atopic dermatitis in childhood and infancy

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Allergy, Immunity and Tolerance in Early Childhood. http://dx.doi.org/10.1016/B978-0-12-420226-9.00003-6

Copyright © 2016 Elsevier Inc. All rights reserved.

Atopic Dermatitis in Infancy and

ChildhoodU. Wahn* , T. Keil § , L. Grabenhenrich§ , T. Werfel ¶

*Department of Pediatric Pneumology and Immunology, Charité University Medicine,

Berlin, Germany; §Institute for Social Medicine, Epidemiology and Health Economics,

Charité, Berlin, Germany; ¶Department of Dermatology and Allergology, Hannover Medical

University, Hannover, Germany

Definition

Atopic dermatitis (AD) is the most common inflammatory skin disease in childhood,with an onset usually in early infancy.1–3 It imposes a considerable burden on patientsand their families and frequently represents the first chronic health problem for manyfamilies.4,5

The clinical manifestation of AD may vary according to age, with a more generalmanifestation in infancy (aside from the diaper region, the face, head, and neck areincluded) (Figure 1) and a more flexural manifestation (elbows and knees) later in

life. It goes along with itch, which may contribute to sleep disturbance and impairedquality of life for both children and their families.

Manifestations are caused by inflammation of the skin, which involves the epi-dermis. Infiltration of T lymphocytes as well as immunoglobulin E (IgE) bindingantigen-presenting dendritic cells and eosinophils drives this inflammatory process.The influence of mediators, particularly TH2 cytokines such as interleukin 4 and 13during the acute and subacute period, has been named responsible for a transientdownregulation of barrier proteins of the skin in affected patients (Figure 2).2,6

Family history and genetics

Parental atopy is associated with the risk and severity of early atopic dermatitis in theoffspring, with the strongest effect being for parental atopic dermatitis.7–10

Recent studies have elegantly demonstrated that in some geographic locationsmore than 20% of patients afflicted with AD have a genetic predisposition for thisdisorder. The most common gene associated with AD is Filaggrin (FLG), which

produces profilaggrin, which is processed in the stratum granulosum into the FLGprotein.11 Filaggrin contributes to the barrier function of the stratum corneum of theskin. It has been shown that the stratum corneum of affected but also clinically unaf-fected skin of patients with AD is abnormal, with reduced expression of FLG andFLG-like proteins.12 This skin barrier is presumed to protect the skin from penetration

3


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34 Allergy, Immunity and Tolerance in Early Childhood

by environmental irritants and allergens.13 Although FLG loss-of-function mutationshave been extensively described in individuals of European and Asian descent, thesemutations obviously vary by race. In an African American cohort with AD, two addi-

tional FLG mutations were associated with more persistent AD, which suggests thatmutations arose in different populations during different time periods and were propa-gated selectively because of a multitude of factors that might include natural selection,genetic drift, or a population bottleneck effect.14 Regardless of FLG mutations, FLGdeficiency has been observed in patients with atopic dermatitis, which suggests thatthe absence of FLG is a key factor in the genesis of this skin condition.15 Applying

Figure 2 Immunological pathway involved in the progression of AD.2 LC = Langerhans cell,MC = mast cell, TSLP = human stromal lymphopoietin, AG = antigen, SAG = superantigen,AICD = activation-induced cell death, CLA = cutaneous lymphocyte antigen, MO = monocyte.

Figure 1 Infantile manifestation of atopicdermatitis.


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35Atopic Dermatitis in Infancy and Childhood

single-molecule direct ribonucleic acid sequencing to analyze the whole transcrip-tome, researchers demonstrated that the extracellular space and lipid metabolism inatopic skin pathology is important independent of the FLG genotype, and that anaberrant defense response is seen in subjects with FLG mutations.16

Natural history of disease

The natural history of atopic dermatitis has been studied extensively during the past 2decades in a variety of birth cohort studies that have been followed longitudinally upto adolescence. In the German Multicenter AllergyStudy (MAS) cohort, 13.4% of allchildren developed the classical manifestation during the first year of life. By the ageof 2 years, the lifetime prevalence amounted to 21.5%.7,8,10,17

The highest incidence of atopic dermatitis is observed in the first 12 months, with aclear dominance of male sex (boys 7%; girls 5%). The annual incidence decreases byschool age to less than 0.5% in both boys and girls (Figure 3).8,18

More than 40% of children with infantile manifestation develop complete remis-sion after age 2 years. Almost one-fifth of children with early atopic dermatitis havepersisting symptoms every year up to age of 7. In addition, intermittent manifestationhas been observed in 30.8% of children with infantile manifestation (Figure 4).

Scratching of the inflamed skin has been considered a marker of severity. Aboutone-third of families report scratching and another third report infrequent scratching.10

To score the severity of disease, a number of instruments have been proposed andvalidated (SCORAD and EASI) that have turned out to be useful in describing thelongitudinal development of the disorder.19,20

Infants with atopic dermatitis who had been observed over 18 months in aplacebo-controlled trial with levocetirizin21 turned out to lose severity (during18 months, approximately 18 points on the SCORAD scale). This loss of severity of

i n c i d e n c e

[ p e r y e a r ]

age [years]

0%

2%

4%

6%

8%

1 2 3 4 5 5-10 10-15 15-20

boys

girls

Figure 3 Annual incidence of atopic dermatitis in childhood and adolescence.Data from MAS.8


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infantile atopic dermatitis seems to be characteristic for young infants despite the per-

sistence of this chronic relapsing disease. In the long-term levocetirizine study, theobservation was independent of any pharmacological intervention (Figure 5).

Another characteristic feature of atopic dermatitis in early childhood is the associa-tion with various comorbid or mostly subsequent manifestations such as food allergy,asthma, rhinitis, and urticaria.22–26

Immunoglobulin E–mediated sensitizations may induce allergic reactions, whichin the case of atopic dermatitis may relate to independent comorbidities (urticaria orrhinitis) as well as factors that contribute to the severity of atopic dermatitis itself.

Allergic sensitization and allergy as comorbidity

Immunoglobulin E responses develop in a characteristic pattern, with reactions to foodproteins such as hen’s egg, cow’s milk, or peanuts during the first year of life;pollen-associated food proteins in subsequent years; and IgE antibodies to indoor(house dust mites or pets) and outdoor (pollen) allergens some years later.27

EPAAC Atopic Dermatitis Severity (SCORAD)

40

30

20

10

00 1 3 6 9 12 15 18

Atopic Dermatitis Severity (SCORAD)

S c o r a d

S c o r e

Months

Placebo

Lctz

Figure 4 Loss of severity over time in a cohort of children with AD treated with eitherplacebo or levocetirizine.Data are unpublished from the EPAAC trial.21

Figure 5 Natural history of AD from infancy to childhood, obtained from the prospectiveGerman MAS.10


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Immunoglobulin E-mediated sensitizations are related to the severity of the diseaseas well the total serum IgE concentration: Multiple IgE responses are associated withhigher prevalence and severity of the disease in the first 3 years of life.8

Only about 30% of young children with sensitization to food proteins show clinicallyrelevant reactions in double-blind, placebo-controlled food challenges, which justifiesdietary avoidance. A considerable proportion of children react to food proteins with urti-caria or gastrointestinal or airway symptoms rather than worsening of atopic dermatitis.28

Rhinitis and asthma as comorbidity

Pooled data of 12 ongoing European cohort studies participating in the Mechanisms

of the Development of Allergy project showed that eczema, rhinitis, and asthma coex-ist in the same child at age 4 and 8 years more often than would be expected if thesediseases were independent. Common underlying mechanisms could exist among thesedifferent manifestations besides IgE sensitization and parental history of allergies.29

Based on the observation that there is a characteristic sequence of manifesta-tions (eczema in infancy and airway disease later in childhood or adolescence),a number of interventional trials have been initiated to block the so-called “allergicmarch.” Unfortunately, the results of these trials were not encouraging (see thechapter by Spergel and Warner). Cetirizine, levocetirizine, desloratadine, and

pimecrolimus failed to reduce the incidence of allergic airway disease in childrenwith infantile atopic dermatitis.

Urticaria as comorbidity

Acute and chronic urticaria are disorders that may be observed in children with atopicdermatitis more often than in unaffected children.30 In prospective cohort studies, the inci-dence of urticaria was approximately 1% per year. The cumulative prevalence in children

up to age 10 years was 14.5% for boys and 16.2% for girls.31 The cumulated prevalenceof acute urticaria over the first decade of life was associated with allergic sensitization topeanuts, soy, weeds, and flowers but not to inhalant allergens. Clinical eczema increasesthe risk for urticaria.32 In a longitudinal study (ETAC) in which 817 children with atopicdermatitis between ages 12 and 24 months were randomized to receive either cetirizine orplacebo for 18 months,30 acute urticaria occurred in 16.2% of children.

In addition to acute urticaria, chronic spontaneous and chronic autoimmune urti-caria are linked to atopic dermatitis. The natural history of this disorder tends to bebenign, with a remission rate of about 50% after 3 years.32

Determinants of the disease

Socioeconomic status

The National Health Survey on children in Germany (KIGGS) confirmed the fre-quently reported observation that unlike many other health problems in childhood,


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atopic dermatitis is not associated with poverty, but rather with high socioeconomicstatus.

In the German birth cohort MAS, this observation could be confirmed. The link

between higher educational degree of the mother and infantile atopic dermatitis wasstatistically significant.8

Infant feeding

In 1936, two pediatricians in Chicago reported that of the 2061 infants they had seen in5 years, infantile eczema occurred seven times as often in infants who received cow’smilk formula and twice as often in partially breast-fed compared with fully breast-fedinfants (see the chapter by Bergmann et al.) All infants had received small amountsof orange juice from week 4, cod liver oil from week 6, and solid food after 4 months.Breast-feeding might reduce infectious morbidity and even mortality in developingcountries, but discussion on the protective role on atopic diseases is ongoing. In theGerman MAS study, the prevalence of atopic eczema in the first 7 years increased witheach additional month of exclusive breast-feeding and the risk was even higher if par-ents had a history of atopic eczema, which suggests that mothers probably extendedbreast-feeding once the infant had developed eczema early in infancy because theybelieved that breast-feeding is protective. This phenomenon of reversed causation con-fuses the ongoing discussion about preventative infantile diets because randomizedcontrolled trials on breast-feeding are considered unethical.25 Guidelines on infantfeeding recommend the use of hydrolyzed infant formula from either whey or caseinas part of primary prevention of atopic dermatitis in case breast milk is not available.The recommendations are based on the results of a large randomized controlled trial inGermany (GINI), which demonstrated some effect on the incidence of atopic dermati-tis, but not on the process of sensitization or the development of airway diseases.33–35 Similar results have been reported from interventional studies with some probiotics(lactobacillus GG) or prebiotics (enrichment of the formula with indigestible oligo-saccharides) in infant formulas. The mechanism of this effect is not completely under-stood; the intervention effect seems to be relatively weak. Although some decades agothe age at which solid food was introduced was considered to have a significant impacton the manifestation of AD, most recent studies do not confirm such an effect.36

Domestic environment

The level of domestic mite and pet allergen exposure, parental smoking, and maternalsmoking during pregnancy, along with the number of older siblings, have not beenfound to have an effect on the manifestation or severity of early AD.10

Key elements of treatment

The aim of therapeutic interventions for atopic dermatitis is not to cure the disease butrather to control the symptoms.


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International guidelines that are based on the results of evidence from placebo-con-trolled trials in the young age group recommend:

1. Providing rehydration for dry, inflamed skin

Two placebo-controlled randomized trials in high-risk neonates demonstrated that parentalinstruction to apply full-body therapy at least once per day starting in the neonatal period hasa protective effect on atopic dermatitis. Upon confirmation of these observations in larger tri-als, emollient therapy from birth may become a simple and low-cost intervention that couldreduce the global burden of AD.37,38

2. Anti-inflammatory topical treatment with topical corticosteroids or calcineurin inhibitors

Low-potency corticosteroids are recommended for maintenance therapy, whereas intermedi-ate- and high-potency corticosteroids should be used cautiously in early childhood and onlyto treat severe exacerbations over short periods of time. In young children, it should always

be taken into consideration that the degree of corticosteroid absorption through the skin andhands increases the potential for systemic adverse effects directly according to the surfacearea of the skin involved as well as the potency of the corticosteroid preparation.2

Topical calcineurin inhibitors may be considered in children older than age 2 years. Tacro-limus ointment and pimecrolimus cream decrease the number of flares, reduce the need forcorticosteroids, and control pruritus without causing skin atrophy. A published long-termsafety study on pimecrolimus in 2439 infants39 demonstrated safe application of intermittentlong-term treatment with a calcineurin inhibitor in children before age 2 years.4

Long-term treatment with antihistamines has failed to prove efficacy. H1 blockers are nolonger recommended in recent guidelines; however, in young children with concomitant

acute urticaria, long-term treatment with cetirizine significantly reduced the number of epi-sodes with acute urticaria.21

3. Diets

Dietary interventions are indicated only in children with proven food allergy. Consideringthe risk of potential nutritional defenses, clinicians should not recommend general elimina-tion diets based only on skin or specific IgE test results. Even with positive skin test results,most patients will react to no or few food items on oral challenge.28

4. Parent education

To achieve effective control of atopic dermatitis in infancy and early childhood, it is essential toeducate parents and caregivers about the chronic nature of the disease and exacerbating factors,

as well as the safety and side effects of medications. Training in skin care techniques, writtentreatment plans, and comprehensive information about the nature of the disease with individualtrigger factors are essential in managing AD. Structured educational programs for children andtheir caregivers have been systematically proven to be of great value.4

Prevention

A number of preventative approaches have been studied. Recommendations for

breast-feeding for 6 months or longer are not based on robust evidence. Because ofother beneficial aspects of breast-feeding, pediatricians all over the world encouragemothers to breast-feed. Some guidelines, particularly in Europe, recommend feedingwith hydrolysates prepared from whey or casein, if mother’s milk is not available insufficient amounts.40 The randomized controlled GINI study in Germany convinc-ingly demonstrated the reduction of atopic dermatitis in the first year of life duringand after feeding with hydrolysates.35 An effect on sensitization to food allergens or


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the development of allergic airway disease was not observed. Results have been dis-appointing and mothers at risk should be discouraged from implementing these poten-tially risky diets.

A bacterial lysate from Escherichia coli and Enterococcus faecalis, applied orally for6 months in young infants at risk, was studied in a large randomized, placebo-controlledtrial. Although it was not effective in the whole study cohort, the incidence of eczemawas reduced in children with only one atopic parent.36

Long-term outcome in adulthood

Most young children with atopic dermatitis grow out of the disease within the first 2decades of life:

About 30% of all children with incidence of eczema in the first year of life willhave remaining eczema by age 20 years despite a loss of severity (Figure 6). Lateronset between the second and fourth years of life will further reduce chronifica-tion and improve the long-term outcome. It appears that boys have a slightly betterprognosis than girls. In addition, predictors of persistence of atopic dermatitis andof disease severity were sensitization to cow’s milk and hen’s eggs and wheeze atschool age.8

MAS 20 years

Eczema: prognosis by age at onset

onset in…

5th year 10%

20%

21%

26%

30%

4th year

3rd year

2nd year

1st year

remaining at 20y…

1 2 3 4 5 until

10

until

15

until

20age [years]

Figure 6 Atopic dermatitis: long-term outcome at age 20 years, by age of onset.Data are from MAS.8


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of asthma in children with atopic dermatitis: 18 months’ treatment and 18 month’s post-treatment follow up. J Allergy Clin Immunol 2001;108:929–37.

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31. Brüske I, Standl M, Weidinger S, Klümper C, Hoffmann B, Schaaf B, et al. Epidemiologyof urticaria in infants and young children I Germany – results from the German LISAplusand GINIplus Birth Cohort Studies. Pediatr Allergy Immunol 2014;25:36–42.

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33. Chansakulporn S, Pongpreuksa S, Sangacharoenkit P, Pacharn P, Visitsunthorn N,Vichyanond P. The natural history of chronic urticaria in childhood. J Am Acad Dermatol 2014;71:663–8.

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35. von Berg A, Filipiak-Pittroff B, Krämer U, Hoffmann B, Link E, Beckmann C, et al. Aller-gies in high risk school children after early intervention with cow’s milk protein hydro-lysates: 10 year results from the German Infant Nutritional Intervention Study (GINI). J

Allergy Clin Immunol 2013;131:1565–73. 36. Lau S, Gerhold K, Zimmermann K, Ockeloen CW, Rossberg S, Wagner P, et al. Oralapplication of bacterial lysate in infancy decreases the risk of atopic dermatitis in childrenwith 1 atopic parent in a randomized, placebo-controlled trial. J Allergy Clin Immunol 2012;129:1040–7.

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Further reading

1. Marenholz I, Kerscher T, Bauerfeind A, Esparza-Gordillo J, Nickel R, Keil T, et al. An inter-action between filaggrin mutations and early food sensitization improves the prediction ofchildhood asthma. J Allergy Clin Immunol 2009;123:911–6.

2. Rodríguez E, Baurecht H, Herberich E, Wagenpfeil S, Brown SJ, Cordell HJ, et al. Meta-anal-ysis of filaggrin polymorphisms in eczema and asthma: robust risk factors in atopic disease.

3. Staab D, Pariser D, Gottlieb AB, Kaufmann R, Eichenfield LF, Langley RG, et al. Low sys-temic absorption and good tolerability of pimecrolimus, administered as 1% cream (Elidel)in infants with atopic dermatitis – a multicenter, 3-week, open-label-study. Pediatr Dermatol September–October 2005;22(5):465–71.

4. Staab D, Diepgen TL, Fartasch M, Kupfer J, Lob-Corzilius T, Ring J, et al. Age related,structured educational programmes for the management of atopic dermatitis in children andadolescents: multicenter, randomized controlled trial. BMJ 2006;332:933–8.

5. Grulee CG, Sanford HN. Breast and artificially fed infants. JAMA 1934:735–8.
http://dx.doi.org/10.1542/peds.2014-1990http://dx.doi.org/10.1542/peds.2014-1990

atopic dermatitis in childhood and infancy

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