COVID-19: Questions and answers

Written by the physician editors at UpToDate

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: November 2022. | This topic last updated: December 12, 2022.

This topic provides answers to some of the most commonly asked questions by UpToDate users. Additional content on COVID-19 is provided separately and can be accessed through the UpToDate COVID-19 homepage or through the links provided below. (See 'Related UpToDate content' below.)

VIROLOGY AND TRANSMISSION

How is SARS-CoV-2 (the virus that causes COVID-19) transmitted?

Direct person-to-person respiratory transmission is the primary means of transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is thought to occur mainly through close-range contact (ie, within approximately six feet or two meters) via respiratory particles; virus released in the respiratory secretions when a person with infection coughs, sneezes, or talks can infect another person if it is inhaled or makes direct contact with the mucous membranes. Infection might also occur if a person's hands are contaminated by these secretions or by touching contaminated surfaces and then they touch their eyes, nose, or mouth, although contaminated surfaces are not thought to be a major route of transmission.

SARS-CoV-2 can also be transmitted longer distances through the airborne route (through inhalation of particles that remain in the air over time and distance), but the extent to which this mode of transmission has contributed to the pandemic is unclear. Scattered reports of SARS-CoV-2 outbreaks (eg, in a restaurant, on a bus) have highlighted the potential for longer-distance airborne transmission in enclosed, poorly ventilated spaces.

While SARS-CoV-2 RNA has been detected in non-respiratory specimens (eg, stool, blood), neither fecal-oral nor bloodborne transmission appear to be significant sources of infection. SARS-CoV-2 infection has been described in animals, but there is no evidence to suggest that animals are a major source of transmission. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Transmission'.)

What is the incubation period for COVID-19?

The incubation period for COVID-19 is thought to be within 14 days following exposure, with most cases occurring approximately three to five days after exposure. The incubation period also varies by viral variant. For example, the incubation period for the Omicron variant (B.1.1.159) appears to be slightly shorter than other variants, with symptoms first appearing around three days after exposure. (See "COVID-19: Clinical features", section on 'Incubation period'.)

What are some of the important SARS-CoV-2 variants?

Multiple SARS-CoV-2 variants have circulated globally since the beginning of the pandemic. Some variants contain mutations in the surface spike protein, which mediates viral attachment to human cells and is a target for natural and vaccine-induced immunity. Thus, these variants have the potential to be more transmissible, cause more severe disease, and/or evade natural or vaccine-induced immune responses. Some of the more important circulating variants are:

●Omicron (B.1.1.529 lineage) was first reported from southern Africa in November 2021 and became the prevalent variant worldwide. Subsequently, various Omicron sublineages (BA.2, then BA.2.12.1, BA.4, and BA.5) with increasingly greater replication advantages emerged, replacing the previous predominant sublineage. Omicron sublineages evade infection- and vaccine-induced humoral immunity to a greater extent than prior variants but are associated with less severe disease.

Other variants that were dominant earlier in the pandemic are no longer widely circulating:

●Alpha (B.1.1.7 lineage), also known as 20I/501Y.V1, was first identified in the United Kingdom in late 2020. This variant was more transmissible than wild-type virus.

●Delta (B.1.617.2 lineage), also known as 20A/S:478K, was identified in late 2020 in India. This variant was more transmissible than B.1.1.7 and was also associated with more severe disease.

These and other variants are listed in this table (table 1) and discussed separately. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Variants of concern' and "COVID-19: Vaccines", section on 'Waning effectiveness over time and with variants of concern'.)

CLINICAL PRESENTATION

What are the clinical presentation and natural history of COVID-19?

The spectrum of illness associated with COVID-19 is wide, ranging from asymptomatic infection to life-threatening respiratory failure. When symptoms are present, they typically arise three to five days after exposure. Most symptomatic infections are mild. Nasal congestion, sneezing, sore throat, cough, myalgias, and headache are the most commonly reported symptoms. Other features, including diarrhea and smell or taste abnormalities, are also well described (table 2).

Pneumonia, with fever, cough, dyspnea, and infiltrates on chest imaging, is the most frequent serious manifestation of infection. Progression from dyspnea to acute respiratory distress syndrome (ARDS) can be rapid; thus, the onset of dyspnea is generally an indication for hospital evaluation and management.

ARDS can be associated with an exuberant inflammatory response, which is characterized by fever, progressive hypoxia and/or hypotension, and markedly elevated inflammatory markers. Other complications of severe illness include thromboembolic events, acute cardiac injury, kidney injury, and inflammatory complications.

The time to recovery is highly variable and depends on age and pre-existing comorbidities in addition to illness severity. Individuals with mild infection are expected to recover relatively quickly (eg, within two weeks), whereas many individuals with severe disease have a longer time to recovery (eg, two to three months). The most common persistent symptoms include fatigue, dyspnea, chest pain, cough, and cognitive deficits.

The overall case fatality rate in unvaccinated individuals is estimated to be between 0.15 and 1 percent, although it varies widely by age and other patient characteristics. While severe and fatal illness can occur in anyone, the risk rises with age and the presence of chronic illnesses, including cardiovascular disease, pulmonary disease, diabetes mellitus, kidney disease, and cancer (table 3). (See "COVID-19: Clinical features".)

What factors are associated with severe COVID-19?

Severe illness can occur in otherwise healthy individuals of any age, but it predominantly occurs in adults with advanced age and/or certain underlying medical comorbidities and among those who are not vaccinated. These comorbidities and other less common comorbidities are compiled in a table by the United States Centers for Disease Control and Prevention (CDC); the strength of evidence informing each association varies (table 3). (See "COVID-19: Clinical features", section on 'Risk factors for severe illness'.)

Is COVID-19 caused by the Omicron variant less severe than infection caused other variants?

Early data suggest that COVID-19 caused by the Omicron variant is less severe than infection caused by prior variants. Some studies have shown a reduced risk of hospitalization, intensive care unit admission, and in-hospital mortality. The relative mildness of disease reported in these studies may reflect the younger age of individuals impacted at this stage of the surge or a higher proportion of reinfections. While illness due to the Omicron may be milder, the high volume of cases continues to lead to high hospitalization rates and may result in excess burden on the health care system. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Omicron (B.1.1.529) and its sublineages'.)

COMPLICATIONS AND ASSOCIATED SYNDROMES

What are the major cardiac complications in patients with COVID-19? And how often do they occur?

Cardiac manifestations are common in hospitalized patients and occur most frequently in critically ill patients. The most common complications are listed here:

●Cardiac troponin elevation, which is a biomarker of myocardial injury, occurs in approximately 10 to 35 percent of hospitalized patients. In the majority of these patients, cardiac signs and symptoms are not present and the cause of the troponin rise is not acute myocardial infarction (MI). However, patients with a clinical presentation (including history or electrocardiogram) suggestive of acute MI require prompt evaluation and treatment.

Usually, troponin elevation in COVID-19 patients is due to other causes of myocardial injury including stress cardiomyopathy, hypoxic injury, myocarditis, right heart strain, microvascular dysfunction, and systemic inflammatory response syndrome. For those without suspected acute MI, further evaluation is focused on testing expected to impact management.

●Arrhythmias have been reported in approximately 5 to 20 percent of hospitalized cases, and most are asymptomatic. Causes may include hypoxia, electrolyte abnormalities, myocardial injury, and drug effects (such as QT-prolonging agents).

●Heart failure is the most common symptomatic cardiac complication. Data on its incidence are limited; however, its presence is associated with increased mortality. Heart failure in patients with COVID-19 may be precipitated by acute illness in patients with pre-existing heart disease (eg, coronary artery disease or hypertensive heart disease) or by an acute myocardial injury (eg, stress cardiomyopathy or acute MI).

The long-term risk of cardiovascular disease (eg, myocardial infarction, arrhythmias, heart failure, stroke) may also be elevated in patients who have had COVID-19. (See "COVID-19: Evaluation and management of cardiac disease in adults" and "COVID-19: Myocardial infarction and other coronary artery disease issues" and "COVID-19: Arrhythmias and conduction system disease" and "COVID-19: Cardiac manifestations in adults", section on 'Long-term cardiovascular effects'.)

What are the major thrombotic complications in patients with COVID-19?

COVID-19 is a hypercoagulable state associated with an increased risk of venous thromboembolism (VTE; including deep vein thrombosis and pulmonary embolism) and arterial thrombosis, including stroke, myocardial infarction, and possibly limb ischemia. The risk is highest in individuals in the intensive care unit (ICU), often despite prophylactic anticoagulation. Bleeding is not common but has been seen, especially in the setting of trauma and/or anticoagulation. (See "COVID-19: Hypercoagulability", section on 'VTE'.)

What are the most common dermatologic syndromes associated with COVID-19?

The most common cutaneous findings reported in patients with COVID-19 include an exanthematous (morbilliform) rash, pernio-like acral lesions, livedo-like lesions, retiform purpura, necrotic vascular lesions, urticaria, vesicular (varicella-like) eruptions, and erythema multiforme-like lesions. An erythematous, polymorphic rash has also been associated with a related multisystem inflammatory syndrome in children. The frequency of cutaneous findings is estimated to range from less than 1 percent to 20 percent of patients with COVID-19.

Uncertainty remains about the strength and mechanisms of associations between reported skin findings and COVID-19. The timing of the appearance of cutaneous findings in relation to the course of COVID-19 has varied, with reports describing skin changes occurring prior to, concomitantly, or following symptoms of COVID-19. (See "COVID-19: Cutaneous manifestations and issues related to dermatologic care".)

What is multisystem inflammatory syndrome associated with COVID-19?

Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious condition that has been reported in patients with current or recent COVID-19 infection or exposure. It shares clinical features with Kawasaki disease (KD), KD shock, and toxic shock syndrome. Clinical features include persistent fever, severe illness with involvement of multiple organ systems, and elevated inflammatory markers (table 4). Most children with MIS-C have survived, although some have required intensive care. Intravenous immune globulin is suggested in all patients who meet criteria for MIS-C, along with glucocorticoids in those with moderate or severe manifestations (algorithm 1). (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis" and "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) management and outcome".)

A very similar syndrome has also been reported in adults in association with COVID-19 infection or exposure and is termed multisystem inflammatory syndrome in adults (MIS-A). (See "COVID-19: Care of adult patients with systemic rheumatic disease", section on 'COVID-19 as a risk factor for rheumatologic disease'.)

What is "long-COVID"?

"Long-COVID," also referred to as post-COVID conditions, post-COVID syndrome, or postacute sequelae of SARS-CoV-2 infection (PASC), generally refers to symptoms that develop during or after acute COVID-19 illness, continue for ≥2 months (ie, 3 months from symptom onset), and are not explained by an alternative diagnosis. It is not yet known whether "long-COVID" represents a new syndrome unique to COVID-19 or overlaps with recovery from similar illnesses. (See "COVID-19: Evaluation and management of adults with persistent symptoms following acute illness ("Long COVID")", section on 'Terminology and stages of recovery'.)

Persistent physical symptoms following acute COVID-19 are common and typically include fatigue, dyspnea, chest pain, and cough. Headache, joint pain, dysgeusia, myalgias, and diarrhea have also been reported. Common psychological and cognitive symptoms include poor concentration, insomnia, anxiety, and depression. The time to symptom resolution depends primarily on premorbid risk factors, the severity of the acute illness, and the spectrum of initial symptoms. However, prolonged symptoms are common even in patients with less severe disease who were never hospitalized. (See "COVID-19: Evaluation and management of adults with persistent symptoms following acute illness ("Long COVID")", section on 'Expected recovery time course'.)

CLINICAL EVALUATION

Is there a way to distinguish COVID-19 clinically from other respiratory illnesses, particularly influenza?

No, the clinical features of COVID-19 overlap substantially with influenza and other respiratory viral illnesses. There is no way to distinguish among them without testing. (See "COVID-19: Clinical features".)

When should patients with confirmed or suspected COVID-19 be advised to stay at home? Have an in-person clinical evaluation?

Home management is appropriate for most patients with mild symptoms (eg, fever, cough, and/or myalgias without dyspnea), provided they can be adequately isolated, monitored, and supported in the outpatient setting. In addition, outpatients who have mild to moderate symptoms and risk factors for severe disease (table 3) or who are ≥65 years of age are candidates for early treatment with COVID-19-specific therapy (algorithm 2). (See 'Which non-hospitalized patients should receive COVID-19-specific therapy?' below.)

Patients being managed at home should be educated about the potential for worsening disease and advised to closely monitor for symptoms such as new or worsening dyspnea, dizziness, or mental status changes. The development of these symptoms should prompt clinical evaluation and may indicate the need for hospitalization.

LABORATORY EVALUATION

What laboratory abnormalities are commonly seen in patients with COVID-19?

Common laboratory abnormalities among hospitalized patients with COVID-19 include:

●Lymphopenia

●Elevated aminotransaminase levels

●Elevated lactate dehydrogenase levels

●Elevated inflammatory markers (eg, ferritin, C-reactive protein, and erythrocyte sedimentation rate)

Abnormalities in coagulation testing, elevated procalcitonin levels, and elevated troponin levels have also been reported. The degree of these abnormalities tends to correlate with disease severity. (See "COVID-19: Epidemiology, virology, and prevention".)

What are the major coagulation abnormalities in patients with COVID-19?

A number of laboratory abnormalities have been reported, including high fibrinogen and D-dimer and mild prolongation of the prothrombin time (PT) and activated partial thromboplastin time (aPTT). Abnormal coagulation studies are mainly used to monitor clinical status and to help determine level of care. Very high D-dimer is associated with a high mortality rate. Atypical findings (eg, severe thrombocytopenia) should be further evaluated. (See "COVID-19: Hypercoagulability", section on 'Coagulation abnormalities'.)

DIAGNOSTIC TESTING

What tests are used to diagnose COVID-19?

There are two types of viral tests used to make the diagnosis of COVID-19 (table 5):

●Nucleic acid amplifications tests (NAATs; eg, reverse-transcription polymerase chain reaction [RT-PCR]) – These detect viral RNA and are the most sensitive viral tests. They are usually laboratory-based tests, although point-of-care and home NAATs are also available. NAAT is performed primarily on upper respiratory specimens (including nasopharyngeal swabs, nasal swabs, and saliva) but can also be performed on lower respiratory tract samples.

A positive NAAT confirms the diagnosis of SARS-CoV-2 infection, although patients can have a positive NAAT for weeks after the onset of infection. For most individuals, a single negative NAAT is sufficient to exclude the diagnosis. However, false-negative NAAT tests (eg, RT-PCR) are well documented. If initial testing is negative, but the suspicion for COVID-19 remains, and determining the presence of infection is important for management or infection control, we suggest repeating the test. For hospitalized patients with evidence of lower respiratory tract involvement, the repeat test can be performed on expectorated sputum or a tracheal aspirate, if available. (See "COVID-19: Diagnosis", section on 'NAAT interpretation'.)

●Antigen tests – These detect viral protein and can be performed rapidly at home or at the point of care. Antigen tests are only validated for use with nasopharyngeal or nasal swabs. Positive tests are indicative of SARS-CoV-2 infection. Because they are less sensitive than NAAT, negative antigen tests performed for symptoms or recent exposure should generally be confirmed with repeat testing (algorithm 3). (See "COVID-19: Diagnosis", section on 'Antigen test interpretation'.)

In general, we suggest NAAT, if readily available with reasonable turnaround time (eg, within 24 to 48 hours), because of its superior sensitivity. However, antigen tests are more accessible, more convenient, provide results faster than laboratory-based NAAT, and are good alternatives as long as users appreciate the potential need for repeat testing to optimize sensitivity. (See "COVID-19: Diagnosis", section on 'Diagnostic approach'.)

What is the role of antibody testing? — Serologic tests measure antibodies to SARS-CoV-2. Because serologic tests are less likely to be reactive in the first several days to weeks of infection, they have very limited utility for diagnosis in the acute setting. They are primarily used to identify patients who have had COVID-19 in the past as well as patients with current infection who have had symptoms for three to four weeks. Sensitivity and specificity are highly variable, and cross-reactivity with other coronaviruses has been reported. (See "COVID-19: Diagnosis", section on 'Serology to identify prior/late infection'.)

COVID-19 vaccination elicits antibodies against the SARS-CoV-2 spike protein. Some serologic tests detect anti-spike antibodies, and these tests cannot distinguish between prior infection and prior vaccination (a reactive result could indicate prior infection, prior vaccination, or both). Some serologic tests only detect antibodies against nucleocapsid protein; vaccines authorized in the United States, Canada, and Europe do not elicit such antibodies, so a reactive result on a nucleocapsid protein-based serologic test in an individual who has received one of these vaccines would suggest a history of infection. (See "COVID-19: Diagnosis", section on 'Testing following COVID-19 vaccination'.)

Serologic testing following vaccination to confirm an antibody response or to determine whether to give additional doses of vaccine (eg, booster doses) is not indicated. Many serologic tests do not detect the type of antibodies elicited by vaccination, and precise immune correlates of protection remain uncertain.

What are the indications for testing asymptomatic individuals?

The primary indication for testing asymptomatic individuals is recent close contact with an individual with COVID-19. We suggest post-exposure testing five to seven days after exposure, although the optimal timing is uncertain.

Screening may also be performed in high-risk settings, such as certain congregate settings (eg, long-term care facilities, correctional and detention facilities, homeless shelters), and among hospitalized patients in high-prevalence regions. Screening may also be indicated prior to time-sensitive surgical procedures or aerosol-generating procedures and prior to receiving immunosuppression. (See "COVID-19: Diagnosis", section on 'Whom to test'.)

Can SARS-CoV-2 variants be reliably detected by available diagnostic assays?

Thus far, yes. Most circulating SARS-CoV-2 variants have mutations in the S gene, which encodes the viral spike protein (table 1).

While many nucleic acid amplification tests target the S gene, they also target other genes. Thus, if a mutation alters one gene target, the other gene targets still function and the test will detect the virus, including the Omicron subvariants.

Notably, some Omicron subvariant viruses contain a mutation that results in S gene target failure for some assays. S gene failure can be used as a marker for the Omicron variant; however, it is nonspecific and can occur with other variants, such as Alpha. Additionally, S gene detection does not rule out Omicron. Most antigen tests target nucleocapsid protein, so mutations in the spike protein would not impact the accuracy of these tests. While the Omicron variant does contain mutations in the gene that encodes the nucleocapsid, antigen testing is thought to be unaffected. (See "COVID-19: Diagnosis", section on 'Impact of SARS-CoV-2 mutations/variants on test accuracy'.)

HOME CARE

Which non-hospitalized patients should receive COVID-19-specific therapy?

COVID-19-specific therapy has been authorized for non-hospitalized patients who have mild to moderate COVID-19 and are at increased risk for progression to severe disease. Specifically, we recommend COVID-19-specific therapy for symptomatic outpatients in the following categories (algorithm 2):

●Adults ≥65 years old, regardless of vaccination status or other risk factors for severe disease (table 3). Those with risk factors are likely to benefit more from treatment than those without because their risk of severe disease may be higher. Nevertheless, advanced age alone is likely associated with a sufficiently high risk of progression to warrant COVID-19-specific therapy.

●Adults of any age who have a moderate to severe immunocompromising condition (table 6), regardless of vaccination status or receipt of pre-exposure prophylaxis.

●Adults of any age who have multiple risk factors for progression to severe disease (table 3), regardless of vaccination status.

●Adults ≥50 years old who are not vaccinated, regardless of risk factors.

If supplies of COVID-19-specific therapies are limited, we prioritize treatment for those at the highest risk of severe disease according to risk tiers outlined by the NIH COVID-19 treatment guidelines panel (table 7). The highest risk groups are immunocompromised individuals who are likely to have a suboptimal response to vaccination and unvaccinated or incompletely vaccinated individuals.

Among individuals who are up to date with COVID-19 vaccinations and have no medical comorbidities, the specific age threshold that should prompt treatment with COVID-19-specific therapy is uncertain. Although the Centers for Disease Control and Prevention (CDC) identifies 50 years as the age threshold for increased risk of severe COVID-19, the risk of severe hospitalization and death does not steeply increase until after age 65 years. Thus, we do not routinely offer COVID-19-specific therapy to immunocompetent, healthy individuals ≤64 years who are up to date with recommended COVID-19 vaccinations (figure 1) and have no other risk factors for progression to severe disease (table 3).

We also do not recommend COVID-19-specific therapy for individuals who have asymptomatic SARS-CoV-2 infection. (See "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Indications for treatment'.)

The treatment of children is discussed in detail elsewhere. (See "COVID-19: Management in children", section on 'Outpatient therapy for select children'.)

What are the preferred COVID-19-specific therapies for non-hospitalized patients?

Nirmatrelvir-ritonavir (Paxlovid), a combination of oral protease inhibitors, is our preferred option for COVID-19-specific therapy for symptomatic outpatients at risk for progression to severe disease. It substantially reduces the risk of hospitalization and mortality in outpatients who have mild to moderate COVID-19 (algorithm 2).

Nirmatrelvir-ritonavir should be administered within five days of symptom onset. It is not recommended for individuals who have severe kidney impairment (estimated glomerular filtration rate [eGFR] <30 mL/min) or severe hepatic impairment (Child-Pugh class C). It also has expected drug interactions with many medications, although some of those interactions can be mitigated by holding or dose-reducing the co-medication. Specific drug interactions can be checked through the Lexicomp Drug Interaction tool embedded in UpToDate or the drug interaction checker from the University of Liverpool.

If nirmatrelvir-ritonavir cannot be used, we generally choose remdesivir as the preferred alternative option. It reduces COVID-19-associated hospitalization but requires three intravenous (IV) doses over three days and thus may be operationally challenging to administer. Administration through infusion centers may also help improve access.

High-titer convalescent plasma is another potential option but requires processes for collection, screening, and quantification that may not be widely available.

Monoclonal antibody bebtelovimab was previously an option but is not active against increasingly prevalent new Omicron variants worldwide (eg, BQ1.1) (table 1). In settings with high prevalence of SARS-CoV-2 variants that are susceptible to bebtelovimab, it can still be considered a reasonable alternative option.

We do not offer molnupiravir as treatment of mild to moderate COVID-19 because it has not been proven to reduce risk of hospitalization or death. (See "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Nirmatrelvir-ritonavir as preferred therapy' and "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Alternative options'.)

How is nirmatrelvir-ritonavir (Paxlovid) dosed?

The dose of nirmatrelvir-ritonavir depends on the kidney function, and there are two different packaging configurations for the different doses:

●For patients with normal kidney function (eGFR ≥60 mL/min) – The dose is nirmatrelvir 300 mg-ritonavir 100 mg orally twice daily for five days. The dose pack contains two 150 mg nirmatrelvir tablets and one 100 mg ritonavir tablet to be taken together for each dose.

●For patients with moderate kidney impairment (eGFR 30 to 59 mL/min) – The dose is nirmatrelvir 150 mg-ritonavir 100 mg orally twice daily for five days. The dose pack contains one 150 mg nirmatrelvir tablet and one 100 mg ritonavir tablet to be taken together for each dose.

For patients without a recent eGFR and in whom there is no suspicion for kidney impairment, it is reasonable to administer full-dose nirmatrelvir-ritonavir without checking a creatinine level.

Prior to prescribing nirmatrelvir-ritonavir, clinicians should assess for potential drug interactions. Specific drug interactions can be checked through the Lexicomp Drug Interaction tool embedded in UpToDate or the drug interaction checker from the University of Liverpool. These tools also offer specific guidance about whether holding or dose-reducing the co-medication can mitigate the potential interaction. (See "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Nirmatrelvir-ritonavir as preferred therapy'.)

What is rebound COVID-19?

“Rebound COVID-19” refers to recurrence of symptoms following initial improvement and/or increase in SARS-CoV-2 viral levels following initial decline (eg, as reflected by return to antigen positivity following conversion to negative antigen testing) within the first few weeks following infection. Increasing reports have described symptom and viral rebound following nirmatrelvir-ritonavir use. We advise patients of the possibility of rebound with nirmatrelvir-ritonavir but do not consider it a reason to avoid treatment in those at risk for progression to severe disease (such as those with advanced age or multiple comorbidities).

The frequency of rebound COVID-19 following nirmatrelvir-ritonavir is uncertain; some studies have reported rates of 1 to 2 percent, whereas clinical experience suggests it occurs slightly more frequently. Recurrent symptoms are typically mild. Rebound is not unique to nirmatrelvir-ritonavir and has been described in individuals with COVID-19 who have not received antiviral treatment.

Patients who have recurrent symptoms following nirmatrelvir-ritonavir treatment should undergo antigen testing. Those who have a repeat positive antigen test should restart the isolation period (algorithm 4). (See "COVID-19: Management of adults with acute illness in the outpatient setting", section on '"Rebound" COVID-19 after nirmatrelvir-ritonavir treatment'.)

How long should patients cared for at home stay isolated?

The United States Centers for Disease Control and Prevention (CDC) has issued recommendations for discontinuing home isolation in the general community. A symptom- or time-based strategy is preferred for most patients.

For symptomatic immunocompetent patients with mild disease who are cared for at home, isolation can usually be discontinued when the following criteria are met (algorithm 4):

●At least five days have passed since symptoms first appeared (day 0 is the date of symptom onset) AND

●At least one day (24 hours) has passed since resolution of fever without the use of fever-reducing medications AND

●There is improvement in symptoms (eg, cough, shortness of breath)

After discontinuing home isolation, patients should continue to wear a well-fitting mask around others. The total duration of isolation plus strict masking is typically 10 days. However, a test-based strategy (two negative rapid antigen tests at least 48 hours apart) may be preferred for determining the duration of masking in some people, such as those who live or work with individuals at high risk for severe disease in settings where masks are not required. Additional information on restrictions (eg, travel) after the five-day isolation period can be found on the CDC website.

For patients who did not have symptoms at the time of laboratory-confirmed SARS-CoV-2 infection, home isolation can usually be discontinued when at least five days have passed since the positive COVID-19 test (followed by strict mask wearing for an additional five days), as long as there was no evidence of subsequent illness.

Although this strategy can be used for many patients, home isolation should continue for a total of 10 days if strict mask wearing is not possible or if the patient had moderate disease. In addition, this strategy should not be used for those who had severe disease or are immunocompromised; for such patients, the duration of isolation may need to be extended beyond 10 days and/or testing may be needed to confirm resolution. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection", section on 'Discontinuation of precautions'.)

What is the significance of a persistently positive RT-PCR for weeks after illness?

Patients diagnosed with COVID-19 can have detectable SARS-CoV-2 RNA in upper respiratory tract specimens for weeks after the onset of symptoms. However, prolonged viral RNA detection does not necessarily indicate prolonged infectiousness. According to the CDC, isolation of infectious virus more than 10 days after illness onset is rare in patients whose symptoms have resolved.

People with COVID-19 are thus generally felt to have low infectiousness after about 10 days, particularly after mild to moderate disease and in the absence of immunocompromise, regardless of whether they continue to have a positive reverse-transcription polymerase chain reaction (RT-PCR) test. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Viral shedding and period of infectiousness'.)

HOSPITAL CARE

What is the preferred approach to oxygenation?

As a general approach, we target a peripheral oxygen saturation between 90 and 96 percent using the lowest possible fraction of inspired oxygen. We also encourage patients to self-prone, when possible, based on data that suggest improved oxygenation and minimal downside to proning.

●For most patients, we use low-flow oxygen (eg, low-flow nasal cannula, simple face mask), which minimizes risk of viral aerosolization. Because exertional desaturation is common and can be profound, providing additional support with activity (eg, going to the bathroom) may be needed.

●For those with acute hypoxemic respiratory failure and higher oxygen needs than low-flow oxygen can provide, we suggest selective use of noninvasive measures. Among the noninvasive modalities, we prefer noninvasive ventilation (NIV) when an indication exists (eg, acute exacerbation of chronic obstructive pulmonary disease, heart failure). In all others, NIV or high-flow nasal cannula (HFNC) is reasonable.

●We have a low threshold for intubation in patients who have any of the following: rapid progression over a few hours; failure to improve despite HFNC >60 L/min and FiO₂ >0.6; development of hypercapnia; and/or hemodynamic instability or multiorgan failure.

●When mechanical ventilation is required, we use low tidal volume ventilation (LTVV) targeting ≤6 mL/kg predicted body weight (PBW; range 4 to 8 mL/kg PBW (table 8 and table 9)) that targets a plateau pressure ≤30 cm H₂O and applies positive end-expiratory pressure (PEEP) as outlined in the table (table 10).

●For patients with COVID-19 who fail LTVV, prone ventilation is the preferred next step (table 11 and table 12).

●For those who fail LTVV and prone ventilation, rescue strategies include alveolar recruitment maneuvers, high PEEP, neuromuscular blocking agents, inhaled pulmonary vasodilators, and, rarely, extracorporeal membrane oxygenation.

(See "COVID-19: Respiratory care of the nonintubated hypoxemic adult (supplemental oxygen, noninvasive ventilation, and intubation)" and "COVID-19: Management of the intubated adult".)

When are antiviral treatment, glucocorticoids, and other COVID-19-specific therapies indicated? And which agents are preferred?

Our approach to COVID-19-specific therapy in hospitalized patients depends on the presence of hypoxia (O₂ saturation ≤94 percent on room air), need for oxygenation or ventilatory support, and the patients’ clinical and laboratory risk factors for severe disease (algorithm 5).

●For patients who do not require oxygen and do not have clinical (table 3) or laboratory (table 13) risk factors for severe disease, care is primarily supportive, with close monitoring for disease progression.

●For patients who do not require oxygen but have clinical (table 3) or laboratory (table 13) risk factors for severe disease and were hospitalized for COVID-19, we suggest remdesivir. Individuals who have risk factors but were hospitalized for other reasons (ie, have incidental SARS-CoV-2 infection) may be eligible for therapies authorized for high-risk outpatients (eg, nirmatrelvir-ritonavir, monoclonal antibodies, remdesivir).

●For patients who are receiving low-flow supplemental oxygen, we suggest low-dose dexamethasone and remdesivir. However, for those who are stable on minimal oxygen supplementation (eg, 1 to 2 L/min), it is reasonable to forgo dexamethasone and treat with remdesivir only, particularly if they are immunocompromised and within 10 days of illness onset.

For patients who have increasing low-flow oxygen requirements despite dexamethasone and remdesivir, have elevated inflammatory markers, and are within 96 hours of hospitalization, we suggest adding tocilizumab or baricitinib. If supplies of tocilizumab or baricitinib are limited, we prioritize them for more severely ill patients on higher levels of oxygen support.

●For hospitalized patients who are receiving high-flow supplemental oxygen or noninvasive ventilation, we recommend low-dose dexamethasone. For those who are within 24 to 48 hours of admission to an intensive care unit (ICU) or receipt of ICU-level care (and within 96 hours of hospitalization), we suggest adding tocilizumab or baricitinib. We also suggest adding remdesivir.

●For hospitalized patients who require mechanical ventilation or extracorporeal membrane oxygenation, we recommend low-dose dexamethasone. For those who are within 24 to 48 hours of admission to an ICU (and within 96 hours of hospitalization), we suggest adding tocilizumab or baricitinib. We suggest not routinely initiating remdesivir in this population, although those who had started it when on less oxygenation support can continue the course.

●If dexamethasone is not available, other glucocorticoids at equivalent doses are reasonable alternatives.

We generally do not use other agents off label for treatment of COVID-19. In particular, we suggest not using hydroxychloroquine or ivermectin, given the lack of benefit and potential for toxicity. (See "COVID-19: Management in hospitalized adults" and "COVID-19: Management in hospitalized adults", section on 'COVID-19-specific therapy'.)

Is anticoagulation indicated in all hospitalized patients? And if so, how much?

Yes, all hospitalized patients with COVID-19 should receive at least prophylactic-dose anticoagulation unless contraindicated (algorithm 6). Low-molecular-weight (LMW) heparin is generally preferred. The intensity of anticoagulation is based on an individualized assessment of bleeding and thrombotic risks. Thromboprophylaxis is typically discontinued upon hospital discharge, with rare exceptions.

●For thromboprophylaxis in patients in the ICU, we suggest prophylactic dosing rather than higher intensity (intermediate or therapeutic) anticoagulation for most inpatients.

●For thromboprophylaxis in non-ICU inpatients admitted for COVID-19, we suggest therapeutic dosing.

●For thromboprophylaxis in non-ICU inpatients admitted for another condition and found incidentally to be infected with SARS-CoV-2, we suggest prophylactic dosing.

●Individuals already receiving full-dose anticoagulation for another indication should continue it.

We have a low threshold for evaluating for venous thromboembolism (VTE; including deep vein thrombosis, pulmonary embolism, or other sites). If VTE is documented or strongly suspected, full-dose anticoagulation is used for at least three months.

Our approach to the evaluation and management of COVID-19 hypercoagulability is presented in the table (table 14) and discussed in detail separately. (See "COVID-19: Hypercoagulability", section on 'Management'.)

OTHER MEDICATION CONSIDERATIONS

Should I use acetaminophen or NSAIDs when providing supportive care?

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been theorized to cause harm in patients with COVID-19, but clinical data are limited. Given the uncertainty, we use acetaminophen as the preferred antipyretic agent for most patients rather than NSAIDs. If NSAIDs are needed, we use the lowest effective dose. We do not routinely discontinue NSAIDs in patients using them for the management of chronic illnesses.

The US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the World Health Organization (WHO) do not recommend that NSAIDs be avoided when clinically indicated. (See "COVID-19: Management in hospitalized adults", section on 'NSAID use'.)

Do ACE inhibitors and ARBs increase the likelihood of severe COVID-19?

Patients receiving angiotensin-converting-enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) should continue treatment with these agents if there is no other reason for discontinuation (eg, hypotension, acute kidney injury). Despite speculation that patients with COVID-19 who are receiving these agents may be at increased risk for adverse outcomes, accumulating evidence does not support an association of ACE inhibitors and ARBs with more severe disease. In addition, stopping these agents in some patients can exacerbate comorbid cardiovascular or kidney disease and increase mortality. (See "COVID-19: Issues related to acute kidney injury, glomerular disease, and hypertension", section on 'Renin angiotensin system inhibitors'.)

SPECIAL POPULATIONS

Asthma/COPD

Should patients using inhaled glucocorticoids for asthma or COPD be advised to stop these medications to prevent COVID-19?

No, patients with asthma or chronic obstructive pulmonary disease (COPD) who need inhaled glucocorticoids to maintain control of their asthma or COPD should continue them at their usual dose. When indicated, inhaled steroids help to minimize risk of an asthma or COPD exacerbation and the associated need for interaction with the health care system. There is no good evidence that inhaled glucocorticoids increase susceptibility to COVID-19 or have an adverse effect on the course of infection; there is even some limited evidence for faster recovery among outpatients with inhaled glucocorticoid use. Stopping them may worsen asthma or COPD control and thereby increase the risk for complications of COVID-19, if acquired. (See "An overview of asthma management", section on 'Advice related to COVID-19 pandemic' and "Stable COPD: Overview of management", section on 'Advice related to COVID-19'.)

Should patients with COVID-19 and an acute exacerbation of asthma or COPD be treated with systemic glucocorticoids?

Yes, patients with COVID-19 infection and a concomitant acute exacerbation of asthma or COPD should receive prompt treatment with systemic glucocorticoids as indicated by usual guidelines. Delaying therapy can increase the risk of a life-threatening exacerbation. While the World Health Organization (WHO) and United States Centers for Disease Control and Prevention (CDC) recommend glucocorticoids not be routinely used in the treatment of COVID-19 infection, exacerbations of asthma and COPD are considered appropriate indications for use. Overall, the known benefits of systemic glucocorticoids for exacerbations of asthma and COPD outweigh the potential harm in COVID-19 infection. (See "An overview of asthma management", section on 'Advice related to COVID-19 pandemic' and "Stable COPD: Overview of management", section on 'Advice related to COVID-19'.)

Pregnancy, delivery, and breastfeeding

What special considerations are there during pregnancy and breastfeeding?

Issues related to COVID-19 during pregnancy, delivery, and the postpartum period are discussed separately. (See "COVID-19: Overview of pregnancy issues" and "COVID-19: Intrapartum and postpartum issues" and "COVID-19 and pregnancy: Questions and answers".)

Pediatrics

What special considerations are there for children?

Specific considerations for children, including an overview of multisystem inflammatory syndrome, are discussed separately. (See "COVID-19: Clinical manifestations and diagnosis in children" and "COVID-19: Management in children" and "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis" and "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) management and outcome" and "COVID-19: Return to sport or strenuous activity following infection".)

Other special populations

What considerations are there for other special populations?

Issues related to the care of other special populations during the COVID-19 pandemic are discussed separately. Refer to the UpToDate COVID-19 homepage and the topics linked below.

●(See "COVID-19: Cutaneous manifestations and issues related to dermatologic care".)

●(See "COVID-19: Considerations in patients with cancer".)

●(See "COVID-19: Care of adult patients with systemic rheumatic disease".)

●(See "COVID-19: Evaluation and management of cardiac disease in adults".)

●(See "COVID-19: Issues related to acute kidney injury, glomerular disease, and hypertension".)

●(See "COVID-19: Issues related to diabetes mellitus in adults".)

●(See "COVID-19: Issues related to end-stage kidney disease".)

●(See "COVID-19: Issues related to gastrointestinal disease in adults".)

●(See "COVID-19: Issues related to liver disease in adults".)

●(See "COVID-19: Issues related to solid organ transplantation".)

●(See "COVID-19: Issues related to wound care and telehealth management".)

●(See "COVID-19: Management in nursing homes".)

●(See "COVID-19: Neurologic complications and management of neurologic conditions".)

●(See "COVID-19: Psychiatric illness".)

INFECTION PREVENTION

Are any medications available to prevent COVID-19 following exposure?

In the United States, the Food and Drug Administration (FDA) has issued an emergency use authorization (EUA) to use the monoclonal antibodies casirivimab-imdevimab and bamlanivimab-etesevimab to prevent SARS-CoV-2 infection in select individuals over 12 years of age. However, since these combinations are not expected to retain activity against Omicron or its subvariants, which predominate in the United States, they are no longer authorized. Although the monoclonal antibody bebtelovimab may retain activity against Omicron subvariants, it has not been studied for post-exposure prophylaxis and should not be used for this purpose.

Other agents (eg, hydroxychloroquine, ivermectin, tixagevimab-cilgavimab [another monoclonal antibody combination]) have not been shown to be effective. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Limited role for post-exposure prophylaxis'.)

What PPE is recommended for health care personnel taking care of patients with suspected or confirmed COVID-19?

Any personnel entering the room of a patient with suspected or confirmed COVID-19, regardless of COVID-19 vaccination status, should wear the appropriate personal protective equipment (PPE): gown, gloves, eye protection (full face shield preferred rather than goggles or a surgical mask with an attached eye shield), and a respirator (eg, an N95 respirator). If the supply of respirators is severely limited, medical masks are an acceptable alternative, except during aerosol-generating procedures (eg, tracheal intubation and extubation, tracheotomy, bronchoscopy, noninvasive ventilation, cardiopulmonary resuscitation).

Health care personnel should be aware of the appropriate sequence of putting on (figure 2) and taking off (figure 3) PPE to avoid contamination. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection".)

What type of room should patients with known or suspected COVID-19 be placed in?

Most hospitalized patients should be placed in a well-ventilated, single-occupancy room with a closed door and dedicated bathroom. When this is not possible, patients with confirmed COVID-19 can be housed together. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection", section on 'Type of room'.)

Patients undergoing aerosol-generating procedures (eg, tracheal intubation and extubation, tracheotomy, bronchoscopy, noninvasive ventilation) should be placed in an airborne isolation room (ie, a single-patient, negative-pressure room), except when these procedures are performed in the operating room or when such rooms are unavailable. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection", section on 'Aerosol-generating procedures/treatments'.)

Special considerations for patients undergoing aerosol-generating procedures in the operating room are discussed elsewhere. (See "COVID-19: Perioperative risk assessment and anesthetic considerations, including airway management and infection control".)

Outside of the operating room, patients with suspected or known COVID-19 should not be placed in positive-pressure rooms. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection".)

Should individuals who are fully vaccinated continue to wear masks and physically distance?

Although SARS-CoV-2 infection might still occur despite vaccination, the risk is lower and the risk of severe disease is substantially lower. Recommendations on public health precautions following vaccination have evolved with new developments in the pandemic (eg, emergence of the highly transmissible Delta and Omicron variants), and the approach should be tailored to the overall rate of transmission in the community.

In the United States, the Centers for Disease Control and Prevention (CDC) recommendations on masking depend on the estimated COVID-19 community level. In locations with low community levels, the CDC suggests that mask wearing be optional; at medium levels, it advises individuals who are immunocompromised or otherwise at risk for severe disease to consider masking in public and advises their close contacts to wear masks; at high levels, the CDC recommends that all individuals wear masks in indoor public settings. All masking recommendations assume that strategies to achieve and maintain high rates of vaccination, including booster doses, are ongoing. The CDC also recommends masks for all individuals on public transportation (including taxis and ride-shares) and at transportation hubs (eg, airports, bus or ferry terminals, railway stations, seaports). Masking is also recommended for all persons who have suspected or documented COVID-19 or exposure to SARS-CoV-2, regardless of community level. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Wearing masks in the community' and "COVID-19: Vaccines", section on 'Post-vaccine public health precautions'.)

What should individuals do after a close contact?

Close contact is defined as being less than 6 feet (2 meters) away for ≥15 minutes within a 24-hour period from a person with SARS-CoV-2 infection, starting from two days prior to symptom onset (or diagnosis of asymptomatic infection) until the end of the isolation period.

Following a close contact, the CDC recommends that all individuals, regardless of vaccination status, wear well-fitting masks for 10 days when around other people indoors. In addition, they should test for SARS-CoV-2 five days after the exposure and if any symptoms of COVID-19 develop. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Post-exposure management'.)

VACCINATION AND IMMUNITY

Immunity and vaccine efficacy

Does protective immunity develop after SARS-CoV-2 infection? Can reinfection occur?

Protective SARS-CoV-2-specific antibodies and cell-mediated responses are induced following infection. Evidence suggests that some of these responses can be detected for at least a year following infection. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Immune responses following infection'.)

The short-term risk of reinfection (eg, within the first several months after initial infection) is low. Several studies estimated the risk of reinfection to be <1 percent in the subsequent six months following initial infection. The risk of reinfection may be greater with the Omicron variant. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Risk of reinfection'.)

How efficacious is vaccination at preventing symptomatic COVID-19?

Vaccine efficacy varies by type. Based on phase III trial data:

●BNT162b2 (Pfizer-BioNTech COVID-19 vaccine) had 95 percent efficacy in preventing symptomatic COVID-19 in adults at or after day 7 following completion of a two-dose series. (See "COVID-19: Vaccines", section on 'BNT162b2 (Pfizer-BioNTech COVID-19 vaccine)'.)

●mRNA-1273 (Moderna COVID-19 vaccine) had 95 percent efficacy in preventing symptomatic COVID-19 in adults at or after day 7 following completion of a two-dose series. (See "COVID-19: Vaccines", section on 'mRNA-1273 (Moderna COVID-19 vaccine)'.)

●NVX-CoV2373 (Novavax COVID-19 vaccine) had 90 percent efficacy in preventing symptomatic COVID-19 in adults. Among participants ≥65 years of age, the estimate of vaccine efficacy was lower but was also less certain because of the small number of cases in this subgroup. (See "COVID-19: Vaccines", section on 'NVX-CoV2373 (Novavax COVID-19 vaccine)'.)

●Ad26.COV2.S (Janssen/Johnson & Johnson COVID-19 vaccine) had 66 percent efficacy against moderate to severe COVID-19 and 85 percent efficacy against severe COVID-19 at or after 28 days following administration of a single dose. (See "COVID-19: Vaccines", section on 'Ad26.COV2.S (Janssen/Johnson & Johnson COVID-19 vaccine)'.)

●ChAdOx1 nCoV-19/AZD1222 (AstraZeneca COVID-19 vaccine) had 70 percent efficacy in preventing symptomatic COVID-19 at or after two weeks following completion of a two-dose series. (See "COVID-19: Vaccines", section on 'ChAdOx1 nCoV-19/AZD1222 (University of Oxford, AstraZeneca, and the Serum Institute of India)'.)

Data suggest that immunity wanes over time and varies for viral variants; mRNA vaccines may be slightly more effective at preventing severe disease than certain other vaccine types. (See "COVID-19: Vaccines", section on 'Immunogenicity, efficacy, and safety of select vaccines'.)

Available data and the efficacy of other vaccines types are discussed separately. (See "COVID-19: Vaccines", section on 'Immunogenicity, efficacy, and safety of select vaccines'.)

How effective is vaccination against Omicron and its subvariants?

Vaccine effectiveness against Omicron and its subvariants (table 1) is reduced against overall infection. However, vaccination continues to reduce the risk of severe disease , particularly following booster doses. (See "COVID-19: Vaccines", section on 'Waning effectiveness over time and with variants of concern'.)

Vaccine availability and indications for vaccination

Which vaccines are currently available in the United States? Worldwide?

In the United States, the following vaccines are available (table 15):

●BNT162b2 (Pfizer-BioNTech COVID-19 vaccine, in a monovalent and a bivalent formulation)

●mRNA-1273 (Moderna COVID-19 vaccine, in a monovalent and a bivalent formulation)

●NVX-CoV2373 (Novavax COVID-19 vaccine, a monovalent vaccine)

●Ad26.COV2.S (Janssen/Johnson & Johnson COVID-19 vaccine, a monovalent vaccine)

BNT162b2 and mRNA-1273 are mRNA vaccines and are delivered in lipid nanoparticles. Once injected and taken up into muscle cells, the mRNA expresses the SARS-CoV-2 surface spike protein. Spike protein mediates viral attachment to human cells (figure 4). Expression of the spike protein induces binding and neutralizing antibody responses. Monovalent vaccines encode the spike protein from the original virus; bivalent mRNA vaccines encode the spike proteins from the original virus and from the BA.4 and BA.5 Omicron subvariants. (See "COVID-19: Vaccines", section on 'BNT162b2 (Pfizer-BioNTech COVID-19 vaccine)' and "COVID-19: Vaccines", section on 'mRNA-1273 (Moderna COVID-19 vaccine)'.)

NVX-CoV2373 is a recombinant protein subunit vaccine composed of trimeric spike glycoproteins and a potent Matrix-M1 adjuvant. (See "COVID-19: Vaccines", section on 'NVX-CoV2373 (Novavax COVID-19 vaccine)'.)

Ad26.COV2.S is based on a replication-incompetent adenovirus 26 vector that expresses a stabilized spike protein. (See "COVID-19: Vaccines".)

Outside of the United States, vaccine availability varies regionally. One widely available vaccine is ChAdOx1 nCoV-19/AZD1222 (University of Oxford, AstraZeneca, and the Serum Institute of India vaccines), an adenovirus vector-based DNA vaccine that also expresses the surface spike protein. (See "COVID-19: Vaccines", section on 'Approach to vaccination in other countries'.)

Available vaccines and vaccine candidates are also catalogued on the World Health Organization website.

What are the indications and contraindications to vaccination?

For individuals in the United States ≥6 months of age, we recommend vaccination with one of the two mRNA vaccines (BNT162b2 [Pfizer-BioNTech COVID-19 vaccine] or mRNA-1273 [Moderna COVID-19 vaccine]) or NVX-CoV2373 (Novavax COVID-19 vaccine) (figure 1). Ad26.COV2.S (Janssen/Johnson & Johnson COVID-19 vaccine) is reserved for adults (≥18 years of age) who cannot or will not receive one of the others.

●BNT162b2 (Pfizer-BioNTech COVID-19 vaccine) is approved by the US Food and Drug Administration (FDA) for individuals ≥12 years of age and is available under emergency use authorization (EUA) for children 6 months to 11 years of age.

●mRNA-1273 (Moderna COVID-19 vaccine) is approved by the FDA for individuals ≥18 years of age and is available under EUA for children 6 months to 17 years of age.

●NVX-CoV2373 (Novavax COVID-19 vaccine) is available under EUA for individuals ≥12 years of age.

●Ad26.COV2.S (Janssen COVID-19 vaccine) is available under EUA for individuals ≥18 years of age.

Contraindications to these vaccines are:

●For any COVID-19 vaccine:

•A severe allergic reaction (eg, anaphylaxis) to a previous COVID-19 vaccine dose of the same type or to a component of that vaccine or a known (diagnosed) allergy to a component of that vaccine.

The mRNA vaccines, BNT162b2 (Pfizer-BioNTech COVID-19 vaccine) and mRNA-1273 (Moderna COVID-19 vaccine), each contain polyethylene glycol. NVX-CoV2373 (Novavax COVID-19 vaccine) and Ad26.COV2.S (Janssen COVID-19 vaccine, also known as the Johnson & Johnson vaccine) each contain polysorbate. Allergic reaction to polysorbate is a contraindication to NVX-CoV2373 and Ad26.COV2.S but a precaution to mRNA vaccines.

●For Ad26.COV2.S, additionally:

•A history of thrombosis with thrombocytopenia following an Ad26.COV2.S or any other adenoviral vector COVID-19 vaccine.

Precautions include immediate allergic reactions to non-COVID-19 vaccines or injectable therapies and prior immediate but nonsevere allergic reaction to that COVID-19 vaccine type. Additionally, an allergy-related contraindication to one type of COVID-19 vaccine is a precaution to other types of COVID-19 vaccine.

Individuals with a precaution to vaccination, as well as any individual with a history of anaphylaxis that does not result in a contraindication to vaccination, should be monitored for 30 minutes after vaccination. All other recipients should be monitored for 15 minutes. (See "COVID-19: Vaccines", section on 'Indications and vaccine selection' and "COVID-19: Vaccines", section on 'Contraindications and precautions (including allergies)'.)

Are vaccine recommendations different for immunocompromised patients?

The United States Advisory Committee on Immunizations Practices (ACIP) recommends that patients with certain moderate to severe immunocompromising conditions receive three mRNA vaccine doses as part of the primary series rather than two doses (figure 5). Immunocompromising conditions that warrant the third dose include active chemotherapy for cancer, hematologic malignancies, hematopoietic cell transplantation (HCT) or solid organ transplantation, advanced or untreated HIV infection with a CD4 count <200 cell/microL, moderate or severe primary immunodeficiency disorder, and use of immunosuppressive medications (eg, mycophenolate mofetil, rituximab, prednisone >20 mg/day for >14 days) (table 6). For those who received COVID-19 vaccination prior to HCT or CAR-T cell therapy, the CDC recommends repeat vaccination with a full primary series at least three months after the transplant or CAR-T administration. Such patients also meet criteria for receiving a three-dose primary series with the mRNA vaccines.

The third dose should be given at least 28 days after the second dose. Following the primary vaccine series, immunocompromised individuals should also receive a booster dose. (See "COVID-19: Vaccines", section on 'Immunocompromised individuals'.)

Who is eligible for a booster dose? What is a bivalent booster? And when should it be administered?

Because of the possibility of waning immunity and decreased efficacy against variants that might escape the immune response directed against spike proteins targeted by the original vaccines, many countries recommend booster doses for individuals who have completed a primary series. (See "COVID-19: Vaccines".)

In the United States, the Food and Drug Administration (FDA) has authorized and the CDC recommends a booster dose with a bivalent mRNA vaccine for individuals five years of age or older who have completed a primary vaccine series (figure 1). This includes individuals who have received one or more booster doses with monovalent vaccines. For children younger than five years old, recommendations on a bivalent booster dose depend on the vaccine received for the primary series (table 15).

The bivalent booster dose should be given at least two months following the most recent monovalent vaccine dose.

Bivalent vaccines are intended to boost waning immunity as well as improve the breadth of immune response against other variants. In the United States, they target the original SARS-CoV-2 strain and the BA.4/BA.5 Omicron subvariants. In some other countries, bivalent vaccines target the original strain and the BA.1 Omicron subvariant. (See "COVID-19: Vaccines", section on 'Role of booster vaccinations' and "COVID-19: Vaccines", section on 'Mixing vaccine types'.)

Booster doses following a primary vaccine series are a distinct issue from administering a third dose of an mRNA vaccine for the primary series in certain immunocompromised patients. (See "COVID-19: Vaccines", section on 'Immunocompromised individuals'.)

Adverse effects

What adverse effects are associated with vaccination?

COVID-19 vaccines are exceedingly safe. The primary safety concerns are a very rare risk of myocarditis with mRNA vaccines and very rare risks of thrombosis with thrombocytopenia and possibly Guillain-Barre syndrome with adenoviral vector vaccines. Although myriad adverse events have been reported in individuals following vaccine administration, no other severe events have been clearly associated with vaccination after hundreds of millions of doses administered.

The more common adverse effects for all vaccine types include local injection site reactions, fever, headache, fatigue, chills, myalgias, and arthralgias (table 15). These reactions are more common in younger individuals and after the second dose (when a two-dose series is given).

Anaphylaxis is a rare adverse event reported following receipt of mRNA vaccines. Most cases evaluated to date have been determined not to be caused by IgE-mediated reactions, and some patients have successfully received the second dose of the same vaccine without incident. Patients with apparent anaphylaxis to a first dose of an mRNA vaccine should be referred to an allergy specialist if possible. Alternatively, a non-mRNA vaccine could be given in place of the second dose of mRNA vaccine, followed by 30 minutes of observation. (See "COVID-19: Allergic reactions to SARS-CoV-2 vaccines".)

The potential associations between thromboembolism and ChAdOx1 nCoV-19/AZD1222 (AstraZeneca COVID-19 vaccine) and Ad26.COV2.S (Janssen/Johnson & Johnson COVID-19 vaccine) are discussed below and in detail in the UpToDate text. (See 'Are COVID-19 vaccines associated with thrombotic complications? If so, which vaccines?' below and "COVID-19: Vaccines", section on 'Thrombosis with thrombocytopenia' and "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)".)

There are rare reports of myocarditis and pericarditis following receipt of the mRNA vaccines (BNT162b2 [Pfizer vaccine] and mRNA-1273 [Moderna COVID-19 vaccine]) and NVX-CoV2373 (Novavax COVID-19 vaccine), though not following receipt of Ad26.COV2.S (Janssen/Johnson & Johnson COVID-19 vaccine). Most reported cases were mild and occurred more commonly in males and in adolescents and young adults. Onset was generally within the first week after vaccine receipt, more commonly after the second dose. (See "COVID-19: Vaccines", section on 'Myocarditis'.)

There is also a possible association between Ad26.COV2.S (Janssen/Johnson & Johnson vaccine) and Guillain-Barre syndrome. (See "COVID-19: Vaccines", section on 'Guillain-Barre syndrome'.)

A detailed list of adverse event rates and how they vary by vaccine type and patient age can be found on the CDC website. (See "COVID-19: Vaccines", section on 'Approach to vaccination in the United States' and "COVID-19: Allergic reactions to SARS-CoV-2 vaccines", section on 'mRNA vaccines'.)

How does the risk-benefit ratio for COVID-19 vaccination differ in children?

The individual benefit of COVID-19 vaccination in young children may be somewhat less than in adults because COVID-19 tends to be less severe in children than in adults.

Nevertheless, there are several compelling reasons to vaccinate children, including the potential to reduce risk of the following:

●Multisystem inflammatory syndrome in children (MIS-C) following acute COVID-19

●Other potential sequelae (eg, "long COVID-19" and indirect effects on mental health and education)

●Severe disease in children with underlying medical conditions

●Acute COVID-19 of any severity

Furthermore, even with the lower risk of severe disease among children, the number of COVID-19 deaths among those 6 months to 11 years old from 2020 to 2021 exceeds the prevaccination era mortality rates of infections for which childhood vaccines are routinely provided (eg, rotavirus, meningococcal disease, varicella).

The risks of vaccination in children are less clearly defined than in adults and adolescents. Concern about the risk of myocarditis in children has been raised because of the association of mRNA COVID-19 vaccines with myocarditis, particularly in adolescents and young adults. While the precise risk of vaccine-associated myocarditis among children from 6 months to 11 years of age is unknown, available data suggest that the risk is not higher than the baseline risk in this age group. In addition, most myocarditis cases following receipt of a COVID-19 mRNA vaccine are mild and short lived. The benefits of COVID-19 vaccination in children are estimated to exceed this risk.

Given the hypothesis that MIS-C is associated with immune dysregulation precipitated by SARS-CoV-2 infection, similar immune-related side effects following vaccination in children are another concern. Vaccine trials in this age group have not identified a potential signal, although rare case reports of MIS in adults following vaccination highlight the importance of monitoring for this possible adverse effect. (See "COVID-19: Vaccines", section on 'Children'.)

Are COVID-19 vaccines associated with thrombotic complications? If so, which vaccines?

Extremely rare cases of thrombotic events (deep vein thrombosis, pulmonary embolism, arterial thrombosis, cerebral venous sinus thrombosis) associated with thrombocytopenia have been reported 5 to 30 days following vaccination with ChAdOx1 nCoV-19/AZD1222 (AstraZeneca COVID-19 vaccine) and Ad26.COV2.S (Janssen/Johnson & Johnson COVID-19 vaccine), a syndrome referred to as vaccine-induced immune thrombotic thrombocytopenia (VITT). The mechanism is similar to autoimmune heparin-induced thrombocytopenia (autoimmune HIT). There are no known risk factors; individuals with risk factors for venous or arterial thromboembolism (or a history of thromboembolism or HIT) do not appear to be at increased risk for VITT.

The features suggestive of VITT are summarized in the table and diagnostic algorithm (table 16 and algorithm 7). (See "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)".)

Because of the rarity of VITT and the potential severity of COVID-19, the overall benefit of vaccination outweighs the risk of VITT for most individuals. Nevertheless, several countries have suspended use of ChAdOx1 nCoV-19/AZD1222 pending additional data, and some are limiting it to individuals over a certain age or those who cannot receive an mRNA vaccine. (See "COVID-19: Vaccines", section on 'Thrombosis with thrombocytopenia'.)

Can analgesics or antipyretics be taken for side effects following vaccination?

Analgesics or antipyretics (eg, nonsteroidal anti-inflammatory drugs [NSAIDs] or acetaminophen) can be taken for local or systemic side effects following vaccination. However, pre-emptive use of these agents prior to vaccination is not recommended because of the uncertain impact on immune response to the vaccine. (See "COVID-19: Vaccines", section on 'Expected adverse effects and their management'.)

Vaccine administration

Can other vaccines be given with COVID-19 vaccine?

Although there are no data regarding safety and efficacy when COVID-19 vaccines are coadministered with other vaccines, the CDC has stated that COVID-19 vaccines can be administered at any time in relation to other non-COVID-19 vaccines, and if needed, can be administered on the same day as other vaccines. It is unknown if local and systemic side effects are more frequent or more intense with coadministration on the same day, but this will be monitored. The main exception is with the orthopoxvirus vaccine to prevent mpox (previously referred to as monkeypox) virus infection. The CDC suggests that it is reasonable to defer COVID-19 vaccination for four weeks after orthopoxvirus vaccination, particularly in adolescent or young adult males, because of the uncertain risk of myocarditis with closely spaced administration. However, recent COVID-19 vaccination should not delay orthopoxvirus vaccination if indicated. (See "COVID-19: Vaccines", section on 'Timing with relation to non-COVID-19 vaccines'.)

Should people who have had SARS-CoV-2 infection be vaccinated? If so, when? What if a patient acquires COVID-19 after the first dose?

Yes, most individuals with a history of SARS-CoV-2 infection should be vaccinated. However, for individuals who had SARS-CoV-2 infection complicated by multisystem inflammatory syndrome (MIS), the decision to vaccinate should weigh the risk of exposure, reinfection, and severe disease with infection against the uncertain safety of vaccination in such individuals. Given the hypothesis that MIS is associated with immune dysregulation precipitated by SARS-CoV-2 infection, it is unknown if a SARS-CoV-2 vaccine could trigger a similar dysregulated response.

Individuals with recent, documented SARS-CoV-2 infection (including those who are diagnosed after initiating a vaccine series) should have at least recovered from acute infection and met criteria for discontinuation of isolation precautions before receiving a vaccine dose. Additionally, given the low risk of reinfection soon after prior infection, it is reasonable for individuals with SARS-CoV-2 infection to wait to receive a vaccine dose until three months after infection. This applies to receipt of any primary series or booster dose. Potential reasons not to delay the vaccine dose in this population include high risk for severe infection, high rates of community transmission, and circulating variants associated with a high risk of reinfection. (See "COVID-19: Vaccines", section on 'History of SARS-CoV-2 infection'.)

When administering a third dose of an mRNA vaccine to eligible individuals as part of the primary series, should the same vaccine type as the initial two doses be used?

Yes, the same mRNA vaccine type should be used when possible. For example, individuals who received mRNA-1273 (Moderna COVID-19 vaccine) for their first two doses should receive mRNA-1273 for their third dose. If the initial vaccine formulation is not available or not known, either mRNA COVID-19 vaccine type can be given. (See "COVID-19: Vaccines", section on 'Immunocompromised individuals' and "COVID-19: Vaccines", section on 'Mixing vaccine types'.)

BLOOD DONATION

What should I tell patients about donating blood or plasma during the pandemic?

Blood donation is particularly important during the pandemic due to concerns that the supply could become critically low. Having a history of COVID-19 is not an exclusion to donation as long as the illness resolved at least 14 days prior to donation. (See "Blood donor screening: Medical history", section on 'COVID-19 pandemic considerations'.)

Vaccination for COVID-19 is also not a contraindication to blood donation. Individuals who have received an mRNA vaccine or other noninfectious vaccine (nonreplicating, inactivated) can donate immediately; those who have received a live-attenuated viral vaccine (or who are unsure if they have) should refrain from donating blood for a short waiting period (eg, 14 days) after receiving the vaccine.

Blood donation facilities may suspend or restart collection of COVID-19 convalescent plasma depending on society recommendations and demand. (See "COVID-19: Convalescent plasma and hyperimmune globulin".)

REFERENCES

Supporting references can be found in the linked UpToDate topics.