Clinical Spectrum of Talaromyces marneffei Infections in HIV-Negative Patients: An 18-Case Series Including a Rare Presentation with Gastrointestinal Onset, Adrenal Mass, and Hemophagocytic Lymphohistiocytosis

Background: Talaromyces marneffei (TM) infections in HIV-negative patients present diagnostic challenges due to heterogeneous manifestations. This study characterizes emerging phenotypes and proposes a diagnostic framework.Methods: Retrospective analysis of 18 patients (from January 2020 to June 2024) assessing underlying diseases, manifestations, co-infections, diagnostics, treatment, and outcomes. Diagnosis required TM positivity via culture, histopathology, or metagenomic next-generation sequencing(mNGS).Results: This cohort (14 male, 4 female; mean age 57.9years) demonstrated diverse comorbidities including renal transplantation (27.8%), malignancy (16.7%), and anti-IFN-gamma autoantibody (AIGA) positivity (11.1%). Common manifestations included respiratory symptoms (72.2%), fever (55.6%), anemia (50%), arthralgia (33.3%), and lymphadenopathy (22.2%). Rare features comprised cutaneous lesions (16.7%), gastrointestinal symptoms (11.1%), hemoptysis (11.1%). Alarmingly, 94.4% of the cases were initially misdiagnosed, primarily as tuberculosis (35.3%) or community-acquired pneumonia (23.5%), resulting in a mean diagnostic delay of 10.6 months. mNGS was the primary diagnostic tool in 77.8% of the cases.We report the first documented TM triad in a patient with systemic lupus erythematosus (SLE) and Epstein-Barr virus (EBV) coinfection: concurrent gastrointestinal onset (manifesting as ileocolonic ulcers), adrenal mass (4.8 3.2 cm regressing to 1.0 0.9 cm post-treatment), and hemophagocytic lymphohistiocytosis (HLH). The outcomes of the cohort study included a mortality rate of 33.3% and two relapses associated with AIGA.Conclusions: TM infection in HIV-negative hosts demonstrates broad clinical heterogeneity, often masked by comorbidities and leading to delayed diagnosis. mNGS is critical for early identification. The unprecedented triad of gastrointestinal onset, adrenal mass, and HLH underscores TM's capacity for atypical dissemination. AIGA may predict relapse.