Author: Denise Baez
Use of tocilizumab for the management of coronavirus disease 2019 (COVID‐19)‐related cytokine release syndrome (CRS) is not without risk, with late-onset infections and drug-related toxicities occurring in many patients, according to a study published in the Journal of Medical Virology.
Among 74 patients with COVID-19 who required mechanical ventilation and were treated with tocilizumab, 17 (23%) developed infections >48 hours after admission compared with 6 of 74 (8%) similar patients who did not receive tocilizumab (P = .013). Most infections were bacterial, with pneumonia being the most common manifestation.
Among patients receiving tocilizumab, liver function test elevations were observed in 51%, neutropenia in 1.4%, and hypertension in 8%.
There were no cases of gastrointestinal perforation or diverticulitis and none of the patients experienced an allergic or infusion-related reaction. The total number of patients that received tocilizumab who developed either post-dose infection or at least 1 toxicity was 45 (61%).
“Late-onset infections were significantly more common among those receiving tocilizumab,” wrote Natasha N. Pettit, MD, University of Chicago Medicine, Chicago, Illinois, and colleagues. “Combining infections and tocilizumab ‐related toxicities, 61% of patients had a possible post‐ tocilizumab complication. While awaiting clinical trial results to establish the efficacy of tocilizumab for COVID‐19 related CRS, the potential for infections and tocilizumab related toxicities should be carefully weighed when considering use.”
The study included all adult inpatients with COVID‐19 who were admitted to an intensive care unit and required mechanical ventilation between March 1 and April 25, 2020.
“During the study period, the institutional guideline recommended administration of intravenous tocilizumab 400 mg intravenous once (with the option of re-dosing based on clinical response within 12-24 hours) if patients presented with severe and rapidly progressing hypoxia in addition to elevated inflammatory markers,” the authors explained. “Tocilizumab use was avoided in patients with confirmed or suspected bacterial infections, neutropenia, thrombocytopenia, or if liver function tests were >10x upper limit of normal. Our protocol for the management of COVID-19 did not recommend corticosteroids or other immune-modulating therapies during the included analysis period.”
The overall infection rate, regardless of onset of infection, was similar between the tocilizumab and control groups (16.2% vs 17.5%, respectively). However, the late-onset infection rate was higher in the tocilizumab group (23% vs 8%). In addition to bacterial infections, culture confirmed invasive fungal infections were present in 3 patients in the tocilizumab group.
The mortality rate among patients treated with tocilizumab was 39% compared with 23% among patients who did not receive the drug (P = .03).
“While the reason for this is unclear, it should be considered that our protocol required both rapidly progressing hypoxemia and presence of elevated inflammatory markers, and among the patients that required mechanical ventilation in the tocilizumab group, the majority received the drug after intubation,” the authors explained. “While the differences were not statistically significant, a larger proportion of patients in the tocilizumab group were male (42% vs 33%), and were immune-compromised at baseline (12% vs 4%). This could have contributed to higher mortality as well.”
The authors also noted that more patients in the tocilizumab group received hydroxychloroquine, which also could have contributed to the observed rates of hepatotoxicity, as hydroxychloroquine can be associated with hepatotoxicity, although rare.
“Until results from randomised and controlled prospective clinical trials evaluating tocilizumab for this indication are available, there remain limited data to definitively establish efficacy or safety in this setting,” the authors concluded. “With the potential for harm, and unclear evidence to support efficacy, clinicians should consider limiting off-label use of tocilizumab for COVID-19 CRS and only using in the setting of clinical trials.”