Clinical Outcomes in COVID‐19 Patients Treated with Tocilizumab: An Individual Patient Data Systematic Review

Antwi‐Amoabeng, Daniel; Kanji, Zahara; Ford, Brent; Beutler, Bryce D.; Riddle, Mark S.; Siddiqui, Faisal

BACKGROUND: Current evidence suggests an important role of interleukin‐6 (IL‐6) pathway in SARS‐CoV‐2‐related cytokine release storm in severely ill COVID‐19 patients. Inhibition of the IL‐6 pathway with tocilizumab has been employed successfully in some of these patients but the data is mostly consistent of case reports and series. METHODS: We performed a systematic search of PubMed, Embase, and Medline from 22(nd) April 2020 and again on 27(th) April 2020 using the following search terms alone or in combination: “COVID‐19”, “coronavirus”, “SARS‐CoV‐2”, “COVID”, “anti‐interleukin 6 receptor antibodies”, “anti‐IL‐6”, “tocilizumab”, “sarilumab”, “siltuximab”. We included studies which reported individual patient data. We extracted and analyzed individual level data on baseline characteristics, laboratory findings, and clinical outcomes. Primary endpoint was in‐hospital mortality. Secondary endpoints included in‐hospital complications, recovery rates, effect of patient characteristics on the primary outcome and changes in levels of inflammatory markers. RESULTS: 352 records were identified through the systematic search of which 10 studies met the inclusion criteria. A single study currently under review was also added. Eleven observational studies encompassing 29 patients were included in the present review. There were more males (24 [82.8%]) and hypertension was the most common comorbidity (16 [48.3 %]). Over an average of 5.4 hospital days, the primary endpoint occurred in 6 (20.7%) patients. Among surviving patients, about 10% had worsened disease and 17% recovered. The most common complication was acute respiratory distress syndrome (8[27.6%]). IL‐6 level was significantly higher after the initiation of tocilizumab with median (IQR) of 376.6 (148‐900.6) pg/mL compared to the baseline of 71.1 (31.9‐122.8) pg/mL (p=0.002). Mean (SD) levels of c‐reactive protein (CRP) were significantly decreased following treatment 24.6 (26.9) mg/L compared to baseline 140.4 (77) mg/L (P< 0.0001). Baseline demographics were not significantly different amongst survivors and non‐survivors by Fisher's exact test. CONCLUSION: In COVID‐19 patients treated with tocilizumab, IL‐6 levels are significantly elevated which are supportive of cytokine storm. Following initiation of tocilizumab, there is elevation in the IL‐6 levels and CRP levels dramatically decrease suggesting an improvement in this hyper‐inflammatory state. Ongoing randomized control trials will allow for further evaluation of this promising therapy. IMPORTANCE: Recent data indicate that severe COVID 19 causes cytokine release storm and is associated with worse clinical outcomes and IL‐6 plays an important role. It is suggestive that anti‐IL6 results in the improvement of this hyperinflammatory state. However, to our knowledge, there is no individual patient data systematic review performed to summarize baseline characteristics and clinical outcomes of COVID 19 patients who received tocilizumab. This article is protected by copyright. All rights reserved.