Key Points

• COVID-19 (coronavirus disease 2019) is a respiratory tract 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 ^r1
• Infection should be suspected based on presentation with a clinically compatible history (eg, fever, upper or lower respiratory tract symptoms); alterations in 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 equivalent specificity but is slightly less sensitive
• Treatments and treatment strategies are emerging; available drugs are administered at different stages of disease based on the pharmacologic mechanism of action and the dominant pathophysiology of the disease phase
  • Casirivimab-imdevimab,^r2sotrovimab,^r3 and bamlanivimab-etesevimab^r4 are monoclonal antibodies that prevent viral entry into human cells; they may be used under emergency use authorization in persons with mild to moderate infection at risk of progressing to severe disease. Bamlanivimab-etesevimab is not being distributed in the United States as of June 25, 2021,^r5 because of the prevalence of circulating virus variants against which its activity is diminished
  • Remdesivir is an FDA-approved antiviral drug^r6 specifically for treatment of COVID-19; it is recommended for hospitalized patients with COVID-19 who require supplemental oxygen^r7r8
  • Dexamethasone also has been associated with significant reduction in mortality rates of patients requiring supplemental oxygen^r9
  • Immunomodulators baricitinib and tocilizumab are recommended for use in conjunction with corticosteroids with or without remdesivir in in patients requiring high-flow oxygen or noninvasive ventilation ^r7
  • Compassionate use and trial protocols^r10 for several other agents are underway. Otherwise, treatment is largely supportive, consisting of supplemental oxygen and conservative fluid administration
• Most common complications are acute respiratory distress syndrome and septic shock; myocardial, renal, and multiorgan failure have been reported
• A significant proportion of clinically evident cases are severe; the mortality rate among diagnosed cases is generally about 3% but varies by country ^r11r12
• Various vaccines are available, including through use authorizations and clinical trials, with good efficacy and safety to date. In the United States, fully vaccinated persons may resume relatively normal activities without using face masks or observing social distancing ^r13

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; regardless, physical distancing is vital to slowing transmission enough to avoid overwhelming health systems
• 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 respiratory tract infection with 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^r14 on March 11, 2020
• 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^r12r11 but varies by country; true overall mortality rate is uncertain, as the total number of cases (including undiagnosed persons with milder illness) is unknown
• 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
  • In late 2020 and early 2021, several variants with potential impact on transmission, clinical disease, and immune protection were recognized. Several are characterized as "variants of concern" or "variants of interest" 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 reduced sensitivity of testing modalities ^r15
    • B1.1.7 (alpha): 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
    • B.1.351 (beta): first noted in South Africa; may confer some resistance to certain vaccines (eg, Moderna mRNA-1273)
    • P.1 (gamma): seems to have originated in Brazil; may mitigate the protective effect of antibodies to the original strain
    • B1.617.2 (delta): first detected in India; characterized by increased transmissibility and possibly reduced neutralization by some monoclonal antibody treatments and postvaccine serum
    • B.1.427 and B.1.429 (both designated epsilon): 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
  • CDC website maintains information about geographical distribution of the variants in the United States ^r16

Classification

• Pathogen is a betacoronavirus,^r17 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^r18r19
  • Designated as SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2); earlier provisional name was 2019-nCoV ^r18r19

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

Standard, contact, and (at least) droplet precautions should be implemented as soon as the diagnosis is suspected; airborne precautions are recommended if resources allow, especially for aerosol-generating procedures ^r70

• 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)

At present, 1 antiviral agent (remdesivir) is FDA-approved specifically for treatment^r6 of this infection, and emergency use authorization has been granted for various monoclonal antibodies that target the viral spike protein (by which the virus gains entry to host cells). Chief among them as of July 2021 are sotrovimab^r71 and casirivimab-imdevimab.^r2 Both bamlanivimab-etesevimab^r5r4 (combination) and bamlanivimab alone^r72 were formerly widely given, but their use has been curtailed as the rise of virus variants has reduced their effectiveness. Several other existing drugs (of other 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 limited clinical experience. One of these (baricitinib^r73), a disease-modifying antirheumatic drug used in refractory rheumatoid arthritis, has received emergency use authorization for administration in conjunction with remdesivir in patients with severe disease. Information on therapeutic trials and expanded access is available at ClinicalTrials.gov^r10

• 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 ^r74
• Remdesivir is an antiviral agent with significant in vitro activity against coronaviruses,^r75r76 some evidence of efficacy in an animal model of MERS,^r76 and some evidence of efficacy in COVID-19^r77
  • Remdesivir is approved to treat hospitalized patients with COVID-19. The FDA approval extends to patients aged 12 years or older who weigh 40 kg or more; the earlier emergency use authorization provides continued access for pediatric patients younger than 12 years and/or who weigh less than 40 kg but more than 3.5 kg ^r6
    • Preliminary^r78 and follow-up^r77 results of the Adaptive COVID-19 Treatment Trial, a placebo-controlled randomized trial in 1062 patients, showed a statistically significant improvement in time to recovery and a nonsignificant trend in lower mortality; several other trials remain active, as well^r79
  • 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 ^r7r8r80r81
    • 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 does not recommend routine use of remdesivir in patients who require mechanical ventilation or extracorporeal membrane oxygenation
      • Infectious Diseases Society of America recommends use of remdesivir over no antiviral in these patients, but it acknowledges that if shortages occur, this consideration should be taken into account in allocating available drug
      • Surviving Sepsis Campaign guideline suggests that remdesivir not be used in patients with critical COVID-19, outside of clinical trials
    • 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
    • Neither guideline recommends remdesivir for less severely ill patients, even if hospitalized
  • WHO does not recommend remdesivir use outside of clinical trials ^r24
• Monoclonal antibodies against SARS-CoV-2 spike protein
  • Emergency use authorizations have been issues for 3 monoclonal antibody products: bamlanivimab-etesevimab^r82r83r4 in combination, casirivimab-imdevimab^r2r84 in combination, and sotrovimab^r71r3
    • In each case, the authorization applies to patients ages 12 years and 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 authorization lists 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
    • Aged 65 years or older
  • NIH guidelines recommend using these agents in outpatients with mild to moderate COVID-19 who are at high risk for clinical progression. They note that they should not be given to patients hospitalized for COVID-19 outside of a clinical trial ^r7
  • Infectious Diseases Society of America guideline suggests their use in ambulatory patients who are at high risk of progression to severe COVID-19; selection of the most appropriate agent should be based on known activity against predominant circulating variants ^r8
    • These guidelines summarize available data on adverse events associated with monoclonal antibodies, and they note that such events were less frequent in patients receiving sotrovimab or casirivimab-imdevimab compared with those receiving placebo. Data for bamlanivimab-etesevimab are less clear, as there were more adverse effects in the treatment arm, but the difference was not clearly meaningful, according to the guideline synopsis
  • 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 ^r4r72
    • Preliminary data from clinical trials on bamlanivimab 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) ^r83
    • 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 ^r82
    • Based on these data, FDA issued an emergency use authorization allowing administration of bamlanivimab in combination with etesevimab^r82. (The emergency use authorization for bamlanivimab alone was revoked because virus variant prevalence has reduced its effectiveness and availability of the combination of bamlanivimab-etesevimab has improved.^r83)
    • However, bamlanivimab and etesevimab, even in combination, appear to have reduced in vitro activity against a number of circulating variants: B.1.351 (South Africa, beta), P.1 (Brazil, gamma), B.1.427/B.1.429 (California, epsilon), and B.1.526 (New York, eta); as of June 25, 2021, distribution of these monoclonal antibodies has been paused in the United States, and the FDA recommends use of the alternative monoclonal antibodies available in place of bamlanivimab-etesevimab ^r5r85
  • Casirivimab-imdevimab ^r2
    • Preliminary clinical studies 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) ^r84
      • 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 ^r84
      • Data submitted with the updated statement indicate efficacy against the major variants circulating as of June 2021 ^r84
  • Sotrovimab targets a highly conserved region in the receptor-binding domain of the SARS-CoV-2 spike protein ^r3
    • 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
      • Data on efficacy against variants are incomplete, but existing information appears to indicate no change in activity against major known variants ^r3
• Chloroquine and hydroxychloroquine have been used in China and South Korea, reportedly with favorable results,^r86 although details are lacking. Initial promise led to an emergency use authorization by FDA in the United States. Subsequent studies have failed to show a significant benefit, but they have highlighted the risk of QT prolongation and cardiac arrhythmias. As a result, FDA emergency use authorization has been withdrawn,^r87 although some clinical trials are still 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 ^r88
  • Surviving Sepsis Campaign guideline on managing critically ill adults with COVID-19 recommends against using hydroxychloroquine ^r80
  • In patients admitted to hospital with COVID-19, Infectious Diseases Society of America recommends against hydroxychloroquine or chloroquine and against the combination of either of those drugs with azithromycin ^r8
  • NIH guidelines recommend against chloroquine or hydroxychloroquine in hospitalized patients; in nonhospitalized patients, they recommend against chloroquine or hydroxychloroquine except in a clinical trial. They recommend against high-dose chloroquine (600 mg twice daily for 10 days) and against the addition of azithromycin to hydroxychloroquine except in a clinical trial. The guidelines note that when chloroquine or hydroxychloroquine is used, patients must be monitored for adverse effects, particularly prolonged QTc interval ^r7
    • Scoring systems are available to determine risk of arrhythmia ^r89r90
  • WHO recommends against use of chloroquine or hydroxychloroquine with or without azithromycin outside of a clinical trial ^r24
  • 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 ^r91
  • 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 ^r92
• 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^r8 did not show significant differences in progression to mechanical ventilation or mortality
  • NIH COVID-19 treatment guideline,^r7Infectious Diseases Society of America guideline on treatment and management of COVID-19,^r8 and Surviving Sepsis Campaign guideline on managing critically ill adults with COVID-19^r81 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 ^r81
  • WHO recommends against use of lopinavir-ritonavir outside of a clinical trial ^r24
• Since last guideline updates, interim results of the WHO SOLIDARITY trial have been released in preprint form (not yet peer reviewed). 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 ^r93
  • 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. The impact of this study on treatment guidelines remains to be seen
• Studies on the therapeutic efficacy of convalescent plasma are underway in various countries^r94
  • Surviving Sepsis Campaign guideline on managing critically ill adults with COVID-19 suggests that convalescent plasma not be used outside of clinical trials ^r80
  • In patients admitted to hospital with COVID-19, Infectious Diseases Society of America recommends against convalescent plasma; in ambulatory patients, it recommends convalescent plasma only in the context of a clinical trial ^r8
  • NIH COVID-19 treatment guideline states that data are insufficient to recommend for or against use of convalescent plasma or hyperimmune immunoglobulin. It recommends against the use of non–SARS-CoV-2 IV immunoglobulin except in a clinical trial or unless there is another indication for it ^r7
  • WHO recommends against use of plasma therapy outside of a clinical trial
  • Since the publication of these guidelines, and based on emerging information, FDA has issued 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: ^r94
    • 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)
    • 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
  • FDA has produced a fact sheet^r95 for providers that includes labeling criteria (high versus low titer), suggested dosing and infusion practices, and potential adverse effects. It suggests starting with a single unit (about 200 mL), taking care to avoid fluid overload in patients with impaired cardiac function; additional doses may be administered based on the patient's response and clinician's judgment

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, tocilizumab^r81 and sarilumab,^r96 both monoclonal antibodies against interleukin-6 receptor; baricitinib^r73 and other Janus kinase inhibitors)

• Baricitinib
  • Baricitinib, a Janus kinase inhibitor currently approved for use in refractory rheumatoid arthritis owing to its antiinflammatory effect, has received emergency use authorization for treatment in combination with remdesivir for severely ill patients on oxygen supplementation (including mechanical ventilation or extracorporeal membrane oxygenation) ^r73
    • 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, O₂ 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 ^r73
    • NIH guidelines recommend use of baricitinib with dexamethasone alone or with remdesivir and dexamethasone in hospitalized patients on high-flow oxygen or noninvasive ventilation who have clinical or laboratory evidence of progressive disease ^r7
      • In patients receiving supplemental oxygen, the guideline panel found insufficient evidence to determine whether adding baricitinib to dexamethasone is of benefit; they recommend baricitinib plus remdesivir for such patients when corticosteroids cannot be used
    • Infectious Diseases Society of America guidelines recommend baricitinib plus remdesivir in hospitalized patients with severe COVID-19 when corticosteroids cannot be used, and they note uncertain benefits in patients who require mechanical ventilation. They recommend use of baricitinib in addition to remdesivir plus steroids only in the context of a clinical trial ^r8
• Tocilizumab
  • NIH COVID-19 treatment guideline recommends tocilizumab with dexamethasone alone or with remdesivir and dexamethasone in hospitalized patients on high-flow oxygen or noninvasive ventilation who have clinical or laboratory evidence of progressive disease ^r7
    • 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 ^r97
    • 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 ^r8
  • In patients admitted to hospital with COVID-19, Infectious Diseases Society of America suggests against the routine use of tocilizumab, based on evidence of low certainty, although it does 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 ^r8
  • Surviving Sepsis Campaign guideline on managing critically ill adults with COVID-19 states that data are insufficient to make a recommendation on the use of tocilizumab; the guideline did not evaluate other monoclonal antibodies ^r81
• WHO recommends against use of immunomodulators outside of a clinical trial ^r24

Corticosteroid therapy is not recommended for viral pneumonia but is suggested by some authorities for patients with COVID-19 who have refractory shock or respiratory insufficiency necessitating oxygen administration ^r24

• 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 ^r9r98
  • 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 ^r99
• Based on these data, NIH COVID-19 treatment guideline recommends use of dexamethasone in patients who require supplemental oxygen with or without mechanical ventilation (optional for patients who require oxygen supplementation only, that is, without high-flow oxygen, noninvasive ventilation, or invasive mechanical ventilation). It recommends against using dexamethasone in patients who do not require oxygen supplementation ^r7
  • 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 who are severely or critically ill with COVID-19, defined as SpO₂ of 94% or less on room air or any requirement for supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation, or with other end-organ dysfunction resulting from COVID-19 ^r8
  • Guideline provides equivalent doses of alternative glucocorticoids if dexamethasone is unavailable
  • Infectious Diseases Society of America recommends against the use of steroids in patients who are not hypoxemic
• 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 ^r80r81
• WHO recommends against routine use of corticosteroids for mild COVID-19, but strongly recommends use in severe COVID-19 ^r24

FDA is investigating a controversy that has arisen regarding the use of NSAIDs in patients with COVID-19; however, there is no published evidence connecting the use of NSAIDs with worsening COVID-19 symptoms ^r100

• NIH COVID-19 treatment guideline recommends that use of acetaminophen and NSAIDs in patients with COVID-19 should not differ from that in patients without COVID-19 ^r7
• A retrospective cohort study of acetaminophen and ibuprofen use in 403 patients with confirmed COVID-19 found that 32% of patients used acetaminophen and 22% used ibuprofen, at some point during the week before onset or during the course of illness, and that there were no differences between the 2 groups in mortality or need for respiratory support ^r101

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 ^r24

Based on concerns about the possible role of micro- and macrovascular thrombosis in the pathophysiology of this disease, the use of anticoagulation is being studied. At present, in the absence of a standard indication for it, published guidelines do not recommend therapeutic anticoagulation but do suggest or recommend use of usual prophylactic regimens in any hospitalized patient with COVID-19, including pregnant patients ^{r7r24r80r102r103r104r105}

• Some experts recommend risk assessment and consideration of continued prophylaxis for up to 45 days after discharge ^r102r104r106

Otherwise, treatment is largely supportive and includes oxygen supplementation and conservative fluid support; usual measures to prevent common complications (eg, pressure injury, stress ulceration, secondary infection) are applicable ^r24

Management of septic shock includes use of vasopressors if fluid administration does not restore adequate perfusion. Surviving Sepsis Campaign,^r81NIH COVID-19 treatment guideline,^r7 and WHO^r24 provide guidance specific to treatment of shock in patients with COVID-19 ^d2

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^r123 into the course of illness and may be quite abrupt ^r122c303
• For patients receiving chloroquine or hydroxychloroquine, monitoring of QTc is recommended ^r89
  • In hospitalized patients, perform ECG at baseline, 2 to 3 hours after second dose of drug, and daily thereafter
    • If QTc increases by more than 60 milliseconds or absolute QTc is greater than 500 milliseconds (or greater than 530 to 550 milliseconds if QRS exceeds 120 milliseconds), reduce dose and (if applicable) discontinue azithromycin
  • In outpatients, perform ECG at baseline, and on day 3, at 2 to 3 hours after dose is taken ^c304
    • If QTc increases by more than 30 to 60 milliseconds or absolute QTc is greater than 500 milliseconds (or greater than 530 to 550 milliseconds if QRS exceeds 120 milliseconds), consider discontinuing therapy
    • In patients deemed to be at low risk by Tisdale^r90 or similar score, may consider no further monitoring
• 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 ^r124c305

Complications

• Most common complication is acute respiratory distress syndrome; other reported complications include: ^r1r20c306d5
  • Septic shock ^c307d2
  • Acute kidney injury ^c308d6
  • Myocardial injury ^c309d7
  • Secondary bacterial and fungal infections ^c310c311
  • Multiorgan failure ^c312
  • Thrombotic events ^{r102c313c314c315}
  • Guillain-Barré syndrome ^r125c316
• Clinicians in Europe and the United States have reported emergence in children of an inflammatory syndrome resembling Kawasaki disease and thought to be associated with COVID-19.^{r126r127r128r129r130} Presentation may follow a diagnosis of or exposure to COVID-19. More recently, a number of adults^r131 have been reported with similar clinical findings and recent history of diagnosed COVID-19 or serologic evidence of recent infection ^c317d8
  • Characteristic features include: ^r128r129d9
    • Persistent fever ^c318
    • Hypotension, syncope, confusion ^{c319c320c321c322}
    • Headache ^c323
    • Sore throat, neck swelling ^{c324c325c326c327c328}
    • Cough, hypoxemia ^c329
    • Abdominal pain, vomiting and diarrhea ^{c330c331c332c333}
    • Rash, conjunctival injection, mucosal inflammation ^{c334c335c336c337c338}
    • Swelling of hands and feet ^c339
    • Lymphadenopathy ^c340c341c342
    • 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) ^c343c344c345
    • Abnormal blood cell counts: anemia, thrombocytopenia, neutrophilia ^{c346c347c348c349c350}
    • Indicators of multiorgan involvement: increased levels of creatinine, BUN, urine protein, transaminases, creatine kinase, troponins, and lactate dehydrogenase ^c351
    • 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
  • Diagnosis is based on clinical presentation and absence of an alternative explanation; CDC^r129 and WHO^r132 provide case definitions for reporting
    • In the absence of laboratory documentation of SARS-CoV-2, 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) ^d10
  • Several professional organizations provide guidance on management ^{r128r133r134r135}
    • 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, troponin, and B-type natriuretic peptide
    • Empiric antibiotic coverage pending culture results
    • Hospitalized children and those who fulfill criteria for Kawasaki syndrome should be treated with IV immunoglobulin 2 g/kg based on ideal body weight; glucocorticoids may be given in conjunction ^d9
      • Volume associated with IV immunoglobulin requires careful monitoring in patients with cardiac dysfunction
    • Low-dose aspirin should be administered to patients with Kawasaki-like features unless contraindicated (eg, thrombocytopenia); patients with aneurysms and a z score of 10 or higher, documented thrombosis, or an ejection fraction less than 35% should receive therapeutic anticoagulation in addition

Prognosis

• Patients who require hospital admission often require prolonged inpatient stay (more than 20 days) and experience significant deconditioning ^r1r20
• Otherwise, short-term and long-term prognosis (eg, recovery of pulmonary function) remains to be seen with time
• It is increasingly recognized that a substantial proportion of patients, including some who did not have severe manifestations of the acute infection, experience persistent symptoms and prolonged recovery. "Long COVID" or "postacute COVID-19" is most commonly characterized by the following symptoms persisting more than 3 weeks from onset of COVID-19: ^r136r137
  • Low-grade fever, which may come and go
  • Fatigue, which may be profound and may be sharply exacerbated by even mild exertion
  • Joint and/or muscle pain
  • Chest pain
  • Cough
  • Headache
  • Cognitive dysfunction
• It is not yet known whether recovery from infection is associated with protective immunity; reinfection has been documented, and the risk of reinfection may be increased with exposure to variant strains that have emerged in the United Kingdom, South Africa, and Brazil, although data are limited ^r123r138
• Mortality rate of diagnosed cases is generally about 3% but varies by country ^r11r12
• Case fatality rates are higher for patients in older age groups and with certain comorbidities
  • Case fatality rates by age in the United States: ^r42
    • 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: ^r123
    • 10.5% for cardiovascular disease
    • 7.3% for diabetes
    • 6.3% for chronic respiratory disease
    • 5.6% for cancer

Screening

Prevention

• Vaccines ^c356
  • Several vaccines against SARS-CoV-2 have entered use in various countries, and more are in development
    • After analyses of data from phase 3 trials, the vaccines in use received emergency or temporary authorizations from various national regulatory authorities under the emergency conditions of the pandemic, and future authorizations in more countries are pending
      • BNT162b2 (Pfizer-BioNTech COVID-19 vaccine) has received use authorization in the United States ^r143(where it has also received full FDA approval for persons aged 16 years and over^r144), the United Kingdom,^r145Canada,^r146 the European Union, and elsewhere. ^c357
      • Moderna COVID-19 vaccine (mRNA-1273) has received use authorization in the United States,^r147 the United Kingdom, Canada, the European Union, and elsewhere ^c358
      • Oxford-AstraZeneca COVID-19 vaccine has received authorization for temporary supply in the United Kingdom^r149 and similar authorizations in other countries. Pauses to investigate rare clotting events have occurred in various countries; vaccination has resumed in some areas based on public health risk-benefit assessments (ie, the apparent rarity of the adverse effect versus the relatively higher risk posed by COVID-19) ^r148c359
      • Janssen COVID-19 vaccine (Johnson and Johnson) has received use authorization in the United States;^r150 use was briefly paused but resumed^r151 with warnings about rare occurrences of cerebral venous sinus thrombosis and thrombocytopenia after administration. Authorizations elsewhere are pending ^c360
      • Various other vaccines are in use in many other countries (eg, BBIBP-CorV, CoronaVac, Sputnik V) but may not have authorizations from agencies that WHO designates with stringent regulatory authority status ^c361c362
    • WHO has issued emergency use listing for BNT162b2^r152 and the AstraZeneca COVID-19 vaccine,^r153 supporting the possibility of regulatory approval and distribution in countries that do not have the resources for an independent evaluation process
    • 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% ^r154
    • CDC recommends vaccination against COVID-19 for everyone aged 12 years and older
    • Efficacy of vaccine-induced immunity against disease caused by circulating variants is being assessed. Results will likely vary among vaccines and variants, but as of August 2021, CDC states that available evidence indicates that the Pfizer-BioNTech (Comirnaty), Moderna and Janssen (Johnson and Johnson) offer protection against known variants, and all strong recommendations in favor of vaccination remain in place (no evidence yet to support any change to those recommendations) ^r155
      • In the United States, the CDC Advisory Committee on Immunization Practices has recommended an additional (third) dose of mRNA vaccine for moderately or severely immunocompromised persons who have received the primary 2-dose series of mRNA vaccine
  • BNT162b2 (tozinameran; Comiranty) ^c363
    • 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% ^r145
      • 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 ^r143
      • 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 ^r143r145
    • 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 ^r143r145
      • 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 ^r143
      • Severe allergic reactions have been described, and facilities at which vaccine is administered must have the ability to treat such reactions (including anaphylaxis) ^r143
      • 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 ^{r156r157r158r159}
    • 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 ^r160
    • 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 ^r161
      • 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 ^r143
      • 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) ^r143
    • FDA approval for ages 16 and older was based on continued follow-up of initial study enrollees and additional data ^r144
  • Moderna COVID-19 vaccine (mRNA-1273) ^r162c364
    • Safety data evaluated for US emergency use authorization (and subsequently published^r163) 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^r164, and for post-anaphylaxis laboratory assessment^r165
      • 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 ^{r156r157r158r159}
  • AstraZeneca COVID-19 vaccine (ChAdOx1-S [recombinant]) ^r149c365
    • 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^r167 (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 ^r166
      • 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 ^r168
      • 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 ^r169c366
    • 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, due 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 ^r170
      • 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 women 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 ^r171
      • Collection and analysis of further data included 9 more cases, for a total of 15 affected persons, all of whom were women aged between 18 and 59 years
      • Specific risk factors for this complication have not been identified ^r151
  • CDC ^r157and the European Medicines Agency^r172 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 ^r157r172
    • American Society of Hematology recommends the following workup for suspected vaccine-induced immune thrombotic thrombocytopenia: ^r173
      • CBC and platelet count; 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
      • Platelet factor 4 platelet activation assay if platelet factor 4/heparin ELISA result is low positive or if the diagnosis is otherwise uncertain
    • Treatment recommendations from the American Society of Hematology include: ^r173
      • 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
        • Fondaprinux
        • Danaparoid
      • Low fibrinogen level or bleeding do not absolutely preclude anticoagulation, especially if platelet count exceeds 20,000 cells/mm³
      • Avoid platelet transfusion
    • Patients with isolated thrombocytopenia without thrombosis or positive test result for platelet factor 4/heparin may have idiopathic thrombocytopenic purpura, not vaccine-induced thrombotic thrombocytopenia ^r173
      • Immune thrombocytopenia has been reported following the AstraZeneca, Janssen, Moderna and Pfizer vaccines
      • Treatment includes IV immunoglobulin and/or steroids; platelet transfusions may be required for bleeding
  • Vaccine contraindications and use in special populations
    • Contraindications include: ^r157r169
      • Severe allergic reaction (eg, anaphylaxis) after a previous dose of a COVID-19 vaccine or 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)
    • Safety and efficacy of these vaccines in pregnant patients has not been determined; whether vaccine is excreted in breast milk is unknown ^{r143r145r149r162}
      • Based on mRNA vaccine data only, American College of Obstetricians and Gynecologists recommends that patients eligible for a COVID-19 vaccine be offered a vaccine regardless of pregnancy status. Patients planning to become pregnant who are eligible for a COVID-19 vaccine are encouraged to complete their vaccination series before conception to ensure maximal protection before pregnancy. If a patient becomes pregnant after the first dose, administer the second dose as indicated. If a patient becomes pregnant within 30 days of receipt of vaccine, encourage participation in CDC's V-safe program^r175 (a mobile phone–based monitoring and reminder system for recipients of COVID-19 vaccines) ^r174
    • Although safety and efficacy have not been studied specifically in patients with cancer, National Comprehensive Cancer Network has issued a recommendation that cancer patients 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 cancer patients ^r176
      • Exceptions include recent recipients of hematopoietic cell transplant or cellular therapy (who should delay vaccination for 3 months) and patients with hematologic malignancies who are neutropenic (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
    • Other immunocompromised persons may receive COVID-19 vaccine, although safety and efficacy data are limited; in particular, they should be counseled that they may not develop a robust immune response. This CDC recommendation is currently specific to mRNA vaccines but will likely be generalized ^r157
    • History of COVID-19 is not a contraindication to vaccine; in fact, guidelines recommend that such persons be offered vaccine, although not until after recovery from the acute illness. Persons who received treatment with convalescent plasma or COVID-specific monoclonal antibodies should defer vaccination for 90 days ^r157
    • Little clinical information exists on the use of vaccine in persons with autoimmune disease, 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 ^r157
    • History of Guillain-Barré syndrome (postinfectious polyneuritis) is not considered to be a contraindication ^r157
    • 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 ^r157
    • 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 ^r157
      • In the United States, the CDC Advisory Committee on Immunization practices has recommended an additional (third) dose of mRNA to moderately and severely immunocompromised persons who were previously vaccinated with the 2-dose series of mRNA vaccine ^r155
  • Until vaccine is widely available, some jurisdictions have developed stratified distribution schemes based on likelihood of exposure (health care workers, first responders) and risk for severe disease (older age, comorbidities) ^{r177r178r179r180}
  • 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)
    • In the United States, emergency use authorizations require health care providers to communicate to the patient, parent, or caregiver information consistent with the vaccine-specific (manufacturer-specific) fact sheet for recipients and caregivers^r181r182r183 before each patient receives the vaccine; such information includes the following: ^r143
      • 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
    • In the United States, emergency use authorizations require health care providers to report^r169r143r162 all vaccine administration errors, exposures during pregnancy, and serious adverse events to VAERS (Vaccine Adverse Event Reporting System)^r184 and to the manufacturer (via Pfizer online report form,^r185 email to ModernaPV@modernatx.com,^r162 or at the Janssen COVID-19 vaccine website^r186) 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
    • 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^r187
  • 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 ^r143r162r175
    • For the mRNA vaccines, CDC advises that second doses that are administered up to 4 days early are considered valid, as are doses that are administered later than the prescribed interval but within 42 days after the first dose ^r157
    • There are no data available on the interchangeability of the COVID-19 vaccines to complete the 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 ^r157
      • In cases in which the original mRNA vaccine manufacturer cannot be verified or the same type of vaccine cannot be obtained, it is permissible to administer either mRNA vaccine or (if no mRNA vaccine is available) the Janssen (Johnson and Johnson) vaccine 28 days after the first dose ^r155
    • 14-day interval is recommended between administration of COVID-19 vaccine and other immunizations unless the need for the other vaccine is deemed urgent (eg, tetanus or rabies prophylaxis) ^r157
  • Vaccine recipients are encouraged to participate in CDC's V-safe monitoring and reminder system,^r175 available as a mobile phone app ^r162

  • 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
    BNT162b2 (tozinameran; Comirnaty)	Pfizer-BioNTech	Nucleoside-modified mRNA of SARS-CoV-2	12 years or older	30 mcg (0.3 mL) intramuscular injection (deltoid) × 2 doses	21 days	FDA approved in the United States for ages 16 years and older; under EUA for other age groups in the United States, and under temporary use authorization in the United Kingdom
    Moderna COVID-19 vaccine (mRNA-1273)	ModernaTX	Synthetic mRNA of SARS-CoV-2	18 years or older	100 mcg (0.5 mL) intramuscular injection	1 month	Investigational; under EUA in the United States and temporary 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	Not applicable (single dose only)	Investigational; under EUA in the United States (use in the United States was paused then resumed in April 2021)

• Post-exposure prophylaxis ^r84
  • In the United States, emergency use authorization has been issued for the use of monoclonal antibodies casirivimab and imdevimab (in combination) as post-exposure prophylaxis of persons aged 12 years and older and weighing at least 40 kg who are at high risk for progression to severe COVID-19 in the following circumstances:
    • Exposed person is not fully vaccinated or not expected to develop protective immunity following vaccination because of immunocompromise (including immunosuppressive treatment) AND
    • Close contact with a person who has infection due to 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
      • Close contact is defined at being within 6 feet for 15 minutes or longer; providing care for a person with COVID-19; close personal contact (hugging, sharing eating or drinking utensils; exposure to respiratory droplets expelled by a cough or sneeze by an infected person
    • Initial dose is casirivimab 600 mg IV or subcutaneously plus imdevimab 600 mg IV or subcutaneously as soon as possible after the exposure. In circumstances of ongoing exposure, additional 300 mg may be administered at 4-week intervals
• Safety recommendations vary geographically and depend on vaccination status and regional disease activity
  • In the United States, subject to more stringent local or state policy, fully vaccinated persons do not need to use masks or observe social distancing; may resume travel; and do not require testing or quarantine after a known exposure unless they develop symptoms suggestive of COVID-19 ^r13
  • For unvaccinated persons and for the general population in regions where prevalence and transmission of COVID-19 remain high, avoidance of ill persons and diligent hand and cough hygiene are recommended, and physical distancing and mask use are recommended ^c367c368
    • Advise as follows:
      • If sick, stay home and call doctor ^r188
      • Avoid large gatherings and unnecessary gatherings; stay home except for critical needs (eg, to resupply food and medicines) during acceleration phase of pandemic or subsequent regional flare-ups
        • Telecommute if nature of job makes it possible
        • When going out in public is unavoidable, cover mouth and nose with a face mask ^r188
        • Greet others without touching; nod or wave instead of shaking hands or hugging. Try to maintain physical distance: at least 1 m (3 ft), preferably 2 m (6 ft)^r188
        • Psychological and emotional toll of physical distancing from family and friends can be mitigated with nonphysical interaction (eg, phone calls, texting, video chats)
      • Wash hands often and thoroughly. Soap and water are best. High-alcohol hand sanitizers are acceptable until next possible handwashing ^r188
      • Cover coughs. Use tissue and throw it away; second choice is sleeve, not hand ^r188
      • Avoid touching face ^r188
• Patients with COVID-19 managed at home
  • 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 cloth face cover during any contact with household members ^{r189c369c370c371}
    • 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
  • Household members/caregivers should:
    • Ideally, wear face mask, gown, and gloves when caring for patient, and remove and discard all when leaving the room (do not reuse); however, if some of these supplies are absent, wear cloth face cover and scrupulously wash hands and laundry ^c372c373c374
      • 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 ^c375c376
    • Not share personal items such as towels, dishes, or utensils before proper cleaning ^c377c378
    • Wash laundry and high-touch surfaces frequently ^c379
      • Wear disposable gloves to handle dirty laundry and use highest possible temperatures for washing and drying, based on washing instructions on the items ^c380c381
      • Clean surfaces with diluted bleach solution or an EPA-approved disinfectant ^c382
    • Restrict contact to minimum number of caregivers and, in particular, ensure that persons with underlying medical conditions are not exposed to the patient
• COVID-19 patients managed in health care facilities (outpatient or inpatient) ^r70r190
  • CDC provides preparedness checklists^r191 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 ^c383c384c385
    • Gloves, gowns, eye protection, and respirator (N95 or better) with adherence to hospital donning and doffing protocols ^c386c387
      • 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; WHO^r190 suggests using 70% ethyl alcohol ^c388c389
• Criteria for discontinuation of isolation precautions ^r124r138r192
  • CDC recommends that a symptom-based strategy should be used to determine when to discontinue isolation in most patients. Two sets of criteria have been established based on observations^r138 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 to moderate illness, no immunocompromise:
      • At least 10 days have passed since symptom onset and
      • At least 24 hours have passed since last fever without use of antipyretics and
      • Symptoms have improved
      • If illness has been entirely asymptomatic, 10 days from first positive specimen is acceptable criterion
    • Severe or critical illness, or immunocompromising condition:
      • At least 10 days and up to 20 days have passed since symptom onset and
      • At least 24 hours have passed since last fever without use of antipyretics and
      • Symptoms have improved
      • For severely immunocompromised persons whose infection has been entirely asymptomatic, precautions may be discontinued when at least 10 days and up to 20 days have passed since first positive specimen
  • A test-based strategy is no longer advised in most cases, because many persons have prolonged positivity reflecting detection of noninfective viral particles. It may be used at discretion of provider (eg, in immunocompromised patients)
    • Demonstration of negative results of molecular assays for SARS-CoV-2 RNA on 2 consecutive respiratory specimens obtained at least 24 hours apart (a single specimen suffices for each test)