Asthma

Food Allergy

Rhinitis

Atopic Dermatitis

Supported by an educational grant from

Nestlé Nutrition Institute

In collaboration with

PROGRAM FACULTYAlan M. Lake, MD Associate Professor of PediatricsThe Johns Hopkins University School of MedicineBaltimore, Maryland

Mark Boguniewicz, MDProfessor, Division of Pediatric Allergy-ImmunologyDepartment of PediatricsNational Jewish Health University of Colorado School of MedicineDenver, Colorado

David M. Fleischer, MD Associate Professor of PediatricsUniversity of ColoradoDirector, Food Challenge UnitChildren’s Hospital ColoradoDepartment of Pediatrics, Section of AllergyAurora, Colorado

PREVENTING vs MANAGING PEDIATRIC ALLERGIES

Clinical and Economic Impact of Nutritional and Environmental Interventions

Provided by

CME COURSE DIRECTORMarguerite M. Mayers, MDAttending PhysicianChildren’s Hospital at MontefioreProfessor of Clinical PediatricsAlbert Einstein College of MedicineBronx, New York

CE COURSE DIRECTOR Kathleen Ronca, DNPDoctor of Nursing PracticePediatric Emergency MedicineChildren’s Hospital at Montefiore Bronx, New York

NEEDS ASSESSMENTThe prevalence of allergic disease, including asthma; rhinitis; anaphylaxis; drug, food, and insect allergy; atopic dermatitis (AD); and urticaria and angioderma, has been rising dramatically during the last 2 decades, particularly among children. Among those up to the age of 17 years, the prevalence of food allergies increased from 3.4% in 1997 to 1999 to 5.1% in 2009 to 2011, and the prevalence of skin allergies increased from 7.4% to 12.5%.1

The economic and emotional burdens of allergic disease are enormous. For AD, for example, the projected third-party payer costs in 1997 to 1998 ranged from $0.9 billion to $3.8 billion when projected across everyone younger than 65 years insured by private insurers and Medicaid. More than one-quarter of all health care costs for patients with AD are attributable to this and comorbid conditions.2 Parents of chil-dren with AD must deal with sleep disruption and their child’s incessant crying and scratching, as well as ostracism from peers. The family of a child with food allergy must maintain constant vigilance when grocery shopping or eating away from home. These stresses take a toll on quality of life and the child’s self-esteem.

More than half of children with AD—generally the first clinical manifestation of immunoglobulin E antibody responses—will go on to develop other allergies, usually by their third birthday.3 It is therefore essential that pediatric clinicians be aware of the growing problem of pediatric allergy and be able to advise parents about how to avoid initial atopy and the subsequent “allergic march” in their children.4 To do so, they must be up to date about the latest research and guidelines with regard to optimal nutritional and environmental strategies. This includes being knowledge-able about the role of breastfeeding and hydrolyzed formula in allergy prevention, the latest findings on diet in pregnancy and lactation, the optimum time to offer infants highly allergenic foods, and the economic impact of primary prevention.

REFERENCES 1. World Allergy Association. WAO White Book on Allergy 2011-2012: Executive Summary.

www.worldallergy.org/publications/wao_white_book.pdf. Accessed March 25, 2014. 2. Ellis CN, Drake LA, Prendergast MM, et al. Cost of atopic dermatitis and eczema in the

United States. J Am Acad Dermatol. 2002;46:361-370. 3. World Allergy Organization. Disease Summaries, The Allergic March. www.worldallergy.

org/professional/allergic_diseases_center/allergic_march. Accessed March 25, 2014. 4. Kapoor R, Menon C, Hoffstad O, et al. The prevalence of atopic triad in children with

physician-confirmed atopic dermatitis. J Am Acad Dermatol. 2008;58:68-73.

LEARNING OBJECTIVESAfter taking part in this educational activity, participants should be better able to: • Describe the effect of the increasing problem of pediatric allergic diseases,

particularly atopic dermatitis, on quality of life for patient and family• Evaluate current evidence about the health economics of preventing vs

managing allergy symptoms in pediatric patients• Assess data that demonstrate the long-term effects of optimal nutrition in

preventing infant allergy • Recommend or implement nutritional and environmental strategies, including

those for pregnant and lactating mothers, to prevent allergy in pediatric patients

• Provide the most up-to-date care and counsel for patients and their families for the prevention of pediatric allergic diseases

INTENDED AUDIENCEPediatricians, pediatric nurse practitioners, pediatric physician assistants, nurses, registered dietitians, and other health care professionals involved in the care of children

ACCREDITATION/DESIGNATION STATEMENTS

PHYSICIANAlbert Einstein College of Medicine of Yeshiva University is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

Albert Einstein College of Medicine of Yeshiva University designates this live educational activity for a maximum of 1.50 AMA PRA Category 1 CreditsTM. Each course participant should only claim credits commensurate with the extent of their participation in the activity.

NURSING Montefiore Learning Network is an approved provider of continuing nursing education by New Jersey State Nurses Association, an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation.

This enduring activity is awarded 1.50 contact hours. Approval Code: NYP268-11/12-15.

DIETITIAN The following activity has been approved by the ACCME, whose approval is rec-ognized by the Commission on Dietetic Registration and, as such, RDs/DTRs will be able to receive 1.50 CPEU.

CONFLICTS OF INTERESTThe “Conflict of Interest Disclosure Policy” of Albert Einstein College of Medicine of Yeshiva University requires that faculty participating in any CME activity disclose to the audience any relationship(s) with a pharmaceutical or equipment company. Any presenter whose disclosed relationships prove to create a conflict of interest with regard to their contribution to the activity, or who refuses to pro-vide all their conflict-of-interest information, will not be permitted to present.

It is the policy of Montefiore Learning Network to ensure balance, independence, objectivity, and scientific rigor in all its educational activities. All faculty par-ticipating in our programs are expected to disclose any relationships they may have with commercial companies whose products or services may be mentioned so that participants may evaluate the objectivity of the presentations. In addi-tion, any discussion of off-label, experimental, or investigational use of drugs or devices will be disclosed by the faculty.

DISCLOSURES Alan M. Lake, MD, has served as a consultant for Nestlé Nutrition Institute-Gerber.

Mark Boguniewicz, MD, has no conflict of interest to report.

David M. Fleischer, MD, has received grant funding from the National Institute of Allergy and Infectious Diseases, grant funding from Monsanto Company, royalties from UpToDate, Inc., and honoraria from the Nestlé Nutrition Institute. He serves on the Medical Advisory Board for the Food Allergy and Anaphylaxis Connectivity Team (FAACT), and is a consultant for LabCorp (Laboratory Corporation of America).

ACCREDITOR STAFF:The staff of the Center for Continuing Medical Education of Albert Einstein College of Medicine of Yeshiva University and Montefiore Learning Network has nothing to disclose with regard to commercial support.

PUBLISHING STAFF:Mary Jo Krey, Marian Freedman, Lori Marrese, and Lynne Callea of Haymarket Medical Education have nothing to disclose with regard to commercial support.

DISCLOSURE OF UNLABELED USEThis educational activity may contain discussion of published and/or investiga-tional uses of agents that are not indicated by the FDA. Nestlé Nutrition Institute, Albert Einstein, Montefiore Learning Network, and Haymarket Medical Education do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of Nestlé Nutrition Institute, Albert Einstein, Montefiore Learning Network, and Haymarket Medical Education. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

DISCLAIMERParticipants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The infor-mation presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

©2015 Haymarket Medical Education LP140 E Ridgewood Ave, Suite 370SParamus, NJ 07652www.myCME.com

Estimated time to complete this activity: 1.5 hoursRelease Date: January 29, 2015 Expiration Date: January 29, 2016

JANUARY 2015 3

By Alan M. Lake, MD; Mark Boguniewicz, MD; David M. Fleischer, MD

Allergies are among the most common of the many medical condi-tions that affect chil-dren, and they have a

huge impact on physical and emotion-al health and quality of life (QoL).1 The prevalence of allergic disease has risen dramatically throughout the world in recent years, particularly among children.2 In the United States, the most common pediatric allergies are food, skin, and respiratory. According to the US Department of Health and Human Services, the prevalence of food allergies among children up to the age of 17 years increased from 3.4% in 1997-1999 to 5.1% in 2009-2011, and of skin aller-gies from 7.4% to 12.5%. Though the prevalence of respiratory allergies did not change during this time, they remained the most common type of allergy among children.

Economic burden. Allergic dis-eases have imposed an increasing eco-nomic burden on the US health care system and families with an atopic child. According to a survey of more than 1,600 caregivers of children with a food allergy, the overall economic cost of food allergy is an estimated $24.8 billion annually. This encom-passes direct medical costs of $4.3 billion and family costs of $20.5 billion annually, including lost labor productivity and out-of-pocket costs.3 An analysis of 1997-1998 claims data showed that costs of atopic dermatitis

(AD) for third-party payers ranged from $0.9 billion to $3.8 billion when projected across all those younger than 65 years who were insured by private insurers and Medicaid.4 Furthermore, the analysis showed that more than one fourth of all health care costs incurred by patients with AD are attributable to AD and comorbid conditions. The costs of asthma also are substantial. From

2002 to 2007, the direct cost of asth-ma for patients of all ages was $3,259 per person per year, and asthma accounted for 3.68 million missed school days.5

A NEW PATIENT WITH ALLERGY CONCERNSMrs. J, who has just moved with her family to a new town, makes her first visit to the new pediatrician for a check-up for her first child. Bryan is a 2-year-old boy who has AD and milk allergy. The AD, which caused Bryan to cry and scratch incessantly, now is controlled with topical treatments, though Bryan occasionally has flare-ups. Mrs. J has learned how to avoid giving Bryan any foods containing cow’s milk pro-tein, which causes him to vomit or break out in hives. Because of the physical and emo-tional problems Bryan’s allergies have caused, Mrs. J, who is 3 months pregnant, is determined to do whatever she can to pre-vent her next baby from having allergies.

AD may have the greatest impact on QoL among pediatric allergic con-ditions. Usually the first manifesta-tion of atopy, AD (also called atopic eczema) is characterized by itchy

Preventing vs Managing Pediatric Allergies:Clinical and Economic Impact of Nutritional and Environmental Interventions

Asthma

Food Allergy

Rhinitis

Atopic Dermatitis

POLLING QUESTION

WHICH OF THE FOLLOWING STATEMENTS ABOUT ALLERGIC DISEASES IS TRUE?

Allergic diseases are increasing primarily in developing countries.

Usually the first manifestation of atopy is asthma.

Allergic diseases are associated with significant morbidity and cost.

Sleep disturbances associated with AD stop once AD is in remission.

4 JANUARY 2015

PREVENTING VS MANAGING PEDIATRIC ALLERGIES: CLINICAL AND ECONOMIC IMPACT OF NUTRITIONAL AND ENVIRONMENTAL INTERVENTIONS

patches on the skin, which may appear as raised bumps, leak fluid, and have scratch marks (Figure 1). These patches in infants are likely to appear first on the face and may involve the extensor aspects of the extremities and trunk.6 The itchiness is worse at night, leading to sleep disturbances. About 86% of surveyed parents of preschoolers with AD reported that during flares their children woke an average of 2.7 times a night—indicat-ing that the parents also lost sleep.7 Many children with AD continue to awaken at night even when their con-dition is in remission.8

AD and psychological/emotional problems. Children with AD also are at higher risk than their peers of developing psychological disturbanc-es. Preschool children with severe AD were found to exhibit signifi-cantly more dependency/clinginess and fearfulness than preschoolers without AD, and more of the mothers of children with AD felt stressed about their parenting.9 In a compari-

son of 30 school-aged children with AD with 30 of their peers, children with moderately severe and severe AD (but not mild AD) were twice as likely to develop psychological prob-lems.10 In a study of almost 3,000 children followed for a decade, even if eczema cleared, AD in infancy sig-nificantly increased the risk of con-duct problems at the age of 10 years.11 In children in whom AD persisted beyond the age of 2 years, the risk of conduct problems increased com-mensurately with the persistence of AD. Perhaps most telling about the distress AD causes, a comparative study of health-related QoL of chil-dren with chronic skin diseases (AD, psoriasis, urticaria, or acne) and other chronic conditions (cerebral palsy, renal disease, or cystic fibrosis) showed that only cerebral palsy had a greater impact on QoL than AD.12

Food and respiratory allergies. Both of these forms of atopy compli-cate daily life. A survey of more than 250 parents of food-allergic children

using standardized QoL scales showed that families with children with 1 or 2 food allergies had significantly lower scores than previously established norms on 3 of 12 scales–those for gen-eral health perception, emotional impact on parents, and limitations on family activities. Dealing with aller-gies to more than 2 foods had an even greater impact, with those families having scores lower than the norm for 7 scales.13 Of 87 caregivers who responded to another questionnaire about the impact of their child’s food allergy on family activities, more than 60% reported that food allergy signifi-cantly affected meal preparation and 49% said that the condition had an effect on social activities. In addition, 41% reported a significant negative effect on parental stress levels, and 34% indicated that the child’s food allergy impacted school attendance; 10% home schooled their children because of food allergies.14

Respiratory allergies negatively impact overall QoL and emotional condition, sleep, social and daily activities, and work or school perfor-mance, among other impairments. A survey of the burden of allergic rhi-nitis in Europe showed that health-related QoL was correlated with disease severity and with the number of days without symptoms during the previous month. Though persis-tent allergic rhinitis caused the most difficulties, about 82% of those with intermittent disease also reported that their condition caused some impairment in daily life.15 In a sur-vey of 185 adolescents with asthma, poorer asthma-specific emotional QoL was associated with poorer control of asthma symptoms, missed school, and visits to the clinician for asthma. About 45% of respon-dents reported feeling depressed, 41% had emergency department visits, and 30% missed school because of asthma.16

FIGURE 1. The misery of atopic dermatitis [Click on picture to see video.]

AD is characterized by dry, itchy skin and can involve swelling, “weeping,” and crusting of the lesions. It may cause incessant crying and scratching in infants.

Courtesy of Mark Boguniewicz, MD.

JANUARY 2015 5

WILL MRS. J’S NEW BABY BE AT HIGH RISK FOR ALLERGIES?The clinician takes a complete medical history for Mrs. J, her husband, and son Bryan. He learns that Mrs. J has allergic rhinitis and her husband has egg allergy.

Because a family history of allergy is the single most important risk factor for developing allergic disease, Bryan’s new pediatrician explores the medical his-tory of the entire family. Since Bryan has allergic disease and both his parents do as well, the as-yet unborn baby is considered at high risk for atopy.

What the studies show. A study in more than 500 infants who were 1 year old showed that compared with children with no family history of allergic disease, those who had 2 or more allergic family members were far more likely to develop food aller-gy. The increase in risk was more modest in children who had only 1 immediate family member with an allergic disease history.17 Interestingly, in a birth cohort followed for 4 years, sibling atopy was a stronger predictor of clinical disease than atopy in either a mother or father, though being born to an asthmatic mother raised by threefold the risk of having asthma.18 Overall, it is believed that a child without allergic parents may have up to a 20% risk of developing allergy; a child with one allergic parent may have a risk of 40% to 50%; and if both parents are allergic, the child’s risk may be as high as 90%.19

Several large epidemiologic studies have shown that loss-of-function mutations in the gene encoding filag-grin, a major skin barrier protein, increase the risk of AD and other allergic disorders. Patients with these mutations have a leaky epidermal barrier, allowing allergens to pen-etrate and leading to sensitization and allergic manifestations (Figure 2).20 An analysis of associations between the 2 most common mutations in the

filaggrin gene in about 7,000 children found that these mutations are strong genetic determinants of early-onset, severe and persistent AD, as well as early wheezing and asthma, especially in the presence of AD.21 In addition, having a filaggrin mutation is associ-ated with increased risk of allergic sensitization to environmental and food allergens.22

Beyond genetics. Even though genetic factors are highly associated with risk of allergy, practitioners should keep in mind that many chil-dren with no family history of atopy also develop allergy and that other factors play a role. One birth-cohort study, for example, showed that for-mula feeding before 3 months of age was associated with asthma at 4 years of age.18 In an investigation in 20,687 mother-infant pairs, a risk factor for infant AD was a maternal education level of less than 12 years, in addition to parental asthma, AD, and allergic rhinitis.23 Environmental risk factors in the home include fungus on the

walls and renovation or painting during pregnancy.

BRYAN AND THE “ALLERGIC MARCH”In exploring the family’s history, the clini-cian learns that Bryan, who was delivered vaginally, developed AD when he was 1 month old. The topical corticosteroids prescribed by his previous pediatrician have largely brought the condition under control. Mrs. J breastfed Bryan exclusively for 2 months and then returned to her fulltime job. At that point, Bryan received expressed breast milk along with a supplemental tradi-tional cow’s milk formula (CMF). Within minutes of formula feedings, he often vom-ited or developed hives. Given Bryan’s new symptoms and his already existing AD, the pediatrician suspected a milk allergy. She switched Bryan to a hydrolyzed formula, and his postprandial symptoms disappeared.

The allergic or atopic march is the sequential development of allergic disease manifestations during early life. Most often the allergic march

FIGURE 2. Skin barrier damage and allergic risk

Damage to the skin barrier because of a mutation in filaggrin, one of the key barrier proteins, allows allergens to penetrate into the subepidermal layer and interact with antigen-presenting cells (APC), leading to allergic sensitization and then to allergic manifestations.

Th2=type 2 T helper cell.

Hudson TJ. Skin barrier function and allergic risk. Nat Genet. 2006;38:399-400.

Intact epithelial barrier Damaged epithelial barrier

Initiation of Th2 immune response

APC

Sensitized host

Clinical outcomes: atopy and asthma

6 JANUARY 2015

PREVENTING VS MANAGING PEDIATRIC ALLERGIES: CLINICAL AND ECONOMIC IMPACT OF NUTRITIONAL AND ENVIRONMENTAL INTERVENTIONS

begins with AD and then proceeds to food allergy (as it did with Bryan), followed by rhinitis and asthma (Figure 3).24 Responses to a question-naire administered to 2,270 children with AD showed that 71.3% had symptoms of either asthma or allergic rhinitis, with 33.3% reporting symp-toms of one condition or the other and 38% reporting symptoms of both.25 By the age of 3 years, nearly 66% had a least one additional form of atopy.

Although AD often improves or remits early in life, other atopic dis-eases still may emerge. In 94 children with AD who were followed up to the age of 7, for example, AD improved in almost 90%, but 43% still developed asthma and 45% allergic rhinitis.26 Development of other allergic symp-toms was most likely in children who had a family history of AD, developed the condition early, had severe AD, had early adverse reactions to foods, or were prone to infections. In a large (1,314 children) prospective birth

cohort study, AD in the first 3 months of life was a risk factor at 5 years of age for aeroallergen sensitization to any of 5 respiratory allergens (mite, cat, dog, birch, grass).27 This aeroal-lergen sensitization is itself a risk factor for future manifestations of allergic airway disease. Risk for sensitization increased with a positive family his-tory for atopic diseases.

HOW CAN MRS. J REDUCE HER NEW BABY’S RISK FOR ALLERGY? The clinician asks Mrs. J about her plans for feeding the infant, to help develop a strategy to reduce the new baby’s risk of allergy. Mrs. J responds that she will pro-ceed as she did with Bryan–breastfeed the newborn exclusively for 2 months postpar-tum and then return to work, relying on expressed milk supplemented by formula. She asks, “While I am pregnant, should I avoid having milk and eggs and other foods that are most likely to cause an allergic reac-tion in my new baby?” The clinician explains that avoiding these or any foods is not currently recommended, but that she should avoid tobacco smoke and stress ( for-tunately, neither Mrs. J nor her husband smokes). He then explains why she should

aim to have a vaginal birth, as she did with Bryan, because being born by cesarian sec-tion (C-section) can increase the risk for food allergy. He commends Mrs. J for planning to primarily provide the baby with breast milk because it has an important role in reducing allergy risk along with its other benefits. With regard to supplemental for-mula, the pediatrician points out that a hydrolyzed formula also provides protective advantages in patients who cannot be exclu-sively breastfed for the first 4 to6 months of life. Lastly, he advises her when and how to introduce complementary foods, including those that are allergenic (Table 1).

Role of hydrolyzed formula. Because Bryan has AD and milk allergy, using a hydrolyzed formula with the next child may reduce the risk of AD compared with standard formulas when used in the first 6 months of life.28 In hydrolyzed for-mulas, the milk protein is broken down and is therefore less likely to provoke an allergic reaction.

The most compelling evidence for this risk-reducing effect comes from the German Infant Nutrition Intervention (GINI) study, which

FIGURE 3. The atopic march

Atopic dermatitis is usually the first allergy to manifest in the allergic march.

Adapted from Barnetson RS, Rogers M. Childhood atopic eczema. BMJ. 2002;324:1376-1379.

POLLING QUESTION

WHICH OF THE FOLLOWING STATEMENTS ABOUT ALLERGIC DISEASES IS TRUE?

The “atopic march” refers to persistence of atopic dermatitis into adulthood.

Early introduction of peanut ingestion in infancy has been reported to be associated with a low prevalence of peanut allergy.

Atopic dermatitis that remits early in life is not associated with development of other allergic diseases.

Development of other allergic symptoms is less likely in children who have a family history of atopic dermatitis.

IgE levels in blood

0 5 10 15Age (years)

Atopic dermatitis

Food allergy

Asthma

Rhinitis

Inci

den

ce

JANUARY 2015 7

enrolled at birth 2,252 infants at high risk for allergy and has followed them through 10 years. The infants were assigned at birth to 1 of 4 supplemental formulas: CMF, partially hydrolyzed whey formula (pHF-W), extensively hydrolyzed whey formula (eHF-W), and extensively hydrolyzed casein for-mula (eHF-C). They received the sup-plemental formulas for the first 4 months, after which time infants gen-erally begin having complementary foods. At the end of a year, the inci-dence of AD was significantly reduced with the pHF-W and eHF-C formu-las, though family history modified

the preventive effect of these hydroly-sates.29 At the 10-year follow-up, investigators found that the significant preventive effect of pHF-W and eHF-C persisted with regard to AD (no preventive effect was seen on asthma or allergic rhinitis.)30 A 2014 meta-analysis of 8 systematic reviews of hydrolyzed formulas studied for the prevention of allergy confirms that in high-risk infants, when exclusive breastfeeding is not possible during the first 4 to 6 months, using hydrolysates may be effective in the prevention of AD.31

Maternal diet. Based on currently available literature and expert opin-

ion, the National Institute of Allergy and Infectious Diseases and the American Academy of Allergy, Asthma & Immunology (AAAAI) do not recommend restricting a wom-an’s diet during pregnancy or lacta-tion as a strategy for preventing food allergy.28,32 This nonrestrictive approach pertains to all foods, includ-ing the most allergenic: cow’s milk, soy, eggs, wheat, peanuts, tree nuts, fish, and shellfish. Data are inconclu-sive with regard to peanuts, however, for which more research is needed.28

What to avoid during pregnan-cy and delivery. Maternal smoking,

TABLE 1. Maternal DOs and DON’Ts for reducing the risk of childhood allergy

DOs

Recommendation Why?

Deliver the baby the “natural” way Babies delivered vaginally acquire maternal gut microbiota that enhance development of the immune system—an advantage denied the baby born by cesarean section

Provide breast milk exclusively for the first 4 to 6 months of the infant’s life

Breast milk is associated with protection against development of allergic disease

In the infant at high risk for allergy, use a hydrolyzed formula clinically shown to reduce risk instead of a standard cow’s milk formula for supplemental feeding if exclusive breastfeeding for 4 to 6 months is not feasible

Feeding with a hydrolyzed formula clinically shown to reduce risk appears to be beneficial in protecting against AD, compared with feeding with a standard cow’s milk formula

Introduce complementary foods, including those that are allergenic, at the age of 4 to 6 months

Recent evidence suggests that early introduction of peanuts and other highly allergenic foods actually reduces the risk of develop-ment of food allergy (the reverse of what was believed previously)

DON’Ts

Recommendation Why?

Do not restrict your diet during pregnancy or lactation Evidence is lacking that such restrictions are a useful strategy for preventing allergy

Do not smoke during pregnancy and after the infant’s birth Both prenatal and postnatal smoking are associated with elevating risk for developing allergy

Do not expose yourself to avoidable stress during pregnancy Prenatal stress seems to alter natural immunoregulatory mechanisms

Do not use soy or amino acid formulas as a strategy to avoid allergy development

Soy is allergenic, and studies have not shown a protective effect using soy formulas. Amino acid formulas have not been studied for prevention of allergy

Fleischer DM, Spergel JM, Assa’ad AH, Pongracic JA. Primary prevention of allergic disease through nutritional interventions. J Allergy Clin Immunol Pract. 2013;1(1):29-36.Sevelsted A, Stokholm J, Bønnelykke K, Bisgaard H. Cesarean section and chronic immune disorders. Pediatrics. 2014 Dec 1 [Epub ahead of print].

8 JANUARY 2015

PREVENTING VS MANAGING PEDIATRIC ALLERGIES: CLINICAL AND ECONOMIC IMPACT OF NUTRITIONAL AND ENVIRONMENTAL INTERVENTIONS

stress, and delivery by C-section have all been associated with development of allergy in offspring.

An investigation in 342 children found that at the age of 3 years, chil-dren who were exposed prenatally to tobacco smoke had a significantly higher risk than unexposed children of becoming sensitized to food aller-gens. This effect was less strong when the exposure was only postnatal, but these children were still 2.2 times more likely to undergo sensitization than unexposed children.33 Other environmental factors related to atopy include exposure to dust mites, molds, animal dander, pollens, ozone and diesel exhaust, and wall fun-gus.23,33 Regarding stress, it appears that intrauterine stress hormone lev-els, both maternal and fetal, may rise

with prenatal maternal stress. This could alter natural immunoregulatory mechanisms and increase the child’s risk for developing inflammatory dis-eases, including allergy and asthma.34

How a baby is delivered affects the immune system of the infant. The infant’s intestine is sterile before birth. With a vaginal birth, the infant acquires bacteria in the mother’s birth canal, and normal maternal intestinal microbiota induce development of the allergic immune system. With delivery via C-section, the newborn misses this opportunity and healthy intestinal flora colonization is delayed for months.35 Compared with babies born vaginally, those delivered by C-section tend to have higher levels of clostridia, gener-ally considered harmful species, and lower levels of bifidobacteria, which appear to be beneficial. In babies born naturally, this balance is reversed. Bifidobacteria predominate in maternal microbiota, which also include other health-promoting species that colonize the newborn’s intestine.36,37 Unsurpri-singly, a meta-analysis of 23 studies showed that children delivered by C-section had a 20% increased risk of developing asthma,38 while another meta-analysis of 26 studies determined that C-section was associated with a moderate risk increase of asthma, aller-gic rhinitis, and possibly food allergy.39

Breast is best. The superiority of human milk over any other form of nutrition for optimum psychological,

nutritional, hormonal, and immuno-logic development of the newborn infant is well established. A meta-analysis showed that compared with conventional formula feeding, exclu-sive breastfeeding for 3 months reduced the incidence of AD in the first 2 years of life in children with a family history of atopy.40 Other research has demonstrated an associa-tion between early exclusive breast-feeding and protection against early-onset wheezing in the first 4 years of life and cow’s milk allergy in the first 2 years.41,42 Based on this and other evidence, the AAAAI recom-mends exclusive breastfeeding for 4 to 6 months as primary prevention of allergic disease, although it notes some conflicting evidence (Table 2).28

Which supplemental formula? In suggesting that Mrs. J use a hydro-lyzed formula to supplement breast milk when she returns to work 2 months after her next baby is born, the clinician is following a recom-mendation of the AAAAI and other professional groups: Infants at high risk for developing allergy who can-not receive breast milk exclusively for at least 4 months should be given breast milk supplemented with a hydrolyzed formula instead of intact CMF for the first 4 to 6 months of life.28 This recommendation is based on results of the GINI study and is supported by recent research.

One large meta-analysis, while not-ing inconsistent findings and meth-odologic shortcomings in some included studies, found limited evi-dence that prolonged feeding with some hydrolyzed formulas vs. a CMF reduces infant and childhood allergy and infant cow’s milk allergy.43 A recent analysis of 8 systematic reviews determined that pHF-W and eHF-C formulas—those with documented efficacy based on clinical trials—are appropriate for reducing the risk of AD up to the age of 4 to 6 months in

TABLE 2. Why the AAAAI recommends exclusive breastfeeding for infants 4 to 6 months of age*

• Possibly reduces the incidence of AD in children younger than 2 years

• Reduces early onset of wheezing before 4 years of age but not necessarily asthma

• Reduces the incidence of cow’s milk protein allergy in the first 2 years of life but not necessarily food allergy in general

AAAAI=American Academy of Allergy Asthma & Immunology; AD=atopic dermatitis.

*No clear effects of breastfeeding on allergic rhinitis have been demonstrated.

Fleischer DM, Spergel JM, Assa’ad AH, Pongracic JA. Primary prevention of allergic disease through nutritional interventions. J Allergy Clin Immunol Pract. 2013;1(1):29-36.

POLLING QUESTION

WHICH OF THE FOLLOWING IS A RISK FACTOR FOR PEDIATRIC ALLERGY?

Breastfeeding for the first 4 to 6 months

Delivery by cesarean section

Maternal ingestion of highly allergenic foods during pregnancy and lactation

Introducing complementary foods between 4 to 6 months of age

JANUARY 2015 9

high-risk infants who cannot be exclusively breastfed.31

An eHF may be slightly more beneficial than a pHF in preventing allergy, but data are inconclusive.28 However, eHFs are more expensive than pHFs because they require more processing.44 Because soy protein is antigenic like cow’s milk protein and soy formulas have not been proven to reduce allergy risk, soy formulas should not be used to prevent aller-gies. Amino acid formulas have not been studied for prevention of allergy, so they should not be used.

Introducing complementary foods. In the past, medical profes-sionals believed that to lower the risk of allergy, parents should delay first exposure to highly allergenic foods, such as egg, peanut, tree nuts, and fish. Since 2000, however, thinking has shifted in light of observational studies showing that early introduc-tion of allergenic foods may actually prevent food allergy. Therefore, allergenic foods can be introduced between 4 and 6 months of age, as are other complementary foods (Table 3).

For example, in more than 3,700 consecutively born children whose dietary exposures were followed, early introduction of fish and egg, as well as of a variety of grain cereals, decreased the risk of asthma and allergic rhinitis.45 In another large study, early introduc-tion of fish decreased the risk of devel-oping AD.46 An additional investigation showed that peanut may be less likely to cause allergy when it is introduced early. The prevalence of peanut allergy was 10-fold higher in a group of chil-dren in the UK than it was in a similar group of children in Israel, where pea-nut protein is introduced earlier and is eaten more often and in larger quanti-ties than in the UK.47 Such findings have led the AAAAI to determine that currently there is no convincing evi-dence for delaying introduction of spe-cific highly allergenic foods.28

PREVENTION MAKES ECONOMIC SENSE After reviewing allergy risk-reduction rec-ommendations, the clinician gives Mrs. J a brochure developed by the AAAAI entitled “Preventing Allergies: What You Should Know About Your Baby’s Nutrition”[Click here for PDF], to remind her of what they have discussed. Mrs. J agrees to follow the recommendations the pediatrician has outlined. If the new baby does not develop allergies, the whole family will be happier and will be spared the expense of extra clinician visits, medica-tions, and missed time at work that they have experienced with Bryan.

Although the costs of prevention strategies, such as avoiding tobacco smoke and following infant feeding guidelines, obviously are less costly than the clinician visits and medica-tions associated with allergic disease, it is only recently that the economic impact of primary prevention has been quantified. In one example, a math-ematical model incorporating market and GINI study data and expert opin-ion estimated the savings associated with preventing AD in a high-risk

infant by using pHF-W instead of standard CMF to supplement breast-feeding (the cost of the 2 formulas is similar). Researchers determined that this substitution would save $473 per child in direct and indirect health care costs in the first 6 years of life because of a reduction in AD incidence and the condition’s associated costs. The savings that would accrue if all high-risk families used a pHF instead of CMF would be an estimated $352 million, based on an estimated 14-percentage point reduction in the incidence of AD.48

WRAPPING IT UPIf nutritional and other interventions can prevent the development of AD, can they stop the allergic march that often follows AD? The answer to this intriguing question remains to be answered. In the meantime, particularly for those with a family history of atopy, the benefits of interventions to prevent allergy in infants are clear: improved physical and mental health for the child, enhanced QoL for the entire family, and reduced costs for family and society.

TABLE 3. Introducing complementary foods*

• Begin introducing single-ingredient foods between the ages of 4 and 6 months**

• Introduce at a rate no faster than 1 new food every 3 to 5 days***

• First introduce highly allergenic foods at home (not in a restaurant or day care) after other common complementary foods such as cereal or fruits/vegetables have been tolerated

• Once age/developmentally appropriate staged foods are tolerated, similar staged highly allergenic foods such as peanut butter and seafood can be introduced

• While cow’s milk should not be introduced prior to age 1 year for non-allergy reasons, other dairy products such as yogurt, cheese, or baked milk products can be introduced prior to age 1 year

* Consult an allergist about introduction in special circumstances such as: poorly controlled AD despite treatment; history of immediate reaction to a food; older sibling with peanut or shellfish allergies.

**Infant must be developmentally ready and able to sit up, with sufficient head and neck control.

*** Acidic fruits may cause facial rash due to contact reactions with histamine release, but this is no reason to delay their introduction.

AD=atopic dermatitis.

Fleischer DM, Spergel JM, Assa’ad AH, Pongracic JA. Primary prevention of allergic disease through nutritional interventions. J Allergy Clin Immunol Pract. 2013;1(1):29-36.

10 JANUARY 2015

PREVENTING VS MANAGING PEDIATRIC ALLERGIES: CLINICAL AND ECONOMIC IMPACT OF NUTRITIONAL AND ENVIRONMENTAL INTERVENTIONS

REFERENCES

1. Jackson KD, Howie LD, Akinbami LJ. NCHS Data Brief, No. 121, May 2013. Trends in allergic conditions among children: United States, 1997-2011. NCHS data brief, no 121. Hyattsville, MD: National Center for Health Statistics. 2013. www.cdc.gov/nchs/databriefs/db121.htm. Accessed October 14, 2014.

2. Pawankar R, Canonica GW, Holgate ST, Lockey RF, World Allergy Organization (WAO). WAO White Book on Allergy 2011-2012: Executive Summary. http://www.worldallergy.org/publications/wao_white_book.pdf. Accessed September 10, 2014.

3. Gupta R, Holdford D, Bilaver L, et al. The economic impact of childhood food allergy in the United States. JAMA Pediatrics. 2013;167:1026-1031.

4. Ellis CN, Drake LA, Prendergast MM, et al. Cost of atopic dermatitis and eczema in the United States. J Am Acad Dermatol. 2002;46:361-370.

5. Barnett SB, Nurmagambetov TA. Costs of Asthma in the United States: 2002-2007. J Allergy Clin Immunol. 2011;127:145-152.

6. Barnetson RS, Rogers M. Childhood atopic eczema. BMJ. 2002;324:1376-1379.

7. Reid P, Lewis-Jones MS. Sleep difficulties and their management in preschoolers with atopic eczema. Clin Exp Dermatol. 1995;20:38-41.

8. Reuveni H, Chapnick G, Tal A, et al. Sleep fragmentation in children with atopic dermatitis. Arch Pediatr Adolesc Med. 1999;153:249-253.

9. Daud LR, Garralda ME, David TJ. Psychological adjustment in preschool children with atopic eczema. Arch Dis Child. 1993;69:670-676.

10. Absolon CM, Cottrell D, Eldridge SM, et al. Psychological disturbance in atopic eczema: the extent of the problem in school-aged children. Br J Dermatol. 1997;137:241-245.

11. Schmitt J, Apfelbacher C, Chen CM, et al. Infant-onset eczema in relation to mental health problems at age 10 years: results from a prospective birth cohort study (German Infant Nutrition Intervention plus). J Allergy Clin Immunol. 2010;125:404-410.

12. Beattie PE, Lewis-Jones MS. A comparative study of impairment of quality of life in children with skin disease and children with other chronic childhood diseases. Br J Dermatol. 2006;155:145-151.

13. Sicherer SH, Noone SA, Muñoz-Furlong A. The impact of childhood food allergy on quality of life. Ann Allergy Asthma Immunol. 2001;87:461-464.

14. Bollinger ME, Dahlquist LM, Mudd K, et al. The impact of food allergy on the daily activities of children and their families. Ann Allergy Asthma Immunol. 2006;96:415-421.

15. Canonica GW, Bousquet J, Mullol J, et al. A survey of the burden of allergic rhinitis in Europe. Allergy. 2007;62 (suppl 85):17-25.

16. Okelo SO, Wu AW, Krishnan JA, et al. Emotional quality-of-life and outcomes in adolescents with asthma. J Pediatr. 2004;145:523-529.

17. Koplin JJ, Allen KJ, Gurrin LC, et al. The impact of family history of allergy on risk of food allergy: a population-

based study of infants. Int J Environ Res Public Health. 2013;10: 5364-5377.

18. Tariq SM, Matthews SM, Hakim EA, et al. The prevalence of and risk factors for atopy in early childhood: a whole population birth cohort study. J Allergy Clin Immunol. 1998;101:587-593.

19. Van Bever HP, Samuel ST, Lee BW. Halting the allergic march. WAO Journal. 2008;1:57-62.

20. Hudson TJ. Skin barrier function and allergic risk. Nat Genet. 2006;38:399-400.

21. Henderson J, Northstone K, Lee SP, et al. The burden of disease associated with filaggrin mutations: a population-based, longitudinal birth cohort study. J Allergy Clin Immunol. 2008;121:872-877.

22. Brough HA, Simpson A, Makinson K, et al. Peanut allergy: effect of environmental peanut exposure in children with filaggrin loss-of-function mutations. J Allergy Clin Immunol. 2014;134(4):867-875.

23. Wen HJ, Chen PC, Chiang TL, et al. Predicting risk for early infantile atopic dermatitis by hereditary and environmental factors. Br J Dermatol. 2009;151:1166-1172.

24. Wahn U. The allergic march. World Allergy Organization. www.worldallergy.org/professional/allergic_diseases_center/allergic_march. Accessed October 23, 2014.

25. Kapoor R, Menon C, Hoffstad O, et al. The prevalence of atopic triad in children with physician-confirmed atopic dermatitis. J Am Acad Dermatol. 2008;58:68-73.

26. Gustafsson D, Sjöberg O, Foucard T. Development of allergies and asthma in infants and young children with atopic dermatitis—a prospective follow-up to 7 years of age. Allergy. 2000;55:240-245.

27. Bergmann RL, Edenharter G, Bergmann KE, et al. Atopic dermatitis in early infancy predicts allergic airway disease at 5 years. Clin Exp Allergy. 1998;28:965-970.

28. Fleischer DM, Spergel JM, Assa’ad AH, Pongracic JA. Primary prevention of allergic disease through nutritional interventions. J Allergy Clin Immunol Pract. 2013;1(1):29-36.

29. Von Berg A, Koletzko S, Grübl A, et al. The effect of hydrolyzed cow’s milk formula for allergy prevention in the first year of life: the German Infant Nutritional Intervention Study, a randomized double-blind trial. J Allergy Clin Immunol. 2003;111:533-540.

30. Von Berg A, Filipiak-Pittroff B, Krämer U, et al. Allergies in high-risk schoolchildren after early intervention with cow’s milk protein hydrolysates; 10-year results from the German Infant Nutritional Intervention (GINI) study. J Allergy Clin Immunol. 2013;131:1565-1573.

31. Vandenplas Y, Bhatia J, Shamir R, et al. Hydrolyzed formulas for allergy prevention. J Pediatr Gastroenterol Nutr. 2014;58:549-552.

32. Boyce JA, Assa’ad A, Burks AW, et al. Guidelines for the diagnosis and management of food allergy in the United States Summary of the NIAID-sponsored expert panel report. www.niaid.nih.gov/topics/FoodAllergy/clinical/Pages/default.aspx. Accessed October 31, 2014.

33. Kulig M, Luck W, Lau S, et al. Effect of pre- and postnatal tobacco smoke exposure on specific

sensitization to food and inhalant allergens during the first 3 years of life. Multicenter Allergy Study Group, Germany. Allergy. 1999;54:220-228.

34. Dave ND, Xiang L, Rehm KE, et al. Stress and allergic diseases. Immunol Allergy Clin North Am. 2011;31:55-68.

35. Grönlund MM, Lehtonen OP, Eerola E, et al. Fecal microflora in healthy infants born by different methods of delivery: permanent changes in intestinal flora after cesarean delivery. J Pediatr Gastroenterol Nutr. 1999;28:19-25.

36. Kalliomäki M, Kirjavainen P, Eerola E, et al. Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing. J Allergy Clin Immunol. 2001;107:129-134.

37. Salminen S, Gibson GR, McCartney AL, et al. Influence of mode of delivery on gut microbiota composition in seven year old children. Gut. 2004;53:1388-1389.

38. Thavagnanam S, Fleming J, Bromley A, et al. A meta-analysis of the association between Caesarean section and childhood asthma. Clin Exp Allergy. 2008;38:629-633.

39. Bager P, Wohlfahrt J, Westergaard T. Caesarean delivery and risk of atopy and allergic disease: meta-analyses. Clin Exp Allergy. 2008;38:634-642.

40. Gdalevich M, Mimouni D, David M, et al. Breast-feeding and the onset of atopic dermatitis in childhood: a systematic review and meta-analysis of prospective studies. J Am Acad Dermatol. 2001;45:520-527.

41. Kull I, Almqvist C, Lilja G, et al. Breast-feeding reduces the risk of asthma during the first 4 years of life. J Allergy Clin Immunol. 2004;114:755-760.

42. 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.

43. Osborn DA, Sinn J. Formulas containing hydrolysed protein for prevention of allergy and food intolerance in infants. Cochrane Database Syst Rev. 2006; Oct 18;(14):CD003664.

44. Exl B-M. A review of recent developments in the use of moderately hydrolyzed whey formulae in infant nutrition. Nutr Res. 2001;21:355-379.

45. Nwaru BI, Takkinen HM, Niemelä O, et al. Timing of infant feeding in relation to childhood asthma and allergic diseases. J Allergy Clin Immunol. 2013;131:78-86.

46. Alm B, Aberg N, Erdes L, et al. Early introduction of fish decreases the risk of eczema in infants. Arch Dis Child. 2009;94(1):11-15.

47. DuToit 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;122:984-991.

48. Bhanegaonkar A. Economic burden of atopic dermatitis in US high-risk infants receiving cow’s milk or partially hydrolyzed 100% whey-based formula (unpublished data, 2014).

POSTTEST

JANUARY 2015 11

1. Which of the following statements about allergic diseases is true?A. >50% of children with atopic dermatitis (AD) will proceed

to develop asthma and allergies, usually by 3 years of age.B. Sleep disruption and mental health problems are associated

with infant-onset eczema.C. Taking an allergy history, including family history, is important.D. All of the above.

2. Which of the following statements is true about the economic impact of allergic diseases?A. Third-party payer costs of illness for atopic dermatitis are an

estimated $4 million.B. Preventing allergic diseases can significantly reduce the

personal and national economic costs of treating them.C. Indirect costs, such as lost labor productivity, out-of-pocket

costs, and lost opportunity costs, have limited impact on overall costs.

D. Americans spend much less on medical care than on either housing or food.

3. What would you tell a new mother who cannot exclusively breastfeed for 4-6 months? A. Current allergy prevention guidelines recommend the use of

certain hydrolyzed infant formulas for primary prevention of AD in patients not exclusively breastfed for 4-6 months.

B. Feeding with the hydrolyzed formulas in the first 4 months has NO preventive effect on cumulative incidence of AD in high-risk children at 10 years.

C. Exclusive breastfeeding is the only proven way to prevent allergy.

D. She should not be concerned about allergy risk unless there is a family history of allergy.

4. What would you tell a new mother about complementary foods and allergy risk?A. Soy protein may help reduce allergy risk. B. She should offer several new food proteins every day.C. There is NO advantage to waiting >6 months to introduce

complementary foods, including highly allergenic foods.D. Waiting >6 months to introduce complementary foods may

help avoid allergy risk.

5. What would you tell a pregnant mother about her diet and avoiding allergy risk?A. During early pregnancy, she should avoid intake of highly

allergenic foods such as peanut, milk, and wheat.B. Maternal avoidance of highly allergenic foods such as milk

and egg during pregnancy and lactation is not recommended at this time.

C. In a high-risk family, peanut avoidance during pregnancy or lactation has been proven to decrease risk of allergy.

D. Higher milk intake during the first trimester is associated with increased asthma.

To participate in this activity and receive your certificate instantly, log on to www.myCME.com and click on the activity to answer the test questions and complete the evaluation form. This program is approved by Albert Einstein College of Medicine of Yeshiva University for physicians for 1.50 AMA PRA Category 1 credits™ and dietitians for 1.5 contact hours and by Montefiore for nurses and nurse practitioners for 1.5 contact hours. To obtain credit, you must receive a score of 70% or better. Expiration date: January 29, 2016.