Disseminated Coccidioidomycosis Treated with Interferon-γ and Dupilumab

Design

Case presentation

A 4-year-old male patient presented with fever and enlarged subcutaneous forehead nodules, which have sustained for three weeks. Physical examination noted three tender masses 3-5 cm in diameter on the forehead and scalp, as well as a scaly plaque on the posterior neck and right wrist and ankle tenderness. The patient had no personal nor family history of recurrent or severe infections, although he did live in a Coccidioides-endemic region in California. Imaging revealed right lung consolidation, along with lymphadenopathy and multiple osteolytic lesions located in the ribs, right radius, right tibia, and skull, which were identified as Coccidioides with polymerase chain reaction (PCR).

The patient was treated with fluconazole and liposomal amphotericin B and surgical debridement of the most prominent osseous lesions, but new soft-tissue lesions developed, prompting escalation of therapy to posaconazole and high-dose (7.5 mg/kg) liposomal amphotericin B with additional debridement and adjunct sertraline. Still, complement-fixation titers were elevated with detectable activity at 1:256 dilution. After discovery of a defect in interleukin-12 receptor signaling, it was posited that monogenic type 1 immunodeficiency was the causal condition.

Based on the patient's refractory disease and previous reported success of interferon-γ treatment, the patient was initiated on subcutaneous interferon-γ 50 mcg/m² of body surface area three times weekly, and gradually increased to 200 mcg/m² three times weekly. Despite this, complement-fixation titers remained elevated with detectable activity at 1:256 dilution, although interleukin-12 signaling was improved by therapy. On week 16, dupilumab was administered at 2 mg/kg weekly, then escalated to 6 mg/kg weekly without adverse effects. Finally, IgE levels decreased substantially, complement-fixation titers became undetectable, and inflammatory markers fell within normal limits, along with resolution of disease 11 weeks later. At discharge, dupilumab was decreased to 4 mg/kg weekly, and at a 1-year follow-up, interferon-γ was reduced to 150 mcg/m² three times weekly, with no new foci of infection present.

Study Author Conclusions

In this patient, genome sequencing did not identify any plausible rare variants that could explain a susceptibility to disseminated coccidioidomycosis. This case found that the combination of interferon-γ and dupilumab successfully controlled a severe case of disseminated coccidioidomycosis. The authors propose that this immunomodulatory approach may have therapeutic potential for other severe fungal infections and speculate it may also be useful in other infections where type 1 immunity is important, including viral and mycobacterial infections.

Interferon-γ and voriconazole combined therapy for refractory meningeal coccidioidomycosis in a patient with interferon-γ deficiency

Design

Case presentation

A 63-year-old female patient presented to the emergency department in 2010 with dry cough and fever; the patients' past medical history was significant for type 2 diabetes mellitus and hypertension. A chest X-ray revealed mediastinal lymphadenopathy. A follow-up lymph node biopsy found necrotizing granulomas, with cultures positive for Coccidioides spp. The patient was initiated on treatment with fluconazole 400 mg daily x 2 months, followed by 200 mg daily x 1 year due to impaired renal function (CrCl < 50 mL/min).  After stopping therapy in 2011, the patient developed fever and meningeal signs, with cerebrospinal fluid antibodies positive for Coccidioides spp, leading to a diagnosis of Coccidioides meningitis. The patient was treated with one week of intravenous liposomal amphotericin B 5 mg/kg daily and then switched to oral fluconazole 800 mg daily due to acute kidney injury. After two weeks, the patient was to begin lifelong suppressive therapy with fluconazole 200 mg daily.

Follow-up visits for several years were clear, until 2017, when the patient presented for frequent falls and memory loss. At this point, an MRI revealed hydrocephalus and recurrent Coccidioides meningitis was eventually considered. The patient underwent shunt placement and was initiated on treatment with IV liposomal amphotericin B (5 mg/kg/daily x 14 days), then switched to fluconazole 400 mg daily.

Over the following months, the patient continued to experience frequent falls, and imaging revealed relapse of Coccidioides meningitis. Laboratory assessment found immunodeficiencies, with low serum levels of INF-γ (< 5 pg/mL). Soon after, in early 2018, the patient was admitted to the hospital with worsening neurological symptoms. Salvage therapy was again initiated with IV liposomal amphotericin B. Due to the patients worsening condition after one month of follow-up, she was switched to voriconazole 6 mg/kg twice daily x 24 hours then 200 mg twice daily.

One month later, adjunctive INF-γ was initiated once weekly, with monitoring of levels. Voriconazole dose was adjusted due to elevated levels and adverse effects, while INF-γ levels were found to gradually increase up to 18 pg/mL with good tolerance. After 10 months of combination therapy, the patient's condition had improved. 

Study Author Conclusions

This case gives insight into probable therapeutic effects of INF-γ in Coccidioides meningitis. However, further studies of INF-γ1b as adjunctive therapy for patients with refractory Coccidioides meningitis are required.

An effective host immune response to Coccidioides spp. infection requires INF-γ and IL-12 for the activation of B-cells, T-cells, and phagocytes. Exogenous IFN-γ appeared to promote the desired T-cell immune response against intracellular pathogens.

Two cases illustrating successful adjunctive interferon-g immunotherapy in refractory disseminated coccidioidomycosis

Design

Case 1

A 30-year-old, previously healthy, African-American, active-duty Navy male stationed in California was diagnosed with disseminated coccidioidomycosis. His medical history included alcohol dependence (in remission for 3 years), negative HIV status, and latent tuberculosis (treated with a 9-month course of isoniazid in 2007). Initially, he presented with non-productive cough, dyspnea, fatigue, night sweats, myalgias, arthralgia, and tachycardia, and he was first misdiagnosed with a viral syndrome. Two weeks later, with symptoms persisting and now including right foot and low back pain and disseminated cutaneous lesions, further tests revealed leukocytosis, mild transaminase elevation, high sedimentation rate (ESR), elevated C-reactive protein (CRP), negative HIV serology but positive Coccidioides serology, and biopsy of cutaneous lesions growing C. immitis. Imaging showed normal chest radiography but reticulonodular disease in chest CT, and MRI revealed osteomyelitis and lesions in various skeletal locations.

Treatment involved liposomal amphotericin B and posaconazole, with amphotericin B discontinued after two months due to side effects but continuing posaconazole treatment. Despite initial improvements, his fevers, fatigue, cough, and night sweats persisted, with slight progression of spinal disease and an increase in complement-fixation titers to 1:128.

The dosage of posaconazole was adjusted without significant clinical, laboratory, or radiographic improvement, and his inflammatory markers remained elevated. He was given adjunctive interferon-γ 100 mcg (50 mg/m2 body surface area) three times weekly.

After 6 months of interferon-γ immunotherapy (when it was discontinued), follow-up magnetic resonance imaging (MRI) findings showed improvements in his lesions. The complement-fixation titer remained at 1:128 while inflammatory markers (erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]) decreased significantly within several weeks of treatment, normalizing by 4 months.

The patient consistently showed improvement in symptoms, most notably decreasing back pain and fatigue. His exercise capacity increased, and eventually, the patient was able to return to work.

Case 2

A 23-year-old, previously healthy, African-American, active-duty male stationed in California experienced severe and persistent back pain in the thoracic and lumbar areas, initially relieved by NSAIDs. Despite having no significant medical or drug history, his condition worsened, accompanying fevers, night sweats, and a significant weight loss of 15 pounds, which led to further medical examination. Laboratory tests revealed 7% eosinophilia, negative HIV, and positive serology for Coccidioides. Magnetic resonance findings and a culture-positive bone biopsy confirmed disseminated coccidioidomycosis affecting the spine, iliac crests, and ribs.

Treatment was initiated with liposomal amphotericin-B and oral itraconazole, but the patient's condition deteriorated, showing progression in bone lesions and developing neurological deficits. Despite switching to posaconazole and maximizing amphotericin dosage, the patient's complement fixation titer increased significantly, and MRI showed lesion progression with spinal involvement. He underwent T12 vertebroplasty and T10 kyphoplasty due to vertebral damage. Over the treatment period, his weight dropped from 170 to 108 pounds. He was then given adjunctive interferon-γ 100 mcg (50 mg/m2 body surface area) three times weekly. 

A marked decrease in bone pain and resolution of neurological defects was noted within 2 weeks of interferon initiation. His ambulation also improved, and his weight increased.

At a follow-up 3 months after interferon therapy, his complement-fixation titers declined to 1:128 (baseline, 1:64), and his ESR and CRP normalized. MRI revealed stable lesions.

Clinical stability was achieved after 6 months of interferon therapy, so treatment was discontinued. However, 4 months later, the patient noted incrementally increasing back pain. A follow-up MRT showed lesion progression with accompanying increases in ESR and CRP.

Interferon-γ therapy was restarted after a 4-month hiatus, and another 4 months later, the patient experienced repeated improvements in clinical symptoms. An MRI revealed stability in bone lesions and regression in soft-tissue involvement, complement-fixation titers decreased to 1:32, and ESR and CRP improved again. 

Study Author Conclusions

Protective immunity and host resistance to coccidioidomycosis require a robust cell-mediated immunity with adequate production of Th1 cytokines, including interleukin-12, and IFN-γ and appropriate regulation and coordinated functionality of Th1/Th2 responses and IL-12/IFN-γ cytokine axes. This case series describes two patients with refractory disease who responded to adjunctive interferon-γ.

Despite no detected quantitative abnormalities in various immune cells, the normal functionality of cytokine expression machinery and innate immune pathways was confirmed through various stimulation tests. The study found that the introduction of IFN-γ resulted in altered cytokine production responses, particularly a blunted increase in TNF-α production under specific stimulations, which may indicate a defect in the IFN-γ signaling pathway. Genetic sequencing of components involved in this pathway did not reveal abnormalities, suggesting that the molecular defect and its impact might vary between patients and could potentially be overcome with higher doses of IFN-γ.

The authors advocate considering IFN-γ as an adjunctive therapy in specific cases of refractory disseminated coccidioidomycosis infections, potentially in conjunction with genetic testing for mutations in the IL-12/IFN-γ axis. However, they also acknowledge limitations, including the retrospective nature of the study and the potential influence of prior therapy on immune response measurements. Further research is encouraged, particularly focusing on the IL-12/IFN-γ axis and its role in immune regulation, to better understand the genetic and immunological factors that could inform treatment strategies for refractory infectious diseases.

Successful Treatment of a Critically Ill Patient with Disseminated Coccidioidomycosis, Using Adjunctive Interferon-γ

Design

Case presentation

A 57-year-old Black female presented with anterior chest pain that progressed over the prior three months, accompanied by night sweats and weight loss. Prednisone prescribed for what was believed to be costochondritis did not resolve the pain. Outpatient imaging was reportedly normal, and no serological tests for coccidioidomycosis were conducted. Eventually, the patient developed left-side head pain, after which a bone scan revealed focal areas of uptake in the sternum and skull. Chest radiography revealed bilateral infiltrates, and bronchoscopy samples after hospital admission revealed C. immitis on culture. 

During her 137-day ICU hospitalization, the patient received a variety of antifungals, including amphotericin B, amphotericin B lipid complex, itraconazole, and, fluconazole. Her complement fixation titers to C. immitis were 1:16 shortly after admission and increased to 1:1024 by week 9 of hospitalization. IFN-γ (50 mcg/m² subcutaneously three times weekly for 9 weeks) was started after the patient's prognosis was judged to be poor, due to inability to wean off ventilatory support and clinical instability despite ten weeks of antifungals.

At the time of IFN-γ initiation, the patient was receiving liposome amphotericin B, which was then switched to intravenous fluconazole. After initiation of IFN-γ therapy, complement fixation titers decreased to 1:16 once more. The patient gradually recovered and was able to be extubated, although she still required supplemental oxygen. Upon discharge, she was initiated on life-long oral fluconazole.

Study Author Conclusions

This paper describes a single case of coccidioidomycosis treated with IFN-γ, but the observations could have significant implications if confirmed. Clinicians who treat serious C. immitis infections have had patients whose disease is only controlled and not cured by current therapies.

The addition of interferon-γ to the therapeutic regimen resulted in improvement and discharge from the hospital. Adjunctive interferon-γ used in the successful treatment of severe coccidioidomycosis has not been reported previously.