Coronavirus Disease 2019 (COVID-19)

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

Updated: March 22, 2021

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 – see below for details
    • Tocilizumab in combination with dexamethasone in certain hospitalized patients who are exhibiting rapid respiratory decompensation
    • Bamlanivimab plus etesevimab for outpatients with mild to moderate COVID-19 who are at high risk of clinical progression
  • Therapies approved for emergency use but NOT recommended routinely by NIH Panel
    • Baricitinib in combination with remdesivir [EUA November 19, 2020]
    • Casirivimab plus imdevimab [EUA November 21, 2020]
  • Therapies for which there is insufficient data to recommend for or against
    • Anti-IL-6 receptor monoclonal antibodies (e.g., sarilumab)
  • Therapies NOT approved nor recommended except in a clinical trial
    • Hydroxychloroquine and chloroquine with or without azithromycin
    • Lopinavir/ritonavir or other HIV protease inhibitors
    • Ivermectin
    • Anti-IL-6 monoclonal antibody (siltuximab)
    • Interferons
    • Bruton’s tyrosine kinase inhibitors (e.g., acalabrutinib, ibrutinib, zanubrutinib)
    • Other Janus kinase inhibitors (e.g., 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 (RDV) 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

Tocilizumab

Box 3: Tocilizumab plus Dexamethasone in Certain Hospitalized Patients with COVID-19

NIH COVID-19 Treatment Guidelines Panel[5]

  • Recommends the use of tocilizumaba (single intravenous dose of 8 mg/kg of actual body weight, up to 800 mg) in combination with dexamethasone (6 mg daily for up to 10 days)b in certain hospitalized patients who are exhibiting rapid respiratory decompensation due to COVID-19.c The patients included in this population are:
    • Recently hospitalized patientsd who have been admitted to the intensive care unit (ICU) within the prior 24 hours and who require invasive mechanical ventilation, noninvasive mechanical ventilation (NIV), or high-flow nasal canula (HFNC) oxygen (>0.4 FiO2/30 L/min of oxygen flow) (BIIa); or
    • Recently hospitalized patientsd (not in the ICU) with rapidly increasing oxygen needs who require NIV or HFNC and have significantly increased markers of inflammation (BIIa) (Note: The RECOVERY trial inclusion criterion for
      inflammation was C-reactive protein [CRP] ≥75 mg/L; see details below).
  • For hospitalized patients with hypoxemia who require conventional oxygen supplementation, recommends using one of the following options: remdesivir (BIIa), dexamethasone plus remdesivir (BIII), or dexamethasone alone (BI).
    • There is insufficient evidence to specify which of these patients would benefit from the addition of tocilizumab. Some Panel members would also give tocilizumab to patients who are exhibiting rapidly increasing oxygen needs while on dexamethasone and have a CRP ≥75 mg/L but who do not yet require NIV or HFNC, as described above.
a Use of tocilizumab should be avoided in patients with any of the following: (1) significant immunosuppression, particularly in those with a history of recent use of other biologic immunomodulating drugs; (2) alanine transaminase >5 times the upper limit of normal; (3) high risk for gastrointestinal perforation; (4) an uncontrolled, serious bacterial, fungal, or non-SARS-CoV-2 viral infection; (5) absolute neutrophil count < 500 cells/mL; or (6) platelet count < 50,000 cells/mL.b As an alternative to dexamethasone, corticosteroids at a dose equivalent to dexamethasone 6 mg are acceptable (see Corticosteroids).c Respiratory decompensation should be due to progressive COVID-19 and not due to alternative causes, such as volume overload or asthma exacerbation.

Bamlanivimab plus etesevimab

Box 4: Bamlanivimab plus etesevimab in Certain Outpatients with COVID-19

NIH COVID-19 Treatment Guidelines Panel[5]

  • Recommends bamlanivimab 700 mg plus etesevimab 1,400 mg for the treatment of outpatients with mild to moderate COVID-19 who are at high risk of clinical progression as defined by the EUA criteria (BIIa). Treatment should be started as soon as possible after the patient has received a positive result on a SARS-CoV-2 antigen or nucleic acid amplification test and within 10 days of symptom onset.
    • It is important to note that the authorized dose of bamlanivimab 700 mg plus etesevimab 1,400 mg is lower than the dose given to participants in the Phase 3 study that provides clinical data in support of this therapy. The authorized dose was extrapolated from data demonstrating its antiviral activity, as well as from in vitro studies and pharmacokinetic/pharmacodynamic modeling.
  • Recommends against the use of bamlanivimab 700 mg plus etesevimab 1,400 mg for patients who are hospitalized because of COVID-19, except in a clinical trial. However, the combination should be considered for persons with mild to moderate COVID-19 who are hospitalized for a reason other than COVID-19 but who otherwise meet the EUA criteria.
  • Given the possibility of a limited supply of bamlanivimab plus etesevimab, as well as challenges of distributing and administering the drugs, priority should be given to patients who are at highest risk for COVID-19 progression based on the EUA criteria.
  • Efforts should be made to ensure that communities most affected by COVID-19 have equitable access to bamlanivimab plus etesevimab.
  • Bamlanivimab plus etesevimab should not be withheld from a pregnant individual who has a condition that poses a high risk of progression to severe COVID-19 if the clinician thinks that the potential benefit of the combination outweighs the potential risk.
  • There are insufficient pediatric data to recommend either for or against the use of bamlanivimab plus etesevimab or other monoclonal antibody products for children with COVID-19 who are not hospitalized but who have risk factors for severe disease. Based on adult studies, bamlanivimab plus etesevimab may be considered on a case-by-case basis for children who meet EUA criteria, especially those who meet more than one criterion or who are aged ≥16 years. In such cases, consultation with a pediatric infectious disease specialist is recommended.

Blood-Derived Products

Box 5: 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 6: 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 7: Other Antiviral Drugs in COVID-19

NIH COVID-19 Treatment Guidelines Panel[5]

  • Insufficient data to recommend either for or against the following drugs except in a clinical trial:
    • Ivermectin for the treatment of COVID-19 [Updated January 14, 2021]
  • 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.

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 8: 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:
    • Baricitinib in combination with corticosteroids. Because both agents are potent immunosuppressants, there is potential for an additive risk of infection.
    • Baricitinib in combination with remdesivir for hospitalized COVID-19 patients when corticosteroids can be used
    • Interleukin (IL)-1 inhibitors (e.g., anakinra)
    • Interferon beta for the treatment of early (i.e., < 7 days from symptom onset) mild to moderate COVID-19
  • Recommends against the use of the following immunomodulators for the treatment of COVID-19, except in a clinical trial:
    • Siltuximab, an anti-IL-6 monoclonal antibody (AIII)
    • Baricitinib without remdesivir (AIII)
    • Interferons (alfa or beta) for the treatment of severely or critically ill patients with COVID-19 (AIII)
    • Kinase inhibitors:
      • Bruton’s tyrosine kinase inhibitors (e.g., acalabrutinib, ibrutinib, zanubrutinib) (AIII)
      • Janus kinase inhibitors other than baricitinib (e.g., ruxolitinib, tofacitinib) (AIII)
  • Non-SARS-CoV-2-specific intravenous immune globulin (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.

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

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Last updated: March 22, 2021