A 78-year-old woman with RA had been treated with infliximab (4 mg/kg) every 8 weeks for 3 years. After the initiation of infliximab, the RA activity was kept under control without remarkable complications. Eight weeks after the last dose of infliximab, she was admitted to our hospital because of a fever that had lasted for 6 weeks. Before the infliximab treatment was initiated, she had not received screening or treatment for a latent TB infection. Upon hospital admission, a laboratory investigation revealed elevated liver enzymes, aspartate aminotransferase of 208 IU/L, alanine aminotransferase of 148 IU/L, lactate dehydrogenase of 464 IU/L, and alkaline phosphatase (ALP) of 1,220 IU/L. Interferon-gamma (IFN-gamma) release assays (QuantiFERON(R)-TB Gold [QFT-G], Cellestis Limited, Carnegie, Victoria, Australia) were positive. A computed tomography (CT) scan showed chronic interstitial pneumonia in the chest (Fig. 1A) and gallstones and thickening of the gallbladder wall in the abdomen. She was diagnosed with cholecystitis and administered Piperacillin/Tazobactam. However, her fever did not fall, and her respiratory condition further deteriorated. On Day 6, she finally underwent tracheal intubation. An arterial blood gas analysis showed the partial pressure of arterial oxygen (PaO2) was 61 mmHg and the partial pressure of arterial carbon dioxide was 39 mmHg. The ventilator settings were set to pressure-control ventilation, a fraction of inspired oxygen (FiO2) of 0.5, pressure support of 3 cmH2O, and positive end-expiratory pressure of 11 cmH2O. Her PaO2/FiO2 (P/F ratio) was 122 mmHg, suggesting moderate ARDS according to the Berlin Definition. A chest CT scan showed bilateral, widespread, patchy, ill-defined lung opacification and interlobular septal thickening, but there were no clear miliary lesions (Fig. 1B).
Because there was the possibility of acute exacerbation of interstitial pneumonia associated with RA triggered by infection, she underwent high-dose corticosteroid therapy and received an antimicrobial agent. Although her respiratory condition improved slightly, with the P/F ratio increasing to 171 mmHg, the fever did not come down. Because of her QFT-positive result on admission and the poor response to treatment thus far, we considered that she might have been suffering from miliary TB induced by infliximab. However, acid-fast staining of the sputum, bronchoalveolar lavage (BAL) fluid, urine, stool, and blood samples were all negative. Furthermore, a Mycobacterium tuberculosis polymerase chain reaction (TB-PCR) of a BAL fluid sample was also negative.
The other differential diagnosis was malignant lymphoma, because the serum soluble interleukin-2 receptor (sIL-2R) level was very high (8,096 U/mL). A bone marrow biopsy of the anterior superior iliac spine was performed on Day 15 under mechanical ventilation, revealing epithelioid granulomas compatible with miliary TB. At that point, miliary lesions became apparent on a chest CT scan (Fig. 1C). TB was diagnosed based on the histopathological findings and clinical manifestation.
Her P/F ratio increased to 305 mmHg, and the fever improved soon after she was administered anti-TB drugs on Day 18 (Fig. 2). Finally, an acid fast bacterial culture of the BAL fluid at intubation was positive for M. tuberculosis in a liquid culture on Day 24. She showed good progress because of the anti-TB treatment, but unfortunately, pneumothorax occurred before extubation. Although treatment with a chest drain was added, she died due to recurrent pneumothorax and a catheter-related blood stream infection. The clinical course, laboratory, and radiological findings are shown in Fig. 2.
The findings of a pathological autopsy revealed diffuse alveolar damage (DAD), interstitial pneumonia, and innumerable granulomas in the lung, liver, bone marrow, spleen, and lymph nodes. Miliary nodules in the lung consisted of more unstructured granulomas. The DAD showed many hyaline membranes with severe inflammation and an increase in collagen fibers. There were numerous Langhans giant cells and epithelioid granulomas with substantial caseous necrosis in the lymph nodes. A few acid fast bacteria were observed in the lungs, lymph nodes, and liver. The details of the pathological findings are shown in Fig. 3.