To the Editors: Signal transducer and activator of transcription-1 gain-of-function (STAT1 GOF) mutations are classically recognized through chronic mucocutaneous candidiasis (CMC), reflecting impaired T helper (Th)17 differentiation and reduced interleukin (IL)-17-mediated antifungal immunity.1–3 However, increasing clinical experience demonstrates that the infectious phenotype extends beyond Candida, encompassing viral, bacterial and invasive fungal pathogens.2,4 This broader susceptibility is thought to reflect dysregulation of interferon (IFN) signaling rather than an isolated mucosal immune defect.1,2 The IFN-γ/IL-12 axis plays a central role in host defense against intracellular pathogens, including mycobacteria and dimorphic fungi.5 Activation of IFN receptors leads to STAT1 phosphorylation, nuclear translocation and transcription of IFN-induced genes that coordinate macrophage activation and cellular immunity.1 In STAT1 GOF disease, delayed STAT1 dephosphorylation and abnormal transcriptional regulation impair downstream immune responses, including IL-17 production and effective macrophage function.1,2 These defects help explain why patients with STAT1 GOF may develop invasive infections caused by intracellular organisms. Consistent with this biology, immunodeficiency cohorts have reported severe endemic mycoses such as disseminated histoplasmosis and coccidioidomycosis in STAT1 GOF patients, suggesting that susceptibility is not Candida-restricted but reflects impaired containment of dimorphic fungi.4,6 Because Blastomyces dermatitidis shares reliance on macrophage-mediated immunity and coordinated Th1/Th17 responses, it represents a biologically plausible yet underrecognized pathogen in this condition.7 Here, we report a child with STAT1 GOF and CMC who developed life-threatening disseminated blastomycosis with central nervous system (CNS) involvement requiring systemic and intraventricular amphotericin therapy, further expanding the infectious spectrum of STAT1 GOF. A 13-year-old boy with a known STAT1 gain-of-function mutation and CMC presented with 3 weeks of progressive headache, fever and fatigue, followed by acute altered mental status. Aside from intermittent thrush—most recently several months earlier—he had been otherwise well. There was a strong family history of CMC, and although he had previously received fluconazole prophylaxis, adherence had been inconsistent. Brain imaging demonstrated diffuse leptomeningeal enhancement, hydrocephalus and posterior fossa lesions consistent with basilar meningitis and microabscess formation (Fig 1). An external ventricular drain was placed because of elevated intracranial pressure. Chest imaging revealed multiple pulmonary nodules, including cavitary upper-lobe lesions. Abdominal imaging demonstrated splenic and visceral microabscesses. Cutaneous examination identified disseminated ulceronecrotic papules, and ophthalmologic evaluation revealed chorioretinitis, all supporting a systemic disseminated infectious process. Although CMC predisposes to mucosal Candida infection, invasive disseminated candidiasis is uncommon, prompting evaluation for alternative fungal pathogens.FIG. 1.: Brain and spine magnetic resonance imaging (MRI) findings. Brain MRI demonstrates diffuse leptomeningeal enhancement involving supratentorial and infratentorial compartments, centered in the basal cisterns and extending along the Sylvian fissures, cerebral sulci, cerebellar fissures and cranial nerves. Multiple small peripherally enhancing lesions in the cerebellum, brainstem, hypothalamus and vermis are consistent with basilar meningitis and microabscess formation. Associated hydrocephalus with mild ventriculomegaly and periventricular edema is present.He had no travel history or tuberculosis exposures. He lived in the Midwestern United States and had frequent exposure to construction areas and mulch at school, representing possible environmental contact with endemic fungi. Initial microbiologic evaluation for bacterial and viral infection was negative, including human immunodeficiency virus testing, herpes simplex virus polymerase chain reaction, meningitis/encephalitis panel and cultures. Bronchoalveolar lavage fungal stain demonstrated broad-based budding yeast, and tissue culture confirmed Blastomyces species (Figure, Supplemental Digital Content 1, https://links.lww.com/INF/G592). Serum, urine and cerebrospinal fluid (CSF) Blastomyces antigen levels were markedly elevated. Histoplasma antigen assays were also positive, consistent with known cross-reactivity among dimorphic fungal antigen tests.8 He was treated with intravenous liposomal amphotericin B with adjunct isavuconazole for CNS penetration. Despite therapy, neurologic inflammation progressed with seizures and worsening imaging findings. Because of concern for inadequate local antifungal delivery and persistent inflammatory burden, intraventricular amphotericin with adjunct corticosteroid therapy was administered. Following combined systemic and intraventricular therapy, CSF antigen levels declined, and neurologic status improved. He completed 6 weeks of amphotericin therapy followed by long-term oral isavuconazole. After more than 18 months of treatment, he remains clinically well with negative serial antigen testing. Given his underlying immune dysregulation, prolonged antifungal suppression was continued. Janus kinase (JAK) inhibition was considered because of the reported benefit in STAT1 GOF immune dysregulation, but was deferred due to concern for worsening invasive fungal infection.9,10 STAT1 GOF mutations produce a complex immune phenotype extending beyond mucocutaneous candidiasis. Excessive STAT1 phosphorylation leads to prolonged nuclear signaling and impaired differentiation of Th17 cells, reducing IL-17-mediated mucosal defense.1–3 In addition to this pathway, STAT1 dysregulation alters cytokine coordination, macrophage activation and intracellular pathogen control, producing vulnerability to organisms that depend on effective cellular immunity.1,2 Experimental and clinical observations suggest that STAT1 GOF represents a broader defect in IFN-mediated immune regulation rather than a Candida-specific disorder.2,4 Enhanced STAT1 activation, delayed dephosphorylation and abnormal transcriptional responses may paradoxically impair macrophage responsiveness to repeated IFN-γ stimulation, reducing intracellular pathogen clearance.1,5 This mechanism provides a plausible explanation for susceptibility to dimorphic fungi that rely on survival within host phagocytes. Dimorphic fungi such as Histoplasma and Coccidioides require coordinated Th1- and Th17-driven immune responses for containment.5,7 Both organisms survive within macrophages and depend on intact cytokine signaling for fungal control.5Blastomyces dermatitidis shares several of these immunologic characteristics, including intracellular persistence and reliance on macrophage activation and cellular immune responses.7 Although blastomycosis can occur in immunocompetent individuals, disseminated disease with CNS involvement is uncommon and typically suggests impaired host defense. Our case, therefore, expands the infectious phenotype associated with STAT1 GOF and supports including blastomycosis within the spectrum of STAT1-related endemic mycoses. JAK inhibitors such as ruxolitinib have been used to reduce STAT1 phosphorylation and improve autoimmune manifestations and refractory candidiasis in STAT1 GOF.9,10 However, clinical experience indicates that JAK inhibition does not fully restore downstream immune signaling and may be associated with persistence or progression of invasive fungal infection.9 For this reason, immune-modulating therapy was deferred in our patient until infection control was achieved. Another notable aspect of this case is the use of intraventricular amphotericin therapy. Evidence specific to blastomycosis is limited, but intrathecal amphotericin has demonstrated benefit in refractory fungal meningitis, including cryptococcosis and coccidioidomycosis.11,12 In our patient, neurologic improvement and declining CSF antigen levels followed combined systemic and intraventricular therapy, suggesting that local antifungal delivery may be considered in selected children with severe CNS blastomycosis. Although blastomycosis may occur in immunocompetent hosts, the severity and dissemination observed here strongly suggest that STAT1 GOF–associated immune dysregulation was a major contributing factor. Recognition of this expanded infectious phenotype is essential for early diagnostic testing, aggressive therapy and careful timing of immune-modulating interventions.
Muayad Alali (Mon,) studied this question.