<i>Pneumocystis jirovecii</i> Pneumonia in Non-HIV, Non-HCT Adults: Real-World Patterns of Overlapping Immunosuppression and PJP-Active Therapy

Background: Pneumocystis jirovecii pneumonia (PJP) is increasingly recognized among immunocompromised adults without HIV, yet prophylaxis use remains inconsistent. Data describing cumulative and overlapping immunosuppressive exposures before PJP diagnosis are limited. Objective: To characterize immunosuppressive exposure patterns and evaluate use of PJP-active therapy among non-HIV, nonhematopoietic cell transplant (non-HCT) adults with PJP. Methods: This retrospective cohort study (2011-2024) used the TriNetX Research Network. Adults without HIV or prior HCT with laboratory-confirmed PJP (positive polymerase chain reaction or antigen from respiratory specimens) were included. Demographics, comorbidities, and exposure to glucocorticoids (GCs), antineoplastics (ANs), and immunosuppressants (ISs) within 90 days before diagnosis were assessed. Overlapping immunosuppressive regimens and their associations with receipt of PJP-active therapy were evaluated. Because prescribing indication and dosing were unavailable, prescriptions for trimethoprim/sulfamethoxazole, atovaquone, dapsone, or pentamidine were grouped as PJP-active therapy, representing prophylactic, preemptive, or empiric use. Results: Among 578 adults with PJP, 87% received GCs, 37% ANs, and 26% ISs. More than half (54%) were exposed to 2 or more drug classes, whereas 10% had no identifiable immunosuppressive medication exposure. Despite frequent multidrug immunosuppression, only 32% received PJP-active therapy before diagnosis. GC exposure was more common among patients who received PJP-active therapy (97% vs 82%, P < 0.001), while AN and IS exposures did not differ between groups. Conclusion and Relevance: PJP in non-HIV, non-HCT adults commonly occurs in the setting of frequent multidrug immunosuppression. These findings reveal a disconnect between cumulative immunosuppressive risk and prophylaxis practices and support approaches that incorporate overall immunologic burden rather than single-agent thresholds.