REVIEW URRENT C OPINION
New insights into the allergic march Marcus Shaker
Purpose of review The allergic march of childhood describes an association between atopic dermatitis, IgE-mediated food allergy, allergic asthma, and allergic rhinitis that begins with an atopic family history. This review summarizes recent insights into the nature of these conditions and their associations. Recent findings In recent years, common allergic diseases have become more prevalent and increased rates of food allergies remain incompletely understood. This review explores a newly described major genetic risk factor, a mutation in the skin matrix protein filaggrin, as it relates to the allergic march of childhood. New paradigms of understanding the interrelationships between atopic dermatitis, food allergy, and asthma are described. A surge of investigative effort has been directed toward the prevention and treatment of food allergy. Risk factors for allergic asthma in young children have been used to predict patient response to treatment. A recent practice parameter on furry animal/pet avoidance updates current understanding of allergen avoidance in modifying allergic phenotypes. Summary Understanding of the interrelationships of atopic diseases allows earlier diagnosis of allergic conditions in at-risk patient populations and may lead to novel approaches to health promotion and disease prevention. Keywords allergic march, asthma, atopic dermatitis, filaggrin, food allergy
INTRODUCTION The allergic march of childhood describes the relationships between atopic genetic risk factors, family history, atopic dermatitis, food allergy, and asthma. A survey of 1 200 000 children from 98 countries investigated the global prevalence of several conditions comprising the allergic march. While significant geographic variation was noted, the prevalence of asthma, rhinoconjunctivits, and eczema in 6–7year-old children was 12, 8.5, and 8%, respectively. In older children of 13–14 years of age, the prevalence of asthma was 14% [1 ]. Increasing rates of food allergy have also been reported. In 2009, Branum and Lukacs [2] reported an 18% increase in self-reported food allergy prevalence (from 1997 to 2007) in children less than 18 years of age in the United States, with food allergy affecting 3.9% of children. Serumspecific immunoglobulin E (IgE) peanut sensitization was detectable for an estimated 9% of children in the United States [2]. More recently, even higher rates of food allergy have been reported. Gupta et al. [3] performed a randomized crosssectional survey of the households in the United States between June 2009 and February 2010. Using data collected from 40 104 children, the &
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prevalence of food allergy was found to be 8% [95% confidence interval (CI) 76–83]. In the group, 38.7% had severe reactions and 30.4% had multiple food allergies. Among children with food allergy, there was a prevalence of 25.2% for peanut allergy, 21.1% for milk, and 17.2% for shellfish [3]. Geographic variability was reported, with food allergies noted more commonly in urban than rural areas (98 versus 62%) [4 ]. One theory to explain these differences invokes the classic hygiene hypothesis, which suggests that early life exposures to certain microbial agents (associated with rural living) may influence the development of allergy. The HealthNuts study evaluated over 2000 unselected 1-year-old Australian infants. At 12 months &&
Department of Pediatrics, Section of Allergy, Asthma, and Immunology, Children’s Hospital at Dartmouth, Lebanon New Hampshire, USA Correspondence to Marcus Shaker, MD, MS, FAAAAI, FAAP, Associate Professor of Pediatrics, Section of Allergy, Asthma, and Immunology, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon NH 03756, USA. Tel: +1 603 653 9885; fax: +1 603 650 0907; e-mail: [email protected] Curr Opin Pediatr 2014, 26:516–520 DOI:10.1097/MOP.0000000000000120 Volume 26 Number 4 August 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
New insights into the allergic march Shaker
KEY POINTS Filaggrin is a skin matrix protein associated with eczema, asthma, allergic rhinitis, and allergen-specific IgE that may play a central role in the development of allergic diseases in some patients. The role of early or delayed introduction of allergenic foods in the prevention of food allergy is under active investigation but, at present, recommendations on timing of food introduction remain in a state of equipoise. Oral and sublingual immunotherapy continues to be evaluated for the treatment of food allergy; however, at present ,these treatment strategies remain investigational. Young children with a positive asthma predictive index are more likely to respond favorably to treatment with inhaled corticosteroids. Children with allergic asthma who are sensitized to pets that reside in their homes are more likely to have improved asthma control when these pets are removed.
of age, skin prick testing and supervised challenge confirmed allergy in 10.4% of this population (95% CI 93–115). This prevalence is one of the highest reported to date [5]. Exposure to siblings and dogs during infancy decreased the incidence of egg allergy [adjusted odds ratios (OR) of 0.72; 95% CI 0.62–0.83 per sibling and 0.72; 95% CI 0.52–0.99, respectively]. These findings again support the role of the hygiene hypothesis in allergy development. Cesarean section delivery, antibiotic use during infancy, childcare attendance, and maternal age were not associated with egg allergy [6 ]. &&
ATOPIC DERMATITIS Often the first manifestation of the allergic march, atopic dermatitis affects 10–20% of children. Schneider et al. [7 ] recently published a 2013 atopic dermatitis practice parameter. This is a useful reference that describes key features and treatment approaches. Food allergy is implicated in one third of children with atopic dermatitis, but asymptomatic food sensitization is also seen. Management involves trigger avoidance, restoration of skin barrier function, antiinflammatory medicine, and occasional antibiotics. Measures for refractory disease include wet dressing and occlusion, phototherapy, and systemic immunosuppressants such as cyclosporine [7 ]. Skin barrier dysfunction is increasingly recognized as a central component in the development of atopic dermatitis. Evidence suggests presentation of allergen to an allergic inflammatory milieu through disruption in skin barrier function may be an &&
&&
important factor in the development of allergic sensitization [8,9]. For example, peanut allergy has been found to be more likely if children are treated with skin preparations containing peanut oil (OR 6.8; 95% CI 1.4–32.9) [10]. The skin matrix protein filaggrin promotes keratin aggregation; abnormal function of this protein has been associated with ichthyosis, eczema, asthma, allergic rhinitis, and specific IgE [11]. McAleer and Irvine [12 ] recently published an excellent review of the role of filaggrin in allergic disease. Approximately 50% of patients with moderate-tosevere atopic dermatitis have at least one filaggrin mutation; however, filaggrin appears to be downregulated even in patients with atopic dermatitis without filaggrin mutations due to the effect of Th2 cytokines interleukin-4 and interleukin-13. The atopic dermatitis phenotype most strongly associated with filaggrin mutations is early onset, severe, and persistent. The skin barrier defect resulting from filaggrin mutations becomes exacerbated following allergic sensitization to environmental allergens. Filaggrin mutations confer a much greater risk of asthma, which tends to have a more difficult course. Filaggrin mutations also increase the risk of peanut allergy (OR 5.3 with a residual OR of 3.8 when corrected for atopic dermatitis) [12 ]. While useful in understanding the pathogenesis of the allergic march, evaluation of filaggrin mutations is not commonplace in the clinical management of children with atopic dermatitis. &&
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FOOD ALLERGY To understand recent developments in food allergy prevention research, it is important to understand their recent historical context. For many years, traditional recommendations for food allergy prevention included avoidance of allergenic foods during the first several years of life. However, evidence suggesting a more crucial role for allergen sensitization through an impaired skin barrier together with studies suggesting a possible protective role for early allergen oral tolerance had called these recommendations into question. In 2008, two population-based prospective birth cohort studies suggested that delayed introduction of solids may not be protective against food allergy and that delayed introduction of allergic foods may even increase the risk of food allergy. The Lifestyle-Related Factors on the Immune System and the Development of Allergies cohort evaluated 2073 German children at 6 years of age and found that delayed food introduction beyond 4 or 6 months was more commonly associated with food sensitization [13]. In a separate analysis of 2558 Dutch infants, greater delay in introduction of cow
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milk products was associated with an increased risk of atopy development at 2 years of age [14]. Two additional publications appeared in 2008 that dramatically changed the prevailing view on the role of delayed food introduction in food allergy risk in young children. Du Toit et al. [15] published results of a nonrandomized cohort evaluation of peanut allergy prevalence using validated questionnaires, comparing two countries with very different peanut feeding practices. In this study, Israeli children tended to receive peanut introduction at an earlier age and consume peanut more frequently and in larger quantities than Jewish children in the United Kingdom (median monthly Israeli peanut consumption in infants 8–14 months of age was 7.1 versus 0 g in the United Kingdom; P < 0.001). Despite these cultural differences (or, perhaps, because of them), the prevalence of peanut allergy in Israel was 0.17 versus 1.85% in the United Kingdom (P < 0.001) [15]. In the same year as these studies were published, the American Academy of Pediatrics (AAP) released an updated statement on the effect of early nutritional interventions on the development of atopic disease in infants and children. The document concluded that there was little evidence to support the contention that delayed introduction of complementary foods beyond 4–6 months of age could prevent atopic disease, and that evidence was insufficient to recommend any dietary intervention beyond 4–6 months of age for the purposes of allergy prevention [16]. This left clinical recommendations regarding early or late infant exposure to potential allergens in a state of uncertainty. The 2008 AAP document did not provide formal recommendations about how and when to introduce potentially allergic foods, given the state of equipoise of evidence. However, in 2012, the Adverse Reactions to Foods Committee of the American Academy of Allergy, Asthma, and Immunology provided advice for primary care physicians and specialists about the primary prevention of allergic disease through nutritional interventions. These recommendations were derived from available literature and expert opinion. This group concluded that avoidance diets during pregnancy and lactation are not recommended at this time, but more research is necessary for peanut. Exclusive breast-feeding for at least 4 and up to 6 months was endorsed. For infants at elevated risk for developing allergic disease (at least one first-degree relative with allergic rhinitis, asthma, or food allergy) who cannot be exclusively breast-fed, it was recommended that hydrolyzed formula be considered. Complementary foods can be introduced between 4 and 6 months of age. It was suggested that once ‘a few typical complementary foods . . . are tolerated, 518
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highly allergic foods may be introduced as complementary foods’. It was recommended that the initial taste of a potentially allergenic food be given at home and in gradually increasing amounts if tolerated. In some cases, allergy consultation was recommended for a personalized plan for introduction of potential food allergens. Specific examples included infants with moderate-to-severe atopic dermatitis, children with a suspected allergic reaction to a food, children with one underlying food allergy, who may be at risk for other food allergies, children sensitized to a food prior to introduction, and siblings of children with peanut allergy (optional patient preference-sensitive decision; careful home introduction encouraged as a reasonable alternative) [17 ]. The possible benefit of early food allergen introduction was again reported in a study by Koplin et al. [18]. When compared with early egg introduction between 4 and 6 months of age, delayed introduction during infancy was associated with a higher rate of challenge-proven egg allergy. Egg allergy was more likely in infants introduced to egg at 10–12 months of age and more than 12 months of age [adjusted odds ratio (aOR) 1.6, 95% CI aOR 3.4, 95% CI 1.8–6.5, respectively] [18]. A more recent report by Grimshaw et al. [19 ] illustrates the confusing state of evidence in regards to food allergy prevention. In this nested case-control study, infants diagnosed with food allergy by 2 years of age were introduced solid foods earlier (less than 16 weeks of age) and were less likely to be receiving breast milk when cow’s milk protein was first introduced into their diets [19 ]. It is in this context that the Learning Early About Peanut Allergy (LEAP) study is being undertaken. This randomized controlled trial aims to provide a better understanding of early versus delayed introduction of allergic foods in high-risk children in the context of food allergy prevention. The LEAP screening cohort consisted of 834 infants (mean age 7.8 months) with (I) mild atopic dermatitis and no egg allergy (118 infants), (II) severe atopic dermatitis, egg allergy, or both with negative peanut skin prick test (542 infants), (III) severe atopic dermatitis, egg allergy, or both with 1–4-mm peanut wheal response on skin prick test (98 infants), and (IV) infants with greater than 4-mm peanut wheal response (76 infants). Interestingly (and unexpectedly), 17% of infants in group II and 56% of infants in group III had a peanut-specific IgE of at least 0.35 kU/l. However, none of the patients in group I and 91% of group IV infants had positive blood allergy testing to peanut. Sensitization to peanut by both skin test and specific IgE were each associated with an increased risk for severe atopic dermatitis. Although this represents an at-risk cohort, the high rate of peanut sensitization noted &&
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New insights into the allergic march Shaker
during infancy was unexpected. Awaited results on the effect of early or delayed introduction of peanut in the LEAP patients are expected to clarify the role of food introduction in allergy prevention [20 ]. Research continues into oral and sublingual desensitization of food allergy, and these methods remain investigational. Vickery et al. [21 ] recently evaluated the effect of peanut oral immunotherapy (OIT) on desensitization and tolerance. Patients of 1–16 years of age were treated for up to 5 years with peanut OIT; 24 out of 39 patients completed the protocol and 12 demonstrated sustained unresponsiveness for 1 month after stopping OIT [21 ]. The distinction between temporary allergen desensitization (while receiving therapy) and more durable allergen tolerance (after completing therapy) is an important one, because patients who experience desensitization without tolerance would remain at an elevated risk for food-associated anaphylaxis in the setting of missed doses or nonadherence. Previous reports from this group have shown a high rate of successful peanut desensitization (93%) while receiving therapy; however, the inability to induce lasting tolerance in 50% of the cohort is concerning. Furthermore, in this study, tolerance was assessed within a very short time frame off therapy. Whether or not immune tolerance would persist for 3, 6, or even 12 months is a matter of speculation. &&
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data, investigators described that children most likely to experience benefit from inhaled corticosteroids were more likely to be white boys, have aeroallergen sensitization, and have a history of hospitalization or emergency visit in the preceding year [25]. Recently, the modified asthma predictive index was evaluated in 289 children (1–3 years of age). The index proved to be a useful tool, demonstrating a 90% posttest probability to predict asthma persistence in later childhood. Positive likelihood ratios ranged from 4.9 to 55 for asthma persistence at 6, 8, and 11 years of age [26 ]. These findings underscore the importance of appreciating childhood asthma phenotypes when discussing asthma prognosis and choosing appropriate management. It has also become clear that, in young preschool children who require inhaled corticosteroid therapy, attempting to maintain the dose of therapy below 10 μg/kg/day fluticasone equivalents is least likely to be associated with impairments in linear growth [27]. The childhood asthma management program extension study reported on final adult height in 943 of 1041 childhood asthma management program participants. Starting at the age of 5–13 years, participants were randomized to receive 400 μg of budesonide, 16 mg of nedocromil, or placebo daily for 4–6 years. Mean adult height was 1.2 cm lower (95% CI 1.9 to 0.5) in the budesonide group compared with the placebo group [28 ]. These data highlight the need to monitor growth in asthmatic patients and may help clinicians select appropriate therapies for children who need them most. &
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ASTHMA Allergic asthma can often be distinguished from nonatopic asthma by age of onset, parental history of asthma, strong association with early childhood atopic dermatitis or food allergy, or allergen-induced wheezing [22,23]. Using these associations, an asthma predictive index has been developed to distinguish children who will have persistent asthma in later years and are more likely to respond to inhaled corticosteroids for asthma treatment. The modified asthma predictive index is useful in children 4 years or less of age with frequent wheezing (at least four episodes per year, lasting for at least 1 day, affecting sleep) with either one major risk factor (parental history of asthma, physician diagnosed atopic dermatitis, or evidence of sensitization to an aeroallergen) or two minor criteria (evidence of sensitization to foods, wheezing apart from colds, or peripheral blood eosinophilia). In the prevention of early asthma in kids study, Guilbert et al. [24] described a beneficial response to inhaled steroids in children with frequent episodes of intermittent asthma and a positive asthma predictive index. In more recent years, patient characteristics for a favorable response have been refined. In a subgroup analysis of the prevention of early asthma in kids
ALLERGEN AVOIDANCE In recent years, allergen avoidance (or exposure) has received renewed attention as a method of disease prevention. A recently published practice parameter reports that 33% of households in the United States own at least one cat and 40% own at least one dog. Of note, a protective effect may occur when exposure to cats and dogs takes place during infancy (i.e., primary prevention before allergic sensitization has occurred). Exposure to two or more cats or dogs in the first year of life may reduce the risk of sensitization to multiple allergens during childhood. However, once cat or dog sensitization has occurred, environmental exposure to the sensitized animal is associated with decreased lung function, particularly in patients with a family history of asthma. Thus, the advice to families of young allergic children sensitized to their pets is clear (secondary prevention): environmental exposure to sensitized animals should be minimized and ongoing allergen exposure may be associated with the development of asthma and with poorer health outcomes [29 ].
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CONCLUSION The allergic march of childhood is strongly linked to a family history of asthma, allergic rhinoconjunctivitis, atopic dermatitis, or food allergy. Recently described genetic risks such as mutations in filaggrin explain this allergic syndrome in some patients, while other inherited factors remain to be elucidated. The role of an atopic, immunologically active, and dysfunctional skin barrier is likely central to the evolution of allergic responses in atopic patients with relevant environmental exposures. A clear understanding of relationships that define the allergic march will lead to earlier diagnosis and appropriate treatment of at-risk children. Continued investigation exploring the directionality of associations between these allergic diseases is expected to lead to the development of effective strategies for allergy prevention. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the period of review, have been highlighted as: & of special interest && of outstanding interest 1. Mallol J, Crane J, von Mutius E, et al. The international study of asthma and allergies in childhood (ISAAC) phase three: a global synthesis. Allergol Immunopathol (Madr) 2013; 41:73. This update on global prevalence of allergic disease reports a 14% rate of asthma in adolescents with significant geographic variation in rates of allergic diseases. 2. Branum AM, Lukacs SL. Food allergy among children in the United States. Pediatrics 2009; 124:1549–1555. 3. Gupta RS, Springston EE, Warrier MR, et al. The prevalence, severity, and distribution of childhood food allergy in the United States. Pediatrics 2011; 128:e9–17. 4. Gupta RS, Springston EE, Smith B, et al. Geographic variability of childhood food allergy in the United States. Clin Pediatr (Phila) 2012; && 51:856–861. This report contrasts the rate of food allergy in urban versus rural areas of the United States. 5. Osborne NJ, Koplin JJ, Martin PE. Prevalence of challenge proven mediated food allergy using population based sampling and predetermined challenge criteria in infants. J Allergy Clin Immunol 2011; 127:668–776. 6. Koplin JJ, Dharmage SC, Ponsonby AL, et al. Environmental and demographic risk factors for egg allergy in a population based study of && infants. Allergy 2012; 67:1215–1222. This timely review of unselected Australian infants describes factors associated with food allergy. 7. Schneider L, Tilles S, Lio P, et al. Atopic dermatitis: a practice parameter update 2012. J Allergy Clin Immunol 2013; 131:259. && This practice parameter reviews key features of atopic dermatitis and treatment paradigms recommended for effective patient management. 8. Kondo H, Ichikawa Y, Imokawa G. Percutaneous sensitization with allergens through barrier-disrupted skin elicits a Th2-dominant cytokine response. Eur J Immunol 1998; 28:769–779. 9. Spergel JM, Mizoguchi E, Brewer JP, et al. Epicutaneous sensitization with protein antigen induces localized allergic dermatitis and hyperresponsiveness to methacholine after single exposure to aerosolized antigen in mice. J Clin Invest 1998; 101:1614–1622. 10. Lack G, Fox D, Northstone K, et al. Factors associated with development of peanut allergy in childhood. N Engl J Med 2003; 348:977–985. &
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11. Barnes KC. An update on the genetics of atopic dermatitis. Scratching the surface in 2009. J Allergy Clin Immunol 2010; 125:16–29. 12. McAleer MA, Irvine AD. The multifunctional role of filaggrin in allergic skin disease. J Allergy Clin Immunol 2013; 131:280–291. && This review summarizes recent developments and understanding of filaggrin mutations in allergic diseases. 13. Zutavern A, Brockow I, Schaaf B, et al. Timing of solid food introduction in relation to eczema, asthma, allergic rhinitis, and food and inhalant sensitization at age 6 years: results from the prospective birth cohort study LISA. Pediatrics 2008; 121:e44–e51. 14. Snijders BE, Thijs C, van Ree R, et al. Age at first introduction of cow milk products and other food products in relation to infant atopic manifestations in the first 2 years of life: the KOALA birth cohort study. Pediatrics 2008; 122:e115–e122. 15. Du Toit G, Katz Y, Sasieni P, et al. Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy. J Allergy Clin Immunol 2008; 122:978–985. 16. Greer FR, Sicherer SH, Burks AW. Effects of early nutritional interventions on the development of atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, timing of introduction of complementary foods, and hydrolyzed formulas. Pediatrics 2008; 121:183–191. 17. Fleischer DM, Spergel JM, Assa’ad AH, et al. Primary prevention of allergic && disease through nutritional interventions. J Allergy Clin Immunol 2013; 1:29–36. This report summarized recommendations from the American Academy of Allergy, Asthma, and Immunology Adverse Reactions to Foods Committee regarding introduction of complementary foods for the prevention of food allergy. 18. Koplin JJ, Osborne NJ, Wake M, et al. Can early introduction of egg prevent allergy in infants? A population-based study. J Allergy Clin Immunol 2010; 126:807–813. 19. Grimshaw KE, Maskell J, Oliver EM, et al. Introduction of complementary & foods and the relationship to food allergy. Pediatrics 2013; 132:e1529– e1538. In this study, infants diagnosed with food allergy by 2 years of age were introduced to solid foods earlier and were less likely to be receiving breast milk when cow’s milk protein was first introduced into their diets. 20. Du Toit G, Roberts G, Sayre PH, et al. Identifying infants at high risk for peanut allergy: the learning early about peanut (LEAP) screening study. J && Allergy Clin Immunol 2013; 131:135–143. The LEAP study is expected to provide greater clarity regarding the risk of early versus late allergen introduction on food allergy. This screening study demonstrates a high rate of peanut sensitization in at -risk infants. 21. Vickery BP, Scurlock AM, Kulis M, et al. Sustained unresponsiveness to peanut in subjects who have completed peanut oral immunotherapy. J && Allergy Clin Immunol 2014; 133:468–475. This study evaluated patients who received peanut oral immunotherapy for up to 5 years to determine sustained unresponsiveness to peanut. While the majority of patients experienced desensitization to peanut, only 50% remained tolerant 1 month after the therapy was completed. 22. Rhodes HL, Sporik R, Thomas P, et al. Early life risk factors for adult asthma: a birth cohort study of subjects at risk. J Allergy Clin Immunol 2001; 108:720–725. 23. Martinez FD, Wright AL, Taussig LM, et al. Asthma and wheezing in the first six years of life: the group health medical associates. N Engl J Med 1995; 332:133–138. 24. Guilbert TW, Morgan WJ, Zeiger RS, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med 2006; 354:1985–1997. 25. Bacharier LB, Guilbert TW, Zeiger RS, et al. Patient characteristics associated with improved outcomes with use of an inhaled corticosteroid in preschool children at risk for asthma. J Allergy Clin Immunol 2009; 123:1077–1082. 26. Chang TS, Lemanske RF, Guilbert TW, et al. Evaluation of a modified asthma predictive index in high-risk preschool children. J Allergy Clin & Immunol 2013; 1:152–156. This evaluation of the modified asthma predictive index illustrates the predictive value of this clinical tool. 27. Guilbert TW, Mauger DT, Allen DB, et al. Growth of preschool children at high risk for asthma 2 years after discontinuation of fluticasone. J Allergy Clin Immunol 2011; 128:956–963. 28. Kelly HW, Sternberg AL, Lescher R, et al. Effect of inhaled glucocorticoids in childhood on adult height. N Engl J Med 2012; && 367:904–912. This most recent report from the childhood asthma management program details changes in final adult height in children treated with inhaled corticosteroids for 4–6 years. 29. Portnoy J, Kennedy K, Bublett J, et al. Environmental assessment and exposure control: a practice parameter – furry animals. Ann Allergy & Asthma Immunol 2012; 108:223. This practice parameter serves as an excellent resource for advice on environmental control of animal dander allergen.
Volume 26 Number 4 August 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
New insights into the allergic march Marcus Shaker
Purpose of review The allergic march of childhood describes an association between atopic dermatitis, IgE-mediated food allergy, allergic asthma, and allergic rhinitis that begins with an atopic family history. This review summarizes recent insights into the nature of these conditions and their associations. Recent findings In recent years, common allergic diseases have become more prevalent and increased rates of food allergies remain incompletely understood. This review explores a newly described major genetic risk factor, a mutation in the skin matrix protein filaggrin, as it relates to the allergic march of childhood. New paradigms of understanding the interrelationships between atopic dermatitis, food allergy, and asthma are described. A surge of investigative effort has been directed toward the prevention and treatment of food allergy. Risk factors for allergic asthma in young children have been used to predict patient response to treatment. A recent practice parameter on furry animal/pet avoidance updates current understanding of allergen avoidance in modifying allergic phenotypes. Summary Understanding of the interrelationships of atopic diseases allows earlier diagnosis of allergic conditions in at-risk patient populations and may lead to novel approaches to health promotion and disease prevention. Keywords allergic march, asthma, atopic dermatitis, filaggrin, food allergy
INTRODUCTION The allergic march of childhood describes the relationships between atopic genetic risk factors, family history, atopic dermatitis, food allergy, and asthma. A survey of 1 200 000 children from 98 countries investigated the global prevalence of several conditions comprising the allergic march. While significant geographic variation was noted, the prevalence of asthma, rhinoconjunctivits, and eczema in 6–7year-old children was 12, 8.5, and 8%, respectively. In older children of 13–14 years of age, the prevalence of asthma was 14% [1 ]. Increasing rates of food allergy have also been reported. In 2009, Branum and Lukacs [2] reported an 18% increase in self-reported food allergy prevalence (from 1997 to 2007) in children less than 18 years of age in the United States, with food allergy affecting 3.9% of children. Serumspecific immunoglobulin E (IgE) peanut sensitization was detectable for an estimated 9% of children in the United States [2]. More recently, even higher rates of food allergy have been reported. Gupta et al. [3] performed a randomized crosssectional survey of the households in the United States between June 2009 and February 2010. Using data collected from 40 104 children, the &
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prevalence of food allergy was found to be 8% [95% confidence interval (CI) 76–83]. In the group, 38.7% had severe reactions and 30.4% had multiple food allergies. Among children with food allergy, there was a prevalence of 25.2% for peanut allergy, 21.1% for milk, and 17.2% for shellfish [3]. Geographic variability was reported, with food allergies noted more commonly in urban than rural areas (98 versus 62%) [4 ]. One theory to explain these differences invokes the classic hygiene hypothesis, which suggests that early life exposures to certain microbial agents (associated with rural living) may influence the development of allergy. The HealthNuts study evaluated over 2000 unselected 1-year-old Australian infants. At 12 months &&
Department of Pediatrics, Section of Allergy, Asthma, and Immunology, Children’s Hospital at Dartmouth, Lebanon New Hampshire, USA Correspondence to Marcus Shaker, MD, MS, FAAAAI, FAAP, Associate Professor of Pediatrics, Section of Allergy, Asthma, and Immunology, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon NH 03756, USA. Tel: +1 603 653 9885; fax: +1 603 650 0907; e-mail: [email protected] Curr Opin Pediatr 2014, 26:516–520 DOI:10.1097/MOP.0000000000000120 Volume 26 Number 4 August 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
New insights into the allergic march Shaker
KEY POINTS Filaggrin is a skin matrix protein associated with eczema, asthma, allergic rhinitis, and allergen-specific IgE that may play a central role in the development of allergic diseases in some patients. The role of early or delayed introduction of allergenic foods in the prevention of food allergy is under active investigation but, at present, recommendations on timing of food introduction remain in a state of equipoise. Oral and sublingual immunotherapy continues to be evaluated for the treatment of food allergy; however, at present ,these treatment strategies remain investigational. Young children with a positive asthma predictive index are more likely to respond favorably to treatment with inhaled corticosteroids. Children with allergic asthma who are sensitized to pets that reside in their homes are more likely to have improved asthma control when these pets are removed.
of age, skin prick testing and supervised challenge confirmed allergy in 10.4% of this population (95% CI 93–115). This prevalence is one of the highest reported to date [5]. Exposure to siblings and dogs during infancy decreased the incidence of egg allergy [adjusted odds ratios (OR) of 0.72; 95% CI 0.62–0.83 per sibling and 0.72; 95% CI 0.52–0.99, respectively]. These findings again support the role of the hygiene hypothesis in allergy development. Cesarean section delivery, antibiotic use during infancy, childcare attendance, and maternal age were not associated with egg allergy [6 ]. &&
ATOPIC DERMATITIS Often the first manifestation of the allergic march, atopic dermatitis affects 10–20% of children. Schneider et al. [7 ] recently published a 2013 atopic dermatitis practice parameter. This is a useful reference that describes key features and treatment approaches. Food allergy is implicated in one third of children with atopic dermatitis, but asymptomatic food sensitization is also seen. Management involves trigger avoidance, restoration of skin barrier function, antiinflammatory medicine, and occasional antibiotics. Measures for refractory disease include wet dressing and occlusion, phototherapy, and systemic immunosuppressants such as cyclosporine [7 ]. Skin barrier dysfunction is increasingly recognized as a central component in the development of atopic dermatitis. Evidence suggests presentation of allergen to an allergic inflammatory milieu through disruption in skin barrier function may be an &&
&&
important factor in the development of allergic sensitization [8,9]. For example, peanut allergy has been found to be more likely if children are treated with skin preparations containing peanut oil (OR 6.8; 95% CI 1.4–32.9) [10]. The skin matrix protein filaggrin promotes keratin aggregation; abnormal function of this protein has been associated with ichthyosis, eczema, asthma, allergic rhinitis, and specific IgE [11]. McAleer and Irvine [12 ] recently published an excellent review of the role of filaggrin in allergic disease. Approximately 50% of patients with moderate-tosevere atopic dermatitis have at least one filaggrin mutation; however, filaggrin appears to be downregulated even in patients with atopic dermatitis without filaggrin mutations due to the effect of Th2 cytokines interleukin-4 and interleukin-13. The atopic dermatitis phenotype most strongly associated with filaggrin mutations is early onset, severe, and persistent. The skin barrier defect resulting from filaggrin mutations becomes exacerbated following allergic sensitization to environmental allergens. Filaggrin mutations confer a much greater risk of asthma, which tends to have a more difficult course. Filaggrin mutations also increase the risk of peanut allergy (OR 5.3 with a residual OR of 3.8 when corrected for atopic dermatitis) [12 ]. While useful in understanding the pathogenesis of the allergic march, evaluation of filaggrin mutations is not commonplace in the clinical management of children with atopic dermatitis. &&
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FOOD ALLERGY To understand recent developments in food allergy prevention research, it is important to understand their recent historical context. For many years, traditional recommendations for food allergy prevention included avoidance of allergenic foods during the first several years of life. However, evidence suggesting a more crucial role for allergen sensitization through an impaired skin barrier together with studies suggesting a possible protective role for early allergen oral tolerance had called these recommendations into question. In 2008, two population-based prospective birth cohort studies suggested that delayed introduction of solids may not be protective against food allergy and that delayed introduction of allergic foods may even increase the risk of food allergy. The Lifestyle-Related Factors on the Immune System and the Development of Allergies cohort evaluated 2073 German children at 6 years of age and found that delayed food introduction beyond 4 or 6 months was more commonly associated with food sensitization [13]. In a separate analysis of 2558 Dutch infants, greater delay in introduction of cow
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milk products was associated with an increased risk of atopy development at 2 years of age [14]. Two additional publications appeared in 2008 that dramatically changed the prevailing view on the role of delayed food introduction in food allergy risk in young children. Du Toit et al. [15] published results of a nonrandomized cohort evaluation of peanut allergy prevalence using validated questionnaires, comparing two countries with very different peanut feeding practices. In this study, Israeli children tended to receive peanut introduction at an earlier age and consume peanut more frequently and in larger quantities than Jewish children in the United Kingdom (median monthly Israeli peanut consumption in infants 8–14 months of age was 7.1 versus 0 g in the United Kingdom; P < 0.001). Despite these cultural differences (or, perhaps, because of them), the prevalence of peanut allergy in Israel was 0.17 versus 1.85% in the United Kingdom (P < 0.001) [15]. In the same year as these studies were published, the American Academy of Pediatrics (AAP) released an updated statement on the effect of early nutritional interventions on the development of atopic disease in infants and children. The document concluded that there was little evidence to support the contention that delayed introduction of complementary foods beyond 4–6 months of age could prevent atopic disease, and that evidence was insufficient to recommend any dietary intervention beyond 4–6 months of age for the purposes of allergy prevention [16]. This left clinical recommendations regarding early or late infant exposure to potential allergens in a state of uncertainty. The 2008 AAP document did not provide formal recommendations about how and when to introduce potentially allergic foods, given the state of equipoise of evidence. However, in 2012, the Adverse Reactions to Foods Committee of the American Academy of Allergy, Asthma, and Immunology provided advice for primary care physicians and specialists about the primary prevention of allergic disease through nutritional interventions. These recommendations were derived from available literature and expert opinion. This group concluded that avoidance diets during pregnancy and lactation are not recommended at this time, but more research is necessary for peanut. Exclusive breast-feeding for at least 4 and up to 6 months was endorsed. For infants at elevated risk for developing allergic disease (at least one first-degree relative with allergic rhinitis, asthma, or food allergy) who cannot be exclusively breast-fed, it was recommended that hydrolyzed formula be considered. Complementary foods can be introduced between 4 and 6 months of age. It was suggested that once ‘a few typical complementary foods . . . are tolerated, 518
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highly allergic foods may be introduced as complementary foods’. It was recommended that the initial taste of a potentially allergenic food be given at home and in gradually increasing amounts if tolerated. In some cases, allergy consultation was recommended for a personalized plan for introduction of potential food allergens. Specific examples included infants with moderate-to-severe atopic dermatitis, children with a suspected allergic reaction to a food, children with one underlying food allergy, who may be at risk for other food allergies, children sensitized to a food prior to introduction, and siblings of children with peanut allergy (optional patient preference-sensitive decision; careful home introduction encouraged as a reasonable alternative) [17 ]. The possible benefit of early food allergen introduction was again reported in a study by Koplin et al. [18]. When compared with early egg introduction between 4 and 6 months of age, delayed introduction during infancy was associated with a higher rate of challenge-proven egg allergy. Egg allergy was more likely in infants introduced to egg at 10–12 months of age and more than 12 months of age [adjusted odds ratio (aOR) 1.6, 95% CI aOR 3.4, 95% CI 1.8–6.5, respectively] [18]. A more recent report by Grimshaw et al. [19 ] illustrates the confusing state of evidence in regards to food allergy prevention. In this nested case-control study, infants diagnosed with food allergy by 2 years of age were introduced solid foods earlier (less than 16 weeks of age) and were less likely to be receiving breast milk when cow’s milk protein was first introduced into their diets [19 ]. It is in this context that the Learning Early About Peanut Allergy (LEAP) study is being undertaken. This randomized controlled trial aims to provide a better understanding of early versus delayed introduction of allergic foods in high-risk children in the context of food allergy prevention. The LEAP screening cohort consisted of 834 infants (mean age 7.8 months) with (I) mild atopic dermatitis and no egg allergy (118 infants), (II) severe atopic dermatitis, egg allergy, or both with negative peanut skin prick test (542 infants), (III) severe atopic dermatitis, egg allergy, or both with 1–4-mm peanut wheal response on skin prick test (98 infants), and (IV) infants with greater than 4-mm peanut wheal response (76 infants). Interestingly (and unexpectedly), 17% of infants in group II and 56% of infants in group III had a peanut-specific IgE of at least 0.35 kU/l. However, none of the patients in group I and 91% of group IV infants had positive blood allergy testing to peanut. Sensitization to peanut by both skin test and specific IgE were each associated with an increased risk for severe atopic dermatitis. Although this represents an at-risk cohort, the high rate of peanut sensitization noted &&
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during infancy was unexpected. Awaited results on the effect of early or delayed introduction of peanut in the LEAP patients are expected to clarify the role of food introduction in allergy prevention [20 ]. Research continues into oral and sublingual desensitization of food allergy, and these methods remain investigational. Vickery et al. [21 ] recently evaluated the effect of peanut oral immunotherapy (OIT) on desensitization and tolerance. Patients of 1–16 years of age were treated for up to 5 years with peanut OIT; 24 out of 39 patients completed the protocol and 12 demonstrated sustained unresponsiveness for 1 month after stopping OIT [21 ]. The distinction between temporary allergen desensitization (while receiving therapy) and more durable allergen tolerance (after completing therapy) is an important one, because patients who experience desensitization without tolerance would remain at an elevated risk for food-associated anaphylaxis in the setting of missed doses or nonadherence. Previous reports from this group have shown a high rate of successful peanut desensitization (93%) while receiving therapy; however, the inability to induce lasting tolerance in 50% of the cohort is concerning. Furthermore, in this study, tolerance was assessed within a very short time frame off therapy. Whether or not immune tolerance would persist for 3, 6, or even 12 months is a matter of speculation. &&
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data, investigators described that children most likely to experience benefit from inhaled corticosteroids were more likely to be white boys, have aeroallergen sensitization, and have a history of hospitalization or emergency visit in the preceding year [25]. Recently, the modified asthma predictive index was evaluated in 289 children (1–3 years of age). The index proved to be a useful tool, demonstrating a 90% posttest probability to predict asthma persistence in later childhood. Positive likelihood ratios ranged from 4.9 to 55 for asthma persistence at 6, 8, and 11 years of age [26 ]. These findings underscore the importance of appreciating childhood asthma phenotypes when discussing asthma prognosis and choosing appropriate management. It has also become clear that, in young preschool children who require inhaled corticosteroid therapy, attempting to maintain the dose of therapy below 10 μg/kg/day fluticasone equivalents is least likely to be associated with impairments in linear growth [27]. The childhood asthma management program extension study reported on final adult height in 943 of 1041 childhood asthma management program participants. Starting at the age of 5–13 years, participants were randomized to receive 400 μg of budesonide, 16 mg of nedocromil, or placebo daily for 4–6 years. Mean adult height was 1.2 cm lower (95% CI 1.9 to 0.5) in the budesonide group compared with the placebo group [28 ]. These data highlight the need to monitor growth in asthmatic patients and may help clinicians select appropriate therapies for children who need them most. &
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ASTHMA Allergic asthma can often be distinguished from nonatopic asthma by age of onset, parental history of asthma, strong association with early childhood atopic dermatitis or food allergy, or allergen-induced wheezing [22,23]. Using these associations, an asthma predictive index has been developed to distinguish children who will have persistent asthma in later years and are more likely to respond to inhaled corticosteroids for asthma treatment. The modified asthma predictive index is useful in children 4 years or less of age with frequent wheezing (at least four episodes per year, lasting for at least 1 day, affecting sleep) with either one major risk factor (parental history of asthma, physician diagnosed atopic dermatitis, or evidence of sensitization to an aeroallergen) or two minor criteria (evidence of sensitization to foods, wheezing apart from colds, or peripheral blood eosinophilia). In the prevention of early asthma in kids study, Guilbert et al. [24] described a beneficial response to inhaled steroids in children with frequent episodes of intermittent asthma and a positive asthma predictive index. In more recent years, patient characteristics for a favorable response have been refined. In a subgroup analysis of the prevention of early asthma in kids
ALLERGEN AVOIDANCE In recent years, allergen avoidance (or exposure) has received renewed attention as a method of disease prevention. A recently published practice parameter reports that 33% of households in the United States own at least one cat and 40% own at least one dog. Of note, a protective effect may occur when exposure to cats and dogs takes place during infancy (i.e., primary prevention before allergic sensitization has occurred). Exposure to two or more cats or dogs in the first year of life may reduce the risk of sensitization to multiple allergens during childhood. However, once cat or dog sensitization has occurred, environmental exposure to the sensitized animal is associated with decreased lung function, particularly in patients with a family history of asthma. Thus, the advice to families of young allergic children sensitized to their pets is clear (secondary prevention): environmental exposure to sensitized animals should be minimized and ongoing allergen exposure may be associated with the development of asthma and with poorer health outcomes [29 ].
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CONCLUSION The allergic march of childhood is strongly linked to a family history of asthma, allergic rhinoconjunctivitis, atopic dermatitis, or food allergy. Recently described genetic risks such as mutations in filaggrin explain this allergic syndrome in some patients, while other inherited factors remain to be elucidated. The role of an atopic, immunologically active, and dysfunctional skin barrier is likely central to the evolution of allergic responses in atopic patients with relevant environmental exposures. A clear understanding of relationships that define the allergic march will lead to earlier diagnosis and appropriate treatment of at-risk children. Continued investigation exploring the directionality of associations between these allergic diseases is expected to lead to the development of effective strategies for allergy prevention. Acknowledgements None. Conflicts of interest There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the period of review, have been highlighted as: & of special interest && of outstanding interest 1. Mallol J, Crane J, von Mutius E, et al. The international study of asthma and allergies in childhood (ISAAC) phase three: a global synthesis. Allergol Immunopathol (Madr) 2013; 41:73. This update on global prevalence of allergic disease reports a 14% rate of asthma in adolescents with significant geographic variation in rates of allergic diseases. 2. Branum AM, Lukacs SL. Food allergy among children in the United States. Pediatrics 2009; 124:1549–1555. 3. Gupta RS, Springston EE, Warrier MR, et al. The prevalence, severity, and distribution of childhood food allergy in the United States. Pediatrics 2011; 128:e9–17. 4. Gupta RS, Springston EE, Smith B, et al. Geographic variability of childhood food allergy in the United States. Clin Pediatr (Phila) 2012; && 51:856–861. This report contrasts the rate of food allergy in urban versus rural areas of the United States. 5. Osborne NJ, Koplin JJ, Martin PE. Prevalence of challenge proven mediated food allergy using population based sampling and predetermined challenge criteria in infants. J Allergy Clin Immunol 2011; 127:668–776. 6. Koplin JJ, Dharmage SC, Ponsonby AL, et al. Environmental and demographic risk factors for egg allergy in a population based study of && infants. Allergy 2012; 67:1215–1222. This timely review of unselected Australian infants describes factors associated with food allergy. 7. Schneider L, Tilles S, Lio P, et al. Atopic dermatitis: a practice parameter update 2012. J Allergy Clin Immunol 2013; 131:259. && This practice parameter reviews key features of atopic dermatitis and treatment paradigms recommended for effective patient management. 8. Kondo H, Ichikawa Y, Imokawa G. Percutaneous sensitization with allergens through barrier-disrupted skin elicits a Th2-dominant cytokine response. Eur J Immunol 1998; 28:769–779. 9. Spergel JM, Mizoguchi E, Brewer JP, et al. Epicutaneous sensitization with protein antigen induces localized allergic dermatitis and hyperresponsiveness to methacholine after single exposure to aerosolized antigen in mice. J Clin Invest 1998; 101:1614–1622. 10. Lack G, Fox D, Northstone K, et al. Factors associated with development of peanut allergy in childhood. N Engl J Med 2003; 348:977–985. &
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11. Barnes KC. An update on the genetics of atopic dermatitis. Scratching the surface in 2009. J Allergy Clin Immunol 2010; 125:16–29. 12. McAleer MA, Irvine AD. The multifunctional role of filaggrin in allergic skin disease. J Allergy Clin Immunol 2013; 131:280–291. && This review summarizes recent developments and understanding of filaggrin mutations in allergic diseases. 13. Zutavern A, Brockow I, Schaaf B, et al. Timing of solid food introduction in relation to eczema, asthma, allergic rhinitis, and food and inhalant sensitization at age 6 years: results from the prospective birth cohort study LISA. Pediatrics 2008; 121:e44–e51. 14. Snijders BE, Thijs C, van Ree R, et al. Age at first introduction of cow milk products and other food products in relation to infant atopic manifestations in the first 2 years of life: the KOALA birth cohort study. Pediatrics 2008; 122:e115–e122. 15. Du Toit G, Katz Y, Sasieni P, et al. Early consumption of peanuts in infancy is associated with a low prevalence of peanut allergy. J Allergy Clin Immunol 2008; 122:978–985. 16. Greer FR, Sicherer SH, Burks AW. Effects of early nutritional interventions on the development of atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, timing of introduction of complementary foods, and hydrolyzed formulas. Pediatrics 2008; 121:183–191. 17. Fleischer DM, Spergel JM, Assa’ad AH, et al. Primary prevention of allergic && disease through nutritional interventions. J Allergy Clin Immunol 2013; 1:29–36. This report summarized recommendations from the American Academy of Allergy, Asthma, and Immunology Adverse Reactions to Foods Committee regarding introduction of complementary foods for the prevention of food allergy. 18. Koplin JJ, Osborne NJ, Wake M, et al. Can early introduction of egg prevent allergy in infants? A population-based study. J Allergy Clin Immunol 2010; 126:807–813. 19. Grimshaw KE, Maskell J, Oliver EM, et al. Introduction of complementary & foods and the relationship to food allergy. Pediatrics 2013; 132:e1529– e1538. In this study, infants diagnosed with food allergy by 2 years of age were introduced to solid foods earlier and were less likely to be receiving breast milk when cow’s milk protein was first introduced into their diets. 20. Du Toit G, Roberts G, Sayre PH, et al. Identifying infants at high risk for peanut allergy: the learning early about peanut (LEAP) screening study. J && Allergy Clin Immunol 2013; 131:135–143. The LEAP study is expected to provide greater clarity regarding the risk of early versus late allergen introduction on food allergy. This screening study demonstrates a high rate of peanut sensitization in at -risk infants. 21. Vickery BP, Scurlock AM, Kulis M, et al. Sustained unresponsiveness to peanut in subjects who have completed peanut oral immunotherapy. J && Allergy Clin Immunol 2014; 133:468–475. This study evaluated patients who received peanut oral immunotherapy for up to 5 years to determine sustained unresponsiveness to peanut. While the majority of patients experienced desensitization to peanut, only 50% remained tolerant 1 month after the therapy was completed. 22. Rhodes HL, Sporik R, Thomas P, et al. Early life risk factors for adult asthma: a birth cohort study of subjects at risk. J Allergy Clin Immunol 2001; 108:720–725. 23. Martinez FD, Wright AL, Taussig LM, et al. Asthma and wheezing in the first six years of life: the group health medical associates. N Engl J Med 1995; 332:133–138. 24. Guilbert TW, Morgan WJ, Zeiger RS, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med 2006; 354:1985–1997. 25. Bacharier LB, Guilbert TW, Zeiger RS, et al. Patient characteristics associated with improved outcomes with use of an inhaled corticosteroid in preschool children at risk for asthma. J Allergy Clin Immunol 2009; 123:1077–1082. 26. Chang TS, Lemanske RF, Guilbert TW, et al. Evaluation of a modified asthma predictive index in high-risk preschool children. J Allergy Clin & Immunol 2013; 1:152–156. This evaluation of the modified asthma predictive index illustrates the predictive value of this clinical tool. 27. Guilbert TW, Mauger DT, Allen DB, et al. Growth of preschool children at high risk for asthma 2 years after discontinuation of fluticasone. J Allergy Clin Immunol 2011; 128:956–963. 28. Kelly HW, Sternberg AL, Lescher R, et al. Effect of inhaled glucocorticoids in childhood on adult height. N Engl J Med 2012; && 367:904–912. This most recent report from the childhood asthma management program details changes in final adult height in children treated with inhaled corticosteroids for 4–6 years. 29. Portnoy J, Kennedy K, Bublett J, et al. Environmental assessment and exposure control: a practice parameter – furry animals. Ann Allergy & Asthma Immunol 2012; 108:223. This practice parameter serves as an excellent resource for advice on environmental control of animal dander allergen.
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