The patient who is male, 11 years and 9 months old, was admitted to our hospital on June 7, 2021, due to recurrent fever, headache, and vomiting for 11 days. On May 25, 2021, the patient underwent deep supratentorial abscess resection and craniotomy decompression in another hospital. Physical examination on admission: The mental response was normal. Dark red rashes about the size of pinpoints were on the neck, trunk, and upper limbs. Mild lumbosacral tenderness, and no abnormality in the cardiopulmonary, abdominal, and nervous system examination. No history of repeated infections or immunodeficiency. One month before admission, the patient developed vomiting and fatigue. The vomiting was progressive aggravation and projectile. Cranial MRI showed a left frontal lobe brain abscess (Fig. 1a). Laboratory findings after admission are as following: blood routine (day 1) test: WBC 12.3 × 109/L, N 69.0%, L 23.9%, HGB 120 g/L, PLT 361 × 109/L, CRP 10.7 mg/L. Liver and kidney function, electrolytes, disseminated intravascular coagulation, cellular and humoral immunity were all normal. CSF routine test (day 2): nucleated cells were 495 × 106/L, 83% were neutral lobulated, 17% were lymphocytes. CSF biochemistry: protein 819.4 mg/L, glucose 0.98 mmol/L, chloride 127.5 mmol/L, lactic dehydrogenase 143 U/L. Pathogens test in CSF: cytomegalovirus was positive, smear and culture were negative. EEG (day 4) was normal. Crainal CT (day 5): brain abscess in left frontal lobe after the operation, which was smaller than before. After admission, ceftriaxone, ceftazidime combined with vancomycin were given for anti-infection, and the child’s temperature was still abnormal. The second CSF routine test (day 6): nucleated cell count was 990 × 106/L, neutral lobulation was 86.0%; biochemical: protein 754.5 mg/L, sugar 0.96 mmol/L, LDH 191 U/L; smear and culture were negative. Serum cytomegalovirus IgG 100 U/mL, IgM, and DNA were negative; EBV IgM, PCR were normal. The cellular/humoral immune screening was unremarkable. The patient’s clinical presentation suggested bacterial intracranial infection, while no pathogenic bacteria were identified, we then performed metagenomic next-generation sequencing (mNGS) on cerebrospinal fluid, patient’s CSF was collected and the DNA was extracted and purified. After obtaining the sequencing data, human reads were removed by mapping reads to human reference genome. The remaining data were aligned to the microbial genome database. The database collected microbial genomes from NCBI. It contains more than 20,000 microorganisms, including 11,910 bacteria, 7103 viruses, 1046 fungi and 305 parasites. Finally get the microbial compositions of the sample. And the mNGS of CSF (day 6) detected S. intermedius. The antibiotic was adjusted to penicillin and combined with vancomycin for anti-infection. After that, the temperature gradually returned to normal, and vancomycin was gradually reduced. Head enhanced MRI (day 10): Changes after brain abscess resection of deep supratentorial lesions: Partial bone defect in the left frontal lobe, cystic mass in the left frontal lobe, the uneven signal in capsule, with surrounding. The brain parenchyma was obviously edematous, and the cyst wall was obviously thickened and enhanced unevenly (Fig. 1b). No abnormality was found in the enhanced MRI of the spinal cord. CSF (day 12): nucleated cell count 300 × 106/L, lymphocytes 62.0%, neutral lobulation 26.0%; protein 632.4 mg/L, sugar 1.16 mmol/L, LDH 50 U/L; smear and culture was normal.
One week after the penicillin treatment, the patient’s body temperature returned to normal but rose again very soon. Blood routine test (day 22): WBC 3.4 × 109/L, N 54.4%, HGB 131 g/L, PLT 197 × 109/L, CRP 8.8 mg/L. Procalcitonin: 0.14 ng/mL. CSF routine test (day 22): nucleated cells were 25 × 106/L, 84.0% were lymphocytes, 12.0% were neutral lobes, 4.0% were monocytes. CSF biochemistry: protein 565.5 mg/L, glucose 1.78 mmol/L, chloride 126.0 mmol/L, LDH 9 U/L, ADA 1.8 U/L. Pathogens tests for CSF and blood were all negative. Cranial CT scan performed on 30th June showed improvement of brain abscess. At this time, the child developed a skin rash, enlargement of bilateral cervical lymph nodes, conjunctival hyperaemia, red and cracked lips, and strawberry-like tongue, followed by swelling of both hands and feet, without hepatosplenomegaly. As Kawasaki disease was suspected, a single high-dose (2 g/kg) intravenous administration of immunoglobulin (IVIG) was given. And the patient’s temperature returned to normal. Blood routine test showed leukopenia and thrombocytopenia (WBC 1.1 × 109/L, ANC 0.25 × 109/L, N 22.7%, L 66.4%, HGB 123 g/L, PLT 74 × 109/L). Liver function indicated elevated liver enzymes and triglycerides (ALT 127 U/L, AST 778 U/L, TG 9.2 mmol/L), hypofibrinogenemia (Fg 70 mg/dL), significantly elevated ferritin (> 16,500 ng/mL). Cytokines level: IL-1β 30.8 pg/mL (< 5 pg/mL), IL-2 1683 U/mL (223–710 U/mL), IL-10 10.70 pg/mL (< 9.1 pg/mL), TNF-α 20.4 pg/mL (8.1 pg/mL). NK cell activity assay and cytotoxic degranulation assay were normal. Bone marrow biopsy found histiocytes phagocytosing blood cells (Fig. 2). Considering the diagnosis of hemophagocytic syndrome due to brain abscess as the most likely possibility, the patient was treated with intravenous methylprednisolone (20 mg/kg/day) for 3 days followed by oral prednisolone in a gradually tapering dose. Blood routine test on July 21, showed WBC 5.9 × 109/L, N 51.7%, ANC 3.05 × 109/L, HGB 119 g/L, PLT 264 × 109/L. ALT was 13 U/L, AST was 26 U/L. Triglycerides was 1.43 mmol/L. Serum Ferritin was 96.80 ng/mL. Cranial MRI on July 23: Compared with the results of June 16, the brain lesions in the left frontal lobe were significantly reduced, the brain tissue edema was significantly reduced, and residual lesions were found in the left frontal lobe. To explore the potential genetic cause of HLH in this patient, a targeted next generation sequencing (NGS) panel was applied, including LYST, CTPS1, PIK3CD, PRF1, SRGN, CD27, LAMP1, ARF6, GZMB, RAB27A, BLOC1S6, CORO1A, UNC13D, STXBP2, GNLY, STK4, PRKCD, AP3B1, ITK, STX11, CARD11, MCM4, MAGT1, SH2D1A, XIAP, and IL2RG genes. And a missense variant (c.600 A>C) in the gene IL2RG was detected. According to ACMG guidelines, the variant was considered a variant of uncertain significance (VUS). Large insertions, deletions, and duplications were not detected. After discharge, the child was given oral prednisone and was followed up for about half a year. Prednisone was gradually reduced and finally stopped after half a year. The symptoms of HLH have not recurred, and the blood routine test was normal.