key: cord-0859550-x103ln9v
authors: Huang, Edmund; Isonaka, Sharon; Yang, Haoshu; Salce, Erin; Rosales, Elisa; Jordan, Stanley C.
title: Tocilizumab Treatment in Critically Ill Patients with COVID-19: A Retrospective Observational Study
date: 2021-02-17
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2021.02.057
sha: 1897cb3c3e6c573b59f29a65191ec94b7668a5df
doc_id: 859550
cord_uid: x103ln9v

Objective Elevated levels of pro-inflammatory cytokines are observed in severe COVID-19 infections and cytokine storm is associated with disease severity. Tocilizumab, an interleukin-6 receptor antagonist, is used to treat chimeric antigen receptor T cell-induced cytokine release syndrome and may attenuate the dysregulated immune response in COVID-19. We compared outcomes among tocilizumab-treated and untreated critically ill COVID-19 patients. Design, Setting, and Participants This was a retrospective observational study conducted at a tertiary referral center investigating all patients admitted to the intensive care unit for COVID-19 who had a disposition from the hospital because of death or hospital discharge between March 1, 2020 and May 18, 2020 (n=96). The percentages of death and secondary infections were compared between patients treated with tocilizumab (n=55) and those who were not (n=41). Measurements and Main Results More tocilizumab-treated patients required mechanical ventilation (44/55, 80%) compared to non-treated patients (15/41, 37%; p<0.001). Of 55 patients treated with tocilizumab, 32 (58%) were on mechanical ventilation at the time of administration and 12 (22%) progressed to mechanical ventilation after treatment. Thirty of 44 (68%) treated ventilated patients were intubated within one day of tocilizumab. Fewer deaths were observed among tocilizumab-treated patients, both in the overall population (15% vs. 37%; p=0.02) and among the subgroup of patients requiring mechanical ventilation (14% vs. 60%; p=0.001). Secondary infections were not different between the two groups (tocilizumab: 31%, non-tocilizumab: 17%; p=0.16) and were predominantly related to invasive devices, such as urinary and central venous catheters. Conclusions Tocilizumab treatment was associated with fewer deaths compared to non-treatment despite predominantly being used in patients with more advanced respiratory disease.

Since the advent of Coronavirus Disease 2019 in Wuhan, China in December 2019 , the virus has spread to virtually every country in the world now accounting for more than 29 million cases worldwide with 937,519 deaths [(https://www.worldometers.info/coronavirus/ (accessed September 15) ]. Despite heroic efforts to develop vaccines and generate data from controlled clinical trials, the clear and prescient morbidity and mortality imposed by SARS-CoV-2 pneumonia requires implementation of therapies, which based on logical deduction from known mechanisms of action and case reports, could be useful.

Early reports from patients with SARS-CoV-2 pneumonia identified interleukin 6 (IL-6) as a potential pathogenic factor in initiation of the acute respiratory distress syndrome (ARDS) (Parsons, et al., 2005) . IL-6 is a pleiotropic cytokine which functions as a mediator of both innate and adaptive immune functions. IL-6 has diverse immune and biologic actions including direction of immune cell differentiation, sentinel responses to invading pathogens and ischemic injury. IL-6 is also critical for plasma cell growth and immunoglobulin production. Excessive and unregulated IL-6 transcription is commonly seen in patients with autoimmune or inflammatory disorders. Emerging data from patients with SARS-CoV-2 infection suggests IL-6 transcription is initiated and sustained after respiratory epithelium is infected. The virus has a proclivity for activation of alveolar and circulating macrophages resulting in copious and sustained IL-6 production manifesting as the cytokine storm, endothelial cell damage, capillary leak and the clinical and pathological features of ARDS (Roschewski, et al., 2020) . This data suggests inhibiting IL-6 production and/or blocking receptor binding could be an important therapeutic option for limiting morbidity and mortality.

is of interest due to its ability to reduce ARDS after chimeric antigen receptor (CAR) T cell therapy. Tocilizumab is a recombinant IgG1 humanized monoclonal antibody which inhibits the binding of IL-6 to the soluble and membrane-bound forms of the IL-6R. Tocilizumab is Food and Drug Administration (FDA) approved for the treatment of severe rheumatoid arthritis, systemic juvenile idiopathic arthritis, giant cell arteritis, and more recently for cytokine release syndrome occurring after CAR T-cell therapy (Le, et al., 2018) .

We recently reported on our experience using tocilizumab for treatment of SARS-CoV-2 pneumonia where we observed favorable responses in temperature and oxygen usage and vasopressor requirements after treatment (Jordan, et al., 2020) . Most of the tocilizumab-treated patients in this report were critically ill requiring mechanical ventilation. The association of tocilizumab with reduced mortality in critically ill patients has also been reported in other observational studies (Gupta, et al., 2020; Somers, et al., 2020) . Further, data from the Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial reported that the greatest benefit of dexamethasone on mortality was seen among patients receiving mechanical ventilation, suggesting that immunomodulation may be more effective when given to patients with more advanced disease (RECOVERY Collaborative Group, et al., 2020). Given these observations, we have expanded on our initial report with a larger cohort of patients treated in the intensive care unit (ICU) with tocilizumab and compare outcomes to ICU patients with SARS-CoV-2 pneumonia patients not treated with tocilizumab.

This observational study was supported by Cedars-Sinai Medical Center and approved by the Institutional Review Board of Cedars-Sinai Medical Center (STUDY00000678; Tocilizumab Effectiveness for Treatment of . The flowchart of study inclusion and exclusion is provided in Figure 1 . We retrospectively analyzed medical records of all patients admitted to Cedars-Sinai Medical Center between March 1, 2020 and May 18, 2020 for a COVID-19related-admission with diagnosis confirmed by a positive nasopharyngeal real-time polymerase chain reaction test for SARS-CoV2 (n=388). We were specifically interested in investigating mortality outcomes associated with tocilizumab treatment in the highest-risk population and therefore restricted the study population to all patients admitted to the ICU (n=140). In order to allow for comparison of outcomes between study groups, we only included patients who had a disposition from the hospital by the end of the study period on May 18, 2020, either because of death or hospital discharge (n=101). Of these, the following were excluded: four patients because of treatment with an investigational IL-6 antagonist, clazakizumab, and one patient for a non-COVID related death. The final study population consisted of 96 patients, 55 of whom were treated with tocilizumab and 41 of whom were not. The treatment protocol consists of a single 400 mg dose of tocilizumab given by intravenous infusion. Antimicrobial prophylaxis is not routinely given after tocilizumab administration. Follow-up measurements of inflammatory markers, including interleukin-6 levels, C-reactive protein, ferritin, d-dimer, and lactate dehydrogenase are periodically done post-administration at the discretion of the treating physician.

Baseline characteristics between tocilizumab-treated and non-tocilizumab treated patients were compared using a t-test or Mann-Whitney U test for numerical variables, as appropriate, and the Fisher's exact test for categorical variables. Data are presented as frequencies (percentage, %) for categorical variables and mean (± standard deviation, SD) or median (range) for numerical variables. The primary outcome of interest was the proportion of patients who died, with statistical comparison performed using the Fisher's exact test. Secondary outcomes included the number of culture-confirmed bacterial or fungal infections, which were extracted by manual chart review. Ventilator-free days at 28 days were calculated as previously described (Yehya, et al., 2019) . Briefly, this metric was defined as the number of ventilator-free hospital days within 28 days of initiation of mechanical ventilation. Ventilator-free days were considered 0 if the patient died or was ventilated for longer than 28 days. Complications were identified from diagnoses codes extracted from hospital billing records reflecting acute diagnoses or diagnoses occurring after ICU admission.

Analyses were performed on the overall population in addition to a subgroup of patients considered to have more severe disease, defined as a requirement for mechanical ventilation at any time during the hospital stay (tocilizumab, n=44; non-tocilizumab, n=15). All calculations were performed using IBM SPSS Statistics for Windows v. 24.0 (IBM Corp.; Armonk, NY). Table 1 compares the baseline characteristics of tocilizumab-treated and non-tocilizumab treated patients. The median number of hospital days prior to tocilizumab treatment was 2 days (range 0-16 days). A higher proportion of tocilizumab-treated patients were male and obese (body mass index ≥30 kg/m 2 ), whereas there were no differences in the distribution of age, race/ethnicity, or other co-morbidities between the two groups. The distribution of sequential organ failure assessment (SOFA) scores, a mortality prediction score, at ICU admission was not different between patients in the non-tocilizumab treated and tocilizumab-treated groups.

However, the vast majority of patients in the tocilizumab group required mechanical ventilation (80%) as opposed to only 37% of patients in the non-tocilizumab group (p<0.001). Initial laboratory values were similar in the two groups aside from a trend toward higher alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) levels in the tocilizumab-treated group. Notably, serum IL-6 and CRP levels were markedly elevated but did not differ between the two groups. A higher proportion of tocilizumab-treated patients received additional medications investigated as therapies for SARS-CoV-2, including hydroxychloroquine, azithromycin, and remdesivir. Only one patient in each group was treated with dexamethasone.

Given that tocilizumab-treated patients had more severe respiratory disease, as indicated by a significantly higher percentage of patients requiring mechanical ventilation, baseline characteristics and initial laboratory values among the subgroup of patients who required mechanical ventilation were also compared in Table 2 . The median number of hospital days prior to tocilizumab treatment was 2 days (range 0-16 days). Of 55 patients treated with tocilizumab, J o u r n a l P r e -p r o o f to mechanical ventilation after treatment (44 ventilated patients total). The distribution of gender, race/ethnicity, and co-morbidities among patients treated with mechanical ventilation was similar to that observed in the overall population. The initial laboratory values in this subgroup were similar to the overall population, although significantly lower values of white blood cell count, absolute neutrophil count, and troponin I were observed in the tocilizumab group compared to the non-tocilizumab treated group.

Fewer deaths were observed in the tocilizumab group. Mortality in the non-tocilizumab group was 15/41 (37%) compared to 8/55 (15%) in the tocilizumab-treated patients (p=0.02). No patients treated with remdesivir died. After excluding remdesivir-treated patients from the analysis, the proportion of deaths in the non-tocilizumab group remained higher than the tocilizumab group (38% vs. 17%; p=0.05). Among patients requiring mechanical ventilation, the mortality difference between the two groups was more pronounced. Nine of 15 (60%) nontocilizumab treated recipients maintained on mechanical ventilation died compared to 6/44 (14%) tocilizumab-treated patients (p=0.001). Among the 6 deaths in the subgroup of tocilizumab recipients who required mechanical ventilation, two patients were treated with tocilizumab before progressing to mechanical ventilation and four patients were treated after initiating mechanical ventilation. (Figure 2a) . Four patients died, two of whom died shortly after treatment (2 and 3 days, respectively). Twenty-two patients were discharged alive at a median 17.5 days after treatment (range 5-28 days). Six patients remained hospitalized at 28 days after treatment; of these, two patients were free of supplemental oxygen and only one remained on mechanical ventilation.

Twelve patients received tocilizumab before progressing to mechanical ventilation ( Figure 2b ). Of these, the median number of days in the ICU prior to tocilizumab administration was 1.5 days (range 0-7 days). Most patients (8/12; 66.7%) were intubated immediately following tocilizumab treatment on the same or next day after administration. Two patients died at 11 and 14 days after treatment and ten patients recovered and were discharged alive from the hospital. 

In this paper, we compared mortality outcomes following ICU admission between patients who received tocilizumab for COVID-19 and those who did not. Although tocilizumabtreated recipients had more severe respiratory disease compared to non-tocilizumab treated patients, fewer deaths were observed among patients treated with tocilizumab. There were numerically more secondary infections in the tocilizumab group, mostly related to nosocomial infections from invasive devices or catheters, although no statistical difference compared to untreated patients.

Early observations of patients with COVID-19 were that severe infections were associated with markedly elevated levels of pro-inflammatory cytokines and that cytokine storm was associated with disease severity . This phenomenon was similarly Zhao, et al., 2020). Inhibition of the IL-6 pathway is an attractive target, particularly because tocilizumab, a monoclonal antibody directed against the IL-6 receptor α, is known to be effective at controlling cytokine storm associated with CAR T-cell therapy (Le, et al., 2018) .

This study is a follow-up to a recent report of our initial experience using tocilizumab in A series of randomized controlled trials comparing tocilizumab treatment to placebo were recently published (Hermine, et al., 2020; Stone, et al., 2020) . All three trials evaluated the use of tocilizumab at earlier stages of illness and were designed to test whether treatment can prevent disease progression. Although the primary endpoints in these studies were not met, fewer tocilizumab-treated patients needed noninvasive or mechanical ventilation or died by day 14 in one of the trials (Hermine, et al., 2020) . Press releases from two other randomized controlled trials reported that IL-6 blockade did not improve clinical status or mortality in patients with COVID-19; however, a third randomized controlled trial reported that non-ventilated patients treated with tocilizumab were less likely to need mechanical ventilation compared to placebo [https://www.clinicaltrialsarena.com/news/roche-actemra-covid-data/ (August 7); https://www.prnewswire.com/news-releases/regeneron-and-sanofi-provide-updateon-kevzara-sarilumab-phase-3-us-trial-in-covid-19-patients-301087849.html (July 2); https://www.roche.com/media/releases/med-cor-2020-09-18.htm (accessed September 23)]. It is possible that the benefit of IL-6 blockade may be limited to specific subgroups, perhaps those with more advanced disease, which will require further study. In the phase III trial of sarilumab, there was a positive signal among critical patients who were mechanically ventilated (https://www.prnewswire.com/news-releases/regeneron-and-sanofi-provide-update-on-kevzarasarilumab-phase-3-us-trial-in-covid-19-patients-301087849.html (July 2). This observation is consistent with findings from our study and others (Biran, et Limitations of this study stem from its retrospective, observational design. Baseline characteristics in the tocilizumab and non-tocilizumab groups were not balanced, which was a consequence of pre-specified criteria that were established at our institution for patients to receive treatment with tocilizumab. These criteria were implemented in order to ration our supply of tocilizumab, which was in a nationwide shortage at the beginning of the COVID-19 pandemic, and were meant to select patients with severe respiratory disease and evidence of a pro-inflammatory state. Given this, tocilizumab-treated patients in this study generally had more advanced respiratory disease than untreated patients. We were unable to statistically adjust for covariate imbalance given that there were only 23 deaths in the study population as a whole.

Additionally, other investigational therapies for COVID-19 were not restricted. However, these therapies mostly consisted of hydroxychloroquine and azithromycin, both of which are now generally considered to be ineffective for COVID-19 (Cavalcanti, et al., 2020) . Relatively few patients in this study received concomitant treatment with remdesivir and/or dexamethasone.

In summary, treatment with tocilizumab in critically ill patients with COVID-19 was associated with lower mortality compared to standard of care treatment without a significant increase in serious secondary infectious complications. While we await further data from randomized controlled trials, this study adds to a growing body of literature suggesting that IL-6 blockade can improve survival in patients with severe COVID-19.

In this study, there were fewer deaths among critically ill patients with COVID-19 treated with tocilizumab, suggesting that IL-6 blockade could be an important therapeutic option for limiting morbidity and mortality.

Edmund Huang and Sharon Isonaka contributed equally to this work.

We remember all those who have suffered from COVID-19. Our thoughts and prayers are with them and their families. Tables: Table 1 . Comparison of baseline characteristics between non-tocilizumab treated and tocilizumab-treated patients. Table 2 . Comparison of baseline characteristics between non-tocilizumab treated and tocilizumab-treated patients who required mechanical ventilation. 

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