Disseminated coccidioidomycosis (DCM) is a serious illness with significant morbidity and mortality, especially in patients with impaired host defense mechanisms in interferon-gamma (IFN-gamma)/interleukin-12 and STAT3 axes. With standard treatments, these patients often require prolonged, sometimes lifelong, antifungal therapy, which are not curative. The therapeutic benefits of adjunctive IFN-gamma in DCM remain unclear.
We conducted a retrospective chart review of DCM patients treated with adjunctive IFN-gamma at our institutions and performed a literature review to identify additional cases. Treatment responses were assessed using modified EORTC/MSG criteria.
We identified 17 cases (12 from our institutions, 5 from the literature; 7 females) who received 19 courses of IFN-gamma therapy. Genetically confirmed inborn errors of immunity included STAT1 gain of function (GOF) in 2 and autosomal dominant partial IFNGR1 deficiency in 1. The median age at first diagnosis was 19 years (range: 4-57), and the median interval from diagnosis to initiation of IFN-gamma therapy was 10 months (range: 0.5-120). All had extensive diseases prior to treatment, as evidenced by multiorgan involvement (median 4, including 5 with CNS involvement), despite various antifungal agents (median 4) and surgical interventions in 13 patients. Five patients required hospitalization in the intensive care unit, including 1 on VV-ECMO. The median maximum dose of IFN-gamma was 50 mcg/m2 (subcutaneous, range: 25-200 mcg/m2, 3×/week) with a median treatment duration of 8 months (range: 2-39). Adverse events were recorded in 8 patients. They were uncomfortable but manageable with supportive care in all, except for three who ultimately discontinued therapy because of cytopenia, headache, and fever, respectively. Of the 19 treatment courses, there were 11 responses, 5 partial responses, and 3 nonresponses, including both STAT1 GOF patients who eventually died from DCM. In those who achieved at least partial responses, significant improvements were observed in C-reactive protein levels (pre- vs. post-treatment, median 42.6 vs. 7.0 mg/L, p = 0.001), and anti-Coccidioides antibody titers (1:128 vs. 1:16, p = 0.002). No neutralizing anti–IFN-gamma autoantibodies were detected before, during, or after IFN-gamma therapy.
IFN-gamma therapy failed in 2 STAT1 GOF patients but may provide benefits for other patients with DCM despite standard treatments.
