A 68-year-old man was admitted to our hospital for the following symptoms: a non-productive cough, malaise, gait difficulty, visual impairment, multiple skin rashes, and a nodule on his middle anterior chest. Until then, he had not visited any medical facilities for many years due to his economic status. According to the patient's recollection, the papules and nodule appeared 3 years previously. His visual impairment started 1 year previously and gradually worsened. His cough started 3 months before this admission, and it was initially wet and then became non-productive. In addition, he experienced general malaise, and he had difficulty walking since 10 days before the hospital visit.
A physical examination on admission showed a blood pressure of 117/63 mmHg, pulse rate of 65 beats per min, and body temperature of 35.8C. Both conjunctivae were moderately anemic without icterus. Viscous discharge was present in both eyes. Erythema was found on his right cheek, anterior and posterior chest, and both lower legs. On his right cheek, painless erythema with scabs was observed. Purulent discharge was observed while gently pressing the rash. A solitary red nodule (5 cm in diameter) was present on his anterior chest (Fig. 1a). Multiple small, red papules (maximum size: 2 mm) were present on his trunk (Fig. 1b). His extremities were edematous, and an erosive rash was present on his legs. Several lymph nodes (maximum size: 15 mm) were palpated around his superficial lateral cervical area. Aside from these lymph nodes, a thumb-sized, painless, soft subcutaneous mass was present on his right lateral neck. On chest auscultation, the breath sounds were weak in his right lower lung.
Laboratory results on admission are shown in Table 1. An increased white blood cell count, C-reactive protein level, and erythrocyte-sedimentation ratio were detected. Normocytic anemia and decreased total protein and albumin levels were noted. M. avium complex (MAC) antibody was slightly increased. Other than MAC antibody, antibodies for hepatitis B and C viruses, human immunodeficiency virus (HIV), and human T cell leukemia virus type 1 were negative. The number of CD4-positive T lymphocytes was 440 cells/muL. Results of an enzyme-linked immunospot assay for IFN-gamma response to Mycobacterium tuberculosis antigens (T-SPOT(R).TB, Oxford Diagnostic Laboratory, Marlborough, USA) on admission showed zero spots for ESAT-6 and CFP-10 antigens (the positive control panel detected 21 spots). When determining the IFN-gamma response to M. tuberculosis antigens by an enzyme-linked immunosorbent assay (QuantiFERON(R) TB-3G, Cellestis, Chadstone, Australia), the test results were considered to be invalid because the IFN-gamma response to phytohemagglutinin (PHA) was not detected in the positive control tube (0.00 IU/mL).
On chest computed tomography, the right inferior lobar bronchus was completely occluded by a tumor-like lesion (1 cmx1 cm in size), resulting in complete atelectasis of his right lower lung (Fig. 2a). Bronchoscopy showed that the tumor-like lesion completely occluded the right lower bronchus (Fig. 2b). An ultrasound analysis indicated that his left cervical mass was a subcutaneous abscess. Brain magnetic resonance imaging (MRI) showed swelling in the retrobulbar part of both optic nerves (Fig. 4c).
Bacterial cultures of the patient's sputum on admission did not indicate any significant common bacteria. However, on Ziehl-Neelsen staining, 2+ for acid-fast bacilli (AFB) were observed in his sputum. A polymerase chain reaction (PCR) analysis showed that the bacilli were M. avium. Lavage fluid from the right lower bronchus also showed 3+ for AFB. In addition to the respiratory specimens, AFB was also detected in the eye discharge (1+), purulent discharge from the right cheek (2+), and a biopsy specimen from a mass-like lesion of the right lower bronchus and the chest nodule (3+) by Ziehl-Neelsen staining (Fig. 1b). All of these AFB were confirmed to be M. avium by PCR.
A biopsy of the tumor-like region in the right lower bronchus indicated the formation of a histiocytic granuloma with numerous AFB (Fig. 3a). Additionally, numerous AFB (Fig. 3b) and a xanthogranuloma with histiocytic infiltration positively stained with CD68 (Fig. 3c) were detected in the chest nodule.
According to these results, the patient was finally diagnosed with disseminated M. avium infection. According to previous reports on the relationship between serum autoantibodies to IFN-gamma and disseminated NTM diseases, we performed an enzyme-linked immunosorbent assay (ELISA) for the autoantibody to IFN-gamma (human interferon-gamma antibody ELISA kit, Cusabio, Wuhan, China) using the patient's serum specimen. The optical density (450 nm) value of the patient's serum was 0.409, with 0.037 in a negative control well. In this assay system, a value 2.1-fold higher than the negative control well (i.e., 0.077 in this case) is considered to be positive for the presence of an autoantibody to IFN-gamma. Subsequently, we tested the concentrations of anti-IFN-gamma autoantibodies and the neutralizing capacity to recombinant human IFN-gamma in the patient's serum using methods previously reported. The serum concentrations of the autoantibody to IFN-gamma were 728.13 ELISA Units (EU) 1 month after treatment, 2015 (1 month after treatment) and 109.29 EU 6 months after treatment 28, 2015 (6 months after treatment). These titers were significantly higher than the normal range (5-50 EU). The signal transducer and activator of transcription-1 in immortalized human T cells was not phosphorylated after stimulation with IFN-gamma by the presence of the patient's serum. According to these results, we determined that the patient's serum had retained neutralizing anti IFN-gamma autoantibodies.
Anti-mycobacterial chemotherapy was started 30 days after admission. A combination of 800 mg of CAM daily, 600 mg of RFP daily, and 750 mg of EB daily was initiated. The rash on the right cheek temporarily worsened around 10 weeks after chemotherapy. After 4 months of chemotherapy, the patient's general condition and the appearance of his skin lesions markedly improved (Fig. 4a and b). Follow-up orbital MRI showed obvious improvement in swelling of both optic nerves (Fig. 4c and d).
A chest computed tomography scan and bronchoscopic findings. a: Atelectasis of the right lower lobe.