Coronavirus Disease 2019 (COVID-19)

How to Cite This Chapter: Loeb M, Alhazzani W, Mertz D, Singhal N, Chagla Z, Pai M, Jaeschke R, Rymer W, Wroczyńska A. Coronavirus Disease 2019 (COVID-19). McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. Accessed July 01, 2022.
Last Updated: April 2, 2022
Last Reviewed: April 2, 2022
Chapter Information

Please note that COVID-19–related information is evolving rapidly, including epidemiology and all modes of prevention and treatments. Different jurisdictions are coming up with new instructions on a monthly 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 (April 2022) different recommendations and patterns of practice surrounding the use of several therapies illustrate this not unexpected phenomenon.


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, India, and Brazil reporting the highest number of cases to date. Current epidemiologic data are available at,, and As of March 2022, there were >450 million confirmed cases and >6 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. Initially 3 main variants of concern (VOCs), which are more transmissible than the wild-type variant, were increasingly circulating in numerous countries, including Canada. These were the United Kingdom (B.1.1.7, Alpha), South African (B.1.135, Beta), and Brazilian (P.1, Gamma) lineages. In the summer 2021 a variant originating from India (B.1.617, Delta) became rapidly dominant in numerous geographic locations, including Canada. In November 2021 a report from South Africa announced the arrival of the (already widespread) B.1.1.529 variant (Omicron; likely more contagious but possibly causing less severe disease). By the end of 2021 that variant has become dominant across North America and Europe. The efficacy of different vaccines in preventing symptomatic and severe illness due to various variants is at present not entirely clear but likely substantial, especially after a booster dose (see Vaccines: COVID-19).Evidence 1Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision and risk of bias. Lopez Bernal J, Andrews N, Gower C, et al. Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant. N Engl J Med. 2021 Jul 21. doi: 10.1056/NEJMoa2108891. Epub ahead of print. PMID: 34289274. Similarly, the efficacy of some preventive or treatment interventions, eg, monoclonal antibodies, may differ for different variants.

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 (cytokine storm). 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 appears to occur more frequently during aerosol-generating medical procedures or in certain circumstances such as indoor, crowded, and poorly ventilated spaces. It becomes clear that the Omicron variant transmits more easily than the previously dominant variants. 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. 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 2Moderate 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, immunosuppression, and lack of vaccination. 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 3Low 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 for the wild-type variant and initial VOCs is typically 2 to 14 days (5 days on average, with >95% of cases developing by day 11). The incubation period for the Omicron variant is likely shorter. Symptomatic individuals may transmit the virus to others; the extent of transmission from those who are presymptomatic is likely substantial.Evidence 4Moderate 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: 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 and is likely shorter for the Omicron variant. A small number of patients with severe COVID-19 may shed replication-competent viruses for up to 3 weeks, particularly in the context of critical illness or significant immunocompromised state.Evidence 5Low 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.

Clinical Features, Natural History, PrognosisTop

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 (MIS-C) and young adults (MIS-A).

At the beginning of the pandemic in ~80% of diagnosed patients the course of the disease was mild. Approximately 15% of symptomatic 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 those hospitalized required ICU admission. The numbers have been similar in the United States over the course of the last year, although overall mortality in hospitalized patients declined from >16% to ~9%.Evidence 6Moderate 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. Bennett TD, Moffitt RA, Hajagos JG, et al; National COVID Cohort Collaborative (N3C) Consortium. Clinical Characterization and Prediction of Clinical Severity of SARS-CoV-2 Infection Among US Adults Using Data From the US National COVID Cohort Collaborative. JAMA Netw Open. 2021 Jul 1;4(7):e2116901. doi: 10.1001/jamanetworkopen.2021.16901. PMID: 34255046; PMCID: PMC8278272. In Ontario, Canada, the mortality rate of patients admitted to ICU was >30% at the beginning of 2022. The severity of the disease caused by the Omicron variant appears lower.

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 7High 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: The overall mortality rate varies by country, pattern of testing, and demographic characteristics in a given report, and as of mid-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 8Moderate 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 among all currently infected (active) patients fluctuates depending on the rate of new infections, testing criteria, and changes in the dominant variant; eg, as of the end of January 2022, the reported proportion of such patients in Canada was ~0.5% (which to a major degree relates to a very large number of infections caused by the Omicron variant). The future may well depend on the virulence of the new variants and vaccination status of affected individuals; eg, in Ontario as of November 2021 the probability of new SARS-CoV-2 infection among those fully vaccinated versus those not vaccinated was ~3.5-fold lower; of requiring hospitalization, ~14-fold lower; and of the need for ICU admission, ~24-fold lower.Evidence 9Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Ontario Dashboard.

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 ( Of note, these were developed for use with initial variants and in an unvaccinated population.

Clinically, patients with mild infection typically recover symptomatically within 1 to 2 weeks, with some experiencing long-term, nonspecific postviral symptoms, lasting 12 weeks or occasionally longer (including dyspnea, fatigue, chest pain, and cough); these may follow acute COVID-19 and resemble chronic fatigue syndrome. The long-term sequelae of the disease (labeled as long COVID-19 or post-COVID syndrome) may have respiratory, cardiac, and/or neurologic manifestations, with no clear specific interventions so far.Evidence 10Moderate Quality of Evidence (moderate confidence that we know true effects). Quality of Evidence lowered due to the risk of bias but increased due to the strength of association. Nasserie T, Hittle M, Goodman SN. Assessment of the Frequency and Variety of Persistent Symptoms Among Patients With COVID-19: A Systematic Review. JAMA Netw Open. 2021 May 3;4(5):e2111417. doi: 10.1001/jamanetworkopen.2021.11417. PMID: 34037731; PMCID: PMC8155823. Walter K. An Inside Look at a Post-COVID-19 Clinic. JAMA. 2021 May 25;325(20):2036-2037. doi: 10.1001/jama.2021.2426. PMID: 33950195. Ayoubkhani D, Khunti K, Nafilyan V, et al. Post-covid syndrome in individuals admitted to hospital with covid-19: retrospective cohort study. BMJ. 2021 Mar 31;372:n693. doi: 10.1136/bmj.n693. PMID: 33789877; PMCID: PMC8010267. Sivan M, Taylor S. NICE guideline on long covid. BMJ. 2020 Dec 23;371:m4938. doi: 10.1136/bmj.m4938. PMID: 33361141. 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. Williams FMK, Muirhead N, Pariante C. Covid-19 and chronic fatigue. BMJ. 2020 Jul 30;370:m2922. doi: 10.1136/bmj.m2922. PMID: 32732337. More data on the prevalence, prognosis, and treatment are clearly needed to delineate this issue.


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); 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]), mid-turbinate swabs, throat swabs, uninduced sputum, and even spit. As the sensitivity of tests may vary, a high index of clinical suspicion has to be considered even in patients with negative test results. Therefore a strategy of initially obtaining an NPS is recommended in hospitalized patients with suspected COVID-19. If the initial test is negative, a lower respiratory sample can then be obtained as needed. Of note, the sensitivity of specimens varies with the course of the illness and sensitivity of upper airway samples may be 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 high specificity but lower sensitivity than PCR tests; however, they 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 or even used as at-home tests.Evidence 11Low 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 clinical tests to diagnose active COVID-19, as they are usually negative early in infection. They have greater utility for epidemiologic purposes. 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 unvaccinated 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 at least 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 shows 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) Clinical monitoring involves following of vital signs including respiratory rate and effort, blood pressure, heart rate, 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 January 2022, a confirmed case is defined as:

1) A person with laboratory detection of ≥1 specific gene target 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).


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).

The most current results from the RECOVERY trial (acetylsalicylic acid [ASA], tocilizumab, convalescent plasma, Regeneron monoclonal antibodies, colchicine, azithromycin, dexamethasone, lopinavir/ritonavir, hydroxychloroquine) can be found at Currently investigated strategies include empagliflozin, monoclonal antibody sotrovimab, molnupiravir, paxlovid, and different doses of steroids.

The SOLIDARITY trial results (remdesivir, hydroxychloroquine, lopinavir, interferon) can be found at Studies on artesunate, imatinib, and infliximab (Solidarity PLUS) are ongoing.

The ACTT trial has already reported on the effects of remdesivir (ACTT-1) and baricitinib (in combination with remdesivir). Further data are expected considering interferon beta-1a (in combination with remdesivir) and considering the addition of baricitinib versus dexamethasone to remdesivir.

The REMAP-CAP has reported at least part of the data on tocilizumab/sarilumab, convalescent plasma, therapeutic anticoagulation, dexamethasone, and hydroxychloroquine or chloroquine with or without a macrolide. The published results can be accessed online at

Note: The unprecedented speed of evidence generation and emergence of new variants have resulted in an unprecedented number of clinical practice guidelines, some already outdated by the time of publication. We attempt to summarize the main elements of the current pattern of practice in our area (Hamilton, Canada, April 2022), while acknowledging that alternative recommendations or suggestions are being followed in other regions, depending on the assessment of evidence and availability of different therapies. The Ontario COVID-19 Science Advisory Table periodically issues new versions of the Clinical Practice Guideline Summary, available online at

Our Pattern of Practice

In general we follow the advice of the Ontario COVID-19 Science Advisory Table published on April 1, 2022. These practice guidelines change frequently and can be accessed from Therapeutic Management of Adult Patients with COVID-19.

Treatment generally depends on the severity of the disease (evaluated mostly by the degree of hypoxia and need for supportive measures) and on where an individual is in the disease course (which roughly corresponds to a viral phase during the first week of illness and a predominantly inflammatory phase thereafter). In most situations the severe phase of the disease, associated with profound hypoxia, is related to the inflammatory phase. The pattern of management continues to evolve and is guided by ongoing studies (including those indicated above).

In the ambulatory outpatient setting (patients not requiring oxygen or hospitalization for other COVID-19 symptoms), asymptomatic and mildly symptomatic patients at low risk of deterioration usually receive no specific treatment. However, early oral and IV therapies may reduce the hospitalization risk and alleviate symptoms in individuals at higher risk due to factors such as the presence of immunosuppression, advanced age, unvaccinated status, last vaccination >6 months ago, comorbidities (obesity [body mass index (BMI) ≥30 kg/m2], undergoing dialysis or with stage 5 kidney disease [estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m2], diabetes, cerebral palsy, intellectual disability of any severity, sickle cell disease, receiving active cancer treatment, post solid organ or stem cell transplant). Largely, these therapies include antiviral therapies, such as paxlovid, remdesivir, and monoclonal antibodies, and disease response modifiers, which reduce inflammation, such as fluvoxamine and inhaled glucocorticoids. Currently in Ontario patients could be offered remdesivir for 3 days (200 mg IV on day 1, then 100 mg IV on days 2 and 3) or oral paxlovid for 5 days, depending on the number of vaccine doses given, access to medications, and number of risk factors (including advanced age). IV sotrovimab 500 mg in a single dose has been offered recently, but it is no longer routinely used due to low responsiveness of the new SARS-CoV-2 variant (BA.2). In patients at lower risk, fluvoxamine and budesonide may be considered. Other oral antiviral treatments such as molnupiravir may also become available and are currently recommended by the WHO guidelines. While these therapies are not appropriate for all patients, those at the highest risk of hospitalization should be considered for early antiviral therapy as soon after the symptom onset as possible.

Depending on availability and patient characteristics and preferences, the developing pattern of practice includes administration of one of the following drugs: paxlovir, remdesivir, or molnupiravir (order as in the NIH guidelines accessed on April 2, 2022; with the use of sotrovimab restricted to the areas where subvariant BA.2 is not dominant).

Inhaled glucocorticoids (budesonide 800 microg bid for 14 days or until symptom resolution) represent a potential low-risk treatment. However, they were investigated only in open-label trials and their efficacy needs further confirmation.Evidence 12Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness and the risk of bias. Ramakrishnan S, Nicolau DV Jr, Langford B, et al. Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial. Lancet Respir Med. 2021 Apr 9:S2213-2600(21)00160-0. doi: 10.1016/S2213-2600(21)00160-0. Epub ahead of print. Erratum in: Lancet Respir Med. 2021 Jun;9(6):e55. PMID: 33844996; PMCID: PMC8040526. Yu LM, Bafadhel M, Dorward J, et al; PRINCIPLE Collaborative Group. Inhaled budesonide for COVID-19 in people at higher risk of adverse outcomes in the community: interim analyses from the PRINCIPLE trial. medRxiv. Published April 12, 2021. doi: The Ontario COVID-19 Advisory Table suggests the possibility of such treatment in symptomatic patients with risk factors (see the list above). Another suggested treatment (based on very low quality of evidence) for patients within 1 week of symptom onset is oral fluvoxamine 50 mg/day titrated up to 100 mg tid for 15 days.

Colchicine, dosed 0.5 mg bid for 3 days followed by once-daily administration for 27 days, is another potential option. However, its use is limited to a specific group of individuals at higher risk for severe disease and by its rather modest efficacy and adverse effects of treatment.Evidence 13Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to lowered due to imprecision and the risk of bias. Tardif JC, Bouabdallaoui N, L'Allier PL, et al; COLCORONA Investigators. Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial. Lancet Respir Med. 2021 May 27:S2213-2600(21)00222-8. doi: 10.1016/S2213-2600(21)00222-8. Epub ahead of print. PMID: 34051877; PMCID: PMC8159193. The Ontario guidelines do not currently support the use of colchicine, vitamin D, or interferon (with or without lopinavir/ritonavir and ribavirin).

Other monoclonal antibodies (casirivimab/imdevimab [REGEN-COV], bamlanivimab/etesevimab) are available; however, with the mutations seen with the Omicron variant, neutralization of these antibodies has diminished to the point where they should not be offered.

In the hospitalized mildly affected patients (those not requiring physiologic support with oxygen and IV hydration) treatment is mostly supportive, but the above considerations of paxlovid, molnupiravir, sotrovimab, remdesivir, budesonide, and fluvoxamine apply, especially for patients hospitalized for other reasons or those with nosocomial infection.

In hospitalized moderately affected patients (broadly defined as those requiring supplemental oxygen) we routinely use a 10-day course of dexamethasone (6-12 mg/d; there is a possibility that 12 mg/d may be more beneficial)Evidence 14Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness and imprecision. COVID STEROID 2 Trial Group; Munch MW, Myatra SN, Vijayaraghavan BKT, et al. Effect of 12 mg vs 6 mg of Dexamethasone on the Number of Days Alive Without Life Support in Adults With COVID-19 and Severe Hypoxemia: The COVID STEROID 2 Randomized Trial. JAMA. 2021 Nov 9;326(18):1807-1817. doi:10.1001/jama.2021.18295. PMID: 34673895; PMCID: PMC8532039. and IL-6 inhibitor tocilizumab (within 14 days of hospital admission, especially in those with evidence of systemic inflammation, a CRP level ≥75 mg/L, rapid disease progression, or a combination of those) and a 5-day course of remdesivir. In settings where tocilizumab is unavailable, the IL-6 inhibitor sarilumab or JAK-2 inhibitors, such as baricitinib (4 mg/d orally for 14 days or until hospital discharge), may be alternatives.Evidence 15Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectnessMarconi VC, Ramanan AV, de Bono S, et al; COV-BARRIER Study Group. Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial. Lancet Respir Med. 2021 Aug 31:S2213-2600(21)00331-3. doi: 10.1016/S2213-2600(21)00331-3. Epub ahead of print. Erratum in: Lancet Respir Med. 2021 Sep 8;: PMID: 34480861; PMCID: PMC8409066. In moderately affected patients without contraindications, we also favor full-dose anticoagulation with low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH). Perceived bleeding risk may modify such an approach.

In severely and critically ill patients (those requiring invasive ventilatory or circulatory support) we use dexamethasone and tocilizumab, but not remdesivir (especially when late in the course of disease). Sarilumab can also be used if tocilizumab supplies are limited. We use prophylactic rather than full-dose or intermediate anticoagulation, as routine full-dose anticoagulation is not recommended and may be harmful unless indicated for a separate condition. Baricitinib is suggested in patients receiving dexamethasone, but not in combination with IL-6 inhibitors (tocilizumab). We individualize the use of remdesivir and anticoagulation in patients requiring oxygen delivery through high-flow nasal cannula or noninvasive ventilation (of note, those interventions were considered as ICU care in anticoagulation trials).

The Ontario COVID-19 Science Advisory Table recommends against the use of chloroquine and hydroxychloroquine, azithromycin, lopinavir/ritonavir, and ivermectin. Casirivimab/imdevimab use is also not recommended in the context of infection with the Omicron variant, which is the dominant variant in Ontario as of the beginning of 2022. The panel suggests other therapies—colchicine, interferon, and vitamin D—to be used in clinical trials (rather than in regular clinical care).

A number of other therapies have been considered, but they have not been used in our setting (except in the context of clinical trials). These include convalescent plasma, ribavirin, favipiravir, vitamin C, zinc, and antibacterial treatment (unless justified for other reasons, which happens relatively frequently in severely ill patients with COVID-19).

Symptomatic and Supportive Treatment

Treatment of COVID-19 is still to a major degree supportive due to sparse evidence of efficacy against different variants and supply shortage. 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. The advice to use antibacterial agents only when needed is obvious but rather general.

Nonspecific treatments with a potential of benefit include prone positioning of nonventilated and ventilated patients and advantage of high-flow oxygen therapy through a nasal cannula not only over conventional oxygen therapyEvidence 16Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Ospina-Tascón GA, Calderón-Tapia LE, García AF, et al; HiFLo-Covid Investigators. Effect of High-Flow Oxygen Therapy vs Conventional Oxygen Therapy on Invasive Mechanical Ventilation and Clinical Recovery in Patients With Severe COVID-19: A Randomized Clinical Trial. JAMA. 2021 Dec 7;326(21):2161-2171. doi:10.1001/jama.2021.20714. PMID: 34874419; PMCID: PMC8652598. but possibly also over noninvasive ventilation.Evidence 17Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness and imprecision. Oczkowski S, Ergan B, Bos L, et al. ERS Clinical Practice Guidelines: high-flow nasal cannula in acute respiratory failure. Eur Respir J. 2021 Oct 28;2101574. doi: 10.1183/13993003.01574-2021. Attention is also directed towards the high prevalence of thrombotic complications with implication of a low threshold for full-dose anticoagulation. As the frequency of thrombotic presentations or thrombotic complications is high, numerous studies evaluated relative merits of prophylactic versus full-dose anticoagulation with heparin. Data available in December 2021 suggest the advantage of full-dose anticoagulation in hospitalized patients who do not require ICU-level organ support, but it is of no proven benefit in patients requiring such ICU-level support (particularly invasive ventilation, inotropes, or vasopressors; the course of action is less clear in patients receiving oxygen through a high-flow nasal cannula or noninvasive ventilation and may depend on the perceived risk of bleeding).Evidence 18Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision, indirectness, and heterogeneity. 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. ATTACC Investigators; ACTIV-4a Investigators; REMAP-CAP Investigators; Lawler PR, Goligher EC, Berger JS, et al. Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19. N Engl J Med. 2021 Aug 4. doi: 10.1056/NEJMoa2105911. Online ahead of print. PMID: 34351721. REMAP-CAP Investigators; ACTIV-4a Investigators; ATTACC Investigators; Goligher EC, Bradbury CA, McVerry BJ, et al. Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19. N Engl J Med. 2021 Aug 4. doi: 10.1056/NEJMoa2103417. Online ahead of print. PMID: 34351722.

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

Some additional specific practice trends, based on collective experience and observational data, include moving away from early intubation and paying particular attention to lung compliance, which may frequently be normal and thus require lower positive end-expiratory pressure (PEEP) and plateau pressures.

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 United States 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), including 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 microbreaches or 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.

Individuals who are vaccinated and exposed to SARS-CoV-2 in the health-care environment were considered to be at reduced risk of acquiring COVID-19; however, vaccination status is less protective in the context of the Omicron variant. Therefore, the recommendations for the need for isolation of health-care workers are dynamic.

In the case of high-risk and medium-risk unvaccinated exposures, the HCP should undergo active monitoring and should be considered to be suspended from work for 10 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).


Specific Prevention

1. Vaccination: see Vaccines: COVID-19.

As of 2022 mass vaccination projects are being conducted 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, hospitalization, critical illness, and death, depending on the variant.Evidence 19Moderate 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.

2. Pharmacologic prevention: Numerous potential strategies are being investigated.

Bamlanivimab, a monoclonal antibody, was shown to markedly reduce the frequency of acquiring symptomatic disease in a very high–risk population, but its applicability to the current epidemiologic situation with different viral variants is unclear.Evidence 20Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Cohen MS, Nirula A, Mulligan MJ, et al; BLAZE-2 Investigators. Effect of Bamlanivimab vs Placebo on Incidence of COVID-19 Among Residents and Staff of Skilled Nursing and Assisted Living Facilities: A Randomized Clinical Trial. JAMA. 2021 Jun 3. doi: 10.1001/jama.2021.8828. Epub ahead of print. PMID: 34081073. Kuritzkes DR. Bamlanivimab for Prevention of COVID-19. JAMA. 2021 Jun 3. doi: 10.1001/jama.2021.7515. Epub ahead of print. PMID: 34081075.

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 1-meter distance from others (odds decreased ~5-fold with the absolute difference in risk ~10% in high-risk situations), with 2 meters providing further protection (~2-fold additional risk decrease).Evidence 21Moderate 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% in high-risk situations); 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 22Low 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% in high-risk situations). This preventing measure is recommended first and foremost for health-care workers and when the above-listed measures cannot be maintained.Evidence 23Low 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 10-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 limited supply of PPE, extended use and reuse protocols as well as reprocessing are still considered.

Precautions for droplet transmission and direct contact transmission (example): 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. The number of visitors should be limited. 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. Throughout the pandemic the WHO and the Public Health Agency of Canada (PHAChave recommended surgical masks as sufficient while providing routine care and reserved N95 respirator masks for aerosol-producing procedures. It should be noted that surgical masks may not provide sufficient protection against airborne transmission of microbes. In the current context of infections with the Omicron variant and the associated uncertainty due to concerns of higher transmissibility, the PHAC recommends the use of an N95 respirator (or equivalent) for care of all individuals with suspected or confirmed COVID-19 in the health-care setting.

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:

2) For droplet precautions, see a video from St Joseph’s Healthcare Hamilton, Canada:

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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