Transcriptomic analyses of mortality in HIV-associated Pneumocystis pneumonia

Pneumocystis jirovecii pneumonia (PCP) remains a leading cause of respiratory failure and mortality in individuals with advanced HIV. 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. A predictive model combining ApoE and arginine achieved high prognostic accuracy. Crucially, using an ex vivo immunodeficient precision-cut lung slice model, we functionally reversed this opsonic deficit with intravenous immunoglobulin, which restored macrophage-mediated fungal clearance. These findings redefine fatal HIV-associated PCP as a syndrome of immunometabolic failure and provide a mechanistic rationale for evaluating immunoglobulin replacement as a host-directed adjunctive therapy.