Coronavirus COVID-19 (SARS-CoV-2)

Updated: March 27, 2020

MICROBIOLOGY

  • Coronaviruses are positive sense, single-strand enveloped RNA virus belonging to the family Coronaviridae.
  • Coronavirus name derived from the Latin corona, meaning crown. Viral envelope under electron microscopy appears crown-like due to small bulbar projections formed by the viral spike (S) peplomers.
  • This topic covers the novel coronavirus 2019 (2019-nCoV) now referred to as SARS-CoV-2.
  • For discussion of other coronaviruses, see:
    • Coronavirus for common human respiratory coronavirus infections.
    • SARS for the SARS-CoV virus, not known to circulate since 2002-2003.
    • MERS for the MERS-CoV virus, causing sporadic infections, mostly in the Arabian peninsula since 2012.
    • Coronaviruses also commonly infect birds and mammals causing gastroenteritis and respiratory infections.
  • SARS-CoV-2 appears to have been a zoonotic infection that has adapted to humans.
    • Origin is uncertain although bats and pangolins currently implicated.
    • Preliminary genetic analysis shows a great similarity to bat SARS-like coronavirus (genus Betacoronavirus, subgenus Sarbecovirus).

CLINICAL

  • COVID-19 is the disease, SARS-CoV-2 is the virus.
  • Epidemiology
    • On the upswing in many countries, cases outside of China now outnumber, including deaths.
      • COVID-19 cases reported in most countries performing testing and all continents except Antarctica. Declared a pandemic by the WHO.
    • Real-time global reports available through Coronavirus COVID-19 Global Cases Dashboard by Johns Hopkins CSSE
    • Older age, especially > 65 yrs and people with comorbidities appear more likely to develop an infection and severe symptoms and die.
      • Early data in the U.S. among hospitalized patients suggest that younger adults are hospitalized.
        • Adults 20-44 account for 20% of hospitalizations, 12% of ICU admissions.
    • Children appear less symptomatic with infection and less prone to severe illness.
  • Transmission
    • By respiratory droplets and by fomite. Virus found in respiratory secretions and saliva.
    • Stool shedding also described, but uncertain what role, if any, that plays.
  • Incubation period
    • Mean of 6.4 days, range 2-12. For people quarantined, 14d observation recommended to exclude infection, though 24d asymptomatic time from exposure described.
    • Viral shedding occurs following recovery, but unclear what role this plays in transmission.
    • Children and intrafamilial spread appear to be a growing means of transmission.
  • Symptoms
    • Fever (83-98%)
    • Cough (46-82%, usually dry)
    • Shortness of breath at onset (31%)
    • Myalgia or fatigue (11-44%)
    • Less common symptoms:
      • Pharyngitis
      • Headache
      • Productive cough
      • GI symptoms
        • Have been described as a presenting symptom
      • Hemoptysis
  • Disease spectrum
    • ~80% of infections are not severe and some may be asymptomatic.
    • Illnesses caused by the virus are primarily upper and lower respiratory tract infections.
    • For hospitalized patients with pneumonia, limited studies suggest the disease course (Wuhan experience):
      • ~50% develop hypoxemia by day 8
      • ARDS develops in 17-29%
      • Patients in the ICU require:
        • Non-invasive ventilation (42%)
        • Mechanical ventilation (47%)
        • High-flow O2 (11%)
        • ECMO (2-5%)
    • Critical Illness experience (Washington State)[7]
      • Small patient series (n = 21)
        • Age: 70 (mean)
        • Comorbidities: in 86%
        • Duration of symptoms: 3.5d (mean)
          • Admission to ICU within 24h of hospitalization: 81%
        • Nearly all had radiographic abnormalities at presentation.
          • Leukopenia: in 67%
        • Mechanical ventilation: in 71%
          • ARDS in 100% of those who required mechanical ventilation, most developed within 72h.
        • Most patients were not in shock, but 67% received vasopressors.
        • Cardiomyopathy: developed in 33%
          • Unclear if direct viral effect v. critical illness stress
        • Mortality: 67% (as of publication date)
  • Differential diagnosis
  • COVID-19 testing
    • With limited testing capacities in many locations, clinicians should use their judgment to determine if a patient has signs and symptoms compatible with COVID-19 and whether the patient should be tested.
    • Priority should be given for those groups below.
    • The most common symptoms include fever1 (subjective or confirmed), cough (usually dry), and shortness of breath.

Priorities for COVID-19 Testing

  1. Hospitalized patients who have signs and symptoms compatible with COVID-19 in order to inform decisions related to infection control.
  2. Chronic medical conditions. Other symptomatic individuals such as older adults and individuals with chronic medical conditions and/or an immunocompromised state that may put them at higher risk for poor outcomes (e.g., diabetes, heart disease, receiving immunosuppressive medications, chronic lung disease, chronic kidney disease).
  3. Close contacts. Any persons including healthcare personnel2 who within 14 days of symptom onset had close contact3 with a suspect or laboratory-confirmed4 COVID-19 patient, or who have a history of travel from affected geographic areas5 (see below) within 14 days of their symptom onset.

Source: U.S. Centers for Disease Control and Prevention. Evaluating and Testing Persons for Coronavirus Disease 2019 (COVID-19) Revised March 9, 2020.

1Fever may be subjective or confirmed

2For healthcare personnel, testing may be considered if there has been exposure to a person with suspected COVID-19 without laboratory confirmation. Because of their often extensive and close contact with vulnerable patients in healthcare settings, even mild signs and symptoms (e.g., sore throat) of COVID-19 should be evaluated among potentially exposed healthcare personnel. Additional information is available from CDC.[19]

3Close contact is defined as—

a) being within approximately 6 feet (2 meters) of a COVID-19 case for a prolonged period of time; close contact can occur while caring for, living with, visiting, or sharing a healthcare waiting area or room with a COVID-19 case

– or –

b) having direct contact with infectious secretions of a COVID-19 case (e.g., being coughed on)

If such contact occurs while not wearing recommended personal protective equipment or PPE (e.g., gowns, gloves, NIOSH-certified disposable N95 respirator, eye protection), criteria for PUI consideration are met.

Additional information is available from CDC.[17]

Data to inform the definition of close contact are limited. Considerations when assessing close contact include the duration of exposure (e.g., longer exposure time likely increases exposure risk) and the clinical symptoms of the person with COVID-19 (e.g., coughing likely increases exposure risk as does exposure to a severely ill patient). Special consideration should be given to healthcare personnel exposed in healthcare settings as described by CDC.[19]

4Documentation of laboratory-confirmation of COVID-19 may not be possible for travelers or persons caring for COVID-19 patients in other countries.

5Affected areas are defined as geographic regions where sustained community transmission has been identified. Relevant affected areas will be defined as a country with at least a CDC Level 2 Travel Health Notice. See all COVID-19 Travel Health Notices.

Other Diagnostic Testing

  • See the Prevention section for screening recommendations.
  • For those with COVID-19 pneumonia
    • Leukopenia in ~70% of hospitalized patients. LDH may be modestly elevated.
    • LFTs elevated more commonly than in typical Community-Acquired Pneumonia cases.
    • Chest CT may show ground-glass opacities that may evolve into consolidation or ARDS.
      • Findings appear to peak at 10d of illness, resolution begins after day 14.
      • CT may show lung findings (such as ground-glass opacities) before the development of symptoms.
    • Among hospitalized patients, about one-third need to be in the ICU/intubated with an ARDS picture.
  • Confirmatory tests, molecular (PCR)
    • Initially, all testing only done at CDC, but for U.S. local health departments and other approved labs able to test once assays validated, per FDA.
      • FDA has announced that they are letting labs and hospitals around the U.S. to conduct testing.
        • Availability of testing locally growing, but capacity remains limited.
        • Quest and LabCorp offer PCR testing (3-4d turnaround), specimens must be performed in a medical office/institution, not at a laboratory site.
    • Testing expanded for all people with respiratory symptoms and fever to be considered, significantly increasing the number of potentially tested patients.
      • Prior CDC Person Under Investigation (PUI) criteria that require close contact with a confirmed case, travel to Hubei province or travel to mainland China or country with a large number of cases (e.g., Iran, Italy).
      • As testing is limited, there are practical issues that are controversial:
        • Testing all who have RTI symptoms would be helpful to limit the spread and free people from concern if not infected, but there is not currently sufficient testing capacity.
        • Putting all patients with undiagnosed pneumonia in airborne isolation not likely possible given resource limitations.
  • Serological testing
    • Developing in the U.S.; since FDA has allowed by-pass of getting federal approval, more assays will likely be soon available including point-of-care testing.
    • The contribution of asymptomatic persons with SARS-CoV-2 to the transmission is not well characterized but will be much better understood when validated antibody testing available.
    • Early data from China using IgM and IgG SARS-CoV-2 specific antibodies that < 40% seropositive if illness less than 7d, rising to ~100% 15d or more after onset.
  • Viral culture
    • Not recommended
  • Currently commercially available respiratory multiplex molecular panels WILL NOT detect COVID-19.
  • Additional details and specimen procurement can be found on the CDC website.

Mortality

  • Note that early data are from China; there appears to be great variability among countries with Italy appearing higher than others.
  • The mortality rate from recent re-analysis of China experience [9th report, WHO Collaborating Center Imperial College, London, UK]
    • Wuhan case fatality rate: 1.38% (0.66% if asymptomatic cases are included)
    • The actual rate remains uncertain due to insufficient of serological testing.
  • The mortality rate is less than that commonly ascribed to severe community-acquired pneumonia (12-15%) but more than seasonal influenza (~0.1%), perhaps 6-10x.
  • Most deaths in patients with comorbidities and often elderly (> 60 considered a "risk factor"), although healthy younger patients also described.
COVID-19 Mortality by Age and Pre-Existing Condition*
COVID-19 Mortality by Age and Co-morbidity

Case fatality rate for COVID-19 based on age and pre-existing conditions.

*Case Fatality Rate (%) = (number of deaths / number of COVID-19 cases) x 100 for each group

Source: Worldometers.info. Accessed 14 March 2020.

  • Mortality rates in the US from early data (March 2020) compiled by the CDC:
Mortality rates for reported COVID–19 cases, by age group —United States

Age (yrs)

Mortality Rate

≥85

10–27%

65–84

3–11%

55-64

1–3%

20–54

< 1%

≤19

0%

Severe Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19) — United States, February 12–March 16, 2020. MMWR Morb Mortal Wkly Rep. ePub: 18 March 2020.[20]

SITES OF INFECTION

  • Pulmonary
    • Co-infection with other viruses described.
  • GI
    • Some patients have nausea, vomiting, or diarrhea.
    • The virus has been recovered from stool, but the significance is uncertain.

TREATMENT

General

  • Supportive care, including oxygen, mechanical ventilation if needed
  • Johns Hopkins Hospital Therapeutic Guidance (PDF document) is available with frequent updates for a more complete discussion of risks/benefits for using off-label medications for COVID.
  • If epidemic is widespread, public health officials may recommend those with minor symptoms to stay home and not seek care in health clinics or hospitals.
    • Limit medical care to those who are short of breath, have severe symptoms, or require oxygen and supportive care that is only available in a hospital.

Antivirals and immunomodulators

  • No proven efficacy of any drug for humans as of March 23, 2020.
    • Chinese Guidelines for COVID-19 suggest using chloroquine, traditional Chinese medicines, and for anti-IL6R drug tocilizumab as an anti-inflammatory in patients with extensive lung disease/severe illness and elevated IL-6 levels. These recommendations are not yet supported by robust clinical evidence.
    • Lopinavir / ritonavir (LPV/RTV) widely used in China; however, COVID RCT in hospitalized patients yielded no benefit[6].
  • A large number of antivirals and immunomodulators are being investigated for treatment or prophylaxis.
    • Caution is advised as to whether any are effective or safe for COVID-19.
      • If a clinical trial available, consider enrolling patients rather than prescribing off-label drug use to assist in understanding whether intervention is efficacious for COVID-19.
    • Types of drugs under investigation include antivirals (protease inhibitors, influenza drugs, nucleoside analogs) anti-inflammatories, surface protein antagonists such as lecithins.
    • Much like with influenza, antiviral drugs if effective, likely need to be started early in infection course, or used as a preventative.
  • Drugs currently under investigation[18]:
    • Remdesivir (Gilead; used to treat Ebola)
      • Currently under study in a trial in Wuhan and U.S.; activity is seen in vitro with SARS-2-CoV, MERS-CoV (also including MERS-CoV primate studies)
      • Likely the most promising drug
      • Drug has been used in the U.S. under compassionate use; however, unclear how long this will last
    • Chloroquine (or hydroxychloroquine; HCQ) has been reported to have some efficacy in vivo and in limited, very low-quality evidence for COVID-19 pneumonia, the mechanism may be by interfering with cellular acidification in the phagolysosome.[10],[11]
      • Gautret et al. suggest decreased SARS-CoV-2 shedding in 6 patients in a post-hoc analysis if HCQ is combined with azithromycin in non-RCT of 36 patients.[21] Small sample size and lack of clinical correlation mean clinicians ought to not base decisions on these limited results.
      • Chloroquine generally unavailable in the U.S., many reporting shortages of hydroxychloroquine.
    • ASC09/ritonavir, lopinavir/ritonavir, with or without umifenovir (not available in U.S.)
      • Negative Clinical trial using LPV/RTV in hospitalized patients with COVID-19[6]
    • ASC09/oseltamivir, ritonavir/oseltamivir, oseltamivir
    • Azvudine
    • Baloxavir marboxil/favipiravir and LPV/RTV in combination(s)
    • Favipiravir (aka T-705, Avigan, or favilavir)
    • Zinc
    • Indomethacin
    • Camostat mesylate
    • Darunavir/cobicistat alone or with lopinavir/ritonavir and thymosin α1 in combination(s)
    • Interferon alfa-2b alone or in combination with LPV/RTV and ribavirin
    • Methylprednisolone
    • Camrelizumab and thymosin
    • Tocilizumab and other IL-6 inhibitors
    • Convalescent sera (from recovered COVID-19 patients)
    • Monoclonal antibodies, specific to SARS-CoV-2

Prevention

  • No vaccine is currently available.
    • Multiple candidate vaccines are in development.
  • As a newly described virus, much remains to be learned.
    • Travel restrictions, quarantines, school closings, mass social distancing of uncertain long-term benefits with this viral infection and remain a source of considerable debate about effectiveness and costs among public health officials and politicians.[3]
    • Difficulty sorting other causes of respiratory illness from the novel coronavirus, especially during influenza season.
  • Healthcare workers and health systems in the U.S.
    • Recommend following CDC Guidance for Risk Assessment and Public Health Management of SARS-CoV-2 (2019-nCoV).[19]
    • Likely that standard contact and respiratory droplet precautions are sufficient (as with SARS, MERS) which is the WHO recommendation; however, some debate using negative pressure rooms for extra safety but then this may divert from known needs such as TB or measles.
      • Current CDC recommendations are for aerosol (e.g., use of negative pressure isolation), but if resources strained, then pivot to droplet and standard precautions.
  • General measures recommended:
    • Avoid sick individuals.
    • Wash hands with soap and water x 20 seconds before eating, after cough/sneezing or bathroom visits.
    • Don’t touch the face, eyes, etc.
    • Stay home if ill.
    • Cover your sneeze.
    • Disinfect frequently touched household objects.
    • Current CDC recommendations do not suggest using a facemask for protection.

FOLLOW UP

  • Early Wuhan experience suggested a case fatality rate as high as 4.3%, but likely 2% elsewhere in China.
    • Preliminary evidence suggests two strains of SARS-2-CoV circulating: one associated with milder illness (~30%), the other with severe illness (70%).
  • Case fatality rates in other countries (as of March 2020) appear lower, but are higher in elderly, sick populations (e.g., Evergreen Health, Seattle, WA; Northern Italy).
  • Preliminary evidence in humans and SARS-CoV-2 infected rhesus macaques suggest that reinfection does not occur.

OTHER INFORMATION

  • Recommendations to consider testing for all respiratory symptomatic patients will be limited by the availability of SARS-CoV-2 testing.
  • Severe illness is likely to strike the same populations at high risk for complications of seasonal influenza (e.g., elderly, immunosuppressed, and with comorbidities).
  • The case fatality rate is probably higher than seasonal influenza (≤0.1%) but lower than initially reported (~ 2-4%).
    • Current estimates suggest COVID-19 is ~6-10x worse than seasonal influenza but has a steep age gradient.
    • Serological testing of larger populations will give a clearer picture of infectious impact.

See also

References

  1. Al-Tawfiq JA, Al-Homoud AH, Memish ZA. Remdesivir as a possible therapeutic option for the COVID-19. Travel Med Infect Dis. 2020.  [PMID:32145386]

    Comment: This parenteral agent appears to be the most promising agent from in vitro and animal data (from MERS-CoV). We await RCT information from China, hopefully, available in April 2020.

  2. Colson P, Rolain JM, Lagier JC, et al. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int J Antimicrob Agents. 2020.  [PMID:32145363]

    Comment: Raoult knows these drugs well from Q fever and Whipple’s disease studies. Caution though is that preliminary in vitro data rarely translates into effectiveness in human infection, hence a plea to only trial drugs within an RCT. How this drug may work is alkalinizing the phagolysosome within cells and may have had some effectiveness in SARS. Early study in China of the in vitro activity of chloroquine against SARS-CoV-2, discovered during culture tests on Vero E6 cells with 50% and 90% effective concentrations (EC50 and EC90 values) of 1.13 μM and 6.90 μM, respectively (antiviral activity being observed when addition of this drug was carried out before or after viral infection of the cells)

  3. Chinazzi M, Davis JT, Ajelli M, et al. The effect of travel restrictions on the spread of the 2019 novel coronavirus (COVID-19) outbreak. Science. 2020.  [PMID:32144116]

    Comment: Although extraordinary measures may have slowed or stopped COVID-19 in China, questions remain whether this is durable and at what cost to society? It may buy time but effective drugs or vaccines remain in the far future it seems. Authors suggest "the travel quarantine of Wuhan delayed the overall epidemic progression by only 3 to 5 days in Mainland China, but has a more marked effect at the international scale, where case importations were reduced by nearly 80% until mid-February. Modeling results also indicate that sustained 90% travel restrictions to and from Mainland China only modestly affect the epidemic trajectory unless combined with a 50% or higher reduction of transmission in the community."

  4. Mizumoto K, Chowell G. Estimating Risk for Death from 2019 Novel Coronavirus Disease, China, January-February 2020. Emerg Infect Dis. 2020;26(6).  [PMID:32168464]

    Comment: An early report and these typically have higher rates of infection due to concentrated, very ill patients than later in epidemics. Authors estimate of the risk for death in Wuhan reached values as high as 12% in the epicenter of the epidemic and ≈1% in other, more mildly affected areas. The elevated death risk estimates are probably associated with a breakdown of the healthcare system.

  5. Liu W, Zhang Q, Chen J, et al. Detection of Covid-19 in Children in Early January 2020 in Wuhan, China. N Engl J Med. 2020.  [PMID:32163697]

    Comment: A retrospective look at 366 children hospitalized for respiratory illness. SARS-CoV-2 detected only in 6 (1.6) of patients. Only 1 of the COVID children required ICU care. Of the COVID patients, fever and cough were common and four had pneumonia.

  6. Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020.  [PMID:32187464]

    Comment: This trial did not yield benefits when given in hospitalized patients with c19. Whether the drug would work if administered earlier is unclear, but has low in vitro activity against this virus compared to HIV.

  7. Arentz M, Yim E, Klaff L, et al. Characteristics and Outcomes of 21 Critically Ill Patients With COVID-19 in Washington State. JAMA. 2020.  [PMID:32191259]

    Comment: Most notable finding is the high rate of cardiac complications that is unclear whether directly viral or related to critical illness. As this is a small series, further reports are needed to confirm.

  8. Zhu N, Zhang D, Wang W, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020.  [PMID:31978945]

    Comment: An early report includes electron microscopy photomicrographs as well as sequence analysis of what is now termed COVID-19 disease and SARS-2-CoV virus.

  9. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020.  [PMID:32015507]

    Comment: Authors have sequenced what is now termed SARS-2-CoV. Its genome 79.5% sequence identify to SARS-CoV. Furthermore, it was found that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus.

  10. Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020.  [PMID:32074550]

    Comment: An early report that suggests the antimalarial chloroquine has shown efficacy against COVID-19 infection in Chinese trials. Of note, this drug has been tried for CHKV and others without good virological effect.

  11. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020.  [PMID:32020029]

    Comment: Summary of earlier in vitro studies suggesting drugs that may work against COVID-19. Remdesivir is currently under investigation in the Wuhan epidemic. This drug has also shown activity in a rhesus macque module of MERS-CoV.

  12. Bajema KL, Oster AM, McGovern OL, et al. Persons Evaluated for 2019 Novel Coronavirus - United States, January 2020. MMWR Morb Mortal Wkly Rep. 2020;69(6):166-170.  [PMID:32053579]

    Comment: People evaluated as per this report in the US mostly were those with a history of travel/contacts from Wuhan City, China which is the apparent epicenter of this epidemic. Of 210 people, 148 (70%) had travel-related risk only, 42 (20%) had close contact with an ill laboratory-confirmed 2019-nCoV patient or PUI, and 18 (9%) had both travel- and contact-related risks. Eleven of these persons had a laboratory-confirmed 2019-nCoV infection. Given reports now around the globe, it is unclear if testing only those with potential links to China is prudent, but the current availability of test kits from the CDC likely precludes wider testing until either FDA-approved or EUA approval is given to current commercially available respiratory panels to include COVID-19.

  13. Benvenuto D, Giovanetti M, Salemi M, et al. The global spread of 2019-nCoV: a molecular evolutionary analysis. Pathog Glob Health. 2020.  [PMID:32048560]

    Comment: Strain analysis to date of COVID-19 suggests that they are very similar to bat SAR-like coronavirus.

  14. Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020.  [PMID:32031570]

    Comment: One of the initial major reports of the Wuhan COVID-19 epidemic. In this series, the median age was 56 and slightly more men (54%) affected. Predominant symptoms include fever, fatigue and dry cough. Leukopenia was seen in ~70%. Thirty-six patients (26.1%) were transferred to the intensive care unit (ICU) because of complications, including acute respiratory distress syndrome (22 [61.1%]), arrhythmia (16 [44.4%]), and shock (11 [30.6%]).

  15. Ai T, Yang Z, Hou H, et al. Correlation of Chest CT and RT-PCR Testing in Coronavirus Disease 2019 (COVID-19) in China: A Report of 1014 Cases. Radiology. 2020.  [PMID:32101510]

    Comment: Chest CT shows early ground-glass infiltrates which may offer speedier "diagnosis" than PCR studies in an epidemic setting as a first finding if molecular assays not readily available.

  16. Kam KQ, Yung CF, Cui L, et al. A Well Infant with Coronavirus Disease 2019 (COVID-19) with High Viral Load. Clin Infect Dis. 2020.  [PMID:32112082]

    Comment: No surprise, here an infant sheds high levels of the virus but is without symptoms. Children are well known "vectors" of viral infection often without significant disease is well known for regular coronavirus infections, influenza and others.

  17. Interim Infection Prevention and Control Recommendations for Patients with Confirmed Coronavirus Disease 2019 (COVID-19) or Persons Under Investigation for COVID-19 in Healthcare Settings. U.S. Centers for Disease Control and Prevention. [https://www.cdc.gov…]
  18. Harrison, C. Coronavirus puts drug repurposing on the fast track. Nature Feb 27, 2020 (https://www.nature.com/articles/d41587-020-00003-1 , accessed 3/3/20)

    Comment: A look at the clinicaltrials.gov and Chinese clinical trial web sites that have registered trials.

  19. Interim U.S. Guidance for Risk Assessment and Public Health Management of Healthcare Personnel with Potential Exposure in a Healthcare Setting to Patients with Coronavirus Disease 2019 (COVID-19). U.S. Centers for Disease Control and Prevention. [https://www.cdc.gov…
  20. Severe Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19) — United States, February 12–March 16, 2020. MMWR Morb Mortal Wkly Rep. ePub: 18 March 2020. [http://dx.doi.org…]
  21. Gautret et al. Hydroxychloroquine and azithromycin as a treatment of COVID‐19: results of an open‐label non‐randomized clinical trial. International Journal of Antimicrobial Agents (In Press). 17 March 2020. [https://www.doi.org…]

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