Outpatient Management of COVID-19: Rapid Evidence Review

Anthony Cheng; Dominic Caruso; Craig McDougall

ANTHONY CHENG, MD, DOMINIC CARUSO, MD, MPH, AND CRAIG MCDOUGALL, MD

A more recent article on outpatient management of COVID-19 is available.

Editor's Note: On February 27, 2021, the FDA issued an Emergency Use Authorization for the Janssen single-dose vaccine for the prevention of COVID-19 in individuals 18 years of age and older. Information on this vaccine's effectiveness and mechanism of action is available from the FDA and the Centers for Disease Control and Prevention. A summary of the FDA report can be found in AFP's COVID-19 Research Brief posted on March 1.

This is an updated version of the article that appeared in print. The update incorporates new information about personal protective equipment requirements and the two COVID-19 vaccines that received Emergency Use Authorization from the U.S. Food and Drug Administration (FDA) in December 2020.

Am Fam Physician. 2020;102(8):478-486

Related editorial: Long COVID: A Primer for Family Physicians

Published online February 26, 2021.

Author disclosure: No relevant financial affiliations.

Common presenting symptoms of coronavirus disease 2019 include fever, dry cough, shortness of breath, and fatigue. However, patients may have a wide range of symptoms representing a spectrum of mild to severe illness. Symptoms in children tend to be milder and may include fever, cough, and feeding difficulty. The incubation period is two to 14 days, although symptoms typically appear within five days of exposure. Multiple testing modalities exist, but infection should be confirmed by polymerase chain reaction testing using a nasopharyngeal swab. Two vaccines are now available in the United States. There are no evidence-based treatments appropriate for use in the outpatient setting; management is supportive and should include education about isolation. In hospitalized patients, remdesivir should be considered to reduce time to recovery, and low-dose dexamethasone should be considered in patients who require supplemental oxygen. Overall, 85% of patients have mild illness, whereas 14% have severe disease requiring hospitalization, including 5% who require admission to an intensive care unit. Predictors of severe disease include increasing age, comorbidities, lymphopenia, neutrophilia, leukocytosis, low oxygen saturation, and increased levels of C-reactive protein, d-dimer, transaminases, and lactate dehydrogenase.

The coronavirus disease 2019 (COVID-19) pandemic is caused by an enveloped single-stranded RNA novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first cases were reported in Wuhan City, China, in December 2019; the United States confirmed its first cases one month later. Middle East Respiratory Syndrome and Severe Acute Respiratory Syndrome, also caused by coronaviruses, have caused significantly lower global mortality.

Clinical recommendation	Evidence rating	Comments
Close contacts of patients with COVID-19 should quarantine for 14 days with daily monitoring for fever and other symptoms.⁸	C	Expert opinion based on disease modeling
Telehealth can be used for initial triage of patients with respiratory symptoms of COVID-19; further care should be based on vital signs, physical examination findings, social considerations, and risk factors.^11,21	C	Expert opinion in the absence of clinical trials
Infection with severe acute respiratory syndrome coronavirus 2 should be confirmed by polymerase chain reaction testing using a nasopharyngeal swab.⁴²	C	Expert opinion and cross-sectional studies of diagnostic accuracy
Management of COVID-19 in the outpatient setting is focused on supportive care and reducing the risk of transmission via isolating at home.⁴⁵	C	Expert opinion
Dexamethasone, 6 mg per day for 10 days, reduces mortality in hospitalized patients with COVID-19 who require supplemental oxygen (NNT = 29) and mechanical ventilation (NNT = 9), but not in hospitalized patients or outpatients who do not require supplemental oxygen.⁵⁰	B	Well-designed RCT
Remdesivir (Veklury) shortens time to recovery in hospitalized patients with COVID-19 but has not been proven to reduce mortality.^52,53	B	Two RCTs, one of which was positive and one of which was negative but underpowered

Epidemiology

The basic reproductive number (infections per index case) of COVID-19 is unknown. One systematic review estimated a range of 1.9 to 6.5.¹
Studies in the United States and Switzerland based on antibody sampling estimated seroprevalence between 1.1% and 10.9%.²
Pathogenic factors contributing to the virulence of SARS-CoV-2 include transmissibility via respiratory droplets and asymptomatic spread via healthy-appearing individuals.
The true incidence of COVID-19 in the United States is unknown and varies geographically.³
It is estimated that only one in approximately 80 COVID-19 infections was diagnosed in March 2020, and there is promise in disease modeling that extrapolates from influenza-like illness.⁴

Screening and Prevention [updated]

Physical distancing of at least 6 ft (1.8 m) slows the spread of infection by decreasing the mean number of people infected per case, particularly when combined with other measures such as mask wearing in public, school closures, and travel restrictions.^5,6
Contact tracing has reduced the spread of infection early during outbreaks in some countries.⁷
The Centers for Disease Control and Prevention (CDC) recommends that close contacts of a person with COVID-19 quarantine for 14 days after the last exposure and monitor for fever and other symptoms daily.⁸ People suspected of having COVID-19 should isolate within their home to prevent infection spread, stay in a specific “sick room” if they live with others, and use a separate bathroom, if possible.⁸
The CDC recommends wearing face masks when in a public space where appropriate physical distancing may be difficult.⁹ This practice may reduce viral transmission (Howard J, et al., and Kai D, et al., unpublished data, 2020), particularly from asymptomatic or presymptomatic individuals.¹⁰
Patients with respiratory symptoms should wear a surgical mask in health care settings. Those without respiratory symptoms should wear a cloth face mask per CDC recommendations.
Table 1 lists recommended personal protective equipment for clinicians based on different clinical scenarios.^11–14
Two vaccines against SARS-CoV-2 are currently available in the United States: BNT162b2 (Pfizer/BioNTech) and mRNA-1273 (Moderna; Table 2^15,16). Both vaccines contain lipid-encapsulated mRNA molecules that are delivered to macrophages. Translation of mRNA results in expression of prefusion-stabilized spike proteins on the cellular surface and an immune reaction. The mRNA is subsequently degraded, and no genetic material enters the nucleus of cells.
Both vaccines were highly effective at preventing symptomatic infection in the short term in randomized, double-blind trials submitted to the U.S. Food and Drug Administration for Emergency Use Authorization. The mRNA-1273 vaccine trial included 30,420 patients 18 years and older, and the BNT162b2 mRNA vaccine trial included 43,548 participants 16 years and older.^15,16
Currently, the data are insufficient to recommend vaccination of children and pregnant patients. We do not know whether the vaccine protects against asymptomatic infection or transmission.
The CDC and National Institutes of Health convened the National Academies of Sciences, Engineering, and Medicine to develop an overarching vaccine allocation framework.¹⁷ This framework is incorporated into the Advisory Committee on Immunization Practices COVID-19 vaccine recommendations, which support allocation of COVID-19 vaccines based on phases 1a, 1b, 1c, and 2 depending on factors such as age, occupation, and comorbidities.¹⁸ Updates are published in Morbidity and Mortality Weekly Report.¹⁹
More than 100 vaccines are in various stages of development. Vaccine strategies include inactivated viruses, replication-incompetent vectors, recombinant spike-proteins, and adenovirus-based DNA vaccines such as AZD1222 and JNJ-78436735.²⁰ The AZD1222 (AstraZeneca) vaccine was approved for emergency use in the United Kingdom on December 30, 2020. Studies of the JNJ-78436735 (Johnson & Johnson) vaccine have been promising. Unlike the mRNA vaccines, some candidates can be stored at refrigerator temperatures or may be effective after one dose.

Scenario	Equipment
Patient without respiratory symptoms	Standard precautions, surgical masks, and eye protection
Patient with respiratory symptoms	Surgical mask, gown, gloves, and eye protection
Collection of nasal swab in patient with suspected or confirmed infection*	Surgical mask, gown, gloves, and eye protection
Non–aerosol-generating procedure	Surgical mask, gown, gloves, and eye protection
Aerosol-generating procedure†	N95 or powered air-purifying respirator, eye protection, isolation gown, gloves

Features	BNT162b2 (Pfizer/BioNTech	mRNA-1273 (Moderna)
Antigenic target	Prefusion spike protein	Prefusion spike protein
Mechanism	RNA	RNA
Efficacy	95% (credible interval 90.3% to 97.6%), 7 days after second dose 52% efficacy observed in the period between doses	94% (credible interval 89.3% to 96.8%), 14 days after second dose
Safety	Four related serious adverse events occurred (shoulder injury related to vaccine administration, right axillary lymphadenopathy, paroxysmal ventricular arrhythmia, and right leg paresthesia) Six deaths occurred during the study (four in the control group), and no deaths were considered by investigators to be related to the vaccine or placebo	Six related serious adverse events occurred Five deaths occurred during the study (three in the control group), and no deaths were considered by investigators to be related to the vaccine or placebo
Reactogenicity	66% to 78% of recipients reported pain at the injection site after each injection Local and systemic symptoms were more common in younger vs. older vaccine recipients, and the most common systemic symptoms were fatigue (51% to 59%) and headache (39% to 52%) After the second dose, severe fatigue and headache were reported in 3.8% and 2.0% of recipients, respectively The frequency and severity of systemic symptoms increased after the second dose compared with the first dose	83% to 90% of recipients reported pain at the injection site after each injection Local and systemic symptoms were more common in younger vs. older vaccine recipients, and the most common systemic symptoms were fatigue (58% to 67%) and headache (46% to 59%) After the second dose, severe fatigue and headache were reported in 9.7% and 4.5% of recipients, respectively The frequency and severity of systemic symptoms increased after the second dose compared with the first dose
Dosing	Two doses injected into the deltoid muscle, 21 days apart	Two doses injected into the deltoid muscle, 28 days apart
Storage	Store at –60°C to –80°C (–76°F to –112°F) Stable for up to five days at 2°C to 8°C (35.6°F to 46.4°F) Stable at room temperature for up to two hours	Store at –25°C to –15°C (–13°F to 5°F) Stable for up to 30 days at 2°C to 8°C Stable at room temperature for up to eight hours

Diagnosis

The diagnosis of COVID-19 is made clinically and is supported by laboratory results and radiographic findings. COVID-19 should be suspected in patients with known or suspected exposure within the past 14 days, or in the setting of active SARS-CoV-2 transmission in the community.
When possible, patients should be triaged via telehealth before they receive in-person care (Figure 1).²¹
Physicians should be aware of anchoring bias when considering a diagnosis of COVID-19. Given the wide variability in presentations, it should be considered as one among several potential etiologies.
The differential diagnosis includes:
○ Acute pulmonary edema
○ Acute respiratory distress syndrome
○ Chronic obstructive pulmonary disease exacerbation
○ Community-acquired pneumonia (bacterial or viral)
○ Influenza
○ Interstitial lung disease
○ Nonspecific viral upper respiratory tract infection
○ Opportunistic pulmonary infection
○ Pulmonary embolism
○ Streptococcal pharyngitis

SIGNS AND SYMPTOMS

The incubation period of SARS-CoV-2 is two to 14 days, although symptoms generally appear within five days of exposure.²²
Common presenting symptoms include fever, dry cough, shortness of breath, and fatigue²³; however, patients may have a wide range of symptoms representing a spectrum of mild to severe illness (Table 3).^24–33
Moderate to severe anosmia and altered taste are commonly reported.²⁸
Symptoms in children tend to be milder than in adults and may include fever, cough, and feeding difficulty (Arnaout R, et al., unpublished data, 2020).²⁵
Pregnant and recently pregnant women are less likely to present with fever and myalgias compared with nonpregnant patients of reproductive age.³⁴
A high proportion of patients with SARS-CoV-2 infection (about 40%) are asymptomatic, particularly younger patients.³⁵
Multisystem inflammatory syndrome in children is thought to be related to COVID-19. Signs include prolonged fever and clinically severe illness with multiorgan involvement. The diagnosis is supported by laboratory confirmation of inflammation, evidence of recent SARS-CoV-2 infection, or exposure and no other obvious microbial cause of inflammation.^36,37

TESTING

There are multiple testing modalities for COVID-19 (Table 4).^2,38–46 Acute infection should be confirmed with polymerase chain reaction testing using a nasopharyngeal swab.⁴² Antibody testing is most useful for epidemiologic purposes. ²⁵ Point-of-care testing provides rapid results, but the reliability of these tests is not clear.⁴¹
The decision to test depends on variables such as availability of test kits and reagents, and implications for treatment, infection control, and public health.
In addition to patients with signs or symptoms of COVID-19, testing should be considered for patients who:
○ Have a known or suspected exposure (including neonates born to a mother diagnosed with COVID-19)
○ Will undergo a planned surgery or aerosol-generating procedure
○ Are undergoing chemotherapy
○ Are part of a group disproportionately affected by COVID-19, such as Black, Latino, Pacific Islander, or American Indian/Alaska Native communities.^11,47
Testing asymptomatic people after an exposure is recommended five to seven days after the exposure based on the median viral incubation period. Testing should not occur for at least 48 hours after exposure. Asymptomatic contacts with negative test results still must quarantine for 14 days.¹¹
Retesting can be considered to confirm disease resolution in immunocompromised patients if enough testing capacity exists.¹¹
Radiographic findings in patients with COVID-19 may include⁴⁵:
○ “Crazy paving” (i.e., ground-glass opacity with superimposed interlobular and intralobular septal thickening)
○ Dense consolidation
○ Ground-glass opacity
○ Multifocal ground-glass opacity
In hospitalized patients, the following laboratory tests can help assess prognosis and identify patients at risk of vascular and thrombotic complications ⁴⁵:
○ Complete blood count with differential
○ C-reactive protein level
○ d-dimer assay
○ Lactate dehydrogenase level
○ Troponin level

Type of test	Comments
Antibody test	The antibody test is most useful for epidemiologic purposes and in children with multisystem inflammatory syndrome to provide evidence of current or past COVID-19 infection.³⁸
	It detects the presence of IgM and IgG antibodies to SARS-CoV-2, which emerge approximately five and 14 days after symptom onset, respectively (Wajnberg A, et al., unpublished data, 2020). A positive result can indicate prior infection or exposure, which is important for detecting infections with few or no symptoms.
	Early evidence suggests that most patients develop a vigorous antibody response to SARS-CoV-2,³⁹ but it is not known if this correlates with resistance to future infection.
	Results should not be used as the sole basis on which to diagnose or exclude SARS-CoV-2 infection.
	A positive result may be due to current or past infection with non–SARS-CoV-2 coronavirus strains.⁴⁰
	Even tests with good specificity can yield more false-positive than true-positive results when population prevalence is low.⁴¹
PCR test	The PCR test detects the presence of coronavirus RNA and is used to confirm the diagnosis of COVID-19.
	Positive results do not rule out bacterial infection or coinfection with other viruses.
	Sensitivity varies depending on time from symptom onset,⁴² so results should be interpreted based on clinical and epidemiologic factors.⁴³
	Nasopharyngeal swabs are somewhat more sensitive than oropharyngeal swabs. If both are collected, they may be combined and tested simultaneously in a single reaction to conserve reagents.⁴⁴
	Reliability is unknown because there is no standard diagnostic test,² there are multiple test types, production methods are inconsistent, and implementation varies around the world. Extrapolating from data on PCR tests for influenza, the PCR rapid test for COVID-19 may be highly specific (90% to 95%), meaning a positive result is good at ruling in infection, but only moderately sensitive (50% to 70%), meaning a negative result does not reliably rule out infection (Arnaout R, et al., unpublished data, 2020).⁴⁵
	A negative result should be taken in the context of other symptoms, exposures, and the clinical presentation to guide recommendations.
Point-of-care tests	Results are available within minutes.
	Nucleic acid amplification testing targets part of the RdRp gene that is specific to SARS-CoV-2.
	Antigen testing uses antibodies and immunofluorescence to detect the presence of SARS-CoV-2.
	The reliability, sensitivity, and specificity of these tests are variable.⁴¹

Treatment

There are no evidence-based treatments for COVID-19 that are appropriate for use in the outpatient setting; management is supportive.⁴⁵
The World Health Organization recommends that infants born to women with COVID-19 not be separated from their mothers, and that these mothers initiate and continue breastfeeding.⁴⁸
Remote patient monitoring via telehealth can be used to detect red flag symptoms that warrant urgent assessment, such as²¹:
○ Fever above 100.4°F (38°C)
○ Heart rate greater than 100 beats per minute with new confusion
○ Oxygen saturation less than 95%
○ Respiratory rate greater than 20 breaths per minute
Figure 2 shows a protocol for discontinuing home isolation after COVID-19 diagnosis.^11,49

DRUG THERAPY

In addition to supportive care, there are several investigational drugs being explored for the treatment of COVID-19 in hospitalized patients.
Dexamethasone, 6 mg per day for 10 days, significantly reduced mortality in hospitalized patients with COVID-19 who required supplemental oxygen (number needed to treat [NNT] = 29) or mechanical ventilation (NNT = 9), but not in hospitalized patients who did not require supplemental oxygen.⁵⁰ Systemic corticosteroids are not recommended for outpatients or for hospitalized patients who do not require supplemental oxygen.⁵¹
Remdesivir (Veklury) was shown in a U.S. randomized trial to significantly reduce time to recovery (11 vs. 15 days) and to nonsignificantly reduce mortality (7.1% vs. 11.9%; P = .059) in hospitalized patients with COVID-19.⁵² A Chinese study found no significant benefit, but the study was underpowered.⁵³ Remdesivir has not been studied in outpatients with nonsevere illness and is not recommended for this population.
Hydroxychloroquine (Plaquenil) has not been shown to have clear benefit in patients with mild to severe COVID-19 symptoms, or for postexposure prophylaxis (Horby P, et al., unpublished data, 2020).^54–57
There is insufficient evidence to recommend the use of the following treatments for COVID-19⁴⁵:
○ Azithromycin (Zithromax)
○ Convalescent plasma
○ Interferon
○ Ivermectin (Soolantra)
○ Lopinavir/ritonavir (Kaletra)
○ Ribavirin (Virazole)
○ Tocilizumab (Actemra)

REFERRAL, CONSULTATION, AND HOSPITALIZATION

In the course of an in-person assessment, the appropriate disposition of patients with symptomatic COVID-19 can be guided by vital signs, physical examination findings, respiratory rate, oxygen saturation, social considerations, and risk factors as outlined in Figure 3.^{11,21,48,58,59}

Prognosis

International data suggest that 85% of people with COVID-19 have only mild illness, whereas 14% have severe disease requiring hospitalization, including 5% of adults and 2% of children who require admission to an intensive care unit.^60–62 Children tend to have a better prognosis than adults (Arnaout R, et al., unpublished data, 2020).⁶²
The overall mortality rate from COVID-19 has been estimated to be 0.66% to 0.9%, although estimates are difficult because of the number of undiagnosed cases.^63,64 Observed rates vary considerably (2.3% to 7.2%) depending on location and test availability. As of July 21, 2020, the Johns Hopkins Center for Health Security reported a U.S. case fatality rate of 3.7%.² Case fatality rates increase with age.^6,60,63,64
Predictors of more severe disease or death include clinical factors, comorbidities, and laboratory findings (Table 5).^41,65–68 Common risk factors in hospitalized patients include^66,67:
○ Cardiovascular disease
○ Chronic kidney disease
○ Chronic liver disease
○ Chronic obstructive pulmonary disease
○ Diabetes mellitus
○ Hypercholesterolemia
○ Hypertension
○ Malignancy
○ Obesity
○ Obstructive sleep apnea
In pregnant women, COVID-19 may increase the risk of complications such as preterm birth and preterm premature rupture of membranes. The risk of vertical transmission and risks to newborns are not well understood.³⁴
A 10-item clinical prediction rule has been developed and externally validated to determine the prognosis of patients with COVID-19 (http://118.126.104.170).⁶⁹ However, it requires imaging and extensive laboratory testing.
Acute complications of COVID-19 include pneumonia, acute respiratory distress syndrome, stroke, and arterial and venous thrombosis. Hospitalized patients may have debility ⁷⁰ and mental health effects.⁷¹ Factors that may increase the risk of these complications include:
○ A diet with inadequate fruits and vegetables (Adams ML, et al., unpublished data, 2020)
○ Body mass index greater than 40 kg per m²⁶⁵
○ Sedentary lifestyle
○ Smoking
The long-term health effects of COVID-19 are under investigation.
Approximately 35% of people with COVID-19 have not returned to their previous level of health 14 to 21 days after diagnosis. These “long haulers” have a syndrome referred to as long COVID.⁷²
Table 6 lists additional COVID-19 resources for clinicians.

BMJ's COVID-19 hub
https://www.bmj.com/coronavirus

European Centre for Disease Prevention and Control: contact tracing for COVID-19
https://www.ecdc.europa.eu/sites/default/files/documents/COVID-19-Contract-tracing-scale-up.pdf

Infectious Diseases Society of America: COVID-19 treatment guidelines
https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management

National Institutes of Health: COVID-19 treatment guidelines
https://www.covid19treatmentguidelines.nih.gov

World Health Organization: interim guidance on clinical management of COVID-19
https://www.who.int/publications-detail/clinical-management-of-severe-acute-respiratory-infection-when-novel-coronavirus-(ncov)-infection-is-suspected

Data Sources: An initial evidence review was performed by the COVID Inquiry Group of the Oregon Health & Science University School of Medicine. Search terms included COVID, COVID-19, and SARD-CoV2. Answers were reviewed by two faculty reviewers. A subsequent literature review was performed using PubMed, Essential Evidence Plus, and the COVID-19 Daily Research Briefs on the AFP website. Search dates: March through September 2020.

This article was based on the Outpatient COVID-19 Reference Guide published in April 2020 by the Oregon Health & Science University (OHSU). The project lead was Jessica Hoyt; other contributors included Johanna Warren, MD; Dominic Caruso, MD; Anthony Cheng, MD; Eric Herman, MD; Debbie Lamberger, MPA; Craig McDougall, MD; Andy Barnett, MD; Daisuke Yamashita, MD; and Emily Barclay, MS. We wish to acknowledge the work of the OHSU COVID Lab Task Force and the OHSU School of Medicine COVID Inquiry Group: co-leads Frances Biagioli, MD, and Kam Pierce, MPA; core faculty members Heather Angier, PhD; Amy Chen, MD; Elizabeth Haney, MD; and Glenn Rodriguez, MD; core student group Hannah Bacheller, Eva Davis, Brett Lewis, Asma Lotfi, Lauren Raymond, Elizabeth Swanson, and Kanwarabijit Thind; contributing authors Brooke Bachelor, DO; Andrea Baron, MPH; Kathryn Bonuck, MS; Elizabeth Bower, MD; Annie Buckmaster, MD; Dominic Caruso, MD; Anthony Cheng, MD; Joshua Cohen, MD; Roopradha Datta, MPH; Shelby Lee Freed, FNP; Natalie Freitas, MD; Laurel Hallock-Koppelman, DNP; Cassandra Kasten-Arias; Roheet Kakaday, MD; Christine Le, MD; Justin Lewis, MD; Ingrid Lindquist, MD; Morgan Lisner, MD; Mustafa Mahmood, MD; Brittany McAdams, MD; Craig McDougall, MD; John Mitchell, MD; Laurence Moore, MD; Cassie Mullen, MD; Ryan Nesbit, MD; Kristen Otto, MD; Gina Phillipi; Megan Quinlan, MD; Sean Robinson, MD; Whitney Roper, MD; Eric Schmidt, MD; Linh Taylor; Erin Urbanowicz; Eric Wiser, MD; Jean Yau, MD; and Hirofumi Yoshida, MD.

Editor's Note: This article has been updated to incorporate new information about personal protective equipment requirements and the two COVID-19 vaccines that received Emergency Use Authorization from the U.S. Food and Drug Administration in December 2020. —Kenny Lin, MD, MPH, deputy editor of AFP

Alimohamadi Y, Taghdir M, Sepandi M. Estimate of the basic reproduction number for COVID-19: a systematic review and meta-analysis. J Prev Med Public Health. 2020;53(3):151-157.

Ai T, Yang Z, Hou H, et al. Correlation of chest CT and RT-PCR testing for coronavirus disease 2019 (COVID-19) in China: a report of 1014 cases. Radiology. 2020;296(2):E32-E40.

Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in real time [correction published online June 12, 2020, at https://bit.ly/33EN4Xb]. Lancet Infect Dis. 2020;20(5):533-534.

Silverman JD, Hupert N, Washburne AD. Using influenza surveillance networks to estimate state-specific prevalence of SARS-CoV-2 in the United States. Sci Transl Med. 2020;12(554):eabc1126.

Nussbaumer-Streit B, Mayr V, Dobrescu AI, et al. Quarantine alone or in combination with other public health measures to control COVID-19: a rapid review. Cochrane Database Syst Rev. 2020(4):CD013574.

Ferguson NM, Laydon D, Nedjati-Gilani G, et al.; Imperial College COVID-19 Response Team. Report 9: impact of non-pharmaceutical interventions (NPIs) to reduce COVID-19 mortality and healthcare demand. March 16, 2020. Accessed June 24, 2020. https://bit.ly/3cf2dT8

European Centre for Disease Prevention and Control. Contact tracing for COVID-19: current evidence, options for scale-up and an assessment of resources needed. April 2020. Accessed June 23, 2020. https://bit.ly/2RDKhrF

Centers for Disease Control and Prevention. Coronavirus disease 19 (COVID-19): quarantine if you might be sick. Updated September 10, 2020. Accessed September 18, 2020. https://bit.ly/32Fn7HH

Centers for Disease Control and Prevention. Coronavirus disease 2019: use of masks to help slow the spread of COVID-19. Updated June 28, 2020. Accessed July 29, 2020. https://bit.ly/32K6WJn

Wei WE, Li Z, Chiew CJ, et al. Presymptomatic transmission of SARSCoV-2 – Singapore, January 23–March 16, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(14):411-415.

Oregon Health & Science University. Outpatient COVID-19 reference guide. April 2020. Accessed July 28, 2020. https://www.ohsu.edu/sites/default/files/2020-05/OHSU-Outpatient-COVID-19-Reference-Guide_0.pdf

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;46(5):854-887.

Chu DK, Akl EA, Duda S, et al. 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;395(10242):1973-1987.

Centers for Disease Control and Prevention. Interim infection prevention and control recommendations for healthcare personnel during the coronavirus disease 2019 (COVID-19) pandemic. Updated July 15, 2020. Accessed September 18, 2020. https://bit.ly/35N2bR2

Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med. 2020;384(5):403-416.

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;383(27):2603-2615.

National Academies of Sciences, Engineering, and Medicine. Framework for Equitable Allocation of COVID-19 Vaccine. National Academies Press; 2020. Accessed January 18, 2021. https://doi.org/10.17226/25917

Dooling K, Marin M, Wallace M, et al. The Advisory Committee on Immunization Practices' updated interim recommendation for allocation of COVID-19 vaccine--United States, December 2020.. MMWR Morb Mortal Wkly Rep. 2021;69(5152):1657-1660.

Advisory Committee on Immunization Practices. COVID-19 ACIP vaccine recommendations. Accessed January 18, 2021. https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/covid-19.html

Krammer F. SARS-CoV-2 vaccines in development. Nature. 2020;586(7830):516-527.

Greenhalgh T, Koh GCH, Car J. COVID-19: a remote assessment in primary care. BMJ. 2020;368:m1182.

Lauer SA, Grantz KH, Bi Q, et al. The incubation period of coronavirus disease 2019 (COVID-19) from publicly reported confirmed cases: estimation and application. Ann Intern Med. 2020;172(9):577-582.

Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19): symptoms of coronavirus. Updated May 13, 2020. Accessed June 24, 2020. https://bit.ly/2ZQ0v5p

Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708-1720.

Parri N, Lenge M, Buonsenso D Coronavirus Infection in Pediatric Emergency Departments (CONFIDENCE) Research Group. Children with COVID-19 in pediatric emergency departments in Italy. N Engl J Med. 2020;383(2):187-190.

Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020;323(11):1061-1069.

Goyal P, Choi JJ, Pinheiro LC, et al. Clinical characteristics of COVID-19 in New York City. N Engl J Med. 2020;382(24):2372-2374.

Spinato G, Fabbris C, Polesel J, et al. Alterations in smell or taste in mildly symptomatic outpatients with SARS-CoV-2 infection. JAMA. 2020;323(20):2089-2090.

Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395(10223):507-513.

Recalcati S. Cutaneous manifestations in COVID-19: a first perspective. J Eur Acad Dermatol Venereol. 2020;34(5):e212-e213.

Fu L, Wang B, Yuan T, et al. Clinical characteristics of coronavirus disease 2019 (COVID-19) in China: a systematic review and meta-analysis. J Infect. 2020;80(6):656-665.

Wang Z, Yang B, Li Q, et al. Clinical features of 69 cases with coronavirus disease 2019 in Wuhan, China. Clin Infect Dis. 2020;71(15):769-777.

Dong Y, Mo X, Hu Y, et al. Epidemiology of COVID-19 among children in China. Pediatrics. 2020;145(6):e20200702.

Allotey J, Stallings E, Bonet M, et al. Clinical manifestations, risk factors, and maternal and perinatal outcomes of coronavirus disease 2019 in pregnancy: living systematic review and meta-analysis. BMJ. 2020;370:m3320.

Lavezzo E, Franchin E, Ciavarella C, et al. Suppression of a SARS-CoV-2 outbreak in the Italian municipality of Vo' [published online June 30, 2020]. Nature. Accessed July 28, 2020. https://go.nature.com/32K13fg

CDC COVID-19 Response Team. Coronavirus disease 2019 in children – United States, February 12–April 2, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(14):422-426.

World Health Organization. Multisystem inflammatory syndrome in children and adolescents temporally related to COVID-19: scientific brief. May 15, 2020. Accessed June 24, 2020. https://bit.ly/2RCrJrE

Hanson KE, Caliendo AM, Arias CA, et al. Infectious Diseases Society of America guidelines on the diagnosis of COVID-19: serologic testing [published online August 18, 2020]. Clin Infect Dis. Accessed September 18, 2020. https://bit.ly/3krfZoo

Centers for Disease Control and Prevention. Serology testing for COVID-19 at CDC. Updated May 23, 2020. Accessed June 24, 2020. https://bit.ly/32H6Hyq

Ebell MH, Barry HC. Beware of false-positive results with SARS-CoV-2 antibody tests [letter to the editor]. Am Fam Physician. 2020;102(1):5-6. Accessed July 28, 2020. https://www.aafp.org/afp/2020/0701/p5a.html

Dinnes J, Deeks JJ, Adriano A, et al. Rapid, point-of-care antigen and molecular-based tests for diagnosis of SARS-CoV-2 infection. Cochrane Database Syst Rev. 2020(8):CD013705.

Patel R, Babady E, Theel ES, et al. Report from the American Society for Microbiology COVID-19 International Summit, 23 March 2020: value of diagnostic testing for SARS-CoV-2/COVID-19 [editorial]. mBio. 2020;11(2):e00722-20.

Ng K, Poon BH, Puar THK, et al. COVID-19 and the risk to health care workers: a case report. Ann Intern Med. 2020;172(11):766-767.

Centers for Disease Control and Prevention. CDC 2019-novel coronavirus (2019-nCoV) real-time RT-PCR diagnostic panel: instructions for use. Catalog #2019-nCoVEUA-01 1000 reactions. Updated July 13, 2020. Accessed July 29, 2020. https://bit.ly/3mxPzTR

Ebell MH, Smith MA, Barry HC, et al. Coronavirus SARS-CoV2 infection (COVID-19). Essential Evidence Plus. Updated August 20, 2020. Accessed September 18, 2020. https://www.essentialevidenceplus.com/content/eee/904

Watson J, Whiting PF, Brush JE. Interpreting a COVID-19 test result. BMJ. 2020;369:m1808.

Oregon Health Authority. COVID-19 testing guidance for health care providers. August 14, 2020. Accessed September 18, 2020. https://bit.ly/3mzquYI

World Health Organization. Clinical management of COVID-19: interim guidance. May 27, 2020. Accessed June 23, 2020. https://bit.ly/3iL2C1N

Centers for Disease Control and Prevention. Discontinuation of isolation for persons with COVID-19 not in healthcare settings: interim guidance. Updated July 20, 2020. Accessed September 17, 2020. https://bit.ly/33In8d5

Horby P, Lim WS, Emberson JR, et al. Dexamethasone in hospitalized patients with COVID-19—preliminary report [published online July 17, 2020]. N Engl J Med. Accessed July 28, 2020. https://bit.ly/39CyO3Z

Lamontagne F, Agoritsas T, Macdonald H, et al. A living WHO guideline on drugs for COVID-19. BMJ. 2020;370:m3379.

NIH clinical trial shows remdesivir accelerates recovery from advanced COVID-19. News release. National Institute of Allergy and Infectious Diseases. April 29, 2020. Accessed June 24, 2020. https://bit.ly/3hM4G8u

Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial [published correction appears in Lancet. 2020;395(10238):1694]. Lancet. 2020;395(10236):1569-1578.

Boulware DR, Pullen MF, Bangdiwala AS, et al. A randomized trial of hydroxychloroquine as postexposure prophylaxis for COVID-19. N Engl J Med. 2020;383(6):517-525.

Skipper CP, Pastick KA, Engen NW, et al. Hydroxychloroquine in nonhospitalized adults with early COVID-19: a randomized trial [published online July 16, 2020]. Ann Intern Med. Accessed September 18, 2020. https://bit.ly/3mx95Qr

Mitjà O, Corbacho-Monné M, Ubals M, et al. Hydroxychloroquine for early treatment of adults with mild COVID-19: a randomized-controlled trial [published online July 16, 2020]. Clin Infect Dis. Accessed September 18, 2020. https://bit.ly/2RFe5UM

Cavalcanti AB, Zampieri FG, Rosa RG, et al. Hydroxychloroquine with or without azithromycin in mild-to-moderate COVID-19 [published online July 23, 2020; correction published online September 10, 2020, at https://bit.ly/2FLCKoa]. N Engl J Med. Accessed September 18, 2020. https://bit.ly/2RCTmRJ

Swiss Society of Intensive Care Medicine. Recommendations for the admission of patients with COVID-19 to intensive care and intermediate care units (ICUs and IMCUs). Swiss Med Wkly. 2020;150:w20227.

Gandhi RT, Lynch JB, Del Rio C. Mild or moderate COVID-19 [published online April 24, 2020]. N Engl J Med. Accessed June 24, 2020. https://bit.ly/3hMzE0J

Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA. 2020;323(13):1239-1242.

Epidemiology Working Group for NCIP Epidemic Response; Chinese Center for Disease Control and Prevention. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China [in Chinese]. Zhonghua Liu Xing Bing Xue Za Zhi. 2020;41(2):145-151.

Liguoro I, Pilotto C, Bonanni M, et al. SARS-CoV-2 infection in children and newborns: a systematic review. Eur J Pediatr. 2020;179(7):1029-1046.

Verity R, Okell LC, Dorigatti I, et al. Estimates of the severity of coronavirus disease 2019: a model-based analysis [published correction appears in Lancet Infect Dis. 2020;20(6):e116]. Lancet Infect Dis. 2020;20(6):669-677.

Onder G, Rezza G, Brusaferro S. Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy. JAMA. 2020;323(18):1775-1776.

Petrilli CM, Jones SA, Yang J, et al. Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study. BMJ. 2020;369:m1966.

CDC COVID-19 Response Team. Preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease 2019 – United States, February 12–March 28, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(13):382-386.

Wynants L, Van Calster B, Collins GS, et al. Prediction models for diagnosis and prognosis of covid-19 infection: systematic review and critical appraisal [published correction appears in BMJ. 2020;369:m2204]. BMJ. 2020;369:m1328.

Centers for Disease Control and Prevention. Coronavirus disease 2019 (COVID-19): older adults. Updated September 11, 2020. Accessed September 17, 2020. https://bit.ly/3iKfoO2

Liang W, Liang H, Ou L, et al. Development and validation of a clinical risk score to predict the occurrence of critical illness in hospitalized patients with COVID-19. JAMA Intern Med. 2020;180(8):1081-1089.

Hashem MD, Nallagangula A, Nalamalapu S, et al. Patient outcomes after critical illness: a systematic review of qualitative studies following hospital discharge. Crit Care. 2016;20(1):345.

Parker AM, Sricharoenchai T, Raparla S, et al. Posttraumatic stress disorder in critical illness survivors: a metaanalysis. Crit Care Med. 2015;43(5):1121-1129.

Greenhalgh T, Knight M, A'Court C, et al. Management of post-acute COVID-19 in primary care. BMJ. 2020;370:m3026.