Annals of Internal MedicineT

In the ClinicT

COVID-19
C
OVID-19, the illness caused by SARS-CoV-2,
became a worldwide pandemic in 2020.
Initial clinical manifestations range from
asymptomatic infection to mild upper respiratory What causes COVID-19?
illness but may progress to pulmonary involvement
with hypoxemia and, in some cases, multiorgan
involvement, shock, and death. Older adults, preg- Prevention
nant persons, those with common comorbidities,
and those with immunosuppression are at greatest Diagnosis
risk for progression. Vaccination is effective in pre-
venting symptomatic infection and reducing risk
for severe disease, hospitalization, and death. Management and
Antiviral treatment and immunomodulators have Treatment
been shown to benefit certain patients. This article
summarizes current recommendations on preven-
tion, diagnosis, management, and treatment of Practice Improvement
COVID-19.

CME/MOC activity available at Annals.org.

Physician Writers doi:10.7326/AITC202310170

Kristen M. Marks, MD, MSc
Roy M. Gulick, MD, MPH
Weill Cornell Medicine, New
York, New York (K.M.M., R.M.G.)
This article was published at Annals.org on 10 October 2023.
CME Objective: To review current evidence for prevention, diagnosis,
management, treatment, and practice improvement of COVID-19.
Funding Source: American College of Physicians.
Disclosures: All relevant financial relationships have been mitigated. Disclosures
can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.
do?msNum¼M23-1392.

With the assistance of additional physician writers, the editors of Annals of

Internal Medicine develop In the Clinic using MKSAP and other resources of
the American College of Physicians.
In the Clinic does not necessarily represent official ACP clinical policy. For ACP
clinical guidelines, please go to https://www.acponline.org/clinical_information/
guidelines/.
© 2023 American College of Physicians

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 The COVID-19 pandemic has accounted tests, antivirals, and immunomodula-
for more than 768 million cases and tors. In this article, we review current
nearly 7 million deaths globally to date prevention, diagnosis, management,
and challenges clinicians worldwide (1). and treatment, noting that knowledge
1. World Health Organization. Significant and rapid progress has been and data are rapidly evolving. Readers
WHO Coronavirus (COVID-
19) Dashboard. Accessed at
made in the prevention, diagnosis, man- should consult the Centers for Disease
https://covid19.who.int on agement, and treatment of COVID-19 Control and Prevention (CDC) website
3 August 2023.
2. Paules CI, Marston HD, over the past 3 years with the develop- or current guidelines for the most up-
Fauci AS. Coronavirus infec-
tions—more than just the ment of effective vaccines, diagnostic to-date information.
common cold. JAMA.
2020;323:707-708. [PMID:
31971553]
3. Zhao Z, Zhang F, Xu M, et
al. Description and clinical
treatment of an early out- What causes COVID-19?
break of severe acute respi-
ratory syndrome (SARS) in Historically, 4 coronaviruses, designated that can progress to lower respiratory
Guangzhou, PR China. J
Med Microbiol. as HKU1, NL63, OC43, and 229E, tract disease with hypoxia and respira-
2003;52:715-720. [PMID:
12867568]
accounted for an estimated 15% to 30% tory failure and/or involve additional
4. Zaki AM, van Boheemen S, of seasonal upper respiratory infections organ systems, leading to multiorgan
Bestebroer TM, et al.
Isolation of a novel corona- (2). The original severe acute respiratory disease and death (7).
virus from a man with
pneumonia in Saudi syndrome coronavirus (SARS-CoV), a
Arabia. N Engl J Med. Coronaviruses can evolve, selecting var-
2012;367:1814-1820.
more pathogenic coronavirus, emerged
iants that may confer advantages in trans-
[PMID: 23075143] in China in 2002 (3) and led to transmis-
5. Zhu N, Zhang D, Wang W, missibility, pathogenicity, or decreased
et al.; China Novel sion and severe respiratory disease in 4
Coronavirus Investigating susceptibility to antivirals or immune
and Research Team. A additional countries before remitting.
novel coronavirus from responses (8). The original SARS-CoV-2
patients with pneumonia Middle East respiratory syndrome coro-
gave rise to a succession of major var-
in China, 2019. N Engl J navirus (MERS-CoV), which is associated
Med. 2020;382:727-733. iants, designated as Alpha, Beta, Gamma,
[PMID: 31978945] with exposure to camels, emerged in
6. Gandhi RT, Lynch JB, Del Delta, and Omicron. The Delta variant
Rio C. Mild or moderate Saudi Arabia in 2012 (4) and still causes
Covid-19. N Engl J Med. had greater transmissibility and pathoge-
2020;383:1757-1766. sporadic cases of human respiratory dis-
[PMID: 32329974] nicity and less susceptibility to some
ease. SARS-CoV-2, the seventh corona-
7. Berlin DA, Gulick RM, monoclonal and vaccine-induced anti-
Martinez FJ. Severe Covid- virus known to infect humans, was first
19. N Engl J Med. bodies than earlier strains. Omicron and
2020;383:2451-2460. described in China in December 2019
[PMID: 32412710] its major subvariants (including BA.1,
8. Li J, Lai S, Gao GF, et al. (5) and is responsible for the current
The emergence, genomic BA.2, BA.4, BA.5, BQ.1, BQ.1.1, XBB.1.5,
diversity and global spread
COVID-19 pandemic.
of SARS-CoV-2. Nature.
XBB.1.16, and EG.5) have even greater
2021;600:408-418. [PMID: To establish infection, SARS-CoV-2 transmissibility and lower susceptibility to
34880490]
9. Kompaniyets L, Pennington attaches to its target cell (typically an additional antibodies, although these
AF, Goodman AB, et al.
Underlying medical condi- upper respiratory epithelial cell) by variants generally cause milder disease.
tions and severe illness
among 540,667 adults
binding to the cellular angiotensin-con- The emergence and impact of subvar-
hospitalized with COVID-
19, March 2020–March
verting enzyme 2 receptor. The virus is iants are influenced by regional popula-
2021. Prev Chronic Dis. internalized, and copies of viral RNA and tion immunity. The CDC has multiple
2021;18:E66. [PMID:
34197283] viral proteins are produced, assembled, surveillance systems to monitor variants
10. Pennington AF,
Kompaniyets L, Summers and released as new virions that may in the United States (see https://covid.
AD, et al. Risk of clinical
severity by age and race/
infect additional cells. An initial COVID- cdc.gov/covid-data-tracker/#variant-
ethnicity among adults 19 upper respiratory tract infection may summary). Researchers use virus genomic
hospitalized for COVID-19
—United States, March– be asymptomatic or may cause typical sequencing data combined with pheno-
September 2020. Open
Forum Infect Dis. 2021;8: symptoms of sore throat, cough, and typic data to predict whether COVID-19
ofaa638. [PMID:
33553477] fever (6). Infection typically resolves but tests, treatments, and vaccines will match
11. Centers for Disease
Control and Prevention.
can induce an inflammatory response emerging variants.
Underlying Medical
Conditions Associated
with Higher Risk for
Severe COVID-19:
Information for
Healthcare Professionals.
Updated 9 February
2023. Accessed at www.
cdc.gov/coronavirus/2019-
ncov/hcp/clinical-care/
underlyingconditions.
html on 3 August 2023.

© 2023 American College of Physicians ITC146 In the Clinic Annals of Internal Medicine October 2023

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 Prevention 12. Adjei S, Hong K, Molinari
NM, et al. Mortality risk
Who is at greatest risk for prior infection, emergence of less path- among patients hospital-
ized primarily for COVID-
complications and hospitalizations? ogenic variants, and improvements in 19 during the Omicron
and Delta variant pan-
Older age is the strongest risk factor treatment. Nevertheless, age and con- demic periods - United
States, April 2020–June
for severe COVID-19, hospitalization, comitant conditions remain important 2022. MMWR Morb
Mortal Wkly Rep.
intensive care, mechanical ventilation, risk factors (12). 2022;71:1182-1189.
[PMID: 36107788]
and death (9, 10); risk increases sub- What is the role of behavioral 13. Meyerowitz EA,
stantially after age 65 years. Other strategies to prevent transmission,
Richterman A, Gandhi RT,
et al. Transmission of
groups at high risk for adverse out- SARS-CoV-2: a review of
and how effective are they? viral, host, and environ-
comes include residents of nursing mental factors. Ann Intern
Med. 2021;174:69-79.
homes and long-term care facilities, Transmission occurs primarily through [PMID: 32941052]
certain racial and ethnic minority direct person-to-person respiratory trans- 14. Duval D, Palmer JC,
Tudge I, et al. Long dis-
groups, pregnant or recently pregnant mission via respiratory particles to people tance airborne transmis-
sion of SARS-CoV-2: rapid
persons, and those with certain under- in close contact, although long-distance systematic review. BMJ.
2022;377:e068743.
lying medical conditions (see the Box: airborne transmission has been docu- [PMID: 35768139]
15. Talic S, Shah S, Wild H, et
Groups at Increased Risk for COVID-19 mented (13, 14). Transmission via conta- al. Effectiveness of public
Complications and Hospitalization) (11). minated surfaces, nonrespiratory secre- health measures in reduc-
ing the incidence of Covid-
Children generally do not experience tions, and contact with infected animals 19, SARS-CoV-2 transmis-
sion, and Covid-19 mortal-
severe COVID-19; however, underlying and in utero transmission are possible ity: systematic review and
meta-analysis. BMJ.
medical conditions, such as obesity, dia- but uncommon. In immunocompetent 2021;375:e068302.
[PMID: 34789505]
betes, and cardiac, lung, or neurologic persons, the peak period of infectious- 16. Bundgaard H, Bundgaard
disorders, increase risk for adverse out- ness occurs from 1 day before symptom JS, Raaschou-Pedersen
DET, et al. Effectiveness of
comes. Over time, severe COVID-19 onset through the first week of symptoms adding a mask recom-
mendation to other public
has diminished because of vaccination, (13). health measures to pre-
vent SARS-CoV-2 infection
in Danish mask wearers:
a randomized controlled
trial. Ann Intern Med.
Groups at Increased Risk for COVID-19 Complications and Hospitalization 2021;174:335-343.
[PMID: 33205991]
Adults aged ≥50 years (risk increases substantially after age 65 years) 17. Jefferson T, Dooley L,
Ferroni E, et al. Physical
Residents of nursing homes and other long-term care facilities interventions to interrupt
Persons who are pregnant or recently postpartum or reduce the spread of
respiratory viruses.
Persons of any age with the following chronic medical conditions: Cochrane Database Syst
• Asthma Rev. 2023;1:CD006207.
[PMID: 36715243]
• Cancer 18. Abaluck J, Kwong LH,
• Cardiac conditions, such as heart failure, coronary artery disease, or cardiomyopathies Styczynski A, et al. Impact
• Cerebrovascular disease of community masking
on COVID-19: a cluster-
• Chronic kidney disease randomized trial in
• Chronic lung disease (bronchiectasis, chronic obstructive pulmonary disease, interstitial lung Bangladesh. Science.
2022;375:eabi9069.
disease, pulmonary embolism, pulmonary hypertension) [PMID: 34855513]
• Chronic liver disease (cirrhosis, nonalcoholic fatty liver disease, alcoholic liver disease, autoim- 19. Massetti GM, Jackson BR,
mune hepatitis) Brooks JT, et al. Summary
of guidance for minimiz-
• Cystic fibrosis ing the impact of COVID-
• Dementia 19 on individual persons,
• Type 1 or 2 diabetes communities, and health
care systems - United
• Disabilities, including Down syndrome* States, August 2022.
• Mental health conditions, including mood disorders and schizophrenia spectrum disorders MMWR Morb Mortal
• Obesity (body mass index >30 kg/m2 or >95th percentile in children) Wkly Rep. 2022;71:1057-
1064. [PMID: 35980866]
• Physical inactivity 20. Polack FP, Thomas SJ,
• Immunocompromising conditions, including primary immunodeficiency, HIV/AIDS, organ trans- Kitchin N, et al.;
plant, or stem cell transplant C4591001 Clinical Trial
Group. Safety and efficacy
• Current or former smoking of the BNT162b2 mRNA
• Use of steroids and immunosuppressive medications Covid-19 vaccine. N Engl
• Tuberculosis J Med. 2020;383:2603-
2615. [PMID: 33301246]
People from certain racial and ethnic minority groups in the United States, including non- 21. Thomas SJ, Moreira ED
Jr., Kitchin N, et al.;
Hispanic Black or African American persons, Hispanic or Latino persons, and American C4591001 Clinical Trial
Group. Safety and efficacy
Indians and Alaska Natives of the BNT162b2 mRNA
* See the source (www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/underlyingconditions. Covid-19 vaccine through
6 months. N Engl J Med.
html) for the full list of disabilities reviewed. 2021;385:1761-1773.
[PMID: 34525277]

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 In the setting of high community trans- A cluster RCT of community-level mask
mission, recommended personal pre- promotion randomly assigned 600 vil-
ventive strategies include handwashing, lages (342 183 adults) in Bangladesh
respiratory hygiene, wearing masks and from November 2020 to April 2021 to
22. Baden LR, El Sahly HM,
Essink B, et al.; COVE
other face protection, adequate ventila- provision of free masks (cloth vs. surgi-
Study Group. Efficacy and tion, and physical distancing. cal) along with information, reminders,
safety of the mRNA-1273
SARS-CoV-2 vaccine. N and community leader role modeling
Engl J Med.
2021;384:403-416. A systematic review (72 studies) and for 8 weeks versus no intervention. The
[PMID: 33378609]
23. El Sahly HM, Baden LR,
meta-analysis (8 studies) of studies pub- intervention group had a 9% decrease
Essink B, et al.; COVE
Study Group. Efficacy of
lished through June 2021 found a in symptomatic SARS-CoV-2 seropreva-
the mRNA-1273 SARS- reduction in COVID-19 incidence with lence versus the control group and 29%
CoV-2 vaccine at comple-
tion of blinded phase. N handwashing, masking, and physical greater proper mask wearing over
Engl J Med.
2021;385:1774-1785. distancing, with relative risk reductions 8 weeks. Of note, the subgroup of 200
[PMID: 34551225] villages randomly assigned to surgical
24. Sadoff J, Gray G,
of 0.47, 0.47, and 0.75, respectively
Vandebosch A, et al.; (15). Only 1 of the included studies was masks had a relative reduction of 11.1%
ENSEMBLE Study Group.
Safety and efficacy of sin- a randomized controlled trial (RCT) (with elderly adults benefiting most),
gle-dose Ad26.COV2.S
vaccine against Covid-19. (16); the rest had case–control, retro- whereas the 100 villages receiving cloth
N Engl J Med.
2021;384:2187-2201. spective cohort, cross-sectional, and masks showed no statistically significant
[PMID: 33882225]
25. Hardt K, Vandebosch A,
natural experiment designs. Residual reduction (18).
Sadoff J, et al.;
ENSEMBLE2 study group.
confounding and measurement bias Given that widespread immunity has
Efficacy, safety, and im- were noted for most studies.
munogenicity of a booster lessened the public health threat, the
regimen of Ad26.COV2.S
vaccine against COVID-19 most recent advice from the CDC is
(ENSEMBLE2): results of a In contrast, a Cochrane review published
that people understand their risk; take
randomised, double- in January 2023 compared the effect of
blind, placebo-controlled,
phase 3 trial. Lancet Infect medical/surgical masks versus no masks steps to protect themselves and others
Dis. 2022;22:1703-1715.
[PMID: 36113538] on the spread of viral respiratory illness through vaccines, therapeutics, and
26. Heath PT, Galiza EP,
(most of the included studies were con- nonpharmaceutical interventions when
Baxter DN, et al;
2019nCoV-302 Study
ducted before the pandemic) and found needed; undergo testing and wear
Group. Safety and efficacy
of NVX-CoV2373 COVID-19 no significant effect on influenza- or masks if they are exposed; and undergo
vaccine. N Engl J Med.
2021;385:1172-1183. COVID-19–like illness or on laboratory- testing when they are symptomatic and
[PMID: 34192426]
27. Dunkle LM, Kotloff KL, confirmed influenza or COVID-19. Most isolate for at least 5 days if they are
Gay CL, et al.; 2019nCoV-
301 Study Group. Efficacy studies were deemed to have unclear or infected (19).
and safety of NVX-
CoV2373 in adults in the
high risk of bias (17). What vaccines are available, and how
United States and Mexico.
N Engl J Med. effective are they?
2022;386:531-543. Two RCTs assessing masking for COVID- Vaccines have been fundamental in
[PMID: 34910859]
28. Pilishvili T, Fleming-Dutra 19 have been published to date.
KE, Farrar JL, et al.;
curbing disease and death during the
Vaccine Effectiveness COVID-19 pandemic. Vaccines that
Among Healthcare DANMASK-19 (Danish Study to Assess
Personnel Study Team. have been used in the United States
Interim estimates of vac- Face Masks for the Protection Against
cine effectiveness of
COVID-19 Infection) randomly assigned include 2 mRNA vaccines, both of
Pfizer–BioNTech and
Moderna COVID-19 vac-
6024 adults in Denmark (April and May which now have bivalent formulations
cines among health care
personnel - 33 U.S. sites, 2020) to either social distancing with a (BNT162b2 [Pfizer–BioNTech] and
January–March 2021.
MMWR Morb Mortal Wkly recommendation to wear a mask (study- mRNA1273.222 [Moderna]); an adeno-
Rep. 2021;70:753-758.
[PMID: 34014909] provided) when outside the home or viral vector monovalent vaccine (Ad26.
29. Surie D, Bonnell L, Adams
K, et al.; IVY Network. social distancing with no mask recom- COV2.S [Janssen/Johnson & Johnson]);
Effectiveness of monova-
mendation (16). SARS-CoV-2 infection at and an adjuvanted recombinant protein
lent mRNA vaccines
against COVID-19–associ- 1 month (primary outcome) was 1.8% in monovalent vaccine (NVX-CoV2373
ated hospitalization
among immunocompe- the mask-recommended group and [Novavax]). At this time, the monovalent
tent adults during BA.1/
BA.2 and BA.4/BA.5 pre- 2.1% in control participants; the differ- mRNA vaccines that were previously
dominant periods of
SARS-CoV-2 Omicron vari- ence was not statistically significant approved by the U.S. Food and Drug
ant in the United States -
IVY Network, 18 states, (odds ratio, 0.82 [95% CI, 0.54 to 1.23]), Administration (FDA) should no longer
December 26, 2021–
August 31, 2022. MMWR
although the study was powered to be used. Bivalent mRNA vaccines avail-
Morb Mortal Wkly Rep. detect a 50% reduction in infection able under FDA emergency use authori-
2022;71:1327-1334.
[PMID: 36264830] (from 2% to 1%). zation (EUA) should be used for primary

© 2023 American College of Physicians ITC148 In the Clinic Annals of Internal Medicine October 2023

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vaccination in unvaccinated persons In September 2022, the ACIP recom-
older than 6 months and as booster mended a bivalent booster dose for all 30. Surie D, DeCuir J, Zhu Y,
et al.; IVY Network. Early
doses. NVX-CoV2373 is also available persons aged 5 years or older, admin- estimates of bivalent
mRNA vaccine effective-
under EUA as a primary vaccine series istered at least 2 months after comple- ness in preventing
(age ≥12 years) and as a booster dose tion of the primary series (or ≥2 months COVID-19–associated hos-
pitalization among immu-
nocompetent adults aged
in certain circumstances. Ad26.COV2.S after receipt of a monovalent booster ≥65 years - IVY Network,
is no longer available in the United dose) (34). In April 2023, ACIP allowed 18 states, September 8–
November 30, 2022.
States. an additional bivalent booster for peo- MMWR Morb Mortal
Wkly Rep. 2022;71:1625-
ple who are aged 65 years or older or 1630. [PMID: 36580424]
Phase 3 RCTs showed excellent efficacy 31. Ferdinands JM, Rao S,
immunocompromised. For children aged Dixon BE, et al. Waning
of these vaccines compared with pla- of vaccine effectiveness
6 months to 4 years, use of a bivalent against moderate and
cebo in preventing symptomatic infec- severe Covid-19 among
booster depends on the primary vaccine adults in the US from the
tion (Appendix Table 1, available at VISION Network: test neg-
series given. The CDC maintains updated
Annals.org) (20–27) early in the pan- ative, case-control study.
vaccine schedule recommendations on BMJ. 2022;379:
demic. However, as neutralizing anti- e072141. [PMID:
its website (www.cdc.gov/vaccines/covid- 36191948]
body levels wane and new genetic 32. Fleming-Dutra KE,
19/clinical-considerations/covid-19- Wallace M, Moulia DL, et
variants emerge, vaccine effectiveness al. Interim recommenda-
vaccines-us.html). Seasonality and opti- tions of the Advisory
in preventing mild infection diminishes Committee on
mal frequency of boosters have not yet Immunization Practices
(28). Booster dosing can restore neu- for use of Moderna and
been determined, but most experts rec- Pfizer–BioNTech COVID-19
tralizing antibody levels to thresholds vaccines in children aged
ognize a need for at least annual dosing
predicted to prevent COVID-19 in the 6 months–5 years -
for high-risk persons due to strain evolu- United States, June 2022.
short term, and studies have shown MMWR Morb Mortal
tion and limited durability of antibody Wkly Rep. 2022;71:859-
that vaccines remain effective in pre- 868. [PMID: 35771731]
response. 33. Centers for Disease
venting severe COVID-19 and related Control and Prevention.
Use of COVID-19 Vaccines
death, particularly in older persons (29, Persons with moderate or severe acute in the United States:
Interim Clinical
30). However, overall vaccine effective- illness with or without fever generally Considerations. Accessed
ness is reduced against the Omicron should not be vaccinated; minor acute at www.cdc.gov/vaccines/
covid-19/clinical-
variants (31), and the CDC currently illness without significant fever is not considerations/covid-19-
vaccines-us.html on 3
recommends an mRNA booster that a contraindication. COVID-19 vaccines August 2023.
34. Rosenblum HG, Wallace
includes the spike antigen sequence can be administered simultaneously M, Godfrey M, et al.
of a recently circulating Omicron with other vaccines and should be Interim recommendations
from the Advisory
variant. administered 1 inch apart or at differ- Committee on
Immunization Practices
ent anatomic sites. For patients receiving for the use of bivalent
Who should be vaccinated, and when? vaccination against orthopox viruses, booster doses of COVID-
19 vaccines - United
The Advisory Committee on Immuni- such as mpox, the CDC suggests admin- States, October 2022.
MMWR Morb Mortal
zation Practices (ACIP) first recom- istering vaccines 4 weeks apart if the Wkly Rep. 2022;71:1436-
1441. [PMID: 36355612]
mended a primary vaccine series for patient is not at risk for severe disease 35. U.S. Food and Drug
Administration. COVID-19
persons aged 16 years or older in because of concerns about myocarditis. Vaccine Safety
Surveillance. 7 December
December 2020 but has progressively 2021. Accessed at www.
COVID-19 vaccines should be adminis-
lowered the age criterion to now fda.gov/vaccines-blood-
tered at least 2 weeks before initiation biologics/safety-
include all children aged 6 months or availability-biologics/
or resumption of immunosuppressive covid-19-vaccine-safety-
older (June 2022) (32, 33). The number, surveillance on 3 August
therapies whenever possible. Patients 2023.
frequency, and time between doses with a history of Guillain–Barre  syn- 36. Centers for Disease
Control and Prevention.
depend on the primary vaccine series drome may receive COVID-19 vaccina- Trends in Demographic
Characteristics of People
received and the age and immune sta- tion. Information about vaccination Receiving COVID-19
Vaccinations in the United
tus of the recipient. Prevention strat- timing and precautions can be found States. Accessed at
egies for infants younger than 6 months on the CDC website, including for per-
https://covid.cdc.gov/
covid-data-tracker/#
(who are not eligible for vaccination) sons with a history of allergic reaction, vaccination-
demographics-trends on
include vaccination of pregnant persons myocarditis, or pericarditis after vacci- 3 August 2023.
37. Shimabukuro TT, Cole M,
and of their household contacts and nation and those with multisystem Su JR. Reports of anaphy-
laxis after receipt of
caregivers. inflammatory syndrome (MIS). mRNA COVID-19 vaccines
in the US—December 14,
2020–January 18, 2021.
JAMA. 2021;325:1101-
1102. [PMID: 33576785]

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 What adverse effects are associated How should clinicians counsel about
38. Goddard K, Hanson KE,
with vaccination? vaccination, and how can they
Lewis N, et al. Incidence More than 676 million doses of COVID- improve vaccine uptake?
of myocarditis/pericarditis
following mRNA COVID- 19 vaccines have been administered in Vaccine hesitancy is a global health
19 vaccination among
children and younger the United States, and safety monitor- threat, and the CDC notes geographic
adults in the United
States. Ann Intern Med.
ing is ongoing by the FDA through and racial and ethnic disparities and
2022;175:1169-1771. both passive and active surveillance
[PMID: 36191323] the need to improve COVID-19 vacci-
39. Greinacher A, Thiele T, systems (35, 36). Common adverse
Warkentin TE, et al. nation coverage in the United States
Thrombotic thrombocyto- effects after primary or booster doses
penia after ChAdOx1 (Appendix Table 1) include local reac- (36). Clinicians are among the most
nCov-19 vaccination. N
Engl J Med. togenicity symptoms, such as pain, trusted sources of vaccine information.
2021;384:2092-2101. One strategy to address vaccine mis-
[PMID: 33835769] swelling, and redness at the injection
40. Opel DJ, Lo B, Peek ME.
Addressing mistrust about
site, as well as systemic reactogenicity trust is “leading with listening”—asking
COVID-19 vaccines among symptoms like fatigue, headache, myal- open-ended questions and displaying
patients of color. Ann
Intern Med. gia, chills, fever, and nausea (in de- empathy, then tailoring responses to
2021;174:698-700.
[PMID: 33556271] scending order of typical frequency). convey to patients that the clinician
41. Centers for Disease
Control and Prevention.
These usually are mild, occur within 1 heard their concerns and respects their
Talking with Patients to 2 days, and are self-limited to 1 to 2
about COVID-19 autonomy. Asking for permission to
Vaccination: An days. The frequency and severity of
Introduction to discuss vaccines or share the clinician’s
Motivational Interviewing
these reactions increase after the sec-
for Healthcare ond dose and are increased in adoles- viewpoint may contribute to less defen-
Professionals. Accessed at
www.cdc.gov/vaccines/ cents and young adults. Syncope can sive posturing. Clinicians should pres-
covid-19/hcp/engaging-
patients.html on 3 August occur with any injection and is more ent simple factual statements about
2023.
42. Levin MJ, Ustianowski A,
common in adolescents. Monitoring of vaccine development and safety as a
De Wit S, et al.; PROVENT recipients for 15 minutes after vaccina- rationale for recommending vaccina-
Study Group.
Intramuscular AZD7442 tion should be considered. tion (40, 41). More resources can be
(tixagevimab–cilgavimab)
for prevention of Covid-
Some reactions may temporarily inter- found at www.cdc.gov/vaccines/covid-
19. N Engl J Med.
2022;386:2188-2200. fere with usual daily activities (about 19/hcp/index.html.
[PMID: 35443106]
43. U.S. Food and Drug 10% to 20% in phase 3 studies) (20, 22, What is the role of antiviral agents in
Administration. FDA
announces Evusheld is 26). Localized axillary lymphadenopa- prevention?
not currently authorized
for emergency use in the thy has been observed with the mRNA To date, no oral antiviral drug is effec-
U.S. 26 January 2023.
and NVX-CoV2373 vaccines, and tempo-
Accessed at www.fda.gov/ tive in preventing COVID-19. An EUA
drugs/drug-safety-and- rary swelling of facial fillers has been seen
availability/fda-releases- was issued for tixagevimab–cilgavimab
important-information- with the mRNA vaccines. Anaphylactic
about-risk-covid-19-due- as preexposure prophylaxis for moder-
certain-variants-not- reactions are reported rarely (<1 per
neutralized-evusheld on 3
200 000 doses administered) (37); vacci- ately to severely immunocompromised
August 2023.
44. Loeb M, Bartholomew A, nation sites should have age-appropri- persons or those not able to be fully
Hashmi M, et al. Medical
masks versus N95 respira- ate epinephrine available. Myocarditis vaccinated, based on demonstrated ef-
tors for preventing COVID-
19 among health care and pericarditis have been reported ficacy earlier in the pandemic (42).
workers: a randomized
trial. Ann Intern Med. more frequently than expected after Unfortunately, resistance of newer
2022;175:1629-1638.
[PMID: 36442064] vaccination, particularly after the second SARS-CoV-2 Omicron subvariants to
45. Chou R, Dana TS. Major
update: masks for preven-
dose of mRNA vaccines in male adoles- existing monoclonal antibodies, includ-
tion of SARS-CoV-2 in cents and young adults (38). Most cases ing tixagevimab–cilgavimab, eliminates
health care and commu-
nity settings—final update are mild and improve rapidly. Cases their role in prevention (43). Thus, mono-
of a living, rapid review.
Ann Intern Med. were also observed in NVX-CoV2373 clonal antibodies are currently not rec-
2023;176:827-835.
[PMID: 37186920] clinical trials and postmarketing studies. ommended for pre- or postexposure
46. Centers for Disease
Control and Prevention.
Thrombosis with thrombocytopenia syn- prophylaxis.
Interim Infection drome has been described after adenovi-
Prevention and Control
Recommendations for rus vector vaccines, including Ad26.COV2. What measures should clinicians take
Healthcare Personnel
During the Coronavirus S, and is attributed in some cases to auto- to prevent SARS-CoV-2 transmission
Disease 2019 (COVID-19)
Pandemic. Updated 8 antibodies directed against the platelet fac- among patients and staff in health
May 2023. Accessed at tor 4 antigen (39). A potential association care institutions?
www.cdc.gov/coronavirus/
2019-ncov/hcp/infection- between Guillain–Barre  syndrome and Health care personnel should stay up-
control-recommendations.
html on 3 August 2023. Ad26.COV2.S has also been reported. to-date with vaccinations unless contra-

© 2023 American College of Physicians ITC150 In the Clinic Annals of Internal Medicine October 2023

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indicated, and they should be priori- infection, health care workers should 47. Centers for Disease
tized for viral testing when they have use standard precautions as well as a Control and Prevention.
Interim Guidance for
symptoms consistent with COVID-19. particulate respirator with an N95 filter, Managing Healthcare
Personnel with SARS-CoV-
Community transmission levels should a gown, gloves, and eye protection. In 2 Infection or Exposure to
SARS-CoV-2. Updated 23
dictate the level of source control rec- inpatient settings, patients with sus- September 2022.
ommended in health care settings. If pected or confirmed COVID-19 should Accessed at www.cdc.gov/
coronavirus/2019-ncov/
community transmission is high, partic- be isolated or, once infection is con- hcp/guidance-risk-
assesment-hcp.html on 3
ulate respirators (N95) or well-fitted firmed, may be cohorted. Aerosol-gen- August 2023.
48. Osman M, Klopfenstein T,
facemasks are recommended for erating procedures should take place Belfeki N, et al. A compar-
everyone when in areas of possible ative systematic review of
in an airborne infection isolation room COVID-19 and influenza.
patient contact. N95 respirators appear Viruses. 2021;13:452.
if possible. Detailed information on du- 49. Centers for Disease
to have a protective advantage over Control and Prevention.
ration of isolation, testing strategies, Overview of testing for
surgical masks in simulation studies but SARS-CoV-2, the virus that
and return-to-work criteria can be causes COVID-19.
have not been conclusively shown to Updated 11 May 2023.
be superior in typical clinical settings found in CDC’s recommendations on Accessed at www.cdc.gov/

(44, 45). Nevertheless, the CDC recom- infection prevention and control and coronavirus/2019-ncov/
hcp/testing-overview.html
mends that when caring for a patient those related to managing health care on 3 August 2023.
50. U.S. Food and Drug
with suspected or known SARS-CoV-2 personnel with COVID-19 (46, 47). Administration. In Vitro
Diagnostics EUAs.
Accessed at www.fda.gov/
medical-devices/
coronavirus-disease-2019-
Prevention... Persons at increased risk for severe COVID-19 outcomes include older covid-19-emergency-use-
authorizations-medical-
adults, residents of nursing homes and long-term care facilities, certain racial and ethnic devices/in-vitro-
minority groups, pregnant or recently pregnant persons, and persons with certain diagnostics-euas on 3
August 2023.
underlying medical conditions. Transmission occurs primarily through direct person-to- 51. U.S. Food and Drug
person respiratory transmission via respiratory particles from infected persons. Administration. SARS-
CoV-2 Viral Mutations:
Behavioral strategies, including masking, appear to reduce risk for COVID-19. Impact on COVID-19
Vaccination is effective and is recommended for all persons aged 6 months or older in Tests. Accessed at www.
fda.gov/medical-devices/
the United States. Antivirals and monoclonal antibodies are currently not recommended coronavirus-covid-19-and-
for pre- or postexposure prophylaxis. medical-devices/sars-cov-
2-viral-mutations-impact-
covid-19-tests on 3
August 2023.
CLINICAL BOTTOM LINE 52. Pilarowski G, Lebel P,
Sunshine S, et al.
Performance characteris-
tics of a rapid severe
acute respiratory syn-
drome coronavirus 2 anti-
gen detection assay at a
public plaza testing site in
Diagnosis San Francisco. J Infect
Dis. 2021;223:1139-
What signs and symptoms should including rashes (maculopapular, mor- 1144. [PMID: 33394052]
53. Centers for Disease
prompt clinicians to suspect SARS- billiform, urticarial, vesicular, or transient Control and Prevention.
Considerations for SARS-
CoV-2 infection? livedo reticularis) or nodules on the dig- CoV-2 Antigen Testing for
its (chilblains), referred to as “COVID Healthcare Providers
Testing Individuals in the
The clinical presentation of COVID-19 toes.” COVID-19 presents rarely with Community. Updated 11
May 2023. Accessed at
spans from asymptomatic infection to neurologic manifestations, such as en- www.cdc.gov/coronavirus/
critical illness (Table 1). Signs and cephalitis, in the absence of other 2019-ncov/lab/resources/
antigen-tests-guidelines.
symptoms of mild COVID-19 frequently symptoms. html on 3 August 2023.
54. Centers for Disease
overlap with those of other respiratory Control and Prevention.
viral infections and include fever or Shortness of breath and dyspnea on How to Report COVID-19
Laboratory Data: Who Can
chills, cough, fatigue, malaise, head- exertion are not present in mild Report. Updated 11 May
2023. Accessed at www.
ache, loss of taste or smell, nasal con- COVID-19 and may indicate lower re- cdc.gov/coronavirus/
gestion or runny nose, sore throat, spiratory tract infection seen with mod- 2019-ncov/lab/reporting-
lab-data.html#who-must-
nausea or vomiting, or diarrhea (6). In erate or severe COVID-19. Moderate report on 3 August 2023.
55. Akinbami LJ, Kruszon-
adults, fatigue, headache, alterations in COVID-19 is defined as evidence of Moran D, Wang CY, et al.
SARS-CoV-2 serology and
taste or smell, and diarrhea are more lower tract disease (clinical or radio- self-reported infection
common with COVID-19 than with logic) with SpO2 measures of 94% or among adults - National
Health and Nutrition
influenza (48). Thus, diagnostic testing higher on room air at sea level. Severe Examination Survey,
United States, August
is necessary to establish a COVID-19 di- COVID-19 criteria include SpO2 below 2021–May 2022. MMWR
agnosis. Less commonly, patients may 94% on room air, PaO2–FIO2 ratio below Morb Mortal Wkly Rep.
2022;71:1522-1525.
present with dermatologic findings, 300 mm Hg, respiratory rate above 30 [PMID: 36454698]

October 2023 Annals of Internal Medicine In the Clinic ITC151 © 2023 American College of Physicians

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56. Wang D, Hu B, Hu C, et
al. Clinical characteristics
of 138 hospitalized
patients with 2019 novel
coronavirus-infected pneu-
monia in Wuhan, China.
JAMA. 2020;323:1061-
1069. [PMID: 32031570]
57. Iuliano AD, Brunkard JM,
Boehmer TK, et al. Trends
in disease severity and
health care utilization dur-
ing the early Omicron var-
iant period compared with
previous SARS-CoV-2 high
transmission periods -
United States, December
2020–January 2022.
MMWR Morb Mortal Wkly
Rep. 2022;71:146-152.
[PMID: 35085225]
58. Gupta A, Madhavan MV,
Sehgal K, et al.
Extrapulmonary manifes-
tations of COVID-19. Nat
Med. 2020;26:1017-
1032. [PMID: 32651579]
59. Yang L, Gou J, Gao J, et
al. Immune characteristics
of severe and critical
COVID-19 patients. Signal
Transduct Target Ther.
2020;5:179. [PMID:
32868756]
60. Chesley CF, Lane-Fall MB,
Panchanadam V, et al.
Racial disparities in occult
hypoxemia and clinically
based mitigation strat-
egies to apply in advance
of technological advance-
ments. Respir Care.
2022;67:1499-1507.
[PMID: 35679133]
61. Feldstein LR, Rose EB,
Horwitz SM, et al;
Overcoming COVID-19
Investigators; CDC COVID-
19 Response Team.
Multisystem inflammatory
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and adolescents. N Engl J
Med. 2020;383:334-346.
[PMID: 32598831]
62. Lerner AM, Robinson DA,
Yang L, et al. Toward
understanding COVID-19
recovery: National
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COVID-19. Ann Intern
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1003. [PMID: 33780290]
63. Lansbury L, Lim B,
Baskaran V, et al. Co-infec-
tions in people with
COVID-19: a systematic
review and meta-analysis.
J Infect. 2020;81:266-
275. [PMID: 32473235]
64. Hoenigl M, Seidel D,
Sprute R, et al. COVID-19–
associated fungal infec-
tions. Nat Microbiol.
2022;7:1127-1140.
[PMID: 35918423]
65. National Institutes of Health.
Coronavirus Disease 2019
(COVID-19) Treatment
Guidelines. Accessed at
www.covid19treat
mentguidelines.nih.gov on 3
August 2023.
66. Hammond J, Leister-
Tebbe H, Gardner A, et
al.; EPIC-HR Investigators.
Oral nirmatrelvir for high-
risk, nonhospitalized
adults with Covid-19. N
Engl J Med.
2022;386:1397-1408.
[PMID: 35172054]
© 2023 American College of Physicians
Table 1. COVID-19 Clinical Spectrum*
Stage
Asymptomatic or presymptomatic
infection
Mild illness
Moderate illness
Severe illness
Critical illness
* From reference 65.
breaths/min, or lung infiltrates consti-
tuting more than 50% of lung fields.
COVID-19 can also present as critical
illness, including acute respiratory dis-
tress syndrome, septic shock, cardiac
shock, exaggerated inflammatory res-
ponse, thrombotic disease, and multi-
organ dysfunction (7). All patients pre-
senting with pneumonia or any of these
critical illness manifestations should be
tested for COVID-19.
When should clinicians test to
confirm a clinical diagnosis, and
which test should be used?
Diagnostic testing is used to identify
current infection in persons with signs
and symptoms of COVID-19 or in per-
sons with exposure to someone with
SARS-CoV-2 infection. Screening iden-
tifies current asymptomatic SARS-CoV-
2 infection in people with no known
exposure (for example, before a medi-
cal procedure or social event) (49). All
persons with known infection should
isolate, and symptomatic people with
risk factors for progression of COVID-
19 should receive treatment.
For diagnostic testing of symptomatic
persons, the specimen (Appendix Table
2, available at Annals.org) should be
collected and tested as soon as possi-
ble. A second test within 1 to 2 days
may be needed to confirm a negative
result. For exposed asymptomatic per-
sons, diagnostic testing should be per-
formed 5 or more days after exposure
or as soon as symptoms develop.
ITC152 In the Clinic
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Symptoms
Positive result for SARS-CoV-2 on a virologic test
No symptoms consistent with COVID-19
Signs and symptoms of COVID-19, such as fever, cough,
fatigue, malaise, muscle pain, headache, loss of taste or smell,
nasal congestion, sore throat, nausea, vomiting, or diarrhea
No shortness of breath, dyspnea, or abnormal chest imaging
results
Evidence of lower respiratory disease during clinical assess-
ment or imaging
SpO2 ≥94% on room air at sea level
SpO2 <94% on room air at sea level, PaO2–FIO2 ratio <300 mm Hg,
respiratory rate >30 breaths/min, or lung infiltrates >50%
Respiratory failure, septic shock, and/or multiple organ
dysfunction
Many different COVID-19 tests have
been authorized by the FDA for home
testing, point-of-care testing, and labora-
tory-based testing (50). Understanding
test characteristics is important for
choosing the best test to use (Appendix
Table 3, available at Annals.org). The
pretest probability based on community
prevalence and clinical presentation
must always be considered in interpre-
tation of results. Genetic variants of
SARS-CoV-2 may result in false-negative
results; using tests with multiple differ-
ent genetic targets reduces this (51).
Nucleic acid amplification tests (NAATs),
including polymerase chain reaction,
have the highest sensitivity, but results
may remain positive for 90 days or lon-
ger after illness. Advantages include
being available in multiplex assays that
can detect other circulating respiratory
viruses. NAAT results are usually re-
ported as positive or negative, but labo-
ratories can also report the cycle thresh-
old value (the number of amplification
cycles required for a positive signal), with
a higher value correlating with a lower vi-
ral level. NAATs are the recommended
test for hospitalized patients and can be
conducted on upper or lower respiratory
tract specimens. Isolation and infection
control measures should not be delayed
while test results are pending. Although
NAATs are also available as point-of-care
tests, a properly collected upper respira-
tory specimen sent for laboratory-based
NAAT is considered the gold standard
Annals of Internal Medicine October 2023
when addressing discrepant results or document past infection. Although se-
results that do not match the presump- rologic testing is not generally useful in
tive clinical diagnosis. prevention, diagnosis, or management
67. Arbel R, Wolff Sagy Y,
of COVID-19, it supports a diagnosis of Hoshen M, et al.
Antigen detection assays include labo- Nirmatrelvir use and
MIS and is also used for surveillance severe Covid-19 outcomes
ratory-based, point-of-care, and over-
purposes. during the Omicron
the-counter tests. The rapid tests yield surge. N Engl J Med.
2022;387:790-798.
results in approximately 10 to 30 [PMID: 36001529]
68. Dryden-Peterson S, Kim
minutes. Because no amplification is What other clinical diagnoses and A, Kim AY, et al.
involved, they have moderate to high evaluations should clinicians Nirmatrelvir plus ritonavir
for early COVID-19 in a
sensitivity depending on the assay consider? large U.S. health system:
a population-based cohort
used, the quality of the specimen, the study. Ann Intern Med.
For hospitalized patients with acute re- 2023;176:77-84. [PMID:
viral load, and the timing of the test 36508742]
spiratory illness, testing for both influ- 69. Shah MM, Joyce B,
(52, 53). Combined tests that include Plumb ID, et al. Paxlovid
enza and COVID-19 should be done
influenza antigens have recently become associated with decreased
when influenza viruses are circulating. hospitalization rate
available. In general, antigen tests are among adults with
Similarly for outpatients, influenza test- COVID-19 - United States,
considered “presumptive” and are not April–September 2022.
ing should be included if the results MMWR Morb Mortal
recommended for confirmatory testing. Wkly Rep. 2022;71:1531-
will change management. Testing for 1537. [PMID: 36454693]
Given the high specificity, a positive anti-
other bacterial and viral pathogens 70. Gottlieb RL, Vaca CE,
gen test result can be assumed to be a Paredes R, et al.; GS-US-
should be considered on the basis of 540-9012 (PINETREE)
true positive in a symptomatic person. Investigators. Early
the clinical circumstances. Clinicians remdesivir to prevent pro-
However, a negative test result may gression to severe Covid-
should avoid “anchoring” on a COVID- 19 in outpatients. N Engl
need confirmatory testing in a sympto- J Med. 2022;386:305-
19 diagnosis and should remain vigi-
matic person, particularly in the first 2 315. [PMID: 34937145]
lant in evaluating symptoms and rele- 71. Jayk Bernal A, Gomes da
days of illness. For confirmation, the Silva MM, Musungaie DB,
vant exposure and travel history. et al.; MOVe-OUT Study
CDC recommends a NAAT performed Group. Molnupiravir for
oral treatment of Covid-
immediately or a serial antigen test per- 19 in nonhospitalized
formed 1 to 2 days later (www.cdc.gov/ When should clinicians consult public patients. N Engl J Med.
2022;386:509-520.
coronavirus/2019-ncov/lab/resources/ health authorities for diagnosis and [PMID: 34914868]
72. Butler CC, Hobbs FDR,
antigen-tests-guidelines.html). One situa- reporting of SARS-CoV-2 infection? Gbinigie OA, et al.;
PANORAMIC Trial
tion in which antigen tests are preferred Collaborative Group.
The Public Health Emergency declara- Molnupiravir plus usual
over NAATs is the evaluation of new ill- care versus usual care
tion for COVID-19 and the requirement
ness or exposure in people who recently alone as early treatment
for reporting of laboratory test data to for adults with COVID-19
recovered from COVID-19. at increased risk of
the federal government ended on 11 adverse outcomes
(PANORAMIC): an open-
Serologic testing of plasma for anti- May 2023. State-specific reporting re- label, platform-adaptive
randomised controlled
body to nucleocapsid can be used to quirements may still apply (54). trial. Lancet.
2023;401:281-293.
[PMID: 36566761]
73. Callaway E. COVID
Diagnosis... SARS-CoV-2 diagnostic testing is recommended to establish a COVID-19 di- rebound is surprisingly
common - even without
agnosis given the widespread availability of testing and implications for isolation and Paxlovid. Nature. 2022.
treatment. NAATs are the most sensitive diagnostic tests, but results may remain positive 74. Beigel JH, Tomashek KM,
Dodd LE, et al.; ACTT-1
from a recent infection, whereas antigen tests offer convenient and low-cost but presump- Study Group Members.
tive results. During respiratory virus season, multiplex assays are useful to identify influ- Remdesivir for the treat-
ment of Covid-19 - final
enza and other respiratory viruses. Serologic testing is not helpful in management of report. N Engl J Med.
COVID-19 but may be helpful in diagnosis of MIS. 2020;383:1813-1826.
[PMID: 32445440]
75. WHO Solidarity Trial
Consortium. Remdesivir
CLINICAL BOTTOM LINE and three other drugs for
hospitalised patients with
COVID-19: final results of
the WHO Solidarity
randomised trial and
updated meta-analyses.
Lancet. 2022;399:1941-
1953. [PMID: 35512728]
Management and Treatment 76. Horby P, Lim WS,
Emberson JR, et al.;
RECOVERY Collaborative
It is important to identify persons with toring and treatment. For many outpa- Group. Dexamethasone in
or at risk for severe COVID-19 and its tients, telemedicine visits can be useful hospitalized patients with
Covid-19. N Engl J Med.
complications in order to focus moni- in assessing someone with acute 2021;384:693-704.
[PMID: 32678530]

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77. Kalil AC, Patterson TF,
Mehta AK, et al.; ACTT-2
Study Group Members.
Baricitinib plus remdesivir
for hospitalized adults
with Covid-19. N Engl J
Med. 2021;384:795-807.
[PMID: 33306283]
78. Marconi VC, Ramanan AV,
de Bono S, et al.; COV-
BARRIER Study Group.
Efficacy and safety of bari-
citinib for the treatment of
hospitalised adults with
COVID-19 (COV-BARRIER):
a randomised, double-
blind, parallel-group, pla-
cebo-controlled phase 3
trial. Lancet Respir Med.
2021;9:1407-1418.
[PMID: 34480861]
79. RECOVERY Collaborative
Group. Tocilizumab in
patients admitted to
hospital with COVID-19
(RECOVERY): a
randomised, controlled,
open-label, platform trial.
Lancet. 2021;397:1637-
1645. [PMID: 33933206]
80. Salama C, Mohan SV.
Tocilizumab in patients
hospitalized with Covid-
19 pneumonia. Reply. N
Engl J Med.
2021;384:1473-1474.
[PMID: 33657287]
81. Gordon AC, Mouncey PR,
Al-Beidh F, et al.; REMAP-
CAP Investigators.
Interleukin-6 receptor
antagonists in critically ill
patients with Covid-19. N
Engl J Med.
2021;384:1491-1502.
[PMID: 33631065]
82. Kyriazopoulou E,
Poulakou G, Milionis H, et
al. Early treatment of
COVID-19 with anakinra
guided by soluble uroki-
nase plasminogen recep-
tor plasma levels: a
double-blind, randomized
controlled phase 3 trial.
Nat Med. 2021;27:1752-
1760. [PMID: 34480127]
83. O'Halloran JA, Ko ER,
Anstrom KJ, et al.; ACTIV-
1 IM Study Group
Members. Abatacept, cen-
icriviroc, or infliximab for
treatment of adults hospi-
talized with COVID-19
pneumonia: a random-
ized clinical trial. JAMA.
2023;330:328-339.
[PMID: 37428480]
84. Lawler PR, Goligher EC,
Berger JS, et al.; ATTACC
Investigators. Therapeutic
anticoagulation with hep-
arin in noncritically ill
patients with Covid-19. N
Engl J Med.
2021;385:790-802.
[PMID: 34351721]
85. Goligher EC, Bradbury CA,
McVerry BJ, et al.;
REMAP-CAP Investigators.
Therapeutic anticoagula-
tion with heparin in crit-
ically ill patients with
Covid-19. N Engl J Med.
2021;385:777-789.
[PMID: 34351722]
© 2023 American College of Physicians
COVID-19 without the risk for transmis-
sion and can be used to follow some-
one longitudinally. For those presenting
with more severe symptoms, in-person
evaluation should be done to assess the
need for hospitalization and closer
monitoring.
When should patients be
hospitalized?
The clinical course of COVID-19 consists
of an initial viral phase and a subse-
quent inflammatory phase (Appendix
Figure, available at Annals.org). In the
viral phase, SARS-CoV-2 infection may
be asymptomatic (about 40% of cases)
(55); many patients with mild to moder-
ate COVID-19 recover fully (6). How-
ever, as many as 20% experience a
heightened SARS-CoV-2–induced inflam-
matory response a median of 5 to 8 days
after symptom onset, leading to clinical
progression to severe COVID-19 with
shortness of breath, hypoxemia, and of-
ten pneumonia requiring supplemental
oxygen and hospitalization (7, 56). As
many as 25% of hospitalized patients
early in the pandemic progressed to criti-
cal COVID-19, characterized by respira-
tory failure requiring mechanical venti-
lation, with some developing multiorgan
failure. With natural and acquired immu-
nity, therapeutic improvements, and
recent SARS-CoV-2 Omicron variants, the
clinical course of disease is milder, with
fewer patients progressing to hospitaliza-
tion and intensive care (57).
What complications are associated
with SARS-CoV-2 infection, and what
are additional laboratory or imaging
tests to consider after the initial
diagnosis?
In addition to causing upper respira-
tory symptoms, COVID-19 can evolve
to respiratory failure requiring intuba-
tion. SARS-CoV-2 can also infect cells
and organ systems throughout the
body, with cardiac, dermatologic, en-
docrine, gastrointestinal, hepatic, neu-
rologic, renal, and thromboembolic
manifestations (58). Immunologically,
COVID-19 is associated with lympho-
penia and lymphocyte dysfunction,
abnormalities of other leukocytes, T-
ITC154 In the Clinic
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cell activation, and increased produc-
tion of antibodies and cytokines lead-
ing to an “inflammatory cascade” (59).
For those with shortness of breath,
pulse oximeters can be used to moni-
tor SpO2, although not all devices are
standardized or FDA-cleared and re-
sults may be less accurate with darker
skin color resulting in occult hypoxemia
(60). People with persistent or progres-
sive shortness of breath, especially with
an SpO2 of 94% or less or other concern-
ing symptoms (such as chest pain or
confusion), should be referred for in-
person assessment and chest imaging.
Inflammatory markers, such as C-reac-
tive protein or D-dimer, may have prog-
nostic value and were used as entry
criteria in some clinical trials, but current
guidelines do not recommend routine
use of them. The clinical course dictates
the need for additional laboratory or
radiologic imaging tests.
Recovery from COVID-19 can be com-
plicated by an MIS seen in children
(MIS-C) and occasionally in young
adults (MIS-A), characterized by fever,
rash, conjunctivitis, and gastrointestinal
symptoms, with some cases progress-
ing to cardiac dysfunction and shock
that responds to systemic immunomo-
dulatory treatment, such as intravenous
c-globulin and/or corticosteroids (61).
When MIS-C or MIS-A is being consid-
ered as the cause of an illness requiring
hospitalization or causing death, the
case definition includes fever, several
clinical criteria, elevated inflammatory
markers (for example, C-reactive pro-
tein), and evidence of current or recent
COVID-19 in the absence of other
explanations. Additional information,
including the complete CDC case defi-
nitions, can be found at www.cdc.gov/
mis/index.html.
Another post–COVID-19 syndrome,
“long COVID” or “PASC” (postacute
sequelae of COVID-19), is character-
ized by multiple persistent or newly
emergent symptoms, although the def-
inition, cause, management, and treat-
ment remain controversial (62).
Annals of Internal Medicine October 2023
When should clinicians suspect
bacterial or other co-infections in
patients believed to have SARS-CoV-2
infection?
In contrast to influenza, bacterial or viral
co-infections are uncommon at COVID-
19 presentation.
A meta-analysis of more than 3800 hos-
pitalized patients found that only 7%
had a bacterial co-infection and only
3% had a viral co-infection (63). The
most common bacterial co-infections were
Mycoplasma pneumoniae, Pseudo-
monas aeruginosa, and Haemophilus
influenzae, and the most common viral
co-infections were respiratory syncytial
virus and influenza A.
Bacterial infection should be suspected
in patients presenting with leukocytosis
or an elevated neutrophil count; viral
infections should be considered if they
are prevalent in the community. How-
ever, bacterial infections may compli-
cate hospitalization for COVID-19, and
fungal co-infections, most often Asper-
gillus, Mucorales, and Candida, can
occur in critically ill patients using
immunomodulators (for example,
corticosteroids and/or interleukin inhibi-
tors) (64). Diagnostic testing should be
performed, and if a diagnosis is con-
firmed, appropriate treatment should
be started.
What is the role of hydration,
antipyretics, other supportive
treatment, and isolation?
The initial approach to COVID-19 man-
agement in most patients is supportive
care (adequate hydration, antipyretics,
and other symptomatic treatment) and
isolation and source control to prevent
transmission to others (65). The CDC
recommends isolation for 5 days from
symptom onset for those with mild dis-
ease and improving symptoms and at
least 10 days for those with moderate
to severe COVID-19. People with
immunocompromise should isolate for
at least 10 and up to 20 days; repeated
testing and infectious diseases consul-
tation are recommended to inform dis-
continuation of isolation.
October 2023 Annals of Internal Medicine
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What are proven pharmacologic
treatments for mild and moderate
COVID-19 in high-risk,
nonhospitalized patients?
High-risk outpatients with symptomatic
mild to moderate COVID-19 benefit
from antiviral therapy that reduces clini-
cal progression. The FDA approved
remdesivir for COVID-19 in outpatients
in April 2022 and nirmatrelvir–ritonavir in
May 2023 and authorized molnupiravir
through an EUA. The current preferred
antiviral is either nirmatrelvir–ritonavir or
remdesivir, with molnupiravir as an alter-
native (65) (Table 2). Corticosteroids are
not recommended in this setting.
In a double-blind phase 3 RCT of 2246
high-risk unvaccinated outpatients (66),
nirmatrelvir–ritonavir, a SARS-CoV-2 pro-
tease inhibitor, decreased progression
of COVID-19 by 89% versus placebo.
Subsequent retrospective data from
largely vaccinated populations showed
clinical benefit in Israel and the United
States (67–69). Nirmatrelvir–ritonavir is
generally well tolerated, with taste
abnormalities and/or gastrointestinal
adverse effects occurring in a small
number of patients. Because the phar-
macoenhancing drug ritonavir is a
potent hepatic cytochrome P450 inhib- 86. Mikkelsen ME, Still M,
Anderson BJ, et al.
itor, significant drug–drug interactions Society of Critical Care
may occur; these can often be man- Medicine's international
consensus conference on
aged by reducing the dose or holding prediction and identifica-
tion of long-term impair-
interacting medications. ments after critical illness.
Crit Care Med. 2020;48:
Remdesivir is also well tolerated but 1670-1679. [PMID:
32947467]
must be administered intravenously daily 87. Zhang H, Zang C, Xu Z, et
for 3 consecutive days, which may pose al. Data-driven identifica-
tion of post-acute SARS-
logistical challenges for outpatients. CoV-2 infection subphe-
notypes. Nat Med.
2023;29:226-235.
In a double-blind phase 3 RCT of 562 high- [PMID: 36456834]
88. Qaseem A, Yost J, Miller
risk unvaccinated outpatients, remdesivir, a MC, et al.; Scientific
SARS-CoV-2 RNA polymerase, decreased Medical Policy Committee
of the American College
clinical progression by 87% compared with of Physicians. Outpatient
treatment of confirmed
placebo (70). COVID-19: living, rapid
practice points from the
American College of
Molnupiravir, a cytidine analogue that Physicians (version 1).
induces lethal mutations in viral DNA, Ann Intern Med.
2023;176:115-124.
has lower efficacy and should only be [PMID: 36442061]
89. Alhazzani W, Evans L,
considered when preferred treatments Alshamsi F, et al.
cannot be used (65). It also should not Surviving Sepsis
Campaign guidelines on
be used in pregnant or breastfeeding the management of
adults with coronavirus
persons or in children.
disease 2019 (COVID-19)
in the ICU: first update.
In a double-blind phase 3 RCT of 1433 Crit Care Med. 2021;49:
e219-e34. [PMID:
high-risk, unvaccinated outpatients, mol- 33555780]
In the Clinic ITC155 © 2023 American College of Physicians
 Table 2. COVID-19 Treatments
Treatment Mechanism
(Reference) of Action
Antivirals
Nirmatrelvir–ritonavir SARS-CoV-2
(66–69) protease
inhibitor
Remdesivir (70, 74, 75) SARS-CoV-2
polymerase
inhibitor
Molnupiravir (71, 72) Lethal mutation EUA; alternative
Monoclonal antibodies SARS-CoV-2
entry inhibitor recommended
Immunomodulators
Dexamethasone (76) Corticosteroid Preferred
Baricitinib (77, 78) JAK-1 inhibitor FDA-approved;
Tocilizumab (79–81) Interleukin-6
inhibitor
ECMO ¼ extracorporeal membrane oxygenation; EUA ¼ emergency use authorization; FDA ¼ U.S. Food and Drug Administration;
JAK-1 ¼ Janus kinase 1.
nupiravir showed a 30% reduction
in clinical progression (71). The
subsequent PANORAMIC study
randomly assigned 26 411 partici-
pants aged 50 years or older (or
aged ≥18 years with comorbid-
ities) with confirmed COVID-19
within 5 days to open-label molnu-
piravir versus usual care (72). The
primary outcome of all-cause hos-
pitalization or death occurred in
1% of participants and did not dif-
fer between groups, but time to re-
covery (secondary outcome) was
shorter in the molnupiravir group
(9 vs. 15 days).
© 2023 American College of Physicians
Regulatory Status; Recommended Dose Demonstrated Clinical Additional
Guideline Population Benefit in Recommend- Considerations
Recommendation ed Population
FDA-approved; High-risk outpatients Oral; 300 mg (nirmatrel- Reduced clinical Drug–drug interac-
preferred within 5 d of vir)/100 mg (ritonavir) progression tions with ritonavir
symptoms twice daily for 5 d
FDA-approved; High-risk outpatients Intravenous; 200-mg Reduced clinical Requires daily infusion
preferred within 7 d of symp- loading dose, then progression for 3 d for
toms; non–critically 100 mg/d for 3 d outpatients
ill inpatients (outpatient) to 5 d
(inpatient)
High-risk outpatients Oral; 800 mg every 12 Modestly reduced Less effective than nir-
within 5 d of h for 5 d clinical progres- matrelvir–ritonavir or
symptoms sion remdesivir
Not currently High-risk outpatients Intravenous; single Reduced clinical Current Omicron sub-
within 5 d of infusion progression with variants resistant
symptoms earlier pre-Omicron
variants
Inpatients receiving Oral or intravenous; Decreased mortality Adverse effects of
supplemental 6 mg/d for 10 d corticosteroids
oxygen
Inpatients receiving Oral; 4 mg/d for 14 d Improved time to Do not use in patients
add to steroids conventional supple- recovery; decreased with active tubercu-
mental oxygen with mortality losis; avoid in
rapidly increasing oxy- patients with other
gen needs and/or sys- active infections
temic inflammation or
those receiving high-
flow nasal cannula,
noninvasive ventila-
tion, mechanical venti-
lation, or ECMO
FDA-approved; Inpatients receiving Intravenous; 8 mg/kg Reduced clinical Do not use in patients
add to steroids conventional supple- of body weight once progression; with active tubercu-
mental oxygen with decreased mortality losis; avoid in
rapidly increasing oxy- patients with other
gen needs and/or sys- active infections
temic inflammation or
those receiving high-
flow nasal cannula,
noninvasive ventila-
tion, mechanical venti-
lation, or ECMO
Earlier in the pandemic, sotrovi- the emergence of drug resistance
mab and other COVID-19 mono- or clinical progression and should
clonal antibodies reduced clinical not affect treatment recommen-
progression in high-risk outpa- dations.
tients with symptomatic COVID-
19, but these are no longer rec- There is no role for convalescent
plasma in immunocompetent
ommended due to decreased
susceptibility of recent Omicron patients. The role in immunocom-
promised patients is not clear.
subvariants (65).
What are proven treatments in
COVID-19 rebound with recur-
rence of symptoms and detection patients hospitalized for
of SARS-CoV-2 occurs uncom- COVID-19?
monly in patients taking COVID- For inpatients hospitalized for
19 antivirals and also occurs in COVID-19 who do not need
patients not taking them (73). oxygen supplementation or who
Rebound is not associated with were hospitalized for other reasons
ITC156 In the Clinic Annals of Internal Medicine October 2023
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and were incidentally found to have
COVID-19, corticosteroids are not
recommended. However, high-risk
symptomatic patients should be
treated with antivirals (nirmatrelvir–
ritonavir or remdesivir) to prevent
progression as noted earlier for out-
patients. For most patients hospital-
ized for COVID-19 and requiring
conventional supplemental oxygen,
treatment typically includes remdesi-
vir, dexamethasone, and anticoa-
gulants (65), with consideration of
other immunomodulators used
either in combination or in
sequence depending on illness se-
verity and progression (the latest
recommendations are available at
www.covid19treatmentguidelines.nih.
gov/tables/therapeutic-management-
of-hospitalized-adults).
Remdesivir was the first drug
approved by the FDA for COVID-
19, based on an early study that
showed reduced time to clinical
recovery (10 days) compared
with placebo (15 days) in hospi-
talized patients (74).
A large, randomized, open-label,
international phase 3 study of
8275 patients with COVID-19
failed to show an overall mortality
benefit with remdesivir. However,
in the large subset of 7569 patients
who were hospitalized and receiv-
ing oxygen but not mechanical
ventilation, remdesivir significantly
reduced both progression to venti-
lation and death (75).
RECOVERY (Randomized Evaluation
of Covid-19 Therapy), a large
phase 3 RCT of 6425 patients
hospitalized with COVID-19,
showed a statistically significant
17% decrease in 28-day mortal-
ity among patients randomly
assigned to dexamethasone
versus usual care (76). The mor-
tality benefit was seen only in
patients requiring oxygen sup-
plementation and was greatest
in patients who were receiving
mechanical ventilation or extra-
corporeal membrane oxygen-
ation (ECMO), where a 35% dec-
October 2023 Annals of Internal Medicine
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rease in 28-day mortality was
seen with dexamethasone.
For inpatients receiving conven-
tional oxygen with rapidly
increasing oxygen needs and/
or systemic inflammation or for
those requiring high-flow nasal
cannula oxygen, noninvasive
ventilation, mechanical ventila-
tion, or ECMO, a second immu-
nomodulator should be added,
such as baricitinib (a Janus ki-
nase inhibitor) or tocilizumab
(an interleukin-6 inhibitor).
Baricitinib was the second drug
approved by the FDA for COVID-
19, based on the results of 2
RCTs of hospitalized patients (77,
78). These studies showed that
baricitinib was associated with
clinical benefits of improved time
to recovery in patients receiving
remdesivir (77) and decreased
mortality in patients, 79% of
whom were using corticosteroids
(78). Tocilizumab, the third drug
approved by the FDA for COVID-
19, was shown to reduce pro-
gression to mechanical ventila-
tion and/or death in studies
where more than 80% of partici-
pants also received concurrent
corticosteroids (79–81). More
recently, additional immunomo-
dulators, such as anakinra (an
interleukin-1 inhibitor), abatacept
(a T-cell activation inhibitor), and
infliximab (a tumor necrosis fac-
tor-a inhibitor), showed some
clinical benefits in patients hospi-
talized with COVID-19 pneumo-
nia (>85% taking corticosteroids)
(82, 83). Despite theoretical con-
cerns, no obvious increase in se-
rious adverse events or infectious
complications associated with
these immunomodulators was
observed.
The inflammatory phase of
COVID-19 can produce a pro-
thrombotic state with resultant
complications, and anticoagula-
tion has been shown to have clini-
cal benefits in some nonpregnant
patients with signs of inflammation
without contraindications (65).
In the Clinic
In the combined results from 3
platform studies, 2219 non–
critically ill patients hospitalized
with COVID-19 were randomly
assigned to open-label thera-
peutic anticoagulation with hep-
arin or standard of care (84).
Therapeutic anticoagulation was
associated with a significant
increase in days free from organ
support (for example, intubation
or blood pressure support) but
no difference in length of stay or
mortality. In contrast, in a phase
3 trial of 1098 patients admitted
to the intensive care unit (ICU)
with severe COVID-19 and ran-
domly assigned to open-label
therapeutic anticoagulation with
heparin or standard-of-care anti-
coagulation (85), therapeutic
anticoagulation did not result in
clinical benefits, including mor-
tality, and was associated with
more major bleeding.
The National Institutes of Health
(NIH) treatment guidelines recom-
mend anticoagulation at prophy-
lactic doses for most patients
hospitalized for COVID-19 without
contraindications (65). For non-
pregnant hospitalized patients
who have above-normal D-dimer
levels and are not at high risk for
bleeding, anticoagulation at thera-
peutic doses is recommended.
What is the role of follow-up
care?
Most patients who are asymp-
tomatic or have mild to moder-
ate COVID-19 recover fully and
do not require follow-up care.
Most high-risk patients who
complete antiviral therapy also
recover fully. Patients with acute
dyspnea require close follow-up
via telemedicine or in-person
evaluation, and caution should
be used because pulmonary dis-
ease may progress rapidly.
Close follow-up for high-risk
patients (for example, older
patients, patients with immuno-
suppression, pregnant patients,
or patients with concomitant
ITC157 © 2023 American College of Physicians
illnesses) is important. Patients
with persistent or progressive
dyspnea, documented hypoxe-
mia (SpO2 ≤94%), or associated
symptoms of chest pain or men-
tal status changes require in-per-
son evaluation.
What is the approach to post–
COVID-19 syndrome?
The U.S. Department of Health
and Human Services defines
PASC (“long COVID”) as signs,
symptoms, and conditions that
continue or develop after initial
SARS-CoV-2 infection and are
present for 4 weeks or more af-
ter the initial phase of infection
(62). PASC likely represents
many potentially overlapping
entities, including the well-
described post-ICU syndrome
(86), with different biological
causes, risk factors, and out-
comes. These may be multisys-
temic and may present with a
relapsing–remitting pattern with
progression over time, with the
possibility of severe and life-
threatening events occurring
months or years after infection.
A large cohort study involving
more than 20 000 patients with
PASC identified 4 groups of symp-
toms and signs: cardiac and renal
(34%); respiratory, sleep, and anxi-
ety (33%); musculoskeletal and
nervous system (23%); and diges-
tive and respiratory (10%) (86).
Given uncertainties about the
cause, diagnosis, and treatment,
assessment and management
should center on symptoms and
affected organ systems.
When should clinicians consult
an infectious diseases or other
specialist for management and
treatment of COVID-19?
Most outpatients and many inpa-
tients with COVID-19 can be
successfully managed by gener-
alists. Nonetheless, for high-risk
outpatients with mild to moder-
ate COVID-19, the choice
among antivirals may require
specialist advice given drug–
drug interactions with nirmatrel-
vir–ritonavir and logistical chal-
lenges of administering 3 days
of intravenous remdesivir. For
inpatients with moderate, severe,
or critical COVID-19, specialist
advice can help address ques-
tions such as when to use antivi-
rals, when and how many
immunomodulators to use, and
when to use therapeutic anticoa-
gulation. For patients with pro-
gressive respiratory disease or
for critically ill patients with end-
organ involvement, specialist
consultation in an intensive care
setting is often required.

Management and Treatment... COVID-19 is characterized by an initial viral phase and, in some patients, a subse-
quent inflammatory phase. Treatment depends on the stage at presentation. For many outpatients with COVID-19, symp-
tomatic treatment is sufficient. High-risk outpatients with mild to moderate COVID-19 benefit from antiviral treatment.
Hospitalized patients with COVID-19 typically require oxygen supplementation and benefit from antivirals, immunomodu-
lators, and anticoagulation depending on the stage and severity of illness. Most patients recover fully from COVID-19;
some may experience a post–COVID-19 syndrome, although the cause and optimal treatment remain undefined.

CLINICAL BOTTOM LINE

Practice Improvement
What do professional
organizations recommend with
regard to prevention and
treatment?
The CDC publishes important vac-
cine updates (www.cdc.gov/vaccines/
covid-19/clinical-considerations/
covid-19-vaccines-us.html) and inte-
rim recommendations, including gui-
dance for interim infection pre-
vention and control (www.cdc.
gov/coronavirus/2019-ncov/hcp/
infection-control-recommendations.
html). The Infectious Diseases
Society of America (IDSA)
publishes guidelines on the
treatment and management of
patients with COVID-19 (www.
idsociety.org/practice-guideline/
covid-19-guideline-treatment-
and-management). The NIH Co-
ronavirus Disease 2019 (COVID-
19) Treatment Guidelines (www.
covid19treatmentguidelines.nih.
gov) are updated frequently.
The American College of Phy-
sicians has published summary
practice points for treatment of
adults with confirmed COVID-19
in an outpatient setting (87). For
ICU management, an update of
the Surviving Sepsis Campaign
Guidelines on the Management
of Adults With COVID-19 was
published in 2021 (88). A dash-
board that consolidates recom-
mendations from multiple guide-
line sources (including the World
Health Organization, CDC, IDSA,
NIH, and the European Society of
Intensive Care Medicine) can be
found at https://opencriticalcare.
org/covid-dashboard. Our recom-
mendations are generally consist-
ent with the recommendations of
these organizations.

© 2023 American College of Physicians ITC158 In the Clinic Annals of Internal Medicine October 2023

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 In the Clinic Patient Information

Tool Kit
www.cdc.gov/coronavirus/2019-ncov/
index.html
www.cdc.gov/coronavirus/2019-ncov/
vaccines/stay-up-to-date.html
Information on COVID-19 and COVID-19
vaccination in English, Spanish, Chinese,
COVID-19 Vietnamese, and Korean from the Centers
for Disease Control and Prevention.

https://medlineplus.gov/
covid19coronavirusdisease2019.html
Information and handouts in English and
other languages from the National
Institutes of Health’s MedlinePlus.
Information for Health Professionals

In the Clinic
www.cdc.gov/coronavirus/2019-nCoV/
hcp/index.html
Guidance for managing patients with
COVID-19, including clinical guidance,
home and hospital care, care for special
populations, and disease severity.

www.cdc.gov/vaccines/covid-19/clinical-
considerations/covid-19-vaccines-us.html
Interim clinical considerations on the use of
COVID-19 vaccines in the United States
from the Centers for Disease Control and
Prevention.

www.idsociety.org/practice-guideline/
covid-19-guideline-treatment-and-
management
Clinical practice guidelines on treatment
and management of COVID-19 from the
Infectious Diseases Society of America.

www.covid19treatmentguidelines.nih.gov
The National Institutes of Health’s COVID-
19 Treatment Guidelines are updated fre-
quently to provide clinicians with evi-
dence-based recommendations on
management of COVID-19.

October 2023 Annals of Internal Medicine In the Clinic ITC159 © 2023 American College of Physicians

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WHAT YOU SHOULD KNOW
ABOUT COVID-19
What Is COVID-19?
COVID-19 is an infection caused by the coronavi-
rus SARS-CoV-2 that can lead to serious health
problems and death, especially among older
people and those with risk factors. COVID-19
affects people of all ages, and symptoms may be
hard to differentiate from those of other viruses,
including the flu or the common cold. Its rapid
spread caused a global pandemic in 2020.
Infection can spread via respiratory particles and,
uncommonly, through nonrespiratory bodily flu-
ids and via contact with infected animals and
contaminated surfaces.
What Are the Signs and Symptoms?
Signs and symptoms include fever, chills, cough,
shortness of breath, feeling tired and weak, mus-
cle pain and soreness, headache, loss of taste or
smell, sore throat, congestion or runny nose,
nausea or vomiting, and (uncommonly) rash or
neurologic symptoms.
How Is It Diagnosed?
Your doctor will ask you questions about your symp-
toms and may perform a physical examination. They
may recommend testing specimens from your nose
or mouth. Some of these tests can be done at home.
Because the results can be negative early in the
infection, you may have to repeat the tests.
Can It Cause Complications?
Most people have no symptoms or mild symptoms
that resolve in 1 to 2 weeks without treatment. In
some, COVID-19 can cause serious complications
including hospitalization or death. You are at higher
risk for complications if you are aged 50 years or
older (especially ≥65 years); are living in a nursing
home; are Black, Hispanic/Latino, or American
Indian; are currently or recently pregnant; or have
lung disease, diabetes, heart disease or stroke, kid-
ney or liver disorders, obesity, a weakened immune
system, tuberculosis, or other medical conditions.
How Is It Treated?
Symptoms are usually treated with rest, drinking
clear fluids, and managing fever and aches with
over-the-counter medicines like acetaminophen or
ibuprofen. If you are at risk for complications or
have worsening symptoms, your doctor may pre-
scribe medicines to help your body fight the virus.
Should I Get a COVID-19 Shot, and
Can I Receive It at the Same Time
as the Flu Vaccine?
Everyone aged 6 months or older should complete
the primary series of approved COVID-19 vac-
cines.
Because the virus can change over time, recommendations
can also change. Up-to-date information is available from
the Centers for Disease Control and Prevention (www.cdc.
gov/coronavirus/2019-ncov/index.html).
© 2023 American College of Physicians ITC160
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In the Clinic
Annals of Internal Medicine
Regular boosters should be considered, espe-
cially if you or a close contact is at high risk for
severe illness from COVID-19.
The shot does not give you COVID-19. Side effects
are usually mild (such as soreness at the injection
site) and last a few days. Some people may get
fever and muscle aches. More serious side
effects, such as inflammation of the heart, can
occur but are rare and often resolve completely.
The COVID-19 vaccine and other vaccines may be
given during the same visit.
How Can I Prevent Spreading
COVID-19?
If you think you have COVID-19, stay home from
work or school. Use a facemask to cover your
mouth and nose, and wash your hands often.
Stay away from others for at least 5 days, even if
Patient Information
you have no symptoms. If you develop symp-
toms, avoid others for at least 5 days. Review the
CDC website for up-to-date information.
Questions for My Doctor
• What is the best way to prevent getting
COVID-19?
• What are the side effects of the COVID-19 shot?
• Can I get a COVID-19 shot and other vaccines at
the same time?
• Do I need to be evaluated for COVID-19 in the
office, or can you diagnose me over the phone or
video?
• Do I need additional testing to confirm that I have
COVID-19 and not the flu or another infection?
• Are antiviral treatments likely to speed my
recovery?
• Is it possible to get COVID-19 and the flu at the
same time?
• How long will my symptoms last?
• How long will I be contagious?
For More Information
In the Clinic Annals of Internal Medicine October 2023
 Appendix Table 1. COVID-19 Vaccines
Name (Reference) Platform/Mechanism and
Regulatory Status
BNT162b2, Pfizer– mRNA
BioNTech (20, 21) EUA for use of BNT162b2
bivalent formulation
Monovalent formulation
(previously FDA-
approved) no longer
available in United States
mRNA-1273, Moderna mRNA
(22, 23) EUA for use of mRNA-
1273.222 bivalent for-
mulation
Monovalent formulation
(previously FDA-
approved) no longer
available in United States
Ad26.COV2.S, Replication-incompetent
Janssen/Johnson & adenovirus 26 vector
Johnson (24, 25) No longer available in
United States
NVX-CoV2373, Recombinant protein,
Novavax (26, 27) adjuvanted
EUA
Indicated Ages Efficacy for Prevention of Rare Adverse Effects†
Symptomatic COVID-19 in
Initial Phase 3 Trials*
≥6 mo 95.0% (95% CI, 90.3%– Anaphylaxis
97.6%); median follow- Myocarditis/pericarditis
up, 2 mo (increased risk in ado-
91.3% (95% CI, 89.0%– lescent and young men)
93.2%); blinded follow-
up through 6 mo
≥6 mo 94.1% (95% CI, 89.3%– Anaphylaxis
96.8%); median follow- Myocarditis/pericarditis
up, 2 mo (increased risk in ado-
93.2% (95% CI, 91.0%– lescent and young men)
94.8%); median follow-
up, 5.3 mo (end of
blinded phase)
≥18 y Single dose: 66.9% (95% Thrombotic complications
CI, 59.0%–73.4%) for associated with thrombo-
moderate to severe cytopenia (increased risk
COVID-19 in women aged 30–50 y)
2-dose series: 75.2% (95% Guillain–Barr
e syndrome
CI, 54.6%–87.3%) for
moderate to severe
COVID-19
≥12 y (primary 90.4% (95% CI, 82.9%– Myocarditis/pericarditis
series) 94.6%); median follow-
≥18 y (booster) up, 3 mo (United States
and Mexico)
89.7% (95% CI, 80.2%–
94.6%); median follow-
up, 3 mo (United
Kingdom)

EUA ¼ emergency use authorization; FDA ¼ U.S. Food and Drug Administration.
* The effect of waning immunity on vaccine efficacy against symptomatic infection was not captured in the initial phase 3 clinical trials
because the primary end point was reached quickly. Vaccine effectiveness research demonstrates continued benefit in protection
from severe disease, hospitalization, and death in adults, including during periods when Omicron variants are predominant.
Effectiveness against infection has waned across all age groups.
† Local injection site reactions and systemic symptoms (fever, chills, fatigue, myalgia, headache) are common and occur with all of
the vaccines shown.

October 2023 Annals of Internal Medicine In the Clinic © 2023 American College of Physicians

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Appendix Table 2. Guidance on Acceptable Specimens for COVID-19 Testing*
Type
Upper respiratory specimen
Lower respiratory specimen
Acceptable Specimen
Nasopharyngeal swab collected by health care professional
Oropharyngeal swab collected by health care professional
Nasal mid-turbinate swab collected by health care professional or by patient after
reviewing and following collection instructions
Anterior nares specimen collected by health care professional or by patient after
reviewing and following collection instructions
Nasopharyngeal wash/aspirate or nasal wash/aspirate specimen collected by health
care professional
Saliva specimen collected by patient with or without supervision
Breath collected by a qualified and trained operator under supervision of health care
professional licensed or authorized to prescribe tests
Sputum from patients with productive cough (sputum induction is not recommended)
Bronchoalveolar lavage, tracheal aspirate, pleural fluid, or lung biopsy, generally per-
formed by physician in hospital setting (endotracheal aspirate preferred for patient
receiving mechanical ventilation†)

* Source: Interim Guidelines for Collecting and Handling of Clinical Specimens for COVID-19 Testing (www.cdc.gov/coronavirus/
2019-ncov/lab/guidelines-clinical-specimens.html). Local laboratories should be contacted to determine what specimens are
accepted.
† From reference 89.

Appendix Table 3. COVID-19 Diagnostic Tests*

Test Method Use Time to Results Performance Notes
NAAT Detects viral RNA Diagnoses current 1–3 d Highly sensitive Should not be
(laboratory) infection and specific; used in person
moderate cost who has had
COVID-19 in pre-
vious 90 d
Available as multi-
plex test with
other viruses
NAAT (point of Detects viral RNA Diagnoses current Minutes to 1 h Moderately to Should not be
care) infection highly sensitive; used in person
highly specific; who has had
moderate cost COVID-19 in pre-
vious 90 d
Antigen test Detects viral Diagnoses current Minutes Less sensitive than Negative results
(over the coun- antigens infection NAAT; highly do not rule out
ter, point of specific; low cost SARS-CoV-2
care, infection, and
laboratory) test should be
repeated per
FDA guidance
Antibody test Detects antibod- Uses antibody to 1–3 d Highly sensitive Not generally use-
ies to nucleocap- nucleocapsid to and specific for ful in COVID-19
sid or spike diagnose past detection of diagnosis or in
protein infection, as anti- antibodies assessment of
body to spike need for vaccina-
protein also tion
induced by Useful in diagno-
vaccine sis of MIS-C or
MIS-A

FDA ¼ U.S. Food and Drug Administration; MIS-A ¼ multisystem inflammatory syndrome in adults; MIS-C ¼ multisystem inflammatory
syndrome in children; NAAT ¼ nucleic acid amplification test.
* From reference 49.

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Appendix Figure. Clinical course of COVID-19 and interventions.

Prevention Antivirals Immuno-

modulators

Stage l Stage ll Stage lll

(Early Infection) (Pulmonary Phase) (Hyperinflammation Phase)

Severity of Illness IIA IIB

Viral response phase

Host inflammatory response phase

Time course

Mild constitutional symptoms Shortness of Breath without ARDS

Clinical (IIA) and with Hypoxia (IIB)
Fever >99.6°F SIRS/Shock
Symptoms (PaO2/FIO2 ≤300 mm Hg)
Dry Cough Cardiac Failure

Elevated inflammatory
Abnormal chest imaging
Clinical markers (CRP, LDH, IL-6,
Lymphopenia Transaminitis
Signs D-dimer, ferritin) Troponin,
Low-normal procalcitonin
NT-proBNP elevation

Modified from The Journal of Heart and Lung Transplantation, Vol. 39, Siddiqi HK, Mehra MR, COVID-19 illness in native and immu-
nosuppressed states: a clinical–therapeutic staging proposal, Pages 405-407, Copyright 2020, with permission from Elsevier. ARDS ¼
acute respiratory distress syndrome; CRP ¼ C-reactive protein; IL-6 ¼ interleukin 6; LDH ¼ lactate dehydrogenase; NT-proBNP ¼ N-
terminal pro–B-type natriuretic peptide; SIRS ¼ systemic inflammatory response syndrome.

October 2023 Annals of Internal Medicine In the Clinic © 2023 American College of Physicians

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