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    Mar.05.2024

    COVID-19

    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 with antiviral action (against SARS-CoV-2 spike protein) were previously used for treatment and prevention, but their use depends on susceptibility to circulating variants; since early 2023, more than 90% of circulating variants in the United States are not susceptible to any such drugs previously under emergency use authorization, and thus those drugs are neither recommended nor available for treatment or prophylaxis r2
    • 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 r3
    • 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 r4

    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 spread globally; it was officially declared by the WHO to be a pandemic on March 11, 2020 r5
      • WHO declared a public health emergency of international concern on January 30, 2020, and ended the declaration on May 5, 2023 (although the pandemic continues) 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 r3
    • 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 and tracked
      • Both WHO and CDC maintain tracking systems for variants r9r10
      • The Omicron variant, which emerged in November 2021, is the dominant variant, with numerous lineages including many subvariants; as of January 2024, the JN.1 and HV.1 subvariants are especially prevalent in the United States r9
      • CDC classifies variants 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 r11
        • 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 descendant lineages): first detected in South Africa; it is now the only variant circulating in the United States (since early 2022), with many subvariants. It is more easily transmitted than earlier variants, and it has reduced susceptibility to the monoclonal antibody products developed for those; efficacy of remdesivir remains true r2r9r12
            • Omicron subvariants are the dominant strains worldwide and in the United States since February 2022 r9r10
              • These subvariants have increased transmissibility and similar disease 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 r13
        • Variants being monitored
          • Earlier variants (evolved before Omicron) remain in this epidemiologic category but are no longer encountered clinically (eg, 0.0% incidence rate in the United States) r9r11

    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 r14r15
      • 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 r16c2c3c4
    • The most common complaints in unvaccinated people are fever/chills and cough, which may or may not be productive r16r17r18c5c6c7c8
      • Fever is often not present at presentation, even in hospitalized patients, and may be very mild (less than 38 °C) r16
      • Myalgia, headache, and fatigue are common; fatigue may be profound r16r18c9c10
      • Upper respiratory tract symptoms (eg, rhinorrhea, sneezing, sore throat) may be present in up to 20% of symptomatic infections r18c11c12c13c14
      • Gastrointestinal symptoms (eg, abdominal pain, nausea, vomiting, diarrhea) are present in 10% to 20% of symptomatic infections r16r18c15c16c17c18c19
      • Alteration in smell and/or taste is less common but highly suggestive r18r19r20c20c21c22
    • Patients with moderate to severe disease often complain of dyspnea;r16 however, it has been recognized that many patients with severe hypoxemia due to COVID-19 do not perceive dyspnear21r22r18c23
      • Hemoptysis has been reported in a small percentage of patients r16c24
      • Pleuritic chest pain has been reported r14c25
    • As the pandemic has progressed, changes in virus variant prevalence and in vaccination status have shifted the ranking of which symptoms are most common. The ZOE Health Study has reported top symptoms (for all test-positive respondents) in the United Kingdom as follows: sore throat, rhinorrhea, blocked nose, sneezing, cough without phlegm, headache, cough with phlegm, hoarse voice, muscle aches and pains, and altered sense of smell r23

    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 r24
        • 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 r25r26r27r28
    • 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 r16c30c31c32c33
    • Conjunctival secretions, injection, and chemosis have been reported r29c34c35c36c37c38
    • A variety of skin changesr30 have been described, including erythematous rashes,r31purpura,r32petechiae,r33 and vesicles;r34acral lesionsr35r36r37 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: r24
        • 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 c84
    • Person-to-person transmission has been confirmed and occurs through the air, in droplets and aerosols of various sizes, particularly with close contact r14r38r39c85
      • Viral shedding appears to peak 24 to 48 hours before symptom onset,r40 with consequent presymptomatic transmission. Several case and cluster reports from various countriesr41r42r43 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 r44
    • Additional means of transmission may occur but are thought to be less common (eg, contact with infected environmental surfaces, fomites, infection from animals) r38c87c88c89

    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 r45
      • 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 r45
      • 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 r45
      • 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 r45d1
    • All age groups are susceptible to COVID-19, but the risk of severe disease and death increases with age r46
      • 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 r45
      • Approximate percentage of total mortality in the United States by age group as of mid-2023 (does not total to 100% due to rounding): r47
        • 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 r45c93c94
    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 r2r48
      • 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 consistently reflect r49r50
    Other risk factors/associations
    • Various underlying medical conditions have been associated with increased risk for severe disease, and many conditions are under investigation r51r52
    • Conditions that have been associated with higher risk for severe outcome (based on systematic review or meta-analysis): r52
      • 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 that are suggestive of higher risk for severe outcomes (based on cohort, case-control, or cross-sectional studies): r52
    • Conditions that might be associated with higher risk for severe disease (based on mixed evidence): r52
    • However, studies indicate that many people who develop severe disease (hospitalization and/or death) have no comorbidities r52
    • 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; CDC guidancer53 on infection prevention and control addresses nursing homes and other health care settings c191c192c193c194c195
    • In areas where vaccines are widely available, being unvaccinated (compared with being fully vaccinated) confers substantially higher risk for infection, hospitalization, and death r54

    Diagnostic Procedures

    Primary diagnostic tools

    • Diagnostic testing for SARS-CoV-2 is the primary means of diagnosis of current infection r55c196c197c198c199c200
      • Testing includes laboratory-performed tests and point of care tests (either at home or in a health care setting), with polymerase chain reaction tests (a type of nucleic acid amplification test) and antigen tests widely available
      • CDCr55 and WHOr24 recommend diagnostic testing in everyone with compatible symptoms, regardless of vaccination status
        • In situations with higher pretest probability of COVID-19 infection (eg, in a person with symptoms, in a person with a close contact or high exposure, or in any locale where there is high community transmission), a positive result on polymerase chain reaction test or on antigen test is highly likely to be a true-positive (ie, the person has current COVID-19 infection); test should be repeated if result was negative
        • In situations with low pretest probability of COVID-19 infection (eg, in a person with no known exposures and no symptoms in a location with low community transmission), a negative result on polymerase chain reaction test or on antigen test is highly likely to be a true-negative (ie, the person does not have current COVID-19 infection); consider repeating test after a positive result, because false-positives do rarely occur
        • For individuals who have had COVID-19 within the last 90 days, antigen testing (repeated as necessary) is preferred over polymerase chain reaction testing, which can detect noninfectious nucleic acid remnants and therefore remain positive for a prolonged period without necessarily indicating a new infection
      • Specimens from upper or lower respiratory tract are recommended for viral testing.r56 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 r56
          • 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 r57
      • 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 as follows: r2r58
        • 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 r24c216d2
        • Coinfections have been reported, but the frequency is unknown r59r60
        • 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 r61
        • 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 r2r62c217
          • 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 r17c218c219c220
      • 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 r63
        • 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 r64
    • 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) r24c221c222c223c224c225c226c227c228c229c230c231c232c233c234c235c236c237c238d3
    • Public health reporting: COVID-19 is a national notifiable condition in the United States, but reporting requirements vary by jurisdiction; reporting is typically performed by laboratories, facilities, and health departments, and clinicians may be contacted by local authorities r65
      • In some jurisdictions or at certain times during the pandemic, public health authorities may facilitate testing and/or undertake contact tracing and monitoring
      • WHO case definitions (primarily for public health purposes) r66
        • Suspected case meets any of the following:
          • 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
        • Probable case meets either of the following:
          • Someone with the clinical criteria above who is a contact of a confirmed or probable case, or is part of a cluster
          • Someone who has respiratory distress and unexplained death who is a contact of a confirmed or probable case, or is part of a cluster
        • Confirmed case meets either of the following:
          • 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)
      • Revised CDC case definitions are primarily based on laboratory evidence r67

    Laboratory

    • Nucleic acid amplification tests are highly sensitive and specific, and the laboratory-performed versions are considered gold standard for diagnosis r55
      • 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 r55c239
        • 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
        • 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 r56
        • 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 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 are preferred
    • Antigen tests are also useful for diagnosis, and they have the advantage of rapid turnaround and accessibility (performed at home or in health care settings) r55
      • In general, these tests are less sensitive than polymerase chain reaction, although specificity is nearly equivalent
        • 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
          • Confirm negative antigen test results either with polymerase chain reaction test or with repeated antigen testing, in patients with symptoms or with known exposure
      • Some evidence indicates that antigen test results correlate with infectiousness
      • A Cochrane review noted wide-ranging performance of antigen tests; summary sensitivities ranged widely from 28.6% to 91.3%, but average specificity was high at 99.1% (symptomatic) to 99.7% (asymptomatic) r68
        • 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
    • Serologic tests (antibody tests) are not used for diagnosis
    • 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 r14r16r17
      • Anemia was noted in about half of patients in one series r17
      • Both elevated and low platelet counts have been seen r14r16r17
      • Prolonged prothrombin time has been reported r69
      • Levels of D-dimer and fibrinogen may be elevated r14r16
      • Elevated levels of lactate dehydrogenase and liver enzymes (ALT and AST) are common r16r17
      • Serum procalcitonin levels are usually within reference range; elevated levels have been seen in patients with secondary infection r16
      • Serum levels of some other acute phase reactants (eg, C-reactive protein, ferritin) are elevated in most patients, as is the erythrocyte sedimentation rate r17
    • Lactate level of 2 mmol/L or higher suggests presence of septic shock r24c244

    Imaging

    • Chest imaging (eg, plain radiography, CT, ultrasonography) has been found to be sensitive but not highly specific to COVID-19 r70
    • 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 r14r16r17r71r72c245c246c247c248
    • CT may be slightly more sensitiver70r73 than plain radiographs, but normal appearance on CT does not preclude the possibility of COVID-19r74
    • 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 r75r76c249c250

    Differential Diagnosis

    Most common

    • Influenza c251d4
      • 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 virus r61
      • 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 r2r62
        • When influenza virus and SARS-CoV-2 are both circulating in the community, testing for both pathogens is recommended for all hospitalized patients and whenever positive results would change clinical management or infection control
          • A positive result for influenza does not rule out COVID-19; a positive result for SARS-CoV-2 does not rule out influenza
        • CDC recommends nucleic acid amplification testing for both pathogens, by either multiplex or individual assay; repeated antigen testing may be performed if nucleic acid amplification is not available, but a single negative result does not rule out either disease
    • Other viral pneumonias c252d2
      • 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 r61
    • Bacterial pneumonia c253d2
      • 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 r24
    Criteria for ICU admission
    • WHO provides criteria for critical respiratory tract disease r77
      • 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 r78
      • 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 checkerr79 is advised
      • Recommendations below summarize major treatment guidelines from NIH, WHO, and Infectious Diseases Society of America r2r24r80r81
    • 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 has periodically updated a listr52 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 guidancer4 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, severe 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
      • In the United States, the federal government currently replenishes the supply of COVID-19 therapeutics weekly through a state and territorial health department ordering process r82
      • Only if access to recommended therapies is limited, NIH suggests the following prioritizations: r2
        • 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 persons not expected to adequately respond to vaccination or COVID-19, and unvaccinated persons 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 not included in tier 1 at high risk (eg, age 65 years or older, or any age with underlying conditions)
          • Tier 3: vaccinated patients at high risk (eg, 65 years or older, or any age with underlying condition); note that those without any booster doses are at higher risk than those up to date with all doses

    Infection control measures: these include isolation, source control, and transmission precautions r53

    • People with COVID-19 at home should isolate at home until they meet criteria to discontinue isolation; 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 r83
    • Patients with COVID-19 in a health care setting should wear a face mask for source control; should be placed in a single-person closed room or cohorted with others with the same pathogen(s); and should have standard precautions, contact precautions, and droplet or airborne precautions as resources allow r53
      • Health care personnel should wear N95 respirator or comparable (eg, FFP2, KN95), gown, gloves, and eye protection
        • Some guidelines suggest that a medical face mask, rather than N95 respirator, is sufficient when not performing aerosol-generating procedures r24
      • If available, the patient room will ideally be one with structural and engineering safeguards against airborne transmission (eg, negative pressure, frequent air exchange), but if caseload or resource limitations preclude the ideal, then 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) r24

    • 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 (eg, hospital or community), epidemiologic risk factors, and local antimicrobial susceptibility patterns r24
    • Surviving Sepsis Campaignr84r85 guideline, NIH COVID-19 treatmentr2 guideline, and WHO guidancer24 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 d5

    Antiviral agents

    • Remdesivir (antiviral RNA polymerase inhibitor) r86
      • Guidelines
        • NIH guidelines recommend, and the Infectious Diseases Society of America and Surviving Sepsis Campaign guidelines suggest, remdesivir for hospitalized patients with COVID-19 who require supplemental oxygen r2r80r84r85
          • 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
            • Persons who may benefit most from the addition of remdesivir include immunocompromised patients, those with evidence of ongoing viral replication (eg, those with a low cycle threshold value on polymerase chain reaction test, or with a positive rapid antigen test result), or those within 10 days of symptom onset r2
        • 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 r2r80r81
          • 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 r87
        • Remdesivir should be offered to pregnant and lactating patients when indicated; breastfeeding may continue while they are taking remdesivir r2
        • Some experts would consider longer or additional courses of remdesivir for immunocompromised patients who have prolonged, symptomatic infection with ongoing viral replication r2
      • Evidence base
        • 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 r88
        • Preliminaryr89 and follow-upr90 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
        • NIH guidelines and Infectious Diseases Society of America guidelines summarize evidence from multiple additional studies showing benefit in various outcomes such as faster time to recovery, lower risk of clinical progression, and/or lower risk of death r2r80
    • Ritonavir-boosted nirmatrelvir (antiviral protease inhibitor with booster to increase plasma concentrations) r91
      • Guidelines
        • 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 r2r80
        • 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 r92
          • Resources are available to help clinicians manage potential drug interactions r79r93
        • Ritonavir-boosted nirmatrelvir should be offered to pregnant and lactating patients when indicated; breastfeeding may continue while taking ritonavir-boosted nirmatrelvir r2
          • Some COVID-19 studies did not include pregnant patients, but ritonavir has been used in pregnant patients with HIV r94r95
          • 2 case series totaling 54 pregnant patients with COVID-19, some with additional risk factors, reported good outcomes of infection and no fetal or neonatal adverse effects r2
        • 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
        • Some experts prescribe longer or additional courses of ritonavir-boosted nirmatrelvir for immunocompromised patients who have prolonged, symptomatic infection with ongoing viral replication r2
          • Using longer or additional courses is off-label and is currently under investigation r2r96
          • When using ritonavir-boosted nirmatrelvir under emergency use authorization (ie, for patients aged 12 to 17 years), clinicians are required to request expanded accessr97 to prescribe longer or additional courses
      • Evidence base
        • FDA-approved for adults aged 18 years or older, and has emergency use authorization in children aged 12 to 17 years and weighing 40 kg or more, for treatment of nonhospitalized persons with mild to moderate COVID-19 who are at high risk for progression to severe disease r98r99
        • 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% r99
          • Because the trial enrolled only unvaccinated high-risk patients, additional studies have attempted to determine benefit for vaccinated patients, or patients not at high risk of progression; thus far, benefit has been seen only in patients at high risk of progression to severe disease r2
    • Molnupiravir (antiviral nucleoside analogue) r100
      • Guidelines
        • NIH recommends use of molnupiravir 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
        • 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 r80
        • WHO suggests use of molnupiravir for adults with nonsevere disease at highest risk of hospitalization; alternative treatments may be preferable where available r81
        • Molnupiravir is not recommended during pregnancy or breastfeeding r2r101
          • Before prescribing to persons of childbearing potential, test for pregnancy
          • For both male and female patients, 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
          • NIH recommends against use of molnupiravir in pregnancy unless there are no other options and therapy is clearly indicated
      • Evidence base
        • 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 r101
        • 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%
        • 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.r102 Use of molnupiravir should be accompanied by robust pharmacovigilance r81

    Systemic corticosteroid therapy is recommended for most hospitalized patients with an oxygen requirement r24

    • Guidelines
      • NIH treatment guidelines recommend use of dexamethasone in most hospitalized patients who require supplemental oxygen, and they recommend against use of dexamethasone (or other corticosteroids) in patients who do not require oxygen supplementation r2
        • Dexamethasone should be the primary immunomodulator for all patients who require high-flow nasal cannula oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation, and for most patients who require conventional oxygen (with additional treatments as indicated)
          • Of patients requiring oxygen, only those requiring minimal conventional oxygen are recommended to receive remdesivir without dexamethasone
        • In the absence of dexamethasone, another glucocorticoid (eg, prednisone, methylprednisolone, hydrocortisone) may be used
        • NIH recommends use in pregnant persons when indicated r2
        • Dexamethasone should also be offered to lactating persons when indicated, and breastfeeding may continue while they are taking dexamethasone r2
      • Similarly, Infectious Diseases Society of America guidelines suggest use of dexamethasone in hospitalized patients with severe illness, and they recommend use in those with critical illness r80
        • These guidelines suggest against the use of steroids in patients who have no oxygen requirement
        • These guidelines provide equivalent doses of alternative glucocorticoids if dexamethasone is unavailable
      • Surviving Sepsis Campaign guidelines on managing critically ill adults with COVID-19 strongly recommend using corticosteroids (preferably dexamethasone) for up to 10 days in patients with severe or critical COVID-19 r84r85
      • WHO recommends use in patients with severe and critical COVID-19, and it suggests against use in patients with nonsevere COVID-19 r24r81
      • Inhaled corticosteroids are not recommended by guidelines r2r80
    • Evidence base
      • 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 r1r103
        • 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

    Immunomodulators of other classes are used to diminish an excessive inflammatory response

    • Baricitinib (a Janus kinase inhibitor) r104
      • Guidelines
        • NIH guidelines recommend use of baricitinib as follows: r2
          • NIH guidelines recommend use of baricitinib (or tocilizumab) as a preferred second immunomodulator 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)
            • NIH guidelines recommend 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 guidelines further recommend use of baricitinib (as a preferred second immunomodulator with dexamethasone) for hospitalized patients who need high-flow oxygen or noninvasive ventilation; due to a stronger evidence base, the recommendation for baricitinib is stronger than for tocilizumab, which is an alternative
          • NIH guidelines further recommend use of baricitinib (as a preferred second immunomodulator with dexamethasone) for hospitalized patients who need mechanical ventilation or extracorporeal membrane oxygenation; there is insufficient evidence to recommend baricitinib over tocilizumab or vice versa for this indication
          • NIH guidelines recommend use of baricitinib for pregnant patients when indicated r2
          • In lactating persons, feeding breast milk to infants should be avoided while on baricitinib and for 4 days after the last dose, with support to maintain breastfeeding r2
        • 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 r80
          • 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 guidelines strongly recommend baricitinib for patients with severe or critical disease; choice of baricitinib versus interleukin-6 blockers should be based on clinical factors and availability r81
      • Evidence base
        • FDA-approved for the treatment of COVID-19 in hospitalized adults receiving systemic corticosteroids and requiring supplemental oxygen, noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation; it has emergency use authorization for children aged 2 years or older for the same indications r105r106
          • 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 r106r107
          • 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 r108
          • NIH guidelines summarize these and additional studies which show some mortality benefit, lower risk of clinical progression, and/or faster time to recovery r2
    • Tocilizumab (monoclonal interleukin-6 receptor blocker) r109
      • Guidelines
        • NIH guidelines recommend use of tocilizumab as follows: r2
          • Use tocilizumab (or baricitinib) as a preferred second immunomodulator with dexamethasone alone or with remdesivir and dexamethasone in hospitalized patients on oxygen who have rapidly increasing oxygen requirements and systemic inflammation
            • There is insufficient evidence to recommend tocilizumab over baricitinib or vice versa for this indication
          • In patients receiving high-flow oxygen or noninvasive ventilation, use tocilizumab as a second immunomodulator with dexamethasone alone or with remdesivir and dexamethasone; tocilizumab is an alternative to baricitinib, which currently has more supporting evidence for this indication
            • Best initiated within 24 hours of admission to ICU
          • In hospitalized patients who need mechanical ventilation or extracorporeal membrane oxygenation, use tocilizumab (or baricitinib) as a preferred second immunomodulator with dexamethasone; there is insufficient evidence to recommend tocilizumab over baricitinib or vice versa for this indication
          • NIH guidelines recommend against giving baricitinib to patients on tocilizumab
          • NIH guidelines recommend use of tocilizumab for pregnant and lactating patients when indicated; breastfeeding may continue while they are taking tocilizumab r2
        • 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 r80
        • WHO guideline recommends use of tocilizumab (or sarilumab) for patients with severe or critical COVID-19, along with corticosteroids r81
      • Evidence base
        • FDA-approved for the treatment of COVID-19 in hospitalized adults receiving systemic corticosteroids and requiring supplemental oxygen, noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation; it has emergency use authorization for children aged 2 years or older for the same indications r110r111
        • 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 r112r113
        • NIH guidelines and Infectious Diseases Society of America guidelines summarize additional trials which show mortality benefit and lower risk of clinical progression r2r80
    • Abatacept (cytotoxic T-lymphocyte–associated antigen 4 agonist) r2
      • Guidelines
        • NIH guidelines recommend use of abatacept (or infliximab) as an alternative second immunomodulator (after baricitinib or tocilizumab, the preferred second immunomodulators) with dexamethasone alone or with remdesivir and dexamethasone in hospitalized patients on oxygen who have rapidly increasing oxygen requirements and systemic inflammation r2
        • NIH guidelines further recommend use of abatacept (or infliximab) as an alternative second immunomodulator (after baricitinib or tocilizumab) with dexamethasone alone or with remdesivir and dexamethasone in hospitalized patients in patients receiving high-flow oxygen or noninvasive ventilation
        • NIH guidelines recommend use of abatacept for pregnant patients when indicated; breastfeeding may be considered while a patient takes abatacept, although minimal data are available on abatacept in breast milk r2
        • WHO guidelines and Infectious Diseases Society of America guidelines do not address abatacept
      • Evidence base
        • FDA approved for inflammatory arthritis and graft-versus-host disease; has been used off-label in COVID-19 treatment
        • ACTIV-1 trial randomized 1971 patients to abatacept, cenicriviroc, infliximab, or placebo in randomized, double-masked protocol; for the primary outcome of time to recovery, there was no difference among all arms r114
          • However, mortality was significantly lower at day 28 among patients receiving abatacept compared with placebo, with no significant increase in serious adverse effects or secondary infection
    • Infliximab (tumor necrosis factor α inhibitor) r115
      • Guidelines
        • NIH guidelines recommend use of infliximab (or abatacept) as an alternative second immunomodulator (after baricitinib or tocilizumab, the preferred second immunomodulators) with dexamethasone alone or with remdesivir and dexamethasone in hospitalized patients on oxygen who have rapidly increasing oxygen requirements and systemic inflammation r2
        • NIH guidelines further recommend use of infliximab (or abatacept) as an alternative second immunomodulator (after baricitinib or tocilizumab) with dexamethasone alone or with remdesivir and dexamethasone in hospitalized patients in patients receiving high-flow oxygen or noninvasive ventilation r2
        • NIH recommends use in pregnant persons when indicated r2
        • NIH guidelines recommend offering to lactating patients when indicated; breastfeeding may continue while they are taking infliximab r2
        • WHO guidelines and Infectious Diseases Society of America guidelines do not address infliximab
      • Evidence base
        • FDA approved for multiple inflammatory diseases; used off-label for COVID-19 treatment
        • ACTIV-1 trial randomized 1971 patients to abatacept, cenicriviroc, infliximab, or placebo in randomized, double-masked protocol; for the primary outcome of time to recovery, there was no difference among all arms r114
          • However, mortality was significantly lower at day 28 among patients receiving infliximab compared with placebo, with no significant increase in serious adverse effects or secondary infection
    • Sarilumab (monoclonal interleukin-6 receptor blocker) r116
      • Guidelines
        • NIH guidelines recommend use of sarilumab (or tofacitinib) with dexamethasone alone or with remdesivir and dexamethasone only when baricitinib, tocilizumab, abatacept, and infliximab are unavailable or not feasible for:
          • Hospitalized patients on oxygen with rapidly increasing oxygen requirement and evidence of systemic inflammation r2
          • Hospitalized patients on high-flow oxygen or noninvasive ventilation
        • NIH guidelines also recommend use of sarilumab (or tofacitinib) with dexamethasone only when baricitinib and tocilizumab are unavailable or not feasible for hospitalized patients requiring mechanical ventilation or extracorporeal membrane oxygenation r2
        • WHO guideline recommends 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 r81
      • Evidence base
        • FDA approved for rheumatoid arthritis and polymyalgia rheumatica; used off-label in COVID-19 treatment
        • REMAP-CAP trial found that sarilumab plus dexamethasone was noninferior to tocilizumab plus dexamethasone, but some trials have demonstrated no benefit; evidence (summarized in NIH guidelines and Infectious Diseases Society of America guidelines) is stronger for the use of tocilizumab r2r80r113
    • Tofacitinib (a Janus kinase inhibitor) r117
      • Guidelines
        • NIH guidelines recommend use of tofacitinib (or sarilumab) with dexamethasone alone or with remdesivir and dexamethasone only when baricitinib, tocilizumab, abatacept, and infliximab are unavailable or not feasible for: r2
          • Hospitalized patients on oxygen with rapidly increasing oxygen requirement and evidence of systemic inflammation
          • Hospitalized patients on high-flow oxygen or noninvasive ventilation
        • NIH guidelines also recommend use of tofacitinib (or sarilumab) with dexamethasone only when baricitinib and tocilizumab are unavailable or not feasible for hospitalized patients requiring mechanical ventilation or extracorporeal membrane oxygenation r2
        • 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) r80
          • Patients should also receive at least prophylactic dose of anticoagulant
          • Patients receiving tofacitinib should not receive tocilizumab or other interleukin-6 inhibitors
        • WHO guidelines suggest against use of tofacitinib or ruxolitinib (another Janus kinase inhibitor) unless baricitinib, tocilizumab, and sarilumab are unavailable, owing to limited evidence r81
      • Evidence base
        • A randomized, placebo-controlled trial of 289 patients in Brazil (STOP-COVID trial) demonstrated a lower risk of death or respiratory failure in patients on tofacitinib compared to placebo r118
    • Vilobelimab (a monoclonal antibody that binds to factor C5a of the complement cascade) r119
      • Guidelines
        • NIH guidelines find insufficient evidence to recommend for or against use; WHO guidelines and Infectious Diseases Society of America guidelines do not address vilobelimab r2r80r81
      • Evidence base
        • FDA emergency use authorization was granted in April 2023 for use in hospitalized adults (aged 18 years or older) within 48 hours of initiation of mechanical ventilation or extracorporeal membrane oxygenation for COVID-19; vilobelimab is not FDA approved for any indication r120r121
        • A randomized, double blinded, placebo-controlled phase 3 trial of 368 patients from 46 hospitals in 9 countries showed a significant decrease in 28-day mortality in patients on vilobelimab compared with placebo (absolute risk reduction, 11%; number needed to treat, 9 patients to prevent 1 death) r122
          • All patients were aged 18 years or older and also received standard of care (eg, corticosteroids, antithrombotic drugs, tocilizumab, baricitinib) in addition to vilobelimab or placebo initiated within 48 hours of invasive mechanical ventilation
          • 28-day mortality was 31.7% in the vilobelimab group compared with 41.6% in the placebo group (hazard ratio, 0.67), and all-cause mortality benefit persisted through 60 days (end of follow-up)
          • Adverse effects were similar between treatment groups (including pneumonia, sepsis, and acute kidney injury)
          • Notably, given the time span in which patients were enrolled (ie, October 2020 through October 2021), many patients were unvaccinated and few patients were infected with the Omicron variant; in addition, few patients received a second immunomodulator (eg, tocilizumab or baricitinib) which makes comparison with current practices difficult r2

    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 r2r84r123r124
    • 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: r2r125r126r127r128
      • For prophylaxis in acutely ill adults: r2r125r127
        • 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 guidelines specify that therapeutic dose should be reserved for patients with an elevated D-dimer level and that other hospitalized patients should receive prophylactic dose
        • NIH guidelines recommend prophylactic-dose heparin in hospitalized pregnant patients without a contraindication (eg, imminent delivery, bleeding complications of pregnancy); there is insufficient evidence to recommend for or against therapeutic-dose anticoagulation in pregnant patients without known venous thromboembolism
        • NIH guidelines recommend use in lactating patients (prophylactic-dose or treatment-dose heparin, as indicated); breastfeeding may continue while they are taking low-molecular-weight heparin or unfractionated heparin
      • For prophylaxis in critically ill adults: r2r127r128
        • 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 guidelines recommend 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 r2r126r127
      • 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 r2r125r128
        • Because of insufficient evidence, NIH guidelines have no recommendation for or against use of therapeutic doses of apixaban for prophylaxis against COVID-19 or for prevention of its progression r2
        • NIH guidelines recommend against therapeutic dose of rivaroxaban for prophylaxis or for prevention of progression r2
      • 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

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

    • Emergency use authorizations were issued in the United States for several monoclonal antibody products: tixagevimab-cilgavimabr129 in combination, bamlanivimab-etesevimabr130r131 in combination, bebtelovimabr132, casirivimab-imdevimabr133 in combination, and sotrovimabr134r135
      • Susceptibility of prevailing variants to monoclonal antibody products varies
        • FDA suspended those authorizations owing to lack of efficacy against prevailing variants, as follows: bamlanivimab-etesevimab (January 24, 2022), casirivimab-imdevimab (January 24, 2022), sotrovimab (April 5, 2022), bebtelovimab (November 30, 2022), and tixagevimab-cilgavimab (January 26, 2023) r136
    • These monoclonal antibody products are no longer in use in the United States and many other locations given lack of activity against Omicron subvariants
      • 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 r129
        • 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 r137
        • 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 were to receive a second dose of 150 mg each as soon as possible
        • However, in January 2023, with more than 90% of circulating variants nonsusceptible to these monoclonal antibodies, the emergency use authorization was suspended and the NIH recommends against their use r2r137
      • 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 r131
        • 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) r131
          • 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 r131
        • 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 r130r138
      • Bebtelovimab is a recombinant neutralizing human monoclonal antibody that binds to the spike protein of SARS-CoV-2, preventing its attachment to the ACE2 receptor (for angiotensin-converting enzyme 2) r132
        • Bebtelovimab does not effectively neutralize the BQ.1 and BQ.1.1 Omicron subvariants prevalent in late 2022, and the FDA suspended the emergency use authorization for bebtelovimab on November 30, 2022 r139
        • Bebtelovimab had been authorized earlier, based on limited clinical data indicating a reduction in viral load in treated patients and improvement in symptoms; the emergency use authorization issued by FDA on February 11, 2022 stated 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" r140
      • Casirivimab and imdevimab are monoclonal antibodies that bind to 2 different regions of the receptor-binding domain of the spike protein, preventing viral binding to human host cells r133
        • 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 r133r138r141
        • 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 r81
      • Sotrovimab targets a highly conserved region in the receptor-binding domain of the SARS-CoV-2 spike protein r134
        • 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 r2r142
        • WHO recommends against treatment with sotrovimab due to evidence that sotrovimab lacks activity against circulating SARS-CoV-2 variants and subvariants (eg, Omicron) r81
        • Sotrovimab had been authorized earlier, based on data supporting efficacy against earlier variants; for example, interim data from the COMET-ICE clinical trial showed 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 r134r135

    Convalescent plasma continues to be investigated; only high-titer formulations have shown any benefitr143

    • Infectious Diseases Society of America guidelines suggest 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. They recommend against use in hospitalized patients r80
    • Surviving Sepsis Campaign guidelines on managing critically ill adults with COVID-19 suggest that convalescent plasma not be used outside of clinical trials r84
    • NIH treatment guidelines recommend against use of convalescent plasma in most situations, except in a clinical trial, and recommend 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)
      • Some experts prescribe convalescent plasma to immunocompromised patients who have prolonged, symptomatic infection with ongoing viral replication r2
        • Use only high-titer COVID-19 convalescent plasma from a vaccinated donor who recently recovered from COVID-19 likely caused by a SARS-CoV-2 variant similar to the variant causing the patient's illness
    • WHO strongly recommends against use of convalescent plasma in nonsevere disease, and it recommends against use in severe or critical disease outside of a clinical trial r81
    • 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: r144r145
      • 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 that could potentially alter response to COVID-19 have been evaluated either for use in treatment and prevention, or for discontinuation to prevent harms r146

    • 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 r2r147r148
      • 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 r80
    • Decisions regarding discontinuing or lowering dosage of chronic immunosuppressive medications in patients with COVID-19 should be made in consultation with relevant specialists r2
    • NIH guidelines recommend against the use of metformin to treat COVID-19 in hospitalized patients; there is insufficient evidence to recommend for or against use in nonhospitalized patients r2
      • Individuals taking metformin for another indication should continue the medication if they have COVID-19

    Other options not currently recommended under NIH, Infectious Diseases Society of America, and WHO guidelines (although some are still under study in clinical trials) r2r80r81

    • Numerous other 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 r2r80r81
    • 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 such as anakinra; Bruton's tyrosine kinase inhibitors; and GM-CSF (granulocyte-macrophage colony-stimulating factor) inhibitors such as lenzilumab, mavrilimumab, namilumab, gimsilumab, and otilimab
      • Interferons
      • IV immunoglobulin (except as indicated for multisystem inflammatory syndrome)
      • Ivermectin
      • Mesenchymal stem cells
      • Metformin
      • 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: 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.
        • Dosages for patients who need mechanical ventilation or extracorporeal membrane oxygenation r86r88d5
          • Remdesivir Solution for injection; Adults: 200 mg IV once on day 1, followed by 100 mg IV once daily for 9 days.
        • 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: 300 mg nirmatrelvir (two 150 mg tablets) and 100 mg ritonavir (one 100 mg tablet) PO twice daily for 5 days.
      • 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.
    • Immunomodulators
      • Corticosteroids
        • Dexamethasone c255
          • Dexamethasone Sodium Phosphate Solution for injection; Adults: 6 mg IV once daily for up to 10 days or until hospital discharge (whichever comes first).
        • Various guidelines provide recommendations for alternative glucocorticoids if dexamethasone is not available r2r80
          • Methylprednisolone c256
            • 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 c257
            • 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.
      • Janus kinase inhibitors
        • Baricitinib c258
          • 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.
        • Tofacitinib
          • Tofacitinib Oral tablet; Adults: 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, IF exhibiting signs of systemic inflammation and rapidly increasing oxygen needs while on dexamethasone. Also, may be given with dexamethasone for patients on high-flow oxygen, noninvasive ventilation, mechanical ventilation, or ECMO. Tofacitinib is an alternative to other immunomodulators. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
      • Monoclonal antibodies against the interleukin-6 receptor
        • Tocilizumab c259
          • 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 c260
          • Sarilumab Solution for injection; Adults: 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 while on dexamethasone. Also, may be given with dexamethasone for patients on high-flow oxygen, noninvasive ventilation, mechanical ventilation, or ECMO. Sarilumab is an alternative to other immunomodulators.
      • Cytotoxic T-lymphocyte–associated antigen 4 agonist
        • Abatacept
          • Abatacept Solution for injection; Adults: 10 mg/kg actual body weight (max: 1,000 mg) IV once over 30 minutes is recommended by the NIH with dexamethasone (with or without remdesivir) to treat hospitalized adults needing supplemental oxygen, IF exhibiting signs of systemic inflammation and rapidly increasing oxygen needs while on dexamethasone OR requiring high-flow oxygen or noninvasive mechanical ventilation. Abatacept is to be used as an alternative.
      • Tumor necrosis factor inhibitor
        • Infliximab
          • Infliximab (Murine) Solution for injection; Adults: 5 mg/kg actual body weight IV once is recommended by the NIH for use with dexamethasone (with or without remdesivir) to treat hospitalized adults needing supplemental oxygen, IF exhibiting signs of systemic inflammation and rapidly increasing oxygen needs while on dexamethasone OR requiring high-flow oxygen or noninvasive mechanical ventilation. Infliximab is to be used as an alternative.
      • Monoclonal antibodies against the C5a factor of the complement system
        • Vilobelimab
          • Vilobelimab Solution for injection; Adults: 800 mg by IV infusion for up to 6 doses while hospitalized. Give first dose within 48 hours of intubation (Day 1), followed by doses on Days 2, 4, 8, 15, and 22

    Nondrug and supportive care c261

    • Excellent supportive care remains the mainstay of treatment in COVID-19 r24c262
      • Majority of patients with COVID-19 will not require hospitalization or medications
      • Patients should be educated about infection control, self-care such as analgesia and hydration, and alarm symptoms which require medical evaluation
    • WHO,r24NIH,r2 and Surviving Sepsis Campaignr85 provide specific guidance for oxygenation, ventilation, and fluid management in COVID-19 d5
      • 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 d5
      • Oxygenation and ventilation c263
        • Begin supplemental oxygen therapy when oxygen saturation falls below 90% to 92% r85
        • Nasal cannula at 5 L/minute or face mask with reservoir bag at 10 to 15 L/minute r24
          • 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 r149c264c265c266c267c268
          • High-flow nasal oxygen is recommended by Surviving Sepsis Campaignr85 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 clinician. Therefore, some authorities reserve these options for settings in which airborne precautions can be taken and close monitoring provided r85
        • 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 d5
        • Extracorporeal membrane oxygenation has been usedr16 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 r150

    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 Americar151 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 r152r153r154r155r156r157
      • 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 r158

    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) r2r159
        • NIH guidelines recommend against withholding COVID-19 treatments or vaccination in pregnant persons specifically because of pregnancy per se
      • 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 r2r159r160r161
      • American College of Obstetricians and Gynecologists recommends that the mode of delivery be determined, as usual, by obstetric indications and patient preference (not COVID-19 per se); complications of COVID-19 raise the odds of necessity of cesarean delivery r162
      • There is little evidence to suggest vertical transmission; however, an infected birthing parent may transmit the virus by the airborne route to the neonate r24r162
        • American College of Obstetricians and Gynecologists and WHO advise that breastfeeding benefits outweigh risks and that neonates should not be separated from birthing parents, who may wear masks to reduce transmission
    • Breastfeeding patients
      • NIH guidelines recommend against withholding COVID-19 treatments or vaccination in lactating persons specifically because of lactation per se r2
      • Vaccination is recommended, including booster shots as indicated, for breastfeeding persons r4
      • A breastfeeding person should take all routine precautions to protect themselves and the breastfed child r83
    • Patients living with HIV
      • Vaccination is recommended r2r92
      • Recommendations on prevention or management for patients with HIV who develop COVID-19 do not differ from standard recommendations
      • 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
      • Potential for drug interactions may complicate treatment or eligibility for a clinical trial for COVID-19; drug interaction checkerr79 is recommended
        • Patients with HIV taking ritonavir-based or cobicistat-based antiretroviral therapy can receive a 5-day course of ritonavir-boosted nirmatrelvir to treat COVID-19 without altering or interrupting their usual antiretroviral therapy r2
      • 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 r52r92
      • Guidance by the US Department of Health and Human Servicesr92 offers strategies for ensuring continuity of antiretroviral medication

    Monitoring

    • Patients who do not require admission should self-monitor temperature and symptoms, and they should return for reevaluation if symptoms worsen r163c275
      • Deterioration may occur a week or more into the course of illness and may be quite abrupt
    • In hospitalized patients with confirmed COVID-19 who are not immunocompromised, continue transmission-based precautions until either clinical or test criteria are met: r53c276
      • Clinical criteria are: at least 10 days have passed since symptom onset, and at least 24 hours since last fever (without the use of fever-reducing medicines), and symptoms have improved
      • Testing criteria are: fever has resolved, and symptoms have improved, and 2 consecutive negative results on testing (antigen or nucleic acid amplification) at least 48 hours apart
      • Patients with immunocompromise may be contagious 20 days or more and should meet testing criteria to discontinue precautions

    Complications and Prognosis

    Complications

    • Most common complication is acute respiratory distress syndrome; other reported complications include: r16r17c277d6
    • MIS (multisystem inflammatory syndrome) is a serious but rare inflammatory condition associated with recent diagnosis of, or exposure to, COVID-19. MIS-C (multisystem inflammatory syndrome in children) occurs in patients younger than 21 years, whereas MIS-A (multisystem inflammatory syndrome in adults) occurs in patients aged 21 years or older r165r166r167c288d9
      • MIS-C and MIS-A are characterized by fever, elevated laboratory markers of inflammation, and evidence of organ dysfunction in cardiac, hematologic, gastrointestinal, and dermatologic systems, along with linkage to COVID-19
      • In children, MIS-C may present similarly to other pediatric hyperinflammatory syndromes such as Kawasaki disease and toxic shock syndrome r168d10
        • Common clinical features in children include fever, hypotension/shock, abdominal pain, vomiting, diarrhea, conjunctivitis, rash, and headache r167r169
        • Common laboratory abnormalities in MIS-C include elevated erythrocyte sedimentation rate; elevated levels of C-reactive protein, ferritin, and D-dimer; abnormal blood cell counts (eg, anemia, thrombocytopenia, neutrophilia); and elevated troponin level c289c290c291
        • In MIS-C, findings on echocardiography and abdominal ultrasonography are frequently abnormal (eg, left ventricular dysfunction, coronary artery abnormalities, ascites, bowel wall thickening)
        • Demographically, Black and Latino children are most commonly affected in the United States; an age shift has taken place, with younger populations more affected recently (Omicron subvariants BA.2/BA.4/BA.5, median age 5 years) compared with prior waves (Delta variant, median age 8 years), a shift that has been seen around the world r170
      • 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 r171
        • 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; CDCr166r167 and WHOr172 provide case definitions for reporting
        • Initial MIS-C case definition from CDC (in 2020) was intentionally broad, to increase sensitivity, and was developed rapidly based on limited cases
          • A new case definition (implemented since January 2023) was developed based on additional data; updated criteria are more specific to better distinguish MIS-C from acute COVID-19, Kawasaki disease, and toxic shock syndrome r167r168r170d11
            • New MIS-C case definition from CDC: a person younger than 21 years, with fever, with illness requiring hospitalization or resulting in death, and with C-reactive protein level of 3 mg/dL or more, along with both clinical manifestations and linkage to SARS-CoV-2 as described below:
              • 2 or more of the following clinical manifestations:
                • Cardiac involvement indicated by left ventricular ejection fraction less than 55%; coronary artery dilatation, aneurysm, or ectasia; or troponin level elevated above laboratory normal range or indicated as elevated in a clinical note
                • Mucocutaneous involvement indicated by rash, inflammation of oral mucosa (eg, mucosal erythema or swelling, drying or fissure of lips, strawberry tongue), conjunctivitis or conjunctival injection, or extremity findings (eg, erythema or edema of hands or feet)
                • Shock
                • Gastrointestinal involvement indicated by abdominal pain, vomiting, or diarrhea
                • Hematologic involvement indicated by platelet count less than 150,000 cells/mm³ or absolute lymphocyte count less than 1000 cells/mm³
              • 1 or more of the following laboratory or epidemiologic links to SARS-CoV-2:
                • Positive viral test (nucleic acid or antigen) during hospitalization or within 60 days prior
                • Positive viral test (nucleic acid or antigen) in a postmortem specimen
                • Detection of SARS-CoV-2–specific antibodies associated with current illness
                • Close contact with a confirmed or probable case of COVID-19 disease in the 60 days before hospitalization
        • MIS-A case definition from CDC: 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: r166
          • 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
      • Several professional organizations provide guidance on management r2r173r174
        • 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 d9
          • 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%) r18r175
      • Risk of severe or critical illness depends on age, underlying comorbidities, and vaccination status r18r54r175
      • Patients who require hospital admission often require prolonged inpatient stay (more than 20 days) and experience significant deconditioning r16r17
      • 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
      • In 2021, CDC estimated 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 r3
      • 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 in 2020 were as follows: r46
            • 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 by common comorbidities in China in 2020 were as follows: r179
            • 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 is common, especially after 90 days from infection r180
        • Vaccination in persons who have already had COVID-19 reduces the risk of reinfection r181
    • 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) r182r183r184
        • 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
          • Pain (chest pain, abdominal pain, joint pain, muscle pain, headache
          • Cough
          • Cognitive dysfunction ("brain fog")
          • Palpitations
          • Paresthesia
          • Diarrhea
          • Mood changes
          • Menstrual irregularities
          • Erectile dysfunction
          • Insomnia
          • Impaired sense of smell and/or taste (reduced, altered, or absent): hyposmia, anosmia; dysgeusia (hypogeusia, parageusia, ageusia)
          • Lightheadedness
        • Research is ongoing; specialized clinics are opening in many locations, and guidance is being developed for evaluation and care of these patients r183
      • 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 r185
        • 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) r186

    Screening and Prevention

    Screening

    Screening tests

    • Screening methods overview
      • Screening of asymptomatic persons in certain circumstances is an important method of interrupting transmission r55
        • 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 r58
    • Screening in health care settings
      • All patients with symptoms or close contact exposure should be tested, wear a face mask for source control, and be isolated until they meet criteria for discontinuing precautions r24r53
        • 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
        • COVID-19 can reasonably be excluded, and transmission-based precautions discontinued (or continued for an alternative pathogen), in patients with 1 negative nucleic acid amplification test result, 2 negative antigen test results 48 hours apart, or 1 negative antigen test result plus 1 confirmatory negative nucleic acid amplification test result
          • If clinical suspicion of COVID-19 is high, maintain precautions until 2 nucleic acid amplification test results are negative
      • Visitors with symptoms, exposure, or positive COVID-19 test result should be excluded from nonurgent visitation until meeting health care criteria for ending isolation (this duration is longer than with community criteria) r53
      • Workers at health care facilities with symptoms of COVID-19, a positive COVID-19 test result, or higher-risk COVID-19 exposure should report to occupational health or other designated contact r53
        • Higher-risk exposure occurs when health care personnel have prolonged close contact with someone with confirmed COVID-19 and:
          • Health care worker was not wearing a respirator
          • Health care worker was wearing a face mask and the other person was not wearing any source-control mask
          • Health care worker was not wearing eye protection and the other person was not wearing any source-control mask
          • Health care worker was not wearing all recommended personal protective equipment (ie, respirator, eye protection, gown, gloves) while in the room during an aerosol-generating procedure (for any length of time)
        • Prolonged is defined as cumulative 15 minutes or longer within 24 hours, and close is defined as being within 6 feet or having direct exposure to respiratory secretions; however, transmission may occur after any length of exposure or at any distance, particularly with poorly ventilated indoor areas
      • Consider screening tests (polymerase chain reaction or antigen testing) for asymptomatic patients (eg, preadmission or preprocedure), but such testing may be low-yield during low- or moderate-transmission phases r53
      • Screening testing (polymerase chain reaction or antigen testing) of staff and patients/residents may be useful for settings in which transmission risk is high and the population is at risk of severe disease, but such testing may be low-yield when disease transmission is not high r53
        • CDC guidance on infection prevention and control for health care professionals addresses specific health care settings r53
    • Screening in workplaces
      • Screening is most useful for workers in close proximity to each other who are isolated from health care resources (eg, fishing vessels, offshore oil platforms, wildland firefighter camps)
      • Specific guidance is available for correctional facilities and homeless shelters r187
    • Screening in public places r188
      • 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 required 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 and public health interventions
    • Vaccinesc292
      • Vaccine authorizations and approvals: various vaccines against SARS-CoV-2 have entered use in many countries, and more are in development r189r190r191r192r193
        • 3 vaccines are currently available in the United States
          • mRNA vaccines
            • Pfizer-BioNTech COVID-19 vaccine, 2023-2024 formula against Omicron XBB.1.5 (raxtozinameran) was granted emergency use authorization in the United States for ages 6 months to 11 years and full FDA approval (Comirnaty) for persons aged 12 years or older on September 11, 2023; it also has authorization or full approval in Canada, the United Kingdom, the European Union, and elsewhere r189r190r192r193c293
              • Original monovalent vaccine (BNT162b2; tozinameran; Comirnaty), which had emergency use authorization for ages 6 months to 11 years and full FDA approval for persons aged 12 years or older, is no longer authorized for use in the United States
              • Previous bivalent vaccine (tozinameran-famtozinameran), which acted against the original strain plus Omicron BA.4/BA.5 variant, is no longer authorized for use in the United States
            • Moderna COVID-19 vaccine, 2023-2024 formula against Omicron XBB.1.5 (andusomeran) was granted emergency use authorization in the United States for ages 6 months to 11 years and full FDA approval (Spikevax) for persons aged 12 years or older on September 11, 2023; it also has authorization or full approval in Canada, the United Kingdom, the European Union, and elsewhere r189r190r192r193c294
              • The original monovalent vaccine (mRNA-1273; elasomeran; Spikevax), which had emergency use authorization for ages 6 months to 17 years and full FDA approval for persons aged 18 years or older, is no longer authorized for use in the United States
              • The previous bivalent vaccine (elasomeran-davesomeran), which acted against the original strain plus Omicron BA.4/BA.5 variant, is no longer authorized for use in the United States
          • Protein subunit vaccine
            • Novavax COVID-19 Vaccine, 2023-2024 formula against Omicron XBB.1.5 was granted emergency use authorization in the United States for people aged 12 years or older on October 3, 2023, and is authorized or approved in the European Union, Canada, and elsewhere r190r192r193
              • Original monovalent vaccine (Novavax recombinant, adjuvanted; Nuvaxovid), which had emergency use authorization for persons aged 12 years or older, is no longer authorized for use in the United States
        • 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 r191c295c296
          • Pfizer, Moderna, and Novavax vaccines are available in Canada, the European Union, and elsewhere, under full approvals and/or emergency authorizations r190r192
          • AstraZeneca (Oxford-AstraZeneca) COVID-19 vaccine (ChAdOx1-S[recombinant]; Vaxzevria), a nonreplicating adenovirus vector vaccine, previously had authorization or full approval in many countries. It is no longer used in the United Kingdom or Canada; it remains authorized in the European Union r189r190r192c297
          • Janssen (Johnson and Johnson) COVID-19 vaccine (Ad26.COV2.S; Jcovden), a nonreplicating adenovirus vector vaccine, previously had authorization in the United States and has authorization or full approval in the European Union and elsewhere r189r190r192r194c298
        • CDC has ongoing vaccine effectiveness monitoring r13
          • Efficacy of vaccine-induced immunity against infection wanes over time, but protection against severe disease, hospitalization, and death remains robust, including against Omicron subvariants
        • 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 r195
        • 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 professionals 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: r194r196r197r198
              • 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
            • Clinicians providing vaccination are required to report certain events to VAERS (Vaccine Adverse Event Reporting System)r199 and are encouraged to report any other events r4
              • Events that require a report to VAERS include:
                • Vaccine administration errors, whether or not an adverse event occurred
                • Serious adverse events, whether or not attributed to the vaccine; these include myocarditis; pericarditis; multisystem inflammatory syndrome; cases of COVID-19 resulting in hospitalization or death; events that are life-threatening, require or prolong hospitalization, or require medical or surgical intervention to prevent hospitalization, disability, or death; birth defects; disability; and death
              • Reporting is encouraged for any other clinically significant adverse event, even if it is uncertain whether the vaccine caused the event
                • 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 r194r196r197r198r200
            • Vaccine recipients in the United States are encouraged to participate in CDC's V-safe monitoring and reminder system,r200 available as a mobile phone app
            • 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 r201
          • 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 siter202
        • SARS-CoV-2 vaccines in the United States.EUA, emergency use authorization.Data from FDA: COVID-19 Vaccines. FDA website. Updated October 3, 2023. Accessed October 17, 2023. https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/covid-19-vaccines
          Product nameManufacturerActive ingredientAge range for useComments
          Moderna COVID-19 vaccine, 2023-2024 formulaModernaTXNucleoside-modified
          messenger RNA encoding the spike (S) glycoprotein of the SARS-CoV-2 Omicron variant lineage XBB.1.5
          6 months or older• Used under EUA in the United States for ages 6 months to 11 years and full FDA approval for ages 12 years or older
          Pfizer-BioNTech COVID-19 vaccine, 2023-2024 formulaPfizer-BioNTechNucleoside-modified messenger
          RNA encoding the spike (S) glycoprotein of SARS-CoV-2 Omicron variant lineage
          XBB.1.5
          6 months or older• Used under EUA in the United States for ages 6 months to 11 years and full FDA approval for ages 12 years or older
          Novavax COVID-19 vaccine, adjuvanted, 2023-2024 formulaNovavaxRecombinant spike protein (rS) of SARS-CoV-2 Omicron variant lineage XBB.1.512 years or older• Used under EUA in the United States
      • Vaccination recommendations
        • CDC recommends vaccination against COVID-19 for everyone aged 6 months or older, including receiving 2023-2024 formula vaccine (1 or more doses depending on clinical factors) r4
          • Any age-appropriate vaccine may be used for vaccination, with no recommendation for one vaccine over any other
          • Follow color coding of products
            • Doses, concentrations, and formulations differ across age groups and manufacturers; therefore, color codingr4 has been established to aid in distinguishing preparations
          • Timing of dosing r4
            • 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 or longer after the erroneous dose
            • Doses administered any time after the recommended interval are valid
          • Primary vaccinations
            • Primary vaccination of nonimmunocompromised persons r4
              • Primary vaccination for persons aged 12 years or older is a single dose of Moderna, a single dose of Pfizer, 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 for 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 r203
              • Primary vaccination for persons aged 5 to 11 years is a single dose of Moderna or a single dose of Pfizer
              • Primary vaccination for children aged 6 months to 4 years is 2 doses of Moderna, with an interval of 4 to 8 weeks between doses; or 3 doses of Pfizer, 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
            • Primary vaccination of moderately or severely immunocompromised persons r4
              • Primary vaccination of moderately or severely immunocompromised persons is 3 doses of Moderna, 3 doses of Pfizer, or 2 doses of Novavax, with intervals determined by age and vaccine
                • Moderna 3-dose series for all age groups: 4 weeks between the first and second doses, and at least 4 weeks between the second and third doses
                • Pfizer 3-dose series for adults and children aged 5 years or older: 3 weeks between the first and second doses, and at least 4 weeks between the second and third doses
                • Pfizer 3-dose series for children aged 6 months to 4 years: 3 weeks between the first and second doses, and at least 8 weeks between the second and third doses
                • Novavax 2-dose series for adults and children aged 12 years or older: 3 weeks between the first and second doses
            • COVID-19 vaccination schedule in the United States for unvaccinated individuals.NA, not applicable. Colors listed in parentheses refer to (cap color/label border color). Any age-appropriate vaccine may be used for primary vaccination. Generally the same vaccine product should be used for all doses of the primary series. The patient's age on the date of vaccination should be used to select the formulation, with the exception that children who transition from 4 years to 5 years should complete vaccination with the 6 month to 4 year old formula from the same manufacturer.Data from CDC: Vaccines and Immunizations: COVID-19 Vaccination: Interim Clinical Considerations for Use of COVID-19 Vaccines in the United States. CDC website. Updated October 6, 2023. Accessed October 17, 2023. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html
              ManufacturerAgeDose 1Dose 2Dose 3Dose 4Notes
              Schedule for unvaccinated individuals who are NOT moderately to severely immunocompromised
              Moderna6 months to 4 yearsPrimary (dark blue/green), 0.25 mLIn 4 to 8 weeks, primary (dark blue/green), 0.25 mLNANAChildren who transition from 4 years to 5 years during primary series should receive both doses of dark blue/green, 0.25 mL
              Moderna5 years to 11 yearsPrimary (dark blue/green), 0.25 mLNANANA
              Moderna12 years or olderPrimary (dark blue/blue), 0.5 mLNANANA
              Pfizer6 months to 4 yearsPrimary (yellow/yellow), 0.3 mLIn 3 to 8 weeks, primary (yellow/yellow), 0.3 mLIn at least 8 weeks, primary (yellow/yellow), 0.3 mLNAYellow formulation requires dilution; children who transition from 4 years to 5 years during primary series should receive all 3 doses of yellow/yellow, 0.3 mL
              Pfizer5 years to 11 yearsPrimary (blue/blue), 0.3 mLNANANA
              Pfizer12 years or olderPrimary (gray/gray), 0.3 mLNANANA
              Novavax12 years or olderPrimary (blue/blue), 0.5 mLIn 3 to 8 weeks, primary (blue/blue), 0.5 mLNANA
              Schedule for unvaccinated individuals who ARE moderately to severely immunocompromised
              Moderna6 months to 4 yearsPrimary (dark blue/green), 0.25 mLIn 4 weeks, primary (dark blue/green), 0.25 mLIn at least 4 weeks, primary (dark blue/green), 0.25 mLNAAt clinician's discretion, additional dose(s) of Moderna only at an interval of at least 2 months
              Moderna5 years to 11 yearsPrimary (dark blue/green), 0.25 mLIn 4 weeks, primary (dark blue/green), 0.25 mLIn at least 4 weeks, primary (dark blue/green), 0.25 mLNAAt clinician's discretion, additional dose(s) of Moderna or Pfizer at an interval of at least 2 months
              Moderna12 years or olderPrimary (dark blue/blue), 0.5 mLIn 4 weeks, primary (dark blue/blue), 0.5 mLIn at least 4 weeks, primary (dark blue/blue), 0.5 mLNAAt clinician's discretion, additional dose(s) of Moderna, Novavax, or Pfizer at an interval of at least 2 months
              Pfizer6 months to 4 yearsPrimary (yellow/yellow), 0.3 mLIn 3 weeks, primary (yellow/yellow), 0.3 mLIn at least 8 weeks, primary (yellow/yellow), 0.3 mLNAYellow formulation requires dilution; children who transition from 4 years to 5 years during primary series should receive all 3 doses of yellow/yellow, 0.3 mL; at clinician's discretion, additional dose(s) of Pfizer only at an interval of at least 2 months
              Pfizer5 years to 11 yearsPrimary (blue/blue), 0.3 mLIn 3 weeks, primary (blue/blue), 0.3 mLIn at least 4 weeks, primary (blue/blue), 0.3 mLNAAt clinician's discretion, additional dose(s) of Pfizer or Moderna at an interval of at least 2 months
              Pfizer12 years or olderPrimary (gray/gray), 0.3 mLIn 3 weeks, primary (gray/gray), 0.3 mLIn at least 4 weeks, primary (gray/gray), 0.3 mLNAAt clinician's discretion, additional dose(s) of Moderna, Novavax, or Pfizer at an interval of at least 2 months
              Novavax12 years or olderPrimary (blue/blue), 0.5 mLIn 3 to 8 weeks, primary (blue/blue), 0.5 mLNANAAt clinician's discretion, additional dose(s) of Moderna, Novavax, or Pfizer at an interval of at least 2 months
          • Vaccination of persons who have had prior doses
            • In the United States, updated vaccine formulations (against the spike protein of Omicron XBB.1.5) were approved by the FDA on September 11, 2023 and October 3, 2023 r193
            • At least 1 dose of 2023-2024 vaccine formulation is recommended for everyone aged 6 months or older
            • Vaccination of nonimmunocompromised persons who have received prior doses r4
              • Adults and children aged 12 years or older who have received any COVID-19 vaccine doses are recommended to receive 1 dose of Moderna, Novavax, or Pfizer vaccine at least 8 weeks after the previous dose
                • This includes persons who have received 1 or more doses of a monovalent or bivalent mRNA vaccine, and those who have received Novavax or Janssen vaccine with or without subsequent mRNA vaccine doses
              • Children aged 5 years to 11 years who have received any prior COVID-19 vaccine doses are recommended to receive 1 dose of either Moderna or Pfizer vaccine at least 8 weeks after the previous dose
              • Children aged 6 months to 4 years who have received 1 or more doses of any mRNA vaccine are recommended to receive 1 or 2 doses (depending on prior doses) of Moderna or Pfizer vaccine from the same manufacturer as prior doses
                • Children aged 6 months to 4 years who have received Moderna dose(s) are authorized to have only Moderna vaccine
                  • Children aged 6 months to 4 years who have received 1 prior dose are recommended to receive 1 dose 2023-2024 formula in 4 to 8 weeks after prior dose
                  • Children aged 6 months to 4 years who have received 2 prior doses are recommended to receive 1 dose 2023-2024 formula in at least 8 weeks after prior dose
                • Children aged 6 months to 4 years who have received Pfizer dose(s) are authorized to have only Pfizer vaccine
                  • Children aged 6 months to 4 years who have received 1 prior dose are recommended to receive 2 doses 2023-2024 formula, the first dose 3 to 8 weeks after the prior dose, and the second dose at least 8 weeks after the first 2023-2024 formula dose
                  • Children aged 6 months to 4 years who have received 2 or more prior doses are recommended to receive 1 dose 2023-2024 formula at least 8 weeks after prior dose
            • Vaccination of moderately or severely immunocompromised persons who have received prior doses r4
              • Adults and children aged 6 months or older who have received 1 prior dose of any mRNA vaccine should receive 2 additional doses from the same manufacturer
                • Adults and children aged 6 months or older who have received 1 prior dose of any Moderna vaccine are recommended to receive the first dose 4 weeks after the prior dose, and the second dose at least 4 weeks after the first 2023-2024 formula dose
                • Adults and children aged 5 years or older who received 1 prior dose of any Pfizer vaccine are recommended to receive the first dose 3 weeks after the prior dose, and the second dose at least 4 weeks after the first 2023-2024 formula dose
                • Adults and children aged 6 months to 4 years who received 1 prior dose of any Pfizer vaccine are recommended to receive the first dose 3 weeks after the prior dose, and the second dose at least 8 weeks after the first 2023-2024 formula dose
              • Adults and children aged 6 months or older who have received 2 prior doses of any mRNA vaccine should receive 1 additional dose from the same manufacturer
                • Adults and children aged 6 months or older who have received 2 prior doses of any Moderna vaccine are recommended to receive the 2023-2024 formula dose at least 4 weeks after the last dose
                • Adults and children aged 5 years or older who received 2 prior doses of any Pfizer vaccine are recommended to receive the 2023-2024 formula dose at least 4 weeks after the last dose
                • Adults and children aged 6 months to 4 years who received 2 prior doses of any Pfizer vaccine are recommended to receive the 2023-2024 formula dose at least 8 weeks after the last dose
              • Children aged 5 years to 11 years who have received 3 or more doses of any mRNA vaccine are recommended to receive 1 dose of either Moderna or Pfizer 2023-2024 formula vaccine at least 8 weeks after the last dose
              • Adults and children aged 12 years or older who have received 3 or more doses of any mRNA vaccine are recommended to receive 1 dose of Moderna, Novavax, or Pfizer 2023-2024 formula vaccine at least 8 weeks after the last dose
              • Adults and children aged 12 years or older who have received Novavax or Janssen vaccine, with or without subsequent mRNA vaccine doses, are recommended to receive 1 dose of Moderna, Novavax, or Pfizer 2023-2024 formula vaccine at least 8 weeks after the last dose
              • Children aged 6 months to 4 years who have received 3 or more doses of any mRNA vaccine are recommended to receive 1 dose of 2023-2024 formula vaccine from the same manufacturer at least 8 weeks after the last dose
              • Additional age-appropriate vaccine booster doses may be administered at the discretion of the health care professional, at intervals of at least 2 months
            • COVID-19 vaccination schedule in the United States for individuals with prior doses.Colors listed in parentheses refer to (cap color/label border color). Generally the same vaccine product should be used for all doses of the primary series. The patient's age on the date of vaccination should be used to select the formulation, with the exception that children who transition from 4 years to 5 years should complete vaccination with the 6 month to 4 year old formula from the same manufacturer.Data from CDC: Vaccines and Immunizations: COVID-19 Vaccination: Interim Clinical Considerations for Use of COVID-19 Vaccines in the United States. CDC website. Updated October 6, 2023. Accessed October 17, 2023. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html
              AgePrior dosesRecommended dosesNotes
              Schedule for individuals who are NOT moderately to severely immunocompromised
              6 months to 4 years1 dose Moderna1 dose Moderna (dark blue/green), 0.25 mL, 4 to 8 weeks after prior dose
              6 months to 4 years2 or more doses Moderna1 dose Moderna (dark blue/green), 0.25 mL, at least 8 weeks after last dose
              6 months to 4 years1 dose Pfizer2 doses Pfizer (yellow/yellow), 0.3 mL: first dose 3 to 8 weeks after prior dose, second dose at least 8 weeks after first 2023-2024 formula doseYellow formulation requires dilution
              6 months to 4 years2 or more doses Pfizer1 dose Pfizer (yellow/yellow), 0.3 mL, at least 8 weeks after last doseYellow formulation requires dilution
              5 years to 11 years1 or more doses of any mRNA vaccine1 dose Moderna (dark blue/green), 0.25 mL, OR 1 dose Pfizer (blue/blue), 0.3 mL, at least 8 weeks after last dose
              12 years or older1 or more doses of any vaccine1 dose Moderna (dark blue/blue), 0.5 mL; OR 1 dose Novavax (blue/blue), 0.5 mL; OR 1 dose Pfizer (gray/gray), 0.3 mL; at least 8 weeks after last dose
              Schedule for individuals who ARE moderately to severely immunocompromised
              6 months to 4 years1 dose Moderna2 doses Moderna (dark blue/green), 0.25 mL: first dose 4 weeks after prior dose, second dose at least 4 weeks after first 2023-2024 formula dose At clinician's discretion, additional dose(s) of Moderna only at an interval of at least 2 months
              6 months to 4 years2 doses Moderna1 dose Moderna (dark blue/green), 0.25 mL, at least 4 weeks after last doseAt clinician's discretion, additional dose(s) of Moderna only at an interval of at least 2 months
              6 months to 4 years3 or more doses Moderna1 dose Moderna (dark blue/green), 0.25 mL, at least 8 weeks after last doseAt clinician's discretion, additional dose(s) of Moderna only at an interval of at least 2 months
              6 months to 4 years1 dose Pfizer2 doses Pfizer (yellow/yellow), 0.3 mL: first dose 3 weeks after prior dose, second dose at least 8 weeks after first 2023-2024 formula doseYellow formulation requires dilution; at clinician's discretion, additional dose(s) of Pfizer only at an interval of at least 2 months
              6 months to 4 years2 or more doses Pfizer1 dose Pfizer (yellow/yellow), 0.3 mL at least 8 weeks after last doseYellow formulation requires dilution; at clinician's discretion, additional dose(s) of Pfizer only at an interval of at least 2 months
              5 years to 11 years1 dose Moderna2 doses Moderna (dark blue/green), 0.25 mL: first dose 4 weeks after prior dose, second dose at least 4 weeks after first 2023-2024 formula doseAt clinician's discretion, additional dose(s) of Moderna or Pfizer at an interval of at least 2 months
              5 years to 11 years2 doses Moderna1 dose Moderna (dark blue/green), 0.25 mL, at least 4 weeks after last doseAt clinician's discretion, additional dose(s) of Moderna or Pfizer at an interval of at least 2 months
              5 years to 11 years1 dose Pfizer2 doses Pfizer (blue/blue), 0.3 mL: first dose 3 weeks after prior dose, second at least 4 weeks after first 2023-2024 formula doseAt clinician's discretion, additional dose(s) of Pfizer or Moderna at an interval of at least 2 months
              5 years to 11 years 2 doses Pfizer1 dose Pfizer (blue/blue), 0.3 mL at least 4 weeks after last doseAt clinician's discretion, additional dose(s) of Pfizer or Moderna at an interval of at least 2 months
              5 years to 11 years3 doses of any mRNA vaccine1 dose Moderna (dark blue/green), 0.25 mL, OR 1 dose Pfizer (blue/blue), 0.3 mL, at least 8 weeks after last doseAt clinician's discretion, additional dose(s) of Moderna or Pfizer at an interval of at least 2 months
              12 years or older1 dose Moderna2 doses Moderna (dark blue/blue), 0.5 mL: first dose 4 weeks after prior dose, second dose at least 4 weeks after first 2023-2024 formula doseAt clinician's discretion, additional dose(s) of Moderna, Novavax, or Pfizer at an interval of at least 2 months
              12 years or older2 doses Moderna1 dose Moderna (dark blue/blue), 0.5 mL at least 4 weeks after last doseAt clinician's discretion, additional dose(s) of Moderna, Novavax, or Pfizer at an interval of at least 2 months
              12 years or older1 dose Pfizer2 doses Pfizer (gray/gray), 0.3 mL: first dose 3 weeks after prior dose, second dose at least 4 weeks after first 2023-2024 formula doseAt clinician's discretion, additional dose(s) of Moderna, Novavax, or Pfizer at an interval of at least 2 months
              12 years or older2 doses Pfizer1 dose Pfizer (gray/gray), 0.3 mL, at least 4 weeks after last doseAt clinician's discretion, additional dose(s) of Moderna, Novavax, or Pfizer at an interval of at least 2 months
              12 years or older3 doses of any mRNA vaccine1 dose Moderna (dark blue/blue), 0.5 mL; OR 1 dose Novavax (blue/blue), 0.5 mL; OR 1 dose Pfizer (gray/gray), 0.3 mL; at least 8 weeks after last doseAt clinician's discretion, additional dose(s) of Moderna, Novavax, or Pfizer at an interval of at least 2 months
              12 years or older1 or more doses Novavax or Janssen, with or without subsequent doses of mRNA vaccine1 dose Moderna (dark blue/blue), 0.5 mL; OR 1 dose Novavax (blue/blue), 0.5 mL; OR 1 dose Pfizer (gray/gray), 0.3 mL; at least 8 weeks after last doseAt clinician's discretion, additional dose(s) of Moderna, Novavax, or Pfizer at an interval of at least 2 months
        • Interchangeability of vaccines r4
          • Data are limited on the interchangeability of the COVID-19 vaccines to complete the primary vaccination series r204
            • Children aged 6 months to 4 years with or without moderate to severe immunocompromise who receive the first dose of any of the vaccines should complete the primary vaccination series with vaccine from the same manufacturer
            • Adults and children aged 6 months or older with moderate or severe immunocompromise should complete a primary vaccination series with vaccine from the same manufacturer
              • Primary vaccination series for immunocompromised patients is 3 doses for mRNA vaccines (Moderna or Pfizer, age 6 months or older) or 2 doses for protein subunit vaccine (Novavax, age 12 years or older)
            • If a child aged 6 months to 4 years (with or without moderate or severe immunocompromise) inadvertently receives mRNA vaccine from different manufacturers, a third dose should be administered at least 8 weeks after the second dose, using 2023-2024 formula vaccine from either Moderna or Pfizer
            • If an adult or child aged 5 years or older with moderate or severe immunocompromise inadvertently receives vaccine from two different manufacturers during primary series vaccination, a third dose should be administered at least 4 weeks after the second dose
              • The third dose should be 2023-2024 formula vaccine from either Moderna or Pfizer for ages 5 to 11 years, or Moderna, Novavax, or Pfizer for ages 12 years or older
          • Limited data suggest that heterologous boosters (ie, booster vaccine different from primary) may produce equivalent or stronger serologic response compared with homologous boosters, with a small increase in minor adverse effects r204r205
        • 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 r4
          • Respiratory syncytial virus vaccine, influenza vaccine, and COVID-19 vaccine may all be administered at the same time in different anatomic sites
          • If orthopoxvirus (mpox) vaccine is recommended, no minimum interval is required between COVID-19 vaccine and orthopoxvirus vaccine, whichever is administered first
            • However, consider a 4-week interval between these 2 vaccines, particularly in adolescent or young adult males, to minimize the low risk of myocarditis with these vaccines; do not delay vaccination when risks of mpox or severe COVID-19 are high
            • Prioritize JYNNEOS vaccine over ACAM2000 when coadministering a COVID-19 vaccine and an orthopoxvirus vaccine
        • History of COVID-19 is not a contraindication to vaccine; guidelines recommend that everyone aged 6 months or older be offered vaccine r4
          • For persons with current COVID-19 infection, vaccination should be deferred until the person meets criteria for discontinuing isolation r4
            • Consider deferring vaccination for 3 months after COVID-19 infection to potentially improve immunogenicity of vaccination
          • 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 r206r207
        • Limited data exist regarding safety and efficacy of vaccination after MIS-C or MIS-A (multisystem inflammatory syndrome, either in children or in adults); the benefits of vaccination should be weighed against the theoretical risk of multisystem inflammatory syndrome or myocarditis after vaccination r4
          • Experts consider that benefits of vaccination for those with MIS-C or MIS-A probably exceed theoretical risk once clinical recovery is achieved (including return to normal myocardial function) and 90 days or more have elapsed since MIS-C or MIS-A diagnosis
            • Vaccination may be considered even for those do not yet meet criteria above, at the discretion of the care team or with additional consultation
            • If MIS-C or MIS-A was diagnosed within 60 days of COVID-19 vaccination, decide on any subsequent dose(s) on an individual basis, in conjunction with the clinical team, the patient and/or the parent(s)
          • Consider consultation with a specialist in infectious diseases, rheumatology, or cardiology, and/or with personnel of the Clinical Immunization Safety Assessment COVIDvax project,r208 to discuss specific cases, particularly if MIS-C or MIS-A occurred after vaccination
        • Vaccine use in special populations
          • Pregnant persons and breastfeeding persons r4r160r161
            • 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
              • Studies indicate that pregnant persons with COVID-19 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 r209
                • 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) r210
                • 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 r206
              • 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 r211
            • 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 monthsr4 (National Comprehensive Cancer Network recommends 6 monthsr211); after this waiting period, follow the vaccine schedule for unvaccinated individuals with moderate to severe immunocompromise
              • 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
          • Persons taking immunosuppressive medications r4
            • Do not delay vaccination for persons taking immunosuppressive medications
            • Where possible, administer vaccine 2 or more weeks before planned immunosuppressive therapy
            • For patients taking short-term B-cell–depleting therapy (eg, rituximab for certain malignancies), revaccinate 6 months after completion following the vaccine schedule for unvaccinated individuals with moderate to severe immunocompromise
            • For patients taking continuous B-cell–depleting therapy, time vaccination 4 weeks before scheduled treatment
            • Clinicians may alter vaccination schedule for individual patients when benefits of vaccination outweigh risks
      • Vaccine contraindications and significant adverse effects
        • Contraindications include: r4
          • 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 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 r4r212r213
          • This adverse effect has been reported after vaccination with AstraZeneca, Moderna, Novavax, and Pfizer vaccines; for mRNA vaccines, the risk appears slightly higher after Moderna vaccination than after Pfizer vaccination r4r214
          • Onset is usually within 7 days after administration of vaccine; the condition is generally short-lived and mild
          • The risk of myocarditis or pericarditis from COVID-19 disease appears higher than the risk of myocarditis or pericarditis from vaccination, and the overall benefits of vaccination far outweigh risks r4r203r215
          • Vaccine recommendations for adolescents and young adults remain unchanged, except that waiting 8 weeks between a first and second dose may decrease the risk (for those recommended to have more than 1 dose), and persons who have had myocarditis within 3 weeks of a dose of vaccine should generally avoid subsequent doses
        • CDCr4 and the European Medicines Agencyr216 have recommended that clinicians maintain a high index of suspicion for thrombotic events and thrombocytopenia among persons who have received the Janssen or AstraZeneca adenovirus vector 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 r4r216
          • 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): r217
            • 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: r217
            • IV immunoglobulin
            • 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 r217
            • 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 r4
        • 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 r4
      • Vaccine-specific details and evidence
        • Pfizer-BioNTech COVID-19 vaccine (Comirnaty) (versions have included raxtozinameran; tozinameran-famtozinameran; tozinameran-riltozinameran; tozinameran [development code BNT162b2]) r198r218c299
          • An mRNA vaccine against the SARS-CoV-2 spike protein (ie, using messenger ribonucleic acid)
          • The first version, tozinameran, was 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% r219
            • 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 the first 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 r198
            • 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 r198r219
          • 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 r198r219
            • 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 r198
            • Severe allergic reactions have been described, and facilities at which vaccine is administered must have the ability to treat such reactions (including anaphylaxis) r198
          • 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 r220
          • FDA approval for ages 16 years or older was based on continued follow-up of initial study enrollees and additional data r198
          • 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 r198
            • 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 r4r198
            • 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 r221
            • 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
          • FDA emergency use authorization for ages 6 months to 11 years and full approval for persons aged 12 years or older was granted on September 11, 2023, for the 2023-2024 formula against Omicron XBB.1.5 r222
            • Authorization and approval were granted on the basis of:
              • Safety and efficacy of the prior formulas, with the same manufacturing process
              • Comparable immunogenicity data (latest versus earlier formulas)
              • Data from currently circulating variants EG.5 and BA.2.86, which showed neutralization at a similar magnitude compared with prior vaccine version neutralization of variants they were developed against
                • Omicron XBB.1.5 was the dominant variant circulating in June, when the FDA advised manufacturers to develop updated vaccines for use in fall 2023; EG.5 and BA.2.86 are similar Omicron variants r9
          • Original monovalent vaccine and bivalent formulas are no longer authorized for use in the United States r198
        • Moderna COVID-19 vaccine (Spikevax) (versions have included andusomeran; elasomeran-davesomeran; elasomeran-imelasomeran; elasomeran [development code mRNA-1273]) r197r223c300
          • An mRNA vaccine against the SARS-CoV-2 spike protein
          • Safety data evaluated for the first US emergency use authorization included 30,351 adults, 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 r224
            • Overall efficacy was 94.1% (95.6% for adults aged 18 through 64 years and 86.4% for adults aged 65 years 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-providing clinicians in preparing for and managing such events,r225 and for postanaphylaxis laboratory assessmentr226
            • Myocarditis and pericarditis have been reported to occur in adolescents and young adults (primarily males) after vaccination with multiple vaccines, most commonly after the second dose; evidence suggests higher risk after Moderna vaccination than after Pfizer vaccination r4r212r213r214
          • After additional review, Moderna vaccine received full FDA approval for persons aged 18 years or older (approved on January 31, 2022) r227
          • Subsequent analysis of data in younger age groups led to FDA emergency use authorization on June 17, 2022, for children and adolescents aged 6 months through 17 years r221
            • 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%
          • FDA emergency use authorization for ages 6 months to 11 years and full approval for persons aged 12 years or older was granted on September 11, 2023, for the 2023-2024 formula against Omicron XBB.1.5 r222
            • Authorization and approval were granted on the basis of:
              • Safety and efficacy of the prior formulas, with the same manufacturing process
              • Comparable immunogenicity data (latest versus earlier formulas)
              • Data from currently circulating variants EG.5 and BA.2.86, which showed neutralization at a similar magnitude compared with prior vaccine version neutralization of variants they were developed against
                • Omicron XBB.1.5 was the dominant variant circulating in June, when the FDA advised manufacturers to develop updated vaccines for use in fall 2023; EG.5 and BA.2.86 are similar Omicron variants r9
          • Original monovalent vaccine and bivalent formulas are no longer authorized for use in the United States r197
        • Novavax COVID-19, Adjuvanted r196
          • Protein subunit vaccine containing SARS-CoV-2 spike protein and Matrix-M adjuvant; prior version was against ancestral (Wuhan) strain spike protein and 2023-2024 formula is against Omicron XBB.1.5 spike protein
          • 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
          • FDA emergency use authorization for persons aged 12 years or older was granted on October 3, 2023, for the 2023-2024 formula against Omicron XBB.1.5 r228
            • Authorization was granted based on:
              • Safety and efficacy of the prior formulas (including versions which were studies but not marketed), with the same manufacturing process
              • Higher neutralizing antibodies against XBB lineages compared to the original formula, to better match currently circulating strains
          • Original formula is no longer authorized for use in the United States
        • Janssen (Johnson and Johnson) COVID-19 vaccine r194c301
          • A replication-deficient adenovirus vector vaccine that generates immunity to the SARS-CoV-2 spike protein
          • On the basis of efficacy and safety data, FDA authorized the vaccine on February 7, 2021 r194
          • From April 12, 2021 through April 23, 2021, use was suspended to investigate a rare thrombotic adverse effect; resumption occurred because the adverse effect was extremely rare r229
            • Characterized by cerebral venous thrombosis with thrombocytopenia occurring 6 to 13 days after administration
            • A total of 15 affected persons, all of whom were females aged between 18 and 59 years, were found among more than 6.8 million doses of vaccine in the United States
          • 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 r230
          • This FDA emergency use authorization ended on June 1, 2023, at Janssen's request, and the vaccine is no longer available in the United States r231
    • Preexposure prophylaxisr2
      • Preexposure prophylaxis with monoclonal antibodies is no longer available, as the previously authorized option (tixagevimab-cilgavimab) is ineffective against Omicron variant
        • Since January 2023, NIH guidelines recommend against preexposure prophylaxis with tixagevimab-cilgavimab r2
          • From December 2021 until January 2023, monoclonal antibodies tixagevimab and cilgavimab had FDA emergency use authorization for coadministration in persons who either (1) were moderately to severely immunocompromised and might not mount an immune response to vaccine or (2) had a contraindication to vaccination (eg, severe allergic reaction to COVID-19 vaccine or components). However, because more than 90% of SARS-CoV-2 variants circulating by January 2023 were resistant to these monoclonal antibodies, the emergency use authorization was suspended r129
    • Postexposure prophylaxisr2
      • Postexposure prophylaxis is no longer available, as the previously authorized options (monoclonal antibodies casirivimab-imdevimab or bamlanivimab-etesevimab) are ineffective against Omicron variant
    • Public health interventions to interrupt transmission (eg, masking, distancing, hygiene, isolation, quarantine): practices vary geographically and depend on regional disease activity and other factors
      • General precautions for all populations r83
        • Keep up to date with vaccinations
        • Monitor for symptoms
        • Test to prevent spread to others (eg, if you have symptoms, exposure, or plans to gather with someone at higher risk)
        • Avoid contact with others (eg, stay home) when you are sick, even if an initial test result comes back negative; many transmissible respiratory infections cocirculate in communities
        • Avoid contact with those who have suspected or confirmed COVID-19
        • Improve ventilation whenever possible; avoid poorly ventilated spaces
        • 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
        • Wear a mask (preferably high quality, such as N95) in indoor settings when community transmission is moderate to high or if you are at high risk
        • Avoid crowds, and physical distance at least 6 feet from others, when community transmission is moderate to high or if you are at high risk
      • Isolation and quarantine measures: overview
        • A Cochrane review of quarantine concluded that quarantine is important in reducing incidence and mortality r232
        • All those who have symptoms of COVID-19, regardless of vaccination status, should isolate themselves, get tested for COVID-19, and wear a mask if they must be near others (eg, to seek medical care, when near household members) r83
          • Persons with symptoms and an initial negative antigen test result should continue to isolate and repeat the test 48 hours later r55
          • Persons with a negative test result but high clinical suspicion for COVID-19 should have repeat testing r55
        • Persons who test positive for COVID-19, regardless of vaccination status or symptoms, should isolate until they meet criteria for discontinuing isolation r180
        • Persons exposed to COVID-19, regardless of vaccination status, should wear a mask around others for 10 days, monitor for symptoms, and get tested r83
          • 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
      • Criteria for discontinuation of isolation precautions r53r180
        • Use a symptom-based strategy to determine when to discontinue isolation in most patients. Criteria have been established based on observations showing that duration of shedding of infective virus varies from less than 10 days in milder cases to 20 days or longer in more severe infections and in immunocompromised persons
          • Asymptomatic, no immunocompromise:
            • Isolate for 5 days after positive test (day of testing is day 0)
            • Wear a mask for 5 additional days (through day 10)
            • If symptoms develop during these 10 days, restart isolation following symptomatic criteria, with first day of symptoms as day 0
          • Mild symptomatic COVID, no immunocompromise:
            • Isolate for at least 5 days after symptom onset (first day of symptoms is day 0), until 24 hours fever free (without use of antipyretics) and symptoms have improved
            • Wear a mask for 5 additional days (through day 10)
          • Moderate COVID-19 (shortness of breath or other difficulty breathing), no immunocompromise:
            • Isolate for 10 days
          • Severe or critical illness (including hospitalized patients), no immunocompromising condition:
            • Isolate at least 10 days and up to 20 days since symptom onset (day 0) and
            • At least 24 hours have passed since last fever without use of antipyretics and
            • Symptoms have improved; continue to wear mask for source control until symptoms resolve
            • Consider testing before discontinuing isolation
          • Moderately or severely immunocompromised persons:
            • Continue isolation for 20 days or longer after symptom onset or first positive SARS-CoV-2 test result
            • Use a test-based strategy to determine duration
            • Consider infectious disease consultation
        • Test-based criteria for discontinuation of isolation include:
          • Fever has resolved and symptoms are improved, and
          • Negative test results from 2 consecutive specimens at least 48 hours apart; polymerase chain reaction or antigen tests are acceptable
            • A nucleic acid amplification test may be used, but results frequently remain positive for days to weeks and do not necessarily correlate with being infectious r55
        • Loss of taste and/or smell may persist for weeks to months and does not need to delay the end of isolation
        • If symptoms recur or worsen after improving, restart isolation at day 0
      • Infection control for at-home management of COVID-19 r83r180
        • 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 c302c303c304
          • 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 c305c306
          • Clean and disinfect regularly c307
          • Restrict contact with the patient 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) r53
        • Immediately provide any patient with suspected COVID-19 a face mask for source control and place the patient in a closed room pending further evaluation and disposition decisions
          • If available, the patient room will ideally be one with structural and engineering safeguards against airborne transmission (eg, negative pressure, frequent air exchange), but if caseload or resource limitations preclude the ideal, then 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 c308c309c310
          • Wear gloves, gowns, eye protection, and respirator (N95 or better) with adherence to hospital donning and doffing protocols c311c312
            • 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) c313c314
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