A 9-year-old boy with intermittent fever for 2 months was transferred to our hospital on November 3, 2021. He was born with alpha thalassemia (-SEA/alphaalpha), and from his birth to 2018, he had received five red blood cell transfusions. He has been Bacilli Calmette-Guerin (BCG) vaccinated at birth under the national vaccination program. He has no recent travel history, and his parents reported no family hereditary diseases, besides thalassemia, no TB history nor TB exposure.
The patient started to develop intermittent fever in August 2021, with the highest body temperature of 38.0 C and night sweats. There were no respiratory symptoms or weight loss. He was admitted to a local children hospital shortly after his fever had persisted for 5 days. His routine blood test on admission showed white blood cell (WBC) 2.6 x 109/L, neutrophils (Neu) 1.15 x 109/L, hemoglobin (Hb) 74 g/L, and platelets (PLT) 211 x 109/L. Ultrasound scan revealed bilateral cervical lymphadenopathy and an enlarged spleen.
In 3 days, his hemoglobin level dropped to 64 g/L, and he was given 2U red blood cell infusion. Repeated blood test on the following day showed decreased level of WBC to 1.5 x 109/L and Neu of 0.51 x 109/L with an elevated Hb level of 90 g/L and an unremarkable change of PLT 201 x 109/L. Viral markers for Epstein-Barr virus (EB DNA) was negative. In addition, subsequent blood interferon-gamma release assays (IGRAs) and skin purified protein derivative (PPD) tests were positive. Lung computed tomography (CT) showed calcification of the right hilum and mediastinal lymph nodes. In the absence of lung infiltration and tuberculous foci, latent tuberculosis infection (LTBI) was suspected. A bone marrow aspiration smear performed the following day showed active bone marrow hyperplasia, significantly decreased neutrophil level, and generally normal morphology. The patient had persistent daily fever between 37.4 C and 38.8 C accompanied with dry cough, fatigue, and loss of appetite. He was empirically administered with amoxicillin 0.25 g three times a day for 3 days and antifebrile for a week. But his fever remained unsolved during the treatment, fluctuating in the same range as before. Pathological findings from his cervical lymph node biopsy showed no caseous necrosis and no acid-fast mycobacteria. The persistent low WBC in peripheral blood had raised concern. To look into possible causes of the persistent fever, a second bone marrow puncture was performed. Bone marrow smear was positive for acid-fast staining (Figure 1). Disseminated TB infection was suspected. But further sputum and cerebrospinal fluid smear were negative for both acid-fast staining and TB-DNA (CapitalBio Technology, China). Thus, pulmonary TB and tuberculous meningitis were ruled out. The bone marrow was presumed as the tuberculous origin. Anti-TB regimen composing isoniazid, rifampicin, pyrazinamide, and ethambutol was initiated from the diagnosis. His temperature resumed to normal range 4 days later. His appetite also improved.
But a week later, he had fever again with the highest measure of 40.0 C. Serum ferritin was observed to have elevated to 3,603.35 ng/ml (reference: < 300 ng/ml). Methylprednisolone 1 mg/kg q12 h was administered as anti-inflammatory therapy, but his fever did not go away. A repeated bone marrow aspiration was performed the following day to investigate the causes for the unresolved fever, elevated serum ferritin, and decreased WBC. Bone marrow biopsy showed active hyperplasia with occasional hemophagocytic histiocytes, mainly phagocytizing white blood cells, red blood cells, and platelets (Figure 2). Bone marrow for real-time PCR (qPCR) assay for TB was positive; moreover, gene sequencing revealed the promotor region of InhA gene mutation (-15C > T), which caused resistance to isoniazid. Bone marrow for TB culture was performed but had finally turned out negative. Serum ferritin was precisely monitored and was found to further elevated to 9612.81 ng/ml in 5 days. HPS was confirmed, and 10 mg/kg of methylprednisolone was prescribed daily. In 2 days, the patient's fever resolved. Serum ferritin dropped to 5,755.54 ng/ml and WBC in peripheral blood was restored to a normal level. Whole-genome sequencing confirmed no variants of exon. This test result rule out the known primary genetic causes of HLH. Diagnosis was confirmed as having (1) bone marrow TB with isoniazid resistance; (2) secondary HPS.
Before administration of isoniazid-resistant TB regimen modification, the patient developed nausea, loss of appetite without fever 18 days after initial anti-TB regimen. Systematic examination revealed yellow skin and sclera with hepatosplenomegaly. Liver function test showed total bilirubin (TBIL) of 111.1 mumol/L, directed bilirubin (DBIL) 67.3 mumol/L, alanine transaminase (ALT) 520.5 U/L, and aspartate transaminase (AST) 321.5 U/L, which were consistent with drug-induced liver injury (DILI). He was transferred to our hospital for specialized tuberculosis management where his regimen was reviewed and modified to the following: linezolid 300 mg/day, ethambutol 0.5 g/day, and levofloxacin 0.25 g/day based on his body weight of 25 kg. Methylprednisolone was reduced to 2 mg/kg/q8h. As serum ferritin was gradually decreasing and his body temperature and WBC were normal, methylprednisolone was lowered to 0.4 mg/kg/q12h 12 days later.
After 15 days of the above therapy, a follow-up evaluation of bone marrow aspirate for metagenomic next-generation sequencing (mNGS) and qPCR assay showed no detection of M. tuberculosis. Subsequent laboratory investigations confirmed normal liver function and a lowered serum ferritin level of 1,150.0 ng/ml. A 0.3-g rifapentine was added twice a week to his anti-TB regimen. He was discharged with the prescribed methylprednisolone at a tapering dose of 4 mg every 10 days (Figure 3) until the next follow-up consultation. He is being followed up in our outpatient unit for the next 2 years for this rare medical condition. The child has no more fever, but his hepatosplenomegaly persisted. He has returned to school and is leading a normal life. As of press time, the patient's anti-TB treatment is still ongoing.