key: cord-0841249-yhzpl90g
authors: Shumaker, Amy Hirsch; Bhimraj, Adarsh
title: PHARMACOLOGIC TREATMENT AND MANAGEMENT OF COVID-19
date: 2022-02-10
journal: Infect Dis Clin North Am
DOI: 10.1016/j.idc.2022.02.001
sha: 3261ce15fca8d156fb77146042e8274f32ca0f94
doc_id: 841249
cord_uid: yhzpl90g

Over the last two years, there has been gradual and sustained progress towards our understanding of pharmacotherapy for COVID-19 as a result of large and small scale randomized controlled trials. Numerous new and repurposed treatments have been evaluated and some have demonstrated benefit in clinically important outcomes like mortality and hospitalization and optimism for oral antiviral treatments is growing. Given the rapidly evolving landscape of COVID-19 treatments, front line clinicians should utilize treatment and management guidelines to guide their approach to each patient, with the individual’s severity and location of illness in mind to appreciate the nuances in the clinical evidence.

At the outset of the pandemic, efficacy data for potential treatments was sparse and of low quality. Despite the dynamic demands of the pandemic, it is remarkable how much our understanding of the efficacy and harms of COVID-19 treatment options has evolved in less than two years. During these months, pivotal adaptive COVID-19 treatment trials like SOLIDARITY 1 and RECOVERY 2,3 were successfully completed and have been instrumental in guiding treatment recommendations for the management of patients with COVID-19.

The Infectious Disease Society of America (IDSA) and the National Institutes of Health have produced comprehensive guidelines for the treatment and management of patients with COVID-19 4,5 . The IDSA Guideline has employed the GRADE Methodology in the development of their treatment guideline. GRADE (Grading of Recommendations Assessment, Development & Evaluation) provides a framework that allows for front-line clinicians to appreciate the confidence in an estimate of treatment effect in a given patient population and for a particular outcome. The IDSA guidelines employs 4 categories of ratings for quality of the evidence: High, moderate, low, or very low, and these ratings are based on the certainty of the treatment effect, as well as any methodological concerns or risk of bias within the supporting evidence base. The word "recommend" in the IDSA COVID guideline indicates a strong recommendation and the word "suggest" indicates a conditional recommendation.

Treatment recommendations are developed around PICO (population, intervention, comparator, outcome) questions. For example, "in hospitalized patients with COVID-19 (population), should hydroxychloroquine (intervention) versus no hydroxychloroquine (comparator) be used?" This question can be applied for various outcomes of COVID-19, like mortality, hospitalization, progression to mechanical ventilation, serious adverse events, etc.

As a clinician applying treatment recommendations to patients with COVID-19, it is vital to classify the patient's current disease severity (population) as subtle differences in the known benefits and harms (outcomes) of various treatments exist (interventions/comparators). Figure 1 displays the spectrum of disease for patients with COVID-19 and certain types of treatments may be more advantageous or harmful at a particular stage of disease. From a mechanistic perspective, early in the infection, when viral burden is high and the host's adaptive immune system has not mounted an adequate response, treatments targeting viral replication can be more effective. Examples would be antiviral therapies like remdesivir, molnupiravir, nirmatrelvir/ritonavir, and neutralizing antibody therapies. Like influenza, the earlier the antiviral therapies are administered the more efficacious they likely would be. There may be subsets of patients like immunocompromised patients or patients who have not had an adaptive immune response, with high viral burden even later in the disease process who may still benefit from antiviral treatments. Treatments like glucocorticoids may also be harmful early in mild or moderate disease.

As a treating clinician it is also important to appreciate contraindications and relative contraindications for COVID-19 treatments as well as the specific criteria in the US FDA Emergency Use Authorizations (EUA's). For example, many trials of immunomodulatory agents such as IL-6 or JAK-inhibitors for autoimmune or hematologic processes excluded patients with active infections, but these are not absolute contraindications to their use except in certain types of infections. Patients with a hypercoagulable state or a history of clots were often excluded from the studies of JAK inhibitors due to the risk of clots, however many severely or critically ill COVID-19 patients are on prophylactic anticoagulation. It is also important to identify if the patients have other acute disease that either mimic COVID-19 or present concomitantly with COVID-19. Patients can have a positive SARS Cov-2 PCR from a nasopharyngeal sample, and present with pulmonary diseases caused by a bacterial pneumonia or pulmonary edema. Patients with COVID-19 can also have pulmonary embolism contributing to their symptoms and hypoxemia. It is important to avoid anchoring bias to COVID-19 and consider other etiologies. Many of the COVID-19 therapies have an Emergency Use Authorization (EUA) from the US FDA, rather than a full approval, so it is necessary to follow the scope of the authorization for these agents.

Here we will provide a review of treatment options by class based on a patient's current clinical stage of disease with a focus on agents that have efficacy demonstrated through well-designed randomized controlled trials (RCT). In this review, we will focus on a few important therapeutic options for the management of patients with COVID-19 and pooled estimates of treatment effect are derived from the IDSA guidelines. Table 1 is a summary table of treatments available in the US. Pre-and post-exposure prophylaxis, as well as anticoagulation are outside the scope of this review and will not be discussed. Because these the evidence behind the guidelines and the guidelines themselves are rapidly being updated, we encourage readers to refer to the continuously updated IDSA and NIH guidelines.

The disease severity for ambulatory patients with COVID-19 can range from asymptomatic to severe disease. Recommendations for ambulatory patients who are asymptomatic or have mild to moderate disease and have risk factors for severe disease should be promptly identified and treated. Mild COVID-19 is when there are clinical features suggestive of upper respiratory tract involvement without features of lung or other end organ involvement. Moderate COVID-19 includes pulmonary involvement without hypoxia. Most patients improve with supportive care at this stage, but patients with risk factors can progress to more severe or critical disease or death and may benefit from pharmacotherapies. There are no universally accepted clinical prediction rules or risk calculators, but the US FDA EUAs mention a few of these risk factors to consider for treatment with anti SARS CoV2 antibodies. More research is needed to identify precise prediction instruments and determinants that both increase or decrease the risk of severe disease and how potentially protective factors like prior infection or vaccination influence risk stratification. Other potential benefits include use of antiviral and antibody therapies in early disease to reduce symptom duration, period of infectivity, and reduce the risk of post-acute sequelae of COVID-19 (PASC), although impact on these outcomes has not been established and is an area of active inquiry.

Certain interventions may provide more benefit and less harm, depending on the patient's severity of disease.

These agents interact with the receptor binding domain of the spike glycoprotein of SARS CoV-2. Neutralizing antibodies directed at SARS-CoV-2 have been derived from convalescent plasma, recombinant approaches using humanized mice, or a combination of the approaches. Modifications to various portions of the antibody can provide advantages that can alter the pharmacokinetics of the various compounds and may be more or less active against potential variants. Bamlanivimab was the first available neutralizing antibody, and it was given FDA EUA status as monotherapy for COVID-19 treatment for those at high risk for severe disease in November 2020. Issuance of the EUA was based on data from the phase 2 BLAZE-1 trial in which bamlanivimab was compared to placebo 6 . Due to the emergence of viral variants and availability of combination neutralizing antibodies, the US FDA revoked the EUA for bamlanivimab monotherapy on April 16, 2021.

Combining two antibodies such as bamlanivimab/etesevimab or casirivimab/imdevimab or developing antibodies that target the highly conserved regions of SARS CoV-2 may help to overcome any decrease in activity due to circulating variants. 7 Similarly, neutralizing antibodies like sotrovimab, that target the highly conserved region of the spike receptor binding domain may offer an advantage against circulating variants. Sotrovimab has been shown to neutralize SARS CoV-2 in-vitro, including variants of concern. 8 In ambulatory patients with mild to moderate COVID-19 who are at high risk for progression to severe disease, early intervention with neutralizing monoclonal antibody treatments has been shown to reduce mortality, 9 progression to hospitalization, [9] [10] [11] and severe disease 11 . Three neutralizing monoclonal antibody treatments, bamlanivimab/etesevimab, casirivimab/imdevimab, and sotrovimab have been granted emergency use authorization for the treatment of COVID-19 in those patients who are at high risk for severe disease. The IDSA treatment guidelines suggest using these agents rather than no neutralizing monoclonal antibody treatment in ambulatory patients with mild to moderate COVID-19 at high risk for progression to severe disease 4 , however it is important to ensure that the neutralizing antibodies are active against the locally circulating variants. Figure 2 lists the risk factors for the progression to severe COVID-19 or hospitalization per US FDA EUA.

Neutralizing monoclonal antibody treatments are well tolerated, however these agents require an intravenous infusion or other parenteral route of injection, and monitoring for one hour postadministration. The CDC recommends that those receiving neutralizing monoclonal antibodies should wait to receive a COVID vaccine for at least 90 days after administration 12 .

In late 2021, several oral antiviral agents were authorized by the US FDA. Logistical challenges associated with infusion of neutralizing antibody treatments may be lessened with the availability of easier to administer oral antiviral agents.

Molnupiravir, is an oral antiviral that targets the genetic machinery that is responsible for SARS COV-2 viral replication. Molnupiravir is an oral pro-drug that is converted to its active form and acts as a substrate for RNA-dependent RNA polymerase. After it is incorporated into the viral RNA, serial mutations develop resulting a virus that is less fit for ongoing viral replication. 13 In the MOVe-OUT trial, patients at risk for severe COVID-19 were randomized to molnupiravir or placebo. In an interim analysis, patients receiving molnupiravir had a lower risk of hospitalization or death through day 29, compared to placebo (RR: 0.52; 95% CI: 0.33, 0.80), 14 however in the final results, the benefits of molnupiravir were diminished. Mortality was lower in patients receiving molnupiravir (RR: 0.11; 95% CI: 0.01, 0.86), however mortality events were sparse 15 . Molnupiravir was granted US FDA EUA on 23 December 2021 for the treatment of mild to moderate COVID-19 patients who are at high risk for progression to severe disease when there are no other alternative COVID-19 treatments available 16 . Molnupiravir should not be used in pregnant individuals due to evidence of fetal harm in animal studies 17 . Molnupiravir must be initiated within five days of symptom onset.

Nirmatrelvir/ritonavir (Paxlovid™), a combination of a novel SARS CoV-2 protease inhibitor, nirmatrelvir and low dose of the HIV protease ritonavir, used as a pharmacokinetic booster, was granted US FDA EUA on 22 December 2021 18 . Data for authorization is based on results from EPIC-HR study, which was a randomized trial of nirmatrelvir/ritonavir compared to placebo in non-hospitalized adult patients with COVID-19 at high risk for severe disease. Nirmatrelvir/ritonavir reduced COVID-19-related hospitalization compared to placebo (RR: 0.12; 95% CI: 0.06, 0.26). Similarly, there were no deaths in those who received nirmatrelvir/ritonavir while there were 12 deaths in the placebo group 19 . Given the use of ritonavir as a boosting agent, there are significant drug interactions even with short course therapy that need careful management, specifically with drugs that are metabolized by CYP3A4. Nirmatrelvir also requires renal dose adjustment in those with moderate renal impairment and is not recommended in those with severe renal impairment.

Remdesivir may be considered in ambulatory patients with mild to moderate COVID-19 who are at risk for progression to severe disease or death, but it should be initiated within 7 days of symptom onset. In the PINETREE trial, treatment with remdesivir for three days, compared to placebo in ambulatory patients showed a reduction in hospitalizations (HR: 0.28; 95% CI: 0.1, 0.75) and COVID-19 related medically attended visits though day 28, (HR: 0.19; 95% CI: 0.07, 0.56). 20 Administering three consecutive days of infusions has significant resource and access challenges, but should be considered for high-risk populations if more accessible alternatives are not available.

Selective serotonin reuptake inhibitors may play a role in systemic inflammation given their affinity for the sigma-1 receptor. Fluvoxamine has been shown to have the highest affinity for these receptors compared to other SSRIs 21 and inhibition of sigma-1 receptors by fluvoxamine resulted in cytokine release in pre-clinical models of bacterial infection 22 . SSRIs also have been shown to decrease platelet aggregation and neutrophil activation, 23,24 which may mitigate inflammatory and thrombotic events related to COVID-19. In-vitro models suggest that fluvoxamine has also demonstrated enhanced viral endocytosis of the SARS CoV-2 spike protein 25 .

Two randomized controlled trials have evaluated the Selective Serotonin Reuptake Inhibitor (SSRI), fluvoxamine in the management of COVID-19 in ambulatory patients with a diagnostic test positive for SARS CoV-2 infection 26, 27 . The two trials compared fluvoxamine 100 mg either two or three times per day compared to placebo. Both trials reported on mortality by day 28 (IDSA guidelines pooled relative risk (2 studies); RR: 0.69, 95% CI: 0.38, 1.27, low certainty of evidence) and hospitalization by day 28 (IDSA guidelines pooled relative risk (2 studies); RR: 0.75, 95% CI: 0.57, 0.99, low certainty of evidence). The primary outcome of the TOGETHER trial was a composite outcome of a prolonged emergency room visit or hospitalization through day 28. In the composite outcome, patients who received fluvoxamine had a lower relative risk of emergency room visit/hospitalization compared to placebo (RR: 0.68; 95% CI: 0.52, 0.88), however the difference in the composite outcome was largely driven by emergency room visits lasting greater than 6 hours. Given the resource constraints in Brazil during the time of the TOGETHER Study, it is unclear if these results would be generalizable to other settings. STOP-COVID 2 was a contactless, randomized trial in outpatients with SARS CoV-2 that compared fluvoxamine to placebo that was stopped prematurely for futility when fluvoxamine was no different from placebo in the outcome of clinical deterioration. In addition, it became difficult to enroll in this study with the widespread availability of vaccines and outpatient monoclonal antibodies 28 .

Hydroxychloroquine, azithromycin, and lopinavir/ritonavir have not shown evidence of benefit in RCT's. 

The US FDA has not authorized the neutralizing monoclonal antibody treatments for patients admitted to the hospital for COVID-19. The ACTIV-3 study was an early trial of bamlanivimab for the management of hospitalized patients with COVID-19 31 ). In this trial, a single dose of bamlanivimab 7000 mg was compared to placebo in hospitalized patients who were positive for SARS CoV-2 who had a duration of illness less than or equal to 12 days. In this trial, over fifty percent of patients in each group were on supplemental oxygen at baseline. Enrollment of this trial was stopped prematurely when the prespecified futility criteria was met and data were censored on 26 October 2020. Patients receiving bamlanivimab had a higher risk of mortality compared to those who did not receive bamlanivimab (HR: 2.00, 95% CI: 0.67, 5.99). The IDSA guideline panel has strongly recommended against the use of bamlanivimab in hospitalized patients based on the lack of clinical benefit demonstrated. 4 To date, emergency use authorizations for all neutralizing antibodies have excluded patients who are hospitalized due to COVID-19 or who require oxygen therapy or who require an increase in baseline oxygen flow due to COVID-19.

In the Recovery trial, hospitalized patients with COVID-19 were randomized to a single dose of casirivimab/imdevimab or usual care. In the overall population, there was no mortality benefit at 28 days, however a pre-specified analysis done prior to unblinding tested the hypothesis that casirivimab/imdevimab would be more beneficial in patients who tested negative for SARS Cov-2 antibodies. In this analysis, in seronegative patients, casirivimab/imdevimab conferred a mortality benefit compared to standard of care (RR: 0.80 95% CI: 0.70, 0.91) 32 . Two subsequent arms of the ACTIV-3 study, including sotrovimab or Brii-196 and Brii-198 were also stopped when futility criteria were met, and there was no clear signal towards benefit for patients in either of these arms who tested negative J o u r n a l P r e -p r o o f for SARS-CoV-2 antibodies at the time of randomization 31 . Currently, no neutralizing monoclonal antibodies have EUA or US FDA approval for patients hospitalized due to COVID or with severe COVID.

Convalescent plasma has been employed as a treatment for COVID-19 since the early days of the pandemic. It works similar to neutralizing antibodies as a passive immunotherapy, where naturally derived antibodies from the convalescent donor infused into an infected patient may inhibit viral entry into cells or assist in viral phagocytosis or antibody dependent cellular cytotoxicity.

Randomized controlled trials in hospitalized patients have demonstrated that convalescent plasma has no effect on mortality compared to no treatment (IDSA guidelines pooled relative risk (18 studies): RR 0.98; 95% CI: 0.93, 1.03), moderate certainty of evidence). In hospitalized patients who receive convalescent plasma compared that those who do not, data suggest a worrying trend towards an increase in the need for mechanical ventilation ((4 studies); RR: 1.10, 95% CI: 0.94, 1.29, low certainty of evidence) and an increase in the risk of adverse events ((11 studies); RR: 1.08, 95% CI: 0.94, 1.26).

Patients with severe COVID-19 are those who have pulmonary disease with hypoxia on room air needing treatment with low flow oxygen. Most existing criteria for trials consider a Sp02 level less than 94% or 90% and tachypnea (respiratory rate >30) as severe COVID-19. Such criteria help standardize classification in trials, but by no means do they capture the complexity of COVID-19 severity, so clinical judgment should supplement such criteria.

Certain patients develop pro-inflammatory state characterized by a clinical worsening approximately seven to ten days after onset of symptoms. This worsening can be characterized by increasing oxygen requirements and the development of acute respiratory distress syndrome (ARDS) as well as symptoms of hypoperfusion, which may result in progressive organ failure, and complications may involve multiple organ systems (See Chapter 1). Typically, this syndrome is marked by increasing systemic markers of inflammation like CRP, d-dimer, ferritin as well as pro-inflammatory cytokines. 33, 34 Antivirals Remdesivir Remdesivir may be considered in patients hospitalized with severe COVID-19, as in the trial ACCT -1 it showed early recovery or time to discharge. However, it did not show a mortality benefit based on a pooled analysis of three studies by the IDSA guideline panel (RR: 0.92; 95%CI: 0.77, 1.10). [35] [36] [37] Unfortunately, given the varied outcomes of these trials pooling of non-mortal events like clinical improvement was not possible, however there was a trend toward greater clinical improvement at day 28 37 and reduced need for mechanical ventilation 36 in patients receiving remdesivir.

Remdesivir is solubilized in a vehicle that is renally eliminated and remdesivir is not recommended for patients with an estimated glomerular filtration rate of less than 30 mL/min. Case series are available to support the use in creatinine clearance < 30 mL/min [38] [39] [40] , however pharmacovigilance reports provide evidence for adverse renal outcomes 41,42 , so providers must assess the risk vs. benefit of remdesivir use and consultation with pharmacy colleagues is recommended. Transaminase elevations may occur with J o u r n a l P r e -p r o o f remdesivir and clinicians should consider discontinuing use if ALT levels increase to greater than 10x the upper limit of normal.

Glucocorticoids, especially dexamethasone, have demonstrated a mortality benefit and their use is recommended by the IDSA guidelines for severe or critical illness. In the RECOVERY trial 3 , patients were randomized with dexamethasone 6 mg daily for 10 days or usual care. Patients receiving dexamethasone had a lower risk of death (RR: 0.83; 95% CI: 0.74, 0.92) and were more likely to be discharged from the hospital through day 28 (RR: 1.11; 95% CI: 1.04, 1.19) . Glucocorticoids are generally well tolerated; however, patients may experience significant hyperglycemia.

Several agents have been studied to attempt to reduce the impact of the inflammatory cascade has on disease course. Tocilizumab is the most frequently studied IL-6 antagonist in randomized controlled trials. To date there are eight randomized controlled trials evaluating tocilizumab compared to no tocilizumab in the management of COVID-19. While enrollment criteria for these studies varied, studies included hospitalized patients with evidence of pneumonia or severe disease. In the eight randomized trials, there is a trend toward reduced mortality at day 28 in those that receive tocilizumab compared to no tocilizumab ((IDSA guidelines pooled relative risk ((8 studies) RR: 0.91, 95% CI: 0.79, 1.04; moderate certainty of evidence). Two studies that seem to show the largest effect on the reduction of mortality included patients who received tocilizumab around the time of an escalation in their oxygen requirements. 43, 44 This may indicate that timing of tocilizumab therapy is an important factor, however this needs to be evaluated a priori in clinical trials. After pooling of all the randomized controlled trials, patients receiving tocilizumab are less likely to develop clinical deterioration, which was characterized by progression to mechanical ventilation or death in most of the trials (IDSA guidelines pooled relative risk ((7 studies) RR: 0.83, 95% CI: 0.77, 0.89; moderate certainty of evidence).

Unfortunately, there have been shortages of tocilizumab, leading front-line clinicians to look for alternative agents. Sarilumab is another IL-6 inhibitor that is being evaluated for the management of severe COVID-19. The IDSA guidelines suggests the use of sarilumab in those who would otherwise qualify for tocilizumab in addition to standard of care, rather than standard of care alone, when tocilizumab is not available. Data from three randomized controlled trials and network meta-analysis support this recommendation 43, [45] [46] [47] .

Janus kinases (JAK) are a group of kinases expressed on many cell surfaces which mediate cytokine signaling. Janus kinase 1 (JAK1) and Janus kinase 2 (JAK2) inhibitors have been developed and utilized in inflammatory conditions such as rheumatoid arthritis and ulcerative colitis. The most studied JAK inhibitor in the management of COVID-19 is baricitinib. In the ACTT-2 trial 48 , baricitinib combined with remdesivir was compared to remdesivir with placebo. Notably, study participants were prohibited from receiving glucocorticoids for COVID-19. These data have limited applicability given the widespread use of glucocorticoids in the management of severe COVID-19; however, this study provides guidance into treatment options for those in whom glucocorticoids are contraindicated.

In a large randomized controlled trial, the COV-BARRIER trial 49 , patients with severe COVID-19 and elevated inflammatory markers were randomized to receive renally dosed baricitinib or no baricitinib. Mortality at day 60 was lower in those receiving baricitinib compared to no baricitinib (HR: 0.62; 95% CI: 0.47-0.83; moderate certainty of evidence). Of note, over two-thirds of study participants received glucocorticoids.

Tofacitinib has also been evaluated in the STOP-COVID trial where it was compared with placebo in recently hospitalized patients with PCR confirmed COVID-19 pneumonia 50 . In this trial, patients receiving tofacitinib had a lower risk of a composite endpoint of death or respiratory failure at 28 days, compared to participants who did not receive tofacitinib (RR: 0.63; 95% CI: 0.41, 0.97). Due to the limited number of mortal events, one cannot exclude a beneficial or harmful effect on mortality (RR: 0.49; 95% CI: 0.15, 1.63). Similarly, the study was not able to exclude a beneficial or harmful effect on progression to mechanical ventilation or ECMO (RR: 0.25; 95% CI: 0.03, 2.20). Participants receiving tofacitinib experienced numerically more serious adverse events by day 28. Unfortunately, this study excluded patients with an immunosuppressive condition so the results should not be generalized to that population which is at risk for severe COVID-19. In addition, the results from the COV-BARRIER Trial and STOP-COVID should not be generalized to other Janus Kinase Inhibitors, such as ruxolitinib, as currently available data does not suggest a clinical benefit 51, 52 .

The US FDA has issued a drug safety communication for tofacitinib after the review of a large, randomized safety trial. Their results indicated an increased risk of serious heart-related events such as heart attack or stroke, cancer, blood clots and death when tofacitinib is used for ulcerative colitis or arthritis. Given the shared mechanism of action, the US FDA broadened its warnings to include other agents used for rheumatoid arthritis and include baricitinib and upadacitinib 53 .

Baricitinib requires renal dose adjustment, see table 2 for dosing.

This severity of critically ill patients requires more ventilator or oxygenation support, either with highflow oxygen or with noninvasive ventilation. High-flow oxygen therapy involves delivery of oxygen via special devices at rates up to 10-15 L/minute.

We strongly recommend systemic glucocorticoids in critically ill patients with COVID-19 as they have shown the highest 28-day mortality benefit when used in this sub-population (OR: 0.66; 95% CI: 0.54; 0.82). 54 In critically ill patients, dexamethasone 6mg/day is preferred but doses up to 20 mg/day can be used if indicated for other reasons. Hydrocortisone 50 mg IV Q6 hours is an alternative that can also be considered. Safety data in critically ill patients is reassuring. 47

In addition to glucocorticoids, we recommend using either IL-6 inhibitors (tocilizumab preferred over sarilumab) or JAK inhibitors (baricitinib preferred over tofacitinib) in those patients who have elevated inflammatory markers like CRP. The trials done so far have not identified specific sub-populations of critically ill patients already being treated with corticosteroids would benefit with additional treatment with IL-6 or JAK inhibitors.

J o u r n a l P r e -p r o o f

The IDSA guidelines recommends dexamethasone rather than no dexamethasone in critically ill patients with COVID-19. Data supporting this recommendation is based on a systematic review of 7 randomized controlled trials which demonstrated a reduction in the odds of mortality in patients treated with glucocorticoids compared to those not treated with glucocorticoids (OR: 0.66; 95%CI: 0.54, 0.82). In addition, patients who received glucocorticoids were more likely to be discharged from the hospital through day 28, compared to those who did not receive glucocorticoids (RR: 1.11; 95% CI: 1.04, 1.19)

To date, there are no randomized trials specifically comparing IL-6 inhibitors to not using IL-6 inhibitors in those on mechanical ventilation and/or ECMO, however a number of trials included patients on mechanical ventilation at baseline 43, 44, 55, 56 and many studies allowed for patients to receive glucocorticoids for COVID-19. The IDSA guidelines suggest the use of tocilizumab in addition to the standard of care, rather than standard of care alone. Systemic inflammatory markers are often elevated in critically ill patients with COVID-19, however there is no randomized trial data to demonstrate a specific cut-off for CRP that would indicate the appropriate patient for tocilizumab. In RECOVERY, patients were required to have a CRP of 75 mg/L or greater to be included in the IL-6 arm.

The role of baricitinib in critically ill patients on invasive mechanical ventilation or ECMO was evaluated in an addendum to the COV-Barrier study 57 . In this small trial with about 50 patients per arm, participants who were on invasive mechanical ventilation or ECMO and at least one elevated inflammatory marker were randomized 1:1 to receive baricitinib or standard of care. In this study, there was a reduction in the 60-day mortality rate in those who received baricitinib compared to no baricitinib (RR: 0.56; 95% CI: 0.47, 0.97).

The IDSA guideline does not suggest the use of remdesivir in critically ill COVID-19 patients as the subgroup analysis of ACCT-1 failed to demonstrate a reduction in mortality (RR: 1.23; 95% CI: 0.99, 1.53) in mechanically ventilated patients 36 Results also failed to demonstrate a beneficial effect of remdesivir on time to clinical recovery (HR: 0.98; 95% CI: 0.70, 1.36)

It is important for front line clinicians managing patients with COVID-19 to evaluate the setting as well as the severity of illness for each patient. Agile clinical guidelines are available to inform clinicians about place in therapy for various treatment options. Rigorous guideline methodologies, like GRADE can be applied in the setting of rapidly emerging and evolving literature to support clinicians and guide decision making. J o u r n a l P r e -p r o o f

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