BRIEF REPORT

Refractory Disseminated is [4–6]. Mutations in the autosomal genes encoding IL-12 p40 subunit (shared with IL-23), IL-12 receptor b1 subunit (IL12Rb1), tyrosine kinase 2 (Tyk2), IFN-g receptor ligand and Mycobacteriosis in Interferon-g binding chain (IFN-gR1), IFN-g receptor accessory chain Receptor 1 Deficiency (IFN-gR2), signal transduction and activator of transcription

1 (STAT1), as well as the X-linked nuclear factork B (NFkB) Downloaded from https://academic.oup.com/cid/article/49/6/e62/337395 by guest on 28 September 2021 essential modulator (NEMO), predispose to severe mycobac- Donald C. Vinh,1 Fares Masannat,2,3 Robert B. Dzioba,4 John N. Galgiani,2,3 and Steven M. Holland1 terial disease and infections with other select bacteria (eg, Sal- g 1Immunopathogenesis Section, Laboratory of Clinical Infectious Diseases, monella ) and viruses. Mutations affecting IFN- R1 and National Institute of Allergy and Infectious Diseases, National Institutes IL-12Rb1 have been linked to severe [7] and of Health, Bethesda, Maryland; and 2Valley Fever Center for Excellence, paracoccidiomycosis [8], respectively. We describe a patient 3 The University of Arizona College of Medicine, Southern Arizona Veterans who had wide-spread coccidioidomycosis and disseminated Administration Health Care System, and 4University Medical Center, Tucson, Arizona 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 Severe coccidioidomycosis is rare, and specific genetic sus- wheezing, cough, and fever with right upper and middle lobe ceptibility to the disease remains unidentified. We describe infiltrates with pleural effusion and leukocytosis. Occlusion of a patient with disseminated recalcitrant coccidioidomycosis the right mainstem bronchus was caused by noncaseating with autosomal dominant interferon-g receptor 1 deficiency granulomatous lesions. Bronchial washings had rare acid-fast caused by a heterozygous IFNGR1 818del4 mutation. There- bacilli (AFB) but no fungi. The tuberculin purified protein fore, the interleukin-12/interferon-g axis appears to be crit- derivative (PPD) skin test induration was 7–8 mm (interme- ical for control of coccidioidomycosis. diate reaction); skin tests for , coccidioidomycosis, and histoplasmosis had negative results. The patient received Coccidioidomycosis is caused by the thermally dimorphic a presumptive diagnosis of tuberculosis and received isoniazid, immitis and , which rifampin, and pyrazinamide. Two months later, he had wors- are endemic to regions of the United States, Mexico, and South ening stridor and dyspnea. Review of culture results showed America. Infection occurs after inhalation of an arthroconidial that an organism identified as “Mycobacterium chelonei” had spore; within the lung, the grows as spherules. Successful grown from multiple respiratory specimens. The patient’s reg- containment of Coccidioides species is histologically represented imen was modified, and his condition slowly improved over by necrotizing granulomata [1, 2]. Most cases are either sub- the ensuing 9 months. ! clinical or manifest with self-limited respiratory disease; 1% At age 11, while living in Phoenix, Arizona, the patient was of all infections lead to extrathoracic dissemination [3]. There admitted to the hospital with fever, cough, anorexia, weight loss, are increased rates of extrathoracic disease in certain ethnic erythema nodosum, and a right lower lobe mass with mediastinal groups. However, only select human leukocyte antigen (HLA) and hilar lymphadenopathy compromising the main stem bron- allele polymorphisms and blood group antigen B have been chi and right pulmonary artery. A PPD skin test had negative associated with severe disease [1]. results, but anti-coccidioidal complement-fixing serum antibod- Monogenic susceptibilities to Mycobacterium tuberculosis ies were detected at 1:1024 (figure 1). Fluconazole administered complex and nontuberculous mycobacteria (NTM) result from at a dosage of 200 mg daily caused minimal improvement. One defects in the interleukin (IL)–12/-23/interferon (IFN)-g ax- month later, the right hilar mass increased in size, with right middle lobe collapse. The patient again had positive PPD skin Received 28 February 2009; accepted 28 April 2009; electronically published 14 August 2009. test results, but sputum samples were negative for AFB. Me- Reprints or correspondence: Dr. Steven M. Holland, Laboratory of Clinical Infectious Diseases, diastinoscopy with lymph node biopsy showed granulomatous National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bldg. 10CRC, Rm. B3-4141 MSC 1684, Bethesda, MD 20892-1684 ([email protected]). inflammation with numerous coccidioidal spherules without Clinical Infectious Diseases 2009;49:e62–5 AFB. Fluconazole therapy was continued. Bone scan uptake at 2009 by the Infectious Diseases Society of America. All rights reserved. T12, L4, and areas of the right costovertebral junction at T4 and 1058-4838/2009/4906-00E2$15.00 DOI: 10.1086/605532 T10 was presumed to be coccidioidal osteomyelitis. Amphoter- e62 • CID 2009:49 (15 September) • BRIEF REPORT 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 A. Ex- ceptionally bright staining of peripheral blood mononuclear cells for IFN-gR1 indicated its overaccumulation on the cell surface, consistent with the autosomal dominant form of IFN-gR1 deficiency. The patient had blunted production of Downloaded from https://academic.oup.com/cid/article/49/6/e62/337395 by guest on 28 September 2021 tumor necrosis factor (TNF)-a in response to IFN-g stimu- lation in vitro. Sequencing of IFNGR1 proved heterozygosity for the hotspot 818del4 mutation. Figure 1. The course of infections and correlation with coccidioidal an- Therapy directed at M. kansasii was initiated with azithro- tibody titers. Coccidioidal serological testing was performed at the University mycin, levofloxacin, and ethambutol. Fluconazole therapy was of California, Davis, by complement fixation (from age 12 to 15 years) and continued for the coccidioidomycosis. Adjunctive subcutane- at the Southern Arizona Veterans Affairs Health Care System (Tucson, ous IFN-g (50 mg/m2) was given 3 times weekly. Four months Arizona) by quantitative immunodiffusion (from age 21 yearas to present), after beginning this regimen, the patient continued to demon- as described elsewhere [22]. IFN, interferon; M. chelonei, Mycobacterium chelonei; M. Kansasii, Mycobacterium kansasii. strate remarkable clinical improvement. Discussion. Exposure to Coccidioides species is common within geographically restricted encatchments and typically re- icin B was given for 6 months with some clinical improvement, sults in a localized granulomatous infection. Disseminated dis- followed by treatment with fluconazole. Despite antifungal ther- ease occurs in !1% of those who are infected [3]. These severe apy, the skeletal lesions progressed. Coccidioidal antibody titers cases may provide insight into human immunity to this fun- never decreased below 1:16. Fluconazole therapy was changed gus. This is the first report of a Mendelian trait causally relat- to itraconazole therapy, which temporarily appeared to stabilize ed to disseminated coccidioidomycosis. the patient’s condition. At age 18 years, sacral lesions and pre- Study of immunity to coccidioidomycosis has primarily sacral lymphadenopathy prompted treatment with amphoteri- focused on T lymphocytes [2]. Murine studies show the im- cin B followed by treatment with voriconazole. When this regi- portance of T cells [9, 10]. Classical human risk factors for men was not tolerated, itraconazole therapy was maintained. disseminated disease include advanced HIV disease, receipt of At age 21 years, biopsy of a tender erythematous nodule over chemotherapy for hematological malignancy, and immuno- the right iliac crest was not diagnostic. Numerous new bony suppression for receipt of a solid-organ transplant [3], which lesions were seen in the lumbar vertebrae, sacrum, sacro-iliac also support the central role of T cells. However, symptomat- joints, and iliac wings. At surgical debridement with implan- ic coccidioidomycosis in association with TNF-a antagonists tation of amphotericin B–impregnated beads, microbiological also implicates macrophages and granulomata in the contain- cultures for bacteria and fungi showed no growth. The patient’s ment of latent infection [11]. In these iatrogenic situations, therapy was switched to posaconazole. however, concomitant broad-spectrum immunosuppression The patient experienced worsening pain in his back, hips, precludes definitive assignment of which immune component and shoulders, and magnetic resonance imaging demonstrated is essential. This case demonstrates the essential role of IFN-g worsening vertebral and paravertebral lesions and irregularly signaling in resistance to coccidioidomycosis, and the macro- enhancing fluid collections in the posterior shoulder soft tis- phage is likely the key effector. sues. More bony lesions led to multiple surgical debridements This is, to our knowledge, the first report of a primary im- with placement of amphotericin B–impregnated beads during munodeficiency associated with disseminated coccidiodomy- the next 10 months. Liposomal amphotericin B was given with- cosis. Severe coccidioidomycosis has not been reported in ge- out benefit. During this period, no fungal organisms were iden- netic immunodeficiencies affecting T lymphocytes (eg, severe tified from specimens, and coccidioidal serological test results combined immunodeficiencies), nor has it been reported in ranged from 1:2 to 1:4. patients with idiopathic CD4+ T lymphocytopenia. These ob- At age 22 years, progressive destruction of the patient’s cer- servations suggest that the IL-12/IFN-g axis, rather than the T vical spine caused instability and a retropharyngeal abscess. cell per se, determines susceptibility to Coccidioides species.

BRIEF REPORT • CID 2009:49 (15 September) • e63 Although histologic and microbiological evidence of infection surface, which impairs the function of the wild-type receptor. was obtained only from mediastinal lymph nodes, the patient’s Pharmacologic doses of IFN-g can overcome this partial defect. extensive vertebral and pelvic osteomyelitis was controlled by Adjunctive IFN-g has previously been used with success in the antifungal drugs for ∼10 years, during which time his cocci- treatment of refractory disseminated coccidioidomycosis [21]. dioidal antibody titers decreased from 1:1024 to 1:2. The pa- Whether susceptibility in these at-risk groups represents a com- tient’s subsequent deterioration appears to be related to the plex trait resulting from anomalies in the IL-12/IFN-g axis emergence of the M. kansasii infection that was diagnosed at remains to be determined. The identification of a primary im- 22 years of age. munodeficiency permissive for disseminated coccidioidomy- The spectrum of fungal infections in IL-12/IFN-g defects is cosis expands our understanding of immunity to Coccidioides distinct from that of chronic granulomatous disease (CGD), species. an inherited defect in the phagocyte NADPH oxidase. In CGD, patients develop infections due to hyaline septated molds, pri- Acknowledgments Downloaded from https://academic.oup.com/cid/article/49/6/e62/337395 by guest on 28 September 2021 marily species, certain (eg, Candida species Financial support. Canadian Institutes of Health Research (CIHR fel- and species), and dematiaceous molds. The one lowship for D.C.V.); Division of Intramural Research, National Institute reported case of coccidioidomycosis in CGD resolved without of Allergy and Infectious Diseases, NIH; US Department of Veterans Affairs. antifungal treatment [12]. In sharp contrast, fungal infections Potential conflicts of interest. All authors: no conflicts. associated with defects in the IL-12/IFN-g pathway include thermally dimorphic endemic mycoses and Cryptococcus spe- References cies, fungi that are not known to be pathogens in CGD. Zerbe 1. Ampel NM. The complex immunology of human coccidioidomycosis. and Holland [7] reported a child with disseminated Histoplas- Ann N Y Acad Sci 2007; 1111:245–58. 2. Shubitz LF, Dial SM, Perrill R, Casement R, Galgiani JN. Vaccine- ma capsulatum infection who developed disseminated Mycobac- induced cellular immune responses differ from innate responses in terium avium complex with the same autosomal dominant susceptible and resistant strains of mice infected with Coccidioides po- IFNGR1 818del4 mutation as in our case. de Moraes-Vascon- sadasii. Infect Immun 2008; 76:5553–64. 3. Laniado-Laborin R. Expanding understanding of epidemiology of coc- celos et al [8] described a patient with BCG adenitis in infancy cidioidomycosis in the Western hemisphere. Ann N Y Acad Sci 2007; and a 7-year bout with disseminated Salmonella enterica se- 1111:19–34. rotype Typhimurium, followed by widespread disease with Par- 4. Bustamante J, Zhang S-Y, von Bernuth H, Abel L, Casanova J-L. From infectious diseases to primary immunodeficiencies. Immunol Allergy acoccidioides brasiliensis, who had recessive complete IL-12Rb1 Clin North Am 2008; 28:235–58. deficiency. Rezai et al [13] described a child with chronic sys- 5. Rosenzweig SD, Holland SM. Defects in the interferon-{gamma} and temic illness, disseminated ,andan interleukin-12 pathways. Immunol Rev 2005; 203:38–47. unspecified IL-12R deficiency. The contrast between the fun- 6. Minegishi Y, Saito M, Morio T, et al. Human tyrosine kinase 2 defi- ciency reveals Its requisite roles in multiple cytokine signals involved gal infections in IL-12/IFN-g defects and CGD illustrate that in innate and acquired immunity. Immunity 2006; 25:745–55. distinct pathways mediate defenses against distinct fungi. 7. Zerbe CS, Holland SM. Disseminated histoplasmosis in persons with Filipinos and black individuals are at 10–175 times higher interferon-g receptor 1 deficiency. Clin Infect Dis 2005; 41:e38–41. 8. de Moraes-Vasconcelos D, Grumach AS, Yamaguti A, et al. Paracocci- risk for disseminated disease than their white counterparts, in- dioides brasiliensis disseminated disease in a patient with inherited de- dependent of exogenous risk factors or exposure [1]. However, ficiency in the b1 subunit of the interleukin (IL)-12/IL-23 receptor. Clin only certain HLA alleles (eg, DRB1*1301) and blood type B have Infect Dis 2005; 41:e31–7. 9. Beaman L, Pappagianis D, Benjamini E. 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