Cellular and immune response in fatal COVID-19 pneumonia.

Summary

In a 160-case autopsy cohort of fatal COVID-19, immunohistochemistry delineated stage-specific changes: early and peak increases in CD4+, macrophages, and IgG4; lower CD4+ in DAD versus ARDS and thrombosis; male patients had higher CD4+. B and NK cells were depleted across stages. Findings suggest immune exhaustion during acute pneumonia/sepsis and cytokine surge in ARDS/thrombosis.

Key Findings

• CD4+, CD68, and IgG4 levels rose early and peaked by day 14 after symptom onset.
• CD4+ was significantly lower in DAD (49.4% ± 15.7%) than in ARDS (66.4% ± 19.3%) and thrombosis (70.2% ± 28.9%) (p < 0.05).
• Male patients had higher CD4+ than females (68.5% ± 21.1% vs 56.9% ± 22.4%) (p < 0.05).
• B cells (CD20) and NK cells were depleted across all stages.
• IgG4 expression reached 80–90% in acute phases but was nearly absent in organization/fibrosis stages.

Clinical Implications

Stage-specific immune patterns (e.g., early IgG4 surge, CD4+ differences between DAD and ARDS) may inform timing and selection of immunomodulatory strategies and risk stratification in severe COVID-19-related ARDS.

Limitations

• Restricted to fatal cases; generalizability to survivors is uncertain.
• Lack of non-COVID control lung tissues.
• Potential misclassification across histologic stages and timing.
• Observational design limits causal inference.

Future Directions

Validate stage-specific immune signatures in non-fatal and prospective cohorts; mechanistic studies on IgG4 and sex differences; integrate with longitudinal biomarkers to guide immunomodulation.