Key Points

• COVID-19 (coronavirus disease 2019) is a systemic infection due to a novel coronavirus, SARS-CoV-2; global pandemic is ongoing
• Infection ranges from asymptomatic to severe; symptoms usually include fever, cough, and (in moderate to severe cases) dyspnea. Disease may evolve over the course of a week or more from mild to severe; deterioration may be sudden and catastrophic
• Infection should be suspected based on presentation with a clinically compatible history (eg, fever, upper or lower respiratory tract symptoms); alterations in senses of smell and taste are particularly suggestive
• Chest imaging in symptomatic patients almost always shows abnormal findings, usually including bilateral infiltrates; laboratory findings are variable but typically include lymphopenia and elevated lactate dehydrogenase and transaminase levels
• Diagnosis is confirmed by detection of viral RNA on polymerase chain reaction test of upper or lower respiratory tract specimens; antigen testing is also available and has near-equivalent specificity but is slightly less sensitive
• Treatments and treatment strategies continue to be refined; available drugs are administered at different stages of disease based on the pharmacologic mechanism of action and the dominant pathophysiology of the disease phase
  • Several antiviral medications are available, including remdesivir, ritonavir-boosted nirmatrelvir, and molnupiravir
  • Dexamethasone has been associated with significant reduction in mortality rates of patients requiring supplemental oxygen ^r1
  • Several immunomodulators are recommended for use in conjunction with corticosteroids with or without remdesivir ^r2
  • Monoclonal antibodies may be used for treatment and prevention, but use depends on susceptibility to circulating variants; as of late January 2023, more than 90% of circulating variants in the United States are not susceptible to any of the monoclonal antibodies previously under emergency use authorization, and thus those drugs are neither recommended nor available for treatment or prophylaxis ^r2
• Most common complications are acute respiratory distress syndrome and septic shock; myocardial, renal, and multiorgan failure are also seen
• A significant proportion of clinically evident cases are severe; the mortality rate among diagnosed cases is generally about 3% but varies by country ^r3
• Emerging evidence indicates that COVID-19 infection may predispose to long-term symptoms or future complications, even after mild or asymptomatic disease
• Vaccination is safe and highly effective, particularly against hospitalization and death, even with new variants ^r4

Urgent Action

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

Pitfalls

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

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 ^r5
• Illness ranges in severity from asymptomatic or mild to severe; a significant proportion of patients with clinically evident infection develop severe disease, which may be complicated by acute respiratory distress syndrome and shock
  • Mortality rate among diagnosed cases (case fatality rate) is generally about 3% globally but varies by country; true overall mortality rate is uncertain, as the total number of cases (including undiagnosed persons with milder illness) is unknown ^r3
• Knowledge of this disease is incomplete and evolving; moreover, coronaviruses are known to mutate and recombine often, presenting an ongoing challenge to our understanding and to clinical management

Classification

• Pathogen is a betacoronavirus, similar to the agents of SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome)
  • Classified as a member of the species Severe acute respiratory syndrome–related coronavirus^r6r7
  • Designated as SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2); earlier provisional name was 2019-nCoV (2019 novel coronavirus) ^r6r7
• 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; as of early 2023, more than 99% of circulating virus in the United States is Omicron variant, most of which is Omicron subvariants XBB.1.5, BQ.1.1, and BQ.1 ^r8
  • 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 ^r9
    • Classification is based on potential for increased transmissibility, greater severity of disease, reduction in protective effect of antibodies generated by previous disease or vaccination, reduced efficacy of available treatments or public health countermeasures, or reduced sensitivity of testing modalities
    • Variants of concern
      • Omicron (B.1.1.529, BA, and BQ lineages): first detected in South Africa; is now essentially the only variant in the United States (since January 2022). It is more easily transmitted than earlier variants, and it has reduced susceptibility to the monoclonal antibody products developed for those; efficacy of remdesivir is thought to be undiminished ^r2r8r10
        • Omicron BA.2 and subsequent subvariants (eg, XBB.1.5, BQ.1.1, BQ.1, XBB, CH.1.1, BN.1, BA.5) are the dominant strains worldwide and in the United States since February 2022. These subvariants have increased transmissibility and similar disease severity compared with Omicron subvariant BA.1; their transmissibility despite antibodies generated by immunization may be increased, but vaccination still greatly reduces the risks of severe illness and death ^r8r11
    • Variants being monitored
      • Earlier variants (evolved before Omicron) remain in this epidemiologic category but are no longer encountered clinically (ie, 0.0% incidence rate in the United States) ^r8r9

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

• 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 ^r81
  • 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 checker^r82 is advised
• Some treatment options are recommended for patients at high risk for severe disease, or for immunocompromised patients who are not expected to mount adequate immune response to vaccination or to COVID-19
  • Common underlying conditions include (but are not limited to): age 65 years or older, diabetes, chronic lung diseases, chronic heart diseases, chronic liver diseases, pregnancy, and mood disorders; the CDC regularly updates a list^r47 based on new evidence
  • Some rare conditions, as well as race and ethnicity, may be associated with increased risk for severe disease, and risk increases when multiple conditions are present; use clinical judgment for individual patients ^r2
  • Common conditions causing moderate to severe immune compromise include (but are not limited to) the following; consult CDC guidance^r4 for updates
    • Active treatment for solid tumor and hematologic malignancies
    • History of solid organ transplant and currently taking immunosuppressive therapy
    • History of CAR T-cell therapy (chimeric antigen receptor T-cell therapy) or hematopoietic cell transplant within the past 2 years, or currently taking immunosuppressive therapy
    • Moderate or severe primary immunodeficiency (eg, severe combined immunodeficiency, DiGeorge syndrome, Wiskott-Aldrich syndrome)
    • Untreated HIV infection or advanced HIV infection (CD4 cell counts less than 200 cells/mm³, history of an AIDS-defining illness without immune reconstitution, or clinical manifestations of symptomatic HIV disease)
    • Immunosuppressive medications, including treatment with high-dose corticosteroids (20 mg or more of prednisone or equivalent per day when administered for 2 or more weeks), alkylating agents, antimetabolites, transplant-related immunosuppressive drugs, cancer chemotherapeutic agents classified as severely immunosuppressive, tumor necrosis factor blockers, and other biologic agents that are immunosuppressive or immunomodulatory
• Throughout the pandemic, many jurisdictions have experienced caseload surges and supply constraints, which may limit the available therapies. Only if access to recommended therapies is limited, NIH suggests the following prioritizations:
  • For preventive therapy, prioritize severely immunocompromised status over moderately immunocompromised status
  • For treatment, risk groups based on age, immune status, clinical risk factors, and vaccination status are as follows:
    • Tier 1: immunocompromised patients not expected to adequately respond to vaccination or COVID-19, and unvaccinated individuals at highest risk due to age and underlying conditions (eg, 75 years or older, or 65 years or older with any underlying condition)
    • Tier 2: unvaccinated patients at high risk not in tier 1 (eg, age 65 years or older, or any age with underlying conditions)
    • Tier 3: vaccinated patients at highest risk (eg, 75 years or older, or 65 years or older with any underlying condition); note that those without any booster doses are at higher risk than those with booster doses
    • Tier 4: vaccinated patients at high risk not in tier 3 (eg, age 65 years or older, or any age with underlying conditions)

Infection control measures: these include isolation, source control, and transmission precautions ^r51

• People with COVID-19 at home should isolate at home, keep separate from others in the household as much as possible; wear a mask when near other people or pets in the household; monitor for serious or worsening symptoms requiring additional medical care; and increase ventilation, cleaning, and disinfection ^r83
• Patients with COVID-19 in a health care setting should wear a face mask to reduce droplet spread; should be placed in a single-person closed room pending further evaluation and disposition decisions; and should have standard precautions, contact precautions, and droplet or airborne precautions as resources allow
  • Health care personnel should wear N95 respirator or comparable (eg, FFP2, KN95), gown, gloves, and eye protection ^r51
    • Some guidelines suggest that a medical face mask, rather than N95 respirator, is sufficient when not performing aerosol-generating procedures ^r22
  • 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) ^r22

• 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 ^r22
• Surviving Sepsis Campaign^r84r85 guideline, NIH COVID-19 treatment^r2 guideline, and WHO guidance^r22 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 ^r86r87r88
  • Preliminary^r89 and follow-up^r90 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 well^r91
  • 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 ^r2r84r85r92
    • In patients who require oxygen via high-flow device or noninvasive ventilation, NIH offers the option of adding remdesivir to dexamethasone plus baricitinib or dexamethasone plus tocilizumab, because remdesivir appears to confer maximum benefit before onset of more severe disease
    • NIH does not recommend use of remdesivir in patients who require mechanical ventilation or extracorporeal membrane oxygenation, and both Infectious Diseases Society of America and Surviving Sepsis Campaign guidelines suggest that remdesivir not be used in patients with critical COVID-19
    • For patients whose condition worsens while they are receiving remdesivir and who require institution of high-flow oxygen, ventilation, or extracorporeal membrane oxygenation, NIH recommends that the treatment course be completed
  • For hospitalized patients with no current oxygen requirement, NIH guidelines suggest consideration of remdesivir for patients at high risk of disease progression, and Infectious Diseases Society of America guidelines suggest use of remdesivir (3-day course)
  • Infectious Diseases Society of America and WHO suggest, and NIH recommends, use of remdesivir in ambulatory patients with mild to moderate COVID-19 who are at high risk for progression to severe disease, to be initiated within 7 days of symptom onset ^r2r92r93
    • 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 ^r94
  • Evidence base: remdesivir has significant in vitro activity against coronaviruses,^r95r96 evidence of efficacy in an animal model of MERS,^r95 and evidence of efficacy in COVID-19^r90
• 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 ^r97
  • 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% ^r97
    • 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 ^r98
      • Resources are available to help clinicians manage potential drug interactions ^r82r99
  • 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 ^r2r92
    • Initial studies did not include pregnant patients, but 2 subsequent case studies totaling 54 pregnant patients, some with additional risk factors, reported good outcomes of infection and no fetal or neonatal adverse effects. NIH guidelines recommend that ritonavir-boosted nirmatrelvir be offered to pregnant patients with COVID-19 ^r100r101
  • Viral rebound and/or recurrence of symptoms and antigen test positivity has been reported following a 5-day course of ritonavir-boosted nirmatrelvir; there is no evidence that additional treatment is needed, but patients should continue to isolate until they meet criteria for discontinuation ^r2
• Molnupiravir, another oral antiviral agent, has emergency use authorization in the United States for treatment of nonhospitalized adults positive for COVID-19 who are at high risk of progression to severe disease, and for whom alternative treatments are not available or not clinically appropriate ^r102
  • 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 ^r102
  • 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 ^r93
  • 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 ^r92
  • Similarly, NIH recommends use of molnupiravir in ambulatory adults at high risk of progression to severe disease only when ritonavir-boosted nirmatrelvir and remdesivir are unavailable, because it has lower efficacy than the preferred treatments ^r2
  • WHO suggests use of molnupiravir for adults with nonsevere disease at highest risk of hospitalization; alternative treatments may be preferable where available

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

• Emergency use authorizations have been issued in the United States for several monoclonal antibody products: bebtelovimab,tixagevimab-cilgavimab in combination, bamlanivimab-etesevimab^r103r104 in combination, casirivimab-imdevimab^r105r106 in combination, and sotrovimab^r107r108
  • Given the predominance of the Omicron variant in the United States and the lack of activity against prevailing Omicron subvariants with bamlanivimab-etesevimab, casirivimab-imdevimab, or sotrovimab, FDA modified the emergency use authorizations for these monoclonal antibodies to state that they are not authorized for use in regions where infection is likely to be caused by a nonsusceptible strain, effectively suspending their use in the United States. With the predominance of BQ.1 and BQ.1.1 Omicron subvariants, the FDA similarly modified the emergency use authorization for bebtelovimab on November 30, 2022 ^r109r110r111
  • These emergency use authorizations, when in effect, apply to patients aged 12 years or older, weighing 40 kg or more, who have mild to moderate disease and who are at high risk for progression to severe disease and/or hospital admission; the authorizations exclude persons who are already hospitalized for COVID-19 or who require supplemental oxygen for COVID-19
  • In January 2023, emergency use authorization was also suspended for tixagevimab-cilgavimab for prophylaxis, because more than 90% of circulating variants are not neutralized by it. NIH guidelines were modified accordingly, and recommend against use as preexposure prophylaxis ^r2
• Distribution of monoclonal antibodies in the United States is currently based on established thresholds for each jurisdiction ^r2r112
• Tixagevimab and cilgavimab are monoclonal antibodies that block spike protein attachment, binding to 2 different regions of the receptor-binding domain of the spike protein
  • FDA granted an emergency use authorization in December 2021 for preexposure prophylaxis in adults and children aged 12 years or older weighing at least 40 kg who have moderate to severe immunocompromise or who are unable to be immunized owing to severe allergic reaction ^r113
  • 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
  • However, in January 2023, with more than 90% of circulating variants nonsusceptible to these monoclonal antibodies, the emergency use authorization was suspended and the NIH recommends against their use ^r2
• Other monoclonal antibody products are no longer in use in the United States and many other locations given lack of activity against Omicron subvariants
  • 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 ^r104
    • 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) ^r103
      • 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 ^r103
    • 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 ^r103
  • Bebtelovimab is a recombinant neutralizing human monoclonal antibody that binds to the spike protein of SARS-CoV-2, preventing its attachment to the ACE2 receptor (for angiotensin-converting enzyme 2) ^r114
    • Bebtelovimab does not effectively neutralize the BQ.1 and BQ.1.1 Omicron subvariants prevalent in late 2022, and the FDA suspended the emergency use authorization for bebtelovimab on November 30, 2022 ^r110
    • Bebtelovimab had been authorized earlier, based on limited clinical data indicating a reduction in viral load in treated patients and improvement in symptoms; the emergency use authorization issued by FDA on February 11, 2022 stated that "based on the totality of evidence available … it is reasonable to believe that bebtelovimab may be effective for the treatment of patients with mild-to-moderate COVID-19 to reduce the risk of progression to hospitalization or death"
  • Casirivimab-imdevimab^r2r105
    • This combination appeared to have reduced activity against the Omicron variant prevalent in late 2021 and early 2022; the emergency use authorization was modified on January 24, 2022, to preclude use of this product when infection is likely to be caused by a nonsusceptible variant such as Omicron, which is now the prevailing variant in the United States ^r106
    • 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 ^r93
  • Sotrovimab targets a highly conserved region in the receptor-binding domain of the SARS-CoV-2 spike protein ^r108
    • 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 ^r2r108r111
    • WHO recommends against treatment with sotrovimab due to evidence that sotrovimab lacks activity against circulating SARS-CoV-2 variants and subvariants (eg, Omicron) ^r93
    • Sotrovimab had been authorized earlier, based on data supporting efficacy against earlier variants; for example, interim data from the COMET-ICE clinical trial showed that in 583 patients with symptomatic COVID-19 and at least 1 comorbidity or age-related risk factor for progressing to severe disease who were randomized to receive sotrovimab or placebo, the risk of progression to severe disease was 85% lower in the sotrovimab arm ^r108

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 tocilizumab^r115 and sarilumab^r116; Janus kinase inhibitors such as baricitinib^r117 and tofacitinib^r118)

• 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 ^r119
    • 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 ^r120r121
    • 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 ^r122
    • NIH guidelines recommend use of baricitinib (or tocilizumab) with dexamethasone alone or with remdesivir and dexamethasone in recently hospitalized patients on high-flow oxygen or noninvasive ventilation who have clinical or laboratory evidence of progressive disease (eg, increasing oxygen needs, increasing inflammatory markers) ^r2
      • Guideline recommends against giving tocilizumab or other interleukin-6 inhibitors to patients on baricitinib
      • There is insufficient evidence to recommend baricitinib over tocilizumab or vice versa for this indication
    • NIH further recommends use of baricitinib (with dexamethasone) for hospitalized patients who need high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation; due to a stronger evidence base, the recommendation for baricitinib is stronger than for tocilizumab, which is an alternative
    • Infectious Diseases Society of America guidelines suggest use of baricitinib in hospitalized patients with severe COVID-19 along with corticosteroids (unless contraindicated) or remdesivir in patients who cannot receive a corticosteroid ^r92
      • Patients receiving baricitinib should not receive tocilizumab or other interleukin-6 inhibitors
      • Some data suggest a reduction in mortality even in patients who require mechanical ventilation
    • WHO guideline strongly recommends baricitinib for patients with severe or critical disease; choice of baricitinib versus interleukin-6 blockers should be based on clinical factors and availability ^r93
• Tocilizumab (monoclonal interleukin-6 receptor blocker)
  • NIH guidelines recommend use of tocilizumab as follows: ^r2
    • Use tocilizumab (or baricitinib) with remdesivir and dexamethasone or with dexamethasone alone in recently hospitalized patients on high-flow oxygen or noninvasive ventilation who have clinical or laboratory evidence of progressive disease (eg, increasing oxygen needs, increasing inflammatory markers)
      • There is insufficient evidence to recommend tocilizumab over baricitinib or vice versa for this indication
    • In patients receiving high-flow oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation, use tocilizumab (with dexamethasone) as an alternative to baricitinib (which currently has more evidence than tocilizumab)
      • Best initiated within 24 hours of admission to ICU
    • Guideline recommends against giving baricitinib to patients on tocilizumab
    • A systematic review and meta-analysis of retrospective trials with data from 240 patients who received tocilizumab and 352 controls concluded that the low-quality evidence available did not demonstrate clear benefit from tocilizumab ^r123
    • 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 ^r92
    • 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 ^r124r125
  • 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 ^r92
  • WHO guidelines recommend use of tocilizumab (or sarilumab) for patients with severe or critical COVID-19, along with corticosteroids ^r93
• Sarilumab (monoclonal interleukin-6 receptor blocker)
  • NIH guidelines recommend use of sarilumab (along with dexamethasone or dexamethasone plus remdesivir) when baricitinib and tocilizumab are unavailable for recently hospitalized patients on high-flow oxygen or noninvasive ventilation who have clinical or laboratory evidence of progressive disease (eg, increasing oxygen needs, increasing inflammatory markers) ^r2
  • NIH guideline also recommends use of sarilumab when baricitinib and tocilizumab are unavailable for hospitalized patients requiring high-flow oxygenation, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation ^r2
  • WHO guidelines recommend use of sarilumab (or tocilizumab) for patients with severe or critical COVID-19, along with corticosteroids; choice of interleukin-6 inhibitor or Janus kinase inhibitor depends on availability and clinical factors ^r93
  • REMAP-CAP trial found that sarilumab plus dexamethasone was noninferior to tocilizumab plus dexamethasone, but evidence for use of tocilizumab is more extensive ^r2r124
• 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) ^r92
    • Patients should also receive at least prophylactic dose of anticoagulant
    • Patients receiving tofacitinib should not receive tocilizumab or other interleukin-6 inhibitors
  • NIH guidelines recommend use of tofacitinib (along with dexamethasone or dexamethasone plus remdesivir) when baricitinib and tocilizumab are unavailable for recently hospitalized patients on high-flow oxygen or noninvasive ventilation who have clinical or laboratory evidence of progressive disease (eg, increasing oxygen needs, increasing inflammatory markers) ^r2
  • NIH guideline also recommends use of tofacitinib when baricitinib and tocilizumab are unavailable for hospitalized patients requiring high-flow oxygenation, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation ^r2
  • WHO guideline suggests against use of tofacitinib or ruxolitinib (another Janus kinase inhibitor) unless baricitinib, tocilizumab, and sarilumab are unavailable, owing to limited evidence ^r93
• Surviving Sepsis Campaign guideline on managing critically ill adults with COVID-19 does not address immunomodulators ^r84r85
• 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 ^r2r92

Systemic corticosteroid therapy is suggested or recommended for most hospitalized patients with an oxygen requirement ^r22

• 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 ^r1r126
  • Compared with usual care alone, deaths in ventilated patients receiving usual care plus dexamethasone were reduced by a third; among patients receiving oxygen without mechanical ventilation, deaths were cut by 20%
  • Overall 28-day mortality was reduced by 17% in the dexamethasone group
• Since that time, multiple randomized trials show improved outcomes, including mortality, in hospitalized patients requiring oxygen; in contrast, systemic corticosteroids for patients not needing oxygen do not improve outcomes and may cause harm ^r2
• NIH treatment guideline recommends use of dexamethasone in most hospitalized patients who require supplemental oxygen, and recommends against use of dexamethasone in patients who do not require oxygen supplementation ^r2
  • In the absence of dexamethasone, another glucocorticoid (eg, prednisone, methylprednisolone, hydrocortisone) may be used
• Similarly, Infectious Diseases Society of America guideline suggests use of dexamethasone in hospitalized patients with severe illness, and recommends use in those with critical illness ^r92
  • Infectious Diseases Society of America suggests against the use of steroids in patients who have no oxygen requirement
  • Guideline provides equivalent doses of alternative glucocorticoids if dexamethasone is unavailable
• Surviving Sepsis Campaign guideline on managing critically ill adults with COVID-19 strongly recommends using corticosteroids (preferably dexamethasone) for up to 10 days in patients with severe or critical COVID-19 ^r84r85
• WHO recommends use in patients with severe and critical COVID-19, and suggests against use in patients with nonsevere COVID-19 ^r22r93
• Inhaled corticosteroids are not recommended by guidelines ^r2r92

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 ^{r2r84r127r128}
• The most current guidelines to address antithrombotic therapy are 3 guidelines from NIH, the American Society of Hematology, and the American College of Chest Physicians. Recommendations are summarized below: ^{r2r129r130r131r132}
  • For prophylaxis in acutely ill adults: ^r2r131r132
    • Therapeutic-dose heparin is recommended or suggested over prophylactic-dose heparin for nonpregnant hospitalized adults with low risk for bleeding in both the American Society of Hematology guidelines and the American College of Chest Physicians guidelines; NIH guideline specifies that therapeutic dose should be reserved for patients with an elevated D-dimer level and that other hospitalized patients should receive prophylactic dose
    • NIH guideline recommends prophylactic-dose heparin in hospitalized pregnant patients; other guidelines do not address anticoagulation in pregnancy
  • For prophylaxis in critically ill adults: ^r2r129r131
    • Prophylactic-dose heparin is recommended or suggested over intermediate-dose or therapeutic-dose for adults in the ICU, including a recommendation to switch from therapeutic to prophylactic dose in patients transferred to an ICU unless a thrombosis has been documented
  • For prophylaxis in children: ^r2
    • NIH guideline recommends prophylactic-dose heparin for hospitalized children aged 12 years or older; there is insufficient evidence to recommend for or against anticoagulation in children younger than 12 years, or to recommend for or against doses other than prophylactic-intensity
  • Prophylactic therapy is not recommended for nonhospitalized patients or as postdischarge therapy after hospitalization in patients without thromboembolic disease ^r2r130r131
  • Standard therapeutic treatment is recommended for patients with COVID-19 and thromboembolism (highly suspected or proven), for those on extracorporeal membrane oxygenation or continuous renal replacement therapy, and for those who have thrombosis related to catheters or extracorporeal filters ^r2
  • Generally, low-molecular-weight heparin is preferred over unfractionated heparin, and heparin is preferred over oral anticoagulants; evidence is limited regarding use of fondaparinux, argatroban, bivalirudin, or other medications ^r2r129r132
  • Risk of bleeding is increased in the following situations:
    • Bleeding within the past 30 days that required an emergency department visit or hospitalization, or gastrointestinal bleeding within the past 3 months
    • History of inherited or acquired bleeding disorder
    • Thrombolysis within the past 7 days or major surgery within the past 14 days
    • Platelet count less than 50 × 10⁹ cells/L; hemoglobin level less than 8 g/dL; or baseline INR more than 2 or activated partial thromboplastin time more than 50 seconds
    • Dual antiplatelet therapy
    • Ischemic stroke, intracranial hemorrhage, or intracranial malignancy
    • Uncontrolled hypertension (systolic more than 200 mm Hg or diastolic more than 120 mm Hg)
    • Presence of epidural or spinal catheter
  • Risk of thrombosis is increased in those with elevated D-dimer levels, prior venous thromboembolism, or additional known risk factors for venous thromboembolism

Convalescent plasma continues to be investigated; only high-titer formulations have shown any benefit^r133

• 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 ^r92
• Surviving Sepsis Campaign guideline on managing critically ill adults with COVID-19 suggests that convalescent plasma not be used outside of clinical trials ^r84
• NIH COVID-19 treatment guideline recommends against use of convalescent plasma in most situations, except in a clinical trial, and recommends against use of convalescent plasma that was collected before the emergence of the Omicron variant ^r2
  • There is insufficient evidence to recommend for or against use of convalescent plasma that was collected after the emergence of the Omicron variant (in hospitalized patients with impaired immunity, or nonhospitalized patients)
• WHO strongly recommends against use of convalescent plasma in nonsevere disease, and recommends against use in severe or critical disease outside of a clinical trial ^r93
• 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 ^r2r137r138
  • 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 ^r92
• Decisions regarding discontinuing or lowering dosage of chronic immunosuppressive medications in patients with COVID-19 should be made in consultation with relevant specialists ^r2

Other options not currently recommended under NIH, Infectious Diseases Society of America, and WHO guidelines (although some are still under study in clinical trials) ^r2r92r93

• Numerous medications have been proposed or attempted for treatment and prevention of COVID-19 based on mechanism of action
• Detailed evidence for the recommendations not to use these medications is available in one or more of the guidelines ^r2r92r93
• Avoid use of the following (unless participating in a clinical trial):
  • Azithromycin
  • Chloroquine and hydroxychloroquine
  • Colchicine
  • Famotidine
  • Fluvoxamine
  • HIV medications, including lopinavir-ritonavir
  • Immunomodulators other than those mentioned earlier, such as the Janus kinase inhibitor ruxolitinib; the interleukin-6 inhibitor siltuximab; interleukin-1 inhibitors; Bruton's tyrosine kinase inhibitors; and GM-CSF inhibitors (against granulocyte-macrophage colony-stimulating factor)
  • Interferons
  • IV immunoglobulin (except as indicated for multisystem inflammatory syndrome)
  • Ivermectin
  • Mesenchymal stem cells
  • Metformin
  • Nitazoxanide
  • Vitamin C, vitamin D, and zinc supplements

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 more^r159 into the course of illness and may be quite abrupt ^r158c275
• In hospitalized patients with confirmed COVID-19, repeated testing may be done to document clearance of virus, defined as 2 consecutive negative results on testing at least 48 hours apart ^r51c276

Complications

• Most common complication is acute respiratory distress syndrome; other reported complications include: ^r14r15c277d5
  • Septic shock ^c278d2
  • Acute kidney injury ^c279d6
  • Myocardial injury ^c280d7
  • Secondary bacterial and fungal infections ^c281c282
  • Multiorgan failure ^c283
  • Thrombotic events ^{r128c284c285c286}
  • Guillain-Barré syndrome ^r160c287
• 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 ^{r161r162r163c288d8}
  • 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 ^r164d9
    • Common clinical features in children include fever, hypotension/shock, abdominal pain, vomiting, diarrhea, conjunctivitis, rash, and headache ^r163r165
    • Common laboratory abnormalities in MIS-C include elevated erythrocyte sedimentation rate; elevated levels of C-reactive protein, ferritin, and D-dimer; abnormal blood cell counts (eg, anemia, thrombocytopenia, neutrophilia); and elevated troponin level ^c289c290c291
    • In MIS-C, findings on echocardiography and abdominal ultrasonography are frequently abnormal (eg, left ventricular dysfunction, coronary artery abnormalities, ascites, bowel wall thickening)
    • Demographically, Black and Latino children are most commonly affected in the United States; an age shift has taken place, with younger populations more affected recently (Omicron subvariants BA.2/BA.4/BA.5, median age 5 years) compared with prior waves (Delta variant, median age 8 years), a shift that has been seen around the world ^r166
  • 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 ^r167
    • 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; CDC^r163r162 and WHO^r168 provide case definitions for reporting
    • Initial CDC MIS-C case definition in 2020 was intentionally broad, to increase sensitivity, and was developed rapidly based on limited cases
      • A new case definition (implementation date January 2023) has been developed based on additional data; updated criteria are more specific to better distinguish MIS-C from acute COVID-19, Kawasaki disease, and toxic shock syndrome ^{r163r164r166d10}
        • New MIS-C case definition: a person younger than 21 years, with fever, with illness requiring hospitalization or resulting in death, and with C-reactive protein level of 3 mg/dL or more, along with both clinical manifestations and linkage to SARS-CoV-2 as described below:
          • 2 or more of the following clinical manifestations:
            • Cardiac involvement indicated by left ventricular ejection fraction less than 55%; coronary artery dilatation, aneurysm, or ectasia; or troponin level elevated above laboratory normal range or indicated as elevated in a clinical note
            • Mucocutaneous involvement indicated by rash, inflammation of oral mucosa (eg, mucosal erythema or swelling, drying or fissure of lips, strawberry tongue), conjunctivitis or conjunctival injection, or extremity findings (eg, erythema or edema of hands or feet)
            • Shock
            • Gastrointestinal involvement indicated by abdominal pain, vomiting, or diarrhea
            • Hematologic involvement indicated by platelet count less than 150,000 cells/mm³ or absolute lymphocyte count less than 1000 cells/mm³
          • 1 or more of the following laboratory or epidemiologic links to SARS-CoV-2:
            • Positive viral test (nucleic acid or antigen) during hospitalization or within 60 days prior
            • Positive viral test (nucleic acid or antigen) in a postmortem specimen
            • Detection of SARS-CoV-2–specific antibodies associated with current illness
            • Close contact with a confirmed or probable case of COVID-19 disease in the 60 days before hospitalization
      • After January 1, 2023, CDC MIS-C webpages will be updated to reflect the new CDC MIS-C surveillance case definition; see those pages for details ^r163
    • 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: ^r162
      • Clinical: fever and at least 3 of the following criteria before hospitalization or within the first 3 days of hospitalization, including at least 1 primary criterion
        • Primary: severe cardiac illness (eg, myocarditis, pericarditis, coronary artery aneurysm, new-onset ventricular dysfunction, new-onset second- or third-degree atrioventricular block, new-onset ventricular tachycardia); rash and nonpurulent conjunctivitis
        • Secondary: new-onset neurologic dysfunction (eg, seizures, encephalopathy, meningeal signs, peripheral neuropathy, Guillain-Barré syndrome); shock or hypotension not attributable to medical treatment; abdominal pain, vomiting, or diarrhea; thrombocytopenia with count less than 150,000 cells/mm³
      • Laboratory: at least 2 of the following markers are elevated: C-reactive protein, ferritin, interleukin-6, erythrocyte sedimentation rate, procalcitonin; plus positive polymerase chain reaction, antigen, or serology test result for COVID-19
  • Several professional organizations provide guidance on management ^r2r169r170
    • Cardiac (telemetry) and blood pressure monitoring; continuous pulse oximetry
    • Prompt ECG and echocardiogram, with serial follow-up studies
    • Close clinical and laboratory monitoring for progressive inflammation and cardiac involvement, including levels of C-reactive protein, troponins, and B-type natriuretic peptide
    • Empiric antibiotic coverage pending culture results
    • Hospitalized children and those who fulfill criteria for Kawasaki Disease should be treated with immunomodulatory and antithrombotic therapy ^d8
      • First line treatment is IV immunoglobulin and glucocorticoids
        • Volume associated with IV immunoglobulin requires careful monitoring in patients with cardiac dysfunction
        • Anakinra, infliximab, or higher-dose glucocorticoids should be given to those who do not respond after initial therapy
          • Unlike in Kawasaki disease, a second dose of IV immunoglobulin is not recommended in refractory disease, owing to risk of volume overload and hemolytic anemia
      • Low-dose aspirin for all patients without risk factors for bleeding, continued for at least 4 weeks until normal coronary arteries and normal platelet count are confirmed
      • In addition to aspirin, therapeutic anticoagulation should be given to patients with large coronary artery aneurysms, documented thrombosis, or moderate to severe left ventricular dysfunction (ejection fraction less than 35%) without risk factors for bleeding
      • Prophylactic or therapeutic anticoagulation should also be considered according to increased risk for thrombosis (eg, indwelling catheterization, age older than 12 years, malignancy, ICU admission, elevated D-dimer level)
    • Treatment for MIS-A has primarily been extrapolated from treatment of MIS-C

Prognosis

• Although most people with COVID-19 have mild to moderate disease, up to 20% may have severe illness (estimated 14%) or critical illness (estimated 5%) ^r16r171
  • Risk of severe or critical illness depends on age, underlying comorbidities, and vaccination status ^r16r52r171
  • Patients who require hospital admission often require prolonged inpatient stay (more than 20 days) and experience significant deconditioning ^r14r15
  • 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 ^r172
• Infection fatality ratio (proportion of deaths among all who are infected, including confirmed cases, undiagnosed cases, and unreported cases) varies across global locations, but it has been estimated as 0.15% ^r173
  • CDC currently estimates the infection fatality ratio by age as follows: ^r174
    • 0 to 17 years: 0.002%
    • 18 to 49 years: 0.05%
    • 50 to 64 years: 0.6%
    • 65 years or older: 9%
• Mortality rate of diagnosed cases is generally about 3% but varies by country ^r3
  • Case fatality rates (proportion of deaths among detected cases; subject to selection bias owing to higher testing in hospitalized cases)
    • These rates are higher for patients in older age groups and with certain comorbidities
    • Case fatality rates by age in the United States: ^r44
      • 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: ^r159
      • 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 ^r159r175
    • Vaccination in persons who have already had COVID-19 may reduce the risk of reinfection (data are limited but encouraging) ^r176
  • Risk of reinfection may be increased with exposure to variant strains, although data are limited
• Risk of breakthrough infection (ie, infection despite vaccination) ^r177
  • 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 ^r178
    • Greatly reduced risk of death ^r178
    • 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) ^r179r180r181
    • 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 ^r180
  • 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 ^r182
    • 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) ^r183

Screening

Prevention

• Overview
  • Preventive measures include vaccination, public health interventions, and (in select populations) preexposure prophylaxis
• Background on vaccines^c296
  • Vaccine authorizations and approvals: various vaccines against SARS-CoV-2 have entered use in many countries, and more are in development ^r189
    • After analyses of data, the vaccines in use have emergency, temporary, or full authorizations from various national regulatory authorities, and future authorizations and full approvals are pending
      • mRNA vaccines
        • Pfizer-BioNTech COVID-19 vaccine (BNT162b2; tozinameran; Comirnaty) has received emergency use authorization in the United States for ages 6 months to 11 years and full FDA approval for persons aged 12 years or older, and authorization or full approval in the United Kingdom, the European Union, Canada, and elsewhere ^{r190r191r192r193c297}
        • Moderna COVID-19 vaccine (mRNA-1273; Spikevax) has received emergency use authorization in the United States for ages 6 months to 17 years and full FDA approval for persons aged 18 years or older, and authorization or full approval in the United Kingdom, Canada, the European Union, and elsewhere ^{r191r192r193r194c298}
      • Adenovirus vector vaccines
        • Janssen (Johnson and Johnson) COVID-19 vaccine (Ad26.COV2.S; Jcovden) has authorization in the United States limited to people aged 18 years or older for whom other approved COVID-19 vaccines are unavailable or not clinically appropriate, or when elected by the recipient who would otherwise not be vaccinated; it also has authorization or full approval in Canada, the United Kingdom, the European Union, and elsewhere ^{r191r192r193r195c299}
        • AstraZeneca (Oxford-AstraZeneca) COVID-19 vaccine (ChAdOx1-S[recombinant]; Vaxzevria) has authorization or full approval in the United Kingdom, Canada, and the European Union ^{r191r192r193c300}
      • Protein subunit vaccine
        • Novavax COVID-19 Vaccine (Novavax recombinant, adjuvanted; Nuvaxovid) has received use authorization in the United States for people aged 12 years or older as a primary series, and is authorized or approved in the European Union, Canada, and elsewhere ^r192r193r196
      • Various other vaccines are in use in many other countries; WHO tracking of vaccine development lists hundreds of vaccines in either clinical development or preclinical phases ^r189c301c302
    • CDC has ongoing vaccine effectiveness monitoring ^r197
      • Efficacy of vaccine-induced immunity against infection wanes over time, but protection against severe disease, hospitalization, and death remains robust including against Omicron variants
    • WHO has issued emergency use listing for more than 10 COVID-19 vaccines; such listing assesses quality, safety, efficacy, and programmatic suitability, and it is a prerequisite for the COVAX vaccine supply and international procurement program ^r198
    • Authorizations in different jurisdictions may differ in details; practitioners should consult the specific authorization issued in their jurisdiction for indications, requirements for patient education and consent, and mandated reporting (eg, adverse events)
      • Vaccine administration information for the United States
        • In the United States, emergency use authorizations require health care providers to communicate to the patient, parent, or caregiver information consistent with the vaccine-specific (manufacturer-specific) fact sheet for recipients and caregivers before each patient receives the vaccine; such information includes the following: ^{r190r194r195r196}
          • Alternatives to receiving the vaccine
          • Option to accept or refuse the vaccine
          • Significant known and potential risks and benefits of the vaccine, and the extent to which such potential risks and benefits are unknown
          • Available alternative preventive vaccines in clinical trials or approved for use under other emergency use authorizations
        • Emergency use authorizations also mandate certain incidents be reported to VAERS (Vaccine Adverse Event Reporting System)^{r199r190r194r195r196}
          • Events which must be reported to VAERS include:
            • Vaccine administration errors, whether or not an adverse event occurred
            • Serious adverse effects, whether or not attributed to the vaccine, including myocarditis; pericarditis; multisystem inflammatory syndrome; cases of COVID-19 resulting in hospitalization or death; events that are life-threatening, require hospitalization, or require medical or surgical intervention to prevent hospitalization, disability, or death; birth defects; disability; and death
          • Clinicians may choose to report any adverse events to VAERS and to the vaccine manufacturer
        • It is recommended that vaccine recipients be given a card containing information about the type of vaccine given, the date of administration, and (if applicable) the interval at which a booster dose should be administered ^r200r201r202
        • Vaccine recipients in the United States are encouraged to participate in CDC's V-safe monitoring and reminder system,^r200 available as a mobile phone app ^r201
        • 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 ^r203
      • 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 site^r204

    • SARS-CoV-2 vaccines in the United States.

      EUA, emergency use authorization.

      Data from FDA: COVID-19 Vaccines. FDA website. Updated December 8, 2022. Accessed December 14, 2022. https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/covid-19-vaccines

      Product name	Manufacturer	Active ingredient	Age range for use	Comments
      Pfizer-BioNTech COVID-19 vaccine (BNT162b2; tozinameran; Comirnaty)	Pfizer-BioNTech	Nucleoside-modified mRNA of SARS-CoV-2	6 months or older	• FDA approved in the United States for ages 12 years or older; used under EUA for ages 6 months to 11 years in the United States
      Moderna COVID-19 vaccine (mRNA-1273; Spikevax)	ModernaTX	Synthetic mRNA of SARS-CoV-2	6 months or older	• FDA approved in the United States for ages 18 years or older; used under EUA for ages 6 months to 17 years in the United States
      Janssen COVID-19 vaccine	Janssen Biotech, Inc (a Janssen Pharmaceutical Company of Johnson and Johnson)	Recombinant, replication-deficient adenovirus 26 vector expressing SARS-CoV-2 spike glycoprotein (S protein)	18 years or older	• Investigational; under EUA in the United States • Use in the United States was paused then resumed in April 2021 • On May 5, 2022, FDA limited the use to people aged 18 years or older for whom other approved COVID-19 vaccines are unavailable or not clinically appropriate, or when elected by the recipient who would otherwise not be vaccinated
      Novavax COVID-19 vaccine, adjuvanted	Novavax	Recombinant spike protein (rS) of SARS-CoV-2	12 years or older	• Investigational; under EUA in the United States

  • Vaccination recommendations
    • CDC recommends vaccination against COVID-19 for everyone aged 6 months or older ^r4
      • mRNA vaccines (Pfizer, Moderna) or Novavax are preferred over Johnson and Johnson (Janssen) owing to higher efficacy and fewer adverse effects
        • Johnson and Johnson (Janssen) may be used when there is a contraindication or allergic reaction to another vaccine, or when the individual will not otherwise accept vaccination
      • Follow color coding of products
        • Doses, concentrations, and formulations differ across age groups and manufacturers; therefore, color coding^r4 has been established to aid in distinguishing preparations
          • Note that some labels on vaccine vials in circulation do not reflect updated FDA authorizations/approvals or CDC guidance; consult websites for current information ^r4r205
            • Pfizer vials with maroon cap and maroon label border may state either "age 2y to <5y" or "age 6m to <5y" and either vial may be used for children aged 6 months to 4 years
            • Moderna vials with dark blue cap and purple label border may state "BOOSTER DOSES ONLY" but may be used as a primary series dose for children aged 6 to 11 years and should not be used as a booster dose
      • Timing of dosing ^r4
        • Doses administered up to 4 days before the recommended interval are considered valid
        • Doses administered more than 4 days before the recommended interval must be reported to VAERS and repeated, with the subsequent dose given the recommended interval after the erroneous dose
        • Doses administered any time after the recommended interval are valid
      • Primary vaccinations
        • Primary vaccination of nonimmunocompromised persons ^r4
          • Primary series for nonimmunocompromised adults aged 18 years or older is 2 doses of Pfizer separated by 3 to 8 weeks, 2 doses of Moderna separated by 4 to 8 weeks, or 2 doses of Novavax separated by 3 to 8 weeks
            • A shorter interval (3 or 4 weeks) is recommended for those at higher risk of infection or of severe disease (eg, when community transmission is elevated, for older adults, or those with chronic conditions)
            • A longer interval (8 weeks) may be preferable in males aged 12 to 39 years to reduce the risk of vaccine-associated myocarditis, and it may be considered to increase peak antibody response in those not at increased risk
              • Risk of myocarditis from COVID-19 disease is substantially higher than the risk from vaccination ^r206
              • Risk of myocarditis in younger males might be lower after vaccination with Pfizer than with Moderna, but findings are not consistent in all monitoring ^r4
          • Primary series for nonimmunocompromised children and adolescents aged 6 months to 17 years
            • Pfizer
              • Ages 6 months to 4 years: 3 doses with an interval of 3 to 8 weeks between the first and second doses and at least 8 weeks between the second and third doses; first and second doses in the primary series are monovalent vaccine and the third primary dose is bivalent vaccine
              • Ages 5 years or older: 2 doses separated by 3 to 8 weeks; a longer interval (8 weeks) may be preferable, particularly in males to reduce the risk of vaccine-associated myocarditis
            • Moderna
              • Age 6 months to 17 years: 2 doses separated by 4 to 8 weeks
            • Novavax
              • Age 12 to 17 years: 2 doses separated by 3 to 8 weeks
        • Primary vaccination of moderately or severely immunocompromised persons ^r4
          • Primary series for immunocompromised adults aged 18 years or older is 3 doses of Pfizer (second dose 3 weeks after first dose, and third dose at least 4 weeks after second dose), 3 doses of Moderna (second dose 4 weeks after first dose, and third dose at least 4 weeks after second dose), or 2 doses of Novavax (second dose 3 weeks after the first)
          • Primary series for children and adolescents
            • Pfizer
              • Ages 6 months through 4 years: 3 doses, with second dose 3 weeks after first dose, and third dose at least 8 weeks after second dose; first and second doses in the primary series are monovalent vaccine and the third primary dose is bivalent vaccine
              • Ages 5 to 17 years: 3 doses, with second dose 3 weeks after first dose, and third dose at least 4 weeks after second dose
            • Moderna
              • Ages 6 months through 17 years: 3 doses, with second dose 4 weeks after first, and third dose at least 4 weeks after second dose
            • Novavax
              • Age 12 to 17 years: 2 doses separated by 3 weeks
        • There are no data available on the interchangeability of the COVID-19 vaccines to complete the primary vaccination series. Patients who receive the first dose of any of the vaccines should complete the primary vaccination series with the same vaccine ^r4
          • In cases in which the original vaccine is unknown or unavailable, or there is a contraindication to that vaccine, it is permissible to administer another authorized vaccine at least 28 days after the first dose
          • If a mixed primary series is inadvertently administered, the series is considered complete
          • If a child aged 6 months to 4 years inadvertently receives 2 different mRNA vaccines for the primary series, a third dose of either mRNA vaccine should be administered at least 8 weeks after the second dose to complete the series
      • Booster vaccinations
        • In the United States, updated bivalent booster vaccines were approved by the FDA on August 31, 2022 ^r205
          • These boosters, from Pfizer and from Moderna, contain an mRNA component against the original strain and one against the Omicron BA.4 and BA.5 subvariants (which have the same spike protein)
        • Bivalent booster vaccines are recommended for everyone aged 6 months or older who has completed primary vaccination, except children aged 6 months to 4 years who receive Pfizer primary series (which now contains bivalent vaccine as the third dose)
          • The original monovalent vaccines are no longer authorized for use as a booster; they are still used as a third primary dose for persons needing a 3-dose primary series as noted above
        • Some data suggest that heterologous boosters (ie, booster vaccine different from primary) produce equivalent or stronger serologic response compared with homologous boosters ^r4
        • Booster dose schedule ^r4
          • Adults and children aged 6 years or older are recommended to receive Moderna or Pfizer bivalent booster at least 2 months after primary series or prior monovalent booster vaccination
          • Children aged 5 years who receive Pfizer primary series are recommended to receive only Pfizer bivalent booster, at least 2 months after primary series
          • Children aged 5 years who receive Moderna primary series are recommended to receive either Moderna or Pfizer bivalent booster, least 2 months after primary series
          • Children aged 6 months to 4 years who receive Moderna primary series are recommended to receive only Moderna bivalent booster, at least 2 months after primary series
          • Children aged 6 months to 4 years who receive Pfizer 3-dose primary series (regardless of whether the third dose was monovalent or bivalent vaccine) are not recommended to receive any booster doses
          • Novavax monovalent vaccine may be used as a booster only if an adult aged 18 years or older, who has received a primary series and no boosters, cannot receive the recommended bivalent mRNA vaccines

      • COVID-19 vaccination schedule in the United States.

        NA, not applicable. Colors listed in parentheses refer to (cap color/label border color). Primary series: Any age-appropriate Moderna, Novavax, and Pfizer-BioNTech vaccine may be used for the primary series; the same vaccine product should be used for all doses of the primary series. Booster doses: any age-appropriate bivalent booster vaccine may be used (regardless of primary series product).

        Data from CDC: Vaccines and Immunizations: COVID-19 Vaccination: Interim Clinical Considerations for Use of COVID-19 Vaccines Currently Approved or Authorized in the United States. CDC website. Updated December 12, 2022. Accessed December 16, 2022. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html#covid-vaccines

        Manufacturer	Age	Dose 1	Dose 2	Dose 3	Dose 4	Notes
        Schedule for individuals who are NOT moderately to severely immunocompromised
        Pfizer	6 months to 4 years	Primary monovalent (maroon/maroon), 0.2 mL	In 3 to 8 weeks, primary monovalent (maroon/maroon), 0.2 mL	In at least 8 weeks, primary bivalent (maroon/maroon), 0.2 mL	NA	Maroon formulation requires dilution; no booster doses for children this age who receive 3-dose Pfizer primary series (regardless of whether third dose was monovalent or bivalent)
        Pfizer	5 years to 11 years	Primary monovalent (orange/orange), 0.2 mL	In 3 to 8 weeks, primary monovalent (orange/orange), 0.2 mL	In at least 2 months, bivalent booster (orange/orange), 0.2 mL	NA	Orange formulation requires dilution; for ages 6 years to 11 years, either Pfizer or Moderna bivalent booster may be used
        Pfizer	12 years and older	Primary monovalent (gray/gray), 0.3 mL	In 3 to 8 weeks, primary monovalent (gray/gray), 0.3 mL	In at least 2 months, bivalent booster (gray/gray), 0.3 mL	NA	Either Pfizer or Moderna bivalent booster may be used
        Moderna	6 months to 5 years	Primary monovalent (dark blue/magenta), 0.25 mL	In 4 to 8 weeks, primary monovalent (dark blue/magenta), 0.25 mL	In at least 2 months, bivalent booster (dark pink/yellow), 0.2 mL	NA	Only Moderna bivalent booster is authorized for children aged 6 months to 4 years who receive Moderna primary series; children aged 5 years may receive Moderna or Pfizer booster
        Moderna	6 years to 11 years	Primary monovalent (dark blue/purple), 0.5 mL	In 4 to 8 weeks, primary monovalent (dark blue/purple), 0.5 mL	In at least 2 months, bivalent booster (dark blue/gray), 0.25 mL	NA	Either Moderna or Pfizer bivalent booster may be used
        Moderna	12 years and older	Primary monovalent (red/light blue), 0.5 mL	In 4 to 8 weeks, primary monovalent (red/light blue), 0.5 mL	In at least 2 months, bivalent booster (dark blue/gray), 0.5 mL	NA	Either Moderna or Pfizer bivalent booster may be used
        Novavax	12 years and older	Primary monovalent (royal blue/no color), 0.5 mL	In 3 to 8 weeks, primary monovalent (royal blue/no color), 0.5 mL	NA	NA	In at least 2 months after last primary dose, should receive either Moderna or Pfizer bivalent booster
        Schedule for individuals who ARE moderately to severely immunocompromised
        Pfizer	6 months to 4 years	Primary monovalent (maroon/maroon), 0.2 mL	In 3 weeks, primary monovalent (maroon/maroon), 0.2 mL	In at least 8 weeks, primary bivalent (maroon/maroon), 0.2 mL	NA	Maroon formulation requires dilution; no booster doses for children this age who receive 3-dose Pfizer primary series (regardless of whether third dose was monovalent or bivalent)
        Pfizer	5 years to 11 years	Primary monovalent (orange/orange), 0.2 mL	In 3 weeks, primary monovalent (orange/orange), 0.2 mL	In at least 4 weeks, primary monovalent (orange/orange), 0.2 mL	In at least 2 months, bivalent booster (orange/orange), 0.2 mL	Orange formulation requires dilution; for ages 6 years to 11 years, either Pfizer or Moderna bivalent booster may be used
        Pfizer	12 years and older	Primary monovalent (gray/gray), 0.3 mL	In 3 to 8 weeks, primary monovalent (gray/gray), 0.3 mL	In at least 4 weeks, primary monovalent (gray/gray), 0.3 mL	In at least 2 months, bivalent booster (gray/gray), 0.3 mL	Either Pfizer or Moderna bivalent booster may be used
        Moderna	6 months to 5 years	Primary monovalent (dark blue/magenta), 0.25 mL	In 4 weeks, primary monovalent (dark blue/magenta), 0.25 mL	In at least 4 weeks, primary monovalent (dark blue/magenta), 0.25 mL	In at least 2 months, bivalent booster (dark pink/yellow), 0.2 mL	Only Moderna bivalent booster is authorized for children aged 6 months to 4 years who receive Moderna primary series; children aged 5 years may receive Moderna or Pfizer booster
        Moderna	6 years to 11 years	Primary monovalent (dark blue/purple), 0.5 mL	In 4 weeks, primary monovalent (dark blue/purple), 0.5 mL	In at least 4 weeks, primary monovalent (dark blue/purple), 0.5 mL	In at least 2 months, bivalent booster (dark blue/gray), 0.25 mL	Either Moderna or Pfizer bivalent booster may be used
        Moderna	12 years and older	Primary monovalent (red/light blue), 0.5 mL	In 4 weeks, primary monovalent (red/light blue), 0.5 mL	In at least 4 weeks, primary monovalent (red/light blue), 0.5 mL	In at least 2 months, bivalent booster (dark blue/gray), 0.5 mL	Either Moderna or Pfizer bivalent booster may be used
        Novavax	12 years and older	Primary monovalent (royal blue/no color), 0.5 mL	In 3 to 8 weeks, primary monovalent (royal blue/no color), 0.5 mL	NA	NA	In at least 2 months after last primary dose, should receive either Moderna or Pfizer bivalent booster

    • COVID-19 vaccine and any other immunizations may be administered on the same day, or at any interval; no delay is required between receipt of another vaccine and COVID-19 vaccination ^r4
      • If orthopoxvirus (monkeypox) vaccine is recommended, it may be administered at any interval after COVID-19 vaccine; however, consider delaying the administration of COVID-19 vaccine for 4 weeks after orthopoxvirus vaccination in males aged 12 to 39 years because there is a low risk of myocarditis with certain orthopoxvirus vaccines and with Moderna, Pfizer, and Novavax COVID-19 vaccines
    • History of COVID-19 is not a contraindication to vaccine; guidelines recommend that such persons be offered vaccine ^r4
      • 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 ^r176r207
    • 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 ^r4
    • Limited data exist regarding safety and efficacy of vaccination after MIS-C or MIS-A; the benefits of vaccination should be weighed against the theoretical risk of multisystem inflammatory syndrome or myocarditis following vaccination ^r4
      • Experts consider that benefits of vaccination for those with MIS-C or MIS-A probably exceed theoretical risk once clinical recovery (including return to normal myocardial function) is achieved, and 90 days or more have elapsed since MIS-C/MIS-A diagnosis
        • If MIS-C or MIS-A was diagnosed within 90 days of COVID-19 vaccination, consider deferral of subsequent doses or additional consultation
        • Vaccination may be considered even for those do not yet meet criteria above, at the discretion of the care team or with additional consultation
      • Consider consultation with a specialist in infectious diseases, rheumatology, or cardiology, and/or with personnel of the Clinical Immunization Safety Assessment COVIDvax project,^r208 to discuss specific cases, particularly if MIS-C or MIS-A occurred after vaccination
    • History of Guillain-Barré syndrome (postinfectious polyneuritis) is a precaution to Johnson and Johnson (Janssen) vaccination; use of Moderna, Novavax, or Pfizer vaccines is recommended ^r4
    • Vaccine use in special populations
      • Pregnant persons and breastfeeding persons ^r4r151r152
        • Vaccination is recommended for pregnant and lactating persons, and those who may become pregnant, by the CDC, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine
          • Any authorized or approved vaccine may be used; as with all populations, for pregnant and lactating patients, Moderna, Pfizer, and Novavax are recommended over Janssen for safety and efficacy reasons
          • Studies indicate that pregnant persons with COVID-19 infection have increased risk for severe illness and death from COVID-19 and may be at increased risk of preterm birth, stillbirth, and other pregnancy complications
          • Growing information on safety and efficacy during pregnancy indicates that benefits of vaccination outweigh risks
            • One study in 35,691 pregnant persons aged 16 to 54 years found no increased rates of pregnancy loss, preterm birth, small-for-gestational-age status, or congenital anomalies, compared with background rates ^r209
            • Overall vaccine effectiveness of vaccination during pregnancy at preventing hospitalizations in infants younger than 6 months was 61%; optimal timing during pregnancy is not known, but effectiveness was higher in those who received the vaccine later in pregnancy (between 21 weeks of gestation and 14 days before delivery) ^r210
            • Vaccination during pregnancy transfers antibodies to infants, and infants born to vaccinated adults had higher antibody titers and greater antibody persistence than those born to COVID-infected adults ^r207
          • Pregnant persons, and those who received vaccination within 30 days before pregnancy, should be encouraged to participate in CDC's V-safe registry program (a mobile phone–based monitoring and reminder system for recipients of COVID-19 vaccines)
      • Persons with cancer ^r211
        • CDC and National Comprehensive Cancer Network recommend that patients with cancer should receive vaccine as soon as possible, with a few exceptions:
          • Recipients of hematopoietic cell transplant or cellular therapy (eg, CAR T-cell therapy, using cells with chimeric antigen receptors) should delay vaccination for at least 3 months
          • Patients receiving intensive cytotoxic chemotherapy (eg, cytarabine/anthracycline-based induction regimens for acute myeloid leukemia) should delay until absolute neutrophil count recovery, or for those not expected to recover, as soon as possible
          • Patients who require major surgical procedures (eg, for solid tumors) should time vaccination for several days before or after the surgery
        • Complete revaccination is recommended 3 months after hematopoietic cell transplant or cellular therapy (eg, CAR T-cell therapy)
      • Persons with autoimmune diseases ^r4
        • Current recommendations advise all persons with autoimmune diseases to be vaccinated; those on medications causing immunocompromise should follow appropriate schedule for persons with moderate to severe immunocompromise
  • Vaccine contraindications and significant adverse effects
    • Contraindications include: ^r4r212
      • Severe allergic reaction (eg, anaphylaxis) to a previous dose of a COVID-19 vaccine or to any of its components
      • Known allergy to any components of a vaccine (eg, polyethylene glycol in Moderna and Pfizer vaccines, or polysorbate 80 in Novavax and Janssen vaccines)
      • For the Johnson and Johnson (Janssen) vaccine, persons who have history of thrombosis with thrombocytopenia syndrome, heparin-induced thrombocytopenia, or other immune-mediated thrombosis syndrome should not receive this vaccine; those with history of Guillain-Barré syndrome within 6 weeks of Johnson and Johnson vaccination should not receive any additional doses of this vaccine
      • Contraindication to one type of vaccine is a precaution to other types of vaccines
    • Myocarditis and pericarditis have been reported to occur rarely in adolescents and young adults (primarily males aged 12 to 39 years) after vaccination, most commonly after the second dose ^{r4r213r214r215}
      • This has been reported after vaccination with AstraZeneca, Moderna, Novavax, and Pfizer vaccines (but not Janssen)
      • Onset is usually several days after administration of vaccine; the condition is generally short-lived
      • Compared with the risk of myocarditis or pericarditis from vaccination, the risk of myocarditis or pericarditis from COVID-19 disease is higher
        • One study showed a very small increase in myocarditis in males aged 13 to 39 years after the second dose of Moderna compared with the risk of myocarditis from COVID-19; other studies have shown that even among this subgroup, the risk of myocarditis from COVID-19 is greater than the risk from vaccination ^r206r213r216
      • Vaccine recommendations for adolescents and young adults remain unchanged, except that waiting 8 weeks between the first and second dose may decrease the risk, and persons who have had myocarditis after a first dose of vaccine should generally avoid a second dose
    • CDC^r4 and the European Medicines Agency^r217 have recommended that clinicians maintain a high index of suspicion for thrombotic events and thrombocytopenia among persons who have received the Janssen or AstraZeneca adenovirus vector vaccines
      • Symptoms may include severe headache, blurred vision, back pain, abdominal pain, chest pain, dyspnea, leg edema, petechiae, or easy bruising; overt bleeding has occurred in some cases ^r4r217
      • 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): ^r218
        • 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: ^r218
        • IV immunoglobulin 1 g/kg daily for 2 days
        • Anticoagulation with one of the following heparin alternatives (avoid heparin):
          • Parenteral direct thrombin inhibitors (argatroban or bivalirudin if baseline value for activated partial thromboplastin time is normal)
          • Direct oral anticoagulants
          • Fondaparinux (Factor Xa inhibitor)
          • Danaparoid (a thrombin generation inhibitor not available in the United States)
        • Low fibrinogen level or bleeding do not absolutely preclude anticoagulation, especially if platelet count exceeds 20,000 cells/mm³
        • No consensus exists on the use of corticosteroids with IV immunoglobulin
        • Avoid platelet transfusion and aspirin
        • Plasma exchange has been tried and may be considered for thrombosis despite IV immunoglobulin and nonheparin anticoagulation
      • Patients with isolated thrombocytopenia without thrombosis, with a negative result on platelet factor 4–heparin assay, may have idiopathic thrombocytopenic purpura, not vaccine-induced thrombotic thrombocytopenia ^r218
        • Immune thrombocytopenia has been reported after vaccination with the AstraZeneca, Janssen, Moderna, and Pfizer vaccines
        • Treatment includes IV immunoglobulin and/or steroids; platelet transfusions may be required for bleeding
    • A small number of cases of Bell palsy have been reported after COVID-19 vaccination, but the incidence is not considered significantly different from that in the general population (background rate), and history of Bell palsy is not a contraindication ^r4
    • A small number of patients who have received cosmetic injections with dermal fillers have experienced mild inflammation at the filled site(s) after COVID-19 vaccination, but a history of such procedures is not a contraindication ^r4
  • Vaccine-specific details and evidence
    • Pfizer-BioNTech BNT162b2 (tozinameran; Comirnaty) ^r190c303
      • An mRNA vaccine against the SARS-CoV-2 spike protein (ie, using messenger ribonucleic acid)
      • Evaluated in a randomized placebo-controlled trial of more than 43,000 participants; at time of submission for authorization in the United Kingdom, safety and efficacy data were available for 19,067 patients evenly distributed in vaccine and placebo groups. Overall efficacy was about 95% ^r219
        • Among subgroups, results were similar in older age groups (older than 65 years) and in persons with comorbidities associated with increased risk for severe disease
      • Data evaluated for 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 ^r202r219
      • 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 ^r202r219
        • 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
      • Trial data were published after release of the emergency use authorization; total numbers of patients in both vaccine and placebo groups were slightly larger, but results (including efficacy calculations) were unchanged ^r220
      • FDA approval for ages 16 years or older was based on continued follow-up of initial study enrollees and additional data ^r190
      • Subsequent trial data on adolescents led to emergency use authorization on May 10, 2021, and full approval on July 8, 2022, for adolescents aged 12 through 15 years ^r190
        • Safety data were derived from 1127 vaccinated adolescents and 1127 placebo patients. Serious events occurred in 0.4% of vaccinated persons and 0.1% of placebo recipients, similar to results in adults
        • Among 1005 vaccinated adolescents aged 12 to 15 years, no cases of COVID-19 occurred. There were 16 cases among 978 placebo recipients. Efficacy was calculated as 100% (confidence interval, 75.3-100)
      • FDA issued an emergency use authorization for children aged 5 through 11 years on October 29, 2021 ^r4r202r221
        • Based on data from a placebo-controlled trial of 4695 children, of whom 3109 received vaccine and 1538 received saline
        • Follow-up found no safety concerns, including in the 1444 children who had follow-up for 2 months or longer
        • By 7 days after the second dose, efficacy is estimated to be 90.7% in preventing COVID-19
      • FDA emergency use authorization was issued on June 17, 2022 for children aged 6 months through 4 years ^r222
        • 1776 children aged 6 months to less than 2 years and 2750 children aged 2 years to 4 years were enrolled in placebo-controlled trials, which showed no safety concerns
        • Effectiveness in children aged 6 months through 4 years is primarily based on measured immune response in 220 vaccine recipients, which was comparable to that of older age groups
    • Moderna COVID-19 vaccine (mRNA-1273; Spikevax) ^r194c304
      • An mRNA vaccine against the SARS-CoV-2 spike protein
      • Safety data evaluated for US emergency use authorization included 30,351 persons, aged 18 years or older, equally divided between vaccine group and placebo group (15,185 versus 15,166, respectively); efficacy data was available for 14,134 vaccine recipients and 14,073 persons who received placebo. Participants included wide ethnic and age diversity; persons with stable comorbidities were included. At time of analysis, participants had been followed for a median of 9 weeks after the second dose ^r223
        • Overall efficacy was 94.1% (95.6% for persons aged 18 through 64 years and 86.4% for persons aged 65 or older)
        • Common adverse effects included pain at injection site, fatigue, headache, myalgia, chills, arthralgia, and fever; these were largely mild to moderate and resolved within a median of 2 to 3 days
        • Bell palsy was reported in 3 vaccine recipients (1 case classed as serious) and 1 placebo recipient; a causal relationship has not been established. Two patients who had previously received facial injection of dermatologic fillers experienced severe facial swelling considered likely vaccine-related. One patient developed intractable vomiting requiring hospital admission, deemed a result of vaccine
        • Severe allergic reactions have been described, and facilities at which vaccine is administered must have the ability to treat such reactions (including anaphylaxis)
          • CDC provides guidance on anaphylaxis to aid vaccine providers in preparing for and managing such events,^r224 and for postanaphylaxis laboratory assessment^r225
        • Myocarditis and pericarditis have been reported to occur in adolescents and young adults (primarily males) after vaccination, most commonly after the second dose, and with some evidence suggesting higher risk after Moderna vaccination than after other vaccines ^{r4r213r214r215}
      • Subsequent analysis of data in younger age groups has led to FDA emergency use authorization on June 17, 2022, for children and adolescents aged 6 months through 17 years ^r222
        • Measured immune response in all segments of children and adolescents was similar to that in vaccinated adults
        • Efficacy against infection was as follows:
          • In adolescents aged 12 to 17 years: 93.3%
          • In children aged 6 through 11 years, an insufficient number of COVID-19 infections occurred to allow reliable calculation of efficacy
          • In 5400 children aged 6 months to 5 years
            • 6 to 23 months: 50.6%
            • 2 to 5 years: 36.8%
    • Novavax COVID-19, Adjuvanted ^r196
      • Protein subunit vaccine containing SARS-CoV-2 spike protein and Matrix-M adjuvant
      • Initial efficacy data were drawn from a randomized placebo-controlled trial comparing occurrence of mild, moderate, and severe COVID-19 in 17,272 nonimmunocompromised participants who received vaccine versus 8385 who received placebo. The overall efficacy in preventing polymerase chain reaction–confirmed and symptomatic mild, moderate, or severe COVID-19 from 7 days after dose 2 was 90.4% (95% CI, 83.8%-94.3%)
        • 17 patients (0.1%) in the vaccinated group acquired mild COVID-19 versus 66 patients (0.8%) in the placebo group
        • No patients in the vaccinated group acquired disease that was moderate or severe, versus 9 patients with moderate disease and 4 patients with severe disease in the placebo group
        • When subgroups were analyzed, vaccine efficacy appeared to be lower in Hispanic or Latino participants and in the older age group (aged 65 years or older)
      • Safety data for the emergency use authorization derive from a trial in the United States and Mexico in which 26,106 participants received at least 1 dose of Novavax; data from trials elsewhere are also available
        • Common reactions were local ones (ie, pain, redness, swelling), which occurred in up to 80.8%, and systemic ones (ie, fever, headache, fatigue/malaise, myalgia, arthralgia, nausea/vomiting), most of which occurred in fewer than half of vaccine recipients
        • Generally, adverse events appeared to be less frequent in recipients aged 65 years or older
        • 4 patients developed myocarditis or pericarditis, including 1 with concurrent COVID-19. Two of the events occurred under circumstances outside of currently authorized use of the vaccine (in one case, the patient was aged 16 years, and in the second case, the adverse event occurred after a booster that followed the primary series)
        • Other events that have been reported but for which there are insufficient data to determine a causative link include cardiomyopathy/cardiac failure, acute cholecystitis, thrombotic/embolic events (noncardiovascular, nonneurovascular), and uveitis
        • Anaphylaxis and additional cases of myocarditis or pericarditis have been reported outside of trials
    • Janssen (Johnsons and Johnson) COVID-19 vaccine ^r195c305
      • A replication-deficient adenovirus vector vaccine that generates immunity to the SARS-CoV-2 spike protein
      • A multinational trial enrolled 44,325 persons randomized to receive the Janssen COVID-19 vaccine or saline placebo; a preliminary efficacy analysis of 39,321 was presented to the FDA, of whom 19,630 received vaccine and 19,691 received placebo. The populations were similar and represented diverse racial and ethnic backgrounds, and patients were distributed across all age ranges 18 years or older. Persons with stable underlying medical conditions (including HIV infection) were included
      • At 14 days after vaccine administration, efficacy against severe/critical COVID-19 was 76.7%, rising to 85.4% at 28 days; for moderate to severe/critical COVID-19, efficacy rates at 14 and 28 days were 66.9% and 66.1%, respectively. At 28 days, efficacy rates did not differ between populations aged 18 to 59 years and those aged 60 years or older
      • Common adverse reactions (reported in more than 10% of participants) included headache, fatigue, myalgia, and nausea; they were reported in 13.1% of vaccine recipients and 12% of placebo patients; other adverse events included urticaria in 5 vaccine recipients (including 1 with angioedema) and 1 placebo recipient
      • 2 unique serious adverse events thought to be related to the vaccine occurred, as follows: 1 patient experienced severe pain in the injected arm unresponsive to analgesics and persistent to 74 days of follow-up, and another patient had fever, headache, and generalized weakness that resolved within 3 days
      • Several events occurred more frequently in vaccine recipients than in placebo recipients, but a causal relationship to the vaccine could not be determined, owing to confounding effects of existing underlying conditions: deep vein thrombosis (6 vaccine recipients versus 2 placebo recipients); pulmonary embolus (4 vaccine recipients versus 2 placebo recipients); transverse sinus thrombosis (single case, in a vaccine recipient); seizures (4 vaccine recipients versus 1 placebo recipient); tinnitus (in 6 vaccine recipients only)
      • On April 12, 2021, CDC and FDA recommended that practitioners in the United States suspend use of this vaccine while reports of an unusual clotting disorder associated with administration of this vaccine were investigated ^r226
        • 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 ^r227
        • 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 ^r228
      • 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 ^r229
• Preexposure prophylaxis^r2
  • Until January 26, 2023, monoclonal antibodies tixagevimab and cilgavimab had emergency use authorization for coadministration in persons 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). However, because more than 90% of SARS-CoV-2 variants circulating in early 2023 are resistant to these monoclonal antibodies, the emergency use authorization was suspended ^r113
    • As of January 30, 2023, NIH guideline recommends against preexposure prophylaxis with tixagevimab-cilgavimab ^r2
• Postexposure prophylaxis^r2
  • Postexposure prophylaxis is no longer available, as the previously authorized options (monoclonal antibodies casirivimab-imdevimab or bamlanivimab-etesevimab) are ineffective against Omicron variants
• Public health interventions to interrupt transmission (eg, masking, distancing, hygiene, isolation, quarantine): practices vary geographically and depend on regional disease activity, vaccination status, and other factors
  • General precautions for all populations ^r83
    • Get vaccinated
    • Wear a mask (preferably high quality, such as N95) in indoor settings when community transmission is high or if you are at high risk
    • Avoid crowds and poorly ventilated spaces; improve ventilation whenever possible
    • Test to prevent spread to others (eg, if you have symptoms, exposure, or plans to gather with someone at higher risk)
    • Physical distance at least 6 feet from others whenever feasible
    • Wash hands (or use hand sanitizer at least 60% alcohol), cover coughs and sneezes with a tissue, and clean and disinfect high-touch surfaces often
    • Monitor for symptoms
    • Avoid contact with others (eg, stay home) when you are sick, even if an initial test result comes back negative
  • Isolation and quarantine measures: overview
    • A Cochrane review of quarantine concluded that quarantine is important in reducing incidence and mortality ^r230
    • All those who have symptoms of COVID-19 should isolate themselves, and get tested for COVID-19, regardless of vaccination status ^r83
      • Persons with symptoms and an initial negative result may need repeated testing ^r54
    • Persons who test positive for COVID-19, regardless of vaccination status or symptoms, should isolate for at least 5 days and wear a mask for an additional 5 days ^r175
      • Those who cannot wear a mask should isolate for 10 days
      • Patients who are moderately to severely ill (eg, lower respiratory disease) should isolate for 10 days
      • Patients who are immunocompromised may have a prolonged period of infectiousness; continue isolation until 2 consecutive antigen test results at least 48 hours apart are negative, and retest if symptoms recur
    • Persons exposed to COVID-19, regardless of vaccination status, should wear a mask around others for 10 days, monitor for symptoms, and get tested ^r83
      • Testing should be performed immediately if symptoms develop
      • Testing is recommended on day 6 (where day 0 is the day of last exposure to someone with COVID-19) regardless of symptoms; if negative, continue to mask until day 10
        • Note for household members that day 0 ("last exposure") starts when the patient has completed isolation
      • Isolate immediately if any test result is positive, regardless of symptoms
      • Close contact is defined as within 6 feet for a cumulative total of 15 minutes or more in 24 hours, but exposure may happen at any distance or time interval depending on aerosolization of virus
  • Infection control for at-home management of COVID-19 ^r83r175
    • Patient is encouraged to stay at home except to seek medical care, to self-isolate to a single area of the house (preferably with a separate bathroom), to practice good hand and cough hygiene, to improve ventilation where possible, and to wear a mask (preferably high quality, such as N95, as tolerated) during any contact with household members ^c306c307c308
      • Isolation is required for everyone with a positive COVID-19 test result, even in the absence of symptoms
    • Household members/caregivers should:
      • Wear a mask, preferably a high-quality one such as N95, when around others
      • Wash hands for at least 20 seconds after all contact; an alcohol-based hand sanitizer is acceptable if soap and water are not available
      • Not share personal items such as towels, dishes, or utensils before proper cleaning ^c309c310
      • Clean and disinfect regularly ^c311
      • Restrict contact to minimum number of caregivers and, in particular, ensure that persons with underlying medical conditions are not exposed to the patient
      • Improve ventilation, where possible
  • Infection control for COVID-19 managed in health care facilities (outpatient or inpatient) ^r51r231
    • CDC provides preparedness checklists^r232 for outpatient and inpatient health care settings
    • Immediately provide the patient with a face mask to reduce droplet spread and place the patient in a closed room pending further evaluation and disposition decisions. The closed room will ideally be one with structural and engineering safeguards against airborne transmission (eg, negative pressure, frequent air exchange), but in the high-prevalence stages of the pandemic (with crowded hospitals), reserve negative pressure isolation rooms for the greatest needs (ie, aerosol-generating procedures; tuberculosis, measles, and varicella)
    • Persons entering the room should follow standard, contact, and droplet or airborne precautions ^c312c313c314
      • Gloves, gowns, eye protection, and respirator (N95 or better) with adherence to hospital donning and doffing protocols ^c315c316
        • 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) ^c317c318
  • Criteria for discontinuation of isolation precautions ^r51r175
    • 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 observations^r175 showing that duration of shedding of infective virus varies from less than 10 days in milder cases to less than 20 days in more severe infections and in immunocompromised persons
      • Mild symptomatic COVID, no immunocompromise:
        • Isolation may be discontinued 5 days after symptom onset (first day of symptoms is day 0) and
        • At least 24 hours have passed since last fever without use of antipyretics and
        • Symptoms have improved and
        • Patient is able to wear a well-fitted mask for the next 5 days
        • If illness has been entirely asymptomatic, isolation may be discontinued 5 days from first positive specimen if the patient is able to wear a well-fitted mask for the next 5 days
          • If a patient develops symptoms during the 10 days, the 5-day isolation period starts over (with day 0 as the first day of symptoms)
      • Moderate COVID-19, no immunocompromise:
        • Isolate for 10 days
      • Severe or critical illness, no immunocompromising condition:
        • It may be reasonable to extend isolation until 10 days and up to 20 days have passed since symptom onset (day 0) and
        • At least 24 hours have passed since last fever without use of antipyretics and
        • Symptoms have improved
        • Repeat testing before discontinuing isolation may be considered (2 consecutive negative antigen tests at least 48 hours apart)
      • Moderately or severely immunocompromised persons:
        • Continue isolation for 20 days or longer after symptom onset or first positive SARS-CoV-2 test result; a test-based strategy to determine further duration may be appropriate. Infectious disease consultation is recommended
        • For moderately or severely immunocompromised persons who were symptomatic, there should be improvement in symptoms and 24 hours have passed since last fever without use of antipyretics
      • Test-based criteria for discontinuation of isolation include:
        • Negative test results from 2 specimens at least 48 hours apart; polymerase chain reaction or antigen tests are acceptable
          • A nucleic acid amplification test may be used but is frequently positive for days to weeks and does not necessarily correlate with being infectious ^r54