key: cord-289973-1mczuxsy
authors: Biran, Noa; Ip, Andrew; Ahn, Jaeil; Go, Ronaldo C; Wang, Shuqi; Mathura, Shivam; Sinclaire, Brittany A; Bednarz, Urszula; Marafelias, Michael; Hansen, Eric; Siegel, David S; Goy, Andre H; Pecora, Andrew L; Sawczuk, Ihor S; Koniaris, Lauren S; Simwenyi, Micky; Varga, Daniel W; Tank, Lisa K; Stein, Aaron A; Allusson, Valerie; Lin, George S; Oser, William F; Tuma, Roman A; Reichman, Joseph; Brusco, Louis; Carpenter, Kim L; Costanzo, Eric J; Vivona, Vincent; Goldberg, Stuart L
title: Tocilizumab among patients with COVID-19 in the intensive care unit: a multicentre observational study
date: 2020-08-14
journal: The Lancet Rheumatology
DOI: 10.1016/s2665-9913(20)30277-0
sha: 
doc_id: 289973
cord_uid: 1mczuxsy

Summary Background Tocilizumab, a monoclonal antibody directed against the interleukin-6 receptor, has been proposed to mitigate the cytokine storm syndrome associated with severe COVID-19. We aimed to investigate the association between tocilizumab exposure and hospital-related mortality among patients requiring intensive care unit (ICU) support for COVID-19. Methods We did a retrospective observational cohort study at 13 hospitals within the Hackensack Meridian Health network (NJ, USA). We included patients (aged ≥18 years) with laboratory-confirmed COVID-19 who needed support in the ICU. We obtained data from a prospective observational database and compared outcomes in patients who received tocilizumab with those who did not. We applied a multivariable Cox model with propensity score matching to reduce confounding effects. The primary endpoint was hospital-related mortality. The prospective observational database is registered on ClinicalTrials.gov, NCT04347993. Findings Between March 1 and April 22, 2020, 764 patients with COVID-19 required support in the ICU, of whom 210 (27%) received tocilizumab. Factors associated with receiving tocilizumab were patients' age, gender, renal function, and treatment location. 630 patients were included in the propensity score-matched population, of whom 210 received tocilizumab and 420 did not receive tocilizumab. 358 (57%) of 630 patients died, 102 (49%) who received tocilizumab and 256 (61%) who did not receive tocilizumab. Overall median survival from time of admission was not reached (95% CI 23 days–not reached) among patients receiving tocilizumab and was 19 days (16–26) for those who did not receive tocilizumab (hazard ratio [HR] 0·71, 95% CI 0·56–0·89; p=0·0027). In the primary multivariable Cox regression analysis with propensity matching, an association was noted between receiving tocilizumab and decreased hospital-related mortality (HR 0·64, 95% CI 0·47–0·87; p=0·0040). Similar associations with tocilizumab were noted among subgroups requiring mechanical ventilatory support and with baseline C-reactive protein of 15 mg/dL or higher. Interpretation In this observational study, patients with COVID-19 requiring ICU support who received tocilizumab had reduced mortality. Results of ongoing randomised controlled trials are awaited. Funding None.

Worldwide more than 20 million individuals have been infected with severe acute respiratory syndrome corona virus 2 (SARSCoV2), the coronavirus causing COVID19. As of Aug 13, 2020, almost 750 000 deaths have been reported globally. 1 Infection causes destruction of alveolar epithelial cells, activation of the innate immune sys tem, and dysregu lation of adaptive immune responses, includ ing release of proinflammatory cytokines and chemo kines. This socalled cytokine storm might have an important role in the progression to respiratory and multi organ failure. 2, 3 Tocilizumab, a recombinant monoclonal antibody against the interleukin (IL) 6 receptor, has been used to miti gate the cytokine release syndrome associated with chi meric antigen receptor (CAR) Tcell therapy and has been proposed as a potential therapy for the cytokine storm syndrome associated with severe COVID19 pneumonia based on small phase 2 studies. [4] [5] [6] [7] [8] [9] [10] Preliminary unpublished results of the phase 2 French CORIMUNOTOCI trial, involving 129 patients, noted a reduction in mortality and requirement for mechanical ventilation in patients who received tocilizumab. 11 A large multinational randomised placebocontrolled phase 3 trial evaluating tocilizumab in the treatment of severe COVID19 pneu monia is under way (NCT04320615). Additional trials of tocilizumab are also ongoing.

Without data from randomised trials, observational studies can provide useful early insights into effective treatment strategies. 12, 13 However, treatment allocations are often based on the clinician's judgment in an observational study, rather than random assignment, which increases the risk of bias and does not account for known and unknown risk factors. Thus, causal inferences on effec tiveness of treat ments are challenging, but confounding effects can be partly mitigated via statistical methods. 14 Understanding the limitations of observational studies, but with the urgency to assess potential therapeutic approaches, the 13 hospitals within the Hackensack Meridian Health network (NJ, USA) considered offlabel use of tocilizumab in patients with severe SARSCoV2 infection who required intensive care unit (ICU) support. To evaluate treatments for COVID19, we established an observational database using an integrated electronic health record system (EPIC; Verona, WI, USA). We aimed to compare outcomes between patients with COVID19 in the ICU who received tocilizumab and those who did not receive tocilizumab.

We did a retrospective, observational, multicentre cohort study at the 13 hospitals within the Hackensack Meridian Health network. We derived data from electronic health records of patients with COVID19 who received ICU support. Our selection criteria were adult patients (aged ≥18 years) with a positive SARSCoV2 diagnosis by RTPCR who were hospitalised at one of Hackensack Meridian Health's 13 hospitals during the study period and required ICU support. We excluded patients who were pregnant and those who were partici pating in a clinical therapeutic trial. Patients receiving tocilizumab for chronic rheumatological conditions were not excluded.

We obtained Institutional Review Board (IRB) approval for access to the prospective observational database. The requirement for patient's informed consent was waived by the IRB because this project represented a noninterventional study using routinely gathered data for secondary research reasons.

We obtained data from Hackensack Meridian Health's electronic health record, which is used throughout the hospital network. Hospitalised patients were flagged by the electronic health record if SARSCoV2 PCR tests were positive. These reports generated by the electronic health record served as our eligible cohort sample. Demographics, clinical characteristics, treatments, and outcomes were manually abstracted by research nurses and clinicians from the John Theurer Cancer Center at Hackensack Meridian Health. Assignment of patients to our data team occurred in real time but was not random ised. Data abstracted by the team were entered, using Research Electronic Data Capture. Quality control was done by two of us (AI and SLG).

Demographic information was gathered on an elec tronic face sheet. Gender and race or ethnicity were selfreported. Academic centres were defined as quaternary referral centres with accredited residency, fellowship, and medical student programmes. Comorbidities were defined as diagnosed before hos pitalisa tion for COVID19. History of cardiovascular disease, chronic lung disease, cancer, renal failure, and rheumatological disease was abstracted from provider notes or medical history sec tions within the electronic health record. If not listed, the patient's comor bidities were recorded as absent. ICU support included all patients receiving mechanical ventilator support, patients hospital ised within a dedicated ICU, and patients with assignment to ICU staff regardless of geographical place ment (over flow during pan demic conditions). Patients who received remdesivir were treated in the context of a clinical study and were excluded. Lopinavir was not on

Evidence before this study We searched PubMed, Embase, Cochrane Reviews, and Scopus from Jan 1 to April 22, 2020, with the terms "tocilizumab" AND "COVID" OR "coronavirus". This search identified an increasing interest in the rationale to use tocilizumab in patients with severe COVID-19 and several case reports or small observational studies reporting a benefit with its use. Preliminary results from France of the phase 2 CORIMUNO-TOCI trial showed a reduction in mortality and requirement for mechanical ventilation in patients who received tocilizumab. A large, multinational, randomised, placebo-controlled phase 3 trial evaluating tocilizumab for treatment of patients with severe COVID-19-related pneumonia is underway (NCT04320615).

We did a retrospective, observational cohort study to investigate mortality in patients with severe COVID-19 needing support in the intensive care unit and receiving tocilizumab. Use of tocilizumab was associated with improvement in median overall survival from time of admission compared with patients who did not receive tocilizumab. In a post-hoc analysis, patients with baseline C-reactive protein levels of 15 mg/dL or higher were most likely to show an associated improved survival with tocilizumab, whereas no association was seen in patients with lower levels of C-reactive protein.

Our findings support the preliminary findings of the CORIMUNO-TOCI trial and show an association between C-reactive protein levels, tocilizumab, and survival, potentially suggesting that tocilizumab might exert its best effects among patients with COVID-19 progressing to an inflammatory state. Current evidence supports continued evaluation of tocilizumab in a randomised trial for patients with severe COVID-19.

Data Capture see https://www. project-redcap.org/ institutional formulary or used for COVID19 treat ment and, if used in another context, data were not gathered.

Presenting clinical information was abstracted from thorough review of unstructured notes and structured data. Hospital readmissions were counted as the same admission, with baseline data used from the initial hos pitalisa tion. If multiple positive or indeter minate results were found in a patient's record for SARSCoV2, the first initial positive test was used as the date of diagnosis. Exposure to tocilizumab was defined as receipt of the drug as found in the electronic health record. If no evidence of tocilizumab administration was found, we recorded that the patient had not received tocilizumab. Offlabel use of tocilizumab within the Hackensack Meridian Health network was guided by the Pharmacy and Therapeutics Committee, with recommendations to consider treatment in patients with evidence of acute respiratory distress syndrome on mechanical ven tila tion, or worsening oxygenation with high oxygen requirements (80-100%) on highflow nasal cannula or 15 L non rebreather mask. Symptoms had to be present for 7 days and documentation of informed consent was needed. However, the final decision to use tocilizumab was at the discretion of the treating clinician. The Pharmacy and Therapeutics Committee suggested one intravenous dose of 400 mg tocilizumab. A randomised placebocontrolled trial of tocilizumab was available at one academic centre within the Hackensack Meridian Health network (Hackensack University Medical Center, Hackensack, NJ, USA). The rationale for selection of the 400 mg intravenous dose of tocilizumab was based on published work from China, 6 albeit preclinical and not peer reviewed at that time, which showed improved oxygenation using a dose of tociliz umab around 4 mg/kg. A second dose of tocilizumab was permitted at the point of worsen ing oxygenation (eg, increased oxygen [O 2 ] require ment, high flow O 2 ) and before mechan ical ven tilation, with adminis tration at the treating clinician's discretion.

The primary outcome measure was hospitalrelated mortality, which was identified on chart review as a note from the treating clinician announcing time of death during hospitalisation or if the electronic health record labelled the patient as deceased after hospital discharge. Cause of death was identified using the electronic health record by identifying the most immediate cause or causes recorded. Respiratory cause of death included any hypoxic condition related to COVID19. Cardiac cause of death included cardiac arrest, myocardial infarction, or arrhyth mia. Infectious cause of death inclu ded bacterial sepsis or secondary infections not includ ing COVID19. Other cause of death included multiorgan failure in addition to alternative causes.

Preplanned secondary outcome measures were changes in inflammatory markers (Creactive protein, IL6, ferritin, and Ddimer), change in oxygena tion require ments, infections (defined as bacteraemia or pneumonia with positive sputum culture), and use of vasopressors.

Demographic and clinical variables of tocilizumab treat ment were summarised using median (IQR) for con tinuous variables and by frequency (%) for categorical variables. Differences in the median and distribution of demographic and clinical variables between patients who received tocilizumab and those who did not were com pared using Mood's median test for continuous variables and Fisher's exact test or Pearson's χ² test for categorical variables.

To analyse overall survival we plotted KaplanMeier curves and did the logrank test to compare outcomes of patients who received tocilizumab and did not receive this drug. The index date used for overall survival was the date of hospital admission. Adjusted Cox proportional hazards regression models were fitted to estimate the associ ation between tocilizumab use and overall survival, using clini cally likely confounders including age, gender, diabetes, chronic obstructive pulmonary disease (COPD) or asthma, hypertension, cancer, renal failure, obesity, oxygena tion less than 94%, quick Sequential Organ Failure Assessment (qSOFA) score, use of steroids, Creactive protein 15 mg/dL or higher, and intubation or mech anical ven tilator support. To account for immortal time bias in the group receiving tocilizumab, time to tocilizumab treatment after admis sion was also adjusted. When the goodnessoffit model was not satisfied, we further reduced all these con founders using stepwise variable selection. 15 Hazard ratios (HRs) and 95% CIs were summarised.

To reduce confounding effects secondary to imbalan ces in receiving tocilizumab treatment inherent to a retro spective cohort study, we did propensity score matching.

Propensity score-matched patients (n=630)* First, we calculated a propensity score of receiv ing tocilizumab treatment for each patient using multi variable logistic regression with the confounders age, gender, diabetes, COPD or asthma, hypertension, cancer, renal failure, obesity, oxygenation less than 94%, qSOFA score, use of steroids, Creactive protein 15 mg/dL or higher, and intubation or mechanical ventilator support. Goodness of fit of the multivariable logistic model was examined using the HosmerLemeshow test. We then used nonparametric nearestneighbour matching of propensity scores to generate a matched cohort in a 1:2 ratio to pair a patient with tocilizumab treatment to two patients who did not receive tocilizumab, using the MatchIt package in R. 16, 17 In the propensity scorematched population, we repeated the adjusted Cox modelling done in the unmatched population. Moreover, we compared the medi ans of each biomarker between patients who received tocilizumab and those who did not receive tocilizumab at days 1, 3, 7, and 14 using Mood's median test. Subgroup analyses were done of patients who received mechanical ventilator support and who were older than 65 years and aged 65 years or younger, using the same datasets. Missing data for categorical con founders with more than 10% missing data were coded as a missing data category and were included in all analyses. Completely observed dataonly analyses were followed. We assessed the sensitivity of HR estimates to varying sets of confounders, including the propensity score as a covariate in the unmatched model and includ ing confounders chosen by stepwise selection.

We judged statistical significance when the p value was less than 0·05. For subgroup analyses, Bonferroni correction (type I error of 0·01) was applied and 99% CIs were also reported (appendix pp 9-13). For secondary outcome analyses, no multiplicity correction was applied. All statistical analyses were done using R version 3.4.

Propensity score-matched patients (n=630)* Data are n (%) or median (IQR). COPD=chronic obstructive pulmonary disorder. qSOFA=quick Sequential Organ Failure Assessment. FiO 2 =fractional concentration of oxygen in inspired air. PEEP=positive end-expiratory pressure. PaO 2 =partial pressure of arterial oxygen. *13 variables were used for propensity score matching: age, gender, diabetes, COPD or asthma, hypertension, cancer, renal failure, obesity, oxygenation <94%, qSOFA score, use of steroids, C-reactive protein >15 mg/dL, and intubation or mechanical ventilator support. Hosmer and Lemeshow goodness-of-fit test, p=0·51. †Number of comorbidities from diabetes, COPD or asthma, hypertension, coronary disease, cerebrovascular disease, heart failure, arrhythmia, cancer renal failure, rheumatological disorder, and body-mass index ≥30 kg/m². The prospective observational database is registered on ClinicalTrials.gov, NCT04347993.

This study received no external funding. AI, SLG, NB, JA, MM, BAS, and SW had access to raw data. The corres ponding author had full access to all data in the study and had final responsibility for the decision to submit for publication.

Between March 1 and April 22, 2020, 3438 patients were flagged in the electronic health record with a diagnosis of COVID19. To reduce sampling bias, data were abstracted for 3323 (97%) patients. The remaining 115 (3%) patients were not abstracted because of limited human resources during the peak of the COVID19 pandemic in New Jersey. 764 (23%) patients needed support in the ICU (figure 1). No patients were known to have been receiving tocili zumab for chronic rheumatological conditions. The distribution of baseline characteristics according to tocilizumab exposure is shown in table 1. In the unmatched population, 210 patients who received at least one infusion of tocilizumab were significantly younger than 554 patients who did not receive tocilizumab (median age 62 years [IQR 53-71] vs 68 years [58-78]; p=0·0003). 220 (40%) of 554 patients who did not receive tocilizumab had three or more comorbidities, compared with 62 (30%) of 210 patients who received tocilizumab. A propensity scorematched population was constructed of 630 patients, 210 who received at least one infusion of tocilizumab and 420 who did not receive tocilizumab. The propensity scorematched population was well balanced except with respect to nursing home residents ( Of 210 patients in the propensity scorematched population who received tocilizumab, 206 (98%) received 400 mg flat dosing, two (1%) received 8 mg/kg, and two (1%) received other doses; 185 (88%) received one infu sion and 25 (12%) received a second infusion. Tocilizumab was administered a median of 9 days (IQR 6-12) after the start of patientreported symptoms, a median of 3 days (1-7) from the date of hospitalisation, and a median of 0 days (0-2) from the date of ICU support.

Patients were followed up until May 22, 2020 . Median followup of patients in the propensity scorematched population was 22 days (IQR 11-53). 358 (57%) of 630 patients died, 102 (49%) of 210 who received tocilizumab and 256 (61%) of 420 who did not receive tocilizumab. Causes of death among the 102 patients who received tocilizumab were respiratory (n=57), cardiac (n=21), infectious (n=3), and other causes (n=10); for 11 patients the cause of death was not apparent. Causes of death among the 256 patients who did not receive tocilizumab were respiratory (n=127), cardiac (n=57), infectious (n=15), and other causes (n=20); for 37 patients the cause of death was not apparent. Median overall survival from time of admission for patients receiving tocilizumab was not reached (95% CI 23 days-not reached) and for those who did not receive tocilizumab it was 19 days (16-26; HR 0·71, 95% CI 0·56-0·89; p=0·0027; figure 2). In the unmatched cohort, there was a similar finding in median overall survival in patients receiving tocilizumab (not reached, 95% CI 23 days-not reached) versus those not receiving tocilizumab (17 days, 15-20; p=0·0002; overall survival data were not available for 12 patients in the unmatched population; appendix p 2). After adjusting for time from initial tocilizumab treat ment, the findings were also similar (appendix p 3). In the primary multivariable Cox regres sion analysis with propensity score matching, exposure to tocilizumab was associated with lower hospitalrelated mortality (HR 0·64, 95% CI 0·47-0·87; p=0·0040; table 2). Sensitivity analyses showed similar associations (appen dix pp 6-8).

In the subgroup of 587 patients in the propensity score matched population who required mechanical ventilation, patients who received tocilizumab had reduced hospital related mortality (HR 0·63, 95% CI 0·46-0·85; p=0·0029; table 3; appendix p 9). Hospitalrelated mortality was slightly reduced in patients younger than 65 years (HR 0·64, 95% CI 0·44-0·94; p=0·023), but not in those aged 65 years or older (0·71, 0·48-1·04; p=0·079; table 3; appendix pp [10] [11] .

Dose intensity of steroid treatment was not obtained in the study. However, use of steroids was not associated with decreased hospitalrelated mortality in the overall propensity scorematched population (HR 0·94, 95% CI 0·73-1·21; p=0·63; table 2), or among any of the patient subpopulations (table 3; appendix p 10). Sensi tivity Inspired by findings of a nonpeerreviewed tocilizumab study, 18 a posthoc analysis was done of Creactive protein (≥15 mg/dL or <15 mg/dL). Creactive protein data were available for 558 (89%) of 630 patients in the propensity scorematched population. A reduction of Creactive protein with tocilizumab exposure was noted at 3, 7, and 14 days after initiation of treatment in the propen sity scorematched population (appendix p 4). Among 286 patients with Creactive protein levels of 15 mg/dL or higher, tocilizumab exposure was associated with decreased hospitalrelated mortality (HR 0·48, 95% CI 0·30-0·77; p=0·0025; table 3; appendix p 12). However, among 272 patients with baseline Creactive protein levels less than 15 mg/dL, little protective association was seen between tocilizumab and hospitalrelated mor tality (HR 0·92, 95% CI 0·57-1·48; p=0·73; table 3; appendix p 13).

A transient increase in IL6 concentration was noted at days 3 and 7 among patients who received toci lizumab. No associations were identified for amounts of Ddimer, ferritin, or lactate dehydrogenase (appendix p 4).

In the propensity scorematched population, 18 (9%) of 210 patients who received tocilizumab and 33 (8%) of 420 who did not receive tocilizumab developed bac ter aemia during ICU support. Positive sputum cultures were identified in 25 (12%) and 30 (7%) patients, respectively. Overall secondary bacterial infections were recorded in 36 (17%) of 210 patients who received tocilizumab and 54 (13%) of 420 patients who did not receive tocilizumab. Cardiac vasopressor support was used equally, regardless of receipt of tocilizumab (88 [42%] of 210 and 176 [42%] of 420, respectively). No association was reported in reduction of fractional concentration of O 2 in inspired air requirements and receipt of tocilizumab at day 1 after treatment, and little association was seen in changes of positive endexpiratory pressure or partial pressure of O 2 in arterial blood values (appendix p 5).

In this multicentre observational study of patients with COVID19 requiring ICU support, receipt of tocilizumab was associated with a reduction in hospitalrelated mortality. Moreover, patients who required mech anical ventilator support and those younger than 65 years showed a favourable reduction in hospitalrelated mortality with tocilizumab. Furthermore, in a posthoc analysis, a reduction in mortality was seen in patients who received tocilizumab who had concentrations of Creactive protein of 15 mg/dL or higher. Therefore, tocilizumab seems to be among the first potentially successful treatments for patients with severe COVID19 requiring ICU support, pending confirmation by an ongoing randomised trial (NCT04320615).

The cytokine storm noted in patients with latestage SARSCoV2 infection is typically the primary cause of death. 19 The aberrant host immune response includes increased concentrations in plasma of pro inflammatory cytokines, including IL6, which trigger further organ tissue damage. 6, 7 In view of similarities between the cytokine storm syndrome of COVID19 and the cytokine release syndrome associated with CAR Tcell therapy, a rationale for IL6directed blockade is easily drawn. 20, 21 We identified an association between concentrations of Creactive protein, tocilizumab, and overall survival, poten tially suggesting that tocilizumab could exert its effects among patients whose COVID19 illness is progressing to an inflammatory state. Patients who received tocilizumab showed a reduction in Creactive protein levels at 3, 7, and 14 days after administration of tocilizumab compared with patients who did not receive tocilizumab. The potential beneficial association of tocilizumab was seen only in patients with Creactive protein of 15 mg/dL or higher at baseline. Creactive protein and IL6 have been reported to be the most sensitive and reliable factors in dis tinguishing disease severity and prognosis. 22 Missing vs no 0·43 (0·20-0·89) 0·024 0·46 (0·21-1·00) 0·051

qSOFA score

Missing regulate Creactive gene expression in transgenic animals and serves as one of the necessary drivers of increased Creactive protein. 23, 24 Several reports have described a correlation between concentrations of ferritin, Ddimer, and lactate dehydro g en ase with severity of COVID19. 25, 26 IL1 blockade has also been reported to reduce COVID19 mortality, and a study from the Groupe Hospitalier Paris SaintJoseph showed a significant decrease in risk for ICU admission, mechanical ventila tion, or death with use of the IL1 receptor antagonist anakinra. 27 Recognition of inflam ma tory markers or other cytokinedirected treatment could have important implications for treatment selection.

Tocilizumab was administered early in the ICU course, typically on the day of admission for ICU support, and a median of 9 days since the start of selfreported symptoms. Whether earlier administration of tocilizumab at the time of hos pital admission might improve outcomes and decrease overall resource use requires study.

In the RECOVERY trial, 28 steroid use was associated with improvement in survival among patients with severe SARSCoV2 infection. Among all patients in our propen sity scorematched population, steroid use was not associ ated with a reduction in hospitalrelated mortality. Baseline mortality for intubated patients in the ICU in our study was significantly higher than in the RECOVERY study (268 [64%] of 420 who did not receive tocilizumab in our study vs 164 [41%] of 400 without dexamethasone in RECOVERY), suggesting possible differences in patient populations.

We did not note an associated increase in secondary bacteraemia with tocilizumab treatment. The frequency of secondary bacterial infec tions was 17% in patients who received tocilizumab and 13% in those who did not. Our infec tion rates seem low for a cohort of critically ill patients. However, we administered a lower dose of tocilizumab (a 400 mg flat dose as a onetime infusion in most patients) by contrast with 8 mg/kg dosing used in the ongoing, international, randomised placebocontrolled trial. An increase in use of hydroxychloroquine was noted in patients who received tocilizumab compared with those who did not receive tocilizumab, which we do not believe had a relevant effect on our findings because most observational studies have not reported a benefit for hydroxychloroquine among hospitalised patients, despite potentially some activity in early SARSCoV2 infection. 29 Our observational study has limitations. First, obser vational studies cannot draw causal inferences because of inherent known and unknown confounders. We attempted to adjust for known confounders using our propensity scorematched approach. We also did several sensitivity analyses, including models with the propensity score as a covariate, models with stepwise selection of covariates based on the Akaike information criterion, and models selected by Lasso. Second, misclassifications of data are possible because we manually abstracted struc tured and unstructured data from electronic health records.

Missing data were addressed by creating a category for missing in the multivariable Cox regression analysis for the key (categorical) confounders with more than 10% missing data. We also did a sensitivity analysis when we excluded patients with missing information (appendix pp 7-8). Our study focused on patients in the US state of New Jersey, limiting applicability to other geographical regions, although this US state's population is diverse and the Hackensack Meridian Health network included 13 hospitals with differing treatment protocols. Further, we acknowledge the possibility of indication bias, because it was not always clear why some patients were given tocilizumab or not. Patients considered to have severe SARSCoV2 infection by institutional guidelines were permitted to receive tocilizumab at the discretion of their treating clinician. Our cohort had a high prevalence of comorbidities and were older, in the setting of an over burdened healthcare system, and represented the peak incidence of SARSCoV2 infec tion, which probably skewed our mortality rates higher than those reported in other cohorts. Finally, we acknow ledge the possibility of sampling bias since we obtained data from a convenience sample in attempts to do a rapid investigation during a pandemic.

Tocilizumab exposure among patients with severe SARSCoV2 infection requiring ICU support was associ ated with a reduction in hospitalrelated mortality. These data could help to inform current clinical practice while randomised controlled trials are underway.

Cytokine release syndrome in severe COVID19: interleukin6 receptor antagonist tocilizumab may be the key to reduce mortality

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FDA approval summary: tocilizumab for treatment of chimeric antigen receptor T cellinduced severe or lifethreatening cytokine release syndrome

Pathological findings of COVID19 associated with acute respiratory distress syndrome

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Offlabel use of tocilizumab for the treatment of SARSCoV2 pneumonia in

Tocilizumab for the treatment of severe COVID19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: a single center study of 100 patients in

Tocilizumab improves significantly clinical outcomes of patients with moderate or severe COVID19 pneumonia

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Use of electronic health record data in clinical investigations: guidance for industry

Framework for FDA's realworld evidence program

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Matching methods for causal inference: a review and a look forward

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Creactive protein: eighty years from discovery to emergence as a major risk marker for cardiovascular disease

The role of biomarkers in diagnosis of COVID19: a systematic review

Ddimer levels on admission to predict inhospital mortality in patients with Covid19

Interleukin1 blockade with highdose anakinra in patients with COVID19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study

Hydroxychloroquine or chloroquine for treatment or prophylaxis of COVID19: a living systematic review

SLG, AI, and NB had the idea for and designed the study. JA, SW, AHG, ISS, and LSK contributed to study design. NB, AI, RCG, and SLG did the literature search. NB, AI, JA, and SW prepared the figures. All authors contributed to data collection and data analysis. NB, AI, JA, SW, and SLG contributed to data interpretation. NB, AI, JA, RCG, SW, DSS, and SLG contributed to writing of the report.

RCG is the primary investigator for the Roche GenentechCOVACTA study at Hackensack University Medical Center. SM reports consultancy for Regional Cancer Care Associates and Hackensack Meridian Health, outside of the submitted work. EH reports consultancy from Regional Cancer Care Associates and Hackensack Meridian Health, outside of the submitted work. DSS reports equity in COTA. AHG is a primary investigator for GenentechHoffman La Roche, during the conduct of the study; reports personal fees and research funding as study investigator from Acerta, AstraZeneca, Celgene, Kite Pharma, Elsevier's PracticeUpdate Oncology, Gilead, Medscape, MJH Associates, OncLive Peer Exchange, Physicians Education Resource, and Xcenda, outside of the submitted work; and reports research funding as study investigator from Constellation, Infinity, Infinity Verastem, Janssen, Karyopharm, and Pharmacyclics, outside of the submitted work. ALP reports equity in COTA. LSK is a coinvestigator for the Roche GenentechCOVACTA study at Hackensack University Medical Center. SLG reports equity in COTA. All other authors declare no competing interests.

This study received no external funding. We thank the nurses, data managers, and clinicians who-after caring for their patients-assisted in abstraction of clinical data.