A 28-year-old Chinese Han man was admitted with a history of intermittent fever for 3 years and erythema nodosa for 7 months. He had the first unprovoked onset of fever with a maximum temperature of 40 C lasting for two weeks. He had a second flare after two months and went to the local hospital, where he was diagnosed with hemophagocytosis and right inferior lobar pneumonia, based on bone marrow smear and chest computed tomography (CT). In 2021, he developed bilateral parotid enlargement, recurrent fever, and erythema nodosa. He was treated with various anti-infective agents, including moxifloxacin, linezolid, vancomycin, voriconazole, and cefoperazone-sulbactam, but the fever continued, mostly in the afternoon and at night.
The physical examination revealed the presence of papules on the trunk and upper extremities. His complete blood count indicated pancytopenia with WBC (0.6-1.3)x109/L, neutrophils (0.3-0.8)x109/L, lymphocytes 0.2x109/L, monocytes 0.00x109/L, hemoglobin (72-90)g/L, and platelets (43-64)x109/L. NK cells activity decreased (1.36%, normal range: >=15.11%), and sCD25 was 6696pg/ml (normal range: <6400pg/ml). His CD107a expression in NK and CTL cells was within the normal range. His NK cell DeltaPerforin was 72.56%, which was lower than the normal level. He also had elevated levels of IL-5 (76.2pg/ml, normal range: 0-17pg/ml), IFN-gamma (106.3pg/ml, normal range:0-95pg/ml), ferritin (895ng/ml, normal range: 80-130ng/ml), C-reactive protein (CRP) (107mg/L, normal range: 0-8mg/L), and erythrocyte sedimentation rate (ESR) (75mm/h, normal range: 0-15mm/h). Antiphospholipid antibodies, antinuclear antibodies and antineutrophil cytoplasmic antibodies were all negative. Multiple lesions in the bilateral lung fields and multiple hypermetabolic lymphadenopathies in the hilum, mediastinum, and supraclavicular area and enlarged spleen were found by CT and PET/CT (Figure 1A). Mediastinum lymph node biopsy revealed a necrotic background with some plasma cells, eosinophils and lymphocytes infiltration. The pathological biopsy of subcutaneous nodules revealed lymphocyte infiltration scattered around the superficial small blood vessels of the dermis and collagen fiber proliferation. A bone marrow biopsy showed proliferation of erythroid series, predominantly of intermediate or late erythroblasts. In local hospital, the patient underwent blood cultures (including cultures for slowly-growing bacteria/mycobacteria), respiratory infection antigen IgM antibody, T-SPOT.TB, G test, GM test, Mycoplasma pneumoniae serological test, CMV-DNA and EBV-DNA, and the results were all negative. Bronchial brushing including Xpert, cryptococcal antigen, Aspergillus antigen, tuberculous smear, Fungal smear, TB-DNA, GM test were all negative. Next-generation sequencing (NGS) technology was conducted in BALF and detected Klebsiella pneumoniae. A diagnosis of HLH was made based on HLH-2004 criteria. He had no relevant family history. He had the heterozygous nonsense variant of the GATA2 gene c.599dupG, p.S201*. His father and sister carried the wild type of the GATA2 gene, and his mother died in an accident (Figure 1B).
Therapies, changes of his complete blood count, ferritin and lactate dehydrogenase during the hospitalization were shown in Figures 1C, D. His fever and erythema nodosa temporarily improved but relapsed after dexamethasone withdrawal. There are multiple pieces of evidence confirming the effectiveness of ruxolitinib combined with dexamethasone in the treatment of HLH, therefore ruxolitinib was added in his treatment with dexamethasone. The blood culture at three weeks after admission revealed the presence of mycobacteria. He was finally diagnosed with HLH triggered by Mycobacterium avium bloodstream infection due to primary immunodeficiency caused by germline GATA2 deficiency. His symptoms did not improve despite 4-drug antituberculosis therapy, combined with dexamethasone and ruxolitinib. Bone marrow biopsy showed the hematopoietic tissue was decreased and myeloid/erythroid ratio was reduced, no typical tuberculosis granuloma or multinucleated giant cells observed. The last bone marrow smear revealed hypoplastic myelopoiesis, myeloid/erythroid ratio=0.63:1, intermediate or late erythroblasts ratio increased. Two weeks after discharge, he was hospitalized in the local hospital due to short of breath, and chest CT scan showed emerging ground glass opacities. He was given antibiotics but died of severe pulmonary infection one month later.