Adult-onset immunodeficiency due to anti-interferon-gamma autoantibody in mainland Chinese

Immunodeficiency due to anti-interferon-gamma (anti-IFN-γ) autoantibody is an emerging adult-onset immunodeficiency syndrome associated with severe or disseminated infections caused by non-tuberculous mycobacteria, non-typhoidal salmonella, Burkholderia sp., Penicillium marneffei, Cryptococcus neoformans, Histoplasma capsulatum, and varicella zoster virus (VZV) in non-HIV-infected patients caused by the presence of high-titer serum neutralizing anti-IFN-γ autoantibodies which inhibit IFN-γ-induced STAT1 phosphorylation and interleukin-12 production.1–3 It was first reported in an otherwise immunocompetent Filipino man with disseminated Mycobacterium chelonae infection in 2004.1 Since then, the condition has been increasingly reported in Asians including Filipino, Thai, Vietnamese, Japanese, and Chinese residents from Hong Kong and Taiwan, and less commonly in other ethnic groups.1,2 A 34-year-old Chinese woman presented with gradual onset of right posterior neck swelling in January 2012. She was born in Xiamen in the Fujian Province of China and resided in Hong Kong from 5 years ago. Her medical history was unremarkable except for chronic hepatitis B. Her condition deteriorated despite herbal medicine in the subsequent 6 months with enlarging cervical lymphadenopathy which progressed to involve the left side, weight loss of 15 pounds, productive cough without hemoptysis, and painful nodular lesions over the lower limbs. Physical examination at 6 months after symptom onset revealed a temperature of 37°C, multiple palpable non-tender cervical lymph nodes, right lung base coarse crepitations, and multiple tender non-ulcerative nodular lesions over bilateral lower limbs suggestive of erythema nodosum. Blood tests showed leukocytosis with neutrophilia (total white cell, 17.6×109/ L; neutrophil, 13.3×109/L), and normal liver and renal function test results. Chest radiograph showed right lower lobe consolidation. Computerized tomography scans of the nasopharynx and neck showed multiple enlarged lymph nodes measuring up to 1.6 cm along bilateral superior, middle, and inferior jugular chain, right submandibular, posterior triangle, and right supraclavicular regions. The lung apices were clear. Fine-needle aspiration of the right submandibular lymph node showed granulomatous inflammation with nests of epithelioid histiocytes and scattered multinucleated giant cells without acid fast bacilli being seen in Ziehl-Neelsen-stained smears. The patient refused a more extensive histopathological examination by excisional biopsy of the cervical lymph node. In view of the clinical manifestations and investigation results, she was started on anti-tuberculosis treatment consisting of isoniazid 300 mg daily, pyridoxine 10 mg daily, rifampicin 600 mg daily, pyrazinamide 1 g daily, and ethambutol 800 mg daily 9 months after symptom onset. However, her condition continued to deteriorate with persistent right lower lobe consolidation, worsening cervical lymphadenopathy, and erythema nodosum after 2 months of treatment. Culture of the right mandibular lymph node subsequently yielded M. chelonae which was susceptible to cefoxitin, clarithromycin, imipenem, and amikacin. The antimicrobial regimen was changed to intravenous imipenem-cilastatin 500 mg q8h, intravenous amikacin 500 mg q24h, and oral clarithromycin 500 mg twice daily which led to good clinical response. Further immunological work-up was performed because of the unusual clinical presentation of disseminated infection caused by M. chelonae in an apparently immunocompetent host. She was tested negative for HIV infection, had unremarkable autoimmune markers, immunoglobulin pattern, and normal lymphocyte count. Finally, she was referred to our center one year after symptom onset and found to be positive for anti-IFN-γ autoantibody using our previously described method.1 Like most of the other cases, our patient had symptom onset in adulthood at around 30–50 years. The condition has an ethnic predilection among Asians which suggests possible genetic predisposition that may be partly explained by an association with two HLA alleles, DRB1* 16:02 and DQB1*05:02.3 The seroprevalence of the autoantibody among Chinese populations in different regions is not well determined. The condition has been reported among patients in Hong Kong and Taiwan, but not those from mainland of China. Interestingly, our patient is also from Xiamen, Fujian, where a large proportion of the general population shares common ancestry with Taiwanese Chinese. We have not found any positive case in over 500 healthy adults in Hong Kong (unpublished data), and only 1/48 (2%) healthy adults in Taiwan, China or Thailand was found to be positive for non-inhibitory anti-IFN-γ autoantibody in a recent study.2 Our description of the first laboratory-confirmed case of immunodeficiency syndrome due to anti-IFN-γ autoantibody in an ethnic Chinese patient born in mainland of China signifies the importance of clinical awareness and availability of laboratory diagnostic tests in enhancing our understanding of the true incidence and possible predisposing genetic factors of the condition in our population. As in our patient, common presenting clinical manifestations include chronic cervical lymphadenopathy caused by non-tuberculous mycobacteria and reactive or infective dermatoses.4 Other presentations include fever of unknown origin or disseminated infection caused by extra-intestinal non-typhoidal salmonella, P. marneffei, C. neoformans, H. capsulatam, and VZV reactivation.1,2 The diagnosis of the underlying immunodeficiency syndrome is often delayed because of the lack of clinical awareness and/or laboratory diagnostic test especially in resourcelimited areas. The diagnosis of our patient was confirmed one year after symptom onset during which she underwent extensive investigations and ineffective treatment. In our locality, many patients who initially presented with cervical lymphadenopathy, fever, and/or pneumonia would be treated empirically with anti-tuberculosis drugs especially if their lymph node biopsies showed evidence of granulomatous inflammation. This is not unreasonable because of the compatible clinical features and high endemicity of tuberculosis in the region. However, with the recognition of this emerging immunodeficiency syndrome which is predominantly found in Southeast Asians, clinicians should consider the need to check for anti-IFN-γ autoantibody in HIV-negative adult patients if there was no microbiological confirmation of tuberculosis, lack of clinical response to anti-tuberculosis drugs unless multidrug-resistant tuberculosis was suspected, or the presence or history of non-tuberculous mycobacterial infection or other opportunistic infections associated with the immunodeficiency syndrome. In such circumstances, testing for anti-IFN-γ autoantibody should be performed after exclusion of other immunosuppressive conditions. While different laboratory diagnostic assays have been used, our previously described method of using a screening enzyme-linked immunosorbent assay followed by another confirmatory spiking assay has the advantages of being inexpensive and non-technically-demanding, and is therefore suitable in resource-limited areas such as the rural parts of China.1 Early diagnosis would allow prompt treatment for the opportunistic infections and the immunological defect in these patients. As in our patient, antimicrobials are often required for prolonged periods in the absence of autoantibody suppression. In our experience, the majority of patients would develop recurrent and occasionally life-threatening infections unless they were maintained on life-long suppressive therapy that was usually given by self-administration home therapy via a central venous catheter. Unfortunately, attempts with corticosteroid, intravenous immunoglobulins, cyclophosphadmide, and/or plasmapheresis to permanently eradicate the autoantibodies have so far been futile. Recently, anti-CD20 (rituximab) has been reported to be effective in reducing the anti-IFN-γ autoantibody levels, improving IFN-γ signaling, and clearing the infection in 4 patients with refractory disease despite plasmapheresis, exogenous IFN-γ and intravenous immunoglobulins.5 The main disadvantages of anti-CD20 are high cost and potential side effects such as infectious complications secondary to the depletion of B-cells. Further studies on effective, safe, and inexpensive treatment options are urgently needed.