The patient was a 62-year-old Chinese woman with no previous disease history. She was admitted to our hospital in August 2016 due to intermittent fever with cough for 2 years, left chest wall redness, and swelling for 3 months. She presented with a fever and cough repeatedly from September 2014. Laboratory tests showed increased white cells and chest computed tomography (CT) suggested patchy infiltration in the left lower lobe, with mediastinal lymph node enlargement (Figure 1A-D). Empirical treatment with cephalosporin was partially effective, but the symptoms were recurrent. In May 2016, she developed redness and a swelling in the left front chest wall with pain and high fever. She was admitted to our hospital for incision and drainage of the disease site and antibiotic administration. At the time of admission, laboratory tests showed white blood cells counts of 20.61x109/L (3.5-9.5x109/L); neutral cell percentages of 0.744 (0.4-0.75); hemoglobin: 79 g/L (130-175g/L), platelets: 384x109/L (125-350x109/L), blood C-reactive protein (CRP): 43.6 mg/L (0-8 mg/L), high levels of Immunoglobin G (IgG): 50.5 g/L (7.51-15.6 g/L); blood (1, 3)-D glucan (G tests): 146.20 pg/mL (<100.5 pg/mL); and blood galactomannan test (GM) positivity (0.64) (<0.5). HIV serology tests were negative, and normal CD4+ T cell counts and serum globulins levels (including IgA, IgM, and total IgE) were within normal reference ranges. Serum cryptococcal capsular antigen tests and blood tuberculosis infection T cell spot tests (T-SPOT.TB) were negative. Chest CT (2016-8-27) showed alveolar consolidation in the anterior segment of the left upper lobe, and an anterior chest wall with rib destruction and multiple lymphadenopathies in the left axillary and mediastinum (Figure 1E-H). Fungal spores were detected in pus from the left chest wall and microbial cultures showed T. marneffei growth. Disseminated T. marneffei (lung, skin, and bone) were established and the patient was administered amphotericin B followed by itraconazole therapy. After 8 months of regular treatment, her condition improved and antifungal drugs were ceased. The patient was followed up regularly in the clinic (Figure 1I-L).
In July 2017, she again developed a high fever. Laboratory examinations after hospital admission showed white blood cells counts of 11.66x109/L; neutral cell percentages of 0.647; hemoglobin: 80 g/L; platelets: 308x109/L; blood CRP: 53.9 mg/L; IgG: 30.2 g/L; erythrocyte sedimentation rates of 66 mm/h (0-20 mm/h); and CD4+ T lymphocyte ratios of 32.6% (34-52%). G-tests, GM, and pro-calcitonin were within the normal range. Repeat chest CT scans showed consolidation in the left and right upper lobes. Bronchoscopy examinations were pathogen negative. After 2 weeks of treatment with beta-lactam antibiotics combined with oral antifungal drugs, no improvement in symptoms was observed and abnormal lung infiltration was observed in CT scans. CT-guided percutaneous right lung biopsy was performed. Pathological examinations demonstrated lung inflammation in the absence of granuloma formation. Mycobacterium avium (M. avium) was cultured and identified from mass spectrometry. Anti-NTM treatment included azithromycin, ethambutol, moxifloxacin, and rifabutin which were prescribed from August 2017. Due to adverse gastrointestinal and allergic reactions of the skin after 1 month of anti-NTM combination therapy, the patient refused treatment and was followed up in the clinic. No recurrence of the fever was observed.
In May 2018, the fever recurred with hand rashes, and the patient was admitted to the hospital a third time. Her body temperature peaked at 40 C with increased pulmonary infiltration accompanied by left sternoclavicular joint destruction (Figure 2A-C). Physical examinations revealed multiple palpable lymph nodes in the left neck, erythematous plaques, and nodules in both hands (Figure 3A). Blood tests were similar to previous examinations in which increased numbers of white blood cells, CRP, and high levels of serum IgG were observed. Immune electrophoresis revealed polyclonal gammopathy, and blood/bone marrow cultures were negative. After biopsy from the left cervical lymph node and left sternoclavicular joint, M. avium was cultured from both sites. Histopathology demonstrated inflammation from the lymph nodes, and small amounts of elastic fibers with small blood vessels. Histopathology of the hand skin showed neutrophil infiltration (Figure 3B and C). Microorganism cultures were negative. The patient was finally confirmed as disseminated NTM secondary to disseminated T. marneffei. In view of the negative microbial cultures in skin biopsy tissues, and the rapid resolution of hand rashes with steroid ointments, Sweet's syndrome was diagnosed. Combination anti-NTM therapy was re-prescribed from June 2018. After 1 year of treatment, the patient's symptoms and pulmonary consolidation improved. Bone destruction and lymphadenopathy, however, remained obvious (Figure 2D-F). Laboratory tests were in the normal range except for IgG (Figure 4). The patient presented multiple intracellular pathogen infections without HIV or immunodeficiency. Serum cytokines including IL-2, IL-4, IL-6, IL-10, TNF-alpha, and IFN-gamma were within the normal range. Serum samples from both patients and controls (blood donors) including anti-IFN-gamma autoantibodies, anti-IL-12 autoantibodies, anti-TNF-alpha, and IL-12 were assessed using ELISA kits (Cloud-Clone Corp). Patient serum was tested as four independent samples and statistical analysis were performed using unpaired t-tests (GraphPad Prism Software). The mean concentration of anti-IFN-gamma antibodies in the serum samples of the patient (range: 33.13-47.06 ng/mL) was 2.85-fold higher than healthy subjects (range: 8.41-20.02 ng/mL) (P<0.01) (Figure 5). No statistically significant differences between patients and controls for TNF-alpha, IL-12, and anti- TNF-alpha were observed (data not shown).
2018-5-8 chest CT showed right upper lobe consolidation, and ,destruction of the left sternoclavicular joint (arrows).