Sub-phenotypes of pneumonia defined by pulmonary histopathological features

Shastry, A.; Hiller, B. E.; Sanders, N. L.; Tseng, A. E.; Kothari, J.; O'Connell, A. K.; Gertje, H. P.; Ha, C. T.; Murzin, E.; Traber, K. E.; Lederer, J. A.; Jones, M. R.; Douam, F.; Beach, T. G.; Remick, D. G.; Crossland, N. A.; Monti, S.; Campbell, J. D.; Mizgerd, J. P.

doi:10.1101/2025.05.18.654716

bioRxiv · 10.1101/2025.05.18.654716

Sub-phenotypes of pneumonia defined by pulmonary histopathological features

Shastry, A.·Hiller, B. E.·Sanders, N. L.·Tseng, A. E.·Kothari, J.·O'Connell, A. K.·Gertje, H. P.·Ha, C. T.·Murzin, E.·Traber, K. E.·Lederer, J. A.·Jones, M. R.·Douam, F.·Beach, T. G.·Remick, D. G.·Crossland, N. A.·Monti, S.·Campbell, J. D.·Mizgerd, J. P.

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Abstract

Establishing sub-phenotypes of pneumonia based on distinct host processes will be a step towards using host-directed therapies (to complement microbe-directed therapies) more rationally and precisely. Although pneumonia is a pulmonary pathophysiology, histological changes within the lungs have not been leveraged for sub-phenotyping. We addressed this by scoring 18 histopathology features (e.g., type 2 cell hyperplasia or necrosis) across rapid autopsy lung samples from 276 elderly subjects with pneumonia. Machine learning algorithms segregated subjects into seven different sub-phenotypes of pneumonia with distinct histopathology signatures. Quantitative immunofluorescence demonstrated associations of macrophages, neutrophils, T cells, and B cells with select histology features and pulmonary pathology sub-phenotypes. Mouse models revealed corollary sub-phenotypes, although some histology features observed in human lungs were never observed in mice. By illuminating this spectrum of histopathologies and discriminating discrete sub-phenotypes of pneumonia, a foundational framework emerges for developing and using host-directed therapies for subsets of pneumonia patients.

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Shastry, A., Hiller, B. E., Sanders, N. L., Tseng, A. E., Kothari, J., O'Connell, A. K., Gertje, H. P., Ha, C. T., Murzin, E., Traber, K. E., Lederer, J. A., Jones, M. R., Douam, F., Beach, T. G., Remick, D. G., Crossland, N. A., Monti, S., Campbell, J. D., Mizgerd, J. P.. 2025-05-20. Sub-phenotypes of pneumonia defined by pulmonary histopathological features. https://doi.org/10.1101/2025.05.18.654716

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