Objective: We used the technique of induced sputum to examine the inflammatory indices associated with persistent cough or allergic asthma in children. We hypothesized that the sputum from children with persistent post-infectious cough would differ from children with allergic asthma in that the former would lack eosinophils compared to the latter.
Study Design: Sputum production was induced with hypertonic saline in thirty-four children: 12 with cough persisting for 1 month or more after an apparent respiratory tract infection, not treated with corticosteroid; 11 with untreated atopic asthma, not using inhaled corticosteroid; and 11 with treated atopic asthma using inhaled corticosteroid.
Results: The percentage of eosinophils in the sputum of children with cough was significantly lower than in the sputum of children with untreated allergic asthma (median of 0.5% versus 14.5%; p<0.0001). Similarly, the percentage of eosinophils in the sputum of children with asthma treated with inhaled steroids was significantly lower as compared to untreated asthmatics, (1.5% vs 14.5%, p<0.0001). The peripheral blood eosinophils, serum ECP and nasal percent eosinophils of the patients with cough were also significantly lower than those from patients with untreated asthma. Methacholine challenge in 6 of the 11 cough patients tested showed moderate hyperresponsiveness (median PC20 of 1.4 mg/ml), and was similar to values measured in untreated allergic asthma, (median PC20 of 0.7mg/ml, p=0.95).
Conclusions: Children with persistent post-infectious cough do not have airway eosinophilia typical of untreated asthma. Despite the absence of eosinophilic inflammation, some of the patients with chronic cough had reactive airways. These results suggest that post-infectious cough in children has a different pathophysiology than allergic asthma and probably represents a different disease.
The technique of induced sputum is a minimally invasive technique that has been extensively studied and validated as a measure of airway inflammation (9-14). Sputum has been shown to yield measures of airway inflammation that correlate well with the more invasive bronchoalveolar lavage in asthma (13). The technique of induced sputum allows the safe examination of the inflammatory events in the airways of children with asthma and/or cough when bronchoalveolar lavage or biopsy of the airways would not be practical or ethical. To date it has been used in only a few studies of childhood asthma (15 - 20).
We expected that sputum eosinophil counts in children with untreated allergic asthma would be higher than the eosinophil counts in sputum from children with allergic asthma patients treated with inhaled steroid. We hypothesised that sputum from patients with post-infectious cough would not be marked by eosinophils but might exhibit neutrophils. We also quantified eosinophils in nasal lavage and peripheral blood to assess systemic levels of eosinophils in these conditions and measured eosinophil cationic protein in sputum and serum as an estimate of eosinophil activation. Interleukin-8 (IL-8) was quantified in sputum as a chemokine associated with neutrophil chemotaxis (21, 22).
Sputum from children with persisting post-infectious cough differed significantly from sputum of children with allergic asthma. The patients with cough lacked evidence for eosinophil mobilization and activation in the airways, nasal passages and blood. They had no more eosinophils in the sputum than allergic asthma patients treated with inhaled steroid and were similar to published values for normal children (18). Thus children with cough persisting for one month or more after an apparent infectious illness have little evidence for involvement of eosinophils in the maintenance of the cough but some of them do have airway hyperreactivity as described previously (3,4). The children with post-infectious cough were significantly younger than the childen with asthma (Table 1) and many children with persisting post-infectious cough could not be enrolled in the present study because they were too young to perform the manoeuvres required for production of sputum. The data suggested that peripheral blood eosinophil counts and serum ECP measurements (Table 3) could be used in younger children as surrogate measures to determine the likelihood of eosinophilic inflammation in association with the cough.
Cough is a common complaint in children. In an epidemiological study of children birth to 5 years of age in the Toronto area, we found that about 10% had wheezing in the year prior to the study while a further 8 - 10 % had episodes of cough (1). Clinically this cough is often for a week to two weeks following viral respiratory tract infections but in some instances the cough persists for 4 weeks or longer and then falls into the category of chronic cough (2).
In 1975, McFadden et al called attention to the fact that cough could be the sole manifestation of asthma (30). This was confirmed by Carrao et al (31) and later by other investigators in studies of children (32). The concept of cough-variant asthma led to persisting cough in children being treated with asthma medication, initially bronchodilators (33) and now more commonly anti-inflammatory medication, particularly inhaled steroid (34). Post-infectious cough occurs more commonly in children than adults (2) but the relationship of post-infectious coughing to cough-variant asthma and to more classical asthma remains poorly understood with little understanding of differences in pathophysiology. A recent epidemiologic study of cough in children suggested that the clinical characteristics of these children was different than asthma and suggested that chronic or recurrent cough in children should be considered a different disease than asthma (5). This suggestion was also made as a result of a study of bronchoalveolar cell profiles in children with asthma or chronic cough, where asthma was associated with eosinophils while chronic cough, as in the present study, was not (35).
The present study shows that post-infectious cough in the children examined was not associated with eosinophilic inflammation but some had reactive airways. This is in contrast to the subset of adult patients with chronic cough described by Gibson et al (6) who had eosinophils in their sputum (eosinophilic bronchitis) but lacked airway hyperreactivity. Although the children with cough did not suffer clinically from wheezing or dyspnea, it is possible if not likely that airway narrowing occurred at some time during the acute episode. An epidemiological study has examined the characteristics of children who coughed episodically with viral illnesses but never complained of wheeze (36). During the acute episode there was a fall in peak flow readings but the severity of their episodes was not influenced by the presence of atopy.
Numerous studies over the past decade using airway lavage and/or biopsy have established the presence of inflammation, particularly eosinophilic inflammation in the airways of adults with asthma, even mild stable asthma (37,38). Because of the invasive nature of these techniques, fewer studies have been done in children (35,39). In the present study, allergic children with asthma who served as the positive controls were chosen from children who were sensitized to a pet in their home but were not on maintenance inhaled steroid. Such children were thought likely to have eosinophils in their sputum despite having only intermittent symptoms and normal spirometry because a similar group of children had been previously found to have elevated peripheral eosinophils and serum ECP which decreased after treatment with inhaled steroid despite the lack of symptoms (40). In the current study a diary of symptoms was not kept prior to induction of sputum but the spirometry was normal in all cases. As well as elevated sputum eosinophils, these children had elevated sputum ECP suggesting that despite the minimal symptoms and normal spirometry, the eosinophils in the sputum were activated. The children did have airway reactivity on methacholine testing fulfilling the criteria for asthma. Five of the eleven children were treated for one month with inhaled steroid and returned for study (data unpublished). The sputum eosinophils had fallen from a median of 23% to a median of 2% (p=0.016). The data suggest that allergic asthmatic patients with minimal symptoms can have elevate eosinophils and ECP in their sputum which are steroid suppressible. These children might be at risk for remodelling of the airways in the absence of treatment or elimination of the relevant allergens in their environment.
In contrast, the children with post-infectious persisting cough examined in the present study lacked any evidence for eosinophilic inflammation in the airways supporting the suggestion that cough in children is different from allergic asthma (5,35). The results suggest that clinical management of such children should be studied separately from allergic asthma in order to determine whether they are at risk for remodelling of the airways and the most appropriate treatment.
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