Transcriptomic analyses of mortality in HIV-associated Pneumocystis pneumonia

While severe disease is classically attributed to hyperinflammation, the specific biological determinants driving fatal outcomes in patients remain poorly understood. To address this, we employed an integrated systems biology approach, performing transcriptomics, proteomics, and metabolomics on bronchoalveolar lavage fluid from a prospective cohort of 42 patients with HIV-associated PCP.

We demonstrate that mortality is not primarily driven by uncontrolled fungal burden or isolated hyperinflammation, but by profound immunometabolic failure. Non-survivors exhibited marked suppression of local humoral immunity, characterised by depletion of immunoglobulins and complement components, together with significant impairment of apolipoprotein E (ApoE)-mediated alveolar repair and dysregulation of arginine-nitric oxide metabolism.