Key Points

• COVID-19 (coronavirus disease 2019) is a systemic infection due to a novel coronavirus, SARS-CoV-2; global pandemic is ongoing
• Infection ranges from asymptomatic to severe; symptoms usually include fever, cough, and (in moderate to severe cases) dyspnea. Disease may evolve over the course of a week or more from mild to severe; deterioration may be sudden and catastrophic
• Infection should be suspected based on presentation with a clinically compatible history (eg, fever, upper or lower respiratory tract symptoms); alterations in senses of smell and taste are particularly suggestive
• Chest imaging in symptomatic patients almost always shows abnormal findings, usually including bilateral infiltrates; laboratory findings are variable but typically include lymphopenia and elevated lactate dehydrogenase and transaminase levels
• Diagnosis is confirmed by detection of viral RNA on polymerase chain reaction test of upper or lower respiratory tract specimens; antigen testing is also available and has near-equivalent specificity but is slightly less sensitive
• Treatments and treatment strategies continue to be refined; available drugs are administered at different stages of disease based on the pharmacologic mechanism of action and the dominant pathophysiology of the disease phase
  • Several antiviral medications are available, including remdesivir, ritonavir-boosted nirmatrelvir, and molnupiravir
  • Monoclonal antibodies including bebtelovimab,^r1sotrovimab,^r2casirivimab-imdevimab,^r3bamlanivimab-etesevimab,^r4r5 and tixagevimab-cilgavimab^r6 have been used for treatment, postexposure prophylaxis, and preexposure prophylaxis, but use depends on susceptibility to circulating variants
  • Dexamethasone also has been associated with significant reduction in mortality rates of patients requiring supplemental oxygen^r7
  • Several immunomodulators are recommended for use in conjunction with corticosteroids with or without remdesivir in patients requiring high-flow oxygen or noninvasive ventilation ^r8
• Most common complications are acute respiratory distress syndrome and septic shock; myocardial, renal, and multiorgan failure are also seen
• A significant proportion of clinically evident cases are severe; the mortality rate among diagnosed cases is generally about 3% but varies by country ^r9r10
• Emerging evidence indicates that COVID-19 infection may predispose to long-term symptoms or future complications, even after mild or asymptomatic disease
• Vaccination is safe and highly effective, particularly against hospitalization and death, even with new variants ^r11

Urgent Action

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

Pitfalls

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

Clinical Clarification

• COVID-19 (coronavirus disease 2019) is a systemic infection (with a predilection for the respiratory system) caused by a newly recognized coronavirus, SARS-CoV-2, thought to have originated as a zoonotic virus that has mutated or otherwise adapted in ways that allow human pathogenicity
  • Disease was provisionally called 2019-nCoV infection at start of outbreak (2019 novel coronavirus infection)
• Outbreak began in China but has since spread globally; it was officially declared by WHO to be a pandemic on March 11, 2020 ^r12
• Illness ranges in severity from asymptomatic or mild to severe; a significant proportion of patients with clinically evident infection develop severe disease, which may be complicated by acute respiratory distress syndrome and shock
  • Mortality rate among diagnosed cases (case fatality rate) is generally about 3% globally but varies by country; true overall mortality rate is uncertain, as the total number of cases (including undiagnosed persons with milder illness) is unknown ^r9r10
• Knowledge of this disease is incomplete and evolving; moreover, coronaviruses are known to mutate and recombine often, presenting an ongoing challenge to our understanding and to clinical management

Classification

• Pathogen is a betacoronavirus, similar to the agents of SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome)
  • Classified as a member of the species Severe acute respiratory syndrome–related coronavirus^r13r14
  • Designated as SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2); earlier provisional name was 2019-nCoV (2019 novel coronavirus) ^r13r14
• Variants
  • Since late 2020, variants with potential impact on transmission, clinical disease, and immune protection have been recognized
  • CDC COVID Data Tracker maintains information about geographical distribution of variants in the United States and globally; at this time, more than 99% of circulating virus in the United States is Omicron variant ^r15
  • CDC classifies them as variants of concern, variants being monitored, or variants of interest; the category of variants of high consequence exists in reserve, in case of future need ^r16
    • Classification is based on potential for increased transmissibility, greater severity of disease, reduction in protective effect of antibodies generated by previous disease or vaccination, reduced efficacy of available treatments or public health countermeasures, or reduced sensitivity of testing modalities
    • Variants of concern
      • Delta (B.1.617.2 and AY lineages): first detected in India; characterized by increased transmissibility and possibly reduced neutralization by some monoclonal antibody treatments and postvaccine serum
      • Omicron (B.1.1.529 and BA lineages): first detected in South Africa; is now essentially the only variant in the United States (since January 2022). Appears to be more easily transmitted than other variants, and has reduced susceptibility to some monoclonal antibody products; efficacy of remdesivir is thought to be undiminished ^r8r15r17
        • Omicron subvariant BA.2 is the dominant strain worldwide and in the United States since mid-February 2022; this subvariant appears to have increased transmissibility, similar severity, and similar susceptibility to antibodies generated by immunization as Omicron subvariant BA.1, the previous most prevalent subvariant ^r15r18
    • Variants being monitored
      • Primary examples are as follows; consult the CDC list for more: ^r16
        • Alpha (B.1.1.7 and Q lineages): appears to have emerged in the United Kingdom; thought to be more easily transmitted and possibly associated with more severe disease than the original strain
        • Beta (B.1.351 and descendent lineages): first noted in South Africa; may confer some resistance to certain vaccines (eg, Moderna mRNA-1273)
        • Gamma (P.1 and descendent lineages): seems to have originated in Brazil; may mitigate the protective effect of antibodies to the original strain
        • Epsilon (B.1.427 and B.1.429): both first detected in California; both associated with slightly increased transmissibility, significant decrease in neutralization effect of some monoclonal antibody treatments, and moderate decrease in neutralization effect of convalescent serum

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 ^r86
  • A strategy has emerged by which drugs are selected according to the mechanism of action most likely to be effective against the dominant pathophysiology at various stages in the disease process. Thus, antivirals and monoclonal antibodies directed at viral components are most effective when used early in the course of infection (to prevent cell entry and viral replication); antiinflammatory drugs (eg, dexamethasone) and immunomodulators are of most benefit during the hyperinflammatory response in later phases of severe disease
  • Given new medications, novel use of existing medications, and the rapid change in guidelines, consulting a drug interaction checker^r87 is advised

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

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

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

• Until a diagnosis of COVID-19 is confirmed by polymerase chain reaction or antigen test, appropriate antimicrobial therapy for other viral pathogens (eg, influenza virus) or bacterial pathogens should be administered in accordance with the severity of clinical disease, site of acquisition (hospital or community), epidemiologic risk factors, and local antimicrobial susceptibility patterns ^r35
• Surviving Sepsis Campaign^r90r91 guideline, NIH COVID-19 treatment^r8 guideline, and WHO guidance^r35 provide recommendations specific to treatment of shock in patients with COVID-19. Management of shock and other complications requiring intensive care are addressed in detail in the Clinical Overview on COVID-19 critical care ^d4

Antiviral agents

• Remdesivir: FDA-approved for treatment of COVID-19 in hospitalized adults and children aged 28 days or older weighing 3 kg or more, and in those with mild to moderate test-positive COVID-19 who are not hospitalized but who are at high risk for progression to severe disease ^r92r93r94
  • Preliminary^r95 and follow-up^r96 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^r97
  • On the basis of these and other data from clinical trials, the NIH guideline recommends, and the Infectious Diseases Society of America and Surviving Sepsis Campaign guidelines suggest, remdesivir for hospitalized patients with COVID-19 who require supplemental oxygen ^r8r90r91r98
    • In patients who require oxygen via high-flow device or noninvasive ventilation, NIH offers the option of remdesivir with dexamethasone or dexamethasone alone, because remdesivir appears to confer maximum benefit before onset of more severe disease, in which dexamethasone alone is associated with markedly reduced mortality
    • NIH recommends against use of remdesivir in patients who require mechanical ventilation or extracorporeal membrane oxygenation, and both Infectious Diseases Society of America and Surviving Sepsis Campaign guideline suggests that remdesivir not be used in patients with critical COVID-19
    • For patients whose condition worsens while they are receiving remdesivir and who require institution of high-flow oxygen, ventilation, or extracorporeal membrane oxygenation, NIH recommends that the treatment course be completed
    • For hospitalized patients with no current oxygen requirement, NIH guidelines suggest consideration of remdesivir for patients at high risk of disease progression, and Infectious Diseases Society of America guidelines suggest use of remdesivir (3-day course)
  • Infectious Diseases Society of America suggests, and NIH recommends, use of remdesivir in ambulatory patients with mild to moderate COVID-19 who are at high risk for progression to severe disease, to be initiated within 7 days of symptom onset ^r8r98
    • For this patient population, NIH guidelines prefer use of ritonavir-boosted nirmatrelvir, when available
    • In a randomized placebo controlled trial of 562 nonhospitalized patients with COVID-19, a 3-day course of remdesivir was associated with an 87% reduction in risk of hospitalization or death ^r99
  • WHO suggests against remdesivir use outside of clinical trials ^r100
  • Evidence base: remdesivir has significant in vitro activity against coronaviruses,^r101r102 evidence of efficacy in an animal model of MERS,^r101 and evidence of efficacy in COVID-19^r96
• Ritonavir-boosted nirmatrelvir has received emergency use authorization in the United States for treatment of nonhospitalized persons aged 12 years or older and weighing 40 kg or more who test positive for COVID-19, who are at high risk for progressing to severe disease, and for whom alternative treatments are not available or not clinically appropriate ^r103
  • Ritonavir-boosted nirmatrelvir was studied in a randomized placebo-controlled trial of 2246 patients with documented COVID-19 who met criteria for high risk of progression to severe disease. The primary end point was COVID-19–related hospitalization or death from any cause within 28 days. The relative risk reduction in patients who received the study drug was 88% ^r103
    • Ritonavir-boosted nirmatrelvir is associated with numerous potential drug interactions
      • Patients with HIV taking a ritonavir- or cobicistat- based antiretroviral regimen should continue to take their antiretroviral regimen as prescribed during ritonavir-boosted nirmatrelvir treatment ^r104
  • NIH recommends and Infectious Diseases Society of America suggests use of ritonavir-boosted nirmatrelvir in ambulatory patients with mild or moderate COVID-19 at high risk for progression to severe disease, to be initiated within 5 days of symptom onset ^r98
• Molnupiravir, another oral antiviral agent, has emergency use authorization in the United States for treatment of nonhospitalized adults positive for COVID-19 who are at high risk of progression to severe disease, and for whom alternative treatments are not available or not clinically appropriate ^r105
  • Molnupiravir was compared with placebo in a randomized trial of 1433 patients with mild to moderate COVID-19 who met criteria for high risk of progression to severe disease. The primary end point was all-cause hospitalization or death through day 29. The relative risk reduction was 30%
    • Molnupiravir is not recommended during pregnancy or breastfeeding; before prescribing to persons of childbearing potential, test for pregnancy and (including for biologic males) ensure reliable contraception through treatment and for 4 days (females) or 3 months (males) after the last dose. Breast milk should be discarded during treatment and for 4 days after the last dose ^r105
  • Mechanism of action of molnupiravir is inducing lethal viral mutations; concerns have arisen regarding emergence of resistance and emergence of new variants as a result. Use of molnupiravir should be accompanied with robust pharmacovigilance ^r100
  • Infectious Diseases Society of America suggests use of molnupiravir in ambulatory adults (aged 18 years or older) with mild to moderate COVID-19 at high risk for progression to severe disease who have no other treatment options (eg, nirmatrelvir-ritonavir or remdesivir), to be initiated within 5 days of symptom onset, rather than no molnupiravir ^r98
  • Similarly, NIH recommends use of molnupiravir (or bebtelovimab) in ambulatory adults at high risk of progression to severe disease ONLY when ritonavir-boosted nirmatrelvir and remdesivir are unavailable, because it has lower efficacy than the preferred treatments ^r8
  • WHO suggests use of molnupiravir for adults with nonsevere disease at highest risk of hospitalization; alternative treatments may be preferable where available

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

• Emergency use authorizations have been issued in the United States for several monoclonal antibody products: bamlanivimab-etesevimab^r4r5 in combination, casirivimab-imdevimab^r3r106 in combination, sotrovimab,^r107r2bebtelovimab,^r1 and tixagevimab-cilgavimab^r6 in combination. Given the predominance of the Omicron variant in the United States and the lack of activity of bamlanivimab-etesevimab, casirivimab-imdevimab, or sotrovimab against specific Omicron subvariants, FDA has modified the emergency use authorizations for these monoclonal antibodies to state that they are not authorized for use in regions where infection is likely to be caused by a nonsusceptible strain,^r108r109 effectively suspending their use in the United States
  • These authorizations apply to patients aged 12 years or older, weighing 40 kg or more, who have mild to moderate disease and who are at high risk (by virtue of older age or concomitant conditions) for progression to severe disease and/or hospital admission; the authorizations exclude persons who are already hospitalized for COVID-19 or who require supplemental oxygen for COVID-19. The emergency use authorizations list recognized criteria for high risk of progression; updated guidance notes that risk is not limited to these conditions:
    • BMI of 25 or higher (for ages 12 to 17 years, BMI in 85th percentile or higher)
    • Chronic kidney disease
    • Diabetes
    • Pregnancy
    • Immunosuppression due to disease or treatment
    • Sickle cell disease
    • Chronic lung disease (eg, chronic obstructive pulmonary disease, moderate to severe asthma, interstitial lung disease, cystic fibrosis, pulmonary hypertension)
    • Cardiovascular disease (including congenital heart disease) or hypertension
    • Neurodevelopmental disorders
    • Dependence on a medical technology such as tracheostomy, gastrostomy, or positive pressure ventilation
    • Older age (ie, 65 years or older)
  • Infectious Diseases Society of America guideline^r98 suggests use of monoclonal antibodies in ambulatory patients who are at high risk of progression to severe COVID-19, with selection of the most appropriate agent based on known activity against predominant circulating variants
• Distribution of monoclonal antibodies is currently coordinated through state/territorial health departments, based on circulating variants, case burden, and product utilization rates ^r8r110r111
• In areas with logistical constraints, administration to all eligible persons may not be possible ^r8
  • Prioritize treatment of COVID-19 over postexposure prophylaxis
  • Prioritize treatment of persons at high risk of progression to severe disease who are not fully vaccinated, and vaccinated persons who may not have an adequate immune response, over fully vaccinated persons who are expected to have adequate immune response to immunization
• Tixagevimab and cilgavimab are monoclonal antibodies which block spike protein attachment, binding to 2 different regions of the receptor-binding domain of the spike protein
  • FDA granted an EUA in December 2021 for preexposure prophylaxis in adults and children aged 12 years or older weighing at least 40 kg who have moderate to severe immunocompromise or who are unable to be immunized owing to severe allergic reaction ^r6
  • Based on decreased susceptibility of BA.1 and BA.1.1 subvariants of Omicron variant to this combination, the recommended dose was increased on February 24, 2022
    • Those who received the original dose of 150 mg each should receive a second dose of 150 mg each as soon as possible
  • Infectious Diseases Society of America suggests use and NIH recommends use of tixagevimab-cilgavimab as preexposure prophylaxis in adults and adolescents who have moderate to severe immunocompromise or who are unable to be fully immunized owing to documented severe allergy
• Bebtelovimab is a recombinant neutralizing human monoclonal antibody that binds to the spike protein of SARS-CoV-2 (including the Omicron variant), preventing its attachment to the ACE2 receptor (for angiotensin-converting enzyme 2) ^r1
  • Limited clinical data indicate a reduction in viral load in treated patients and improvement in symptoms; the emergency use authorization issued by FDA on February 11, 2022 states that "based on the totality of evidence available … it is reasonable to believe that bebtelovimab may be effective for the treatment of patients with mild-to-moderate COVID-19 to reduce the risk of progression to hospitalization or death"
  • NIH recommends use of bebtelovimab (or molnupiravir) in ambulatory adults at high risk of progression to severe disease only when ritonavir-boosted nirmatrelvir and remdesivir are unavailable or not clinically feasible ^r8
  • Infectious Diseases Society of America guideline recommends use of bebtelovimab only in clinical trials, owing to lack of data
• Sotrovimab targets a highly conserved region in the receptor-binding domain of the SARS-CoV-2 spike protein ^r2
  • Interim data from the ongoing COMET-ICE clinical trial show that in 583 patients with symptomatic COVID-19 and at least 1 comorbidity or age-related risk factor for progressing to severe disease who were randomized to receive sotrovimab or placebo, the risk of progression to severe disease was 85% lower in the sotrovimab arm ^r2
    • Although sotrovimab is active against the Omicron BA.1 and BA.1.1 subvariants, it has substantially decreased in vitro activity against the Omicron BA.2 subvariant, and as of April 5, 2022, it is no longer authorized by FDA for use in the United States ^r2r8r108
  • NIH guidelines no longer recommend using sotrovimab, bamlanivimab-etesevimab, or casirivimab-imdevimab, owing to their ineffectiveness against the prevailing Omicron variant/subvariants in the United States ^r8
  • WHO suggests treatment with sotrovimab for those at highest risk of hospitalization ^r100
    • Benefit of use is unclear for patients with severe or critical illness who are seronegative; use depends on availability of rapid and accurate antibody testing before treatment
• Bamlanivimab and etesevimab are monoclonal antibodies designed to target the SARS-CoV-2 spike protein, disabling viral attachment and entry into human cells; the 2 antibodies target different regions of the spike protein ^r5
  • Preliminary data from clinical trials on bamlanivimab (before emergence of Omicron variant) demonstrated a reduction in the incidence of COVID-19–associated emergency department visits and hospital admissions (3% for patients treated with bamlanivimab versus 10% for patients who received placebo) ^r4
    • A subsequent trial (BLAZE-1) of bamlanivimab in combination with etesevimab showed a 70% reduction in COVID-19–related hospitalization or death by any cause ^r4
  • Based on these data, FDA issued emergency use authorizations; however, the emergency use authorization for bamlanivimab alone was since revoked because virus variant prevalence reduced its effectiveness, and similarly, for bamlanivimab in combination with etesevimab, the emergency use authorization has subsequently been revised to preclude use when infection is likely to be caused by a nonsusceptible variant, such as Omicron ^r4
    • Bamlanivimab and etesevimab, even in combination, appear to have reduced in vitro activity against a number of circulating variants: beta (eg, B.1.351), gamma (eg, P.1), epsilon (ie, B.1.427 or B.1.429), eta (eg, B.1.526) and Omicron (eg, B.1.1. 529), which has become the dominant circulating variant in the United States ^r4r112
• Casirivimab-imdevimab^r8r106
  • This combination appears to have reduced activity against the Omicron variant prevalent in late 2021 and early 2022; the emergency use authorization was modified on January 24, 2022, to preclude use of this product when infection is likely to be caused by a nonsusceptible variant such as Omicron, which is now the prevailing variant in the United States ^r3
  • Similarly, with Omicron predominating worldwide, WHO no longer recommends use of casirivimab-imdevimab except in cases where rapid genotyping confirms infection with a variant that is susceptible ^r100
  • Data on efficacy against susceptible variants
    • Preliminary clinical studies (conducted before emergence of Omicron variant) evaluated effect on viral load and on medically attended illness. In a placebo-controlled trial of 799 patients with mild to moderate COVID-19, reduction in viral load in days 1 through 7 was significantly greater for the monoclonal antibody combination compared with placebo (P < .0001). Treatment was also associated with fewer emergency department visits and hospital admissions (2.8% for patients treated with casirivimab-imdevimab versus 6.5% for those who received placebo) ^r3
      • An updated statement from the manufacturer includes data from 4567 patients with at least 1 risk factor for severe COVID-19, randomized to 2 different doses (either 600 mg or 1200 mg of each component) or placebo. The 2 doses resulted in a 70% and 71% reduction in risk for hospitalization ^r3
      • Data submitted with the updated statement indicated efficacy against the major variants circulating as of June 2021, but Omicron subvariants in 2022 have defeated this efficacy ^r3
    • In a phase 3 trial of nonhospitalized patients with COVID-19, patients randomized to casirivimab-imdevimab treatment had a lower risk of hospitalization and of death, and had faster resolution of symptoms, than those randomized to placebo. Relative risk reduction of hospitalization plus death was 71.3% in the group that received a 2400-mg dose, and was 70.4% in those who received the 1200-mg dose ^r113

Immunomodulators are also being investigated for mitigation of cytokine release syndrome believed to be a factor in severe acute respiratory distress syndrome and shock in COVID-19 (eg, monoclonal antibodies against interleukin-6 receptors, such as tocilizumab^r114 and sarilumab^r115; Janus kinase inhibitors such as baricitinib^r116 and tofacitinib^r117)

• Baricitinib (a Janus kinase inhibitor)
  • Baricitinib is FDA-approved for the treatment of COVID-19 in hospitalized adults requiring supplemental oxygen, noninvasive or invasive mechanical ventilation, or extracorporeal membrane oxygenation ^r118
    • FDA reviewed data from the ACTT-2 trial (Adaptive COVID-19 Treatment Trial 2), which compared remdesivir plus baricitinib (515 patients) against remdesivir plus placebo (518 patients) in patients with documented SARS-CoV-2 infection and either pulmonary infiltrates, oxygen saturation less than 94%, or requirement for some degree of oxygen supplementation. Patients who received baricitinib were more likely to have better clinical status (based on an 8-point score) at day 15 than those who did not. Median time to recovery was 7 days in the baricitinib group versus 8 days in the placebo group. The odds of dying or progressing to noninvasive/high-flow oxygen or invasive ventilation were significantly lower for patients in the baricitinib group ^r119r120
    • In another phase 3 randomized trial of hospitalized adults with documented SARS-CoV-2 infection, pneumonia or active and symptomatic COVID-19, and at least 1 elevated inflammatory marker who were receiving standard of care, including corticosteroids and/or antivirals, there was no significant difference in disease progression (defined as progression to high-flow oxygen, noninvasive mechanical ventilation, invasive mechanical ventilation, or death) with baricitinib (764 patients) versus placebo (761 patients). However, the 28-day all-cause mortality was significantly lower in patients treated with baricitinib (8%) compared to placebo (13%), a 38.2% relative reduction in mortality. ^r121
    • NIH guidelines recommend use of baricitinib (or tocilizumab) with dexamethasone alone or with remdesivir and dexamethasone in recently hospitalized patients on high-flow oxygen or noninvasive ventilation who have clinical or laboratory evidence of progressive disease (eg, increasing oxygen needs, increasing inflammatory markers) ^r8
      • Guideline recommends against giving tocilizumab or other IL-6 inhibitors to patients on baricitinib
      • There is insufficient evidence to recommend baricitinib over tocilizumab or vice versa
    • Infectious Diseases Society of America guidelines suggest use of baricitinib in hospitalized patients with severe COVID-19 along with corticosteroids (unless contraindicated) or remdesivir in patients who cannot receive a corticosteroid ^r98
      • Patients receiving baricitinib should not receive tocilizumab or other IL-6 inhibitors
      • Some data suggest a reduction in mortality even in patients who require mechanical ventilation
    • WHO guideline strongly recommends baricitinib for patients with severe or critical disease; choice of baricitinib versus IL-6 blockers should be based on clinical factors and availability ^r100
• Tocilizumab (monoclonal IL-6 receptor blocker)
  • NIH guidelines recommend use of tocilizumab in 2 situations, as follows: ^r8
    • Use tocilizumab (or baricitinib) with dexamethasone alone or with remdesivir and dexamethasone in recently hospitalized patients on high-flow oxygen or noninvasive ventilation who have clinical or laboratory evidence of progressive disease (eg, increasing oxygen needs, increasing inflammatory markers)
      • There is insufficient evidence to recommend tocilizumab over baricitinib or vice versa
    • Use tocilizumab with dexamethasone within 24 hours of admission to ICU for patients requiring mechanical ventilation or extracorporeal membrane oxygenation
    • In patients receiving supplemental oxygen, the guideline panel found insufficient evidence to determine whether adding tocilizumab to dexamethasone is of benefit; they recommend tocilizumab plus remdesivir for such patients when corticosteroids cannot be used
    • Guideline recommends against giving baricitinib to patients on tocilizumab
    • A systematic review and meta-analysis of retrospective trials with data from 240 patients who received tocilizumab and 352 controls concluded that the low-quality evidence available did not demonstrate clear benefit from tocilizumab ^r122
    • A review of data from 5 randomized controlled trials comparing tocilizumab to usual care (with or without placebo) did not show a 28-day mortality benefit, but it did show a lower relative risk of clinical deterioration (ie, ICU admission, mechanical ventilation, death), although evidence was of low certainty ^r98
    • REMAP-CAP and RECOVERY trials both indicate a mortality benefit for tocilizumab among patients who experienced rapid respiratory decompensation and were recently admitted to the ICU, and the RECOVERY trial showed benefit in those who require high-flow oxygen or noninvasive ventilation ^r123r124
  • In patients admitted to hospital with COVID-19, Infectious Diseases Society of America suggest tocilizumab in addition to standard care (steroids) for patients with progressive severe or critical COVID-19 who have elevated levels of markers of systemic inflammation ^r98
  • WHO guidelines recommend use of tocilizumab (or sarilumab) for patients with severe or critical COVID-19, along with corticosteroids ^r100
• Sarilumab (monoclonal IL-6 receptor blocker)
  • NIH guidelines recommend use of sarilumab only when baricitinib and tocilizumab are unavailable for recently hospitalized patients on high-flow oxygen or noninvasive ventilation who have clinical or laboratory evidence of progressive disease (eg, increasing oxygen needs, increasing inflammatory markers), along with dexamethasone or dexamethasone plus remdesivir ^r8
  • WHO guidelines recommend use of sarilumab (or tocilizumab) for patients with severe or critical COVID-19, along with corticosteroids ^r100
  • REMAP-CAP trial found that sarilumab plus dexamethasone was noninferior to tocilizumab plus dexamethasone, but the evidence for the use of tocilizumab is more extensive ^r8r123
• Tofacitinib (a Janus kinase inhibitor)
  • Infectious Diseases Society of America guidelines suggest use of tofacitinib in hospitalized patients with severe but noncritical COVID-19 (ie, not on mechanical ventilation), along with remdesivir and corticosteroids (unless contraindicated)
    • Patients should also receive at least prophylactic dose of anticoagulant
    • Patients receiving tofacitinib should not receive tocilizumab or other IL-6 inhibitors
  • NIH guidelines recommend use of tofacitinib only when baricitinib and tocilizumab are unavailable for recently hospitalized patients on high-flow oxygen or noninvasive ventilation who have clinical or laboratory evidence of progressive disease (eg, increasing oxygen needs, increasing inflammatory markers), along with dexamethasone or dexamethasone plus remdesivir
  • WHO guideline suggests against use of tofacitinib or ruxolitinib (another Janus kinase inhibitor) unless baricitinib, tocilizumab and sarilumab are unavailable ^r100
• Surviving Sepsis Campaign guideline on managing critically ill adults with COVID-19 does not address immunomodulators ^r90r91
• Monoclonal antibodies against GM-CSF (granulocyte-macrophage colony-stimulating factor), such as lenzilumab, mavrilimumab, namilumab, gimsilumab, and otilimab, are under investigation and are not currently recommended under any guidelines ^r8r98

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

• A randomized controlled trial in more than 6000 hospitalized patients with COVID-19 found that dexamethasone reduced deaths in patients with severe respiratory complications requiring supplemental oxygen ^r7r125
  • Compared with usual care alone, deaths in ventilated patients receiving usual care plus dexamethasone were reduced by a third; among patients receiving oxygen without mechanical ventilation, deaths were cut by 20%
  • Overall 28-day mortality was reduced by 17% in the dexamethasone group
• A smaller study comparing standard care with and without a 3-day course of methylprednisolone early in the disease course showed an association between corticosteroid use and a reduction in the 3 components of the composite end point: transfer to ICU, need for mechanical ventilation, and mortality. Guidelines do not currently support administration of steroids early in the disease course ^r126
• Based on these data, NIH COVID-19 treatment guideline recommends use of dexamethasone in any hospitalized patient who requires supplemental oxygen, and recommends against use of dexamethasone in patients who do not require oxygen supplementation ^r8
  • In the absence of dexamethasone, another glucocorticoid (eg, prednisone, methylprednisolone, hydrocortisone) may be used
• Similarly, Infectious Diseases Society of America guideline suggests use of dexamethasone in hospitalized patients with severe illness, and recommends use in those with critical illness ^r98
  • Infectious Diseases Society of America suggests against the use of steroids in patients who have no oxygen requirement, and suggests against the use of inhaled steroids in ambulatory patients with mild to moderate disease
  • Guideline provides equivalent doses of alternative glucocorticoids if dexamethasone is unavailable
• Surviving Sepsis Campaign guideline on managing critically ill adults with COVID-19 strongly recommends using corticosteroids (preferably dexamethasone) for up to 10 days in patients with severe or critical COVID-19 ^r90r91
• WHO recommends use in patients with severe and critical COVID-19, and suggests against use in patients with nonsevere COVID-19 ^r35r100

Antithrombotic Therapy

• COVID-19 is associated with inflammation and prothrombotic state, including macrovascular and microvascular thromboembolism in both the venous and arterial vessels, as well as disseminated intravascular coagulation ^{r8r91r127r128r129r130r131}
• The most current guidelines to address antithrombotic therapy are the NIH, American Society of Hematology, and CHEST (American College of Chest Physicians) guidelines. Recommendations are summarized below: ^r8r130r131
  • NIH guideline recommends prophylactic dose heparin for hospitalized adults, including pregnant patients, without evidence of venous thromboembolism; CHEST guideline suggests therapeutic dose heparin with careful balance of the risk of thrombosis and the risk of bleeding
  • Therapeutic-dose heparin is recommended for hospitalized nonpregnant patients requiring oxygen who have elevated D-dimer levels (NIH guideline) or other indicators of increased risk of thrombosis (CHEST guideline), if they do not have increased risk of bleeding; there is insufficient evidence in pregnant patients
  • Prophylactic-dose heparin is recommended in both guidelines for patients in the ICU, including switching from therapeutic to prophylactic dose in patients transferred to an ICU unless a thrombosis has been documented
  • Standard therapeutic treatment is recommended for patients with COVID-19 and thromboembolism (highly suspected or proven), and for those on extracorporeal membrane oxygenation or continuous renal replacement therapy or who have thrombosis related to catheters or extracorporeal filters
  • Prophylactic therapy is not recommended for nonhospitalized patients, and guidelines also recommend against continuing prophylactic therapy following hospitalization in patients without thromboembolic disease
    • Based on additional evidence, the American Society of Hematology also now recommends against posthospitalization thromboprophylaxis ^r132
  • Generally low molecular weight heparin is preferred over unfractionated heparin, and heparin is preferred over oral anticoagulants
  • Risk of bleeding is increased in the following situations:
    • Bleeding within the past 30 days that required an emergency department visit or hospitalization, or gastrointestinal bleeding within the past 3 months
    • History of inherited or acquired bleeding disorder
    • Thrombolysis within the past 7 days or major surgery within the past 14 days
    • Platelet count less than 50 × 10⁹ cells/L; hemoglobin level less than 8 g/dL; or baseline INR more than 2 or activated partial thromboplastin time more than 50 seconds
    • Dual antiplatelet therapy
    • Ischemic stroke, intracranial hemorrhage, or intracranial malignancy
    • Uncontrolled hypertension (systolic more than 200 mm Hg or diastolic more than 120 mm Hg)
    • Presence of epidural or spinal catheter
  • Risk of thrombosis is increased in those with elevated D-dimer levels, prior venous thromboembolism, or additional known risk factors for venous thromboembolism
• American Society of Hematology guideline also recommends anticoagulation for hospitalized patients and for patients in intensive care; however, this guideline is expected to be revised with additional information from trials comparing prophylactic dose, intermediate dose, and therapeutic dose ^r127r132

Convalescent plasma continues to be investigated; only high-titer formulations have shown any 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 ^r98
• Surviving Sepsis Campaign guideline on managing critically ill adults with COVID-19 suggests that convalescent plasma not be used outside of clinical trials ^r91
• NIH COVID-19 treatment guideline recommends against use of convalescent plasma in most situations, except in a clinical trial, and recommends against use of convalescent plasma that was collected before the emergence of the Omicron variant ^r8
  • There is insufficient evidence to recommend for or against use of convalescent plasma that was collected after the emergence of the Omicron variant (in hospitalized patients with impaired immunity, or nonhospitalized patients)
• WHO strongly recommends against use of convalescent plasma in nonsevere disease, and recommends against use in severe or critical disease outside of a clinical trial ^r100
• FDA has issued and revised an emergency use authorization, citing, among other reasons, the observational safety and efficacy data from 20,000 patients who received convalescent plasma through a program sponsored by the Mayo Clinic: ^r134r135
  • Serious adverse events were uncommon, and they were judged not to exceed the known incidence in transfusion of plasma to critically ill patients
  • There was some evidence of improved survival in the subset of patients treated with convalescent plasma containing higher titers of neutralizing antibody compared with patients who received plasma with lower levels (ie, there appeared to be a dose-response gradient)
    • Expanded access use focuses on high-titer product used in patients with immunosuppressive disease or receiving immunosuppressive treatment
  • Early administration (eg, before mechanical ventilation is required) appeared more likely to be beneficial, but the possibility of benefit even to intubated patients could not be excluded

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

• NIH guidelines recommend that patients taking ACE inhibitors, angiotensin receptor blockers, statin drugs, NSAIDs, corticosteroids (oral, inhaled, or intranasal), and acid suppressive drugs for underlying medical conditions should not discontinue these medications ^r8r137r138
• In addition, none of the above classes of medications should be started for the purpose of treatment or prevention of COVID-19, except as noted above for corticosteroid treatment
• Infectious Diseases Society of America guidelines similarly do not recommend initiating or discontinuing any of the above medications for treatment or prevention of COVID-19 ^r98

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

• Interim results of the WHO SOLIDARITY trial have been published. Remdesivir, lopinavir-ritonavir, hydroxychloroquine, and interferon were compared with one another (open-label) and with standard care (no placebo) in a total population of over 11,000 patients in over 400 hospitals in 30 countries worldwide ^r139
  • End points were in-hospital mortality, initiation of ventilation, and duration of hospital stay. No differences among the groups were noted for any of these parameters. The authors acknowledge that length of stay may have been influenced in some cases by the requirements of antiviral administration (eg, 10 days of IV administration for remdesivir), but they argue that the similarity in percentages of patients in each group remaining in the hospital beyond the course of the study drug indicates a lack of benefit to any treatment arm
• Lopinavir-ritonavir is FDA-approved for treatment of HIV infection. It has been used in China in conjunction with interferon alfa for treatment of some patients with COVID-19, but reported results have been disappointing
  • 3 randomized placebo-controlled trials have evaluated the effects of lopinavir-ritonavir in the treatment of COVID-19. The combined data^r98 did not show significant differences in progression to mechanical ventilation or mortality
  • NIH COVID-19 treatment^r8 guideline, Infectious Diseases Society of America guideline on treatment and management of COVID-19,^r98 and Surviving Sepsis Campaign guideline on managing critically ill adults with COVID-19^r91 recommend against use of lopinavir-ritonavir
  • Surviving Sepsis Campaign guideline on managing critically ill adults with COVID-19 recommends against use of recombinant interferons, based on lack of data in COVID-19 and on data from studies on MERS showing lack of efficacy ^r90r91
  • WHO recommends against use of lopinavir-ritonavir outside of a clinical trial ^r100
• Ivermectin, an antiparasitic drug with some activity against viruses, has been proposed for COVID-19 treatment or prevention
  • Infectious Diseases Society of America and WHO guidelines suggest against use of ivermectin, and NIH guidelines recommend against use, outside clinical trials ^r8r98r100
  • CDC issued a health advisory warning clinicians that ivermectin is not approved by FDA for treatment of COVID-19 and that adverse effects from the use and misuse of ivermectin are increasing ^r140
  • FDA issued a consumer update warning the public against use of ivermectin, particularly medications meant for animal use ^r141
• Chloroquine and hydroxychloroquine: letters reporting favorable results in China and South Korea early in the pandemic^r142 suggested promise, leading to an emergency use authorization by FDA in the United States. Subsequent studies have found no significant benefit, but they highlighted the risk of QT prolongation and cardiac arrhythmias. As a result, FDA emergency use authorization was withdrawn,^r143 although some clinical trial use may still be in progress
  • Azithromycin has been used in combination with hydroxychloroquine in some protocols; however, azithromycin is also associated with cardiac arrhythmias, and the possible increased risk posed by the combination must be considered ^r144
    • Scoring systems are available to determine risk of arrhythmia ^r145r146
  • A systematic review and meta-analysis of studies comparing standard care with and without hydroxychloroquine included 6 studies comprising 1331 patients. There was no difference in mortality between the 2 groups, although a subgroup receiving hydroxychloroquine plus azithromycin experienced significantly higher mortality than the standard care group ^r147
  • A subsequently published randomized controlled open-label trial (RECOVERY) of 1561 patients treated with hydroxychloroquine and 3155 treated without showed no survival advantage among patients treated with hydroxychloroquine ^r148
  • Infectious Diseases Society of America, NIH, and WHO guidelines all recommend against using hydroxychloroquine, with or without azithromycin, and the Surviving Sepsis guideline recommends against using hydroxychloroquine (but does not mention azithromycin) ^r8r91r98r100

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^r170 into the course of illness and may be quite abrupt ^r169c283
• In hospitalized patients with confirmed COVID-19, repeated testing may be done to document clearance of virus, defined as 2 consecutive negative results on polymerase chain reaction tests at least 24 hours apart ^r171c284

Complications

• Most common complication is acute respiratory distress syndrome; other reported complications include: ^r21r22c285d5
  • Septic shock ^c286d2
  • Acute kidney injury ^c287d6
  • Myocardial injury ^c288d7
  • Secondary bacterial and fungal infections ^c289c290
  • Multiorgan failure ^c291
  • Thrombotic events ^{r129c292c293c294}
  • Guillain-Barré syndrome ^r172c295
• MIS-C (multisystem inflammatory syndrome in children) has been associated with recent diagnosis of or exposure to COVID-19. A number of young adults^r176 have also been reported with similar clinical findings and recent history of diagnosed COVID-19 or serologic evidence of recent infection, termed MIS-A (multisystem inflammatory syndrome in adults) ^{r173r174r175c296}
  • Characteristic features in children include: ^r174r177
    • Persistent fever ^c297
    • Hypotension, syncope, confusion ^{c298c299c300c301}
    • Headache ^c302
    • Sore throat, neck swelling ^{c303c304c305c306c307}
    • Cough, hypoxemia ^c308
    • Abdominal pain, vomiting, diarrhea ^{c309c310c311c312}
    • Rash, conjunctival injection, mucosal inflammation ^{c313c314c315c316c317}
    • Swelling of hands and feet ^c318
    • Lymphadenopathy ^c319c320c321
    • Laboratory markers of inflammation (eg, elevated erythrocyte sedimentation rate; elevated levels of C-reactive protein, ferritin, D-dimer, fibrinogen, procalcitonin, lactate dehydrogenase, interleukin-6, and interleukin-10; low level of serum albumin) ^c322c323c324
    • Abnormal blood cell counts: anemia, thrombocytopenia, neutrophilia ^{c325c326c327c328c329}
    • Indicators of multiorgan involvement: increased levels of creatinine, BUN, urine protein, transaminases, creatine kinase, troponins, and lactate dehydrogenase ^c330
    • Imaging
      • Chest radiograph or CT scan: bilateral patchy pulmonary infiltrates, pleural effusions
      • Echocardiogram: pericardial effusion, myocardial dysfunction, valvulitis, coronary artery dilatation
      • Abdominal ultrasonography: ascites, colitis, ileitis, hepatosplenomegaly, lymphadenopathy
  • In a systematic review covering 221 adults with MIS-A, the age range was 19 to 34 years; 70% were male; and Black and Hispanic people were disproportionately affected ^r178
    • Common features included fever, hypotension, cardiac dysfunction, shortness of breath, and diarrhea, along with laboratory evidence of coagulopathy and/or inflammation
    • Median number of organ systems involved was 5
    • Most patients (57%) required ICU care, and 7% died
  • Diagnosis is based on clinical presentation and absence of an alternative explanation; CDC^r174 and WHO^r179 provide case definitions for reporting
    • CDC MIS-C case definition: a person younger than 21 years with fever, laboratory evidence of inflammation (see above), and clinically severe illness requiring hospitalization, with involvement of 2 or more organ systems; plus no alternative diagnosis; plus current or recent COVID-19 or exposure within the past 4 weeks ^r174
      • Patients may meet partial or full criteria for Kawasaki disease but regardless should be reported if they meet case definition of MIS-C ^d8
    • CDC MIS-A case definition: a person aged 21 years or older with hospitalization for 24 hours or more, or an illness resulting in death, with clinical and laboratory criteria below, and with no alternative diagnosis: ^r175
      • Clinical: fever and at least 3 of the following criteria before hospitalization or within the first 3 days of hospitalization, including at least 1 primary criterion
        • Primary: severe cardiac illness (eg, myocarditis, pericarditis, coronary artery aneurysm, new-onset ventricular dysfunction, new-onset second- or third-degree atrioventricular block, new-onset ventricular tachycardia); rash and nonpurulent conjunctivitis
        • Secondary: new-onset neurologic dysfunction (eg, seizures, encephalopathy, meningeal signs, peripheral neuropathy, Guillain-Barré syndrome); shock or hypotension not attributable to medical treatment; abdominal pain, vomiting, or diarrhea; thrombocytopenia with count less than 150,000 cells/mm³
      • Laboratory: at least 2 of the following markers are elevated: C-reactive protein, ferritin, interleukin-6, erythrocyte sedimentation rate, procalcitonin; plus positive polymerase chain reaction, antigen, or serology test result for COVID-19
  • It may be difficult to distinguish this syndrome from Kawasaki disease or toxic shock syndrome; bacterial sepsis must also be considered and appropriate cultures obtained (including blood cultures) ^d9
  • Several professional organizations provide guidance on management ^r8r177r180
    • Cardiac (telemetry) and blood pressure monitoring; continuous pulse oximetry
    • Prompt ECG and echocardiogram, with serial follow-up studies
    • Close clinical and laboratory monitoring for progressive inflammation and cardiac involvement, including levels of C-reactive protein, troponins, and B-type natriuretic peptide
    • Empiric antibiotic coverage pending culture results
    • Hospitalized children and those who fulfill criteria for Kawasaki Disease should be treated with immunomodulatory and antithrombotic therapy ^d10
      • First line treatment is IV immunoglobulin 2 g/kg (based on ideal body weight) and glucocorticoids
        • Volume associated with IV immunoglobulin requires careful monitoring in patients with cardiac dysfunction
        • Anakinra, infliximab, or higher-dose glucocorticoids should be given to those who do not respond after initial therapy
          • Unlike in Kawasaki disease, a second dose of IV immunoglobulin is not recommended in refractory disease, owing to risk of volume overload and hemolytic anemia
      • Low dose aspirin (3-5 mg/kg/day) for all patients without risk factors for bleeding, continued for at least 4 weeks until normal coronary arteries and normal platelet count are confirmed
      • In addition to aspirin, therapeutic anticoagulation should be given to patients with large coronary artery aneurysms, documented thrombosis, or moderate to severe left ventricular dysfunction (ejection fraction less than 35%) without risk factors for bleeding
      • Prophylactic or therapeutic anticoagulation should also be considered according to increased risk for thrombosis (eg, indwelling catheterization, age older than 12 years, malignancy, ICU admission, elevated D-dimer level)
    • Treatment for MIS-A has primarily been extrapolated from treatment of MIS-C

Prognosis

• Although most people with COVID-19 have mild to moderate disease, up to 20% may have severe illness (estimated 14%) or critical illness (estimated 5%) ^r23r181
  • Risk of severe or critical illness depends on age, underlying comorbidities, and vaccination status ^r23r57r181
  • Patients who require hospital admission often require prolonged inpatient stay (more than 20 days) and experience significant deconditioning ^r21r22
  • Risk scoring systems continue to be developed and revised at many institutions, in the effort to improve prediction of disease progression (to severe or critical illness), mortality, or both (with those concepts being correlated). To date no single scoring system has emerged as dominant in clinical use across institutions ^r182
• Infection fatality ratio (proportion of deaths among all who are infected, including confirmed cases, undiagnosed cases, and unreported cases) varies across global locations, but has been estimated as 0.15% ^r183
  • CDC currently estimates the infection fatality ratio by age as follows: ^r184
    • 0 to 17 years: 0.002%
    • 18 to 49 years: 0.05%
    • 50 to 64 years: 0.6%
    • 65 years and older: 9%
• Mortality rate of diagnosed cases is generally about 3% but varies by country ^r9r10
  • Case fatality rates (proportion of deaths among detected cases; subject to selection bias owing to higher testing in hospitalized cases)
    • These rates are higher for patients in older age groups and with certain comorbidities
    • Case fatality rates by age in the United States: ^r53
      • 10% to 27% for those aged 85 years or older
      • 3% to 11% for those aged 65 to 84 years
      • 1% to 3% for those aged 55 to 64 years
      • Less than 1% for those aged 0 to 54 years
    • Case fatality rates for disease in Chinese patients with common comorbidities: ^r170
      • 10.5% for cardiovascular disease
      • 7.3% for diabetes
      • 6.3% for chronic respiratory disease
      • 5.6% for cancer
• Risk of reinfection
  • Recovery from infection is associated with short-term protective immunity, but reinfection has been documented, especially after 90 days from infection ^r170r185
    • Vaccination in persons who have already had COVID-19 may reduce the risk of reinfection (data are limited but encouraging) ^r186
  • Risk of reinfection may be increased with exposure to variant strains, although data are limited
• Risk of breakthrough infection (ie, infection despite vaccination) ^r187
  • Breakthrough infection is common, but explain to patients and families that this fact does not negate the value of vaccination, which lies in improved course of disease in most vaccinated people, yielding the following benefits:
    • Greatly reduced risk of progression to severe or critical disease ^r188
    • Greatly reduced risk of death ^r188
    • Lessened community transmission (ie, meaningfully reduced albeit not eliminated, leading to lesser burden of disease and death in population)
• Risk of postacute or chronic complications
  • A substantial proportion of patients, including some who had mild or asymptomatic infection, experience persistent symptoms and prolonged recovery more than 4 weeks from onset of COVID-19. This syndrome is known by many names, including long COVID, postacute COVID-19, chronic COVID, or PASC (postacute sequelae of SARS-CoV-2 infection) ^r189r190r191
    • Most common symptoms (symptoms may be new or persistent since infection):
      • Shortness of breath
      • Fatigue, which may be profound and may be sharply exacerbated by even mild exertion (postexertional malaise)
      • Low-grade fever, which may come and go
      • Joint and/or muscle pain
      • Chest pain
      • Cough
      • Headache
      • Cognitive dysfunction
      • Palpitations
      • Paresthesia
      • Abdominal pain or diarrhea
      • Mood changes
      • Menstrual irregularities
      • Impaired senses of smell or taste (reduced, altered, or absent): hyposmia, anosmia; dysgeusia (parageusia, ageusia, hypogeusia)
    • Research is ongoing; specialized clinics are opening in many locations, and guidance is being developed for evaluation and care of these patients ^r192
  • Evidence is emerging of increased risk for other sequelae after COVID-19 infection (even mild or asymptomatic infection)
    • Risk of all-cause mortality is elevated during 12 months after hospitalization for COVID-19; in studies, most of the deaths were not attributable to respiratory or cardiovascular conditions ^r193
    • In the 12 months after diagnosis of COVID-19, the risk of new-onset diabetes was increased 40% in a cohort of more than 270,000 adults (receiving care via the US Department of Veterans Affairs) ^r194

Screening

Prevention

• Overview
  • Preventive measures include vaccination, public health interventions, postexposure prophylaxis, and (in select populations) preexposure prophylaxis
• Background on vaccines^c335
  • Vaccine authorizations and approvals: various vaccines against SARS-CoV-2 have entered use in many countries, and more are in development ^r201
    • After analyses of data, the vaccines in use have emergency, temporary, or full authorizations from various national regulatory authorities, and future authorizations and full approvals are pending
      • BNT162b2 (Pfizer-BioNTech COVID-19 vaccine; tozinameran; Comirnaty) has received use authorization^r202 in the United States (where it has also received full FDA approval for persons aged 16 years or older^r203), the United Kingdom,^r204 the European Union, Canada,^r205 and elsewhere ^c336
      • Moderna COVID-19 vaccine (mRNA-1273) has received use authorization^r206 in the United States (where it has also received full FDA approval for persons aged 18 years or older^r207), the United Kingdom, Canada, the European Union, and elsewhere ^c337
      • Oxford-AstraZeneca COVID-19 vaccine has received authorization for temporary supply in the United Kingdom^r208 and similar authorizations in other countries.^r209 Pauses to investigate rare clotting events have occurred in various countries; vaccination has resumed based on public health risk-benefit assessments (ie, the apparent rarity of the adverse effect versus the relatively higher risk posed by COVID-19) ^c338
      • Janssen COVID-19 vaccine (Johnson and Johnson) has received use authorization in the United States;^r210 in 2021, its use was briefly paused but resumed^r211 with warnings about rare occurrences of cerebral venous sinus thrombosis and thrombocytopenia after administration. However, on May 5, 2022, FDA limited its use^r212 to people aged 18 years or older for whom other approved COVID-19 vaccines are unavailable or not clinically appropriate, or when elected by the recipient who would otherwise not be vaccinated ^c339
      • Various other vaccines are in use in many other countries; WHO tracking of vaccine development currently lists 153 vaccines in clinical development, with 196 in preclinical phases ^r201c340c341
    • CDC has compiled a summary of studies done in various countries (ie, the United States, the United Kingdom, several European countries, and Israel) on the effectiveness of various vaccines (ie, Pfizer-BioNTech, Moderna, Johnson and Johnson/Janssen, AstraZeneca) used in real-world conditions. Most studies found effectiveness rates greater than 90% ^r213
      • Efficacy of vaccine-induced immunity against disease caused by circulating variants is under ongoing assessment. Results will likely vary among vaccines and variants. Some vaccination recommendations have changed as a result of additional data ^r11
        • Evidence suggests a modest decrease in vaccine effectiveness over time; however, vaccination remains strongly protective, particularly in prevention of hospitalization and death ^{r57r188r213r214}
    • WHO has issued emergency use listing for 7 vaccines thus far; such listing assesses quality, safety, efficacy, and programmatic suitability, and it is a prerequisite for the COVAX vaccine supply and international procurement program ^r215
      • Authorizations in different jurisdictions may differ in details; practitioners should consult the specific authorization issued in their jurisdiction for indications, requirements for patient education and consent, and mandated reporting (eg, adverse events)
        • Vaccine administration information for the United States
          • In the United States, emergency use authorizations require health care providers to communicate^r202r216r217 to the patient, parent, or caregiver information consistent with the vaccine-specific (manufacturer-specific) fact sheet for recipients and caregivers^r218r219r220 before each patient receives the vaccine; such information includes the following:
            • Alternatives to receiving the vaccine
            • Option to accept or refuse the vaccine
            • Significant known and potential risks and benefits of the vaccine, and the extent to which such potential risks and benefits are unknown
            • Available alternative preventive vaccines in clinical trials or approved for use under other emergency use authorizations
          • Emergency use authorizations also require health care providers to report^r217r216r202 all vaccine administration errors, exposures during pregnancy, and serious adverse events to VAERS (Vaccine Adverse Event Reporting System)^r221 and to the manufacturer (via Pfizer online report form,^r222 email to ModernaPV@modernatx.com,^r217 or at the Janssen COVID-19 vaccine website^r223) within 7 calendar days from onset of event. Additionally, they must report cases of COVID-19 resulting in hospitalization or death and cases of multisystem inflammatory syndrome that occur in vaccinated patients
          • It is recommended that vaccine recipients be given a card containing information about the type of vaccine given, the date of administration, and (if applicable) the interval at which a booster dose should be administered ^r202r217r224
          • Vaccine recipients in the United States are encouraged to participate in CDC's V-safe monitoring and reminder system,^r224 available as a mobile phone app ^r217
          • Clinicians should follow best practices for vaccine administration, including documentation required by law, regardless of whether vaccines are FDA-approved or authorized for emergency use ^r225
        • In the United Kingdom, a site has been established to report suspected adverse events related to vaccines, diagnostic tests, and therapies for COVID-19: Coronavirus Yellow Card reporting site^r226
  • Vaccination recommendations
    • CDC recommends vaccination against COVID-19 for everyone aged 5 years or older ^r11
      • mRNA vaccines are preferred over Johnson and Johnson (Janssen) owing to higher efficacy and lower adverse effects
        • Johnson and Johnson (Janssen) may be considered under certain circumstances (eg, where there is a contraindication or allergic reaction to an mRNA vaccine)
      • Primary vaccinations
        • Primary vaccination of nonimmunocompromised persons
          • Primary series for nonimmunocompromised persons aged 18 years or older is 2 doses of Pfizer separated by 3 to 8 weeks or 2 doses of Moderna separated by 4 to 8 weeks
            • A shorter interval (3 or 4 weeks) is recommended for those at higher risk of infection or of severe disease (eg, when community transmission is elevated, for older adults or those with chronic conditions)
            • A longer interval (8 weeks) may be preferable in males aged 12 to 39 years to reduce the risk of vaccine-associated myocarditis, and it may be considered to increase peak antibody response in those not at increased risk
              • Risk of myocarditis from COVID-19 disease is substantially higher than the risk from vaccination ^r227
              • Risk of myocarditis in younger males may be lower after vaccination with Pfizer than with Moderna ^r11
          • Primary series for nonimmunocompromised children aged 12 years to 17 years is 2 doses of Pfizer separated by 3 to 8 weeks
            • A longer interval (8 weeks) may be preferable in males to reduce the risk of vaccine-associated myocarditis
          • Primary series for nonimmunocompromised children aged 5 years to 11 years is 2 doses of Pfizer separated by 3 weeks
        • Primary vaccination of moderately or severely immunocompromised persons
          • Primary series for immunocompromised persons aged 18 years or older is 3 doses of Pfizer (second dose 3 weeks after first dose, and third dose 4 weeks after second dose) or 3 doses of Moderna (each dose separated by 4 weeks)
          • Primary series for immunocompromised children aged 5 to 17 years is 3 doses of Pfizer, with second dose 3 weeks after first dose, and third dose 4 weeks after second dose
        • There are no data available on the interchangeability of the COVID-19 vaccines to complete the primary vaccination series. Patients who receive the first dose of any of the vaccines should receive a second dose of the same vaccine to complete the vaccination series ^r11
          • In cases in which the original mRNA vaccine manufacturer cannot be verified or obtained, or there is a contraindication to that vaccine, it is permissible to administer another authorized vaccine at least 28 days after the first dose. If a delay in obtaining the mRNA vaccine is expected to be temporary, it is preferable to delay the second dose in order to complete the series with the same vaccine ^r11
      • Booster vaccinations
        • Some data suggest that heterologous boosters (ie, booster vaccine different from primary) produce equivalent or stronger serologic response compared with homologous boosters ^r11
        • First booster dose ^r11
          • All nonimmunocompromised persons aged 5 years or older should receive a first booster dose with an mRNA vaccine 5 months or more after the completion of the primary series of either mRNA vaccine, or 2 months or more after Johnson and Johnson.
            • Only Pfizer may be used in those aged 5 to 17 years
          • Moderately or severely immunocompromised persons aged 5 years or older who have received a third primary dose of mRNA vaccine should receive a first booster dose with an mRNA vaccine 3 months or more after the completion of the primary series; first booster dose with an mRNA vaccine is recommended 2 months after the second primary dose if Johnson and Johnson was received
            • Only Pfizer may be used in those aged 5 to 17 years
        • Second booster dose
          • CDC recommendation released April 21, 2022: persons in certain subpopulations "may choose to receive" a second booster dose, using an mRNA COVID-19 vaccine (eg, Pfizer, Moderna) at least 4 months after their first booster dose. On May 19, 2022, CDC strengthened its recommendation, urging first and second boosters in the following groups, particularly if they have not received a dose of vaccine since December 2021: ^r11r228
            • Immunocompetent adults who received Johnson and Johnson (Janssen) vaccine for both primary series and first booster may receive a second booster with either of the mRNA vaccines 4 months or more after the first booster
            • Immunocompetent adults aged 50 years or older should receive an additional booster with either of the mRNA vaccines, 4 months or more after the first booster
            • Moderately or severely immunocompromised persons aged 12 years or older should receive a second booster with an mRNA vaccine licensed for their age group, at least 4 months after the first booster (total of 5 doses for mRNA vaccines, or 4 doses if Johnson and Johnson was primary vaccination)
              • Only Pfizer may be used in those aged 12 to 17 years
    • COVID-19 vaccine and any other immunizations may be administered on the same day, or at any interval; no delay is required between receipt of another vaccine and COVID-19 vaccination ^r11
    • History of COVID-19 is not a contraindication to vaccine; guidelines recommend that such persons be offered vaccine ^r11
      • Vaccination (either first or subsequent doses, if a series has been started) should be deferred until the person meets criteria for discontinuing isolation
      • Some evidence indicates that protection after vaccination may be stronger than immunity produced by previous infection, including increased antibodies in infants born to adults who received vaccination during pregnancy, compared with pregnant persons who had COVID-19 disease ^r186r229
    • Persons who received treatment with convalescent plasma or COVID-19–specific monoclonal antibodies do not need to delay vaccination by any interval; individuals who are candidates for tixagevimab and cilgavimab should wait at least 14 days after vaccination to receive the product ^r11
    • No data exist regarding safety and efficacy of vaccination after MIS-C or MIS-A; theoretical risk of dysregulated immune response from vaccination causing multisystem inflammatory syndrome should be weighed against risk of morbidities from COVID-19 infection ^r11
      • CDC guidance notes that some experts consider that benefits of vaccination probably exceed risks when the following criteria are met:
        • High or substantial transmission of SARS-CoV-2 in the community
        • Clinical recovery (including return to normal myocardial function)
        • 90 days or more have elapsed since MIS-C diagnosis
        • MIS-C occurred before patient received any dose of COVID-19 vaccine
      • Consider consultation with a specialist in infectious diseases, rheumatology, cardiology, and/or Clinical Immunization Safety Assessment COVIDvax project^r230 personnel to discuss specific cases
    • History of Guillain-Barré syndrome (postinfectious polyneuritis) is not a contraindication, but is a precaution, to Johnson and Johnson (Janssen) vaccination; consider use of an mRNA vaccine if available ^r11
    • Vaccine use in special populations
      • Pregnant persons and breastfeeding persons ^r11r162r163
        • Vaccination is recommended for pregnant and lactating persons, and those who may become pregnant, by the CDC, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine
          • Any authorized or approved vaccine may be used; however, given the small risk of rare vaccine-induced thrombotic thrombocytopenia seen in females younger than 50 years after vaccination with Janssen (Johnson and Johnson) product, an mRNA vaccine is recommended
          • Studies indicate that pregnant persons with COVID-19 infection have increased risk for severe illness and death from COVID-19 and may be at increased risk of preterm birth, stillbirth, and other pregnancy complications
          • Growing information on safety and efficacy during pregnancy indicates that benefits of vaccination outweigh risks
            • One study in 35,691 pregnant persons aged 16 to 54 years found no increased rates of pregnancy loss, preterm birth, small-for-gestational-age infants, or congenital anomalies compared with background rates ^r231
            • Overall vaccine effectiveness of vaccination during pregnancy at preventing hospitalizations in infants younger than 6 months was 61%; optimal timing during pregnancy is not known, but effectiveness was higher in those who received the vaccine later in pregnancy (between 21 weeks of gestation and 14 days before delivery) ^r232
            • Vaccination during pregnancy transfers antibodies to infants, and infants born to vaccinated adults had higher antibody titers and greater antibody persistence than those born to COVID-infected adults ^r229
          • Pregnant persons, and those who received vaccination within 30 days before pregnancy, should be encouraged to participate in CDC's V-safe registry program (a mobile phone–based monitoring and reminder system for recipients of COVID-19 vaccines)
      • Persons with cancer ^r233
        • Although safety and efficacy in patients with cancer is still being studied, the National Comprehensive Cancer Network recommends that patients with cancer should receive vaccine when available; this recommendation is based on the extra risk for COVID-19 complications conferred by malignancy, as well as on the absence of any clear-cut known or theoretical vaccine-associated risks unique to patients with cancer
        • Exceptions include recent recipients of hematopoietic cell transplant or cellular therapy (who should delay vaccination for 3 months) and patients with hematologic malignancies who have neutropenia (who should await recovery of absolute neutrophil count). Patients who require major surgical procedures should time vaccination for several days before or after the surgery
      • Persons with autoimmune diseases ^r11
        • Little clinical information exists on the use of vaccine in persons with autoimmune diseases, but no unusual responses were noted in vaccine trial participants with autoimmune conditions, and current recommendations do not advise against vaccination of persons with autoimmune diseases
  • Vaccine contraindications and significant adverse effects
    • Contraindications include: ^r11r216
      • Severe allergic reaction (eg, anaphylaxis) to a previous dose of a COVID-19 vaccine or to any of its components
      • Immediate allergic reaction of any severity to a previous dose of an mRNA COVID-19 vaccine or any of its components (including polyethylene glycol) or to polysorbate (because of possible cross-reacting immune response against polyethylene glycol)
      • For the Johnson and Johnson (Janssen) vaccine, contraindications include thrombosis with thrombocytopenia syndrome, heparin-induced thrombocytopenia, or other immune-mediated thrombosis syndrome; individuals who had Guillain-Barré syndrome after Johnson and Johnson vaccination should not receive any additional doses of this vaccine
    • CDC^r11 and the European Medicines Agency^r234 have recommended that clinicians maintain a high index of suspicion for thrombotic events and thrombocytopenia among persons who have received the Janssen or AstraZeneca vaccines
      • Symptoms may include severe headache, blurred vision, back pain, abdominal pain, chest pain, dyspnea, leg edema, petechiae, or easy bruising; overt bleeding has occurred in some cases ^r11r234
      • Condition was more often seen in females younger than 50 years
      • American Society of Hematology recommends the following workup for suspected vaccine-induced thrombotic thrombocytopenia (also known as thrombosis with thrombocytopenia syndrome): ^r235
        • CBC with platelet count and smear (to rule out pseudothrombocytopenia from platelet clumping); range in reported cases has been 9000 to 107,000 cells/mm³
        • Imaging guided by presentation (eg, CT or MRI venogram of brain, thorax, abdomen, or other clinically indicated site)
        • D-dimer level (markedly elevated in reported cases)
        • Fibrinogen level (may be low)
        • Platelet factor 4–heparin ELISA assay; all reported cases have been positive
          • Non-ELISA rapid immunoassays for heparin-induced thrombocytopenia are not sensitive or specific for vaccine-induced thrombotic thrombocytopenia and should not be used
      • Treatment recommendations from the American Society of Hematology include: ^r235
        • IV immunoglobulin 1 g/kg daily for 2 days
        • Anticoagulation with 1 of the following heparin alternatives (avoid heparin):
          • Parenteral direct thrombin inhibitors (argatroban or bivalirudin if baseline value for activated partial thromboplastin time is normal)
          • Direct oral anticoagulants
          • Fondaparinux (Factor Xa inhibitor)
          • Danaparoid (a thrombin generation inhibitor not available in the United States)
        • Low fibrinogen level or bleeding do not absolutely preclude anticoagulation, especially if platelet count exceeds 20,000 cells/mm³
        • No consensus exists on the use of corticosteroids with IV immunoglobulin
        • Avoid platelet transfusion and aspirin
        • Plasma exchange has been tried and may be considered for thrombosis despite IV immunoglobulin and nonheparin anticoagulation
      • Patients with isolated thrombocytopenia without thrombosis, with a negative result on platelet factor 4–heparin assay, may have idiopathic thrombocytopenic purpura, not vaccine-induced thrombotic thrombocytopenia ^r235
        • Immune thrombocytopenia has been reported after vaccination with the AstraZeneca, Janssen, Moderna, and Pfizer vaccines
        • Treatment includes IV immunoglobulin and/or steroids; platelet transfusions may be required for bleeding
    • A small number of cases of Bell palsy have been reported after COVID-19 vaccination, but the incidence is not considered significantly different from that in the general population, and history of Bell palsy is not a contraindication ^r11
    • A small number of patients who have received cosmetic injections with dermal fillers have experienced mild inflammation at the filled site(s) after COVID-19 vaccination, but a history of such procedures is not considered to be a contraindication ^r11
  • Vaccine-specific details and evidence
    • Pfizer-BioNTech BNT162b2 (tozinameran; Comirnaty) ^c342
      • Evaluated in a randomized placebo-controlled trial of more than 43,000 participants; at time of submission for authorization in the United Kingdom, safety and efficacy data were available for 19,067 patients evenly distributed in vaccine and placebo groups. Overall efficacy was about 95% ^r204
        • Among subgroups, results were similar in older age groups (older than 65 years) and in persons with comorbidities associated with increased risk for severe disease
      • Data evaluated for US emergency use authorization included 36,621 persons, aged 12 years or older, equally divided between vaccine group and placebo group (18,242 versus 18,379, respectively), with wide ethnic and age diversity, and incorporating a large percentage of persons with comorbidities. At time of analysis, participants had been followed for a median of 2 months after the second dose ^r202
        • Vaccine efficacy was greater than 94.6% in all groups including all ages and with or without evidence of prior SARS-CoV-2 infection
      • At time of data analysis for these authorizations, 8 cases of COVID-19 had occurred in the vaccine group compared with 162 cases in the placebo group ^r202r204
      • Adverse events
        • Common adverse effects included pain at injection site, fatigue, headache, myalgia, chills, arthralgia, and fever; these were largely mild to moderate and resolved within a few days ^r202r204
        • Appendicitis was reported in 8 vaccine recipients and 4 persons who received placebo. Bell palsy was reported in 4 vaccine recipients. Although both of these adverse events are reported as "imbalances" between vaccine and placebo populations, data are insufficient to determine a causal relationship ^r202
        • Severe allergic reactions have been described, and facilities at which vaccine is administered must have the ability to treat such reactions (including anaphylaxis) ^r202
        • Myocarditis and pericarditis have been reported to occur in adolescents and young adults (primarily males) after vaccination with both mRNA vaccines, most commonly after the second dose. Onset is usually several days after administration of vaccine; the condition is generally short-lived. Vaccine recommendations for adolescents and young adults remain unchanged, although it is recommended that persons who have had myocarditis after a first dose of vaccine defer the second dose ^{r11r236r237r238}
      • Trial data were published after release of the emergency use authorization; total numbers of patients in both vaccine and placebo groups were slightly larger, but results (including efficacy calculations) were unchanged ^r239
      • Subsequent trial data on adolescents led to extension of the US emergency use authorization on May 10, 2021, to include adolescents aged 12 through 15 years, effectively permitting use in all persons aged 12 years or older who do not have a contraindication ^r240
        • Safety data were derived from 1127 vaccinated adolescents and 1127 placebo patients. Serious events occurred in 0.4% of vaccinated persons and 0.1% of placebo recipients, similar to results in adults ^r202
        • Among 1005 vaccinated adolescents aged 12 to 15 years, no cases of COVID-19 occurred. There were 16 cases among 978 placebo recipients. Efficacy was calculated as 100% (confidence interval, 75.3-100) ^r202
      • FDA issued an emergency use authorization for children aged 5 through 11 years on October 29, 2021; CDC recommends that children aged 5 through 11 years without contraindications receive Pfizer-BioNTech pediatric COVID-19 vaccine ^r11r220r241
        • Based on data from a placebo-controlled trial of 4695 children, of whom 3109 received vaccine and 1538 received saline
        • Follow-up found no safety concerns, including in the 1444 children who had follow-up for 2 months or longer
        • By 7 days after the second dose, efficacy is estimated to be 90.7% in preventing COVID-19
      • FDA approval for ages 16 years and older was based on continued follow-up of initial study enrollees and additional data ^r203
    • Moderna COVID-19 vaccine (mRNA-1273; Spikevax) ^r217c343
      • Safety data evaluated for US emergency use authorization (and subsequently published^r242) included 30,351 persons, aged 18 years or older, equally divided between vaccine group and placebo group (15,185 versus 15,166, respectively); efficacy data was available for 14,134 vaccine recipients and 14,073 persons who received placebo. Participants included wide ethnic and age diversity; persons with stable comorbidities were included. At time of analysis, participants had been followed for a median of 9 weeks after the second dose
        • Overall efficacy was 94.1% (95.6% for persons aged 18 through 64 years and 86.4% for persons aged 65 or older)
        • Common adverse effects included pain at injection site, fatigue, headache, myalgia, chills, arthralgia, and fever; these were largely mild to moderate and resolved within a median of 2 to 3 days
        • Bell palsy was reported in 3 vaccine recipients (1 case classed as serious) and 1 placebo recipient; a causal relationship has not been established. Two patients who had previously received facial injection of dermatologic fillers experienced severe facial swelling considered likely vaccine-related. One patient developed intractable vomiting requiring hospital admission, deemed a result of vaccine
        • Severe allergic reactions have been described, and facilities at which vaccine is administered must have the ability to treat such reactions (including anaphylaxis)
          • CDC provides guidance on anaphylaxis to aid vaccine providers in preparing for and managing such events^r243, and for postanaphylaxis laboratory assessment^r244
        • Myocarditis and pericarditis have been reported to occur in adolescents and young adults (primarily males) after vaccination with both mRNA vaccines, most commonly after the second dose. Onset is usually several days after administration of vaccine; the condition is generally short-lived. Vaccine recommendations for adolescents and young adults remain unchanged, although it is recommended that persons who have had myocarditis after a first dose of vaccine defer the second dose ^{r11r236r237r238}
    • AstraZeneca COVID-19 vaccine (ChAdOx1-S [recombinant]) ^r208c344
      • Safety data considered in the UK authorization for temporary use came from 23,745 persons who were enrolled in a clinical trial. The most common adverse effects included injection site tenderness (more than 60%) and injection site pain, headache, or fatigue (more than 50%). Less common adverse effects included myalgia or malaise (more than 40%), fever or chills (more than 30%), and arthralgia or nausea (more than 20%). Most of these symptoms resolved within a week. Adverse reactions were less common after the second dose and were less common overall in older recipients
      • Authorizing body considered efficacy data from 11,636 persons enrolled in a multinational trial: 5,807 patients received the COVID-19 vaccine and 5,829 received meningococcal vaccine (placebo). Vaccine efficacy measured at least 22 days after the first dose was 73%, and it was similar for patients with comorbidities compared with those without
      • Use of the vaccine has been interrupted in several regions while reports of unusual clotting disorders after administration were investigated; vaccination has resumed in some areas based on public health risk-benefit assessments^r246 (ie, the apparent rarity of the disorder versus the relatively higher risk posed by COVID-19). About 30 cases have been reported among about 5 million persons receiving this vaccine in Europe ^r245
        • Characterized by venous thrombosis and thrombocytopenia associated with high levels of platelet factor 4–polyanion complexes (ie, similar to heparin-induced thrombocytopenia, but in the absence of heparin exposure; thus termed vaccine-induced immune thrombotic thrombocytopenia)
        • One published series reported 5 cases (in persons aged 32 to 54 years) in a population of more than 130,000 vaccine recipients; patients experienced onset of severe thromboses (some with embolization), associated with thrombocytopenia (some with hemorrhage), occurring 7 to 10 days after vaccination ^r247
        • Another series reported 11 cases in Germany and Austria (total number of vaccinations administered was not given); 9 of 11 patients were female, and the mean age was 36 years. Patients experienced severe and multiple venous thromboses (cerebral, splanchnic, pulmonary, other) associated with thrombocytopenia and, in some cases, disseminated intravascular coagulation
    • Janssen COVID-19 vaccine ^r216c345
      • A replication-deficient adenovirus vector vaccine that generates immunity to the SARS-CoV-2 spike protein. The vaccine is administered as a single 1-time dose
      • A multinational trial enrolled 44,325 persons randomized to receive the Janssen COVID-19 vaccine or saline placebo; a preliminary efficacy analysis of 39,321 was presented to the FDA, of whom 19,630 received vaccine and 19,691 received placebo. The populations were similar and represented diverse racial and ethnic backgrounds, and patients were distributed across all age ranges 18 years and older. Persons with stable underlying medical conditions (including HIV infection) were included
      • At 14 days after vaccine administration, efficacy against severe/critical COVID-19 was 76.7%, rising to 85.4% at 28 days; for moderate to severe/critical COVID-19, efficacy rates at 14 and 28 days were 66.9% and 66.1%, respectively. At 28 days, efficacy rates did not differ between populations aged 18 to 59 years and those aged 60 years or older
      • Common adverse reactions (reported in more than 10% of participants) included headache, fatigue, myalgia, and nausea; they were reported in 13.1% of vaccine recipients and 12% of placebo patients; other adverse events included urticaria in 5 vaccine recipients (including 1 with angioedema) and 1 placebo recipient
      • 2 unique serious adverse events thought to be related to the vaccine occurred, as follows: 1 patient experienced severe pain in the injected arm unresponsive to analgesics and persistent to 74 days of follow-up, and another patient had fever, headache, and generalized weakness that resolved within 3 days
      • Several events occurred more frequently in vaccine recipients than in placebo recipients, but a causal relationship to the vaccine could not be determined, owing to confounding effects of existing underlying conditions: deep vein thrombosis (6 vaccine recipients versus 2 placebo recipients); pulmonary embolus (4 vaccine recipients versus 2 placebo recipients); transverse sinus thrombosis (single case, in a vaccine recipient); seizures (4 vaccine recipients versus 1 placebo recipient); tinnitus (in 6 vaccine recipients only)
      • On April 12, 2021, CDC and FDA recommended that practitioners in the United States suspend use of this vaccine while reports of an unusual clotting disorder associated with administration of this vaccine were investigated ^r248
        • Characterized by cerebral venous thrombosis with thrombocytopenia occurring 6 to 13 days after administration
        • Initial data included 6 cases among more than 6.8 million persons immunized with this vaccine in the United States; all were in females aged 18 to 48 years
      • On April 23, 2021, CDC and FDA recommended that use of this product could resume because occurrence of the observed clotting disorder is extremely rare and benefit of vaccination against COVID-19 is felt to outweigh risk ^r249
        • Collection and analysis of further data included 9 more cases, for a total of 15 affected persons, all of whom were females aged between 18 and 59 years
        • Specific risk factors for this complication have not been identified ^r211
      • On May 5, 2022, after further analysis in light of more available data, FDA limited use in the United States to persons aged 18 years or older for whom alternative COVID-19 vaccines were not accessible or clinically appropriate, or when elected by a patient of that age group who would otherwise not receive any vaccine ^r212

  • Vaccines against SARS-CoV-2 that have reached authorization status in some jurisdictions.

    EUA, emergency use authorization.

    Product name	Manufacturer	Active ingredient	Age range for use	Dose and route	Dosing interval	Comments
    Pfizer-BioNTech COVID-19 vaccine (BNT162b2; tozinameran; Comirnaty)	Pfizer-BioNTech	Nucleoside-modified mRNA of SARS-CoV-2	5 years or older	12 years and older: 30 mcg (0.3 mL) intramuscular injection for 2 doses for primary series, including third dose if indicated; booster dose grey cap [no dilution]; purple cap [must dilute]. 5-11 years: 10 mcg (0.2 mL) intramuscular injection for 2 doses for primary series including third dose if indicated; booster dose orange cap [must dilute]:	3 weeks Additional (third primary series) dose: 28 days or more since second dose Booster: 5 months or more after completing primary series Second booster (if indicated): 4 months or more after the first booster	FDA approved in the United States for ages 16 years or older; used under EUA for 5-15 year age groups in the United States Under temporary use authorization in the United Kingdom
    Moderna COVID-19 vaccine (mRNA-1273; Spikevax)	ModernaTX	Synthetic mRNA of SARS-CoV-2	18 years or older	100 mcg (0.5 mL) intramuscular injection (primary series, including third dose if indicated) Booster: 50 mcg (0.25 mL)	1 month Additional (third primary) dose: 28 days or more since second dose Booster: 6 months or more since completing primary series	FDA approved in the United States for ages 18 years or older Under temporary use authorization in the United Kingdom
    Oxford-AstraZeneca COVID-19 vaccine (ChAdOx1-S recombinant)	AstraZeneca	Recombinant, replication-deficient chimpanzee adenovirus vector encoding SARS-CoV-2 spike glycoprotein (S protein)	18 years or older	0.5 mL intramuscular injection	4 to 12 weeks	Investigational; under temporary authorization in the United Kingdom
    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	0.5 mL intramuscular injection (primary and booster)	Booster: 2 months or more since primary dose	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

• Postexposure prophylaxis^r8
  • Postexposure prophylaxis is not a substitute for vaccination, which remains the most effective prevention against infection, severe morbidity, and mortality. Additionally, postexposure prophylaxis is expected to be ineffective against variants less susceptible to these agents (eg, Omicron)
  • In the United States, emergency use authorization has been issued for the use of monoclonal antibodies casirivimab and imdevimab (in combination) or bamlanivimab and etesevimab (in combination) as postexposure prophylaxis for those at high risk of progression to severe disease under the following circumstances:
    • Exposed person is not fully vaccinated or not expected to develop protective immunity after vaccination because of immunocompromise (including immunosuppressive treatment), and
    • Close contact with a person who has infection with SARS-CoV-2 or is at high risk of exposure to a person infected with SARS-CoV-2 in an institutional setting in which COVID-19 is occurring, and
    • Prevailing virus variants are susceptible
  • Close contact is defined as being within 6 feet for 15 minutes or longer; providing care for a person with COVID-19; or close personal contact (hugging; sharing eating or drinking utensils; exposure to respiratory droplets expelled by a cough or sneeze by an infected person)
  • Casirivimab and imdevimab may be used for persons aged 12 years or older and weighing at least 40 kg ^r3
    • Omicron variant prevalence precludes most use; casirivimab and imdevimab are not authorized for use in places in which the combined frequency of variants resistant to them exceeds 5%
    • Initial dose is casirivimab 600 mg plus imdevimab 600 mg IV (in a single infusion) or subcutaneously (in 4 injections at different sites of 2.5 mL each) as soon as possible after the exposure. In circumstances of ongoing exposure, additional 300 mg may be administered at 4-week intervals
  • Bamlanivimab and etesevimab may be used for persons aged 12 years or older and weighing at least 40 kg ^r4
    • Omicron variant prevalence precludes most use; bamlanivimab and etesevimab are not authorized for use in places in which the combined frequency of variants resistant to them exceeds 5%
    • Dose is bamlanivimab 700 mg plus etesevimab 1400 mg IV in a single infusion as soon as possible after the exposure
• Preexposure prophylaxis^r8
  • Experimental monoclonal antibodies tixagevimab and cilgavimab have received emergency use authorization for coadministration in persons aged 12 years or older, weighing 40 kg or more, who either (1) are moderately to severely immunocompromised and may not mount an immune response to vaccine or (2) have a contraindication to vaccination (eg, severe allergic reaction to COVID-19 vaccine or components) ^r6
    • Infectious Diseases Society of America guideline suggests preexposure prophylaxis with tixagevimab-cilgavimab for those who qualify ^r98
    • Adults and adolescents 12 years and older, weighing 40 kg or more: 150 mg of tixagevimab and 150 mg of cilgavimab administered as 2 separate consecutive intramuscular (IM) injections. The doses can be administered once every 6 months to persons who continue to qualify for preexposure prophylaxis; however, no safety and efficacy data are available for repeat dosing. The recommendation for repeat dosing is based on pharmacology and clinical trial data ^r250
• Public health interventions to interrupt transmission (eg, masking, distancing, hygiene, isolation, quarantine): practices vary geographically and depend on regional disease activity, vaccination status, and other factors
  • General precautions for all populations ^r251
    • Get vaccinated
    • Wear a mask in indoor settings when community transmission is high or if you are at high risk
    • Avoid crowds and poorly ventilated spaces; improve ventilation whenever possible
    • Test to prevent spread to others (eg, if you have symptoms, exposure, or plans to gather with someone at higher risk)
    • Physical distance at least 6 feet from others whenever feasible
    • Wash hands (or use hand sanitizer at least 60% alcohol), cover coughs and sneezes with a tissue, and clean and disinfect high-touch surfaces often
    • Monitor for symptoms
  • Isolation and quarantine measures: overview
    • A Cochrane review of quarantine concluded that quarantine is important in reducing incidence and mortality ^r252
    • All those who have symptoms of COVID-19 should isolate themselves, and get tested for COVID-19, regardless of vaccination status ^r251
    • Persons who test positive for COVID-19, regardless of vaccination status, should isolate for 5 days and wear a mask for an additional 5 days ^r253
    • In the United States, subject to more stringent local or state policy, fully vaccinated persons may resume travel and do not require quarantine after a known exposure unless they develop symptoms suggestive of COVID-19 ^r198
      • Given the resurgence of case numbers in late 2021 and early 2022, all persons, including those fully vaccinated, are recommended to wear masks in indoor public settings in areas of high transmission, or if they are immunocompromised or at increased risk of severe disease ^r251
      • Fully vaccinated persons in close contact with someone with COVID-19 but who have no symptoms should be tested 5 days after the exposure, and should wear a mask for 10 days after exposure ^r253
      • For unvaccinated, asymptomatic persons in close contact with someone with COVID-19, quarantine is necessary for 5 days from the exposure followed by mask-wearing for an additional 5 days ^r253
      • Close contact is defined as within 6 feet for a cumulative total of 15 minutes or more in 24 hours
      • Testing should be performed immediately if symptoms develop
  • Infection control for at-home management of COVID-19
    • Patient is encouraged to stay at home except to seek medical care, to self-isolate to a single area of the house (preferably with a separate bathroom), to practice good hand and cough hygiene, and to wear a mask or cloth face cover during any contact with household members ^{r89c346c347c348}
      • Patients should be advised that if a need for medical care develops, they should call their health care provider in advance so that proper isolation measures can be undertaken promptly on their arrival at the health care setting
      • Isolation is required for everyone with a positive COVID-19 test result, even in the absence of symptoms
    • Household members/caregivers should: ^r254
      • Ideally, wear mask and gloves when directly contacting body fluids or dirty dishes. Remove and discard disposable products when leaving the room (do not reuse), and wash hands afterwards. If some of these supplies are absent, wear cloth face cover and scrupulously wash hands ^c349c350c351
        • Dispose of disposable items in a container lined with a trash bag that can be removed and tied off or sealed before disposal in household trash
      • Wash hands for at least 20 seconds after all contact; an alcohol-based hand sanitizer is acceptable if soap and water are not available ^c352c353
      • Not share personal items such as towels, dishes, or utensils before proper cleaning ^c354c355
      • Clean and disinfect regularly ^c356
        • Wear gloves to handle any dishes or utensils used by the person with COVID-19
        • Clean surfaces with diluted bleach solution or an EPA-approved disinfectant ^c357
      • Restrict contact to minimum number of caregivers and, in particular, ensure that persons with underlying medical conditions are not exposed to the patient
  • Infection control for COVID-19 managed in health care facilities (outpatient or inpatient) ^r88r255
    • CDC provides preparedness checklists^r256 for outpatient and inpatient health care settings
    • Immediately provide the patient with a face mask (or, if supplies are critically low, at least a cloth face cover) to reduce droplet spread and place the patient in a closed room pending further evaluation and disposition decisions. The closed room will ideally be one with structural and engineering safeguards against airborne transmission (eg, negative pressure, frequent air exchange), but in the high-prevalence stages of the pandemic (with crowded hospitals), reserve negative pressure isolation rooms for the greatest needs (ie, aerosol-generating procedures; tuberculosis, measles, and varicella)
    • Persons entering the room should follow standard, contact, and droplet or airborne precautions ^c358c359c360
      • Gloves, gowns, eye protection, and respirator (N95 or better) with adherence to hospital donning and doffing protocols ^c361c362
        • In circumstances in which supplies of N95 respirators and other protective equipment are short, their use should be prioritized for aerosol-generating procedures; standard surgical face masks should be used for other situations
      • Equipment used for patient care should be single-use (disposable) or should be disinfected between patients (eg, 70% ethyl alcohol) ^c363c364
  • Criteria for discontinuation of isolation precautions ^r171r185
    • CDC recommends that a symptom-based strategy should be used to determine when to discontinue isolation in most patients. Criteria have been established based on observations^r185 showing that duration of shedding of infective virus varies from less than 10 days in milder cases to less than 20 days in more severe infections and in immunocompromised persons
      • Mild symptomatic COVID, no immunocompromise:
        • Isolation may be discontinued 5 days after symptom onset (first day of symptoms is day 0) and
        • At least 24 hours have passed since last fever without use of antipyretics and
        • Symptoms have improved and
        • Patient is able to wear a well-fitted mask for the next 5 days
        • If illness has been entirely asymptomatic, isolation may be discontinued 5 days from first positive specimen if the patient is able to wear a well-fitted mask for the next 5 days
      • Moderate COVID-19, no immunocompromise:
        • Isolate for 10 days
      • Severe or critical illness, no immunocompromising condition:
        • It may be reasonable to extend isolation until 10 days and up to 20 days have passed since symptom onset (day 0) and
        • At least 24 hours have passed since last fever without use of antipyretics and
        • Symptoms have improved
        • Repeat testing before discontinuing isolation may be considered
      • Moderately or severely immunocompromised persons:
        • Continue isolation for 20 days or longer after symptom onset or first positive SARS-CoV-2 test result; a test-based strategy to determine further duration may be appropriate. Infectious disease consultation is recommended
      • Test-based criteria for discontinuation of isolation include:
        • Negative test results from 2 specimens 24 hours apart; polymerase chain reaction or antigen tests are acceptable
        • For moderately or severely immunocompromised persons who were symptomatic, there should be improvement in symptoms and 24 hours have passed since last fever without use of antipyretics