Immunomodulation in the Treatment of Disseminated Coccidioidomycosis

Introduction Coccidioidomycosis, commonly known as Valley fever, is an endemic fungal infection with a growing impact in the western United States. Patients with disseminated coccidioidomycosis (DCM) represent a rare and life-threatening subset of Valley fever who face years or a lifetime of antifungals to manage their disease. Immunocompromised patients with defective type 1 immunity or excessive type 2 immunity have an increased risk of dissemination. We previously published a single case employing the IL4/IL13 blocker dupilumab as an adjuvant to antifungal therapy. Here we present ten cases of patients in which adjuvant immunomodulation was provided for severe coccidioidomycosis. Methods This is not an interventional trial. Cases were identified at UCLA by infectious disease experts in conjunction with immunology, and all subjects were deemed to be maximally treated with multiple conventional antifungals. Informed consent was obtained. We performed intracellular cytokine staining on CD4+ T cells and measured proportions of interferon gamma (IFN-γ), IL-4, and IL-17A–producing T cells. Treatment with IFN-γ was offered to those subjects showing life-threatening progression of disease despite maximal conventional care. Treatment with dupilumab was offered to those with excessive type-2 skewing. Clinical outcomes were assessed by laboratory studies, imaging results, and mycosis score. Results Our data follow 10 subjects for a median of 6 months after treatment. Our subjects showed excessive type 2-to-1 ratios, mostly due to excessive type 2 immune skewing and less often in subjects with poor type 1 responses. We found reduction of polyclonal type 2 responses in response to treatment with dupilumab. Clinical outcomes in all ten subjects were improved above the baseline state. Conclusions Our work offers a new treatment employing immune modulation by cytokine blockade to treat a life-threatening infectious disease. Patients with poorly controlled disease may benefit from IFN-γ. Furthermore, subjects exhibiting a Th2-skewed response may benefit from dupilumab. Following the Casadevall damage–response framework, this tailored approach aligns immunomodulation with the underlying immunopathology. These observations provide evidence to support proper clinical trials of IFN-γ and dupilumab. Further research is needed to better characterize why cocci disseminates in certain subjects and which patients will benefit from immunomodulation.