A 28-year-old female was admitted to our hospital on August 17, 2017, with lymphadenomegaly on her right cervical area for approximately 2 months and repeated fever for more than 1 month, accompanied by a red rash, edema, and painful subcutaneous nodules in bilateral legs. Physical examination revealed lymphadenopathy in the right cervical bone and painful erythema nodosum in the bilateral calf. The patient had a history of pet rat bites in 2015.
Laboratory tests showed that hemoglobin (9.4 g/dL) and hematocrit (28.8%) levels were decreased, while white blood cell count (16.27x109/L), neutrophils (78.6%), platelet count (418x109/L), blood C-reactive protein (138.15 mg/L) and erythrocyte sedimentation rate (88 mm/h) were elevated. HIV serology and serum cryptococcal capsular antigen tests were negative. Immunoglobulin levels and lymphocyte subsets were normal. T cell spot test (T-SPOT) was indeterminate. Culture of blood, sputum, bronchoalveolar lavage fluid (BALF), and skin lesions were all negative. Chest computed tomography (CT) displayed patchy infiltrates in the right upper lung with enlargement of hilus pulmonis and mediastinal lymph nodes (Figure 1A). Pathological examination of the cervical lymph nodes suggested granulomatous inflammation, but acid-fast staining and periodic acid-Schiff (PAS) staining were negative (Figure 2A and B). EBUS-TBNA biopsy examination showed scattered granulomatous inflammation. During the course, empirical treatments with cefoxitin (CFX), levofloxacin (LVFX), moxifloxacin (MFX), cefodizime (CDZ), clarithromycin (CLA), etimicin (ETM) and anti-tuberculosis isoniazid (H), rifampicin (R), pyrazinamide (Z), ethambutol (E) regimen were successively administered, but no improvement was observed. By the end of October 2017, the patient developed pain in the head, right shoulder, gingiva, and knee-joint. Cerebrospinal fluid examination was normal, its smear and culture were all negative. Although bone marrow biopsy was consistent with infection and there was no evidence of hematological malignancy, the culture of bone marrow and lymph node tissue was both negative. Pathology examination of cervical lymph nodes showed suppurative necrotizing lymphadenitis, no fungus, and PAS (-). Positron emission tomography-computed tomography displayed enlargement of multiple lymph nodes of the right hilar, mediastinum, right supraclavicular and right neck, splenomegaly and increased bone metabolism in multiple places. The symptoms persisted after multiple rounds of antibiotic treatments, raising the possibility of a fungal infection. As the patient had a history of rat bites, an important natural reservoir for T. marneffei, we conducted T. marneffei qPCR and obtained a result of 1798 copies/uL. Therefore, the patient was diagnosed with disseminated T. marneffei infection, and intravenous antifungal therapy with amphotericin B liposome (AMPB) commenced on November 6, 2017. Owing to suspicion of coinfection with NTM, the patient was also treated with cefoxitin beginning on November 10, 2017. Subsequently, her body temperature dropped to normal, and symptoms of cough and sputum improved. The patient returned to the local hospital and continued treatment with itraconazole and cefoxitin.
However, the lymph nodes remained enlarged. In December 2018, the patient presented with hemoptysis and recurrent intermittent fever, cough, sputum, fever, and rash. The patient presented with recurrent fever, rash and lymph node enlargement, which did not improve despite treatment with various antibiotics and anti-infective treatment for T. marneffei and M. tuberculosis. The pathological manifestations were granulomatous inflammation, but we could not rule out NTM infection because the cultures for M. tuberculosis and NTM were negative. Therefore, we performed an mNGS test, which revealed M. fortuitum in the lymph nodes. Additionally, in January 2020, qPCR analysis of a BALF sample detected T. marneffei. The patient was diagnosed with coinfection with M. fortuitum and T. marneffei and was treated with a combination of amphotericin B, voriconazole (VRC), linezolid (LZD) and ETM. Her body temperature returned to normal and respiratory symptoms improved. On March 19, 2020, chest CT showed patchy infiltrates, banded and nodular shadows, as well as pleural effusion (Figure 3A). Emission computed tomography suggested abnormal concentration of imaging agent in various parts of the bone. One month later, the therapy was adjusted to a combination regimen of VRC, LZD, MFX and CLA, which have continued to date. During follow-up in May and August 2020, the patient had no fever, the symptoms of cough and sputum had improved, and the rash had subsided. Re-examination of chest CT indicated that the enlarged hilar lymph nodes had gradually shrank (Figure 1B-E), and the lung lesions were significantly absorbed (Figure 3A-C). The patient experienced significant pain for more than 2 years between onset to the definitive diagnosis. The hospitalization and drug administration process throughout the history is summarized in Figure 4. Unfortunately, we overlooked the possibility of immunodeficiency in HIV-negative patient coinfected with M. fortuitum and T. marneffei.