A 19-year-old Japanese woman was admitted to a local community hospital (day 1) with a 6-day history of a fever, chills, dyspnea, and general malaise. Chest computed tomography (CT) obtained at the hospital showed diffuse ground-glass opacity in both lungs and multiple mediastinal lymphadenopathy (Fig. 1), and empiric antibiotic therapy (SBT/ABPC, MINO) was started. She underwent a transbronchial lung biopsy (TBLB) and bronchoalveolar lavage (BAL) on day 4 that disclosed noncaseating epithelioid granuloma without any organisms. Acid-fast staining of the sputum (three sets) and bronchoalveolar lavage fluid (BALF) also showed negative results. After a bronchoscopic examination, she developed respiratory failure, and steroid pulse therapy was started (day 4). After the steroid pulse therapy, her breathing state and pulmonary abnormal findings on computed tomography (CT) improved (day 9). However, on day 13, the high fever recurred during steroid reduction, and her multiple mediastinal lymphadenopathy persisted. In addition, her plasma soluble interleukin-2 receptor (sIL-2R) level was elevated (2,587 pg/mL). Therefore, the previous doctor suspected malignant lymphoma, and she was referred to our hospital for a definitive diagnosis.
On admission to our hospital (day 15), she presented with a fever and general malaise. She did not smoke or consume alcohol or travel, and she had no remarkable medical history. Her grandfather had a history of tuberculosis three years prior, and she occasionally interacted with him. Her body temperature was 40  C, heart rate 90 beats/min, blood pressure 109/62 mmHg, respiratory rate 18 breaths/min, and oxygen saturation 93% under normal conditions. On a physical examination, the edge of the liver could be felt 2-3 cm below the right costal margin without splenomegaly or lymphadenopathy. There were no rales on chest auscultation, and a cardiac examination revealed a regular rate and rhythm with no murmurs. Chest X-ray and CT obtained on admission revealed consolidation in the left upper lung field, ground-glass opacity in both lungs, and multiple mediastinal lymphadenopathy (Fig. 2). Abdominal ultrasound showed hepatosplenomegaly with coursing echogenicity of the liver. Laboratory work-up revealed decreased levels of hemoglobin and elevated levels of AST, ALT, ALP, gamma-GTP, LDH, CRP, TG, fibrinogen, FDP, D-dimer, ferritinm, sIL-2R, and ACE (Table 1). A peripheral blood smear showed monocytosis with hemophagocytosis. Further evaluations, including (1,3)beta-D-glucan, legionella, mycoplasma, chlamydia, cytomegalovirus, Epstein-Barr virus antigen titers, and HIV ELISA, were all negative. The result of QuantiFERON-TB 3Gold (QFT-3G) was indeterminate. Several sets of blood cultures were negative, and sputum culture disclosed only yeast-like microorganisms.
On day 22, pancytopenia developed (white blood count cell count of 2,320x103/muL, hemoglobin 7.3 g/dL, platelet count 8.0x104/muL), and these results and clinical course suggested potential diagnoses of HPS, malignant lymphoma, sarcoidosis, hypersensitivity pneumonia, and tuberculosis. Therefore, we performed a bone marrow biopsy and TBLB again (day 23). The biopsy showed hemophagocytosis and noncaseating granulomatous inflammation without evidence of acid-fast bacilli or lymphoma. TBLB also disclosed noncaseating epithelioid granulomatous inflammation without evidence of acid-fast bacilli (Fig. 3). After a bronchoscopic examination, she developed respiratory failure, and steroid pulse therapy (intravenous methylprednisolone 1,000 mg/body for three days) was started on the same day. Both acid-fast staining and tuberculosis-polymerase chain reaction (PCR) testing of the BALF showed negative results. On day 24, we learned that the BALF culture obtained at the previous hospital had grown Mycobacterium tuberculosis. The patient then underwent tuberculosis-PCR testing of the urine, and the result was positive. Our patient now met five of the eight criteria for HPS. Therefore, a diagnosis of tuberculosis associated with HPS was given.
Antituberculous therapy (isoniazid 5 mg/kg/day, rifampicin 10 mg/kg/day, ethambutol 15 mg/kg/day, and pyrazinamide 20 mg/kg/day) was started on day 24. She responded well to the treatment, and her fever and respiratory failure improved on day 31. In addition, her hematological abnormalities resolved, and her radiological abnormalities improved on day 38. Four weeks later, it was revealed that the sputum culture obtained on admission at our hospital had also grown M. tuberculosis. The patient has been in a stable condition without any recurrence during or after treatment for two years.