Uncovering the impact of co-infections on disease severity and mortality in pulmonary cryptococcosis

Increasing case reports and monocentric studies suggest that co-infections may be associated with poorer outcomes in patients with pulmonary cryptococcosis (PC), including both people living with HIV (PLWH) and HIV-negative individuals. However, systematic cohort-based evidence evaluating the prognostic impact of co-infections remains limited. Total of 454 patients with PC (239 PLWH and 215 non-HIV) were included to compare clinical characteristics, CT imaging features, and relevant prognostic factors according to their co-infection status. Among non-HIV patients, co-infections were linked to older age (53.42 vs. 45.46 years, p = 0.02), while no age difference was observed among PLWH. No HIV-negative patient had multiple co-infections, and all 1-year deaths occurred in those with bacterial co-infection; in contrast, 20% of PLWH had dual co-infections, most commonly tuberculosis. PLWH more frequently presented with fever and central nervous system symptoms, and co-infected PLWH had greater disease severity, reflected by higher SOFA, CURB-65, and APACHE II scores. Among co-infected patients, disease severity and 52-week median survival were comparable across HIV and dissemination status, although non-HIV patients experienced a markedly longer diagnostic delay [13.5 vs. 2.0 days; p < 0.0001]. Over 52 weeks, Pneumocystis jirovecii pneumonia (PCP), identified only in PLWH, was independently associated with mortality (HR = 3.81; p = 0.002), whereas bacterial co-infection showed a non-significant increase in mortality risk (HR = 1.51; p = 0.44). In the overall cohort, a high-risk APACHE II score was associated with more than a 15-fold increase in mortality, while nodular-plus-patchy CT lesions were associated with a greater than fivefold increase. PLWH had an 11.3-fold higher mortality risk than non-HIV patients, with SOFA score ≥ 2, high-risk APACHE II score, and absence of standard antifungal therapy further associated with poorer survival. Co-infection patterns differed by HIV status: multiple and diverse co-infections were common in PLWH, whereas bacterial co-infections predominated in non-HIV patients. Among co-infected patients, survival was comparable regardless of HIV status or extrapulmonary dissemination. Earlier recognition and timely diagnosis may improve the clinical management of pulmonary cryptococcosis. Not applicable.