COVID-19

Key Points

• COVID-19 (coronavirus disease 2019) is a systemic infection due to a novel coronavirus, SARS-CoV-2, which has circulated globally since 2020
• Infection ranges from asymptomatic to severe; the most common signs and symptoms are respiratory
• Infection should be suspected based on compatible symptoms, because exposure is frequently unknown
• Diagnosis is confirmed by polymerase chain reaction or antigen testing
• Treatments are administered at different stages of disease based on the pharmacologic mechanism of action and the dominant pathophysiology of the disease phase
  • Several antiviral medications are available, including remdesivir, ritonavir-boosted nirmatrelvir, and molnupiravir
  • Dexamethasone has been associated with significant reduction in mortality rates of patients requiring supplemental oxygen ^r1
  • Several immunomodulators are recommended for use in conjunction with corticosteroids with or without remdesivir
• Complications include acute respiratory distress syndrome, septic shock, renal failure, and multiorgan failure
• A significant proportion of clinically evident cases are severe; risk of death has decreased over time but remains higher than that of seasonal influenza ^r2r3r4
• 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 against hospitalization and death, even with changing variants ^r5

Urgent Action

• Screening is recommended in health care settings to identify patients, visitors, and health care personnel with symptoms or exposure, and to promptly institute appropriate infection control
• 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 virus

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

Clinical Clarification

• COVID-19 (coronavirus disease 2019) is a systemic infection (with a predilection for the respiratory system) caused by a recently recognized coronavirus, SARS-CoV-2, thought to have originated as a zoonotic virus that 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) ^r6
• Outbreak began in China but spread globally; it was officially declared by the WHO to be a pandemic on March 11, 2020 ^r7
  • WHO declared a public health emergency of international concern on January 30, 2020, and ended the declaration on May 5, 2023 (although the pandemic continues) ^r8
• 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 ratio) for most countries is 2% or lower but varies widely; true overall mortality rate is uncertain, as the total number of cases (including undiagnosed cases in persons with milder illness) is unknown ^r2
  • Risk of death has decreased over the course of the pandemic, due to differences in testing, clinical care, and immunity; estimated mortality remains higher than that of seasonal influenza ^r3r4r9r10
• Knowledge of this disease is evolving; variants with different clinical effects emerge regularly and reinfections are common

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 coronavirus^r6
  • Designated as SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2); earlier provisional name was 2019-nCoV (2019 novel coronavirus) ^r6
• Variants
  • Since late 2020, variants with potential impact on transmission, clinical disease, and immune protection have been recognized and tracked
    • Classification is based on factors such as disease severity, vaccine effectiveness, and changing epidemiological effects; variants are characterized as variants of concern, variants of interest, and variants under monitoring ^r11
    • Both WHO and CDC maintain tracking systems for variants ^r11r12
  • The Omicron variant (B.1.1.529 and descendant lineages) emerged in November 2021 in South Africa; since early 2022, is the only variant circulating in the US and the world, with numerous lineages including many subvariants ^r11r12
    • Similar disease severity but more easily transmitted than earlier variants, despite antibodies from prior disease, vaccination, or monoclonal antibody products; vaccination still greatly reduces the risks of severe illness and death

Clinical Presentation

Causes and Risk Factors

Diagnostic Procedures

Differential Diagnosis

Goals

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

Disposition

Treatment Options

Overview

• 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 ^r67
  • Select drugs according to the mechanism of action most likely to be effective against the dominant pathophysiology at various stages in the disease process ^r54
    • 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)
    • Anti-inflammatory drugs (eg, dexamethasone) and immunomodulators are of most benefit during the hyperinflammatory response in later phases
  • Consult a drug interaction checker^r68 to prevent or minimize drug-drug interactions
  • Recommendations below summarize major treatment guidelines from NIH, WHO, and Infectious Diseases Society of America ^r24r53r56r69
• Some treatment options are recommended for patients at high or moderate risk for severe disease, or for immunocompromised patients who are not expected to mount adequate immune response to vaccination or to COVID-19
  • Common underlying conditions include (but are not limited to): age 65 years or older, diabetes, chronic lung diseases, chronic heart diseases, chronic liver diseases, pregnancy, and mood disorders
    • CDC periodically updates a list based on new evidence ^r42
    • WHO separates moderate and high risk; any patients not in moderate or high risk categories are considered low risk ^r53
      • High risk is defined as 6% risk of hospitalization: patients with immunodeficiency syndromes, or those receiving immunosuppressants for solid organ transplant or autoimmune illness
      • Moderate is defined as 3% risk of hospitalization: patients older than 65 years; or patients who have obesity, diabetes, chronic cardiopulmonary disease, chronic kidney disease, chronic liver disease, active cancer, or disabilities; or patients with comorbidities of chronic disease
  • Some rare conditions, as well as race and ethnicity, may be associated with increased risk for severe disease, and risk increases when multiple conditions are present; use clinical judgment for individual patients ^r42
  • Common conditions causing moderate to severe immune compromise include (but are not limited to) the following; consult CDC guidance^r5 for updates
    • Active treatment for solid tumor and hematologic malignancies
    • History of solid organ transplant or islet transplant and currently taking immunosuppressive therapy
    • History of hematologic malignancies associated with poor responses to COVID-19 vaccines regardless of current treatment status (eg, chronic lymphocytic leukemia, non-Hodgkin lymphoma, multiple myeloma, acute leukemia)
    • History of CAR T-cell therapy (chimeric antigen receptor T-cell therapy) or hematopoietic cell transplant within the past 2 years, or currently taking immunosuppressive therapy
    • Moderate or severe primary immunodeficiency (eg, severe combined immunodeficiency, common variable immunodeficiency disease, DiGeorge syndrome, Wiskott-Aldrich syndrome)
    • Untreated HIV infection or advanced HIV infection (CD4 cell counts less than 200 cells/mm³, history of an AIDS-defining illness without immune reconstitution, or clinical manifestations of symptomatic HIV disease)
    • Immunosuppressive medications, including treatment with high-dose corticosteroids (20 mg or more of prednisone or equivalent per day when administered for 2 or more weeks), alkylating agents, antimetabolites, transplant-related immunosuppressive drugs, cancer chemotherapeutic agents classified as severely immunosuppressive, tumor necrosis factor blockers, and other biologic agents that are immunosuppressive or immunomodulatory
• Throughout the pandemic, many jurisdictions have experienced caseload surges and supply constraints, which may limit the available therapies
  • Only if access to recommended therapies is limited, NIH suggests prioritizing based on age, immune status, clinical risk factors, and vaccination status: ^r56
    • Tier 1: immunocompromised persons not expected to adequately respond to vaccination or COVID-19, and unvaccinated persons at highest risk due to age and underlying conditions (eg, 75 years or older, or 65 years or older with any underlying condition)
    • Tier 2: unvaccinated patients not included in tier 1 at high risk (eg, age 65 years or older, or any age with underlying conditions)
    • Tier 3: vaccinated patients at high risk (eg, 65 years or older, or any age with underlying condition); note that those without any booster doses are at higher risk than those up to date with all doses

Infection control measures: these include isolation, source control, and transmission precautions ^r70

• People with COVID-19 at home should stay at home until fever and symptoms are improved; keep separate from others in the household as much as possible; wear a mask when near other people or pets in the household; monitor for serious or worsening symptoms requiring additional medical care; and increase ventilation, cleaning, and disinfection ^r71
• Patients with COVID-19 in a health care setting should wear a face mask for source control; should be placed in a single-person closed room or cohorted with others with the same pathogen(s); and should have standard precautions, contact precautions, and droplet or airborne precautions as resources allow ^r70
  • Health care personnel should wear N95 respirator or comparable (eg, FFP2, KN95), gown, gloves, and eye protection
    • Some guidelines suggest that a medical face mask, rather than N95 respirator, is sufficient when not performing aerosol-generating procedures ^r24
  • If available, the patient room will ideally be one with structural and engineering safeguards against airborne transmission (eg, negative pressure, frequent air exchange), but if caseload or resource limitations preclude the ideal, then reserve negative pressure isolation rooms for the greatest needs (ie, aerosol-generating procedures; tuberculosis, measles, and varicella)
  • Do not cohort patients with suspected COVID-19 and patients with confirmed COVID-19 (confirm before cohorting)

Supportive care^r24

• For the majority of patients who do not require hospitalization or medications, provide symptomatic treatment (eg, fever control, hydration), advise infection control practices to reduce spread, and educate on warning signs and symptoms that require additional medical care
• For hospitalized patients, supportive care includes oxygenation and ventilation, conservative fluid support, and measures to prevent common complications (eg, pressure injury, stress ulceration, secondary infection)
  • Treat empirically for coinfections or alternative diagnoses (eg, bacterial sepsis, influenza) when appropriate, until diagnosis or diagnoses are confirmed ^r24
  • Surviving Sepsis Campaign^r72r73 guideline, NIH COVID-19 treatment^r56 guideline, and WHO guidance^r24 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 ^d6

Antiviral agents

• Remdesivir (antiviral RNA polymerase inhibitor) ^r74
  • Guidelines ^r56r69r72r73
    • Use remdesivir for hospitalized patients with COVID-19 who require supplemental oxygen
      • Initiate before onset of more severe disease for maximum benefit; for patients who already require oxygen via high-flow device or noninvasive ventilation, consider addition of remdesivir to other medications (eg, dexamethasone plus baricitinib or dexamethasone plus tocilizumab)
        • Persons who may benefit most from the addition of remdesivir include immunocompromised patients, those with evidence of ongoing viral replication (eg, those with a low cycle threshold value on polymerase chain reaction test, or with a positive rapid antigen test result), or those within 10 days of symptom onset ^r56
    • Avoid use of remdesivir for most patients with critical COVID-19 (eg, requiring mechanical ventilation or extracorporeal membrane oxygenation)
      • 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
    • Consider remdesivir for patients at high risk of disease progression (ambulatory, or hospitalized with no current oxygen requirement)
      • For this patient population, NIH guidelines prefer use of ritonavir-boosted nirmatrelvir, when available ^r56
    • Remdesivir should be offered to pregnant and lactating patients when indicated; breastfeeding may continue while they are taking remdesivir ^r56
    • Some experts would consider longer or additional courses of remdesivir for immunocompromised patients who have prolonged, symptomatic infection with ongoing viral replication ^r56
  • Evidence base
    • FDA-approved for treatment of COVID-19 in hospitalized adults and children from birth weighing 1.5 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 ^r75
    • Preliminary^r76 and follow-up^r77 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
    • 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 ^r78
    • NIH guidelines and Infectious Diseases Society of America guidelines summarize evidence from multiple additional studies showing benefit in various outcomes such as faster time to recovery, lower risk of clinical progression, and/or lower risk of death ^r56r69
• Ritonavir-boosted nirmatrelvir (antiviral protease inhibitor with booster to increase plasma concentrations) ^r79
  • Guidelines
    • Use 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 ^r56r69
      • Ritonavir-boosted nirmatrelvir is preferred for this indication; remdesivir and molnupiravir are alternatives
    • Consider ritonavir-boosted nirmatrelvir in ambulatory patients with mild or moderate COVID-19 at moderate risk of hospitalization ^r53
    • 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 ^r56
      • Resources are available to help clinicians manage potential drug interactions ^r68r80
    • Ritonavir-boosted nirmatrelvir should be offered to pregnant and lactating patients when indicated; breastfeeding may continue while they are taking ritonavir-boosted nirmatrelvir ^r56
      • Some COVID-19 studies did not include pregnant patients, but ritonavir has been used in pregnant patients with HIV ^r81r82
      • 2 case series totaling 54 pregnant patients with COVID-19, some with additional risk factors, reported good outcomes of infection and no fetal or neonatal adverse effects ^r56
    • Viral rebound and/or recurrence of symptoms and antigen test positivity has been reported after a 5-day course of ritonavir-boosted nirmatrelvir; there is no evidence that additional treatment is needed, but patients should continue to isolate until they meet criteria for discontinuation ^r56
    • Some experts prescribe longer or additional courses of ritonavir-boosted nirmatrelvir for immunocompromised patients who have prolonged, symptomatic infection with ongoing viral replication ^r56
      • Using longer or additional courses is off-label and is currently under investigation ^r83
      • When using ritonavir-boosted nirmatrelvir under emergency use authorization (ie, for patients aged 12 to 17 years), clinicians are required to request expanded access^r84 to prescribe longer or additional courses
  • Evidence base
    • FDA-approved for adults aged 18 years or older, and has emergency use authorization in children aged 12 to 17 years and weighing 40 kg or more, for treatment of nonhospitalized persons with mild to moderate COVID-19 who are at high risk for progression to severe disease ^r85r86
    • 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% ^r85
      • Because the trial enrolled only unvaccinated high-risk patients, additional studies have attempted to determine benefit for vaccinated patients, or patients not at high risk of progression; thus far, benefit has been seen only in patients at high risk of progression to severe disease ^r56
• Molnupiravir (antiviral nucleoside analogue) ^r87
  • Guidelines
    • Use molnupiravir in ambulatory adults with nonsevere disease at high risk of progression to severe disease only when alternatives (eg, nirmatrelvir-ritonavir or remdesivir) are unavailable or not feasible, because molnupiravir is less effective than alternatives ^r53r56r69
    • Molnupiravir is not recommended during pregnancy or breastfeeding ^r56r88
      • Before prescribing to persons of childbearing potential, test for pregnancy
      • For both male and female patients, ensure reliable contraception through treatment and for 4 days (females) or 3 months (males) after the last dose
      • Breast milk should be discarded during treatment and for 4 days after the last dose
      • NIH recommends against use of molnupiravir in pregnancy unless there are no other options and therapy is clearly indicated
  • Evidence base
    • Has emergency use authorization in the United States for treatment of nonhospitalized adults positive for COVID-19 who are at high risk of progression to severe disease, and for whom alternative treatments are not available or not clinically appropriate ^r88
    • Molnupiravir was compared with placebo in a randomized trial of 1433 patients with mild to moderate COVID-19 who met criteria for high risk of progression to severe disease. The primary end point was all-cause hospitalization or death through day 29. The relative risk reduction was 30%
    • Mechanism of action of molnupiravir is inducing lethal viral mutations; concerns have arisen regarding emergence of resistance and emergence of new variants as a result.^r89 Use of molnupiravir should be accompanied by robust pharmacovigilance ^r53

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

• Guidelines
  • Use dexamethasone in hospitalized patients who require supplemental oxygen ^{r24r53r56r69r72r73}
    • Dexamethasone should be the primary immunomodulator for all patients who require high-flow nasal cannula oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation, and for most patients who require conventional oxygen (with additional treatments as indicated)
      • Of patients requiring oxygen, only those requiring minimal conventional oxygen are recommended to receive remdesivir without dexamethasone ^r56
    • In the absence of dexamethasone, another glucocorticoid (eg, prednisone, methylprednisolone, hydrocortisone) may be used
    • Use in pregnant persons when indicated ^r56
    • Offer dexamethasone to lactating patients when indicated, and breastfeeding may continue while they are taking dexamethasone ^r56
  • Avoid dexamethasone in patients who do not require oxygen supplementation (patients without severe or critical disease) ^r24r53r56r69
  • Avoid inhaled corticosteroids for this indication ^r56r69
• Evidence base
  • A randomized controlled trial in more than 6000 hospitalized patients with COVID-19 found that dexamethasone reduced deaths in patients with severe respiratory complications requiring supplemental oxygen ^r1
    • Compared with usual care alone, deaths in ventilated patients receiving usual care plus dexamethasone were reduced by a third; among patients receiving oxygen without mechanical ventilation, deaths were cut by 20%
    • Overall 28-day mortality was reduced by 17% in the dexamethasone group
  • Since that time, multiple randomized trials show improved outcomes, including mortality, in hospitalized patients requiring oxygen; in contrast, systemic corticosteroids for patients not needing oxygen do not improve outcomes and may cause harm ^r56

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

• Baricitinib (a Janus kinase inhibitor) ^r90
  • Guidelines ^r53r56r69
    • Use baricitinib with dexamethasone (or with dexamethasone and remdesivir, when indicated) in hospitalized patients with severe or critical disease
      • Baricitinib (along with tocilizumab) is a preferred second immunomodulator with dexamethasone 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) and for hospitalized patients who need mechanical ventilation or extracorporeal membrane oxygenation
        • There is insufficient evidence to recommend baricitinib over tocilizumab or vice versa for these indications
      • Baricitinib is the preferred second immunomodulator with dexamethasone for hospitalized patients who need high-flow oxygen or noninvasive ventilation, due to a stronger evidence base than for tocilizumab, an alternative
    • Avoid giving tocilizumab or other interleukin-6 inhibitors to patients taking baricitinib
    • NIH guidelines recommend use of baricitinib for pregnant patients when indicated ^r56
    • In lactating persons, feeding breast milk to infants should be avoided while on baricitinib and for 4 days after the last dose, with support to maintain breastfeeding ^r56
  • Evidence base
    • FDA-approved for the treatment of COVID-19 in hospitalized adults receiving systemic corticosteroids and requiring supplemental oxygen, noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation; it has emergency use authorization for children aged 2 years or older for the same indications ^r91r92
      • 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 ^r91r93
      • In another phase 3 randomized trial of hospitalized adults with documented SARS-CoV-2 infection, pneumonia or active and symptomatic COVID-19, and at least 1 elevated inflammatory marker who were receiving standard of care, including corticosteroids and/or antivirals, there was no significant difference in disease progression (defined as progression to high-flow oxygen, noninvasive mechanical ventilation, invasive mechanical ventilation, or death) with baricitinib (764 patients) versus placebo (761 patients). However, the 28-day all-cause mortality was significantly lower in patients treated with baricitinib (8%) compared with placebo (13%), a 38.2% relative reduction in mortality ^r94
      • NIH guidelines summarize these and additional studies which show some mortality benefit, lower risk of clinical progression, and/or faster time to recovery ^r56
• Tocilizumab (monoclonal interleukin-6 receptor blocker) ^r95
  • Guidelines ^r53r56r69
    • Use tocilizumab with dexamethasone (or with dexamethasone and remdesivir, when indicated) in hospitalized patients with severe or critical disease
      • Tocilizumab (along with baricitinib) is a preferred second immunomodulator with dexamethasone 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) and for hospitalized patients who need mechanical ventilation or extracorporeal membrane oxygenation
        • There is insufficient evidence to recommend tocilizumab over baricitinib or vice versa for these indications
      • Tocilizumab is an alternative second immunomodulator with dexamethasone for hospitalized patients who need high-flow oxygen or noninvasive ventilation, due to a stronger evidence base for baricitinib
        • Best initiated within 24 hours of admission to ICU
    • Avoid giving baricitinib or other Janus kinase inhibitors to patients taking tocilizumab
    • NIH guidelines recommend use of tocilizumab for pregnant and lactating patients when indicated; breastfeeding may continue while they are taking tocilizumab ^r56
  • Evidence base
    • FDA-approved for the treatment of COVID-19 in hospitalized adults receiving systemic corticosteroids and requiring supplemental oxygen, noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation; it has emergency use authorization for children aged 2 years or older for the same indications ^r96r97
    • 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 ^r98r99
    • NIH guidelines and Infectious Diseases Society of America guidelines summarize additional trials which show mortality benefit and lower risk of clinical progression ^r56r69
• Abatacept (cytotoxic T-lymphocyte–associated antigen 4 agonist) ^r100
  • Guidelines ^r56
    • Use abatacept as an alternative second immunomodulator (if baricitinib or tocilizumab are not used) for hospitalized patients receiving conventional oxygen with rapidly increasing oxygen requirements, high-flow oxygen, or noninvasive ventilation
    • Use abatacept for pregnant patients when indicated; breastfeeding may be considered while a patient takes abatacept, although minimal data are available on abatacept in breast milk
  • Evidence base
    • FDA approved for inflammatory arthritis and graft-versus-host disease; has been used off-label in COVID-19 treatment
    • ACTIV-1 trial randomized 1971 patients to abatacept, cenicriviroc, infliximab, or placebo in randomized, double-masked protocol; for the primary outcome of time to recovery, there was no difference among all arms ^r101
      • However, mortality was significantly lower at day 28 among patients receiving abatacept compared with placebo, with no significant increase in serious adverse effects or secondary infection
• Infliximab (tumor necrosis factor α inhibitor) ^r102
  • Guidelines ^r56
    • Use infliximab as an alternative second immunomodulator (if baricitinib or tocilizumab are not used) for hospitalized patients receiving conventional oxygen with rapidly increasing oxygen requirements, high-flow oxygen, or noninvasive ventilation
    • Use for pregnant persons when indicated
    • Offer to lactating patients when indicated; breastfeeding may continue while they are taking infliximab
  • Evidence base
    • FDA approved for multiple inflammatory diseases; used off-label for COVID-19 treatment
    • ACTIV-1 trial randomized 1971 patients to abatacept, cenicriviroc, infliximab, or placebo in randomized, double-masked protocol; for the primary outcome of time to recovery, there was no difference among all arms ^r101
      • However, mortality was significantly lower at day 28 among patients receiving infliximab compared with placebo, with no significant increase in serious adverse effects or secondary infection
• Sarilumab (monoclonal interleukin-6 receptor blocker) ^r103
  • Guidelines ^r53r56r69
    • Use sarilumab with dexamethasone alone or with remdesivir and dexamethasone for patients with severe or critical COVID-19 primarily when preferred and alternate treatments (eg, baricitinib, tocilizumab, abatacept, infliximab) are unavailable or not feasible
  • Evidence base
    • FDA approved for rheumatoid arthritis and polymyalgia rheumatica; used off-label in COVID-19 treatment
    • REMAP-CAP trial found that sarilumab plus dexamethasone was noninferior to tocilizumab plus dexamethasone, but some trials have demonstrated no benefit; evidence (summarized in NIH guidelines and Infectious Diseases Society of America guidelines) is stronger for the use of tocilizumab ^r56r69r98
• Tofacitinib (a Janus kinase inhibitor) ^r104
  • Guidelines
    • Use tofacitinib with dexamethasone alone or with remdesivir and dexamethasone for patients with severe or critical COVID-19 primarily when preferred and alternate treatments (eg, baricitinib, tocilizumab, abatacept, infliximab) are unavailable or not feasible
      • Infectious Diseases Society of America guidelines suggest use of tofacitinib in hospitalized patients with severe but noncritical COVID-19 (ie, not on mechanical ventilation) ^r69
        • Patients should also receive at least prophylactic dose of anticoagulant
    • Avoid giving tocilizumab or other interleukin-6 inhibitors to patients taking tofacitinib
  • Evidence base
    • A randomized, placebo-controlled trial of 289 patients in Brazil (STOP-COVID trial) demonstrated a lower risk of death or respiratory failure in patients on tofacitinib compared to placebo ^r105
• Vilobelimab (a monoclonal antibody that binds to factor C5a of the complement cascade) ^r106
  • Guidelines ^r53r56r69
    • NIH guidelines find insufficient evidence to recommend for or against use; WHO guidelines and Infectious Diseases Society of America guidelines do not address vilobelimab
  • Evidence base
    • FDA emergency use authorization was granted in April 2023 for use in hospitalized adults (aged 18 years or older) within 48 hours of initiation of mechanical ventilation or extracorporeal membrane oxygenation for COVID-19; vilobelimab is not FDA approved for any indication ^r107
    • A randomized, double blinded, placebo-controlled phase 3 trial of 368 patients from 46 hospitals in 9 countries showed a significant decrease in 28-day mortality in patients on vilobelimab compared with placebo (absolute risk reduction, 11%; number needed to treat, 9 patients to prevent 1 death) ^r108
      • All patients were aged 18 years or older and also received standard of care (eg, corticosteroids, antithrombotic drugs, tocilizumab, baricitinib) in addition to vilobelimab or placebo initiated within 48 hours of invasive mechanical ventilation
      • 28-day mortality was 31.7% in the vilobelimab group compared with 41.6% in the placebo group (hazard ratio, 0.67), and all-cause mortality benefit persisted through 60 days (end of follow-up)
      • Adverse effects were similar between treatment groups (including pneumonia, sepsis, and acute kidney injury)
      • Notably, given the time span in which patients were enrolled (ie, October 2020 through October 2021), many patients were unvaccinated and few patients were infected with the Omicron variant; in addition, few patients received a second immunomodulator (eg, tocilizumab or baricitinib), which makes comparison with current practices difficult ^r56

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 ^r56r72
• Multiple guidelines address antithrombotic therapy, including NIH, International Society of Thrombosis and Haemostasis, American Society of Hematology, and American College of Chest Physicians. Recommendations are summarized below: ^{r56r109r110r111r112r113}
  • For prophylaxis in acutely ill adults: ^{r56r110r111r113}
    • Use therapeutic-dose heparins for hospitalized, non-critically ill adults with low risk of bleeding
      • Patients with elevated D-dimer levels are particularly likely to benefit from therapeutic dose over prophylactic dose
      • There is insufficient evidence to recommend for or against therapeutic-dose anticoagulation in pregnant patients without known venous thromboembolism
    • Use prophylactic-dose heparins for hospitalized, non-critically ill adults, who are not prescribed therapeutic-dose heparins
      • Use for hospitalized pregnant patients without a contraindication (eg, imminent delivery, bleeding complications of pregnancy)
    • Avoid adding antiplatelet therapy; continue antiplatelet therapy for patients for another indication
    • NIH guidelines recommend use in lactating patients (prophylactic-dose or treatment-dose heparin, as indicated); breastfeeding may continue while they are taking low-molecular-weight heparin or unfractionated heparin
  • For prophylaxis in critically ill adults: ^{r56r110r111r112}
    • Use prophylactic-dose heparin for adults in the ICU, including a recommendation to:
      • Switch from therapeutic to prophylactic dose in patients transferred to an ICU unless a thrombosis has been documented
      • Avoid adding antiplatelet therapy; continue antiplatelet therapy for patients for another indication
  • For prophylaxis in children: ^r56
    • NIH guidelines recommend prophylactic-dose heparin for hospitalized children aged 12 years or older; there is insufficient evidence to recommend for or against anticoagulation in children younger than 12 years, or to recommend for or against doses other than prophylactic-intensity
  • Prophylactic therapy is not recommended for nonhospitalized patients or as postdischarge therapy after hospitalization in patients without thromboembolic disease ^{r56r109r110r111}
    • Consider prophylactic rivaroxaban for 30 days of postdischarge therapy for select patients at high risk of thromboembolism (eg, high score on International Medical Prevention Registry on Venous Thromboembolism risk assessment model) ^r110
  • Generally, low-molecular-weight heparin is preferred over unfractionated heparin; evidence is limited regarding use of apixaban, rivaroxaban, fondaparinux, argatroban, bivalirudin, or other medications ^{r56r110r112r113}
  • Standard therapeutic treatment is recommended for patients with COVID-19 and thromboembolism (highly suspected or proven), for those on extracorporeal membrane oxygenation or continuous renal replacement therapy, and for those who have thrombosis related to catheters or extracorporeal filters ^r56
  • Risk of bleeding is increased in the following situations:
    • Bleeding within the past 30 days that required an emergency department visit or hospitalization, or gastrointestinal bleeding within the past 3 months
    • History of inherited or acquired bleeding disorder
    • Thrombolysis within the past 7 days or major surgery within the past 14 days
    • Platelet count less than 50 × 10⁹ cells/L; hemoglobin level less than 8 g/dL; or baseline INR more than 2 or activated partial thromboplastin time more than 50 seconds
    • Dual antiplatelet therapy
    • Ischemic stroke, intracranial hemorrhage, or intracranial malignancy
    • Uncontrolled hypertension (systolic more than 200 mm Hg or diastolic more than 120 mm Hg)
    • Presence of epidural or spinal catheter
  • Risk of thrombosis is increased in those with elevated D-dimer levels, prior venous thromboembolism, or additional known risk factors for venous thromboembolism

Monoclonal antibodies with antiviral action

• Monoclonal antibodies have been developed which bind to different areas of SARS-CoV-2 spike protein and block attachment; these have been used in prophylaxis or treatment
  • Emergency use authorizations were issued in the United States for various products, including pemivibart^r114, tixagevimab-cilgavimab^r115 in combination, bamlanivimab-etesevimab^r116 in combination, bebtelovimab^r117, casirivimab-imdevimab^r118 in combination, and sotrovimab^r119
• However, susceptibility of prevailing variants to monoclonal antibody products varies
  • FDA suspended emergency use authorizations owing to lack of efficacy against prevailing variants, as follows: bamlanivimab-etesevimab (January 24, 2022), casirivimab-imdevimab (January 24, 2022), sotrovimab (April 5, 2022), bebtelovimab (November 30, 2022), and tixagevimab-cilgavimab (January 26, 2023) ^r120
    • These monoclonal antibody products are no longer in use in the United States and many other locations given lack of activity against Omicron subvariants
  • FDA restricted use of pemivibart on August 26, 2024, to areas where the prevalence of variants with reduced susceptibility to pemivibart is 90% or less; pemivibart is not effective against a growing proportion of variants ^r120

Convalescent plasma

• Guidelines suggest use of convalescent plasma in clinical trials or in situations in which patients have no other treatment options ^r53r56r69r72
  • Use only high-titer COVID-19 convalescent plasma from a vaccinated donor who recently recovered from COVID-19 likely caused by a SARS-CoV-2 variant similar to the variant causing the patient's illness

Concomitant medications (various drug classes)

• Several medications with a mechanism of action that could potentially alter response to COVID-19 have been evaluated either for use in treatment and prevention, or for discontinuation to prevent harms ^r121
  • 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 ^r56
    • 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 ^r69
  • Decisions regarding discontinuing or lowering dosage of chronic immunosuppressive medications in patients with COVID-19 should be made in consultation with relevant specialists ^r56
  • NIH guidelines recommend against the use of metformin to treat COVID-19 in hospitalized patients; there is insufficient evidence to recommend for or against use in nonhospitalized patients ^r56
    • Individuals taking metformin for another indication should continue the medication if they have COVID-19

Other options not currently recommended in guidelines, although some are under study in clinical trials: ^r53r56r69

• Numerous other medications have been proposed or attempted for treatment and prevention of COVID-19 based on mechanism of action
• Detailed evidence for the recommendations not to use these medications is available in one or more of the guidelines ^r53r56r69
• Avoid use of the following (unless participating in a clinical trial):
  • Azithromycin
  • Chloroquine and hydroxychloroquine
  • Colchicine
  • Famotidine
  • Fluvoxamine
  • HIV medications, including lopinavir-ritonavir
  • Immunomodulators other than those mentioned earlier, such as the Janus kinase inhibitor ruxolitinib; the interleukin-6 inhibitor siltuximab; interleukin-1 inhibitors such as anakinra; Bruton's tyrosine kinase inhibitors; and GM-CSF (granulocyte-macrophage colony-stimulating factor) inhibitors such as lenzilumab, mavrilimumab, namilumab, gimsilumab, and otilimab
  • Interferons
  • IV immunoglobulin (except as indicated for multisystem inflammatory syndrome)
  • Ivermectin
  • Mesenchymal stem cells
  • Metformin
  • Nitazoxanide
  • Vitamin C, vitamin D, and zinc supplements
  • VV116

Monitoring

• Most patients may be cared for at home; patients and caretakers should monitor for urgent symptoms (eg, significant difficulty breathing, chest pain, lightheadedness, confusion, dehydration) ^r24c260
  • Deterioration may occur a week or more into the course of illness and may be quite abrupt
• Hospitalized patients require routine monitoring for their level of care

Complications

• Most common complication is acute respiratory distress syndrome; other complications include: ^r24c261d7
  • Septic shock ^c262d4
  • Venous and arterial thromboembolism ^c263c264c265
  • Acute kidney injury ^c266d8
  • Myocardial injury ^c267d9
  • Secondary bacterial and fungal infections ^c268c269
  • Multiorgan failure ^c270
  • Guillain-Barré syndrome ^r128c271
• MIS (multisystem inflammatory syndrome) is a serious but rare inflammatory condition associated with recent diagnosis of, or exposure to, COVID-19. MIS-C (multisystem inflammatory syndrome in children) occurs in patients younger than 21 years, whereas MIS-A (multisystem inflammatory syndrome in adults) occurs in patients aged 21 years or older ^r58c272d10
  • MIS-C and MIS-A are characterized by fever, elevated laboratory markers of inflammation, and evidence of organ dysfunction in cardiac, hematologic, gastrointestinal, and dermatologic systems, along with linkage to COVID-19
  • In children, MIS-C may present similarly to other pediatric hyperinflammatory syndromes such as Kawasaki disease and toxic shock syndrome ^r129d11
    • Common clinical features in children include fever, hypotension/shock, abdominal pain, vomiting, diarrhea, conjunctivitis, rash, and headache ^r130
  • Common features in adults with MIS-A include fever, hypotension, cardiac dysfunction, shortness of breath, and diarrhea, along with laboratory evidence of coagulopathy and/or inflammation ^r131

Prognosis

• Over the course of the pandemic, risk of hospitalization and death has decreased due to many factors, including increased immunity (especially from vaccination), treatment improvements, and differences in variants; severity remains higher than influenza ^{r3r4r9r10r43r48}
• 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%) ^r16r132
  • Risk of severe or critical illness depends on age, underlying comorbidities, and vaccination status ^{r16r48r49r132}
  • Patients who require hospital admission often require prolonged inpatient stay (more than 20 days) and experience significant deconditioning ^r9r15r17
  • Risk scoring systems continue to be developed and assessed; no single scoring system is reliable enough to be in widespread use ^r133r134r135
• Cumulative global mortality ratio is 0.9% (7,059,612 deaths out of 776 million cases worldwide as of August 2024) but varies by country ^r2r3
  • Case fatality ratio for omicron variants is estimated to be 0.2 to 0.7% ^r10r136
  • Infection fatality ratio (proportion of deaths among all who are infected, including confirmed cases, undiagnosed cases, and unreported cases) is difficult to determine and varies with location and time, but has been estimated as 0.15% ^r3r137
• Reinfection is common, although infection is associated with short-term immunity and vaccination reduces the risk of reinfection ^r138
• Risk of postacute or chronic complications
  • A substantial proportion of patients, including some who had mild or asymptomatic infection, experience symptoms 3 or more months after onset of COVID-19 ^r139r140
    • This syndrome is known by many names, including long COVID, post–COVID-19 conditions, and PASC (postacute sequelae of COVID-19)
    • Numerous different symptoms affect patients, and they may be clustered into different phenotypes (eg, cardiovascular phenotype, myalgic encephalitis phenotype, respiratory phenotype)
    • Worldwide prevalence is estimated at over 40%; higher rates are reported among women, unvaccinated persons, and persons with comorbidities ^r139r141
    • Research is ongoing; specialized clinics are opening in many locations, and guidance is being developed for evaluation and care of these patients ^r139
  • 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 ^r142
    • After diagnosis of COVID-19, the risk of new-onset diabetes, both type 1 and type 2, is elevated (pooled hazard ratio, 1.46) ^r143r144
    • Associations with subsequent cardiovascular disease, liver disease, kidney disease, and altered brain function are reported and continue to be investigated ^r145r146r147

Screening

Prevention

• Vaccines^c273
  • Vaccine authorizations and approvals: numerous vaccines against SARS-CoV-2 have been developed and are authorized or approved in various jurisdictions around the world ^{r149r150r151r152}
    • 3 vaccines are currently available in the United States
      • mRNA vaccines
        • Moderna COVID-19 vaccines, 2024-2025 formula, against the spike protein of Omicron variant KP.2 ^r153r154
          • Vaccine for ages 6 months to 11 years has emergency use authorization, and Spikevax (updated formula) has full FDA approval for ages 12 years and older
          • Prior formulations are no longer available
        • Pfizer-BioNTech COVID-19 vaccines, 2024-2025 formula, against the spike protein of Omicron variant KP.2 ^r155r156
          • Vaccine for ages 6 months to 11 years has emergency use authorization, and Comirnaty (updated formula) has full FDA approval for ages 12 years and older
          • Prior formulations are no longer available
      • Protein subunit vaccine
        • Novavax COVID-19 vaccine, adjuvanted, 2024-2025 formula, containing purified recombinant spike protein from Omicron variant JN.1 ^r157
          • Vaccine for ages 12 years and older has emergency use authorization
          • Prior formulations are no longer available
    • Numerous vaccines are in use in many other countries; additional vaccines are in clinical development or preclinical phases ^{r149r150r151r152c274c275}
      • 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)
  • Vaccination recommendations
    • CDC recommends vaccination against COVID-19 for everyone aged 6 months or older, including receiving 2024-2025 formula vaccine (1 or more doses depending on clinical factors) ^r5
      • Any age-appropriate vaccine may be used for vaccination, with no recommendation for one vaccine over any other
    • Primary vaccinations
      • Primary vaccination of nonimmunocompromised persons ^r5
        • Primary vaccination for persons aged 12 years or older is a single dose of Moderna, a single dose of Pfizer, or 2 doses of Novavax separated by 3 to 8 weeks
          • Choose the minimum interval (3 weeks) for those at higher risk of severe disease (eg, adults aged 65 years or older, people with chronic conditions)
          • Consider a longer interval (8 weeks) for others, especially in males aged 12 to 39 years, to reduce the low risk of vaccine-associated myocarditis
            • Risk of myocarditis from COVID-19 disease is substantially higher than the risk from vaccination ^r158
        • Primary vaccination for persons aged 5 to 11 years is a single dose of Moderna or a single dose of Pfizer
        • Primary vaccination for children aged 6 months to 4 years is 2 doses of Moderna, with an interval of 4 to 8 weeks between doses; or 3 doses of Pfizer, with an interval of 3 to 8 weeks between the first and second doses and at least 8 weeks between the second and third doses
      • Primary vaccination of moderately or severely immunocompromised persons ^r5
        • Primary vaccination of moderately or severely immunocompromised persons is 3 doses of Moderna, 3 doses of Pfizer, or 2 doses of Novavax, with intervals determined by age and vaccine
          • Moderna 3-dose series for all age groups: 4 weeks between the first and second doses, and at least 4 weeks between the second and third doses
          • Pfizer 3-dose series for adults and children aged 5 years or older: 3 weeks between the first and second doses, and at least 4 weeks between the second and third doses
          • Pfizer 3-dose series for children aged 6 months to 4 years: 3 weeks between the first and second doses, and at least 8 weeks between the second and third doses
          • Novavax 2-dose series for adults and children aged 12 years or older: 3 weeks between the first and second doses

      • COVID-19 vaccination schedule for unvaccinated persons in the United States.

        NA, not applicable. Any age-appropriate vaccine may be used for primary vaccination. Generally the same vaccine product should be used for all doses of the primary series. Children who transition to an older age category should complete the series with the formulation for the older age.

        Data from CDC: Vaccines and Immunizations: Interim Clinical Considerations for Use of COVID-19 Vaccines in the United States. CDC website. Updated September 6, 2024. Accessed September 13, 2024. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html

        Manufacturer	Age	Dose 1	Dose 2	Dose 3	Notes
        Schedule for unvaccinated individuals who are NOT moderately to severely immunocompromised
        Moderna	6 months to 4 years	25 mcg/0.25 mL	In 4 to 8 weeks, 25 mcg/0.25 mL	NA
        Moderna	5 years to 11 years	25 mcg/0.25 mL	NA	NA	Children who transition from 4 years to 5 years should receive one additional dose 4 to 8 weeks after the first dose.
        Moderna	12 years and older	50 mcg/0.5 mL	NA	NA
        Pfizer-BioNTech	6 months to 4 years	3 mcg/0.3 mL	In 3 to 8 weeks, 3 mcg/0.3 mL	In at least 8 weeks, 3 mcg/0.3 mL	Multidose vials (yellow cap and label) require dilution.
        Pfizer-BioNTech	5 years to 11 years	10 mcg/0.3 mL	NA	NA	Children who transition from 4 years to 5 years should receive one additional dose with formulation for 5 to 11 years. If this is the second dose, administer 3 to 8 weeks after the first dose. If this is the third dose, administer at least 8 weeks after the second dose.
        Pfizer-BioNTech	12 years and older	30 mcg/0.3 mL	NA	NA
        Novavax	12 years and older	5 mcg recombinant S protein and 50 mcg Matrix-M adjuvant/0.5 mL	In 3 to 8 weeks, 5 mcg recombinant S protein and 50 mcg Matrix-M adjuvant/0.5 mL	NA
        Schedule for unvaccinated individuals who ARE moderately to severely immunocompromised
        Moderna	6 months to 4 years	25 mcg/0.25 mL	In 4 weeks, 25 mcg/0.25 mL	In at least 4 weeks, 25 mcg/0.25 mL	At clinician's discretion, additional dose(s) of Moderna only can be administered at an interval of at least 2 months.
        Moderna	5 years to 11 years	25 mcg/0.25 mL	In 4 weeks, 25 mcg/0.25 mL	In at least 4 weeks, 25 mcg/0.25 mL	At clinician's discretion, additional dose(s) of Moderna or Pfizer-BioNTech can be administered at an interval of at least 2 months.
        Moderna	12 years and older	50 mcg/0.5 mL	In 4 weeks, 50 mcg/0.5 mL	In at least 4 weeks, 50 mcg/0.5 mL	Children who transition from 11 years to 12 years should complete the series with the formulation for 12 years and older. At clinician's discretion, additional dose(s) of Moderna, Novavax, or Pfizer-BioNTech can be administered at an interval of at least 2 months.
        Pfizer-BioNTech	6 months to 4 years	3 mcg/0.3 mL	In 3 weeks, 3 mcg/0.3 mL	In at least 8 weeks, 3 mcg/0.3 mL	Multidose vials (yellow cap and label) require dilution. At clinician's discretion, additional dose(s) of Pfizer-BioNTech only can be administered at an interval of at least 2 months.
        Pfizer-BioNTech	5 years to 11 years	10 mcg/0.3 mL	In 3 weeks, 10 mcg/0.3 mL	In at least 4 weeks, 10 mcg/0.3 mL	Children who transition from 4 years to 5 years should complete the series with formulation for 5 to 11 years. At clinician's discretion, additional dose(s) of Pfizer-BioNTech or Moderna can be administered at an interval of at least 2 months.
        Pfizer-BioNTech	12 years and older	30 mcg/0.3 mL	In 3 weeks, 30 mcg/0.3 mL	In at least 4 weeks, 30 mcg/0.3 mL	Children who transition from 11 years to 12 years should complete the series with the formulation for 12 years and older. At clinician's discretion, additional dose(s) of Moderna, Novavax, or Pfizer-BioNTech can be administered at an interval of at least 2 months.
        Novavax	12 years and older	5 mcg recombinant S protein and 50 mcg Matrix-M adjuvant/0.5 mL	In 3 weeks, 5 mcg recombinant S protein and 50 mcg Matrix-M adjuvant/0.5 mL	NA	At clinician's discretion, additional dose(s) of Moderna, Novavax, or Pfizer-BioNTech can be administered at an interval of at least 2 months.

    • Vaccination of persons who have had prior doses
      • 2024-2025 vaccine formula is recommended for everyone aged 6 months or older (1 or more doses depending on clinical factors)
      • Vaccination of nonimmunocompromised persons who have received prior doses, excluding 2024-2025 formula ^r5
        • Adults and children aged 12 years or older who have received any prior formula COVID-19 mRNA vaccine doses, or 2 prior formula Novavax doses, are recommended to receive 1 dose of Moderna, Novavax, or Pfizer vaccine at least 8 weeks after the previous dose
          • Adults and children aged 12 years or older who have received only 1 Novavax dose (any formula) are recommended to receive 1 dose of Novavax 2024-2025 formula 3 to 8 weeks after the previous dose
        • Children aged 5 years to 11 years who have received any prior COVID-19 vaccine doses are recommended to receive 1 dose of either Moderna or Pfizer vaccine at least 8 weeks after the previous dose
        • Children aged 6 months to 4 years who have received 1 or more doses of any mRNA vaccine are recommended to receive 1 or 2 doses (depending on prior doses) of Moderna or Pfizer vaccine from the same manufacturer as prior doses
          • Children aged 6 months to 4 years who have received any prior Moderna doses are authorized to have only Moderna vaccine
            • Children aged 6 months to 4 years who have received 1 prior dose are recommended to receive 1 dose 2024-2025 formula in 4 to 8 weeks after prior dose
            • Children aged 6 months to 4 years who have received 2 prior doses are recommended to receive 1 dose 2024-2025 formula in at least 8 weeks after prior dose
          • Children aged 6 months to 4 years who have received any prior Pfizer doses are authorized to have only Pfizer vaccine
            • Children aged 6 months to 4 years who have received 1 prior dose are recommended to receive 2 doses 2024-2054 formula, the first dose 3 to 8 weeks after the prior dose, and the second dose at least 8 weeks after the first 2024-2025 formula dose
            • Children aged 6 months to 4 years who have received 2 or 3 prior doses are recommended to receive 1 dose 2024-2025 formula at least 8 weeks after prior dose
      • Vaccination of moderately or severely immunocompromised persons who have received prior doses ^r5
        • Adults and children aged 6 months or older who have received 1 prior dose of any mRNA vaccine should receive 2 additional doses from the same manufacturer
          • Adults and children aged 6 months or older who have received 1 prior dose of any Moderna vaccine are recommended to receive the first dose 4 weeks after the prior dose, and the second dose at least 4 weeks after the first 2024-2025 formula dose
          • Adults and children aged 5 years or older who received 1 prior dose of any Pfizer vaccine are recommended to receive the first dose 3 weeks after the prior dose, and the second dose at least 4 weeks after the first 2024-2025 formula dose
          • Adults and children aged 6 months to 4 years who received 1 prior dose of any Pfizer vaccine are recommended to receive the first dose 3 weeks after the prior dose, and the second dose at least 8 weeks after the first 2024-2025 formula dose
        • Adults and children aged 6 months or older who have received 2 prior doses of any mRNA vaccine should receive 1 additional dose from the same manufacturer
          • Adults and children aged 6 months or older who have received 2 prior doses of any Moderna vaccine are recommended to receive the 2024-2025 formula dose at least 4 weeks after the last dose
          • Adults and children aged 5 years or older who received 2 prior doses of any Pfizer vaccine are recommended to receive the 2024-2025 formula dose at least 4 weeks after the last dose
          • Adults and children aged 6 months to 4 years who received 2 prior doses of any Pfizer vaccine are recommended to receive the 2024-2025 formula dose at least 8 weeks after the last dose
        • Children aged 6 months to 11 years who have received 3 or more doses of any mRNA vaccine are recommended to receive 1 dose 2024-2025 formula vaccine at least 8 weeks after the last dose
          • For children age 6 months to 4 years, the dose should be from the same manufacturer
          • For children age 5 years to 11 years, the dose may be either Moderna or Pfizer
        • Adults and children aged 12 years or older who have received 3 or more doses of any mRNA vaccine are recommended to receive 1 dose of Moderna, Novavax, or Pfizer 2024-2025 formula vaccine at least 8 weeks after the last dose
        • Adults and children aged 12 years or older who have received only 1 Novavax dose (any formula) are recommended to receive 1 dose of Novavax 2024-2025 formula 3 weeks after the previous dose
        • Adults and children aged 12 years or older who have received 2 doses prior formula Novavax are recommended to receive 1 dose of Moderna, Novavax, or Pfizer 2024-2025 formula vaccine at least 8 weeks after the last dose
        • Additional age-appropriate vaccine booster doses may be administered at the discretion of the health care professional, at intervals of at least 2 months

      • COVID-19 vaccination schedule for persons with prior doses in the United States.

        Generally the same vaccine product should be used for all doses of the primary series.

        Data from CDC: Vaccines and Immunizations: Interim Clinical Considerations for Use of COVID-19 Vaccines in the United States. CDC website. Updated September 6, 2024. Accessed September 13, 2024. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html

        Age	Prior doses	Recommended doses	Notes
        Schedule for individuals who are NOT moderately to severely immunocompromised
        6 months to 4 years	1 dose Moderna	1 dose Moderna 25 mcg/0.25 mL, 4 to 8 weeks after prior dose
        6 months to 4 years	2 or more doses Moderna, excluding 2024-2025 formula	1 dose Moderna 25 mcg/0.25 mL, at least 8 weeks after last dose	If at least one prior doses was the 2024-2025 formula, no further doses needed.
        6 months to 4 years	1 dose Pfizer-BioNTech	2 doses Pfizer-BioNTech 3 mcg/0.3 mL: first dose 3 to 8 weeks after prior dose, second dose at least 8 weeks after first 2024-2025 formula dose	Multidose vials (yellow cap and label) require dilution.
        6 months to 4 years	2 or more doses Pfizer-BioNTech, excluding 2024-2025 formula	1 dose Pfizer-BioNTech 3 mcg/0.3 mL, at least 8 weeks after last dose	Multidose vials (yellow cap and label) require dilution. If at least one prior dose was the 2024-2025 formula, no further doses needed.
        5 years to 11 years	1 or more doses of any mRNA vaccine	1 dose Moderna 25 mcg/0.25 mL, OR 1 dose Pfizer-BioNTech 10 mcg/0.3 mL, at least 8 weeks after last dose	If any prior dose was the 2024-2025 formula, no further doses needed.
        12 years or older	1 or more doses of any vaccine, excluding 2024-2025 formula	1 dose Moderna 50 mcg/0.5 mL OR 1 dose Novavax 5 mcg recombinant S protein and 50 mcg Matrix-M adjuvant/0.5 mL OR 1 dose Pfizer-BioNTech 30 mcg/0.3 mL at least 8 weeks after last dose	If only prior dose was a single Novavax, may receive Novavax 2024-2025 formula in 3 to 8 weeks after first dose. If any prior dose was the 2024-2025 formula, no further doses needed.
        Schedule for individuals who ARE moderately to severely immunocompromised
        6 months to 4 years	1 dose Moderna	2 doses Moderna 25 mcg/0.25 mL: first dose 4 weeks after prior dose, second dose at least 4 weeks after first 2024-2025 formula dose	At clinician's discretion, additional dose(s) of Moderna only can be administered at an interval of at least 2 months.
        6 months to 4 years	2 doses Moderna	1 dose Moderna 25 mcg/0.25 mL, at least 4 weeks after last dose	At clinician's discretion, additional dose(s) of Moderna only can be administered at an interval of at least 2 months.
        6 months to 4 years	3 or more doses Moderna, excluding 2024-2025 formula	1 dose Moderna 25 mcg/0.25 mL, at least 8 weeks after last dose	If at least one prior doses was the 2024-2025 formula, no further doses needed. At clinician's discretion, additional dose(s) of Moderna only can be administered at an interval of at least 2 months.
        6 months to 4 years	1 dose Pfizer-BioNTech	2 doses Pfizer-BioNTech 3 mcg/0.3 mL: first dose 3 weeks after prior dose, second dose at least 8 weeks after first 2024-2025 formula dose	Multidose vials (yellow cap and label) require dilution. At clinician's discretion, additional dose(s) of Pfizer-BioNTech only can be administered at an interval of at least 2 months.
        6 months to 4 years	2 or more doses Pfizer-BioNTech	1 dose Pfizer-BioNTech 3 mcg/0.3 mL at least 8 weeks after last dose	Multidose vials (yellow cap and label) require dilution. At clinician's discretion, additional dose(s) of Pfizer-BioNTech only can be administered at an interval of at least 2 months.
        6 months to 4 years	3 or more doses of Pfizer-BioNTech, excluding 2024-2025 formula	1 dose of Pfizer-BioNTech 3 mcg/0.3 mL, at least 8 weeks after last dose	If at least one prior doses was the 2024-2025 formula, no further doses needed. At the clinician's discretion additional dose(s) of Pfizer-BioNTech only can be administered at an interval of at least 2 months.
        5 years to 11 years	1 dose Moderna	2 doses Moderna 25 mcg/0.25 mL: first dose 4 weeks after prior dose, second dose at least 4 weeks after first 2024-2025 formula dose	At clinician's discretion, additional dose(s) of Moderna or Pfizer-BioNTech can be administered at an interval of at least 2 months.
        5 years to 11 years	2 doses Moderna	1 dose Moderna 25 mcg/0.25 mL, at least 4 weeks after last dose	At clinician's discretion, additional dose(s) of Moderna or Pfizer-BioNTech can be administered at an interval of at least 2 months.
        5 years to 11 years	1 dose Pfizer-BioNTech	2 doses Pfizer-BioNTech10mcg/0.3 mL: first dose 3 weeks after prior dose, second at least 4 weeks after first 2024-2025 formula dose	At clinician's discretion, additional dose(s) of Pfizer-BioNTech or Moderna can be administered at an interval of at least 2 months.
        5 years to 11 years	2 doses Pfizer-BioNTech	1 dose Pfizer-BioNTech 10 mcg/0.3 mL at least 4 weeks after last dose	At clinician's discretion, additional dose(s) of Pfizer-BioNTech or Moderna can be administered at an interval of at least 2 months.
        5 years to 11 years	3 doses of any mRNA vaccine, excluding 2024-2025 formula	1 dose Moderna 25 mcg/0.25 mL, OR 1 dose Pfizer-BioNTech 10 mcg/0.3 mL, at least 8 weeks after last dose	If at least one prior doses was the 2024-2025 formula, no further doses needed. At clinician's discretion, additional dose(s) of Moderna or Pfizer-BioNTech can be administered at an interval of at least 2 months.
        12 years or older	1 dose Moderna	2 doses Moderna 50 mcg/0.5 mL: first dose 4 weeks after prior dose, second dose at least 4 weeks after first 2024-2025 formula dose	At clinician's discretion, additional dose(s) of Moderna, Novavax, or Pfizer-BioNTech can be administered at an interval of at least 2 months.
        12 years or older	2 doses Moderna	1 dose Moderna 50 mcg/0.5 mL at least 4 weeks after last dose	At clinician's discretion, additional dose(s) of Moderna, Novavax, or Pfizer-BioNTech can be administered at an interval of at least 2 months.
        12 years or older	1 dose Pfizer-BioNTech	2 doses Pfizer-BioNTech 30mcg/0.3 mL: first dose 3 weeks after prior dose, second dose at least 4 weeks after first 2024-2025 formula dose	At clinician's discretion, additional dose(s) of Moderna, Novavax, or Pfizer-BioNTech can be administered at an interval of at least 2 months.
        12 years or older	2 doses Pfizer-BioNTech	1 dose Pfizer-BioNTech 30 mcg/0.3 mL, at least 4 weeks after last dose	At clinician's discretion, additional dose(s) of Moderna, Novavax, or Pfizer-BioNTech can be administered at an interval of at least 2 months.
        12 years or older	3 doses of any mRNA vaccine, excluding 2024-2025 formula	1 dose Moderna 50 mcg/0.5 mL OR 1 dose Novavax 5 mcg recombinant S protein/50 mcg Matrix-M adjuvant/0.5 mL OR 1 dose Pfizer 30 mcg/0.3 mL, at least 8 weeks after last dose	If at least one prior doses was the 2024-2025 formula, no further doses needed. At clinician's discretion, additional dose(s) of Moderna, Novavax, or Pfizer can be administered at an interval of at least 2 months.
        12 years or older	1 dose Novavax	1 dose Novavax 5 mcg recombinant S protein/50 mcg Matrix-M adjuvant/0.5 mL 3 weeks after last dose	At clinician's discretion, additional dose(s) of Moderna, Novavax, or Pfizer can be administered at an interval of at least 2 months.
        12 years or older	2 doses Novavax, excluding 2024-2025 formula	1 dose Moderna 50 mcg/0.5 mL OR 1 dose Novavax 5 mcg recombinant S protein/50 mcg Matrix-M adjuvant/0.5 mL OR 1 dose Pfizer-BioNTech 30 mcg/0.3 mL, at least 8 weeks after last dose	If at least one prior doses was the 2024-2025 formula, no further doses needed. At clinician's discretion, additional dose(s) of Moderna, Novavax, or Pfizer can be administered at an interval of at least 2 months.

  • Additional clinical guidance
    • Interchangeability of vaccines ^r5
      • In general, complete a primary vaccination series (where multiple doses are indicated) with doses from the same manufacturer
      • Allow substitution of doses from a different manufacturer if the same vaccine is not available at the time of the clinic visit, if the prior manufacturer is unknown, if the patient would otherwise not receive a recommended vaccine dose, or if a contraindication developed
      • If a child aged 6 months to 4 years receives mRNA vaccine from different manufacturers, the second dose (if not yet given) should be 4 to 8 weeks after the first dose (4 weeks preferred for patients with moderate or severe immunocompromise), and the third dose should be administered at least 8 weeks after the second dose, using 2024-2025 formula vaccine from either Moderna or Pfizer
      • If an adult or child aged 5 years or older with moderate or severe immunocompromise receives mRNA vaccine from different manufacturers during primary series vaccination, the second dose (if not yet given) should be 4 weeks after the first dose, and the third dose should be administered at least 4 weeks after the second dose, using 2024-2025 formula vaccine from either Moderna or Pfizer
    • Timing of dosing ^r5
      • Intervals
        • Doses administered up to 4 days before the recommended interval are considered valid
        • Doses administered more than 4 days before the recommended interval should be reported to VAERS (Vaccine Adverse Event Reporting System) and repeated, with the subsequent dose given the recommended interval or longer after the erroneous dose
        • Doses administered any time after the recommended interval are valid
      • COVID-19 vaccine and any other immunizations may be administered on the same day, or at any interval; no delay is required between receipt of another vaccine and COVID-19 vaccination ^r5
        • Respiratory syncytial virus vaccine, influenza vaccine, and COVID-19 vaccine may all be administered at the same time in different anatomical sites
        • If orthopoxvirus vaccine (against mpox) is recommended, no minimum interval is required between COVID-19 vaccine and orthopoxvirus vaccine, whichever is administered first
          • However, consider a 4-week interval between these 2 vaccines, particularly in adolescent or young adult males, to minimize the low risk of myocarditis with these vaccines; do not delay vaccination when risks of mpox or severe COVID-19 are high
          • Prioritize Jynneos vaccine over ACAM2000 when coadministering a COVID-19 vaccine and an orthopoxvirus vaccine
      • For persons with current or recent COVID-19 infection, consider deferring vaccination for 3 months after COVID-19 infection to potentially improve immunogenicity of vaccination ^r5
      • Delay administration of pemivibart for 2 weeks after COVID-19 vaccination ^r5
    • Vaccine use in special populations
      • Pregnant persons and breastfeeding persons ^r5r126r127
        • Vaccination (with any COVID-19 vaccine) 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
          • Pregnant persons with COVID-19 have increased risk for severe illness and death from COVID-19 and increased risk of preterm birth, stillbirth, and other pregnancy complications
          • Vaccines during pregnancy and lactation are safe and effective ^{r126r127r159r160r161}
          • Encourage pregnant persons and those who may become pregnant to participate in CDC's V-safe registry program ^r162
      • Persons undergoing immunosuppressive treatments ^r5
        • Do not delay vaccine administration
        • Where possible, administer vaccine 2 or more weeks before planned immunosuppressive therapy
        • For patients taking continuous B-cell–depleting therapy, time vaccination 4 weeks before next scheduled treatment
        • For patients taking limited B-cell–depleting therapy (eg, rituximab for certain malignancies), revaccinate 6 months after completion, following the vaccine schedule for unvaccinated individuals with moderate to severe immunocompromise
        • Clinicians may alter vaccination schedule for individual patients when benefits of vaccination outweigh risks
      • Persons who have had multisystem inflammatory syndrome
        • For those with MIS-C or MIS-A diagnosed more than 60 days after COVID-19 vaccination or diagnosed in unvaccinated persons, benefits of vaccination likely outweigh the theoretical risk of multisystem inflammatory syndrome or myocarditis once the patient has fully recovered (including return to normal myocardial function) and 90 days or more have elapsed since MIS-C or MIS-A diagnosis ^r5
          • Vaccination may be considered even for those do not yet meet criteria above, at the discretion of the care team or with additional consultation
        • For those with MIS-C or MIS-A diagnosed within 60 days of COVID-19 vaccination, decide on any subsequent dose(s) on an individual basis, in conjunction with the clinical team, the patient and/or the parent(s)
        • Consider consultation with a specialist in infectious diseases, rheumatology, or cardiology, and/or with personnel of the Clinical Immunization Safety Assessment project, to discuss specific cases, particularly if MIS-C or MIS-A occurred after vaccination ^r162
    • Adverse effects
      • CDC and FDA have ongoing vaccine safety and effectiveness monitoring ^r162r163
        • Request a consultation from the Clinical Immunization Safety Assessment Project for complicated vaccine safety questions
        • FDA fact sheets for health care providers contain details documenting vaccine safety and effectiveness ^{r153r154r155r156r157}
      • Common adverse effects vary by age and vaccine; they include:
        • Pain, redness, swelling at the injection site
          • Rarely, patients who have dermal fillers may have swelling near the site of the filler
        • Axillary or groin tenderness or lymphadenopathy (depending on injection site)
        • Fatigue or sleepiness
        • Headache
        • Myalgia, arthralgia
        • Fever, chills
        • Nausea, vomiting, diarrhea
      • Serious adverse effects are rare
        • Anaphylaxis is estimated at 5 per million doses administered
          • Prepare for management of anaphylaxis before administering any vaccine ^r164r165
        • Myocarditis and pericarditis have been reported in adolescents and young adults (primarily males aged 12 to 39 years) after vaccination, most commonly within 7 days after a second dose ^r5r166r167
          • Condition is generally short-lived and mild, with clinical presentation including acute chest pain, shortness of breath, and/or palpitations, and, in young children, irritability, vomiting, poor feeding, tachypnea, or lethargy
          • The risk of myocarditis or pericarditis from COVID-19 disease appears higher than the risk of myocarditis or pericarditis from vaccination, and the overall benefits of vaccination far outweigh risks ^r5r158r168
          • Vaccine recommendations for adolescents and young adults remain unchanged, except that waiting 8 weeks between a first and second dose may decrease the risk (for those recommended to have more than 1 dose), and persons who have had myocarditis within 3 weeks of a dose of vaccine should generally avoid subsequent doses
      • Contraindications include: ^r5
        • Severe allergic reaction (eg, anaphylaxis) to a previous dose of a COVID-19 vaccine or to any of its components
        • Known allergy to any components of a vaccine (eg, polyethylene glycol in Moderna and Pfizer vaccines, or polysorbate 80 in Novavax vaccine)
        • Contraindication to one type of vaccine is a precaution to other types of vaccines
  • Vaccine administration information for the United States
    • In the United States, emergency use authorizations require health care professionals to communicate to the patient, parent, or caregiver information consistent with the vaccine-specific (manufacturer-specific) fact sheet for recipients and caregivers before each patient receives the vaccine; such information includes the following: ^r153r156r157
      • Alternatives to receiving the vaccine
      • Option to accept or refuse the vaccine
      • Significant known and potential risks and benefits of the vaccine, and the extent to which such potential risks and benefits are unknown
      • Available alternative preventive vaccines in clinical trials or approved for use under other emergency use authorizations
    • Clinicians providing vaccination are required to report certain events to VAERS and are encouraged to report any other events ^r5r162
      • Report the following to VAERS:
        • Vaccine administration errors, whether or not an adverse event occurred
        • Serious adverse events, whether or not attributed to the vaccine; these include myocarditis; pericarditis; multisystem inflammatory syndrome; cases of COVID-19 resulting in hospitalization or death; events that are life-threatening, require or prolong hospitalization, or require medical or surgical intervention to prevent hospitalization, disability, or death; birth defects; disability; and death
      • Reporting is encouraged for any other clinically significant adverse event, even if it is uncertain whether the vaccine caused the event
        • Clinicians may choose to report any adverse events to VAERS and to the vaccine manufacturer
    • Follow best practices for vaccine administration, regardless of whether vaccines are FDA-approved or authorized for emergency use ^r169
      • Encourage vaccine recipients in the United States to participate in CDC's V-safe monitoring and reminder system, available as a mobile phone app ^r162
• Preexposure prophylaxis
  • Preexposure prophylaxis with monoclonal antibodies has limited availability, as authorized options demonstrate diminished efficacy over time
    • Pemivibart is currently authorized for emergency use only when the proportion of circulating variants with substantially reduced susceptibility to pemivibart is 90% or less ^r114
      • Use for adults and children aged 12 years or older (weight 40 kg or more) with moderate to severe immunocompromise, who would not be expected to mount an adequate response to immunization ^r69
    • From December 2021 until January 2023, monoclonal antibodies tixagevimab and cilgavimab had FDA emergency use authorization for coadministration in persons who either (1) were moderately to severely immunocompromised and might not mount an immune response to vaccine or (2) had a contraindication to vaccination (eg, severe allergic reaction to COVID-19 vaccine or components). However, because more than 90% of SARS-CoV-2 variants circulating by January 2023 were resistant to these monoclonal antibodies, the emergency use authorization was suspended ^r115
• Postexposure prophylaxis^r56
  • Postexposure prophylaxis is no longer available, as the previously authorized options (monoclonal antibodies casirivimab-imdevimab or bamlanivimab-etesevimab) are ineffective against Omicron variant
• Public health interventions to interrupt transmission (eg, masking, distancing, hygiene, isolation, quarantine): practices vary geographically and depend on regional disease activity and other factors
  • General precautions for all populations ^r71
    • Keep up to date with vaccinations
    • Practice good hygiene and help prevent spread to others
      • Wash hands (or use hand sanitizer at least 60% alcohol), cover coughs and sneezes with a tissue, and clean and disinfect high-touch surfaces often
      • Monitor for symptoms
      • Avoid contact with others (eg, stay home) when you are sick, even if an initial test result comes back negative; many transmissible respiratory infections cocirculate in communities
      • Avoid contact with those who have suspected or confirmed COVID-19
    • Improve ventilation whenever possible; avoid poorly ventilated spaces
    • Test to prevent spread to others (eg, if you have symptoms, exposure, or plans to gather with someone at higher risk)
    • Wear a mask (preferably high quality, such as N95) in indoor settings when community transmission is moderate to high or if you are at high risk
    • Avoid crowds, and physical distance at least 6 feet from others, when community transmission is moderate to high or if you are at high risk
  • Precautions for community settings ^r71
    • Persons with symptoms of respiratory illness should stay home until they are fever free and symptoms are improved, and wear a mask and take extra precautions for an additional 5 days:
      • Ensure excellent hygiene and good ventilation when indoors
      • Avoid contact with anyone at greater risk of severe illness
      • Consider testing
        • Repeat a negative antigen test in 48 hours; a total of 2 negative antigen test results in someone with symptoms helps overcome false-negatives ^r50
    • Persons who test positive for COVID-19 but have no symptoms should wear a mask and take extra precautions for an additional 5 days; if symptoms develop, they should start over, using guidance for symptomatic persons
    • Persons exposed to COVID-19 should monitor for symptoms and consider testing
      • Repeat negative antigen test in 48 hours, and again 48 hours later; a total of 3 negative antigen test results in someone without symptoms helps overcome false-negatives ^r50
      • If symptoms develop, start over, using guidance for symptomatic persons
  • Precautions for patients in health care settings ^r70
    • Use a symptom-based strategy to determine when to discontinue isolation in most patients. Criteria have been established based on observations showing that duration of shedding of infective virus varies from less than 10 days in milder cases to 20 days or longer in more severe infections and in immunocompromised persons
      • Asymptomatic, no immunocompromise:
        • Wear a mask for 10 days
        • If symptoms develop during these 10 days, restart isolation following symptomatic criteria, with first day of symptoms as day 0
      • Mild to moderate COVID-19, no immunocompromise:
        • Wear a mask for at least 10 days after symptom onset (first day of symptoms is day 0), until 24 hours fever free (without use of antipyretics) and symptoms have improved
      • Severe to critical illness (including hospitalized patients), no immunocompromise:
        • Wear a mask at least 10 days and up to 20 days since symptom onset (day 0) and
        • At least 24 hours have passed since last fever without use of antipyretics and symptoms have improved
        • Consider testing before discontinuing isolation
      • Moderately or severely immunocompromised persons:
        • Continue isolation for 20 days or longer after symptom onset or first positive SARS-CoV-2 test result
        • Use a test-based strategy to determine duration
        • Consider infectious disease consultation
    • Test-based criteria for discontinuation of isolation include:
      • Fever has resolved and symptoms are improved, and
      • Negative test results from 2 consecutive specimens at least 48 hours apart; polymerase chain reaction or antigen tests are acceptable
        • A nucleic acid amplification test may be used, but results frequently remain positive for days to weeks and do not necessarily correlate with being infectious ^r50
    • Loss of taste and/or smell may persist for weeks to months and does not need to delay the end of isolation