Coronavirus Disease 2019 (COVID-19)

William M. Detmer, MD, supported by the Unbound Medicine Team

Updated: November 16, 2020

What’s New Here

Coronavirus 2019-20 Outbreak Overview

Coronaviruses (CoV)

A large family of viruses that cause a variety of illness:

  • Common cold
  • Middle East Respiratory Syndrome (MERS-CoV)
  • Severe Acute Respiratory Syndrome (SARS-CoV)

Novel Coronavirus (SARS-CoV-2; 2019-nCoV) History

  • In late 2019, a new coronavirus – not seen previously in humans – was identified as the cause of human illness in China and given the name 2019-nCoV.
  • By late January 2020, outbreak declared a public health emergency of international concern by WHO and US Centers for Disease Control and Prevention (CDC).[1],[2]
  • Categorized as a pandemic by WHO in March 2020.[3]

Epidemiology

  • Spread by human-to-human transmission via respiratory droplets or fomites.
  • Median incubation period from exposure to symptoms onset is 4–5 days.
  • One study reported that 97.5% of persons with COVID-19 who develop symptoms will do so within 11.5 days of SARS-CoV-2 infection.[4]

Case Definition and Patient Under Investigation (PUI)

  • COVID-19 name given by WHO to the disease caused by the SARS-CoV-2 (2019-nCoV) virus.
  • See Case Definitions for WHO Surveillance Case Definition and CDC Patient Under Investigation (PUI) Clinical Criteria for COVID-19.
  • If a PUI for COVID-19 is identified, notify your health department immediately. See Reporting COVID-19 in the United States for details.
  • A detailed travel history is recommended for all patients being evaluated with fever and acute respiratory illness.

Drug Treatment

Overview

  • Care is primarily supportive (see Supportive Therapy below)
  • FDA-approved therapies
    • Remdesivir [October 22, 2020] -- see below for details
  • Additional therapies recommended by NIH Guidelines Panel
    • Dexamethasone
  • Therapies NOT recommended except in a clinical trial
    • Hydroxychloroquine and chloroquine
    • Lopinavir/ritonavir and Ivermectin
    • Anti-IL-6 receptor monoclonal antibodies (e.g., sarilumab, tocilizumab) or anti-IL-6 monoclonal antibody (siltuximab)
    • Interferons
    • Bruton’s tyrosine kinase inhibitors (e.g., acalabrutinib, ibrutinib, zanubrutinib)
    • Janus kinase inhibitors (e.g., baricitinib, ruxolitinib, tofacitinib)
  • Many other treatments are being investigated in clinical trials

General recommendations

  • The NIH COVID-19 Treatment Guidelines Panel recommends the following strategies for managing patients with different severities of disease.[5]
  • Details on each therapeutic agent can be found below this section.
Pharmacologic Management of Patients with COVID-19
Drug Treatment of Patient with COVID-19

Recommendations are based on COVID-19 disease severity.

Recommendation Rating Scheme

Strength of Recommendation

Quality of Evidence for Recommendation

  1. Strong recommendation for the statement
  2. Moderate recommendation for the statement
  3. Optional recommendation for the statement

  1. One or more randomized trials with clinical outcomes and/or validated laboratory endpoints
  2. One or more well-designed, nonrandomized trials or observational cohort studies
  3. Expert opinion

Remdesivir (Gilead)

News

  • On October 22, 2020 the U.S. FDA:
    • Approved remdesivir (Veklury®) for adults and pediatric patients (12 years and older and weighing at least 40 kg) for the treatment of COVID-19 requiring hospitalization. Under its approval, Veklury should only be administered in a hospital or in a healthcare setting capable of providing acute care comparable to inpatient hospital care.[6]
    • Authorized continued emergency use to treat suspected or laboratory-confirmed COVID-19 in hospitalized pediatric patients weighing 3.5 kg to less than 40 kg or hospitalized pediatric patients less than 12 years of age weighing at least 3.5 kg.

Box 1: Remdesivir for COVID-19
NIH COVID-19 Treatment Guidelines Panel Recommendations[5]

For Hospitalized Adult and Pediatric Patients (Aged ≥12 Years and Weighing ≥40 kg)

  • For Patients Who Are Not Mechanically Ventilated and/or on ECMO:
    • Remdesivir 200 mg IV over 30–120 minutes on Day 1, followed by remdesivir 100 mg IV on Day 2 through Day 5 (AI)
    • In patients who have not shown clinical improvement after 5 days of therapy, treatment may be extended up to 10 days.
  • For Mechanically Ventilated Patients and/or Patients on ECMO:
    • Remdesivir 200 mg IV over 30–120 minutes on Day 1, followed by remdesivir 100 mg IV on Day 2 through Day 10 (AIII)

Suggested Dose in EUAa for Hospitalized Pediatric Patients Weighing 3.5 kg to < 40 kg or Aged < 12 Years and Weighing ≥3.5 kg

  • For Patients Weighing 3.5 kg to < 40 kg:
    • Remdesivir 5 mg/kg IV over 30–120 minutes on Day 1, followed by remdesivir 2.5 mg/kg once daily starting on Day 2
    • For patients who are not mechanically ventilated and/or on ECMO, the recommended treatment duration is 5 days. If patients have not shown clinical improvement after 5 days of therapy, treatment may be extended up to 10 days.
    • For mechanically ventilated patients and/or patients on ECMO, the recommended treatment duration is 10 days.
  • For Patients Aged < 12 Years and Weighing ≥40 kg:
    • Same dose as for adults and children aged >12 years and weighing >40 kg

Not Recommended

  • If eGFR is < 30 mL/min
  • May need to be discontinued if ALT levels increase to >10 times the upper limit of normal and should be discontinued if there is an increase in ALT level and signs or symptoms of liver inflammation are observed.

aThe FDA EUA permits the emergency use of RDV for the treatment of suspected COVID-19 or laboratory-confirmed SARS-CoV-2 infection in hospitalized pediatric patients weighing 3.5 kg to < 40 kg or aged < 12 years and weighing ≥3.5 kg.

ALT = alanine transaminase; ECMO = extracorporeal membrane oxygenation; eGFR = estimated glomerular filtration rate; EUA = Emergency Use Authorization; FDA = Food and Drug Administration;

Remdesivir Research Studies

  • Broad antiviral activity including against SARS-CoV-2 in vitro.[7]
  • Preliminary results of an NIH-sponsored clinical trial (ACTT; NCT04280705) published in NEJM showed remdesivir accelerated recovery from advanced COVID-19.[8]

Remdesivir

Placebo

Significance

Median Time to Recovery (Days)

11

15

p< 0.001

Mortality

8.0%

11.6%

p=0.059

†Preliminary Results from Adaptive COVID-19 Treatment Trial (ACTT).[8]
  • NEJM study in patients with severe COVID-19 not requiring mechanical ventilation did not show a significant difference between a 5-day and 10-day course of remdesivir. With no placebo control, the magnitude of benefit of treatment could not be determined.[9]
  • The Lancet reported on a RCT (ClinicalTrials.gov NCT04257656) at ten hospitals in Hubei, China. Remdesivir was not associated with statistically significant clinical benefits, although some authors have concluded that the study was underpowered to detect a statistical difference.
  • NEJM study of compassionate-use remdesivir in severe COVID-19 showed clinical improvement in 36 of 53 patients (68%). However, no conclusion about true efficacy could be made from this small and non-controlled study.[10]
  • Many additional clinical trials are underway.

Dexamethasone (Corticosteroids)

Box 2: Dexamethasone for COVID-19

NIH COVID-19 Treatment Guidelines Panel[5]

  • Recommends using dexamethasone (at a dose of 6 mg per day for up to 10 days) in patients with COVID-19 who are mechanically ventilated (AI) and in patients with COVID-19 who require supplemental oxygen but who are not mechanically ventilated (BI).
  • Recommends against using dexamethasone in patients with COVID-19 who do not require supplemental oxygen (AI).
  • If dexamethasone is not available, the Panel recommends using alternative glucocorticoids such as prednisone, methylprednisolone, or hydrocortisone (AIII).

Additional Considerations

  • Whether use of other corticosteroids (e.g., prednisone, methylprednisolone, hydrocortisone) for the treatment of COVID-19 provides the same benefit as dexamethasone is unclear. The total daily dose equivalencies to dexamethasone 6 mg (oral or intravenous [IV]) for these drugs are:
    • Prednisone 40 mg
    • Methylprednisolone 32 mg
    • Hydrocortisone 160 mg
  • Half-life, duration of action, and frequency of administration vary among corticosteroids.
    • Long-Acting Corticosteroid: Dexamethasone; half-life: 36 to 72 hours, administer once daily.
    • Intermediate-Acting Corticosteroids: Prednisone and methylprednisolone; half-life: 12 to 36 hours, administer once daily or in two divided doses daily.
    • Short-Acting Corticosteroid: Hydrocortisone; half-life: 8 to 12 hours, administer in two to four divided doses daily.
  • Hydrocortisone is commonly used to manage septic shock in patients with COVID-19; please refer to the Critical Care section for more information. Unlike other corticosteroids previously studied in ARDS, dexamethasone lacks mineralocorticoid activity and thus has minimal effect on sodium balance and fluid volume.

Dexamethasone Research Studies

  • Preliminary results from the UK RECOVERY trial published in NEJM showed Dexamethasone 6 mg once daily, taken orally or by injection for 10 days reduced the 28 day mortality rate by 17% (0.83 (0.74 to 0.92); P=0.0007) with the greatest benefit among patients needing ventilation (see table below).
Table 3: Dexamethasone Effect on 28-Day Mortality†

Respiratory Support
at Randomization

Dexamethasone

% mortality

Usual Care

% mortality

Rate Ratio
(95% CI)

Invasive mechanical ventilation

29.3

41.4

0.64 (0.51 to 0.81)

Oxygen only

23.3

26.2

0.82 (0.72 to 0.94)

No oxygen received

17.8

14.0

1.19 (0.91 to 1.55)

†Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report.[11]

CI = Confidence Interval

Blood-Derived Products

Box 3: Blood-Derived Products in COVID-19

NIH COVID-19 Treatment Guidelines Panel[5]

  • Insufficient data to recommend either for or against the use of the following blood-derived products for the treatment of COVID-19:
    • COVID-19 convalescent plasma
    • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulins
  • Recommends against the use of the following blood-derived products for the treatment of COVID-19, except in a clinical trial:
    • Mesenchymal stem cells (AII)
    • Non-SARS-CoV-2-specific intravenous immunoglobulin (IVIG) (AIII). This recommendation should not preclude the use of IVIG when it is otherwise indicated for the treatment of complications that arise during the course of COVID-19.

Convalescent Plasma Research Studies

  • PNAS: In an uncontrolled case series of 10 adult patients with severe COVID-19 who were given one dose of convalescent plasma with the neutralizing antibody titers above 1:640, clinical symptoms significantly improved with an increase of oxyhemoglobin saturation within 3 d, accompanied by rapid neutralization of viremia.[12]
  • JAMA: In an uncontrolled case series of 5 critically ill patients with COVID-19 and ARDS, administration of convalescent plasma containing neutralizing antibody was followed by improvement in clinical status.[13]
  • U.S. FDA has provided guidance for the use of COVID-19 convalescent plasma under an Emergency Investigational New Drug Application
  • Other Convalescent Plasma Clinical Trials are underway.

Hydroxychloroquine (HCQ) and Chloroquine (CQ)

Box 4: Hydroxychloroquine / Chloroquine in COVID-19

NIH COVID-19 Treatment Guidelines Panel[5]

  • Recommends against the use of chloroquine or hydroxychloroquine with or without azithromycin in hospitalized or nonhospitalized patients (AI).
  • Recommends against the use of high-dose chloroquine (600 mg twice daily for 10 days) for the treatment of COVID-19 (AI).

Hydroxychloroquine Research Studies

  • Inhibits growth of SARS-CoV-2 in vitro,[14] but no clinical trials have demonstrated conclusively their effectiveness in humans.
  • ⇒ NEJM article reported that HCQ, alone or with azithromycin, did not improve clinical status in patients hospitalized with mild-moderate COVID-19 at 15 days as compared with standard care.[15]
  • ⇒ Annals of Internal Medicine reported on randomized trial of of 491 patients where HCQ given to nonhosptialized adults with early COVID-19 did not substantially reduce symptom severity or improve outcomes
  • UK RECOVERY trial: HCQ treatment arm stopped after preliminary analysis showed HCQ did not reduce mortality or improve other outcomes in hospitalized COVID-19 patients.[16]
  • NEJM reported a randomized trial showing HCQ did not prevent COVID-19 infection when used as postexposure prophylaxis within 4 days after exposure.[17]
  • Observational study published in JAMA showed amongst 1,438 hospitalized COVID-19 patients those receiving hydroxychloroquine, azithromycin, or both had no significant differences in mortality.[18]
  • Observational study published in NEJM showed HCQ not associated with either a greatly lowered or an increased risk of the composite end point of intubation or death.[19]
  • An increasing number of studies have reported clinically significant QT Interval prolongation from CQ/HCQ +/- azithromycin[18], with some authors cautioning "first, do no harm."[20]

Other Antiviral Drugs

Box 5: Other Antiviral Drugs in COVID-19

NIH COVID-19 Treatment Guidelines Panel[5]

  • Recommends against using the following drugs to treat COVID-19 except in a clinical trial:
    • Lopinavir/ritonavir (AI) or other HIV protease inhibitors (AIII) to treat COVID-19.
    • Ivermectin for the treatment of COVID-19, except in a clinical trial (AIII).

Lopinavir-ritonavir (AbbVie; Kaletra, Aluvia)

  • Showed "no benefit" in hospitalized adult patients with severe COVID-19 according to a study published in the New England of Journal of Medicine.[21]
  • Many other trials are underway, see Lopinavir-Ritonavir Clinical Trials.

Other Immunomodulators

Box 6: Other Immunomodulators in COVID-19

NIH COVID-19 Treatment Guidelines Panel[5]

  • There are insufficient data for the Panel to recommend either for or against the use of the following immunomodulators for the treatment of COVID-19:
    • Interleukin-1 inhibitors (e.g., anakinra)
    • Interferon-beta for the treatment of early (i.e., < 7 days from symptom onset) mild and moderate COVID-19.
  • Recommends against the use of the following immunomodulators for the treatment of COVID-19, except in a clinical trial:
    • Anti-IL-6 receptor monoclonal antibodies (e.g., sarilumab, tocilizumab) or anti-IL-6 monoclonal antibody (siltuximab) (BI).
    • Interferons (alfa or beta) for the treatment of severely or critically ill patients with COVID-19 (AIII).
    • Bruton’s tyrosine kinase inhibitors (e.g., acalabrutinib, ibrutinib, zanubrutinib) and Janus kinase inhibitors (e.g., baricitinib, ruxolitinib, tofacitinib) (AIII).

Tocilizumab (Genentech; Actemra) Research Studies

Supportive therapy and monitoring

Mild to Moderate Disease

  • Patients with a mild clinical presentation (absence of viral pneumonia and hypoxia) can often manage their illness at home.
  • Outpatient or inpatient monitoring may be required, depending on:
    • Clinical presentation, need for supportive care, risk factors for severe disease, and the ability to self-isolate at home.
    • Risk factors for severe illness: these patients should be monitored closely given the possible risk of progression to severe illness in the second week after symptom onset.

Severe Disease

  • Inpatient management of COVID-19 is supportive and focused on the mmanagement of complications (see below). For details see NEJM review of treatment of severe COVID-19.[22]
Complications of Severe COVID-19

  • Pneumonia
  • Acute Respiratory Distress Syndrome (ARDS)
  • Sepsis and septic shock
  • Cardiomyopathy and arrhythmia
  • Acute kidney injury
  • Complications from prolonged hospitalization
    • Nosocomial infection
    • Thromboembolism
    • Gastrointestinal bleeding
    • Critical illness polyneuropathy/myopathy

Preparedness Checklist

Front-line healthcare personnel in the United States should be prepared to evaluate patients for coronavirus disease 2019 (COVID-19). The following checklist from the CDC highlights key steps for healthcare personnel in preparation for transport and arrival of patients with confirmed or possible COVID-19.[23]

  • Stay up to date on the latest information about signs and symptoms, diagnostic testing, and case definitions for coronavirus disease 2019
  • Review your infection prevention and control policies and CDC infection control recommendations for COVID-19 for:
    • Assessment and triage of patients with acute respiratory symptoms
    • Patient placement
    • Implementation of Standard, Contact, and Airborne Precautions, including the use of eye protection
    • Visitor management and exclusion
    • Source control measures for patients (e.g., put face mask on suspect patients)
    • Requirements for performing aerosol generating procedures
  • Be alert for patients who meet the persons under investigation (PUI) definition
  • Know how to report a potential COVID-19 case or exposure to facility infection control leads and public health officials
  • Know who, when, and how to seek evaluation by occupational health following an unprotected exposure (i.e., not wearing recommended PPE) to a suspected or confirmed coronavirus disease 2019 patient
  • Remain at home, and notify occupational health services, if you are ill
  • Know how to contact and receive information from your state or local public health agency (See Reporting COVID-19 in the United States)

Case Definitions

World Health Organization

Objectives of global surveillance

  1. Monitor trends in COVID-19 disease at national and global levels.
  2. Rapidly detect new cases in countries where the virus is not circulating, and monitor cases in countries where the virus has started to circulate.
  3. Provide epidemiological information to conduct risk assessments at the national, regional and global level.
  4. Provide epidemiological information to guide preparedness and response measures.

Surveillance Case Definitions for COVID-19

  • Case and contact definitions are based on the current available information and are regularly revised as new information accumulates.
  • Countries may need to adapt case definitions depending on their local epidemiological situation and other factors.
  • All countries are encouraged to publish definitions used online and in regular situation reports, and to document periodic updates to definitions which may affect the interpretation of surveillance data.

WHO Surveillance Case Definitions for COVID-19†

Suspected Case

The case definitions are based on the current information available and will be revised as new information accumulates. Countries may need to adapt case definitions depending on their own epidemiological situation.

  1. Patient with acute respiratory illness (fever and at least one sign/symptom of respiratory disease (e.g., cough, shortness of breath), AND a history of travel to or residence in a location reporting community transmission of COVID-19 disease during the 14 days prior to symptom onset;
    OR
  2. Patient with any acute respiratory illness AND having been in contact with a confirmed or probable COVID-19 case (see below for definition of contact) in the last 14 days prior to symptom onset;
    OR
  3. A patient with severe acute respiratory illness (fever and at least one sign/symptom of respiratory disease, e.g., cough, shortness of breath; AND requiring hospitalization) AND in the absence of an alternative diagnosis that fully explains the clinical presentation.

Probable case

  1. A suspect case for whom testing for COVID-19 is inconclusive.1
    OR
  2. A suspect case for whom testing could not be performed for any reason.

Confirmed case

  • A person with laboratory confirmation of COVID-19 infection[24], irrespective of clinical signs and symptoms.

*Definition of contact

A contact is a person who experienced any one of the following exposures during the 2 days before and the 14 days after the onset of symptoms of a probable or confirmed case:

  1. Face-to-face contact with a probable or confirmed case within 1 meter and for more than 15 minutes;
    OR
  2. Direct physical contact with a probable or confirmed case;
    OR
  3. Direct care for a patient with probable or confirmed COVID-19 disease without using proper personal protective equipment;2
    OR
  4. Other situations as indicated by local risk assessments.
Note: for confirmed asymptomatic cases, the period of contact is measured as the 2 days before through the 14 days after the date on which the sample was taken which led to confirmation.

†Source: Global surveillance for COVID-19 caused by human infection with COVID-19 virus. World Health Organization. Revised 20 March 2020.[25]

1 Inconclusive being the result of the test reported by the laboratory.
2 World Health Organization. Infection prevention and control during health care when COVID-19 is suspected.

Classification of transmission scenarios

  • WHO recommends using the following categories to describe transmission patterns at national and sub-national levels (wherever possible) to guide decisions for preparedness, readiness and response activities.
Definition of the categories for transmission pattern

Category number

Category name

Definition

1

No cases

Countries/territories/areas with no cases

2

Sporadic cases

Countries/territories/areas with one or more cases, imported or locally detected

3

Clusters of cases

Countries/territories/areas experiencing cases, clustered in time, geographic locationand/or by common exposures

4

Community transmission

Countries/area/territories experiencing larger outbreaks of local transmission defined through an assessment of factors including, but not limited to: - Large numbers of cases not linkable to transmission chains - Large numbers of cases from sentinel lab surveillance - Multiple unrelated clusters in several areas of the country/territory/area

Recommendations for laboratory testing

Any suspected case should be tested for COVID-19 infection using available molecular tests.[24] However, depending on the intensity of the transmission, the number of cases and the laboratory capacity, only a subset of the suspect cases may prioritized for testing.

During community transmission WHO recommends prioritizing persons to be tested as indicated in the WHO global testing strategy for COVID-19.

To monitor the full extent of the circulation of the virus in the general population, WHO recommends implementing testing for COVID-19 via existing national sentinel surveillance sites for influenza-like illness (ILI) and severe acute respiratory infection (SARI). Guidance will be made available here:

U.S. Centers for Disease Control

  • For any patient meeting criteria for evaluation for COVID-19, clinicians are encouraged to contact and collaborate with their state or local health department. See Reporting COVID-19 in the United States.
  • For patients that are severely ill, evaluation for COVID-19 may be considered even if a known source of exposure has not been identified.

COVID-19 testing

  • 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. Asymptomatic infection with SARS-CoV-2 has been reported.
  • The most common symptoms include fever (subjective or confirmed) and/or symptoms of acute respiratory illness (e.g., cough, difficulty breathing) but some people may present with other symptoms.
  • Other considerations that may guide testing are epidemiologic factors such as:
    • Occurrence of local community transmission of COVID-19 infections in a jurisdiction
    • Known exposure to an individual who has tested positive for SARS-CoV-2
    • Occurrence of local community transmission or transmission within a specific setting/facility (e.g., nursing homes) of COVID-19.
  • Another population in which to prioritize testing of minimally symptomatic and even asymptomatic persons are long-term care facility residents, especially in facilities where one or more other residents have been diagnosed with symptomatic or asymptomatic COVID-19.
  • Clinicians are strongly encouraged to test for other causes of respiratory illness, for example influenza, in addition to testing for SARS-CoV-2.
Priorities for COVID-10 Testing (Nucleic Acid or Antigen)†

High Priority

  • Hospitalized patients with symptoms
  • Healthcare facility workers, workers in congregate living settings, and first responders with symptoms
  • Residents in long-term care facilities or other congregate living settings, including prisons and shelters, with symptoms

Priority

  • Persons with symptoms of potential COVID-19 infection, including: fever, cough, shortness of breath, chills, muscle pain, new loss of taste or smell, vomiting or diarrhea, and/or sore throat.
  • Persons without symptoms who are prioritized by health departments or clinicians, for any reason, including but not limited to: public health monitoring, sentinel surveillance, or screening of other asymptomatic individuals according to state and local plans.

†Source: U.S. Centers for Disease Control and Prevention. Evaluating and Testing Persons for Coronavirus Disease 2019 (COVID-19) Revised May 3, 2020.

Recommendations for Reporting, Testing, and Specimen Collection

Infection Control

  • On March 19th, WHO issued guidance on infection prevention and control strategies for healthcare workers (HCW) when COVID-19 is suspected.
  • See [26] for full details and references.
  • Infection prevention and control (IPC) strategies to prevent or limit transmission in health care settings include the following:
    1. Ensuring triage, early recognition, and source control (isolating patients with suspected COVID-19);
    2. Applying standard precautions for all patients;
    3. Implementing empiric additional precautions (droplet and contact and, whenever applicable, airborne precautions) for suspected cases of COVID-19;
    4. Implementing administrative controls;
    5. Using environmental and engineering controls.

Contact and droplet precautions

  • In addition to using standard precautions, all individuals, including family members, visitors and HCWs, should use contact and droplet precautions before entering the room of suspected or confirmed COVID-19 patients.

Treatment areas

  • Patients should be placed in adequately ventilated single rooms. For general ward rooms with natural ventilation, adequate ventilation is considered to be 60 L/s per patient.
  • When single rooms are not available, patients suspected of having COVID-19 should be grouped together.
  • All patients’ beds should be placed at least 1 metre apart regardless of whether they are suspected to have COVID-19.
  • Where possible, a team of HCWs should be designated to care exclusively for suspected or confirmed cases to reduce the risk of transmission.

Healthcare Worker (HCW) Protection

  • HCWs should:
    • Wear a medical mask.
    • Wear eye protection (goggles) or facial protection (face shield) to avoid contamination of mucous membranes.
    • Wear a clean, non-sterile, long-sleeved gown.
    • Use gloves.
    • Boots, coverall, and apron is not required during routine care.
    • Carry out hand hygiene and appropriate doffing and disposal of all Personal Protective Equipment (PPE) after care of each patient.
    • Refrain from touching eyes, nose, or mouth with potentially contaminated gloved or bare hands.
    • Use new set of PPE when care is given to a different patient.

Healthcare setting

  • Equipment should be either single-use and disposable or dedicated equipment (e.g., stethoscopes, blood pressure cuffs and thermometers).
  • If equipment needs to be shared among patients, clean and disinfect it between use for each individual patient (e.g., by using ethyl alcohol 70%).
  • Avoid moving and transporting patients out of their room or area unless medically necessary.
  • Use designated portable X-ray equipment or other designated diagnostic equipment. If transport is required, use predetermined transport routes to minimize exposure for staff, other patients and visitors, and have the patient wear a medical mask.
  • Ensure that HCWs who are transporting patients perform hand hygiene and wear appropriate PPE as described in this section.
  • Notify the area receiving the patient of any necessary precautions as early as possible before the patient’s arrival.
  • Routinely clean and disinfect surfaces with which the patient is in contact.
  • Limit the number of HCWs, family members, and visitors who are in contact with suspected or confirmed COVID-19 patients.
  • Maintain a record of all persons entering a patient’s room, including all staff and visitors.

Airborne precautions for aerosol-generating procedures

  • Some aerosol-generating procedures, such as tracheal intubation, non-invasive ventilation, tracheotomy, cardiopulmonary resuscitation, manual ventilation before intubation, and bronchoscopy, have been associated with an increased risk of transmission of coronaviruses.
  • Ensure that HCWs performing aerosol-generating procedures:
    • Perform procedures in an adequately ventilated room – that is, natural ventilation with air flow of at least 160 L/s per patient or in negative- pressure rooms with at least 12 air changes per hour and controlled direction of air flow when using mechanical ventilation.
    • Use a particulate respirator at least as protective as a US National Institute for Occupational Safety and Health (NIOSH)-certified N95, European Union (EU) standard FFP2, or equivalent.
    • When HCWs put on a disposable particulate respirator, they must always perform the seal check.Note that facial hair (e.g. a beard) may prevent a proper respirator fit.
    • Use eye protection (i.e., goggles or a face shield).
    • Wear a clean, non-sterile, long-sleeved gown and gloves. If gowns are not fluid-resistant, HCWs should use a waterproof apron for procedures expected to create high volumes of fluid that might penetrate the gown.
    • Limit the number of persons present in the room to the absolute minimum required for the patient’s care and support.

Clinical Course

  • For abbreviations used below see Glossary of Coronavirus terms.
  • Syndromes range from mild upper respiratory infection to severe pneumonia, ARDS and death.
  • All age groups are susceptible to the virus, but elderly patients with comorbidities are more likely to experience severe illness.

Risk Factors

  • Major risk factors for severe illness and mortality from COVID-19:
    • Age
    • Comorbidities: heart disease, hypertension, prior stroke, diabetes, chronic lung disease, and chronic kidney disease have all been associated with increased illness severity and adverse outcomes.
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%

†Source: 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.[27]
Mortality rates for reported COVID–19 cases, by comorbidities—China†

Comorbidities

Mortality Rate

Cardiovascular disease

10.5%

Diabetes

7.3%

Chronic respiratory disease

6.3%

Hypertension

6.3%

Cancer

5.6%

None

0.9%

†Source: The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China.[28]

Mortality associated with COVID-19 in the United States has been reported to be similar to China.[27]

Symptoms

Symptoms of Coronavirus COVID-19†

Common Symptoms

  • Fever (83–98%)
  • Non-productive cough (59–82%)
  • Fatigue (44–70%)
  • Anorexia (40–84%)
  • Shortness of breath (31–41%)
  • Sputum production (28–33%)
  • Myalgia (11–35%)

Less common (< 10%)

  • Sore throat
  • Diarrhea
  • Dizziness
  • Headache
  • Other GI symptoms

†Sources: Guan WJ,[29] Chen N,[30] Wang D et al. [31]
  • Anosmia or ageusia preceeding the onset of respiratory symptoms has been reported anecdotally, but more information is needed to understand its role in identifying COVID-19.

Asymptomatic and Pre-Symptomatic Infection

  • Several studies have documented SARS-CoV-2 infection in patients who never develop symptoms (asymptomatic) and in patients not yet symptomatic (pre-symptomatic).[32],[33],[34],[35],[36]
  • Since asymptomatic persons are not routinely tested, the prevalence of asymptomatic infection and detection of pre-symptomatic infection is not well understood.
  • One study found that as many as 13% of RT-PCR-confirmed cases of SARS-CoV-2 infection in children were asymptomatic.[32]
  • Patients may have abnormalities on chest imaging before the onset of symptoms.[37],[35]
  • Although transmission of SARS-CoV-2 from asymptomatic or pre-symptomatic persons has been reported, risk of transmission is thought to be greatest when patients are symptomatic.
  • Viral RNA shedding, measured indirectly by RT-PCR cycle threshold values, is greatest at the time of symptom onset and declines over the course of several days to weeks.[38],[39]
  • The exact degree of SARS-CoV-2 viral RNA shedding that confers risk of transmission is not yet clear.

Disease Severity

In 44,600 COVID-19 cases from China, disease severity was classified as:[40]

  • Mild to moderate (mild symptoms up to mild pneumonia): 81%
  • Severe (dyspnea, hypoxia, or >50% lung involvement on imaging): 14%
  • Critical (respiratory failure, shock, or multiorgan system dysfunction): 5%
    • Case fatality rate was 49% among patients in this group and 2.3% overall.

Among 2,143 pediatric patients studied in China[32]

  • 94% had asymptomatic, mild or moderate disease
  • 5% had severe disease
  • < 1% had critical disease
  • Only one (< 0.1%) death was reported in a person under 18 years old.

Among U.S. COVID-19 cases with known disposition[27]

  • Hospitalized: 19%
  • Admitted to the intensive care unit (ICU): 6%

Clinical Progression

  • Among patients who developed severe disease, the mean duration to develop the following conditions: [41][42]
    • Dyspnea: 5–8 days
    • Acute respiratory distress syndrome (ARDS): 8–12 days
    • ICU admission: 10–12 days.
    • Some patients can rapidly deteriorate one week after illness onset.
  • Mortality among patients admitted to the ICU: 39%–72%
  • Median length of hospitalization among survivors: 10–13 days

Reinfection

  • There are no current data concerning reinfection with SARS-CoV-2 after recovery from COVID-19.
  • Viral RNA shedding declines with resolution of symptoms, and may continue for days to weeks.[39] However, the detection of RNA during convalescence does not necessarily indicate the presence of viable infectious virus.
  • Clinical recovery has been correlated with the detection of IgM and IgG antibodies which signal the development of immunity.[43],[44]

COVID-19 Diagnostic Tests

Samples to be collected

  • Respiratory material
    • Nasopharyngeal and oropharyngeal (URT) swab in ambulatory patients and sputum (if produced) and/or endotracheal aspirate or bronchoalveolar lavage (LRT) in patients with more severe respiratory disease.
    • Send for SARS-CoV-2 testing by reverse transcription polymerase chain reaction (RT-PCR).
    • In hospitalized patients with confirmed SARS-CoV-2 infection
      • Repeat URT and LRT samples should be collected to demonstrate viral clearance.
      • Frequency of specimen collection will depend on local circumstances but should be at least every 2 to 4 days until there are two consecutive negative results (both URT and LRT samples if both are collected) in a clinically recovered patient at least 24 hours apart.
      • If local infection control practice requires two negative results before removal of droplet precautions, specimens may be collected as often as daily. [45]
  • Serum for serological testing, acute sample and convalescent sample (this is additional to respiratory materials and can support the identification of the true agent, once serologic assay is available). Serology for diagnostic purposes is recommended only when RT-PCR is not available.[45]
  • Blood cultures for bacteria that cause pneumonia and sepsis, when indicated, ideally before antimicrobial therapy.

Interpretation

  • Detection of SARS-CoV-2 RNA by RT-PCR
    • Diagnostic for COVID-19
    • Detection better in nasopharynx compared to throat samples and lower compared to upper respiratory samples
    • Detection in blood may be a marker of severe illness
    • A single negative RT-PCR result, particularly if this is from an upper respiratory specimen, does not exclude infection. Repeat sampling and testing or lower respiratory tract specimen is strongly recommended in severe or progressive disease.
  • Viral RNA shedding
    • 7–12 days in moderate cases
    • My be longer for older persons and those who had severe illness requiring hospitalization (12–20 days).
  • Serology
    • U.S. FDA issued Emergency Use Authorization (EUA) for the first serologic test for SARS-CoV-2 immunoglobulins (Cellex; qSARS-CoV-2 IgG/IgM Rapid Test) on April 1[46] and additional serologic test have received EUA status.[47]
    • Serology among 173 patients in an early study from China:[48]
      • Median seroconversion time for Total Antibody (Ab), IgM and then IgG were day-11, day-12 and day-14 from symptom onset.
      • Presence of antibodies was < 40% among patients within 1-week from symptom onset, and rapidly increased to 100.0% (Ab), 94.3% (IgM) and 79.8% (IgG) at day-15 after onset.
      • A higher titer of Ab was independently associated with a worse clinical classification (p=0.006).
Diagnostic Test Sensitivity in the Days After Symptom Onset†

Days after Symptom Onset

SARS-CoV-2 Test

1–7

8–14

15–39

RNA by RT-PCR

67%

54%

45%

Total Antibody

38%

90%

100%

IgM

29%

73%

94%

IgG

19%

54%

80%

Adapted from: Zhao J et al. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019. Clin Infect Dis. 2020 Mar 28.[48]

Laboratory Findings

  • Most common: lymphopenia (83% of hospitalized patients).[29]
  • Associated with greater illness severity: [29][42][49][50]
    • Lymphopenia, neutrophilia
    • ↑ serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH)
    • ↑ C-reactive protein (CRP), ferritin.
  • Associated with greater mortality: ↑ D-dimer and lymphopenia.[29][42][50]

Radiographic Findings

  • Chest X-ray (CXR)
    • Bilateral air-space consolidation
    • May be unremarkable early in the disease
  • Chest CT
    • Bilateral, peripheral ground glass opacities – a non-specific pattern seen in other infections
  • Role of radiologic imaging in COVID-19 diagnosis
    • Because radiologic findings are non-specific, the American College of Radiology does not recommend CXR or CT for screening or as a first-line test for diagnosis of COVID-19.[51]

Discontinuation of Precautions or Isolation

Recommendations on discontinuation of Transmission-Based Precautions or home isolation for patients who have recovered from COVID-19 (all from CDC):

See Also

For health professionals

For the Public

References

  1. Statement on the second meeting of the International Health Regulations (2005) Emergency Committee regarding the outbreak of novel coronavirus (2019-nCoV). World Health Organization. 30 January 2020. [https://www.who.int/news-room/detail/30-01-2020-statement-on-the-second-me...]
  2. Determination that a Public Health Emergency Exists. US Department of Health and Human Services. 31 January 2020. [https://www.phe.gov/emergency/news/healthactions/phe/Pages/2019-nCoV.aspx]
  3. WHO Director-General’s opening remarks at the media briefing on COVID-19. World Health Organization. 11 March 2020. [https://www.who.int/dg/speeches/detail/who-director-general-s-opening-rema...]
  4. Lauer SA, Grantz KH, Bi Q, et al. The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application. Ann Intern Med. 2020.  [PMID:32150748]
  5. COVID-19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. National Institutes of Health. Available at https://www.covid19treatmentguidelines.nih.gov/. Updated: November 3, 2020
  6. FDA-Approved Drugs: Remdesivir. Drugs@FDA. Accessed October 22, 2020. [https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm...]
  7. Choy KT, Yin-Lam Wong A, Kaewpreedee P, et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antiviral Res. 2020.  [PMID:32251767]
  8. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 - Preliminary Report. N Engl J Med. 2020.  [PMID:32445440]
  9. Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 Days in Patients with Severe Covid-19. N Engl J Med. 2020.  [PMID:32459919]
  10. Grein J, Ohmagari N, Shin D, et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. N Engl J Med. 2020.  [PMID:32275812]
  11. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report. N Engl J Med. 2020.  [PMID:32678530]
  12. Duan K, Liu B, Li C, et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. Proc Natl Acad Sci U S A. 2020;117(17):9490-9496.  [PMID:32253318]
  13. Shen C, Wang Z, Zhao F, et al. Treatment of 5 Critically Ill Patients With COVID-19 With Convalescent Plasma. JAMA. 2020.  [PMID:32219428]
  14. Yao X, Ye F, Zhang M, et al. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020.  [PMID:32150618]
  15. Cavalcanti AB et al. Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19. N Engl J Med. July 23, 2020 DOI: 10.1056/NEJMoa2019014
  16. Skipper CP, Pastick KA, Engen NW, et al. Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19: A Randomized Trial. Ann Intern Med. 2020.  [PMID:32673060]
  17. Boulware DR, Pullen MF, Bangdiwala AS, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med. 2020.  [PMID:32492293]
  18. Mercuro NJ, Yen CF, Shim DJ, et al. Risk of QT Interval Prolongation Associated With Use of Hydroxychloroquine With or Without Concomitant Azithromycin Among Hospitalized Patients Testing Positive for Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. 2020.  [PMID:32356863]
  19. Geleris J, Sun Y, Platt J, et al. Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19. N Engl J Med. 2020.  [PMID:32379955]
  20. DeJong C, Wachter RM. The Risks of Prescribing Hydroxychloroquine for Treatment of COVID-19-First, Do No Harm. JAMA Intern Med. 2020.  [PMID:32347894]
  21. 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]
  22. Berlin DA, Gulick RM, Martinez FJ. Severe Covid-19. N Engl J Med. 2020.  [PMID:32412710]
  23. Healthcare Professional Preparedness Checklist For Transport and Arrival of Patients With Confirmed or Possible COVID-19. US Centers for Disease Control and Prevention. Accessed 26 February 2020. [https://www.cdc.gov/coronavirus/2019-ncov/hcp/hcp-personnel-checklist.html]
  24. Laboratory testing for 2019 novel coronavirus (2019-nCoV) in suspected human cases. World Health Organization. Updated 17 January 2020. [https://www.who.int/publications-detail/laboratory-testing-for-2019-novel-coronavirus-in-suspected-human-cases-20200117]
  25. Global Surveillance for human infection with coronavirus disease (COVID-19). World Health Organization. Updated 20 March 2020. [https://www.who.int/publications-detail/global-surveillance-for-human-infection-with-novel-coronavirus-(2019-ncov)]
  26. Infection prevention and control during health care when COVID-19 is suspected. World Health Organization. 19 March 2020. [https://www.who.int/publications-detail/infection-prevention-and-control-d...]
  27. CDC COVID-19 Response Team. Severe Outcomes Among Patients with Coronavirus Disease 2019 (COVID-19) - United States, February 12-March 16, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(12):343-346.  [PMID:32214079]
  28. Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. [The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China]. Zhonghua Liu Xing Bing Xue Za Zhi. 2020;41(2):145-151.  [PMID:32064853]
  29. Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020.  [PMID:32109013]
  30. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507-513.  [PMID:32007143]
  31. 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]
  32. Dong Y, Mo X, Hu Y, et al. Epidemiological Characteristics of 2143 Pediatric Patients With 2019 Coronavirus Disease in China. Pediatrics. 2020.  [PMID:32179660]
  33. Lu X, Zhang L, Du H, et al. SARS-CoV-2 Infection in Children. N Engl J Med. 2020.  [PMID:32187458]
  34. Chan JF, Yuan S, Kok KH, et al. A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster. Lancet. 2020.  [PMID:31986261]
  35. Wang Y, Liu Y, Liu L, Wang X, Luo N, Ling L. Clinical outcome of 55 asymptomatic cases at the time of hospital admission infected with SARS-Coronavirus-2 in Shenzhen, China. The Journal of infectious diseases. 2020.
  36. Pan X, Chen D, Xia Y, et al. Asymptomatic cases in a family cluster with SARS-CoV-2 infection. The Lancet Infectious diseases. 2020.
  37. Hu Z, Song C, Xu C, et al. Clinical characteristics of 24 asymptomatic infections with COVID-19 screened among close contacts in Nanjing, China. Sci China Life Sci. 2020.  [PMID:32146694]
  38. Young BE, Ong SWX, Kalimuddin S, et al. Epidemiologic Features and Clinical Course of Patients Infected With SARS-CoV-2 in Singapore. JAMA. 2020.  [PMID:32125362]
  39. Zou L, Ruan F, Huang M, et al. SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients. N Engl J Med. 2020;382(12):1177-1179.  [PMID:32074444]
  40. Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020.  [PMID:32091533]
  41. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020.  [PMID:32105632]
  42. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-1062.  [PMID:32171076]
  43. To KK, Tsang OT, Leung WS, et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infect Dis. 2020.  [PMID:32213337]
  44. Zhang W, Du RH, Li B, et al. Molecular and serological investigation of 2019-nCoV infected patients: implication of multiple shedding routes. Emerg Microbes Infect. 2020;9(1):386-389.  [PMID:32065057]
  45. Laboratory testing for Middle East Respiratory Syndrome Coronavirus: Interim guidance. World Health Organization. 2018 [https://www.who.int/csr/disease/coronavirus_infections/mers-laboratory-tes...].
  46. qSARS-CoV-2 IgG/IgM Rapid Test Letter of Authorization. U.S. Food and Drug Administration. [https://www.fda.gov/media/136622/download]
  47. EUA Authorized Serology Test Performance. U.S. Food & Drug Administration(FDA). [https://www.fda.gov/medical-devices/emergency-situations-medical-devices/e...]
  48. Zhao J, Yuan Q, Wang H, et al. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019. Clin Infect Dis. 2020.  [PMID:32221519]
  49. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020.  [PMID:31986264]
  50. Wu C, Chen X, Cai Y, et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020.  [PMID:32167524]
  51. ACR Recommendations for the use of Chest Radiography and Computed Tomography (CT) for Suspected COVID-19 Infection. Updated March 22. [https://www.acr.org/Advocacy-and-Economics/ACR-Position-Statements/Recomme...]
  52. A Multicenter, Adaptive, Randomized Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for the Treatment of COVID-19 in Hospitalized Adults. ClinicalTrials.gov NCT04280705. [https://clinicaltrials.gov/ct2/show/NCT04280705]
  53. ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012;307(23):2526-33.  [PMID:22797452]
  54. About new coronavirus infectious disease confirmed in cruise ship during quarantine in Yokohama Port, Japan Ministry of Health, Labor and Welfare. 27 February 2020. [https://www.mhlw.go.jp/stf/newpage_09783.html]
  55. Advice on the use of masks in the community, during home care and in health care settings in the context of the novel coronavirus (2019-nCoV) outbreak. World Health Organization. Updated 28 January 2020
  56. 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]
  57. Alhazzani W, Møller MH, Arabi YM, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med. 2020;46(5):854-887.  [PMID:32222812]
  58. Alshahrani MS, Sindi A, Alshamsi F, et al. Extracorporeal membrane oxygenation for severe Middle East respiratory syndrome coronavirus. Ann Intensive Care. 2018;8(1):3.  [PMID:29330690]
  59. Alzghari SK, Acuña VS. Supportive Treatment with Tocilizumab for COVID-19: A Systematic Review. J Clin Virol. 2020;127:104380.  [PMID:32353761]
  60. Arabi YM, Mandourah Y, Al-Hameed F, et al. Corticosteroid Therapy for Critically Ill Patients with Middle East Respiratory Syndrome. Am J Respir Crit Care Med. 2018;197(6):757-767.  [PMID:29161116]
  61. Arabi YM, Arifi AA, Balkhy HH, et al. Clinical course and outcomes of critically ill patients with Middle East respiratory syndrome coronavirus infection. Ann Intern Med. 2014;160(6):389-97.  [PMID:24474051]
  62. 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]
  63. Backer JA, Klinkenberg D, Wallinga J. Incubation period of 2019 novel coronavirus (2019-nCoV) infections among travellers from Wuhan, China, 20-28 January 2020. Euro Surveill. 2020;25(5).  [PMID:32046819]
  64. Bai HX, Hsieh B, Xiong Z, et al. Performance of radiologists in differentiating COVID-19 from viral pneumonia on chest CT. Radiology. 2020.  [PMID:32155105]
  65. Bai Y, Yao L, Wei T, et al. Presumed Asymptomatic Carrier Transmission of COVID-19. JAMA. 2020.  [PMID:32083643]
  66. Bernheim A, Mei X, Huang M, et al. Chest CT Findings in Coronavirus Disease-19 (COVID-19): Relationship to Duration of Infection. Radiology. 2020.  [PMID:32077789]
  67. Bourouiba L. Turbulent Gas Clouds and Respiratory Pathogen Emissions: Potential Implications for Reducing Transmission of COVID-19. JAMA. 2020.  [PMID:32215590]
  68. Briel M, Meade M, Mercat A, et al. Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and meta-analysis. JAMA. 2010;303(9):865-73.  [PMID:20197533]
  69. Brouwer PJM, Caniels TG, van der Straten K, et al. Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability. Science. 2020.  [PMID:32540902]
  70. Cai J, Xu J, Lin D, et al. A Case Series of children with 2019 novel coronavirus infection: clinical and epidemiological features. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2020.
  71. Chandrashekar A, Liu J, Martinot AJ, et al. SARS-CoV-2 infection protects against rechallenge in rhesus macaques. Science. 2020.  [PMID:32434946]
  72. Chen H, Guo J, Wang C, et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records. Lancet. 2020;395(10226):809-815.  [PMID:32151335]
  73. Chen W, Lan Y, Yuan X, et al. Detectable 2019-nCoV viral RNA in blood is a strong indicator for the further clinical severity. Emerg Microbes Infect. 2020;9(1):469-473.  [PMID:32102625]
  74. Chen YT, Shao SC, Hsu CK, et al. Incidence of acute kidney injury in COVID-19 infection: a systematic review and meta-analysis. Crit Care. 2020;24(1):346.  [PMID:32546191]
  75. Cheng HY, Jian SW, Liu DP, et al. Contact Tracing Assessment of COVID-19 Transmission Dynamics in Taiwan and Risk at Different Exposure Periods Before and After Symptom Onset. JAMA Intern Med. 2020.  [PMID:32356867]
  76. Chia PY, Coleman KK, Tan YK, et al. Detection of air and surface contamination by SARS-CoV-2 in hospital rooms of infected patients. Nat Commun. 2020;11(1):2800.  [PMID:32472043]
  77. Chu DK, Akl EA, Duda S, et al. Physical distancing, face masks, and eye protection to prevent person-to-person transmission of SARS-CoV-2 and COVID-19: a systematic review and meta-analysis. Lancet. 2020.  [PMID:32497510]
  78. Clinical management of severe acute respiratory infection when novel coronavirus (nCoV) infection is suspected. World Health Organization. Updated 28 January 2020. [https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected]
  79. Combes A, Hajage D, Capellier G, et al. Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome. N Engl J Med. 2018;378(21):1965-1975.  [PMID:29791822]
  80. Combes A, Brodie D, Bartlett R, et al. Position paper for the organization of extracorporeal membrane oxygenation programs for acute respiratory failure in adult patients. Am J Respir Crit Care Med. 2014;190(5):488-96.  [PMID:25062496]
  81. Corman VM, Albarrak AM, Omrani AS, et al. Viral Shedding and Antibody Response in 37 Patients With Middle East Respiratory Syndrome Coronavirus Infection. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2016;62(4):477-483.
  82. Coronavirus (COVID-19) Update: FDA Continues to Facilitate Development of Treatments [News]. March 19, 2020. [https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-u...]
  83. Coronavirus Disease 2019 (COVID-19) Situation Reports. World Health Organization. [https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-...]
  84. Coronavirus Disease 2019 (COVID-19) in the U.S. Centers for Disease Control and Prevention. [https://www.cdc.gov/coronavirus/2019-ncov/cases-in-us.html]
  85. Coronavirus disease (COVID-19) technical guidance: Laboratory testing for 2019-nCoV in humans. World Health Organization. Accessed February 29, 2020. [https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-...]
  86. Criteria to Guide Evaluation of PUI for COVID-19. US Centers for Disease Control and Prevention. Revised February 27, 2020. [https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-criteria.html]
  87. Dashraath P, Wong JLJ, Lim MXK, et al. Coronavirus disease 2019 (COVID-19) pandemic and pregnancy. Am J Obstet Gynecol. 2020;222(6):521-531.  [PMID:32217113]
  88. Davis AL, Carcillo JA, Aneja RK, et al. American College of Critical Care Medicine Clinical Practice Parameters for Hemodynamic Support of Pediatric and Neonatal Septic Shock. Crit Care Med. 2017;45(6):1061-1093.  [PMID:28509730]
  89. Delaney JW, Pinto R, Long J, et al. The influence of corticosteroid treatment on the outcome of influenza A(H1N1pdm09)-related critical illness. Crit Care. 2016;20:75.  [PMID:27036638]
  90. Detsky ME, Jivraj N, Adhikari NK, et al. Will This Patient Be Difficult to Intubate?: The Rational Clinical Examination Systematic Review. JAMA. 2019;321(5):493-503.  [PMID:30721300]
  91. Ding Q, Lu P, Fan Y, Xia Y, Liu M. The clinical characteristics of pneumonia patients co-infected with 2019 novel coronavirus and influenza virus in Wuhan, China. Journal of medical virology. 2020.
  92. Docherty AB, Harrison EM, Green CA, et al. Features of 20 133 UK patients in hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: prospective observational cohort study. BMJ. 2020;369:m1985.  [PMID:32444460]
  93. Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis. 2020.  [PMID:32087114]
  94. Fan E, Del Sorbo L, Goligher EC, et al. An Official American Thoracic Society/European Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice Guideline: Mechanical Ventilation in Adult Patients with Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. 2017;195(9):1253-1263.  [PMID:28459336]
  95. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020.  [PMID:32171062]
  96. Flaxman S, Mishra S, Gandy A, et al. Estimating the effects of non-pharmaceutical interventions on COVID-19 in Europe. Nature. 2020.  [PMID:32512579]
  97. Fosbøl EL, Butt JH, Østergaard L, et al. Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use With COVID-19 Diagnosis and Mortality. JAMA. 2020.  [PMID:32558877]
  98. Ganyani T, Kremer C, Chen D, et al. Estimating the generation interval for coronavirus disease (COVID-19) based on symptom onset data, March 2020. Euro Surveill. 2020;25(17).  [PMID:32372755]
  99. 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]
  100. Gao Q, Bao L, Mao H, et al. Rapid development of an inactivated vaccine candidate for SARS-CoV-2. Science. 2020.  [PMID:32376603]
  101. Garg S, Kim L, Whitaker M, et al. Hospitalization Rates and Characteristics of Patients Hospitalized with Laboratory-Confirmed Coronavirus Disease 2019 - COVID-NET, 14 States, March 1-30, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(15):458-464.  [PMID:32298251]
  102. Goldsmith CS, Tatti KM, Ksiazek TG, et al. Ultrastructural characterization of SARS coronavirus. Emerg Infect Dis. 2004;10(2):320-6.  [PMID:15030705]
  103. Goligher EC, Tomlinson G, Hajage D, et al. Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome and Posterior Probability of Mortality Benefit in a Post Hoc Bayesian Analysis of a Randomized Clinical Trial. JAMA. 2018;320(21):2251-2259.  [PMID:30347031]
  104. Grasselli G, Zangrillo A, Zanella A, et al. Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy. JAMA. 2020.  [PMID:32250385]
  105. Guérin C, Reignier J, Richard JC, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013;368(23):2159-68.  [PMID:23688302]
  106. Hager DN, Krishnan JA, Hayden DL, et al. Tidal volume reduction in patients with acute lung injury when plateau pressures are not high. Am J Respir Crit Care Med. 2005;172(10):1241-5.  [PMID:16081547]
  107. Harrison C. Coronavirus puts drug repurposing on the fast track [News]. Nature Biotechnology. February 27, 2020. [https://www.nature.com/articles/d41587-020-00003-1]
  108. He X, Lau EHY, Wu P, et al. Temporal dynamics in viral shedding and transmissibility of COVID-19. Nat Med. 2020;26(5):672-675.  [PMID:32296168]
  109. Helms J, Kremer S, Merdji H, et al. Neurologic Features in Severe SARS-CoV-2 Infection. N Engl J Med. 2020;382(23):2268-2270.  [PMID:32294339]
  110. Hendren NS, Drazner MH, Bozkurt B, et al. Description and Proposed Management of the Acute COVID-19 Cardiovascular Syndrome. Circulation. 2020;141(23):1903-1914.  [PMID:32297796]
  111. Hoehl S, Rabenau H, Berger A, et al. Evidence of SARS-CoV-2 Infection in Returning Travelers from Wuhan, China. N Engl J Med. 2020;382(13):1278-1280.  [PMID:32069388]
  112. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181(2):271-280.e8.  [PMID:32142651]
  113. Holshue ML, DeBolt C, Lindquist S, et al. First Case of 2019 Novel Coronavirus in the United States. N Engl J Med. 2020.  [PMID:32004427]
  114. Horby P, Lim WS, Emberson J, Mafham M, Bell J, et al. Effect of dexamethasone in hospitalized patients with COVID-19: preliminary report. medRxiv. Published online June 22, 2020. :24
  115. Hung IF, Lung KC, Tso EY, et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet. 2020.  [PMID:32401715]
  116. Interim Guidance for Coronavirus Disease 2019 (COVID-19) for Event Planners. US Centers for Disease Control. March 15, 2020. [https://www.cdc.gov/coronavirus/2019-ncov/community/large-events/mass-gath...]
  117. Interim Infection Prevention and Control Recommendations for Patients with Confirmed 2019 Novel Coronavirus (2019-nCoV) or Persons Under Investigation for 2019-nCoV in Healthcare Settings. US Centers for Disease Control and Prevention (CDC). Updated February 3, 2020. [https://www.cdc.gov/coronavirus/2019-ncov/hcp/infection-control.html]
  118. Interpretation of Epidemic (Epi) Curves during Ongoing Outbreak Investigations. US Centers for Disease Control and Prevention. [https://www.cdc.gov/foodsafety/outbreaks/investigating-outbreaks/epi-curves.html]
  119. Jüni P, Rothenbühler M, Bobos P, et al. Impact of climate and public health interventions on the COVID-19 pandemic: A prospective cohort study. CMAJ. 2020.  [PMID:32385067]
  120. Kam KQ, Yung CF, Cui L, et al. A Well Infant with Coronavirus Disease 2019 (COVID-19) with High Viral Load. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2020.
  121. Kimball A HK, Arons M, et al. Asymptomatic and Presymptomatic SARS-CoV-2 Infections in Residents of a Long-Term Care Skilled Nursing Facility — King County, Washington, March 2020. MMWR Morbidity and mortality weekly report. 2020;ePub: 27 March 2020.
  122. Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020;191:145-147.  [PMID:32291094]
  123. Kucirka LM, Lauer SA, Laeyendecker O, et al. Variation in False-Negative Rate of Reverse Transcriptase Polymerase Chain Reaction-Based SARS-CoV-2 Tests by Time Since Exposure. Ann Intern Med. 2020.  [PMID:32422057]
  124. Lai CC, Shih TP, Ko WC, et al. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges. Int J Antimicrob Agents. 2020.  [PMID:32081636]
  125. Lamontagne F, Meade MO, Hébert PC, et al. Higher versus lower blood pressure targets for vasopressor therapy in shock: a multicentre pilot randomized controlled trial. Intensive Care Med. 2016;42(4):542-550.  [PMID:26891677]
  126. Lechien JR, Chiesa-Estomba CM, De Siati DR, et al. Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study. Eur Arch Otorhinolaryngol. 2020.  [PMID:32253535]
  127. Lee MK, Choi J, Park B, et al. High flow nasal cannulae oxygen therapy in acute-moderate hypercapnic respiratory failure. Clin Respir J. 2018;12(6):2046-2056.  [PMID:29392846]
  128. Lei J, Li J, Li X, et al. CT Imaging of the 2019 Novel Coronavirus (2019-nCoV) Pneumonia. Radiology. 2020;295(1):18.  [PMID:32003646]
  129. Levi M, Thachil J, Iba T, et al. Coagulation abnormalities and thrombosis in patients with COVID-19. Lancet Haematol. 2020;7(6):e438-e440.  [PMID:32407672]
  130. Levin M. Childhood Multisystem Inflammatory Syndrome - A New Challenge in the Pandemic. N Engl J Med. 2020.  [PMID:32598829]
  131. Levy MM, Evans LE, Rhodes A. The Surviving Sepsis Campaign Bundle: 2018 update. Intensive Care Med. 2018;44(6):925-928.  [PMID:29675566]
  132. Lewis D. Is the coronavirus airborne? Experts can't agree. Nature. 2020;580(7802):175.  [PMID:32242113]
  133. Li L, Zhang W, Hu Y, et al. Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial. JAMA. 2020.  [PMID:32492084]
  134. Li Q, Guan X, Wu P, et al. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. N Engl J Med. 2020.  [PMID:31995857]
  135. Lim J, Jeon S, Shin HY, et al. Case of the Index Patient Who Caused Tertiary Transmission of COVID-19 Infection in Korea: the Application of Lopinavir/Ritonavir for the Treatment of COVID-19 Infected Pneumonia Monitored by Quantitative RT-PCR. J Korean Med Sci. 2020;35(6):e79.  [PMID:32056407]
  136. 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]
  137. Liu Y, Yan LM, Wan L, et al. Viral dynamics in mild and severe cases of COVID-19. Lancet Infect Dis. 2020.  [PMID:32199493]
  138. Livingston E, Bucher K. Coronavirus Disease 2019 (COVID-19) in Italy. JAMA. 2020.  [PMID:32181795]
  139. Loubani OM, Green RS. A systematic review of extravasation and local tissue injury from administration of vasopressors through peripheral intravenous catheters and central venous catheters. J Crit Care. 2015;30(3):653.e9-17.  [PMID:25669592]
  140. Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020;395(10224):565-574.  [PMID:32007145]
  141. Luo Y, Ou R, Ling Y, et al. [The therapeutic effect of high flow nasal cannula oxygen therapy for the first imported case of Middle East respiratory syndrome to China]. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2015;27(10):841-4.  [PMID:27132449]
  142. Lurie N, Saville M, Hatchett R, et al. Developing Covid-19 Vaccines at Pandemic Speed. N Engl J Med. 2020;382(21):1969-1973.  [PMID:32227757]
  143. Mahase E. Covid-19: Low dose steroid cuts death in ventilated patients by one third, trial finds. BMJ. 2020;369:m2422.  [PMID:32546467]
  144. Mahévas M, Tran VT, Roumier M, et al. Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data. BMJ. 2020;369:m1844.  [PMID:32409486]
  145. Mancia G, Rea F, Ludergnani M, et al. Renin-Angiotensin-Aldosterone System Blockers and the Risk of Covid-19. N Engl J Med. 2020.  [PMID:32356627]
  146. Mao L, Jin H, Wang M, et al. Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. 2020.  [PMID:32275288]
  147. Mao R, Qiu Y, He JS, et al. Manifestations and prognosis of gastrointestinal and liver involvement in patients with COVID-19: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol. 2020.  [PMID:32405603]
  148. Marini JJ, Gattinoni L. Management of COVID-19 Respiratory Distress. JAMA. 2020.  [PMID:32329799]
  149. Markel H, Lipman HB, Navarro JA, et al. Nonpharmaceutical interventions implemented by US cities during the 1918-1919 influenza pandemic. JAMA. 2007;298(6):644-54.  [PMID:17684187]
  150. McMichael TM CS, Pogosjans S, et al. COVID-19 in a Long-Term Care Facility — King County, Washington, February 27–March 9, 2020. MMWR Morbidity and mortality weekly report. 2020.
  151. McMichael TM CS, Pogosjans S, et al. COVID-19 in a Long-Term Care Facility — King County, Washington, February 27–March 9, 2020. MMWR Morbidity and mortality weekly report. 2020;69:339-342.
  152. Mehra MR, Desai SS, Ruschitzka F, et al. Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet. 2020.  [PMID:32450107]
  153. Messerole E, Peine P, Wittkopp S, et al. The pragmatics of prone positioning. Am J Respir Crit Care Med. 2002;165(10):1359-63.  [PMID:12016096]
  154. Middeldorp S, Coppens M, van Haaps TF, et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. 2020.  [PMID:32369666]
  155. Myers LC, Parodi SM, Escobar GJ, et al. Characteristics of Hospitalized Adults With COVID-19 in an Integrated Health Care System in California. JAMA. 2020.  [PMID:32329797]
  156. NIH Clinical Trial Shows Remdesivir Accelerates Recovery from Advanced COVID-19 [News]. US National Institute of Allergy and Infectious Diseases. April 29, 2020. [https://www.niaid.nih.gov/news-events/nih-clinical-trial-shows-remdesivir-...]
  157. NIH clinical trial of investigational vaccine for COVID-19 begins: study enrolling Seattle-based healthy adult volunteers [News]. March 16, 2020. [https://www.nih.gov/news-events/news-releases/nih-clinical-trial-investiga...]
  158. NIH clinical trial of remdesivir to treat COVID-19 begins [News]. National Institutes of Health. Accessed Febrary 28, 2020. [https://www.nih.gov/news-events/news-releases/nih-clinical-trial-remdesivir-treat-covid-19-begins]
  159. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med. 2006;354(24):2564-75.  [PMID:16714767]
  160. National Heart, Lung, and Blood Institute PETAL Clinical Trials Network, Moss M, Huang DT, et al. Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome. N Engl J Med. 2019;380(21):1997-2008.  [PMID:31112383]
  161. Ou X, Hua Y, Liu J, et al. Effect of high-flow nasal cannula oxygen therapy in adults with acute hypoxemic respiratory failure: a meta-analysis of randomized controlled trials. CMAJ. 2017;189(7):E260-E267.  [PMID:28246239]
  162. Pan L, Mu M, Ren HG, et al. Clinical characteristics of COVID-19 patients with digestive symptoms in Hubei, China: a descriptive, cross-sectional, multicenter study. Am J Gastroenterol. 2020;[Epub ahead of print].
  163. Pan A, Liu L, Wang C, et al. Association of Public Health Interventions With the Epidemiology of the COVID-19 Outbreak in Wuhan, China. JAMA. 2020.  [PMID:32275295]
  164. Pan F, Ye T, Sun P, et al. Time Course of Lung Changes On Chest CT During Recovery From 2019 Novel Coronavirus (COVID-19) Pneumonia. Radiology. 2020.  [PMID:32053470]
  165. Papazian L, Forel JM, Gacouin A, et al. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med. 2010;363(12):1107-16.  [PMID:20843245]
  166. Park SY, Kim YM, Yi S, et al. Coronavirus Disease Outbreak in Call Center, South Korea. Emerg Infect Dis. 2020;26(8).  [PMID:32324530]
  167. Pham TM, Carpenter JR, Morris TP, et al. Ethnic Differences in the Prevalence of Type 2 Diabetes Diagnoses in the UK: Cross-Sectional Analysis of the Health Improvement Network Primary Care Database. Clin Epidemiol. 2019;11:1081-1088.  [PMID:32021464]
  168. Prescott HC, Angus DC. Enhancing Recovery From Sepsis: A Review. JAMA. 2018;319(1):62-75.  [PMID:29297082]
  169. Price-Haywood EG, Burton J, Fort D, et al. Hospitalization and Mortality among Black Patients and White Patients with Covid-19. N Engl J Med. 2020.  [PMID:32459916]
  170. Qin C, Zhou L, Hu Z, et al. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2020.
  171. Randomised Evaluation of COVID-19 Therapy (RECOVERY). Low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe respiratory complications of COVID-19. 2020. Available at: https://www.recoverytrial.net/news/low-cost-dexamethasone-reduces-death-by-up-to-one-third-in-hospitalised-patients-with-severe-respiratory-complications-of-covid-19. Accessed June 23, 2020.
  172. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43(3):304-377.  [PMID:28101605]
  173. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA. 2020.  [PMID:32320003]
  174. Rochwerg B, Alhazzani W, Gibson A, et al. Fluid type and the use of renal replacement therapy in sepsis: a systematic review and network meta-analysis. Intensive Care Med. 2015;41(9):1561-71.  [PMID:25904181]
  175. Rochwerg B, Alhazzani W, Sindi A, et al. Fluid resuscitation in sepsis: a systematic review and network meta-analysis. Ann Intern Med. 2014;161(5):347-55.  [PMID:25047428]
  176. Rodrigo C, Leonardi-Bee J, Nguyen-Van-Tam J, et al. Corticosteroids as adjunctive therapy in the treatment of influenza. Cochrane Database Syst Rev. 2016;3:CD010406.  [PMID:26950335]
  177. Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez-Ocampo E, et al. Clinical, laboratory and imaging features of COVID-19: A systematic review and meta-analysis. Travel Med Infect Dis. 2020;34:101623.  [PMID:32179124]
  178. Rosenberg ES, Dufort EM, Udo T, et al. Association of Treatment With Hydroxychloroquine or Azithromycin With In-Hospital Mortality in Patients With COVID-19 in New York State. JAMA. 2020.  [PMID:32392282]
  179. Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet. 2020;395(10223):473-475.  [PMID:32043983]
  180. Sanders JM, Monogue ML, Jodlowski TZ, et al. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. JAMA. 2020.  [PMID:32282022]
  181. Scavone C, Brusco S, Bertini M, et al. Current pharmacological treatments for COVID-19: What's next? Br J Pharmacol. 2020.  [PMID:32329520]
  182. Schultz MJ, Dunser MW, Dondorp AM, et al. Current challenges in the management of sepsis in ICUs in resource-poor settings and suggestions for the future. Intensive Care Med. 2017;43(5):612-624.  [PMID:28349179]
  183. Sethuraman N, Jeremiah SS, Ryo A. Interpreting Diagnostic Tests for SARS-CoV-2. JAMA. 2020.  [PMID:32374370]
  184. Shi H, Han X, Zheng C. Evolution of CT Manifestations in a Patient Recovered from 2019 Novel Coronavirus (2019-nCoV) Pneumonia in Wuhan, China. Radiology. 2020;295(1):20.  [PMID:32032497]
  185. Shi H, Han X, Jiang N, et al. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis. 2020;20(4):425-434.  [PMID:32105637]
  186. Spinato G, Fabbris C, Polesel J, et al. Alterations in Smell or Taste in Mildly Symptomatic Outpatients With SARS-CoV-2 Infection. JAMA. 2020.  [PMID:32320008]
  187. Stockman LJ, Bellamy R, Garner P. SARS: systematic review of treatment effects. PLoS Med. 2006;3(9):e343.  [PMID:16968120]
  188. Sungnak W, Huang N, Bécavin C, et al. SARS-CoV-2 entry factors are highly expressed in nasal epithelial cells together with innate immune genes. Nat Med. 2020;26(5):681-687.  [PMID:32327758]
  189. Tabata S, Imai K, Kawano S, et al. Clinical characteristics of COVID-19 in 104 people with SARS-CoV-2 infection on the Diamond Princess cruise ship: a retrospective analysis. Lancet Infect Dis. 2020.  [PMID:32539988]
  190. Tang N, Li D, Wang X, et al. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18(4):844-847.  [PMID:32073213]
  191. Tang W, Cao Z, Han M, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020;369:m1849.  [PMID:32409561]
  192. Thachil J, Tang N, Gando S, et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19. J Thromb Haemost. 2020;18(5):1023-1026.  [PMID:32338827]
  193. Thanh Le T, Andreadakis Z, Kumar A, et al. The COVID-19 vaccine development landscape. Nat Rev Drug Discov. 2020;19(5):305-306.  [PMID:32273591]
  194. The Lancet Editors . Expression of concern: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet. 2020.  [PMID:32504543]
  195. Tian S, Hu N, Lou J, et al. Characteristics of COVID-19 infection in Beijing. J Infect. 2020.  [PMID:32112886]
  196. Tobin MJ. Basing Respiratory Management of COVID-19 on Physiological Principles. Am J Respir Crit Care Med. 2020;201(11):1319-1320.  [PMID:32281885]
  197. Torjesen I. Covid-19: Hydroxychloroquine does not benefit hospitalised patients, UK trial finds. BMJ. 2020;369:m2263.  [PMID:32513810]
  198. Tracking Every Coronavirus Case in the U.S.: Full Map. New York Times. [https://www.nytimes.com/interactive/2020/us/coronavirus-us-cases.html]
  199. Treon SP, Castillo J, Skarbnik AP, et al. The BTK-inhibitor ibrutinib may protect against pulmonary injury in COVID-19 infected patients. Blood. 2020.  [PMID:32302379]
  200. Verdoni L, Mazza A, Gervasoni A, et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet. 2020.  [PMID:32410760]
  201. Wadhera RK, Wadhera P, Gaba P, et al. Variation in COVID-19 Hospitalizations and Deaths Across New York City Boroughs. JAMA. 2020.  [PMID:32347898]
  202. Wang C, Li W, Drabek D, et al. A human monoclonal antibody blocking SARS-CoV-2 infection. Nat Commun. 2020;11(1):2251.  [PMID:32366817]
  203. 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;30(3):269-271.  [PMID:32020029]
  204. Wang W, Xu Y, Gao R, et al. Detection of SARS-CoV-2 in Different Types of Clinical Specimens. JAMA. 2020.  [PMID:32159775]
  205. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395(10236):1569-1578.  [PMID:32423584]
  206. Wang Y, Dong C, Hu Y, et al. Temporal Changes of CT Findings in 90 Patients with COVID-19 Pneumonia: A Longitudinal Study. Radiology. 2020.  [PMID:32191587]
  207. Wei M, Yuan J, Liu Y, et al. Novel Coronavirus Infection in Hospitalized Infants Under 1 Year of Age in China. JAMA. 2020.  [PMID:32058570]
  208. Wei WE, Li Z, Chiew CJ, et al. Presymptomatic Transmission of SARS-CoV-2 - Singapore, January 23-March 16, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(14):411-415.  [PMID:32271722]
  209. Whittaker E, Bamford A, Kenny J, et al. Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2. JAMA. 2020.  [PMID:32511692]
  210. Williams E, Bond K, Zhang B, et al. Saliva as a non-invasive specimen for detection of SARS-CoV-2. J Clin Microbiol. 2020.  [PMID:32317257]
  211. Williamson BN, Feldmann F, Schwarz B, et al. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. Nature. 2020.  [PMID:32516797]
  212. Writing Group for the Alveolar Recruitment for Acute Respiratory Distress Syndrome Trial (ART) Investigators, Cavalcanti AB, Suzumura ÉA, et al. Effect of Lung Recruitment and Titrated Positive End-Expiratory Pressure (PEEP) vs Low PEEP on Mortality in Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA. 2017;318(14):1335-1345.  [PMID:28973363]
  213. Wu Y, Guo C, Tang L, et al. Prolonged presence of SARS-CoV-2 viral RNA in faecal samples. The Lancet Gastroenterology & Hepatology. 2020.
  214. Wölfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized patients with COVID-2019. Nature. 2020;581(7809):465-469.  [PMID:32235945]
  215. Xie X, Zhong Z, Zhao W, et al. Chest CT for Typical 2019-nCoV Pneumonia: Relationship to Negative RT-PCR Testing. Radiology. 2020.  [PMID:32049601]
  216. Xu XW, Wu XX, Jiang XG, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series. BMJ (Clinical research ed). 2020;368:m606.
  217. Xu X, Yu C, Qu J, et al. Imaging and clinical features of patients with 2019 novel coronavirus SARS-CoV-2. Eur J Nucl Med Mol Imaging. 2020;47(5):1275-1280.  [PMID:32107577]
  218. Xu Z, Shi L, Wang Y, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020;8(4):420-422.  [PMID:32085846]
  219. Yang W, Cao Q, Qin L, et al. Clinical characteristics and imaging manifestations of the 2019 novel coronavirus disease (COVID-19):A multi-center study in Wenzhou city, Zhejiang, China. J Infect. 2020;80(4):388-393.  [PMID:32112884]
  220. Zaki AM, van Boheemen S, Bestebroer TM, et al. Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. N Engl J Med. 2012;367(19):1814-20.  [PMID:23075143]
  221. Zeng L, Xia S, Yuan W, et al. Neonatal early-onset infection with SARS-CoV-2 in 33 neonates born to mothers with COVID-19 in Wuhan, China.  JAMA Pediatr. Published online March 26, 2020.
  222. Zhang C, Shi L, Wang FS. Liver injury in COVID-19: management and challenges. Lancet Gastroenterol Hepatol. 2020.  [PMID:32145190]
  223. Zhang L, Liu Y. Potential Interventions for Novel Coronavirus in China: A Systematic Review. J Med Virol. 2020.  [PMID:32052466]
  224. Zhao J, Yuan Q, Wang H, et al. Antibody responses to SARS-CoV-2 in patients of novel coronavirus disease 2019.  Clin Infect Dis. Published online March 28, 2020.
  225. Zhao W, Zhong Z, Xie X, et al. Relation Between Chest CT Findings and Clinical Conditions of Coronavirus Disease (COVID-19) Pneumonia: A Multicenter Study. AJR Am J Roentgenol. 2020.  [PMID:32125873]
  226. Zhong NS, Zheng BJ, Li YM, et al. Epidemiology and cause of severe acute respiratory syndrome (SARS) in Guangdong, People's Republic of China, in February, 2003. Lancet. 2003;362(9393):1353-8.  [PMID:14585636]
  227. Zhu N, Zhang D, Wang W, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020;382(8):727-733.  [PMID:31978945]
  228. Zou X, Chen K, Zou J, et al. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front Med. 2020;14(2):185-192.  [PMID:32170560]
  229. van Doremalen N, Bushmaker T, Morris DH, et al. Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1. N Engl J Med. 2020;382(16):1564-1567.  [PMID:32182409]
Last updated: November 16, 2020