Disseminated Talaromyces marneffei and Mycobacterium abscessus in a Patient With Anti-Interferon-γ Autoantibodies

A 72-year-old Thai man, from Northern Thailand, with a past medical history of diabetes mellitus and cerebrovascular accident with left hemiparesis, presented with cervical lymphadenopathy for 15 months. The patient was initially diagnosed with tuberculosis (TB) at a local hospital based on the histopathology finding of cervical lymph node fine-needle aspiration, which showed caseous granuloma formation. However, the tissue was negative for acid-fast bacteria (AFB) stain, and AFB culture was not performed. His initial chest x-ray revealed no definitive infiltration. He had been treated with a standard anti-TB regimen including isoniazid (H), rifampicin (R), pyrazinamide, and ethambutol for 2 months and continued with HR treatment with good adherence. During the 4th month of anti-TB treatment, he developed new cervical lymphadenopathy, low-grade fever, and erythematous patches at anterior chest wall. After completing 6 months of anti-TB treatment, he developed axillary lymphadenopathy and progression of the skin lesion. The patient was then referred for further evaluation at our hospital. On admission, the patient's vital signs were within normal ranges. Multiple cervical lymph nodes and right axillary lymph nodes (3 cm in diameter) were palpated. Skin examination revealed erythematous plagues with crusted lesions at right cheek and upper chest area. The skin lesions were reminiscent of reactive dermatoses (Figure ​(Figure1A1A and ​and1B).1B). Laboratory data revealed a white blood cell count of 16 800/µL (neutrophil 72.5%, lymphocyte 10.6%, eosinophil 11.3%, monocyte 4%, basophil 1.6%), hemoglobin of 9 g/dL, and platelet of 390 000/µL. Laboratory results of liver and renal functions were unremarkable except for albumin of 1.9 g/dL. A third-generation human immunodeficiency virus (HIV) antibody assay was nonreactive. Computer tomography of the chest and abdomen revealed reticulonodular opacities in the right lower lung field and multiple enlarged intra-abdominal lymph nodes. Skin biopsy was performed and tissue pathology showed small-sized, yeast-like organisms with binary fission, predominant inflammatory cells: plasma cells and lymphocytes without papillary dermal edema (Figure ​(Figure1C).1C). The biopsied skin tissue culture revealed fungal organism growth consistent with Talaromyces (Penicillium) marneffei (Figure ​(Figure1D).1D). Bronchoalveolar lavage (BAL) was performed and revealed no endobronchial lesion. The BAL fluid with Gomori Methenamine Silver staining also showed multiple yeast-like organisms. However, the BAL culture did not recover any organisms. The treatment regimen for T marneffei infection was intravenous liposomal amphotericin-B for 2 weeks, followed by oral itraconazole (400 mg/day) for 10 weeks, and secondary prophylaxis (200 mg/day). A repeat cervical lymph node biopsy was performed, and tissue culture revealed growth of Mycobacterium abscessus confirmed by sequencing of the first 500 base pairs of the 16S ribosomal ribonucleic acid (RNA) gene. The minimal inhibitory concentration (MIC) of M abscessus isolate was further performed using the broth microdilution method. The MIC results were as follows: 8 µg/mL amikacin, >128 µg/mL cefoxitin, >4 µg/mL ciprofloxacin, >16 µg/mL clarithromycin, >16 µg/mL doxycycline, 32 µg/mL linezolid, and > 8/152 μg/mL trimethoprim/sulfamethoxazole. The treatment for M abscessus infection was intravenous amikacin plus imipenem-cilastatin for 28 days (initially as empirical regimens for non-TB treatment) follow by amikacin 3 times a week plus clarithromycin and ciprofloxacin (Table ​(Table1).1). Given the patient's clinical presentation with multiple intracellular pathogen infections, a cellular-mediated immune defect was suspected. A final diagnosis of anti-interferon (IFN)-γ autoantibodies was confirmed based upon on a positive anti-IFN-γ antibody assay (inhibition enzyme-linked immunosorbent assay [ELISA]), which was performed at the Cellular and Molecular Immunology Unit (Center for Research and Development of Medical Diagnostic Laboratories, Khon Kaen University, Khon Kane, Thailand) using a cytokine detection ELISA kit (BD Biosciences). After 6 months of treatment for T marneffei infection and 3 months of treatment for M abscessus infection, the patient developed new enlarged cervical lymph nodes without improvement of skin lesions and pulmonary infiltrates. He further received 1000 mg of methylprednisolone plus 375 mg/m2 rituximab weekly to control B cell-derived anti-IFN autoantibodies. After 8 weeks of methylprednisolone and rituximab treatment, his skin lesions improved. Although M abscessus isolates from this patient had a low MIC only for amikacin, the patient developed renal toxicity and hearing loss from amikacin. An adjusted treatment regimen with linezolid was performed (Table ​(Table1).1). However, the patient also developed adverse effects from linezolid (thrombocytopenia) and ciprofloxacin (QT prolongation). Given the limited treatment options, he continued to receive clarithromycin plus ethambutol for M abscessus treatment for 14 months. Six months later, the patient received the second course of methylprednisolone plus rituximab. The patient responded well to the therapy with no new skin lesions and lymphadenopathy at least 9 months after all antimicrobial treatments were discontinued. The level of anti-IFN-γ autoantibodies titer had decreased from more than 1:10 000 (reference range <1:100) before the combined methylprednisolone and rituximab treatment to 1:5000 after 2 courses of the therapy (12 months after the first titers tested). Table 1. Demonstrated Cases of Disseminated Talaromyces (Penicillium) marneffei Infection With Anti-IFN-γ Autoantibodies With Complete Patient Informationa Figure 1. (A and B) Erythematous plaque with multiple crusted lesions at anterior chest wall and right side of head and neck. (C) Histopathology findings of biopsied skin lesion showed small-sized, yeast-like organisms sized 2–4 µm with binary fission ...