Ciclesonide

Cytokine storm, a life-threatening hyperinflammatory response seen in severe infections like COVID-19, autoimmune diseases, and certain therapies, remains difficult to treat due to limited approved therapeutics. To support preclinical drug development and repurposing in line with 3R principles, we present a novel in vitro model for screening of cytokine-modulating compounds. Herein, we demonstrate that lymphoblastoid cell lines (LCL cells), derived from healthy donors, provide a translationally relevant and phenotypically diverse platform for cytokine profiling and drug screening. Upon stimulation with PMA/ionomycin, LCL cells exhibited a robust secretion of pro-inflammatory (IL-6, IL-8, TNF-α) and anti-inflammatory (IL-10) cytokines, closely mirroring the cytokine profile of activated whole blood. Compared to established immune cell lines THP-1 and Jurkat, LCL cells showed broader cytokine responses and retained interindividual variability. We validated the model for cytokine-modulating drug screening using two well-established immunosuppressants, dexamethasone and cyclosporin A. Dexamethasone reduced IL-6 by 21 %, IL-8 by 71 %, IL-12 by 68 %, TNF-α by 83 %, and increased IL-10 by 51 %. Cyclosporin A lowered IL-6 by 34 %, IL-8 by 69 %, IL-10 by 48 %, and TNF-α by 41 %. Subsequently, we tested a panel of clinically investigated COVID-19 therapies, selected based on a comprehensive literature review. Ciclesonide and acalabrutinib showed strong suppression of all measured cytokines by more than 60 %, while baricitinib, which has become a standard of care for severe COVID-19, reduced IL-6 by 70 %, IL-12 by 68 %, and TNF-α by 47 %, but had minimal effect on IL-8. Notably, LCL cells retained interindividual variability, as demonstrated by diverse cytokine as well as divergent NF-κB nuclear translocation responses, supporting the model's capacity to reveal real-world patient heterogeneity. Collectively, our findings establish LCL cells as a reproducible, immunologically responsive, and patient-representative platform for cytokine storm research and high-content drug testing, providing both mechanistic insight and translational relevance.

Inhaled corticosteroids have been proposed as treatment for acute COVID‐19 infection in the community. We sought to determine the efficacy and safety of inhaled ciclesonide 320 mcg daily for 14 days compared to placebo in reducing the time to first recovery from all symptoms within 28 days of randomisation.

We conducted a two‐arm, double blind, placebo‐controlled, community‐based randomised trial. Participants received inhaled ciclesonide 320 mcg daily or matching placebo for 14 days. The primary outcome was time to recovery of symptoms to day 28. An updated systematic review of all controlled trials of inhaled corticosteroids for acute COVID‐19 was then undertaken.

There were 189 people randomised and 185 completed treatment; 96% were COVID‐19 vaccinated. No difference was seen in the time to first recovery using a proportional hazards analysis, recovery rate ratio 1.04 (95% CI; 0.77, 1.40). The median time to recovery with ciclesonide was 7 days (95% CI 6–9), compared with placebo of 7 days (95% CI 6–9), p  = 0.84. There were no significant differences in secondary outcomes, including time to sustained recovery and respiratory symptoms. The treatment was safe and well tolerated.

In a highly vaccinated (> 90%) population exposed to Omicron variants of SARS‐CoV‐2, the addition of inhaled ciclesonide had no effect on accelerating recovery from acute symptoms. These trial results and updated combined evidence of placebo‐controlled trials do not support the use of inhaled corticosteroids for the treatment of COVID‐19.

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