A previously healthy 57-year-old woman visited a local hospital for a cough and nasal discharge persisting for 3 months. Blood tests revealed severe leukopenia (700/muL), and a computed tomography (CT) scan revealed pneumonia in the right lung and mild-to-moderate splenomegaly (Fig. 1a and b). She was therefore suspected of having a hematological disorder and was referred to our hospital.
Upon the initial visit to our hospital, she was afebrile, and her vital signs were unremarkable. No skin lesions were observed. She had a history of pregnancy, and she had no family history of hematological or autoimmune diseases. She had taken no medication for at least three months. Her white blood cell count was 710/muL (neutrophils: 11%; lymphocytes: 57%), red blood cell count was 4.23x106/muL, hemoglobin was 12.2 g/dL, hematocrit was 36.3%, mean corpuscular volume was 85.8 fL, reticulocyte count was 85x103/muL, and platelet count was 141x103/muL. Her findings for serum biochemical tests were all normal (Supplementary Table 1). C-reactive protein was weakly positive (0.5 mg/dL), and soluble interleukin-2 receptor (sIL-2R) was elevated (1,880 U/mL). Serological tests excluded infection with hepatitis B and C viruses, HIV, Mycoplasma pneumoniae, Chlamydia pneumoniae, and Mycobacterium tuberculosis, and tests for Epstein-Barr virus indicated a previous but not recent infection (supplementary Table 1). Fluorodeoxyglucose (FDG) positron emission tomography-CT revealed diffuse and mild FDG uptake in the spleen and the bone marrow of the trunk and proximal extremities. A bone marrow biopsy revealed a slightly hypercellular marrow with mild reticulin fibrosis (Fig. 2a). Bone marrow smears revealed a decrease in mature segmented neutrophils (0.4%) with a relative increase in myelocytes without an increase in blastic cells (Fig. 2b, Supplementary Table 2). Phenotypically abnormal lymphoid populations were not detected by flow cytometry. Morphological dysplasia was not detected in any of the hematological cell lineages. The myeloid:erythroid ratio was 2.27. Flow cytometric analyses detected no abnormal cell populations in the bone marrow cells, and a chromosomal analysis showed a normal karyotype.
To screen for autoimmune diseases, a series of autoantibodies were measured. The results indicated that anti-single stranded DNA antibody was positive (209 AU/mL), rheumatoid factor was weakly positive (11.7 IU/mL), and antinuclear antibody was weakly positive, with a titer of 1:40. Other autoantibodies, including anti-double stranded DNA, anti-ribonucleoprotein (RNP), and anti-SS/A antibodies were negative. The indirect granulocyte immunofluorescence test (GIFT) detected antibodies that reacted with both human neutrophil antigen (HNA)-1a and HNA-1b in her serum (Table 1). HNA typing by the GIFT revealed that the patient had HNA-1a/1b alleles, indicating that the antibodies detected in her serum were autoantibodies. Because her symptoms and signs did not meet the diagnostic criteria for common autoimmune disorders, such as rheumatoid arthritis, Sjogren's syndrome, or systemic lupus erythematosus, the patient was diagnosed with primary AIN.
Oral levofloxacin and itraconazole were administered for pneumonia, and, because spontaneous recovery of her neutrophil count was expected, she was followed as an outpatient. However, 5 weeks later, severe neutropenia persisted, and we admitted the patient to our hospital and began daily subcutaneous injections of G-CSF at a dose of 5 mug/kg. She developed a high-grade fever on the day of admission, and oral levofloxacin was switched to intravenous tazobactam/piperacillin. Her body temperature normalized on post-admission day 3. However, her neutrophil count, which was 130/muL on admission, did not respond to G-CSF therapy through day 8, so we discontinued G-CSF therapy and started oral prednisolone at a dose of 0.5 mg/kg/day (Fig. 3). Her neutrophil count began to increase immediately (Fig. 3). Chest X-ray taken 15 days after the initiation of prednisone showed that the pneumonia had improved. Twenty-eight days after starting prednisolone, autoantibodies against HNA-1a and HNA-1b had disappeared from her serum (Table 1). Abdominal CT revealed improvement in her splenomegaly (Fig. 1c), and she was discharged four days later. The prednisolone dosage was gradually tapered and was discontinued 10 months after its initiation (Fig. 3). Her neutrophil count remained normal at her last visit (two months after discontinuation of prednisolone).
Computed tomography (CT) scans. CT scans taken during the initial visit to a local hospital showed mild pneumonia in the right upper lobe.