [ ] . the disease caused by sars-cov- has been named covid- , a highly transmittable and pathogenic respiratory infection, which has become a public health emergency of international concern as no clinically approved antiviral drug or vaccine is available-though few broad spectrum antiviral drugs and drug combinations in clinical trials have resulted in clinical recovery [ ] [ ] [ ] [ ] [ ] . convalescent plasma (cp) therapy has recently been shown to be well tolerated, and severe covid- cases could potentially improve the clinical outcomes by neutralizing viremia [ ] . transmission is via respiratory droplets or aerosols on exposure to coughing, sneezing, and close contact with an infected person [ ] . social distancing, face masks, and frequent hand sanitization are recommended preventive measures. personal protective gear as recommended is to be used by healthcare workers for their safety. containing the outbreak before it can spread is the best way to prevent pandemics. border closures, screening at airports, and checkpoints-classical measures implemented in pandemics-can reduce spread of the virus but will not be a fool-proof strategy [ , ] . millions of people travel every day from one country to another; a disease originating in one country can rapidly spread to other countries regardless of distances between them. this is particularly visible in the rapid spread of covid- , which affected almost every country in the world within months of the first reported case. information technology is playing its own role with numerous apps coming up, purportedly helping cope with awareness, management, and controlling spread of this disease-like "aarogya setu app" in india. this disease can remain asymptomatic during around days incubation period of sars-cov- . the sars and mers covs evade immune responses during longer incubation periods. the spectrum of covid- disease is broad-most commonly reported symptoms of are fever, myalgia or fatigue, dry cough, and dyspnea. around % of infections are mild, resolving within a week without any specific treatment or hospitalization. amongst hospitalized cases, pneumonia, sepsis, respiratory failure, and ards are frequently encountered complications, and in severe cases, progressive respiratory failure can be fatal [ ] [ ] [ ] . overproduction of early response pro-inflammatory cytokines can result in cytokine storm leading to vascular hyperpermeability, reduced anticoagulant concentration, impaired anticoagulant-procoagulant balance predisposing to development of microthrombosis, disseminated vascular coagulation, and multi-organ failure [ ] . this is evidenced in severe covid- pneumonia where raised d-dimer is a poor prognostic feature and disseminated intravascular coagulation is common in non-survivors [ ] . as clinical manifestations of covid- range from mild to moderate, more systematic symptoms and severe radiological abnormalities are seen in older patients [ ] . children and younger adults can remain as asymptomatic carriers [ ] [ ] [ ] . the possibility for gastrointestinal involvement in sars-cov- infection and feco-oral transmission has been suggested [ ] . who has estimated overall mortality rate of . % in spite of the significant infectivity rate, majority deaths typically occurring amongst elderly patients, patients having multiple comorbidities, and immune compromised population [ ] . the covid- epidemic has reached worldwide resonance; global efforts are being undertaken to characterize the molecular features and evolutionary origins of this virus. covs are typically harboured in mammals and birds-being common in camels, cattle, cats, bats, and other animals [ ] [ ] [ ] . alpha and beta coronaviruses circulate in mammals, including bats. gamma coronaviruses mostly infect avian species and a few mammalian species, whereas delta coronaviruses infect birds and mammals [ , ] . animal covs are known to cause important diseases in animals and are responsible for economic losses in domestic animals or bird. although rare, zoonotic events do occur wherein animal covs acquire the ability to infect humans and further spread through human-to-human transmission [ , ] . studies have shown that bats harbour covs that are ancestral to sars-cov which have been circulating in bats for a long time before genetically changing and jumping to humans [ ] . rhinolophus bats were found to have anti-sars-cov antibodies suggesting bats as a source of viral replication [ ] . further, studies have revealed that palm civets and raccoon dogs, of chinese local food markets, harbour sars-related covs (sarsr-covs) suggesting that they could be key reservoir of infection and may be secondary hosts. this detection of sarsr-covs in bats and small animals in retail markets may indicate an interspecies transmission from bats to small animals and finally to humans [ ] . in , samples from the healthy persons of hong kong on molecular assessment showed . % frequency rate of antibodies against sars-cov, indicating that sars-cov might have been circulating in humans before causing the outbreak in [ ] . mers-cov reportedly has camels as a zoonotic source or primary host [ ] . in a recent study, mers-cov was also detected in pipistrellus and perimyotisbats, favouring bats as key host and transmitting medium of this virus [ ] . metagenomics analysis of phylogenetic relationships between sars-cov- , sars-cov, bat sars r-covs, and bat cov revealed that sars-cov- genome (~ . kb) shares . % sequence identity with sars-cov. again, close phylogenetic relationship between sars-cov- and a bat cov, % identical at whole genome level, points to bat origin of sars-cov- and bats as probable "key reservoirs" [ ] . overall, these studies highlight bats as carriers of viruses with zoonotic and devastating potential. however, intermediate source of origin and transfer to humans is not known; further studies are needed to determine whether the virus was transmitted to humans by an intermediate host. nevertheless, rapid human-to-human transfer has been widely confirmed, already reported from more than countries in the world [ , ] . coronaviruses will continue to infect multiple species and cell types, including humans due to their ability to recombine and mutate. the source and spread of these covs necessitate to be evidently firmed; urgency finance for investigation on systematic basis of their spread and their pools is required to frame preventive plans to hold and regulate such outbreaks. in the phylogenetic connection between extremely pathogenic covs, their transitional zoonotic source requires to be vigorously studied. role of variations in human doings, biomes, and environment in leading to such pandemics requires to be studied as the changes in pathogen types, disease burden, and distribution have arisen largely due to human activity. in the last century, there was a reduced burden of infectious diseases due to improved nutrition, better hygiene, and use of vaccines and antimicrobials. however, in recent decades, there is an upsurge of disease emergence and propensity to pandemics much due to swelling global travel and trade, increasing human and livestock populations. viruses have broad range of hosts and are emerging pathogens [ ] . in , the united nations environment programme (unep) warned that zoonotic diseases are related to the health of ecosystems. zoonoses are opportunistic and increase with changes in animal or human hosts, environment, or pathogen itself. pathogens have passed between animals and humans in the last century due to reduction in ecosystems by human intervention and population growth. humans have encroached into animal habitats and disturbed natural buffer zones between animals and humans leading to emergence of zoonosis. livestock serves as a bridge between wildlife and human infections and forms a part of wildlife-livestock-human interface. consumer demand for livestock has increased due to economic growth leading to rigorous livestock farming near and around cities, thereby, expanding chances of zoonotic diseases. in addition, natural source of disease resistance is genetic diversity but "intensive livestock rearing" often produces genetic similarities within herds and flocks, making them susceptible to pathogen spillover from wild animals. consumption of wild animals in wet markets can also facilitate animal to human transmission. frequent climate change tells upon the survival of microbes in the environment, suggesting the more frequency of pandemics due to rapid change in climate [ ] . thus, if we need to stop such pandemics in the future, we need to focus on the influence of human activities on ecosystems. experiments on monitoring of human and wildlife health will improve understanding and preparedness for potential pandemics. it invites for collaborative, trans-disciplinary, and international efforts as summarized by the "one health approach"-a concept of combining human, animal, and environmental components to address global health challenges having ecological interdependence. "one health approach" wherever adopted is seen to have significant impacts on control of infectious diseases [ ] . ultimately, "if we have a robust plan for protecting nature, nature will protect humanity". last but not the least, strategies to curb the transmission of virus should be put in place in a more stringent way. the correct use of personal protective equipment (ppe) and regular and thorough hand hygiene are key measures in the prevention and control against infection through contact transmission, droplet transmission, and airborne virus particles. in addition, maintaining a constant and regular supply of drugs is indispensable during the pandemic. healthcare professionals are at three times higher risk than common individuals so their body temperature, nucleic acid, and specific antibodies for covid- should be monitored regularly. during pandemic, psychological illness is rampant so individuals especially healthcare workers should be evaluated for psychological illness, if any. our understanding of the virus deepens, and with the constant improvement of diagnosis, treatment, and strategies for prevention and control, healthcare professionals should continue to actively collect and improve their services based on the latest information [ ] . a crucial need to counteract the covid- pandemic has arisen; no specific drug or vaccine is available as yet. for effective therapeutics and vaccine development elucidation of genetic features and molecular constituents of covs including sars-cov- , unravelling the mechanisms of infection, molecular basis of virus-host interaction, its regulation, and host responses is needed. global efforts are being undertaken-biotechnological, molecular, and bioinformatic advances have been helpful in making available details related to the genomics and proteomics of these covs, especially sars-cov- in a very short time [ ] . the covs are~ - nm in diameter, containing singlestranded rna ranging from to kbs in length as nucleic material, being enveloped in lipid bilayer derived from the host cell membrane. the structural together with few nonstructural proteins (nsps) are coded within the ′ end of the viral genome, whereas the ′ two-thirds of the genome codes for nsps that are important in viral replication, including the rna-dependent rna polymerase (rdrp) [ , ] . rna of covs codes for four major structural proteins involved in its replication as well, termed as spike (s), membrane (m), envelope (e), and nucleocapsid (n) proteins. some beta coronaviruses also code for protein hemagglutinin esterase (he). the s, m, and e proteins lie in the viral envelope. the s protein is heavily glycosylated forming homotrimeric spikes on the surface of the viral particle required for binding and entry into host cells. amongst the four, m protein is the most abundant and important protein giving the virion primarily its shape; besides, it interacts with other structural proteins to perform various functions. interaction of s proteins with m proteins is needed for its incorporation into new virions [ ] [ ] [ ] . in the same way, m protein along with the smallest one e protein which is found in small quantities is involved in virus assembly, forming of mature viral envelopes, and release of viral particles from host cells. e protein is mostly expressed in the infected cell; it is important for production and maturation of the virus, and its interaction with psd /dlg/zo- (pdz) proteins involved in host cell processes is important for viral infection. the n protein is located in the core of the viral particle forming the nucleocapsid of viral rna and is involved in replication [ , ] . generally, the transcription and replication of covs take place in the host cell cytoplasm following viral entry. spike proteins of the virus bind with the host receptor, structural changes occur followed by endocytosis, which is ph dependent [ ] , and the virus releases its rna inside the host cell cytoplasm. translation of the ′ end of viral rna produces the rdrp, which uses viral rna as a template to generate series of virus-specific mrnas or sub-genomic mrnas from sub-genomic negative strand intermediates. translation of sub-genomic mrnas leads to production of structural and nonstructural viral proteins; they share the same ′ ends and the same leader sequence of - nucleotides at their ′ ends [ ] . once sufficient, structural proteins and genomic viral rna are synthesized; viral assembly and budding occur in smooth-walled vesicles in the endoplasmic reticulum-golgi intermediate compartment (ergic) [ ] . rna of coronavirus is polycistronic containing approximately seven genes: ′ region mainly contains large replicase gene for replication and transcription process, and the ′ region contains nonessential accessory proteins expressed from sub-genomic mrnas [ ] . the large replicase gene at ′ end encodes replication-transcription complexes (rtcs) amongst covs which comprise of two overlapping open reading frames (orfs), orf a and orf b. translation of these orfs results in two very large polyproteins, polyprotein a (pp a) and polyprotein ab (pp ab), further leading to formation of nonstructural proteins by co-and post-translational modifications by various proteinases. orf b encodes enzymes which are needed in rna replication and its transcription. all covs contain specific genes in orf downstream regions that encode proteins for viral replication, nucleocapsid, and spike formation [ , ] . covs contain doublemembrane vesicles (dmvs) which are attached with rtcs; these dmvs are derived from network of modified er membranes, also referred to as convoluted membranes (cms) [ ] . the replication of covs is inhibited by addition of drugs in the early-secretory phase or by addition of rnai [ ] . genome of this lethal virus has been isolated; a total of whole genome sequences of sars-cov- could be downloaded from the gisaid database as depicted in fig. (https://www.gisaid.org/cov /). sequences that likely had spurious mutations resulting from sequencing errors were indicated in the comment field of the gisaid data. its genome is a +ssrna virus having , bp length with ′ poly a tail and ′ cap. genbank: mn . ; locus mn (https://www. ncbi.nlm.nih.gov/nuccore/mn ), having aa protein sequence; locus qhi (https://www.ncbi. nlm.nih.gov/protein/qhi . ). the genome of the sars-cov- reportedly is over % identical to the previous sars-like bat cov, and according to the evolutionary tree, sars-cov- lies close to sars-cov. the orf ab is the largest gene in sars-cov- which encodes the pp ab protein and nsps. the orf a gene encodes for pp a protein which also contains nsps. further, the pp a and pp ab encoded by the orf a/b give rise to viral proteases, papain-like protease (plpro), and c cleavage-like protease ( clpro/mpro), for creating non-structural proteins (rdrp, helicases) [ ] . mpro is a crucial enzyme facilitating viral replication and transcription. recent studies have indicated notable variations in sars-cov and sars-cov- such as the absence of a protein and fluctuation in the number of amino acids in b and c protein in sars-cov- [ , ] . spike glycoprotein of the sars-cov- has reportedly modified via homologous recombination; it is a mixture of bat sars-cov and a not known beta-cov [ ] . attachment and entry of covs into host cells is mediated by "s" protein on outer surface of covs. s protein has two domains: s and s [ ] . within s domain, receptor-binding domain (rbd), located at the c-terminus in sars-cov and mers-cov, mediates binding to the associated host cell receptor, while the s domain brings about the merger between viral and host cell membranes through endosomal pathway, leading to the entry of the viral genome into the cytoplasm of host cell. the virus may infect multiple hosts as the receptorbinding domain (rbd) is loosely attached to it [ , ] . covs mostly identify carbohydrates or amino peptidases as a key receptor for entry to human cells [ ] . the mechanism of entry of cov in host cell is governed by cellular proteases including human airway trypsin-like protease (hat), cathepsins, and transmembrane protease serine (tmprss ) which cleave spike protein and start further infiltration [ ] . varied covs bind to diverse receptors on host cells. mers-cov binds to dipeptidyl-peptidase (dpp , also known as cd ) receptor. human angiotensin-converting enzyme (hace ), a zinc-dependent carboxypeptidase, responsible for regulating blood pressure, also acts as a receptor of entry for sars-cov, hcov-nl , and sars-cov- [ ] [ ] [ ] . the critical lysine residue on the hace receptor recognizes glutamine residues in the rbd region of sars-cov- [ ] . comprehensive pathogenic mechanism of sars-cov- is depicted in fig. [ ] . current studies have indicated % homology between amino acid sequence of rbd of sars-cov- and sars-cov [ ] and notable variations between sars-cov and sars-cov- such as the absence of a protein and variation in the number of amino acids in b and c protein in sars-cov- [ ] . as per a recent study, s protein of sars-cov- has higher affinity to ace receptor as compared with s protein of sars-cov which might be attributed to the n t mutation in spike protein of sars-cov- . the spike protein of sars-cov- binds to hace which is highly expressed in the lungs and heart. studies suggest that there is an elevation in angiotensin ii in covid- patients which advocates that binding of covid- to ace leads to enhanced conversion of angiotensin ii from angiotensin i through the renin-angiotensin-aldosterone system (raas) thereby increasing cardio-myocyte hypertrophy and high blood pressure leading to myocardial injury, myocarditis, and cardiac arrhythmias [ ] . in case of diabetics, there is an altered production of cytokine, impaired t cell-mediated immune response, inhibition of neutrophil chemotaxis, ineffective microbial clearance, and phagocytic cell dysfunction which together with the entry of coronavirus into host pneumocytes mediated by ace receptor adds to the severity of covid- in patients with diabetes mellitus. so, ace may play a key role in the severity of covid- infection in diabetic patients [ ] . the coronavirus-human interactome x-ray crystallography has determined the crystal structures of cov-human interactomes to fully understand the initial step of infection at molecular level. for the first time, crystalline structure for hcov-nl s -ctd complexed with human ace was discovered followed by sars-cov s -ctd complexed with ace , displaying common receptors [ , ] which was followed by mers-cov s -ctd complexed with human dpp [ ] . overall binding mode of ace with sars-cov- -rbd is nearly identical to that of the sars-cov-rbd as per the recent elucidation of their crystal structure. there are amino acid residues in rbd of sars-co-v, majority of which are highly conserved, or share alike side chain properties with rbd of sars-cov. crystal structure of sars-cov- -rbd complexed with ace is available at protein data bank (pdb) [ ] . presently, no registered antiviral drug for use in patients with covid- is there. on top of it, there is no efficient vaccine available for covid- in humans. the standard of care is "supportive" and includes drugs like protease inhibitors (lopinavir/ritonavir; darunavir + ritonavir; darunavir/ cobicistat); chloroquine or hydroxychloroquine; tocilizumab, monoclonal antibody against chimeric antigen receptor t cells; nucleotide inhibitor like remdesivir (a broad-spectrum antiviral); methylprednisolone mg × /day; and antibiotic therapy using third-generation cephalosporin, clarithromycin, or azithromycin or alternatively fluoroquinolones in case of secondary bacterial infections [ ] . a crucial need for a clinical research and therapeutic strategy to counteract this epidemiological outbreak remains. we have no empirical enveloped cure or vaccine for this potentially fatal disease; coordinated international efforts for developing therapeutics and vaccines for sars-cov- are needed. although several clinical trials are currently underway to test possible therapies, current response to the covid- outbreak has been largely limited to monitoring/containment. various biotechnological, molecular tools, and advances in bioinformatics have been instrumental in making available details related to the genomics and proteomics of this virus. some light has been shed on genetic features, molecular constituents, and mechanisms of infection. armed with this information research is progressing at a rapid pace to develop therapeutic strategies, neutralizing antibodies and vaccines to address this disease covid- which has spread as a pandemic of mammoth proportions. a wide variety of therapeutic options are being evaluated in an earnest attempt to find a cure. a drug, from time of its inception to qualifying all three phases of clinical trials, can take years to reach market; nevertheless, coordinated international efforts and adequate funding can make drugs against covid- available within a record time. bioinformatics and in silico drug modelling, a boon for speedy drug development, are being exploited. recent in silico master regulator analysis has shed light on sars-cov- /human interactome detailing the host receptor recognition. features of the human interactome most affected by the infection including apoptotic and mitochondrial mechanisms and downregulation of the ace protein receptor have been propounded [ ] . there is an upregulation of ace in diabetes and hypertension as they are being treated by ace inhibitors and angiotensin ii type-i receptor blockers (arbs). ace is also increased by drugs such as thiazolidinediones and ibuprofen. consequently, the increased expression of ace would facilitate infection with covid- and increase the risk of developing severe fatal covid- viral infection. a further aspect that should be investigated is the genetic predisposition for an increased risk of sars-cov- infection, which might be due to ace polymorphisms that have been linked to diabetes mellitus, cerebral stroke, and hypertension, specifically in asian populations. summarizing this information, the sensitivity of an individual might result from a combination of both therapy and ace polymorphism [ ] . expectedly, development of neutralizing antibodies may take less time due to their speedy trials and high specificity, as a prompt option repurposing of broad spectrum antiviral agents and their combinations is being frantically evaluated. since its emergence, sars-cov- has drawn well-deserved attention. it led to a pandemic that has shocked and devastated the human world, shattering its economy-massive economic recession is predicted. it is likely that these coronaviruses will continue to emerge and evolve, causing both human and veterinary outbreaks due to their ability to recombine, mutate, and infect multiple species and cell types, including humans. the future of human cov outbreaks will depend not only on how the viruses will evolve but also on the development of efficient prevention, treatment strategies, and our preparedness to deal with them. priority funding for research on mechanistic basis of transmission of coronaviruses from one species to other, their reservoirs, zoonotic diseases, possible role of environmental changes, and pollution in leading to such epidemics is needed to face the imminent challenge of such repeated outbreaks. very rapid and efficient human-to-human transmission is confirmed which is of immense concern necessitating speedy development of therapeutic modalities. neutralizing antibodies and vaccines could play significant roles in controlling covid- . studies on humancoronavirus interactome developing suitable therapeutic agents and vaccines are needed. research at accelerated pace is needed to translate into therapies and vaccines. hopefully, lessons from handling this outbreak will allow us to be better prepared in the future-the viruses can keep coming. coronaviruses of man 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 occurrence and frequency of coronavirus infections in humans as determined by enzyme-linked immunosorbent assay human coronaviruses: what do they cause? antivir ther viral infection of the lower respiratory tract identification of a novel coronavirus in patients with severe acute respiratory syndrome severe acute respiratory syndrome isolation of a novel coronavirus from a man with pneumonia in saudi arabia clinical features and viral diagnosis of two cases of infection with middle east respiratory syndrome coronavirus: a report of nosocomial transmission a new coronavirus associated with human respiratory disease in china a pneumonia outbreak associated with a new coronavirus of probable bat origin a novel coronavirus outbreak of global health concern management and prevention of sars in china . van den brand jma, smits sl, haagmans bl. pathogenesis of middle east respiratory syndrome coronavirus who. middle east respiratory syndrome coronavirus world-health-organization statement on the second meeting of the international health regulations centers-of-disease-control-and-prevention confirmed -ncov cases globally european centre for disease prevention and control data china's cdc detects a large number of new coronaviruses in the south china seafood market in wuhan novel coronavirus: where we are and what we know return of the coronavirus clinical features of patients infected with novel coronavirus in wuhan the continuing -ncov epidemic threat of novel coronaviruses to global health -the latest novel coronavirus outbreak in wuhan, china clinical features of patients infected with novel coronavirus in wuhan effectiveness of convalescent plasma therapy in severe covid- patients epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study pneumonia of unknown origin -china from sars-cov to wuhan ncov outbreak: similarity of early epidemic and prediction of future trends a familial cluster of pneumonia associated with the novel coronavirus indicating personto-person transmission: a study of a family cluster clinical course and outcomes of critically ill patients with middle east respiratory syndrome coronavirus infection a novel coronavirus from patients with pneumonia in china covid- : consider cytokine storm syndromes and immunosuppression d-dimer levels on admission to predict in-hospital mortality in patients with covid- . j thrombosis hemostasis ct imaging features of novel coronavirus ( -ncov) clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china clinical course and risk factors for mortality of adult in patients with covid- in wuhan, china: a retrospective cohort study clinical characteristics of patients infected by sars-cov- in wuhan analysis of factors associated with disease outcomes in hospitalised patients with novel coronavirus disease an epidemiological study on covid- : a rapidly spreading disease coronaviruses in avian speciesreview with focus on epidemiology and diagnosis in wild birds middle east respiratory syndrome coronavirus neutralising serum antibodies in dromedary camels: a comparative serological study severe acute respiratory syndrome coronavirus-like virus in sn compr chinese horseshoe bats molecular evolution of human coronavirus genomes epidemiology, genetic recombination, and pathogenesis of coronaviruses epidemiology and cause of severe acute respiratory syndrome (sars) in people's republic of china zoonotic origins of human coronaviruses the proximal origin of sars-cov- possible bat origin of severe acute respiratory syndrome coronavirus . emerg infect dis wet markets-a continuing source of severe acute respiratory syndrome and influenza? covid- infection: origin, transmission, and characteristics of human coronaviruses bat origin of human coronaviruses the origin, transmission and clinical therapies on coronavirus disease (covid- ) outbreak -an update on the status molecular epidemiology, evolution and phylogeny of sars coronavirus world-health-organization coronavirus disease (covid- ) outbreak human coronaviruses: a review of virus-host interactions zoonosis emergence linked to agricultural intensification and environmental change zoonoses and one health: a review of the literature wuchang fangcang shelter hospital: practices, experiences, and lessons learned in controlling covid- . sn compr clin med cryo-electron tomography of mouse hepatitis virus: insights into the structure of the coronavirion the molecular biology of coronaviruses coronavirus: organization, replication and expression of genome mechanisms and enzymes involved in sars coronavirus genome expression pre-fusion structure of a human coronavirus spike protein the m, e, and n structural proteins of the severe acute respiratory syndrome coronavirus are required for efficient assembly, trafficking, and release of virus-like particles the role of flexibility and conformational selection in the binding promiscuity of pdz domains genomic characterisation and epidemiology of novel coronavirus: implications for virus origins and receptor binding role of endocytosis and low ph in murine hepatitis virus strain a cell entry subgenomic negative-strand rna function during mouse hepatitis virus infection a contemporary view of coronavirus transcription current insights into the genomics of novel coronavirus: sars-cov- an overview of their replication and pathogenesis intracellular processing of the n-terminal orf a proteins of the coronavirus mhv-a requires multiple proteolytic events sars-coronavirus replication is supported by a reticulovesicular network of modified endoplasmic reticulum e glycoprotein and broadly neutralizing antibodies that target them coronaviruses: drug discovery and therapeutic options structure-based design of antiviral drug candidates targeting the sars-cov- main protease emerging coronaviruses: genome structure, replication, and pathogenesis discovery of bat coronaviruses through surveillance and probe capture-based next-generation sequencing. msphere multibasic cleavage site in the spike protein of sars-cov- is essential for infection of human lung cells structure of sars coronavirus spike receptor binding domain complexed with the receptor structure of mers-cov spike receptor-binding domain complexed with human receptor dpp the bittersweet promise of glycobiology the novel coronavirus ( -ncov) uses the sars-coronavirus receptor ace and the cellular protease tmprss for entry into target cells angiotensin-converting enzyme is a functional receptor for the sars coronavirus human coronavirus nl employs the severe acute respiratory syndrome coronavirus receptor for cellular entry ace of the heart: from angiotensin i to angiotensin ( - ) identification of a coronavirus hemagglutinin-esterase with a substrate specificity different from those of influenza c virus and bovine coronavirus covid- infection: origin, transmission, and characteristics of human coronaviruses genome composition and divergence of the novel coronavirus ( -ncov) originating in china the association of cardiovascular diseases and diabetes mellitus with covid- (sars-cov- ) and their possible mechanisms crystal structure of nl respiratory coronavirus receptor-binding complexed with its human receptor structural basis of receptor recognition by sars-cov- molecular basis of binding between novel human coronavirus mers-cov and its receptor cd crystal structure of sars-cov- spike receptor-binding domain bound with ace clinical management of adult coronavirus infection disease (covid- ) positive in the setting of low and medium intensity of care: a short practical review master regulator analysis of the sars-cov- /human interactome covid- outbreak: an update on therapeutic options publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations acknowledgements we acknowledge all the patients who have been key: cord- -j v k o authors: conway, j.; gould, a.; westley, r.; khan, s.; emmerton, d.; raju, s. a.; oklopcic, a.; broadbent, a.; abdelhafiz, a. h. title: chinese and british hospitalised patients with covid- —a comparative case series analysis date: - - journal: sn compr clin med doi: . /s - - -w sha: doc_id: cord_uid: j v k o the covid- pandemic initially started in china then spread to europe. it is not known whether covid- affects patients differently across the two continents. we aimed to describe our cohort of patients admitted to a single british centre with covid- in comparison to a chinese cohort of similar size and admitted over a similar time period to chinese centres. we present a comparison of chinese and british cases hospitalised for covid- . cases in both sites were confirmed by a positive rt-pcr of nasopharyngeal swabs. comparison analysis highlighted some differences between both populations. the most striking difference is the significantly older age of the british population ( % of the british ≥ years compared to only % of the chinese patients, difference of %, % confidence interval (ci) . % to . %, respectively) and the associated significant premorbid conditions ( % of patients vs %, difference of %, % ci to %, respectively). gastrointestinal and general symptoms were more common clinical presentation in the british while respiratory symptoms were more prominent in the chinese cohort. mortality was significantly higher in the british cohort % compared to none in the chinese cohort (difference of %, % ci . to . %). we conclude that covid- does present differently in these two cohorts, but the apparent differences in the clinical presentations could be explained by the inherent differences in the demographics and case mix between both countries. in december , a respiratory disease caused by the severe acute respiratory syndrome coronavirus- covid- was initially reported in china. the disease later spread to europe to cause a global pandemic. affected patients usually present with respiratory, gastrointestinal or general and non-specific symptoms. mortality is high especially in those with premorbid chronic conditions. because the pandemic started first in china, most of the literature on covid- describes chinese populations. in this analysis, we aimed to describe a comparative analysis between a chinese and a british cohort to explore the differences of covid- patients across asia and europe. in this case series, we aimed to describe a comparative analysis between a chinese and a british cohort to explore the differences of covid- patients between the two countries. data were collected on patients admitted with covid- to a single district general hospital in the uk. for comparison, we used a published chinese case series of similar population size, similar methodology and similar data collection period [ ] . cases on both sites were confirmed by a positive rt-pcr of nasopharyngeal swabs. british cohort included patients ( white british) and the chinese patients (all chinese). the most striking difference was the significantly older age of the british population ( % of the british were ≥ years old compared to only % of the chinese patients, difference of %, % confidence interval (ci) . % to . %, respectively). the pre-existing morbidities were also significantly higher in the british compared to the chinese cohort ( % of patients vs %, difference of %, % ci % to %, respectively). however, the only comorbidity which was higher in the chinese cohort was the chronic liver disease ( % vs % difference of %, % ci . to . %). gastrointestinal and general symptoms were more common clinical presentations in the british while respiratory symptoms were more prominent in the chinese cohort (table ) . mortality was significantly higher in the british cohort of % compared to none in the chinese cohort (difference of %, % ci . to . %). the significant older age in the british cohort is likely due to the fact that the prevalence of older people (≥ years) is higher in the uk than in china ( % vs %) [ ] . similarly, the larger number of comorbidities in the british cohort is likely related to the higher prevalence of older age groups. the only comorbidity that was significantly more common in the chinese cohort was the chronic liver disease which reflects the higher prevalence of liver cirrhosis in asia than in europe [ ] . respiratory symptoms were more prominent in the chinese cohort probably due to the fact that the chinese media and national advocacy have instructed patients with fever, cough, expectoration and other upper respiratory tract symptoms to go to the hospital at an early stage, while in uk, social distancing and self-isolation at home was more encouraged [ ] . the british cohort presented with slightly more gastrointestinal symptoms such as diarrhoea and general symptoms such as myalgia and fatigue which may represent atypical clinical presentation of covid- infection in the elderly [ ] . the mortality rate was significantly higher in the british cohort reflecting their older age and the associated higher comorbid conditions. older age was identified as a risk factor for mortality from covid- pneumonia in a previous study (odds ratio (or) . , % ci . to . , p = · ) [ ] . ageing appears to play a significant role in mortality rate differences between countries affected. for example, the overall case fatality rate in italy ( . %) is substantially higher than that in china ( . %) but when data are stratified by age groups, the case fatality rate in italy and china appear very similar up to the age of years. individuals aged ≥ years represent . % of cases in italy and only . % in china which may explain that the higher overall case fatality rate is due to the high prevalence of older age groups in italy compared to china [ ] . also, in an initial british report of , patients with severe covid- who were hospitalised, median age was years (iqr , ). increased age was a strong predictor of in-hospital mortality after adjusting for comorbidity, reference age < years, - years (hazard ratio (hr) . , % ci . to . , p < . ), - years hr . ( . to . , p < . ), ≥ years hr . (ci . to . , p < . ) [ ] . in a chinese nationwide analysis of hospitalised patients with covid- , a minimum one comorbidity was present in only . % of patients. two or more comorbidities were reported in . % of patients, and the number of comorbidities proportionally increased the risk of adverse outcomes [ ] . in europe, the prevalence of comorbidities was much higher. for example, early on of the outbreak in italy in february , when most cases were in the northern region, case fatality rates were similar between italy and china of . %. travel-related cases were the main source of covid- cases during that period of the epidemic in italy. in both countries, fatalities appear to affect mostly individuals with known comorbidities. however, case fatalities in italy were more common in older people. for example, % of people who died were ≥ years old in italy compared to only % in china [ ] . later on, a report for italy, published in april , showed that mortality rate has risen to %, most cases that died were > years old, a male to female ratio of : with at least comorbidity and cardiovascular disease was the highest risk condition. these data were different from the epidemiologic results observed in other asian countries at that time where mortality rate ranged between and % and a male/female ratio of : . this variation can be explained by the difference in the local demography due to the higher prevalence of cardiovascular disease both in italy compared to china and in men compared to women [ ] . a chart review of patients who died with covid- in italy, the mean (sd) number of comorbidities was . ( . ). overall, . % of patients had comorbidities, . % had one comorbidity, . % had comorbidities and . % had ≥ comorbidities suggesting that mortality is proportional to the number of comorbidities [ ] . similarly, in the british report of , patients hospitalised with severe covid- , % of patients had a documented comorbidity which was associated with increased hospital mortality [ ] . this suggests that older age and comorbidities were more common in european cohorts affected by covid- than in china, and they have a significant impact on mortality difference between the two continents. table summarises age and comorbidities of covid- patients reported from china, uk and italy. the main difference in this comparison was the significantly older age of the british population and its associated significant premorbid conditions. this may reflect the fact that the prevalence of older people (≥ years) is higher in the uk than in china ( % vs %) [ ] . the larger number of comorbidities such as hypertension, diabetes mellitus, chronic obstructive pulmonary disease, cardiovascular disease and chronic kidney disease was much more common in the british cohort likely related to the higher prevalence of older age group. the only comorbidity that was significantly more common in the chinese cohort was the chronic liver disease which also reflects the higher prevalence of liver cirrhosis in asia than in europe [ ] . respiratory symptoms dominated in the chinese cohort which may be due to the fact that chinese media and national advocacy have instructed patients with fever, cough, expectoration and other upper respiratory tract symptoms to go to the hospital at an early stage while in the uk, social distancing and self-isolation at home was encouraged [ ] . the british cohort presented with slightly more gastrointestinal symptoms like diarrhoea and general symptoms like myalgia and fatigue which may represent atypical clinical presentation of covid- infection in older age groups [ ] . the mortality was significantly higher in the british cohort which is likely related to old age and morbidities. older age was identified as a risk factor for mortality from covid- pneumonia in a previous study (odds ratio (or) . , % confidence interval (ci) . to . , p = · ) [ ] . we conclude that covid- clinical presentation of hospitalised patients across china and uk appears to be similar. the apparent differences in presentations are likely due to the inherent differences of the demographic features and case mix between the two countries. we conclude that covid- clinical presentation of hospitalised patients across china and uk appears to be slightly different; however, these apparent differences could be due to the inherent differences of demographic features and case mix between the two countries. literature review suggests that this demographic pattern may also extend to represent the difference between other european countries and china. the aged population is currently concentrated in the wealthier developed countries, which are able to absorb the financial impact of the pandemic and limit its spread to other countries. with the global demographic shift towards old age, the sector of older people will exponentially expand, especially in lowand middle-income countries where heath care resources to face a future pandemic are limited and thus increases the risk of uncontrollable global spread. therefore, who and governments around the world must consider this potential threat in health care planning. also, uncertainty about covid- trajectories remains substantial. comparative measures are still required, in addition to the traditional deaths per-capita method, to calculate covid- deaths and to compare progression of the disease across different countries. current projections seem to underestimate the eventual impact of covid- on the annual life expectancy at birth. indirect standardization as an alternative to death per capita has estimated that in the usa, the covid- impact would reach twice that of hiv infections or opioid overdoses, reducing the life expectancy to its lowest level since [ ] . clinical findings in a group of patients infected with the novel coronavirus (sars-cov- ) outside of wuhan, china: retrospective case series liver cirrhosis mortality in countries between and : a systematic analysis atypical presentation of covid- in a frail older person clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study italy and the uk country population main findings china [ ] patients a. mean (sd) age was . years ( . ) b. . % have ≥ comorbidity c mortality risk increased by comorbidity (hr . , % ci . to . ) for ≥ comorbidity and . ( . to . ) for ≥ comorbidities comorbidities were diabetes mellitus ( . %), ischaemic heart disease ( %), atrial fibrillation ( . %), active cancer ( . %), stroke ( . %) and dementia patients a. median age years (iqr , ) b. % had documented comorbidity common comorbidities were cardiac disease ( %), uncomplicated diabetes ( %), non-asthmatic chronic respiratory disease ( %) and ckd ( %) mortality rate % increased age and morbidity predicted mortality ds standard deviation, hr hazard ratio, ci confidence interval, iqr interquartile range, ckd chronic kidney disease sn compr case-fatality rate and characteristics of patients dying in relation to covid- in italy features of uk patients in hospital with covid- using the isaric who clinical characterisation protocol: prospective observational cohort study comorbidity and its impact on patients with covid- in china: a nationwide analysis similarity in case fatality rates (cfr) of covid- /sars-cov- in italy and china mortality rate and gender differences in covid- patients dying in italy: a comparison with other countries beyond deaths per capita: three covid- mortality indicators for temporal and international comparisons. medrxiv publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations conflict of interest none.ethical approval approved by the rotherham hospital foundation trust research and development department. key: cord- -k ejqb authors: elmajjaoui, sanaa; ismaili, nabil; benjaafar, noureddine title: covid- , brachytherapy, and gynecologic cancers: a moroccan experience date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: k ejqb the treatment of gynecological cancers is the main activity of brachytherapy units. however, during covid- pandemic, precautions should be done in order to reduce the spread of the virus while maintaining all chances to recovery for all patients (radiother oncol , - , ). despite the extent of the pandemic in our country, limited data are available to establish recommendations with a sufficient level of evidence (radiother oncol , - , ). more recently, the american brachytherapy society published some clarifications in this regard and international expert consensus recommendations of radiation therapy for gynecologic malignancies during the covid- pandemic were published (https://www.americanbrachytherapy.org/about-abs/abs-news/abs-statement-on-coronavirus/, gynecol oncol , ). in this commentary, we sought to share the procedures adopted for the management of gynecological cancer patients during covid- pandemic in our brachytherapy unit. despite the extent of the pandemic in our country, limited data are available to establish recommendations with a sufficient level of evidence [ ] . more recently, the american brachytherapy society published some clarifications in this regard and international expert consensus recommendations of radiation therapy for gynecologic malignancies during the covid- pandemic were published [ , ] . in this commentary, we sought to share the procedures adopted for the management of gynecological cancer patients during covid- pandemic in our brachytherapy unit. this article is part of the topical collection on cervical cancer is the most common gynecological cancer in our country. in the majority of cases, the treatment is based on ebrt (exclusive in early stages and with concurrent chemotherapy in locally advanced stages), followed by intracavitary brachytherapy (icbt) which constitutes a cornerstone in its management [ ] . brachytherapy is one of the radiotherapy techniques offering the most interesting therapeutic index by delivering high doses in a very conformational way. however, omission of brachytherapy results in important reduction in the curative potential of treatment [ ] . the development of high-dose rate brachytherapy guided by imaging, as well as endo-cavitary and interstitial hybrid techniques and dose escalation strategies [ ] , has contributed more in improving local control and overall survival (os) while reducing rate of late urinary, intestinal, and gynecological toxicities [ ] [ ] [ ] . technical advances in ebrt (imrt, vmat, and stereotaxic radiotherapy) have led to replacing brachytherapy boost by rt boost [ , ] . however, local control, progression-free survival (pfs), and safety were significantly better with brachytherapy [ ] [ ] [ ] [ ] [ ] . therefore, icbt boost remains the procedure of choice. brachytherapy should be delivered immediately after ebrt. longer treatment duration has been shown to be a worse prognostic factor for local control (an overall duration of treatment that exceeds days results in a loss of % of local control per day) [ ] [ ] [ ] [ ] [ ] [ ] . this encourages us to respect as much as possible the time between ebrt and brachytherapy. therefore, there are no major changes in brachytherapy procedures for patients with cervical cancers. however, to minimize the risk of contamination, precautionary measures have been implemented: & prefer the schemes with a reduced number of fractions: × gy or × gy. in our unit, we use the hdr icbt schedule of gy per fraction for fractions in insertions week apart. for each insertion, the patients receive fractions per day separated by a -h interval [ , ] . for patients over years of age or with significant comorbidities (chronic respiratory or cardiac pathology, immunosuppression, etc.) who have small tumors or responding well to external beam radiotherapy (ebrt), a more shortened schedule of gy per fraction in fractions at week apart may be considered. [ , ] & the brachytherapy program is adapted by limiting number of patients hospitalized, without compromising the treatment time duration. patients without covid- symptoms, who have already started their icbt, should complete their schedule without delay. under normal conditions, all icbt applications are done using spinal anesthesia and ultrasound guidance; however, the concern during covid- pandemic is the lack of anesthesiologist and their staff [ ] . in this case, we may consider pudendal nerve block or local anesthesia by paracervical block, or by the use of medical hypnosis technique [ ] . if all of these tools are not available, consider to insert applicator with uterine tandem which diameter not exceeding mm, without anesthesia. for covid- -positive patient, delivering icbt on time is recommended. however, in our department, as well as in other centers, we have only one brachytherapy operating room and a single bunker. therefore, treatment should be postponed for at least days or until the infection is resolved. for patients with early endometrial cancer, surgical treatment remains the standard of care. adjuvant treatment by ebrt and/or brachytherapy is recommended according to the prognostic factors in the anatomopathological report. vaginal vault brachytherapy (vvb) is recommended in intermediate risk endometrial cancer. it significantly reduces the rate of vaginal relapse. however, there is no significant difference in terms of long-term relapse, dfs, or os [ , ] . consequently, delaying vvb may be appropriate for this risk group. in the setting of covid- outbreak, we suggest postponing brachytherapy up to weeks [ ] . for patients with significant comorbidities, exposing them to the risk of severe complications of covid- infection (old age, chronic respiratory or cardiac diseases, immunosuppression, etc.), it may be judicious to delay brachytherapy for months. for patients who should start vvb, consider the schedule of gy for fractions to a depth dose of . cm, to limit the number of patient displacement. an interval spacing of days between the fractions is also acceptable. however, for high-risk patients who received adjuvant external rt, omitting bvv may be reasonable because of no evidence for combining of rt and vvb (except in the case of positive margins) [ , ] . for stage ii endometrial cancers, adjuvant vvb is delivered exclusively (if invasion < % of the myometrium, g and ) or after ebrt (if invasion > % of the myometrium, g ). in both cases, consider to postpone brachytherapy by to months. in the case of a covid- positive patient, postpone treatment for at least days [ ]. for early vaginal cancer (stage i, < mm of invasion), exclusive brachytherapy is the treatment of choice with eqd of - gy to the tumor with cm margin ( gy for fractions) [ ] . in patients with significant comorbidities (old age, chronic respiratory pathology or cardiac, immunosuppression ...), consider to postpone brachytherapy by to months. for advanced stage, which represent the vast majority of cases, consider radio(chemotherapy) treatment followed by vaginal brachytherapy ( gy for fractions) [ ] . brachytherapy treatment should be started on time without any delay. prioritization list in gynecological brachytherapy: contributors all authors contributed to the conception and design, drafting, and critical revision of this manuscript. all authors have given final approval of this version to be published, and all authors accept responsibility for its contents. conflict of interest the authors declare that they have no conflict of interest. ethical approval this article does not contain any studies with human participants performed by any of the authors. disclosures the authors declare that there is no source of support in the form of grants, bursaries, free use of equipment, drugs or any other benefits to disclose. covid- and gynecological cancers: a moroccan point-of-view radiation therapy for gynecologic malignancies during the 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standardized contours covid- impact on timing of brachytherapy treatment and strategies for risk mitigation rtog . a phase ii study of bevacizumab in combination with definitive radiother-apy and cisplatin chemotherapy in untreated patients with locally advanced cervical carcinoma phase iii randomized study of cisplatin and radiotherapy with versus without tirapazamine in patients with stage ib, iia, iib, iiib, or iva carcinoma of the cervix long-term outcome and prognostic factors in patients with cervical carcinoma: a retrospective study the effect of treatment time in locally advanced cervical cancer in the era of concurrent chemoradiotherapy impact of treatment time and dose escalation on local control in locally advanced cervical cancer treated by chemoradiation and image-guided pulsed-dose rate adaptive brachytherapy high-dose-rate brachytherapy in uterine cervical carcinoma efficacy and toxicity of concomitant cisplatin with external beam pelvic radiotherapy and two high-dose-rate brachytherapy insertions for the treatment of locally advanced cervical cancer intravaginal brachytherapy in figo stage i low-risk endometrial cancer: a controlled randomized study vaginal brachytherapyversus pelvic external beam radiotherapy for patients with endometrial cancer of highintermediate risk (portec- ): an open-label, non-inferiority, randomised trial publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations 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- -vam bli authors: höring, steffen; fussen, rené; neusser, johannes; kleines, michael; laurentius, thea; bollheimer, leo cornelius; keller, doris; lemmen, sebastian title: management of a hospital-wide covid- outbreak affecting patients and healthcare workers date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: vam bli to the best of our knowledge, here, we describe the first hospital-wide outbreak of sars-cov- that occurred in germany in april . we aim to share our experience in order to facilitate the management of nosocomial covid- outbreaks in healthcare facilities. all patients and hospital workers were screened for sars-cov- repeatedly. an infection control team on the side was installed. strict spatial separation of patients and intensified hygiene training of healthcare workers (hcw) were initiated. by the time of reporting, patients and hospital workers were infected with a cluster of cases in the geriatric department. fourteen patients developed covid- consistent symptoms and five patients with severe pre-existing medical conditions died. the outbreak was successfully contained after intensified infection control measures were implemented and no further cases among patients were detected over a period of days. strict application of standard infection control measures proved to be successful in the management of nosocomial sars-cov- outbreaks. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. since the beginning of the novel coronavirus disease pandemic (covid- ), inadvertent exposure of hospitalized patients and hcw to severe respiratory syndrome coronavirus (sars-cov- ) has been a major concern [ ] . here, we report a large nosocomial outbreak of sars-cov- that occurred at a satellite hospital of the university hospital aachen, germany, with patients and healthcare workers infected. the hospital, a formerly church-run facility, was integrated to the university hospital in january , hosting a geriatric department, a dermatological ward, and a mixed ward for multiple surgical disciplines with beds in total. located in aachen, the hospital is situated in close proximity to the district of heinsberg, the region where community transmission of sars-cov- was first observed in germany and where the cumulative incidence of sars-cov- is still among the highest in germany [ ] . our report provides a narrative description of a nosocomial covid- outbreak. furthermore, we present the infection control measures implemented to contain the outbreak and describe potential sources of the outbreak. against the background of the ongoing covid- pandemic, the hospital's policy and clinical processes were already adapted to prevent nosocomial transmission of sars-cov- . all hcw were obliged to wear a surgical face mask steffen höring and rené fussen contributed equally to this work. electronic supplementary material the online version of this article (https://doi.org/ . /s - - - ) contains supplementary material, which is available to authorized users. throughout their working hours and visitors were no longer permitted. furthermore, the university hospital's peripheral and intensive care capacities were steadily increased, for instance by postponing elective surgeries, in expectation of a rise in covid- case numbers. in this context, the first sars-cov- -infected patient was revealed in the geriatric department on april . although the patient, a -year-old man, showed no signs of infection, polymerase chain reaction (pcr) testing was performed since public health regulations demanded sars-cov- testing prior to his admission to a long-term care facility. as the hospital's pandemic policies required a reduced operation mode, only patients were present at the hospital at the time the first patient was detected. hence, the potential index patient and all contact patients could be transferred immediately to single rooms. in addition, all patients of the geriatric department were screened for sars-cov- by nasopharyngeal swabs and pcr analysis (realstar® sars-cov- rt-pcr kit, altona diagnostics, germany) on april . the screening revealed ten more oligosymptomatic sars-cov- infected patients on two spatially separated geriatric wards. facing this high detection rate, cohorting of patients on a separated isolation ward was initiated by the infection control department on the same day. in parallel, on april , a -year-old nurse working in the geriatric department presented at the university hospital's covid- screening center. during the absence from work, she had developed mild symptoms with fever, dry cough, and myalgia outside and was subsequently tested positive for sars-cov- . the nurse belonged to a religious community of seven nuns, all of them working as nurses in the hospital. the remaining six nurses presented the next day at the screening center reporting headache and faintness. in retrospect, the mild symptoms were considered covid- -consistent. pcr testing revealed five of them as sars-cov- -positive. considering the numerous covid- cases among patients and hcw, a hospital-wide screening was initiated on april for all remaining sars-cov- -negative patients and entire hospital staff. this hospital-wide screening revealed five more cases among patients as well as six nurses, one physiotherapist, and one resident of the dermatology department. while the cases were distributed in departments all over the hospital, there was a cluster among patients and hcw in the geriatric department. follow-up screening of all sars-cov- -negative patients and hospital staff was conducted repeatedly. the first follow-up screening between april and april revealed ten more infected patients, four more cases among nursing staff, and two infected occupational therapists. the second follow-up screening between april and yielded one more infected hospital employee, a pastoral worker, but no new cases among patients. the last screening sessions, conducted on april / and april / , revealed no further cases among patients or hospital workers. in total, pcr analyses were conducted on patients and pcr analyses were conducted on hospital workers during the observational period. by the time of reporting (may ), out of patients and out of tested hcw were infected, resulting in an attack rate of % and . %, respectively. the median age of patients affected was years and all patients had at least one or even several underlying diseases. twenty-two of the affected patients were patients of the geriatric department; the remaining four were dermatological and orthopedic patients. figure demonstrates the occurrence of cases among patients and hcw during the outbreak period. while twelve patients were asymptomatic, nine patients developed covid- with mild to moderate symptoms. however, five elderly patients (mean age . years; range: - years) with severe pre-existing conditions (mean charlson comorbidity index . ; range: - ) succumbed to the infection; according to their wishes, no life-supporting measures were undertaken. thus, a case fatality rate of . % ( out of patients) among infected patients was observed. among healthcare workers, one nurse was hospitalized due to worsening of her general condition and respiratory distress. by the time of reporting, she had been discharged and has recovered from the infection. on april , an isolation ward with -bed capacity was established for confirmed sars-cov- cases. on this ward, intensified clinical monitoring was conducted by measuring vital signs and oxygen saturation at least six times a day. infection control personnel (icp) and an infectious diseases doctor were present during ward rounds to observe working processes and to support clinical decision-making on a daily basis. the ward facilities were partially restructured with a sluice area and a changing room at the entrance. in the time before the outbreak, it was common practice for nursing staff to work on different wards and to switch their deployments from day to day. with the implementation of the isolation ward, medical staff exclusively worked on one ward without intrahospital fluctuation. a permanent on-site outbreak team was installed on april . the team met daily and consisted of members of the infectious disease and infection control department, the geriatric department, head nurses, and the hospital's managing director. throughout the outbreak, all hospital workers wore a surgical face mask during their working hours. when caring for sars-cov- -positive patients, gloves, goggles, and a protective gown were worn additionally and an ffp- face mask was used whenever aerosol-producing procedures were expected. in order to ensure safe handling of the personal protection equipment, i.e., preventing self-inoculation during ungloving, gowning, and masking, the medical staff was trained by icp repeatedly. since april , the geriatric clinic was closed for new admissions, and from april on, this regulation was applied for the entire hospital. spatial distancing was additionally ensured by keeping all sars-cov- -negative patients in single rooms outside the isolation ward. as outlined above, sars-cov- screening of patients and hospital staff was performed twice weekly by nasopharyngeal swabs and pcr analysis. examination of hospital workers, including hcw as well as administrational or technical personnel, was conducted as a voluntary mass screening during working hours. sars-cov- -positive staff were released from work and put under domestic quarantine until symptoms entirely for at least h and pcr testing proved negative twice in a row. on the one hand, there was the first case among patients, detected on april . the high viral load (ct: ) at the time of diagnosis and the fact that symptoms worsened after diagnosis point to a recently acquired covid- infection. at the time of diagnosis, the patient was already hospitalized for several weeks. due to colonization with multi-resistant bacteria, single-room isolation precautions were already performed; thus, no patient-to-patient contact occurred during the hospital stay. following the hospitals' pandemic regulations, no visitors were allowed in the preceding weeks. therefore, we conclude a nosocomial infection transmitted via an infected hcw. considering the date of admission and onset of symptoms, a further cases among patients are categorized as nosocomial infections. however, in one case, sars-cov- virus was detected only h after hospital admission pointing to a community-acquired infection. in three other cases, the date of admission was within the assumed incubation period; thereby, no definite mode of acquisition can be stated for these patients. on the other hand, we analyzed the first cases among hospital staff, starting with the potential index nurse tested positive for sars-cov- on the th of april. low ct values and worsening of symptoms in the days after diagnosis suggest a recently acquired covid- infection with a high potential for viral spreading. five of her household members, all of them nuns living together in a religious community, were infected showing lower viral loads but a simultaneous onset of symptoms. contacts to patients and other hospital workers could not be traced back reliably since all affected nurses shifted teams and wards frequently within the hospital on a needs basis. no definite index case or source of infection can be determined for this cluster. this report presents our first experience in managing a nosocomial covid- outbreak. in total, patients and hcw were infected with sars-cov- . since mainly elderly patients with severe pre-existing medical conditions were affected, a high case fatality rate of % was observed during the outbreak. nevertheless, intensified infection control measures eventually led to successful containment. the outbreak occurred during the onset of the covid- pandemic in germany. by the time the outbreak emerged, the hospital policy already comprised preemptive infection control measures in order to prevent intrahospital spread of sars-cov- . nevertheless, the outbreak could only be contained after all potential routes of intrahospital virus transmission were addressed by additional infection control measures (table ) . & first, the patient-to-patient transmission of sars-cov- had to be prevented. the reduction of contacts between geriatric patients was partially challenging since several patients suffered from cognitive impairment and did not follow social distancing recommendations or single-room isolation. thus, cohorting of infected patients on an isolation ward proved to be an ideal solution in this scenario. patients could move freely within the limits of the isolation ward and social contacts between patients were permitted without putting non-infected patients at risk. the second route of transmission addressed by our measures was infected hcw, who potentially spread sars-cov- to patients as well as to their co-workers. on the one hand, geriatric care requires close physical contacts thereby facilitating viral spreading from hcw to patients. consistently, first reports on outbreaks in nursing homes and geriatric wards show high attack rates and transmission dynamics comparable to our outbreak scenario [ ] [ ] [ ] . we assume that by identifying asymptomatic sars-cov- -infected patients and officially declaring the circumstances a nosocomial outbreak, not only personal protective equipment (ppe) was used more consequently but also hcws' practice of care, for example avoiding close face-to-face contact with infected patients, might have altered temporarily. on the other hand, the viral spread might also occur between hcw. in our case, for instance, hcw occasionally reported not to have worn facemasks during breaks although spatial distance could not be kept in these situations. both routes of transmission, hcw to patients and hcw to hcw, were successfully addressed in infection control training sessions in which hcw were instructed in the correct handling of personal protective equipment and in social distancing measures. several reports point out the importance of verbal training sessions demonstrating that hcw education does not only improve the handling of ppe but also reduces anxiety and increases the sense of preparedness [ , ] . last, our measures aimed to prevent the introduction of new covid- cases into the hospital. thus, the hospital was closed for new admissions during the ongoing outbreak. in the post-outbreak period, we have continued to screen all patients on their day of admission and all geriatric inpatients once weekly for sars-cov- in order to detect new cases timely. serial screening proved necessary since detection of a newly acquired covid- infection cannot reliably be achieved by a single pcr test. viral rna shedding starts approximately a day before the onset of symptoms and peaks in the first week of the disease with no detectable rna in the first days post infection [ ] [ ] [ ] . this explains why, in our case, seven hcw were initially tested negative, while follow-up examinations revealed a covid- infection. eventually, the infection control measures undertaken in response to the outbreak (table ) turned out to be effective since no further case among patients was detected after april and only one last case among healthcare workers occurred on april . this report emphasizes the necessity of an infection control team on-site in an outbreak situation. unlike many german hospitals, where infection control specialists are not present permanently, a well-established infection control infrastructure with sufficient manpower was available in our case. concerning the source of this outbreak, patient-to-patient contacts did not seem to be the main factor. most affected patients were bedridden and had no contact with other patients. nevertheless, three patients suffering from dementia showed a tendency to wander around on the wards and entered other patients' rooms without permission. this behavior might have led to sars-cov- transmissions in singular cases in the weeks preceding the outbreak. a greater contribution to outbreak dynamics might have been made by infected, asymptomatic or paucisymptomatic hcws. although we have not revealed any erroneous infection control behavior on the side of hcws, we assume they played a crucial role in introducing and spreading sars-cov- in the hospital. the cluster observed among hcws in the religious community serves as a good example of this • outbreak investigation assumption. the order of nuns lived under circumstances that clearly fostered viral transmission. they stayed together in a dormitory on the hospital's premises, shared a household, and attended service together. all of them simultaneously developed symptoms pointing to a commonly acquired infection, most likely outside their working hours. however, all of them were still employed in patient care during their assumed incubation period and therefore could have introduced and spread the virus on the wards as asymptomatic carriers. we therefore hypothesize that sars-cov- might have initially spread and incubated among hcws and was subsequently transmitted to patients and further co-workers. nevertheless, we must discuss alternative ways of sars-cov- introduction to the hospital. in one patient for example, a community-acquired infection was clearly given. therefore, we assume that the outbreak was based on multiple routes of introduction and transmission. eventually, a definite single outbreak source could not be determined. further molecular investigation, e.g., next-generation sequencing (ngs), might have been useful to clarify infection chains retrospectively. nevertheless, we state that no additional benefits for the actual outbreak management would have derived from further molecular diagnostics since the outbreak dynamics obviously suggested a nosocomial spread of sars-cov- in our case. we therefore claim that our report emphasizes the sufficiency of standard diagnostic methods under the exceptional circumstances of a nosocomial sars-cov- outbreak. there are exceptional infrastructural aspects that clearly facilitated the outbreak management in our case. although the hospital affected was small with a bed capacity of beds only, as a satellite hospital, it could fall back on the infrastructure and the financial power of a large tertiary care university hospital. this ideal setting not only allowed the closure of the entire facility to new admissions but also provided fast diagnostic processes with same day pcr results and an infection control team on site. we are aware of the fact that these settings are not a common standard and therefore, the management of sars-cov- -outbreaks can be more difficult for other hospitals and healthcare facilities. finally, we plead for a frank and detailed communication of nosocomial sars-cov- outbreaks during the ongoing covid- pandemic. despite concerns of negative publicity, reporting of nosocomial outbreaks is essential to allow all parties in the healthcare sector to benefit from each other's experience. our report demonstrates a successful containment strategy for nosocomial covid- outbreaks. multiple routes of transmission and delayed pcr-based diagnosis of early-stage infections presented pitfalls and hampered the definite investigation of the outbreak. nevertheless, routine diagnostics and standard infection control measures, e.g., contact precautions and screening of patients and hcw, proved to be efficient when applied to this novel pathogen and allowed successful outbreak management. author contribution sh and rf contributed equally to the study by writing the first draft and editing further versions of the manuscript. the conceptual idea was developed by sh, rf, sl, and cb. pcr testing was performed by mk. sh, rf, jn, tl, and dk collected and analyzed data. all authors critically reviewed the manuscript. all authors read and approved the final manuscript. funding open access funding enabled and organized by projekt deal. conflict of interest the authors declare that they have no conflict of interest. ethics statement this study was approved by the ethics committee of the aachen university hospital (ek / ) 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 holder. to view a copy of this licence, visit http://creativecommons.org/licenses/by/ . /. clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan rapid nosocomial spread of sarscov- in a french geriatric unit presymptomatic sars-cov- infections and transmission in a skilled nursing facility epidemiology of covid- in a long-term care facility in king county, washington how to rapidly design and operationalise ppe donning and doffing areas for a covid- care facility: quality improvement initiative the impact of covid- on healthcare worker wellness: a scoping review temporal dynamics in viral shedding and transmissibility of covid- temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by sars-cov- : an observational cohort study 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- - yk dzxf authors: brika, marine; bossu, maëva; fautrelle, lilian; mourey, france; kubicki, alexandre title: geriatric rehabilitation and covid- : a case report date: - - journal: sn compr clin med doi: . /s - - - sha: doc_id: cord_uid: yk dzxf the covid- infection has particularly affected older adults. clinical observations in this population highlight major respiratory impairment associated with the development or aggravation of the patient’s frailty state. mr. p is a -year-old frail patient, hospitalized after a covid- infection. the assessment process of this patient has been supported by an innovative multi-systemic tool developed in view of the covid- clinical consequences and a systemic evaluation of motor functions by the frail’bestest. this process allowed a mixed clinical picture associated with significant respiratory distress (linked with acute respiratory distress syndrome) and an evident motor frailty. the care plan was developed accordingly, and four assessments were done in the same manner until mr. p returned home. this case report allows us to see a holistic covid- clinical picture, showing the different axes of clinical reasoning to enhance the rehabilitation process. furthermore, this case report illustrates the importance of rehabilitation in the covid- context. the covid- pandemic targets aged adults, especially when they carry comorbidities [ ] . in elderly adults, frailty corresponds to the clinical consequences of physiological function decline, involving pathological aging. frailty is characterized by a loss of functional supplies, leading to a high risk of falls, institutionalization, and sometimes death [ ] . aged adults who survive covid- could present several frailty criteria following respiratory distress and may sometimes need to spend several days in an intensive care unit. there are multiple clinical pictures associating respiratory and vascular consequences, bed rest effects, and medication effects in a psychological context of anxiety [ , ] . the case report of mr. p aims to underline the mixed clinical picture of acute respiratory distress syndrome (ards) and motor frailty. this case seems highly generalizable in the pandemic context where high age and associated diseases are major causing factors of death. on march , , mr. p is hospitalized for a covid- infection, confirmed by a thoracic scan showing the typical ground-glass opacities (fig. ) . his pulmonary function decreased, entailing oxygen supplementation of l/min. his clinical evolution confirms oxygen dependency between and l/min with high concentration mask. mr. p is transferred to the rehabilitation unit on april , . mr. p lives alone in his house with a bedroom on the first floor. he is able to walk without technical support, both inside and outside. during the examination, mr. p clearly expresses that he wants to go back at home once he regained his previous functional level. a significant fear of falling is observed, measured at / with the short fes [ ] . mr. p also indicates that he fell twice in , when walking in his garden, and explains that he had difficulties getting up from the floor. about medical treatment, the therapeutic drugs related to the covid- affection were -plaquenil mg in the morning and evening on march , . then the plaquenil was prescribed only in the morning for days. -methylprednisolone (corticoid) mg on april , and mg on april , . -tolicizumab mg on april , and mg on april , . -augmentin g times a day (morning, noon, and evening) from april , to may , . mr. p also has an anti-coagulant treatment: lovenox ml ( ui). this drug is administered subcutaneously every h starting march , . from april , , the drug is administered over h. regarding comorbidities, mr. p's treatment included the following: -furosemide ( mg) by direct intravenous injection every h (in the morning) on april - , . this drug was introduced due to edema in the lower limbs. -kardegic . -perindopril ( mg) morning and evening then decreased to only in the morning from april onward. in addition, two indexes of comorbidity, the cumulative illness rating scale (cirs) ( table ) and charlson comorbidity index (table ) , were carried out. we conducted the evaluation using a two-fold analysis. first, we evaluated the deficiencies linked with the covid- infection and the associated ards, using a specific covid- aggregation of scales. next, we targeted the patient's motor function using the frail'bestest [ ] so as to guide the clinical reasoning. -social and behavioral functions are evaluated with the ramsay score [ ] and the rass scale [ ] . -some items from the hamilton scale (hdrs) are used to measure the psychological and emotional states [ ] . & the simplified cardiac and respiratory evaluation allows us to measure the usual parameters with the mmrc dyspnea scale [ ] and the borg scale [ ] . the peak cough flow rate (pcfr) is also measured [ , ] . & in accordance with the loss of mass frequently described [ ] , the body mass index is noted. swallowing function is evaluated with simple tests. & frailty detection is based on several tests showing good sensitivity: the gait speed measure [ ] , the chair test in min [ ] , the functional reach test [ ] , and the grip strength test [ ] . & neuromotor functions are evaluated by the pfit score [ ] and the mmrc [ , ] . a few items from the mini motor test [ ] and the bestest [ ] allow a global view of the patient. & a binary analysis of statesthesia and tact are proposed, in addition to the other senses. & regarding sensitivity, a double assessment including statesthesia and touch [ ] is done. the evaluation synthesis of mr. p is featured in fig. a and b. the frail'bestest has been developed to make it possible to include frail older adults in systemic evaluations [ ] . therapists can therefore directly manage therapeutic intervention for different types of balance deficiencies. overall, six sub-systems have been addressed: ( ) anticipations, ( ) reactions, ( ) locomotion, ( ) sensorial orientation, ( ) biomechanical constraints, and ( ) asymmetric gait. mr. p, a -year-old patient, presents with a respiratory dysfunction linked to a covid- infection (saturation at % with l of oxygen supplementation), subsequent effort incapacity, and postural-motor deficiencies. motor automatisms are impaired, and several articular and muscular constraints remain. mr. p seems enlisted in a frailty process, leading to increased dependency, an impossibility to return home, and relative social isolation. the protocol was carried out in accordance with legal and international requirements (declaration of helsinki, ). mr. p was informed about the published project and gave his written consent before the evaluation. mr. p followed a rehabilitation program which primarily included physical therapy and nutritional monitoring. he received one session of physical therapy per day. this session lasted on average of min. considering the physiotherapeutic diagnosis of mr. p, as well as the agespecific lung physiology of the patient [ ] , some cardiopulmonary rehabilitation exercises allowing both the maintenance of ventilator functions and the improvement of hematosis can be proposed. during all of these exercises, precautions, red flags, and stop criteria indicated in the has quick response [ ] should be followed. the next paragraph will show the aims and exercise samples that have been proposed to mr. p. we would like to improve both the transverse abdominis and the diaphragm via active, functional, and resistive treatments including threshold systems, hypopressive exercise, and functional ventilation during movement [ ] [ ] [ ] . in order to limit physiological impairment, some exercises including thoracic movement with the arms, chest, and spine mobility are introduced during global therapy in both directions: inhale and exhale [ , ] . in order to improve oxygenation and prevent congestion, ventilation should be harmonized throughout the lung territories, and mucociliary clearance should be promoted. thus, the treatment involves high-volume ventilation-type work that includes tele-inspiratory holds, while avoiding specific collapses associated with senescence. for example, edic, itla (inspiratory technical for lifting atelectasis), elpr, and acbttype exercises with open glottis are proposed [ , ] . concerning rehabilitation with effort, it is necessary to increase the ventilatory threshold in order to improve muscular function and decrease dyspnea. this will also improve hematosis and oxidative metabolism. an early and progressive cardiopulmonary rehabilitation program is established and based on the borg scale [ , ] . for mr. p, it includes optimal loading, aerobic work measured by paliers, as well as endurance. this program mainly uses functional exercises such as treadmill walking (between and % of the tm or the chair-test or top toes test) [ ] . it also seems important to prevent dysphagia in the medium term and to optimize the use of the functions of the nose (to warm, filter, and humidify the air). so, nasal ventilation and correction of the tongue position is essential. for example, mindless nasal ventilation and the tongue palate position is monitored, and lingual resistive exercise and sensitive work are proposed. in a final perspective on the patient's autonomy, throughout the rehabilitation process, education on the perception of effort, use of the borg scale, the patient's self-assessment of his respiratory capacities, and the criteria of alerts are all carried out [ ] . on the other hand, in connection with the systemic evaluation of the balance function and motor frailty of mr. p, several sensory-motor exercises are proposed. to improve the efficiency of postural-movement coordination, self-paced perturbations of balance were worked on with speed and variability [ ] . for example, mr. p had to reach a colored target on the ground as quickly as possible once the physiotherapist indicated the color he has to hit. to reactivate postural adaptations and fall avoidance reactions, mr. p performs exercises that work on extrinsic imbalances (unpredictable balance perturbation) [ ] . for example, mr. p had to react to manual pushes from the physiotherapist. in order to improve muscular power, functional muscular exercises were performed in a closed chain and under a time constraint [ ] . for example, mr. p had to go up and down a step to the beat of a metronome. in order to regain physiological ankle mobility and enhance the rolling of feet when walking, active mobilization exercises were carried out during physiotherapy sessions and also by the patient independently in his room [ ] . to reduce podal dependency, mr. p performed static and dynamic balance exercises on different ground textures (e.g., standing on foam, walking on a mat, walking outside in the grass). finally, exercises incorporating the work of spatial and temporal parameters of walking and changes of direction were carried out. these exercises were aimed at improving walking kinetics and would contribute to the evolution of help with technical walking. the four assessments performed by the specific covid- evaluation showed an overall improvement of the patient in several functions. in terms of psychological and emotional state, the anxiety with regard to oxygen dependence disappeared. indeed, during the initial assessment, the patient had l of oxygen in the high-concentration face mask. during the final evaluation, he had only l of oxygen left in the nasal cannula. pulmonary auscultation, which initially revealed a lack of ventilation associated with congestion of the middle and distal airways, also improved. final auscultation was evaluated without particularities. the assessment of cognitive and behavioral functions remained unchanged over the course of the four assessments. initial clinical observations did not show impairment of these functions. the initial preliminary assessment of the vascular and cutaneous system had shown the presence of a stage pressure ulcer (as per the national pressure ulcer advisory panel stage classification) behind the ears due to the oxygen mask. upon final evaluation, the pressure ulcer was no longer present. no vascular disorders occurred during the hospitalization. moreover, there was no significant change in swallowing function, as mr. p did not present any swallowing problems. changes to the scores of quantitative outcomes of the different functions are summarized in table . the four frail'bestest assessments show an improvement in the score of some subsystems. the results are summarized in table . this case allows us to underline the global approach that is necessary in a geriatric rehabilitation context associated with the covid- infection. although the long-term follow-up is not yet available, it seems important to continue the clinical pictures description associated with this virus in order to better organize rehabilitation strategies. indeed, the rehabilitation process represents the other challenge of the pandemic situation in several countries characterized by a high proportion of frail patients [ ] . in our opinion, it is important to understand that the issue is not only to rescue a patient from their acute respiratory problem, but more so to prevent the functional dependency associated with the infection's consequences, especially in intensive care units where chronic diseases are frequently acquired. mr. p was probably lucky to return home with a high level of independency. his age and relative frailty were, at the beginning, considered to be bad prognosis factors. as is common in geriatric rehabilitation, age is not only a question of numbers. in the same manner, frailty should not be questioned as an independence level, but more in terms of functional reserves. mr. p presented sufficient functional reserves, although he was certainly frail upon arriving at the hospital. several papers have described the physiotherapy associated with the covid- infection since the pandemic began. a lot of them describe adult patients, often aged up to years, considering 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remains neutral with regard to jurisdictional claims in published maps and institutional affiliations acknowledgments the authors thank dr. julie caissutti for her precious help. conflict of interest the authors declare that they have no conflict of interest.ethical approval the protocol performed in this case report is in accordance with the ethical standards of the institutional and/or national research committee and with the helsinki declaration and its later amendments or comparable ethical standards.informed consent mr. p was informed about the publication of the project and gave his consent.