RECOVERY Trial. Accessed October 4, 2020. https://www.recoverytrial.net/
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.
World Health Organization. Draft landscape of COVID-19 candidate vaccines. Accessed September 9, 2020. Updated September 9, 2020. https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines
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.
Ontario. Ministry of Health and Long-Term Care. COVID-19 Guidance for the Health Sector. Case Definition – Coronavirus Disease (COVID-19). Updated August 6, 2020. Accessed October 4, 2020. http://health.gov.on.ca/en/pro/programs/publichealth/coronavirus/2019_guidance.aspx
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.
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.
Half Marathon COVID19. European Society of Intensive Care Medicine webinar. May 16, 2020. Accessed May 16, 2020. https://esicm-tv.org/covid-19-half-marathon.html
Bhimraj A, Morgan RL, Shumaker AH, et al. Infectious Diseases Society of America Guidelines on the Treatment and Management of Patients with COVID-19. Clin Infect Dis. 2020 Apr 27. pii: ciaa478. doi: 10.1093/cid/ciaa478. [Epub ahead of print] PubMed PMID: 32338708.
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.
National Institutes of Health. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. Updated April 21, 2020. Accessed April 27, 2020. https://covid19treatmentguidelines.nih.gov/
Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19): A Review. JAMA. 2020 Apr 13. doi: 10.1001/jama.2020.6019. [Epub ahead of print] PubMed PMID: 32282022.
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.
Multicenter collaboration group of Department of Science and Technology of Guangdong Province and Health Commission of Guangdong Province for chloroquine in the treatment of novel coronavirus pneumonia. [Expert consensus on chloroquine phosphate for the treatment of novel coronavirus pneumonia]. Zhonghua Jie He He Hu Xi Za Zhi. 2020 Mar 12;43(3):185-188. doi: 10.3760/cma.j.issn.1001-0939.2020.03.009. Chinese. PubMed PMID: 32164085.
Murthy S, Gomersall CD, Fowler RA. Care for Critically Ill Patients With COVID-19. JAMA. 2020 Mar 11. doi: 10.1001/jama.2020.3633. [Epub ahead of print] PubMed PMID: 32159735.
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). https://www.cdc.gov/coronavirus/2019-ncov/hcp/guidance-risk-assesment-hcp.html. Updated March 7, 2020. Accessed March 8, 2020.
World Health Organization. Global surveillance for COVID-19 disease caused by human infection with the 2019 novel coronavirus: Interim guidance, 27 February 2020. https://www.who.int/publications-detail/global-surveillance-for-human-infection-with-novel-coronavirus-(2019-ncov). Accessed March 8, 2020.
Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmun. 2020 Feb 26:102433. doi: 10.1016/j.jaut.2020.102433. [Epub ahead of print] Review. PubMed PMID: 32113704.
Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19). 16-24 February 2020. https://www.who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-covid-19-final-report.pdf. Accessed March 8, 2020.
World Health Organization. Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected: Interim guidance, 28 January 2020. https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected. Accessed March 8, 2020.
Please note that COVID-19–related information is evolving rapidly, including epidemiology and all modes of prevention and potential treatments. Different jurisdictions are coming up with new instructions on a daily basis.
The first cases of coronavirus disease 2019 (COVID-19) occurred in China and quickly developed into an epidemic centered in Hubei province. At present, the pandemic has spread globally, with the United States reporting the highest number of cases to date. Current epidemiologic data are available at www.who.int, www.cdc.gov, and www.ecdc.europa.eu. As of mid-October, there were ~40,5 million cases (including presidents of Brazil and the United States and the prime minister of the United Kingdom) and >1,1 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.
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.
The primary mode of human-to-human transmission occurs by inhalation, predominantly through large respiratory droplets. However, airborne transmission during aerosol-generating medical procedures and transmission by direct contact is likely and its role continues to remain controversial (as of October 2020). Other transmission routes are under consideration. The virus may be also 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 individuals with COVID-19 but also by those in the presymptomatic stage or 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. While experimental conditions suggest a potential for transmission by aerosols in less well-ventilated, enclosed settings, based on epidemiologic data to date there is no conclusive evidence that transmission by airborne particles is a major concern.
4. Risk factors for infection: Epidemiologic risk factors include a history of travel to epidemic areas, household contact with an infected person, provision of direct medical care for an infected patient, and sharing an enclosed space (eg, classroom, meeting room, waiting room in a hospital) with an infected individual. Transmission is enhanced by face-to-face or direct physical contact with an infected person (eg, handshake), contact with secretions of an infected person while not wearing protective equipment, handling of specimens collected from an infected person by laboratory personnel without adequate protective equipment, and likely travel by plane or other transportation modes in close proximity to a person infected with SARS-CoV-2. Prolonged contact increases the risk of infection.
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 from September 2020 suggested a slightly higher risk for intensive care unit (ICU) admission and ventilation, with the main risk factors being preexisting diabetes, hypertension, elevated body mass index (BMI), and advanced maternal age. The risk of preterm labor and maternal death was reported to be elevated about 3-fold.Evidence 2Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias. Pettirosso E, Giles M, Cole S, Rees M. COVID-19 and pregnancy: A review of clinical characteristics, obstetric outcomes and vertical transmission. Aust N Z J Obstet Gynaecol. 2020 Aug 10:10.1111/ajo.13204. doi: 10.1111/ajo.13204. Epub ahead of print. PMID: 32779193; PMCID: PMC7436616.
5. Incubation and contagious period: The incubation period is usually from 2 to 14 days (5 days on average, with >95% of cases developing by day 11). Symptomatic individuals may transmit the virus to others; the extent of transmission from those who are presymptomatic is still not clear but 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 not clearly established. Patients with mild infection typically recover symptomatically within 1 to 2 weeks, while those with severe infection recover within 3 to 6 weeks.
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: No features of severe pneumonia listed below are seen.
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%.
At the beginning of the pandemic, in ~80% of diagnosed patients the course of the disease was mild. Approximately 15% of patients developed severe infection with dyspnea and hypoxia and most had progressive radiographic features of pneumonia. During the first months of the pandemic, ~5% of diagnosed symptomatic patients became critically ill with acute respiratory failure, shock, and multiorgan dysfunction. Among critically ill patients with COVID-19, the mortality rate initially approached 50%. In a described cohort of Italian patients, 16% of hospitalized patients required ICU admission.Evidence 4Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Grasselli G, Pesenti A, Cecconi M. Critical Care Utilization for the COVID-19 Outbreak in Lombardy, Italy: Early Experience and Forecast During an Emergency Response. JAMA. 2020 Mar 13. doi: 10.1001/jama.2020.4031. [Epub ahead of print] PubMed PMID: 32167538.
In the results of the SOLIDARITY trial released in October 2020, based on >11,000 hospitalized patients, the overall mortality rate was 12% and the mortality rate among those ventilated at trial entry was 39%.Evidence 5High 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 and demographic characteristics in a given report and as of mid-October 2020, it is ~2.8% in diagnosed patients worldwide, including >10% in Mexico. 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, it is still at least ~50%.Evidence 6Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Gudbjartsson DF, Norddahl GL, Melsted P, et al. Humoral Immune Response to SARS-CoV-2 in Iceland. N Engl J Med. 2020 Sep 1. doi: 10.1056/NEJMoa2026116. Epub ahead of print. PMID: 32871063. The reported proportion of severely and critically ill patients appears to be declining; for example, as of October 4, the reported proportion of such patients among all active cases in Canada was ~1%.
In September 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. A similar 10-factor risk calculator was previously developed in China to predict the risk of requiring ICU admission, requiring invasive ventilation, or death at the time of hospital admission. It is available online at http://188.8.131.52/.
An additional emerging topic is the reported presence of long-term and sometimes disabling postviral symptoms, which may follow acute COVID-19 illness and resemble chronic fatigue syndrome.Evidence 7Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias. Williams FMK, Muirhead N, Pariante C. Covid-19 and chronic fatigue. BMJ. 2020 Jul 30;370:m2922. doi: 10.1136/bmj.m2922. PMID: 32732337. When covid-19 becomes a chronic illness. The Economist. August 22, 2020. https://www.economist.com/science-and-technology/2020/08/22/when-covid-19-becomes-a-chronic-illness More valid data 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) and real-time RT-PCR. The main specimens for testing are still nasopharyngeal swabs (NPSs), with sputum-based tests hopefully available soon. Other specimen types include lower respiratory tract samples (only in intubated patients; endotracheal aspirates [ETAs] or bronchoalveolar lavage [BAL]) and uninduced sputum. As the sensitivity of tests is still not entirely clear, a high index of clinical suspicion has to be considered even in patients with negative test results. Of note, the sensitivity of upper airway samples is lower than 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.
2. Serologic tests: Serologic tests are not yet widely recommended as a clinical test to diagnose active COVID-19 infection, although the October 2020 case definitions from the Ministry of Health in Ontario include such testing (see Diagnostic Criteria, below). Another application of serologic tests may be in the presence of postinfectious complications, such as multisystem inflammatory syndrome in children (MIS-C) where NPS testing is negative. These tests are also being 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 with immunoglobulins, with titers remaining relatively stable over several months.
3. Other tests:
1) Laboratory tests: Patients commonly have leukopenia and lymphopenia, but leukocytosis may also occur. Procalcitonin levels are usually normal but may be elevated in patients requiring admission to an ICU. Serum aminotransferase levels may be increased. Thrombocytopenia and D-dimer levels correlate with disease severity.
a) Chest radiography: Most frequently features of bilateral pneumonia.
b) Chest computed tomography (CT): Radiographic abnormalities can be seen early, even before symptom onset. They are usually bilateral, show peripheral distribution, and are more often located in the inferior lobes. Extensive ground-glass opacification can be seen especially in the second week of the disease, which progresses to a mixed pattern by week 3 or 4. Patients may also have pleural thickening, pleural effusion, and lymphadenopathy. More detailed discussion of CT findings: see COVID-19: Computed Tomography.
3) Chest ultrasonography, including point-of-care ultrasonography, may provide information and limit the number of required CT scans. More detailed discussion of ultrasound findings: see COVID-19: Point-of-Care Ultrasonography.
4) Monitoring involves monitoring of blood pressure, SpO2, and the quick sequential organ failure assessment (qSOFA) (see Sepsis and Septic Shock).
Case definitions are used mostly for surveillance purposes and change with the evolution of the epidemiologic situation. Current Ontario definitions include confirmed case and probable case definitions.
As of October 4, 2020, a confirmed case is defined as a person with laboratory confirmation of SARS-CoV-2 infection using a validated assay, consisting of a positive nucleic acid amplification test (NAAT) (eg, real-time PCR or nucleic acid sequencing) on ≥1 specific genome target or a person with a positive detection of serum/plasma IgG antibodies to SARS-CoV-2 from a laboratory in Ontario licensed to conduct serology tests for clinical purposes.
A probable case is defined as:
1) A person who has not had a laboratory test and is having symptoms compatible with COVID-19 who:
a) Traveled to an affected area (including inside of Canada) in the 14 days prior to symptom onset; or
b) Had close contact with a confirmed case of COVID-19; or
c) Lived in or worked in a facility known to be experiencing an outbreak of COVID-19 (eg, long-term care, prison).
2) A person with symptoms compatible with COVID-19 in whom laboratory diagnosis of COVID-19 is inconclusive.
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).
As of October 18, 2020, treatment of COVID-19 is still predominantly supportive, although results of randomized controlled trials rapidly conducted in hospitalized patients are becoming available and may influence the care of this higher-risk group. The most convincing data available are for glucocorticoids, with preliminary 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 may be beneficial (see below), although preliminary data from the World Health Organization (WHO) SOLIDARITY trial do not provide additional support for its use among hospitalized patients.
On August 23, 2020, using mostly observational data, the US Food and Drug Administration (FDA) issued an Emergency Use Authorization for the use of COVID-19 convalescent plasma in the United States to treat suspected or laboratory-confirmed COVID-19 cases in hospitalized patients. Of note, on the basis of unpublished and preliminary data suggesting benefit among nonhospitalized patients, a dose of the antiviral monoclonal antibody cocktail REGN-COV2 was given to the president of the United States. This drug is currently included among regimens studied in the RECOVERY trial, in addition to azithromycin, tocilizumab, convalescent plasma, and—in children only—low-dose dexamethasone.
On the other hand, data considering hydroxychloroquine and lopinavir/ritonavir led investigators of the RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial to stop recruitment in these arms, concluding that trial results excluded any meaningful mortality benefit of these drugs. Preliminary results of the SOLIDARITY trial confirm these conclusions. A recent study similarly has not confirmed the benefit of hydroxychloroquine prophylaxis.Evidence 8Low 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 Emergency Use Authorization 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. It provides data on in-hospital treatment with lopinavir/ritonavir, antimalarial agents, low-dose dexamethasone, azithromycin, tocilizumab, and convalescent plasma. The arms testing antimalarials and lopinavir/ritonavir were stopped due to the lack of efficacy. A new arm investigating monoclonal antibodies (REGN-COV2) was added. The arm using dexamethasone 6 mg daily for 10 days 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 9Moderate 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 on September 2, 2020, confirmed the benefit of glucocorticoids, which will likely be used in patients requiring supplemental oxygen or higher levels of ventilatory support.Evidence 10Moderate 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.
Remdesivir use is supported by preliminary data from a large international study and a smaller Chinese study.Evidence 11Moderate 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. Individuals presenting with pneumonia and most frequently (~90% of patients) requiring supplemental oxygen who received this treatment had a shorter time to recovery. As indicated above, the SOLIDARITY trial results published on October 15 in a very preliminary form (preprint) do not support major clinical benefit of this drug.Evidence 12Low 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
The first randomized study of lopinavir/ritonavir was interpreted as not showing benefit, although it was too small to exclude relevant mortality benefit.Evidence 13Low 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.
Numerous other treatments are being studied, including interferon beta-1b and beta-1a, ribavirin, and favipiravir.
Treatment of COVID-19 is still predominantly 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. Empiric antibiotics are routinely used in patients with COVID-19 and pneumonia as part of supportive care.
Nonspecific treatments with a potential of benefit include proning of nonventilated patients and, especially, increased doses of deep vein thrombosis (DVT) prophylaxis with a low threshold for full anticoagulation, particularly in the presence of high levels of D-dimer. Further studies, including management strategies of full anticoagulation, are ongoing, with some suggestions of benefit of full anticoagulation among ventilated patients.Evidence 14Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision and indirectness. Lemos ACB, do Espírito Santo DA, Salvetti MC, et al. Therapeutic versus prophylactic anticoagulation for severe COVID-19: A randomized phase II clinical trial (HESACOVID). Thromb Res. 2020 Sep 21;196:359-366. doi: 10.1016/j.thromres.2020.09.026. Epub ahead of print. PMID: 32977137; PMCID: PMC7503069.
Management in sepsis and septic shock: see Sepsis and Septic Shock.
Some specific practice trends, based on collective experience and observational data, include moving away from very early intubation; paying particular attention to lung compliance, which may frequently be normal and thus require lower positive end-expiratory pressure (PEEP) and plateau pressures; early use of prone ventilation; and attention to the level of D-dimer and a high risk of thromboembolism.
An exposure leading to infection refers to mucosal contamination with biological materials that may contain the virus. According to the US Centers for Disease Control and Prevention (CDC), materials that warrant postexposure management include respiratory secretions; there is no evidence indicating that other fluids (blood, urine, stool, and vomit) contain viable, infectious SARS-CoV-2. To assess the risk of transmission of SARS-CoV-2, consider:
1) Duration of exposure (longer exposure increases the risk of transmission).
2) Clinical symptoms of the patient.
3) Whether a facemask (including what type) and eye protection were used by the health-care provider (HCP).
4) Whether the HCP used other personal protective equipment (PPE).
5) Whether aerosol-generating procedures were performed.
6) Whether a facemask was used by the patient.
High-risk exposures are defined as situations where an HCP is not wearing PPE that protects their mouth, nose, and eyes in the setting of droplets (eg, coughing) or during an aerosol-generating procedure, or situations where an HCP has direct unprotected contact with secretions from a patient with COVID-19 (cardiopulmonary resuscitation, intubation, extubation, bronchoscopy, nebulization, sputum induction).
Medium-risk exposures are defined as situations where an HCP without proper PPE has prolonged contact with a patient with COVID-19, which may result in mucosal or cutaneous exposure to potentially infectious materials.
Low-risk exposures are defined as situations where an HCP is using appropriate PPE but has prolonged close contact with patients with COVID-19. Although the currently available guidance on hygiene, sanitary standards, and use of PPE should be sufficient, it is nevertheless possible that due to oversight mistakes can be made (eg, during the doffing procedure), leading to SARS-CoV-2 transmission.
No occupational risk of exposure to SARS-CoV-2 is a risk category for HCPs who have no direct contact with COVID-19 patients, do not enter hospital wards or isolation wards for COVID-19 patients, and follow the routine safety precautions.
In case of exposure to biological materials from a patient with suspected SARS-CoV-2 infection, the exposed HCP should be treated as having high-risk or medium-risk exposure.
In the case of high-risk and medium-risk exposures, the HCP should undergo active monitoring and should be considered to be suspended from work for ≤14 days following the exposure. Some jurisdictions also recommend testing 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).
According to the European Centre for Disease Prevention and Control (ECDC), in the case of low-risk exposure, for 14 days after the exposure the HCP should perform self-monitoring with delegated supervision, which means the HCP performs self-monitoring with oversight by their health-care facility’s occupational health or infection control program or public health authorities. The exposed HCPs measure their temperature and assess themselves for other symptoms of respiratory tract infection. Temperature should be measured twice daily, including before starting work. HCPs who do not develop fever or other symptoms are not restricted from work. HCPs who develop symptoms consistent with COVID-19 should immediately self-isolate and notify public health authorities to arrange further evaluation.
HCPs who develop clinical symptoms consistent with COVID-19 must contact their point of contact (public health authorities or their health-care facility’s occupational health program) before returning to work, regardless of their risk exposure category.
In the majority of cases COVID-19 has a mild course. In the elderly patients and those with chronic medical conditions the risk of acute respiratory failure and death is substantially higher.
Vaccination: None available yet, with major efforts directed towards the development and advanced testing of multiple vaccines. As of October 15, 2020, there were 42 candidate vaccines being tested in clinical studies, including several in phase 3 trials.
1. General recommendations:
1) Frequently performing hand hygiene with soap and water or alcohol-based hand sanitizers.
2) Avoiding touching the face.
3) Reducing travel to a minimum.
4) Avoiding crowds and large gatherings.
5) Maintaining at least a 1-meter distance from others (odds decreased ~5-fold with the absolute difference in risk ~10%), with 2 meters providing further protection (~2-fold additional risk decrease).Evidence 15Moderate 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 eye protection (goggles, safety glasses; odds of infection decreased ~4-5-fold with the absolute difference in risk ~10%).Evidence 16Low 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) Reducing exposure and infections by wearing facemasks (odds decreased 6-7-fold with the absolute difference in risk ~14%; this represents combined data from the evaluation of surgical masks and N95 masks; surgical masks alone likely provide a 3-fold decrease in the odds of infection).Evidence 17Low 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.
8) Avoiding contact with individuals with respiratory symptoms.
2. Quarantine or self-isolation: Healthy individuals who had contact with an infected person undergo a 14-day quarantine (the duration is shorter in some jurisdictions). The duration and type of quarantine (self-observation, staying at home, quarantine in a hospital) may depend on the type of contact (high-risk vs low-risk exposure) and is determined by local public health authorities.
3. Isolation of infected individuals: Isolation precautions can be used (1) to prevent droplet transmission or direct contact transmission or (2) during aerosol-generating procedures, to prevent airborne transmission. Before entering the patient room, don a set of PPE. After leaving the room, PPE should be removed in a designated area with a waste container for single-use PPE and hand decontamination equipment. However, given the worldwide supply shortage of PPE, extended use and reuse protocols as well as reprocessing can be considered.
Precautions for droplet transmission and direct contact transmission: Patients should be placed in well-ventilated rooms with access to a washroom (in rooms with natural ventilation an average ventilation rate of 60 L/s per patient should be provided). If available, single-patient rooms are preferred. Patients with confirmed SARS-CoV-2 infection can be cohorted. When possible, designated HCPs should be assigned to provide care for the patients. The number of visitors should be restricted. A log of all persons entering the room should be kept (including HCPs and visitors). Medical equipment should be single-use or dedicated for a single patient only (in the case of reusable equipment, eg, stethoscope, thermometer, blood pressure monitor, pulse oximeter). If reusable equipment is shared by different patients, it should be disinfected between uses. Room surfaces and equipment in the patient’s environment should be regularly cleaned and disinfected. Transport of patients within the hospital should be limited to a minimum. When feasible, portable diagnostic equipment should be used (eg, bedside radiograph). If the patient must be transported (eg, for diagnostic evaluation), use the shortest route and notify the HCPs in the receiving area in advance. The patient should be wearing a facemask. Transport personnel and receiving personnel having contact with the patient must use PPE. Minimize exposure for staff, other patients, and visitors during transport.
Precautions for airborne transmission (airborne infection isolation rooms [AIIRs]): If available, aerosol-generating medical procedures should be performed in well-ventilated rooms maintaining constant negative pressure, providing ≥12 air exchanges per hour, and with controlled direction of airflow (preferably) or in a naturally ventilated room with an average ventilation rate ≥160 L/s per patient.
4. PPE: A minimum set of PPE should include (recommendations in different jurisdictions differ and evolve):
1) PPE for respiratory protection: Surgical or procedural masks should be used, with the level of fluid resistance depending on the potential risk of splashes. Currently the WHO and the Public Health Agency of Canada recommend surgical masks as sufficient while providing routine care and reserve N95 respirator masks for aerosol-producing procedures. It should be noted that surgical masks do 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.