Caspase-1 activation, IL-1/IL-6 signature and IFNγ-induced chemokines in lungs of COVID-19 patients.

Summary

Using post-mortem lungs, BALF, and serum, the authors show activated caspase-1 and a dominant IL-1β/IL-6 signature in the lungs of steroid-treated C-ARDS, with IFNγ-induced chemokines also elevated. IL-1β was compartmentalized in BALF, while circulating IL-6 and IL-1Ra tracked with severity; TNFα/TNFR1/CXCL8 were higher in NC-ARDS.

Key Findings

• Activated caspase-1 and diffuse alveolar damage co-occurred in post-mortem C-ARDS lungs with vascular lesions.
• BALF from steroid-treated C-ARDS showed high IL-1β, IL-1Ra, IL-6, and IFNγ/CXCL10; IL-1β was concentrated in BALF.
• Circulating IL-6 and IL-1Ra correlated with severity, while TNFα, TNFR1, and CXCL8 were higher in NC-ARDS than C-ARDS.

Clinical Implications

Supports evaluating IL-1/caspase-1 and IL-6 axis inhibitors and underscores the value of lung-compartment sampling (e.g., BALF) since IL-1β is compartmentalized. Steroid-only approaches may be insufficient to blunt inflammasome-driven damage.

Limitations

• BALF cohort size was modest (19 vs 19) and cross-sectional
• Steroid treatment may confound cytokine levels; no interventional testing

Future Directions

Prospective longitudinal sampling to map compartmental dynamics and trials testing IL-1/caspase-1 or IL-6 blockade in ARDS (COVID and non-COVID), with stratification by lung-compartment biomarkers.