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Background In the antiretroviral therapy (ART) era, Pneumocystis jirovecii pneumonia (PJP) has become uncommon among people living with HIV (PWH) receiving effective treatment, while its burden has progressively shifted toward patients with non–HIV-related immunosuppression. This epidemiological transition challenges HIV reference centers, which increasingly manage opportunistic infections across a broader spectrum of immunodeficiency.Methods We conducted a single-center retrospective observational cohort study including all adult patients with microbiologically confirmed Pneumocystis jirovecii pneumonia (PJP) diagnosed between 2021 and 2024 at a tertiary referral center. Demographic characteristics, type of immunosuppression, comorbidities, clinical severity at diagnosis, treatment strategies, and in-hospital outcomes were collected and compared between PWH and non–HIV immunocompromised patients. Clinical severity was assessed using the SOFA score and oxygen requirement at diagnosis. Univariate and multivariate logistic regression analyses were performed to identify factors independently associated with in-hospital mortality.Results A total of 127 patients were included; 18% were PWH and 82% had non–HIV-related immunosuppression. Almost all PWH were ART-naïve at PJP diagnosis, with a median CD4 count of 16 cells/mm 3. Compared with PWH, non–HIV patients were significantly older (median age 63 vs 44 years, p<0.001) and had a higher burden of comorbidities, including hematologic malignancies, solid organ or stem cell transplantation, autoimmune diseases, and chronic corticosteroid exposure. Disease severity at presentation was markedly greater in the non–HIV group, with higher SOFA scores (median 7 vs 4, p<0.001), greater oxygen requirements, more frequent need for invasive mechanical ventilation, and higher ICU admission rates. Overall in-hospital mortality was 39%, significantly higher among non–HIV patients compared with PWH (38% vs 4.3%). At multivariate analysis, SOFA score >3 was independently associated with increased mortality (OR 42.0, 95% CI 5.26–336.1, p<0.001), whereas adjunctive corticosteroid therapy was independently protective (OR 0.27, 95% CI 0.10–0.67, p 0.005).Conclusions In this cohort, non–HIV immunocompromised patients with PJP had higher in-hospital mortality than PWH. However, non–HIV status was not independently associated with in-hospital mortality after multivariate adjustment. SOFA score was the main predictor of adverse outcome, while adjunctive corticosteroids were independently protective, supporting their role in reducing mortality also in non–HIV patients. These data stress the need for early recognition and optimized care, particularly in non–HIV patients.Table 1, table 2Abstract P121 Table 1General characteristics of PjP patients (N=127)Abstract P121 Table 2Factors associated with in-hospital mortality (N=125)