Immunomodulation for ARDS: Insights From Proteomics in COVID-19

Background: The success of targeted immunomodulation in COVID-19 underscores its potential for ARDS resulting from other causes. However, it is important to understand both its targeted and broader impacts on the inflammatory host response. To guide future ARDS studies, we explored this in patients with COVID-19 using targeted proteomics. Research Question: How do different immune modulators affect the immune profiles of patients who are critically ill with COVID-19-related ARDS? Study Design and Methods: In this multicenter cohort study, we used 2 Dutch biorepositories to compare patients with COVID-19 with acute respiratory failure treated with: no immunotherapy (n = 18), corticosteroids (n = 21), anakinra plus corticosteroids (n = 9), or tocilizumab plus corticosteroids (n = 22). Plasma proteins related to inflammation and cardiovascular injury were measured using proximity extension assays on ICU days 0 through 1, ICU days 2 through 4 (T3), and ICU days 6 through 8 (T7) after treatment initiation. Results: We observed lower expression of inflammatory biomarkers immediately after tocilizumab administration and from T3 onward after anakinra administration. After treatment with corticosteroids alone, fewer inflammatory biomarkers were suppressed, and only at T3. Multivariate analyses at T3 identified tumor necrosis factor-related apoptosis-inducing ligand, IL-1 receptor-like 2, and tumor necrosis factor β as markedly increased and proto-oncogene tyrosine-protein kinase (SRC) and serine/threonine kinase 4 (STK4) as decreased, solely after tocilizumab. At T7, lower concentrations of 2,4-dienoyl-CoA reductase 1, signaling lymphocytic activation molecule family member 7, SRC, and STK4 were observed in patients treated with tocilizumab or anakinra, whereas interferon γ, chemokine (C-X-C motif) ligand 9, and chemokine (C-C motif) ligand 19 were decreased only after anakinra treatment. Interpretation: In this exploratory study, adding tocilizumab or anakinra to corticosteroids triggered a much broader immunoregulatory response than can be explained by their receptor-specific actions. The response after tocilizumab occurred more rapidly than that after anakinra, offering a potential advantage in the time-sensitive ICU setting. Additionally, tocilizumab preserved the interferon pathway, crucial for antiviral defense, whereas anakinra suppressed it.