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 (ARDS) and multiorgan dysfunction. Our understanding of the spectrum of disease as well as optimal management strategies continues to evolve, particularly with the emergence of SARS-CoV-2 variants.

This topic will address the management of adult patients with acute COVID-19 in the outpatient setting (eg, <12 weeks after illness onset), including self-care advice, telehealth and outpatient management, emergency department (ED) referral, and post-hospital discharge care. Data informing outpatient management strategies continue to evolve, and the approach described here is based upon a rapidly developing evidence base. In addition, clinicians should take into the account an individual patient's circumstances as well as available local resources when considering treatment options.

The diagnosis and epidemiology and virology of COVID-19, as well as infection control measures, care for hospitalized patients, and system-specific COVID-19 complications are discussed in detail elsewhere, as are considerations for special populations.

COVID-19 virology, epidemiology, diagnosis, infection control, and prevention:

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

●(See "COVID-19: Diagnosis".)

●(See "COVID-19: Clinical features".)

●(See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection".)

●(See "COVID-19: Vaccines".)

COVID-19 hospital management:

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

●(See "COVID-19: Management of the intubated adult".)

●(See "COVID-19: Perioperative risk assessment and anesthetic considerations, including airway management and infection control".)

●(See "COVID-19: Extracorporeal membrane oxygenation (ECMO)".)

System-specific COVID-19 considerations, including manifestations, management, and issues related to recovery:

●(See "COVID-19: Evaluation and management of adults following acute viral illness".)

●(See "COVID-19: Acute limb ischemia".)

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

●(See "COVID-19: Arrhythmias and conduction system disease".)

●(See "COVID-19: Cardiac manifestations in adults".)

●(See "COVID-19: Myocardial infarction and other coronary artery disease issues".)

●(See "COVID-19: Intensive care ventilation with anesthesia machines".)

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

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

●(See "COVID-19: Hypercoagulability".)

●(See "COVID-19: Convalescent plasma and hyperimmune globulin".)

●(Related Pathway(s): COVID-19: Anticoagulation in adults with COVID-19.)

Issues related to COVID-19 in specific adult populations:

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

●(See "COVID-19: Intrapartum and postpartum issues".)

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

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

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

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

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

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

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

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

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

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

Issues related to COVID-19 in the pediatric population:

●(See "COVID-19: Clinical manifestations and diagnosis in children".)

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

●(See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis".)

●(See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) management and outcome".)

GENERAL PRINCIPLES

Continuum of care — When possible, we favor managing all patients with suspected or confirmed COVID-19 within an outpatient continuum of care management program that includes:

●Self-assessment tools. (See 'Patient self-assessment tools' below.)

●Initial telephone triage. (See 'Initial telephone triage' below.)

●Coordinated outreach and management approach based upon individual patient risk, severity of symptoms, and time course of disease. (See 'Risk stratification' below and 'Determine if in-person evaluation warranted' below.)

●Clinician telehealth (telephone call or video platform-based) visits (initial evaluation and follow-up visits) [1,2]. (See 'Home management without in-person evaluation for others' below and 'Reevaluation for worsening dyspnea' below.)

●COVID-19 testing. (See 'Suspicion for COVID-19 and role of testing' below.)

●A separate outpatient respiratory clinic or dedicated space within an ambulatory clinic appropriated for the care of patients with COVID-19 and other respiratory problems. Strategies to reduce the risk of exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by staff and other patients should be employed [3]. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection", section on 'Infection prevention in the health care setting'.)

In addition, the outpatient clinic should have a close, coordinated relationship with the local emergency department (ED) and function in partnership within the continuum of care program. (See 'Rationale for outpatient management and remote care' below.)

●A close working relationship with local public health officials and community leaders.

In such a system, patients could enter the ambulatory COVID-19 care program by contacting their primary health care provider or following discharge from the ED or an inpatient hospital stay.

In addition, during the course of illness and recovery, patients would be able to transition to different sites of care for follow-up as dictated by clinical need (eg, from self-care home management, to outpatient clinic or ED evaluation, to telehealth follow-up, and back to self-care management).

In resource-limited settings, an extension of this continuum of care may include health care provider home visits to evaluate patients and at-risk family members [4,5]. In-person home evaluations may facilitate more effective medical management of the patient, assessment of potentially infected household contacts, and provide an opportunity to promote infection control measures.

Rationale for outpatient management and remote care — Outpatient management is appropriate for most patients with COVID-19; in the majority of patients, illness is mild and does not warrant medical intervention or hospitalization [6,7], particularly in vaccinated individuals [8]. In addition, remote (telehealth) management is preferred for the majority of patients for the following reasons:

●Remote management can prevent unnecessary in-person medical visits, including visits to urgent care facilities and EDs, thus avoiding additional, unnecessary strain on already overburdened and overwhelmed health care systems.

●In-person health care provider visits require the patient to leave their home, traveling via public, private, or emergency transport and potentially exposing others to SARS-CoV-2. In addition, upon arrival at a health care facility, patients may expose other patients and health care workers to the virus.

Creating a comprehensive, coordinated outpatient care program that incorporates these components may allow more patients to receive supportive care at home and, if necessary, in the ambulatory clinic setting, further reducing ED and hospital resource utilization.

Telehealth has been used for patient management during previous disease outbreaks, including SARS, Middle East respiratory syndrome (MERS), and influenza A H1N1 [9]. Remote evaluation and management of patients with COVID-19 continues to be evaluated, and there is accumulating evidence demonstrating the appropriateness and efficacy of this approach [10-15]. (See "COVID-19: Considerations in patients with cancer".)

Telehealth evaluation for COVID-19 during the pandemic can be performed by telephone call, video-based telemedicine platform, or commercial video chat platform; the format chosen should be compliant with applicable patient privacy regulations [16].

Flexibility in approach to care — High-quality data supporting the superiority of any single outpatient management strategy are lacking, and treatment protocols are being developed and modified as understanding of the disease evolves.

Our approach is based upon our clinical experience of treating patients with COVID-19 and places additional emphasis on avoiding infection transmission, preserving limited resources, and reducing the burden on overwhelmed health care systems. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Prevention' and "COVID-19: Diagnosis", section on 'COVID-19 testing not readily available' and "COVID-19: Infection prevention for persons with SARS-CoV-2 infection", section on 'When PPE is limited'.)

Some institutions have been able to establish dedicated outpatient respiratory clinics devoted to managing COVID-19 patients, with available in-person and remote management options; in many other locations, these patients are being managed by primary care clinicians, often in consultation with a team of specially trained clinicians. Some health care systems have created “hospital-at-home” care with “virtual observation units” for COVID-19 patients [17,18].

Additionally, institutions may need to revise protocols, even over a several-week period, in response to surges in the number of patients with suspected infection they are managing [19].

INITIAL EVALUATION — Most patients who have concerns about COVID-19, even those with mild symptoms, will likely initiate contact with the health care system. For those patients, self-assessment tools, or remote (telehealth) evaluation are the preferred initial management approaches [20-22].

Patient self-assessment tools — Patient education materials, including self-assessment tools, can help patients determine if medical evaluation is necessary, and proactive dissemination of these materials may increase awareness and encourage their use. Various online self-assessment tools published by medical institutions [23] and governmental health agencies can guide patients through questions and suggest when to seek medical care; by following the guidance, most patients with mild illness may be able to recover at home on their own without needing to come in direct contact with a health care provider. Before recommending a specific assessment tool, however, clinicians should vet the options carefully, as they may exceed the abilities of patients with limited health literacy or can become quickly out-of-date based upon rapidly changing guidelines. Clinicians should recognize that many of these self-assessment tools do not inform eligible patients about the possibility of COVID-19 specific therapy.

In one study, use of a self-assessment tool embedded into the electronic health record allowed 40 percent of symptomatic patients to be appropriately triaged to self-care [22]. This study, however, was conducted in the setting of relatively low community prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and might not be representative of settings with widespread community transmission.

Initial telephone triage — In addition to self-assessment tools, an initial triage call by clinic staff can often determine which patients are appropriate for self-care at home, which patients warrant a timely clinician telehealth visit (televisit), which patients may be eligible for treatment with a COVID-19-specific therapy, and which patients warrant an outpatient clinic visit or urgent emergency department (ED) evaluation [24,25]. (See 'Risk stratification' below and 'Treatment with COVID-19-specific therapies' below.) (Related Pathway(s): COVID-19: Initial telephone triage of adult outpatients.)

Any patient with symptoms suggestive of respiratory compromise or hypoxia (eg, significant dyspnea at rest or mental confusion) should be referred for urgent in-person evaluation; the appropriate site of care depends upon the severity of symptoms and is discussed elsewhere. (See 'In-person evaluation for moderate/severe dyspnea, hypoxia, and concern for higher acuity level' below.)

Suspicion for COVID-19 and role of testing — During a pandemic, patients who live in regions with widespread community transmission and have compatible symptoms are generally managed presumptively as having COVID-19, even if they have not been tested or have an initial negative test result.

Patients with COVID-19 typically first 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), influenza-like symptoms (eg, fever, chills, headache, myalgias), or gastroenteritis (eg, nausea, vomiting, diarrhea) (table 1) [26,27]. Loss of smell and taste may also occur [28-30], with olfactory loss typically reported early in the course of illness [31,32]. Dyspnea, if it develops, tends to occur between four to eight days after the onset of symptoms, although it can occur after 10 days [26]. In addition, even in locations with a high prevalence of COVID-19, the possibility of other etiologies of symptoms should be considered. (See 'Managing other potential causes of symptoms' below and "COVID-19: Clinical features", section on 'Initial presentation'.)

In patients with less typical symptoms such as isolated rhinorrhea or headache, the likelihood of illness due to COVID-19 should take into account the local prevalence of disease as well as vaccination status, as mild symptoms commonly occur in breakthrough infections in previously vaccinated individuals [8].

The widespread use of testing is important for epidemiologic purposes, although the availability of testing for SARS-CoV-2 varies widely. If resources are limited, SARS-CoV-2 testing in outpatients with mild disease may not be readily available; in the United States, the Infectious Diseases Society of America has proposed priorities for testing (table 2). (See "COVID-19: Diagnosis", section on 'COVID-19 testing not readily available'.)

In patients who are able to undergo testing, the diagnosis of COVID-19 is usually made by direct detection of SARS-CoV-2 RNA by nucleic acid amplification tests (NAATs), most commonly reverse-transcription polymerase chain reaction (RT-PCR), in upper respiratory tract specimens. However, given the potential for false-negative results, in part because of sampling variability and viral load variation, a single negative test does not exclude infection in all patients [33,34]. If initial testing is negative but the suspicion for COVID-19 remains (eg, suggestive symptoms without evident alternative cause) and confirming the presence of infection is important for management or infection control, we advise repeating the test. (See "COVID-19: Diagnosis", section on 'Negative initial NAAT result'.)

Rapid tests that detect SARS-CoV-2 antigen can be performed at home or at the point of care and thus may be more accessible with a faster time to results than some NAATs. However, antigen tests are typically less sensitive than NAATs (table 3); clinicians should be aware of the possibility of false-negative results with antigen tests, and a negative antigen test does not rule out SARS-CoV-2 infection. (See "COVID-19: Diagnosis", section on 'Antigen testing as an alternative to NAAT'.)

Antibody detection has no utility for diagnosis in the acute outpatient setting; we do not use serology to exclude or diagnose acute COVID-19 infection. (See "COVID-19: Diagnosis", section on 'Serology to identify prior/late infection'.)

Laboratory testing for SARS-CoV-2 is reviewed in detail elsewhere. (See "COVID-19: Diagnosis".)

Risk stratification — Our patient-centered continuum of care management approach is based upon stratification of risk for developing severe disease as well as evaluation of clinical acuity.

Assess risk for severe disease — Risk for severe disease informs the need for evaluation and eligibility for treatment with a COVID-19-specific therapy (see 'Treatment with COVID-19-specific therapies' below). Older age and certain chronic medical conditions have been associated with more severe illness and higher mortality from COVID-19. Specific risk factors other than age are detailed in the table (table 4).

Evidence on specific 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 [7,35-43]. 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"). It is also important to note that although patients who are older or have poorly controlled chronic medical conditions have a higher risk for hospitalization and death, infection with SARS-CoV-2 may cause catastrophic illness in any patient, even among those without any risk factors. (See "COVID-19: Clinical features", section on 'Risk factors for severe illness'.)

Additionally, in the United States, African American and Hispanic American patients have represented a disproportionately high percentage of hospitalizations and deaths [7,36,37,39,44,45]. The reasons for this finding are unclear but are most likely related to inequalities in the social determinants of health (eg, access to health care, economic stability, living environment, community experience, education) [46,47].

COVID-19 has also disproportionately affected residents of nursing homes and long-term care facilities due to the high proportion of frail older adults and those with underlying chronic conditions [48]. These factors increase both the prevalence and severity of infection, resulting in high mortality rates among this population [49]. (See "COVID-19: Management in nursing homes", section on 'Scope of the problem'.)

In addition, although the vast majority of children with COVID-19 have mild disease [50,51], infants and children with underlying medical conditions warrant close monitoring; severe disease is most likely to occur in children with underlying medical conditions [52]. Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious condition that has been reported in children and adolescents in association with current or recent COVID-19 infection or exposure [53-57]. Rare cases of a similar syndrome have been reported in adults (multisystem inflammatory syndrome in adults [MIS-A]) [58]. This is reviewed in detail elsewhere. (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" and "COVID-19: Cardiac manifestations in adults", section on 'Multisystem inflammatory syndrome in adults (MIS-A)'.)

Assess symptom duration and severity

Time course and development of dyspnea — For any patient with suspected or confirmed COVID-19, we establish the illness timeline: the first day symptoms began, the presence of dyspnea, and the day of dyspnea onset. While mild dyspnea is common, worsening dyspnea, particularly dyspnea at rest, and more severe chest discomfort/tightness, are concerning symptoms and suggest the development or progression of pulmonary involvement. The trajectory of dyspnea over the days following its onset is particularly important, as significant worsening and acute respiratory distress syndrome (ARDS) can manifest soon after the onset of dyspnea; in studies among patients who develop ARDS, progression to ARDS occurred a median of 2.5 days after onset of dyspnea [59-63]. In patients with any risk factors for severe disease (table 4), outreach efforts should be focused particularly on the days following the onset of dyspnea to assess for any worsening of respiratory status.

It is unclear what percentage of patients with COVID-19 develop dyspnea, as available reports are likely not representative of all patients with SARS-CoV-2 infection. However, of patients with symptomatic infection, dyspnea likely develops in only a subgroup of patients. As examples, dyspnea developed in 19 percent of approximately 1000 COVID-19 patients admitted to a hospital in Wuhan, China [64]. However, in a CDC study of laboratory-confirmed COVID-19 patients in the United States, 43 percent of symptomatic adults and 13 percent of symptomatic children developed dyspnea [52]. Among patients who develop dyspnea, it typically begins at least several days after the onset of illness. In one study of 41 hospitalized patients in China, dyspnea developed, on average, eight days after the onset of symptoms [65]. (See "COVID-19: Clinical features", section on 'Clinical manifestations'.)

Dyspnea assessment — Remote assessment of dyspnea should focus on the patient's subjective symptoms, as well as an objective assessment of breathing, including deterioration in respiratory function [66]. We begin by asking if patients have developed any difficulty with their breathing, other than that associated with coughing. If yes, we ask the patient to describe the difficulty in their own words and assess the ease and comfort of their speech (eg, if they can speak comfortably in complete sentences).

In addition, we ask questions that provide a more objective assessment of changes in respiratory status, including [66]:

●"What activities that you could previously do without difficulty are now causing you to be out of breath?"

●"Has this gotten worse over the last one, two, or three days?"

●"Are you breathing harder or faster than usual when sitting still?"

●"Can you no longer do your usual household activities due to shortness of breath?"

●"Does walking cause you to feel dizzy?"

We use this assessment to categorize dyspnea by severity:

●Mild dyspnea – Dyspnea that does not interfere with daily activities (eg, mild shortness of breath with activities such as climbing one to two flights of stairs or walking briskly).

●Moderate dyspnea – Dyspnea that creates limitations to activities of daily living (eg, shortness of breath that limits the ability to walk up one flight of stairs without needing to rest, or interferes with meal preparation and light housekeeping tasks).

●Severe dyspnea – Dyspnea that causes shortness of breath at rest, renders the patient unable to speak in complete sentences, and interferes with basic activities such as toileting and dressing.

If available, telemedicine consultation with video capability may allow an even better evaluation of respiratory status, by allowing the clinician to observe the patient's respiratory pattern, including the use of accessory muscles of respiration [20].

Dyspnea may not correlate with the presence or degree of hypoxia in all patients [67], but dyspnea, along with risk factors for developing severe disease (table 4), can be used to guide clinicians in determining whether a patient requires in-person evaluation. (See 'Assess risk for severe disease' above and 'Determine if in-person evaluation warranted' below.)

Oxygenation assessment — If a patient with COVID-19 already has access to a pulse oximeter at home, and can adequately measure and report the results to the clinician, we consider the oxygen saturation as an additional piece of information to assess their clinical status. Patients are advised to use their pulse oximeter on warm fingers, as readings obtained on cold digits may not be as accurate [68,69]. In the outpatient setting, we instruct patients to check their oximetry twice daily and inform us if the value drops below 95 percent.

●For any patient with an oxygen saturation of ≤94 percent on room air, in-person evaluation is warranted. (See 'In-person evaluation for moderate/severe dyspnea, hypoxia, and concern for higher acuity level' below.)

●For patients who have an oxygen saturation of ≥95 percent on room air, the decision on in-person evaluation depends on other clinical features such as severity of dyspnea, risk for severe disease, and assessment of overall acuity. (See 'Determine if in-person evaluation warranted' below.)

However, oximetry should only be considered within the context of the patient's overall clinical presentation; a normal oxygen saturation level cannot be used to exclude clinically significant respiratory involvement in a patient with concerning symptoms such as progressive or severe dyspnea or high overall acuity level (see 'Assessment of overall acuity level' below). In addition, although normal oximetry can be reassuring, results may be not always be accurate, particularly in patients with darker skin pigmentation [69,70] (see "Pulse oximetry", section on 'Falsely normal or high reading'), and there is no guarantee that respiratory status will not deteriorate as illness progresses.

We do not advise that all patients diagnosed with COVID-19 purchase a pulse oximeter. Further, we do not consider oxygen saturation readings obtained through an application ("app") on a mobile telephone accurate enough to depend upon for clinical use [71].

As with dyspnea, the availability of telemedicine with video capability may allow the indirect assessment of hypoxia by the observation of cyanosis, if present [20].

Assessment of overall acuity level — In addition to evaluation of respiratory status, we assess the patient's overall acuity level by asking questions regarding orthostasis, dizziness, falls, hypotension (if home blood pressure measurement is available), mental status change (eg, lethargy, confusion, change in behavior, difficulty in rousing), observed cyanosis, and urine output. While mild orthostasis symptoms may be addressed with instruction to increase fluids, mental status changes, falls, cyanosis, hypotension, anuria, and chest pain suggestive of acute coronary syndrome are concerning and warrant in-person evaluation. (See 'In-person evaluation for moderate/severe dyspnea, hypoxia, and concern for higher acuity level' below.)

Assess home setting and social factors — We assess the ability of patients to monitor their symptoms and to understand the importance of seeking medical attention should symptoms progress. Patients who lack the ability to self-monitor and self-report may need more intensive staff outreach in order to be adequately managed at home.

In addition, in accordance with interim CDC guidelines on home management, we assess if the patient's residential setting is appropriate for home management and recovery [72]; patients managed at home should be capable of adhering to appropriate infection control and isolation precautions for the duration of illness and recovery (including using a separate bedroom if not living alone). Other important home resources include an available caregiver, adequate access to food, and assistance with activities of daily living if necessary. Whether the patient has any household members who have risk factors for severe disease is another consideration (table 4). (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection", section on 'Infection prevention in the home setting'.)

DETERMINE IF IN-PERSON EVALUATION WARRANTED — Based upon the above assessment, in particular the risk for developing severe disease, dyspnea and oxygenation, and overall acuity level, we determine the urgency and appropriate setting (in-person evaluation versus scheduled telehealth follow-up or self-care) for further management.

For those patients who warrant in-person evaluation, we decide if outpatient clinic or emergency department (ED) evaluation is appropriate. (Related Pathway(s): COVID-19: Initial telephone triage of adult outpatients.)

While we use the following general criteria to determine the most appropriate clinical setting for in-person evaluation, these criteria are not fixed and will vary by institution, region, and over time with changing resource availability and treatment options.

In-person evaluation for moderate/severe dyspnea, hypoxia, and concern for higher acuity level — All patients with moderate or severe dyspnea, an initial oxygen saturation ≤94 percent on room air (if oximetry information available), or any symptoms suggestive of higher acuity level warrant in-person evaluation, either in the ED or in an outpatient clinic, depending upon the severity of findings.

Criteria for ED evaluation and likely hospital admission — We typically refer patients with one or more of the following features to the ED for further management and likely hospital admission:

●Severe dyspnea (dyspnea at rest, and interfering with the ability to speak in complete sentences) (see 'Dyspnea assessment' above)

●Oxygen saturation on room air of ≤90 percent, regardless of severity of dyspnea (see 'Oxygenation assessment' above)

●Concerning alterations in mentation (eg, confusion, change in behavior, difficulty in rousing) or other signs and symptoms of hypoperfusion or hypoxia (eg, falls, hypotension, cyanosis, anuria, chest pain suggestive of acute coronary syndrome) (see 'Assessment of overall acuity level' above)

Patients meeting the above criteria will typically be admitted to the hospital for inpatient evaluation and management. In the United States, the National Institutes of Health (NIH) COVID-19 Treatment Guidelines Panel suggests hospitalization for patients with any of the following: an oxygen saturation of <94 percent on room air, respiratory rate of >30 breaths/minute, PaO₂/FiO₂ <300 mmHg, or lung infiltrates >50 percent [73]. While most patients with this presentation will require inpatient care, there are no fixed criteria for inpatient hospital admission with COVID-19; criteria vary by country, region, and availability of COVID-19-specific therapy (see "COVID-19: Management in hospitalized adults", section on 'COVID-19-specific therapy'). Further, in areas of high infection prevalence, the criteria may also vary with the availability of hospital resources; a lower threshold for hospitalization may be feasible in settings where the burden of disease does not exceed resource availability. In addition to clinical considerations, there are social factors that might support earlier hospitalization. Models to predict the likelihood of critical illness in hospitalized COVID-19 patients are being developed, although none have been validated for the evaluation and management of outpatients [74].

We have established an outpatient system to closely follow-up and monitor such patients who do not get admitted. However, this approach may not be appropriate in settings with more limited outpatient resources. (See 'Patients appropriate for evaluation in clinic' below.)

Patients appropriate for evaluation in clinic — Patients with one or more of the following features are typically appropriate for evaluation in an outpatient clinic (ideally a dedicated respiratory/COVID-19 clinic if available), provided they do not meet any of the above criteria for evaluation in the ED:

●Mild dyspnea in a patient with an oxygen saturation on room air between 91 to 94 percent (see 'Dyspnea assessment' above)

●Mild dyspnea in a patient with risk factors for severe disease (table 4) (see 'Assess risk for severe disease' above and 'Dyspnea assessment' above)

●Moderate dyspnea in any patient

●Symptoms concerning enough to warrant in-person evaluation (eg, mild orthostasis) but not severe enough to require ED referral (see 'Assessment of overall acuity level' above)

Clinic evaluation — For patients evaluated in an outpatient clinic (if feasible, a respiratory/COVID-19 clinic), we assess the patient's respiratory and circulatory status, and we evaluate for other potentially treatable causes of symptoms [26]. (See 'Managing other potential causes of symptoms' below.)

Based upon a careful clinical history and physical examination, including vital signs as well as measurements of oxygen saturation at rest and with ambulation, we then determine if the patient is appropriate for home-management/self-care, initiation of COVID-19-specific therapy (see 'Treatment with COVID-19-specific therapies' below), or transfer to the ED for further evaluation or possible inpatient hospital admission.

In our practice, we have found laboratory testing and chest imaging to be of limited utility in the evaluation of most patients with COVID-19 in the outpatient clinic; the patient's clinical presentation is a more important consideration in our management decision. (See "COVID-19: Clinical features", section on 'Laboratory findings' and "COVID-19: Clinical features", section on 'Imaging findings'.)

●Patients who require supplemental oxygen are transferred to the ED for hospital admission. Management of hospitalized adults with COVID-19 is discussed elsewhere. (See "COVID-19: Management in hospitalized adults", section on 'Defining disease severity' and "COVID-19: Management in hospitalized adults", section on 'Approach'.)

●Some patients without a supplemental oxygen requirement may also need further ED evaluation and possible hospital admission (eg, those with confusion, weakness, progressive dyspnea). (See 'Criteria for ED evaluation and likely hospital admission' above.)

●Other patients with less severe disease may be referred for inpatient admission or treated in the outpatient clinic; the decision to manage such patients in an ambulatory setting (eg, the ability to administer intravenous fluids, COVID-19-specific therapy [if appropriate], or other medications, and to arrange for outpatient follow-up) or admit as inpatients will vary between institutions, by region, by hospital resource availability and capacity, and over time, and thus influence this determination. We also consider the patient's home setting and social factors in determining the appropriateness of continued outpatient management.

The use of home oximetry monitoring is being evaluated for patients seen in the ambulatory or ED setting and discharged home [75]. However, there is no high-quality evidence that patient outcomes are improved using this approach.

Home management without in-person evaluation for others — The majority of patients without moderate or severe dyspnea, hypoxia (if oximetry information available), or symptoms suggestive of higher overall acuity level can remain at home for management without in-person evaluation.

●Patients who have any risk factors for severe disease (table 4) are evaluated by telephone for consideration of COVID-19-specific therapy. (See 'Treatment with COVID-19-specific therapies' below.)

●Patients without risk factors for severe disease (table 4) are not scheduled for in-person evaluation or follow-up telehealth visits.

At the time of initial contact, all patients receive instructions to contact their clinician with any worsening or concerning symptoms (see 'Counseling on warning symptoms' below). Although we generally do not schedule routine telehealth follow-up visits for patients managed at home, we reach out to those patients about whom we have concerns (eg, older adults living alone, individuals who may not be able to reliably self-report worsening of symptoms) by telephone as our resources permit.

In addition, all patients receive counseling on home management; components are discussed below. (See 'Management and counseling for all outpatients' below.)

Supervised residential care to facilitate isolation — Patients who would be appropriate for home care but are unable to be adequately managed in their usual residential setting are candidates for temporary shelter in supervised residential care facilities, if available [76].

In particular, patients who may be unable to adequately self-isolate (eg, patients living in multigenerational households, patients living with individuals who have any risk factors for severe disease (table 4), patients experiencing homelessness) should be provided resources such as dedicated housing units, where available [77-80]. Disruption of families should be minimized as much as possible. Every attempt should be made to avoid hospitalization simply for the purpose of facilitating self-isolation, as this option is not realistic in regions with widespread disease.

Unfortunately, dedicated residential care facilities for COVID-19 patients are not widely available in many countries and regions, and community-based solutions to self-isolation should be explored.

MANAGEMENT AND COUNSELING FOR ALL OUTPATIENTS — When clinically appropriate, it is generally preferable to manage patients with suspected or confirmed COVID-19 remotely via telehealth visits. (See 'Rationale for outpatient management and remote care' above and "Telemedicine for adults", section on 'Telemedicine during COVID-19 pandemic'.)

Interim recommendations on the outpatient management of patients with COVID-19 are provided by the World Health Organization, the Centers for Disease Control and Prevention (CDC) in the United States, National Institute for Health and Care Excellence (NICE) in the United Kingdom, and several academic medical centers [81-85]. (See "COVID-19: Management in hospitalized adults", section on 'Institutional protocols'.)

Treatment with COVID-19-specific therapies

Our approach (indications, selection, prioritization)

●Indications – Among adult outpatients with mild to moderate COVID-19 and risk for progression to severe disease (eg, based on older age, immune status, and comorbidities associated with progression (table 4)), we recommend treatment with COVID-19-specific therapy. We do not use COVID-19-specific therapy for individuals without any risk factors for progression or for individuals who have asymptomatic SARS-CoV-2 infection. Even among symptomatic individuals with risk factors, limited supplies may warrant prioritization of COVID-19-specific therapy for those at the highest risk of severe disease (table 5).

Most data demonstrating benefit of COVID-19 therapies are among unvaccinated individuals. Immunocompetent, vaccinated individuals are also likely to benefit, although their overall risk is lower than in unvaccinated individuals or immunocompromised patients who may not respond optimally to vaccination. It is reasonable to forgo treatment in immunocompetent vaccinated individuals if the risk of progression is not especially high (eg, they are relatively young with only a single risk factor).

●Selecting among therapies – For COVID-19-specific therapy, we recommend nirmatrelvir-ritonavir or monoclonal antibody therapy that is active against circulating variants (eg, sotrovimab, which is active against the Omicron variant) (table 6). These interventions substantially reduce the risk of hospitalization and mortality in outpatients who have mild to moderate COVID-19 and risk factors for progression to severe disease. The choice between therapies depends upon local availability, ease of prompt access to treatment (as all therapies must be given early in the course of illness), susceptibility to prevalent viral variants (table 6), and specific patient factors (eg, comorbid conditions, potential drug-drug interactions with nirmatrelvir-ritonavir). The time window after symptom onset that these agents are authorized for also vary. (See 'Nirmatrelvir-ritonavir' below and 'Monoclonal antibodies' below.)

If neither of these is an available option, we suggest remdesivir or high-titer convalescent plasma. Each has been demonstrated to reduce the risk of COVID-19 associated hospitalization. However, we consider them alternatives for various reasons. Remdesivir involves three days of intravenous (IV) infusion, which may be operationally complicated and best suited for those residing in institutional settings, such as skilled nursing facilities. Convalescent plasma requires a process to collect, screen, and verify it as high titer, which may not be widely available; low-titer convalescent plasma is not appropriate. (See 'Remdesivir' below and 'High-titer convalescent plasma' below.)

If none of these is a feasible option, molnupiravir is a final alternative. However, it may not be as effective as the other interventions and there are other safety considerations. (See 'Molnupiravir' below.)

We do not combine therapies for outpatients and only select one from the options. Administration of each of the different options are discussed in the sections that follow. (See 'Our preferred options' below and 'Alternative options' below.)

●Prioritizing the highest risk patients – When the incidence of SARS-CoV-2 infection is high, supplies of these agents (and the resources required to administer them) may be insufficient to offer treatment to all eligible adults. In such settings, we agree with the NIH COVID-19 treatment guidelines panel to prioritize these treatments for individuals most likely to benefit, ie, immunocompromised individuals who are likely to have a suboptimal response to vaccination and unvaccinated or incompletely vaccinated individuals with the highest risk for progression to severe disease [86] (table 5). (See "COVID-19: Vaccines", section on 'Immunocompromised individuals'.)

An additional practical consideration is that the resources and infrastructure required for administration of the parenteral options (monoclonal antibodies or remdesivir) may divert resources from other COVID-19 care efforts and may favor use in resource-rich over resource-limited communities [87]. It is essential that equitable access to all COVID-19 treatments be ensured.

Our preferred options

Nirmatrelvir-ritonavir — Nirmatrelvir-ritonavir, a combination of oral protease inhibitors, is one of our preferred options for COVID-19-specific therapy for symptomatic outpatients with risk for progression to severe disease. (See 'Our approach (indications, selection, prioritization)' above.)

●Dose – The dose is 300 mg nirmatrelvir (two 150 mg tablets) with one 100 mg ritonavir tablet taken together orally twice daily for 5 days. It should be initiated as soon as possible following COVID-19 diagnosis and within five days of symptom onset.

For patients with moderately reduced kidney function (eGFR 30 to 59 mL/min), the dose is one 150 mg nirmatrelvir tablet and one 100 mg ritonavir tablet taken together twice daily for five days. Nirmatrelvir-ritonavir is not recommended for patients with eGFR <30 mL/min or for patients with severe hepatic impairment (Child-Pugh class C) (table 7).

●Drug interactions – Nirmatrelvir-ritonavir is a CYP3A inhibitor, and coadministration is contraindicated with many drugs that are highly dependent upon CYP3A for clearance and in which an elevated level may be dangerous (eg, piroxicam, amiodarone, colchicine, clozapine, lurasidone, lovastatin, simvastatin, triazolam) [88]. Coadministration is also contraindicated with potent CYP3A inducers (eg, carbamazepine, phenobarbital, phenytoin, rifampin, St. John's Wort) (table 8), which may reduce levels of nirmatrelvir and/or ritonavir and result in loss of efficacy or resistance.

●Caution in patients with uncontrolled/untreated HIV – The decision to use nirmatrelvir-ritonavir in such patients should factor in the potential risk of selecting for HIV protease inhibitor resistance.

●Efficacy – Support for the use of nirmatrelvir-ritonavir comes from two randomized trials in outpatients with mild to moderate COVID-19, which shows reduction in hospitalization and death:

•In the randomized EPIC-HR (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) trial, which included 2246 unvaccinated adult outpatients with at least one risk factor for severe disease, nirmatrelvir/ritonavir, administered 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) [89]. Results were similar when the drug was administered within five days of symptom onset. Further, all 13 trial deaths were COVID-19 related and occurred in the placebo group; there was no increase in drug-related adverse effects compared with placebo.

•In an interim analysis of phase 2/3 of the unpublished EPIC-SR (Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients) trial, including 991 outpatients (unvaccinated adults and vaccinated adults who have one or more risk factors for progression to severe disease), nirmatrelvir/ritonavir reduced the risk of hospitalization compared with placebo (0.7 versus 2.4 percent), although the difference did not achieve statistical significance [90]. There were no deaths in either trial group. Complete trial results are not available for review.

Nirmatrelvir blocks the activity of the SARS-CoV-2-3CL protease, an enzyme required for viral replication, and coadministration with ritonavir slows the metabolism of nirmatrelvir so it remains active in the body for longer and at higher concentrations. The combination is expected to retain activity against the Omicron variant.

Monoclonal antibodies — Anti-SARS-CoV-2 monoclonal antibodies are one of our preferred options for COVID-19-specific therapy for symptomatic outpatients with risk for progression to severe disease [91-93]. However, these agents have limited availability, require parenteral administration, and must be given early in the course of illness; these factors make administration operationally complicated in many outpatient settings. (See 'Our approach (indications, selection, prioritization)' above.)

Among monoclonal antibody preparations, we suggest sotrovimab, which is available in the United States through an EUA for non-hospitalized patients with mild to moderate COVID-19 (eg, not requiring supplemental oxygen or, if on chronic supplemental oxygen, without an increased oxygen requirement) who have certain risk factors for severe disease (table 9) [94]. Sotrovimab has activity against the Omicron variant, which is the dominant variant in the United States and in most parts of the world (table 6) [95].

●Sotrovimab administration – Sotrovimab is administered as a single 500 mg IV dose.

According to the EUAs for monoclonal antibody therapy, treatment should be given as soon as possible after diagnosis and within 10 days of symptom onset; we favor administering it within five days, and sooner if feasible. Although evidence on the timing of monoclonal antibody therapy is limited, data suggest that benefit is maximized with early administration.

●Sotrovimab efficacy – Sotrovimab and other monoclonal antibody therapies have demonstrated benefit in reducing hospitalization and death in trials of high-risk unvaccinated populations, as detailed below. Limited observational data also suggest that they are associated with reduced hospitalization in vaccinated patients with symptomatic COVID-19, particularly those with multiple risk factors for severe disease [96]. However, high-quality data in vaccinated populations are lacking.

In a randomized clinical trial of non-hospitalized adults with early, mild to moderate COVID-19 and one or more risk factors for severe disease or age ≥55 years, sotrovimab (500 mg) administered within five days of illness onset was compared with placebo [97]. According to an interim analysis that included 583 participants, sotrovimab reduced the combined rates of hospitalization and death at 29 days compared with placebo (1 versus 7.2 percent; 85 percent relative risk [RR] reduction, 97% CI 44-96). The five intensive care admissions and the single study death occurred in the placebo group. The rate of adverse events was similar in both groups; infusion-related reactions and diarrhea each occurred in 1 percent of patients taking sotrovimab.

Another monoclonal antibody, bebtelovimab, is active against the Omicron variant and has also received EUA in the United States for non-hospitalized patients who have mild to moderate COVID-19, are at risk for progression to severe disease, and cannot get other COVID-19 therapies [98]. We reserve bebtelovimab for such patients when other preferred and alternative agents are unavailable. It is administered as a single 175 mg IV dose as soon as possible after diagnosis and within seven days of symptom onset. However, data to support its use are limited mainly to an unpublished trial among low-risk outpatients, in which bebtelovimab reduced the time to sustained symptom resolution to six days from eight days with placebo. The risk of COVID-19 associated hospitalization and death was similarly low with bebtelovimab and placebo (1.6 percent) [98].

Other monoclonal antibody therapies, casirivimab-imdevimab (600-600 mg as a single IV or subcutaneous dose) and bamlanivimab-etesevimab (700-1400 mg as a single IV dose), had also received EUA for the treatment of nonsevere COVID-19 in outpatients at risk for progression, and had been demonstrated in randomized trials to reduce the risk of COVID-19 associated hospitalization or death in such patients by approximately 70 to 85 percent compared with placebo [92,99-102]. Evidence suggests that casirivimab-imdevimab may also reduce the progression from asymptomatic SARS-CoV-2 infection to symptomatic COVID-19 [103]. However, these monoclonal antibody formulations are not authorized for use in regions where COVID-19 infection is likely due to SARS-CoV-2 variants that are not susceptible (ie, Omicron), and their use in such locations is not recommended [104,105].

Similarly, the European Medicines Agency (EMA) had approved the use of the monoclonal antibody regdanvimab (40 mg/kg as a single IV dose, maximum 8000 mg) for outpatients with COVID-19 who have certain risk factors for severe disease and who do not require supplemental oxygen [106,107]. The agent was also available for use in South Korea [108] and Australia [109]. However, in vitro studies suggest that regdanvimab is likely ineffective against the Omicron variant [110].

Alternative options

Remdesivir — We consider remdesivir, a nucleotide analogue that inhibits the SARS-CoV-2 RNA polymerase, an alternative option for COVID-19-specific therapy for symptomatic outpatients with risk for progression to severe disease (table 4) who cannot use preferred agents. Although remdesivir might reduce the risk of hospitalization in such patients, it requires parenteral administration over three days, which makes administration operationally complicated in many outpatient settings. Remdesivir may be most feasible for those residing in institutional settings, such as skilled nursing facilities. (See 'Our approach (indications, selection, prioritization)' above.)

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.

In a randomized controlled trial of 562 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, initiation of a three-day course of intravenous 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) [111]. 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.

In the trial, adverse effects were reported to be minimal and similar to placebo, although nausea, bradycardia, hypotension, and hypersensitivity reactions have been reported following administration of remdesivir [112-114]. This is discussed elsewhere. (See "COVID-19: Management in hospitalized adults", section on 'Remdesivir'.)

High-titer convalescent plasma — We consider high-titer convalescent plasma an alternative option for COVID-19-specific therapy for symptomatic outpatients with risk for progression to severe disease (table 4) who cannot use preferred agents. Some data suggest a clinical benefit, but this approach requires a process to collect, screen, and verify convalescent plasma as high titer, which may not be widely available. (See 'Our approach (indications, selection, prioritization)' above.)

If given, high-titer convalescent plasma should be administered as soon as possible following COVID-19 diagnosis; some experts suggest administering it within eight days of symptom onset [115]. In locations where the Omicron variant is prevalent, we suggest using convalescent plasma collected from individuals who likely had Omicron infection (eg, based on timing of infection). Convalescent plasma that is not verified as having a high titer should not be used.

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

High-quality trials suggest that high-titer convalescent plasma may reduce the risk of progression to severe disease and reduce hospitalization in selected outpatients without severe disease [116,117], although not all trials in this population have demonstrated a benefit [118,119]. The reasons for the differences in these trials are unclear and may be related to differences in the study population or unknown variables related to the components of plasma. The titer thresholds used to define “high-titer” plasma cannot be compared across these trials, as they used different assays, and titer measurement is not standardized across assays. The impact on mortality is uncertain.

In one unpublished randomized trial that included 1181 adults with nonsevere COVID-19, including individuals who had been vaccinated, administration of high-titer (>1:1620) convalescent plasma within nine days of symptom onset reduced the risk of COVID-19 associated hospitalization compared with control plasma (6.3 to 2.9 percent; RR 0.46, 95% upper limit CI 0.733); no individuals who had been fully vaccinated were hospitalized, regardless of plasma receipt [116]. In another trial that included 160 adults with nonsevere COVID-19 who were aged ≥75 years or aged ≥65 years with at least one medical comorbidity, administration of high-titer convalescent plasma (>1:1000) within 72 hours of symptom onset reduced the risk of progression to severe respiratory disease compared with placebo (16 versus 31 percent; RR 0.52, 95% CI 0.29-0.94); plasma with a titer over the median level was associated with greater benefits [117].

However, another placebo-controlled trial that included 511 high-risk adults who were seen in an emergency department for COVID-19 and deemed appropriate for outpatient management failed to identify a clinical benefit of high-titer convalescent plasma (≥1:250; median 1:650) administered within seven days of symptom onset [118].

Among those three trials, the overall mortality rate was too low to make a precise estimate about the impact of convalescent plasma [115].

Molnupiravir — Molnupiravir is a nucleoside analogue that inhibits SARS-CoV-2 replication. We consider it an alternative option for COVID-19-specific therapy for symptomatic outpatients with risk for progression to severe disease (table 4) who cannot use preferred or other alternative agents. (See 'Our approach (indications, selection, prioritization)' above.)

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 [120].

No dose adjustment is necessary based upon kidney or hepatic impairment.

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; although there are no human pregnancy data, animal studies demonstrate fetal developmental abnormalities with molnupiravir exposure. We avoid use of molnupiravir in any individuals of childbearing potential unless no other treatment alternatives are available (see "COVID-19: Antepartum care of pregnant patients with symptomatic infection", section on 'Antiviral drugs and other COVID-19-specific therapies'). 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 are advised to use reliable contraception during and for four days following therapy. Males who are sexually active with females of childbearing potential should use a reliable method of contraception consistently during and for at least three months following therapy.

There are no medications that are contraindicated for coadministration with molnupiravir.

In an international randomized controlled trial including 1433 non-hospitalized, unvaccinated adults who had onset of mild to moderate COVID-19 within five days and at least one risk factor for severe disease, molnupiravir reduced the risk of hospitalization or death by approximately 31 percent (hazard ratio 0.69, 95% CI 0.48-1.01); the combined outcome occurred in 6.8 versus 9.7 percent of patients compared with placebo, which trended toward, but did not achieve statistical significance [121]. Of the 10 deaths reported among trial participants, one occurred in the molnupiravir group and nine occurred in the placebo group. The rates of drug-related adverse events were comparable between the two groups.

Therapies of limited or uncertain benefit — Other outpatient COVID-19 treatments are under investigation, and evidence supporting their efficacy continues to evolve. However, high-quality data are limited and none are recommended for use outside of a clinical trial [122].

●Fluvoxamine – Data suggest that the antidepressant fluvoxamine may reduce progression to severe disease in early, mild COVID-19, although trials indicating benefit are hampered by methodologic issues, reducing certainty about any effect. Although potentially promising, additional data are needed to inform the utility of fluvoxamine before recommending its widespread use outside of a clinical trial. In a randomized trial from Brazil that included 1497 outpatients who had COVID-19 onset or SARS-CoV-2 diagnosis within the past seven days (about 44 percent within the past three days) and had at least one risk factor for severe disease, fluvoxamine (100 mg twice daily for 10 days) reduced the 28-day rate of hospitalization compared with placebo (11 versus 16 percent, RR 0.68, 95% CI 0.52-0.88); however, the definition of hospitalization included stay in an emergency setting for at least six hours, and most of the reduction in hospitalization reflected a reduction in such emergency visits [123]. A mortality reduction was not identified among the entire trial population. Although a mortality reduction was observed among those who reported at least 80 percent adherence to the study medication (<1 versus 2 percent with placebo, RR 0.09, 0.01-0.47), the validity of this finding is uncertain because more individuals in the fluvoxamine than placebo group were nonadherent, and the resulting mortality rate among those who were nonadherent was disproportionately high compared with the overall rate, suggesting potential confounders. A prior smaller trial had suggested that fluvoxamine (100 mg orally twice daily for two days, then three times daily for a total of 15 days of treatment) reduced clinical (respiratory) deterioration compared with placebo (0 versus 8.3 percent; adjusted RR 8.7, 95% CI 1.8-16.4) but was limited by loss to follow-up and short study duration [124]. Observational data has also suggested that fluvoxamine is associated with lower hospitalization rates than observation alone [125].

●Inhaled glucocorticoids – Evidence regarding the benefits of inhaled glucocorticoids is mixed. Although two smaller trials suggested a reduction in emergency department evaluation and hospital admission, the largest trial, which included outpatients at risk for severe disease, did not. Some of the trials were open-label design, which reduces confidence in the findings, and no trials have identified a mortality benefit.

•In the non-placebo-controlled steroids in COVID-19 (STOIC) trial, 139 adult outpatients with mild, early COVID-19 were treated with inhaled budesonide 800 mcg twice daily (an average of seven days) or assigned to usual care [126]. Among those treated with inhaled budesonide, fewer patients required urgent medical evaluation or hospitalization (1.4 versus 14.4 percent) at 28 days.

•In an open-label trial (the PRINCIPLE trial) including 1856 COVID-19 outpatients ≥65 years old or ≥50 years old with risk factors for severe disease, treatment with inhaled budesonide 800 mcg twice daily reduced the time to self-reported recovery, but did not reduce the risk of hospitalization or death at 28 days compared with usual care [127]. Furthermore, the use of a subjective, 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.

•In a randomized controlled trial including 400 adults and children aged ≥12 with nonsevere COVID-19, treatment with inhaled ciclesonide (320 mcg twice daily for 30 days) initiated within 72 hours of a positive SARS-CoV-2 test did not reduce time to recovery, but reduced the combined outcome of emergency department visit or hospital admission within 30 days compared with placebo (1 versus 5.4 percent; OR 0.18, 95% CI 0.04-0.85) [128]. However, there was no reduction in the sole outcome of hospital admissions (1.5 versus 3.4 percent; OR 0.45, 95% CI 0.11-1.84); no deaths occurred in either study group.

Despite a suggestion of benefit, additional randomized controlled trials are necessary to determine the efficacy of inhaled corticosteroids for outpatients with early, nonsevere COVID-19.

●Systemic glucocorticoids – In non-hospitalized patients, we do not treat COVID-19 with dexamethasone, prednisone, or other corticosteroids [129]. Extrapolating from the results of studies of hospitalized patients, there is no evidence that corticosteroids benefit patients without a supplemental oxygen requirement, and further, they may be associated with poorer clinical outcomes [130]. However, 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 [122]. In addition, patients with COVID-19 and a concomitant acute exacerbation of asthma or COPD should receive appropriate treatment with systemic glucocorticoids as indicated by usual guidelines. This is reviewed in detail elsewhere. (See "COVID-19: Management in hospitalized adults" and "COVID-19: Management in hospitalized adults", section on 'Dexamethasone and other glucocorticoids' and "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'.)

●Colchicine – Although there are some data demonstrating a benefit from the use of colchicine in early, mild to moderate COVID-19, the benefit is modest, there is no reduction in mortality, and adverse effects are common.

In a randomized trial including over 4100 adult outpatients (≥age 40) with early, mild to moderate COVID-19, treatment with oral colchicine (0.5 mg twice daily for three days, followed by 0.5 mg daily for a total of 30 days), initiated within one day of diagnosis, 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 [131]. 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).

Therapies that we do not recommend — Other COVID-19 treatments are under investigation but should not be prescribed in the ambulatory setting outside of a clinical trial, as high-quality data supporting the efficacy of many of these treatments are lacking [124,132]. In addition, there are concerns for potential toxicities with some of these agents when administered in an unmonitored setting [125,133]. (See "COVID-19: Management in hospitalized adults", section on 'Specific treatments'.)

●Hydroxychloroquine and azithromycin – Hydroxychloroquine and azithromycin have received attention as agents with possible antiviral activity, but trials have not suggested a clinical benefit for patients with COVID-19, including those managed in the outpatient setting [134-139]. Although some observational and unpublished anecdotal reports have suggested a clinical benefit of hydroxychloroquine, those are subject to a number of potential confounders [140], and randomized trials offer higher-quality evidence that hydroxychloroquine has no proven role for COVID-19. As an example, in an open-label trial including 293 patients with mild COVID-19 who did not warrant hospitalization, hydroxychloroquine administered within five days of symptom onset did not reduce viral levels at day 3 or 7 compared with no treatment, and there was no statistically significant reduction in hospitalization rates or time to symptom resolution [134]. The rate of adverse effects, primarily gastrointestinal symptoms, were greater with hydroxychloroquine.

●Ivermectin – As with other interventions that do not have a clear benefit, ivermectin should not be used for treatment of COVID-19 outside a clinical trial. Several meta-analyses have highlighted that the effect of ivermectin in patients with COVID-19 remains uncertain because of a lack of high-quality data [141-144]. As an example, in a July 2021 meta-analysis that identified four trials comparing ivermectin with placebo or standard care in outpatients with mild COVID-19, there was no clear reduction in all-cause mortality at 28 days (RR 0.33 in two trials, 95% CI 0.01-8.05), no reduction in need for invasive mechanical ventilation at 14 days (RR 2.97 in one trial; 95% CI 0.12-72.47), and no clear impact on symptom resolution at 14 days (RR 1.04 in one trial, 95% CI 0.89-1.21) [141]. The quality of the evidence for these outcomes was deemed low to very low because of imprecision and risk of bias. Although the meta-analysis also did not identify any increased risk of adverse effects with ivermectin, steep increases in calls to poison control centers about ivermectin toxicity compared with pre-pandemic rates have been reported [145,146]. Several of these calls involved ivermectin obtained without prescription (eg, from internet or veterinary sources); some patients were hospitalized for neurologic adverse effects related to uncertain dosages.

●Others – Other treatments are being evaluated in outpatients with mild to moderate illness, including vitamin and mineral supplementation as well as antiviral agents and anticoagulants.

•Limited observational data suggest a possible association between certain vitamin and mineral deficiencies and more severe disease [147-150]. However, there are no high-quality data that supplementation with vitamin C, vitamin D, or zinc reduces the severity of COVID-19 in non-hospitalized patients [151]. 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 [137]. In addition, although treatment with peginterferon lambda may induce more rapid reduction in SARS-CoV-2 viral load in patients with early, mild disease, its impact on clinically important outcomes is unclear [152].

•In a randomized trial including 243 adults with mild to moderate COVID-19 but risk factors for progression to severe disease, treatment with sulodexide (a glycosaminoglycan with anticoagulant and antiinflammatory properties) within three days of symptom onset 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 [153]. Further trials are required to determine if there is a clinical role for this agent in treating outpatients with COVID-19.

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'.)

Clinicians are encouraged to 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.

For patients with documented COVID-19, treatment with antibiotics is not indicated. Data are limited, but bacterial superinfection does not appear to be a prominent feature of COVID-19. Treatment for bacterial pneumonia may be reasonable if the diagnosis is uncertain, or in patients with documented COVID-19 in whom there is clinical suspicion (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 select patients'.)

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 or is participating in a clinical trial [154]. 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'.)

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 antiinflammatory drug (NSAID) use is acceptable if symptoms do not respond to acetaminophen. (See "COVID-19: Management in hospitalized adults", section on 'NSAID use'.)

Some patients with cough or dyspnea may experience symptomatic improvement with self-proning (resting in the prone rather than the supine position) [155]. In addition, we provide education on breathing exercises (table 10); these exercises are used to help patients with lung disease manage dyspnea, although they have not been evaluated in patients with COVID-19.

However, patients are cautioned that progressive respiratory symptoms, particularly worsening dyspnea, should prompt contact with their clinician for further evaluation. (See 'Reevaluation for worsening dyspnea' below.)

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.

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 patients with mild disease recover in two weeks and those with more severe disease recover in three to six weeks [156], accumulating data suggest that the course of recovery is more variable and may depend upon premorbid risk factors (eg, age, health status), illness severity [157], as well as vaccination status. (See "COVID-19: Clinical features", section on 'Recovery and long-term sequelae'.)

As an example, in a survey of 292 outpatients recovering from COVID-19, an average of 35 percent had not returned to baseline health by 14 to 21 days; younger patients were less likely to have residual symptoms compared with older patients (26 percent of those age 18 to 34 versus 47 percent of those >50 years) [158]. In addition, the number of medical comorbidities was associated with prolonged illness among all age groups; young and healthy patients with mild disease typically recovered sooner, while patients with multiple comorbidities had a more prolonged recovery. Fatigue, dyspnea, and headache were the symptoms most commonly reported to persist.

Management of chronic medications — In general, the patient's usual home medication regimen is not adjusted, although some changes may be needed.

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 'Avoiding 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 (CPAP) or bilevel positive airway pressure (BPAP) 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.

For patients taking an immunomodulating medication, we consult with the prescribing clinician about the relative risks and benefits of temporarily discontinuing it, which depend upon 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".)

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 'Avoiding 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".)

Managing other potential causes of symptoms — Since symptoms of COVID-19 can overlap with those of many common conditions, it is important to consider other possible etiologies of symptoms including other respiratory infections (eg, influenza, streptococcal pharyngitis, community-acquired pneumonia [CAP]), congestive heart failure, asthma or COPD exacerbations, and even anxiety [26].

We also consider the prevalence of COVID-19 in the community in our determination whether to evaluate the patient in-person; clinical judgement, however, remains the most important consideration in this decision. As an example, in regions where COVID-19 prevalence is high, efforts should be made to avoid or minimize in-person evaluations if possible; remote evaluation and management of mild dyspnea, if clinically appropriate, is preferred.

Counseling on warning symptoms — We counsel all patients on the warning symptoms that should prompt reevaluation by telehealth visit and in-person, including ED evaluations. These include new onset of dyspnea, worsening dyspnea, dizziness, and mental status changes such as confusion. Patients are educated about the time course of symptoms and the possible development of respiratory decline that may occur, on average, one week after the onset of illness. In addition, we assess the availability of support at home, ensure that they know who to call should they need assistance, and reinforce when and how to access emergency medical services.

Patients with obstructive lung disease (eg, COPD or asthma) are specifically advised to closely monitor their respiratory status and are cautioned not to presume that any worsening shortness of breath is due to an exacerbation of their underlying lung disease. (See 'Reevaluation for worsening dyspnea' below.)

Reevaluation for worsening dyspnea — All patients who develop worsening dyspnea require further evaluation and management. Even though some patients with worsening symptoms may be managed remotely, we perform an in-person evaluation if their complaints are suggestive of progression to more severe COVID-19 or conditions that are not amenable to telehealth management, such as severe CAP (eg, new productive cough, pleuritic chest discomfort), asthma or COPD exacerbation (eg, cough, increasing wheezing), pulmonary embolism (eg, worsening dyspnea, pleuritic chest pain, hemoptysis), heart failure (increasing dyspnea, edema, orthopnea) or acute pericarditis (eg, chest pain). This evaluation can take place in a respiratory (COVID-19) clinic or appropriate clinical care setting. Discussion of the evaluation and management of these conditions can be found in the relevant UpToDate topics.

In particular, 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 usually indicated. (See "An overview of asthma management", section on 'Advice related to COVID-19 pandemic' and "COPD exacerbations: Management".)

Infection control — With all patients, we reinforce the importance of infection control and self-isolation and provide instructions on the anticipated duration of isolation. These 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'.)

Addressing goals of care — Given the potential severity of COVID-19, all patients should have updated health care proxy and advance directive information in their electronic health record.

For patients with significant underlying medical comorbidities and poor health status, COVID-19 may cause catastrophic illness including respiratory failure due to acute respiratory distress syndrome (ARDS). Among such patients, those who develop life-threatening complications are likely to have a poor outcome despite the use of aggressive measures such as mechanical ventilation. For patients who are at highest risk of complications and who have the lowest likelihood of survival, the appropriateness of hospitalization and ventilator assistance should be discussed in advance of significant deterioration in clinical condition. For these patients, it may be appropriate to address home palliative care strategies in anticipation of need. Many institutions have palliative care and hospice programs to provide skilled nursing and social work support for patients and families. (See "COVID-19: Management of the intubated adult", section on 'Surge capacity and resource allocation' and "COVID-19: Management of the intubated adult", section on 'End of life issues' and "Advance care planning and advance directives", section on 'COVID-19 resources'.)

COVID-19 vaccination after recovery from acute illness — Advice on COVID-19 vaccination after recovery from acute infection, including individuals who received monoclonal antibody treatment is reviewed in detail elsewhere. (See "COVID-19: Vaccines", section on 'History of SARS-CoV-2 infection'.)

OUTPATIENT MANAGEMENT FOLLOWING INPATIENT OR ED DISCHARGE — After discharge from the inpatient hospital setting or the emergency department (ED), clinician follow-up is warranted, either in outpatient clinic or via telehealth visit [159]. At each encounter, we provide counseling on the warning symptoms which should prompt reevaluation. (See 'Infection control' above and 'Counseling on warning symptoms' above.)

In some cases, patients are discharged home or to supervised residential care from the inpatient hospital setting on low flow oxygen therapy, with oximetry monitoring by telehealth (preferred if available) or visiting nurse. The practice of sending patients home on supplemental oxygen is widely variable, however, and if done warrants careful patient selection and close monitoring [160].

Some patients discharged from the hospital, including those with documented venous thromboembolism (VTE) as well as some who are at high risk for VTE, will be discharged on anticoagulation. Management of anticoagulation is discussed in detail elsewhere. (See "COVID-19: Hypercoagulability", section on 'Patients discharged from the hospital'.) (Related Pathway(s): COVID-19: Anticoagulation in adults with COVID-19.)

Patients discharged home

●Patients discharged from the inpatient setting require a follow-up clinician visit following discharge; depending upon their clinical and social situation, telehealth visit [161] or in-person visit may be appropriate.

●For patients evaluated and discharged from the ED who are felt to need follow-up care, telehealth visits may also be appropriate. The timing of such visits will vary depending upon patient acuity and indication.

Patients discharged to supervised residential care for recovery — As part of the continuum of care of patients with COVID-19, temporary housing in supervised residential care facilities may also be appropriate for patients discharged from the ED. (See 'Supervised residential care to facilitate isolation' above.)

Depending upon the type of facility, the patient's medical acuity, and available resources, telehealth follow-up may be appropriate; the intensity of telehealth follow-up will vary depending upon patient acuity.

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: Recovery after COVID-19 (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Outpatient management strategies continue to evolve – Data informing outpatient coronavirus disease 2019 (COVID-19) management strategies continue to evolve, particularly in the setting of emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants; the approach described here is based upon a rapidly developing evidence base. Clinicians should take into account the individual patient's clinical and social circumstances as well as the available resources when considering treatment options. (See 'Introduction' above.)

●Outpatient management appropriate for majority of patients – Outpatient management is appropriate for most patients with COVID-19. When possible, we favor a coordinated care management program that includes initial risk stratification, clinician telehealth visits, a dedicated outpatient respiratory clinic, and a close relationship with a local emergency department (ED). (See 'General principles' above.)

●Initial evaluation; evaluation of acuity and risk stratification – On initial evaluation, we assess risk factors for severe disease (table 4), dyspnea severity and duration (and oxygenation status of those with dyspnea, if that information is available), overall level of acuity, and the patient’s home setting to determine who warrants an in-person evaluation at an outpatient clinic or in the ED. The additional criteria we use to make this determination are not fixed and will vary by institution, region, and over time as resource availability and treatment options evolve. (See 'Risk stratification' above.) (Related Pathway(s): COVID-19: Initial telephone triage of adult outpatients.)

We typically refer patients with one or more of the following features to the ED for further management and likely hospital admission (see 'Criteria for ED evaluation and likely hospital admission' above):

•Severe dyspnea (dyspnea at rest, and interfering with the ability to speak in complete sentences)

•Oxygen saturation on room air of ≤90 percent, regardless of severity of dyspnea

•Concerning alterations in mentation (eg, confusion, change in behavior, difficulty in rousing) or other signs and symptoms of hypoperfusion or hypoxia (eg, falls, hypotension, cyanosis, anuria, chest pain suggestive of acute coronary syndrome)

We refer patients for evaluation in an outpatient clinic if they have one or more of the following features without any of the preceding features (see 'Patients appropriate for evaluation in clinic' above):

•Mild dyspnea in a patient with an oxygen saturation on room air between 91 to 94 percent

•Mild dyspnea in a patient with any risk factors for severe disease (table 4)

•Moderate dyspnea in any patient

•Symptoms concerning enough to warrant in-person evaluation (eg, mild orthostasis) but not severe enough to require ED referral

The decision to refer patients for hospital admission or manage at home depends upon several factors, including their requirement for supplemental oxygen, an assessment of their overall acuity level, and hospital resources and capacity. (See 'Clinic evaluation' above.)

Other patients can generally remain at home for management without in-person evaluation if they can reliably report worsened symptoms and can self-isolate for the anticipated duration of illness. Some outpatients may be candidates for COVID-19-specific therapy, if available. We generally do not schedule routine telehealth follow-up visits for patients managed at home, although we reach out to those patients about whom we have concerns (eg, older adults who live alone, individuals who may not be able to reliably self-report worsening of symptoms) by telephone as our resources permit. (See 'Home management without in-person evaluation for others' above.)

●COVID-19 specific-therapy – Our recommendations for treating outpatients with symptomatic COVID-19 depend on their vaccination status and risk for progression. We do not use COVID-19-specific therapy for individuals without risk factors for severe disease or for individuals who have asymptomatic SARS-CoV-2 infection. All COVID-19 specific therapies should be administered as soon as possible after symptom onset. (See 'Our approach (indications, selection, prioritization)' above.)

•Unvaccinated individuals or those with likely inadequate vaccine response – For such individuals who have symptomatic mild to moderate COVID-19 and risk for progression (table 4), we recommend early treatment with nirmatrelvir-ritonavir or sotrovimab rather than no therapy (Grade 1B). These agents can reduce the risk of COVID-19 associated hospitalization and death.

•Vaccinated individuals – For immunocompetent, vaccinated individuals who have symptomatic mild to moderate COVID-19 and are at high risk for progression to severe disease (table 4), we also suggest treatment with nirmatrelvir-ritonavir or sotrovimab rather than no therapy (Grade 2C). However, it is reasonable to forgo treatment for such patients if the risk of progression is not especially high (eg, they are relatively young with only a single risk factor). Immunocompetent vaccinated patients are likely to benefit from these treatments, although their overall risk is lower than in unvaccinated individuals.

Remdesivir and high-titer convalescent plasma are alternative treatments when nirmatrelvir-ritonavir or sotrovimab are not available; low-titer convalescent plasma is not appropriate. For those who cannot use or access any of these agents, molnupiravir is an option; however, it may not be as effective and is potentially teratogenic.

The monoclonal antibody bebtelovimab is active against the globally prevalent Omicron variant, but data to support its use are limited. Other monoclonal antibodies available for treatment are not active against Omicron but may become appropriate for therapy if other variants emerge (table 9).

When supplies of these agents (and the resources necessary for administration) are insufficient to offer treatment to all eligible adults, we agree with the NIH COVID-19 treatment guidelines panel to prioritize immunocompromised individuals who are likely to have a suboptimal response to vaccination and unvaccinated or incompletely vaccinated individuals who have the highest risk for progression to severe disease (table 5). (See 'Our approach (indications, selection, prioritization)' above.)

●Outpatient therapies of limited or uncertain benefit – Other treatments are under investigation for outpatients with nonsevere COVID-19, and evidence supporting their efficacy continues to evolve. However, high-quality data are limited and none are recommended for use outside of a clinical trial. A catalog of clinical trials can be found at covid-trials.org; the list of trials can be filtered by setting (eg, outpatient versus inpatient). (See 'Therapies of limited or uncertain benefit' above and 'Therapies that we do not recommend' above.)

In non-hospitalized patients, we do not treat COVID-19 with dexamethasone, prednisone, or other corticosteroids. However, 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. In addition, patients with a concomitant acute exacerbation of asthma or chronic obstructive pulmonary disease (COPD) should receive appropriate treatment with systemic glucocorticoids as indicated.

For patients with documented COVID-19, treatment with antibiotics is not indicated. Data are limited, but bacterial superinfection does not appear to be a prominent feature of COVID-19. Further, we do not routinely initiate anticoagulation or antiplatelet therapy.

●Counseling on warning symptoms – We counsel all patients on the warning symptoms that should prompt reevaluation, including new onset or worsening dyspnea, dizziness, and mental status changes such as confusion. (See 'Counseling on warning symptoms' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Jessamyn Blau, MD, who contributed to an earlier version of this topic review.