Yue C, Song W, Wang L, et al. Enhanced transmissibility of XBB.1.5 is contributed by both strong ACE2 binding and antibody evasion. bioRxiv. Preprint posted online January 5, 2023. doi: https://doi.org/10.1101/2023.01.03.522427s.
RECOVERY Trial. Accessed December 28, 2022. https://www.recoverytrial.net
National Institutes of Health. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. Updated December 28, 2022. Accessed December 29, 2022. https://covid19treatmentguidelines.nih.gov
Bhimraj A, Morgan RL, Shumaker AH, et al. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19. Updated November 21, 2022. Accessed January 8, 2023. https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/
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 September 23, 2022. Accessed December 29, 2022.https://www.cdc.gov/coronavirus/2019-ncov/hcp/guidance-risk-assesment-hcp.html
World Health Organization. Global surveillance for COVID-19 disease caused by human infection with the 2019 novel coronavirus: Interim guidance. Updated July 22, 2022. Accessed December 29, 2022. https://www.who.int/publications-detail/global-surveillance-for-human-infection-with-novel-coronavirus-(2019-ncov)
Clinical Practice Guideline Summary: Recommended Drugs and Biologics in Adult Patients with COVID-19. Published April 1, 2022. Accessed October 8, 2022. https://covid19-sciencetable.ca/sciencebrief/clinical-practice-guideline-summary-recommended-drugs-and-biologics-in-adult-patients-with-covid-19-version-11-0
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.
Chalmers JD, Crichton ML, Goeminne PC, et al. Management of hospitalized 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.
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.
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
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.
Please note that COVID-19–related information is evolving rapidly, including epidemiology and all modes of prevention and treatments. Different variants and subvariants of SARS-CoV-2 become dominant within weeks, with data on treatment and prevention obtained earlier becoming only indirectly applicable. Jurisdictions are coming up with new instructions on a monthly basis. Judgment of various professional and international organizations assessing the same body of evidence differs, which may be reflected in the divergent levels of confidence in the data and different values and preferences associated with distinct outcomes, including availability of resources and interventions. As of this update (January 2023), different recommendations and patterns of practice surrounding the use of several therapies illustrate these not unexpected phenomena.
We started developing this chapter in the spring of 2020, when high-quality data essentially did not exist. With frequent updates, we proceeded through the publication of the first antiviral and anti-inflammatory treatment studies, platform trials, meta-analyses, and network meta-analyses concerning different interventions, as well as numerous practice guidelines. At the beginning of 2023, our goal is to limit the review of original evidence and to provide readers with access to translation of the ever-increasing amount of data into actionable recommendations.
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 January 2023, there were >650 million confirmed cases and >6.5 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)—more transmissible than the wild-type variant—were increasingly circulating in numerous countries, including Canada: the United Kingdom (B.1.1.7, Alpha), South African (B.1.135, Beta), and Brazilian (P.1, Gamma) lineages. In the summer of 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 had become dominant across North America and Europe. In the summer of 2022, subvariants of Omicron (BA.4 and BA.5) were dominant in many parts of the world. As of December 2022, the most prevalent forms of the virus included (according to global World Health Organization [WHO] data) Omicron descendants BQ.1 (42.5%), BA.5 with one or several additional mutations (S:R346X, S:K444X, S:V445X, S:N450D, S:N460X; 13.4%), BA.2.75 (9.8%), XBB (6.1%), BA.4.6 (1%), and BA.2.30.2 (0.1%). Early 2023 data from the United States suggest the XBB.1.5 variant to be the dominant one, which may have features of immune escape and angiotensin-converting enzyme 2 (ACE2) binding. Based on current evidence, there is no indication of increased severity associated with these variants under monitoring compared with the former Omicron lineages.
2. Pathogenesis: To enter the cell, the virus uses 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. However, transmission from animal to human species has been described.
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 likely occurs more frequently during aerosol-generating medical procedures or in certain settings such as indoor, crowded, and poorly ventilated spaces. It has become 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 1Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. van Doremalen N, Bushmaker T, Morris DH, et al. Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1. N Engl J Med. 2020 Mar 17. doi: 10.1056/NEJMc2004973. [Epub ahead of print] PubMed PMID: 32182409. Johansson MA, Quandelacy TM, Kada S, al. SARS-CoV-2 Transmission From People Without COVID-19 Symptoms. JAMA Netw Open. 2021 Jan 4;4(1):e2035057. doi: 10.1001/jamanetworkopen.2020.35057. PMID: 33410879; PMCID: PMC7791354.
4. Risk factors for infection: Epidemiologic risk factors include any setting with a higher likelihood of exposure to an infected individual, in particular through direct contact in an indoor environment (eg, classroom, meeting room, waiting room in a hospital). Prolonged contact increases the risk of infection. Transmission by contact with objects or materials (fomites) seems less important than originally assumed.
Risk factors for severe versus mild infection include advanced age (in patients aged ≥80 years mortality rates with earlier variants were 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 2Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias. Pettirosso E, Giles M, Cole S, Rees M. COVID-19 and pregnancy: A review of clinical characteristics, obstetric outcomes and vertical transmission. Aust N Z J Obstet Gynaecol. 2020 Aug 10:10.1111/ajo.13204. doi: 10.1111/ajo.13204. Epub ahead of print. PMID: 32779193; PMCID: PMC7436616.
5. Incubation and contagious period: The incubation period 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 and estimated to be 3.5 days. Symptomatic individuals may transmit the virus to others; the extent of transmission from those who are presymptomatic is likely substantial.Evidence 3Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Arons MM, Hatfield KM, Reddy SC, et al. Presymptomatic SARS-CoV-2 Infections and Transmission in a Skilled Nursing Facility. N Engl J Med. 2020 Apr 24. doi: 10.1056/NEJMoa2008457. [Epub ahead of print] PubMed PMID: 32329971. Gandhi M, Yokoe DS, Havlir DV. Asymptomatic Transmission, the Achilles' Heel of Current Strategies to Control Covid-19. N Engl J Med. 2020 Apr 24. doi: 10.1056/NEJMe2009758. [Epub ahead of print] PubMed PMID: 32329972. Li R, Pei S, Chen B, et al. Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV2). Science. 2020 Mar 16. pii: eabb3221. doi: 10.1126/science.abb3221. [Epub ahead of print] PubMed PMID: 32179701. Wei WE, Li Z, Chiew CJ, Yong SE, Toh MP, Lee VJ. Presymptomatic Transmission of SARS-CoV-2 — Singapore, January 23–March 16, 2020. MMWR Morb Mortal Wkly Rep. ePub: 1 April 2020. DOI: http://dx.doi.org/10.15585/mmwr.mm6914e1 Viral load/shedding is probably the highest at the time of symptom onset and shortly afterwards; however, it may last longer in patients who develop severe infection. The duration of the contagious period is estimated as a maximum of 10 days from the onset of symptoms for most cases and is likely shorter for the Omicron variant. A small number of patients with severe COVID-19 may shed replication-competent viruses for several weeks, particularly in the context of critical illness or significant immunocompromised state.Evidence 4Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Centers for Disease Control and Prevention. Duration of Isolation and Precautions for Adults with COVID-19. Updated October 19, 2020. Accessed November 29, 2020. https://www.cdc.gov/coronavirus/2019-ncov/hcp/duration-isolation.html
Clinical Features and Natural HistoryTop
The clinical course may be varied and ranges from asymptomatic/subclinical infection to severe pneumonia with ARDS:
1) Symptomatic uncomplicated infection: Patients have nonspecific manifestations, such as fever, cough, shortness of breath, malaise, myalgias, sore throat, headache, diarrhea, runny nose or nasal congestion, conjunctivitis, and anosmia. Patients with mild or uncomplicated infections do not have dehydration, dyspnea, or features of sepsis. Elderly individuals and immunocompromised patients may have atypical symptoms.
2) Mild pneumonia: Absence of the features of severe pneumonia listed below.
3) Severe pneumonia: Fever or other symptoms of respiratory tract infection with ≥1 of severe respiratory distress, tachypnea >30/min, or hemoglobin oxygen saturation in arterial blood (measured with pulse oximetry) (SpO2) on room air <90%.
4) ARDS occurs in up to 15% of hospitalized patients with COVID-19.
5) Sepsis and septic shock: The incidence of sepsis in patients with COVID-19 is not well described. The incidence of shock in published reports was highly variable, ranging between 2% and 20%.
6) Postinfectious phenomena, such as multisystem inflammatory syndrome (MIS)—a disorder similar to Kawasaki disease—has been described in children (MIS-C) and adults aged ≥21 years (MIS-A).
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), with RT-PCR from nasopharyngeal swabs (NPSs) 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, the strategy of obtaining an NPS first 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 the sensitivity of upper airway samples may be lower than 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.
By the end of 2022, COVID-19 antigen tests, predominantly offered as point-of-care rapid tests, were widely 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 used as at-home tests.Evidence 5Low 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 usually yield negative results in early 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. Additionally, the target of serologic testing may depend on vaccination status. Anti-spike (S) antibodies are generated with both vaccination and infection, whereas anti-nucleocapsid (N) antibodies are generated by infection alone. However, the conversion of N antibodies in individuals with infection after vaccination may be diminished, and needs to be interpreted with caution.Evidence 6Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Follmann D, Janes HE, Buhule OD, et al. Antinucleocapsid Antibodies After SARS-CoV-2 Infection in the Blinded Phase of the Randomized, Placebo-Controlled mRNA-1273 COVID-19 Vaccine Efficacy Clinical Trial. Ann Intern Med. 2022 Sep;175(9):1258-1265. doi: 10.7326/M22-1300. Epub 2022 Jul 5. PMID: 35785530; PMCID: PMC9258784.
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 the ICU. Serum aminotransferase levels may be increased. Thrombocytopenia, ferritin, CRP, and 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 (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 evolving epidemiologic situation. Current Ontario definitions include confirmed case (see below) and probable case definitions.
As of December 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). Many jurisdictions consider a positive rapid antigen test result in a symptomatic patient as evidence of a confirmed case.
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 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).
Results from the RECOVERY trial (acetylsalicylic acid [ASA], baricitinib, tocilizumab, convalescent plasma, monoclonal antibodies, colchicine, azithromycin, dexamethasone, lopinavir/ritonavir, hydroxychloroquine) can be found at www.recoverytrial.net. Currently investigated strategies include empagliflozin, monoclonal antibody sotrovimab, molnupiravir, nirmatrelvir/ritonavir (brand name Paxlovid), and different doses of glucocorticoids.
SOLIDARITY trial results (remdesivir, hydroxychloroquine, lopinavir, interferon) can be found at www.who.int. 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). Data considering the addition of baricitinib versus dexamethasone to remdesivir were published in May 2022.
The REMAP-CAP trial has reported at least partial 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 www.remapcap.org. Recent results may reignite the debate about the use of antiplatelet drugs.
Note: The exceptional 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, beginning of 2023) while acknowledging that alternative recommendations or suggestions are being followed in other regions, depending on the assessment of evidence and availability of different therapies.
Examples of such guidelines include those prepared by the Infectious Diseases Society of America (www.idsociety.org), National Institute of Health (NIH; www.covid19treatmentguidelines.nih.gov), WHO (app.magicapp.org), and Ontario Government (www.ontario.ca).
The examples of graphs summarizing suggested management could be found on NIH sites: for hospitalized patients (www.covid19treatmentguidelines.nih.gov) and nonhospitalized patients (www.covid19treatmentguidelines.nih.gov). Examples for both hospitalized and nonhospitalized individuals are also available on the WHO site (app.magicapp.org). Detailed information from those documents, especially on the use of monoclonal and convalescent antibodies, may differ and is likely governed by local guidelines and regulations.
Treatment generally depends on the severity of the disease (evaluated mostly by the degree of hypoxia and need for supportive measures), presence of risk factors, vaccination status, and disease stage (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).
1. In the ambulatory outpatient setting asymptomatic patients with a positive test result would typically not receive any treatment. Symptomatic patients not requiring oxygen or hospitalization for COVID-19 symptoms who are at low risk of deterioration based on age and risk factors 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 older age (as of December 2022 this criterion was lowered in Ontario from 70 to 60 years), presence of immunosuppression, lack of immunity from previous infection or vaccination, last vaccination >6 months ago, comorbidities (obesity [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 transplantation). Largely, these therapies include antiviral therapies, such as Paxlovid or remdesivir. All monoclonal antibodies have shown poor in vitro activity against variants in late 2022 and early 2023; however, real-world data against prior in vitro resistant variants suggest some preservation of clinical activity.Evidence 7Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Zheng B, Green ACA, Tazare J, et al. Comparative effectiveness of sotrovimab and molnupiravir for prevention of severe covid-19 outcomes in patients in the community: observational cohort study with the OpenSAFELY platform. BMJ. 2022 Nov 16;379:e071932. doi: 10.1136/bmj-2022-071932. PMID: 36384890; PMCID: PMC9667468. Given these concerns, widespread use of monoclonal antibodies is currently not our practice. Disease response modifiers, which reduce inflammation, such as fluvoxamine and inhaled glucocorticoids, are occasionally used.
Due to the ease of oral administration, Paxlovid for 5 days is considered first choice where available and in the absence of contraindications or interactions. Alternatively, patients could be offered remdesivir for 3 days (200 mg IV on day 1, then 100 mg IV on days 2 and 3), particularly those at high risk with contraindications to Paxlovid. 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, NIH, and European guidelines as an oral alternative when Paxlovid (or remdesivir) cannot be used; however, recent randomized data may suggest only minimal, if any, benefits in a high-risk cohort.Evidence 8Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Butler CC, Hobbs FDR, Gbinigie OA, et al. Molnupiravir plus usual care versus usual care alone as early treatment for adults with COVID-19 at increased risk of adverse outcomes (PANORAMIC): an open-label, platform-adaptive randomised controlled trial. Lancet. 2022 Dec 22;S0140-6736(22)02597-1. doi: 10.1016/S0140-6736(22)02597-1. PMID: 36566761; PMCID: PMC9779781. 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. Of note, eligibility criteria to receive those therapies differ depending on jurisdiction and change rapidly.
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 9Weak 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 Another potential option for symptomatic patients with risk factors (see the list above; based on low quality of evidence) for patients within 1 week of symptom onset is oral fluvoxamine 50 mg/d 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 10Weak 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.
2. In hospitalized mildly affected patients (not requiring physiologic support with oxygen and IV hydration) treatment is mostly supportive, but the above considerations of Paxlovid, remdesivir, molnupiravir, budesonide, and fluvoxamine apply, especially in the case of patients hospitalized for other reasons or those with nosocomial infection.
3. 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 11Low 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 interleukin 6 (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 12Weak 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.Marconi 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. A combination of baricitinib and IL-6 inhibitors is currently not recommended in Ontario, although the RECOVERY trial suggests the possibility of an additive beneficial effect, and WHO guidelines suggest a possibility of combining glucocorticoids, an IL-6 inhibitor, and a JAK-2 inhibitor. In moderately affected patients without contraindications, we also favor full-dose anticoagulation with low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH). The perceived bleeding risk may modify this approach.
4. In severely and critically ill patients (those requiring invasive ventilatory or circulatory support) we use dexamethasone and tocilizumab, but not remdesivir (especially late in disease course). 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 in Ontario not in combination with IL-6 inhibitors (tocilizumab). Of note, WHO guidelines allow for the combination of those 3 classes of drugs.
We individualize the use of remdesivir and anticoagulation in patients requiring oxygen delivery through high-flow nasal cannula or noninvasive ventilation (of note, these interventions were considered as ICU care in anticoagulation trials).
We recommend against the use of chloroquine and hydroxychloroquine, azithromycin, lopinavir/ritonavir, and ivermectin. We do not use monoclonal antibodies. We also do not recommend casirivimab/imdevimab (as of summer 2022). Other therapies—colchicine, interferon, and vitamin D—should 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
In addition to the treatments above, supportive care is key. In patients with features of respiratory failure and shock, oxygen therapy should be administered (see Oxygen Therapy), 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, a meta-analysis has shown the incidence of bacterial coinfections 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 common use of high-flow oxygen therapy through a nasal cannula (see Nasal High-Flow Therapy (NHFT)).Evidence 13Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness, heterogeneity, and imprecision. Frat J-P, Quenot J-P, Julio Badie J, et al; SOHO-COVID Study Group and the REVA Network. Effect of High-Flow Nasal Cannula Oxygen vs Standard Oxygen Therapy on Mortality in Patients With Respiratory Failure Due to COVID-19: The SOHO-COVID Randomized Clinical Trial. JAMA. 2022 Sep 27;328(12):1212-1222. doi: 10.1001/jama.2022.15613. PMID: 36166027; PMCID: PMC9516287. Perkins GD, Ji C, Connolly BA, et al; RECOVERY-RS Collaborators. Effect of Noninvasive Respiratory Strategies on Intubation or Mortality Among Patients With Acute Hypoxemic Respiratory Failure and COVID-19: The RECOVERY-RS Randomized Clinical Trial. JAMA. 2022 Feb 8;327(6):546-558. doi: 10.1001/jama.2022.0028. PMID: 35072713; PMCID: PMC8787685. 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. 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 suggested the advantage of full-dose anticoagulation in hospitalized patients who did not require ICU-level organ support, but it was 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 14Moderate 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 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.
Occupational Exposure of Health-Care Personnel
The management of occupational and nonoccupational high-risk exposures differs 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 but not after exposure to body fluids on intact skin. To assess the risk of transmission of SARS-CoV-2, consider:
1) Duration of exposure (longer exposure increases the risk of transmission).
2) The patient’s clinical symptoms.
3) Whether a well-fitted facemask was 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). An example of a nonoccupational high-risk exposure is a household member with an active infection.
Medium-risk and low-risk exposures are typically no longer considered as relevant from a contact-tracing perspective at this point of the pandemic.
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 in the pre-Omicron era; however, vaccination status is less protective in the context of the Omicron variant and such management of vaccinated and unvaccinated HCPs with high-risk exposure should be identical. This may change with bivalent vaccines introduced in the fall of 2022 specifically developed to target subvariants of Omicron, including BA.4 and BA.5.
The management of high-risk exposures in HCPs differs based on organizational or jurisdictional rules as well as staffing shortages. Some jurisdictions may still suspend an HCP from work for 10 days following the exposure, with or without testing during this period. Most jurisdictions would only require the HCP to actively monitor for the presence of symptoms and potentially to perform PCR (often around day 5 post exposure) or rapid antigen testing.
At the beginning of the pandemic the course of the disease was mild in ~80% of diagnosed patients. 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 2021, although overall mortality in hospitalized patients declined from >16% to ~9%.Evidence 15Moderate 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, at the beginning of 2022 the mortality rate of patients admitted to ICUs was >30%. The severity of the disease caused by the Omicron variant appears lower, presumably also due to natural and vaccine-induced immunity and availability of early treatment options for the most vulnerable populations.
The overall mortality rate varies by country, pattern of testing, and demographic characteristics in a given report. As of late 2022, it was likely <1% in diagnosed patients worldwide. However, even these declining rates have a wide margin of error and are probably inflated as, due to selective testing, there may be an overrepresentation of severely ill patients with confirmed infection. 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 16Moderate 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 patients (with active infection) fluctuates depending on the rate of new infections, testing criteria, and changes in the dominant variant; towards the end of 2022, the reported proportion of such patients in Canada was <0.1%. The future may depend on the virulence of the new variants and vaccination status of affected individuals (eg, in October 2022 in Ontario the probability of a new SARS-CoV-2 infection among those vaccinated with ≥2 doses vs those not vaccinated was ~2.5-fold lower; of requiring hospitalization, ~4-fold lower; and of the need for ICU admission, ~4-fold lower).Evidence 17Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Ontario Dashboard. https://covid19-sciencetable.ca/ontario-dashboard COVID-19 Indicator Roadmap. https://covid19-sciencetable.ca/covid-19-indicator-roadmap
An 8-factor risk score to predict 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). Of note, these tools were developed for use with initial variants and in the unvaccinated population.
Clinically, patients with mild infection typically recover symptomatically within 1 to 2 weeks. Some experience long-term, nonspecific postviral symptoms, lasting 12 weeks or occasionally longer.Evidence 18Moderate Quality of Evidence (moderate confidence that we know true effects). Quality of Evidence lowered due to changing epidemiology and severity of disease (indirectness). Global Burden of Disease Long COVID Collaborators; Wulf Hanson S, Abbafati C, Aerts JG, et al. Estimated Global Proportions of Individuals With Persistent Fatigue, Cognitive, and Respiratory Symptom Clusters Following Symptomatic COVID-19 in 2020 and 2021. JAMA. 2022 Oct 25;328(16):1604-1615. doi: 10.1001/jama.2022.18931. PMID: 36215063; PMCID: PMC9552043. 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. These long-term sequelae of the disease (labeled long COVID or post-COVID syndrome) occur in >6% of patients, >3% of whom have persistent fatigue with bodily pain or mood swings resembling chronic fatigue syndrome, >2% have cognitive problems, and ~4% have ongoing respiratory problems with dyspnea and cough. In those aged ≥20 years, long COVID symptoms are more common in women than in men (10.6% vs 5.4%). In both sexes aged <20 years, ~3% of patients are affected. At present, no clear specific interventions have been recommended. The mean duration of long COVID symptoms was reported to last 9 months in hospitalized patients and 4 months in the nonhospitalized group. Among those with long COVID symptoms at 3 months after infection, a minority (~15%) continued to have symptoms at 12 months.
1. Vaccination: see Vaccines: COVID-19.
In 2022, mass vaccination projects were being conducted around the world. Several vaccines were approved by various national and international agencies, including mRNA, viral vector, and inactivated virus vaccines. With the Omicron VOC, reports suggested an efficacy rate of ~50% in preventing symptomatic disease with significant waning of the effect in the months following the vaccine. A higher and longer-lasting efficacy with less significant waning is observed in preventing hospitalization, critical illness, and death.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. https://www.fda.gov/advisory-committees/advisory-committee-calendar/vaccines-and-related-biological-products-advisory-committee-december-17-2020-meeting-announcement Altarawneh HN, Chemaitelly H, Ayoub HH, et al. Effects of Previous Infection and Vaccination on Symptomatic Omicron Infections. N Engl J Med. 2022 Jul 7;387(1):21-34. doi: 10.1056/NEJMoa2203965. Epub 2022 Jun 15. PMID: 35704396; PMCID: PMC9258753. Chalkias S, Harper C, Vrbicky K, et al. A Bivalent Omicron-Containing Booster Vaccine against Covid-19. N Engl J Med. 2022 Oct 6;387(14):1279-1291. doi: 10.1056/NEJMoa2208343. Epub 2022 Sep 16. PMID: 36112399; PMCID: PMC9511634. Barouch DH. Covid-19 Vaccines - Immunity, Variants, Boosters. N Engl J Med. 2022 Sep 15;387(11):1011-1020. doi: 10.1056/NEJMra2206573. Epub 2022 Aug 31. PMID: 36044620; PMCID: PMC9454645.Bivalent vaccines were introduced in Ontario in October 2022 with intention to act against the BA.1 (Moderna) as well as BA.4 and BA.5 (Moderna/Pfizer) Omicron variants.
2. Pharmacologic prevention: Numerous potential strategies are being investigated.
Prophylaxis with tixagevimab/cilgavimab (brand name Evusheld) against COVID-19 is used in heavily immunocompromised patients unable to mount immunity from vaccines.Evidence 20Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Levin MJ, Ustianowski A, De Wit S, et al; PROVENT Study Group. Intramuscular AZD7442 (Tixagevimab-Cilgavimab) for Prevention of Covid-19. N Engl J Med. 2022 Jun 9;386(23):2188-2200. doi: 10.1056/NEJMoa2116620. Epub 2022 Apr 20. PMID: 35443106; PMCID: PMC9069994. However, concerns over resistance to newer variants in late 2022 has led to a recommendation against its routine use.
See Nonspecific Methods of Infection Prevention Among Medical Staff.
1. General recommendations:
1) Frequently performing hand hygiene with soap and water or alcohol-based hand sanitizers.
2) Avoiding touching the face.
3) Avoiding crowds and large gatherings.
4) Maintaining at least 1- to 2-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.
5) 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, with surgical masks alone likely providing 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.
6) Avoiding contact with individuals with respiratory symptoms.
7) 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 prevention measure is recommended first and foremost for HCPs.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 may want to reduce social contacts for 5 to 10 days or may require self-isolation as per public health rules in a given jurisdiction.
3. Isolation advice for individuals with COVID-19: The rules differ across jurisdictions and over time. The current advice in Ontario (www.ontario.ca) includes staying at home until symptoms have been improving for ≥24 hours (or 48 hours if nausea, vomiting, and/or diarrhea are present), there is no fever, and no additional symptoms developed. When no longer isolating at home, an individual is advised for the total of 10 days from symptom onset to wear a well-fitted mask in all public settings, avoid nonessential activities where one needs to take off the mask (eg, dining out), avoid nonessential visits to anyone who is immunocompromised or may be at higher risk of illness (eg, seniors), and avoid nonessential visits to the highest-risk settings in the community, such as hospitals and long-term care homes.
4. Isolation of infected individuals in high-risk settings: 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’s 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. Often, extended use and reuse protocols as well as reprocessing are still considered, although a more reliable supply chain makes these measures unnecessary in many settings.
Precautions for droplet transmission and direct contact transmission (example, the rules differ with time): 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, or they can be cohorted with recently recovered patients. The number of visitors should be limited. 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 well-fitting 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: Well-fitting 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 (PHAC) have 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. However, recent randomized controlled trial data suggest that medical masks are noninferior to N95 respirators for routine care.Evidence 24Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to heterogeneity and indirectness. Loeb M, Bartholomew A, Hashmi M, et al. Medical Masks Versus N95 Respirators for Preventing COVID-19 Among Health Care Workers : A Randomized Trial. Ann Intern Med. 2022 Dec;175(12):1629-1638. doi: 10.7326/M22-1966. Epub 2022 Nov 29. PMID: 36442064; PMCID: PMC9707441.
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: www.youtube.com/watch?v=syh5UnC6G2k.
2) For droplet precautions, see a video from St Joseph’s Healthcare Hamilton, Canada: www.youtube.com/watch?v=i_J2qtM1Aus.
The sequence of wearing (donning) PPE: Before donning PPE, disinfect hands. Then don the gown followed by the respirator mask. Make sure the respirator mask fits snugly to the face (in the case of filtering facepiece 2 [FFP2] and 3 [FFP3] standard respirators all exhaled air should be filtered by the respirator; facial hair can interfere with the proper fit). Put on goggles or a face shield. The goggles should fit over the respirator mask. The last step is donning gloves, which should extend to cover the wrists and cuffs of the gown.
Removing (doffing) PPE (when using a gown for body protection; some details of the procedures differ between jurisdictions): This procedure requires particular caution, because the surface of PPE may be contaminated with infectious material. Incorrect or careless removal of PPE may result in accidental contamination followed by virus transmission. Single-use equipment should be discarded immediately after removal in an infectious waste container. Reusable equipment (eg, face shields or goggles) should be placed in a designated container and decontaminated before next use according to the manufacturer’s instructions. Start by disinfecting your hands. First remove the gloves in a way that minimizes hand contamination. Then disinfect the hands. You may consider donning a new pair of gloves (not done in Hamilton). With the new gloves on (if used), remove the gown. The back of the gown should be grabbed and pulled away from the body, keeping the contaminated front part inside the gown. Turn the sleeves inside out. (Avoid touching the contaminated front part of the gown.) Disinfect the hands again. Remove the goggles/face shield without touching their front part. You may disinfect the hands. Remove the respirator mask (grasp the straps and carefully remove the respirator without touching its outer surface). Disinfect the hands. Discard the gloves put on before removing the gown (if a second pair of gloves is used). Disinfect the hands again. Individual health-care facilities should adjust the procedures for donning and removing PPE based on the type of available equipment.
5. Individuals caring for infants: Infants cannot use respirator masks or facemasks and require special precautions to prevent viral transmission. Adults should use a respirator mask, perform hand hygiene before touching the infant, and regularly disinfect toys and other objects in the infant’s environment.
6. Reporting: Individuals traveling from countries where COVID-19 is present or who had contact with a patient infected with SARS-CoV-2 should notify public health authorities and discuss further management.
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