Pyroptosis endotypes and nonlinear biomarker-mortality relationships in older adults with community-acquired pneumonia: the amplifying role of malnutrition.

BACKGROUND

Despite their disproportionately high mortality from community-acquired pneumonia (CAP), older adults remain understudied regarding inflammasome-mediated cell death pathways. We sought to determine whether distinct pyroptosis activation patterns exist in this population and how nutritional status modifies their prognostic impact.

METHODS

This retrospective cohort study enrolled 282 patients aged ≥75 years hospitalized for CAP. We quantified circulating pyroptosis effectors (gasdermin D [GSDMD], NLRP3, caspase-1) and assessed nutritional status using the Mini Nutritional Assessment-Short Form (MNA-SF). K-means clustering identified biological endotypes; generalized additive models (GAMs) characterized nonlinear biomarker-mortality relationships. The primary endpoint was 28-day all-cause mortality.

RESULTS

Three pyroptosis endotypes emerged with markedly divergent outcomes: hyper-pyroptotic (n=73; mortality 57.5%), intermediate-pyroptotic (n=128; mortality 10.2%), and hypo-pyroptotic (n=81; mortality 1.2%). The hyper-pyroptotic endotype was characterized by severe malnutrition (48.2% with MNA-SF ≤7) and elevated cytokines (median IL-6: 98.4 pg/mL). GAM analysis revealed threshold-dependent, nonlinear relationships-mortality risk escalated sharply when GSDMD exceeded 3.5 ng/mL but showed attenuation at extreme values. Notably, two-dimensional analyses demonstrated supra-additive risk in patients with concurrent nutritional compromise and pyroptosis activation. An integrated prognostic model achieved AUC 0.898 (95% CI: 0.847-0.943), significantly outperforming the Pneumonia Severity Index alone (AUC 0.793; P<0.001), with superior net benefit across clinically relevant decision thresholds (10-30%).

CONCLUSION

Geriatric CAP comprises biologically distinct pyroptosis endotypes. Malnutrition was associated with a stronger relationship between pyroptosis markers and short-term mortality, consistent with effect modification. These findings support integrating nutritional assessment with pyroptosis biomarker profiling for risk stratification and generate hypotheses for prospective mechanistic and interventional studies.