RECOVERY Trial. Accessed July 25, 2021. https://www.recoverytrial.net
Ontario. Ministry of Health and Long-Term Care. COVID-19 Guidance for the Health Sector. Case Definition – Coronavirus Disease (COVID-19). Updated July 23, 2021. Accessed July 25, 2021. http://health.gov.on.ca/en/pro/programs/publichealth/coronavirus/2019_guidance.aspx
National Institutes of Health. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. Updated July 8, 2021. Accessed July 25, 2021. https://covid19treatmentguidelines.nih.gov
World Health Organization. Draft landscape of COVID-19 candidate vaccines. Updated July 3, 2021. https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines
National Institutes of Health. The COVID-19 Treatment Guidelines Panel’s Statement on the Emergency Use Authorization of Anti-SARS-CoV-2 Monoclonal Antibodies for the Treatment of COVID-19. Updated April 8, 2021. https://www.covid19treatmentguidelines.nih.gov/statement-on-anti-sars-cov-2-monoclonal-antibodies-eua
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 April 6, 2021. Accessed July 25, 2021. https://covid19-sciencetable.ca/sciencebrief/clinical-practice-guideline-summary-recommended-drugs-and-biologics-in-adult-patients-with-covid-19-version-2-0
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.
Rochwerg B, Siemieniuk RA, Agoritsas T, et al. A living WHO guideline on drugs for covid-19. BMJ. 2020 Sep 4;370:m3379. doi: 10.1136/bmj.m3379. Update in: BMJ. 2020 Nov 19;371:m4475. Update in: BMJ. 2021 Mar 31;372:n860. PMID: 32887691.
Centers for Disease Control and Prevention. Interim U.S. Guidance for Risk Assessment and Public Health Management of Healthcare Personnel with Potential Exposure in a Healthcare Setting to Patients with Coronavirus Disease (COVID-19). Updated March 10, 2021. Accessed April 5, 2021.https://www.cdc.gov/coronavirus/2019-ncov/hcp/guidance-risk-assesment-hcp.html
Chalmers JD, Crichton ML, Goeminne PC, et al. Management of hospitalised adults with coronavirus disease-19 (COVID-19): A European Respiratory Society living guideline. Eur Respir J. 2021 Mar 10:2100048. doi: 10.1183/13993003.00048-2021. Epub ahead of print. PMID: 33692120; PMCID: PMC7947358.
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/
Alhazzani W, Evans L, Alshamsi F, et al. Surviving Sepsis Campaign Guidelines on the Management of Adults With Coronavirus Disease 2019 (COVID-19) in the ICU. Crit Care Med. Published online January 28, 2021. doi:10.1097/CCM.0000000000004899.
World Health Organization. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected: Interim guidance, 25 January 2021. Accessed June 10, 2021. https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected
World Health Organization. Global surveillance for COVID-19 disease caused by human infection with the 2019 novel coronavirus: Interim guidance, 16 December, 2020. Accessed June 10, 2021. https://www.who.int/publications-detail/global-surveillance-for-human-infection-with-novel-coronavirus-(2019-ncov)
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
Hunt RH, East JE, Lanas A, et al. COVID-19 and Gastrointestinal Disease. Implications for the Gastroenterologist. Dig Dis. 2020 Oct 9. doi: 10.1159/000512152. Epub ahead of print. PMID: 33040064.
Knight SR, Ho A, Pius R, et al; ISARIC4C investigators. Risk stratification of patients admitted to hospital with covid-19 using the ISARIC WHO Clinical Characterisation Protocol: development and validation of the 4C Mortality Score. BMJ. 2020 Sep 9;370:m3339. doi: 10.1136/bmj.m3339. PMID: 32907855.
Allotey J, Stallings E, Bonet M, et al; for PregCOV-19 Living Systematic Review Consortium. Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis. BMJ. 2020 Sep 1;370:m3320. doi: 10.1136/bmj.m3320. PMID: 32873575; PMCID: PMC7459193.
Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review. JAMA. 2020 Jul 10. doi: 10.1001/jama.2020.12839. Epub ahead of print. PMID: 32648899.
Gandhi RT, Lynch JB, Del Rio C. Mild or Moderate Covid-19. N Engl J Med. 2020 Apr 24. doi: 10.1056/NEJMcp2009249. [Epub ahead of print] Review. PubMed PMID: 32329974.
Alhazzani W, Møller MH, Arabi YM, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med. 2020 Mar 28. doi: 10.1007/s00134-020-06022-5. [Epub ahead of print] PubMed PMID: 32222812; PubMed Central PMCID: PMC7101866.
Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19). 16-24 February 2020. Accessed March 8, 2020. https://www.who.int/publications/i/item/report-of-the-who-china-joint-mission-on-coronavirus-disease-2019-(covid-19)
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 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 (August 2021) 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 www.who.int, www.cdc.gov, and www.ecdc.europa.eu. As of the end of July 2021, there were close to 200 million confirmed cases and >4.1 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 United Kingdom (B.1.1.7, Alpha), South African (B.1.135, Beta), and Brazilian (P.1, Gamma) lineages. Some of them may lead to more severe disease. As of June 2021, a new variant originating from India (B.1.617 or Delta variant) has become rapidly dominant in numerous geographic locations, including Canada. The efficacy of different vaccines in preventing symptomatic and severe illness due to those variants is at present not entirely clear (see Vaccines: SARS-CoV-2 (COVID-19)), although it seems to be at least substantial.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.
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 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, 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 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 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 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: 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 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. https://www.cdc.gov/coronavirus/2019-ncov/hcp/duration-isolation.html
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 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 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 2021.
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: 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 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; for example, as of the end of July 2021, the reported proportion of such patients in Canada was ~4%.
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 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.Evidence 9Moderate 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. https://www.economist.com/science-and-technology/2020/08/22/when-covid-19-becomes-a-chronic-illness 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.
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. 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 10Low 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 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.
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).
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 June 2021, 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.
2. Other viral respiratory infections.
3. Atypical pneumonia.
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).
Note: The unprecedented speed of evidence generation has 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, August 2021), while acknowledging that alternative recommendations or suggestions are being followed in other regions.
Treatment generally depends on the severity of the disease (measured 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.
In the ambulatory outpatient setting, asymptomatic and mildly symptomatic patients usually receive no specific treatment, although multiple options are being actively pursued.
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 11Weak 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: https://doi.org/10.1101/2021.04.10.21254672
Colchicine, dosed 0.5 mg bid for 3 days followed by once-daily administration for 27 days, is another promising 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 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 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.
There is a suggestion that monoclonal antibodies may show benefit and some clinicians consider using those in populations at high risk for clinical progression (immunocompromised, with multiple comorbidities). In July 2021 the NIH issued a recommendation to use sotrovimab or a combination of casirivimab plus imdevimab in this population with mild to moderate disease. They recommended against the use of bamlanivimab plus etesevimab in these patients due to an increase in the prevalence of potentially resistant variants. However, the patient-important benefits in different populations are unclear and those therapies are not frequently used in our area.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). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to 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. 2021 Jan 21;384(3):229-237. doi: 10.1056/NEJMoa2029849. Epub 2020 Oct 28. PMID: 33113295; PMCID: PMC7646625. Similarly, the use of monoclonal antibodies in individuals who had household exposure to a person with SARS-CoV-2 infection decreased the risk of acquiring infection and, if the infection was acquired, it shortened its duration.Evidence 14Weak 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 indirectness. O'Brien MP, Forleo-Neto E, Musser BJ, et al. Subcutaneous REGEN-COV Antibody Combination to Prevent Covid-19. N Engl J Med. 2021 Aug 4. doi: 10.1056/NEJMoa2109682. Online ahead of print. PMID: 34347950.
In hospitalized mildly affected patients (those not requiring physiologic support with oxygen and IV hydration treatment is mostly supportive and specific antiviral agents (remdesivir) or systemic immunomodulating therapies (systemic steroids, interleukin-6 [IL-6] receptor antagonists, monoclonal antibodies, convalescent plasma, ivermectin) are not used in our setting outside of clinical trials.
In moderately affected patients (broadly defined as those requiring supplemental oxygen) we routinely use a 10-day course of dexamethasone and consider tocilizumab (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 (or we use remdesivir in clinical trials). In those patients we also favor full-dose anticoagulation with the 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), and prophylactic anticoagulation. Routine full-dose anticoagulation is not recommended and may be harmful unless indicated for a separate condition.
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).
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, colchicine, vitamin D, ivermectin, chloroquine, hydroxychloroquine, lopinavir/ritonavir, interferon, antibacterial treatment (unless justified for other reasons, which happens relatively frequently).
As of June 2021, treatment of COVID-19 is 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 inconclusive but promising nature of inhaled glucocorticoids and colchicine in ambulatory patients is mentioned above. For hospitalized patients, 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 even more controversial, with ongoing systematic reviews, meta-analyses, and living guidelines.Evidence 15Moderate 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/ Rochwerg B, Siemieniuk RA, Agoritsas T, et al. A living WHO guideline on drugs for covid-19. BMJ. 2020 Sep 4;370:m3379. doi: 10.1136/bmj.m3379. Update in: BMJ. 2020 Nov 19;371:m4475. Update in: BMJ. 2021 Mar 31;372:n860. PMID: 32887691. Anticoagulation may play an important role (see Symptomatic Treatment, below).
In August 2020, using mostly observational data, the United States 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 in hospitalized patients. However, subsequent randomized controlled trials (including RECOVERY with >10,000 randomized patients) failed to show benefit from the use of convalescent plasma. This was confirmed in subsequent meta-analyses.Evidence 16Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Piechotta V, Chai KL, Valk SJ, et al. Convalescent plasma or hyperimmune immunoglobulin for people with COVID-19: a living systematic review. Cochrane Database Syst Rev. 2020 Jul 10;7(7):CD013600. doi: 10.1002/14651858.CD013600.pub2. Update in: Cochrane Database Syst Rev. 2020 Oct 12;10:CD013600. PMID: 32648959; PMCID: PMC7389743. 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. A combination of 2 monoclonal antibodies, casirivimab and imdevimab (known as REGEN-COV in the United States), was investigated in the RECOVERY trial in addition (as of June 2021) to baricitinib, dimethyl fumarate, and different doses of glucocorticoids. The preliminary results indicate that REGEN-COV may be beneficial in a subgroup of hospitalized patients with COVID-19 who have not yet mounted an antibody response. Trial arms investigating colchicine (recruitment stopped without clear indication of benefit), aspirin (preliminary results are interpreted by authors as showing no sufficient benefit), and—in children only—low-dose dexamethasone were stopped, with full results pending publication.Evidence 17Low 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. 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.
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 different study, similarly, has not confirmed the benefit of hydroxychloroquine prophylaxis.Evidence 18Low 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/d 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 19Moderate 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 20Moderate 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 21Moderate 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 22Low 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 23Low 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–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 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 24Low 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. 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 25Low 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.
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. The advice to use antibacterial agents only when needed is obvious but rather general.
Nonspecific treatments with a potential of benefit include proning of nonventilated patients and, especially, attention to potential thrombotic complications with 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 August 2021 suggest the advantage of full-dose anticoagulation in hospitalized patients who do not require the ICU level of organ support (high-flow nasal cannula, noninvasive ventilation, invasive ventilation, inotropes or vasopressors), but it is of no proven benefit in patients requiring such ICU-level support.Evidence 26Moderate 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. https://www.nih.gov/news-events/news-releases/full-dose-blood-thinners-decreased-need-life-support-improved-outcome-hospitalized-covid-19-patients 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 specific practice trends, based on collective experience and observational data, include using noninvasive ventilation and moving away from 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.
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.
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).
1. Vaccination: see Vaccines: SARS-CoV-2 (COVID-19).
As of mid-2021, 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.Evidence 27Moderate 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
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 28Low 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.
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 29Moderate 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 30Low 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 31Low 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 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. 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.