A case of tuberculosis meningitis after allogeneic hematopoietic stem cell transplantation for relapsed Acute Myeloid Leukemia

Abstract We report a case of tuberculosis (TB) meningitis after allogeneic hematopoietic stem cell transplantation (HSCT) for relapsed acute myeloid leukemia. The patient was 52‐year‐old woman who had relapsed leukemia with a remission duration of 7 months, and she received re‐induction with consolidation, allogeneic HSCT. After 4 days of engraftment, she had headache with fever and cerebrospinal fluid (CSF) analysis presented increased intracerebral pressure, white blood cell counts with dominant neutrophils, elevated glucose and protein level. Brain imaging showed diffuse leptomeningeal enhancement with scattered miliary TB lesions suggesting disseminated TB disease. Mycobacterium tuberculosis was detected in CSF and sputum anti‐TB medication was started. She was IGRA positive before transplantation but did not receive treatment for LTBI prior or during the transplant. Unfortunately, she expired because of intracerebral hemorrhage. TB meningitis is a rare but important complication of HSCT as it can cause serious neurologic sequelae, even death. So in transplant recipients having high risk of TB reactivation, LTBI treatment is recommended before or along with transplantation. If latent TB is not treated, vigilant suspicion and early diagnosis of TB meningitis could improve the transplant outcome.

Three days after conditioning, the patient developed a fever up to 38.3℃. She received empirical antibiotics (piperacillin/tazobactam and vancomycin). By that time, fever was subsided the following day and even if IGRA was positive, the risk of TB development was low and we should considered more common causes of fever immediately after conditioning such as bacterial infection or drug fever. On 10 days after conditioning, Candida glabrata was isolated at the site of the Hickmann catheter so anti-fungal agent was added.
The patient became drowsy and showed respiratory depression, and she was transferred to the intensive care unit for mechanical ventilation. For intracranial pressure (ICP) control, mannitol and dexamethasone were used. Twenty-eight days after HSCT, sputum Xpert MTB/RIF (Cepheld) was positive, sputum, CSF culture, and MTB PCR of the CSF were also positive, so TB infection was confirmed. Table 1 represents the drug susceptibility test of M tuberculosis isolated from cerebrospinal fluid. Chest x-ray showed increased opacity in both lungs, and chest CT demonstrated two tiny nodules in the superior segment of the LLL and diffuse interlobular septal thickening in both lungs ( Figure 2). Although the radiologists suggested that the nodules were too small to be characterized, pulmonary TB was strongly suspected. All findings were evaluated together, and she was diagnosed with TB meningo-encephalitis along with pulmonary miliary TB. There was no evidence of TB involvement in the bone marrow. Two days after starting anti-TB medication, bilirubin increased to 8.7 mg/dL, AST to 351 U/L, and ALT to 63 U/L. Therefore, INH was discontinued, and cycloserine, meropenem and amoxicillin/clavulanic acid were added to achieve the synergistic effect of clavulanic acid and carbapenem. Seven days after starting anti-TB medication, liver enzymes normalized, so the first regimen including INH was resumed. At 10 days after initiation of anti-TB medication, RIF was added, and LZD and AMK were discontinued. However, progressive hyperbilirubinemia led to again changing INH to LZD on day 13. Two days later, GI bleeding occurred. Therefore, oral RIF was changed to IV rifaldin, and EMB was switched to AMK IV ( Figure 3).
Thereafter, progression of pancytopenia was noted, and LZD was changed to INH and EMB. At day 27, rifaldin was discontinued because a drug fever was suspected. For management of TB meningo-encephalitis, we administered dexamethasone 10mg four times a day for 6 days and then tapered over a period of 2 months. In addition, mannitol and glycerin were given to control increased ICP.
Unfortunately, although the TB meningo-encephalitis and pulmonary miliary TB were well controlled, the patient expired 115 days after stem cell transplantation because of an intracerebral hemorrhage that developed suddenly owing to prolonged thrombocytopenia.

F I G U R E 3
Transition of anti-tuberculosis medication regimens is showed with changes in liver enzymes, total bilirubin, and white blood cell counts have an excellent penetration rate through the blood-brain barrier.
In solid organ transplantation, the American Society of Transplantation recommends that all cases of LTBI be treated. 8  Clinicians must also consider drug-drug interactions of anti-TB medication in transplant recipients. HSCT recipients usually receive immunosuppressants and prophylactic antibiotics, so there could be toxicities and drug interactions that would make it difficult to interpret laboratory abnormalities.
Generally, it is difficult to delay HSCT because more than 3 months of LTBI treatment would increase the relapse risk of the underlying diseases.
In the present case, the patient was IGRA positive at the screening test before transplantation, but as there was no active lung lesion on chest radiographs, we did not treat LTBI according to our institutional protocol.
Furthermore, we could not delay stem cell transplantation for LTBI treatment, considering the relatively short duration of remission of 7 months. In our center, 1187 transplant recipients underwent testing for IGRA from February 2014 to March 2020. IGRA was positive in 225 (18.9%) patients, and the number of patients who were documented to have active TB after transplantation was 12 (5.3%). Among the 12 cases (10 patients were allogeneic and 2 were autologous SCT) of documented active TB after transplantation, there were 7 cases of pulmonary TB, 3 of TB pleurisy, 1 of TB lymphadenitis, and the present case was the only one confirmed to have TB meningitis. Two other patients were suspected to have TB meningitis, an incidence of 0.25%.
The patient in the present case and one of the suspected TB meningitis patients expired, underlining the high mortality rate of TB meningitis.
Another study from Korea showed IGRA positivity in 40 of 224