Disseminated Aspergillosis with Central Nervous System Involvement Among Patients with Hematologic Malignancies: A 30-Year Institutional Cohort of Clinical Features, Management, and Outcomes

Background: Disseminated invasive aspergillosis (IA) is an uncommon but devastating manifestation of disease, particularly when the central nervous system (CNS) is involved. The clinical features and outcomes of CNS dissemination, compared with isolated invasive pulmonary aspergillosis (IPA) and other disseminated forms, remain poorly characterized. Methods: Using an institutional database of 1157 cancer patients diagnosed with IA between 1993 and 2024, we identified 43 patients with disseminated IA, defined as infection involving ≥2 non-contiguous organ systems, including 8 with CNS involvement. Patients with disseminated IA were matched 1:3 to patients with IPA based on year of diagnosis. We compared clinical features, antifungal treatment, and outcomes between: (1) CNS-disseminated IA and IPA, and (2) CNS-disseminated IA and other forms of disseminated IA. Results: Baseline characteristics, including hematologic malignancy subtype, hematopoietic stem cell transplantation status, neutropenia, and antifungal prophylaxis, were similar across groups. Aspergillus fumigatus was the predominant species in all cohorts. No patients with CNS-disseminated IA achieved clinical response at end of therapy, versus 35% with IPA (p = 0.05) and 30% with other disseminated IA (p = 0.17). Twelve-week IA-associated mortality was significantly higher in CNS-disseminated IA than in IPA (88% vs. 45%, p = 0.028) and was higher than in other disseminated IA (88% vs. 46%, p = 0.05). Combination antifungal therapy was more frequently used in CNS-disseminated IA than in IPA (63% vs. 31%) and other disseminated IA (63% vs. 43%), while rates of ICU admission and mechanical ventilation were similar across groups. Conclusions: CNS involvement in disseminated IA defines a distinct, high-risk phenotype, with profoundly reduced treatment response and survival despite comparable baseline characteristics. Given the small number of CNS cases and the predominance of cases diagnosed during earlier study periods, these findings should be interpreted with caution. Although combination antifungal therapy was used more frequently in CNS-disseminated IA, no significant outcome benefit was observed, underscoring the need for improved therapeutic approaches for CNS aspergillosis in immunocompromised hosts.