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Although there is increasing evidence that neutrophilic inflammation is involved in enhanced bronchial reactivity and exacerbation of bronchial asthma,1,2 the definitive role of neutrophil mediated inflammation in the pathophysiology has not been fully established. To investigate this further, we performed a historical cohort study of 64 children with primary autoimmune neutropenia (AIN) and compared the incidence of asthma with a control group. The study was approved by the Human Research Committee of Shinshu University.
Between January 1997 and December 2000, 64 patients (31 boys and 33 girls) of mean (SD) age 6.1 (1.9) years (range 4.8–10.3) were recruited from our hospitals (table 1). They were followed up for at least 3 years. All were diagnosed with AIN by the age of 12 months, and they had no signs of other autoimmune diseases or haematological disorders. Neutropenia is defined as an absolute neutrophil count of less than 1000/μl blood lasting for 6 months. The diagnosis of AIN was determined by the presence of antineutrophil antibodies and bone marrow findings. Neutropenia resolved in 46 patients (71.9%) within 16–60 months after diagnosis. 415 control subjects (218 boys and 197 girls) were recruited from lists of preschool children who resided in areas of Matsumoto, Toyoshina and Moriguchi. They were matched with each of the index children in terms of age, sex, and indoor family smoking. A diagnosis of bronchial asthma was established by interviewing the parents with the modified ATS-DLD structured questionnaire3,4 and paediatric pulmonologists reviewed the clinical symptoms and responses to asthma medications under 5 years of age (before school age). The results were analysed using the χ2 test (with Yate’s correction) for categorical variables. The frequency of asthma and eczema in first degree relatives was identical for the two groups (8.2% v 7.1% and 16.1% v 18.2%, respectively).
In controls, the prevalence of asthma was 9.9%. By contrast, none of the patients with AIN developed asthma (p = 0.0243) during the neutropenic period and/or suffered from recurrent wheezing. Interestingly, some of them had episodes of respiratory infections but none showed typical bronchiolitis. More interesting was the fact that atopic dermatitis was observed in nine patients in the AIN group (p>0.90) and three developed wheezing episodes at >6 years of age (after the resolution of neutropenia). In addition, the incidence of asthma in AIN patients was significantly lower than reported in recent data from primary school children in the first grade in Fukuoka City, Japan (112/1456 (7.7%), p = 0.0496).4
Our findings strongly suggest that neutrophilic inflammation contributes to the onset of childhood asthma. It is well known that, in infants, common viral infections of the respiratory tract such as respiratory syncytial virus (RSV) can induce small airway bronchiolitis and persistent infantile wheezing without significant eosinophilia.5 Injurious viral infections are common precipitants of exacerbations of asthma. It has been proposed that interleukin (IL)-8 and neutrophil elastase are key factors in this process. Antineutrophil antibodies in AIN usually recognise HNA-1 and HNA-2 antigens that are not detected on eosinophils and mast cells, and eosinophils are observed in the peripheral blood of patients with AIN. One possible explanation is that their propensity towards autoimmunity affects dysregulation of the Th1/Th2 balance. However, it has been reported that severe RSV bronchiolitis in infancy is highly associated with the development of asthma up to age 7.5 We hypothesise that a large proportion of asthma cases may be the result of neutrophilic airway inflammation in early childhood.
This work was supported in part by Grants-in-Aid from the Japanese Ministry of Education, Culture, Sports and Science.