A 75-year-old woman with SAPHO syndrome was started on bi-weekly adalimumab, which improved her joint pain. She had a brother with a history of TB. A chest radiograph showed calcification of mediastinum lymph nodes, suggestive of past TB infection. She started preventative isoniazid therapy, but discontinued after 3 weeks at her physician's discretion. Five months after starting adalimumab therapy, she presented with fever and pain in the right upper jaw and was admitted to the previous hospital, where adalimumab was discontinued. A high-resolution computer tomography (HRCT) scan of the thorax at 1-mm slice thickness revealed multiple small nodules, ranging from 2 to 5 mm in diameter, and diffuse ground glass opacities in the lung, which was suggestive of disseminated TB (Fig. 1). The presence of Mycobacterium tuberculosis was confirmed by polymerase chain reaction on gastric lavage obtained on admission to the previous hospital (day -1). Growth of M. tuberculosis in solid culture was detected in 3 weeks and susceptibility testing using the culture isolate showed no resistance to anti-TB agents.
To assist in the diagnosis of TB and monitor the efficacy of anti-TB agents, successive testing of whole-blood IFNgamma levels in vitro was started on day 0, using two types of IGRAs. The first was the T-SPOT. TB, which enumerates the effector T cells that respond to the TB antigens ESAT-6 and CFP-10 by capturing IFNgamma around the T-cells from which it was secreted, based on an enzyme-linked immunospot method (Oxford Immunotec Ltd., Marlborough, MA, USA). The second is the QuantiFERON TB Gold-In-Tube, which measures the amount of serum IFNgamma produced by T cells responding to ESAT6, CFP-10, and TB7.7 peptide antigens in an enzyme-linked immunosorbent assay (ELISA) (Cellestis Ltd., Carnegie, Australia).
Two weeks after discontinuation of adalimumab (day 0), anti-TB treatment using isoniazid (200 mg), rifampicin (450 mg), pyrazinamide (1.2 g), and ethambutol (750 mg) was initiated in the previous hospital, with high dose of methylprednisolone (500 mg) for severe disseminated TB. On day 3, she was transferred to Jikei Daisan Hospital with oxygen saturation of 92% while receiving 4 L/min of oxygen. Her respiratory failure improved, and the high dose of methylprednisolone was replaced by 30 mg of prednisolone (representing an effective dose of approximately 15 mg, due to the drug interaction between the steroid and rifampicin). Three weeks after initiation of anti-TB treatment, the patient's condition deteriorated into acute respiratory distress syndrome, disseminated intravascular coagulopathy, and shock. On day 25, the complication of a PR was confirmed, as an HRCT scan revealed consolidation, extensive bilateral ground-glass opacities, and pleural effusion. Automated liquid cultures of sputum, pleural fluid, and urine on day 25 yielded a positive result only for M. tuberculosis in 2 weeks. To reconfirm the absence of resistance to anti-TB agents, susceptibility tests were performed with those isolates, but no resistance to anti-TB drugs were found. On day 26, noradrenaline was initiated at an infusion rate of 0.05-0.2 mug kg-1 min-1. She was intubated and mechanically ventilated with 100% oxygen and at 20-cm positive end-expiratory pressure. Liver injury led to replacement of pyrazinamide with levofloxacin (250 mg). As hepatotoxicity was sustained, ethambutol was discontinued, which resulted in the improvement of liver damage. Since the efficacy of adjunctive corticosteroid therapy was unclear, the dose of prednisolone was tapered to 10 mg.
Serial IGRAs were performed on days 0, 14, 28, 35, and 42. The T-SPOT panel A and B (normalized to negative control, normal range for each: <= 5) were 71 and 102 on day 0; 19 and 38 on day 14; 0, and 2 on day 35; and 2 and 5 on day 42, respectively. The results of T-SPOT. TB were positive on day 0 and 14, and borderline on day 35 and 42. The QFT TB (amount of IFNgamma [IU/ml] produced in response to TB antigen), QFT Mitogen (amount of IFNgamma produced in response to stimulator), and QFT Nil (non-specific baseline IFNgamma level) were 6.25, 0.60, and 4.91, respectively, on day 14; 0.21, 0.18, and 0.69, respectively, on day 28; 0.40, 0.15, and 0.77, respectively, on day 35; and 0.44, 0.32, and 1.11, respectively, on day 42. The results of QuantiFERON TB Gold-In-Tube kits were positive on day 14, 35 and 42, and indeterminate on day 28. The results of both IGRAs were obtained using manufacturer's diagram for interpretation of the value.
Serum samples on days 28 and 45 were analyzed for TNFalpha using an ELISA assay (Human TNF-alpha Quantikine HS ELISA Kit, R&D) to assess the severity of the immunological response. The value of TNFalpha was 605 pg/ml on day 28, and 615 pg/ml on day 45 (normal range: 0.6-2.8 pg/ml). TNFalpha level was not measured on day 0 and 14 owing to insufficient amount of serum samples to be tested.
Eight weeks after the diagnosis of TB, the patient's condition progressively deteriorated, resulting in death.