Therapeutic Management of Hospitalized Adults With COVID-19

Last Updated: December 16, 2021

Therapeutic Management for Hospitalized Adults With COVID-19 Based on Disease Severity

Table A. Dosing Regimens for the Drugs Recommended in Figure 2

Table A. Dosing Regimens for the Drugs Recommended in Figure 2
Drug Name	Dosing Regimen	Comments
Remdesivir	RDV 200 mg IV once, then RDV 100 mg IV once daily for 4 days or until hospital discharge.	If the patient progresses to more severe illness, complete the course of RDV. For a discussion on using RDV in patients with renal insufficiency, see Remdesivir.
Dexamethasone	DEX 6 mg IV or PO once daily for up to 10 days or until hospital discharge.	If DEX is not available, an equivalent dose of another corticosteroid may be used. For more information, see Corticosteroids.
Baricitinib	Baricitinib dose is dependent on eGFR; duration of therapy is up to 14 days or until hospital discharge.	eGFR ≥60 mL/min/1.73 m²: Baricitinib 4 mg PO once daily eGFR 30 to <60 mL/min/1.73 m²: Baricitinib 2 mg PO once daily eGFR 15 to <30 mL/min/1.73 m²: Baricitinib 1 mg PO once daily eGFR <15 mL/min/1.73 m²: Baricitinib is not recommended.
Tofacitinib	Tofacitinib 10 mg PO twice daily for up to 14 days or until hospital discharge.	Use as an alternative immunomodulatory drug if baricitinib is not available or not feasible to use (BIIa). eGFR <60 mL/min/1.73 m²: Tofacitinib 5 mg PO twice daily
Tocilizumab	Tocilizumab 8 mg/kg actual body weight (up to 800 mg) administered as a single IV dose.	In clinical trials, a third of the participants received a second dose of tocilizumab 8 hours after the first dose if no clinical improvement was observed.
Sarilumab	Use the single-dose, prefilled syringe (not the prefilled pen) for SQ injection. Reconstitute sarilumab 400 mg in 100 cc 0.9% NaCl and administer as an IV infusion over 1 hour.	Use as an alternative immunomodulatory drug if tocilizumab is not available or not feasible to use (BIIa). In the United States, the currently approved route of administration for sarilumab is SQ injection. In the REMAP-CAP trial, the SQ formulation was used to prepare the IV infusion.
Key: DEX = dexamethasone; eGFR = estimated glomerular filtration rate; IV = intravenous; PO = oral; RDV = remdesivir; SQ = subcutaneous

Introduction

Two main processes are thought to drive the pathogenesis of COVID-19. Early in the clinical course, the disease is primarily driven by the replication of SARS-CoV-2. Subsequently, the disease appears to be also driven by a dysregulated immune/inflammatory response to SARS-CoV-2 that leads to tissue damage. Based on this understanding, therapies that directly target SARS-CoV-2 are anticipated to have the greatest effect early in the course of the disease, whereas immunosuppressive/anti-inflammatory therapies are likely to be more beneficial after COVID-19 has progressed to stages characterized by hypoxia.

Patients Who Do Not Require Supplemental Oxygen

Recommendations

The COVID-19 Treatment Guidelines Panel (the Panel) recommends against the use of dexamethasone (AIIa) or other corticosteroids (AIII) for the treatment of COVID-19. Patients with COVID-19 who are receiving dexamethasone or another corticosteroid for an underlying condition should continue this therapy as directed by their health care provider.
There is insufficient evidence to recommend either for or against the routine use of remdesivir for the treatment of COVID-19 in hospitalized patients who do not require supplemental oxygen, but use may be appropriate in patients at high risk of disease progression.

Rationale for Recommending Against the Use of Dexamethasone or Other Corticosteroids

In the RECOVERY trial, a multicenter, open-label trial in the United Kingdom, hospitalized patients with COVID-19 were randomized to receive dexamethasone plus standard of care or standard of care alone (control arm).¹ No survival benefit for dexamethasone was observed among the participants who did not require supplemental oxygen at enrollment: 17.8% of participants in the dexamethasone arm and 14% in the control arm died within 28 days of enrollment (rate ratio 1.19; 95% CI, 0.91–1.55). See Table 4a for additional information. Based on these data, the Panel recommends against the use of dexamethasone (AIIa) or other corticosteroids (AIII) for the treatment of COVID-19 in hospitalized patients who do not require supplemental oxygen, unless the patient has another indication for corticosteroid therapy.

Rationale for Determining That There Is Insufficient Evidence to Recommend Either for or Against the Use of Remdesivir

ACTT-1 was a multinational randomized controlled trial that compared intravenous (IV) remdesivir to placebo in hospitalized patients with COVID-19. Remdesivir showed no significant benefit in patients with mild to moderate disease, which was defined as oxygen saturation >94% on room air or a respiratory rate <24 breaths/min without supplemental oxygen (rate ratio for recovery 1.29; 95% CI, 0.91–1.83); however, there were only 138 patients in this subgroup.²

In a manufacturer-sponsored, open-label randomized trial that included 596 patients with moderate COVID-19, patients who received 5 days of remdesivir had higher odds of a better clinical status on Day 11 (based on a 7-point ordinal scale) than those who received standard of care (OR 1.65; 95% CI, 1.09–2.48; P = 0.02).³

The Solidarity trial was a large, multinational, open-label randomized controlled trial that compared a 10-day course of remdesivir to standard of care. About 25% of hospitalized patients in both arms did not require supplemental oxygen at study entry. The primary outcome of in-hospital mortality occurred in 11 of 661 patients (2%) in the remdesivir arm and 13 of 664 patients (2.1%) in the control arm (rate ratio 0.90; 99% CI, 0.31–2.58).⁴ Please see Table 2a for additional information.

Data supporting the clinical benefit of early treatment with remdesivir emerged from PINETREE, a randomized placebo-controlled trial in nonhospitalized patients with COVID-19 at high risk of clinical progression. Participants were randomized to receive 3 days of IV remdesivir or placebo as outpatients. At treatment initiation, the median duration of symptoms was 5 days. By Day 28, there was a significant decrease in hospitalization and/or death among the patients who received remdesivir: the primary endpoint occurred in 0.7% of remdesivir recipients versus 5.3% of placebo recipients (HR 0.13; 95% CI, 0.03–0.59; P = 0.008).⁵

Because these trials produced conflicting results regarding the benefits of remdesivir, the Panel finds the available evidence insufficient to recommend either for or against routine treatment with remdesivir for all hospitalized patients with moderate COVID-19. However, the Panel recognizes that clinicians may judge that remdesivir is appropriate for some hospitalized patients with moderate disease (e.g., those at particularly high risk for clinical deterioration).

Patients Who Require Supplemental Oxygen

Patients who require supplemental oxygen, but not high-flow oxygen, noninvasive ventilation (NIV), or mechanical ventilation are a heterogeneous group. Some of these patients will have mild disease that will improve after a short period with or without treatment with remdesivir, dexamethasone, or both; others will develop progressive disease despite treatment and require a more intensive level of care. There is no consensus on which clinical or laboratory parameters allow for reliable risk-stratification to guide therapy and/or identify which subsets of patients will experience progressive lung injury and hypoxemia.

Some studies have tried to define this group according to traditional risk factors for COVID-19 progression and/or by the presence of elevated inflammatory markers like C-reactive protein (CRP), but evidence to support a specific identifying biomarker or clinical threshold is lacking.

Recommendations

The Panel recommends using 1 of the following options for hospitalized patients who require supplemental oxygen:

Remdesivir (e.g., for patients who require minimal supplemental oxygen) (BIIa)
Dexamethasone plus remdesivir (BIIb)
Dexamethasone (BI); for patients on dexamethasone who have rapidly increasing oxygen needs and systemic inflammation, add a second immunomodulatory drug (e.g., tocilizumab or baricitinib) (CIIa)

If dexamethasone is not available, an alternative corticosteroid such as prednisone, methylprednisolone, or hydrocortisone can be used (BIII). See Corticosteroids for dosing recommendations.

Rationale for the Use of Remdesivir

In the ACTT-1 trial, remdesivir was associated with improved time to recovery in the 435 participants who required oxygen supplementation but not high-flow oxygen, NIV, or mechanical ventilation (7 days for remdesivir vs. 9 days for placebo; recovery rate ratio 1.45; 95% CI, 1.18–1.79). Fewer patients in the remdesivir arm than in the placebo arm progressed to requiring high-flow oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO) (17% vs. 24%). In a post hoc analysis of deaths by Day 29, remdesivir appeared to confer a substantial survival benefit in this subgroup (HR for death 0.30; 95% CI, 0.14–0.64).²

The Solidarity trial reported no difference in the rate of in-hospital deaths between patients who received remdesivir and those who received standard of care (rate ratio for death in the overall study population 0.95; 95% CI, 0.81–1.11; rate ratio for death in patients who did not require mechanical ventilation at entry 0.86; 99% CI, 0.67–1.11). There was no difference between patients who received remdesivir and those who received standard of care in the percentage of those who progressed to mechanical ventilation (11.9% vs. 11.5%) or in length of hospital stay.⁴ However, an open-label trial like Solidarity is less well-suited to assess time to recovery than a placebo-controlled trial. In the Solidarity trial, because both clinicians and patients knew that remdesivir was being administered, it is possible that hospital discharge was delayed in order to complete the 10-day course of therapy.

DisCoVeRy was a multinational, open-label randomized controlled trial that compared up to 10 days of remdesivir plus standard of care to standard of care alone in hospitalized patients with moderate or severe COVID-19. There was no significant difference in the odds of improved clinical status by Day 15 between the patients in the remdesivir arm and the standard of care arm (OR 0.98; 95% CI, 0.77–1.25). At Day 28, there were also no differences between the arms in either mortality (8% in remdesivir arm vs. 9% in standard of care arm) or clinical status. The DisCoVeRy trial shared with the Solidarity trial the major limitation of open-label design. Additionally, 440 of the 832 participants in the DisCoVeRy trial (219 in the remdesivir arm and 221 in the standard of care arm) were also Solidarity trial participants.⁶

Although the open-label Solidarity and DisCoVeRy trials demonstrated no mortality benefit for remdesivir, in the large randomized placebo-controlled ACTT-1 trial, remdesivir significantly reduced time to clinical recovery. In a post hoc analysis, this clinical benefit of remdesivir was most evident in those who had symptoms for ≤10 days. The evidence from the ACTT-1 and PINETREE trials suggests that remdesivir will have its greatest impact when administered early in the clinical course, which is also the case for antiviral agents used to treat other viral infections.⁵ The Panel recommends remdesivir (without dexamethasone) as a treatment option for certain patients with COVID-19 who require minimal supplemental oxygen and are in the early course of the disease (BIIa). In these individuals, the hyperinflammatory state where corticosteroids might be most beneficial may not yet be present or fully developed.

Although several trials studied a 10-day course of remdesivir,^2,4 a 5-day course has been shown to be comparable to 10 days of therapy in hospitalized patients with moderate-to-severe COVID-19.^3,7 For more information, please see Table 2a.

Rationale for the Use of Remdesivir Plus Dexamethasone

Data on the safety and efficacy of combination therapy consisting of remdesivir with corticosteroids are primarily derived from observational studies, with some (but not all) suggesting a clinical benefit of remdesivir plus dexamethasone.^8-10 Remdesivir plus dexamethasone has not been directly compared to dexamethasone alone in a large randomized clinical trial. Patients with severe COVID-19 may develop a systemic inflammatory response that leads to multiple organ dysfunction syndrome. The potent anti-inflammatory effects of corticosteroids might prevent or mitigate these hyperinflammatory effects. Thus, the combination of an antiviral agent, such as remdesivir, with an anti-inflammatory agent, such as dexamethasone, may treat the viral infection and dampen the potentially injurious inflammatory response that is a consequence of the infection.

Based on the theoretical combined benefit of antiviral and anti-inflammatory therapies, the Panel recommends the combination of dexamethasone plus remdesivir as a treatment option for patients who require supplemental oxygen (BIIb), despite important limitations of observational data.

Rationale for the Use of Dexamethasone

In the RECOVERY trial, treatment with dexamethasone conferred a survival benefit among participants who required supplemental oxygen at enrollment. Among these participants, fewer participants in the dexamethasone arm than in the standard of care arm died within 28 days of enrollment (23.3% vs. 26.2%; rate ratio 0.82; 95% CI, 0.72–0.94).¹ However, the amount of supplemental oxygen that participants were receiving and the proportions of participants who required oxygen through a high-flow device or NIV were not reported. It is possible that the benefit of dexamethasone was greatest in those who required more respiratory support. It should be noted that <0.1% of patients in the RECOVERY trial received concomitant remdesivir. For more information, see Corticosteroids.

Some experts prefer not to use dexamethasone monotherapy in patients who require supplemental oxygen because of the theoretical concern that corticosteroids might slow viral clearance when administered without an antiviral drug. Corticosteroids have been associated with delayed viral clearance and/or worse clinical outcomes in patients with other viral respiratory infections.^11-13 Some studies have suggested that corticosteroids slow SARS-CoV-2 clearance, but the results to date are inconclusive.^14-18

Rationale for Adding a Second Immunomodulatory Drug to Dexamethasone in Certain Patients Who Require Rapidly Increasing Oxygen Supplementation

Several major randomized trials evaluating the use of interleukin (IL)-6 inhibitors or Janus Kinase (JAK) inhibitors with or without corticosteroids in patients with COVID-19 have included patients who required only low-flow supplemental oxygen. However, subgroup analyses in these trials have not clearly defined which patients in this heterogeneous group are most likely to benefit from corticosteroids with another immunomodulator. Direct comparison between trials is not possible because in some trials, background therapies (e.g., corticosteroids) and inclusion criteria (e.g., the requirement for elevated inflammatory markers) differed. Nonetheless, some trials suggest that adding a second immunomodulator to dexamethasone provided benefits in patients requiring low-flow supplemental oxygen.^19-21 For example, the RECOVERY trial demonstrated a mortality benefit for adding tocilizumab to dexamethasone compared to usual care alone (including dexamethasone) in a subgroup that included patients on low-flow oxygen.¹⁹ Similarly, data on JAK inhibitors are also inconclusive; for example, the COV-BARRIER trial did not find a statistically significant benefit of baricitinib versus placebo in patients on low-flow oxygen,²⁰ whereas the placebo-controlled STOP-COVID trial demonstrated a reduction in respiratory failure or death in the subgroup of patients on low-flow oxygen who received tofacitinib.²¹

Given the uncertainty concerning which patients in this group would benefit from adding a second immunomodulator, such as baricitinib or tocilizumab, to dexamethasone treatment, the Panel recommends considering these therapies on a case-by-case basis for individuals with rapidly increasing oxygen requirements and elevated markers of systemic inflammation (CIIa). Because there are no studies that directly compare the use of baricitinib and tocilizumab as treatments for COVID-19, the Panel has insufficient evidence to recommend 1 drug over the other. Treatment decisions should be based on local guidance, drug availability, and patient comorbidities.

Additional Considerations

Baricitinib or tocilizumab should only be given in combination with dexamethasone or another corticosteroid. Some clinicians may assess a patient’s clinical response to dexamethasone before deciding whether adding baricitinib or tocilizumab as a second immunomodulatory drug is necessary.
Because there are no studies that directly compare the use of baricitinib and tocilizumab as treatments for COVID-19, the Panel has insufficient evidence to recommend 1 drug or class of drugs (i.e., JAK inhibitors, anti-IL-6 receptor mAbs) over the other. Treatment decisions should be based on local guidance, drug availability, and patient comorbidities.
If baricitinib and IV tocilizumab are not available or not feasible to use, tofacitinib can be used instead of baricitinib (BIIa) and IV sarilumab can be used instead of IV tocilizumab (BIIa).
The Panel recommends against the use of baricitinib in combination with tocilizumab for the treatment of COVID-19, except in a clinical trial (AIII). Because both baricitinib and tocilizumab are potent immunosuppressants, there is the potential for an additive risk of infection.
Combination immunosuppressive therapy (e.g., dexamethasone with baricitinib or tocilizumab) may increase the risk of opportunistic infections or reactivation of latent infections; however, randomized trials to date have not demonstrated an increase in the frequency of infections.
Cases of severe and disseminated strongyloidiasis have been reported in patients with COVID-19 during treatment with tocilizumab and corticosteroids.^22,23 Many clinicians would initiate empiric treatment for strongyloidiasis (e.g., with the antiparasitic drug ivermectin) with or without serologic testing in patients from areas where Strongyloides is endemic (i.e., tropical, subtropical, or warm temperate areas).

Patients Who Require Oxygen Through a High-Flow Device or Noninvasive Ventilation

Recommendations

The Panel recommends using 1 of the following options for hospitalized patients who require oxygen through a high-flow device or NIV:
- Dexamethasone (AI)
- Dexamethasone plus remdesivir (BIII)
For patients who have rapidly increasing oxygen needs and have increased markers of inflammation, add either baricitinib (BIIa) or tocilizumab (BIIa) (drugs are listed alphabetically) to 1 of the 2 options above.

Additional Considerations

If dexamethasone is not available, an equivalent dose of another corticosteroid such as prednisone, methylprednisolone, or hydrocortisone may be used (BIII). See Corticosteroids for more information.
Immunosuppressive therapy (e.g., dexamethasone with or without baricitinib or tocilizumab) may increase the risk of opportunistic infections or reactivation of latent infections; however, randomized trials to date have not demonstrated an increase in the frequency of infections.
Cases of severe and disseminated strongyloidiasis have been reported in patients with COVID-19 during treatment with tocilizumab and corticosteroids.^22,23 Many clinicians would initiate empiric treatment for strongyloidiasis (e.g., with the antiparasitic drug ivermectin) with or without serologic testing in patients from areas where Strongyloides is endemic (i.e., tropical, subtropical, or warm temperate areas).

Rationale for the Use of Dexamethasone

In the RECOVERY trial, treatment with dexamethasone conferred a survival benefit among participants who required supplemental oxygen without mechanical ventilation at enrollment: 23.3% of the participants in the dexamethasone arm versus 26.2% in the standard of care arm died within 28 days of enrollment (rate ratio 0.82; 95% CI, 0.72–0.94).¹

Rationale for the Use of Remdesivir Plus Dexamethasone

As discussed above, data on the safety and efficacy of combination therapy of remdesivir with corticosteroids are primarily derived from observational studies, with some, but not all suggesting clinical benefit of remdesivir plus dexamethasone.^8-10 Remdesivir plus dexamethasone has not been directly compared to dexamethasone alone in a large randomized clinical trial. Patients with severe COVID-19 may develop a systemic inflammatory response that leads to multiple organ dysfunction syndrome. The potent anti-inflammatory effects of corticosteroids might prevent or mitigate these hyperinflammatory effects. Thus, the combination of an antiviral agent, such as remdesivir, with an anti-inflammatory agent, such as dexamethasone, may treat the viral infection and dampen the potentially injurious inflammatory response that is a consequence of the infection. Based on the theoretical combined benefit of antiviral and anti-inflammatory therapies, the Panel recommends the combination of dexamethasone plus remdesivir as a treatment option for patients who require high-flow oxygen or NIV (BIIb), despite important limitations of observational data.

Rationale for Not Recommending Remdesivir Monotherapy

In the ACTT-1 trial, there was no observed difference in time to recovery between the remdesivir and placebo arms in the subgroup of 193 participants who required high-flow oxygen or NIV at enrollment (recovery rate ratio 1.09; 95% CI, 0.76–1.57). A post hoc analysis did not show a survival benefit for remdesivir at Day 29, but the trial was not powered to detect this difference.² The Panel does not recommend using remdesivir monotherapy in patients who require high-flow oxygen or NIV because there is uncertainty regarding whether remdesivir alone confers a clinical benefit in this subgroup (AIIa). Dexamethasone alone or remdesivir plus dexamethasone are better treatment options for COVID-19 in this group of patients.

For patients who start remdesivir monotherapy and then progress to requiring oxygen through a high-flow device or NIV, the Panel recommends initiating dexamethasone and continuing remdesivir until the treatment course is completed. Clinical trials that evaluated the use of remdesivir categorized patients based on their severity of illness at the start of treatment with remdesivir; therefore, patients may benefit from remdesivir even if their clinical course progresses to a severity of illness for which the benefits of remdesivir are less certain.

Rationale for Adding a Second Immunomodulatory Drug to Dexamethasone in Certain Hospitalized Patients

Several large clinical trials suggest that adding a second immunomodulatory drug, such as baricitinib or tocilizumab, to dexamethasone provides clinical benefit in patients who require oxygen supplementation through a high-flow device or NIV.

The REMAP-CAP and RECOVERY trials, the 2 largest randomized controlled trials of tocilizumab to date, have both reported a mortality benefit for tocilizumab among patients with rapid respiratory decompensation who require oxygen delivery through a high-flow device or NIV.^19,24 Most patients in both studies received corticosteroids.

In the REMAP-CAP trial, patients admitted to an intensive care unit (ICU) with severe-to-critical COVID-19 and rapid respiratory decompensation were randomized to receive open-label tocilizumab or usual care. The use of tocilizumab reduced in-hospital mortality (28% in tocilizumab arm vs. 36% in usual care arm) and, during 21 days of follow-up, increased the median number of days free of respiratory and cardiovascular organ support (10 days in tocilizumab arm vs. 0 days in usual care arm; OR 1.64; 95% CI, 1.25–2.14). Enrollment occurred within 24 hours of ICU admission and within a median of 1.2 days of hospitalization (IQR 0.8–2.8 days), suggesting that the benefit of tocilizumab occurs in patients experiencing rapid respiratory decompensation. The RECOVERY trial also suggested a mortality benefit for tocilizumab plus dexamethasone in a subset of patients that included those who required NIV or high-flow oxygen. In this study, a subset of participants with hypoxemia and CRP ≥75 mg/L were randomized to receive tocilizumab or usual care. Tocilizumab reduced all-cause mortality in these patients; by Day 28, 29% of participants in the tocilizumab arm versus 33% in the usual care arm had died (rate ratio 0.86; 95% CI, 0.77–0.96).

In the COV-BARRIER trial, 1,525 hospitalized patients with COVID-19 and ≥1 elevated inflammatory biomarker were randomized 1:1 to receive oral baricitinib 4 mg or placebo in addition to the local standard of care for up to 14 days (or until hospital discharge).²⁰ Overall, there was no difference in the occurrence of the primary endpoint of progression to high-flow oxygen, NIV, mechanical ventilation, or death by Day 28 between the baricitinib arm (27.8% of patients) and the placebo arm (30.5% of patients; OR 0.85; 95% CI, 0.67–1.08; P = 0.18). However, all-cause mortality by Day 28 was 8.1% in the baricitinib arm and 13.1% in the placebo arm, resulting in a 38.2% reduction in mortality for baricitinib (HR 0.57; 95% CI, 0.41–0.78; nominal P = 0.002). The difference in mortality was most pronounced in the subgroup of 370 patients receiving high-flow oxygen or NIV at baseline (17.5% in the baricitinib arm vs. 29.4% in the placebo arm; HR 0.52; 95% CI, 0.33–0.80; nominal P = 0.007). The occurrence of adverse events, serious adverse events, serious infections, and venous thromboembolic events in the arms was comparable.

The ACTT-2 trial demonstrated that baricitinib used in combination with remdesivir improved time to recovery in hospitalized patients with COVID-19. The effect was most pronounced in patients who were receiving high-flow oxygen or NIV. However, patients receiving corticosteroids were excluded from the ACTT-2 trial, limiting the generalizability of these findings.

Given the clinical trial data (see Table 4e), the Panel recommends adding baricitinib or tocilizumab as a second immunomodulatory treatment in combination with dexamethasone for patients who are receiving oxygen supplementation through a high-flow device or NIV (BIIa).

Additional Considerations

Baricitinib or tocilizumab should only be given in combination with dexamethasone or another corticosteroid. Some clinicians may assess a patient’s clinical response to dexamethasone before deciding whether adding baricitinib or tocilizumab is necessary.
Studies that directly compare baricitinib to tocilizumab as treatments for COVID-19 are not available. Therefore, there is insufficient evidence for the Panel to recommend 1 drug over the other. Treatment decisions should be based on local guidance, drug availability, and patient comorbidities.
If baricitinib and IV tocilizumab are not available or not feasible to use, tofacitinib can be used instead of baricitinib (BIIa) and IV sarilumab can be used instead of IV tocilizumab (BIIa).
Although approximately a third of patients in the REMAP-CAP and RECOVERY trials received a second dose of tocilizumab at the discretion of their treating physician, data on outcomes based on receipt of 1 or 2 doses is not available. Therefore, there is insufficient evidence to determine which patients, if any, would benefit from an additional dose of the drug.

Rationale for Recommending Against the Use of the Combination of Baricitinib and Tocilizumab

The Panel recommends against the use of the combination of baricitinib and tocilizumab for the treatment of COVID-19, except in a clinical trial (AIII), because there is insufficient evidence for the use of this combination. Given that both baricitinib and tocilizumab are potent immunosuppressants, there is the potential for an additive risk of infection.

Rationale for Recommending Sarilumab and Dexamethasone as an Alternative to Tocilizumab and Dexamethasone in Certain Hospitalized Patients

In an updated report from the REMAP-CAP trial, the efficacy of tocilizumab and sarilumab in improving survival and reducing the duration of organ support was similar. Compared to noncontemporary control patients who received placebo plus dexamethasone, patients who received sarilumab and dexamethasone demonstrated reduced mortality, shorter time to ICU discharge, and more organ support-free days.²⁵

In the REMAP-CAP trial, sarilumab in combination with dexamethasone (n = 483) was noninferior to tocilizumab with dexamethasone (n = 943) with regards to the number of organ support-free days and mortality with a probability of 99% and 98%, respectively.

Even though the REMAP-CAP trial supports that sarilumab and tocilizumab have similar efficacy in the treatment of hospitalized patients with COVID-19, the Panel recommends sarilumab only when tocilizumab is not available or is not feasible to use (BIIa). The rationales for this recommendation are:

The evidence of efficacy for tocilizumab is more extensive than for sarilumab, and
Currently, sarilumab is only approved as a subcutaneous (SQ) injection in the United States.

In the REMAP-CAP trial, a single dose of sarilumab 400 mg for SQ injection was reconstituted in 50 ml or 100 ml of normal saline and administered as an IV infusion over 1 hour.

Rationale for Recommending the Use of Tofacitinib Plus Dexamethasone in Certain Hospitalized Patients

In the STOP-COVID trial, a double-blind randomized placebo-controlled trial, use of tofacitinib was associated with a decreased risk of respiratory failure and death (risk ratio 0.63; 95% CI, 0.41–0.97). All-cause mortality within 28 days was 2.8% in the tofacitinib arm (n = 144) and 5.5% in the placebo arm (n = 145) (HR 0.49; 95% CI, 0.15–1.63). Approximately 80% of participants in each arm also received corticosteroids.²¹

The STOP-COVID trial supports that tofacitinib plus steroids is effective in improving outcomes in hospitalized patients with COVID-19. Both baricitinib and tofacitinib belong to the same class of anti-inflammatory drugs, the kinase inhibitors, and have overlapping mechanisms of action. The Panel recommends tofacitinib as an alternative to baricitinib only when baricitinib is not available or not feasible to use (BIIa) because the evidence of efficacy for tofacitinib is less extensive than for baricitinib.

Patients Who Require Mechanical Ventilation or Extracorporeal Membrane Oxygenation

Recommendations

The Panel recommends using dexamethasone for hospitalized patients with COVID-19 who require mechanical ventilation or ECMO (AI).
The Panel recommends using dexamethasone plus tocilizumab for patients with COVID-19 who are within 24 hours of admission to the ICU (BIIa).

Additional Considerations

If dexamethasone is not available, an equivalent dose of an alternative corticosteroid (e.g., prednisone, methylprednisolone, hydrocortisone) may be used (BIII).
For patients who initially received remdesivir monotherapy and progressed to requiring mechanical ventilation or ECMO, dexamethasone should be initiated and remdesivir should be continued until the treatment course is completed.
The Panel recommends against the initiation of remdesivir monotherapy (AIIa) in patients who require mechanical ventilation or ECMO.
Tocilizumab should be given only in combination with dexamethasone (or another corticosteroid at an equivalent dose).
Although some patients in the REMAP-CAP and RECOVERY trials received a second dose of tocilizumab at the discretion of their treating physician, there is insufficient evidence to determine which patients, if any, would benefit from an additional dose of the drug.
The combination of dexamethasone and tocilizumab may increase the risk of opportunistic infections or reactivation of latent infections. Prophylactic treatment for strongyloidiasis (e.g., with the antiparasitic drug ivermectin) should be considered for patients who are from areas where Strongyloides is endemic.

Rationale for the Use of Dexamethasone Monotherapy

As COVID-19 progresses, a systemic inflammatory response may lead to multiple organ dysfunction syndrome. The anti-inflammatory effects of corticosteroids mitigate the inflammatory response, and the use of corticosteroids has been associated with improved outcomes in people with critical COVID-19.

Dexamethasone reduces mortality in critically ill patients with COVID-19 according to a meta-analysis that aggregated 7 randomized trials and included data on 1,703 critically ill patients.²⁶ The largest trial in the meta-analysis was the RECOVERY trial, whose subgroup of mechanically ventilated patients was included.¹ For details about the meta-analysis and the RECOVERY trial, see Corticosteroids and Table 4a. Because the benefits of dexamethasone outweigh the potential harms, the Panel recommends using dexamethasone in hospitalized patients with COVID-19 who require mechanical ventilation or ECMO (AI).

Considerations Related to the Use of Dexamethasone Plus Remdesivir Combination Therapy

Dexamethasone plus remdesivir combination therapy has not been evaluated in controlled studies; therefore, there is insufficient information to make a recommendation either for or against the use of this combination therapy. However, there is a theoretical reason to administer dexamethasone plus remdesivir to patients who have recently been intubated. Antiviral therapy may prevent a steroid-related delay in viral clearance. This delay has been reported in the setting of other viral infections.^11,12

Some studies have suggested that corticosteroids slow SARS-CoV-2 clearance, but the studies to date are not definitive. For example, an observational study in patients with nonsevere COVID-19 suggested that viral clearance was delayed in those who received corticosteroids,²⁷ whereas a more recent study in patients with moderate to severe COVID-19 found no relationship between the use of corticosteroids and the rate of viral clearance.¹⁸ Given the conflicting results from observational studies and the lack of clinical trial data, some Panel members would coadminister dexamethasone and remdesivir in patients who have recently been placed on mechanical ventilation (CIII) until more conclusive evidence becomes available, based on their concerns about delayed viral clearance in patients who received corticosteroids. Other Panel members would not coadminister dexamethasone and remdesivir due to uncertainties about the benefit of using remdesivir in critically ill patients.

Rationale for Recommending the Use of Tocilizumab Plus Dexamethasone in Patients Within 24 Hours of Admission to the Intensive Care Unit

The REMAP-CAP and RECOVERY trials, the 2 largest randomized controlled trials of tocilizumab to date, both reported a mortality benefit for tocilizumab in patients who experienced rapid respiratory decompensation and were recently admitted to the ICU, including those who required mechanical ventilation.^19,24 The REMAP-CAP trial enrolled patients within 24 hours of admission to the ICU. Previous trials that enrolled patients later in the course of ICU care and/or who received oxygen support >24 hours after ICU admission have failed to show consistent clinical benefits for tocilizumab (see Table 4e). Thus, it is unclear whether there is a clinical benefit for tocilizumab in patients who received mechanical ventilation for >24 hours. Findings from the RECOVERY trial suggest a clinical benefit for tocilizumab plus corticosteroids among patients with rapid clinical progression who received mechanical ventilation. Please see the Rationale for Adding a Second Immunomodulatory Drug to Dexamethasone in Certain Hospitalized Patients section above for additional details on the clinical trial data and rationale for using tocilizumab in this situation.

Rationale for Recommending Against the Use of Remdesivir Monotherapy

A clear benefit of remdesivir monotherapy has not been demonstrated in patients who require mechanical ventilation or ECMO. In the ACTT-1 trial, remdesivir did not improve the recovery rate in this subgroup of participants (recovery rate ratio 0.98; 95% CI, 0.70–1.36), and in a post hoc analysis of deaths by Day 29, remdesivir did not improve survival in this subgroup (HR 1.13; 95% CI, 0.67–1.89).² In the Solidarity trial, there was a trend toward increased mortality among patients who received mechanical ventilation and were randomized to receive remdesivir rather than standard of care (rate ratio 1.27; 95% CI, 0.99–1.62).⁴ Taken together, these results do not demonstrate a clear benefit of remdesivir in critically ill patients.

For patients who start remdesivir monotherapy and then progress to requiring mechanical ventilation or ECMO, the Panel recommends initiating dexamethasone and continuing remdesivir until the treatment course is completed. Clinical trials that evaluated remdesivir categorized patients based on their severity of illness at study enrollment; therefore, patients may benefit from receiving remdesivir even if their clinical course progresses to a severity of illness for which the benefits of remdesivir are less certain.

Rationale for Recommending the Use of Sarilumab and Dexamethasone as an Alternative to Tocilizumab and Dexamethasone in Certain Hospitalized Patients

Please refer to the Patients Who Require Oxygen Through a High-Flow Device or Noninvasive Ventilation section above for the rationale regarding the use of sarilumab and dexamethasone as an alternative to tocilizumab and dexamethasone in certain hospitalized patients.

Rationale for Determining That There is Insufficient Evidence to Recommend the Use of Baricitinib in Addition to Standard of Care in Mechanically Ventilated Individuals

A cohort of critically ill patients was added to the COV-BARRIER trial after the completion of the original study. The results for the cohort were not included in the primary results of the main trial.²⁸ In this addendum, 101 patients on mechanical ventilation or ECMO were randomized 1:1 to receive baricitinib 4 mg (n = 51) or placebo (n = 50) for up to 14 days in combination with standard of care. Baricitinib significantly reduced 28-day all-cause mortality (39.2% in the baricitinib arm vs. 58.0% in the placebo arm; HR 0.54; 95% CI, 0.31–0.96; P = 0.030). However, given the small sample size, the Panel considered the evidence insufficient to issue a recommendation for patients on mechanical ventilation or ECMO.

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