Ninety 9- to 10-year-old children (49 males) were enrolled and divided into three groups of 30 children each. The Study group comprised of children with mild to moderate asthma as classified by the GINA guidelines and a self-reported history of aspirin-allergy. The Allergic control group had children with allergic rhinitis or atopic dermatitis, and the Healthy control group included healthy children attending our hospital for vaccination. The children in the allergy and healthy control groups had no history of aspirin-allergy. Forced expiratory volume in the first second (FeV1) and Fractional exhaled nitric oxide (FeNO) measurements (NIOX MINO system, Phadia) were performed for each participant every morning before breakfast for 3 consecutive days. The participants took ibuprofen 2.5 mg/kg 4 times a day. We defined bronchospasm as a ³20% decrease from baseline in FeV1, and ibuprofen-sensitivity as bronchospasm following administration of ibuprofen. Asthma exacerbation was defined as an increase in FeNO level from baseline (20 ppb) with increased coughing frequency and chest tightness clinically, increased use of inhaled corticosteroids (ICS) or short-acting beta-agonists, and a decrease in PaO2 of less than 90%. Children taking systemic steroids within one week of the initiation of the study were excluded. This study was approved by the Institutional Review Board of our hospital, and all of the participants’ parents or guardians provided written informed consent.

After the children had received the intervention for two days, a worsening of pulmonary function and asthma exacerbation was seen in a significant number of children in the study group (Table I). The allergy control group only showed an increased FeNO level but no change in FeV1. In the healthy control group, both PFT and FeNO were maintained at the baseline level (Fig. 1).

TABLE I  Clinical and Laboratory Parameters in the Study Population After Taking Ibuprofen for Two Days

Fig. 1 (a) The FEV1 changes in the study group after treatment of ibuprofen for 3 consecutive days; (b) The FeNO changes in the study group after treatment with ibuprofen for 3 consecutive days.

As ibuprofen has cross-intolerance with aspirin, the children with mild to moderate asthma in this study had an increased frequency of coughing with or without short of breath, and required double the dose of ICS or the use of short acting beta-agonists to ease the exacerbation of asthma symptoms. Patients with aspirin-exacerbated respiratory diseases typically experience severe bronchoconstriction and/or rhinoconjunctival reactions to aspirin and other NSAIDs, even those which they have not encountered previously [7]. Aspirin-intolerance, as determined in broncho-provocation studies, may be apparent in 5% of asthmatic children [8]. Palmer reported that NSAID-exacerbated asthma may occur in up to 2% of asthmatic children [6].

Kanabar, et al. [9] reported that ibuprofen use was associated with a low relative risk for hospitalization (0.63) and outpatient visits (0.56) for asthma compared with acetaminophen. In addition, Kidon, et al. [10] also reported that ibuprofen at antipyretic doses may cause acute respiratory problems in only a very small number of mild to moderate asthmatic children. Furthermore, a cross-reactive hypersensitivity response to NSAIDs was reported in 45% of young Asian atopic children through their history, and in 25% through diagnostic challenge [11]. Of the patients with hypersensitivity reactions to NSAIDs, 76% had cross-intolerance and 24% were selective responders. The most important drugs involved in cross-intolerance are propionic acid derivatives, in most cases ibuprofen, and in selective responders, pyrazolones. In cross-intolerance, the most frequent clinical entities are urticaria and angioedema, and to a lesser extent airway involvement [1]. Jenkins, et al. [12] reported that cross-intolerance to doses of NSAIDs was present in most patients with aspirin-induced asthma (ibuprofen, 98%; naproxen, 100%; and diclofenac, 93%). On the other hand, beneficial effects of ibuprofen have been reported in cystic fibrosis [13]. In addition, due to the inflammatory pathogenesis of asthma, the anti-inflammatory effect of ibuprofen may possibly reduce morbidity in children with asthma.