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Oct.18.2022

Coronavirus: Novel Coronavirus (COVID-19) Infection

Synopsis

Key Points

  • COVID-19 (coronavirus disease 2019) is a systemic infection due to a novel coronavirus, SARS-CoV-2; global pandemic is ongoing
  • Infection ranges from asymptomatic to severe; symptoms usually include fever, cough, and (in moderate to severe cases) dyspnea. Disease may evolve over the course of a week or more from mild to severe; deterioration may be sudden and catastrophic
  • Infection should be suspected based on presentation with a clinically compatible history (eg, fever, upper or lower respiratory tract symptoms); alterations in senses of smell and taste are particularly suggestive
  • Chest imaging in symptomatic patients almost always shows abnormal findings, usually including bilateral infiltrates; laboratory findings are variable but typically include lymphopenia and elevated lactate dehydrogenase and transaminase levels
  • Diagnosis is confirmed by detection of viral RNA on polymerase chain reaction test of upper or lower respiratory tract specimens; antigen testing is also available and has near-equivalent specificity but is slightly less sensitive
  • Treatments and treatment strategies continue to be refined; available drugs are administered at different stages of disease based on the pharmacologic mechanism of action and the dominant pathophysiology of the disease phase
    • Several antiviral medications are available, including remdesivir, ritonavir-boosted nirmatrelvir, and molnupiravir
    • Dexamethasone has been associated with significant reduction in mortality rates of patients requiring supplemental oxygen r1
    • Several immunomodulators are recommended for use in conjunction with corticosteroids with or without remdesivir r2
    • Monoclonal antibodies may be used for treatment and prevention, but use depends on susceptibility to circulating variants
  • Most common complications are acute respiratory distress syndrome and septic shock; myocardial, renal, and multiorgan failure are also seen
  • A significant proportion of clinically evident cases are severe; the mortality rate among diagnosed cases is generally about 3% but varies by country r3r4
  • Emerging evidence indicates that COVID-19 infection may predispose to long-term symptoms or future complications, even after mild or asymptomatic disease
  • Vaccination is safe and highly effective, particularly against hospitalization and death, even with new variants r5

Urgent Action

  • Triage screening is recommended at registration for medical care to identify patients with symptoms and exposure history that suggest the possibility of COVID-19, and to promptly institute isolation measures
  • Patients with respiratory distress require prompt administration of supplemental oxygen; patients with respiratory failure require intubation
  • Patients in shock require urgent fluid resuscitation and administration of empiric antimicrobial therapy to cover possible bacterial pathogens and/or influenza

Pitfalls

  • Persons with prodromal or asymptomatic infection may spread infection, making effective prevention more challenging
  • Knowledge of this disease is incomplete and evolving; moreover, coronaviruses are known to mutate and recombine often, presenting an ongoing challenge to our understanding and to clinical management

Terminology

Clinical Clarification

  • COVID-19 (coronavirus disease 2019) is a systemic infection (with a predilection for the respiratory system) caused by a newly recognized coronavirus, SARS-CoV-2, thought to have originated as a zoonotic virus that has mutated or otherwise adapted in ways that allow human pathogenicity
    • Disease was provisionally called 2019-nCoV infection at start of outbreak (2019 novel coronavirus infection)
  • Outbreak began in China but has since spread globally; it was officially declared by WHO to be a pandemic on March 11, 2020 r6
  • Illness ranges in severity from asymptomatic or mild to severe; a significant proportion of patients with clinically evident infection develop severe disease, which may be complicated by acute respiratory distress syndrome and shock
    • Mortality rate among diagnosed cases (case fatality rate) is generally about 3% globally but varies by country; true overall mortality rate is uncertain, as the total number of cases (including undiagnosed persons with milder illness) is unknown r3r4
  • Knowledge of this disease is incomplete and evolving; moreover, coronaviruses are known to mutate and recombine often, presenting an ongoing challenge to our understanding and to clinical management

Classification

  • Pathogen is a betacoronavirus, similar to the agents of SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome)
    • Classified as a member of the species Severe acute respiratory syndrome–related coronavirusr7r8
    • Designated as SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2); earlier provisional name was 2019-nCoV (2019 novel coronavirus) r7r8
  • Variants
    • Since late 2020, variants with potential impact on transmission, clinical disease, and immune protection have been recognized
    • CDC COVID Data Tracker maintains information about geographical distribution of variants in the United States and globally; at this time, more than 99% of circulating virus in the United States is Omicron variant, nearly all of which is Omicron BA.5 subvariant r9
    • CDC classifies them as variants of concern, variants being monitored, or variants of interest; the category of variants of high consequence exists in reserve, in case of future need r10
      • Classification is based on potential for increased transmissibility, greater severity of disease, reduction in protective effect of antibodies generated by previous disease or vaccination, reduced efficacy of available treatments or public health countermeasures, or reduced sensitivity of testing modalities
      • Variants of concern
        • Omicron (B.1.1.529 and BA lineages): first detected in South Africa; is now essentially the only variant in the United States (since January 2022). Appears to be more easily transmitted than other variants, and has reduced susceptibility to some monoclonal antibody products; efficacy of remdesivir is thought to be undiminished r2r9r11
          • Omicron BA.2 and subsequent subvariants (eg, BA.3, BA.4, BA.5) are the dominant strains worldwide and in the United States since February 2022. These subvariants appear to have increased transmissibility and similar severity compared with Omicron subvariant BA.1; their transmissibility despite antibodies generated by immunization may be increased, but vaccination still greatly reduces the risks of severe illness and death r9r12
      • Variants being monitored
        • Primary examples are as follows; consult the CDC list for more: r10
          • Alpha (B.1.1.7 and Q lineages): appears to have emerged in the United Kingdom; thought to be more easily transmitted and possibly associated with more severe disease than the original strain
          • Beta (B.1.351 and descendent lineages): first noted in South Africa; may confer some resistance to certain vaccines (eg, Moderna mRNA-1273)
          • Gamma (P.1 and descendent lineages): seems to have originated in Brazil; may mitigate the protective effect of antibodies to the original strain
          • Delta (B.1.617.2 and AY lineages): first detected in India; characterized by increased transmissibility and possibly reduced neutralization by some monoclonal antibody treatments and postvaccine serum
          • Epsilon (B.1.427 and B.1.429): both first detected in California; both associated with slightly increased transmissibility, significant decrease in neutralization effect of some monoclonal antibody treatments, and moderate decrease in neutralization effect of convalescent serum

Diagnosis

Clinical Presentation

History

  • Incubation period is typically within 14 days of exposure, and within 5 days in most patients. Incubation for more than 14 days occurs in a small percentage of patients r13r14
    • Patients may or may not report close contact with an infected person; the high transmissibility of the Omicron variant contributes to the number of cases with unknown exposure history c1
  • In symptomatic patients, illness may evolve over the course of a week or longer, beginning with mild symptoms that progress in some cases to the point of respiratory distress and shock r15c2c3c4
  • The most common complaints in unvaccinated people are fever/chills and cough, which may or may not be productive r15r16r17c5c6c7c8
    • Fever is often not present at presentation, even in hospitalized patients, and may be very mild (less than 38 °C) r15
    • Myalgia, headache, and fatigue are common; fatigue may be profound r15r17c9c10
    • Upper respiratory tract symptoms (eg, rhinorrhea, sneezing, sore throat) may be present in up to 20% of symptomatic infections r17c11c12c13c14
    • Gastrointestinal symptoms (eg, abdominal pain, nausea, vomiting, diarrhea) are present in 10% to 20% of symptomatic infections r15r17c15c16c17c18c19
    • Alteration in smell and/or taste is less common but highly suggestive r17r18r19c20c21c22
  • Patients with moderate to severe disease often complain of dyspnea;r20r21 however, it has been recognized that many patients with severe hypoxemia due to COVID-19 do not perceive dyspnear22r23r24r25r26r27c23
    • Hemoptysis has been reported in a small percentage of patients r15c24
    • Pleuritic chest pain has been reported r14c25
  • When COVID-19 is acquired after vaccination, a shift in the most common symptoms has been reported: headache, rhinorrhea, sneezing, sore throat, and loss of smell are most prominent, whereas cough and fever are less common than in unvaccinated people r28

Physical examination

  • Clinicians should be particularly attuned to pulmonary and hemodynamic indicators of severe disease
    • Patients with severe disease may appear quite ill, with tachypnea and labored respirations c26c27
    • Patients in apparent distress require immediate assessment of airway, breathing, and circulation (eg, pulses, blood pressure)
    • Clinicians should be aware of the COVID-19–related phenomenon of silent (or "happy") hypoxemia: absence of signs of respiratory distress may be misleading c28c29
    • Oxygenation should be assessed promptly by peripheral saturation (eg, pulse oximetry) or other methods as needed r29
      • Pulse oximetry has been demonstrated to be less effective in patients with darker skin tones of all ages, with risk of occult hypoxemia (ie, arterial oxygen saturation less than 88% with concurrent pulse oximetry value of 92% or more) highest in Black patients r30r31r32r33
  • Fever is typical, often exceeding 39 °C, but may be low-grade or absent in early disease, especially in vaccinated people. Patients in the extremes of age or with immunodeficiency may not develop fever r15c30c31c32c33
  • Conjunctival secretions, injection, and chemosis have been reported r34c34c35c36c37c38
  • A variety of skin changesr35 have been described, including erythematous rashes,r36purpura,r37petechiae,r38 and vesicles;r39acral lesionsr40r41r42 resembling chilblains or Janeway lesions have been seen, particularly in young patients c39c40c41c42c43c44c45c46c47c48c49c50c51c52c53c54c55c56c57c58c59c60c61c62c63c64c65c66c67
  • Hypotension, tachycardia, and cool/clammy extremities suggest shock c68c69c70c71
    • In children, shock manifests as hypotension plus 2 or more of the following criteria: r29
      • Altered mental status c72
      • Tachycardia (heart rate more than 160 beats per minute in infants or 150 in older children) or bradycardia (heart rate less than 90 in infants or 70 in older children) c73c74
      • Prolonged capillary refill (more than 2 seconds) or warm vasodilation and bounding pulses c75c76c77
      • Tachypnea c78
      • Mottled skin, petechiae, or purpura c79c80c81
      • Oliguria c82
      • Hyperthermia or hypothermia c83

Causes and Risk Factors

Causes

  • Infection due to SARS-CoV-2 (2019 novel coronavirus) c84
  • Person-to-person transmission has been confirmed and occurs through the air, in droplets and aerosols of various sizes, particularly with close contact r14r43r44c85
    • Viral shedding appears to peak 24 to 48 hours before symptom onset,r45 with consequent presymptomatic transmission. Several case and cluster reports from various countriesr46r47r48 indicating asymptomatic and presymptomatic transmission have been reported, and (regarding widespread clinical experience) cases without known history of exposure are not unusual c86
    • A study of viral loads found similar levels in presymptomatic and symptomatic infected persons r49
  • Additional means of transmission may occur but are thought to be less common (eg, contact with infected environmental surfaces, fomites, infection from animals) r44c87c88c89

Risk factors and/or associations

Age
  • Age distribution of cases has shifted substantially during the pandemic, as vaccination rates and public health responses have changed c90c91c92
    • During the first peak in the United States (in April 2020, when no vaccines were available), the incident case rate per 100,000 population was highest in the age groups of 75 years or older, 50 to 64 years, 40 to 49 years, and 65 to 74 years r50
    • In January 2021, the incident case rate per 100,000 population was highest in the age groups of 18 to 29 years, 30 to 39 years, 40 to 49 years, and 16 to 17 years r50
    • By August 2021, the incident case rate per 100,000 population was highest in the age groups of 16 to 17 years, 12 to 15 years, 30 to 39 years, and 18 to 29 years r50
    • Trend of higher caseload in younger populations continued during the Omicron wave (late 2021 onward), in large part owing to higher vaccination rates among those aged 65 years or older r50
  • All age groups are susceptible to COVID-19, but the risk of severe disease and death increases with age r51
    • Despite the change in case rates in the United States, those aged 75 years or older, 65 to 74 years, and 50 to 64 years have remained the age groups with the most deaths per 100,000 population throughout the pandemic r50
    • Approximate percentage of total mortality in the United States by age group (does not total to 100% due to rounding): r52
      • 0 to 39 years: 2.6%
      • 40 to 49 years: 4.3%
      • 50 to 64 years: 18.6%
      • 65 to 74 years: 22.9%
      • 75 to 84 years: 25.8%
      • 85 years or older: 26%
Sex
  • Overall, where sex or gender data are available, it appears that females are more often affected, but disease is more severe in males r50c93c94
Ethnicity/race
  • In the United States, persons in racial and ethnic minority groups, including Black, Hispanic, and Native American populations, have been disproportionately affected by COVID-19, including increased risk of infection, severe disease, and death r53r54
    • Risk is mediated through complex inequities (eg, increased exposure, inequities in housing and health care access, and other social determinants of health) and not genetic or biologic factors, which race does not reflect r55r56
Other risk factors/associations
  • Various underlying medical conditions have been associated with increased risk for severe disease, and many conditions are under investigation r54r57
  • Conditions which have been associated with higher risk for severe outcome (based on systematic review or meta-analysis): r54
    • Asthma c95
    • Cerebrovascular disease c96c97
    • Chronic kidney disease c98c99
    • Specific chronic lung diseases: interstitial lung disease, pulmonary embolism, pulmonary hypertension, bronchiectasis, chronic obstructive pulmonary disease c100c101c102
    • Specific chronic liver diseases: cirrhosis, nonalcoholic fatty liver disease, alcoholic liver disease, autoimmune hepatitis c103c104c105c106
    • Serious cardiac conditions (eg, heart failure, coronary artery disease, cardiomyopathy) c107c108c109c110c111c112c113c114c115c116c117c118c119c120c121c122c123c124
    • Cystic fibrosis c125c126c127
    • Diabetes mellitus, type 1 and type 2 c128c129
    • Malignancy c130
    • Pregnancy and recent pregnancy c131
    • Obesity (BMI of 30 kg/m² or higher, or 95th percentile or higher in children) c132c133c134
    • Smoking, current and former c135c136c137c138c139c140c141c142c143c144c145c146
    • Specific mental health disorders: mood disorders, including depression and anxiety; schizophrenia spectrum disorders
    • Disabilities including attention-deficit/hyperactivity disorder, cerebral palsy, congenital malformations, intellectual and developmental disabilities, learning disabilities, spinal cord injuries, and limitations of activities of daily living
    • HIV disease
    • Dementia
    • Primary immunodeficiencies and use of immunosuppressive medications including glucocorticoids
    • Solid organ or blood cell transplant c147c148c149c150c151c152
    • Tuberculosis
    • Physical inactivity
  • Conditions which are suggestive of higher risk for severe outcomes (based on cohort, case-control, or cross-sectional studies): r54
  • Conditions which might be associated with higher risk for severe disease (based on mixed evidence): r54
  • However, studies indicate that many people who develop severe disease (hospitalization and/or death) have no comorbidities r54
  • Residents of nursing homes and long-term care facilities are at high risk for acquiring infection and for severe disease, probably owing to a combination of heightened transmission in a close-quarters community and prevalence of compromised health status r58c191c192c193c194c195
  • In areas where vaccines are widely available, being unvaccinated (compared with being fully vaccinated) confers substantially higher risk for infection, hospitalization, and death r59

Diagnostic Procedures

Primary diagnostic tools

  • Diagnostic testing (laboratory or point of care tests): polymerase chain reaction tests are the standard for diagnosis; antigen testingr63 is also widely available in the United States. Public health authorities may assist in testing in some areas. Attempts to culture the virus are not recommended. Serologic testsr64 are not recommended for diagnostic purposes in most circumstances r60r61r62c196c197c198c199c200
    • CDCr60 and WHOr65r66 both recommend diagnostic testing in everyone with compatible symptoms, regardless of vaccination status, but they differ slightly on screening
      • WHO r65r66
        • All persons who meet the suspected or probable case definition should be tested; testing of asymptomatic persons is recommended to be limited to contacts of confirmed or probable COVID-19 and health care workers, including long-term care workers, who are frequently exposed; widespread screening of asymptomatic persons is not currently recommended
          • Case definitions: suspected case (any of the following): r66
            • Clinical criteria: acute onset of fever and cough or acute onset of any 3 or more of a specified list of symptoms (ie, fever, cough, general weakness/fatigue, headache, myalgia, sore throat, coryza, dyspnea, anorexia/nausea/vomiting, diarrhea)
            • Epidemiologic criteria: contact with a probable or confirmed case, or linked to a COVID-19 cluster
            • Severe acute respiratory tract infection: onset within the past 10 days of such an infection requiring hospital admission and without an alternative etiologic diagnosis
            • Asymptomatic person with positive antigen test result (via either professionally administered test or self-test) but with no epidemiologic link; recommend polymerase chain reaction for confirmation
          • Case definitions: probable case r66
            • Someone with the clinical symptoms above, or who died of an unexplained respiratory illness, who is a contact of a confirmed or probable case or is part of a cluster
            • Someone with a suspected case who also has chest imaging findings suggestive of COVID-19
              • Characteristic chest radiograph findings include hazy opacities with peripheral and lower lung distribution; CT findings include multiple bilateral ground-glass opacities with peripheral and lower lung distribution; lung ultrasonography findings include thickened pleural lines, B lines, and consolidative patterns
          • Case definitions: confirmed case r66
            • Someone with positive result on nucleic acid amplification test, regardless of clinical criteria or epidemiologic criteria
            • Someone meeting clinical criteria and/or epidemiologic criteria who has positive result on antigen test (via either professionally administered test or self-test)
        • In situations where it is not possible to test all who meet the case definitions, WHO recommends prioritizing the following: r65
          • Those at high risk for severe disease
          • Health care workers
          • Inpatients in health facilities
          • First symptomatic persons in closed space environment (eg, schools, long-term care facilities, hospitals, prisons), representing possible index cases in a suspected outbreak
      • CDC r60
        • Recommends that all persons with signs or symptoms, or with known or suspected exposure, be offered diagnostic testing; routine testing to end isolation is no longer recommended but may be considered in immunocompromised patients, who may still be infectious longer than 20 days from symptom onset
          • Polymerase chain reaction and antigen tests both have a role in diagnosis, with advantages and disadvantages for each (see Table 1 of CDC recommendationsr60)
            • For a person with symptoms, a positive result on polymerase chain reaction or antigen test confirms that the person has COVID-19; a negative antigen result needs to be confirmed with polymerase chain reaction test
            • For a person with no symptoms and no known exposure, a negative result on polymerase chain reaction or antigen test indicates that the person does not have current infection
            • For a person with exposure but no symptoms, a negative result suggests no current infection but the test may need to be repeated or confirmed with additional testing (eg, in cases of high probability of infection or ongoing exposure)
    • Specimens from upper or lower respiratory tract are recommended for viral testing.r67 Care must be taken to minimize risks associated with aerosolization during specimen collection
      • CDC provides instructions for collection and handling of specimens. Commercial, institutional, and public health laboratories may have different requirements and should be consulted for questions about collection site, swabs, transport media, or handling r67
        • Upper respiratory tract
          • Nasopharyngeal, deep nasal (midturbinate), anterior nare, oropharyngeal, or saliva specimens may be submitted. Only synthetic fiber (eg, polyester) swabs with plastic or wire shafts are acceptable. Flocked swabs are recommended for obtaining deep nasal specimens. If more than one swab is collected, they may be placed in the same container. Nasopharyngeal or nasal washings or aspirates are also acceptable. Note that not all tests are designed for use on all specimens c201c202c203c204c205c206c207c208c209c210c211c212
            • For nasopharyngeal specimen, insert swab into nostril parallel to palate. Leave swab in place for a few seconds to absorb secretions, then remove while gently rotating. It is not necessary to repeat on the other side if the first effort produces a good specimen (ie, swab is saturated)
            • For deep nasal specimen, insert a flocked swab about 2 cm and rotate; repeat on opposite side, using the same swab
            • For anterior nares, insert a flocked swab about 1 cm, rotate in contact with mucus membrane, and leave in place for 10 to 15 seconds; repeat on opposite side, using same swab
            • For oropharyngeal specimen, swab the posterior pharynx, avoiding tongue and tonsils
            • For tests designed for use on saliva, supervised self-collection of 1 to 5 mL is recommended
          • Nasopharyngeal wash (or aspirate) or nasal aspirate specimens (using 1 to 1.5 mL of nonbacteriostatic saline) are also acceptable c213
          • Because testing methods vary, it is advisable to check with the laboratory to determine which specimens are suitable for the available test
        • Lower respiratory tract
          • Bronchoalveolar lavage or tracheal aspirate are suitable lower respiratory tract specimens c214
          • A deep cough sputum specimen (collected after mouth rinse) is also acceptable c215
            • WHO and CDC advise against attempts to induce sputum, because the process may increase aerosolization and risk of transmission
      • A systematic review and meta-analysis compared frequency with which SARS-CoV-2 RNA was detected in sputum, nasopharyngeal swabs, and oropharyngeal swabs in patients with documented COVID-19. Overall positivity was 71% for sputum, 54% for nasopharyngeal swabs, and 43% for oropharyngeal swabs. Earlier testing resulted in higher positivity rates in all specimens r68
    • Serologic (antibody) testing is not recommended for use in acute diagnosis. Use in other situations, such as assessment of immune response to immunization in immunocompromised patients, or determining the need for monoclonal antibody treatment, is currently under investigation. Serologic testing may be considered: r2r69
      • To diagnose multisystem inflammatory syndrome in children or adults
      • To determine who may be eligible to donate convalescent plasma
      • When differentiating between immune response to infection versus immunization, as no currently available vaccines use the nucleocapsid protein but certain serologic tests detect antibodies to nucleocapsid protein
      • For evaluating the proportion of population who have been exposed to SARS-CoV-2
    • Other testing should be performed concurrently, if indicated, to identify alternative pathogens (eg, influenza, respiratory syncytial, and other viruses; bacterial pathogens); such tests should not delay arrangements for SARS-CoV-2 testing r29c216d1
      • Coinfections have been reported, but the frequency is unknown r70r71
      • Circulation of common respiratory viruses has been altered by public health measures to prevent COVID-19; be alert for off-season circulation and for increases in transmission when COVID-19 mitigation measures are relaxed r72
      • Influenza may be clinically indistinguishable from COVID-19; additionally, coinfection can occur. Therefore, when influenza and SARS-CoV-2 are both circulating in the community, testing for both viruses is recommended for all patients hospitalized with acute respiratory infection. In patients who present with acute respiratory illness but who do not require hospitalization, influenza testing is recommended in addition to testing for SARS-CoV-2, if influenza test results would alter management r2r73c217
        • CDC recommends nucleic acid detection over antigen testing for both pathogens, by either multiplex or individual assay
  • Chest imaging: may be indicated to assess severity; plain radiography, CT, and ultrasonography have been used r16c218c219c220
    • Recommendations for COVID-19–specific diagnostic use differ regionally, according to availability of testing, prevalence of disease, and public policy
      • During the peak of the outbreak in Wuhan, China, CT scan was considered a surrogate diagnostic modality, based on the following factors: greater sensitivity compared with chest radiographs; the observation that CT may find characteristic abnormalities even in the absence of a positive molecular test result; the high prevalence of COVID-19 in that geographic area at the time; and the public health goal of detecting and isolating all infected persons r74
      • CDC recommends against using chest radiograph or CT as a specific diagnostic measure for COVID-19; American College of Radiology cautions that findings are not specific to that disease and overlap with other viral pneumonias r75
  • Routine blood work as appropriate: should be ordered for clinical management based on disease severity (eg, CBC, coagulation studies, chemistry panel including tests of hepatic and renal function and—if sepsis is suspected—lactate level and blood cultures) r29c221c222c223c224c225c226c227c228c229c230c231c232c233c234c235c236c237c238d2
  • Public health reporting: requirements vary by jurisdiction; clinicians should consult local authorities. In some regions, public health authorities may be able to facilitate testing and undertake contact tracing and monitoring

Laboratory

  • Nucleic acid amplification tests are highly sensitive and specific, and the laboratory-performed versions are considered gold standard for diagnosis r60
    • Reverse transcription polymerase chain reaction is the most common nucleic acid amplification test, but isothermal amplification methods may also be used (eg, loop-mediated isothermal amplification)
    • Positive identification of SARS-CoV-2 RNA by nucleic acid amplification test is considered confirmation of diagnosis c239
      • Laboratory-based polymerase chain reaction testing has high sensitivity and high specificity and is thus the reference standard. Point of care polymerase chain reaction testing has moderate sensitivity and high specificity r60r76
      • False-negative results have been reported and may be due to a variety of factors, including inadequate sensitivity, poor or unrepresentative specimen, or time course of disease. Repeated sampling should be considered if suspicion for COVID-19 is high and initial result is negative; in patients with severe pulmonary involvement, lower respiratory tract specimens may provide a higher yield r76r77
      • Polymerase chain reaction results may remain positive when a person is no longer infectious; it is not recommended to use polymerase chain reaction tests for determining resolution of infection in most cases
        • In addition, repeating nucleic acid amplification tests in asymptomatic patients is not recommended in the 90 days after diagnosis of COVID-19, because RNA may intermittently be detectable but does not necessarily represent live virus
  • Antigen tests: also available for use in diagnosis, and they have the advantage of rapid turnaround
    • In general, these tests are less sensitive than polymerase chain reaction, although specificity is nearly equivalent r63
      • False-positive results are uncommon, but they do occur and are more likely in a low-prevalence setting
      • False-negatives are common, depending on the test. A negative result may warrant retesting (preferably within 2 days) with polymerase chain reaction, or repeated antigen testing, if there is a high suspicion for infection based on clinical or epidemiologic indicators
      • 2 algorithms may assist in determining when an antigen test should be confirmed: for congregate care and community settings r63
    • Some evidence indicates that antigen test results correlate with infectiousness
    • A Cochrane review noted wide-ranging performance of antigen tests; summary sensitivities ranged from 34.1% to 88.1%, but average specificity was 99.6% r78
      • Sensitivity is higher in symptomatic versus asymptomatic cases, in the first week after symptom onset versus later, and in those with Ct values (cycle threshold) on polymerase chain reaction test of 25 or less versus higher; all of these correlations reflect improved sensitivity with higher viral loads
      • Performance varies across brands. Antigen tests with sufficient sensitivity and specificity may be considered as a replacement for polymerase chain reaction tests when rapid decisions about patient care must be made and when timely polymerase chain reaction test is unavailable, with confirmatory polymerase chain reaction test advised in lower-prevalence settings. Evidence on screening asymptomatic populations has been limited
    • CDC provides guidance on antigen testing, including screening in congregate care and community settings, when confirmatory testing is indicated (based on symptoms, exposure, vaccination status, and setting), as well as serial testing r63
  • Antibody tests: a Cochrane reviewr79 notes that antibody tests are most likely to be clinically useful 15 days or more into the course of infection and that data are scarce regarding antibody tests beyond 35 days. For instances when clinicians judge that antibody testing is indicated, Infectious Diseases Society of Americar64 makes the following recommendations:
    • Testing 3 to 4 weeks after symptom onset maximizes sensitivity
      • Sensitivity at 1 week ranges from 0.23 to 0.63; at 2 weeks, from 0.68 to 0.96
    • Test should measure anti–SARS-CoV-2 IgG or total antibody; a high-specificity test should be used
      • Unlike the usual pattern of antibody production, IgM antibody response to SARS-CoV-2 is somewhat delayed, occurring almost simultaneously with IgG production, so there is no advantage to testing selectively for the IgM fraction
  • Routine blood work is not diagnostic, but a pattern of typical abnormalities has emerged, particularly in patients with severe illness: c240c241c242c243
    • Leukopenia may be observed and relative lymphopenia is common, especially in patients with more severe illness r14r15r16
    • Anemia was noted in about half of patients in one series r16
    • Both elevated and low platelet counts have been seen r14r15r16
    • Prolonged prothrombin time has been reported r80
    • Levels of D-dimer and fibrinogen may be elevated r14r15
    • Elevated levels of lactate dehydrogenase and liver enzymes (ALT and AST) are common r15r16
    • Serum procalcitonin levels are usually within reference range; elevated levels have been seen in patients with secondary infection r15
    • Serum levels of some other acute phase reactants (eg, C-reactive protein, ferritin) are elevated in most patients, as is the erythrocyte sedimentation rate r16
  • Lactate level of 2 mmol/L or higher suggests presence of septic shock r29c244

Imaging

  • Chest imaging (eg, plain radiography, CT, ultrasonography) has been found to be sensitive but not highly specific to COVID-19 r81
  • Chest imaging has shown abnormalities in most reported cases; it usually shows bilateral involvement, varying from consolidation in more severely ill patients to ground-glass opacities in less severe cases and in recovering pneumonia r14r15r16r82r83c245c246c247c248
  • CT appears to be more sensitiver84r81 than plain radiographs, but normal appearance on CT does not preclude the possibility of COVID-19r85
  • Bedside ultrasonography is widely used to monitor progression of pulmonary infiltrates and to assess cardiac function and fluid status; it may also be used to detect deep vein thrombosis or vascular catheter thrombosis, which appear to be common in patients with COVID-19 r76r86c249c250

Differential Diagnosis

Most common

  • Influenza c251d3
    • Presentation includes fever, coryza, sore throat, dry cough, and myalgias; unlike COVID-19, influenza usually has fairly sudden onset
    • Most cases are self-limited, but older adults (eg, those aged 65 years or older) or those with significant comorbidities often require hospitalization
    • Usually occurs in winter months in temperate climates but is less seasonal in equatorial regions
      • Mitigation measures for COVID-19 may alter the timing and amount of circulating respiratory viruses, including influenza r72
    • Patients with severe disease may have abnormal chest radiographic findings suggesting influenzal pneumonia or secondary bacterial pneumonia
    • Positive result on rapid influenza diagnostic test confirms influenza diagnosis with high specificity during typical season; negative result does not rule out influenza
    • Influenza may be clinically indistinguishable from COVID-19; additionally, coinfection can occur. Therefore, when influenza and SARS-CoV-2 are both circulating in the community, testing for both viruses is recommended for all patients hospitalized with acute respiratory infection. In patients who present with acute respiratory illness but who do not require hospitalization, influenza testing is recommended in addition to testing for SARS-CoV-2, if influenza test results would alter management r2r73
      • CDC recommends nucleic acid detection over antigen testing for both pathogens, by either multiplex or individual assay
  • Other viral pneumonias c252d1
    • Presentations include fever, dry cough, and dyspnea
    • Physical examination may find scattered rales
    • Chest radiography usually shows diffuse patchy infiltrates
    • Diagnosis is usually clinical. Testing for specific viral causes may be done; multiplex panels can test simultaneously for a number of common viral respiratory pathogens (such as respiratory syncytial virus, adenovirus, and others)
    • As with influenza, timing and amount of circulating respiratory viruses may be altered by COVID-19 mitigation measures r72
  • Bacterial pneumonia c253d1
    • Presentation includes fever, cough, and dyspnea; pleuritic pain occurs in some cases
    • Physical examination may find signs of consolidation (eg, dullness to percussion, auscultatory rales, tubular breath sounds)
    • Chest radiography usually shows lobar consolidation or localized patchy infiltrate
    • Sputum examination may find abundant polymorphonuclear leukocytes and a predominant bacterial organism
    • Pneumococcal or legionella antigens may be detectable in urine; sputum culture may find those or other pathogens

Treatment

Goals

  • Ensure adequate oxygenation and hemodynamic support during acute phase of illness
  • Prevent complications where possible (eg, thromboses)

Disposition

Admission criteria

Nonsevere pneumonia

  • Radiographic evidence of pneumonia; progressive clinical illness; risk factors for severe disease; inadequate care at home r29
Criteria for ICU admission
  • WHO provides criteria for critical respiratory tract disease r87
    • Characterized by tachypnea (respiratory rate greater than 30 breaths or less than 10 breaths per minute), severe respiratory distress, inadequate oxygenation (eg, SpO₂ less than 92%)
      • Pediatric criteria include central cyanosis or SpO₂ less than 90%; signs of severe respiratory distress (eg, grunting, chest retractions); inability to drink or breastfeed; lethargy, altered level of consciousness, or seizures; or severe tachypnea defined by age:
        • Younger than 1 month: 60 or more breaths per minute or 20 or fewer breaths per minute
        • Aged 1 to 12 months: 50 or more breaths per minute or 10 or fewer breaths per minute
        • Aged 1 year or older: 40 or more breaths per minute
  • Presence of severe complications (eg, septic shock, acute respiratory distress syndrome)

Recommendations for specialist referral

  • All patients should be managed according to public health policies in their jurisdiction
  • Consult infectious disease specialist to coordinate diagnosis and management with public health authorities
  • Consult pulmonologist to aid in obtaining deep specimens for diagnosis and managing mechanical ventilation if necessary
  • Consult critical care specialist to manage fluids, mechanical ventilation, and hemodynamic support as needed

Treatment Options

Overview

  • Current standard treatment options include infection control measures, routine supportive care, and medications including antiviral, monoclonal antibody, immunomodulator, and corticosteroid drugs
    • Many other drugs (of several classes) have been or still are being used under clinical trial and compassionate use protocols based on in vitro activity (against this or related viruses) and clinical experience. Information on therapeutic trials and expanded access is available at ClinicalTrials.gov r88
    • A strategy has emerged by which drugs are selected according to the mechanism of action most likely to be effective against the dominant pathophysiology at various stages in the disease process. Thus, antivirals and monoclonal antibodies directed at viral components are most effective when used early in the course of infection (to prevent cell entry and viral replication); antiinflammatory drugs (eg, dexamethasone) and immunomodulators are of most benefit during the hyperinflammatory response in later phases of severe disease
    • Given new medications, novel use of existing medications, and the rapid change in guidelines, consulting a drug interaction checkerr89 is advised
  • Some treatment options are recommended for patients at high risk for severe disease, or for immunocompromised patients who are not expected to mount adequate immune response to vaccination or to COVID-19
    • Common underlying conditions include (but are not limited to): age 65 years or older, diabetes, chronic lung diseases, chronic heart diseases, chronic liver diseases, pregnancy, and mood disorders; the CDC regularly updates a listr54 based on new evidence
    • Some rare conditions, as well as race and ethnicity, may be associated with increased risk for severe disease, and risk increases when multiple conditions are present; use clinical judgment for individual patients r2
    • Common conditions causing moderate to severe immune compromise include (but are not limited to) the following; consult CDC guidancer5 for updates
      • Active treatment for solid tumor and hematologic malignancies
      • History of solid organ transplant and currently taking immunosuppressive therapy
      • History of CAR T-cell therapy (chimeric antigen receptor T-cell therapy) or hematopoietic cell transplant within the past 2 years, or currently taking immunosuppressive therapy
      • Moderate or severe primary immunodeficiency (eg, severed combined immunodeficiency, DiGeorge syndrome, Wiskott-Aldrich syndrome)
      • Untreated HIV infection or advanced HIV infection (CD4 cell counts less than 200 cells/mm³, history of an AIDS-defining illness without immune reconstitution, or clinical manifestations of symptomatic HIV disease)
      • Immunosuppressive medications, including treatment with high-dose corticosteroids (20 mg or more of prednisone or equivalent per day when administered for 2 or more weeks), alkylating agents, antimetabolites, transplant-related immunosuppressive drugs, cancer chemotherapeutic agents classified as severely immunosuppressive, tumor necrosis factor blockers, and other biologic agents that are immunosuppressive or immunomodulatory
  • Throughout the pandemic, many jurisdictions have experienced caseload surges and supply constraints, which may limit the available therapies. Only if access to recommended therapies is limited, NIH suggests the following prioritizations:
    • For preventive therapy, prioritize severely immunocompromised status over moderately immunocompromised status
    • For treatment, risk groups based on age, immune status, clinical risk factors, and vaccination status are as follows:
      • Tier 1: immunocompromised patients not expected to adequately respond to vaccination or COVID-19, and unvaccinated individuals at highest risk due to age and underlying conditions (eg, 75 years or older, or 65 years or older with any underlying condition)
      • Tier 2: unvaccinated patients at high risk not in tier 1 (eg, age 65 years or older, or any age with underlying conditions)
      • Tier 3: vaccinated patients at highest risk (eg, 75 years or older, or 65 years or older with any underlying condition); note that those without any booster doses are at higher risk than those with booster doses
      • Tier 4: vaccinated patients at high risk not in tier 3 (eg, age 65 years or older, or any age with underlying conditions)

Infection control measures: these include isolation, source control, and transmission precautions r90

  • People with COVID-19 at home should isolate at home, keep separate from others in the household as much as possible; wear a mask when near other people or pets in the household; monitor for serious or worsening symptoms requiring additional medical care; and increase ventilation, cleaning, and disinfection r91
  • Patients with COVID-19 in a health care setting should wear a face mask to reduce droplet spread; should be placed in a single-person closed room pending further evaluation and disposition decisions; and should have standard precautions, contact precautions, and droplet or airborne precautions as resources allow
    • Health care personnel should wear N95 respirator or comparable (eg, FFP2, KN95), gown, gloves, and eye protection r90
      • Some guidelines suggest that a medical face mask, rather than N95 respirator, is sufficient when not performing aerosol-generating procedures r29
    • If available, the patient room will ideally be one with structural and engineering safeguards against airborne transmission (eg, negative pressure, frequent air exchange), but in the high-prevalence stages of the pandemic (with crowded hospitals), reserve negative pressure isolation rooms for the greatest needs (ie, aerosol-generating procedures; tuberculosis, measles, and varicella)

Supportive care: for all patients; in hospitalized patients, such care includes oxygenation and ventilation, conservative fluid support, and measures to prevent common complications (eg, pressure injury, stress ulceration, secondary infection) r29

  • Until a diagnosis of COVID-19 is confirmed by polymerase chain reaction or antigen test, appropriate antimicrobial therapy for other viral pathogens (eg, influenza virus) or bacterial pathogens should be administered in accordance with the severity of clinical disease, site of acquisition (hospital or community), epidemiologic risk factors, and local antimicrobial susceptibility patterns r29
  • Surviving Sepsis Campaignr92r93 guideline, NIH COVID-19 treatmentr2 guideline, and WHO guidancer29 provide recommendations specific to treatment of shock in patients with COVID-19. Management of shock and other complications requiring intensive care are addressed in detail in the Clinical Overview on COVID-19 critical care d4

Antiviral agents

  • Remdesivir: FDA-approved for treatment of COVID-19 in hospitalized adults and children aged 28 days or older weighing 3 kg or more, and in those with mild to moderate test-positive COVID-19 who are not hospitalized but who are at high risk for progression to severe disease r94r95r96
    • Preliminaryr97 and follow-upr98 results of the Adaptive COVID-19 Treatment Trial, a placebo-controlled randomized trial in 1062 patients, showed a statistically significant improvement in time to recovery and a nonsignificant trend in lower mortality; several other trials remain active, as wellr99
    • On the basis of these and other data from clinical trials, the NIH guideline recommends, and the Infectious Diseases Society of America and Surviving Sepsis Campaign guidelines suggest, remdesivir for hospitalized patients with COVID-19 who require supplemental oxygen r2r92r93r100
      • In patients who require oxygen via high-flow device or noninvasive ventilation, NIH offers the option of adding remdesivir to dexamethasone plus baricitinib or dexamethasone plus tocilizumab, because remdesivir appears to confer maximum benefit before onset of more severe disease
      • NIH does not recommend use of remdesivir in patients who require mechanical ventilation or extracorporeal membrane oxygenation, and both Infectious Diseases Society of America and Surviving Sepsis Campaign guidelines suggest that remdesivir not be used in patients with critical COVID-19
      • For patients whose condition worsens while they are receiving remdesivir and who require institution of high-flow oxygen, ventilation, or extracorporeal membrane oxygenation, NIH recommends that the treatment course be completed
    • For hospitalized patients with no current oxygen requirement, NIH guidelines suggest consideration of remdesivir for patients at high risk of disease progression, and Infectious Diseases Society of America guidelines suggest use of remdesivir (3-day course)
    • Infectious Diseases Society of America and WHO suggest, and NIH recommends, use of remdesivir in ambulatory patients with mild to moderate COVID-19 who are at high risk for progression to severe disease, to be initiated within 7 days of symptom onset r2r100r101
      • For this patient population, NIH guidelines prefer use of ritonavir-boosted nirmatrelvir, when available
      • In a randomized placebo-controlled trial of 562 nonhospitalized patients with COVID-19, a 3-day course of remdesivir was associated with an 87% reduction in risk of hospitalization or death r102
    • Evidence base: remdesivir has significant in vitro activity against coronaviruses,r103r104 evidence of efficacy in an animal model of MERS,r104 and evidence of efficacy in COVID-19r98
  • Ritonavir-boosted nirmatrelvir has received emergency use authorization in the United States for treatment of nonhospitalized persons aged 12 years or older and weighing 40 kg or more who test positive for COVID-19, who are at high risk for progressing to severe disease, and for whom alternative treatments are not available or not clinically appropriate r105
    • Ritonavir-boosted nirmatrelvir was studied in a randomized placebo-controlled trial of 2246 patients with documented COVID-19 who met criteria for high risk of progression to severe disease. The primary end point was COVID-19–related hospitalization or death from any cause within 28 days. The relative risk reduction in patients who received the study drug was 88% r105
      • Ritonavir-boosted nirmatrelvir is associated with numerous potential drug interactions
        • Patients with HIV taking a ritonavir- or cobicistat-based antiretroviral regimen should continue to take their antiretroviral regimen as prescribed during ritonavir-boosted nirmatrelvir treatment r106
        • Resources are available to help clinicians manage potential drug interactions r89r107
    • NIH recommends and Infectious Diseases Society of America suggests use of ritonavir-boosted nirmatrelvir in ambulatory patients with mild or moderate COVID-19 at high risk for progression to severe disease, to be initiated within 5 days of symptom onset r100
    • Viral rebound and/or recurrence of symptoms and antigen test positivity has been reported following a 5-day course of ritonavir-boosted nirmatrelvir; there is no evidence that additional treatment is needed, but patients should continue to isolate until they meet criteria for discontinuation r2
  • Molnupiravir, another oral antiviral agent, has emergency use authorization in the United States for treatment of nonhospitalized adults positive for COVID-19 who are at high risk of progression to severe disease, and for whom alternative treatments are not available or not clinically appropriate r108
    • Molnupiravir was compared with placebo in a randomized trial of 1433 patients with mild to moderate COVID-19 who met criteria for high risk of progression to severe disease. The primary end point was all-cause hospitalization or death through day 29. The relative risk reduction was 30%
      • Molnupiravir is not recommended during pregnancy or breastfeeding; before prescribing to persons of childbearing potential, test for pregnancy and (including for biologic males) ensure reliable contraception through treatment and for 4 days (females) or 3 months (males) after the last dose. Breast milk should be discarded during treatment and for 4 days after the last dose r108
    • Mechanism of action of molnupiravir is inducing lethal viral mutations; concerns have arisen regarding emergence of resistance and emergence of new variants as a result. Use of molnupiravir should be accompanied with robust pharmacovigilance r101
    • Infectious Diseases Society of America suggests use of molnupiravir in ambulatory adults (aged 18 years or older) with mild to moderate COVID-19 at high risk for progression to severe disease who have no other treatment options (eg, nirmatrelvir-ritonavir or remdesivir), to be initiated within 5 days of symptom onset, rather than no molnupiravir r100
    • Similarly, NIH recommends use of molnupiravir (or bebtelovimab) in ambulatory adults at high risk of progression to severe disease only when ritonavir-boosted nirmatrelvir and remdesivir are unavailable, because it has lower efficacy than the preferred treatments r2
    • WHO suggests use of molnupiravir for adults with nonsevere disease at highest risk of hospitalization; alternative treatments may be preferable where available

Monoclonal antibodies with antiviral action (against SARS-CoV-2 spike protein)

  • Emergency use authorizations have been issued in the United States for several monoclonal antibody products: bebtelovimab,tixagevimab-cilgavimab in combination, bamlanivimab-etesevimabr109r110 in combination, casirivimab-imdevimabr111r112 in combination, and sotrovimabr113r114
    • Given the predominance of the Omicron variant in the United States and the lack of activity against prevailing Omicron subvariants with bamlanivimab-etesevimab, casirivimab-imdevimab, or sotrovimab, FDA has modified the emergency use authorizations for these monoclonal antibodies to state that they are not authorized for use in regions where infection is likely to be caused by a nonsusceptible strain, effectively suspending their use in the United States r115r116
    • Emergency use authorizations apply to patients aged 12 years or older, weighing 40 kg or more, who have mild to moderate disease and who are at high risk for progression to severe disease and/or hospital admission; the authorizations exclude persons who are already hospitalized for COVID-19 or who require supplemental oxygen for COVID-19
  • Distribution of monoclonal antibodies is currently coordinated through state/territorial health departments, based on circulating variants, case burden, and product utilization rates r2r117r118
  • Tixagevimab and cilgavimab are monoclonal antibodies that block spike protein attachment, binding to 2 different regions of the receptor-binding domain of the spike protein
    • FDA granted an emergency use authorization in December 2021 for preexposure prophylaxis in adults and children aged 12 years or older weighing at least 40 kg who have moderate to severe immunocompromise or who are unable to be immunized owing to severe allergic reaction r119
    • Based on decreased susceptibility of BA.1 and BA.1.1 subvariants of Omicron variant to this combination, the recommended dose was increased on February 24, 2022
      • Those who received the original dose of 150 mg each should receive a second dose of 150 mg each as soon as possible
    • Infectious Diseases Society of America suggests use and NIH recommends use of tixagevimab-cilgavimab as preexposure prophylaxis in adults and adolescents who have moderate to severe immunocompromise or who are unable to be fully immunized owing to documented severe allergy
  • Bebtelovimab is a recombinant neutralizing human monoclonal antibody that binds to the spike protein of SARS-CoV-2 (including the Omicron variant), preventing its attachment to the ACE2 receptor (for angiotensin-converting enzyme 2) r120
    • Limited clinical data indicate a reduction in viral load in treated patients and improvement in symptoms; the emergency use authorization issued by FDA on February 11, 2022 states that "based on the totality of evidence available … it is reasonable to believe that bebtelovimab may be effective for the treatment of patients with mild-to-moderate COVID-19 to reduce the risk of progression to hospitalization or death"
    • NIH recommends use of bebtelovimab (or molnupiravir) in ambulatory adults at high risk of progression to severe disease only when ritonavir-boosted nirmatrelvir and remdesivir are unavailable or not clinically feasible r2
    • Infectious Diseases Society of America guideline also suggests use of bebtelovimab in the same population only when alternatives are not possible
  • Other monoclonal antibody products are no longer in use in the United States and many other locations given lack of activity against Omicron subvariants
    • Sotrovimab targets a highly conserved region in the receptor-binding domain of the SARS-CoV-2 spike protein r113
      • Interim data from the ongoing COMET-ICE clinical trial show that in 583 patients with symptomatic COVID-19 and at least 1 comorbidity or age-related risk factor for progressing to severe disease who were randomized to receive sotrovimab or placebo, the risk of progression to severe disease was 85% lower in the sotrovimab arm r113
        • Although sotrovimab is active against the Omicron BA.1 and BA.1.1 subvariants, it has substantially decreased in vitro activity against the Omicron BA.2 subvariant, and as of April 5, 2022, it is no longer authorized by FDA for use in the United States r2r113r116
      • WHO recommends against treatment with sotrovimab due to evidence showing sotrovimab lacks activity against circulating SARS-CoV-2 variants and subvariants (eg, Omicron) r101
    • Bamlanivimab and etesevimab are monoclonal antibodies designed to target the SARS-CoV-2 spike protein, disabling viral attachment and entry into human cells; the 2 antibodies target different regions of the spike protein r110
      • Preliminary data from clinical trials on bamlanivimab (before emergence of Omicron variant) demonstrated a reduction in the incidence of COVID-19–associated emergency department visits and hospital admissions (3% for patients treated with bamlanivimab versus 10% for patients who received placebo) r109
        • A subsequent trial (BLAZE-1) of bamlanivimab in combination with etesevimab showed a 70% reduction in COVID-19–related hospitalization or death by any cause r109
      • Based on these data, FDA issued emergency use authorizations; however, the emergency use authorization for bamlanivimab alone was since revoked because virus variant prevalence reduced its effectiveness, and similarly, for bamlanivimab in combination with etesevimab, the emergency use authorization has subsequently been revised to preclude use when infection is likely to be caused by a nonsusceptible variant, such as Omicron r109
    • Casirivimab-imdevimabr2r111
      • This combination appeared to have reduced activity against the Omicron variant prevalent in late 2021 and early 2022; the emergency use authorization was modified on January 24, 2022, to preclude use of this product when infection is likely to be caused by a nonsusceptible variant such as Omicron, which is now the prevailing variant in the United States r112
      • Similarly, with Omicron predominating worldwide, WHO no longer recommends use of casirivimab-imdevimab except in cases where rapid genotyping confirms infection with a variant that is susceptible r101

Immunomodulators are also being investigated for mitigation of cytokine release syndrome believed to be a factor in severe acute respiratory distress syndrome and shock in COVID-19 (eg, monoclonal antibodies against interleukin-6 receptors, such as tocilizumabr121 and sarilumabr122; Janus kinase inhibitors such as baricitinibr123 and tofacitinibr124)

  • Baricitinib (a Janus kinase inhibitor)
    • Baricitinib is FDA-approved for the treatment of COVID-19 in hospitalized adults requiring supplemental oxygen, noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation r125
      • FDA reviewed data from the ACTT-2 trial (Adaptive COVID-19 Treatment Trial 2), which compared remdesivir plus baricitinib (515 patients) against remdesivir plus placebo (518 patients) in patients with documented SARS-CoV-2 infection and either pulmonary infiltrates, oxygen saturation less than 94%, or requirement for some degree of oxygen supplementation. Patients who received baricitinib were more likely to have better clinical status (based on an 8-point score) at day 15 than those who did not. Median time to recovery was 7 days in the baricitinib group versus 8 days in the placebo group. The odds of dying or progressing to noninvasive/high-flow oxygen or invasive ventilation were significantly lower for patients in the baricitinib group r126r127
      • In another phase 3 randomized trial of hospitalized adults with documented SARS-CoV-2 infection, pneumonia or active and symptomatic COVID-19, and at least 1 elevated inflammatory marker who were receiving standard of care, including corticosteroids and/or antivirals, there was no significant difference in disease progression (defined as progression to high-flow oxygen, noninvasive mechanical ventilation, invasive mechanical ventilation, or death) with baricitinib (764 patients) versus placebo (761 patients). However, the 28-day all-cause mortality was significantly lower in patients treated with baricitinib (8%) compared with placebo (13%), a 38.2% relative reduction in mortality r128
      • NIH guidelines recommend use of baricitinib (or tocilizumab) with dexamethasone alone or with remdesivir and dexamethasone in recently hospitalized patients on high-flow oxygen or noninvasive ventilation who have clinical or laboratory evidence of progressive disease (eg, increasing oxygen needs, increasing inflammatory markers) r2
        • Guideline recommends against giving tocilizumab or other interleukin-6 inhibitors to patients on baricitinib
        • There is insufficient evidence to recommend baricitinib over tocilizumab or vice versa for this indication
      • NIH further recommends use of baricitinib (with dexamethasone) for hospitalized patients who need high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation; due to a stronger evidence base, the recommendation for baricitinib is stronger than for tocilizumab, which is an alternative
      • Infectious Diseases Society of America guidelines suggest use of baricitinib in hospitalized patients with severe COVID-19 along with corticosteroids (unless contraindicated) or remdesivir in patients who cannot receive a corticosteroid r100
        • Patients receiving baricitinib should not receive tocilizumab or other interleukin-6 inhibitors
        • Some data suggest a reduction in mortality even in patients who require mechanical ventilation
      • WHO guideline strongly recommends baricitinib for patients with severe or critical disease; choice of baricitinib versus interleukin-6 blockers should be based on clinical factors and availability r101
  • Tocilizumab (monoclonal interleukin-6 receptor blocker)
    • NIH guidelines recommend use of tocilizumab as follows: r2
      • Use tocilizumab (or baricitinib) with remdesivir and dexamethasone or with dexamethasone alone in recently hospitalized patients on high-flow oxygen or noninvasive ventilation who have clinical or laboratory evidence of progressive disease (eg, increasing oxygen needs, increasing inflammatory markers)
        • There is insufficient evidence to recommend tocilizumab over baricitinib or vice versa for this indication
      • In patients receiving high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation, use tocilizumab (with dexamethasone) as an alternative to baricitinib (which currently has more evidence than tocilizumab)
        • Best initiated within 24 hours of admission to ICU
      • Guideline recommends against giving baricitinib to patients on tocilizumab
      • A systematic review and meta-analysis of retrospective trials with data from 240 patients who received tocilizumab and 352 controls concluded that the low-quality evidence available did not demonstrate clear benefit from tocilizumab r129
      • A review of data from 5 randomized controlled trials comparing tocilizumab to usual care (with or without placebo) did not show a 28-day mortality benefit, but it did show a lower relative risk of clinical deterioration (ie, ICU admission, mechanical ventilation, death), although evidence was of low certainty r100
      • REMAP-CAP and RECOVERY trials both indicate a mortality benefit for tocilizumab among patients who experienced rapid respiratory decompensation and were recently admitted to the ICU, and the RECOVERY trial showed benefit in those who require high-flow oxygen or noninvasive ventilation r130r131
    • In patients admitted to hospital with COVID-19, Infectious Diseases Society of America suggest tocilizumab in addition to standard care (steroids) for patients with progressive severe or critical COVID-19 who have elevated levels of markers of systemic inflammation r100
    • WHO guidelines recommend use of tocilizumab (or sarilumab) for patients with severe or critical COVID-19, along with corticosteroids r101
  • Sarilumab (monoclonal interleukin-6 receptor blocker)
    • NIH guidelines recommend use of sarilumab (along with dexamethasone or dexamethasone plus remdesivir) when baricitinib and tocilizumab are unavailable for recently hospitalized patients on high-flow oxygen or noninvasive ventilation who have clinical or laboratory evidence of progressive disease (eg, increasing oxygen needs, increasing inflammatory markers) r2
    • NIH guideline also recommends use of sarilumab when baricitinib and tocilizumab are unavailable for hospitalized patients requiring high-flow oxygenation, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation r2
    • WHO guidelines recommend use of sarilumab (or tocilizumab) for patients with severe or critical COVID-19, along with corticosteroids; choice of interleukin-6 inhibitor or Janus kinase inhibitor depends on availability and clinical factors r101
    • REMAP-CAP trial found that sarilumab plus dexamethasone was noninferior to tocilizumab plus dexamethasone, but evidence for use of tocilizumab is more extensive r2r130
  • Tofacitinib (a Janus kinase inhibitor)
    • Infectious Diseases Society of America guidelines suggest use of tofacitinib in hospitalized patients with severe but noncritical COVID-19 (ie, not on mechanical ventilation), along with remdesivir and corticosteroids (unless contraindicated) r100
      • Patients should also receive at least prophylactic dose of anticoagulant
      • Patients receiving tofacitinib should not receive tocilizumab or other interleukin-6 inhibitors
    • NIH guidelines recommend use of tofacitinib (along with dexamethasone or dexamethasone plus remdesivir) when baricitinib and tocilizumab are unavailable for recently hospitalized patients on high-flow oxygen or noninvasive ventilation who have clinical or laboratory evidence of progressive disease (eg, increasing oxygen needs, increasing inflammatory markers) r2
    • NIH guideline also recommends use of tofacitinib when baricitinib and tocilizumab are unavailable for hospitalized patients requiring high-flow oxygenation, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation r2
    • WHO guideline suggests against use of tofacitinib or ruxolitinib (another Janus kinase inhibitor) unless baricitinib, tocilizumab, and sarilumab are unavailable, owing to limited evidence r101
  • Surviving Sepsis Campaign guideline on managing critically ill adults with COVID-19 does not address immunomodulators r92r93
  • Monoclonal antibodies against GM-CSF (granulocyte-macrophage colony-stimulating factor), such as lenzilumab, mavrilimumab, namilumab, gimsilumab, and otilimab, are under investigation and are not currently recommended under any guidelines r2r100

Systemic corticosteroid therapy is suggested or recommended for hospitalized patients with an oxygen requirement r29

  • A randomized controlled trial in more than 6000 hospitalized patients with COVID-19 found that dexamethasone reduced deaths in patients with severe respiratory complications requiring supplemental oxygen r1r132
    • Compared with usual care alone, deaths in ventilated patients receiving usual care plus dexamethasone were reduced by a third; among patients receiving oxygen without mechanical ventilation, deaths were cut by 20%
    • Overall 28-day mortality was reduced by 17% in the dexamethasone group
  • Since that time, multiple randomized trials show improved outcomes, including mortality, in hospitalized patients requiring oxygen; in contrast, systemic corticosteroids for patients not needing oxygen do not improve outcomes and may cause harm r2
  • NIH treatment guideline recommends use of dexamethasone in any hospitalized patient who requires supplemental oxygen, and recommends against use of dexamethasone in patients who do not require oxygen supplementation r2
    • In the absence of dexamethasone, another glucocorticoid (eg, prednisone, methylprednisolone, hydrocortisone) may be used
  • Similarly, Infectious Diseases Society of America guideline suggests use of dexamethasone in hospitalized patients with severe illness, and recommends use in those with critical illness r100
    • Infectious Diseases Society of America suggests against the use of steroids in patients who have no oxygen requirement
    • Guideline provides equivalent doses of alternative glucocorticoids if dexamethasone is unavailable
  • Surviving Sepsis Campaign guideline on managing critically ill adults with COVID-19 strongly recommends using corticosteroids (preferably dexamethasone) for up to 10 days in patients with severe or critical COVID-19 r92r93
  • WHO recommends use in patients with severe and critical COVID-19, and suggests against use in patients with nonsevere COVID-19 r29r101
  • Inhaled corticosteroids are not recommended by guidelines r2r100

Antithrombotic therapy

  • COVID-19 is associated with inflammation and prothrombotic state, including macrovascular and microvascular thromboembolism in both the venous and arterial vessels, as well as disseminated intravascular coagulation r2r93r133r134
  • The most current guidelines to address antithrombotic therapy are 3 guidelines from NIH, the American Society of Hematology, and the American College of Chest Physicians. Recommendations are summarized below: r2r135r136r137r138
    • For prophylaxis in acutely ill adults: r2r135r137
      • Therapeutic-dose heparin is recommended or suggested over prophylactic-dose heparin for nonpregnant hospitalized adults with low risk for bleeding in both the American Society of Hematology guidelines and the American College of Chest Physicians guidelines; NIH guideline specifies that therapeutic dose should be reserved for patients with an elevated D-dimer level and that other hospitalized patients should receive prophylactic dose
      • NIH guideline recommends prophylactic-dose heparin in hospitalized pregnant patients; other guidelines do not address anticoagulation in pregnancy
    • For prophylaxis in critically ill adults: r2r136r137
      • Prophylactic-dose heparin is recommended or suggested over intermediate-dose or therapeutic-dose for adults in the ICU, including a recommendation to switch from therapeutic to prophylactic dose in patients transferred to an ICU unless a thrombosis has been documented
    • For prophylaxis in children: r2
      • NIH guideline recommends prophylactic-dose heparin for hospitalized children aged 12 years or older; there is insufficient evidence to recommend for or against anticoagulation in children younger than 12 years, or to recommend for or against doses other than prophylactic-intensity
    • Prophylactic therapy is not recommended for nonhospitalized patients or as postdischarge therapy after hospitalization in patients without thromboembolic disease r2r137r138
    • Standard therapeutic treatment is recommended for patients with COVID-19 and thromboembolism (highly suspected or proven), for those on extracorporeal membrane oxygenation or continuous renal replacement therapy, and for those who have thrombosis related to catheters or extracorporeal filters r2
    • Generally, low-molecular-weight heparin is preferred over unfractionated heparin, and heparin is preferred over oral anticoagulants; evidence is limited regarding use of fondaparinux, argatroban, bivalirudin, or other medications r2r135r136
    • Risk of bleeding is increased in the following situations:
      • Bleeding within the past 30 days that required an emergency department visit or hospitalization, or gastrointestinal bleeding within the past 3 months
      • History of inherited or acquired bleeding disorder
      • Thrombolysis within the past 7 days or major surgery within the past 14 days
      • Platelet count less than 50 × 10⁹ cells/L; hemoglobin level less than 8 g/dL; or baseline INR more than 2 or activated partial thromboplastin time more than 50 seconds
      • Dual antiplatelet therapy
      • Ischemic stroke, intracranial hemorrhage, or intracranial malignancy
      • Uncontrolled hypertension (systolic more than 200 mm Hg or diastolic more than 120 mm Hg)
      • Presence of epidural or spinal catheter
    • Risk of thrombosis is increased in those with elevated D-dimer levels, prior venous thromboembolism, or additional known risk factors for venous thromboembolism

Convalescent plasma continues to be investigated; only high-titer formulations have shown any benefitr139

  • Infectious Diseases Society of America suggests use of high-titer convalescent plasma in ambulatory patients with mild to moderate disease at high risk of progression who have no other treatment options. It recommends against use in hospitalized patients r100
  • Surviving Sepsis Campaign guideline on managing critically ill adults with COVID-19 suggests that convalescent plasma not be used outside of clinical trials r93
  • NIH COVID-19 treatment guideline recommends against use of convalescent plasma in most situations, except in a clinical trial, and recommends against use of convalescent plasma that was collected before the emergence of the Omicron variant r2
    • There is insufficient evidence to recommend for or against use of convalescent plasma that was collected after the emergence of the Omicron variant (in hospitalized patients with impaired immunity, or nonhospitalized patients)
  • WHO strongly recommends against use of convalescent plasma in nonsevere disease, and recommends against use in severe or critical disease outside of a clinical trial r101
  • FDA has issued and revised an emergency use authorization, citing, among other reasons, the observational safety and efficacy data from 20,000 patients who received convalescent plasma through a program sponsored by the Mayo Clinic: r140r141
    • Serious adverse events were uncommon, and they were judged not to exceed the known incidence in transfusion of plasma to critically ill patients
    • There was some evidence of improved survival in the subset of patients treated with convalescent plasma containing higher titers of neutralizing antibody compared with patients who received plasma with lower levels (ie, there appeared to be a dose-response gradient)
      • Expanded access use focuses on high-titer product used in patients with immunosuppressive disease or receiving immunosuppressive treatment
    • Early administration (eg, before mechanical ventilation is required) appeared more likely to be beneficial, but the possibility of benefit even to intubated patients could not be excluded

Several medications with a mechanism of action which could potentially alter response to COVID-19 have been evaluated either for use in treatment and prevention, or for discontinuation to prevent harms r142

  • NIH guidelines recommend that patients taking ACE inhibitors, angiotensin receptor blockers, statin drugs, NSAIDs, corticosteroids (oral, inhaled, or intranasal), and acid suppressive drugs for underlying medical conditions should not discontinue these medications r2r143r144
    • In addition, none of the above classes of medications should be started for the purpose of treatment or prevention of COVID-19, except as noted above for corticosteroid treatment
    • Infectious Diseases Society of America guidelines similarly do not recommend initiating or discontinuing any of the above medications for treatment or prevention of COVID-19 r100
  • Decisions regarding discontinuing or lowering dosage of chronic immunosuppressive medications in patients with COVID-19 should be made in consultation with relevant specialists r2

Other options not currently recommended under NIH, Infectious Diseases Society of America, and WHO guidelines (although some are still under study in clinical trials) r2r100r101

  • Numerous medications have been proposed or attempted for treatment and prevention of COVID-19 based on mechanism of action
  • Detailed evidence for the recommendations not to use these medications is available in one or more of the guidelines r2r100r101
  • Avoid use of the following (unless participating in a clinical trial):
    • Azithromycin
    • Chloroquine and hydroxychloroquine
    • Colchicine
    • Famotidine
    • Fluvoxamine
    • HIV medications, including lopinavir-ritonavir
    • Immunomodulators other than those mentioned earlier, such as the Janus kinase inhibitor ruxolitinib; the interleukin-6 inhibitor siltuximab; interleukin-1 inhibitors; Bruton's tyrosine kinase inhibitors; and GM-CSF inhibitors (against granulocyte-macrophage colony-stimulating factor)
    • Interferons
    • IV immunoglobulin (except as indicated for multisystem inflammatory syndrome)
    • Ivermectin
    • Mesenchymal stem cells
    • Nitazoxanide
    • Vitamin C, vitamin D, and zinc supplements

Drug therapy

  • Antiviral agents c254
    • Remdesivir
      • For patients requiring oxygen but NOT invasive mechanical ventilation and/or extracorporeal membrane oxygenation
        • Remdesivir Solution for injection; Adults NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO): 200 mg IV once on day 1, followed by 100 mg IV once daily for 4 days; may extend treatment for up to 5 additional days if no clinical improvement. The NIH recommends treatment for 5 days or until hospital discharge.
      • Dosages for patients who REQUIRE mechanical ventilation or extracorporeal membrane oxygenation have been established r95r145d4
        • Remdesivir Solution for injection; Adults requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO): 200 mg IV once on day 1, followed by 100 mg IV once daily for 9 days. The NIH recommends against starting remdesivir, but treatment may be continued (in combination with dexamethasone) in patients who progress to mechanical ventilation or ECMO.
      • 3-day regimen for persons with mild to moderate disease at high risk for progression
        • Remdesivir Solution for injection; Adults: 200 mg IV once on day 1, followed by 100 mg IV once daily for 2 days.
    • Nirmatrelvir-ritonavir
      • Nirmatrelvir Oral tablet, Ritonavir Oral tablet; Adults weighing 40 kg or more: 300 mg nirmatrelvir (two 150 mg tabs) and 100 mg ritonavir (one 100 mg tab) taken together by mouth twice daily for 5 days. Start as soon as possible after the positive test for SARS-CoV-2 and within 5 days of symptom onset.
    • Molnupiravir
      • Molnupiravir Oral capsule; Adults: 800 mg PO every 12 hours for 5 days. Start as soon as possible and within 5 days of symptom onset.
  • Monoclonal antibodies with antiviral action
    • Tixagevimab and cilgavimab in combination
      • Cilgavimab Solution for injection, Tixagevimab Solution for injection; Children and Adolescents 12 years and older weighing 40 kg or more: 300 mg tixagevimab and 300 mg cilgavimab given as 2 separate consecutive IM injections. For persons who received the previously authorized lower dose, give an additional 150 mg tixagevimab and 150 mg cilgavimab dose as soon as possible if the initial dose was within the past 3 months; if the initial dose was more than 3 months ago, give 300 mg tixagevimab and 300 mg cilgavimab as soon as possible. If ongoing protection is required, repeat dosing of 300 mg tixagevimab and 300 mg cilgavimab may be administered every 6 months. Time repeat dosing from the date of the most recent dose.
      • Cilgavimab Solution for injection, Tixagevimab Solution for injection; Adults weighing 40 kg or more: 300 mg tixagevimab and 300 mg cilgavimab given as 2 separate consecutive IM injections. For persons who received the previously authorized lower dose, give an additional 150 mg tixagevimab and 150 mg cilgavimab dose as soon as possible if the initial dose was within the past 3 months; if the initial dose was more than 3 months ago, give 300 mg tixagevimab and 300 mg cilgavimab as soon as possible. If ongoing protection is required, repeat dosing of 300 mg tixagevimab and 300 mg cilgavimab may be administered every 6 months. Time repeat dosing from the date of the most recent dose.
    • Bebtelovimab
      • Bebtelovimab Solution for injection; Adults: 175 mg as a single intravenous injection. Administer as soon as possible after positive test for SARS-CoV-2 and within 7 days of symptom onset.
  • Immunomodulators
    • Baricitinib c255
      • Baricitinib Oral tablet; Adults: 4 mg PO once daily for 14 days or until hospital discharge, whichever comes first. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    • Tocilizumab c256
      • Tocilizumab Solution for injection; Adults: 8 mg/kg (Max: 800 mg/dose) IV infusion once with a systemic corticosteroid. If symptoms worsen or do not improve, 1 additional dose may be administered at least 8 hours after the first.
    • Sarilumab c257
      • Sarilumab Solution for injection; Adults: The NIH COVID-19 treatment guidelines recommend a single 400 mg IV dose given with dexamethasone (with or without remdesivir) to treat hospitalized adults on supplemental oxygen, IF exhibiting signs of systemic inflammation and rapidly increasing oxygen needs. Also, may be given with dexamethasone for patients on high-flow oxygen, noninvasive ventilation, mechanical ventilation, or ECMO. Sarilumab is an alternative if tocilizumab is not available or cannot be used.
    • Tofacitinib
      • Tofacitinib Oral tablet; Adults: The NIH COVID-19 treatment guidelines recommend 10 mg PO twice daily for up to 14 days or until hospital discharge (whichever comes first) to treat hospitalized adults on supplemental oxygen, including noninvasive ventilation, high-flow oxygen, mechanical ventilation, or ECMO. MUST be given with dexamethasone (with or without remdesivir). Tofacitinib is an alternative if baricitinib is not available or cannot be used.
  • Corticosteroid
    • Dexamethasone c258
      • Dexamethasone Sodium Phosphate Solution for injection; Adults: 6 mg IV once daily for up to 10 days or until hospital discharge (whichever comes first) for hospitalized patients who require supplemental oxygen, including those on high-flow oxygen, noninvasive ventilation, mechanical ventilation, or ECMO.
    • Various guidelines provide recommendations for alternative glucocorticoids if dexamethasone is not available r2r100
      • Methylprednisolone c259
        • Methylprednisolone Sodium Succinate Solution for injection; Adults: 8 mg IV every 6 hours or 16 mg IV every 12 hours for 7 to 10 days. The WHO strongly recommends systemic corticosteroids in patients with severe or critical COVID-19. The NIH recommends methylprednisolone as an alternative corticosteroid for hospitalized patients who require supplemental oxygen, including those on high-flow oxygen, noninvasive ventilation, mechanical ventilation, or ECMO. The NIH recommends 32 mg IV once daily (or in 2 divided doses) for up to 10 days or until hospital discharge (whichever comes first). Before starting therapy, review the patient's medical history and assess the potential risks and benefits.
      • Prednisone c260
        • Prednisone Oral tablet; Adults: 40 mg PO daily for 7 to 10 days. The WHO strongly recommends systemic corticosteroids in patients with severe or critical COVID-19. The NIH recommends prednisone as an alternative corticosteroid for hospitalized patients who require supplemental oxygen, including those on high-flow oxygen, noninvasive ventilation, mechanical ventilation, or ECMO. The NIH recommends 40 mg PO once daily (or in 2 divided doses) for up to 10 days or until hospital discharge (whichever comes first). Before starting therapy, review the patient's medical history and assess the potential risks and benefits.

Nondrug and supportive care c261

  • Excellent supportive care remains the mainstay of treatment to date in COVID-19 c262
  • WHO,r29NIH,r2 and Surviving Sepsis Campaignr92 provide specific guidance for oxygenation, ventilation, and fluid management in COVID-19 d4
    • Patients with severe respiratory distress, obstructed or absent breathing, central cyanosis, shock, seizures, or coma require aggressive airway management (which may include intubation) and oxygen d4
    • Oxygenation and ventilation c263
      • Begin supplemental oxygen therapy when oxygen saturation falls below 90% to 92% r92
      • Nasal cannula at 5 L/minute or face mask with reservoir bag at 10 to 15 L/minute r29
        • Titrate to reach SpO₂ of 94% or more initially
        • Once stable, target SpO₂ of 90% or higher in nonpregnant adults; 92% or higher in pregnant patients
        • In most children the target SpO₂ is 90% or greater; for those who require urgent resuscitation (eg, those with apnea or obstructed breathing, severe respiratory distress, central cyanosis, shock, seizures, or coma), a target SpO₂ of 94% or higher is recommended
      • High-flow nasal oxygen or noninvasive ventilation has been used to achieve adequate oxygenation in some patients r146c264c265c266c267c268
        • High-flow nasal oxygen is recommended by Surviving Sepsis Campaignr92 and NIHr2 for patients with COVID-19 who develop hypoxemic respiratory failure despite conventional oxygen therapy; there is some evidence that it averts the need for intubation and mechanical ventilation. Noninvasive positive pressure ventilation may be used if high-flow nasal oxygen is not available
        • However, there is concern that these techniques may result in higher risk of aerosolization of the virus. Additionally, sudden deterioration may require emergent intubation, which is associated with more risk to both patient and provider. Therefore, some authorities reserve these options for settings in which airborne precautions can be taken and close monitoring provided r92
      • Mechanical ventilation may become necessary for patients in whom oxygenation targets cannot be met with less invasive measures or who cannot maintain the work of breathing (eg, PaO₂/FIO₂ ratio of less than 300 mm Hg)r76c269
        • Although optimal technique has not been fully defined, COVID-19–specific recommendations are emerging d4
      • Extracorporeal membrane oxygenation has been usedr15 in severely ill patients, and it can be considered if resources and expertise are available c270
    • Fluid management
      • Overhydration should be avoided, because it may precipitate or exacerbate acute respiratory distress syndrome c271
      • An assessment of likely fluid responsiveness may be made by measuring the change in cardiac output (by echocardiography or transpulmonary thermodilution) on passive leg raise; an increase in cardiac output after 1 minute of passive leg raise has been shown to be a reliable predictor of response and helps to avoid overhydration in patients unlikely to respond r147

Comorbidities

  • Severe COVID-19 has been associated with chronic conditions such as diabetes, hypertension, and other cardiovascular conditions r2c272c273c274
  • Owing to the role of the ACE2 receptor in the pathogenesis of COVID-19, controversy arose at the start of the pandemic regarding the positive or negative effects that ACE inhibitors and angiotensin receptor blockers may have on the disease. A joint statement by the American College of Cardiology, American Heart Association, and Heart Failure Society of Americar148 recommends that persons who are currently taking these medications for appropriate indications should continue to do so; the NIH guidelines for treatmentr2 concur
    • Several analyses of data from large numbers of patients with COVID-19 have shown no association between ACE inhibitors or angiotensin receptor blockers and either acquisition of COVID-19 or severity of infection r149r150r151r152r153r154
    • A prospective cohort study based on routinely collected data from more than 8 million persons enrolled in general practices in England identified more than 19,000 persons with COVID-19. Use of ACE inhibitors or angiotensin receptor blockers was associated with reduced risk of COVID-19 disease and was not associated with increased risk of requiring intensive care. The reduction in risk was less for Black people of Caribbean and African descent r155

Special populations

  • Pregnant patients
    • Pregnant patients are at higher risk for severe disease (including increased risk for hospitalization, requiring mechanical ventilation, and death) and for adverse pregnancy outcomes (eg, preterm birth, stillbirth) r156
    • Vaccination is recommended for pregnant persons and those who may become pregnant, by the CDC, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine r2r156r157r158
    • American College of Obstetricians and Gynecologists recommends that the mode of delivery be determined based on obstetric indications and patient preference; cesarean delivery is recommended only for the usual medically justified indications r159
    • There is little evidence to suggest vertical transmission;r159r161r29 however, an infected mother may transmit the virus by the airborne route to the neonate. CDC and WHO differ somewhat in their recommendations r160
      • Because of concerns for transmission, CDC has recommended that separation of neonates from mothers known or suspected to have COVID-19 can be considered until isolation can be discontinued per usual protocol. The decision is best individualized in consultation with patient wishes. If temporary separation is chosen, breast milk may be pumped and fed to the infant by another caregiver r160
      • Focusing on ensuring successful initiation of breastfeeding, WHO advises that postpartum females and their neonates room in (cohabit), including the practice of skin-to-skin and kangaroo care r29
  • Breastfeeding patients r162
    • Vaccination is recommended
    • People without suspected or confirmed COVID-19 and who have not been in close contact with someone who has COVID-19, or who have received a COVID-19 vaccine, do not need to take special precautions when feeding at the breast or expressing milk
    • A breastfeeding person who is not fully vaccinated against COVID-19 should take precautions to protect themselves and the breastfed child when either of them has suspected or confirmed COVID-19
      • CDC strongly recommends vaccination for adults, with few contraindications
  • Patients with HIV
    • Vaccination is recommended r2r163
    • Well-controlled HIV infection may not alter risk for infection or severe outcome. Advanced HIV infection (eg, CD4 count less than 200 cells/mm³) may increase the risk for severe disease or complications r54r163
    • It is recommended that patients continue their current antiretroviral regimen; specifically, empiric addition of lopinavir-ritonavir (for possible efficacy against or protection from SARS-CoV-2) is not recommended outside of a clinical trial
    • A guideliner163 by the US Department of Health and Human Services offers strategies for ensuring continuity of antiretroviral medication
    • Recommendations for management of patients with HIV who develop COVID-19 do not differ from standard recommendations
    • Potential for drug interactions may complicate eligibility for enrollment in a clinical trial for COVID-19 or treatment; drug interaction checkerr89 is recommended

Monitoring

  • Patients who do not require admission should self-monitor temperature and symptoms, and they should return for reevaluation if symptoms worsen; deterioration may occur a week or morer165 into the course of illness and may be quite abrupt r164c275
  • In hospitalized patients with confirmed COVID-19, repeated testing may be done to document clearance of virus, defined as 2 consecutive negative results on testing at least 48 hours apart r90c276

Complications and Prognosis

Complications

  • Most common complication is acute respiratory distress syndrome; other reported complications include: r15r16c277d5
  • MIS-C (multisystem inflammatory syndrome in children) has been associated with recent diagnosis of or exposure to COVID-19. A number of young adultsr170 have also been reported with similar clinical findings and recent history of diagnosed COVID-19 or serologic evidence of recent infection, termed MIS-A (multisystem inflammatory syndrome in adults) r167r168r169c288d8
    • Characteristic features in children include: r169r171
      • Persistent fever c289
      • Hypotension, syncope, confusion c290c291c292c293
      • Headache c294
      • Sore throat, neck swelling c295c296c297c298c299
      • Cough, hypoxemia c300
      • Abdominal pain, vomiting, diarrhea c301c302c303c304
      • Rash, conjunctival injection, mucosal inflammation c305c306c307c308c309
      • Swelling of hands and feet c310
      • Lymphadenopathy c311c312c313
      • Laboratory markers of inflammation (eg, elevated erythrocyte sedimentation rate; elevated levels of C-reactive protein, ferritin, D-dimer, fibrinogen, procalcitonin, lactate dehydrogenase, interleukin-6, and interleukin-10; low level of serum albumin) c314c315c316
      • Abnormal blood cell counts: anemia, thrombocytopenia, neutrophilia c317c318c319c320c321
      • Indicators of multiorgan involvement: increased levels of creatinine, BUN, urine protein, transaminases, creatine kinase, troponins, and lactate dehydrogenase c322
      • Imaging
        • Chest radiograph or CT scan: bilateral patchy pulmonary infiltrates, pleural effusions
        • Echocardiogram: pericardial effusion, myocardial dysfunction, valvulitis, coronary artery dilatation
        • Abdominal ultrasonography: ascites, colitis, ileitis, hepatosplenomegaly, lymphadenopathy
    • In a systematic review covering 221 adults with MIS-A, the age range was 19 to 34 years; 70% were male; and Black and Hispanic people were disproportionately affected r172
      • Common features included fever, hypotension, cardiac dysfunction, shortness of breath, and diarrhea, along with laboratory evidence of coagulopathy and/or inflammation
      • Median number of organ systems involved was 5
      • Most patients (57%) required ICU care, and 7% died
    • Diagnosis is based on clinical presentation and absence of an alternative explanation; CDCr169 and WHOr173 provide case definitions for reporting
      • CDC MIS-C case definition: a person younger than 21 years with fever, laboratory evidence of inflammation (see above), and clinically severe illness requiring hospitalization, with involvement of 2 or more organ systems; plus no alternative diagnosis; plus current or recent COVID-19 or exposure within the past 4 weeks r169
        • Patients may meet partial or full criteria for Kawasaki disease but regardless should be reported if they meet case definition of MIS-C d9
      • CDC MIS-A case definition: a person aged 21 years or older with hospitalization for 24 hours or more, or an illness resulting in death, with clinical and laboratory criteria below, and with no alternative diagnosis: r168
        • Clinical: fever and at least 3 of the following criteria before hospitalization or within the first 3 days of hospitalization, including at least 1 primary criterion
          • Primary: severe cardiac illness (eg, myocarditis, pericarditis, coronary artery aneurysm, new-onset ventricular dysfunction, new-onset second- or third-degree atrioventricular block, new-onset ventricular tachycardia); rash and nonpurulent conjunctivitis
          • Secondary: new-onset neurologic dysfunction (eg, seizures, encephalopathy, meningeal signs, peripheral neuropathy, Guillain-Barré syndrome); shock or hypotension not attributable to medical treatment; abdominal pain, vomiting, or diarrhea; thrombocytopenia with count less than 150,000 cells/mm³
        • Laboratory: at least 2 of the following markers are elevated: C-reactive protein, ferritin, interleukin-6, erythrocyte sedimentation rate, procalcitonin; plus positive polymerase chain reaction, antigen, or serology test result for COVID-19
    • It may be difficult to distinguish this syndrome from Kawasaki disease or toxic shock syndrome; bacterial sepsis must also be considered and appropriate cultures obtained (including blood cultures) d10
    • Several professional organizations provide guidance on management r2r171r174
      • Cardiac (telemetry) and blood pressure monitoring; continuous pulse oximetry
      • Prompt ECG and echocardiogram, with serial follow-up studies
      • Close clinical and laboratory monitoring for progressive inflammation and cardiac involvement, including levels of C-reactive protein, troponins, and B-type natriuretic peptide
      • Empiric antibiotic coverage pending culture results
      • Hospitalized children and those who fulfill criteria for Kawasaki Disease should be treated with immunomodulatory and antithrombotic therapy d8
        • First line treatment is IV immunoglobulin and glucocorticoids
          • Volume associated with IV immunoglobulin requires careful monitoring in patients with cardiac dysfunction
          • Anakinra, infliximab, or higher-dose glucocorticoids should be given to those who do not respond after initial therapy
            • Unlike in Kawasaki disease, a second dose of IV immunoglobulin is not recommended in refractory disease, owing to risk of volume overload and hemolytic anemia
        • Low-dose aspirin for all patients without risk factors for bleeding, continued for at least 4 weeks until normal coronary arteries and normal platelet count are confirmed
        • In addition to aspirin, therapeutic anticoagulation should be given to patients with large coronary artery aneurysms, documented thrombosis, or moderate to severe left ventricular dysfunction (ejection fraction less than 35%) without risk factors for bleeding
        • Prophylactic or therapeutic anticoagulation should also be considered according to increased risk for thrombosis (eg, indwelling catheterization, age older than 12 years, malignancy, ICU admission, elevated D-dimer level)
      • Treatment for MIS-A has primarily been extrapolated from treatment of MIS-C

Prognosis

  • Although most people with COVID-19 have mild to moderate disease, up to 20% may have severe illness (estimated 14%) or critical illness (estimated 5%) r17r175
    • Risk of severe or critical illness depends on age, underlying comorbidities, and vaccination status r17r59r175
    • Patients who require hospital admission often require prolonged inpatient stay (more than 20 days) and experience significant deconditioning r15r16
    • Risk scoring systems continue to be developed and revised at many institutions, in the effort to improve prediction of disease progression (to severe or critical illness), mortality, or both (with those concepts being correlated). To date no single scoring system has emerged as dominant in clinical use across institutions r176
  • Infection fatality ratio (proportion of deaths among all who are infected, including confirmed cases, undiagnosed cases, and unreported cases) varies across global locations, but it has been estimated as 0.15% r177
    • CDC currently estimates the infection fatality ratio by age as follows: r178
      • 0 to 17 years: 0.002%
      • 18 to 49 years: 0.05%
      • 50 to 64 years: 0.6%
      • 65 years or older: 9%
  • Mortality rate of diagnosed cases is generally about 3% but varies by country r3r4
    • Case fatality rates (proportion of deaths among detected cases; subject to selection bias owing to higher testing in hospitalized cases)
      • These rates are higher for patients in older age groups and with certain comorbidities
      • Case fatality rates by age in the United States: r51
        • 10% to 27% for those aged 85 years or older
        • 3% to 11% for those aged 65 to 84 years
        • 1% to 3% for those aged 55 to 64 years
        • Less than 1% for those aged 0 to 54 years
      • Case fatality rates for disease in Chinese patients with common comorbidities: r165
        • 10.5% for cardiovascular disease
        • 7.3% for diabetes
        • 6.3% for chronic respiratory disease
        • 5.6% for cancer
  • Risk of reinfection
    • Recovery from infection is associated with short-term protective immunity, but reinfection has been documented, especially after 90 days from infection r165r179
      • Vaccination in persons who have already had COVID-19 may reduce the risk of reinfection (data are limited but encouraging) r180
    • Risk of reinfection may be increased with exposure to variant strains, although data are limited
  • Risk of breakthrough infection (ie, infection despite vaccination) r181
    • Breakthrough infection is common, but explain to patients and families that this fact does not negate the value of vaccination, which lies in improved course of disease in most vaccinated people, yielding the following benefits:
      • Greatly reduced risk of progression to severe or critical disease r182
      • Greatly reduced risk of death r182
      • Lessened community transmission (ie, meaningfully reduced albeit not eliminated, leading to lesser burden of disease and death in population)
  • Risk of postacute or chronic complications
    • A substantial proportion of patients, including some who had mild or asymptomatic infection, experience persistent symptoms and prolonged recovery more than 4 weeks from onset of COVID-19. This syndrome is known by many names, including long COVID, postacute COVID-19, chronic COVID, or PASC (postacute sequelae of SARS-CoV-2 infection) r183r184r185
      • Most common symptoms (symptoms may be new or persistent since infection):
        • Shortness of breath
        • Fatigue, which may be profound and may be sharply exacerbated by even mild exertion (postexertional malaise)
        • Low-grade fever, which may come and go
        • Joint and/or muscle pain
        • Chest pain
        • Cough
        • Headache
        • Cognitive dysfunction
        • Palpitations
        • Paresthesia
        • Abdominal pain or diarrhea
        • Mood changes
        • Menstrual irregularities
        • Impaired senses of smell or taste (reduced, altered, or absent): hyposmia, anosmia; dysgeusia (parageusia, ageusia, hypogeusia)
      • Research is ongoing; specialized clinics are opening in many locations, and guidance is being developed for evaluation and care of these patients r186
    • Evidence is emerging of increased risk for other sequelae after COVID-19 infection (even mild or asymptomatic infection)
      • Risk of all-cause mortality is elevated during 12 months after hospitalization for COVID-19; in studies, most of the deaths were not attributable to respiratory or cardiovascular conditions r187
      • In the 12 months after diagnosis of COVID-19, the risk of new-onset diabetes was increased 40% in a cohort of more than 270,000 adults (receiving care via the US Department of Veterans Affairs) r188

Screening and Prevention

Screening

At-risk populations

  • Health care workers
    • At increased risk because of occupational exposure; in turn, undetected infection in health care worker poses risk for nosocomial transmission to patients and coworkers
  • Residents of congregate care facilities
    • At increased risk owing to age, prevalence of comorbidities, and congregate setting
  • Patients presenting for care
    • Triage screening is recommended at points of medical care to identify patients with symptoms and exposure history that suggest the possibility of COVID-19, so that prompt isolation measures can be instituted r29r90
      • At least during high-prevalence phases of the pandemic, the following principles apply to the isolation areas:
        • Set up separate, well-ventilated triage areas; place patients with suspected or confirmed COVID-19 in private rooms with the door closed and with private bathrooms (as possible); many hospitals designate building wings to be dedicated to probable COVID-19 r90
        • Reserve airborne infection isolation rooms for patients with COVID-19 undergoing aerosol-generating procedures and for care of patients with pathogens transmitted by airborne route (eg, tuberculosis, measles, varicella) r90
    • Guidelines released by Infectious Diseases Society of America also recommend testing of asymptomatic persons in health care settings under the following circumstances, given sufficient testing supplies: r77
      • Admission to hospital for unrelated condition, if community prevalence is high
      • Immunosuppression, about to undergo immunosuppressive treatment, and on hospital admission (for any reason)
      • About to undergo major surgery that is time-sensitive
      • About to undergo aerosol-generating procedure that is time-sensitive and personal protective equipment is lacking; but if protective gear is adequate, then the guidelines recommend against routine testing in asymptomatic persons who are not known to have been exposed to COVID-19
      • About to undergo transplant (hematopoietic stem cell or solid organ)

Screening tests

  • Screening methods overview
    • Screening of asymptomatic persons in certain circumstances is an important method of interrupting transmission r60
      • Health equity should be a priority in determining which groups to screen, as minority populations have been disproportionately affected by COVID-19
      • Serial testing and frequent testing improve the ability of screening to detect infection and interrupt transmission; frequency may be determined by transmission levels, the risk of transmission, and tiers based on exposure
      • Examples of groups to consider for screening include:
        • Teachers, staff, and/or students in school or child care settings
        • Residents and staff of congregate care settings, such as long-term care facilities, homeless shelters, or correctional facilities
        • Patients in health care settings
        • Employees in occupations with high exposure to the public (eg, transportation workers, first responders, health care workers)
      • Currently there is no role for routine antibody screening (eg, testing all vaccinated persons for evidence of immunity). Antibody testing may be considered for public health purposes (eg, serologic survey of a population to assess for past infection), but it should not be used for diagnostic purposes r69
  • Screening in health care settings
    • Screening of patients, and subsequent triage to isolation and testing with polymerase chain reaction, is based on clinical presentation and exposure history: r29r60r90
      • Presence of COVID-19 symptoms (CDC, WHO) c323c324
      • Close contact with a person with known or suspected COVID-19 while that person was ill (WHO, CDC) c325
      • Work in a health care setting in which patients with severe respiratory illnesses are managed, without regard to place of residence or history of travel (WHO)
      • Unusual or unexpected deterioration of an acute illness despite appropriate treatment, without regard to place of residence or history of travel, even if another cause has been identified that fully explains the clinical presentation (WHO) c326
    • Health care facilities should also have a process for identifying visitors and staff who have symptoms of COVID-19, who have a positive COVID-19 test result, or who meet quarantine or isolation criteria r90
      • Visitors meeting any of the above criteria should be excluded from the facility
      • Health care workers with COVID-19 should follow symptom-based return-to-work guidelines; those with exposure may be able to continue working if asymptomatic, fully vaccinated, and following all guidelines for testing and personal protective equipment r189
      • Direct temperature screening is no longer considered necessary owing to lack of evidence of effectiveness
    • Screening tests (polymerase chain reaction or antigen testing) for asymptomatic patients may be indicated (eg, preadmission or preprocedure), but such testing may be low-yield during low- or moderate-transmission phases r90
    • Antigen testing may be useful for health care workers and for residents and staff of congregate care facilities r63
      • Serial testing (every 3 days or twice per week) can reduce disease transmission r190
      • During an outbreak in a facility, serial antigen testing is recommended every 3 to 7 days until there are no new cases for 14 days r63
      • Specific guidance is available for nursing homes and long-term care facilities r58
  • Screening in workplaces
    • All workers should be instructed to stay home and to report to their employer if they have a positive test result for COVID-19, symptoms of COVID-19, or, for unvaccinated workers, exposure to someone with COVID-19 r191
      • Fully vaccinated persons with no symptoms should be tested 3 to 5 days after known exposure, and should wear a mask for 14 days after exposure or until test results are negative; fully vaccinated persons with symptoms should be tested and isolated immediately r192
    • Certain workplaces have higher risk for rapid spread and should be considered for screening tests (polymerase chain reaction or antigen testing): r193
      • High-density workplaces where distancing is not feasible (eg, food processing plants)
      • Workplaces where employees live in congregate housing (eg, farms, fishing vessels)
      • Workplaces with populations at risk for severe illness (eg, homeless shelters, places with older workforces)
      • Universities, colleges, schools, and child care locations
    • Specific guidance is available for correctional facilities and homeless shelters r193
  • Screening in public places r194
    • Screening in public places with infrared thermometers (to detect fever) has been used in some regions but has limited sensitivity as a screening tool for infection; there is currently no evidence of effectiveness
    • Screening at travel hubs (eg, airports) with symptom assessments, direct temperature measurements, assessment of known exposure, or travel history, alone or in combinations, might slightly reduce transmission, but evidence for the effect size is of low certainty, and real-world evidence shows that such efforts have not prevented SARS-CoV-2 from crossing borders (regardless of whether they might help reduce case burden slightly)
    • Many locations have begun requiring proof of vaccination, recent negative result on COVID-19 testing (polymerase chain reaction or antigen), or both in order to enter (eg, countries, concert venues, sports arenas), but as yet there is no assessment of effectiveness; many locales have discontinued such requirements when pandemic surges are not underway

Prevention

  • Overview
    • Preventive measures include vaccination, public health interventions, and (in select populations) preexposure prophylaxis
  • Background on vaccinesc327
    • Vaccine authorizations and approvals: various vaccines against SARS-CoV-2 have entered use in many countries, and more are in development r195
      • After analyses of data, the vaccines in use have emergency, temporary, or full authorizations from various national regulatory authorities, and future authorizations and full approvals are pending
        • mRNA vaccines
          • Pfizer-BioNTech COVID-19 vaccine (BNT162b2; tozinameran; Comirnaty) has received emergency use authorization in the United States for ages 6 months to 11 years and full FDA approval for persons aged 12 years or older, and authorization or full approval in the United Kingdom, the European Union, Canada, and elsewhere r196r197r198r199c328
          • Moderna COVID-19 vaccine (mRNA-1273; Spikevax) has received emergency use authorization in the United States for ages 6 months to 17 years and full FDA approval for persons aged 18 years or older, and authorization or full approval in the United Kingdom, Canada, the European Union, and elsewhere r196r198r199r200c329
        • Adenovirus vector vaccines
          • Janssen (Johnson and Johnson) COVID-19 vaccine (Ad26.COV2.S; Jcovden) has authorization in the United States limited to people aged 18 years or older for whom other approved COVID-19 vaccines are unavailable or not clinically appropriate, or when elected by the recipient who would otherwise not be vaccinated; it also has authorization or full approval in Canada, the United Kingdom, the European Union, and elsewhere r196r198r199r201c330
          • AstraZeneca (Oxford-AstraZeneca) COVID-19 vaccine (ChAdOx1-S[recombinant]; Vaxzevria) has authorization or full approval in the United Kingdom, Canada, and the European Union r196r198r199c331
        • Protein subunit vaccine
          • Novavax COVID-19 Vaccine (Novavax recombinant, adjuvanted; Nuvaxovid) has received use authorization in the United States for people aged 12 years or older as a primary series, and is authorized or approved in the European Union, Canada, and elsewhere r196r198r202
        • Various other vaccines are in use in many other countries; WHO tracking of vaccine development lists hundreds of vaccines in either clinical development or preclinical phases r195c332c333
      • CDC has ongoing vaccine effectiveness monitoring r203
        • Efficacy of vaccine-induced immunity against infection wanes over time, but protection against severe disease, hospitalization, and death remains robust including against Omicron variants
      • WHO has issued emergency use listing for more than 10 COVID-19 vaccines; such listing assesses quality, safety, efficacy, and programmatic suitability, and it is a prerequisite for the COVAX vaccine supply and international procurement program r204
      • Authorizations in different jurisdictions may differ in details; practitioners should consult the specific authorization issued in their jurisdiction for indications, requirements for patient education and consent, and mandated reporting (eg, adverse events)
        • Vaccine administration information for the United States
          • In the United States, emergency use authorizations require health care providers to communicate to the patient, parent, or caregiver information consistent with the vaccine-specific (manufacturer-specific) fact sheet for recipients and caregivers before each patient receives the vaccine; such information includes the following: r197r200r201r202
            • Alternatives to receiving the vaccine
            • Option to accept or refuse the vaccine
            • Significant known and potential risks and benefits of the vaccine, and the extent to which such potential risks and benefits are unknown
            • Available alternative preventive vaccines in clinical trials or approved for use under other emergency use authorizations
          • Emergency use authorizations also mandate certain incidents be reported to VAERS (Vaccine Adverse Event Reporting System)r205r197r200r201r202
            • Events which must be reported to VAERS include:
              • Vaccine administration errors, whether or not an adverse event occurred
              • Serious adverse effects, whether or not attributed to the vaccine, including myocarditis; pericarditis; multisystem inflammatory syndrome; cases of COVID-19 resulting in hospitalization or death; events that are life-threatening, require hospitalization, or require medical or surgical intervention to prevent hospitalization, disability, or death; birth defects; disability; and death
            • Clinicians may choose to report any adverse events to VAERS and to the vaccine manufacturer
          • It is recommended that vaccine recipients be given a card containing information about the type of vaccine given, the date of administration, and (if applicable) the interval at which a booster dose should be administered r206r207r208
          • Vaccine recipients in the United States are encouraged to participate in CDC's V-safe monitoring and reminder system,r208 available as a mobile phone app r207
          • Clinicians should follow best practices for vaccine administration, including documentation required by law, regardless of whether vaccines are FDA-approved or authorized for emergency use r209
        • In the United Kingdom, a site has been established to report suspected adverse events related to vaccines, diagnostic tests, and therapies for COVID-19: Coronavirus Yellow Card reporting siter210
      • Vaccines against SARS-CoV-2 that have reached authorization status in some jurisdictions.EUA, emergency use authorization.
        Product nameManufacturerActive ingredientAge range for useComments
        Pfizer-BioNTech COVID-19 vaccine (BNT162b2; tozinameran; Comirnaty)Pfizer-BioNTechNucleoside-modified mRNA of SARS-CoV-26 months or older• FDA approved in the United States for ages 12 years or older; used under EUA for ages 6 months to 11 years in the United States

        • Under conditional marketing authorization in the United Kingdom
        Moderna COVID-19 vaccine (mRNA-1273; Spikevax)ModernaTXSynthetic mRNA of SARS-CoV-26 months or older• FDA approved in the United States for ages 18 years or older; used under EUA for ages 6 months to 17 years in the United States

        • Under temporary use authorization in the United Kingdom
        Oxford-AstraZeneca COVID-19 vaccine (ChAdOx1-S recombinant)AstraZenecaRecombinant, replication-deficient chimpanzee adenovirus vector encoding SARS-CoV-2 spike glycoprotein (S protein)18 years or older• Investigational; under temporary authorization in the United Kingdom
        Janssen COVID-19 vaccineJanssen
        Biotech, Inc (a Janssen Pharmaceutical Company of Johnson and Johnson)
        Recombinant, replication-deficient adenovirus
        26 vector expressing SARS-CoV-2 spike glycoprotein (S protein)
        18 years or older• Investigational; under EUA in the United States

        • Use in the United States was paused then resumed in April 2021

        • On May 5, 2022, FDA limited the use to people aged 18 years or older for whom other approved COVID-19 vaccines are unavailable or not clinically appropriate, or when elected by the recipient who would otherwise not be vaccinated
        Novavax COVID-19 vaccine, adjuvantedNovavaxRecombinant spike protein (rS) of SARS-CoV-212 years or older• Investigational; under EUA in the United States
    • Vaccination recommendations
      • CDC recommends vaccination against COVID-19 for everyone aged 6 months or older r5
        • mRNA vaccines (Pfizer, Moderna) or Novavax are preferred over Johnson and Johnson (Janssen) owing to higher efficacy and fewer adverse effects
          • Johnson and Johnson (Janssen) may be used when there is a contraindication or allergic reaction to another vaccine, or when the individual will not otherwise accept vaccination
        • Follow color coding of products
          • Doses, concentrations, and formulations differ across age groups and manufacturers; therefore, color codingr5 has been established to aid in distinguishing preparations
            • Note that some labels on vaccine vials in circulation do not reflect updated FDA authorizations/approvals or CDC guidance; consult websites for current information r5r211
              • Pfizer vials with maroon cap and maroon label border may state either "age 2y to <5y" or "age 6m to <5y" and either vial may be used for children aged 6 months to 4 years
              • Moderna vials with dark blue cap and purple label border may state "BOOSTER DOSES ONLY" but may be used as a primary series dose for children aged 6 to 11 years and should not be used as a booster dose
        • Timing of dosing r5
          • Doses administered up to 4 days before the recommended interval are considered valid
          • Doses administered more than 4 days before the recommended interval must be reported to VAERS and repeated, with the subsequent dose given the recommended interval after the erroneous dose
          • Doses administered any time after the recommended interval are valid
        • Primary vaccinations
          • Primary vaccination of nonimmunocompromised persons r5
            • Primary series for nonimmunocompromised adults aged 18 years or older is 2 doses of Pfizer separated by 3 to 8 weeks, 2 doses of Moderna separated by 4 to 8 weeks, or 2 doses of Novavax separated by 3 to 8 weeks
              • A shorter interval (3 or 4 weeks) is recommended for those at higher risk of infection or of severe disease (eg, when community transmission is elevated, for older adults or those with chronic conditions)
              • A longer interval (8 weeks) may be preferable in males aged 12 to 39 years to reduce the risk of vaccine-associated myocarditis, and it may be considered to increase peak antibody response in those not at increased risk
                • Risk of myocarditis from COVID-19 disease is substantially higher than the risk from vaccination r212
                • Risk of myocarditis in younger males might be lower after vaccination with Pfizer than with Moderna, but findings are not consistent in all monitoring r5
            • Primary series for nonimmunocompromised children and adolescents aged 6 months to 17 years
              • Pfizer
                • Ages 6 months to 4 years: 3 doses with an interval of 3 to 8 weeks between the first and second doses and at least 8 weeks between the second and third doses
                • Ages 5 years or older: 2 doses separated by 3 to 8 weeks; a longer interval (8 weeks) may be preferable, particularly in males to reduce the risk of vaccine-associated myocarditis
              • Moderna
                • Age 6 months to 17 years: 2 doses separated by 4 to 8 weeks
              • Novavax
                • Age 12 to 17 years: 2 doses separated by 3 to 8 weeks
          • Primary vaccination of moderately or severely immunocompromised persons r5
            • Primary series for immunocompromised adults aged 18 years or older is 3 doses of Pfizer (second dose 3 weeks after first dose, and third dose at least 4 weeks after second dose), 3 doses of Moderna (second dose 4 weeks after first dose, and third dose at least 4 weeks after second dose), or 2 doses of Novavax (second dose 3 weeks after the first)
            • Primary series for children and adolescents
              • Pfizer
                • Ages 5 to 17 years: 3 doses, with second dose 3 weeks after first dose, and third dose at least 4 weeks after second dose
                • Ages 6 months through 4 years: 3 doses, with second dose 3 weeks after first dose, and third dose at least 8 weeks after second dose
              • Moderna
                • Ages 6 months through 17 years: 3 doses, with second dose 4 weeks after first, and third dose at least 4 weeks after second dose
              • Novavax
                • Age 12 to 17 years: 2 doses separated by 3 weeks
          • There are no data available on the interchangeability of the COVID-19 vaccines to complete the primary vaccination series. Patients who receive the first dose of any of the vaccines should complete the primary vaccination series with the same vaccine r5
            • In cases in which the original vaccine is unknown or unavailable, or there is a contraindication to that vaccine, it is permissible to administer another authorized vaccine at least 28 days after the first dose
            • If a mixed primary series is inadvertently administered, the series is considered complete
            • If a child aged 6 months to 4 years inadvertently receives 2 different mRNA vaccines for the primary series, a third dose of either mRNA vaccine should be administered at least 8 weeks after the second dose to complete the series
        • Booster vaccinations
          • In the United States, updated bivalent booster vaccines were approved by the FDA on August 31, 2022 r211
            • These boosters, from Pfizer and from Moderna, contain an mRNA component against the original strain and one against the Omicron BA.4 and BA.5 subvariants (which have the same spike protein)
          • Bivalent booster vaccines are recommended for everyone aged 5 years or older who has completed primary vaccination
            • The original monovalent vaccines are no longer authorized for use as a booster; they are still used as a third primary dose for persons needing a 3-dose primary series as noted above
          • Some data suggest that heterologous boosters (ie, booster vaccine different from primary) produce equivalent or stronger serologic response compared with homologous boosters r5
          • Booster dose schedule r5
            • Adults and children age 6 years and older are recommended to receive Moderna or Pfizer bivalent booster at least 2 months after primary series or prior booster vaccination
            • Children age 5 years may only receive Pfizer bivalent booster (at least 2 months after primary series or prior booster vaccination), because Moderna bivalent is only authorized for ages 6 years and older
            • No booster doses are authorized for children age 6 months to 4 years
        • COVID-19 vaccination schedule.NA, not applicable. Colors listed in parentheses refer to (cap color/label border color). Primary series: Any age-appropriate Moderna, Novavax, and Pfizer-BioNTech vaccine may be used for the primary series; the same vaccine product should be used for all doses of the primary series. Booster doses: any age-appropriate bivalent booster vaccine may be used (regardless of primary series product).CDC: Vaccines and Immunizations: COVID-19 Vaccination: Interim Clinical Considerations for Use of COVID-19 Vaccines Currently Approved or Authorized in the United States. CDC website. Updated October 12, 2022. Accessed October 12, 2022. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html#covid-vaccines
          ManufacturerAgeDose 1Dose 2Dose 3Dose 4Notes
          Schedule for individuals who are NOT moderately to severely immunocompromised
          Pfizer6 months to 4 yearsPrimary (maroon/maroon), 0.2 mLIn 3 to 8 weeks, primary (maroon/maroon), 0.2 mLIn at least 8 weeks, primary (maroon/maroon), 0.2 mLNAMaroon formulation requires dilution
          Pfizer5 years to 11 yearsPrimary (orange/orange), 0.2 mLIn 3 to 8 weeks, primary (orange/orange), 0.2 mLIn at least 2 months, bivalent booster (orange/orange), 0.2 mLNAOrange formulation requires dilution; for ages 6 years to 11 years, either Pfizer or Moderna bivalent booster may be used
          Pfizer12 years and olderPrimary (gray/gray), 0.3 mLIn 3 to 8 weeks, primary (gray/gray), 0.3 mLIn at least 2 months, bivalent booster (gray/gray), 0.3 mLNAEither Pfizer or Moderna bivalent booster may be used
          Moderna6 months to 5 yearsPrimary (dark blue/magenta), 0.25 mLIn 4 to 8 weeks, primary (dark blue/magenta), 0.25 mLNANAAge 5 years only: in at least 2 months after primary series, should receive Pfizer bivalent booster
          Moderna6 years to 11 yearsPrimary (dark blue/purple), 0.5 mLIn 4 to 8 weeks, primary (dark blue/purple), 0.5 mLIn at least 2 months, bivalent booster (dark blue/gray), 0.25 mLNAEither Moderna or Pfizer bivalent booster may be used
          Moderna12 years and olderPrimary (red/light blue), 0.5 mLIn 4 to 8 weeks, primary (red/light blue), 0.5 mLIn at least 2 months, bivalent booster (dark blue/gray), 0.5 mLNAEither Moderna or Pfizer bivalent booster may be used
          Novavax12 years and olderPrimary (royal blue/no color), 0.5 mLIn 3 to 8 weeks, primary (royal blue/no color), 0.5 mLNANAIn at least 2 months after last primary dose, should receive either bivalent booster
          Schedule for individuals who ARE moderately to severely immunocompromised
          Pfizer6 months to 4 yearsPrimary (maroon/maroon), 0.2 mLIn 3 weeks, primary (maroon/maroon), 0.2 mLIn at least 8 weeks, primary (maroon/maroon), 0.2 mLNAMaroon formulation requires dilution
          Pfizer5 years to 11 yearsPrimary (orange/orange), 0.2 mLIn 3 weeks, primary (orange/orange), 0.2 mLIn at least 4 weeks, primary (orange/orange), 0.2 mLIn at least 2 months, bivalent booster (orange/orange), 0.2 mLOrange formulation requires dilution; for ages 6 years to 11 years, either Pfizer or Moderna bivalent booster may be used
          Pfizer12 years and olderPrimary (gray/gray), 0.3 mLIn 3 to 8 weeks, primary (gray/gray), 0.3 mLIn at least 4 weeks, primary (gray/gray), 0.3 mLIn at least 2 months, bivalent booster (gray/gray), 0.3 mLEither Pfizer or Moderna bivalent booster may be used
          Moderna6 months to 5 yearsPrimary (dark blue/magenta), 0.25 mLIn 4 weeks, primary (dark blue/magenta), 0.25 mLIn at least 4 weeks, primary (dark blue/magenta), 0.25 mLNAAge 5 years only: in at least 2 months after primary series, should receive Pfizer bivalent booster
          Moderna6 years to 11 yearsPrimary (dark blue/purple), 0.5 mLIn 4 weeks, primary (dark blue/purple), 0.5 mLIn at least 4 weeks, primary (dark blue/purple), 0.5 mLIn at least 2 months, bivalent booster (dark blue/gray), 0.25 mLEither Moderna or Pfizer bivalent booster may be used
          Moderna12 years and olderPrimary (red/light blue), 0.5 mLIn 4 weeks, primary (red/light blue), 0.5 mLIn at least 4 weeks, primary (red/light blue), 0.5 mLIn at least 2 months, bivalent booster (dark blue/gray), 0.5 mLEither Moderna or Pfizer bivalent booster may be used
          Novavax12 years and olderPrimary (royal blue/no color), 0.5 mLIn 3 to 8 weeks, primary (royal blue/no color), 0.5 mLNANAIn at least 2 months after last primary dose, should receive either bivalent booster
      • COVID-19 vaccine and any other immunizations may be administered on the same day, or at any interval; no delay is required between receipt of another vaccine and COVID-19 vaccination r5
        • If orthopoxvirus (monkeypox) vaccine is recommended, it may be administered at any interval after COVID-19 vaccine; however, consider delaying the administration of COVID-19 vaccine for 4 weeks after orthopoxvirus vaccination in males aged 12 to 39 years because there is a low risk of myocarditis with certain orthopoxvirus vaccines and with Moderna, Pfizer, and Novavax COVID-19 vaccines
      • History of COVID-19 is not a contraindication to vaccine; guidelines recommend that such persons be offered vaccine r5
        • Vaccination (either first or subsequent doses, if a series has been started) should be deferred until the person meets criteria for discontinuing isolation
        • Some evidence indicates that protection after vaccination may be stronger than immunity produced by previous infection, including increased antibodies in infants born to adults who received vaccination during pregnancy, compared with pregnant persons who had COVID-19 disease r180r213
      • Persons who received treatment with convalescent plasma or COVID-19–specific monoclonal antibodies do not need to delay vaccination by any interval; individuals who are candidates for tixagevimab and cilgavimab should wait at least 14 days after vaccination to receive the product r5
      • Limited data exist regarding safety and efficacy of vaccination after MIS-C or MIS-A; theoretical risk of dysregulated immune response from vaccination causing multisystem inflammatory syndrome should be weighed against risk of morbidities from COVID-19 infection r5
        • Experts consider that benefits of vaccination for children and adolescents with MIS-C probably exceed theoretical risk once clinical recovery (including return to normal myocardial function) is achieved, and 90 days or more have elapsed since MIS-C diagnosis
          • Vaccination may be considered for children and adolescents even if they do not yet meet criteria above, at the discretion of the care team
        • Vaccination may be considered for adults after MIS-A when full clinical recovery is achieved, or in consultation with experts
        • Consider consultation with a specialist in infectious diseases, rheumatology, or cardiology, and/or with personnel of the Clinical Immunization Safety Assessment COVIDvax project,r214 to discuss specific cases, particularly if MIS-C or MIS-A occurred after vaccination
      • History of Guillain-Barré syndrome (postinfectious polyneuritis) is a precaution to Johnson and Johnson (Janssen) vaccination; use of Moderna, Novavax, or Pfizer vaccines is recommended r5
      • Vaccine use in special populations
        • Pregnant persons and breastfeeding persons r5r157r158
          • Vaccination is recommended for pregnant and lactating persons, and those who may become pregnant, by the CDC, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine
            • Any authorized or approved vaccine may be used; as with all populations, for pregnant and lactating patients, Moderna, Pfizer, and Novavax are recommended over Janssen for safety and efficacy reasons
            • Studies indicate that pregnant persons with COVID-19 infection have increased risk for severe illness and death from COVID-19 and may be at increased risk of preterm birth, stillbirth, and other pregnancy complications
            • Growing information on safety and efficacy during pregnancy indicates that benefits of vaccination outweigh risks
              • One study in 35,691 pregnant persons aged 16 to 54 years found no increased rates of pregnancy loss, preterm birth, small-for-gestational-age status, or congenital anomalies, compared with background rates r215
              • Overall vaccine effectiveness of vaccination during pregnancy at preventing hospitalizations in infants younger than 6 months was 61%; optimal timing during pregnancy is not known, but effectiveness was higher in those who received the vaccine later in pregnancy (between 21 weeks of gestation and 14 days before delivery) r216
              • Vaccination during pregnancy transfers antibodies to infants, and infants born to vaccinated adults had higher antibody titers and greater antibody persistence than those born to COVID-infected adults r213
            • Pregnant persons, and those who received vaccination within 30 days before pregnancy, should be encouraged to participate in CDC's V-safe registry program (a mobile phone–based monitoring and reminder system for recipients of COVID-19 vaccines)
        • Persons with cancer r217
          • CDC and National Comprehensive Cancer Network recommend that patients with cancer should receive vaccine as soon as possible, with a few exceptions:
            • Recipients of hematopoietic cell transplant or cellular therapy (eg, CAR T-cell therapy, using cells with chimeric antigen receptors) should delay vaccination for at least 3 months
            • Patients receiving intensive cytotoxic chemotherapy (eg, cytarabine/anthracycline-based induction regimens for acute myeloid leukemia) should delay until absolute neutrophil count recovery, or for those not expected to recover, as soon as possible
            • Patients who require major surgical procedures (eg, for solid tumors) should time vaccination for several days before or after the surgery
          • Complete revaccination is recommended 3 months after hematopoietic cell transplant or cellular therapy (eg, CAR T-cell therapy)
          • Preexposure prevention with tixagevimab plus cilgavimab is recommended for all persons undergoing active cancer therapy, but it is not a substitute for vaccination
        • Persons with autoimmune diseases r5
          • Current recommendations advise all persons with autoimmune diseases to be vaccinated; those on medications causing immunocompromise should follow appropriate schedule for persons with moderate to severe immunocompromise
    • Vaccine contraindications and significant adverse effects
      • Contraindications include: r5r218
        • Severe allergic reaction (eg, anaphylaxis) to a previous dose of a COVID-19 vaccine or to any of its components
        • Known allergy to any components of a vaccine (eg, polyethylene glycol in Moderna and Pfizer vaccines, or polysorbate 80 in Novavax and Janssen vaccines)
        • For the Johnson and Johnson (Janssen) vaccine, persons who have history of thrombosis with thrombocytopenia syndrome, heparin-induced thrombocytopenia, or other immune-mediated thrombosis syndrome should not receive this vaccine; those with history of Guillain-Barré syndrome within 6 weeks of Johnson and Johnson vaccination should not receive any additional doses of this vaccine
        • Contraindication to one type of vaccine is a precaution to other types of vaccines
      • Myocarditis and pericarditis have been reported to occur rarely in adolescents and young adults (primarily males aged 12 to 39 years) after vaccination, most commonly after the second dose r5r219r220r221
        • This has been reported after vaccination with AstraZeneca, Moderna, Novavax, and Pfizer vaccines (but not Janssen)
        • Onset is usually several days after administration of vaccine; the condition is generally short-lived
        • Compared with the risk of myocarditis or pericarditis from vaccination, the risk of myocarditis or pericarditis from COVID-19 disease is higher
          • One study showed a very small increase in myocarditis in males aged 13 to 39 years after the second dose of Moderna compared with the risk of myocarditis from COVID-19; other studies have shown that even among this subgroup, the risk of myocarditis from COVID-19 is greater than the risk from vaccination r212r219r222
        • Vaccine recommendations for adolescents and young adults remain unchanged, except that waiting 8 weeks between the first and second dose may decrease the risk, and persons who have had myocarditis after a first dose of vaccine should generally avoid a second dose
      • CDCr5 and the European Medicines Agencyr223 have recommended that clinicians maintain a high index of suspicion for thrombotic events and thrombocytopenia among persons who have received the Janssen or AstraZeneca vaccines
        • Symptoms may include severe headache, blurred vision, back pain, abdominal pain, chest pain, dyspnea, leg edema, petechiae, or easy bruising; overt bleeding has occurred in some cases r5r223
        • Condition was more often seen in females younger than 50 years
        • American Society of Hematology recommends the following workup for suspected vaccine-induced thrombotic thrombocytopenia (also known as thrombosis with thrombocytopenia syndrome): r224
          • CBC with platelet count and smear (to rule out pseudothrombocytopenia from platelet clumping); range in reported cases has been 9000 to 107,000 cells/mm³
          • Imaging guided by presentation (eg, CT or MRI venogram of brain, thorax, abdomen, or other clinically indicated site)
          • D-dimer level (markedly elevated in reported cases)
          • Fibrinogen level (may be low)
          • Platelet factor 4–heparin ELISA assay; all reported cases have been positive
            • Non-ELISA rapid immunoassays for heparin-induced thrombocytopenia are not sensitive or specific for vaccine-induced thrombotic thrombocytopenia and should not be used
        • Treatment recommendations from the American Society of Hematology include: r224
          • IV immunoglobulin 1 g/kg daily for 2 days
          • Anticoagulation with one of the following heparin alternatives (avoid heparin):
            • Parenteral direct thrombin inhibitors (argatroban or bivalirudin if baseline value for activated partial thromboplastin time is normal)
            • Direct oral anticoagulants
            • Fondaparinux (Factor Xa inhibitor)
            • Danaparoid (a thrombin generation inhibitor not available in the United States)
          • Low fibrinogen level or bleeding do not absolutely preclude anticoagulation, especially if platelet count exceeds 20,000 cells/mm³
          • No consensus exists on the use of corticosteroids with IV immunoglobulin
          • Avoid platelet transfusion and aspirin
          • Plasma exchange has been tried and may be considered for thrombosis despite IV immunoglobulin and nonheparin anticoagulation
        • Patients with isolated thrombocytopenia without thrombosis, with a negative result on platelet factor 4–heparin assay, may have idiopathic thrombocytopenic purpura, not vaccine-induced thrombotic thrombocytopenia r224
          • Immune thrombocytopenia has been reported after vaccination with the AstraZeneca, Janssen, Moderna, and Pfizer vaccines
          • Treatment includes IV immunoglobulin and/or steroids; platelet transfusions may be required for bleeding
      • A small number of cases of Bell palsy have been reported after COVID-19 vaccination, but the incidence is not considered significantly different from that in the general population (background rate), and history of Bell palsy is not a contraindication r5
      • A small number of patients who have received cosmetic injections with dermal fillers have experienced mild inflammation at the filled site(s) after COVID-19 vaccination, but a history of such procedures is not a contraindication r5
    • Vaccine-specific details and evidence
      • Pfizer-BioNTech BNT162b2 (tozinameran; Comirnaty) r197c334
        • An mRNA vaccine against the SARS-CoV-2 spike protein (ie, using messenger ribonucleic acid)
        • Evaluated in a randomized placebo-controlled trial of more than 43,000 participants; at time of submission for authorization in the United Kingdom, safety and efficacy data were available for 19,067 patients evenly distributed in vaccine and placebo groups. Overall efficacy was about 95% r225
          • Among subgroups, results were similar in older age groups (older than 65 years) and in persons with comorbidities associated with increased risk for severe disease
        • Data evaluated for US emergency use authorization included 36,621 persons, aged 12 years or older, equally divided between vaccine group and placebo group (18,242 versus 18,379, respectively), with wide ethnic and age diversity, and incorporating a large percentage of persons with comorbidities. At time of analysis, participants had been followed for a median of 2 months after the second dose r206
          • Vaccine efficacy was greater than 94.6% in all groups including all ages and with or without evidence of prior SARS-CoV-2 infection
        • At time of data analysis for these authorizations, 8 cases of COVID-19 had occurred in the vaccine group compared with 162 cases in the placebo group r206r225
        • Adverse events
          • Common adverse effects included pain at injection site, fatigue, headache, myalgia, chills, arthralgia, and fever; these were largely mild to moderate and resolved within a few days r206r225
          • Appendicitis was reported in 8 vaccine recipients and 4 persons who received placebo. Bell palsy was reported in 4 vaccine recipients. Although both of these adverse events are reported as "imbalances" between vaccine and placebo populations, data are insufficient to determine a causal relationship r206
          • Severe allergic reactions have been described, and facilities at which vaccine is administered must have the ability to treat such reactions (including anaphylaxis) r206
        • Trial data were published after release of the emergency use authorization; total numbers of patients in both vaccine and placebo groups were slightly larger, but results (including efficacy calculations) were unchanged r226
        • FDA approval for ages 16 years or older was based on continued follow-up of initial study enrollees and additional data r197
        • Subsequent trial data on adolescents led to emergency use authorization on May 10, 2021, and full approval on July 8, 2022, for adolescents aged 12 through 15 years r197
          • Safety data were derived from 1127 vaccinated adolescents and 1127 placebo patients. Serious events occurred in 0.4% of vaccinated persons and 0.1% of placebo recipients, similar to results in adults
          • Among 1005 vaccinated adolescents aged 12 to 15 years, no cases of COVID-19 occurred. There were 16 cases among 978 placebo recipients. Efficacy was calculated as 100% (confidence interval, 75.3-100)
        • FDA issued an emergency use authorization for children aged 5 through 11 years on October 29, 2021 r5r227r228
          • Based on data from a placebo-controlled trial of 4695 children, of whom 3109 received vaccine and 1538 received saline
          • Follow-up found no safety concerns, including in the 1444 children who had follow-up for 2 months or longer
          • By 7 days after the second dose, efficacy is estimated to be 90.7% in preventing COVID-19
        • FDA emergency use authorization was issued on June 17, 2022 for children aged 6 months through 4 years r229
          • 1776 children aged 6 months to less than 2 years and 2750 children aged 2 years to 4 years were enrolled in placebo-controlled trials, which showed no safety concerns
          • Effectiveness in children aged 6 months through 4 years is primarily based on measured immune response in 220 vaccine recipients, which was comparable to that of older age groups
      • Moderna COVID-19 vaccine (mRNA-1273; Spikevax) r200c335
        • An mRNA vaccine against the SARS-CoV-2 spike protein
        • Safety data evaluated for US emergency use authorization included 30,351 persons, aged 18 years or older, equally divided between vaccine group and placebo group (15,185 versus 15,166, respectively); efficacy data was available for 14,134 vaccine recipients and 14,073 persons who received placebo. Participants included wide ethnic and age diversity; persons with stable comorbidities were included. At time of analysis, participants had been followed for a median of 9 weeks after the second dose r230
          • Overall efficacy was 94.1% (95.6% for persons aged 18 through 64 years and 86.4% for persons aged 65 or older)
          • Common adverse effects included pain at injection site, fatigue, headache, myalgia, chills, arthralgia, and fever; these were largely mild to moderate and resolved within a median of 2 to 3 days
          • Bell palsy was reported in 3 vaccine recipients (1 case classed as serious) and 1 placebo recipient; a causal relationship has not been established. Two patients who had previously received facial injection of dermatologic fillers experienced severe facial swelling considered likely vaccine-related. One patient developed intractable vomiting requiring hospital admission, deemed a result of vaccine
          • Severe allergic reactions have been described, and facilities at which vaccine is administered must have the ability to treat such reactions (including anaphylaxis)
            • CDC provides guidance on anaphylaxis to aid vaccine providers in preparing for and managing such events,r231 and for postanaphylaxis laboratory assessmentr232
          • Myocarditis and pericarditis have been reported to occur in adolescents and young adults (primarily males) after vaccination, most commonly after the second dose, and with some evidence suggesting higher risk after Moderna vaccination than after other vaccines r5r219r220r221
        • Subsequent analysis of data in younger age groups has led to FDA emergency use authorization on June 17, 2022, for children and adolescents aged 6 months through 17 years r229
          • Measured immune response in all segments of children and adolescents was similar to that in vaccinated adults
          • Efficacy against infection was as follows:
            • In adolescents aged 12 to 17 years: 93.3%
            • In children aged 6 through 11 years, an insufficient number of COVID-19 infections occurred to allow reliable calculation of efficacy
            • In 5400 children aged 6 months to 5 years
              • 6 to 23 months: 50.6%
              • 2 to 5 years: 36.8%
      • Novavax COVID-19, Adjuvanted r202
        • Protein subunit vaccine containing SARS-CoV-2 spike protein and Matrix-M adjuvant
        • Initial efficacy data were drawn from a randomized placebo-controlled trial comparing occurrence of mild, moderate, and severe COVID-19 in 17,272 nonimmunocompromised participants who received vaccine versus 8385 who received placebo. The overall efficacy in preventing polymerase chain reaction–confirmed and symptomatic mild, moderate, or severe COVID-19 from 7 days after dose 2 was 90.4% (95% CI, 83.8%-94.3%)
          • 17 patients (0.1%) in the vaccinated group acquired mild COVID-19 versus 66 patients (0.8%) in the placebo group
          • No patients in the vaccinated group acquired disease that was moderate or severe, versus 9 patients with moderate disease and 4 patients with severe disease in the placebo group
          • When subgroups were analyzed, vaccine efficacy appeared to be lower in Hispanic or Latino participants and in the older age group (aged 65 years or older)
        • Safety data for the emergency use authorization derive from a trial in the United States and Mexico in which 26,106 participants received at least 1 dose of Novavax; data from trials elsewhere are also available
          • Common reactions were local ones (ie, pain, redness, swelling), which occurred in up to 80.8%, and systemic ones (ie, fever, headache, fatigue/malaise, myalgia, arthralgia, nausea/vomiting), most of which occurred in fewer than half of vaccine recipients
          • Generally, adverse events appeared to be less frequent in recipients aged 65 years or older
          • 4 patients developed myocarditis or pericarditis, including 1 with concurrent COVID-19. Two of the events occurred under circumstances outside of currently authorized use of the vaccine (in one case, the patient was aged 16 years, and in the second case, the adverse event occurred after a booster that followed the primary series)
          • Other events that have been reported but for which there are insufficient data to determine a causative link include cardiomyopathy/cardiac failure, acute cholecystitis, thrombotic/embolic events (noncardiovascular, nonneurovascular), and uveitis
          • Anaphylaxis and additional cases of myocarditis or pericarditis have been reported outside of trials
      • Janssen (Johnsons and Johnson) COVID-19 vaccine r201c336
        • A replication-deficient adenovirus vector vaccine that generates immunity to the SARS-CoV-2 spike protein
        • A multinational trial enrolled 44,325 persons randomized to receive the Janssen COVID-19 vaccine or saline placebo; a preliminary efficacy analysis of 39,321 was presented to the FDA, of whom 19,630 received vaccine and 19,691 received placebo. The populations were similar and represented diverse racial and ethnic backgrounds, and patients were distributed across all age ranges 18 years or older. Persons with stable underlying medical conditions (including HIV infection) were included
        • At 14 days after vaccine administration, efficacy against severe/critical COVID-19 was 76.7%, rising to 85.4% at 28 days; for moderate to severe/critical COVID-19, efficacy rates at 14 and 28 days were 66.9% and 66.1%, respectively. At 28 days, efficacy rates did not differ between populations aged 18 to 59 years and those aged 60 years or older
        • Common adverse reactions (reported in more than 10% of participants) included headache, fatigue, myalgia, and nausea; they were reported in 13.1% of vaccine recipients and 12% of placebo patients; other adverse events included urticaria in 5 vaccine recipients (including 1 with angioedema) and 1 placebo recipient
        • 2 unique serious adverse events thought to be related to the vaccine occurred, as follows: 1 patient experienced severe pain in the injected arm unresponsive to analgesics and persistent to 74 days of follow-up, and another patient had fever, headache, and generalized weakness that resolved within 3 days
        • Several events occurred more frequently in vaccine recipients than in placebo recipients, but a causal relationship to the vaccine could not be determined, owing to confounding effects of existing underlying conditions: deep vein thrombosis (6 vaccine recipients versus 2 placebo recipients); pulmonary embolus (4 vaccine recipients versus 2 placebo recipients); transverse sinus thrombosis (single case, in a vaccine recipient); seizures (4 vaccine recipients versus 1 placebo recipient); tinnitus (in 6 vaccine recipients only)
        • On April 12, 2021, CDC and FDA recommended that practitioners in the United States suspend use of this vaccine while reports of an unusual clotting disorder associated with administration of this vaccine were investigated r233
          • Characterized by cerebral venous thrombosis with thrombocytopenia occurring 6 to 13 days after administration
          • Initial data included 6 cases among more than 6.8 million persons immunized with this vaccine in the United States; all were in females aged 18 to 48 years
        • On April 23, 2021, CDC and FDA recommended that use of this product could resume because occurrence of the observed clotting disorder is extremely rare and benefit of vaccination against COVID-19 is felt to outweigh risk r234
          • Collection and analysis of further data included 9 more cases, for a total of 15 affected persons, all of whom were females aged between 18 and 59 years
          • Specific risk factors for this complication have not been identified r235
        • On May 5, 2022, after further analysis in light of more available data, FDA limited use in the United States to persons aged 18 years or older for whom alternative COVID-19 vaccines were not accessible or clinically appropriate, or when elected by a patient of that age group who would otherwise not receive any vaccine r236
      • AstraZeneca COVID-19 vaccine r196r199c337
        • A replication-deficient adenovirus vector vaccine against SARS-CoV-2 spike protein (ChAdOx1-S [recombinant])
        • Safety data considered in the UK authorization for temporary use came from 23,745 persons who were enrolled in a clinical trial. The most common adverse effects included injection site tenderness (more than 60%) and injection site pain, headache, or fatigue (more than 50%). Less common adverse effects included myalgia or malaise (more than 40%), fever or chills (more than 30%), and arthralgia or nausea (more than 20%). Most of these symptoms resolved within a week. Adverse reactions were less common after the second dose and were less common overall in older recipients
        • Authorizing body considered efficacy data from 11,636 persons enrolled in a multinational trial: 5,807 patients received the COVID-19 vaccine and 5,829 received meningococcal vaccine (placebo). Vaccine efficacy measured at least 22 days after the first dose was 73%, and it was similar for patients with comorbidities compared with those without
        • Use of the vaccine has been interrupted in several regions while reports of unusual clotting disorders after administration were investigated; vaccination has resumed based on public health risk-benefit assessmentsr238 (ie, the apparent rarity of the disorder versus the relatively higher risk posed by COVID-19). About 30 cases have been reported among about 5 million persons receiving this vaccine in Europe r237
          • Characterized by venous thrombosis and thrombocytopenia associated with high levels of platelet factor 4–polyanion complexes (ie, similar to heparin-induced thrombocytopenia, but in the absence of heparin exposure; thus termed vaccine-induced immune thrombotic thrombocytopenia)
          • One published series reported 5 cases (in persons aged 32 to 54 years) in a population of more than 130,000 vaccine recipients; patients experienced onset of severe thromboses (some with embolization), associated with thrombocytopenia (some with hemorrhage), occurring 7 to 10 days after vaccination r239
          • Another series reported 11 cases in Germany and Austria (total number of vaccinations administered was not given); 9 of 11 patients were female, and the mean age was 36 years. Patients experienced severe and multiple venous thromboses (cerebral, splanchnic, pulmonary, other) associated with thrombocytopenia and, in some cases, disseminated intravascular coagulation
  • Preexposure prophylaxisr2
    • Monoclonal antibodies tixagevimab and cilgavimab have received emergency use authorization for coadministration in persons aged 12 years or older, weighing 40 kg or more, who either (1) are moderately to severely immunocompromised and may not mount an immune response to vaccine or (2) have a contraindication to vaccination (eg, severe allergic reaction to COVID-19 vaccine or components) r119
      • NIH guideline recommends preexposure prophylaxis with tixagevimab-cilgavimab for those who qualify, to be repeated every 6 months r2
      • Infectious Diseases Society of America guideline similarly suggests preexposure prophylaxis with tixagevimab-cilgavimab for those who qualify, but has not been updated regarding repeat doses r100
  • Postexposure prophylaxisr2
    • Postexposure prophylaxis is no longer available, as the previously authorized options (monoclonal antibodies casirivimab-imdevimab or bamlanivimab-etesevimab) are ineffective against Omicron variants
  • Public health interventions to interrupt transmission (eg, masking, distancing, hygiene, isolation, quarantine): practices vary geographically and depend on regional disease activity, vaccination status, and other factors
    • General precautions for all populations r91
      • Get vaccinated
      • Wear a mask (preferably high quality, such as N95) in indoor settings when community transmission is high or if you are at high risk
      • Avoid crowds and poorly ventilated spaces; improve ventilation whenever possible
      • Test to prevent spread to others (eg, if you have symptoms, exposure, or plans to gather with someone at higher risk)
      • Physical distance at least 6 feet from others whenever feasible
      • Wash hands (or use hand sanitizer at least 60% alcohol), cover coughs and sneezes with a tissue, and clean and disinfect high-touch surfaces often
      • Monitor for symptoms
      • Avoid contact with others (eg, stay home) when you are sick, even if an initial test result comes back negative
    • Isolation and quarantine measures: overview
      • A Cochrane review of quarantine concluded that quarantine is important in reducing incidence and mortality r240
      • All those who have symptoms of COVID-19 should isolate themselves, and get tested for COVID-19, regardless of vaccination status r91
        • Persons with symptoms and an initial negative result may need repeated testing r60
      • Persons who test positive for COVID-19, regardless of vaccination status or symptoms, should isolate for at least 5 days and wear a mask for an additional 5 days r179
        • Those who cannot wear a mask should isolate for 10 days
        • Patients who are moderately to severely ill (eg, lower respiratory disease) should isolate for 10 days
        • Patients who are immunocompromised may have a prolonged period of infectiousness; continue isolation until 2 consecutive antigen test results at least 48 hours apart are negative, and retest if symptoms recur
      • Persons exposed to COVID-19, regardless of vaccination status, should wear a mask around others for 10 days, monitor for symptoms, and get tested r91
        • Testing should be performed immediately if symptoms develop
        • Testing is recommended on day 6 (where day 0 is the day of last exposure to someone with COVID-19) regardless of symptoms; if negative, continue to mask until day 10
          • Note for household members that day 0 ("last exposure") starts when the patient has completed isolation
        • Isolate immediately if any test result is positive, regardless of symptoms
        • Close contact is defined as within 6 feet for a cumulative total of 15 minutes or more in 24 hours, but exposure may happen at any distance or time interval depending on aerosolization of virus
    • Infection control for at-home management of COVID-19 r91r179
      • Patient is encouraged to stay at home except to seek medical care, to self-isolate to a single area of the house (preferably with a separate bathroom), to practice good hand and cough hygiene, to improve ventilation where possible, and to wear a mask (preferably high quality, such as N95, as tolerated) during any contact with household members c338c339c340
        • Isolation is required for everyone with a positive COVID-19 test result, even in the absence of symptoms
      • Household members/caregivers should:
        • Wear a mask, preferably a high-quality one such as N95, when around others
        • Wash hands for at least 20 seconds after all contact; an alcohol-based hand sanitizer is acceptable if soap and water are not available
        • Not share personal items such as towels, dishes, or utensils before proper cleaning c341c342
        • Clean and disinfect regularly c343
        • Restrict contact to minimum number of caregivers and, in particular, ensure that persons with underlying medical conditions are not exposed to the patient
        • Improve ventilation, where possible
    • Infection control for COVID-19 managed in health care facilities (outpatient or inpatient) r90r241
      • CDC provides preparedness checklistsr242 for outpatient and inpatient health care settings
      • Immediately provide the patient with a face mask to reduce droplet spread and place the patient in a closed room pending further evaluation and disposition decisions. The closed room will ideally be one with structural and engineering safeguards against airborne transmission (eg, negative pressure, frequent air exchange), but in the high-prevalence stages of the pandemic (with crowded hospitals), reserve negative pressure isolation rooms for the greatest needs (ie, aerosol-generating procedures; tuberculosis, measles, and varicella)
      • Persons entering the room should follow standard, contact, and droplet or airborne precautions c344c345c346
        • Gloves, gowns, eye protection, and respirator (N95 or better) with adherence to hospital donning and doffing protocols c347c348
          • In circumstances in which supplies of N95 respirators and other protective equipment are short, their use should be prioritized for aerosol-generating procedures; standard surgical face masks should be used for other situations
        • Equipment used for patient care should be single-use (disposable) or should be disinfected between patients (eg, 70% ethyl alcohol) c349c350
    • Criteria for discontinuation of isolation precautions r90r179
      • CDC recommends that a symptom-based strategy should be used to determine when to discontinue isolation in most patients. Criteria have been established based on observationsr179 showing that duration of shedding of infective virus varies from less than 10 days in milder cases to less than 20 days in more severe infections and in immunocompromised persons
        • Mild symptomatic COVID, no immunocompromise:
          • Isolation may be discontinued 5 days after symptom onset (first day of symptoms is day 0) and
          • At least 24 hours have passed since last fever without use of antipyretics and
          • Symptoms have improved and
          • Patient is able to wear a well-fitted mask for the next 5 days
          • If illness has been entirely asymptomatic, isolation may be discontinued 5 days from first positive specimen if the patient is able to wear a well-fitted mask for the next 5 days
            • If a patient develops symptoms during the 10 days, the 5-day isolation period starts over (with day 0 as the first day of symptoms)
        • Moderate COVID-19, no immunocompromise:
          • Isolate for 10 days
        • Severe or critical illness, no immunocompromising condition:
          • It may be reasonable to extend isolation until 10 days and up to 20 days have passed since symptom onset (day 0) and
          • At least 24 hours have passed since last fever without use of antipyretics and
          • Symptoms have improved
          • Repeat testing before discontinuing isolation may be considered (2 consecutive negative antigen tests at least 48 hours apart)
        • Moderately or severely immunocompromised persons:
          • Continue isolation for 20 days or longer after symptom onset or first positive SARS-CoV-2 test result; a test-based strategy to determine further duration may be appropriate. Infectious disease consultation is recommended
          • For moderately or severely immunocompromised persons who were symptomatic, there should be improvement in symptoms and 24 hours have passed since last fever without use of antipyretics
        • Test-based criteria for discontinuation of isolation include:
          • Negative test results from 2 specimens at least 48 hours apart; polymerase chain reaction or antigen tests are acceptable
            • A nucleic acid amplification test may be used but is frequently positive for days to weeks and does not necessarily correlate with being infectious r60
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