Coronavirus Disease 2019 (COVID-19)

How to Cite This Chapter: Loeb M, Alhazzani W, Mertz D, Singhal N, Chagla Z, Jaeschke R, Rymer W, Wroczyńska A. Coronavirus Disease 2019 (COVID-19). McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. https://empendium.com/mcmtextbook/chapter/B31.II.18.1.12. Accessed April 12, 2021.
Last Updated: March 31, 2021
Last Reviewed: March 31, 2021
Chapter Information

Please note that COVID-19–related information is evolving rapidly, including epidemiology and all modes of prevention and potential treatments. Different jurisdictions are coming up with new instructions on a daily basis. In addition, the judgment of different professional and international organizations assessing the same body of evidence differs, which may reflect different confidence in the data and different values and preferences associated with different outcomes. As of this update (beginning of 2021) different recommendations surrounding the use of remdesivir illustrate this not unexpected phenomenon.

EpidemiologyTop

The first cases of coronavirus disease 2019 (COVID-19) occurred in China and quickly developed into an epidemic centered in Hubei province. At present, the pandemic has spread globally, with the United States reporting the highest number of cases to date. Current epidemiologic data are available at www.who.int, www.cdc.gov, and www.ecdc.europa.eu. As of the end of March 2021, there were close to 130 million confirmed cases and close to 3 million deaths worldwide.

Etiology and PathogenesisTop

1. Etiologic agent: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an RNA virus that belongs to the Betacoronavirus (BetaCoV) genus. The genus also includes SARS-CoV, which was responsible for the epidemic in 2002 and 2003.

Throughout the COVID-19 pandemic, SARS-CoV-2 has mutated, leading to the emergence of viral variants. Three main variants of concern (VOCs) that are more transmissible are increasingly circulating in numerous countries, including Canada. These are the UK (B.1.1.7), South African (B.1.135), and Brazilian (P.1) lineages. Some of them may lead to more severe disease.

2. Pathogenesis: Not fully understood. To enter the cell, the virus uses angiotensin-converting enzyme 2 (ACE2) as a receptor, binding to ACE2 using the spike glycoprotein on the viral envelope. In response to viral antigens, immune cells release proinflammatory cytokines and chemokines, which can result in an uncontrolled systemic inflammatory response. This is one of the key mechanisms leading to the development of acute respiratory distress syndrome (ARDS).

3. Reservoir and transmission: An animal reservoir has not been clearly identified to date but the virus has most likely originated in bats. In the current epidemic the reservoir for SARS-CoV-2 is infected humans.

SARS-CoV-2 spreads between people mainly when an infected person is in close contact with another person. The virus can be spread in small liquid particles of different sizes, ranging from large droplets to smaller aerosols. The evidence to support transmission through fomites (contaminated objects) is limited, although it is considered a possible mode of transmission. Aerosol transmission can occur when there are procedures performed that generate aerosols. Outside of medical facilities, aerosol transmission can occur in certain circumstances, such as indoor, crowded, and poorly ventilated spaces. The virus may be found in blood at the early stages of the disease and in stool, but transmission through blood or the fecal-oral route has not been confirmed to date. The infection is spread predominantly by symptomatic and presymptomatic individuals with COVID-19 but also by those with asymptomatic infection with SARS-CoV-2.Evidence 1Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. 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 Mar 17. doi: 10.1056/NEJMc2004973. [Epub ahead of print] PubMed PMID: 32182409. Johansson MA, Quandelacy TM, Kada S, al. SARS-CoV-2 Transmission From People Without COVID-19 Symptoms. JAMA Netw Open. 2021 Jan 4;4(1):e2035057. doi: 10.1001/jamanetworkopen.2020.35057. PMID: 33410879; PMCID: PMC7791354.

4. Risk factors for infection: Epidemiologic risk factors include any setting with a higher likelihood of exposure to an infected individual, in particular through direct contact in an indoor environment (eg, classroom, meeting room, waiting room in a hospital). Prolonged contact increases the risk of infection. Transmission by contact with objects or materials (fomites) seems less important than originally assumed.

Risk factors for severe versus mild infection include advanced age (in patients aged ≥80 years mortality rates are reported to be up to 15%, although some mildly symptomatic patients may not be counted, thus increasing the observed risk), male sex, chronic respiratory disease, cardiovascular disease including hypertension, malignancy, diabetes mellitus, active smoking, obesity, and likely immunosuppression. Residents of long-term care facilities are particularly vulnerable. The role of pregnancy as a risk factor for severe disease is under debate; a systematic review suggested a slightly higher risk for intensive care unit (ICU) admission and ventilation, with the main risk factors being preexisting diabetes, hypertension, elevated body mass index (BMI), and advanced maternal age. The risk of preterm labor and maternal death was reported to be elevated about 3-fold.Evidence 2Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias. Pettirosso E, Giles M, Cole S, Rees M. COVID-19 and pregnancy: A review of clinical characteristics, obstetric outcomes and vertical transmission. Aust N Z J Obstet Gynaecol. 2020 Aug 10:10.1111/ajo.13204. doi: 10.1111/ajo.13204. Epub ahead of print. PMID: 32779193; PMCID: PMC7436616.

5. Incubation and contagious period: The incubation period is usually from 2 to 14 days (5 days on average, with >95% of cases developing by day 11). Symptomatic individuals may transmit the virus to others; the extent of transmission from those who are presymptomatic is likely substantial.Evidence 3Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Arons MM, Hatfield KM, Reddy SC, et al. Presymptomatic SARS-CoV-2 Infections and Transmission in a Skilled Nursing Facility. N Engl J Med. 2020 Apr 24. doi: 10.1056/NEJMoa2008457. [Epub ahead of print] PubMed PMID: 32329971. Gandhi M, Yokoe DS, Havlir DV. Asymptomatic Transmission, the Achilles' Heel of Current Strategies to Control Covid-19. N Engl J Med. 2020 Apr 24. doi: 10.1056/NEJMe2009758. [Epub ahead of print] PubMed PMID: 32329972. Li R, Pei S, Chen B, et al. Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV2). Science. 2020 Mar 16. pii: eabb3221. doi: 10.1126/science.abb3221. [Epub ahead of print] PubMed PMID: 32179701. Wei WE, Li Z, Chiew CJ, Yong SE, Toh MP, Lee VJ. Presymptomatic Transmission of SARS-CoV-2 — Singapore, January 23–March 16, 2020. MMWR Morb Mortal Wkly Rep. ePub: 1 April 2020. DOI: http://dx.doi.org/10.15585/mmwr.mm6914e1 Viral load/shedding is probably the highest at the time of symptom onset and shortly afterwards; however, it may last longer in patients who develop severe infection. The duration of the contagious period is estimated as a maximum of 10 days from the onset of symptoms for most cases, while a small number of patients with severe COVID-19 may shed replication-competent virus for up to 3 weeks, particularly in the context of critical illness or significant immunocompromised state.Evidence 4Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Centers for Disease Control and Prevention. Duration of Isolation and Precautions for Adults with COVID-19. Updated October 19, 2020. Accessed November 29, 2020. https://www.cdc.gov/coronavirus/2019-ncov/hcp/duration-isolation.html

Clinical Features and Natural HistoryTop

The clinical course may be varied and ranges from asymptomatic/subclinical infection to severe pneumonia with ARDS:

1) Symptomatic uncomplicated infection: Patients have nonspecific manifestations, such as fever, cough, shortness of breath, malaise, myalgias, sore throat, headache, diarrhea, runny nose or nasal congestion, conjunctivitis, and anosmia. Patients with mild or uncomplicated infections do not have dehydration, dyspnea, or features of sepsis. Elderly individuals and immunocompromised patients may have atypical symptoms.

2) Mild pneumonia: Absence of the features of severe pneumonia listed below.

3) Severe pneumonia: Fever or other symptoms of respiratory tract infection with ≥1 of severe respiratory distress, tachypnea >30/min, or hemoglobin oxygen saturation in arterial blood (measured with pulse oximetry) (SpO2) on room air <90%.

4) ARDS occurs in up to 15% of hospitalized patients with COVID-19.

5) Sepsis and septic shock: The incidence of sepsis in patients with COVID-19 is not well described. The incidence of shock in published reports was highly variable, ranging between 2% and 20%.

6) Postinfectious phenomena, such as multisystem inflammatory syndrome (MIS)—a disorder similar to Kawasaki disease—has been described in children and young adults.

At the beginning of the pandemic, in ~80% of diagnosed patients the course of the disease was mild. Approximately 15% of patients developed severe infection with dyspnea and hypoxia and most had progressive radiographic features of pneumonia. During the first months of the pandemic, ~5% of diagnosed symptomatic patients became critically ill with acute respiratory failure, shock, and multiorgan dysfunction. Among critically ill patients with COVID-19, the mortality rate initially approached 50%. In a described cohort of Italian patients, 16% of hospitalized patients required ICU admission.Evidence 5Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Grasselli G, Pesenti A, Cecconi M. Critical Care Utilization for the COVID-19 Outbreak in Lombardy, Italy: Early Experience and Forecast During an Emergency Response. JAMA. 2020 Mar 13. doi: 10.1001/jama.2020.4031. [Epub ahead of print] PubMed PMID: 32167538.

In the results of the SOLIDARITY trial released in October 2020, based on >11,000 hospitalized patients, the overall mortality rate was 12% and the mortality rate among those ventilated at trial entry was 39%.Evidence 6High Quality of Evidence (high confidence that we know true effects of the intervention). WHO Solidarity trial consortium, Pan H, Peto R, Abdool Karim Q, et al. Repurposed antiviral drugs for COVID-19 –interim WHO SOLIDARITY trial results. Preprint posted online October 15, 2020. doi: https://doi.org/10.1101/2020.10.15.20209817 The overall mortality rate varies by country, pattern of testing, and demographic characteristics in a given report, and as of the beginning of 2021 it is ~2% in diagnosed patients worldwide, including >5% in some countries. However, these rates have a wide margin of error and are likely inflated as, due to selective testing, there is probably an overrepresentation of severely ill patients in whom the infection has been confirmed. Many patients with mild infection would not have undergone testing and are therefore missing in the denominator; it is estimated that the proportion of such missed cases was as high as 90% to start with and, when evaluated using serologic surveillance, may still be as high as ~50%.Evidence 7Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Gudbjartsson DF, Norddahl GL, Melsted P, et al. Humoral Immune Response to SARS-CoV-2 in Iceland. N Engl J Med. 2020 Sep 1. doi: 10.1056/NEJMoa2026116. Epub ahead of print. PMID: 32871063. The reported proportion of severely and critically ill patients appears to be declining; for example, as of the end of March 2021, the reported proportion of such patients among all active cases in Canada was ~1.5%.

In late 2020, an 8-factor risk score of mortality among patients hospitalized with COVID-19 was published in the British Medical Journal (BMJ) (doi: 10.1136/bmj.m3339). It is based on age, sex, number of comorbidities, Glasgow Coma Scale, respiratory rate, oxygen saturation, urea level, and C-reactive protein (CRP) level. Numerous other calculators are available online (eg, at MDCalc), including the 4C calculator used to predict in-hospital mortality (mdcalc.com/4c-mortality-score-covid-19).

Clinically, patients with mild infection typically recover symptomatically within 1 to 2 weeks, with some experiencing long-term nonspecific symptoms, lasting 12 weeks or occasionally longer, and disabling postviral symptoms (including dyspnea, fatigue, chest pain, and cough); these may follow acute COVID-19 illness and resemble chronic fatigue syndrome.Evidence 8Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias. Williams FMK, Muirhead N, Pariante C. Covid-19 and chronic fatigue. BMJ. 2020 Jul 30;370:m2922. doi: 10.1136/bmj.m2922. PMID: 32732337. Del Rio C, Collins LF, Malani P. Long-term Health Consequences of COVID-19. JAMA. 2020 Oct 5. doi: 10.1001/jama.2020.19719. Epub ahead of print. PMID: 33031513. When covid-19 becomes a chronic illness. The Economist. August 22, 2020. https://www.economist.com/science-and-technology/2020/08/22/when-covid-19-becomes-a-chronic-illness More data, optimally from longitudinal follow-up of inception cohorts, are clearly needed to delineate this issue.

DiagnosisTop

Diagnostic Tests

1. Identification of the etiologic agent: The key diagnostic method is detection of genetic material from the virus using reverse transcriptase–polymerase chain reaction (RT-PCR) and real-time RT-PCR; in fact, RT-PCR from nasopharyngeal swabs (NPSs) is considered the reference standard. Other specimen types include lower respiratory tract samples (only in intubated patients; endotracheal aspirates [ETAs] or bronchoalveolar lavage [BAL]) and uninduced sputum. As the sensitivity of tests may vary, a high index of clinical suspicion has to be considered even in patients with negative test results. A strategy of initially obtaining an upper respiratory specimen (eg, NPS) rather than a lower respiratory sample is recommended in hospitalized patients with suspected COVID-19 lower respiratory tract infection. If the initial test is negative, a lower respiratory sample can then be obtained. Of note, the sensitivity of specimens varies with the course of the illness and sensitivity of upper airway samples is lower than sensitivity of those obtained from lower airways later in the course of symptomatic disease. In general, sensitivity is likely highest at the beginning of symptoms and then declines.

COVID-19 antigen tests, predominantly offered as point-of-care rapid tests, are also available for the diagnosis of active infection. They have lower sensitivity than PCR tests but have the benefit of fast turnaround times and are less likely to pick up residual RNA in patients who are no longer infectious. They also require less operator training and can be done in fairly remote settings.Evidence 9Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Mina MJ, Parker R, Larremore DB. Rethinking Covid-19 Test Sensitivity - A Strategy for Containment. N Engl J Med. 2020 Nov 26;383(22):e120. doi: 10.1056/NEJMp2025631. Epub 2020 Sep 30. PMID: 32997903.

2. Serologic tests: Serologic tests are not generally recommended as a clinical test to diagnose active COVID-19 infection, as they are usually negative early in infection. They have greater utility for epidemiologic purposes, such as case definitions (eg, current [March 2021] case definitions from the Ministry of Health in Ontario). One application of serologic tests may be in the presence of postinfectious complications, such as MIS in children (MIS-C) where NPS testing is negative. They can be used in symptomatic patients where there is a high clinical suspicion and repeatedly negative RT-PCR testing. These tests are most widely used to better understand the epidemiology of COVID-19 and to gain knowledge about the immune response. The vast majority of patients who have recovered from COVID-19 mount an immune response that includes an antibody response, with titers remaining relatively stable over several months.

3. Other tests:

1) Laboratory tests: Patients commonly have leukopenia and lymphopenia, but leukocytosis may also occur. Procalcitonin levels are usually normal but may be elevated in patients requiring admission to an ICU. Serum aminotransferase levels may be increased. Thrombocytopenia, ferritin, and CRP as well as D-dimer levels correlate with disease severity.

2) Radiography:

a) Chest radiography: Most frequently features of bilateral pneumonia.

b) Chest computed tomography (CT): Radiographic abnormalities can be seen early, even before symptom onset. They are usually bilateral, show peripheral distribution, and are more often located in the inferior lobes. Extensive ground-glass opacification can be seen especially in the second week of the disease, which progresses to a mixed pattern by week 3 or 4. Patients may also have pleural thickening, pleural effusion, and lymphadenopathy. More detailed discussion of CT findings: see COVID-19: Computed Tomography.

3) Chest ultrasonography, including point-of-care ultrasonography, may provide information and limit the number of required CT scans. More detailed discussion of ultrasound findings: see COVID-19: Point-of-Care Ultrasonography.

4) Monitoring involves monitoring of blood pressure, SpO2, and the quick sequential organ failure assessment (qSOFA) (see Sepsis and Septic Shock).

Diagnostic Criteria

Case definitions are used mostly for surveillance purposes and change with the evolution of the epidemiologic situation. Current Ontario definitions include confirmed case (see below) and probable case definitions.

As of March 2021, a confirmed case is defined as:

1) A person with laboratory detection of ≥1 specific gene targets by a validated laboratory-based nucleic acid amplification test (NAAT) (eg, real-time PCR or nucleic acid sequencing) performed at a community, hospital, or reference laboratory; or by a validated point-of-care NAAT that has been deemed acceptable by the Ontario Ministry of Health to provide a final result (ie, does not require confirmatory testing).

2) A person with seroconversion in viral-specific antibody in serum or plasma within a 4-week interval demonstrated using a validated laboratory-based serologic assay for SARS-CoV-2.

Individual countries may need to adapt the case definitions based on their local epidemiologic situation.

Differential Diagnosis

1. Influenza.

2. Other viral respiratory infections.

3. Atypical pneumonia.

4. Pneumocystosis.

5. Other causes of ARDS (see Acute Respiratory Distress Syndrome).

6. Middle East respiratory syndrome (MERS).

TreatmentTop

Antiviral Treatment

Note: Several major research projects investigating numerous potential therapies are ongoing. Among them are the RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial coordinated out of the United Kingdom, SOLIDARITY trial coordinated by the World Health Organization (WHO), ACTT (Adaptive COVID-19 Treatment Trial) coordinated by the National Institutes of Health (NIH), and REMAP-CAP trial (A Randomised, Embedded, Multi-factorial, Adaptive Platform Trial for Community-Acquired Pneumonia).

As of March 2021, treatment of COVID-19 is still to a major degree supportive, although results of randomized controlled trials rapidly conducted in hospitalized and community patients are becoming available and influence the care of various risk groups. The most convincing data available are for glucocorticoids, with reports showing benefits of dexamethasone in individuals requiring mechanical ventilation or supplemental oxygen. There is also a suggestion that a 5-day course of remdesivir among hospitalized patients may be beneficial (see below), although due to conflicting data authorities differ in their recommendations and suggestions for its use. There are increasing data supporting the use of tocilizumab. The use of any other medications is more controversial, with ongoing systematic reviews, meta-analyses, and living guidelines.Evidence 10Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to heterogeneity. Data for different interventions have different certainty of evidence behind them. Morris AM, Stall NM, Bobos P, et al; Ontario COVID-19 Drugs and Biologics Clinical Practice Guidelines Working Group, Ontario COVID-19 Science Advisory Table. Tocilizumab for Hospitalized Patients with COVID-19. Published March 1, 2021. https://covid19-sciencetable.ca/sciencebrief/tocilizumab-for-hospitalized-patients-with-covid-19/ Ontario COVID-19 Drugs and Biologics Clinical Practice Guidelines Working Group. Clinical Practice Guideline Summary: Recommended Drugs and Biologics in Adult Patients with COVID-19. Published February 25, 2021. https://covid19-sciencetable.ca/sciencebrief/clinical-practice-guideline-summary-recommended-drugs-and-biologics-in-adult-patients-with-covid-19/ Siemieniuk RA, Bartoszko JJ, Ge L, et al. Drug treatments for covid-19: living systematic review and network meta-analysis. BMJ. 2020 Jul 30;370:m2980. doi: 10.1136/bmj.m2980. Update in: BMJ. 2020 Sep 11;370:m3536. Update in: BMJ. 2020 Dec 17;371:m4852. PMID: 32732190; PMCID: PMC7390912. Anticoagulation may play an important role (see Symptomatic Treatment, below).

In August 2020, using mostly observational data, the US Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for the use of COVID-19 convalescent plasma in the United States to treat suspected or laboratory-confirmed COVID-19 cases in hospitalized patients. However, a randomized controlled trial published in November 2020 failed to show benefit from the use of convalescent plasma and the news release of January 15 from the RECOVERY trial reported lack of mortality benefit, leading to the decision to stop recruitment to this part of the trial after randomizing >10,000 patients. This was confirmed in a subsequent meta-analysis.Evidence 11Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Janiaud P, Axfors C, Schmitt AM, et al. Association of Convalescent Plasma Treatment With Clinical Outcomes in Patients With COVID-19: A Systematic Review and Meta-analysis. JAMA. 2021 Feb 26. doi: 10.1001/jama.2021.2747. Epub ahead of print. PMID: 33635310. Simonovich VA, Burgos Pratx LD, Scibona P, et al; PlasmAr Study Group. A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia. N Engl J Med. 2020 Nov 24. doi: 10.1056/NEJMoa2031304. Epub ahead of print. PMID: 33232588.

On the basis of unpublished and preliminary data predominantly showing a reduction in viral load among nonhospitalized patients, a dose of the antiviral monoclonal antibody cocktail REGN-COV2 was given to the president of the United States. This drug, which received an EUA from the FDA on November 21, 2020, is still included among regimens studied in the RECOVERY trial, in addition (as of the end of March 2021) to baricitinib and dimethyl fumarate. Trial arms investigating colchicine (recruitment stopped without clear indication of benefit), aspirin, and—in children only—low-dose dexamethasone were stopped in March 2021, with full results pending publication. Preliminary data on colchicine from a different study on outpatients with risk factors for more severe disease who were given the treatment within 24 hours of diagnosis suggested a reduction in the need for subsequent hospitalization.Evidence 12Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias and incomplete data. Montreal Heart Institute. Colchicine reduces the risk of COVID-19-related complications. Positive results from COLCORONA trial show that colchicine is the only effective oral medication for treating non-hospitalized patients. Published January 22, 2021. https://www.globenewswire.com/news-release/2021/01/23/2163109/0/en/Colchicine-reduces-the-risk-of-COVID-19-related-complications.html

Data considering hydroxychloroquine and lopinavir/ritonavir led investigators of the RECOVERY trial to stop recruitment in these arms, concluding that trial results excluded any meaningful mortality benefit of these drugs. Preliminary results of the SOLIDARITY trial confirm these conclusions. A recent study similarly has not confirmed the benefit of hydroxychloroquine prophylaxis.Evidence 13Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision. Boulware DR, Pullen MF, Bangdiwala AS, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med. 2020 Aug 6;383(6):517-525. doi: 10.1056/NEJMoa2016638. Epub 2020 Jun 3. PMID: 32492293; PMCID: PMC7289276. The EUA for chloroquine and hydroxychloroquine, issued in March 2020, was revoked on June 15, 2020.

Clinical trials of numerous strategies are ongoing. One of the most advanced trials is RECOVERY, a platform trial testing several interventions simultaneously. The arm using dexamethasone 6 mg daily for 10 days (or until hospital discharge) was closed to adult patients because of evidence of efficacy (lowering of overall mortality from 25.7% to 22.9%); this effect was most pronounced among patients requiring mechanical ventilation at the time of randomization (mortality 41.4% vs 29.3%) and among those requiring oxygen support without invasive mechanical ventilation at the entry to the trial (26.2% vs 23.3%). There was no suggestion of benefit among those who were hospitalized but at the time of trial entry did not need oxygen support.Evidence 14Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to subgroup analysis. RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, et al. Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report. N Engl J Med. 2020 Jul 17. doi: 10.1056/NEJMoa2021436. Epub ahead of print. PMID: 32678530. A meta-analysis published in September 2020 confirmed the benefit of glucocorticoids, which are widely used in patients requiring supplemental oxygen or higher levels of ventilatory support.Evidence 15Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Sterne JAC, Murthy S, Diaz JV, et al. Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis. JAMA. 2020 Sep 2. doi: 10.1001/jama.2020.17023. Epub ahead of print. PMID: 32876694.

Results from 2 studies, a small Chinese study and a larger international study (ACTT-1), support the use of remdesivir, predominantly in nonventilated hospitalized individuals requiring supplemental oxygen.Evidence 16Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision. Beigel JH, Tomashek KM, Dodd LE, et al; ACTT-1 Study Group Members. Remdesivir for the Treatment of Covid-19 - Final Report. N Engl J Med. 2020 Oct 8:NEJMoa2007764. doi: 10.1056/NEJMoa2007764. Epub ahead of print. PMID: 32445440; PMCID: PMC7262788. 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 May 16;395(10236):1569-1578. doi: 10.1016/S0140-6736(20)31022-9. Epub 2020 Apr 29. Erratum in: Lancet. 2020 May 30;395(10238):1694. PMID: 32423584; PMCID: PMC7190303. In these trials those who received remdesivir had a shorter time to recovery. As indicated above, results from the larger SOLIDARITY trial, released on October 15, 2020, in a preliminary form, do not support any clinically significant benefits of this drug in COVID-19.Evidence 17Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the incomplete report. WHO Solidarity trial consortium, Pan H, Peto R, Abdool Karim Q, et al. Repurposed antiviral drugs for COVID-19 –interim WHO SOLIDARITY trial results. Preprint posted online October 15, 2020. doi: https://doi.org/10.1101/2020.10.15.20209817 At this time, different expert groups have varying recommendations around the use of remdesivir, with some recommending its use in hospitalized patients requiring oxygen and others recommending against the use of remdesivir in anyone with COVID-19. In both cases the experts realize the limited confidence in the data available and the need for additional research.

The first randomized study of lopinavir/ritonavir was interpreted as not showing benefit, although it was too small to exclude relevant mortality benefit.Evidence 18Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to major imprecision. 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 Mar 18. doi: 10.1056/NEJMoa2001282. [Epub ahead of print] PubMed PMID: 32187464. Preliminary data from the much larger RECOVERY and SOLIDARITY trials suggest no mortality benefit, but a full report is pending.

Initial studies on the use of tocilizumab, an anti–interleukin-6 (IL-6) receptor antibody, demonstrated variable results, with some suggesting potential benefit with less need for mechanical ventilation but no difference in mortality, some showing no benefit, and some raising the possibility of harm in critically ill patients. The REMAP-CAP trial showed an increase in organ support–free days, decreased in-hospital mortality, and improved 90-day survival with the use of anti–IL-6 receptor antagonists tocilizumab and sarilumab, specifically in critically ill patients requiring respiratory or cardiovascular organ support who were enrolled within 24 hours of their ICU admission.Evidence 19Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to heterogeneity and imprecision. Veiga VC, Prats JAGG, Farias DLC, et al; Coalition covid-19 Brazil VI Investigators. Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial. BMJ. 2021 Jan 20;372:n84. doi: 10.1136/bmj.n84. PMID: 33472855; PMCID: PMC7815251. Salama C, Han J, Yau L, et al. Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med. 2021;384:20-30. doi:10.1056/NEJMoa2030340. Wise J. Covid-19: Critically ill patients treated with arthritis drug tocilizumab show improved outcomes, researchers report. BMJ. 2020 Nov 19;371:m4530. doi: 10.1136/bmj.m4530. PMID: 33214134. Stone JH, Frigault MJ, Serling-Boyd NJ, et al; BACC Bay Tocilizumab Trial Investigators. Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. N Engl J Med. 2020 Oct 21:NEJMoa2028836. doi: 10.1056/NEJMoa2028836. Epub ahead of print. PMID: 33085857; PMCID: PMC7646626. Preliminary results from the RECOVERY trial that included hospitalized patients with progressive COVID-19, defined as those receiving any oxygen therapy and having a CRP level ≥75 mg/L, show a decrease in 28-day mortality, reduction in need for invasive mechanical ventilation, and earlier hospital discharge with the receipt of tocilizumab. Upcoming meta-analyses and practice guidelines support the use of this drug in hospitalized patients, especially those with evidence of severe inflammatory processes.

In November 2020 an EUA was issued for another immunomodulating drug, the Janus kinase (JAK) inhibitor baricitinib, in combination with remdesivir in moderately to severely ill individuals, based on preliminary data (ACTT-2) showing an average of 1-day reduction in the time to recovery. Another potential therapy with a monoclonal antibody, SARS-CoV-2 neutralizing antibody LY-CoV555 (bamlanivimab; approved in Canada), received an EUA in nonhospitalized patients with early infection and at high risk of developing severe disease.Evidence 20Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to heterogeneity and indirectness. Chen P, Nirula A, Heller B, et al; BLAZE-1 Investigators. SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19. N Engl J Med. 2020 Oct 28:NEJMoa2029849. doi: 10.1056/NEJMoa2029849. Epub ahead of print. PMID: 33113295; PMCID: PMC7646625.  The ongoing ACTT-3 (interferon beta-1a) and ACTT-4 (baricitinib vs dexamethasone) are investigating the effects of adding different anti-inflammatory medications to antiviral remdesivir.

Numerous other treatments are being studied, including ivermectin, interferon beta-1b and beta-1a, ribavirin, fluvoxamine, favipiravir, vitamin C, vitamin D, and zinc.

Symptomatic Treatment

Treatment of COVID-19 is still to a major degree supportive. In patients with features of respiratory failure and shock, oxygen therapy should be administered, with a target of SpO2 ≥90% (≥92%-95% in pregnant women). Start from an oxygen flow rate of 5 L/min and titrate as needed. Antibiotic treatment should be used if bacterial superinfection is suspected. Although empiric antibiotics are frequently used in patients with COVID-19 and pneumonia as part of supportive care, the incidence of bacterial coinfections has been shown in a recent meta-analysis to be low (6.9%), with slightly higher rates in ventilated patients. Further data are needed on the appropriate selection of hospitalized individuals with COVID-19 that may benefit from antibiotics.

Nonspecific treatments with a potential of benefit include proning of nonventilated patients and, especially, increased doses of deep vein thrombosis (DVT) prophylaxis with a low threshold for full anticoagulation, particularly in the presence of high levels of D-dimer. As the frequency of thrombotic presentations or thrombotic complications is high, further studies are ongoing or in early stages of reporting. There are early and preliminary suggestions that therapeutic anticoagulation may have beneficial effects in those with moderate COVID-19 but may cause harm in those with severe COVID-19.Evidence 21Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision, indirectness, heterogeneity, and preliminary nature of data. National Institutes of Health. Full-dose blood thinners decreased need for life support and improved outcome in hospitalized COVID-19 patients. Published January 22, 2021. https://www.nih.gov/news-events/news-releases/full-dose-blood-thinners-decreased-need-life-support-improved-outcome-hospitalized-covid-19-patients Phend C. Trials Halt Full-Dose Clot Prophylaxis for Severe COVID-19 — Safety concerns cited in ACTIV-4, REMAP CAP, and ATTACC. MedPage Today. Published December 21, 2020. Lemos ACB, do Espírito Santo DA, Salvetti MC, et al. Therapeutic versus prophylactic anticoagulation for severe COVID-19: A randomized phase II clinical trial (HESACOVID). Thromb Res. 2020 Sep 21;196:359-366. doi: 10.1016/j.thromres.2020.09.026. Epub ahead of print. PMID: 32977137; PMCID: PMC7503069.

Management in sepsis and septic shock: see Sepsis and Septic Shock.

Some specific practice trends, based on collective experience and observational data, include using noninvasive ventilation and moving away from very early intubation; paying particular attention to lung compliance, which may frequently be normal and thus require lower positive end-expiratory pressure (PEEP) and plateau pressures; early use of prone ventilation; and attention to a high risk of thromboembolism.

Special ConsiderationsTop

Occupational Exposure of Health-Care Personnel

Note that the specific recommendations may differ depending on the country, epidemiologic situation, and resources.

An exposure leading to infection refers to mucosal contamination with biological materials that may contain the virus. According to the US Centers for Disease Control and Prevention (CDC), materials that warrant postexposure management include respiratory secretions; there is no evidence indicating that other fluids (blood, urine, stool, and vomit) contain viable, infectious SARS-CoV-2. To assess the risk of transmission of SARS-CoV-2, consider:

1) Duration of exposure (longer exposure increases the risk of transmission).

2) Clinical symptoms of the patient.

3) Whether a facemask (including what type) and eye protection were used by the health-care provider (HCP).

4) Whether the HCP used other personal protective equipment (PPE), in particular eye protection.

5) Whether aerosol-generating procedures were performed.

6) Whether a face covering was used by the patient.

High-risk exposures are defined as situations where an HCP is not wearing PPE that protects their mouth, nose, and eyes in the setting of droplets (eg, coughing) or during an aerosol-generating procedure, or situations where an HCP has direct unprotected contact with secretions from a patient with COVID-19 (cardiopulmonary resuscitation, intubation, extubation, bronchoscopy, nebulization, sputum induction).

Medium-risk exposures are defined as situations where an HCP without proper PPE has prolonged contact with a patient with COVID-19, which may result in mucosal or cutaneous exposure to potentially infectious materials.

Low-risk exposures are defined as situations where an HCP is using appropriate PPE but has prolonged close contact with patients with COVID-19. Although the currently available guidance on hygiene, sanitary standards, and use of PPE should be sufficient, it is nevertheless possible that due to oversight mistakes can be made (eg, during the doffing procedure), leading to SARS-CoV-2 transmission.

No occupational risk of exposure to SARS-CoV-2 is a risk category for HCPs who have no direct contact with COVID-19 patients, do not enter hospital wards or isolation wards for COVID-19 patients, and follow the routine safety precautions.

In case of exposure to biological materials from a patient with suspected SARS-CoV-2 infection, the exposed HCP should be treated as having high-risk or medium-risk exposure.

In the case of high-risk and medium-risk exposures, the HCP should undergo active monitoring and should be considered to be suspended from work for 14 days following the exposure. Some jurisdictions also recommend testing around day 7 to 10 of exposure or towards the end of the incubation period to exclude asymptomatic infection. Active monitoring refers to monitoring performed by a public health authority that regularly contacts the individuals potentially exposed to SARS-CoV-2 to assess them for the presence of symptoms. Communication may include telephone calls or internet-based means and should occur at least once a day. If an exposed HCP develops symptoms consistent with COVID-19, they should immediately self-isolate and notify public health authorities to arrange further evaluation (epidemiologic studies, need for hospitalization).

PrognosisTop

In the majority of cases COVID-19 has a mild course. In the elderly patients and those with chronic medical conditions the risk of acute respiratory failure and death is substantially higher.

PreventionTop

Specific Prevention

Vaccination: see Vaccines: SARS-CoV-2 (COVID-19).

As of the beginning of 2021, mass vaccination projects were being launched around the world. Several vaccines have been approved by various national and international agencies, including mRNA, viral vector, and inactivated virus vaccines, with reports suggesting some vaccines have >90% efficacy in preventing symptomatic disease.Evidence 22Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Polack FP, Thomas SJ, Kitchin N, et al; C4591001 Clinical Trial Group. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 2020 Dec 31;383(27):2603-2615. doi: 10.1056/NEJMoa2034577. Epub 2020 Dec 10. PMID: 33301246; PMCID: PMC7745181. Vaccines and Related Biological Products Advisory Committee Meeting: December 17, 2020. FDA Briefing Document: Moderna COVID-19 Vaccine. Published December 17, 2020. Accessed December 24, 2020. https://www.fda.gov/advisory-committees/advisory-committee-calendar/vaccines-and-related-biological-products-advisory-committee-december-17-2020-meeting-announcement

Nonspecific Prevention

1. General recommendations:

1) Frequently performing hand hygiene with soap and water or alcohol-based hand sanitizers.

2) Avoiding touching the face.

3) Reducing travel to a minimum.

4) Avoiding crowds and large gatherings.

5) Maintaining at least a 1-meter distance from others (odds decreased ~5-fold with the absolute difference in risk ~10%), with 2 meters providing further protection (~2-fold additional risk decrease).Evidence 23Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of studies and increased due to the large effect size and dose-response gradient. Chu DK, Akl EA, Duda S, Solo K, Yaacoub S, Schünemann HJ; COVID-19 Systematic Urgent Review Group Effort (SURGE) study authors. 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 Jun 1;395(10242):1973–87. doi: 10.1016/S0140-6736(20)31142-9. Epub ahead of print. PMID: 32497510; PMCID: PMC7263814.

6) Reducing exposure and infections by wearing facemasks (odds decreased 6-7-fold with the absolute difference in risk ~14%; this represents combined data from the evaluation of surgical masks and N95 masks; surgical masks alone likely provide a 3-fold decrease in the odds of infection).Evidence 24Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of data. Chu DK, Akl EA, Duda S, Solo K, Yaacoub S, Schünemann HJ; COVID-19 Systematic Urgent Review Group Effort (SURGE) study authors. 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 Jun 1;395(10242):1973–87. doi: 10.1016/S0140-6736(20)31142-9. Epub ahead of print. PMID: 32497510; PMCID: PMC7263814.

7) Avoiding contact with individuals with respiratory symptoms.

8) Reducing exposure and infections by wearing eye protection (goggles, safety glasses; odds of infection decreased ~4-5-fold with the absolute difference in risk ~10%). This preventing measure is recommended first and foremost for health-care workers and when the above-listed measures cannot be maintained.Evidence 25Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of data. Chu DK, Akl EA, Duda S, Solo K, Yaacoub S, Schünemann HJ; COVID-19 Systematic Urgent Review Group Effort (SURGE) study authors. 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 Jun 1;395(10242):1973–87. doi: 10.1016/S0140-6736(20)31142-9. Epub ahead of print. PMID: 32497510; PMCID: PMC7263814.

2. Quarantine or self-isolation: Healthy individuals who had contact with an infected person undergo a 14-day quarantine (the duration is shorter in some jurisdictions). The duration and type of quarantine (self-observation, staying at home, quarantine in a hospital) may depend on the type of contact (high-risk vs low-risk exposure) and is determined by local public health authorities.

3. Isolation of infected individuals: Isolation precautions can be used (1) to prevent droplet transmission or direct contact transmission or (2) during aerosol-generating procedures, to prevent airborne transmission. Before entering the patient room, don a set of PPE. After leaving the room, PPE should be removed in a designated area with a waste container for single-use PPE and hand decontamination equipment. However, given the worldwide supply shortage of PPE, extended use and reuse protocols as well as reprocessing can be considered.

Precautions for droplet transmission and direct contact transmission: Patients should be placed in well-ventilated rooms with access to a washroom (in rooms with natural ventilation an average ventilation rate of 60 L/s per patient should be provided). If available, single-patient rooms are preferred. Patients with confirmed SARS-CoV-2 infection can be cohorted. When possible, designated HCPs should be assigned to provide care for the patients. The number of visitors should be restricted. A log of all persons entering the room should be kept (including HCPs and visitors). Medical equipment should be single-use or dedicated for a single patient only (in the case of reusable equipment, eg, stethoscope, thermometer, blood pressure monitor, pulse oximeter). If reusable equipment is shared by different patients, it should be disinfected between uses. Room surfaces and equipment in the patient’s environment should be regularly cleaned and disinfected. Transport of patients within the hospital should be limited to a minimum. When feasible, portable diagnostic equipment should be used (eg, bedside radiograph). If the patient must be transported (eg, for diagnostic evaluation), use the shortest route and notify the HCPs in the receiving area in advance. The patient should be wearing a facemask. Transport personnel and receiving personnel having contact with the patient must use PPE. Minimize exposure for staff, other patients, and visitors during transport.

Precautions for airborne transmission (airborne infection isolation rooms [AIIRs]): If available, aerosol-generating medical procedures should be performed in well-ventilated rooms maintaining constant negative pressure, providing ≥12 air exchanges per hour, and with controlled direction of airflow (preferably) or in a naturally ventilated room with an average ventilation rate ≥160 L/s per patient.

4. PPE: A minimum set of PPE should include (recommendations in different jurisdictions differ and evolve):

1) PPE for respiratory protection: Surgical or procedural masks should be used, with the level of fluid resistance depending on the potential risk of splashes. Currently the WHO and the Public Health Agency of Canada recommend surgical masks as sufficient while providing routine care and reserve N95 respirator masks for aerosol-producing procedures. It should be noted that surgical masks may not provide sufficient protection against airborne transmission of microbes.

2) PPE for eye protection: Goggles or a face shield.

3) PPE for body protection: A long-sleeved gown or protective suit.

4) PPE for hand protection: Gloves.

Health-care facilities should have PPE in different sizes.

Video instructions on wearing and removing PPE:

1) For airborne precautions (aerosol-generating procedures), see a video from Sunnybrook Health Sciences Centre, Toronto, Canada: https://youtu.be/syh5UnC6G2k.

2) For droplet precautions, see a video from St Joseph’s Healthcare Hamilton, Canada: https://youtu.be/i_J2qtM1Aus.

The sequence of wearing (donning) PPE: Before donning PPE, disinfect hands. Then don the gown followed by the respirator mask. Make sure the respirator mask fits snugly to the face (in the case of filtering facepiece 2 [FFP2] and 3 [FFP3] standard respirators all exhaled air should be filtered by the respirator; facial hair can interfere with the proper fit). Put on goggles or a face shield. The goggles should fit over the respirator mask. The last step is donning gloves, which should extend to cover the wrists and cuffs of the gown.

Removing (doffing) PPE (when using a gown for body protection; some details of the procedures differ between jurisdictions): This procedure requires particular caution, because the surface of PPE may be contaminated with infectious material. Incorrect or careless removal of PPE may result in accidental contamination followed by virus transmission. Single-use equipment should be discarded immediately after removal in an infectious waste container. Reusable equipment (eg, face shields or goggles) should be placed in a designated container and decontaminated before next use according to the manufacturer’s instructions. Start by disinfecting your hands. First remove the gloves in a way that minimizes hand contamination. Then disinfect the hands. You may consider donning a new pair of gloves (not done in Hamilton). With the new gloves on (if used), remove the gown. The back of the gown should be grabbed and pulled away from the body, keeping the contaminated front part inside the gown. Turn the sleeves inside out. (Avoid touching the contaminated front part of the gown.) Disinfect the hands again. Remove the goggles/face shield without touching their front part. You may disinfect the hands. Remove the respirator mask (grasp the straps and carefully remove the respirator without touching its outer surface). Disinfect the hands. Discard the gloves put on before removing the gown (if a second pair of gloves is used). Disinfect the hands again. Individual health-care facilities should adjust the procedures for donning and removing PPE based on the type of available equipment.

5. Individuals caring for infants: Infants cannot use respirator masks or facemasks and require special precautions to prevent viral transmission. Adults should use a respirator mask, perform hand hygiene before touching the infant, and regularly disinfect toys and other objects in the infant’s environment.

6. Reporting: Individuals traveling from countries where COVID-19 is present or who had contact with a patient infected with SARS-CoV-2 should notify public health authorities and discuss further management.

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