COVID-19: Evaluation and management of adults with acute infection in the outpatient setting

INTRODUCTION — 

At the end of 2019, a novel coronavirus rapidly spread throughout the world, resulting in a global pandemic. The virus was designated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the illness it caused coronavirus disease 2019 (COVID-19). The spectrum of COVID-19 in adults ranges from asymptomatic infection to mild respiratory tract symptoms to severe pneumonia with acute respiratory distress syndrome and multiorgan dysfunction.

This topic will address the evaluation and management of adult patients with acute COVID-19 in the outpatient setting. The primary objective of COVID-19 specific therapy is to reduce the risk of severe illness, which has decreased due to widespread immunization, immunity from previous infections, and prevalence of newer variants associated with milder disease.

The evaluation and management of patients with persistent symptoms following recovery from acute viral infection is reviewed elsewhere. (See "COVID-19: Clinical presentation and diagnosis of adults with persistent symptoms following acute illness ("long COVID")" and "COVID-19: Management of adults with persistent symptoms following acute illness ("long COVID")".)

Selected topics reviewing the diagnosis, epidemiology and virology of COVID-19, the care of hospitalized patients, and considerations in special populations can be found elsewhere:

●(See "COVID-19: Epidemiology, virology, and prevention".)

●(See "COVID-19: Diagnosis".)

●(See "COVID-19: Clinical features".)

●(See "COVID-19: Management in hospitalized adults".)

●(See "COVID-19: Overview of pregnancy issues".)

●(See "COVID-19: Antepartum care of pregnant patients with symptomatic infection".)

●(See "COVID-19: Vaccines".)

CLINICAL EVALUATION AND TRIAGE — 

The primary objectives when evaluating an outpatient with suspected or confirmed COVID-19 are to establish the diagnosis, assess symptom severity and home setting to determine appropriate site of care, and assess time course of infection and risk of progression to severe disease to determine appropriateness of COVID-19-specific therapies (table 1).

Some aspects of the initial evaluation may be conducted during telephone triage by clinical staff who can determine which patients are appropriate for self-care at home and which patients warrant a timely clinician telehealth visit (televisit) or in-person visit [1,2].

Locations where patients can find COVID-19 medications, as well as sites that offer both testing and treatment, can be found on the United States Department of Health and Humans (HHS) services website.

Establish the diagnosis — We establish the presumptive diagnosis of COVID-19 by confirming the patient has compatible clinical symptoms and excluding alternative diagnoses, since symptoms of COVID-19 can overlap with many common conditions. Confirming the diagnosis requires testing.

●Typical clinical presentation – The typical clinical presentation of COVID-19 varies depending on the individual's immune status and comorbidities, as well as the virus variant. Most patients experience a viral-type illness with symptoms ranging from a mild upper respiratory tract infection (eg, pharyngitis, rhinorrhea) to a lower respiratory tract infection (eg, cough, fever, dyspnea), influenza-like symptoms (eg, fever, chills, headache, myalgias), or gastroenteritis (eg, nausea, vomiting, diarrhea) (table 2) [3]. Loss of smell and taste was a common symptom during early stages of the pandemic, with olfactory loss typically reported early in the course of illness [4-8], but is less commonly reported with newer variants. (See "COVID-19: Clinical features".)

●Confirmatory testing in selected patients – For patients who may be candidates for COVID-specific treatment, we confirm the diagnosis with rapid antigen testing (which can frequently be done at home) or nucleic acid amplification testing (including reverse-transcription polymerase chain reaction testing [PCR]). Testing may also be helpful for infection prevention and isolation considerations. Choice among diagnostic tests is discussed elsewhere. (See "COVID-19: Diagnosis".)

●Exclude alternative diagnoses – As part of the evaluation of all patients, even those with diagnostic testing indicating COVID-19 infection, we assess for other potential causes of symptoms. Depending on the patient's specific symptoms, other etiologies to consider may include other infectious conditions (eg, influenza, respiratory syncytial virus [RSV], streptococcal pharyngitis, community-acquired pneumonia), congestive heart failure, asthma or chronic obstructive pulmonary disease exacerbations, pulmonary embolism, or acute pericarditis. Discussion of the evaluation and management of these conditions can be found in the relevant UpToDate topics.

Given the high prevalence and mild symptoms of most COVID-19 infections, clinicians should not assume that SARS-CoV-2 is responsible for a patient's illness even in the setting of a positive test. Clinicians should be mindful that the SARS-CoV-2 infection might be incidental to the clinical process and have a low threshold to evaluate patients in person to determine if an alternative process is responsible for the symptoms. Given the decreasing acuity of symptoms from SARS-CoV-2 infections due to widespread immunization, immunity from previous infections, and prevalence of new variants associated with milder infection, it is increasingly important to evaluate all patients with moderate or severe illness to confirm that an alternative disease process is not responsible for the clinical presentation.

Symptom severity — Although there are no formally established criteria for mild versus moderate or severe illness, we generally categorize symptom severity as follows:

●Mild symptoms – Mild symptoms typically include predominantly only upper respiratory symptoms (eg, rhinorrhea or pharyngitis) and cough. Patients may have fever, fatigue, or mild orthostasis, but generally do not have other systemic symptoms.

●Moderate to severe symptoms – Moderate to severe symptoms include dyspnea, chest pain or pressure, orthostasis that persists despite fluid intake, dizziness, falls, hypotension (if home blood pressure measurement is available), and mental status change (eg, lethargy, confusion, change in behavior, difficulty in rousing). Presence of any of these symptoms indicates at least moderate severity symptoms. Presence of hypoxia distinguishes severe from moderate illness.

Disposition — We determine patient disposition primarily based on symptom severity. Other considerations include the patient's home setting and social factors and their ability to self-monitor and report symptom worsening. When possible, we favor a coordinated care management program that includes initial risk stratification, clinician telehealth visits, with in-person evaluation when needed.

●Patients with mild illness severity – For most patients with mild illness severity, we perform initial triage, counseling, and treatment (if warranted) via telehealth (algorithm 1). We prescribe COVID-19-specific therapy (for appropriate patient in whom diagnosis has been confirmed) during the initial telehealth evaluation visit (see 'Patient selection' below).

In addition, we provide counseling regarding symptoms that would indicate worsening illness severity and ensure they know when and how to access medical services in the event of worsening symptoms. Specifically, we advise patients to seek re-evaluation if they develop symptoms consistent with moderate to severe infection (see 'Symptom severity' above).

For patients with obstructive lung disease (eg, chronic obstructive pulmonary disease [COPD] or asthma), we also warn that worsening shortness of breath should not be dismissed as exacerbation of their underlying lung disease. All patients who develop worsening dyspnea require further evaluation.

●Patients with moderate illness severity – We evaluate patients with moderate illness severity in-person to evaluate clinical status, assess for alternate etiologies, and determine the need for emergency department evaluation or hospitalization. Most patients with moderate symptoms can initially be evaluated in an outpatient clinic setting; however, for patients who report hypoxia or other signs of organ damage, initial in-person evaluation in the emergency room is appropriate.

•Outpatient clinic evaluation – In the outpatient clinic setting, we assess the patient's clinical status and evaluate for other potential etiologies of their symptoms [3] (see 'Establish the diagnosis' above). Based on a careful clinical history and physical examination, including vital signs, we then determine if the patient has indications for COVID-19-specific therapy (algorithm 1) and if they need emergency department evaluation or hospitalization.

•Considerations for emergency department evaluation and hospitalization – Patients who are acutely ill and have evidence of organ dysfunction (eg, moderate to severe dyspnea, change in mentation) should be managed in the emergency department. Most such patients will also need hospitalization if these symptoms persist despite initial emergency management, although criteria vary by country, region, and availability of COVID-19-specific therapy.

Patients with COVID-19 and dyspnea who have underlying obstructive lung disease (including COPD and asthma) present unique management challenges. For such patients, dyspnea may be simply due to an exacerbation of obstruction, and it is generally not possible to differentiate clinically between an isolated exacerbation of underlying pulmonary disease and an exacerbation related to COVID-19. In such cases, an in-person evaluation is necessary to assess clinical status; additional features that would warrant emergency care and hospitalization include frequent exacerbations, severe airflow limitation, and lack of response to rescue inhalers. (See "COPD exacerbations: Management", section on 'Triage to inpatient versus outpatient care' and "Acute exacerbations of asthma in adults: Home and office management", section on 'Disposition'.)

●Patients with severe illness severity – Patients with severe illness severity (ie, hypoxia), generally require hospitalization with inpatient evaluation and management (see "COVID-19: Management in hospitalized adults", section on 'COVID-19-specific therapy').

Additional features that may warrant hospitalization include:

•Oxygen saturation of <94 percent on room air (in a patient with normal baseline)

•Respiratory rate of >30 breaths/minute

•PaO₂/FiO₂ <300 mmHg

•Lung infiltrates >50 percent

Our approach outlined above is based on guidelines [1], as well as our own clinical experience of treating patients with COVID-19. High-quality data supporting the superiority of any single outpatient management strategy are lacking. Furthermore, the criteria for determining the most appropriate clinical setting for in-person evaluation are not fixed and will vary by institution, by region, and over time with changing resource availability and treatment options.

Factors that inform decision to treat — We assess for factors that help determine patient eligibility for COVID-19 outpatient treatment, including ensuring confirmatory has been obtained, asking about the timing of symptom onset, and determining risk of progression to severe disease. COVID-19 therapeutics are most beneficial when initiated within several days of onset of symptoms (algorithm 1).

●Rapid diagnostic testing – Patients being considered for COVID-19 treatment should receive rapid diagnostic testing to confirm COVID-19 infection, if not already obtained, prior to receiving treatment. We do not prescribe COVID-19 specific therapy unless a home or in-clinic test confirms the COVID-19 diagnosis, as symptoms of COVID-19 overlap with numerous other respiratory viruses. (See "COVID-19: Diagnosis", section on 'Diagnostic approach'.)

●Time course – We specifically determine the day of symptom onset in relation to the current day of illness. When indicated, COVID-19-specific therapies should be given within the first several days of illness; we prefer to start treatment within 24 to 48 hours of symptom onset if possible. Nirmatrelvir-ritonavir and molnupiravir should be initiated within five days of symptom onset, whereas remdesivir can be initiated within seven days of symptom onset.

●Presence of risk factors – We assess for risk factors for developing severe illness, including older age and comorbidities associated with more severe illness and higher mortality from COVID-19 [9]. Specific risk factors are detailed in the table (table 1).

COVID-19-specific therapies can be prescribed at the time of the initial evaluation during a telehealth visit and should not be deferred to an in-person visit if SARS-CoV-2 infection has been established.

TREATMENT WITH COVID-19-SPECIFIC THERAPIES

Goals of treatment — Our goals of treatment with COVID-19 specific therapies are to reduce progression to severe illness and decrease rates of hospitalization and death related to infection.

Although some data support decreased rates of prolonged COVID-19 symptoms with some treatments (eg, molnupiravir), we do not offer treatment solely for this purpose, as there is uncertainty in the evidence, the absolute benefits appear to be low, and the optimal patient population has not been established.

Outcomes with different therapies are discussed in the relevant sections below. (See 'Efficacy and rationale' below and 'Molnupiravir' below and 'Therapies with limited role or uncertain benefit' below.)

Patient selection — We favor outpatient treatment for patients who are at risk for progression to severe disease, including those with older age, immunocompromising conditions, or multiple comorbidities. Patients without these risk factors are less likely to substantially benefit from treatment, as their absolute risk of progression is low even without treatment. However, we engage all symptomatic patients in shared decision-making to discuss their risk factors as well as values in preferences. We advise against treatment in patients who are asymptomatic and those who have rebound infection.

●Symptomatic patients at high risk for severe disease – In the outpatient setting, we suggest COVID-19-specific therapy for symptomatic outpatients at the highest risk for progressing to severe disease, specifically those in the following categories (algorithm 1):

•Adults ≥75 years old, regardless of vaccination status or other risk factors for severe disease. Those with multiple risk factors (table 1) 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 3), regardless of vaccination status. The expected benefit of COVID-19-specific treatment in such individuals is substantial because they may have suboptimal immune response and protection from prior vaccination or infection. Furthermore, other preventive strategies in this population are limited, as the effectiveness of monoclonal antibody prophylactic strategies depends on the circulating viral variants.

•Adults of any age who have multiple risk factors for progression to severe disease (table 1), regardless of vaccination status. We evaluate all risk factors on a spectrum and consider the overall clinical picture when determining whether to prescribe treatment; those with more advanced disease states are more likely to benefit than those with milder disease states.

In the early phases of the pandemic, vaccination status was considered an important risk factor for progression to severe disease, but the vast majority of immunocompetent individuals have developed some immune response to the virus, whether through exposure or vaccination. Thus, we no longer use vaccination status as a risk factor to determine whether to initiate treatment.

Treatment with COVID-19-specific therapies can be repeated with each new episode of infection.

This approach is consistent with the indications outlined by the United States Centers for Disease Control and Prevention (CDC) for available COVID-19-specific therapies (ie, mild to moderate COVID-19 and high risk of progression to severe disease). However, not all patients who meet the eligibility criteria for COVID-19-specific therapy would derive clear benefit from it. In particular, for patients without medical comorbidities, the specific age threshold that should prompt treatment with COVID-19-specific therapy is uncertain. Although the 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 and is especially high after age 75 [10-12]. Based on United States data collected from the beginning of the pandemic through June 2022, compared with adults younger than age 30, the risk of death from COVID-19 is 25 times higher among those ages 50 to 64, 65 times higher among those ages 65 to 74, 140 times higher among those ages 75 to 84, and 330 times higher among those age 85 and above [10].

Evidence on the impact of other risk factors comes from a variety of studies, including meta-analyses, systematic reviews, individual observational cohort studies, and case series, in which patients with these underlying conditions had higher rates of severe disease and death [13-21]. However, patients with a particular underlying condition do not all have a uniformly high risk of severe disease. As an example, the risk of severe COVID-19 among patients with cancer may depend upon several variables, including the type of malignancy as well as the use of chemotherapy. (See "COVID-19: Considerations in patients with cancer".)

●Symptomatic patients at low risk for severe disease – We generally do not treat immunocompetent, healthy individuals <75 years (algorithm 1) who have one or no risk factors for progression to severe disease (table 1). In such patients, the overall risk of progression to severe disease is so low that the absolute benefit of treatment does not outweigh any potential risk of harm (eg, medication adverse effects, potential drug interactions) [22,23].

Nevertheless, it is reasonable to engage these patients in shared clinical decision-making regarding COVID-19-specific therapy, taking into account their individual risk factors as well as values and preferences.

●Asymptomatic patients and those with rebound infection – We do not use COVID-19-specific therapy for:

•Individuals who have asymptomatic SARS-CoV-2 infection

•Individuals with "rebound" COVID-19 who have already received COVID-19-specific therapy for initial symptoms (see '"Rebound" COVID-19 after treatment' below)

Evidence supporting the benefit of COVID-19 specific therapy in different populations is discussed elsewhere. (See 'Efficacy and rationale' below and 'Alternative options' below.)

Patients with severe COVID-19 (ie, with hypoxia) generally warrant hospitalization; management of severe disease is discussed elsewhere. (See "COVID-19: Management in hospitalized adults", section on 'Approach'.)

Nirmatrelvir-ritonavir as preferred therapy — Nirmatrelvir-ritonavir, a combination of oral protease inhibitors, is our preferred COVID-19-specific therapy for symptomatic outpatients who warrant treatment. It substantially reduces the risk of hospitalization and mortality in high-risk outpatients who have mild to moderate COVID-19 (ie, no hypoxia).

Nirmatrelvir blocks the activity of the SARS-CoV-2-3CL protease, an enzyme required for viral replication. Coadministration with ritonavir slows the metabolism of nirmatrelvir, so it remains active in the body for longer and at higher concentrations [24].

Dosing, administration, and precautions — When indicated, nirmatrelvir-ritonavir should be initiated as soon as possible following COVID-19 diagnosis and within five days of symptom onset (with the first day of symptoms counting as day one) (algorithm 1).

●Dosing – The dose depends on the kidney function, and there are three different packaging configurations for the different doses:

•For patients with normal kidney function (estimated glomerular filtration rate [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 with severe kidney impairment (eGFR <30 mL/min) – The dose is nirmatrelvir 300 mg-ritonavir 100 mg orally once on the first day of treatment, followed by nirmatrelvir 150 mg-ritonavir 100 mg orally once daily for the next four days. For patients on hemodialysis, medication should be taken after hemodialysis on hemodialysis days.

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.

When prescribing nirmatrelvir-ritonavir, the numeric dose for each active ingredient should be specified (eg, nirmatrelvir-ritonavir 300 mg/100 mg, nirmatrelvir-ritonavir 150 mg/100 mg).

●Administration – Nirmatrelvir-ritonavir tablets are not approved to be chewed, broken, crushed, or administered via feeding tube.

●Contraindications – Nirmatrelvir-ritonavir is not recommended for patients with severe hepatic impairment (Child-Pugh class C) (table 4). It is also contraindicated in patients on certain medications due to drug interactions. (See 'Drug interactions' below.)

Although there is a concern that the use of nirmatrelvir-ritonavir in patients with uncontrolled human immunodeficiency virus (HIV) may select for HIV protease inhibitor resistance, this is not a contraindication. We treat these patients with nirmatrelvir-ritonavir given the benefit of treatment in high-risk patients.

●Side effects – Common side effects include dysgeusia and diarrhea. If a patient experiences bothersome side effects, the therapy may be stopped early if those side effects are thought to outweigh the expected benefits.

●Possibility of resistance – Nirmatrelvir resistance mutations have been identified in SARS-CoV-2 after treatment with nirmatrelvir-ritonavir, particularly in immunosuppressed patients [25]. However, these mutations do not appear to be clinically meaningful (eg, low frequency and transient) and do not affect our decision to use this medication for appropriate patients. (See 'Patient selection' above.)

For outpatients, we suggest nirmatrelvir-ritonavir as monotherapy and do not combine it with other COVID-19-specific therapies. (See 'Alternative options' below.)

The use of nirmatrelvir-ritonavir during pregnancy is discussed elsewhere. (See "COVID-19: Antepartum care of pregnant patients with symptomatic infection", section on 'Use of antiviral therapy'.)

Drug interactions — Prior to prescribing nirmatrelvir-ritonavir, we review the patient's prescribed medications, over-the-counter medications, and dietary supplements (including herbal preparations) and use a high-quality tool to assess specific drug interactions and potential ways to mitigate them.

High-quality tools to assess drug interactions include:

●Drug interaction checker from the University of Liverpool

●Drug interactions program included with UpToDate

●US Food and Drug Administration (FDA) Patient Eligibility Screening Checklist Tool

Nirmatrelvir-ritonavir has the potential for numerous drug interactions because it is both an inhibitor of metabolic enzymes and transporters such as the CYP3A enzyme (predominantly because of the ritonavir component), as well as a substrate of CYP3A [26]. Because it is an inhibitor of CYP3A, concentrations of drugs that are CYP3A substrates may increase while on this medication. In addition, if a patient is on a medication that induces CYP3A, nirmatrelvir may be ineffective due to increased metabolism and reduced levels.

The approach to managing drug interactions depends on the type of interaction and whether the concomitant medication can be temporarily held or replaced:

●CYP3A substrates – Because ritonavir inhibits the CYP3A enzyme, CYP3A substrates can be expected to increase in concentration.

For medications that are highly dependent on CYP3A for clearance and could be harmful at elevated levels, coadministration with nirmatrelvir-ritonavir is contraindicated. Such medications include alfuzosin, amiodarone, colchicine, clozapine, lurasidone, lovastatin, rivaroxaban, salmeterol, simvastatin, and triazolam.

However, if safe to do so, some of these medications (eg, statins) can be held while nirmatrelvir-ritonavir is administered. In some cases, reducing the dose of the concomitant medication with monitoring for potential adverse effects is a reasonable approach. Because the short course of nirmatrelvir-ritonavir is not expected to result in lasting inhibition of CYP3A, the concomitant medication (or the original dose) can be restarted at least three days after the course has been completed; for older adult patients, in whom the inhibitory effect may persist for slightly longer, and for agents with very narrow therapeutic windows, it is reasonable to wait a longer period of time before restarting.

However, the approach of stopping or dose reducing concomitant medications is not appropriate for medications that have a long half-life, such as amiodarone, as it would not mitigate the potential harm of the drug interaction; in such cases, an alternative COVID-19 therapy should be used.

●CYP3A inducers – If a patient is on medication that is a potent CYP3A inducer (eg, carbamazepine, phenobarbital, phenytoin, rifampin, St. John's wort) (table 5), nirmatrelvir-ritonavir should not be used because the increased CYP3A activity can lead to reduced nirmatrelvir levels, loss of antiviral efficacy, and resistance. Because the effect of these agents on CYP3A persists after discontinuation, temporarily holding them in order to administer nirmatrelvir-ritonavir would not mitigate the interaction and is not recommended.

Nirmatrelvir-ritonavir should not be dose-adjusted to avoid potential drug interactions.

Efficacy and rationale — Support for the use of nirmatrelvir-ritonavir comes from several randomized trials and observational studies in symptomatic outpatients with COVID-19, in which some, but not all, demonstrated reduction in symptom duration, hospitalization, and death [11,27-36]. Overall, nirmatrelvir-ritonavir appears to reduce the risk of hospitalization and death in patients with COVID-19 by approximately one-half. As an example, in one meta-analysis, patients who received nirmatrelvir-ritonavir had reduced rates of hospitalization and all-cause mortality compared with those who did not receive nirmatrelvir-ritonavir (relative risk [RR] for hospitalization 0.53, 95% CI 0.24-0.69; RR for all-cause mortality 0.36, 95% CI 0.27-0.50) [37].

The absolute benefits of nirmatrelvir-ritonavir are most substantial in patients who are at highest risk for progressing to severe disease (eg, immunocompromised individuals, age over 65 with multiple comorbidities). As an example, in the randomized EPIC-HR (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) trial, which was conducted between July and December of 2021 and included 2246 unvaccinated adult outpatients with at least one risk factor for severe disease, administration of nirmatrelvir-ritonavir within three days of symptom onset reduced the risk of hospitalization or death at 28 days by 89 percent compared with placebo (0.7 versus 6.5 percent, risk difference -5.8, 95% CI -7.8 to -3.8) [27].

In contrast, the absolute benefit of nirmatrelvir-ritonavir is low when the baseline risk of severe COVID-19 in a population is low, as is with the majority of individuals who have pre-existing immunity from vaccination and/or prior infection. As an example, the phase 2/3 EPIC-SR trial (Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients) did not show a reduction in death, COVID-19 related hospitalization, or symptom duration with nirmatrelvir-ritonavir treatment, although there was a statistically non-significant trend toward benefit (risk of hospitalization due to COVID-19 or death from any cause 0.8 versus 1.6 percent, 95% CI -2.0 to 0.4) [38]. Symptom duration was also similar with nirmatrelvir-ritonavir versus placebo (12 versus 13 days). This trial included almost 1300 standard-risk outpatients who either were unvaccinated without risk factors or vaccinated with one or more risk factors for progression to severe disease; the low baseline risk of severe COVID-19 in this population was highlighted by the stark difference in COVID-19 associated hospitalizations and deaths in the placebo groups between the EPIC-HR (6.5 percent) and EPIC-SR trial (2.2 percent). Thus, the trial solidifies the notion that any potential benefit of nirmatrelvir-ritonavir is very limited in patients without underlying risk factors for severe COVID-19 disease.

Several large observational studies performed before and after emergence of the Omicron variant further support that the benefit of nirmatrelvir-ritonavir is limited to high-risk individuals [11,12,28,29,39-42]. As an example, in an observational matched cohort study of over 8000 high-risk patients with COVID-19 conducted in Quebec, Canada, nirmatrelvir-ritonavir was associated with reduced risk of hospitalization (relative risk [RR] 0.31, 95% CI 0.28-0.36) [41].

Limited observational data also suggest that nirmatrelvir-ritonavir is associated with a lower risk of post-COVID-19 conditions, including persistent symptoms and cardiovascular, neurologic, or hematologic sequelae [43,44]. However, data on this are mixed, and other studies have not confirmed this finding [45].

Although COVID-19-specific therapies have not been directly compared, outcomes data are more robust for nirmatrelvir-ritonavir than for the alternative options, and it is more practical than those alternatives that are given parenterally.

"Rebound" COVID-19 after treatment — We counsel patients that although some people develop "rebound" symptoms after initial improvement, the risk does not appear to be increased with treatment and is not generally a factor in our decision to treat.

"Rebound" of 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 after having converted to negative antigen tests) within the first few weeks (usually 10 to 14 days) following infection. Estimates of incidence vary from 2 percent to 15 percent [46-51], but the risk appears to be similar regardless of treatment with nirmatrelvir-ritonavir [37,49].

Consistent with CDC guidance, given the mild nature of most rebound episodes, we do not routinely retreat patients with nirmatrelvir-ritonavir (or any other COVID-19-specific therapy) [52]. However, for selected patients with significant immunosuppression (eg, solid organ and hematopoietic transplant patients) and rebound COVID-19, some experts offer retreatment with a five-day course of nirmatrelvir-ritonavir, although there is a lack of high-quality evidence to support this approach.

Alternative options — Potential alternatives to nirmatrelvir-ritonavir include remdesivir and molnupiravir.

Selecting among alternatives — If nirmatrelvir-ritonavir is not available or appropriate, potential alternative options include remdesivir and molnupiravir (algorithm 1).

We use remdesivir as our preferred alternative option. Remdesivir reduces COVID-19-associated hospitalization but requires three intravenous (IV) doses over three days and thus may be operationally challenging to administer. Among outpatients, remdesivir may be best suited for those residing in institutional settings, such as skilled nursing facilities.

If neither nirmatrelvir-ritonavir nor remdesivir is available or appropriate, molnupiravir is a potential option. We use this for patients at highest risk for severe disease (eg, immunocompromised patients) who are most likely to benefit from treatment. It has an Emergency Use Authorization (EUA) for mild to moderate symptomatic COVID-19 in patients at risk for progression and is recommended by some guidelines. It is not our preferred agent because studies do not consistently demonstrate efficacy against hospitalization or death, and any potential benefit is likely less substantial compared with other agents. Molnupiravir is generally not recommended for pregnant patients due to lack of clear benefit and potential risk for the fetus (see 'Molnupiravir' below). Selection of COVID-19-specific therapy in pregnancy is reviewed in detail elsewhere. (See "COVID-19: Antepartum care of pregnant patients with symptomatic infection", section on 'Use of antiviral therapy'.)

We do not combine therapies for outpatients and only select one from the options.

Previously, convalescent plasma was also an option, but it is no longer commonly used due to lack of availability. In addition, monoclonal antibodies (eg, bebtelovimab) are no longer an option because they are not active against variants circulating worldwide.

Remdesivir — For symptomatic outpatients in whom COVID-19 specific treatment is indicated (table 1) and who cannot use nirmatrelvir-ritonavir, remdesivir, a nucleotide analog that inhibits the SARS-CoV-2 ribonucleic acid (RNA) polymerase, is our preferred alternative. (See 'Selecting among alternatives' above.)

•Dosing and administration – Remdesivir is administered as 200 mg IV on day 1, followed by 100 mg IV daily on days 2 and 3. This dosing is distinct from that used for patients hospitalized for COVID-19. It should be initiated as soon as possible following COVID-19 diagnosis and within seven days of symptom onset (algorithm 1).

•Efficacy – In one randomized trial (patients enrolled between September 2020 and April 2021) of over 550 unvaccinated outpatients (≥12 years of age with at least one risk factor for progression to severe disease or ≥60 years of age) with mild to moderate COVID-19 (ie, no hypoxia), initiation of a three-day course of IV remdesivir (200 mg on day one and 100 mg on days two and three) within seven days of symptom onset reduced the risk of COVID-19 related hospitalization by 87 percent compared with placebo (HR 0.13, 95% CI 0.03-0.59) [53]. The risk of all-cause hospitalization was also lower with remdesivir (HR 0.28, 95% CI 0.10-0.75). At day 28, there were no deaths recorded in either study group. Although these data cannot inform the impact of remdesivir on mortality, a reduction in hospitalization remains a patient-important outcome as well as an important consideration for overwhelmed health care systems.

•Adverse effects – Adverse effects are minimal. Nausea, bradycardia, hypotension, and hypersensitivity have all been reported [54-56]. This is discussed elsewhere. (See "COVID-19: Management in hospitalized adults", section on 'Remdesivir'.)

A newer oral formulation of remdesivir has completed phase III trials successfully, demonstrating similar time to sustained clinical recovery compared with nirmatrelvir-ritonavir [57,58]; however, it has not been approved by the US FDA yet.

Molnupiravir — We use molnupiravir for patients at the highest risk for severe disease (eg, immunocompromised patients) when nirmatrelvir-ritonavir and remdesivir are not options. Molnupiravir is a nucleoside analog that inhibits SARS-CoV-2 replication by inducing lethal mutations in the viral RNA.

•Dosing and administration – The dose is 800 mg (four 200 mg capsules) taken orally every 12 hours for five days. It should be initiated as soon as possible following COVID-19 diagnosis and within five days of symptom onset (algorithm 1) [59]. No dose adjustment is necessary based on kidney or hepatic impairment. There are no medications that are contraindicated for coadministration with molnupiravir.

•Contraindications and patient counseling related to conception – Molnupiravir is contraindicated for use in patients younger than 18 years due to bone and cartilage toxicity. It is also not recommended during pregnancy and lactation unless there are extenuating circumstances because the potential benefit does not appear to outweigh the potential risks to the fetus. Use in individuals (males and females) of childbearing potential should be avoided unless no other treatment alternatives are available. If used, prior to initiating molnupiravir, the possibility of pregnancy should be assessed. In females of childbearing potential, a pregnancy test is recommended if they have irregular menstrual cycles, are unsure of the first day of their last menstrual cycle, or are not consistently using effective contraception. Females who may become pregnant are advised to use reliable contraception during and for four days following therapy. Males who are sexually active with females who may become pregnant should use a reliable method of contraception consistently during and for at least three months following therapy.

Additional information about use of molnupiravir during pregnancy is discussed elsewhere. (see "COVID-19: Antepartum care of pregnant patients with symptomatic infection", section on 'COVID-19-specific inpatient treatments').

•Efficacy – The efficacy of molnupiravir is uncertain. The totality of evidence suggests there may be a benefit for mortality and hospitalization, but any effect is likely small [34,40,60-66]. As an example, in a meta-analysis of nine randomized trials evaluating over 30,000 adults with mild or moderate COVID-19 infection, molnupiravir reduced mortality (0.03 versus 0.11 percent; RR 0.43, 95% CI 0.20-0.94) and the risk of hospitalization (1.2 versus 1.4 percent; RR 0.67, 95% CI 0.45-0.99) [67]. It also reduced time to symptom resolution (mean difference 2.4 fewer days, 95% CI 1.1 to 3.7). However, confidence in these findings is limited due to imprecision and the low number of events across studies.

In addition, there is some evidence that molnupiravir may reduce the risk of prolonged COVID-19 symptoms. In one large randomized trial, patients treated with molnupiravir during acute COVID-19 infection were less likely to experience persistent symptoms at three months and six months follow up compared with those who received usual care (8.5 versus 11.0 percent at six months) [68]. However, we do not use molnupiravir solely to reduce the risk of long-COVID, as the absolute risk reduction is low and the optimal patient population who may benefit is not known.

Molnupiravir is generally well-tolerated. However, use has been associated with selection of specific SARS-CoV-2 mutations, which have been subsequently transmitted and perpetuated in circulating viruses [69]. The clinical implications of this finding are uncertain.

Therapies with limited role or uncertain benefit — We generally do not use the following therapies due to uncertain benefit and/or lack of availability.

•Metformin – We do not use metformin for the treatment of acute COVID-19 infection, as it has not been clearly demonstrated to reduce hospitalizations or death. While there is some evidence that metformin may reduce the likelihood of post-COVID-19 conditions ("long COVID"), more studies are needed before this can be incorporated into routine clinical practice.

Although observational studies have indicated a possible association between pre-admission metformin use and decreased COVID-19 related mortality among hospitalized patients [70,71], randomized trials have not consistently shown that metformin in metformin-naïve patients reduces mortality or progression to severe disease in patients with mild to moderate COVID-19.

Two trials have evaluated whether administration of metformin to metformin-naïve patients decreases COVID-19 related mortality, hospitalization rate, ED visits, or the number of symptomatic days. In one randomized trial of over 400 unvaccinated nonhospitalized patients with recent (≤7 days of symptoms) COVID-19 infection and increased risk of progressing to severe disease, there was no improvement in viral clearance, clinical improvement, or time to hospitalization or death in those who received extended-release metformin 750 mg compared with placebo [72]. The study was stopped early for futility. A subsequent paper pointed out some potential errors in analysis that are being addressed by the study authors but are not yet available [72]. The second randomized trial included over 1300 nonhospitalized symptomatic patients with COVID-19 and also did not detect a statistically significant difference in the primary composite outcome (hypoxemia, ED visit, hospitalization, or death) with immediate-release metformin 1500 mg compared with placebo (24 percent versus 27 percent; adjusted OR 0.84, 95% CI 0.66-1.09) [73]. However, in a pre-specified secondary analysis, metformin appeared to decrease the composite of ED visits, hospitalizations, and death (4 percent versus 7 percent; adjusted OR 0.58, 95% CI 0.35-0.94), primarily due to a decrease in ED visits (3 percent versus 5 percent). A meta-analysis of the two trials did not detect a statistically significant decrease in hospitalization with metformin (OR 0.70, 95% CI 0.43-1.13) [74]. However, in another meta-analysis of only metformin-naive patients from these two studies, metformin was associated with a decreased risk of ED visit or hospitalization (RR 0.56, 95% CI 0.39-0.79) [75].

In addition, a subsequent analysis of the latter trial demonstrated a lower incidence of post-COVID-19 conditions ("long COVID") with metformin compared with placebo (6 percent versus 10 percent; HR 0.59, 95% CI 0.39-0.89) [76].

Taken together, although metformin shows promise in potentially reducing COVID-19-related ED visits and hospitalizations, as well as post-COVID-19 conditions, no clear conclusion can be drawn based on the inconsistency of the results between trials. More studies are needed to confirm these findings and identify the optimal patient population who would benefit before metformin is routinely recommended.

•Inhaled glucocorticoids – We do not routinely use inhaled glucocorticoids in the treatment of COVID-19, as it does not clearly improve symptoms or reduce hospitalization or death.

While several small trials have indicated a possible benefit of fewer urgent care or emergency department visits and hospitalizations with inhaled glucocorticoids [77,78], two large trials have not demonstrated this benefit:

-In a randomized trial of almost 1300 individuals with COVID-19, fluticasone (200 mcg daily for 14 days started a median of five days after symptom onset) did not reduce time to recovery (HR 1.01, 95% CI 0.91-1.12) or the combined rate of urgent-care/emergency department visits, hospitalizations, or death compared with placebo (3.7 versus 2.1 percent; HR 1.9, 95% CI 0.8-3.5) [79]. Approximately 65 percent of the trial population had received at least two vaccine doses and many participants did not have risk factors for disease progression; accordingly, the baseline risk of severe disease was low, and there were no deaths and only three hospitalizations in each group during the trial.

-A separate open-label trial (the PRINCIPLE trial) that included nearly 1900 individuals with COVID-19 who had risk factors for severe disease (≥65 years old or ≥50 years old with comorbidities) suggested a trend towards reduced hospitalization or death rates with inhaled glucocorticoid (budesonide 800 mcg twice daily) compared with usual care (6.8 versus 8.8 percent; OR 0.75, 95% CI 0.55-1.03), but the difference was not statistically significant [77]. Although there was a shorter time to self-reported recovery with budesonide (11.8 versus 14.7 days), the use of a self-reported outcome in an open-label trial, inclusion of participants with presumed but not confirmed COVID-19, and enrollment of the usual care group over a longer period of time than the intervention group all increase the risk of bias and reduce confidence in the finding of a potential benefit of budesonide.

Our guidance against using inhaled corticosteroids to treat COVID-19 is consistent with recommendations from the Infectious Diseases Society of America (IDSA) [80].

•Systemic glucocorticoids in outpatients – We do not routinely use systemic glucocorticoids (eg, dexamethasone or prednisone) in outpatients with COVID-19. In studies of hospitalized patients, systemic glucocorticoids do not lead to clinical benefit in patients without a supplemental oxygen requirement, and may lead to poorer outcomes, including increased mortality. Situations in which it is reasonable to use systemic glucocorticoids in the outpatient setting include:

-In resource-limited settings with limited hospital capacity, it may be reasonable to treat select COVID-19 outpatients who have a new or increased supplemental oxygen requirement with dexamethasone if close clinical follow-up can be assured.

-Patients with COVID-19 and a concomitant acute exacerbation of asthma or chronic obstructive pulmonary disease should receive appropriate treatment with systemic glucocorticoids as indicated by usual guidelines. This is reviewed in detail elsewhere. (See "Acute exacerbations of asthma in adults: Home and office management", section on 'Initiation of oral glucocorticoids' and "COPD exacerbations: Management", section on 'Glucocorticoids (outpatient)'.)

Use of glucocorticoids for hospitalized patients with COVID-19 is discussed in detail elsewhere. (See "COVID-19: Management in hospitalized adults", section on 'Dexamethasone and other glucocorticoids'.)

•High-titer convalescent plasma – Although data indicate that high-titer convalescent plasma is effective in reducing the risk of severe disease and hospitalization in some outpatients [81-87], it is rarely used due to limited availability. It requires processes for collection, screening, and quantification; these have been largely reduced or stopped in most centers. The use of low-titer convalescent plasma is not appropriate or authorized [88].

In a meta-analysis of five randomized controlled trials that included over 2600 patients, administration of convalescent plasma had a lower rate of hospitalization compared with placebo (8.5 versus 12.2 percent; absolute risk reduction 3.7, 95% CI 1.3-6.0) [86]. Those who received the convalescent plasma within five days of symptoms or received high-titer (defined as ≥median neutralization titer for each study) convalescent plasma had an even greater reduction in hospitalization.

The collection, preparation, administration, and adverse effects of convalescent plasma are discussed in detail elsewhere. (See "COVID-19: Convalescent plasma and hyperimmune globulin".)

•Pegylated interferon lambda – Early evidence regarding the benefits of pegylated interferon lambda is promising, but it is not available for treatment. In a randomized trial of almost 2000 mostly vaccinated patients with symptomatic mild to moderate COVID-19 illness and at least one risk factor for severe disease, those who received one dose of pegylated interferon lambda (180 micrograms) within seven days of symptom onset had a lower rate of COVID-19 related hospitalization compared with those who received placebo (2.3 versus 3.9 percent; RR 0.58, 95% CI 0.34-0.96) [89]. Rates of adverse events were similar between the two groups (15 versus 17 percent). However, other smaller randomized trials did not show a difference in hospitalization rates between interferon-treated and placebo groups; they may not have been powered to detect a difference [90,91].

•Olgotrelvir – Olgotrelvir is an oral protease inhibitor that prevents SARS-CoV-2 replication by inhibiting the protease enzyme as well as the human cathepsin L enzyme that is involved in SARS-CoV-2 entry into host cells. In a randomized trial conducted in China in 2023 of over 1200 patients with mild COVID-19 (almost all vaccinated), five days of olgotrelvir reduced time to symptom resolution by 59 hours (205 versus 264 hours), although there was no difference in recovery by day 29 (86 versus 83 percent) [92]. Olgotrelvir has not been approved by the FDA in the United States.

•Simnotrelvir-ritonavir – Simnotrelvir-ritonavir is a combination of protease inhibitors that acts similarly to nirmatrelvir-ritonavir by inhibiting the protease enzyme that is required for viral replication. Coadministration of simnotrelvir with ritonavir slows the metabolism of simnotrelvir so it remains active in the body for longer and at higher concentrations. In a randomized trial of over 1000 patients with mild to moderate COVID-19 (majority fully vaccinated), five days of simnotrelvir-ritonavir reduced time to symptom resolution by 1.5 days compared with placebo [93]. Although the study showed clinical efficacy of the drug for symptom resolution, it remains unknown whether the drug reduces hospitalization or death. The drug is approved for use under emergency conditional authorization in China; it has not been approved by the FDA in the United States.

•Ensitrelvir – Ensitrelvir is an oral protease inhibitor that prevents SARS-CoV-2 replication. In large randomized trials, ensitrelvir did not reduce the mean time to symptom resolution by more than one day; it remains unknown whether it reduces hospitalization or death, as there were no patient deaths and very few hospitalizations in the trials [94,95]. Ensitrelvir is approved for use in Japan and Singapore; it is not approved by the FDA in the United States.

Therapies that we do not recommend — Other COVID-19 treatments should not be prescribed for outpatients. High-quality data supporting the efficacy of these treatments are lacking [96,97]. In addition, there are concerns for potential toxicities with some of these agents when administered in an unmonitored setting [98,99]. (See "COVID-19: Management in hospitalized adults", section on 'Specific treatments'.)

●Hydroxychloroquine and azithromycin – Although some observational and unpublished anecdotal reports early in the pandemic suggested a possible role for hydroxychloroquine and azithromycin in the treatment of COVID-19 [80,100], randomized trials have not indicated a benefit with these agents [101-106].

●Ivermectin – We do not use ivermectin in the treatment of COVID-19, as high-quality data indicate lack of efficacy [73,107-110]. Serious adverse effects leading to hospitalization have been reported with ivermectin, including confusion, ataxia, and seizures [111,112].

●Fluvoxamine – We do not use the antidepressant fluvoxamine to treat COVID-19, as there is insufficient evidence supporting a possible benefit. Although early limited data suggested that fluvoxamine may reduce progression to severe disease [113], higher quality randomized trials have not demonstrated a benefit [73,114-116].

●Colchicine – Although there are some data demonstrating a benefit from the use of colchicine in early nonsevere COVID-19, the benefit is modest, there is no reduction in mortality, and adverse effects are common [117,118]. As an example, in a randomized trial of over 4100 adult outpatients with early COVID-19, treatment with colchicine reduced the risk of hospitalization compared with placebo (4.5 versus 5.9 percent of patients; OR 0.75, 95% CI 0.57-0.99); there was no reduction in mortality [117]. Gastrointestinal side effects (eg, diarrhea) were more common, and pulmonary embolism occurred more frequently in the colchicine compared with the placebo group (24 versus 15 percent; and 0.5 versus 0.1 percent, respectively).

●Antibiotics – Treatment with antibiotics is not routinely indicated for COVID-19, as bacterial superinfection is not a prominent feature of the illness. Treatment with antibiotics may be reasonable if there is clinical suspicion for bacterial pneumonia (eg, new fever after defervescence with new consolidation on chest imaging). (See "COVID-19: Management in hospitalized adults" and "COVID-19: Management in hospitalized adults", section on 'Empiric treatment for bacterial pneumonia in selected patients'.)

●Monoclonal antibodies – Anti-SARS-CoV-2 monoclonal antibodies were previously alternative options for COVID-19-specific therapy [119-121]. However, monoclonal antibodies have variable activity against the different SARS-CoV-2 variants, and there are no monoclonal antibodies approved for treatment of COVID-19 with activity against the variants circulating worldwide (table 6).

●Anticoagulation/antiplatelet therapy – Outpatients with COVID-19 who are already receiving anticoagulant or antiplatelet therapy for underlying conditions should continue these medications. However, we do not initiate anticoagulation or antiplatelet therapy unless the patient has specific indications for treatment [118]. Consultation with an appropriate specialist (eg, hematology, pulmonology) may be helpful in circumstances where anticoagulation is being considered. (See "COVID-19: Hypercoagulability", section on 'Patients not admitted to the hospital'.)

●Others – Other treatments that have been evaluated in outpatients with nonsevere illness include vitamin and mineral supplementation, antiviral agents, and anticoagulants.

•Although some observational data suggest a possible association between certain vitamin and mineral deficiencies and more severe disease [122-125], there are limited high-quality data that supplementation with vitamin C, vitamin D, or zinc reduces the severity of COVID-19 in nonhospitalized patients [126,127]. Issues related to vitamin D and COVID-19 are reviewed in detail elsewhere. (See "Vitamin D and extraskeletal health", section on 'COVID-19'.)

•There is no evidence that treatment with lopinavir-ritonavir improves outcomes in outpatients with mild disease [104].

•Montelukast does not appear to reduce duration of symptoms or improve other health outcomes related to COVID-19 infection [128].

•In a randomized trial including approximately 250 adults with nonsevere COVID-19 at risk for progression to severe disease, treatment with sulodexide (a glycosaminoglycan with anticoagulant and antiinflammatory properties) reduced hospitalizations and the need for supplemental oxygen compared with placebo (RR 0.60, 95% CI 0.37-0.96 and RR 0.71, 95% CI 0.50-1.00, respectively), but not mortality or thromboembolic events [129]. Further trials are required to determine if there is a clinical role for this agent in treating outpatients with COVID-19.

Clinicians may refer patients for participation in available clinical trials of investigational COVID-19 therapies. A catalog of clinical trials can be found at covid-trials.org; the list of trials can be filtered by location, type of study, patient setting (ie, outpatient versus inpatient), and many other criteria.

Other COVID-19-specific therapies are being used to treat hospitalized patients; these therapies are discussed in detail elsewhere. (See "COVID-19: Management in hospitalized adults", section on 'COVID-19-specific therapy'.)

OTHER MANAGEMENT ISSUES

Symptom management and recovery expectation — Symptomatic treatment includes antipyretics and analgesics for fever, myalgias, and headaches. We generally prefer acetaminophen; however, we inform patients that nonsteroidal anti-inflammatory drug (NSAID) use is acceptable if symptoms do not respond to acetaminophen. (See "COVID-19: Management in hospitalized adults", section on 'NSAID use'.)

Nasal corticosteroids have not been shown to be helpful in alleviating symptoms of olfactory dysfunction [130]. We do not use nasal corticosteroids for the symptomatic treatment of nasal congestion.

All other care is generally supportive, similar to that advised for other acute viral illnesses:

●We advise that patients stay well hydrated, particularly those patients with sustained or higher fevers, in whom insensible fluid losses may be significant.

●Cough that is persistent, interferes with sleep, or causes discomfort can be managed with an over-the-counter cough medication (eg, dextromethorphan) or prescription benzonatate, 100 to 200 mg orally three times daily as needed.

●We advise rest as needed during the acute illness; for patients without hypoxia, frequent repositioning and ambulation is encouraged. In addition, we encourage all patients to advance activity as soon as tolerated during recovery.

●Patients are cautioned that progressive respiratory symptoms, particularly worsening dyspnea, should prompt contact with their clinician for further evaluation.

In addition, we educate patients about the wide variability in time to symptom resolution and complete recovery from COVID-19. Although early data from China suggested that unvaccinated patients with mild disease recovered in two weeks and those with more severe disease recovered in three to six weeks [131], accumulating data suggest that the course of recovery is more variable and depends on a variety of contributors including patient factors (eg, age, health status), illness severity [132], SARS-CoV-2 variant, and vaccination status. In our experience, most patients recover within two weeks; however, a substantial minority have symptoms that gradually resolve over a longer period of time, usually two to three months. Evaluation and management of patients who have symptoms that persist beyond three months is discussed elsewhere. (See "COVID-19: Clinical features", section on 'Recovery and long-term sequelae' and "COVID-19: Clinical presentation and diagnosis of adults with persistent symptoms following acute illness ("long COVID")".)

Isolation and preventing spread of infection — With all patients, we reinforce the importance of infection control and self-isolation and provide instructions on the anticipated duration of isolation (table 7). In the United States, guidance on isolation and infection control in the community can be found on the Centers for Disease Control and Prevention (CDC) website. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection", section on 'Infection prevention in the home setting'.)

Advice on infection control measures and duration of isolation are reviewed in detail elsewhere. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection", section on 'Infection prevention in the home setting' and "COVID-19: Infection prevention for persons with SARS-CoV-2 infection", section on 'Duration and subsequent precautions'.)

Management of chronic medications — In general, the patient's usual home medication regimen is not adjusted, although some changes may be needed. In patients who are taking nirmatrelvir-ritonavir for COVID-19 therapy, chronic medications may need to be temporarily adjusted because of drug interactions. (See 'Drug interactions' above.)

●Nebulized medications or positive airway pressure devices – We advise patients who use nebulized medications to avoid their use in the presence of others and to use a metered dose inhaler preparation instead, when possible, to avoid potential aerosolization of SARS-CoV-2. (See "COVID-19: Management in hospitalized adults", section on 'Nebulized medications' and "COVID-19: Respiratory care of the nonintubated hypoxemic adult (supplemental oxygen, noninvasive ventilation, and intubation)", section on 'Nebulized medications'.)

If patients already use a continuous positive airway pressure or bilevel positive airway pressure device for management of obstructive sleep apnea, they may continue to use their machine; as with nebulizers, they are advised to use the device only when isolated from others.

●Immunomodulating medications – For patients taking an immunomodulating medication, we consult with the prescribing clinician about the relative risks and benefits of temporarily discontinuing it, which depend on its indication and the severity of the underlying condition. (See "COVID-19: Issues related to solid organ transplantation", section on 'Adjusting immunosuppression' and "COVID-19: Care of adult patients with systemic rheumatic disease", section on 'Medication management with documented or presumptive COVID-19' and "COVID-19: Issues related to gastrointestinal disease in adults", section on 'Adjusting IBD medications' and "COVID-19: Considerations in patients with cancer".)

●Anticoagulation or antiplatelet therapy – Outpatients with COVID-19 who are already receiving anticoagulant or antiplatelet therapy for underlying conditions should continue these medications. (See "COVID-19: Hypercoagulability", section on 'Patients not admitted to the hospital'.)

Management of medications is reviewed in more detail elsewhere. (See "COVID-19: Management in hospitalized adults", section on 'Managing chronic medications' and "COVID-19: Management in hospitalized adults", section on 'NSAID use' and "COVID-19: Management in hospitalized adults", section on 'Nebulized medications' and "COVID-19: Management in hospitalized adults", section on 'Immunomodulatory agents' and "COVID-19: Issues related to acute kidney injury, glomerular disease, and hypertension", section on 'Renin angiotensin system inhibitors' and "Dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus", section on 'Immune function' and "COVID-19: Issues related to diabetes mellitus in adults".)

Persistent infection in immunocompromised patients — Active, persistent SARS-CoV-2 infection can occur in immunocompromised patients, particularly those with severe B-cell depletion (eg, on rituximab or following hematopoietic cell transplantation). In such cases, patients typically test positive for SARS CoV-2 on reverse-transcriptase polymerase chain reaction (PCR) for prolonged periods of time (weeks to months) with a low cycle threshold (which suggests a high viral RNA level). Genomic studies have distinguished such persistent infection from reinfection with prevalent variants by the pattern of viral evolution [133].

Data to guide the optimal management of these patients are limited, and clinical practice is variable. Persistent infection can often be difficult to treat due to the accelerated pace of viral evolution and development of escape mutations [134-137]. Potential options for individuals with symptomatic persistent infection despite initial treatment (see 'Treatment with COVID-19-specific therapies' above) that have been posed by members of the National Institute of Health (NIH) COVID-19 treatment guidelines panel include prolonged or repeated courses of nirmatrelvir-ritonavir or remdesivir, or high-titer convalescent plasma (eg, from an individual with a recent infection with the same variant as in the immunocompromised patient) [100]. Case series have also reported cure of infection with combinations of antiviral therapy (eg, nirmatrelvir-ritonavir and/or remdesivir) and antibody-based therapies (eg, high-titer convalescent plasma or active monoclonal antibodies) [134,138-142].

Clinicians may have difficulties obtaining a prolonged course of nirmatrelvir-ritonavir for patients given the duration proscribed in the original authorization; if needed, clinicians can try to obtain the medication through an expanded access program by contacting the manufacturer.

Persistent infection in immunocompromised patients is a distinct issue from "long COVID-19," which is characterized by prolonged symptoms despite no evidence of ongoing infection, does not warrant repeat antiviral treatment, and is discussed in detail elsewhere. (See "COVID-19: Clinical presentation and diagnosis of adults with persistent symptoms following acute illness ("long COVID")" and "COVID-19: Management of adults with persistent symptoms following acute illness ("long COVID")".)

COVID-19 vaccination after recovery from acute illness — Immediate vaccination after recovery is not necessary, as most patients develop natural immunity to SARS-CoV-2 following infection. Advice on COVID-19 vaccination after recovery from acute infection is reviewed in detail elsewhere. (See "COVID-19: Vaccines", section on 'History of SARS-CoV-2 infection'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: COVID-19 – Index of guideline topics".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: COVID-19 overview (The Basics)" and "Patient education: COVID-19 and pregnancy (The Basics)" and "Patient education: COVID-19 and children (The Basics)" and "Patient education: Long COVID (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Clinical evaluation and triage

•Establishing the diagnosis – We establish the presumptive diagnosis of COVID-19 by confirming the patient has compatible clinical symptoms and excluding alternative diagnoses, since symptoms of COVID-19 can overlap with many common conditions. Alternative considerations include other respiratory infections (eg, influenza, streptococcal pharyngitis, community-acquired pneumonia), congestive heart failure, and asthma or chronic obstructive pulmonary disease exacerbations. Testing to confirm the diagnosis is necessary in some situations (eg, prior to initiation of COVID-19 specific treatment). (See 'Establish the diagnosis' above.)

•Determining disposition – Disposition is based primarily on symptom severity; additional considerations include home and social factors and the patient's ability to self-monitor and self-report symptoms.

-Patients with mild disease (eg, those with upper respiratory symptoms but without shortness of breath) can be evaluated, counseled, and treated (if appropriate) via telehealth.

-Patients with moderate severity symptoms (eg, shortness of breath, chest pain, dizziness) should be evaluated in person, usually in the outpatient clinic, to assess clinical status, evaluate for other etiologies of their symptoms, and determine appropriateness of COVID-specific therapies.

-Patients with severe COVID-19 (ie, hypoxia) and those with other evidence of end-organ dysfunction (eg, change in mentation) should be evaluated in the emergency department and usually require hospitalization. Specific criteria for hospitalization vary by institution, region, and resource availability. (See 'Disposition' above.)

●COVID-19-specific therapy – We engage all eligible patients (ie, symptomatic patients with acute infection) in shared clinical decision-making regarding COVID-19-specific therapy, considering their individual risk factors as well as values and preferences.

•Symptomatic adults at high risk for severe disease – We suggest early treatment with nirmatrelvir-ritonavir rather than no therapy for the following patients, regardless of vaccination history (algorithm 1) (Grade 2C):

-Adults ≥75 years.

-Adults of any age with an immunocompromising condition (table 3). Prior receipt of preexposure prophylaxis does not impact the decision to treat.

-Immunocompetent adults of any age who have multiple risk factors for progression to severe disease (table 1), particularly those with more severe disease states.

Our threshold to treat has increased due to a decline in illness severity from widespread immunization, immunity from previous infections, and prevalence of newer variants associated with milder disease. Among the above, we are most likely to offer treatment to individuals with severe immunocompromising conditions and to those who are older with multiple comorbidities because these patients are at the highest risk for hospitalization or death and most likely to achieve a substantial benefit from the treatment. Other people who meet the above criteria may also benefit from treatment, but their absolute risk is likely small even without treatment.

•Symptomatic adults at low risk for severe disease – We generally do not treat patients who do not meet the high-risk criteria outlined above. This includes immunocompetent adults aged <75 years who have one or no risk factors for progression to severe disease (table 1). In such patients, the overall risk of progression to severe disease is so low that the absolute benefit of treatment would not outweigh any potential risk of harm (eg, medication adverse effects, drug-drug interactions).

•Asymptomatic infection or "rebound" infection – We do not use COVID-19-specific therapy for individuals who have asymptomatic SARS-CoV-2 infection or rebound infection. (See 'Patient selection' above.)

●Administration of nirmatrelvir-ritonavir – Nirmatrelvir-ritonavir should be administered as soon as possible and within five days after symptom onset (algorithm 1). (See 'Nirmatrelvir-ritonavir as preferred therapy' above.)

•Dose – For patients with normal kidney function (estimated glomerular filtration rate [eGFR] ≥60 mL/min), the dose is nirmatrelvir 300 mg-ritonavir 100 mg orally twice daily for five days. 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. For those with severe kidney impairment (eGFR <30), the dose is nirmatrelvir 300 mg-ritonavir 100 mg orally once on the first day of treatment, followed by nirmatrelvir 150 mg-ritonavir 100 mg orally once daily for the next four days. For those on hemodialysis, medication should be taken after hemodialysis on hemodialysis days.

•Drug interactions – Prior to prescribing nirmatrelvir-ritonavir, clinicians should review all medications and assess potential drug interactions using an online tool. Although many medications have interactions with nirmatrelvir-ritonavir, some interactions may be mitigated by holding or dose-reducing the comedication, and some interactions only warrant monitoring. Specific drug interactions can be checked through the drug interaction program within UpToDate or the drug interaction checker from the University of Liverpool. (See 'Drug interactions' above.)

●Alternative treatment options – If nirmatrelvir-ritonavir is not available or appropriate, alternative options include remdesivir and molnupiravir (algorithm 1). Both have limitations. Remdesivir requires three intravenous (IV) doses over three days. Molnupiravir appears to be less efficacious than other options. (See 'Alternative options' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Jessamyn Blau, MD, who contributed to earlier versions of this topic review.