By Kathryn Radigan, MD

Attending Physician, Division of Pulmonary and Critical Care, Stroger Hospital of Cook County, Chicago

SYNOPSIS: In this retrospective analysis of COVID-19 patients hospitalized with cytokine storm, the use of corticosteroids combined with tocilizumab was associated with superior survival when compared to no immunomodulatory treatment; a combination of corticosteroids and anakinra; or corticosteroids, tocilizumab, or anakinra alone. Patients who received corticosteroids, either alone or in combination with anakinra, also experienced lower hospital mortality compared to no treatment.

SOURCE: Narain S, Stefanov DG, Chau AS, et al. Comparative survival analysis of immunomodulatory therapy for coronavirus disease 2019 cytokine storm. Chest 2021;159:933-948.

COVID-19 cytokine storm (CCS), often identified by elevations in ferritin, C-reactive protein (CRP), and lactate dehydrogenase (LDH), is a marker of COVID-19 illness severity and increased mortality. Immunomodulatory therapies, such as tocilizumab and anakinra, have been repurposed in an attempt to improve survival in COVID-19 patients with CCS. Narain and colleagues performed a retrospective analysis of the electronic health records of 14,489 COVID-19 patients across the Northwell Health System between March 1, 2020, and April 24, 2020. Patients were subdivided into six groups: no immunomodulatory treatment, corticosteroids only, tocilizumab only, anakinra only, corticosteroids and tocilizumab, and corticosteroids and anakinra. The primary outcome was hospital mortality. Inclusion criteria were COVID-19 positivity as determined by polymerase chain reaction testing of nasopharyngeal swabs, age > 18 years, and meeting CCS criteria with either an elevated ferritin (> 700 ng/mL), CRP (> 30 mg/dL), or LDH (> 300 U/L).

Hospitalized COVID-19 patients treated with combination corticosteroids and tocilizumab had lower mortality compared with patients receiving no immunomodulatory treatment (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.35-0.55; P < 0.0001), patients treated with corticosteroids alone (HR, 0.66; 95% CI, 0.53-0.83; P = 0.004), or patients treated with corticosteroids and anakinra (HR, 0.64; 95% CI, 0.50-0.81; P = 0.003). Compared to no immunomodulatory treatment, there was improved hospital survival when corticosteroids were given alone (HR, 0.66; 95% CI, 0.57-0.76; P < 0.0001), with tocilizumab (HR, 0.43; 95% CI, 0.35-0.55; P < 0.0001), and with anakinra (HR, 0.68; 95% CI, 0.57-0.81; P < 0.0001). A randomized clinical trial comparing tocilizumab plus corticosteroids to corticosteroids alone is necessary to define patients with the greatest benefit from combination therapy.

COMMENTARY

Recently, the United States has reported more than 33 million COVID-19 cases and more than a half a million deaths.1 Repurposed immunomodulatory drugs aimed at cytokine storm in COVID-19 have been used in an attempt to improve mortality. Corticosteroids were of initial interest mainly because of their profound anti-inflammatory and immunoregulatory properties. The RECOVERY trial found that dexamethasone 6 mg daily for 10 days reduced the death rate in mechanically ventilated patients by 35% and in oxygen-dependent patients by 20% compared to patients who received standard care. There was no benefit in patients who were not receiving respiratory support.2

Interleukin-6 (IL-6) also was of significant interest because it was known to be an important mediator of inflammation and was specifically higher in patients with more severe COVID-19.3 It was theorized that IL-6 blockade in patients not yet requiring mechanical ventilation would interrupt the cytokine storm associated with COVID-19. Tocilizumab, a recombinant anti-IL-6 receptor monoclonal antibody, was hypothesized to disrupt the cytokine storm associated with COVID-19 with subsequent prevention of the most severe disease consequences, including acute respiratory distress syndrome. Unfortunately, early studies in the pandemic that evaluated tocilizumab monotherapy were negative. Stone and colleagues conducted a randomized, double-blind, placebo-controlled trial and found that tocilizumab had no significant effect on the risk of intubation, death, worsening of disease, or the time of discontinuation of supplemental oxygen.4 In this trial, glucocorticoids were administered to 23 patients (18 [11%] in the tocilizumab group and five [6%] in the placebo group). In contrast, subsequent open-label trials and non-randomized case series suggested that IL-6 receptor blockade had substantial positive effects on patients with COVID-19, such as a reduced rate of mechanical ventilation and decreased hospital mortality.5,6

The current study supports the practice of corticosteroids, either alone or with tocilizumab or anakinra, since it was associated with reduced hospital mortality for patients with cytokine storm. Although this current study was retrospective, subsequent studies, including the RECOVERY and the REMAP-CAP studies, were prospective and also found tocilizumab to be beneficial. The RECOVERY trial was a randomized, controlled, open-label, platform trial evaluating several possible treatments in 21,550 patients hospitalized with COVID-19 in the United Kingdom.7 A subset of patients with hypoxemia and CRP levels ≥ 75 mg/L were offered enrollment in a second randomization to receive tocilizumab or usual care. In all, 4,116 (19%) of the participants underwent a second randomization into the tocilizumab intervention arm. In these hospitalized patients with hypoxia and systemic inflammation, tocilizumab improved survival and the chances of discharge from the hospital alive, and reduced the chances of progressing to require invasive mechanical ventilation compared to usual care. Notably, in contrast to previous trials, 82% of the trial participants also were on glucocorticoids, mainly dexamethasone. Tocilizumab resulted in a 6% reduction in mortality when given with dexamethasone but no reduction in mortality when given alone.

The REMAP-CAP study, also a randomized controlled trial, revealed that treatment with the IL-6 receptor antagonists, tocilizumab and sarilumab, was associated with better outcomes, such as shorter time to clinical improvement and survival, in patients with severe to critical COVID-19 who were exhibiting rapid respiratory decompensation.8 Tocilizumab (n = 353) and sarilumab (n = 48) each reduced in-hospital mortality in patients enrolled within 24 hours of intensive care unit (ICU) admission compared with standard of care (28% vs. 22% vs. 36%, respectively; adjusted odds ratio [OR], 1.64; 95% credible interval [CrI], 1.14-2.35, for tocilizumab; OR, 2.01; 95% CrI, 1.18-4.71, for sarilumab). In the REMAP-CAP study, corticosteroids were given to 88% of patients, and remdesivir was given to 33% of patients. Since enrollment occurred within 24 hours of ICU admission and within a median of 1.2 days of hospitalization (interquartile range [IQR], 0.8-2.8 days), results suggest the benefit of tocilizumab may occur specifically in patients who are experiencing rapid respiratory decompensation.

The National Institutes of Health (NIH) panel currently acknowledges there may be some hospitalized patients who are receiving conventional oxygen therapy with progressive hypoxemia associated with significant systemic inflammation who may benefit from tocilizumab.9 The panel currently recommends using tocilizumab 8 mg/kg in combination with dexamethasone 6 mg daily for up to 10 days in hospitalized patients within three days of admission who are: admitted to the ICU within the prior 24 hours and who require invasive mechanical ventilation, noninvasive mechanical ventilation, or high-flow nasal cannula (HFNC) oxygen (> 0.4 FiO2/30 L/min of oxygen flow), or not admitted to the ICU, but have rapidly increasing oxygen needs and require noninvasive ventilation or HFNC and who have significantly increased markers of inflammation (CRP ≥ 75 mg/L). Some panel members would consider the administration of tocilizumab to patients with rapidly increasing oxygen needs while on dexamethasone and who have a CRP ≥ 75 mg/L but who do not yet require noninvasive ventilation or HFNC oxygen.

In general, tocilizumab should be avoided in the significantly immunosuppressed, in patients with alanine aminotransferase greater than five times the upper limit of normal, in patients at high risk for gastrointestinal perforation, and/or in those who have uncontrolled serious bacterial, fungal, or coinciding viral infection. Ivermectin also should be considered for patients who are from strongyloidiasis-endemic areas. Similarly, the Infectious Diseases Society of America (IDSA) suggests adding tocilizumab to standard of care (i.e., glucocorticoids) for hospitalized adults who have progressive severe or critical COVID-19 and have elevated markers of systemic inflammation.10

Although the benefit of tocilizumab in hospitalized patients who require more aggressive ventilator support or are progressing with significantly increased markers of inflammation appears to be more clear, larger prospective randomized controlled trials with a head-to-head comparison of tocilizumab plus corticosteroids vs. corticosteroids alone may be beneficial to further define patient populations with greatest benefit.

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