Refractory Disseminated Coccidioidomycosis and Mycobacteriosis in Interferon-γ Receptor 1 Deficiency

Abstract

Severe coccidioidomycosis is rare, and specific genetic susceptibility to the disease remains unidentified. We describe a patient with disseminated recalcitrant coccidioidomycosis with autosomal dominant interferon-γ receptor 1 deficiency caused by a heterozygous IFNGR1 818del4 mutation. Therefore, the interleukin-12/interferon-γ axis appears to be critical for control of coccidioidomycosis.

Coccidioidomycosis is caused by the thermally dimorphic molds Coccidioides immitis and Coccidioides posadasii , which are endemic to regions of the United States, Mexico, and South America. Infection occurs after inhalation of an arthroconidial spore; within the lung, the fungus grows as spherules. Successful containment of Coccidioides species is histologically represented by necrotizing granulomata [1, 2]. Most cases are either subclinical or manifest with self-limited respiratory disease; <1% of all infections lead to extrathoracic dissemination [3]. There are increased rates of extrathoracic disease in certain ethnic groups. However, only select human leukocyte antigen (HLA) allele polymorphisms and blood group antigen B have been associated with severe disease [1].

Monogenic susceptibilities to Mycobacterium tuberculosis complex and nontuberculous mycobacteria (NTM) result from defects in the interleukin (IL)-12/-23/interferon (IFN)-γ axis [4–6]. Mutations in the autosomal genes encoding IL-12 p40 subunit (shared with IL-23), IL-12 receptor β1 subunit (IL12Rβ1), tyrosine kinase 2 (Tyk2), IFN-γ receptor ligand binding chain (IFN-γR1), IFN-γ receptor accessory chain (IFN-γR2), signal transduction and activator of transcription 1 (STAT1), as well as the X-linked nuclear factorκ B (NFκB) essential modulator (NEMO), predispose to severe mycobacterial disease and infections with other select bacteria (eg, Salmonella species) and viruses. Mutations affecting IFN-γR1 and IL-12Rβ1 have been linked to severe histoplasmosis [7] and paracoccidiomycosis [8], respectively. We describe a patient who had wide-spread coccidioidomycosis and disseminated Mycobacterium kansasii with a mutation in IFNGR1 .

Case report. An 11-month old white boy who was native to Texas was admitted with a 1-month history of progressive wheezing, cough, and fever with right upper and middle lobe infiltrates with pleural effusion and leukocytosis. Occlusion of the right mainstem bronchus was caused by noncaseating granulomatous lesions. Bronchial washings had rare acid-fast bacilli (AFB) but no fungi. The tuberculin purified protein derivative (PPD) skin test induration was 7-8 mm (intermediate reaction); skin tests for aspergillosis, coccidioidomycosis, and histoplasmosis had negative results. The patient received a presumptive diagnosis of tuberculosis and received isoniazid, rifampin, and pyrazinamide. Two months later, he had worsening stridor and dyspnea. Review of culture results showed that an organism identified as “Mycobacterium chelonei” had grown from multiple respiratory specimens. The patient's regimen was modified, and his condition slowly improved over the ensuing 9 months.

At age 11, while living in Phoenix, Arizona, the patient was admitted to the hospital with fever, cough, anorexia, weight loss, erythema nodosum, and a right lower lobe mass with mediastinal and hilar lymphadenopathy compromising the main stem bronchi and right pulmonary artery. A PPD skin test had negative results, but anti-coccidioidal complement-fixing serum antibodies were detected at 1:1024 (figure 1). Fluconazole administered at a dosage of 200 mg daily caused minimal improvement. One month later, the right hilar mass increased in size, with right middle lobe collapse. The patient again had positive PPD skin test results, but sputum samples were negative for AFB. Mediastinoscopy with lymph node biopsy showed granulomatous inflammation with numerous coccidioidal spherules without AFB. Fluconazole therapy was continued. Bone scan uptake at T12, L4, and areas of the right costovertebral junction at T4 and T10 was presumed to be coccidioidal osteomyelitis. Amphotericin B was given for 6 months with some clinical improvement, followed by treatment with fluconazole. Despite antifungal therapy, the skeletal lesions progressed. Coccidioidal antibody titers never decreased below 1:16. Fluconazole therapy was changed to itraconazole therapy, which temporarily appeared to stabilize the patient's condition. At age 18 years, sacral lesions and presacral lymphadenopathy prompted treatment with amphotericin B followed by treatment with voriconazole. When this regimen was not tolerated, itraconazole therapy was maintained.

Figure 1

The course of infections and correlation with coccidioidal antibody titers. Coccidioidal serological testing was performed at the University of California, Davis, by complement fixation (from age 12 to 15 years) and at the Southern Arizona Veterans Affairs Health Care System (Tucson, Arizona) by quantitative immunodiffusion (from age 21 yearas to present), as described elsewhere [22]. IFN, interferon; M. chelonei, Mycobacterium chelonei; M. Kansasii, Mycobacterium kansasii .

At age 21 years, biopsy of a tender erythematous nodule over the right iliac crest was not diagnostic. Numerous new bony lesions were seen in the lumbar vertebrae, sacrum, sacro-iliac joints, and iliac wings. At surgical debridement with implantation of amphotericin B-impregnated beads, microbiological cultures for bacteria and fungi showed no growth. The patient's therapy was switched to posaconazole.

The patient experienced worsening pain in his back, hips, and shoulders, and magnetic resonance imaging demonstrated worsening vertebral and paravertebral lesions and irregularly enhancing fluid collections in the posterior shoulder soft tissues. More bony lesions led to multiple surgical debridements with placement of amphotericin B-impregnated beads during the next 10 months. Liposomal amphotericin B was given without benefit. During this period, no fungal organisms were identified from specimens, and coccidioidal serological test results ranged from 1:2 to 1:4.

At age 22 years, progressive destruction of the patient's cervical spine caused instability and a retropharyngeal abscess. Cervical debridement and drainage of the abscess showed no AFB but yielded several colonies of M. kansasii .

Because of disseminated NTM and coccidioidomycosis, an immune defect was sought. CD3⁺T cells and subsets, CD20⁺B cells, and CD16⁺natural killer cells were normal. Human immunuodeficiency virus (HIV) test results were repeatedly negative. Neutrophil oxidative burst was normal. HLA was A* 24, 32 and DRB1* 01, 04. The patient had blood type A. Exceptionally bright staining of peripheral blood mononuclear cells for IFN-γR1 indicated its overaccumulation on the cell surface, consistent with the autosomal dominant form of IFN-γR1 deficiency. The patient had blunted production of tumor necrosis factor (TNF)-α in response to IFN-γ stimulation in vitro. Sequencing of IFNGR1 proved heterozygosity for the hotspot 818del4 mutation.

Therapy directed at M. kansasii was initiated with azithromycin, levofloxacin, and ethambutol. Fluconazole therapy was continued for the coccidioidomycosis. Adjunctive subcutaneous IFN-γ (50 µg/m²) was given 3 times weekly. Four months after beginning this regimen, the patient continued to demon strate remarkable clinical improvement.

Discussion. Exposure to Coccidioides species is common within geographically restricted encatchments and typically results in a localized granulomatous infection. Disseminated disease occurs in <1% of those who are infected [3]. These severe cases may provide insight into human immunity to this fungus. This is the first report of a Mendelian trait causally related to disseminated coccidioidomycosis.

Study of immunity to coccidioidomycosis has primarily focused on T lymphocytes [2]. Murine studies show the importance of T cells [9, 10]. Classical human risk factors for disseminated disease include advanced HIV disease, receipt of chemotherapy for hematological malignancy, and immunos uppression for receipt of a solid-organ transplant [3], which also support the central role of T cells. However, symptomatic coccidioidomycosis in association with TNF-α antagonists also implicates macrophages and granulomata in the containment of latent infection [11]. In these iatrogenic situations, however, concomitant broad-spectrum immunosuppression precludes definitive assignment of which immune component is essential. This case demonstrates the essential role of IFN-γ signaling in resistance to coccidioidomycosis, and the macrophage is likely the key effector.

This is, to our knowledge, the first report of a primary immunodeficiency associated with disseminated coccidiodomycosis. Severe coccidioidomycosis has not been reported in genetic immunodeficiencies affecting T lymphocytes (eg, severe combined immunodeficiencies), nor has it been reported in patients with idiopathic CD4⁺T lymphocytopenia. These observations suggest that the IL-12/IFN-γ axis, rather than the T cell per se, determines susceptibility to Coccidioides species. Although histologic and microbiological evidence of infection was obtained only from mediastinal lymph nodes, the patient's extensive vertebral and pelvic osteomyelitis was controlled by antifungal drugs for ∼10 years, during which time his coccidioidal antibody titers decreased from 1:1024 to 1:2. The patient's subsequent deterioration appears to be related to the emergence of the M. kansasii infection that was diagnosed at 22 years of age.

The spectrum of fungal infections in IL-12/IFN-γ defects is distinct from that of chronic granulomatous disease (CGD), an inherited defect in the phagocyte NADPH oxidase. In CGD, patients develop infections due to hyaline septated molds, primarily Aspergillus species, certain yeasts (eg, Candida species and Trichosporon species), and dematiaceous molds. The one reported case of coccidioidomycosis in CGD resolved without antifungal treatment [12]. In sharp contrast, fungal infections associated with defects in the IL-12/IFN-γ pathway include thermally dimorphic endemic mycoses and Cryptococcus species, fungi that are not known to be pathogens in CGD. Zerbe and Holland [7] reported a child with disseminated Histoplasma capsulatum infection who developed disseminated Mycobacterium avium complex with the same autosomal dominant IFNGR1 818del4 mutation as in our case. de Moraes-Vasconcelos et al [8] described a patient with BCG adenitis in infancy and a 7-year bout with disseminated Salmonella enterica serotype Typhimurium, followed by widespread disease with Paracoccidioides brasiliensis , who had recessive complete IL-12Rβ1 deficiency. Rezai et al [13] described a child with chronic systemic illness, disseminated Cryptococcus neoformans , and an unspecified IL-12R deficiency. The contrast between the fungal infections in IL-12/IFN-γ defects and CGD illustrate that distinct pathways mediate defenses against distinct fungi.

Filipinos and black individuals are at 10-175 times higher risk for disseminated disease than their white counterparts, independent of exogenous risk factors or exposure [1]. However, only certain HLA alleles (eg, DRB1*1301) and blood type B have been associated with disseminated disease, molecular phenotypes that may simply be surrogate markers for the at-risk ethnic populations. Mutation in IFNGR1 , in this case, helps to focus on specific pathways for investigation in these at-risk populations. Although primary immunodeficiencies in the IL-12/IFN-γ axis have primarily manifested with NTM infections, polymorphisms that affect the same pathways are associated with susceptibility to M. tuberculosis in certain populations [14, 15]. In additon, patients have been identified with disseminated NTM disease in association with autoantibodies to IFN-γ [16–20], mostly in women of East Asian descent. It will be interesting to determine whether a similar phenomenon contributes to susceptibility to disseminated coccidioidomycosis in women of Filipino descent.

The 818del4 mutation results in partial IFNGR1 deficiency, leading to over-accumulation of mutant IFN-γR1 on the cell surface, which impairs the function of the wild-type receptor. Pharmacologic doses of IFN-γ can overcome this partial defect. Adjunctive IFN-γ has previously been used with success in the treatment of refractory disseminated coccidioidomycosis [21]. Whether susceptibility in these at-risk groups represents a complex trait resulting from anomalies in the IL-12/IFN-γ axis remains to be determined. The identification of a primary immunodeficiency permissive for disseminated coccidioidomycosis expands our understanding of immunity to Coccidioides species.

Acknowledgments

Financial support. Canadian Institutes of Health Research (CIHR fellowship for D.C.V.); Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH; US Department of Veterans Affairs.

Potential conflicts of interest. All authors: no conflicts.