Effect of Nedocromil Sodium on Aspecific Bronchial Hyper-Reactivity in Asthmatic Children

The purpose of this study was to evaluate whether nedocromil sodium benefits urban asthmatic children showing seasonal bronchial hyper-reactivity to ultrasonic nebulization of distilled water (UNDW). A prospective, randomized, placebo-controlled, parallel-group, double-blind study was carried out at the outpatient pulmonology service at a tertiary-care teaching hospital. Twelve children living in Milan, who were 7–17 years of age, who were SPT and RAST-negative to perennial allergens, who were suffering from episodic asthma, and showing seasonal bronchial hyper-reactivity to UNDW during winter, participated in this study. All the children received either placebo or nedocromil sodium, 4 mg every 6 h for 6 weeks. Spirometry and UNDW challenge were done at the following times: day−7; day 0; day 1; day 7; day 14; day 28; day 42. No differences were found in the basal spirometric parameters, which were normal in both nedocromil and placebo groups. Bronchial reactivity to UNDW was found to be significantly decreased in the group treated with nedocromtl starting from day 7. It is therefore concluded that nedocromil sodium can reverse bronchial hyper-reactivity caused by seasonal factors such as cold, viral infections and atmospheric pollutants in children suffering from asthma.


Introduction
Bronchial hyper-reactivity (i.e. exaggerated bronchoconstrictive response to various stimuli) is a characteristic of asthma both in children and adults. 1," Bronchial hyper-reactivity is, in part, genetically determined and, in part, a consequence of airway inflammation, and it is closely related to the severity of the disease. Studies performed on animal models show that exposure to such environmental pollutants as SO4 and ozone may induce bronchial hyper-reactivity, and it has been suggested that climate-therapy may attenuate these effects. 9,1 In children living in urban areas, exposure to pollution has been associated with an increase in the number of cases of secretive chronic bronchitis and to a reduction in respiratory function, 11 as well as to an increase in asthma 1" and to a higher risk of allergic sensitization.
Anti-inflammatory drugs, such as inhaled corticosteroids and cromones, are widely used to reverse bronchial hyper-reactivity.  The aim of this study was to evaluate the protective effect of nedocromil sodium on bronchial hyper-reactivi.ty in a group of non-atopic asthmatic children who were showing seasonal bronchoreactivity, and who were living in town. UNDW was administered according to Allegra and Bianco. 21 A test was judged positive when after challenge FEV1 (forced expiratory volume in l s) dropped 20% or more, and/or MMEF (maximal midexpiratory flow) dropped 35% or more. Spirometric evaluations and flow/volume curve recordings were always performed at the same time (14.00-16.00 h), 6 h after the last administration of nedocromil, using a Spirostar FG 90 spirometer (Werner-Gut AG, Bern, CH), equipped with a n.2 Fleisch pneumotachograph; reference parameters were according to Zapletal. 2" Before challenge, a basal spirometric examination was performed, and measurements were taken at 1, 2, 5, 10 and 15 min after the challenge. Fourteen children fulfilling the abovelisted criteria were included in this trial. The subjects were nine males and five females, aged 7.33-16.92 years (mean age: 10.12 _+ 3.52 years; median age: 11.40 years). After informed consent was obtained, children were randomly assigned to treatment with nedocromil sodium, 2 puffs four times per day for 42 days (group N; seven subjects), or to the placebo group (group P).
In case of asthmatic episodes, salbutamol could be taken (Ventolin MDI, Glaxo, Verona, Italy), at a dose of 1 puff, corresponding to 200 btg, up to four times daily. Cromones, corticosteroids and antihistamines were not allowed throughout the study period. Aspecific challenge by inhalation of UNDW was performed at the following times: -7 days (time-7); day 0 (time 0); day 1 (time 1); day 7 (time 7); day 14 (time 14); day 28

Results
Two girls of group P dropped out of the study; one because of an airway infection, probably caused by a virus, and the other because of an asthma attack that was treated with systemic steroid. The data of these two subjects were not included in the final evaluation. Therefore, 12 Fig. 1, there was no difference at any time for VC (vital capacity; baseline/expected), PEF (peak expiratory flow), FEV1 and FEF25-75 (forced expiratory flow between 25 and 75% of vital capacity) between the treated and placebo groups. The data show a parallel trend which was fairly constant in time; therefore, nedocromil sodium treatment did not affect the parameters measured.
Bronchoreactivoty to challenge with UNDW: Fig 2 shows the median percentage variations (UNDW/ baseline) of vital capacity, FEV1, PEF, and FEF25-75 in the treated and in the placebo group. The change in vital capacity after UNDW was substantially less in the treated group, even before therapy (t -7), but the difference became significant during treatment ( Table 2). At day-7, FEV1 changes after UNDW were similar in the two groups. Differences were observed at day 7: bronchoreactivity in the placebo group remained stable, and decreased significantly in the treated group (Table 3).
The profile of PEF after UNDW was almost parallel in the two groups; only at day 42 was there a   (Table 4). FEF 25-75 changes after UNDW, which were initially comparable, showed a progressive decrease in bronchoreactivity in group N, and no change in group P (Table 5).

Discussion
Although changes in bronchial reactivity have been reported in adult and young asthmatic patients, few attempts have been made to identiy the cause of this behaviour. In allergic children, bronchial reactivity may increase during the season of exposure to the allergen. 14,15 Children affected by episodic asthma or by seasonal, non-atopic, recurrent asthma, whose hyper-reactivity was seasonal (i.e. it appeared in winter and disappeared in summer) were studied. In these cases, alteration in reactivity may reflect an inflammatory process induced, in winter, by such Table 4. Median + SE and percentage 6f PEF (after UNDW/ baseline) in groups N and P at different times  Tables 2-5. factors as cold, exposure to viral infection, and atmospheric pollutants. These patients, who were somewhat rare, were selected in order to test the efficacy of nedocromil sodium in extrinsic non-allergic asthma.
The results of .this study indicate that nedocromil sodium was beneficial in these patients. From the second week of treatment, patients showed a better spirometric performance, and maintained good clinical conditions. Despite the small number of subjects and the relatively short study period, the data are statistically significant: this confirms the efficacy of nedocromil sodium as a prophylactic treatment. No difference in functional parameters was found between the two groups in baseline conditions, but there was a progressive improvement in the values of the N group measured after UNDW. This is consistent with clinical data and recruitment criteria (i.e. children with episodic asthma, whose resting respiratory function was very close to normal); functional disorders only occurred after aspecific challenge. To our knowledge, our data are the first to show that nedocromil sodium affords protection against UNDW challenge in asthmatic children.
Our results are consistent with previous reports of preadministration of 2 and 4 mg of nedocromil sodium, 10-30 min before aspecific challenge prevents bronchospasm induced by UNDW. 17 However, we performed the test at least 6 h after administration of S46 Mediators of Inflammation. Vol 3 (Supplement). 1994 nedocromil sodium; therefore, the effect obtained cannot be attributed to an immediate inhibition, but rather to a reduction in the airway inflammation underlying the hyper-reactivity. Nedocromil sodium is known to exhibit a series of anti-inflammatory activities: it prevents the generation of neutrophil chemotactic peptides as IL-8, '3 inhibits human neutrophil chemotaxis, '<'5 decreases the bronchospastic response induced by SO,. inhalation in animal models, '6 and prevents infiltration of neutrophils from bronchial mucosa of dogs exposed to ozone. 8 Recent findings suggest that nedocromil sodium downregulates activation of cells involved in the latephase asthmatic reaction, such as eosinophils, '7 mastcells and T-cells. 28 Although it inhibits the development of mucosal inflammation, it was uncertain whether nedocromil sodium eliminates or reduces existing inflammatory changes. '9 Our data suggest that it can do this, as clinical trials have demonstrated its efficacy in diminishing the late phase asthmatic reaction. Therefore, the drug not only prevents the seasonal increase in aspecific bronchial reactivity as previously reported in patients naturally exposed to allergens, 15,16 but it is also useful in the treatment of non-allergic asthma.
In conclusion, nedocromil sodium, which may be used as prophylaxis in atopic asthmatic subjects with symptoms and bronchial hyper-reactivity upon natural exposure to allergens, may also be used to treat children suffering from episodic asthma, in whom airway inflammation increases bronchial reactivity.