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May.26.2022

Coronavirus: Novel Coronavirus (COVID-19) Infection

Synopsis

Key Points

  • COVID-19 (coronavirus disease 2019) is a systemic infection due to a novel coronavirus, SARS-CoV-2; global pandemic is ongoing
  • Infection ranges from asymptomatic to severe; symptoms usually include fever, cough, and (in moderate to severe cases) dyspnea. Disease may evolve over the course of a week or more from mild to severe; deterioration may be sudden and catastrophic
  • Infection should be suspected based on presentation with a clinically compatible history (eg, fever, upper or lower respiratory tract symptoms); alterations in senses of smell and taste are particularly suggestive
  • Chest imaging in symptomatic patients almost always shows abnormal findings, usually including bilateral infiltrates; laboratory findings are variable but typically include lymphopenia and elevated lactate dehydrogenase and transaminase levels
  • Diagnosis is confirmed by detection of viral RNA on polymerase chain reaction test of upper or lower respiratory tract specimens; antigen testing is also available and has near-equivalent specificity but is slightly less sensitive
  • Treatments and treatment strategies continue to be refined; available drugs are administered at different stages of disease based on the pharmacologic mechanism of action and the dominant pathophysiology of the disease phase
    • Several antiviral medications are available, including remdesivir, ritonavir-boosted nirmatrelvir, and molnupiravir
    • Monoclonal antibodies including bebtelovimab,r1sotrovimab,r2casirivimab-imdevimab,r3bamlanivimab-etesevimab,r4r5 and tixagevimab-cilgavimabr6 have been used for treatment, postexposure prophylaxis, and preexposure prophylaxis, but use depends on susceptibility to circulating variants
    • Dexamethasone also has been associated with significant reduction in mortality rates of patients requiring supplemental oxygenr7
    • Several immunomodulators are recommended for use in conjunction with corticosteroids with or without remdesivir in patients requiring high-flow oxygen or noninvasive ventilation r8
  • 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 r9r10
  • 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 r11

Urgent Action

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

Pitfalls

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

Terminology

Clinical Clarification

  • COVID-19 (coronavirus disease 2019) is a systemic infection (with a predilection for the respiratory system) caused by a newly recognized coronavirus, SARS-CoV-2, thought to have originated as a zoonotic virus that has mutated or otherwise adapted in ways that allow human pathogenicity
    • Disease was provisionally called 2019-nCoV infection at start of outbreak (2019 novel coronavirus infection)
  • Outbreak began in China but has since spread globally; it was officially declared by WHO to be a pandemic on March 11, 2020 r12
  • 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 r9r10
  • 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 coronavirusr13r14
    • Designated as SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2); earlier provisional name was 2019-nCoV (2019 novel coronavirus) r13r14
  • Variants
    • Since late 2020, variants with potential impact on transmission, clinical disease, and immune protection have been recognized
    • CDC COVID Data Tracker maintains information about geographical distribution of variants in the United States and globally; at this time, more than 99% of circulating virus in the United States is Omicron variant r15
    • CDC classifies them as variants of concern, variants being monitored, or variants of interest; the category of variants of high consequence exists in reserve, in case of future need r16
      • 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
        • Delta (B.1.617.2 and AY lineages): first detected in India; characterized by increased transmissibility and possibly reduced neutralization by some monoclonal antibody treatments and postvaccine serum
        • Omicron (B.1.1.529 and BA lineages): first detected in South Africa; is now essentially the only variant in the United States (since January 2022). Appears to be more easily transmitted than other variants, and has reduced susceptibility to some monoclonal antibody products; efficacy of remdesivir is thought to be undiminished r8r15r17
          • Omicron subvariant BA.2 is the dominant strain worldwide and in the United States since mid-February 2022; this subvariant appears to have increased transmissibility, similar severity, and similar susceptibility to antibodies generated by immunization as Omicron subvariant BA.1, the previous most prevalent subvariant r15r18
      • Variants being monitored
        • Primary examples are as follows; consult the CDC list for more: r16
          • Alpha (B.1.1.7 and Q lineages): appears to have emerged in the United Kingdom; thought to be more easily transmitted and possibly associated with more severe disease than the original strain
          • Beta (B.1.351 and descendent lineages): first noted in South Africa; may confer some resistance to certain vaccines (eg, Moderna mRNA-1273)
          • Gamma (P.1 and descendent lineages): seems to have originated in Brazil; may mitigate the protective effect of antibodies to the original strain
          • Epsilon (B.1.427 and B.1.429): both first detected in California; both associated with slightly increased transmissibility, significant decrease in neutralization effect of some monoclonal antibody treatments, and moderate decrease in neutralization effect of convalescent serum

Diagnosis

Clinical Presentation

History

  • Incubation period is typically within 14 days of exposure, and within 5 days in most patients. Incubation for more than 14 days occurs in a small percentage of patients r19r20
    • 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 r21c2c3c4
  • The most common complaints in unvaccinated people are fever/chills and cough, which may or may not be productive r21r22r23c5c6c7c8
    • Fever is often not present at presentation, even in hospitalized patients, and may be very mild (less than 38 °C) r21
    • Myalgia, headache, and fatigue are common; fatigue may be profound r21r23c9c10
    • Upper respiratory tract symptoms (eg, rhinorrhea, sneezing, sore throat) may be present in up to 20% of symptomatic infections r23c11c12c13c14
    • Gastrointestinal symptoms (eg, abdominal pain, nausea, vomiting, diarrhea) are present in 10% to 20% of symptomatic infections r21r23c15c16c17c18c19
    • Alteration in smell and/or taste is less common but highly suggestive r23r24r25c20c21c22
  • Patients with moderate to severe disease often complain of dyspnea;r26r27 however, it has been recognized that many patients with severe hypoxemia due to COVID-19 do not perceive dyspnear28r29r30r31r32r33c23
    • Hemoptysis has been reported in a small percentage of patients r21c24
    • Pleuritic chest pain has been reported r19c25
  • When COVID-19 is acquired after vaccination, a shift in the most common symptoms has been reported: headache, rhinorrhea, sneezing, sore throat, and loss of smell are most prominent, whereas cough and fever are less common than in unvaccinated people r34

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) r35
  • 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 r21c30c31c32c33
  • Conjunctival secretions, injection, and chemosis have been reported r36c34c35c36c37c38
  • A variety of skin changesr37 have been described, including erythematous rashes,r38purpura,r39petechiae,r40 and vesicles;r41acral lesionsr42r43r44 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: r35
      • Altered mental status c72
      • Tachycardia (heart rate more than 160 beats per minute in infants or 150 in older children) or bradycardia (heart rate less than 90 in infants or 70 in older children) c73c74
      • Prolonged capillary refill (more than 2 seconds) or warm vasodilation and bounding pulses c75c76c77
      • Tachypnea c78
      • Mottled skin, petechiae, or purpura c79c80c81
      • Oliguria c82
      • Hyperthermia or hypothermia c83

Causes and Risk Factors

Causes

  • Infection due to SARS-CoV-2 (2019 novel coronavirus) c84
  • Person-to-person transmission has been confirmed and occurs through the air, in droplets and aerosols of various sizes, particularly with close contact r19r45r46c85
    • Viral shedding appears to peak 24 to 48 hours before symptom onset,r47 with consequent presymptomatic transmission. Several case and cluster reports from various countriesr48r49r50 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 r51
  • Additional means of transmission may occur but are thought to be less common (eg, contact with infected environmental surfaces, fomites, infection from animals) r46c87c88c89

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 r52
    • 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 r52
    • 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 r52
    • 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 r52
    • Incident case rate for 0 to 4 years in August 2021 (155 per 100,000) was higher than that of 75 years or older in April 2020 (122 per 100,000)
  • All age groups appear susceptible to COVID-19, but the risk of severe disease and death increases with age r53
    • 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 r52
    • Approximate percentage of total mortality in the United States by age group: r54
      • 0 to 39 years: 2.5%
      • 40 to 49 years: 4.3%
      • 50 to 64 years: 18.8%
      • 65 to 74 years: 23%
      • 75 to 84 years: 25.8%
      • 85 years or older: 25.6%
Sex
  • Overall, where sex or gender data are available, it appears that females are more often affected, but disease is more severe in males r52c93c94
Other risk factors/associations
  • Various underlying medical conditions have been associated with increased risk for severe disease, and many conditions are under investigation r55
  • Conditions which have been associated with higher risk for severe outcome (based on systematic review or meta-analysis): r55
    • Cerebrovascular disease c95c96
    • Chronic kidney disease c97c98
    • Specific chronic lung diseases: interstitial lung disease, pulmonary embolism, pulmonary hypertension, bronchiectasis, chronic obstructive pulmonary disease c99c100c101
    • Specific chronic liver diseases: cirrhosis, nonalcoholic fatty liver disease, alcoholic liver disease, autoimmune hepatitis c102c103c104c105
    • Serious cardiac conditions (eg, heart failure, coronary artery disease, cardiomyopathy) c106c107c108c109c110c111c112c113c114c115c116c117c118c119c120c121c122c123
    • Cystic fibrosis c124c125c126
    • Diabetes mellitus, type 1 and type 2 c127c128
    • Malignancy c129
    • Pregnancy and recent pregnancy c130
    • Obesity (BMI of 30 kg/m² or higher) c131c132c133
    • Smoking, current and former c134c135c136c137c138c139c140c141c142c143c144c145
    • Specific mental health disorders: mood disorders, including depression; 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 c146c147c148c149c150c151
    • Tuberculosis
  • Conditions which are suggestive of higher risk for severe outcomes (based on cohort, case-control, or cross-sectional studies): r55
  • Conditions which might be associated with higher risk for severe disease (based on mixed evidence): r55
  • However, studies indicate that many people who develop severe disease (hospitalization and/or death) have no comorbidities r55
  • 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 r56c196c197c198c199c200
  • In areas where vaccines are widely available, being unvaccinated (compared with being fully vaccinated) confers substantially higher risk for infection, hospitalization, and death r57

Diagnostic Procedures

Primary diagnostic tools

  • Diagnostic testing (laboratory or point of care tests): polymerase chain reaction tests are the standard for diagnosis; antigen testingr61 is also widely available in the United States. Public health authorities may assist in testing in some areas. Attempts to culture the virus are not recommended. Serologic testsr62 are not recommended for diagnostic purposes in most circumstances r58r59r60c201c202c203c204c205
    • CDCr60 and WHOr63r64 both recommend diagnostic testing in everyone with compatible symptoms, regardless of vaccination status, but they differ slightly on screening
      • WHO r63r64
        • All persons who meet the suspected or probable case definition should be tested; testing of asymptomatic persons is recommended to be limited to contacts of confirmed or probable COVID-19 and health care workers, including long-term care workers, who are frequently exposed; widespread screening of asymptomatic persons is not currently recommended
          • Case definitions: suspected case r64
            • 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, altered mental status) plus 1 of the following:
              • Living or working in a setting with high risk of transmission of SARS-CoV-2 (eg, closed residential facilities, refugee camps) at any time during the 14 days preceding symptom onset
              • A history of travel to or residence in an area reporting local transmission of COVID-19 during the 14 days preceding symptom onset
              • Working in any health care setting at any time during the 14 days preceding symptom onset
            • Onset within the past 10 days of a severe acute respiratory tract infection requiring hospital admission without an alternative etiologic diagnosis
            • Asymptomatic person with positive antigen test result (but no epidemiologic link); recommend polymerase chain reaction for confirmation
          • Case definitions: probable case r64
            • Someone with the clinical symptoms above, or who died of an unexplained respiratory illness, who is a contact of a confirmed or probable case or is part of a cluster
            • Someone with acute lack of taste or smell with no alternative diagnosis
            • Someone with a suspected case who also has chest imaging suggestive of COVID-19
              • Characteristic chest radiograph findings include hazy opacities with peripheral and lower lung distribution; CT findings include multiple bilateral ground-glass opacities with peripheral and lower lung distribution; lung ultrasonography findings include thickened pleural lines, B lines, and consolidative patterns
        • In situations where it is not possible to test all who meet the case definitions, WHO recommends prioritizing the following: r63
          • Those at high risk for severe disease
          • Health care workers
          • Inpatients in health facilities
          • First symptomatic persons in closed space environment (eg, schools, long-term care facilities, hospitals, prisons), representing possible index cases in a suspected outbreak
      • CDC r60
        • Recommends that all persons with signs or symptoms, or with known or suspected exposure, be offered diagnostic testing; routine testing to end isolation is no longer recommended but may be considered in immunocompromised patients, who may still be infectious longer than 20 days from symptom onset
          • Polymerase chain reaction and antigen tests both have a role in diagnosis, with advantages and disadvantages for each (see Table 1 of CDC recommendationsr60)
            • For a person with symptoms, a positive result on polymerase chain reaction or antigen test indicates that the person has COVID-19; a negative antigen result needs to be confirmed with polymerase chain reaction test
            • For a person with no symptoms and no known exposure, a negative result on polymerase chain reaction or antigen test indicates that the person does not have current infection
            • For a person with exposure but no symptoms, a negative result suggests no current infection but the test may need to be repeated or confirmed with additional testing (eg, in cases of high probability of infection or ongoing exposure)
    • Specimens from upper or lower respiratory tract are recommended for viral testing.r65 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 r65
        • 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 c206c207c208c209c210c211c212c213c214c215c216c217
            • 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 c218
          • 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 c219
          • A deep cough sputum specimen (collected after mouth rinse) is also acceptable c220
            • WHO and CDC advise against attempts to induce sputum, because the process may increase aerosolization and risk of transmission
      • Infectious Diseases Society of America guidelines provide additional guidance and an algorithm, including indications for repeated testing when suspicion for disease is high but initial test result is negative r66
        • Favor nasopharyngeal, nasal, or midturbinate specimens, saliva specimen, or combined anterior nasal/oropharyngeal swab over oropharyngeal swab alone for SARS-CoV-2 RNA testing
        • For patients with high likelihood of disease but negative initial result, repeated testing is recommended; in patients with lower respiratory tract symptoms, sputum or other lower respiratory tract specimen is recommended for repeated testing
      • 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 r67
    • Serologic 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: r8r68
      • 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 r35c221d1
      • Coinfections have been reported, but the frequency is unknown r69r70
      • 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 r71
      • 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 r8r72c222
        • 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 r22c223c224c225
    • 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 r73
      • 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 r74
  • 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) r35c226c227c228c229c230c231c232c233c234c235c236c237c238c239c240c241c242c243d2
  • Public health reporting: requirements vary by jurisdiction; clinicians should consult local authorities. In some regions, public health authorities may be able to facilitate testing and undertake contact tracing and monitoring

Laboratory

  • Polymerase chain reaction tests: Positive identification of SARS-CoV-2 RNA by such test is considered confirmation of diagnosis c244
    • 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 r60r75
    • 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 r66r75
    • 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
  • Antigen tests: also available for use in diagnosis, and they have the advantage of rapid turnaround
    • In general, these tests are less sensitive than polymerase chain reaction, although specificity is nearly equivalent r61
      • False-positive results are uncommon, but occur and are more likely in a low-prevalence setting
      • False-negatives are common, depending on the test. A negative result may warrant retesting (preferably within 2 days) with polymerase chain reaction if there is a high suspicion for infection based on clinical or epidemiologic indicators
      • 2 algorithms may assist in determining when an antigen test should be confirmed: for congregate care and community settings r61
    • A Cochrane review noted wide-ranging performance of antigen tests; summary sensitivities ranged from 34.1% to 88.1%, but average specificity was 99.6% r76
      • Sensitivity is higher in symptomatic versus asymptomatic cases, in the first week after symptom onset versus later, and in those with Ct values (cycle threshold) on polymerase chain reaction test of 25 or less versus higher; all of these correlations reflect improved sensitivity with higher viral loads
      • Performance varies across brands. Antigen tests with sufficient sensitivity and specificity may be considered as a replacement for polymerase chain reaction tests when rapid decisions about patient care must be made and when timely polymerase chain reaction test is unavailable, with confirmatory polymerase chain reaction test advised in lower-prevalence settings. Evidence on screening asymptomatic populations has been limited
    • CDC provides guidance on antigen testing, including screening in congregate care and community settings, when confirmatory testing is indicated (based on symptoms, exposure, vaccination status, and setting), as well as serial testing r61
  • Antibody tests: a Cochrane reviewr77 notes that antibody tests are most likely to be clinically useful 15 days or more into the course of infection and that data are scarce regarding antibody tests beyond 35 days. For instances when clinicians judge that antibody testing is indicated, Infectious Diseases Society of Americar62 makes the following recommendations:
    • Testing 3 to 4 weeks after symptom onset maximizes sensitivity
      • Sensitivity at 1 week ranges from 0.23 to 0.63; at 2 weeks, from 0.68 to 0.96
    • Test should measure anti–SARS-CoV-2 IgG or total antibody; a high-specificity test should be used
      • Unlike the usual pattern of antibody production, IgM antibody response to SARS-CoV-2 is somewhat delayed, occurring almost simultaneously with IgG production, so there is no advantage to testing selectively for the IgM fraction
  • Routine blood work is not diagnostic, but a pattern of typical abnormalities has emerged, particularly in patients with severe illness: c245c246c247c248
    • Leukopenia may be observed and relative lymphopenia is common, especially in patients with more severe illness r19r21r22
    • Anemia was noted in about half of patients in one series r22
    • Both elevated and low platelet counts have been seen r19r21r22
    • Prolonged prothrombin time has been reported r78
    • Levels of D-dimer and fibrinogen may be elevated r19r21
    • Elevated levels of lactate dehydrogenase and liver enzymes (ALT and AST) are common r21r22
    • Serum procalcitonin levels are usually within reference range; elevated levels have been seen in patients with secondary infection r21
    • Serum levels of some other acute phase reactants (eg, C-reactive protein, ferritin) are elevated in most patients, as is the erythrocyte sedimentation rate r22
  • Lactate level of 2 mmol/L or higher suggests presence of septic shock r35c249

Imaging

  • Chest imaging (eg, plain radiography, CT, ultrasonography) has been found to be sensitive but not highly specific to COVID-19 r79
  • 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 r19r21r22r80r81c250c251c252c253
  • CT appears to be more sensitiver79r82 than plain radiographs, but normal appearance on CT does not preclude the possibility of COVID-19r83
  • 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 r75r84c254c255

Differential Diagnosis

Most common

  • Influenza c256d3
    • 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 r71
    • Patients with severe disease may have abnormal chest radiographic findings suggesting influenzal pneumonia or secondary bacterial pneumonia
    • Positive result on rapid influenza diagnostic test confirms influenza diagnosis with high specificity during typical season; negative result does not rule out influenza
    • Influenza may be clinically indistinguishable from COVID-19; additionally, coinfection can occur. Therefore, when influenza and SARS-CoV-2 are both circulating in the community, testing for both viruses is recommended for all patients hospitalized with acute respiratory infection. In patients who present with acute respiratory illness but who do not require hospitalization, influenza testing is recommended in addition to testing for SARS-CoV-2, if influenza test results would alter management r8r72
      • CDC recommends nucleic acid detection over antigen testing for both pathogens, by either multiplex or individual assay
  • Other viral pneumonias c257d1
    • 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 r71
  • Bacterial pneumonia c258d1
    • 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 r35
Criteria for ICU admission
  • WHO provides criteria for critical respiratory tract disease r85
    • 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 in consultation with public health authorities
  • 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 r86
    • 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 checkerr87 is advised

Infection control measures: these include isolation, source control, and transmission precautions r88

  • People with COVID-19 at home should isolate at home, keep separate from others in the household as much as possible, wear a mask when near other people or pets in the household, monitor for serious or worsening symptoms requiring additional medical care, and increase cleaning and disinfection r89
  • Patients with COVID-19 in a health care setting should wear a face mask (or, if supplies are critically low, at least a cloth face cover) to reduce droplet spread, should be placed in a single-person closed room pending further evaluation and disposition decisions, and should have standard precautions, contact precautions, and droplet or airborne precautions as resources allow
    • Health care personnel should wear N95 respirator or comparable (eg, FFP2, KN95), gown, gloves, and eye protection r88
      • Some guidelines suggest that a medical face mask, rather than N95 respirator, is sufficient when not performing aerosol-generating procedures r35
    • If available, the patient room will ideally be one with structural and engineering safeguards against airborne transmission (eg, negative pressure, frequent air exchange), but in the high-prevalence stages of the pandemic (with crowded hospitals), reserve negative pressure isolation rooms for the greatest needs (ie, aerosol-generating procedures; tuberculosis, measles, and varicella)

Supportive care: for all patients; in hospitalized patients, such care includes oxygenation and ventilation, conservative fluid support, and measures to prevent common complications (eg, pressure injury, stress ulceration, secondary infection) r35

  • Until a diagnosis of COVID-19 is confirmed by polymerase chain reaction or antigen test, appropriate antimicrobial therapy for other viral pathogens (eg, influenza virus) or bacterial pathogens should be administered in accordance with the severity of clinical disease, site of acquisition (hospital or community), epidemiologic risk factors, and local antimicrobial susceptibility patterns r35
  • Surviving Sepsis Campaignr90r91 guideline, NIH COVID-19 treatmentr8 guideline, and WHO guidancer35 provide recommendations specific to treatment of shock in patients with COVID-19. Management of shock and other complications requiring intensive care are addressed in detail in the Clinical Overview on COVID-19 critical care d4

Antiviral agents

  • Remdesivir: FDA-approved for treatment of COVID-19 in hospitalized adults and children aged 28 days or older weighing 3 kg or more, and in those with mild to moderate test-positive COVID-19 who are not hospitalized but who are at high risk for progression to severe disease r92r93r94
    • Preliminaryr95 and follow-upr96 results of the Adaptive COVID-19 Treatment Trial, a placebo-controlled randomized trial in 1062 patients, showed a statistically significant improvement in time to recovery and a nonsignificant trend in lower mortality; several other trials remain active, as wellr97
    • On the basis of these and other data from clinical trials, the NIH guideline recommends, and the Infectious Diseases Society of America and Surviving Sepsis Campaign guidelines suggest, remdesivir for hospitalized patients with COVID-19 who require supplemental oxygen r8r90r91r98
      • In patients who require oxygen via high-flow device or noninvasive ventilation, NIH offers the option of remdesivir with dexamethasone or dexamethasone alone, because remdesivir appears to confer maximum benefit before onset of more severe disease, in which dexamethasone alone is associated with markedly reduced mortality
      • NIH recommends against use of remdesivir in patients who require mechanical ventilation or extracorporeal membrane oxygenation, and both Infectious Diseases Society of America and Surviving Sepsis Campaign guideline suggests 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 suggests, 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 r8r98
      • 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 r99
    • WHO suggests against remdesivir use outside of clinical trials r100
    • Evidence base: remdesivir has significant in vitro activity against coronaviruses,r101r102 evidence of efficacy in an animal model of MERS,r101 and evidence of efficacy in COVID-19r96
  • Ritonavir-boosted nirmatrelvir has received emergency use authorization in the United States for treatment of nonhospitalized persons aged 12 years or older and weighing 40 kg or more who test positive for COVID-19, who are at high risk for progressing to severe disease, and for whom alternative treatments are not available or not clinically appropriate r103
    • 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% r103
      • 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 r104
    • 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 r98
  • Molnupiravir, another oral antiviral agent, has emergency use authorization in the United States for treatment of nonhospitalized adults positive for COVID-19 who are at high risk of progression to severe disease, and for whom alternative treatments are not available or not clinically appropriate r105
    • Molnupiravir was compared with placebo in a randomized trial of 1433 patients with mild to moderate COVID-19 who met criteria for high risk of progression to severe disease. The primary end point was all-cause hospitalization or death through day 29. The relative risk reduction was 30%
      • Molnupiravir is not recommended during pregnancy or breastfeeding; before prescribing to persons of childbearing potential, test for pregnancy and (including for biologic males) ensure reliable contraception through treatment and for 4 days (females) or 3 months (males) after the last dose. Breast milk should be discarded during treatment and for 4 days after the last dose r105
    • Mechanism of action of molnupiravir is inducing lethal viral mutations; concerns have arisen regarding emergence of resistance and emergence of new variants as a result. Use of molnupiravir should be accompanied with robust pharmacovigilance r100
    • 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 r98
    • Similarly, NIH recommends use of molnupiravir (or bebtelovimab) in ambulatory adults at high risk of progression to severe disease ONLY when ritonavir-boosted nirmatrelvir and remdesivir are unavailable, because it has lower efficacy than the preferred treatments r8
    • WHO suggests use of molnupiravir for adults with nonsevere disease at highest risk of hospitalization; alternative treatments may be preferable where available

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

  • Emergency use authorizations have been issued in the United States for several monoclonal antibody products: bamlanivimab-etesevimabr4r5 in combination, casirivimab-imdevimabr3r106 in combination, sotrovimab,r107r2bebtelovimab,r1 and tixagevimab-cilgavimabr6 in combination. Given the predominance of the Omicron variant in the United States and the lack of activity of bamlanivimab-etesevimab, casirivimab-imdevimab, or sotrovimab against specific Omicron subvariants, FDA has modified the emergency use authorizations for these monoclonal antibodies to state that they are not authorized for use in regions where infection is likely to be caused by a nonsusceptible strain,r108r109 effectively suspending their use in the United States
    • These authorizations apply to patients aged 12 years or older, weighing 40 kg or more, who have mild to moderate disease and who are at high risk (by virtue of older age or concomitant conditions) for progression to severe disease and/or hospital admission; the authorizations exclude persons who are already hospitalized for COVID-19 or who require supplemental oxygen for COVID-19. The emergency use authorizations list recognized criteria for high risk of progression; updated guidance notes that risk is not limited to these conditions:
      • BMI of 25 or higher (for ages 12 to 17 years, BMI in 85th percentile or higher)
      • Chronic kidney disease
      • Diabetes
      • Pregnancy
      • Immunosuppression due to disease or treatment
      • Sickle cell disease
      • Chronic lung disease (eg, chronic obstructive pulmonary disease, moderate to severe asthma, interstitial lung disease, cystic fibrosis, pulmonary hypertension)
      • Cardiovascular disease (including congenital heart disease) or hypertension
      • Neurodevelopmental disorders
      • Dependence on a medical technology such as tracheostomy, gastrostomy, or positive pressure ventilation
      • Older age (ie, 65 years or older)
    • Infectious Diseases Society of America guideliner98 suggests use of monoclonal antibodies in ambulatory patients who are at high risk of progression to severe COVID-19, with selection of the most appropriate agent based on known activity against predominant circulating variants
  • Distribution of monoclonal antibodies is currently coordinated through state/territorial health departments, based on circulating variants, case burden, and product utilization rates r8r110r111
  • In areas with logistical constraints, administration to all eligible persons may not be possible r8
    • Prioritize treatment of COVID-19 over postexposure prophylaxis
    • Prioritize treatment of persons at high risk of progression to severe disease who are not fully vaccinated, and vaccinated persons who may not have an adequate immune response, over fully vaccinated persons who are expected to have adequate immune response to immunization
  • Tixagevimab and cilgavimab are monoclonal antibodies which block spike protein attachment, binding to 2 different regions of the receptor-binding domain of the spike protein
    • FDA granted an EUA 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 r6
    • Based on decreased susceptibility of BA.1 and BA.1.1 subvariants of Omicron variant to this combination, the recommended dose was increased on February 24, 2022
      • Those who received the original dose of 150 mg each should receive a second dose of 150 mg each as soon as possible
    • Infectious Diseases Society of America suggests use and NIH recommends use of tixagevimab-cilgavimab as preexposure prophylaxis in adults and adolescents who have moderate to severe immunocompromise or who are unable to be fully immunized owing to documented severe allergy
  • Bebtelovimab is a recombinant neutralizing human monoclonal antibody that binds to the spike protein of SARS-CoV-2 (including the Omicron variant), preventing its attachment to the ACE2 receptor (for angiotensin-converting enzyme 2) r1
    • Limited clinical data indicate a reduction in viral load in treated patients and improvement in symptoms; the emergency use authorization issued by FDA on February 11, 2022 states that "based on the totality of evidence available … it is reasonable to believe that bebtelovimab may be effective for the treatment of patients with mild-to-moderate COVID-19 to reduce the risk of progression to hospitalization or death"
    • NIH recommends use of bebtelovimab (or molnupiravir) in ambulatory adults at high risk of progression to severe disease only when ritonavir-boosted nirmatrelvir and remdesivir are unavailable or not clinically feasible r8
    • Infectious Diseases Society of America guideline recommends use of bebtelovimab only in clinical trials, owing to lack of data
  • Sotrovimab targets a highly conserved region in the receptor-binding domain of the SARS-CoV-2 spike protein r2
    • Interim data from the ongoing COMET-ICE clinical trial show that in 583 patients with symptomatic COVID-19 and at least 1 comorbidity or age-related risk factor for progressing to severe disease who were randomized to receive sotrovimab or placebo, the risk of progression to severe disease was 85% lower in the sotrovimab arm r2
      • 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 r2r8r108
    • NIH guidelines no longer recommend using sotrovimab, bamlanivimab-etesevimab, or casirivimab-imdevimab, owing to their ineffectiveness against the prevailing Omicron variant/subvariants in the United States r8
    • WHO suggests treatment with sotrovimab for those at highest risk of hospitalization r100
      • Benefit of use is unclear for patients with severe or critical illness who are seronegative; use depends on availability of rapid and accurate antibody testing before treatment
  • 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 r5
    • 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) r4
      • 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 r4
    • 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 r4
      • Bamlanivimab and etesevimab, even in combination, appear to have reduced in vitro activity against a number of circulating variants: beta (eg, B.1.351), gamma (eg, P.1), epsilon (ie, B.1.427 or B.1.429), eta (eg, B.1.526) and Omicron (eg, B.1.1. 529), which has become the dominant circulating variant in the United States r4r112
  • Casirivimab-imdevimabr8r106
    • This combination appears 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 r3
    • 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 r100
    • Data on efficacy against susceptible variants
      • Preliminary clinical studies (conducted before emergence of Omicron variant) evaluated effect on viral load and on medically attended illness. In a placebo-controlled trial of 799 patients with mild to moderate COVID-19, reduction in viral load in days 1 through 7 was significantly greater for the monoclonal antibody combination compared with placebo (P < .0001). Treatment was also associated with fewer emergency department visits and hospital admissions (2.8% for patients treated with casirivimab-imdevimab versus 6.5% for those who received placebo) r3
        • An updated statement from the manufacturer includes data from 4567 patients with at least 1 risk factor for severe COVID-19, randomized to 2 different doses (either 600 mg or 1200 mg of each component) or placebo. The 2 doses resulted in a 70% and 71% reduction in risk for hospitalization r3
        • Data submitted with the updated statement indicated efficacy against the major variants circulating as of June 2021, but Omicron subvariants in 2022 have defeated this efficacy r3
      • In a phase 3 trial of nonhospitalized patients with COVID-19, patients randomized to casirivimab-imdevimab treatment had a lower risk of hospitalization and of death, and had faster resolution of symptoms, than those randomized to placebo. Relative risk reduction of hospitalization plus death was 71.3% in the group that received a 2400-mg dose, and was 70.4% in those who received the 1200-mg dose r113

Immunomodulators are also being investigated for mitigation of cytokine release syndrome believed to be a factor in severe acute respiratory distress syndrome and shock in COVID-19 (eg, monoclonal antibodies against interleukin-6 receptors, such as tocilizumabr114 and sarilumabr115; Janus kinase inhibitors such as baricitinibr116 and tofacitinibr117)

  • Baricitinib (a Janus kinase inhibitor)
    • Baricitinib is FDA-approved for the treatment of COVID-19 in hospitalized adults requiring supplemental oxygen, noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation r118
      • 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 r119r120
      • 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 to placebo (13%), a 38.2% relative reduction in mortality. r121
      • NIH guidelines recommend use of baricitinib (or tocilizumab) with dexamethasone alone or with remdesivir and dexamethasone in recently hospitalized patients on high-flow oxygen or noninvasive ventilation who have clinical or laboratory evidence of progressive disease (eg, increasing oxygen needs, increasing inflammatory markers) r8
        • Guideline recommends against giving tocilizumab or other IL-6 inhibitors to patients on baricitinib
        • There is insufficient evidence to recommend baricitinib over tocilizumab or vice versa
      • 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 r98
        • Patients receiving baricitinib should not receive tocilizumab or other IL-6 inhibitors
        • Some data suggest a reduction in mortality even in patients who require mechanical ventilation
      • WHO guideline strongly recommends baricitinib for patients with severe or critical disease; choice of baricitinib versus IL-6 blockers should be based on clinical factors and availability r100
  • Tocilizumab (monoclonal IL-6 receptor blocker)
    • NIH guidelines recommend use of tocilizumab in 2 situations, as follows: r8
      • Use tocilizumab (or baricitinib) 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)
        • There is insufficient evidence to recommend tocilizumab over baricitinib or vice versa
      • Use tocilizumab with dexamethasone within 24 hours of admission to ICU for patients requiring mechanical ventilation or extracorporeal membrane oxygenation
      • In patients receiving supplemental oxygen, the guideline panel found insufficient evidence to determine whether adding tocilizumab to dexamethasone is of benefit; they recommend tocilizumab plus remdesivir for such patients when corticosteroids cannot be used
      • Guideline recommends against giving baricitinib to patients on tocilizumab
      • A systematic review and meta-analysis of retrospective trials with data from 240 patients who received tocilizumab and 352 controls concluded that the low-quality evidence available did not demonstrate clear benefit from tocilizumab r122
      • A review of data from 5 randomized controlled trials comparing tocilizumab to usual care (with or without placebo) did not show a 28-day mortality benefit, but it did show a lower relative risk of clinical deterioration (ie, ICU admission, mechanical ventilation, death), although evidence was of low certainty r98
      • 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 r123r124
    • 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 r98
    • WHO guidelines recommend use of tocilizumab (or sarilumab) for patients with severe or critical COVID-19, along with corticosteroids r100
  • Sarilumab (monoclonal IL-6 receptor blocker)
    • NIH guidelines recommend use of sarilumab only when baricitinib and tocilizumab are unavailable for recently hospitalized patients on high-flow oxygen or noninvasive ventilation who have clinical or laboratory evidence of progressive disease (eg, increasing oxygen needs, increasing inflammatory markers), along with dexamethasone or dexamethasone plus remdesivir r8
    • WHO guidelines recommend use of sarilumab (or tocilizumab) for patients with severe or critical COVID-19, along with corticosteroids r100
    • REMAP-CAP trial found that sarilumab plus dexamethasone was noninferior to tocilizumab plus dexamethasone, but the evidence for the use of tocilizumab is more extensive r8r123
  • Tofacitinib (a Janus kinase inhibitor)
    • Infectious Diseases Society of America guidelines suggest use of tofacitinib in hospitalized patients with severe but noncritical COVID-19 (ie, not on mechanical ventilation), along with remdesivir and corticosteroids (unless contraindicated)
      • Patients should also receive at least prophylactic dose of anticoagulant
      • Patients receiving tofacitinib should not receive tocilizumab or other IL-6 inhibitors
    • NIH guidelines recommend use of tofacitinib only when baricitinib and tocilizumab are unavailable for recently hospitalized patients on high-flow oxygen or noninvasive ventilation who have clinical or laboratory evidence of progressive disease (eg, increasing oxygen needs, increasing inflammatory markers), along with dexamethasone or dexamethasone plus remdesivir
    • WHO guideline suggests against use of tofacitinib or ruxolitinib (another Janus kinase inhibitor) unless baricitinib, tocilizumab and sarilumab are unavailable r100
  • Surviving Sepsis Campaign guideline on managing critically ill adults with COVID-19 does not address immunomodulators r90r91
  • Monoclonal antibodies against GM-CSF (granulocyte-macrophage colony-stimulating factor), such as lenzilumab, mavrilimumab, namilumab, gimsilumab, and otilimab, are under investigation and are not currently recommended under any guidelines r8r98

Corticosteroid therapy is suggested or recommended for hospitalized patients with an oxygen requirement r35

  • 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 r7r125
    • 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
  • A smaller study comparing standard care with and without a 3-day course of methylprednisolone early in the disease course showed an association between corticosteroid use and a reduction in the 3 components of the composite end point: transfer to ICU, need for mechanical ventilation, and mortality. Guidelines do not currently support administration of steroids early in the disease course r126
  • Based on these data, NIH COVID-19 treatment guideline recommends use of dexamethasone in any hospitalized patient who requires supplemental oxygen, and recommends against use of dexamethasone in patients who do not require oxygen supplementation r8
    • In the absence of dexamethasone, another glucocorticoid (eg, prednisone, methylprednisolone, hydrocortisone) may be used
  • Similarly, Infectious Diseases Society of America guideline suggests use of dexamethasone in hospitalized patients with severe illness, and recommends use in those with critical illness r98
    • Infectious Diseases Society of America suggests against the use of steroids in patients who have no oxygen requirement, and suggests against the use of inhaled steroids in ambulatory patients with mild to moderate disease
    • Guideline provides equivalent doses of alternative glucocorticoids if dexamethasone is unavailable
  • Surviving Sepsis Campaign guideline on managing critically ill adults with COVID-19 strongly recommends using corticosteroids (preferably dexamethasone) for up to 10 days in patients with severe or critical COVID-19 r90r91
  • WHO recommends use in patients with severe and critical COVID-19, and suggests against use in patients with nonsevere COVID-19 r35r100

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 r8r91r127r128r129r130r131
  • The most current guidelines to address antithrombotic therapy are the NIH, American Society of Hematology, and CHEST (American College of Chest Physicians) guidelines. Recommendations are summarized below: r8r130r131
    • NIH guideline recommends prophylactic dose heparin for hospitalized adults, including pregnant patients, without evidence of venous thromboembolism; CHEST guideline suggests therapeutic dose heparin with careful balance of the risk of thrombosis and the risk of bleeding
    • Therapeutic-dose heparin is recommended for hospitalized nonpregnant patients requiring oxygen who have elevated D-dimer levels (NIH guideline) or other indicators of increased risk of thrombosis (CHEST guideline), if they do not have increased risk of bleeding; there is insufficient evidence in pregnant patients
    • Prophylactic-dose heparin is recommended in both guidelines for patients in the ICU, including switching from therapeutic to prophylactic dose in patients transferred to an ICU unless a thrombosis has been documented
    • Standard therapeutic treatment is recommended for patients with COVID-19 and thromboembolism (highly suspected or proven), and for those on extracorporeal membrane oxygenation or continuous renal replacement therapy or who have thrombosis related to catheters or extracorporeal filters
    • Prophylactic therapy is not recommended for nonhospitalized patients, and guidelines also recommend against continuing prophylactic therapy following hospitalization in patients without thromboembolic disease
      • Based on additional evidence, the American Society of Hematology also now recommends against posthospitalization thromboprophylaxis r132
    • Generally low molecular weight heparin is preferred over unfractionated heparin, and heparin is preferred over oral anticoagulants
    • 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
  • American Society of Hematology guideline also recommends anticoagulation for hospitalized patients and for patients in intensive care; however, this guideline is expected to be revised with additional information from trials comparing prophylactic dose, intermediate dose, and therapeutic dose r127r132

Convalescent plasma continues to be investigated; only high-titer formulations have shown any benefitr133

  • Infectious Diseases Society of America suggests use of high-titer convalescent plasma in ambulatory patients with mild to moderate disease at high risk of progression who have no other treatment options. It recommends against use in hospitalized patients r98
  • Surviving Sepsis Campaign guideline on managing critically ill adults with COVID-19 suggests that convalescent plasma not be used outside of clinical trials r91
  • NIH COVID-19 treatment guideline recommends against use of convalescent plasma in most situations, except in a clinical trial, and recommends against use of convalescent plasma that was collected before the emergence of the Omicron variant r8
    • There is insufficient evidence to recommend for or against use of convalescent plasma that was collected after the emergence of the Omicron variant (in hospitalized patients with impaired immunity, or nonhospitalized patients)
  • WHO strongly recommends against use of convalescent plasma in nonsevere disease, and recommends against use in severe or critical disease outside of a clinical trial r100
  • 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: r134r135
    • Serious adverse events were uncommon, and they were judged not to exceed the known incidence in transfusion of plasma to critically ill patients
    • There was some evidence of improved survival in the subset of patients treated with convalescent plasma containing higher titers of neutralizing antibody compared with patients who received plasma with lower levels (ie, there appeared to be a dose-response gradient)
      • Expanded access use focuses on high-titer product used in patients with immunosuppressive disease or receiving immunosuppressive treatment
    • Early administration (eg, before mechanical ventilation is required) appeared more likely to be beneficial, but the possibility of benefit even to intubated patients could not be excluded

Several medications with a mechanism of action which could potentially alter response to COVID-19 have been evaluated either for use in treatment and prevention, or for discontinuation to prevent harms r136

  • 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 r8r137r138
  • 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 r98

Other options not currently recommended under any guidelines (although some are still under study in clinical trials)

  • Interim results of the WHO SOLIDARITY trial have been published. Remdesivir, lopinavir-ritonavir, hydroxychloroquine, and interferon were compared with one another (open-label) and with standard care (no placebo) in a total population of over 11,000 patients in over 400 hospitals in 30 countries worldwide r139
    • End points were in-hospital mortality, initiation of ventilation, and duration of hospital stay. No differences among the groups were noted for any of these parameters. The authors acknowledge that length of stay may have been influenced in some cases by the requirements of antiviral administration (eg, 10 days of IV administration for remdesivir), but they argue that the similarity in percentages of patients in each group remaining in the hospital beyond the course of the study drug indicates a lack of benefit to any treatment arm
  • Lopinavir-ritonavir is FDA-approved for treatment of HIV infection. It has been used in China in conjunction with interferon alfa for treatment of some patients with COVID-19, but reported results have been disappointing
    • 3 randomized placebo-controlled trials have evaluated the effects of lopinavir-ritonavir in the treatment of COVID-19. The combined datar98 did not show significant differences in progression to mechanical ventilation or mortality
    • NIH COVID-19 treatmentr8 guideline, Infectious Diseases Society of America guideline on treatment and management of COVID-19,r98 and Surviving Sepsis Campaign guideline on managing critically ill adults with COVID-19r91 recommend against use of lopinavir-ritonavir
    • Surviving Sepsis Campaign guideline on managing critically ill adults with COVID-19 recommends against use of recombinant interferons, based on lack of data in COVID-19 and on data from studies on MERS showing lack of efficacy r90r91
    • WHO recommends against use of lopinavir-ritonavir outside of a clinical trial r100
  • Ivermectin, an antiparasitic drug with some activity against viruses, has been proposed for COVID-19 treatment or prevention
    • Infectious Diseases Society of America and WHO guidelines suggest against use of ivermectin, and NIH guidelines recommend against use, outside clinical trials r8r98r100
    • CDC issued a health advisory warning clinicians that ivermectin is not approved by FDA for treatment of COVID-19 and that adverse effects from the use and misuse of ivermectin are increasing r140
    • FDA issued a consumer update warning the public against use of ivermectin, particularly medications meant for animal use r141
  • Chloroquine and hydroxychloroquine: letters reporting favorable results in China and South Korea early in the pandemicr142 suggested promise, leading to an emergency use authorization by FDA in the United States. Subsequent studies have found no significant benefit, but they highlighted the risk of QT prolongation and cardiac arrhythmias. As a result, FDA emergency use authorization was withdrawn,r143 although some clinical trial use may still be in progress
    • Azithromycin has been used in combination with hydroxychloroquine in some protocols; however, azithromycin is also associated with cardiac arrhythmias, and the possible increased risk posed by the combination must be considered r144
      • Scoring systems are available to determine risk of arrhythmia r145r146
    • A systematic review and meta-analysis of studies comparing standard care with and without hydroxychloroquine included 6 studies comprising 1331 patients. There was no difference in mortality between the 2 groups, although a subgroup receiving hydroxychloroquine plus azithromycin experienced significantly higher mortality than the standard care group r147
    • A subsequently published randomized controlled open-label trial (RECOVERY) of 1561 patients treated with hydroxychloroquine and 3155 treated without showed no survival advantage among patients treated with hydroxychloroquine r148
    • Infectious Diseases Society of America, NIH, and WHO guidelines all recommend against using hydroxychloroquine, with or without azithromycin, and the Surviving Sepsis guideline recommends against using hydroxychloroquine (but does not mention azithromycin) r8r91r98r100

Drug therapy

  • Antiviral agents c259
    • Remdesivir
      • For patients requiring oxygen but NOT invasive mechanical ventilation and/or extracorporeal membrane oxygenation
        • Remdesivir Solution for injection; Adults NOT requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO): 200 mg IV once on day 1, followed by 100 mg IV once daily for 4 days; may extend treatment for up to 5 additional days if no clinical improvement. The NIH recommends treatment for 5 days or until hospital discharge.
      • Dosages for patients who REQUIRE mechanical ventilation or extracorporeal membrane oxygenation have been established r149r150d4
        • Remdesivir Solution for injection; Adults requiring invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO): 200 mg IV once on day 1, followed by 100 mg IV once daily for 9 days. The NIH recommends against starting remdesivir; but, treatment may be continued (in combination with dexamethasone) in patients who progress to mechanical ventilation or ECMO.
      • 3-day regimen for persons with mild to moderate disease at high risk for progression
        • Remdesivir Solution for injection; Adults: 200 mg IV once on day 1, followed by 100 mg IV once daily for 2 days. According to the NIH, up to 5 days of therapy may be considered for patients with new/increasing need for oxygen but who cannot be admitted to the hospital because resources are limited.
    • Nirmatrelvir-ritonavir
      • Nirmatrelvir Oral tablet, Ritonavir Oral tablet; Adults weighing 40 kg or more: 300 mg nirmatrelvir (two 150 mg tabs) and 100 mg ritonavir (one 100 mg tab) taken together by mouth twice daily for 5 days. Start as soon as possible after the positive test for SARS-CoV-2 and within 5 days of symptom onset.
    • Molnupiravir
      • Molnupiravir Oral capsule; Adults: 800 mg PO every 12 hours for 5 days. Start as soon as possible and within 5 days of symptom onset.
  • Monoclonal antibodies with antiviral action
    • Tixagevimab and cilgavimab in combination
      • Cilgavimab Solution for injection, Tixagevimab Solution for injection; Children and Adolescents 12 years and older weighing 40 kg or more: 300 mg tixagevimab and 300 mg cilgavimab given as 2 separate consecutive IM injections. For persons who received the previously authorized lower dose, give an additional 150 mg tixagevimab and 150 mg cilgavimab dose as soon as possible if the initial dose was within the past 3 months; if the initial dose was more than 3 months ago, give 300 mg tixagevimab and 300 mg cilgavimab as soon as possible. Data are currently insufficient to recommend repeat dosing. 
      • Cilgavimab Solution for injection, Tixagevimab Solution for injection; Adults weighing 40 kg or more: 300 mg tixagevimab and 300 mg cilgavimab given as 2 separate consecutive IM injections. For persons who received the previously authorized lower dose, give an additional 150 mg tixagevimab and 150 mg cilgavimab dose as soon as possible if the initial dose was within the past 3 months; if the initial dose was more than 3 months ago, give 300 mg tixagevimab and 300 mg cilgavimab as soon as possible. Data are currently insufficient to recommend repeat dosing.
    • Bebtelovimab
      • Bebtelovimab Solution for injection; Adults: 175 mg as a single intravenous injection. Administer as soon as possible after positive test for SARS-CoV-2 and within 7 days of symptom onset.
    • Sotrovimab
      • For use only when infection is likely to be caused by a susceptible variant (but Omicron subvariant BA.2 is nonsusceptible)
      • For patients aged 12 years or older, weighing 40 kg or more, with mild to moderate disease (not requiring supplemental oxygen and not hospitalized) at risk for progression
        • Sotrovimab Solution for injection; Adults weighing 40 kg or more: 500 mg as a single IV infusion. Give as soon as possible after the positive test for SARS-CoV-2 and within 7 days of symptom onset.
    • Casirivimab-imdevimab c260
      • For use only when infection is likely to be caused by a susceptible variant (but Omicron is nonsusceptible)
      • For patients aged 12 years or older, weighing 40 kg or more, with mild to moderate disease (not requiring supplemental oxygen and not hospitalized) at risk for progression
        • Casirivimab, Imdevimab Solution for injection; Children and Adolescents 12 to 17 years weighing 40 kg or more: Give 600 mg casirivimab and 600 mg imdevimab via 4 subcutaneous injections at different sites. Give as soon as possible after the positive test for SARS-CoV-2 and within 10 days of symptom onset.
    • Bamlanivimab-etesevimab c261
      • Context of use
        • For use only when infection is likely to be caused by a susceptible variant (but Omicron is nonsusceptible)
        • Bamlanivimab and etesevimab MUST be administered in combination. Neither drug is authorized for administration as a single agent (ie, monotherapy)
        • For patients aged 12 years or older with mild to moderate disease (not requiring supplemental oxygen and not hospitalized) at risk for progression
      • Bamlanivimab component
        • Bamlanivimab Solution for injection; Adults: 700 mg of bamlanivimab and 1,400 mg of etesevimab together in a single IV infusion. Give as soon as possible after the positive SARS-CoV-2 test and within 10 days of symptom onset.
      • Etesevimab component c262
        • Etesevimab Solution for injection; Adults: 700 mg of bamlanivimab and 1,400 mg of etesevimab together in a single IV infusion. Give as soon as possible after the positive SARS-CoV-2 test and within 10 days of symptom onset.
  • Immunomodulators
    • Baricitinib c263
      • Baricitinib Oral tablet; Adults: 4 mg PO once daily for 14 days or until hospital discharge, whichever comes first. The NIH COVID-19 guidelines recommend use with dexamethasone (with or without remdesivir) IF on supplemental oxygen, including noninvasive ventilation or high-flow oxygen, AND there is evidence of systemic inflammation and rapidly increasing oxygen needs while on dexamethasone.
    • Tocilizumab c264
      • Tocilizumab Solution for injection; Adults: 8 mg/kg (max: 800 mg) IV infusion once. If symptoms worsen or do not improve, 1 additional dose may be administered at least 8 hours after the first. The EUA requires concurrent use with a systemic corticosteroid. The NIH COVID-19 treatment guidelines recommend a single 8 mg/kg (actual body weight, up to 800 mg) IV dose given with dexamethasone (with or without remdesivir) for hospitalized patients on supplemental oxygen, including high-flow oxygen and noninvasive ventilation, IF exhibiting signs of systemic inflammation and rapidly increasing oxygen needs. Also, NIH recommends use with dexamethasone for patients on mechanical ventilation or ECMO IF admitted to an ICU within the prior 24 hours.
    • Sarilumab c265
      • Sarilumab Solution for injection; Adults: The NIH COVID-19 treatment guidelines recommend a single 400 mg IV dose given with dexamethasone (with or without remdesivir) to treat hospitalized adults on supplemental oxygen, including high-flow oxygen and noninvasive ventilation, IF exhibiting signs of systemic inflammation and rapidly increasing oxygen needs. Also, may be given with dexamethasone for patients on mechanical ventilation or ECMO IF admitted to an ICU within the prior 24 hours. Sarilumab is an alternative if tocilizumab is not available or cannot be used.
    • Tofacitinib
      • Tofacitinib Oral tablet; Adults: The NIH COVID-19 treatment guidelines recommend 10 mg PO twice daily for up to 14 days or until hospital discharge (whichever comes first) to treat hospitalized adults on supplemental oxygen, including noninvasive ventilation and high-flow oxygen, with rapidly increasing oxygen needs and systemic inflammation. MUST be given with dexamethasone (with or without remdesivir). Tofacitinib is an alternative if baricitinib is not available or cannot be used.
  • Corticosteroid
    • Dexamethasone c266
      • Dexamethasone Sodium Phosphate Solution for injection; Adults: 6 mg IV once daily for up to 10 days or until hospital discharge (whichever comes first) is recommended by the NIH guidelines for use in hospitalized patients who require supplemental oxygen, including those on high-flow oxygen, noninvasive ventilation, mechanical ventilation, or ECMO. The WHO strongly recommends systemic corticosteroids for 7 to 10 days in patients with severe or critical COVID-19. Before starting therapy, review the patient's medical history and assess the potential risks and benefits.
    • Various guidelines provide recommendations for alternative glucocorticoids if dexamethasone is not available r8r98
      • Methylprednisolone c267
        • 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 c268
        • Prednisone Oral tablet; Adults: 40 mg PO daily for 7 to 10 days. The WHO strongly recommends systemic corticosteroids in patients with severe or critical COVID-19. The NIH recommends prednisone as an alternative corticosteroid for hospitalized patients who require supplemental oxygen, including those on high-flow oxygen, noninvasive ventilation, mechanical ventilation, or ECMO. The NIH recommends 40 mg PO once daily (or in 2 divided doses) for up to 10 days or until hospital discharge (whichever comes first). Before starting therapy, review the patient's medical history and assess the potential risks and benefits.

Nondrug and supportive care c269

  • Excellent supportive care remains the mainstay of treatment to date in COVID-19 c270
  • WHO,r35NIH,r8 and Surviving Sepsis Campaignr90 provide specific guidance for oxygenation, ventilation, and fluid management in COVID-19 d4
    • Patients with severe respiratory distress, obstructed or absent breathing, central cyanosis, shock, seizures, or coma require aggressive airway management (which may include intubation) and oxygen d4
    • Oxygenation and ventilation c271
      • Begin supplemental oxygen therapy when oxygen saturation falls below 90% to 92% r90
      • Nasal cannula at 5 L/minute or face mask with reservoir bag at 10 to 15 L/minute r35
        • 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 r151c272c273c274c275c276
        • High-flow nasal oxygen is recommended by Surviving Sepsis Campaignr90 and NIHr8 for patients with COVID-19 who develop hypoxemic respiratory failure despite conventional oxygen therapy; there is some evidence that it averts the need for intubation and mechanical ventilation. Noninvasive positive pressure ventilation may be used if high-flow nasal oxygen is not available
        • However, there is concern that these techniques may result in higher risk of aerosolization of the virus. Additionally, sudden deterioration may require emergent intubation, which is associated with more risk to both patient and provider. Therefore, some authorities reserve these options for settings in which airborne precautions can be taken and close monitoring provided r90
      • 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)r75c277
        • Although optimal technique has not been fully defined, COVID-19–specific recommendations are emerging d4
      • Extracorporeal membrane oxygenation has been usedr21 in severely ill patients, and it can be considered if resources and expertise are available c278
    • Fluid management
      • Overhydration should be avoided, because it may precipitate or exacerbate acute respiratory distress syndrome c279
      • 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 r152

Comorbidities

  • Severe COVID-19 has been associated with chronic conditions such as diabetes, hypertension, and other cardiovascular conditions r8c280c281c282
  • Owing to the role of the ACE2 receptor in the pathogenesis of COVID-19, controversy has arisen over 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 Americar153 recommends that persons who are currently taking these medications for appropriate indications should continue to do so; the NIH guidelines for treatmentr8 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 r154r155r156r157r158r159
    • 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 r160

Special populations

  • Pregnant patients
    • Pregnant patients are at higher risk for severe disease (including increase risk for hospitalization, requiring mechanical ventilation, and death) and for adverse pregnancy outcomes such as preterm birth and stillbirth r161
    • 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 r8r161r162r163
    • American College of Obstetricians and Gynecologists recommends that the mode of delivery be determined based on obstetric indications and patient preference; cesarean delivery is recommended only for the usual medically justified indications r164
    • There is little evidence to suggest vertical transmission;r166r35r164 however, an infected mother may transmit the virus by the airborne route to the neonate. CDC and WHO differ somewhat in their recommendations r165
      • Because of concerns for transmission, CDC has recommended that separation of neonates from mothers known or suspected to have COVID-19 can be considered until isolation can be discontinued per usual protocol. The decision is best individualized in consultation with patient wishes. If temporary separation is chosen, breast milk may be pumped and fed to the infant by another caregiver r165
      • Focusing on ensuring successful initiation of breastfeeding, WHO advises that postpartum females and their neonates room in (cohabit), including the practice of skin-to-skin and kangaroo care r35
  • Breastfeeding patients r167
    • Vaccination is recommended
    • People without suspected or confirmed COVID-19 and who have not been in close contact with someone who has COVID-19, or who have received a COVID-19 vaccine, do not need to take special precautions when feeding at the breast or expressing milk
    • A breastfeeding person who is not fully vaccinated against COVID-19 should take precautions to protect themselves and the breastfed child when either of them has suspected or confirmed COVID-19
      • CDC strongly recommends vaccination for adults, with few contraindications
  • Patients with HIV
    • Vaccination is recommended r8r168
    • 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 r55r168
    • It is recommended that patients continue their current antiretroviral regimen; specifically, empiric addition of lopinavir-ritonavir (for possible efficacy against or protection from SARS-CoV-2) is not recommended outside of a clinical trial
    • A guideliner168 by the US Department of Health and Human Services offers strategies for ensuring continuity of antiretroviral medication
    • Recommendations for management of patients with HIV who develop COVID-19 do not differ from standard recommendations
    • Potential for drug interactions may complicate eligibility for enrollment in a clinical trial for COVID-19 or treatment; drug interaction checkerr87 is recommended

Monitoring

  • Patients who do not require admission should self-monitor temperature and symptoms, and they should return for reevaluation if symptoms worsen; deterioration may occur a week or morer170 into the course of illness and may be quite abrupt r169c283
  • In hospitalized patients with confirmed COVID-19, repeated testing may be done to document clearance of virus, defined as 2 consecutive negative results on polymerase chain reaction tests at least 24 hours apart r171c284

Complications and Prognosis

Complications

  • Most common complication is acute respiratory distress syndrome; other reported complications include: r21r22c285d5
  • MIS-C (multisystem inflammatory syndrome in children) has been associated with recent diagnosis of or exposure to COVID-19. A number of young adultsr176 have also been reported with similar clinical findings and recent history of diagnosed COVID-19 or serologic evidence of recent infection, termed MIS-A (multisystem inflammatory syndrome in adults) r173r174r175c296
    • Characteristic features in children include: r174r177
      • Persistent fever c297
      • Hypotension, syncope, confusion c298c299c300c301
      • Headache c302
      • Sore throat, neck swelling c303c304c305c306c307
      • Cough, hypoxemia c308
      • Abdominal pain, vomiting, diarrhea c309c310c311c312
      • Rash, conjunctival injection, mucosal inflammation c313c314c315c316c317
      • Swelling of hands and feet c318
      • Lymphadenopathy c319c320c321
      • Laboratory markers of inflammation (eg, elevated erythrocyte sedimentation rate; elevated levels of C-reactive protein, ferritin, D-dimer, fibrinogen, procalcitonin, lactate dehydrogenase, interleukin-6, and interleukin-10; low level of serum albumin) c322c323c324
      • Abnormal blood cell counts: anemia, thrombocytopenia, neutrophilia c325c326c327c328c329
      • Indicators of multiorgan involvement: increased levels of creatinine, BUN, urine protein, transaminases, creatine kinase, troponins, and lactate dehydrogenase c330
      • Imaging
        • Chest radiograph or CT scan: bilateral patchy pulmonary infiltrates, pleural effusions
        • Echocardiogram: pericardial effusion, myocardial dysfunction, valvulitis, coronary artery dilatation
        • Abdominal ultrasonography: ascites, colitis, ileitis, hepatosplenomegaly, lymphadenopathy
    • In a systematic review covering 221 adults with MIS-A, the age range was 19 to 34 years; 70% were male; and Black and Hispanic people were disproportionately affected r178
      • 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; CDCr174 and WHOr179 provide case definitions for reporting
      • CDC MIS-C case definition: a person younger than 21 years with fever, laboratory evidence of inflammation (see above), and clinically severe illness requiring hospitalization, with involvement of 2 or more organ systems; plus no alternative diagnosis; plus current or recent COVID-19 or exposure within the past 4 weeks r174
        • Patients may meet partial or full criteria for Kawasaki disease but regardless should be reported if they meet case definition of MIS-C d8
      • CDC MIS-A case definition: a person aged 21 years or older with hospitalization for 24 hours or more, or an illness resulting in death, with clinical and laboratory criteria below, and with no alternative diagnosis: r175
        • Clinical: fever and at least 3 of the following criteria before hospitalization or within the first 3 days of hospitalization, including at least 1 primary criterion
          • Primary: severe cardiac illness (eg, myocarditis, pericarditis, coronary artery aneurysm, new-onset ventricular dysfunction, new-onset second- or third-degree atrioventricular block, new-onset ventricular tachycardia); rash and nonpurulent conjunctivitis
          • Secondary: new-onset neurologic dysfunction (eg, seizures, encephalopathy, meningeal signs, peripheral neuropathy, Guillain-Barré syndrome); shock or hypotension not attributable to medical treatment; abdominal pain, vomiting, or diarrhea; thrombocytopenia with count less than 150,000 cells/mm³
        • Laboratory: at least 2 of the following markers are elevated: C-reactive protein, ferritin, interleukin-6, erythrocyte sedimentation rate, procalcitonin; plus positive polymerase chain reaction, antigen, or serology test result for COVID-19
    • It may be difficult to distinguish this syndrome from Kawasaki disease or toxic shock syndrome; bacterial sepsis must also be considered and appropriate cultures obtained (including blood cultures) d9
    • Several professional organizations provide guidance on management r8r177r180
      • 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 d10
        • First line treatment is IV immunoglobulin 2 g/kg (based on ideal body weight) 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 (3-5 mg/kg/day) 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%) r23r181
    • Risk of severe or critical illness depends on age, underlying comorbidities, and vaccination status r23r57r181
    • Patients who require hospital admission often require prolonged inpatient stay (more than 20 days) and experience significant deconditioning r21r22
    • 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 r182
  • Infection fatality ratio (proportion of deaths among all who are infected, including confirmed cases, undiagnosed cases, and unreported cases) varies across global locations, but has been estimated as 0.15% r183
    • CDC currently estimates the infection fatality ratio by age as follows: r184
      • 0 to 17 years: 0.002%
      • 18 to 49 years: 0.05%
      • 50 to 64 years: 0.6%
      • 65 years and older: 9%
  • Mortality rate of diagnosed cases is generally about 3% but varies by country r9r10
    • 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: r53
        • 10% to 27% for those aged 85 years or older
        • 3% to 11% for those aged 65 to 84 years
        • 1% to 3% for those aged 55 to 64 years
        • Less than 1% for those aged 0 to 54 years
      • Case fatality rates for disease in Chinese patients with common comorbidities: r170
        • 10.5% for cardiovascular disease
        • 7.3% for diabetes
        • 6.3% for chronic respiratory disease
        • 5.6% for cancer
  • Risk of reinfection
    • Recovery from infection is associated with short-term protective immunity, but reinfection has been documented, especially after 90 days from infection r170r185
      • Vaccination in persons who have already had COVID-19 may reduce the risk of reinfection (data are limited but encouraging) r186
    • Risk of reinfection may be increased with exposure to variant strains, although data are limited
  • Risk of breakthrough infection (ie, infection despite vaccination) r187
    • Breakthrough infection is common, but explain to patients and families that this fact does not negate the value of vaccination, which lies in improved course of disease in most vaccinated people, yielding the following benefits:
      • Greatly reduced risk of progression to severe or critical disease r188
      • Greatly reduced risk of death r188
      • Lessened community transmission (ie, meaningfully reduced albeit not eliminated, leading to lesser burden of disease and death in population)
  • Risk of postacute or chronic complications
    • A substantial proportion of patients, including some who had mild or asymptomatic infection, experience persistent symptoms and prolonged recovery more than 4 weeks from onset of COVID-19. This syndrome is known by many names, including long COVID, postacute COVID-19, chronic COVID, or PASC (postacute sequelae of SARS-CoV-2 infection) r189r190r191
      • Most common symptoms (symptoms may be new or persistent since infection):
        • Shortness of breath
        • Fatigue, which may be profound and may be sharply exacerbated by even mild exertion (postexertional malaise)
        • Low-grade fever, which may come and go
        • Joint and/or muscle pain
        • Chest pain
        • Cough
        • Headache
        • Cognitive dysfunction
        • Palpitations
        • Paresthesia
        • Abdominal pain or diarrhea
        • Mood changes
        • Menstrual irregularities
        • Impaired senses of smell or taste (reduced, altered, or absent): hyposmia, anosmia; dysgeusia (parageusia, ageusia, hypogeusia)
      • Research is ongoing; specialized clinics are opening in many locations, and guidance is being developed for evaluation and care of these patients r192
    • 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 r193
      • 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) r194

Screening and Prevention

Screening

At-risk populations

  • Health care workers
    • At increased risk because of occupational exposure; in turn, undetected infection in health care worker poses risk for nosocomial transmission to patients and coworkers
  • Residents of congregate care facilities
    • At increased risk owing to age, prevalence of comorbidities, and congregate setting
  • Patients presenting for care
    • Triage screening is recommended at points of medical care to identify patients with symptoms and exposure history that suggest the possibility of COVID-19, so that prompt isolation measures can be instituted r35r88
      • At least during high-prevalence phases of the pandemic, the following principles apply to the isolation areas:
        • Set up separate, well-ventilated triage areas; place patients with suspected or confirmed COVID-19 in private rooms with the door closed and with private bathrooms (as possible); many hospitals designate building wings to be dedicated to probable COVID-19 r88
        • Reserve airborne infection isolation rooms for patients with COVID-19 undergoing aerosol-generating procedures and for care of patients with pathogens transmitted by airborne route (eg, tuberculosis, measles, varicella) r88
    • Guidelines released by Infectious Diseases Society of America also recommend testing of asymptomatic persons in health care settings under the following circumstances, given sufficient testing supplies: r66
      • Admission to hospital for unrelated condition, if community prevalence is high
      • Immunosuppression, about to undergo immunosuppressive treatment, and on hospital admission (for any reason)
      • About to undergo major surgery that is time-sensitive
      • About to undergo aerosol-generating procedure that is time-sensitive and personal protective equipment is lacking; but if protective gear is adequate, then the guidelines recommend against routine testing in asymptomatic persons who are not known to have been exposed to COVID-19
      • About to undergo transplant (hematopoietic stem cell or solid organ)

Screening tests

  • Screening methods overview
    • Screening of asymptomatic persons in certain circumstances is an important method of interrupting transmission r60
      • Health equity should be a priority in determining which groups to screen, as minority populations have been disproportionately affected by COVID-19
      • Serial testing and frequent testing improve the ability of screening to detect infection and interrupt transmission; frequency may be determined by transmission levels, the risk of transmission, and tiers based on exposure
      • Examples of groups to consider for screening include:
        • Teachers, staff, and/or students in school or child care settings
        • Residents and staff of congregate care settings, such as long-term care facilities, homeless shelters, or correctional facilities
        • Patients in health care settings
        • Employees in occupations with high exposure to the public (eg, transportation workers, first responders, health care workers)
      • Currently there is no role for routine antibody screening (eg, testing all vaccinated persons for evidence of immunity). Antibody testing may be considered for public health purposes (eg, serologic survey of a population to assess for past infection), but it should not be used for diagnostic purposes r68
  • Screening in health care settings
    • Screening of patients and subsequent triage to isolation and testing with polymerase chain reaction is based on clinical presentation and exposure history: r35r60r88
      • Presence of COVID-19 symptoms (CDC, WHO) c331c332
      • Close contact with a person with known or suspected COVID-19 while that person was ill (WHO, CDC) c333
      • Work in a health care setting in which patients with severe respiratory illnesses are managed, without regard to place of residence or history of travel (WHO)
      • Unusual or unexpected deterioration of an acute illness despite appropriate treatment, without regard to place of residence or history of travel, even if another cause has been identified that fully explains the clinical presentation (WHO) c334
    • Health care facilities should also have a process for identifying visitors and staff who have symptoms of COVID-19, who have a positive COVID-19 test result, or who meet quarantine or isolation criteria r88
      • Visitors meeting any of the above criteria should be excluded from the facility
      • Health care workers with COVID-19 should follow symptom-based return-to-work guidelines; those with exposure may be able to continue working if asymptomatic, fully vaccinated, and following all guidelines for testing and personal protective equipment r195
      • Direct temperature screening is no longer considered necessary owing to lack of evidence of effectiveness
    • Screening tests (polymerase chain reaction or antigen testing) for asymptomatic patients may be indicated (eg, preadmission or preprocedure), but such testing may be low-yield during low- or moderate-transmission phases r88
    • Antigen testing may be useful for health care workers and for residents and staff of congregate care facilities r61
      • Serial testing (every 3 days or twice per week) can reduce disease transmission r196
      • During an outbreak in a facility, serial antigen testing is recommended every 3 to 7 days until there are no new cases for 14 days r61
      • Specific guidance is available for nursing homes and long-term care facilities r56
  • Screening in workplaces
    • All workers should be instructed to stay home and to report to their employer if they have a positive test result for COVID-19, symptoms of COVID-19, or, for unvaccinated workers, exposure to someone with COVID-19 r197
      • Fully vaccinated persons with no symptoms should be tested 3 to 5 days after known exposure, and should wear a mask for 14 days after exposure or until test results are negative; fully vaccinated persons with symptoms should be tested and isolated immediately r198
    • Certain workplaces have higher risk for rapid spread and should be considered for screening tests (polymerase chain reaction or antigen testing): r199
      • High-density workplaces where distancing is not feasible (eg, food processing plants)
      • Workplaces where employees live in congregate housing (eg, farms, fishing vessels)
      • Workplaces with populations at risk for severe illness (eg, homeless shelters, places with older workforces)
      • Universities, colleges, schools, and child care locations
    • Specific guidance is available for correctional facilities and homeless shelters r199
  • Screening in public places r200
    • 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 slow the importation of infected cases, but evidence is of low certainty
    • Many locations have begun requiring proof of vaccination, recent negative result on COVID-19 testing (polymerase chain reaction or antigen), or both in order to enter (eg, countries, concert venues, sports arenas), but as yet there is no assessment of effectiveness

Prevention

  • Overview
    • Preventive measures include vaccination, public health interventions, postexposure prophylaxis, and (in select populations) preexposure prophylaxis
  • Background on vaccinesc335
    • Vaccine authorizations and approvals: various vaccines against SARS-CoV-2 have entered use in many countries, and more are in development r201
      • After analyses of data, the vaccines in use have emergency, temporary, or full authorizations from various national regulatory authorities, and future authorizations and full approvals are pending
        • BNT162b2 (Pfizer-BioNTech COVID-19 vaccine; tozinameran; Comirnaty) has received use authorizationr202 in the United States (where it has also received full FDA approval for persons aged 16 years or olderr203), the United Kingdom,r204 the European Union, Canada,r205 and elsewhere c336
        • Moderna COVID-19 vaccine (mRNA-1273) has received use authorizationr206 in the United States (where it has also received full FDA approval for persons aged 18 years or olderr207), the United Kingdom, Canada, the European Union, and elsewhere c337
        • Oxford-AstraZeneca COVID-19 vaccine has received authorization for temporary supply in the United Kingdomr208 and similar authorizations in other countries.r209 Pauses to investigate rare clotting events have occurred in various countries; vaccination has resumed based on public health risk-benefit assessments (ie, the apparent rarity of the adverse effect versus the relatively higher risk posed by COVID-19) c338
        • Janssen COVID-19 vaccine (Johnson and Johnson) has received use authorization in the United States;r210 in 2021, its use was briefly paused but resumedr211 with warnings about rare occurrences of cerebral venous sinus thrombosis and thrombocytopenia after administration. However, on May 5, 2022, FDA limited its user212 to people aged 18 years or older for whom other approved COVID-19 vaccines are unavailable or not clinically appropriate, or when elected by the recipient who would otherwise not be vaccinated c339
        • Various other vaccines are in use in many other countries; WHO tracking of vaccine development currently lists 153 vaccines in clinical development, with 196 in preclinical phases r201c340c341
      • CDC has compiled a summary of studies done in various countries (ie, the United States, the United Kingdom, several European countries, and Israel) on the effectiveness of various vaccines (ie, Pfizer-BioNTech, Moderna, Johnson and Johnson/Janssen, AstraZeneca) used in real-world conditions. Most studies found effectiveness rates greater than 90% r213
        • Efficacy of vaccine-induced immunity against disease caused by circulating variants is under ongoing assessment. Results will likely vary among vaccines and variants. Some vaccination recommendations have changed as a result of additional data r11
          • Evidence suggests a modest decrease in vaccine effectiveness over time; however, vaccination remains strongly protective, particularly in prevention of hospitalization and death r57r188r213r214
      • WHO has issued emergency use listing for 7 vaccines thus far; such listing assesses quality, safety, efficacy, and programmatic suitability, and it is a prerequisite for the COVAX vaccine supply and international procurement program r215
        • Authorizations in different jurisdictions may differ in details; practitioners should consult the specific authorization issued in their jurisdiction for indications, requirements for patient education and consent, and mandated reporting (eg, adverse events)
          • Vaccine administration information for the United States
            • In the United States, emergency use authorizations require health care providers to communicater202r216r217 to the patient, parent, or caregiver information consistent with the vaccine-specific (manufacturer-specific) fact sheet for recipients and caregiversr218r219r220 before each patient receives the vaccine; such information includes the following:
              • Alternatives to receiving the vaccine
              • Option to accept or refuse the vaccine
              • Significant known and potential risks and benefits of the vaccine, and the extent to which such potential risks and benefits are unknown
              • Available alternative preventive vaccines in clinical trials or approved for use under other emergency use authorizations
            • Emergency use authorizations also require health care providers to reportr217r216r202 all vaccine administration errors, exposures during pregnancy, and serious adverse events to VAERS (Vaccine Adverse Event Reporting System)r221 and to the manufacturer (via Pfizer online report form,r222 email to ModernaPV@modernatx.com,r217 or at the Janssen COVID-19 vaccine websiter223) within 7 calendar days from onset of event. Additionally, they must report cases of COVID-19 resulting in hospitalization or death and cases of multisystem inflammatory syndrome that occur in vaccinated patients
            • 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 r202r217r224
            • Vaccine recipients in the United States are encouraged to participate in CDC's V-safe monitoring and reminder system,r224 available as a mobile phone app r217
            • 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 r225
          • 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 siter226
    • Vaccination recommendations
      • CDC recommends vaccination against COVID-19 for everyone aged 5 years or older r11
        • mRNA vaccines are preferred over Johnson and Johnson (Janssen) owing to higher efficacy and lower adverse effects
          • Johnson and Johnson (Janssen) may be considered under certain circumstances (eg, where there is a contraindication or allergic reaction to an mRNA vaccine)
        • Primary vaccinations
          • Primary vaccination of nonimmunocompromised persons
            • Primary series for nonimmunocompromised persons aged 18 years or older is 2 doses of Pfizer separated by 3 to 8 weeks or 2 doses of Moderna separated by 4 to 8 weeks
              • A shorter interval (3 or 4 weeks) is recommended for those at higher risk of infection or of severe disease (eg, when community transmission is elevated, for older adults or those with chronic conditions)
              • A longer interval (8 weeks) may be preferable in males aged 12 to 39 years to reduce the risk of vaccine-associated myocarditis, and it may be considered to increase peak antibody response in those not at increased risk
                • Risk of myocarditis from COVID-19 disease is substantially higher than the risk from vaccination r227
                • Risk of myocarditis in younger males may be lower after vaccination with Pfizer than with Moderna r11
            • Primary series for nonimmunocompromised children aged 12 years to 17 years is 2 doses of Pfizer separated by 3 to 8 weeks
              • A longer interval (8 weeks) may be preferable in males to reduce the risk of vaccine-associated myocarditis
            • Primary series for nonimmunocompromised children aged 5 years to 11 years is 2 doses of Pfizer separated by 3 weeks
          • Primary vaccination of moderately or severely immunocompromised persons
            • Primary series for immunocompromised persons aged 18 years or older is 3 doses of Pfizer (second dose 3 weeks after first dose, and third dose 4 weeks after second dose) or 3 doses of Moderna (each dose separated by 4 weeks)
            • Primary series for immunocompromised children aged 5 to 17 years is 3 doses of Pfizer, with second dose 3 weeks after first dose, and third dose 4 weeks after second dose
          • There are no data available on the interchangeability of the COVID-19 vaccines to complete the primary vaccination series. Patients who receive the first dose of any of the vaccines should receive a second dose of the same vaccine to complete the vaccination series r11
            • In cases in which the original mRNA vaccine manufacturer cannot be verified or obtained, or there is a contraindication to that vaccine, it is permissible to administer another authorized vaccine at least 28 days after the first dose. If a delay in obtaining the mRNA vaccine is expected to be temporary, it is preferable to delay the second dose in order to complete the series with the same vaccine r11
        • Booster vaccinations
          • Some data suggest that heterologous boosters (ie, booster vaccine different from primary) produce equivalent or stronger serologic response compared with homologous boosters r11
          • First booster dose r11
            • All nonimmunocompromised persons aged 5 years or older should receive a first booster dose with an mRNA vaccine 5 months or more after the completion of the primary series of either mRNA vaccine, or 2 months or more after Johnson and Johnson.
              • Only Pfizer may be used in those aged 5 to 17 years
            • Moderately or severely immunocompromised persons aged 5 years or older who have received a third primary dose of mRNA vaccine should receive a first booster dose with an mRNA vaccine 3 months or more after the completion of the primary series; first booster dose with an mRNA vaccine is recommended 2 months after the second primary dose if Johnson and Johnson was received
              • Only Pfizer may be used in those aged 5 to 17 years
          • Second booster dose
            • CDC recommendation released April 21, 2022: persons in certain subpopulations "may choose to receive" a second booster dose, using an mRNA COVID-19 vaccine (eg, Pfizer, Moderna) at least 4 months after their first booster dose. On May 19, 2022, CDC strengthened its recommendation, urging first and second boosters in the following groups, particularly if they have not received a dose of vaccine since December 2021: r11r228
              • Immunocompetent adults who received Johnson and Johnson (Janssen) vaccine for both primary series and first booster may receive a second booster with either of the mRNA vaccines 4 months or more after the first booster
              • Immunocompetent adults aged 50 years or older should receive an additional booster with either of the mRNA vaccines, 4 months or more after the first booster
              • Moderately or severely immunocompromised persons aged 12 years or older should receive a second booster with an mRNA vaccine licensed for their age group, at least 4 months after the first booster (total of 5 doses for mRNA vaccines, or 4 doses if Johnson and Johnson was primary vaccination)
                • Only Pfizer may be used in those aged 12 to 17 years
      • 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 r11
      • History of COVID-19 is not a contraindication to vaccine; guidelines recommend that such persons be offered vaccine r11
        • Vaccination (either first or subsequent doses, if a series has been started) should be deferred until the person meets criteria for discontinuing isolation
        • Some evidence indicates that protection after vaccination may be stronger than immunity produced by previous infection, including increased antibodies in infants born to adults who received vaccination during pregnancy, compared with pregnant persons who had COVID-19 disease r186r229
      • Persons who received treatment with convalescent plasma or COVID-19–specific monoclonal antibodies do not need to delay vaccination by any interval; individuals who are candidates for tixagevimab and cilgavimab should wait at least 14 days after vaccination to receive the product r11
      • No data exist regarding safety and efficacy of vaccination after MIS-C or MIS-A; theoretical risk of dysregulated immune response from vaccination causing multisystem inflammatory syndrome should be weighed against risk of morbidities from COVID-19 infection r11
        • CDC guidance notes that some experts consider that benefits of vaccination probably exceed risks when the following criteria are met:
          • High or substantial transmission of SARS-CoV-2 in the community
          • Clinical recovery (including return to normal myocardial function)
          • 90 days or more have elapsed since MIS-C diagnosis
          • MIS-C occurred before patient received any dose of COVID-19 vaccine
        • Consider consultation with a specialist in infectious diseases, rheumatology, cardiology, and/or Clinical Immunization Safety Assessment COVIDvax projectr230 personnel to discuss specific cases
      • History of Guillain-Barré syndrome (postinfectious polyneuritis) is not a contraindication, but is a precaution, to Johnson and Johnson (Janssen) vaccination; consider use of an mRNA vaccine if available r11
      • Vaccine use in special populations
        • Pregnant persons and breastfeeding persons r11r162r163
          • 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; however, given the small risk of rare vaccine-induced thrombotic thrombocytopenia seen in females younger than 50 years after vaccination with Janssen (Johnson and Johnson) product, an mRNA vaccine is recommended
            • Studies indicate that pregnant persons with COVID-19 infection have increased risk for severe illness and death from COVID-19 and may be at increased risk of preterm birth, stillbirth, and other pregnancy complications
            • Growing information on safety and efficacy during pregnancy indicates that benefits of vaccination outweigh risks
              • One study in 35,691 pregnant persons aged 16 to 54 years found no increased rates of pregnancy loss, preterm birth, small-for-gestational-age infants, or congenital anomalies compared with background rates r231
              • 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) r232
              • 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 r229
            • 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 r233
          • Although safety and efficacy in patients with cancer is still being studied, the National Comprehensive Cancer Network recommends that patients with cancer should receive vaccine when available; this recommendation is based on the extra risk for COVID-19 complications conferred by malignancy, as well as on the absence of any clear-cut known or theoretical vaccine-associated risks unique to patients with cancer
          • Exceptions include recent recipients of hematopoietic cell transplant or cellular therapy (who should delay vaccination for 3 months) and patients with hematologic malignancies who have neutropenia (who should await recovery of absolute neutrophil count). Patients who require major surgical procedures should time vaccination for several days before or after the surgery
        • Persons with autoimmune diseases r11
          • Little clinical information exists on the use of vaccine in persons with autoimmune diseases, but no unusual responses were noted in vaccine trial participants with autoimmune conditions, and current recommendations do not advise against vaccination of persons with autoimmune diseases
    • Vaccine contraindications and significant adverse effects
      • Contraindications include: r11r216
        • Severe allergic reaction (eg, anaphylaxis) to a previous dose of a COVID-19 vaccine or to any of its components
        • Immediate allergic reaction of any severity to a previous dose of an mRNA COVID-19 vaccine or any of its components (including polyethylene glycol) or to polysorbate (because of possible cross-reacting immune response against polyethylene glycol)
        • For the Johnson and Johnson (Janssen) vaccine, contraindications include thrombosis with thrombocytopenia syndrome, heparin-induced thrombocytopenia, or other immune-mediated thrombosis syndrome; individuals who had Guillain-Barré syndrome after Johnson and Johnson vaccination should not receive any additional doses of this vaccine
      • CDCr11 and the European Medicines Agencyr234 have recommended that clinicians maintain a high index of suspicion for thrombotic events and thrombocytopenia among persons who have received the Janssen or AstraZeneca vaccines
        • Symptoms may include severe headache, blurred vision, back pain, abdominal pain, chest pain, dyspnea, leg edema, petechiae, or easy bruising; overt bleeding has occurred in some cases r11r234
        • 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): r235
          • 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: r235
          • IV immunoglobulin 1 g/kg daily for 2 days
          • Anticoagulation with 1 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 r235
          • 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, and history of Bell palsy is not a contraindication r11
      • 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 considered to be a contraindication r11
    • Vaccine-specific details and evidence
      • Pfizer-BioNTech BNT162b2 (tozinameran; Comirnaty) c342
        • 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% r204
          • Among subgroups, results were similar in older age groups (older than 65 years) and in persons with comorbidities associated with increased risk for severe disease
        • Data evaluated for US emergency use authorization included 36,621 persons, aged 12 years or older, equally divided between vaccine group and placebo group (18,242 versus 18,379, respectively), with wide ethnic and age diversity, and incorporating a large percentage of persons with comorbidities. At time of analysis, participants had been followed for a median of 2 months after the second dose r202
          • 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 r202r204
        • 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 r202r204
          • 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 r202
          • Severe allergic reactions have been described, and facilities at which vaccine is administered must have the ability to treat such reactions (including anaphylaxis) r202
          • Myocarditis and pericarditis have been reported to occur in adolescents and young adults (primarily males) after vaccination with both mRNA vaccines, most commonly after the second dose. Onset is usually several days after administration of vaccine; the condition is generally short-lived. Vaccine recommendations for adolescents and young adults remain unchanged, although it is recommended that persons who have had myocarditis after a first dose of vaccine defer the second dose r11r236r237r238
        • 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 r239
        • Subsequent trial data on adolescents led to extension of the US emergency use authorization on May 10, 2021, to include adolescents aged 12 through 15 years, effectively permitting use in all persons aged 12 years or older who do not have a contraindication r240
          • 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 r202
          • 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) r202
        • FDA issued an emergency use authorization for children aged 5 through 11 years on October 29, 2021; CDC recommends that children aged 5 through 11 years without contraindications receive Pfizer-BioNTech pediatric COVID-19 vaccine r11r220r241
          • 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 approval for ages 16 years and older was based on continued follow-up of initial study enrollees and additional data r203
      • Moderna COVID-19 vaccine (mRNA-1273; Spikevax) r217c343
        • Safety data evaluated for US emergency use authorization (and subsequently publishedr242) included 30,351 persons, aged 18 years or older, equally divided between vaccine group and placebo group (15,185 versus 15,166, respectively); efficacy data was available for 14,134 vaccine recipients and 14,073 persons who received placebo. Participants included wide ethnic and age diversity; persons with stable comorbidities were included. At time of analysis, participants had been followed for a median of 9 weeks after the second dose
          • Overall efficacy was 94.1% (95.6% for persons aged 18 through 64 years and 86.4% for persons aged 65 or older)
          • Common adverse effects included pain at injection site, fatigue, headache, myalgia, chills, arthralgia, and fever; these were largely mild to moderate and resolved within a median of 2 to 3 days
          • Bell palsy was reported in 3 vaccine recipients (1 case classed as serious) and 1 placebo recipient; a causal relationship has not been established. Two patients who had previously received facial injection of dermatologic fillers experienced severe facial swelling considered likely vaccine-related. One patient developed intractable vomiting requiring hospital admission, deemed a result of vaccine
          • Severe allergic reactions have been described, and facilities at which vaccine is administered must have the ability to treat such reactions (including anaphylaxis)
            • CDC provides guidance on anaphylaxis to aid vaccine providers in preparing for and managing such eventsr243, and for postanaphylaxis laboratory assessmentr244
          • Myocarditis and pericarditis have been reported to occur in adolescents and young adults (primarily males) after vaccination with both mRNA vaccines, most commonly after the second dose. Onset is usually several days after administration of vaccine; the condition is generally short-lived. Vaccine recommendations for adolescents and young adults remain unchanged, although it is recommended that persons who have had myocarditis after a first dose of vaccine defer the second dose r11r236r237r238
      • AstraZeneca COVID-19 vaccine (ChAdOx1-S [recombinant]) r208c344
        • Safety data considered in the UK authorization for temporary use came from 23,745 persons who were enrolled in a clinical trial. The most common adverse effects included injection site tenderness (more than 60%) and injection site pain, headache, or fatigue (more than 50%). Less common adverse effects included myalgia or malaise (more than 40%), fever or chills (more than 30%), and arthralgia or nausea (more than 20%). Most of these symptoms resolved within a week. Adverse reactions were less common after the second dose and were less common overall in older recipients
        • Authorizing body considered efficacy data from 11,636 persons enrolled in a multinational trial: 5,807 patients received the COVID-19 vaccine and 5,829 received meningococcal vaccine (placebo). Vaccine efficacy measured at least 22 days after the first dose was 73%, and it was similar for patients with comorbidities compared with those without
        • Use of the vaccine has been interrupted in several regions while reports of unusual clotting disorders after administration were investigated; vaccination has resumed in some areas based on public health risk-benefit assessmentsr246 (ie, the apparent rarity of the disorder versus the relatively higher risk posed by COVID-19). About 30 cases have been reported among about 5 million persons receiving this vaccine in Europe r245
          • Characterized by venous thrombosis and thrombocytopenia associated with high levels of platelet factor 4–polyanion complexes (ie, similar to heparin-induced thrombocytopenia, but in the absence of heparin exposure; thus termed vaccine-induced immune thrombotic thrombocytopenia)
          • One published series reported 5 cases (in persons aged 32 to 54 years) in a population of more than 130,000 vaccine recipients; patients experienced onset of severe thromboses (some with embolization), associated with thrombocytopenia (some with hemorrhage), occurring 7 to 10 days after vaccination r247
          • Another series reported 11 cases in Germany and Austria (total number of vaccinations administered was not given); 9 of 11 patients were female, and the mean age was 36 years. Patients experienced severe and multiple venous thromboses (cerebral, splanchnic, pulmonary, other) associated with thrombocytopenia and, in some cases, disseminated intravascular coagulation
      • Janssen COVID-19 vaccine r216c345
        • A replication-deficient adenovirus vector vaccine that generates immunity to the SARS-CoV-2 spike protein. The vaccine is administered as a single 1-time dose
        • A multinational trial enrolled 44,325 persons randomized to receive the Janssen COVID-19 vaccine or saline placebo; a preliminary efficacy analysis of 39,321 was presented to the FDA, of whom 19,630 received vaccine and 19,691 received placebo. The populations were similar and represented diverse racial and ethnic backgrounds, and patients were distributed across all age ranges 18 years and older. Persons with stable underlying medical conditions (including HIV infection) were included
        • At 14 days after vaccine administration, efficacy against severe/critical COVID-19 was 76.7%, rising to 85.4% at 28 days; for moderate to severe/critical COVID-19, efficacy rates at 14 and 28 days were 66.9% and 66.1%, respectively. At 28 days, efficacy rates did not differ between populations aged 18 to 59 years and those aged 60 years or older
        • Common adverse reactions (reported in more than 10% of participants) included headache, fatigue, myalgia, and nausea; they were reported in 13.1% of vaccine recipients and 12% of placebo patients; other adverse events included urticaria in 5 vaccine recipients (including 1 with angioedema) and 1 placebo recipient
        • 2 unique serious adverse events thought to be related to the vaccine occurred, as follows: 1 patient experienced severe pain in the injected arm unresponsive to analgesics and persistent to 74 days of follow-up, and another patient had fever, headache, and generalized weakness that resolved within 3 days
        • Several events occurred more frequently in vaccine recipients than in placebo recipients, but a causal relationship to the vaccine could not be determined, owing to confounding effects of existing underlying conditions: deep vein thrombosis (6 vaccine recipients versus 2 placebo recipients); pulmonary embolus (4 vaccine recipients versus 2 placebo recipients); transverse sinus thrombosis (single case, in a vaccine recipient); seizures (4 vaccine recipients versus 1 placebo recipient); tinnitus (in 6 vaccine recipients only)
        • On April 12, 2021, CDC and FDA recommended that practitioners in the United States suspend use of this vaccine while reports of an unusual clotting disorder associated with administration of this vaccine were investigated r248
          • Characterized by cerebral venous thrombosis with thrombocytopenia occurring 6 to 13 days after administration
          • Initial data included 6 cases among more than 6.8 million persons immunized with this vaccine in the United States; all were in females aged 18 to 48 years
        • On April 23, 2021, CDC and FDA recommended that use of this product could resume because occurrence of the observed clotting disorder is extremely rare and benefit of vaccination against COVID-19 is felt to outweigh risk r249
          • Collection and analysis of further data included 9 more cases, for a total of 15 affected persons, all of whom were females aged between 18 and 59 years
          • Specific risk factors for this complication have not been identified r211
        • 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 r212
    • Vaccines against SARS-CoV-2 that have reached authorization status in some jurisdictions.EUA, emergency use authorization.
      Product nameManufacturerActive ingredientAge range for useDose and routeDosing intervalComments
      Pfizer-BioNTech COVID-19 vaccine (BNT162b2; tozinameran; Comirnaty)Pfizer-BioNTechNucleoside-modified mRNA of SARS-CoV-25 years or older
      12 years and
      older: 30 mcg (0.3
      mL) intramuscular
      injection for 2 doses
      for primary
      series, including
      third dose if
      indicated; booster dose
      grey cap [no
      dilution]; purple cap
      [must dilute].
      5-11 years: 10 mcg
      (0.2 mL) intramuscular
      injection
      for 2 doses for primary
      series including third dose if indicated; booster dose orange
      cap [must dilute]:
      3 weeks

      Additional (third primary series) dose: 28 days or more since second dose

      Booster: 5 months or more after completing primary series


      Second booster (if indicated): 4 months or more after the first booster
      FDA approved in the United States for ages 16 years or older; used under EUA for 5-15 year age groups in the United States

      Under temporary use authorization in the United Kingdom
      Moderna COVID-19 vaccine (mRNA-1273; Spikevax)ModernaTXSynthetic mRNA of SARS-CoV-218 years or older100
      mcg (0.5 mL) intramuscular injection (primary series, including third dose if indicated)

      Booster: 50 mcg (0.25 mL)
      1 month

      Additional (third primary) dose: 28 days or more since second dose

      Booster: 6 months or more since completing primary series
      FDA approved in the United States for ages 18 years or older

      Under temporary use authorization in the United Kingdom
      Oxford-AstraZeneca COVID-19 vaccine (ChAdOx1-S recombinant)AstraZenecaRecombinant, replication-deficient chimpanzee adenovirus vector encoding SARS-CoV-2 spike glycoprotein (S protein)18 years or older0.5 mL intramuscular injection4 to 12 weeksInvestigational; under temporary authorization in the United Kingdom
      Janssen COVID-19 vaccineJanssen
      Biotech, Inc (a Janssen Pharmaceutical Company of Johnson and Johnson)
      Recombinant, replication-deficient adenovirus
      26 vector expressing SARS-CoV-2 spike glycoprotein (S protein)
      18 years or older0.5 mL intramuscular injection (primary and booster)Booster: 2 months or more since primary doseInvestigational; under EUA in the United States

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

      On May 5, 2022, FDA limited the use to people aged 18 years or older for whom other approved COVID-19 vaccines are unavailable or not clinically appropriate, or when elected by the recipient who would otherwise not be vaccinated
  • Postexposure prophylaxisr8
    • Postexposure prophylaxis is not a substitute for vaccination, which remains the most effective prevention against infection, severe morbidity, and mortality. Additionally, postexposure prophylaxis is expected to be ineffective against variants less susceptible to these agents (eg, Omicron)
    • In the United States, emergency use authorization has been issued for the use of monoclonal antibodies casirivimab and imdevimab (in combination) or bamlanivimab and etesevimab (in combination) as postexposure prophylaxis for those at high risk of progression to severe disease under the following circumstances:
      • Exposed person is not fully vaccinated or not expected to develop protective immunity after vaccination because of immunocompromise (including immunosuppressive treatment), and
      • Close contact with a person who has infection with SARS-CoV-2 or is at high risk of exposure to a person infected with SARS-CoV-2 in an institutional setting in which COVID-19 is occurring, and
      • Prevailing virus variants are susceptible
    • Close contact is defined as being within 6 feet for 15 minutes or longer; providing care for a person with COVID-19; or close personal contact (hugging; sharing eating or drinking utensils; exposure to respiratory droplets expelled by a cough or sneeze by an infected person)
    • Casirivimab and imdevimab may be used for persons aged 12 years or older and weighing at least 40 kg r3
      • Omicron variant prevalence precludes most use; casirivimab and imdevimab are not authorized for use in places in which the combined frequency of variants resistant to them exceeds 5%
      • Initial dose is casirivimab 600 mg plus imdevimab 600 mg IV (in a single infusion) or subcutaneously (in 4 injections at different sites of 2.5 mL each) as soon as possible after the exposure. In circumstances of ongoing exposure, additional 300 mg may be administered at 4-week intervals
    • Bamlanivimab and etesevimab may be used for persons aged 12 years or older and weighing at least 40 kg r4
      • Omicron variant prevalence precludes most use; bamlanivimab and etesevimab are not authorized for use in places in which the combined frequency of variants resistant to them exceeds 5%
      • Dose is bamlanivimab 700 mg plus etesevimab 1400 mg IV in a single infusion as soon as possible after the exposure
  • Preexposure prophylaxisr8
    • Experimental monoclonal antibodies tixagevimab and cilgavimab have received emergency use authorization for coadministration in persons aged 12 years or older, weighing 40 kg or more, who either (1) are moderately to severely immunocompromised and may not mount an immune response to vaccine or (2) have a contraindication to vaccination (eg, severe allergic reaction to COVID-19 vaccine or components) r6
      • Infectious Diseases Society of America guideline suggests preexposure prophylaxis with tixagevimab-cilgavimab for those who qualify r98
      • Adults and adolescents 12 years and older, weighing 40 kg or more: 150 mg of tixagevimab and 150 mg of cilgavimab administered as 2 separate consecutive intramuscular (IM) injections. The doses can be administered once every 6 months to persons who continue to qualify for preexposure prophylaxis; however, no safety and efficacy data are available for repeat dosing. The recommendation for repeat dosing is based on pharmacology and clinical trial data r250
  • Public health interventions to interrupt transmission (eg, masking, distancing, hygiene, isolation, quarantine): practices vary geographically and depend on regional disease activity, vaccination status, and other factors
    • General precautions for all populations r251
      • Get vaccinated
      • Wear a mask in indoor settings when community transmission is high or if you are at high risk
      • Avoid crowds and poorly ventilated spaces; improve ventilation whenever possible
      • Test to prevent spread to others (eg, if you have symptoms, exposure, or plans to gather with someone at higher risk)
      • Physical distance at least 6 feet from others whenever feasible
      • Wash hands (or use hand sanitizer at least 60% alcohol), cover coughs and sneezes with a tissue, and clean and disinfect high-touch surfaces often
      • Monitor for symptoms
    • Isolation and quarantine measures: overview
      • A Cochrane review of quarantine concluded that quarantine is important in reducing incidence and mortality r252
      • All those who have symptoms of COVID-19 should isolate themselves, and get tested for COVID-19, regardless of vaccination status r251
      • Persons who test positive for COVID-19, regardless of vaccination status, should isolate for 5 days and wear a mask for an additional 5 days r253
      • In the United States, subject to more stringent local or state policy, fully vaccinated persons may resume travel and do not require quarantine after a known exposure unless they develop symptoms suggestive of COVID-19 r198
        • Given the resurgence of case numbers in late 2021 and early 2022, all persons, including those fully vaccinated, are recommended to wear masks in indoor public settings in areas of high transmission, or if they are immunocompromised or at increased risk of severe disease r251
        • Fully vaccinated persons in close contact with someone with COVID-19 but who have no symptoms should be tested 5 days after the exposure, and should wear a mask for 10 days after exposure r253
        • For unvaccinated, asymptomatic persons in close contact with someone with COVID-19, quarantine is necessary for 5 days from the exposure followed by mask-wearing for an additional 5 days r253
        • Close contact is defined as within 6 feet for a cumulative total of 15 minutes or more in 24 hours
        • Testing should be performed immediately if symptoms develop
    • Infection control for at-home management of COVID-19
      • 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, and to wear a mask or cloth face cover during any contact with household members r89c346c347c348
        • Patients should be advised that if a need for medical care develops, they should call their health care provider in advance so that proper isolation measures can be undertaken promptly on their arrival at the health care setting
        • Isolation is required for everyone with a positive COVID-19 test result, even in the absence of symptoms
      • Household members/caregivers should: r254
        • Ideally, wear mask and gloves when directly contacting body fluids or dirty dishes. Remove and discard disposable products when leaving the room (do not reuse), and wash hands afterwards. If some of these supplies are absent, wear cloth face cover and scrupulously wash hands c349c350c351
          • Dispose of disposable items in a container lined with a trash bag that can be removed and tied off or sealed before disposal in household trash
        • Wash hands for at least 20 seconds after all contact; an alcohol-based hand sanitizer is acceptable if soap and water are not available c352c353
        • Not share personal items such as towels, dishes, or utensils before proper cleaning c354c355
        • Clean and disinfect regularly c356
          • Wear gloves to handle any dishes or utensils used by the person with COVID-19
          • Clean surfaces with diluted bleach solution or an EPA-approved disinfectant c357
        • Restrict contact to minimum number of caregivers and, in particular, ensure that persons with underlying medical conditions are not exposed to the patient
    • Infection control for COVID-19 managed in health care facilities (outpatient or inpatient) r88r255
      • CDC provides preparedness checklistsr256 for outpatient and inpatient health care settings
      • Immediately provide the patient with a face mask (or, if supplies are critically low, at least a cloth face cover) to reduce droplet spread and place the patient in a closed room pending further evaluation and disposition decisions. The closed room will ideally be one with structural and engineering safeguards against airborne transmission (eg, negative pressure, frequent air exchange), but in the high-prevalence stages of the pandemic (with crowded hospitals), reserve negative pressure isolation rooms for the greatest needs (ie, aerosol-generating procedures; tuberculosis, measles, and varicella)
      • Persons entering the room should follow standard, contact, and droplet or airborne precautions c358c359c360
        • Gloves, gowns, eye protection, and respirator (N95 or better) with adherence to hospital donning and doffing protocols c361c362
          • 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) c363c364
    • Criteria for discontinuation of isolation precautions r171r185
      • CDC recommends that a symptom-based strategy should be used to determine when to discontinue isolation in most patients. Criteria have been established based on observationsr185 showing that duration of shedding of infective virus varies from less than 10 days in milder cases to less than 20 days in more severe infections and in immunocompromised persons
        • Mild symptomatic COVID, no immunocompromise:
          • Isolation may be discontinued 5 days after symptom onset (first day of symptoms is day 0) and
          • At least 24 hours have passed since last fever without use of antipyretics and
          • Symptoms have improved and
          • Patient is able to wear a well-fitted mask for the next 5 days
          • If illness has been entirely asymptomatic, isolation may be discontinued 5 days from first positive specimen if the patient is able to wear a well-fitted mask for the next 5 days
        • Moderate COVID-19, no immunocompromise:
          • Isolate for 10 days
        • Severe or critical illness, no immunocompromising condition:
          • It may be reasonable to extend isolation until 10 days and up to 20 days have passed since symptom onset (day 0) and
          • At least 24 hours have passed since last fever without use of antipyretics and
          • Symptoms have improved
          • Repeat testing before discontinuing isolation may be considered
        • Moderately or severely immunocompromised persons:
          • Continue isolation for 20 days or longer after symptom onset or first positive SARS-CoV-2 test result; a test-based strategy to determine further duration may be appropriate. Infectious disease consultation is recommended
        • Test-based criteria for discontinuation of isolation include:
          • Negative test results from 2 specimens 24 hours apart; polymerase chain reaction or antigen tests are acceptable
          • For moderately or severely immunocompromised persons who were symptomatic, there should be improvement in symptoms and 24 hours have passed since last fever without use of antipyretics
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