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Re: CIAR Application -"Deveiopment of Inhalant AllergIr and Asthma in Children" The second phase of our ER study (Specific Aim 1) has developed very rapidly. We have already enrolled 72 children and the enrollment of children over age 4 years is nearly complete. This has allowed us to focus on the details of our prospective studies (Specific Aim 2). Thus far, we have enrolled 27 young children (17 wheezing patients and 10 controls) from the ER (ages 2 to 18 month>). We will be visiting the houses of these patients twice in the first six months and p lan a more detailed assessment of the home environment including: 1) dust sample collections for measurements of indoor allergen concentrations; 2) saliva samp{es for measuring cotinine from all individuals living in the home; 3) an evalualon of humidity in the home; and 4) assessments of airborne particles. We think that it will be important for us to expand our protocol to include the sizing of airborne particles because we have the impression that low ventilation rates, which are a characteristic feature of low income housing, increase airborne particles, particularly srr all particles which, for example, carry cat allergen. In our initial report of data from the ER study P i trics. Oct. 1993), the prevalence of IgE antibody in sera from wheezing children increased markedly after age 2 years and was significantly higher in wheezing patierts than controls after the age of 4. However, serum IgE antibody and skin tests to allergens in allergic individuals remain positive during the presence or absence of symptoms. It is for this reason that we examined nasal secretions from wheezing and control patients for eosinophiis and observed that 91% of those with nasal eosinophilia also had serum IgE ab to aeroallergens. Eosinophils are often present in nasal secretions in response to natural allergen exposure. These cells and their mediatars also have a well recognized role in allergic inflammation. Thus, we feel that their presence in secretions considerably strengthens the possibility that allergen exposure is contributing to the production of respiratory symptoms. However, in 36% of i:he asthma patients who were sensitized to these allergens we did not observe nasal eosinophilia. It is possible that 1) the assessment of eosinophils underestimates the involvement of these cells in the respiratory tract; 2) that bacterial infection in the upper airways has elicited a neutrophilic response which inhibits or obscures the recruitment of eosinophils; or 3) that allergen exposure is unlikely to be contributing to the symptoms in these patients. Pertinent to this problem, we have been very encouraged by the results of our measurements of eosinophilic cationic protein (ECP) in nasal wash fluid from children seen in the ER. In the attached abstract, we report that vey high levels of ECP were detected in wash fluid from wheezing patients. At this point, 12 of 28 (43%) wheezing patients compared to 1 of 25 (4%) control patients over age two had ECP levels > 400 ng/ml, p< 0.001 (the mean for controls = 35 ng/ml). In addition, ECP levels were elevated in secretions from several patients who did r ot have eosinophilia in their stained secretions. Thus, ECP determinations may prove 0 be a better method for judging the involvement of eosinophils in the pathogenesis of respiratory tract symptoms.

_ We are continuing to collect saliva samples from children seen in the ER and " we are also collecting samples from their mothers. When we initially evaluated our assay for cotinine, we put several members from our laboratory in a smoke filled room where the density of smoke was visible. No elevations in scdivary cotinine could be detected after 3 hours. Thus, we believe that cotinine, when elevated, indicates chronic heavy smoke exposure and, since the half life of cotinine is 3 days, its measurement is unlikely to reflect intermittent fluctuations in smoke exposure. Thus, we will continue to monitor cotinine levels in the patients enrolled in our prospective studies as well as in other members of their family. These levels as well as the levels of allergen in dust samples will be correlated with the development of sensitization to aeroallergens and with recurrent wheezing. Overall, we feel that the strength of this research is based on objective assessments of three common environmental factors which have been linked to airway hyperresponsiveness and wheezing in children. From previous studies, it has been very difficutt to judge the relative importance of these exposures because most investigations focus their assessments on one factor in isol-ation of the others. Thus far, clear differences in the prevalence of IgE to aeroallergens and virus infections are apparent between wheezing and control patients in our studies. However, the wheezing and control patients in the ER do not differ as much in their exposure to tobacco smoke as judged by questionnaire analysis and elE:vated salivary cotinine levels, particularly after the age of two. As these studies continue, we feel that measurements of ECP and other mediators in respiratory seacretions, combined with newer techniques for rhinovirus (via PCR analysis) detection, and a more detailed assessment of the home environment will put us in a very strong position to understand factors which influence the development of persistent lower airway symptoms in early childhood.