COVID-19: Management in hospitalized adults

INTRODUCTION — Coronaviruses are important human and animal pathogens. At the end of 2019, a novel coronavirus was identified as the cause of a cluster of pneumonia cases in Wuhan, a city in the Hubei Province of China. It rapidly spread, resulting in a global pandemic. The disease is designated COVID-19, which stands for coronavirus disease 2019 [1]. The virus that causes COVID-19 is designated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

This topic will discuss the management of COVID-19 in hospitalized adults. Our approach to hospital management evolves rapidly as clinical data emerge. Clinicians should consult their own local protocols for management, which may differ from our approach. Guidance has been issued by the World Health Organization and, in the United States, by the National Institutes of Health COVID-19 Treatment Guidelines Panel [2]. Links to these and other related society guidelines are found elsewhere. (See 'Society guideline links' below.)

The management of patients with COVID-19 in the home and outpatient setting is discussed in detail elsewhere. (See "COVID-19: Management of adults with acute illness in the outpatient setting".) (Related Pathway(s): COVID-19: Anticoagulation in adults with COVID-19.)

Respiratory and critical care of patients with COVID-19 are also discussed separately. (See "COVID-19: Respiratory care of the nonintubated hypoxemic adult (supplemental oxygen, noninvasive ventilation, and intubation)" and "COVID-19: Management of the intubated adult".)

The epidemiology, clinical features, diagnosis, and prevention of COVID-19 are discussed in detail elsewhere. (See "COVID-19: Epidemiology, virology, and prevention" and "COVID-19: Clinical features" and "COVID-19: Diagnosis" and "COVID-19: Infection prevention for persons with SARS-CoV-2 infection" and "COVID-19: Vaccines".)

EVALUATION — Our objective in the evaluation of hospitalized patients with documented or suspected COVID-19 is to evaluate for features associated with severe illness (table 1) and identify organ dysfunction or other comorbidities that could complicate potential therapy. The diagnosis of COVID-19 is discussed in detail elsewhere. (See "COVID-19: Diagnosis", section on 'Diagnostic approach'.)

This approach to evaluation reflects our institution’s practice, which was established with interdisciplinary input. Although we check several laboratory tests to evaluate patients with documented or suspected COVID-19, the prognostic value of many of them remains uncertain, and other institutions may not include all these tests.

At least initially, we check the following laboratory studies:

●Complete blood count (CBC) with differential, with a focus on the total lymphocyte count trend, daily

●Basic metabolic panel daily

●Hepatic panel every other day (or daily if elevated or in the intensive care unit)

We check the following studies for patients with severe COVID-19 (with hypoxia or in need of oxygen/ventilatory support) and repeat them if abnormal or with clinical worsening:

●C-reactive protein (CRP)

●Lactate dehydrogenase

●Prothrombin time (PT)/partial thromboplastin time (PTT)/fibrinogen/D-dimer

●Troponin

●Electrocardiogram (ECG), with at least one repeat test after starting any QTc-prolonging agent (see "COVID-19: Arrhythmias and conduction system disease", section on 'Monitoring for QT prolongation')

We also check hepatitis B virus serologies, hepatitis C virus antibody, and HIV antigen/antibody testing if these have not been previously performed. Chronic viral hepatitis could affect interpretation of transaminase elevations and exacerbate hepatotoxicity of certain therapies; underlying HIV infection may change the assessment of the patient's risk for deterioration and would warrant initiation of antiretroviral therapy.

We check a portable chest radiograph in hospitalized patients with COVID-19; for most patients, this is sufficient for initial evaluation of pulmonary complications and extent of lung involvement. We reserve chest CT for circumstances that might change clinical management, in part to minimize infection control issues related to transport. This is consistent with recommendations from the American College of Radiology [3]. Although certain characteristic chest CT findings may be seen in COVID-19, they cannot reliably distinguish COVID-19 from other causes of viral pneumonia. (See "COVID-19: Clinical features", section on 'Imaging findings'.)

We do not routinely obtain echocardiograms on patients with COVID-19; developments that might warrant an echocardiogram include increasing troponin levels with hemodynamic compromise or other cardiovascular findings suggestive of cardiomyopathy. Acute myocardial injury has been a described complication of COVID-19. (See "COVID-19: Evaluation and management of cardiac disease in adults", section on 'Targeted cardiac evaluation'.)

Secondary bacterial infection occurs in the minority of patients with COVID-19; if this is suspected (eg, based on chest imaging or sudden deterioration), we check two sets of blood cultures and sputum Gram stain and culture. Procalcitonin can be checked to assess the risk of secondary bacterial infection; however, since elevated procalcitonin levels have been reported as COVID-19 progresses, they may be less specific for bacterial infection later in the disease course [4-7].

As above, the prognostic value of the results of some of the tests we use to evaluate patients with COVID-19 is uncertain, and the optimal use of these markers remains unknown. As an example, although some clinicians also note the potential utility of troponin levels to inform the risk of severe COVID-19 and provide a baseline for comparison in patients who develop manifestations of myocardial injury [8], others reserve troponin level testing for patients who have specific clinical suspicion for acute coronary syndrome [9]. One concern is that the results could lead to unnecessary use of medical resources (eg, serial troponins, electrocardiograms and cardiology consults for elevated troponin). If troponin is checked in a patient with COVID-19, clinicians should be aware that an elevated level does not necessarily indicate acute coronary syndrome. This is discussed in detail elsewhere. (See "COVID-19: Evaluation and management of cardiac disease in adults", section on 'Troponin'.)

GENERAL MANAGEMENT ISSUES

Empiric treatment for influenza during influenza season — The clinical features of seasonal influenza and COVID-19 overlap, and they can only be reliably distinguished by microbiologic testing. Additionally, coinfection with both is possible, so the diagnosis of COVID-19 does not rule out the possibility of influenza. We agree with the United States National Institutes of Health (NIH) COVID-19 Treatment Guidelines Panel, which recommends empiric therapy for influenza for patients hospitalized with suspected or documented COVID-19 in locations where influenza virus is circulating [2]. Antiviral therapy for influenza should be discontinued if molecular testing for influenza is negative from upper respiratory tract specimens in non-intubated patients and from both upper and lower respiratory tract specimens in intubated patients. Antiviral therapy for seasonal influenza is discussed in detail elsewhere. (See "Seasonal influenza in nonpregnant adults: Treatment".)

Empiric treatment for bacterial pneumonia in selected patients — For patients with documented COVID-19, we do not routinely administer empiric therapy for bacterial pneumonia. Bacterial superinfection has been reported in the minority (fewer than 20 percent) of patients hospitalized for COVID-19. (See "COVID-19: Clinical features", section on 'Acute course and complications'.)

However, since the clinical features of COVID-19 may be difficult to distinguish from bacterial pneumonia, empiric treatment for community-acquired pneumonia is reasonable when the diagnosis is uncertain. Empiric treatment for bacterial pneumonia may also be reasonable in patients with documented COVID-19 if there is clinical suspicion for it (eg, new fever after defervescence with new consolidation on chest imaging). If empiric antibiotic therapy is initiated, we attempt to make a microbial diagnosis (eg, through sputum Gram stain and culture, urinary antigen testing) and reevaluate the need to continue antibiotic therapy daily. In such settings, a low procalcitonin may be helpful to suggest against a bacterial pneumonia; however, elevated procalcitonin has been described in COVID-19, particularly late in the course of illness, and does not necessarily indicate bacterial infection [4-7]. (See "Procalcitonin use in lower respiratory tract infections", section on 'Guiding antibiotic therapy'.)

The diagnosis of and empiric antibiotic regimens for community-acquired and health care-associated pneumonia are discussed elsewhere. (See "Overview of community-acquired pneumonia in adults" and "Epidemiology, pathogenesis, microbiology, and diagnosis of hospital-acquired and ventilator-associated pneumonia in adults" and "Treatment of hospital-acquired and ventilator-associated pneumonia in adults".)

Prevention of and evaluation for venous thromboembolism — We favor pharmacologic prophylaxis of venous thromboembolism for all hospitalized patients with COVID-19. Dosing and selection of pharmacologic agents to prevent venous thromboembolism in hospitalized patients with COVID-19, including whether to use therapeutic-dose anticoagulation, are discussed in detail elsewhere (algorithm 1). (See "COVID-19: Hypercoagulability", section on 'Inpatient VTE prophylaxis'.)

Several studies suggest a high rate of thromboembolic complications among hospitalized patients with COVID-19, particularly those who are critically ill. The thromboembolic risk with COVID-19 as well as the evaluation for and management of these complications are discussed in detail elsewhere. (See "COVID-19: Hypercoagulability", section on 'VTE' and "COVID-19: Hypercoagulability", section on 'Management'.)

NSAID use — As with the general approach to fever reduction in adults, we use acetaminophen as the preferred antipyretic agent in patients with COVID-19 and, if non-steroidal anti-inflammatory drugs (NSAIDs) are needed, use the lowest effective dose to minimize common adverse effects (see "Pathophysiology and treatment of fever in adults", section on 'Treatment of fever and hyperpyrexia'). We do not discontinue NSAIDs in patients who are on them chronically for other conditions, unless there are other reasons to stop them (eg, renal injury, gastrointestinal bleeding).

Initial concerns about potential negative effects of NSAIDs in patients with COVID-19 [10] have not been supported by most observational data, which have failed to identify worse COVID-19 outcomes with NSAID use compared with acetaminophen or no antipyretic use [11-15]. As an example, in a study of patients who were hospitalized for COVID-19 in the United Kingdom, rates of in-hospital mortality, invasive ventilation, and oxygen requirement were not different among the 4205 patients who had used systemic NSAIDs the two weeks prior to hospitalization compared with propensity score-matched controls [15].

The European Medicines Agency (EMA), WHO, and the United States NIH COVID-19 Treatment Guidelines Panel do not recommend that NSAIDs be avoided when clinically indicated [2,16,17].

Nebulized medications — If a nebulizer must be used, appropriate infection control precautions should be taken. These are discussed in detail elsewhere. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection", section on 'Aerosol-generating procedures/treatments' and "COVID-19: Respiratory care of the nonintubated hypoxemic adult (supplemental oxygen, noninvasive ventilation, and intubation)", section on 'Nebulized medications'.)

Managing chronic medications

ACE inhibitors/ARBs — Patients receiving angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) should continue treatment with these agents if there is no other reason for discontinuation (eg, hypotension, acute kidney injury). This approach is supported by multiple guidelines panels [18-22]. Despite speculation that patients with COVID-19 who are receiving these agents may be at increased risk for adverse outcomes, accumulating evidence does not support an association between renin angiotensin system inhibitor use and more severe disease. This is discussed in detail elsewhere. (See "COVID-19: Issues related to acute kidney injury, glomerular disease, and hypertension", section on 'Renin angiotensin system inhibitors'.)

Conversely, data suggest that modulation of the renin-angiotensin pathway does not improve COVID-19 outcomes and that ACE inhibitors or ARBs should not be initiated for the purpose of treating COVID-19 [23,24].

Statins and aspirin — We make a point of continuing statins in hospitalized patients with COVID-19 who are already taking them. We also continue aspirin unless there are concerns about bleeding risk. A high proportion of patients with severe COVID-19 have underlying cardiovascular disease, diabetes mellitus, and other indications for use of statins and aspirin. Moreover, acute cardiac injury is a reported complication of COVID-19. Although clinicians may be concerned about hepatotoxicity from statins, particularly since transaminase elevations are common in COVID-19, most evidence indicates that liver injury from statins is uncommon. (See "Statins: Actions, side effects, and administration", section on 'Hepatic dysfunction'.)

We do not initiate statins or aspirin in patients with COVID-19 who do not have pre-existing indications for them. Although observational studies had suggested a potential mortality benefit in hospitalized patients with COVID-19, randomized trials have not confirmed these findings.

In a randomized trial of nearly 600 adults who were admitted to an intensive care unit (ICU) with COVID-19 and had no pre-existing indication for statin therapy, there was no statistically significant reduction in all-cause 30-day mortality with atorvastatin for 30 days compared with placebo (31 versus 35 percent; odds ratio 0.84, 95% CI 0.58-1.22) [25]. This result contrasted with those of retrospective studies in which statin use was associated with a lower rate of ICU admission or death [26-30]. Whether the timing of statin administration has an effect is uncertain.

Similarly, aspirin use during hospitalization for COVID-19 did not reduce 28-day mortality or the risk of progression to mechanical ventilation compared with standard of care or placebo in randomized trials [31,32]. A follow-up analysis of one of those trials suggested that aspirin could be associated with decreased 180-day mortality, but the reduction was not statistically significant [33]. (See "COVID-19: Hypercoagulability", section on 'Aspirin/antiplatelet agents'.)

Immunomodulatory agents — Use of immunosuppressing agents has been associated with increased risk for severe disease with other respiratory viruses, and the decision to discontinue prednisone, biologics, or other immunosuppressive drugs in the setting of COVID-19 must be determined on a case-by-case basis.

These issues are discussed in detail elsewhere:

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

●(See "COVID-19: Issues related to solid organ transplantation", section on 'Adjusting immunosuppression'.)

●(See "COVID-19: Care of adult patients with systemic rheumatic disease", section on 'Medication management with documented or presumptive COVID-19'.)

●(See "COVID-19: Issues related to gastrointestinal disease in adults", section on 'Adjusting IBD medications'.)

●(See "COVID-19: Cutaneous manifestations and issues related to dermatologic care", section on 'Continuation of immunosuppressive therapies'.)

Infection control — Infection control is an essential component of management of patients with suspected or documented COVID-19. This is discussed in detail elsewhere. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection".)

COVID-19-SPECIFIC THERAPY

Approach — The optimal approach to treatment of COVID-19 is evolving. Based on the pathogenesis of COVID-19, approaches that target the virus itself (eg, antivirals, passive immunity, interferons) are more likely to work early in the course of infection, whereas approaches that modulate the immune response may have more impact later in the disease course (figure 1).

Defining disease severity — Mild disease is characterized by fever, malaise, cough, upper respiratory symptoms, and/or less common features of COVID-19, in the absence of dyspnea. Most of these patients do not need hospitalization.

If patients develop dyspnea, that raises concern that they have at least moderate severity disease, and these patients often warrant hospitalization. Patients can have infiltrates on chest imaging and still be considered to have moderate disease, but the presence of any of the following features indicates severe disease:

●Hypoxemia (oxygen saturation ≤94 percent on room air)

●Need for oxygenation or ventilatory support

Given oxygen saturation targets in patients with hypoxemia, most individuals with severe disease warrant some form of oxygen supplementation. Assessment of oxygen saturation in individuals with dark skin pigmentation warrants special attention, as pulse oximetry may overestimate the oxygen saturation in such patients. This is discussed in detail elsewhere, as are recommended thresholds for oxygen supplementation. (See "COVID-19: Respiratory care of the nonintubated hypoxemic adult (supplemental oxygen, noninvasive ventilation, and intubation)", section on 'Oxygenation targets'.)

This definition of severe disease is consistent with the definition used by the US Food and Drug Administration [34]. Some studies have used other features in addition to hypoxemia to characterize severe disease, such as tachypnea, respiratory distress, and >50 percent involvement of the lung parenchyma on chest imaging [35].

Patients without oxygen requirement — For most hospitalized patients who do not need oxygen supplementation, our approach to management depends on whether they have clinical (table 2) or laboratory risk factors (table 1) associated with progression to more severe disease and the reason for hospitalization.

●For those with risk factors for severe disease who were hospitalized for COVID-19, we suggest remdesivir. Trial data suggest that remdesivir may improve time to recovery in such patients, although the magnitude of effect is uncertain [36-38]. We suggest not using dexamethasone, which may be associated with worse outcomes in such patients [39]. Administration and dosing of remdesivir and evidence informing its use are discussed elsewhere. (See 'Remdesivir' below.)

●For those with risk factors for severe disease who were hospitalized for a non-COVID-19 reason and have incidental SARS-CoV-2 infection (or acquired infection during hospitalization), we evaluate eligibility for therapies authorized for certain high-risk outpatients (algorithm 2). Administration, dosing, and efficacy of these therapies for nonsevere COVID-19 are discussed in detail elsewhere. (See "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Treatment with COVID-19-specific therapies'.)

●For patients who have no oxygen requirement and who have no risk factors for progression to severe disease, we suggest supportive care only.

These patients warrant monitoring for clinical worsening. If they develop an oxygen requirement related to COVID-19, we treat them as described below. (See 'Patients with oxygen requirement/severe disease' below.)

We also encourage enrollment in clinical trials for treatment of nonsevere disease, if available. A list of international clinical trials can be found at covid19.trackvaccines.org/vaccines.

In the United States, an emergency use authorization (EUA) has been granted for convalescent plasma for selected patients. However, we do not use convalescent plasma outside of clinical trials for hospitalized patients. (See 'Limited role for antibody-based therapies (monoclonal antibodies and convalescent plasma)' below.)

Patients with oxygen requirement/severe disease — We prioritize COVID-19-specific therapy for hospitalized patients who have severe disease and require oxygen supplementation due to COVID-19. The approach depends on the oxygen or ventilatory requirement; doses and duration are listed in the algorithm (algorithm 3):

●Patients receiving low-flow supplemental oxygen – For most patients on low-flow supplemental oxygen, we suggest both low-dose dexamethasone and remdesivir. However, for those who are stably on minimal supplemental oxygen (eg, 1 to 2 L/min), it is reasonable to forgo dexamethasone and use remdesivir alone, particularly if there are concerns about use of glucocorticoids or if the patient is immunocompromised and early in the course of illness (eg, <10 days). Trial data suggest that dexamethasone improves mortality in patients who are on noninvasive oxygen supplementation; it is uncertain if there are particular patients in this relatively heterogeneous group who would benefit more than others, and those stable on minimal oxygen may not have the excess inflammation that dexamethasone is intended to address. Some but not all trials also suggest that remdesivir may improve survival and reduce mechanical ventilation in patients on noninvasive oxygen supplementation. (See 'Dexamethasone and other glucocorticoids' below and 'Remdesivir' below.)

For patients who are on low-flow supplemental oxygen but have elevated inflammatory markers, have escalating oxygen requirements despite initiation of dexamethasone, and are within 96 hours of hospitalization, we suggest adding baricitinib or tocilizumab on a case-by-case basis. We define escalating oxygen requirements as a rapid increase of 6 L/min or more within 24 hours, a 10 L/min or more requirement, or escalating beyond nasal cannula. Trial data suggest that adding either baricitinib or tocilizumab to dexamethasone in such individuals may further reduce mortality; however, for stable patients with low expected mortality, the absolute mortality benefit may be very low and not outweigh the potential risks. (See 'Baricitinib and JAK inhibitors' below and 'IL-6 pathway inhibitors (eg, tocilizumab)' below.)

●Patients receiving high-flow supplemental oxygen or non-invasive ventilation – For patients on high-flow oxygen or noninvasive ventilation, we recommend low-dose dexamethasone. For those who are within 24 to 48 hours of admission to an ICU or receipt of ICU-level care and within 96 hours of hospitalization, we also suggest adjunctive baricitinib or tocilizumab. Trial data suggest that dexamethasone improves mortality in patients who are on noninvasive oxygen supplementation and that the addition of baricitinib or tocilizumab further reduces mortality. (See 'Dexamethasone and other glucocorticoids' below and 'Baricitinib and JAK inhibitors' below and 'IL-6 pathway inhibitors (eg, tocilizumab)' below.)

We also suggest remdesivir, particularly in immunocompromised patients, based on the theoretic benefit of adding antiviral therapy to anti-inflammatory treatment. (See 'Remdesivir' below.)

●Patients who require mechanical ventilation or extracorporeal membrane oxygenation (ECMO) – For such patients, we recommend low-dose dexamethasone; for those who are within 24 to 48 hours of admission to an ICU and within 96 hours of hospitalization, we also suggest adjunctive tocilizumab or baricitinib. Trial data suggest that dexamethasone and the addition of tocilizumab or baricitinib each improve mortality in this population when used early in hospitalization. We suggest not routinely starting remdesivir in this population. Although it is reasonable to add remdesivir in individuals who have only been intubated for a short time (eg, 24 to 48 hours), the clinical benefit of this is uncertain. Those who had initiated remdesivir when they had lower oxygenation support needs can continue the course of remdesivir. (See 'Dexamethasone and other glucocorticoids' below and 'Baricitinib and JAK inhibitors' below and 'IL-6 pathway inhibitors (eg, tocilizumab)' below.)

For all these patients, if dexamethasone is not available, other glucocorticoids at equivalent doses are reasonable alternatives. (See 'Dexamethasone and other glucocorticoids' below.)

When baricitinib or tocilizumab is warranted, we only use these agents in patients receiving glucocorticoids, and we do not use baricitinib in patients who have received tocilizumab and vice versa. There are no data directly comparing baricitinib with tocilizumab, and the choice between them depends on availability; if baricitinib is unavailable, tofacitinib may be a reasonable alternative. (See 'Baricitinib and JAK inhibitors' below and 'IL-6 pathway inhibitors (eg, tocilizumab)' below.)

Remdesivir is approved or available for emergency use in some countries but is not universally available [40-42]. (See 'Remdesivir' below.)

Specific treatments

Dexamethasone and other glucocorticoids

●Use of dexamethasone – We recommend dexamethasone for severely ill patients with COVID-19 who are on supplemental oxygen or ventilatory support (algorithm 3). We use dexamethasone at a dose of 6 mg daily for 10 days or until discharge, whichever is shorter. If dexamethasone is not available, it is reasonable to use other glucocorticoids at equivalent doses (eg, total daily doses of hydrocortisone 150 mg, methylprednisolone 32 mg, or prednisone 40 mg), although data supporting use of these alternatives are more limited than those for dexamethasone. In contrast, we recommend that dexamethasone (or other glucocorticoids) not be used for either prevention or treatment of mild to moderate COVID-19 (patients not on oxygen). These recommendations are largely consistent with those of other expert and governmental groups [2,43-46]. (See 'Patients with oxygen requirement/severe disease' above.)

Glucocorticoids may also have a role in the management of refractory shock in critically ill patients with COVID-19. These issues are discussed elsewhere. (See "COVID-19: Management of the intubated adult", section on 'Use of glucocorticoids for non-COVID-19 reasons'.)

●Monitoring for adverse effects – Patients receiving glucocorticoids should be monitored for adverse effects. In severely ill patients, these include hyperglycemia and an increased risk of infections (including bacterial, fungal, and Strongyloides infections); the rates of these infections in patients with COVID-19 are uncertain. Nevertheless, pre-emptive treatment of Strongyloides prior to glucocorticoid administration is reasonable for patients from endemic areas (ie, tropical and subtropical regions). This is discussed elsewhere (see "Strongyloidiasis", section on 'Preventive treatment'). Major side effects of glucocorticoids are also discussed in detail elsewhere. (See "Major side effects of systemic glucocorticoids".)

●Efficacy – Data from randomized trials overall support the role of glucocorticoids for severe COVID-19 [47-50]. In a meta-analysis of seven trials that included 1703 critically ill patients with COVID-19, glucocorticoids reduced 28-day mortality compared with standard care or placebo (32 versus 40 percent, odds ratio [OR] 0.66, 95% CI 0.53-0.82) and were not associated with an increased risk of severe adverse events [47]. In another systematic review and network meta-analysis of randomized trials that evaluated interventions for COVID-19 and were available through mid-August 2020, glucocorticoids were the only intervention for which there was at least moderate certainty in a mortality reduction (OR 0.87, 95% CI 0.77-0.98) or risk of mechanical ventilation (OR 0.74, 95% CI 0.58-0.92) compared with standard care [48].

The majority of the efficacy data on glucocorticoids in these meta-analyses comes from a large open-label trial in the United Kingdom in which 2104 and 4321 patients with confirmed or suspected COVID-19 were randomly assigned to receive dexamethasone (given at 6 mg orally or intravenously daily for up to 10 days) or usual care, respectively [39]. Dexamethasone reduced 28-day mortality in:

•Patients on invasive mechanical ventilation or ECMO at baseline – 36 percent relative reduction (29.3 versus 41.4 percent, RR 0.64, 95% CI 0.51-0.81). Age-adjusted analysis suggested a 12.3 percent absolute mortality reduction.

•Patients on noninvasive oxygen therapy (including noninvasive ventilation) at baseline – 18 percent relative reduction (23.3 versus 26.2 percent, RR 0.82, 95% CI 0.72-0.94). Age-adjusted analysis suggested a 4.1 percent absolute mortality reduction.

In contrast, a benefit was not seen among patients who did not require either oxygen or ventilatory support; there was a nonstatistically significant trend towards higher mortality (17.8 versus 14 percent, RR 1.19, 95% CI 0.91-1.55). Results were similar when analysis was restricted to the patients with laboratory-confirmed COVID-19 (89 percent of the total population). Other studies have also suggested potential harm with glucocorticoids in this population [51].

For individuals who are ready for discharge before completing a 10-day course of dexamethasone, continuing the medication following discharge has not been associated with additional benefit [52].

The optimal dose of dexamethasone is uncertain. In a randomized trial from Europe and India that included nearly 1000 adults with COVID-19 who needed at least 10 L of supplemental oxygen or ventilatory support, 12 mg daily of dexamethasone resulted in trends toward more days alive without life support at 28 days (22 versus 20.5 days; adjusted mean difference 1.3 days, 95% CI 0-2.6) and lower 28-day mortality (27 versus 32 percent, adjusted RR 0.86, 95% CI 0.68-1.08) compared with 6 mg daily, but these differences were not statistically significant [53]. Other smaller trials have not identified a reduction in mechanical ventilation or mortality rates with high- versus lower-dose dexamethasone [54-56]. Furthermore, in another trial that included 1272 patients who required only low amounts of supplemental oxygen, mortality rates were higher with high-dose dexamethasone (20 mg daily for five days then 10 mg daily for five days) compared with the usual 6 mg daily dose (19 versus 12 percent; RR 1.59, 95% CI 1.2-2.1) [57]. Similarly, data do not suggest a benefit of adding other glucocorticoids to dexamethasone [58]. Unless additional trial data indicate that a higher dose is superior in a particular patient population, we continue to use the same 6 mg dose studied in the large trial from the United Kingdom.

Data on the efficacy of other glucocorticoids are limited to small trials, several of which were stopped early because of the findings of the trial above [59-61]. Individual trials of hydrocortisone in critically ill patients failed to demonstrate a clear benefit [59,60]; in a meta-analysis that included three trials evaluating hydrocortisone, there was a nonstatistically significant trend toward reduced 28-day mortality compared with usual care or placebo (OR 0.69, 95% CI 0.43-1.12) [47]. Trials evaluating methylprednisone have not demonstrated a clear benefit. In a randomized trial from Brazil that included 393 patients with suspected or confirmed severe COVID-19 (77 percent of whom were on oxygen or ventilatory support), there was no difference in 28-day mortality rates with methylprednisolone compared with placebo (37 versus 38 percent) [62]. It is uncertain whether the apparent difference in results compared with the larger dexamethasone trial is related to the glucocorticoid formulation and dose, other differences between the trial populations, or issues related to statistical power.

Adjunctive immunomodulators

Baricitinib and JAK inhibitors — Baricitinib is a Janus kinase (JAK) inhibitor used for treatment of rheumatoid arthritis. In addition to immunomodulatory effects, it is thought to have potential antiviral effects through interference with viral entry.

●Use of baricitinib – We suggest baricitinib as an option for patients requiring high-flow oxygen or noninvasive ventilation and for select patients who are on low-flow oxygen but are progressing toward needing higher levels of respiratory support despite initiation of dexamethasone (algorithm 3). Baricitinib is also a reasonable alternative to tocilizumab, if it is not available, in patients who are on mechanical ventilation or ECMO. We generally reserve baricitinib for those who are within 96 hours of hospitalization or within 24 to 48 hours of initiation of ICU-level care, similar to the study population in the large trials. We do not use baricitinib in patients who have also received an interleukin (IL)-6 pathway inhibitor, as the safety and additive benefit of combining these agents are uncertain. As with tocilizumab, we only use baricitinib with caution in immunocompromised patients. This approach is largely consistent with recommendations from the NIH COVID-19 Treatment Guidelines Panel [2]. In the United States, baricitinib is US Food and Drug Administration (FDA) approved for hospitalized adults requiring supplemental oxygen, noninvasive or invasive mechanical ventilation, or ECMO [63]. Tofacitinib, another JAK inhibitor, may be an alternative if baricitinib is not available. (See 'Patients with oxygen requirement/severe disease' above.)

Baricitinib is given at 4 mg orally once daily for up to 14 days. The dose is reduced in patients with renal insufficiency, and its use is not recommended if the estimated glomerular filtration rate (eGFR) is <15 mL/min per 1.73 m². Baricitinib is also not recommended in patients with COVID-19 with lymphopenia (absolute lymphocyte count <200 cells/microL) or neutropenia (absolute neutrophil count <500 cells/microL)

●Efficacy – Data suggest that baricitinib provides a mortality benefit for patients with severe disease, even if they are already on dexamethasone [64]. In an open-label randomized trial of over 8000 hospitalized patients with COVID-19, baricitinib reduced 28-day mortality compared with usual care alone (12 versus 14 percent; relative risk 0.87, 95% CI 0.77-0.99) [65]. Almost all participants (95 percent) were receiving glucocorticoids, 20 percent were receiving remdesivir, and 23 percent had received tocilizumab. These results were similar to those of prior trials of baricitinib [66-70], although the relative mortality reduction was slightly lower in this trial. The reasons for this difference are uncertain; however, this trial included a broader patient population, and it is feasible that certain patient populations are more likely than others to benefit from baricitinib.

As an example, in a placebo-controlled trial of 1525 hospitalized adults with COVID-19 who were not receiving invasive mechanical ventilation but had at least one elevated inflammatory marker (median CRP was 65 mg/L), adding baricitinib to standard of care reduced 28-day mortality (8.1 versus 13.1 percent with placebo; hazard radio [HR] 0.57, 95% CI 0.41-0.78); the reduction in mortality was maintained at 60 days [66]. Most participants (79 percent) were also receiving glucocorticoids, mainly dexamethasone, and 20 percent received remdesivir. Among the subgroup of patients who were on high-flow oxygen or noninvasive ventilation at baseline, the mortality with baricitinib was 17.5 percent versus 29.4 percent with placebo (HR 0.52, 95% CI 0.33-0.80); mortality rates with baricitinib were also lower than with placebo for individuals who were not on oxygen or on low-flow oxygen at baseline, but these differences were not statistically significant. A smaller trial suggested that baricitinib also reduced mortality compared with placebo among 101 patients on mechanical ventilation or ECMO at enrollment (39 versus 58 percent, HR 0.54, 95% CI 0.31-0.96) [71].

These data are consistent with other findings of potential benefit with baricitinib [67-70]. In other randomized trials, adding baricitinib to remdesivir reduced time to recovery compared with placebo [67], and baricitinib plus remdesivir resulted in similar rates of mechanical ventilation-free survival with fewer associated adverse effects compared with dexamethasone plus remdesivir in patients on oxygen or noninvasive ventilation [70].

Tofacitinib may also have clinical benefit, although data are more limited. In a randomized trial of 289 patients hospitalized with COVID-19, most of whom were receiving glucocorticoids, tofacitinib (10 mg twice daily for up to 14 days) reduced the combined outcome of death and respiratory failure at 28 days compared with placebo (18 versus 29 percent, relative risk 0.63, 95% CI 0.41-0.97) [72]. There was also a trend toward lower all-cause mortality (2.8 versus 5.5 percent, HR 0.49, 95% CI 0.15-1.63), but this was not statistically significant. In contrast, trials have not demonstrated a benefit with ruxolitinib, another JAK inhibitor [73,74].

●Adverse effects – In these studies, there was no apparent increase in the rate of adverse effects, including infection rates and venous thromboembolism, with baricitinib or tofacitinib. In the large placebo-controlled trial discussed above, treatment-emergent infections (16 percent) and thromboembolic events (3 percent) occurred at similar frequencies in both the baricitinib and placebo groups [66]. However, the number of immunocompromised patients included in this trial was not specified.

IL-6 pathway inhibitors (eg, tocilizumab) — Markedly elevated inflammatory markers (eg, D-dimer, ferritin) and elevated pro-inflammatory cytokines (including interleukin [IL]-6) are associated with critical and fatal COVID-19, and blocking the inflammatory pathway may prevent disease progression [75]. Several agents that target the IL-6 pathway have been evaluated in randomized trials for treatment of COVID-19; these include the IL-6 receptor blockers tocilizumab and sarilumab and the direct IL-6 inhibitor siltuximab.

●Use of tocilizumab – We suggest tocilizumab (8 mg/kg as a single intravenous dose) as an option for individuals who require high-flow oxygen or more intensive respiratory support (algorithm 3). If supplies of medication allow, we also suggest tocilizumab on a case-by-case basis as an option for select patients on low-flow oxygen supplementation if they are clinically progressing toward high-flow oxygen despite initiation of dexamethasone and have significantly elevated inflammatory markers (eg, C-reactive protein [CRP] level ≥75 mg/L). More specifically, we would give tocilizumab to such patients if they had progressively greater oxygen requirements for reasons related to COVID-19 but not if their oxygen requirement is stable or is worsening due to other causes of respiratory decompensation (eg, asthma exacerbation, congestive heart failure). We generally reserve tocilizumab for those who are within 96 hours of hospitalization or within 24 to 48 hours of initiation of ICU-level care, similar to the study population in the large trials. (See 'Patients with oxygen requirement/severe disease' above.)

We only use tocilizumab in patients who are also taking dexamethasone (or another glucocorticoid) and generally limit it to a single dose. We do not use tocilizumab in patients who are receiving baricitinib, as these agents have not been studied together and the safety of coadministration is uncertain. Tocilizumab should be avoided in individuals with hypersensitivity to tocilizumab, uncontrolled serious infections other than COVID-19, absolute neutrophil count (ANC) <1000 cells/microL, platelet counts <50,000, alanine aminotransferase (ALT) >10 times the upper limit of normal (ULN), and elevated risk for gastrointestinal perforation. Tocilizumab should be used with caution in immunocompromised individuals as very few were included in randomized trials. Data regarding sarilumab are less robust than those for tocilizumab.

Recommendations from expert and governmental guideline groups vary slightly. In the United States, tocilizumab is FDA approved for hospitalized adults who are receiving systemic corticosteroids and require supplemental oxygen, noninvasive or invasive mechanical ventilation, or ECMO [76]. The National Institutes of Health (NIH) COVID-19 Treatment Guidelines Panel recommends adding tocilizumab to dexamethasone in recently hospitalized patients who are on high-flow oxygen or greater support and have either been admitted to the ICU within the prior 24 hours or have significantly increased inflammatory markers of inflammation; some panel members also suggested adding tocilizumab to patients on conventional oxygen supplementation if they had rapidly increasing oxygen needs and a CRP level ≥75 mg/L [2]. The Infectious Diseases Society of America (IDSA) suggests adding tocilizumab to standard of care (ie, glucocorticoids) for hospitalized adults who have progressive severe or critical COVID-19 and have elevated markers of systemic inflammation [44]. The National Health Service in the United Kingdom recommends consideration of tocilizumab as an adjunct to dexamethasone in patients with severe COVID-19 [77]. These include patients who have hypoxemia (oxygen saturation repeatedly <92 percent on room air) or are on supplementary oxygen and have a CRP ≥75 mg/L as well as those who started on respiratory support (high-flow oxygen, noninvasive ventilation, or invasive mechanical ventilation) in the prior 24 hours. For the latter group, sarilumab is recommended as an alternative if tocilizumab supplies are limited.

●Efficacy – Overall, evidence suggests a mortality benefit with IL-6 inhibitors, with most studies evaluating tocilizumab [49,78,79]. In a meta-analysis of 27 randomized trials of over 10,000 patients hospitalized with COVID-19, all-cause mortality was lower among those who received tocilizumab compared with placebo or standard of care (odds ratio 0.83, 95% CI 0.74-0.92) [78,79]. The two largest trials in that analysis were conducted in patients with severe and critical COVID-19 and support the use of tocilizumab, as detailed below.

•In an open-label trial in the United Kingdom that included 4116 patients with suspected or confirmed COVID-19, hypoxemia (oxygen saturation <92 percent on room air or oxygenation supplementation of any kind), and a CRP level ≥75 mg/L, adding one to two doses of weight-based tocilizumab to usual care reduced the 28-day mortality rate compared with usual care alone (31 versus 35 percent, relative risk 0.85, 95% CI 0.76-0.94) [80]. Among those who were not on mechanical ventilation at baseline, tocilizumab similarly reduced the combined endpoint of progression to mechanical ventilation or death. There did not appear to be a statistically significant difference in mortality risk reduction by level of baseline respiratory support. Most of the trial participants (82 percent) were also using glucocorticoids, mainly dexamethasone, and subgroup analysis suggested that they were more likely to benefit from tocilizumab than were individuals who did not receive glucocorticoids.

•Another open-label international randomized trial suggested a long-term mortality benefit of IL-6 pathway inhibitors among patients with severe COVID-19 who were admitted to the intensive care unit in the prior 24 hours and required initiation of either respiratory or cardiovascular support [81]. Tocilizumab (n = 353) and sarilumab (n = 48) each reduced in-hospital mortality compared with standard of care (28 and 22 versus 36 percent; adjusted odds ratio for hospital survival 1.64, 95% credible interval [CrI] 1.14-2.35 for tocilizumab and 2.01, 95% CrI 1.18-4.71 for sarilumab). In a follow-up analysis that included additional participants, IL-6 pathway inhibitors (n = 948 for tocilizumab and 485 for sarilumab) were associated with lower 180-day mortality (adjusted HR 0.76, 95% CrI 0.61-0.93) [33].

Several other trials failed to identify a mortality benefit or other clear clinical benefit with these agents [82-89]. As an example, one double-blind, randomized trial of 243 patients with severe COVID-19 who were not intubated but had evidence of a pro-inflammatory state (with elevations in CRP, ferritin, D-dimer, or lactate dehydrogenase) did not detect a difference in the rate of intubation or death with a single dose of tocilizumab compared with placebo (10.6 versus 12.5 percent, HR 0.83, 95% CI 0.38-1.81) [85]. Although there were more subjects older than 65 years in the tocilizumab arm, the HR was not statistically significant after adjustment for age and other clinical features. Tocilizumab also did not reduce the risk of disease progression (eg, worsening oxygen requirements).

The reasons for the different findings among trials are uncertain. The trials that suggested a benefit with tocilizumab reported somewhat higher overall mortality rates compared with other trials, potentially reflecting more severely ill populations. This possibility is supported by a post-hoc analysis of a trial that did not originally show a benefit, in which tocilizumab was associated with a reduction in death and mechanical ventilation only among those with a CRP level >150 mg/L [90]. Trials that suggested a benefit also reported a high rate of concomitant glucocorticoid use, which most other trials did not; whether this is a relevant factor is uncertain. Finally, some of the trials that failed to show a benefit reported non-statistically significant trends towards a benefit, and these trials may have been underpowered to identify an effect.

●Adverse effects – Serious adverse events in trials were not greater with IL-6 pathway inhibitors than comparators. Although use of IL-6 pathway inhibitors may be associated with an increased risk of secondary infections [91,92], this risk was not observed in several randomized trials [85-87]. However, patients with active infections other than COVID-19 were typically excluded from trial participation. (See "Secondary immunodeficiency induced by biologic therapies", section on 'Tocilizumab'.)

Other authorized immunomodulators — In the United States, several other immunomodulatory agents have received EUA for severely or critically ill patients with COVID-19. However, we do not routinely use these other agents, in part because they do not offer clear advantages over other immunomodulatory agents that have demonstrated efficacy (eg, IL-6 inhibitors or JAK inhibitors). However, if IL-6 inhibitors or JAK inhibitors are not available, these are reasonable alternatives for patients who meet the authorization criteria.

●IL-1 inhibitors (eg, anakinra) – The interleukin-1 (IL-1) inhibitor anakinra is authorized for hospitalized patients with severe COVID-19 who are receiving supplemental oxygen, are at risk of progressing to severe respiratory failure, and are likely to have an elevated plasma soluble urokinase plasminogen activator receptor (suPAR), a biomarker that has been associated with disease progression in some studies [93]. When used for this purpose, anakinra is dosed at 100 mg subcutaneously daily for 10 days. However, we do not routinely use anakinra because of other available options and because the suPAR biomarker is not widely available (including in the United States), and it is thus challenging to identify the patient population expected to benefit from anakinra.

Support for anakinra comes primarily from a randomized trial performed in Italy and Greece that evaluated subcutaneous anakinra for 10 days in hospitalized patients with COVID-19 who had an elevated suPAR level (≥6 ng/mL); most participants were also receiving dexamethasone [94]. At 28 days, anakinra increased the likelihood of clinical recovery (50.4 versus 26.5 percent; unadjusted odds of a worse clinical severity score 0.36, 95% CI 0.26-0.49) and reduced mortality compared with placebo (3.2 versus 6.9 percent, hazard ratio 0.45, 95% CI 0.21-0.98). In the absence of suPAR testing, meeting three of the following eight criteria has been proposed as a surrogate for having an elevated suPAR level: age ≥75 years, severe pneumonia, current/previous smoking, Sequential Organ Failure Assessment (SOFA) score ≥3, neutrophil-to-lymphocyte ratio ≥7, hemoglobin ≤10.5 g/dL, history of ischemic stroke, blood urea ≥50 mg/dL and/or medical history of renal disease. However, outcomes with anakinra among patients meeting these criteria are unknown.

However, some other trials of IL-1 inhibitors (including anakinra in hospitalized patients with nonsevere and severe COVID-19 [33,95,96] and canakinumab in patients with severe COVID-19 [96,97]) have not identified a reduction in ventilator-free or overall survival or improved outcomes at 180 days.

●Vilobelimab – This monoclonal antibody complement inhibitor is authorized for hospitalized patients with COVID-19 who have initiated invasive mechanical ventilation or extracorporeal membrane oxygenation within the last 48 hours [98]. The dose is 800 mg intravenously, given up to six times on days 1, 2, 4, 8, 15, and 22, while the patient is still hospitalized. Hospitalization should not be extended simply to give all doses of vilobelimab. We do not routinely use vilobelimab given the availability of other immunomodulatory options and some uncertainties around the data.

Authorization was based on results of an unpublished multinational randomized trial that included 368 adults hospitalized for COVID-19 who had started mechanical ventilation in the last 48 hours; almost all were also receiving dexamethasone [99]. The 28-day mortality rate was lower with vilobelimab compared with placebo, although the difference was not statistically significant (32 versus 42 percent, hazard ratio 0.73, 95% CI 0.50-1.06). Other analyses (eg, without site stratification) did show a statistically significant difference. Nevertheless, the noted imprecision reduces confidence in the finding that vilobelimab reduces mortality. Furthermore, more individuals in the placebo group required additional organ support beyond mechanical ventilation, which introduces further uncertainty.

Vilobelimab was also associated with a slight excess of non-fatal secondary infections, including pneumonia and sepsis.

Remdesivir — Remdesivir is a novel nucleotide analog that has in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [100].

●Use of remdesivir – If available, we suggest remdesivir for hospitalized patients with severe COVID-19 who are not on mechanical ventilation because some data suggest it may reduce time to recovery and risk of mechanical ventilation (algorithm 3). Guidelines from the IDSA, the NIH, and the WHO recommend remdesivir for severe COVID-19 [2,44,46,101]. (See 'Patients with oxygen requirement/severe disease' above.)

In the United States, the FDA approved remdesivir for hospitalized children ≥12 years and adults with COVID-19, regardless of disease severity [102]. The suggested adult dose is 200 mg intravenously on day 1 followed by 100 mg daily for 5 days total (with extension to 10 days if there is no clinical improvement). If a patient is otherwise ready for discharge prior to completion of the course, remdesivir can be discontinued. Remdesivir can be used in patients with renal impairment, including those on dialysis, without dose adjustment [103]. Despite initial concerns about its cyclodextrin vehicle, which can accumulate in renal impairment, the risks in patients with renal impairment were deemed low [104], and studies have reported safe use of remdesivir in patients with acute kidney injury and chronic kidney disease [105,106]. Liver enzymes should be checked before and during remdesivir administration; alanine aminotransferase elevations >10 times the upper limit of normal should prompt consideration of remdesivir discontinuation.

●Efficacy – Remdesivir has been evaluated for both severe and non-severe COVID-19 in hospitalized patients:

•Severe COVID-19 – Data from randomized trials do not clearly or consistently demonstrate a major clinical benefit with remdesivir among hospitalized patients overall, although there may be a benefit (faster recovery, reduced risk of mechanical ventilation, and mortality reduction) for a select subgroup of patients with severe disease who are not on ventilatory support at the time of treatment initiation [36,37,48,107-113]. As an example, in the WHO-sponsored, multinational SOLIDARITY trial of patients hospitalized with COVID-19, there was a small difference in overall 28-day mortality between the 4146 patients randomly assigned to open-label remdesivir and the 4129 patients assigned to standard care, but it was not statistically significant (14.5 versus 15.6 percent; RR 0.91, 95% CI 0.82-1.02) [37]. However, among those who were not on ventilatory support, remdesivir reduced both mortality (RR 0.86, 95% CI 0.76-0.98) and progression to ventilation (RR 0.88, 95% CI 0.77-1.00). Similar findings were reported in a subsequent meta-analysis of randomized trials that included over 6000 patients with COVID-19 who required supplemental oxygen but not ventilatory support [112]. Among this population, remdesivir reduced 28-day mortality compared with standard care or placebo (adjusted OR 0.79, 95% CI 0.69-0.92).

Although these trials evaluated 10 days of remdesivir, 5 days of therapy may result in similar outcomes in patients who do not need mechanical ventilation or ECMO [114].

•Nonsevere COVID-19 – Among hospitalized patients with nonsevere disease (ie, no hypoxia or oxygen requirement), remdesivir may have a modest benefit, but the clinical significance of the benefit is uncertain [36-38]. In an open-label randomized trial, 584 patients with moderate severity COVID-19 (pulmonary infiltrates on imaging but oxygen saturation >94 percent on room air) were assigned to receive remdesivir for up to 5 days, remdesivir for up to 10 days, or standard of care [38]. By day 11, the five-day remdesivir group had better clinical status according to a seven-point scale compared with standard of care (odds ratio 1.65, 95% CI 1.09 to 2.48). There was not a statistically significant difference at day 11 in clinical status between the 10-day remdesivir group and the standard of care group. Although discharge rates by day 14 were higher with remdesivir (76 percent in each of the remdesivir groups versus 67 percent with standard of care), these differences were not statistically significant. Interpretation of this trial is limited by the open-label design and an imbalance in co-therapies. Additionally, whether remdesivir reduces mortality in this population is uncertain, in part because the risk of COVID-19-associated mortality in individuals without severe disease is low. In a meta-analysis of randomized trials that included over 2000 hospitalized patients with COVID-19 who did not require oxygen or ventilatory support, there was a trend toward lower mortality in such patients receiving remdesivir compared with those on standard care, but the difference was not statistically significant (adjusted OR 0.86, 95% CI 0.53-1.4) [112]. Trials of remdesivir in outpatients with nonsevere COVID-19 are discussed elsewhere. (See "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Remdesivir'.)

●Adverse effects – Reported side effects include nausea, vomiting, and transaminase elevations. In one trial, the most common adverse events were anemia, acute kidney injury, fever, hyperglycemia, and transaminase elevations; the rates of these were overall similar between remdesivir and placebo [36]. However, in another trial, remdesivir was stopped early because of adverse events (including gastrointestinal symptoms, aminotransferase or bilirubin elevations, and worsened cardiopulmonary status) more frequent than with placebo (12 percent versus 5 percent) [107]. Cases of bradycardia attributable to remdesivir have also been reported [115-117].

Limited role for antibody-based therapies (monoclonal antibodies and convalescent plasma)

●Monoclonal antibodies – Results from available trials do not demonstrate a benefit of monoclonal antibodies in most hospitalized patients [118,119]. Although data had suggested a potential benefit for a subset of hospitalized patients (eg, those without detectable anti-SARS-CoV-2 antibodies at presentation) [120,121], the increasing prevalence of SARS-CoV-2 variants that escape clinically available monoclonal antibodies has rendered the therapy ineffective (table 3). (See "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Therapies of limited or uncertain benefit'.)

●Convalescent plasma – Convalescent plasma from individuals who have recovered from COVID-19 has been hypothesized to have clinical benefit for COVID-19, and in the United States, EUA has been granted for high-titer convalescent plasma among hospitalized patients with COVID-19 who have impaired humoral immunity [122]. However, the available evidence does not support a clear role for convalescent plasma in patients with severe disease, and because of the lack of evident benefit, we suggest not using convalescent plasma for mechanically ventilated patients and not using it outside the context of clinical trials for other hospitalized patients. Limited randomized trial data and observational data suggest that convalescent plasma may have a role for individuals with immunocompromising conditions or deficits in antibody production (eg, those receiving anti-CD20 therapies, those with hematologic malignancies) [123-126]. Convalescent plasma is also being evaluated in outpatient populations with nonsevere COVID-19. (See 'Patients with oxygen requirement/severe disease' above and "COVID-19: Convalescent plasma and hyperimmune globulin" and "COVID-19: Considerations in patients with cancer", section on 'Cancer therapy in infected patients' and "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Therapies of limited or uncertain benefit'.)

Despite some evidence suggesting that early administration of convalescent plasma with high antibody titers was associated with lower mortality rates, randomized trials in hospitalized patients have not demonstrated a clear clinical benefit of convalescent plasma, including large trials that stopped enrollment for lack of mortality benefit [127-137]. Trials of hyperimmune globulin have also not demonstrated benefit [138,139]. (See "COVID-19: Convalescent plasma and hyperimmune globulin".)

Others — Many other agents with known or putative antiviral or immunomodulating effects have been proposed for use in patients with COVID-19 but have insufficient evidence of clinical benefit. Use of these agents for COVID-19 should be limited to clinical trials, if used at all; their efficacy has not been proven, and extensive off-label use may result in excess toxicity and critical shortages of drugs for proven indications.

A list of international clinical trials can be found at covid19.trackvaccines.org/vaccines, as well as on the WHO website and at clinicaltrials.gov.

●Ivermectin – In patients with COVID-19, we reserve ivermectin for prevention of Strongyloides reactivation in select individuals receiving glucocorticoids (see "Strongyloidiasis", section on 'Preventive treatment'). We do not use ivermectin for treatment of COVID-19 outside of clinical trials, as with other interventions that are not supported by high-quality data and consistent with recommendations from the WHO [140]. Systematic reviews and meta-analyses comparing ivermectin with placebo or standard of care have highlighted that the data on ivermectin for COVID-19 are of low quality and overall do not indicate a clear benefit [48,49,141,142]. Although ivermectin administered in a hospital setting has not been associated with excess serious adverse events in studies, gastrointestinal and neurologic side effects have been reported in individuals who obtained ivermectin at high or uncertain doses without prescription (eg, from internet or veterinary sources) [143]. Ivermectin had originally been proposed as a potential therapy based on in vitro activity against SARS-CoV-2; however, the drug levels used in the in vitro studies far exceed those achieved in vivo with safe drug doses [144].

●Other immunomodulatory agents – In addition to JAK inhibitors (see 'Baricitinib and JAK inhibitors' above), IL-6 pathway inhibitors (see 'IL-6 pathway inhibitors (eg, tocilizumab)' above) and IL-1 inhibitors and complement inhibitors (see 'Other authorized immunomodulators' above), immunomodulatory agents from various other classes, including other cytokine inhibitors [145], other kinase inhibitors [146-149], bradykinin pathway inhibitors [150], and hematopoietic colony-stimulating factors agonist and antagonists [151,152], are being evaluated. Their use has been described mainly in case series and other observational studies. Although a randomized trial suggested a survival benefit of lenzilumab, an anti-granulocyte-macrophage colony stimulating factor (GM-CSF) monoclonal antibody, in patients with severe COVID-19, uncertainties in trial design and outcomes reduce confidence in these findings [153].

●Vitamin D – In patients with COVID-19, vitamin D supplementation may be appropriate to meet the recommended intake or treat deficiency. However, we do not exceed the recommended upper level of intake, and there is no clear evidence that vitamin D supplementation or high-dose vitamin D improves COVID-19 outcomes. These data are discussed elsewhere. (See "Vitamin D and extraskeletal health", section on 'COVID-19'.)

Novel agents under evaluation for severe COVID-19 in hospitalized patients include sabizabulin, a microtubule disruptor purported to have antiviral and anti-inflammatory effects through disruption of intracellular transport [154]. Sabizabulin reduced mortality in a randomized trial of hospitalized patients with severe COVID-19 that was stopped early for benefit, but the mortality rate in the placebo group was higher than expected; additional study is warranted to confirm the findings.

Agents that do not appear to have a clinical benefit in hospitalized patients with COVID-19 include hydroxychloroquine [155-161], colchicine [162-164], lopinavir-ritonavir [37,161,165,166], interferon beta [37,167,168], and azithromycin [159,169-171].

Other agents that have been proposed for COVID-19 therapy include the HCV antivirals sofosbuvir plus daclatasvir [172-175], the selective serotonin receptor blocker fluvoxamine [176], famotidine [177-179], and zinc [180]. Clinical data thus far are insufficient to support a role for these agents in hospitalized patients, and as above, their use for COVID-19 should be limited to clinical trials.

MANAGEMENT OF HYPOXEMIA, ARDS, AND OTHER COMPLICATIONS — Patients with severe disease typically need oxygen supplementation. Respiratory care for patients with severe disease is discussed in detail elsewhere. (See "COVID-19: Respiratory care of the nonintubated hypoxemic adult (supplemental oxygen, noninvasive ventilation, and intubation)".)

Some patients may develop acute respiratory distress syndrome (ARDS) and warrant intubation with mechanical ventilation. Management of ARDS in patients with COVID-19 and other critical care issues are discussed in detail elsewhere (table 4). (See "COVID-19: Management of the intubated adult".)

In addition to ARDS, other complications of infection include arrhythmias, acute cardiac injury, acute kidney injury, thromboembolic events, and shock. Management of these complications is discussed elsewhere.

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

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

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

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

DISCHARGE — The decision to discharge a patient with COVID-19 is generally the same as that for other conditions and depends on the need for hospital-level care and monitoring.

Continued need for infection control precautions should not prevent discharge home if the patient can appropriately self-isolate there; long-term care facilities may have specific requirements prior to accepting patients with COVID-19. Criteria for discontinuing precautions and infection control issues in long-term care facilities are discussed in detail elsewhere. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection", section on 'Discontinuation of precautions'.)

Older age (eg, >65 years), underlying medical comorbidities, and discharge to a skilled nursing facility have been associated with an increased risk of readmission following hospitalization for COVID-19 [181]. Patients with COVID-19 generally warrant outpatient follow-up through telehealth or an in-person visit following discharge from the hospital. (See "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Post-discharge management'.)

SPECIAL SITUATIONS

Pregnant and breastfeeding women — The management of pregnant and breastfeeding women with COVID-19 is discussed elsewhere. (See "COVID-19: Overview of pregnancy issues".)

People with HIV — The impact of HIV infection on the natural history of COVID-19 is uncertain. However, many of the comorbid conditions associated with severe COVID-19 (eg, cardiovascular disease) occur frequently among patients with HIV, and these, in addition to CD4 cell count, should be considered in risk stratification. (See "COVID-19: Clinical features", section on 'People with HIV'.)

Overall, the management of COVID-19 in patients with HIV is the same as in patients without HIV; HIV should not be a reason to exclude a patient from clinical trials or other interventions [182]. However, drug interactions with antiretroviral agents are important to assess before starting any new therapies.

Although certain antiretroviral agents have been hypothesized to have efficacy against SARS-CoV-2, antiretroviral regimens should not be adjusted based on concern for COVID-19.

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 topic (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: COVID-19 vaccines (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Indications for hospitalization – Many patients with known or suspected COVID-19 have mild disease that does not warrant hospital-level care; having such patients recover at home is preferred. Indications for hospitalization are discussed in detail elsewhere.

●Evaluation – The evaluation should assess for features associated with severe illness (table 1) and identify organ dysfunction or other comorbidities that could complicate potential therapy. (See 'Evaluation' above.)

●Thromboprophylaxis – Patients hospitalized with COVID-19 should receive pharmacologic prophylaxis for venous thromboembolism (algorithm 1). Dosing and selection of anticoagulants, including when to use therapeutic-dose anticoagulation, are discussed in detail elsewhere. (See "COVID-19: Hypercoagulability".)

●Antipyretics – As in the general population, we suggest acetaminophen for fever reduction in patients with COVID-19 rather than non-steroidal anti-inflammatory drugs (NSAIDs) (Grade 2C). If NSAIDs are needed, we use the lowest effective dose. However, we do not discontinue NSAIDs in patients who are on them chronically for other conditions if there are no other reasons to stop them. Observational data do not indicate an association between NSAIDs and poor COVID-19 outcomes. (See 'NSAID use' above.)

●Continuing chronic medications – Specific concern for COVID-19 should not impact the decision to start or stop angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). People who are on an ACE inhibitor or ARB for another indication should not stop their medication. (See "COVID-19: Issues related to acute kidney injury, glomerular disease, and hypertension", section on 'Renin angiotensin system inhibitors'.)

We continue statins in hospitalized patients with COVID-19 who are already taking them. We also continue aspirin unless there is concern for bleeding risk. (See 'Statins and aspirin' above.)

●Approach to patients with no oxygen requirement – For such patients who have clinical (table 2) or laboratory (table 1) risk factors for severe disease and were hospitalized for COVID-19, we suggest remdesivir (Grade 2C). Individuals who have risk factors but were hospitalized for other reasons (ie, have incidental SARS-CoV-2 infection) may be eligible for therapies that have been authorized for high-risk outpatients. For patients without any risk factors, care is primarily supportive. All patients warrant close monitoring for disease progression. (See 'Patients without oxygen requirement' above and "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Treatment with COVID-19-specific therapies'.)

●Approach to patients with oxygen requirement/severe disease – For patients who require oxygen supplementation because of COVID-19, the approach to COVID-19-specific therapy depends on the level of support; doses and duration are listed in the algorithm (algorithm 3) (see 'Patients with oxygen requirement/severe disease' above and 'Specific treatments' above):

•For patients receiving low-flow supplemental oxygen, we suggest low-dose dexamethasone and remdesivir (Grade 2C). It is reasonable to defer dexamethasone for those who are stable on minimal oxygen supplementation (eg, 1 to 2 L/min), particularly if they are immunocompromised and within 10 days of symptom onset.

For patients who have escalating oxygen requirements despite dexamethasone, have elevated inflammatory markers, and are within 96 hours of hospitalization, we suggest adding either baricitinib or tocilizumab (Grade 2C). If supplies of tocilizumab or baricitinib are limited, we prioritize them for more severely ill patients on higher levels of oxygen support.

•For patients receiving high-flow supplemental oxygen or non-invasive ventilation, we recommend low-dose dexamethasone (Grade 1B). If they are within 24 to 48 hours of admission to an intensive care unit (ICU) or receipt of ICU-level care (and within 96 hours of hospitalization), we suggest either baricitinib or tocilizumab in addition to dexamethasone (Grade 2B). We also suggest adding remdesivir (Grade 2C).

•For patients who require mechanical ventilation or extracorporeal membrane oxygenation, we recommend low-dose dexamethasone (Grade 1B). For those who are within 24 to 48 hours of admission to an ICU (and within 96 hours of hospitalization), we suggest adding tocilizumab or baricitinib to dexamethasone (Grade 2B). We suggest not routinely initiating remdesivir in this population (Grade 2C).

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

●Limited role for other therapies – We generally do not use other agents off label for treatment of COVID-19. In particular, we suggest not using ivermectin for COVID-19 therapy in hospitalized patients (Grade 2C). We suggest not routinely using convalescent plasma for hospitalized patients (Grade 2B). (See 'Others' above and 'Limited role for antibody-based therapies (monoclonal antibodies and convalescent plasma)' above.)

●Management of hypoxemia – Patients with severe disease often need respiratory support. This is discussed in detail elsewhere. (See "COVID-19: Respiratory care of the nonintubated hypoxemic adult (supplemental oxygen, noninvasive ventilation, and intubation)" and "COVID-19: Management of the intubated adult".)

●Infection control – Infection control is an essential component of management of patients with suspected or documented COVID-19. This is discussed in detail elsewhere. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection".)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Eric Meyerowitz, MD, Camille Kotton, MD, Michael Mansour, MD, Pritha Sen, MD, Ramy Elshaboury, PharmD, Ronak Gandhi, PharmD, and Boris Juelg, MD, for their contributions to this topic review.