key: cord-0902422-mudxyy68 authors: Kaur, Ishmeet; Sharma, Aseem; Jakhar, Deepak; Das, Anupam; Aradhya, Sujala Sacchidanand; Sharma, Rashmi; Jindal, Veenu; Mhatre, Madhulika title: Coronavirus disease (COVID‐19): An updated review based on current knowledge and existing literature for dermatologists date: 2020-05-24 journal: Dermatol Ther DOI: 10.1111/dth.13677 sha: 0592b1289293f477165dd9e52b8166f34b4b9fea doc_id: 902422 cord_uid: mudxyy68 The world entered the year 2020 with reports of the emergence of a new viral illness in Wuhan city, Hubei province, China. In January 2020, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) was identified to be the causative novel coronavirus for the cluster of patients suffering from pneumonia in China. The disease was later named as coronavirus disease (COVID‐19) and was declared a pandemic by the World Health Organization on March 11, 2020. Several studies, since then, have tried to study and explain the origin of SARS‐CoV‐2, its structure and pathogenicity, epidemiology, modes of transmission, spectrum of illness and causes of mortality and morbidity. The current management strategies focus on supportive care and prevention of complications. With no definite treatment, as of now, encouraging reports of some anti‐viral and anti‐malarial drugs in the management of COVID‐19 generate some hope. This review intends to cover the current known aspects of COVID‐19 and SARS‐CoV‐19, based on the available literature. The multiplication of the virus is facilitated by aminopeptidase-N and sialic acid-containing receptors. The sites of receptor binding domains (RBD) within the S1 region of a coronavirus S protein vary depending on the virus. SARS-CoV (Severe Acute Respiratory Syndrome associated coronavirus) has the RBD at the C-terminus of S1. It is worth mentioning that the Sprotein/receptor interaction is the primary determinant for a coronavirus to infect a host species. SARS-CoV uses angiotensin-converting enzyme 2 (ACE2) as their receptor, to gain entry into human cells. 6, 10, 11 Following entry, the glycoprotein envelope is removed. Thereafter, the virus enters the host cell cytosol by acid-dependent proteolytic cleavage of S protein by a cathepsin, TMPRRS2 or another protease, followed by fusion of the viral and cellular membranes. The subsequent step is transcription followed by translation of the replicase gene from the virion genomic RNA. CoV messenger RNAs have a tendency to form a "nested set" with common 3′ ends; the uniqueness being the translation of only 5' ends. 8 During translation, proteins are assembled at the cell membrane and genomic RNA gets incorporated, when complete viral particle is formed as a result of budding from internal cell membranes. 7, 10 Coronaviruses cause a large variety of diseases in animals, including pigs, cows, chickens, dogs and cats. MERS-CoV had utilized Dipeptidyl peptidase 4 (DPP4) as its receptor and it was noted that the virus was only able to use the receptors from certain species such as bats, humans, camels, rabbits, and horses, to establish an infection. It is thought that SARS-CoV-2 has This article is protected by copyright. All rights reserved. originated from an animal reservoir only (most likely bats, but substantial evidence is yet to be found). 10 The virus is transmitted via inhalation of contaminated droplets (aerosol). But it should be kept in mind that the virus can also be transmitted through hands and via the nasal, oral and ocular mucosa. 7 The virus invades the respiratory tract, portal of entry being the nose. Following an incubation period of 2-14 days, the patient presents with a flu-like illness characterized by running nose, myalgia, fever, dry cough; which gradually progresses towards a more severe illness in the form of a productive cough and respiratory distress. 6, 7 The initial four cases were reported on 29 December 2019 and were all traced back to the Huanan (Southern China) Seafood Market. The cases were identified by local hospitals using a surveillance mechanism for 'pneumonia of unknown etiology' that was established in the wake of the 2003 Severe Acute Respiratory Syndrome (SARS) outbreak, with the aim of allowing timely identification of novel pathogens such as 2019-nCoV. 12 While the virus is zoonotic, human-to-human transmission is responsible for its rapid spread. Initial reports estimated that, on an average, one infected person would infect between two and three more. 13 A study found that cases of COVID-19 were doubling in number approximately every 7.4 days. 12 The incubation period for COVID-19 is currently estimated at between 2 and This article is protected by copyright. All rights reserved. 14 days. 12, 13 Coronaviruses are known to mutate effectively, which makes them highly contagious. 14,15 SARS-CoV-2 also seems to be having an easy and sustainable community spread in certain affected geographical areas. 16 Human-to-human transmission among close contacts has occurred since the middle of December and spread out gradually within a month after that. 12 Researchers believe that the viruses transmit via fluids (mucus) in the respiratory system, produced when an infected person coughs or sneezes. Various modes of transmission of the virus are enlisted in Table 1 . [13] [14] [15] [16] [17] It has been observed that not only the symptomatic infected people are capable of transmitting the disease, but there is evidence suggesting that transmission can also occur from an asymptomatic infected person. 13,16 A research group analyzed the viral load in nasal and throat swabs of 17 symptomatic patients in relation to day of onset of any symptoms. Higher viral loads in the nose than in the throat, were detected soon after symptom onset. This study also demonstrated that the viral load detected in asymptomatic patients was similar to that in symptomatic patients; which suggests the transmission potential of minimally symptomatic or asymptomatic patients. These findings are in agreement with reports which state that the transmission may occur early in the course of infection. 1 Based on the available data, the World Health Organization has defined four transmission scenarios for COVID-19 as depicted in Table 2 . 19 This article is protected by copyright. All rights reserved. Studies suggest that the virus can survive for several hours on surfaces such as tables and door handles. 13 A comparative experiment between the SARS-CoV-1 and SARS-CoV-2, proved SARS-CoV-2 to be more stable on plastic and stainless steel than on copper and cardboard. Although the virus titre greatly reduced after application, viable virus was detected up to 72 hours on plastic and 48 hours on stainless steel, while no viable virus was measured on copper after 4 hours and on cardboard after 24 hours. 20 Another study found that SARS-CoV and human coronavirus (HCoV) strain 229E persisted up to 5 days on metals like steel, 8 hours on aluminium, 4 days on wood, 4-5 days on paper and glass, 5 days on ceramic and teflon, 5-6 days on plastic, 2 days on a disposable surgical gown but only up to 8 hours on a latex surgical glove. 21 Comparative data obtained with SARS-CoV, demonstrated that persistence of the virus was longer with a higher inoculum. The susceptibility to temperature, humidity and other environmental factors is still not proven and it is only speculated that the SARS-CoV-2 is susceptible to higher temperatures. The range of temperature and time duration to inactivate the virus is still being studied. Inactivation studies of coronaviruses with various biocidal agents show that ethanol (78-95%), 2-propanol (70-100%), the combination of 45% 2-propanol with 30% 1-propanol, glutardialdehyde (0.5-2.5%), formaldehyde (0.7-1%) and povidone iodine (0.23-7.5%) readily This article is protected by copyright. All rights reserved. inactivate coronavirus infectivity by approximately 4 log10 or more. Other agents effective against coronaviruses include: sodium hypochlorite (0.21%) and hydrogen peroxide (0.5%). Data obtained with benzalkonium chloride and chlorhexidine digluconate was insufficient to prove their effectiveness. The usual contact time for these biocidal agents to disinfect the surfaces is at least 1 minute. 21 Definitions for a confirmed, probable and a suspected case of COVID-19 have been recommended by the World Health Organization. The case definitions are based on current information and are subjected to constant revision as new information gets collected. Different countries have also modified and adapted these case definitions depending on their own epidemiological situation. [22] [23] [24] Suspected case: A. Patient with acute respiratory illness (that is, fever and at least one sign or symptom of respiratory disease, for example, cough or shortness of breath) AND with no other etiology that fully explains the clinical presentation AND a history of travel to or residence in a country, area or territory that has reported local transmission of COVID-19 disease during the 14 days prior to symptom onset. This article is protected by copyright. All rights reserved. OR C. Patient with severe acute respiratory infection (that is, fever and at least one sign or symptom of respiratory disease, for example, cough or shortness breath) AND who requires hospitalization AND who has no other etiology that fully explains the clinical presentation. A. A suspect case for whom testing for COVID-19 is inconclusive (Inconclusive being the result of the test reported by the laboratory) OR B. A suspected person whose testing could not be performed due to any reason. This article is protected by copyright. All rights reserved. A contact is a person who is involved in any of the following within 14 days after the onset of symptoms in the patient; 1. Providing direct care for patients with COVID-19 disease without using proper personal protective equipment 2. Staying in the same close environment as a COVID-19 patient (including sharing a workplace, classroom or household or being at the same gathering) 3. Travelling in close proximity with (that is, having less than 1m separation from) a COVID-19 patient in any kind of conveyance. The clinical manifestations due to COVID-19 greatly resemble that of a viral pneumonia. Therefore, the illness caused by this virus was named "novel coronavirus-infected pneumonia" (NCIP). The infection shows a male predominance and is more commonly seen in individuals in their 40s. [25] [26] [27] [28] This article is protected by copyright. All rights reserved. The clinical spectrum may range from an asymptomatic infection to a mild-moderate infection, acute respiratory distress syndrome, septic shock and multi-organ failure and death. 22, [25] [26] [27] [28] [29] The most common initial symptoms being reported are fever (>90%), malaise/fatigue (upto 70%), cough or chest tightness (around 75%), and dyspnea (around 50%). [25] [26] [27] [28] [29] Cough is usually dry or non-productive. However few cases have shown productive cough with white sputum. Most cases are reported to experience a mild illness course. Small subsets of patients have also been reported to have hemoptysis, gastrointestinal symptoms such as anorexia, abdominal pain, nausea, vomiting and diarrhea. 28--29 In a study by Huang et al, out of a total of 41 infected patients, 73% were male with average age of 49 years. Fever was seen in 40 patients (98%), cough [76%], and myalgia or fatigue in 44%. Less common symptoms observed were sputum production (28%), headache (8%), haemoptysis (5%), and diarrhoea (3%). Dyspnoea developed in 22 (55%). 29 There are few asymptomatic cases reported in the literature, where the patient may present with respiratory symptoms without any fever or cough. Asymptomatic carriers or close contacts have tested positive without presentation of any signs or symptoms. [28] [29] [30] WHO has provided guidelines and definitions of various clinical syndromes associated with COVID-19 infection (Table 3) . 23 In pediatric population, fever and cough are again the most common symptoms. Most of the cases show a consolidation with a surrounding halo sign on CT scan of the lungs. This finding has been observed to be different from adults. It is suggested that underlying co-infection may be This article is protected by copyright. All rights reserved. more common in pediatrics, and the consolidation with a surrounding halo sign is considered as a typical sign in pediatric patients. 32 In pregnant females, the clinical manifestations have been observed to be similar to those reported for non-pregnant adult patients. 33 Although, it may have adverse effects on newborns like fetal distress, premature labor, respiratory distress, thrombocytopenia along with abnormal liver function, and even death. there is currently no concrete evidence for intrauterine infection caused by vertical transmission in women who develop COVID-19 pneumonia in late pregnancy. 33, 34 Recently, a second trimester miscarriage in a female infected with SARS-CoV-2 was reported without any identifiable cause. During labor, amniotic fluid and vaginal swabs tested negative for the virus. Immediately, after the miscarriage, swabs from umbilical cord blood, fetus and placenta were also tested. While all the samples tested negative, the placental swabs (from both periphery and near umbilical cord) tested positive. This could imply the risk of placental transfer and risk of miscarriage in pregnant females with COVID-19. 35 Data regarding the relative frequency of severe illness is likely to be skewed at present by detection bias towards these cases, with sicker patients more likely to present for clinical assessment; these cases may therefore be over-represented in recent data. 28, 31 Dermatological manifestation in COVID-19 can occur either as a direct implication of coronavirus infection or due to PPE. Joob et al reported a patient who presented with petechiea, This article is protected by copyright. All rights reserved. later developed respiratory symptoms and turned out to be positive for COVID-19. 36 This article is protected by copyright. All rights reserved. Kolivras et al demonstrated histopathological finding in a 23 year old COVID-19 patient with chilblain like lesion, which showed papillary dermal edema and perivascular and perieccrine lymphocytic infiltration along with scatter necrotic keratinocytes in the superficial layers of epidermis. 44 They also correlated the this chilblain like presentation in young individual as a good prognostic factor, occurring as a consequence of immune response generating Type-1 interferons (IFN-I). However, in older age group, the presentation is due to acral ischemia due to a delayed or insufficient IFN-I response (muted response) which indicate poor prognosis and increases the risk of morbiditiy and mortality. 44 Gianotti et al studied histopathological findings in COVID-19 patients presenting with different cutaneous lesions in varying stage and degree of severity. Maculopapular rash in its early stage revealed only telengiectatic small blood veseels in upper dermis. As it progressed, presence of langerhan cells was observed. In purpuric maculopapular rash, increased Langerhans cells, perivascular lymphocytic infiltration with eosinophils and extravasated erythrocytes was seen. Intravascular microthrombi in upper dermal vessels was appreciated in a patient with severe macular hemorrhagic rash while lesions mimicking Grover disease revealed dykeratosis, multinucleated giant cells and necrotic keratinocytes. 45 Exacerbation of pre-existing skin condition such as rosacea, eczema, atopic dermatitis and neurodermatitis have also been observed in one report. 46 Drug reactions such as acute urticaria This article is protected by copyright. All rights reserved. and urticarial vasculitis have been reported by Zheng et al owing to the increased use of potential anti-coronavirus drugs, chinese herbs and other antibiotics. 46 The spectrum of dermatological manifestations would become clear as new studies become available. The signs and symptoms pertaining to skin also occur as a consequence of the preventive measures taken by the healthcare workers (HCWs) and the general population to avoid the spread of infection. A high incidence of cutaneous complications related to prolonged wearing of personal protective equipment (PPE) like face mask, face shield, eye goggles, double gloves has been observed among healthcare workers treating patients with the Coronavirus (COVID- 19) infection. 47, 48 In a study by Lan et al, 97.0% (526/542) of frontline healthcare workers showed some sign of skin damage secondary to the preventive health measures taken. Most common sites affected were the nasal bridge, hands, cheek and forehead. The nasal bridge was the most commonly affected site (83.1%). The dermatological signs and symptoms in the health workers following preventive measures include dryness, redness, tenderness, itching, desquamation, tightness and less commonly maceration, fissures, papules, vesicles, ulcers and wheals on the skin. Frequent hand hygiene and wearing of double gloves was associated with a higher incidence of hand dermatitis. Both the N95 mask and goggles were implicated in most of the facial injuries. The symptoms on the corresponding sites were observed in healthcare workers wearing PPE for more This article is protected by copyright. All rights reserved. than 6 hours. Table 4 summarizes the dermatological manifestations of COVID-19 secondary to PPE. 47 Due to the skin lesions associated with symptoms such as itching/burning on the central face, the HCW may be forced to touch his/her face or adjust the mask in an unconscious effort to relieve a source of itching. This may expose the HCW to further spread of infection. 49 COVID-19 has been observed to be more severe in older populations with higher incidence of comorbidities and with weaker immune functions. 25, 29, 52 Serum cytokines were found to be This article is protected by copyright. All rights reserved. whereas immunoglobulins (IgA, IgG and IgM) and complement proteins (C3 and C4) were within normal range. Amongst the lymphocyte subsets, total number of B cells, T cells and NK cells were significantly decreased in patients. All the lab changes were more evident in severe cases as compared to the non-severe cases. 55 In another study of 41 patients admitted in a hospital, high amounts of IL1B, IP10, IFNγ, and According to yet another study, CD4+ T lymphocytes get activated following the infection to convert to Th-1 cells and start producing GM-CSF. The excess cytokines released induce inflammatory monocytes with increased IL-6 production which accelerates the inflammation. Severe COVID-19 patients were found to have abundant inflammatory cells in the lungs. 56, 57 The aberrant monocytes and the Th1 cells may flood the pulmonary circulation and disable lung function to increase morbidity and mortality. 58 This article is protected by copyright. All rights reserved. lavage/tracheal aspirate for a lower respiratory tract infection. Specimen should be stored at 2-8°C and tested within 72 hours of collection. 59 Nucleic acid amplification tests (NAAT) for COVID-19 virus Cases are detected using NAAT such as real-time reverse transcription polymerase chain reaction (rRT-PCR) and further confirmed by nucleic acid sequencing if required. These techniques target unique sequences of viral RNA like N, E, S and RdRP genes. 60 To reduce the false negative rates of PCR, specimen collection from multiple body sites is preferred. For example, in Guangzhou city, China, nasal swabs were found out to be positive while throat and/or anal swabs were negative in patients after discharge. 61 Serological testing Serological tests are useful in epidemiological studies to determine the attack rate and the extent of spread. Paired samples can be assessed in suspicious cases with persistent negative NAAT. 60 One challenge with serological testing is the presence of cross reactivity to other coronaviruses. 62 Viral sequencing Viral sequencing has an additional benefit of detecting viral genome mutations. It also aids in molecular epidemiology studies. 60 This article is protected by copyright. All rights reserved. Viral culture is not advised as a routine procedure at present. 60 A study of 1099 patients in China showed lymphocytopenia in 83.2% of the patients, thrombocytopenia in 36.2%, and leukopenia in 33.7%. Acute phase reactants such as C-reactive protein, alanine aminotransferase, aspartate aminotransferase, creatine kinase, and d-dimer were also elevated although less commonly. 28 In another study by Wang et al comprising of 138 patients, severe cases had more pronounced lab findings especially lymphocytopenia, presence of d-dimer and fibrin degradation products in the serum. 26 In the same study by Wang et al, chest radiography abnormalities were found in a majority of patients in the form of ground glass opacities. 26 Huang et al reported chest CT changes in 41 patients out of which, 98% had bilateral involvement. While patients in ICU had multiple segmental and lobular areas of consolidation, non-severe cases showed ground glass opacities and sub-segmental consolidations. 29 In a retrospective study of 112 patients by Inui et al, changes of pneumonia on CT were observed even in 54% of asymptomatic patients. 63 This article is protected by copyright. All rights reserved. The autopsy findings of lungs showed desquamated pneumocytes, interstitial lymphocyte infiltration and hyaline membrane formation indicating ARDS. Viral cytopathic changes such as syncytial cells with atypical pneumocytes and large nuclei and prominent nucleoli were also observed. 56 At the time this article was being written, the new case detection rate had taken a steep curve, with more than 4 million cases (as on May 13, 2020). 64 The coronavirus disease (COVID- 19) exemplifies Benjamin Franklin's famous words -"An ounce of prevention is worth a pound of cure." Given the highly contagious nature of the SARS-Cov-2, and the relatively rapid escalation of the disease outbreak to a pandemic, preventive public health measures have been recommended by the World Health Organization (WHO). 65 These are multi-pronged in approach to facilitate prevention, infection containment and disease control at various levels -global, community and personal. The aim of containment at each echelon is to contain the COVID-19 outbreak in a particular region to a particular stage, be it imported case, local transmission, community transmission, epidemic or pandemic. This article is protected by copyright. All rights reserved. While no formal restrictions have been imposed by the WHO on travel, it does recommend the conduction of exit and entry interviews which comprise a cursory clinical examination and recording of temperature, from countries that have reported the incidence and community transmission of COVID-19. 66 While not as foolproof as genetic testing, this may still identify a major subset of potentially infected individuals. Global summits, international conferences and meetings have been discouraged by the WHO, the Centre for Disease Control and Prevention (CDC, Atlanta, USA) and many other nations as part of a complete or partial lockdown. [67] [68] [69] The mainstay of preventing community transmission is social distancing -1m between 2 individuals, and an overall avoidance of closed spaces and large gatherings. These include, and are not limited to, public transport by land (road, rail), air and sea, schools, colleges and educational institutions, retirement communities, convenience stores, workplaces and places of worship. Law enforcement agencies, the armed forces and healthcare professionals and workers, unfortunately, have to continue their duties, albeit with personal protective measures, which is covered in the following section. 70 Another element of community protection is environmental disinfection. Since the SARS-Cov-2 is transmitted via respiratory droplets / aerosols, this faction has not been given due importance as it eliminates fomite infectivity. Although sufficient data on surface RNA detection, persistence and infectivity of SARS-Cov-2 is not available, the other members of the Coronaviridae family have shown persistence on inanimate objects with This article is protected by copyright. All rights reserved. detectable infectivity for 5-10 days after exposure. 71 Fortunately, routine disinfectants can easily combat the colonization of this novel Coronavirus as well. 21 These are the measures which must be implemented at the grassroot level, and are the most rate limiting factors in the transmission of COVID-19. Standard WHO and CDC guidelines include hand hygiene, respiratory etiquette and facial hygiene. Other measures like social distancing, avoiding large gatherings, and disinfection have to be followed, as for community prevention. Hand hygiene involves frequent washing of hands for at least 20 seconds if soiled, usage of medical grade alcohol routinely, and avoiding shaking hands as a social gesture. 72 Respiratory etiquette involves covering one's mouth and nose while sneezing to maintain droplet precautions, followed by diligent hand hygiene, and avoiding touching the face unnecessarily. 73 The utility of protective masks has been a bone of contention and a topic of mass debate, as far as COVID-19 transmission is concerned. However, the current consensus states that even in a COVID-19 transmissible zone, for people not caring for an infected person directly, a mask offers no additional benefit, and may cause an economical and logistical burden. [74] [75] On an outpatient basis, HCWs in direct contact with infected or potentially infected individuals, a mask becomes necessary. However, a simple procedural mask with loops, or a surgical mask with ties is sufficient to prevent airborne transmission of SARS-Cov-2. Particulate masks such as N95 and N99 offer no seemingly additional benefit, as per the current consensus. 75 HCWs at This article is protected by copyright. All rights reserved. quarantine centres need Personal Protective Equipment (PPE) suits, as mandated by WHO. 76 Containment of non-emergent health services and elective surgeries has been recommended, in COVID-19 transmission area, even though no formal statement exists at the time. Management measures vary for the presenting symptomatology and history of travel, and can be divided by attending HCWs into the following groups: This article is protected by copyright. All rights reserved. tracing is of paramount importance in these individuals, from an epidemiological and pathological point of view. 77, 78, 80 3. Same guidelines as mentioned under Sl no 2. Patients who are asymptomatic but have tested positive via RT-PCR on consecutive nasopharyngeal swabs: Same guidelines as mentioned under Sl no 2. Patients who are symptomatic and have a history of travel and/ or contact or have tested positive: Clinical and laboratory testing is performed, as mentioned previously, and the patient is classified on the basis of severity and progression of the disease. Patients with a mild form of the disease are put on self-quarantine or home isolation, which may be revoked on full symptomatic recovery if testing facilities are scarce, and two negative nasopharyngeal swabs in addition to an afebrile state for over 72 hours. 77, 78, 81 Needless to say, all patient groups mentioned here must be given reassurance, proper guidance to allay their anxiety and fears. 79, 82 Patients who develop severe disease are admitted in a hospital setting for specific care. Extensive lung involvement, persistent dyspnea and/ or fever and non-resolution of mild disease, are few of the factors that mandate hospital admission for disease control, auxiliary, ancillary care and specific treatment. 83 This must not be confused with a hospital quarantine, which serves an additional epidemiological role. Severe viral pneumonia warrants high-flow oxygenation, and This article is protected by copyright. All rights reserved. Most of these drugs have in vitro evidence but lack sufficient clinical evidence. Of these, the highest levels of evidence are in favor of the following drugs: Tocilizumab -This disease-modifying anti-rheumatic drug (DMARD) targets the viral cytokine storm by selectively inhibiting IL-6. It has recently entered a Phase III trial. 86, 87 Sarelumab is another drug in the same class that is being repurposed for use in the ongoing pandemic. 88 Antimalarials -Hydroxychloroquine and chloroquine phosphate have shown antiviral effects by lysosomal inhibition, as monotherapy and combination therapy, in various in vitro studies and ongoing trials. The dosage of hydroxycholoroquine (HCQS) ranges from 400-800mg This article is protected by copyright. All rights reserved. in daily and weekly regimes. Combinations with macrolide antibiotic azithromycin have also been documented to have a therapeutic effect on COVID-19, albeit amongst concerns of the combination having the potential to cause QT interval prolongation. There are anecdotal reports of the utility of HCQS as a prophylactic agent, especially in HCWs. 89 This article is protected by copyright. All rights reserved. Patient with pneumonia and no signs of severe pneumonia. Child with nonsevere pneumonia has cough or difficulty breathing + fast breathing: fast breathing (in breaths/min) Adolescent or adult: fever or suspected respiratory infection, plus one of respiratory rate >30 breaths/min, severe respiratory distress, or SpO2 <90% on room air. Child with cough or difficulty in breathing, plus at least one of the following: central cyanosis or SpO2<90%. severe respiratory distress (e.g. grunting, very severe chest indrawing); signs of pneumonia with a general danger sign: inability to breastfeed or drink, lethargy or unconsciousness, or convulsions. Other signs of pneumonia may be present: chest indrawing, fast breathing (in breaths/min): This article is protected by copyright. All rights reserved. Characteristics of and Important Lessons from the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases from the Chinese Center for Disease Control and Prevention On the origin and continuing evolution of SARS-CoV-2. National Science Review Molecular evolution of the SARS coronavirus during the course of the SARS epidemic in China Coronaviruses: an overview of their replication and pathogenesis Coronaviruses: structure and genome expression This article is protected by copyright. All rights reserved Assembly of coronavirus spike protein into trimers and its role in epitope expression Coronavirus Pathogenesis and the Emerging Pathogen Severe Acute Respiratory Syndrome Coronavirus Coronavirus genome structure and replication Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia Clinical Characteristics of Coronavirus Disease 2019 in China This article is protected by copyright. All rights reserved SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1 Persistence of coronaviruses on inanimate surfaces and their inactivation with biocidal agents World Health Organization. Coronavirus disease (COVID-19) outbreak Global Surveillance for human infection with coronavirus disease (COVID-19) Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected: interim guidance. 2020. This article is protected by copyright Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan Review of the Clinical Characteristics of Coronavirus Disease 2019 (COVID-19) Clinical Characteristics of Coronavirus Disease 2019 in China Clinical features of patients infected with 2019 novel coronavirus in Wuhan Transmission of 2019-nCoV Infection from an Asymptomatic Contact inGermany This article is protected by copyright. All rights reserved Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Clinical and CT features in pediatric patients with COVID-19 infection: Different points from adults Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records Clinical analysis of 10 neonates born to mothers with 2019-nCoV pneumonia Second-Trimester Miscarriage in a Pregnant Woman With SARS-CoV-2 Infection COVID-19 can present with a rash and be mistaken for Dengue Cutaneous manifestations in COVID-19: a first perspective This article is protected by copyright. All rights reserved Classification of the cutaneous manifestations of COVID-19: a rapid prospective nationwide consensus study in Spain with 375 cases A case of COVID-19 presenting in clinical picture resembling chilblains disease. First report from the Middle East Cutaneous manifestations in COVID-19: a new contribution Vascular skin symptoms in COVID-19: a french observational study Acute limb ischemia in patients with COVID-This article is protected by copyright Clinical and coagulation characteristics of 7 patients with critical COVID-2019 pneumonia and acro-ischemia. Zhonghua Xue Ye Xue Za COVID-19) infection-induced chilblains: a case report with histopathological findings Clinical and histopathological study of skin dermatoses in patients affected by COVID-19 infection in the Northern part of Italy Dermatology staff participate in fight against Covid-19 in China Skin damage among healthcare workers managing coronavirus disease-2019 This article is protected by copyright. All rights reserved Letter from the Editor: Occupational skin disease among healthcare workers during the Coronavirus (COVID-19) epidemic Behavioral considerations and impact on personal protective equipment (PPE) use: Early lessons from the coronavirus (COVID-19) outbreak Consensus of Chinese Experts on Protection of Skin and Mucous Membrane Barrier for Healthcare Workers Fighting Against Coronavirus Disease Clinical Predictors of Mortality Due to COVID-19 Based on an Analysis of Data of 150 patients From Wuhan, China. Intensive Care Epidemiological and clinical features of the 2019 novel coronavirus outbreak in China Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile Dysregulation of immune response in patients with COVID-19 in Wuhan Pathological findings of COVID-19 associated with acute respiratory distress syndrome Pulmonary pathology of early phase 2019 novel coronavirus (COVID-19) pneumonia in two patients with lung cancer Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients Centers for Disease Control and Prevention. Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens from Persons Under Investigation (PUIs) for Coronavirus Disease Laboratory testing for coronavirus disease 2019 (COVID-19) in suspected human cases: interim guidance. 2020. No. WHO/COVID-19/laboratory/2020.4. World Health Organization False negative rate of COVID-19 is eliminated by using nasal swab test Serological assays for emerging coronaviruses: challenges and pitfalls Chest CT Findings in Cases from the Cruise Ship "Diamond Princess COVID-19) -events as they happen Updated WHO advice for international traffic in relation to the outbreak of the novel coronavirus 2019-nCoV. Who COVID-19) Academy Meeting cancellation and refund support. Aad.org COVID-19) -Preventing COVID-19 Spread in Co Inactivation of surrogate coronaviruses on hard surfaces by health care germicides Healthcare Settings | CDC. Cdc.gov Respiratory Hygiene/Cough Etiquette in Healthcare Settings | CDC Advice on the use of masks in the community, during home care and in healthcare settings in the context of the novel coronavirus (COVID-19) outbreak. Who during-home-care-and-in-healthcare-settings-in-the-context-of-the-novel-coronavirus-(2019-ncov)-outbreak Rational use of face masks in the COVID-19 pandemic Home care for patients with COVID-19 presenting with mild symptoms and management of their contacts COVID-19) Guidance for patients COVID-19 outbreak What further should be done to control COVID-19 outbreaks in addition to cases isolation and contact tracing measures? This article is protected by copyright. All rights reserved COVID-19) COVID-19) Recent advances in understanding and treating ARDS Search of: covid-19 -List Results -ClinicalTrials.gov. Clinicaltrials.gov Tocilizumab in COVID-19 Pneumonia (TOCIVID-19) -Full Text View -ClinicalTrials.gov. Clinicaltrials.gov Phase 3 Trial to Evaluate Tocilizumab for Severe COVID-19 Pneumonia Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review Chloroquine and hydroxychloroquine as available weapons to fight COVID-19 Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19 Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV T-705 (favipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections Japanese flu drug 'clearly effective' in treating coronavirus, says China". The Guardian This article is protected by copyright. All rights reserved Favipiravir shows good clinical efficacy in treating COVID-19: official Chinese Clinical Trial Register (ChiCTR) -The world health organization international clinical trials registered organization registered platform Safety and Immunogenicity Study of 2019-nCoV Vaccine (mRNA-1273) to prevent SARS-CoV-2 Infection -Full Text View -ClinicalTrials Table 1: The potential routes of transmission of Coronaviruses Aerosol/Droplet spread: Sneezing and coughing (within about 6 feet) Human-to human intimacy: Shaking hands, kissing and physical contact in any form Touching the nose, eyes, or mouth after making contact with a surface or object that has the viral load on it Animal-to-human Oro-fecal transmission: SARS-CoV-2 has been detected in the gastrointestinal ≥5 cmH2O, 7 or non-ventilated8 ) 100 mmHg < PaO2/FiO2 ≤200 mmHg with PEEP ≥5 cmH2O PaO2/FiO2 ≤ 100 mmHg with PEEP ≥5 cmH2O, 7 or non-ventilated8 ) • When PaO2 is not available, SpO2/FiO2 ≤315 suggests ARDS (including in non-ventilated patients) Oxygenation (children; note OI = Oxygenation Index and OSI = Oxygenation Index using SpO2 • Bilevel NIV or CPAP ≥5 cmH2O via full face mask: PaO2/FiO2 ≤ 300 mmHg or SpO2/FiO2 ≤264 4 ≤ OI < 8 or 5 ≤ OSI < Sepsis Adults: life-threatening organ dysfunction caused by a dysregulated host response to suspected or proven infection, with organ dysfunction*. Signs of organ dysfunction include: altered mental status, difficult or fast breathing, low oxygen saturation, reduced urine output, fast heart rate, weak pulse, cold extremities or low blood pressure, skin mottling, or laboratory evidence of coagulopathy, thrombocytopenia, acidosis, high lactate or hyperbilirubinemia. Children: suspected or proven infection and ≥2 SIRS criteria Septic Shock Adults: persisting hypotension despite volume resuscitation, requiring vasopressors to maintain MAP ≥65 mmHg and serum lactate level >2 mmol/L. Children (based on [ 12]): any hypotension (SBP 2 SD below normal for age) or 2-3 of the following: altered mental state; tachycardia or bradycardia (HR 160 bpm in infants and HR 150 bpm in children); prolonged capillary refill (>2 sec) or warm vasodilation with bounding pulses; tachypnea; mottled skin or petechial or purpuric rash OSI, Oxygenation Index using SpO2 SD, standard deviation; SIRS, systemic inflammatory response syndrome; SpO2, oxygen saturation. *If altitude is higher than 1000m, then correction factor should be calculated as follows: PaO2/FiO2 x Barometric pressure/760. * The SOFA score ranges from 0 to 24 and includes points related to 6 organ systems: respiratory (hypoxemia defined by low PaO2/FiO2), coagulation (low platelets)