Atopic risk score for allergy prevention

Asian Biomedicine Vol. 3 No. 2 April 2009;121-126 Original article Atopic risk score for allergy prevention Jarungchit Ngamphaiboon, Chanyarat Tansupapol, Pantipa Chatchatee Allergy and Immunology Unit, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand Background: There have been recommendations for allergy prevention in cases of high risk infants; nevertheless, there has been no definite criterium to identify those at risk. Objective: To develop an atopic risk score to identify infants who are at risk and deserve allergy prevention by noting a history of atopic diseases of their 1 st degree related family. The scoring is weighted by genetic correlation to each atopic disease to determine the score that is the most appropriate for predictive screening for the development of atopic diseases. Method: This is a retrospective study designed by a team of family pediatricians. Three-thousands five-hundred two children aged 1-5 years from Bangkok and other provinces of Thailand were included between April 2005 and March 2006. From their clinics, the family pediatricians recorded the patients family history of atopic diseases by using the atopic risk score that had been designed, and the health status that had been recorded in the past one-five years. Main outcome parameters were allergic manifestations including cow s milk allergy, atopic dermatitis (AD), chronic rhinitis, and recurrent wheeze. Results: Study subjects were 3,502 children; female (56.4%) and male (43.6%) attending health care facilities in Bangkok and other provinces. The average age of onset of atopic disease was 14.7 months (2 weeks to 5 years) with the median age 9 months. 35.2% had developed atopic diseases mostly during the first year of life (78.3%) and had either a positive or negative family history of atopy. Male children developed significantly more atopic disease than the female with P value <0.001 (OR=1.5; 95%CI=1.300-1.719). The association of the atopic risk score with the development of atopic diseases was determined by using odds ratio as risk estimates. All scores from score one were associated significantly with the development of atopic diseases by OR=2.64-3.22 with p-value <0.001 and 95%CI. The score that could be used for screening of the high-risk infant, was more than 2. Conclusion: The atopic risk score is a practical method to identify the infants with high risk who deserve allergy prevention. Keywords: Allergy prevention, atopic risk score, children. Allergic diseases are now a major health problem in Asian countries and worldwide [1]. Not only do they severely impair the quality of life of the patient, but they are also a great socioeconomic burden on health resource utilization. Atopy is defined as the genetic propensity to generate immunoglobulin E (IgE) antibodies against common environmental allergens. Asthma, atopic dermatitis (AD), and rhinoconjunctivitis are clinical expressions of atopy. These diseases are a major cause of mortality and morbidity in children and continues into adulthood [2]. Thus, attempts at successfully Correspondence to: Assoc. Prof. Jarungchit Ngamphaiboon, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand. E-mail: ngamphaiboon_j @yahoo.com preventing the development of these diseases by limiting exposure to allergens in genetically predisposed infants must take priority. In those who are genetically at risk, food allergy (FA) and AD are common in the first few years of life, followed by asthma and allergic rhinitis [3]. Allergy has a strong genetic predisposition and this has been used to identify children at risk of developing these diseases. This is used to achieve more effective preventive measures [4,5].While recommendations for allergy prevention have been proposed for high-risk infants [6-8], there has been no explicit criterium to identify those who are at risk. A family history of atopic disease in the first degree relatives is commonly used to define high-risk infants but details regarding types of atopic disease and how strong the disease manifests itself in family history is lacking.

122 J. Ngamphaiboon, et al. The objective of this study was to develop an atopic risk score to identify infants who are at risk and would benefit from allergy preventive measures. The family history of atopic disease in first degree relatives was used to develop a scoring system that was weighted by genetic correlation of each atopic disease in order to determine the score that was the most appropriate for screening high-risk infants. Material and methods Between April 2005 and March 2006, we retrospectively analysed the medical charts of children aged 1-5 years who were seen by 34 family pediatricians in Bangkok and other provinces in Thailand. Family pediatricians recorded their family history of atopic diseases by using our specially designed atopic risk score and the medical history of the children as had been recorded during the 1-5 years. Charts were reviewed and data were extracted by two investigators using a uniform data extraction tool including the atopic risk score that had been developed for this study (Table 1). In this atopic risk scoring system, two categories of allergic symptoms are evaluated: 1) major allergic symptoms, which include asthma, atopic dermatitis, allergic rhinitis, and cow s milk allergy (CMA), and 2) minor allergic symptoms, which include urticaria, drug allergy, other food allergies except CMA, and allergic conjunctivitis. For each of these categories, a score of 0-3 was assigned depending on severity, resulting in a minimum possible score of 0 and a maximum possible score of 10.The scoring system was based on evidence that atopic mothers had more risk than atopic fathers [9] or siblings [9], and that asthma, atopic dermatitis, and allergic rhinitis have a strong correlation with the development of atopic disease in infants and even the history of cow s milk allergy (CMA) in an older brother or sister is a strong risk factor for a younger brother or sister [10]. The full scores of the father and siblings were 2, 1 and 0 depending on the degree, but the full scores of the mother were 3, 2 and 0, respectively. The minor symptom group which had a history of urticaria, drug allergy, allergic conjunctivitis, and other food allergies except CMA had the same full score which was 1, 0.5 and 0, respectively, for every member of the family. If they had an overt clinical evidence of at least one major and minor symptom, the total score would be 10. We counted only one disease in each major and minor symptom group. Therefore, if this infant was the first child of a family, the maximum possible score would be 7, and if they have more than one siblings, the score would be obtained from only the one that had atopic disease. Written informed consent was obtained from parents whose children were recruited. The study was approved by the Research Ethics Committee of the Faculty of Medicine, Chulalongkorn University. Outcome parameters The clinical diagnosis of allergic manifestations (AM) that included AD (atopic dermatitis), food allergy especially CMA, chronic rhinitis, and recurrent wheezing was made by family pediatricians of whom one-fourth were pediatric allergists and immunologists. Recurrent wheeze Because an asthma diagnosis is often not given for infants and young children, the criteria were defined by at least three separate episodes of persistent wheezing (>3 days duration) or nighttime cough without infection or regular use of asthma medication for obstructive symptoms (β 2 -agonists, inhaled or systemic steroids, or leukotriene inhibitors). Table 1. Atopic risk score. Type and degree of allergy symptoms Family Major* Minor** Total Overt Probable Absent Overt Probable Absent Father 2 1 0 1 0.5 0 4.5 Mother 3 2 0 1 0.5 0 6.5 Sibling 2 1 0 1 0.5 0 4.5 *asthma, atopic dermatitis, allergic rhinitis, CMA. **urticaria, drug allergy, other food allergies except CMA, allergic conjunctivitis.

Vol. 3 No. 2 April 2009 Atopic risk score for allergy prevention 123 Atopic dermatitis The diagnosis of AD was based on the 16 criteria by Hanifin and Rajka [11]. Chronic rhinitis The diagnosis of chronic rhinitis was made when typical nasal blockage, rhinorrhea, and sneezing were present all year or during the summer season. Cow s milk allergy (CMA) Diagnosis of CMA requires a significant clinical improvement in response to avoidance of cow s milk and a recurring of symptoms after re-exposure to cow s milk formula. Statistical analysis Relationships between scores and atopic diseases were assessed by using appropriate parametric tests and statistics, including χ 2 and t-tests. A logistic regression analysis was used to estimate the odds for development of atopic disease at particular cutoff points in children with higher scores relative to children with lower scores. The results are reported as odds ratios (OR) and 95% confidence intervals (CIs). The data were analyzed by using SPSS package program (Release 11.0; SPSS Inc, Chicago, USA). P <0.001 was considered significant for all tests. A receiver operating characteristic (ROC) curve analysis was used to derive an optimal cut-off point. Results Characteristics of the study patients Four thousand twenty-five children were recruited for the study by their family pediatricians. After a review of medical records, 523 children were excluded because of incomplete data. Of the 3,502 evaluated children, 1,976 were females (56.4%) and 1,526 were males (43.6%). Around one-third (1,233 of 3,502, 35.2%) eventually developed atopic diseases mostly during their first year of life (966 of 1,233, 78.3%). The average age onset of atopic disease was 14.7 months (2 weeks - 5 years) with a median age of 9 months regardless of the family history of atopy. Males developed significantly more atopic diseases than females (OR=1.50; 95%CI=1.30-1.72). The atopic diseases included atopic dermatitis, chronic rhinitis, recurrent wheeze, and cow s milk allergy (CMA). The largest group of children studied scored = 0 (1,396 of 3,502, 39.9%), followed by 3 (608, 17.4%), and 2 (517, 14.8%). Around one-third scored more than 3 (Table 2). The association of atopic risk score in the development of atopic diseases was assessed by an odds ratio (OR) as risk estimates. Children who had an atopic risk score of 1 and above were significantly associated with the development of atopic diseases (OR=2.64-3.22; p <0.001 (Table 3). To determine the score that could be used as a cut-off point for selecting high-risk infants for allergy prevention interventions, the receiver operating characteristic (ROC) curve analysis was applied and score >2 was found to be the most appropriate to be used as a screening score to identify high-risk infants with a sensitivity of 68.8 and specifi city of 56%, which was the highest of the area under the curve as shown in Table 4. When we used the atopic risk score of 2 or more as marking the high-risk group, the incidence of atopic disease in that group was 68.8%, significantly higher than in the low-risk group (score <2, see Fig. 1). Table 2. Atopic risk score frequency. Score Frequency % 0 1,396 39.9 0.5 13 0.4 1.0 240 6.9 1.5 6 0.2 2.0 517 14.8 2.5 13 0.4 3.0 608 17.4 3.5 9 0.3 4.0 275 7.9 4.5 5 0.1 5.0 246 7.0 5.5 6 0.2 6.0 84 2.4 6.5 3 0.1 7.0 62 1.8 8.0 14 0.4 9.0 4 0.1 9.5 1.0 Total 3,502 100

124 J. Ngamphaiboon, et al. Table 3. Association of atopic risk score in development of atopic disease. Score P-value OR 95% CI 1 < 0.001 2.81 2.417-3.282 1.5 < 0.001 2.82 2.437-3.266 2 < 0.001 2.80 2.425-3.248 2.5 < 0.001 2.67 2.313-3.082 3 < 0.001 2.65 2.302-3.068 3.5 < 0.001 2.66 2.249-3.149 5 < 0.001 2.64 2.142-3.244 6 < 0.001 3.08 2.244-4.245 7 < 0.001 3.22 2.037-5.076 8 0.001 4.32 1.658-11.28 9 0.449 1.84 0.371-9.130 9.5 0.297 0.999 0.998-1.000 Table 4. The receiver operating characteristic (ROC) curve analysis. Score Sensitivity Specificity Area under curve 1 75.0% 48.5% 0.617 1.5 69.0% 55.8% 0.624 2 68.8% 56.0% 0.624 2.5 53.1% 70.2% 0.617 3 52.6% 70.5% 0.616 3.5 31.0% 85.6% 0.583 4 30.7% 85.8% 0.583 Incidence Fig. 1 Incidence of atopic disease at atopic risk score of (N = 1,233, P <0.001). Discussion Allergic diseases in children and young adults have become more prevalent over the last decades. Reasons for this increase are not known and may simply represent greater recognition due to improved health care. The development of allergic diseases, including food allergy, depends on an interaction between genetic and several environmental factors, such as exposure to allergens and non-specific factors (e.g. tobacco smoke, air pollution, infections, and dietary factors). The expression of allergic disease may vary with age and certain symptoms may disappear and be replaced by other symptoms. In infancy, the common symptoms are atopic dermatitis, gastrointestinal symptoms, and recurrent wheezing, whereas bronchial asthma and allergic rhinoconjunctivitis are predominant later in childhood. Allergy prevention should be planned from the intrauterine period. It is important to be aware that sensitization to foods may precede development of allergy or may be a normal and often transitory harmless phenomenon particularly in early childhood and may even be present prenatally [6,12]. Two interventions have been recommended. They are food intervention and environmental control. However, for allergic prevention, we have to identify who are the infants at risk. Previous reports that food intervention during infancy including avoidance of cow s milk in high-risk infants is associated with reduction of atopic dermatitis and cow s milk allergy during the first 2-4 years of life [12-14]. The result of our study also confirms that high-risk infants had a significantly higher chance of developing atopic diseases than the low-risk group. This atopic risk score would be practical for general physicians to apply. An atopic risk score of 2 or more will predict the development of atopic disease with a sensitivity of 68.8% and specificity of 56%. 78.3% of CMA cases developed atopic diseases during the first year of life with or without a positive family history of atopy. The male developed significantly more atopic disease than the females with p value < 0.001) (OR=1.5; 95%CI=1.300-1.719). One-fourth of the participating pediatricians were pediatric allergists and immunologists. The others were general pediatrician, who can reliably diagnose atopic dermatitis, chronic rhinitis, and recurrent wheezing and manage it by appropriate medications. We used any atopic risk score of 2 or more for the high-risk group. In this study, the incidence of atopic diseases in the high risk group was

Vol. 3 No. 2 April 2009 Atopic risk score for allergy prevention 125 68.8%, much higher than in the low risk group. Those infants were recommended exclusive breast-feeding for at least 4-6 months or, in case that breast-feeding was insufficient, a partial hydrolysate formula (phf) or an extensive hydrolysate formula (ehf) [15] and delayed introduction of allergenic foods such as egg yolk until after sixth months of life [16] were recommended. Conclusion The atopic risk score is a practical index for identifying infants who are at high risk for allergic manifestations (sensitivity of 68.8% and specificity of 56%). The score >2 is the most appropriate for use. Acknowledgement We would like to thank Panyasang V, statistician from Chulalongkorn Medical Research Center and Sangsupawanich P from Songklanakarin University for their statistical advice, and the whole team of family pediatricians namely: Wannasatit W, Chongcharoenyanon W, Chaichoophong K, Chanta C, Kaninworapan K, Rojwirun S, Dachanan S, Silalai S, Wong-U-Railertkun P, Wirojwong P, Kobkuachaiyapong S, Srivilai D, Hanpol R, Rutsamitut P, Wichitsripornkul W, Saengsiriwut A, Suppakit W, Sagoolngam S, Wongpiromsarn T, Jamsri S, Viratanapanu P, Nantasuk C, Kitjawijit W, Chotnarumol S, Sateinsagpong P, Vilaipan P, Pitaksin N, Siriworadon N, Numkiatwongsa S, Chevathavorn T, Santiprarom P, for their participation and data collection. The authors have no conflict of interest to declare. References 1. Asher MI, Montefort S, Bjorksten B, Lai CK, Strachan DP, Weiland SK, et al. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys.lancet. 2006; 368:733-43. 2. Braman SS. The global burden of asthma. Chest 2006; 130(Suppl 1):4s-12s. 3. Spergel JM, Paller AS. Atopic dermatitis and the atopic march. J Allergy Clin Immunol. 2003; 112: S118-27. 4. Dold S, Wjst M, Mutius EV, Reitmeir P, Stiepel E. Genetic risk for asthma, allergic rhinitis and atopic dermatitis. Arch Dis Child. 1992; 67:1018-22. 5. Hide DW. The Isle of Wight study, approach to allergy prevention. Pediatr Allergy Immunol. 1994; 5 (Suppl 6):61-4. 6. Muraro A, Dreborg S, Halken S, Host A, Alberse R, et al. Dietary prevention of allergic diseases in infants and small children. Part I: immunologic background and criteria for hypoallergenicity. Pediatr Allergy Immunol. 2004; 15:103-11. 7. Kull I, Almqvist C, Lilja G, Pershagen G, Wickman M. Breast-feeding reduces the risk of asthma during the first 4 years of life. J Allergy Clin Immunol. 2004; 114:755-60. 8. Asher I, Dgena-Cagnani C, Baner A, Canonica GW, Chuchalin A, Custovic A, et al. World Allergy Organization guidelines for prevention of allergy and allergic asthma. Int Arch Allergy Immunol. 2004; 135: 83-92. 9. Tariq SM, Matthews SM, Hakim EA, Stevens M, Arshad SH, Hide DW. The prevalence of and risk factors for atopy in early childhood: a whole population birth cohort study. J Allergy Clin Immunol. 1998; 101:587-93. 10. Kulig M, Bergmann R, Niggemann B, Burow G, Wahn U. Prediction of sensitization to inhalant allergens in childhood: evaluating family history, atopic dermatitis and sensitization to food allergens. Clin Exp Allergy. 1998; 28:1397-403. 11. Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis.acta Derm Venereol.1983; 92 (Suppl 10): 44-7. 12. Halken S. Prevention of allergic disease in childhood: clinical and epidemiological aspects of primary and secondary allergy prevention. Pediatr Allergy Immunol. 2004; 15(Suppl 16): 9-32. 13. Muraro A, Dreborg S, Halken S, Host A, Niggemann B, Aalberse R, et al. Dietary prevention of allergic diseases in infants and small children. Part II, Evaluation of methods in allergy prevention studies and sensitization markers. Definitions and diagnostic criteria of allergic diseases. Pediatr Allergy Immunol. 2004; 15:196-205. 14. Muraro A, Dreborg S, Halken S, Host A, Niggemann B, Aalberse R, et al. Dietary prevention of allergic diseases in infants and small children. Part III: Critical review of published peer-reviewed observational and interventional studies and final recommendations. Pediatr Allergy Immunol. 2004; 15: 291-307.

126 J. Ngamphaiboon, et al. 15. von Berg A, Koletzko S, Filipiak-Pittroff B, Laubereau B, Grubl A, Wichmann HE, et al. Certain hydrolyzed formulas reduce the incidence of atopic dermatitis but not that of asthma: three-year results of the German infant nutritional intervention study. J Allergy Clin Immunol. 2007; 119:718-25. 16. Host A, Halken S. Primary prevention of food allergy in infants who are at risk. Curr Opin Allergy Clin Immunol. 2005; 5:255-9.