Efficacy and Safety of Sequential Combined Immunomodulatory Systemic Therapies Used in the Management of Refractory Cytokine Release Syndrome in Critically Ill Patients with COVID-19.

Abstract

Introduction/objective: Severe Coronavirus Disease 2019 (COVID-19) is characterized by systemic hyperinflammation and cytokine storm, a series of clinical conditions caused by excessive immune reactions. Although numerous studies have been conducted on anti-inflammatory treatments for severe COVID-19, no specific recommendations have been made regarding drugs to use in patients with Refractory Cytokine Release Syndrome (CRS) after the use of first-line anticytokine drugs. The objective of this report was to evaluate the efficacy of sequential immunomodulatory therapies in the management of refractory CRS in COVID-19 patients.

Methods: From March 2020 to March 2023, 1,025 patients with COVID-19 were admitted to the Infectious and Tropical Diseases ward at the Annunziata Cosenza Hub Hospital in Cosenza, Italy. To determine how many patients with refractory COVID-19-associated CRS were treated with combinedsequential therapy involving tocilizumab, a recombinant humanized anti-Interleukin-6 (IL-6) receptor monoclonal antibody, and baricitinib, a Janus kinase inhibitor, or anakinra, a recombinant human interleukin- 1 receptor antagonist, the electronic medical records of all hospitalized patients with COVID-19 were reviewed. The primary outcome was the incidence of CRS by day 29. Secondary outcomes included in-hospital mortality and 30-day mortality, to assess hospital performance and patient safety. Electronic databases such as MEDLINE, EMBASE, and Cochrane Central were searched through June 30, 2026, for case-series and studies evaluating the efficacy of sequential combined immunomodulatory systemic therapies in the management of refractory CRS in critically ill patients with COVID-19.

Results: From January 2021 to December 2023, a total of 25 patients received sequential combined immunomodulatory systemic therapies, including tocilizumab and baricitinib or anakinra, in the management of COVID-19-related CRS. After 72 hours from the introduction of the new anti-cytokine therapy, a significant improvement of respiratory parameters, clinical state, inflammatory markers, and blood counts was observed. All patients survived, and those 5 previously mechanically ventilated patients were extubated. Non-infectious or infectious pulmonary or systemic complications were observed in all patients who underwent sequential combined immunomodulatory systemic therapies.

Discussion: The study's findings suggest that tocilizumab used in sequential combination with baricitinib or anakinra, in conjunction with standard of care treatments, was associated with improved outcomes in critically ill patients with COVID-19 disease and early discharge from the hospital.

Conclusion: There is clear rationale for using combined immunomodulatory systemic therapies in critically ill patients who develop refractory CRS. The results of the experience, supported by a review of the current literature, suggest the need for larger-scale studies on sequential and combined systemic immunomodulatory therapies to manage refractory CRS in critically ill patients with COVID-19.