The Return of Tocilizumab for Patients with COVID-19 Pneumonia

The COVID-19 pandemic has now impacted the global population for over a year. It has been devastating for many and has challenged us all in many ways. While the advent of vaccinations looks to curtail the number of cases, multiple challenges to ending the pandemic remain, including the advent of variants, vaccine hesitancy, access to vaccines, and the impaired efficacy of vaccines in immunocompromised persons. Thus, it is still essential to continue investigating treatments for COVID-19.


Introduction
The COVID-19 pandemic has now impacted the global population for over a year. It has been devastating for many and has challenged us all in many ways. While the advent of vaccinations looks to curtail the number of cases, multiple challenges to ending the pandemic remain, including the advent of variants, vaccine hesitancy, access to vaccines, and the impaired efficacy of vaccines in immunocompromised persons. Thus, it is still essential to continue investigating treatments for COVID-19.
SARS-COV-2 infections can result in severe hyperinflammatory states. This has led to an increased interest in the use of anti-inflammatory agents and immune modulators in the management of severe and critical COVID-19 disease.
Interleukin-6 (IL-6) is one cytokine that has garnered much attention with this disease. Elevated IL-6 has been associated with a number of inflammatory conditions. In patients with acute lung injury, IL-6 has been associated with morbidity and mortality [1]. Elevated IL-6 has been correlated with the progression of severe COVID-19 [2]. IL-6 blockade has been used in the management of cytokine release syndrome associated with CAR T cell therapy used in some cancer therapies.
Tocilizumab is an interleukin-6 receptor inhibitor monoclonal antibody that has been studied in the treatment of severe COVID-19 pneumonia since the beginning of the pandemic in late 2019. Opinions about the utility of tocilizumab has changed over the course of this pandemic. In late 2020, we reported our experiences in the beginnings of the pandemic in the United States of America with tocilizumab in mechanically ventilated patients with PCR confirmed COVID-19 pneumonia, finding no clear benefit in this population [3]. Our knowledge about the management of COVID-19 and potential role of various therapeutics has grown considerably since then. Here, we review the trials using tocilizumab in the treatment of severe COVID-19 since our reported experience.

Trials
The study of Rosas et al. [4] suggested lack of clinical condition improvement and mortality at 28 days with tocilizumab when compared to placebo. This randomized controlled trial analyzed 438 patients in Europe and North America. Adults with COVID-19 pneumonia on laboratory work and imaging with an oxygen saturation of ≤ 93% or a PaO2/FiO2 <300 mmHg were included. Patients were randomized in a 2:1 ratio of tocilizumab 8 mg/kg or placebo. A second dose was administered if no improvement was observed within 24 hours of the initial dose. Patients were also given standard of care at that time, which included antivirals, glucocorticoids, and convalescent plasma. 19.4% of patients received glucocorticoids in the tocilizumab group compared to 28.5% in the placebo group. 24.1% of patients received antivirals in the tocilizumab group compared to 29.2% in the placebo group.
Use of tocilizumab did not improve clinical condition or mortality at 28 days, but there was a possible benefit in shortening the time in the intensive care unit and hospital stay. One of the limiting factors of this study was that standard treatment was different across trial sites. Antiviral therapies included hydroxychloroquine and lopinavir-ritonavir. There were more patients on glucocorticoids in the placebo group than in the tocilizumab group. Those who received glucocorticoids seemed to have higher mortality in each group, which may reflect a worse overall clinical condition. However, more clinical data published after this study period has demonstrated the benefit of corticosteroid use in hypoxic patients with COVID-19 [5]. This confounding factor was evident in various studies, such as in Fisher et al. [3], Somers et al. [6] and Biran et al. [7] which had 77%, 25%, and 43% of their overall patients on steroids respectively. Stone et al. [8] studied the efficacy of tocilizumab in hospitalized patients with moderately severe COVID-19 pneumonia. The outcome of this study suggested that tocilizumab is not effective at preventing intubation or death. All patients in this study required less than 10 liters of supplemental oxygen. Patients received remdesivir, but only 11% of the tocilizumab group and 6% in the placebo group received glucocorticoids. Of the 161 patients who received tocilizumab and 81 patients who received placebo, 17 patients from the tocilizumab (10.6%) and 10 (12.5%) from the placebo group were intubated or died within 28 days (hazard ratio 0.83 (95% confidence interval [CI], 0.38 to 1.81; P=0.64)). This randomized double-blind control trial did not suggest benefits in using tocilizumab for moderate COVID-19 pneumonia in preventing intubation or death. Limitations of this study was that it was conducted early in the pandemic when treatments that are now standard of care were still being investigated.
In the retrospective observational study by Huang et al. [9], fewer deaths were seen in patients treated with tocilizumab compared to non-treatment. Most of the tocilizumab treated patients needed mechanical ventilation (80% vs 37%, P<0.001); some were intubated prior to the start of treatment or within one day of treatment, which may suggest a more severe disease in this group compared to the non-treatment group. The median time to treatment was two hospital days (0-16 days). In contrast, despite the advanced disease, fewer deaths occurred in both the overall (15% vs 37%; P=0.02) as well as the intubated (14% vs 60%; P=0.001). Only 1 patient in each group was treated with dexamethasone and although more patients in the tocilizumab treatment group concurrently received remdesivir, their reported data still shows a statistically significant decrease in death.
In the study of Mariette et al. [10] treatment with tocilizumab was shown to be beneficial only when CRP levels were greater than 15.0 mg/dL. This randomized clinical trial investigated patients between March 31, 2020 to April 18, 2020. 131 patients were recruited from nine hospitals in France. Patients in this study were hospitalized, required ≥ 3L oxygen, but did not require high flow or mechanical ventilation. 64 patients received tocilizumab (8 mg/kg) with standard of care while 67 patients received only standard of care [11]. Standard of care at that time included antibiotics, antivirals, steroids, and anticoagulants. 16% of patients in the tocilizumab group and 18% in the standard of care group were taking glucocorticoids. The primary endpoint of the study were patients who required noninvasive ventilation, mechanical ventilation, or death. In patients treated with tocilizumab with CRP levels greater than 15.0 mg/dL, 18% of patients received noninvasive or invasive ventilation or died compared to 57% with those in the standard of care groups (HR, 0.18; 95% CI, 0.06-0.59). 90day mortality was 9% in the tocilizumab group and 25% in the usual care group (HR, 0.18; 95% CI, 0.04-0.89). Limitations in this study include different standard of care among centers. This trial suggests the benefit of administering tocilizumab for patients with elevated CRP.
Recently, tocilizumab has reemerged as a treatment for patients with severe COVID-19 pneumonia due to a large, randomized controlled trial in the United Kingdom with the RECOVERY Collaborative Group [12]. In this trial, it was found that those who received tocilizumab were less likely to require mechanical ventilation or reach death and were more likely to be discharged from hospitalization within 28 days. The study enrolled 4116 adults who had an oxygen saturation <92% Limitations include different standard of care among centers especially since tocilizumab and sarilumab were approved at different timeframes. In addition, not all patients had confirmed COVID-19 infection as those suspected to have COVID-19 infection were included in the study.

Conclusion
Numerous studies have investigated the detrimental effects of markedly elevated inflammatory cytokines and a dysregulated immune system resulting in severe respiratory disease [1,9]. The research summarized here varies in study designs with some being randomized controlled trials and others being observational studies (Table 1). All took place during a dynamic year where the standard of care differed in each hospital and every month as new data emerged from around the world. Of these studies, some suggest efficacy of tocilizumab [9,10,12,13] while others have proposed the contrary [4,5,8,14].
Some conclusions can be drawn from the above studies. First, timing looks to be critical. No substantial benefit was seen in persons using supplemental low flow oxygen and in those on prolonged mechanical ventilation or ECMO. Persons entering the hyperinflammatory phase of COVID-19 as evidenced by high oxygen requirements and elevated inflammatory serum markers appeared to benefit the most from tocilizumab. Second, IL-6 blockade by itself is not enough. Tocilizumab should be combined with corticosteroids to derive the most benefit for patients.
Questions remain regarding the use of tocilizumab. Is there a benefit to repeat dosing of tocilizumab? While some of the above studies allowed for a second dose if there was no clinical improvement, this variable was not controlled. Are there longterm consequences to the use of tocilizumab in persons with COVID-19?
Tocilizumab has now become a recommended intervention in certain persons with COVID-19 pneumonia. Patient selection is crucial to maximizing the benefits. Further research is needed to better define the best timing for tocilizumab to improve morbidity and mortality.