A 44-year-old female with a history of incompletely treated latent TB was diagnosed with acute promyelocytic leukemia (APL). She was treated with arsenic trioxide plus all-trans retinoic acid. She also received dexamethasone for suspected pulmonary differentiation syndrome. Her initial treatment was complicated by neutropenic fever, hepatoxicity, and suspected acalculous cholecystitis. She later underwent a cholecystectomy tube replacement with subsequent tube removal. Approximately one month after her APL diagnosis, she was transferred to our facility for a higher level of care. Blood cultures obtained as part of evaluation for neutropenic fever were positive for Mycobacterium tuberculosis (TB); follow up respiratory cultures were also positive for TB. A bone marrow biopsy showed multiple granulomas. Computed tomography (CT) imaging of the chest/abdomen/pelvis demonstrated diffuse lymphadenopathy and a pericardial effusion. Due to abnormal liver function tests, a liver biopsy was performed and showed multiple foci of confluent coagulative necrosis. In addition to receiving empiric antimicrobials for neutropenic fever, initial TB treatment was adjusted for her liver disease and included rifampin (RIF), pyrazinamide (PZA), moxifloxacin (MFX), and ethambutol (EMB) (Fig. 1). Given concern for liver toxicity, PZA and MFX were changed to levofloxacin, amikacin and linezolid (LZD). When her liver enzymes improved, isoniazid (INH) and PZA were added, and levofloxacin was changed back to MFX. When her neutropenia resolved, she was discharged home on RIF, INH, PZA, EMB, LZD, and MFX despite persistent fevers which were attributed to widely disseminated TB with potential TB immune reconstitution inflammatory syndrome (IRIS).
The blood isolate was sent to Reference Lab A for DST by agar proportion method and rapid molecular multi-drug resistant TB screen by line-probe assay. While the phenotypic DST results were pending, the line-probe assay showed no mutations in rpoB, katG, or inhA targeted regions, suggesting susceptibility to RIF and INH (Table 1). Therefore, moxifloxacin and linezolid were stopped. However, 10 days later, the phenotypic DST results returned and showed resistance to EMB and INH, but susceptibility to RIF and PZA. In the meantime, the patient was re-admitted to the hospital for persistent fevers and congestive heart failure, which improved with diuresis. Continued fevers were attributed to disseminated TB and TB IRIS. The persistent fevers, the need to resume APL treatment, and the drug resistance profile of the blood isolate prompted the treatment team to switch to a 5-drug regime: para-aminosalicylic acid (PAS), cycloserine, LZD, RIF and levofloxacin. The patient could not tolerate PAS which was then replaced by PZA and amikacin, leaving the regimen to include 6 drugs: PZA, RIF, cycloserine, LZD, levofloxacin, and amikacin.
The respiratory isolate (1 month post admission) was sent to Reference Lab B and was susceptible to all first-line drugs as determined by liquid broth (MGIT) method. To investigate the discrepancy observed in DST results between the blood and sputum isolates, WGS was performed (Table 1). WGS revealed both isolates were of the Euro-American (LAM) lineage 4 and closely related to pan-drug sensitive TB CTRI-2 strain. Drug resistance prediction analysis using TB-profiler and ResFinder showed no known mutations to confer resistance to all first and second-line drugs (Table 1). Single nucleotide variant (SNV) analysis using CLC Genomics Workbench v12.0 (Qiagen, Germany) was performed using CTRI-2 (NCBI Reference Sequence: NC_017524.1) as the reference genome and showed only 5 SNVs between the blood and sputum isolate, confirming these two isolates are of the same lineage. Generally, the rate of change is 0.5 SNPs per genome per year and highly related isolates have within 5 SNPs differences. None of the 5 SNVs were within any drug resistance related genetic regions. The results of the WGS investigation were communicated to the California Department of Public Health (CDPH) TB Control team, who requested both isolates sent to the CDPH laboratory for confirmatory phenotypic DST and pyrosequencing. The results confirmed both isolates were susceptible to all first and second-line drugs, and no mutations were identified in the targeted regions for RIF and INH. At this point, 4 months had passed from the initial positive blood culture of TB, and treatment regime was reduced to 3 drugs: RIF, PZA, and levofloxacin for another 5 months. Patient successfully completed the treatment and achieved resolution of fever without the use of anti-inflammatory medications.