Differentiating proven progressive disseminated histoplasmosis from other diagnoses in hospitalized persons with HIV and suspected progressive disseminated histoplasmosis: Findings from a clinical and demographic study in Mexico

Background Progressive disseminated histoplasmosis (PDH) is a leading cause of morbidity and mortality among persons with HIV (PWH) in the Americas. Clinical presentation often overlaps with other opportunistic infections —especially tuberculosis (TB)— and sensitive diagnostics are frequently unavailable. In Mexico, epidemiological data on histoplasmosis in PWH are scarce. This study aims to describe the clinical and demographic characteristics along with final diagnosis of hospitalized PWH who had clinical suspicion of progressive disseminated histoplasmosis. Methodology/Principal Findings We conducted a multicenter, prospective, cross-sectional study involving 415 hospitalized PWH and clinical suspicion of PDH across ten tertiary care hospitals in Mexico. Participants underwent comprehensive evaluation for Histoplasmosis infection, including cultures, histopathology, and urine antigen testing. Of the total cohort, 108 patients (26%) had proven PDH, 162 (39%) received an alternative diagnosis, and 145 (35%) had no definitive diagnosis. In univariate analyses, proven PDH was more frequently associated with skin lesions, thrombocytopenia, elevated AST and LDH levels (>2x ULN), and micronodular infiltrates on chest imaging. In contrast, lymphadenopathy, tree-in-bud patterns, pleural effusion, hepatomegaly, and splenomegaly in imaging were more commonly observed in patients without proven PDH. Among patients without proven PDH, 41 met the criteria for probable PDH. Compared with proven PDH, probable cases exhibited higher rates of lymphadenopathy (73% vs 50%). Conversely, elevated AST (61% vs 39%) and LDH (74% vs 35%) levels were more frequent in proven PDH cases. While radiographic lung involvement was common in both groups, mediastinal lymphadenopathy (29% vs 12%), pleural effusion (17% vs 3.7%), and hepatomegaly (56% vs 37%) were significantly more frequent in probable PDH cases. Clinical response to antifungal therapy was higher in proven PDH (38% vs 24%), although this difference was not statistically significant. Compared to patients with tuberculosis (TB) alone, those with proven PDH alone showed more profound immunosuppression, with a greater proportion presenting CD4 + counts 3 . Skin lesions, LDH elevation, and micronodular pulmonary infiltrates were also more frequent in the proven PDH group, underscoring their diagnostic relevance. In contrast, lymphadenopathy, tree-in-bud opacities, hepatomegaly, and splenomegaly were more common in TB. Importantly, TB coinfection was present in 13 patients with proven PDH (12%) and in 12 with probable PDH (29%). In an exploratory analysis of predictors for proven PDH, elevated LDH level was the strongest predictor (adjusted prevalence odds ratio [aPOR] of 6.82, 95% CI 3.56 – 13.4, p  Conclusions/Significance Histoplasmosis represents a substantial diagnostic burden among PWH in Mexico, particularly in those with advanced disease. Our findings highlight the urgent need to expand access to rapid and sensitive diagnostic tools, improve clinical awareness, and promote routine screening for PDH in PWH presenting with febrile illness, especially in TB-endemic regions. Elevated LDH levels, skin lesions, and micronodular infiltrates on chest imaging were the most useful features to differentiate proven histoplasmosis from tuberculosis and probable histoplasmosis.