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Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergology and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report

      There are remarkable differences in the diagnostic and therapeutic management of atopic dermatitis practiced by dermatologists and pediatricians in different countries. Therefore, the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma and Immunology nominated expert teams who were given the task of finding a consensus to serve as a guideline for clinical practice in Europe as well as in North America. The consensus report is part of the PRACTALL initiative, which is endorsed by both academies.

      Key words

      Abbreviations used:

      AD (Atopic dermatitis), APT (Atopy patch test), CyA (Cyclosporine A), DC (Dendritic cell), IDEC (Inflammatory dendritic epidermal cell), LC (Langerhans cell), MnSOD (Manganese superoxide dismutase), pDC (Plasmacytoid dendritic cell), SPT (Skin prick test), TCI (Topical calcineurin inhibitors), TReg (T regulatory)
      Atopic dermatitis (AD) is a chronic inflammatory pruritic skin disease that affects a large number of children and adults in industrialized countries. The 12-month prevalence in 11-year-old children, as studied in the Global International Study of Asthma and Allergies in Childhood trial, ranged from 1% to 20%, with the highest prevalence typically found in Northern Europe.
      • Anonymous
      Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee.
      In 45% of children, the onset of AD occurs during the first 6 months of life, during the first year of life in 60%, and before the age of 5 years in at least 85% of affected individuals.
      • Kay J.
      • Gawkrodger D.J.
      • Mortimer M.J.
      • Jaron A.G.
      The prevalence of childhood atopic eczema in a general population.
      In those children with onset before the age of 2 years, 20% will have persisting manifestations of the disease, and an additional 17% will have intermittent symptoms by the age of 7 years (Fig 1).
      • Illi S.
      • von Mutius E.
      • Lau S.
      • Nickel R.
      • Gruber C.
      • Niggemann B.
      • et al.
      The natural course of atopic dermatitis from birth to age 7 years and the association with asthma.
      In adults with AD, only 16.8% had onset after adolescence.
      • Williams H.C.
      • Strachan D.P.
      The natural history of childhood eczema: observations from the British 1958 birth cohort study.
      • Ozkaya E.
      Adult-onset atopic dermatitis.
      Figure thumbnail gr1
      Fig 1The natural history of AD from infancy to childhood obtained from the prospective birth cohort study Multicenter Atopy Study.
      • Illi S.
      • von Mutius E.
      • Lau S.
      • Nickel R.
      • Gruber C.
      • Niggemann B.
      • et al.
      The natural course of atopic dermatitis from birth to age 7 years and the association with asthma.
      The clinical pattern of AD varies with age. Infants typically present with erythematous papules and vesicles on the cheeks, forehead, or scalp, which are intensely pruritic. The childhood phase typically occurs from 2 years of age to puberty. Children are less likely to have the exudative lesions of infancy and instead exhibit more lichenified papules and plaques representing the more chronic disease and involving the hands, feet, wrists, ankles, and antecubital and popliteal regions. The adult phase of AD begins at puberty and frequently continues into adulthood. Predominant areas of involvement include the flexural folds, the face and neck, the upper arms and back, and the dorsa of the hands, feet, fingers, and toes. The eruption is characterized by dry, scaling erythematous papules and plaques and the formation of large lichenified plaques from lesional chronicity.

      Genetic and other risk factors for AD

      Parental atopy, in particular AD, is significantly associated with the manifestation and severity of early AD in children. The circumstance by which the genetics of AD might play a role in the level of natural history and development has been reflected in 2 forms of genetic studies:
      • genome-wide screens that identify broad regions of the genome linked with AD and
      • candidate gene studies that examine a presumed contribution of genetic variants of disease-process genes in case-control association studies.
      Both approaches highlight the search for disease-specific AD alleles, as well as identifying overlapping genes associated with other allergic characteristics and disorders. This process has been recently reviewed.
      • Hoffjan S.
      • Epplen J.T.
      The genetics of atopic dermatitis: recent findings and future options.
      A European study of about 200 families with affected sibs looked at phenotypes for AD, as well as allergic sensitization, and found a region of highest linkage at human chromosome 3q21.
      • Lee Y.A.
      • Wahn U.
      • Kehrt R.
      • Tarani L.
      • Businco L.
      • Gustafsson D.
      • et al.
      A major susceptibility locus for atopic dermatitis maps to chromosome 3q21.
      Another study of 148 nuclear families in which AD, as well as other intermediate phenotypes, including asthma phenotype and total serum IgE level, were examined identified association with 5 regions, including 1q21, 17q25, 20p, 16q, and 5q31.
      • Cookson W.O.
      • Ubhi B.
      • Lawrence R.
      • Abecasis G.R.
      • Walley A.J.
      • Cox H.E.
      • et al.
      Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci.
      A Swedish study of 197 affected sib pairs identified 4 phenotypes, as well as 11 locations, associated with all of the different phenotypes that ranged from severity of AD, specific IgE, and direct diagnosis of AD.
      • Bradley M.
      • Soderhall C.
      • Luthman H.
      • Wahlgren C.F.
      • Kockum I.
      • Nordenskjold M.
      Susceptibility loci for atopic dermatitis on chromosomes 3, 13, 15, 17 and 18 in a Swedish population.
      Finally, a Danish study looked at a small number of affected sib pairs and found association with 3 locations within the genome.
      • Haagerup A.
      • Bjerke T.
      • Schiotz P.O.
      • Dahl R.
      • Binderup H.G.
      • Tan Q.
      • et al.
      Atopic dermatitis—a total genome-scan for susceptibility genes.
      Not all of these locations are highly robust, and most of these associations from genome-wide screens might not yield effective identification of specific genes when examined in more detail; these are summarized in Table I.
      • Lee Y.A.
      • Wahn U.
      • Kehrt R.
      • Tarani L.
      • Businco L.
      • Gustafsson D.
      • et al.
      A major susceptibility locus for atopic dermatitis maps to chromosome 3q21.
      • Cookson W.O.
      • Ubhi B.
      • Lawrence R.
      • Abecasis G.R.
      • Walley A.J.
      • Cox H.E.
      • et al.
      Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci.
      • Bradley M.
      • Soderhall C.
      • Luthman H.
      • Wahlgren C.F.
      • Kockum I.
      • Nordenskjold M.
      Susceptibility loci for atopic dermatitis on chromosomes 3, 13, 15, 17 and 18 in a Swedish population.
      • Haagerup A.
      • Bjerke T.
      • Schiotz P.O.
      • Dahl R.
      • Binderup H.G.
      • Tan Q.
      • et al.
      Atopic dermatitis—a total genome-scan for susceptibility genes.
      Table II
      • Novak N.
      • Kruse S.
      • Potreck J.
      • Weidinger S.
      • Fimmers R.
      • Bieber T.
      Single nucleotide polymorphisms of the IL18 gene are associated with atopic eczema.
      • Weidinger S.
      • Klopp N.
      • Rümmler L.
      • Wagenpfeil S.
      • Novak N.
      • Baurecht H.J.
      • et al.
      Association of NOD1 polymorphisms with atopic eczema and related phenotypes.
      • Weidinger S.
      • Rümmler L.
      • Klopp N.
      • Wagenpfeil S.
      • Baurecht H.J.
      • Fischer G.
      • et al.
      Association study of mast cell chymase polymorphisms with atopy.
      summarizes the findings of candidate gene studies and their association with atopy and asthma.
      Table IGenome-wide screens of AD
      ReferenceStudy populationSamplePhenotypesRegions of highest linkage
      Lee et al,
      • Lee Y.A.
      • Wahn U.
      • Kehrt R.
      • Tarani L.
      • Businco L.
      • Gustafsson D.
      • et al.
      A major susceptibility locus for atopic dermatitis maps to chromosome 3q21.
      2000
      European199 families with 2 affected siblingsAD3q21
      Allergic sensitization3q21
      Cookson et al,
      • Cookson W.O.
      • Ubhi B.
      • Lawrence R.
      • Abecasis G.R.
      • Walley A.J.
      • Cox H.E.
      • et al.
      Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci.
      2001
      British148 nuclear families recruited through children with active ADAD1q21
      17q25
      AD plus asthma20p
      Serum IgE16q-tel
      5q31
      Bradley et al,
      • Bradley M.
      • Soderhall C.
      • Luthman H.
      • Wahlgren C.F.
      • Kockum I.
      • Nordenskjold M.
      Susceptibility loci for atopic dermatitis on chromosomes 3, 13, 15, 17 and 18 in a Swedish population.
      2002
      Swedish109 families (197 affected full sib pairs, 9 affected half sib pairs)AD3p24-22
      5p13
      6q16
      10p13-12
      AD plus specific IgE18q21
      4q24-26
      6p
      1p32
      Extreme AD18p
      21q21
      7p14
      Severity score of AD13q14
      15q14-15
      17q21
      3q14
      Haagerup et al,
      • Haagerup A.
      • Bjerke T.
      • Schiotz P.O.
      • Dahl R.
      • Binderup H.G.
      • Tan Q.
      • et al.
      Atopic dermatitis—a total genome-scan for susceptibility genes.
      2004
      Danish23 affected sib-pair familiesAD plus specific IgE3p26-24
      4p15-14
      18q11-12
      Table IICandidate gene studies in AD
      GeneGene nameLocationVariantPhenotypePopulationAssociation
      TLR2Toll-like receptor 24q32Arg753GlnSevere ADGermanYes
      ADGermanNo
      IRF2Interferon regulatory factor 24q35−467 G/AADJapaneseYes
      CSF2Colony-stimulating factor 25q31−677 A/CADBritishYes
      3606 T/C, 3928 C/TAD at 12 and 24 moCanadianYes
      IL4IL-45q31−590 C/TADJapaneseYes
      Extrinsic ADGermanYes
      ADAustralianNo
      Intrinsic ADJapaneseNo
      IL13IL-135q31Arg130GlnADCanadianYes
      ADJapaneseYes
      ADGermanYes
      −111 C/TADDutchYes
      ADJapaneseNo
      IL5IL-55q31−703 C/TBlood eosinophilia in ADJapanese
      IL18
      • Novak N.
      • Kruse S.
      • Potreck J.
      • Weidinger S.
      • Fimmers R.
      • Bieber T.
      Single nucleotide polymorphisms of the IL18 gene are associated with atopic eczema.
      IL-1811q22−137 G/C, −133 C/GADGermanYes
      113 T/G, 127 G/T
      CARD4
      • Weidinger S.
      • Klopp N.
      • Rümmler L.
      • Wagenpfeil S.
      • Novak N.
      • Baurecht H.J.
      • et al.
      Association of NOD1 polymorphisms with atopic eczema and related phenotypes.
      Caspase recruitment domain-containing protein 47p14-p15-rs2736726ADGermanYes
      rs2075817
      rs2975632
      rs2075822
      rs2907749
      rs2907748
      CD14Monocyte differentiation antigen CD145q31−159 C/TAD (interaction with dog ownership)AmericanYes
      ADGermanNo
      IL12BIL-12B5q31-331188 A/CAD, psoriasisJapaneseYes
      SPINK5Serine protease inhibitor, Kazal-type 5Glu420LysADBritishYes
      ADJapaneseYes
      ADJapaneseYes
      Asthma with ADGermanYes
      Disease severity and food allergy in ADJapaneseYes
      FCER1BHigh-affinity IgE receptor β chain11q13RsaIin2, RsaIex7ADBritishYes
      GSTP1Glutathione-S-transferase, PI11q13Ile105ValADRussianYes
      HaplotypesADRussianYes
      PHF11Plant homeodomain zinc finger 11 protein13q14T/C intron3, G/A 3 UTRChildhood ADAustralianYes
      CMA1Mast cell chymase14q11BstXIADJapaneseYes
      ADJapaneseYes
      ADJapaneseNo
      ADItalianNo
      −1903 G/AIgE levels in ADBritishYes
      ADGerman
      • Weidinger S.
      • Rümmler L.
      • Klopp N.
      • Wagenpfeil S.
      • Baurecht H.J.
      • Fischer G.
      • et al.
      Association study of mast cell chymase polymorphisms with atopy.
      Yes
      IL4RAIL-4 Receptor chain16p12Gln551ArgSevere ADAmericanYes
      Adult ADJapaneseYes
      Ad (interaction with infection)BritishYes
      Intrinsic ADJapaneseNo
      −3223 C/TExtrinsic ADGermanYes
      ADJapaneseYes
      CARD15Caspase recruitment domain-containing protein 1516q122722 G/CADGermanYes
      ADGerman
      • Novak N.
      • Kruse S.
      • Potreck J.
      • Weidinger S.
      • Fimmers R.
      • Bieber T.
      Single nucleotide polymorphisms of the IL18 gene are associated with atopic eczema.
      Yes
      RANTESRegulated on activation, normally T cell expressed plus secreted17q11-q12−403 A/GADGermanYes
      ADHungarianNo
      EOTAXINEotaxin17q21−426 C/T, −384 A/GIgE levels in ADJapaneseYes
      TGFβ1TGF-β119q13.1Arg25ProADBritishYes
      SCCEStratum corneum chymotryptic enzyme19q13AACCinsADBritishYes
      Among nongenetic determinants for the development of AD, the role of infantile feeding has been investigated.
      • Laubereau B.
      • Brockow I.
      • Zirngibl A.
      • Koletzko S.
      • Gruebl A.
      • von Berg A.
      • et al.
      Effect of breast-feeding on the development of atopic dermatitis during the first 3 years of life—results from the GINI-birth cohort study.
      A recent meta-analysis suggests that the incidence of infantile AD is reduced by breast-feeding for a least 4 months,
      • Schafer T.
      [Prevention of atopic eczema. Evidence based guidelines].
      but this effect is most probably transient and tends to disappear after 3 years of age.
      Environmental factors also play a role in the development of AD. In contrast to asthma, the role of passive tobacco smoke exposure in AD is inconclusive. However, exposure to aeroallergens (pets, mites, and pollen) has been clearly shown to increase the risk factors for AD and AD severity.
      • Capristo C.
      • Romei I.
      • Boner A.L.
      Environmental prevention in atopic eczema dermatitis syndrome (AEDS) and asthma: avoidance of indoor allergens.
      • Purvis D.J.
      • Thompson J.M.
      • Clark P.M.
      • Robinson E.
      • Black P.N.
      • Wild C.J.
      • et al.
      Risk factors for atopic dermatitis in New Zealand children at 3.5 years of age.
      • Schafer T.
      • Heinrich J.
      • Wjst M.
      • Adam H.
      • Ring J.
      • Wichmann H.E.
      Association between severity of atopic eczema and degree of sensitization to aeroallergens in schoolchildren.
      In addition, aeroallergens are a trigger for exacerbations in adult AD. Sensitization to food allergens (cow's milk and hen's eggs) is associated with infantile AD and related to disease severity. Food allergen sensitization is also predictive for persistence of symptoms throughout childhood.
      • Illi S.
      • von Mutius E.
      • Lau S.
      • Nickel R.
      • Gruber C.
      • Niggemann B.
      • et al.
      The natural course of atopic dermatitis from birth to age 7 years and the association with asthma.
      Only in a minority of those with food sensitization (up to 33% of patients with moderate-to-severe disease of all age groups) are food allergens of clinical relevance, as demonstrated by food challenge studies.
      • Eigenmann P.A.
      • Sicherer S.H.
      • Borkowski T.A.
      • Cohen B.A.
      • Sampson H.A.
      Prevalence of IgE-mediated food allergy among children with atopic dermatitis.
      Another risk factor for persistent AD symptoms is the severity of disease in infancy.
      Children with AD are at high risk of allergic asthma and allergic rhinitis. Of those with AD during the first 2 years of life, 50% will have asthma during subsequent years.
      • Warner J.O.
      • ETAC Study Group
      A double-blinded, randomized, placebo-controlled trial of cetirizine in preventing the onset of asthma in children with atopic dermatitis: 18 months' treatment and 18 months' posttreatment follow-up.
      The severity of AD, including early sensitization to food, increases the risk of asthma and allergic rhinitis.
      • Illi S.
      • von Mutius E.
      • Lau S.
      • Nickel R.
      • Gruber C.
      • Niggemann B.
      • et al.
      The natural course of atopic dermatitis from birth to age 7 years and the association with asthma.
      • Gustafsson D.
      • Sjoberg 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.
      The exact mechanism for the progression of the disease in children with AD is unknown; however, it appears to be a complex interaction of genetics, environmental exposure, and sensitization. For children with a family history of atopy, early AD, and sensitization, almost all are expected to have asthma.
      In murine models of AD, epicutaneous sensitization leads to systemic allergic responses, increased IgE levels, airway eosinophilia, airway sensitization, and airway hyperresponsiveness similar to that seen in human asthma and allergy.
      • Spergel J.M.
      • Mizoguchi E.
      • Brewer J.P.
      • Martin T.R.
      • Bhan A.K.
      • Geha R.S.
      Epicutaneous sensitization with protein antigen induces localized allergic dermatitis and hyperresponsiveness to methacholine after single exposure to aerosolized antigen in mice.
      In human subjects a recent report suggests that in selected individuals sensitization to peanut allergen might occur through the skin.
      • Lack G.
      • Fox D.
      • Northstone K.
      • Golding J.
      • Avon Longitudinal Study of Parents and Children Study Team
      Factors associated with the development of peanut allergy in childhood.

      Immunopathology

      The pathophysiology of AD is the product of a complex interaction between various susceptibility genes, host environments, infectious agents, defects in skin barrier function, and immunologic responses.
      • Novak N.
      • Bieber T.
      • Leung D.Y.
      Immune mechanisms leading to atopic dermatitis.
      Activation of T lymphocytes, dendritic cells (DCs), macrophages, keratinocytes, mast cells, and eosinophils are characteristic of AD skin inflammatory responses.

       Histopathology

      Clinically unaffected skin in AD is not normal. It is frequently dry and has a greater irritant skin response than normal healthy skin. Microscopic studies reveal a sparse perivascular T-cell infiltrate in unaffected AD skin that is not seen in normal healthy skin (Fig 2).
      • Leung D.Y.M.
      • Bhan A.K.
      • Schneeberger E.E.
      • Geha R.S.
      Characterization of the mononuclear cell infiltrate in atopic dermatitis using monoclonal antibodies.
      Figure thumbnail gr2
      Fig 2Immunologic pathway involved in the progression of AD. Updated from Leung DY. Atopic dermatitis: new insights and opportunities for therapeutic intervention. J Allergy Clin Immunol 2000;105:860-76. LC, Langerhans cell; MC, mast cell; TSLP, human thymic stromal lymphopoietin; Ag, antigen; SAg, superantigen; AICD, activation-induced cell death; CLA, cutaneous lymphocyte antigen; MO, monocyte.
      Acute AD skin lesions present to the physician as intensely pruritic, erythematous papules associated with excoriation and serous exudation. There is a marked infiltration of CD4+ activated memory T cells in acute AD. Antigen-presenting cells (eg, Langerhans cells [LCs], inflammatory dendritic epidermal cells [IDECs], and macrophages) in lesional and, to a lesser extent, in nonlesional skin bear IgE molecules.
      • Novak N.
      • Kraft S.
      • Bieber T.
      IgE receptors.
      Mast cell degranulation can be observed.
      Chronic AD skin lesions have undergone tissue remodeling caused by chronic inflammation. These skin lesions are associated with thickened plaques with increased skin markings (lichenification), increased collagen deposition in the dermis, and dry fibrotic papules. Macrophages dominate the dermal mononuclear cell infiltrate. Eosinophils also contribute to the inflammatory response, and T cells remain present, although in smaller numbers than seen in acute AD.

       Cytokines and chemokines

      AD skin lesions are orchestrated by the local tissue expression of proinflammatory cytokines and chemokines.
      • Leung D.Y.
      • Boguniewicz M.
      • Howell M.D.
      • Nomura I.
      • Hamid Q.A.
      New insights into atopic dermatitis.
      Cytokines, such as TNF-α and IL-1 from resident cells (keratinocytes, mast cells, and DCs), binds to receptors on the vascular endothelium, activating cellular signaling, including the nuclear factor (NF) κB pathway, and inducing expression of vascular endothelial cell adhesion molecules. These events initiate the process of tethering, activation, and adhesion to the endothelium, followed by extravasation of inflammatory cells. Once the inflammatory cells have infiltrated into the tissue, they respond to chemotactic gradients established by chemoattractant cytokines and chemokines, which emanate from sites of injury or infection. These molecules play a central role in defining the nature of the inflammatory infiltrate in AD.
      The onset of acute AD is strongly associated with the production of TH2-produced cytokines, notably IL-4 and IL-13, levels of which are significantly higher in AD individuals compared with control subjects.
      • Hamid Q.
      • Boguniewicz M.
      • Leung D.Y.
      Differential in situ cytokine gene expression in acute versus chronic dermatitis.
      Mediating isotype switching to IgE synthesis and upregulating expression of adhesion molecules on endothelial cells, IL-4 and IL-13 are implicated in the initial phase of tissue inflammation, whereas the TH2 cytokine IL-5, which is involved in eosinophil development and survival, predominates in the chronic form of the disease.
      • Hamid Q.
      • Boguniewicz M.
      • Leung D.Y.
      Differential in situ cytokine gene expression in acute versus chronic dermatitis.
      Increased production of GM-CSF in patients with AD is reported to inhibit apoptosis of monocytes, thereby contributing to the chronicity of this condition.
      • Bratton D.L.
      • Hamid Q.
      • Boguniewicz M.
      • Doherty D.E.
      • Kailey J.M.
      • Leung D.Y.
      Granulocyte macrophage colony-stimulating factor contributes to enhanced monocyte survival in chronic atopic dermatitis.
      The maintenance of chronic AD also involves production of the TH1-like cytokines IL-12 and IL-18, as well as several remodeling-associated cytokines, such as IL-11 and TGF-β1, which are expressed preferentially in chronic forms of the disease.
      • Toda M.
      • Leung D.Y.
      • Molet S.
      • Boguniewicz M.
      • Taha R.
      • Christodoulopoulos P.
      • et al.
      Polarized in vivo expression of IL-11 and Il-17 between acute and chronic skin lesions.
      Increased expression of C-C chemokines (monocyte chemoattractant protein 4, eotaxin, and RANTES) contributes to infiltration of macrophages, eosinophils, and T cells into acute and chronic AD skin lesions.
      • Taha R.A.
      • Minshall E.M.
      • Leung D.Y.
      • Boguniewicz M.
      • Luster A.
      • et al.
      Evidence for increased expression of eotaxin and monocyte chemotactic protein-4 in atopic dermatitis.
      Cutaneous T cell–attracting chemokine (CCL27) is highly upregulated in AD and preferentially attracts cutaneous lymphocyte antigen–positive T cells into the skin. Finally, selective recruitment of CCR4-expressing TH2 cells is mediated by macrophage-derived chemokine and thymus and activation-regulated cytokine, levels of which are increased in patients with AD.
      • Leung D.Y.
      • Boguniewicz M.
      • Howell M.D.
      • Nomura I.
      • Hamid Q.A.
      New insights into atopic dermatitis.
      Severity of AD has been linked to magnitude of thymus and activation-regulated cytokine levels.
      • Hijnen D.
      • De Bruin-Weller M.
      • Oosting B.
      • Lebre C.
      • De Jong E.
      • Bruijnzeel-Koomen C.
      • et al.
      Serum thymus and activation-regulated chemokine (TARC) and cutaneous T cell–attracting chemokine (CTACK) levels in allergic diseases: TARC and CTACK are disease-specific markers for atopic dermatitis.
      In addition, chemokines, such as fractalkine,
      • Echigo T.
      • Hasegawa M.
      • Shimada Y.
      • Takehara K.
      • Sato S.
      Expression of fractalkine and its receptor, CX3CR1, in atopic dermatitis: possible contribution to skin inflammation.
      IFN-γ–inducible protein 10, monokine induced by IFN-γ, and IFN-γ–inducible α chemoattractant, are strongly upregulated in keratinocytes
      • Klunker S.
      • Trautmann A.
      • Akdis M.
      • Verhagen J.
      • Schmid-Grendelmeier P.
      • Blaser K.
      • et al.
      A second step of chemotaxis after transendothelial migration: keratinocytes undergoing apoptosis release IFN-gamma-inducible protein 10, monokine induced by IFN-gamma, and IFN-gamma-inducible alpha-chemoattractant for T cell chemotaxis toward epidermis in atopic dermatitis.
      and contribute to TH1 cell migration toward the epidermis.

       IgE and IgE receptors

      In about 80% of adult patients with AD, the disease is associated with increased serum IgE levels (>150 kU/L), sensitization against aeroallergens and food allergens, and/or concomitant allergic rhinitis and asthma.
      • Novak N.
      • Bieber T.
      Allergic and nonallergic forms of atopic diseases.
      • Schmid-Grendelmeier P.
      • Simon D.
      • Simon H.U.
      • Akdis C.A.
      • Wuthrich B.
      Epidemiology, clinical features, and immunology of the “intrinsic” (non-IgE-mediated) type of atopic dermatitis (constitutional dermatitis).
      In contrast, 20% of adult patients with AD have normal serum IgE levels. This subtype of AD often has a late onset (>20 years of life) and a lack of IgE sensitization against inhalant or food allergens.
      • Novak N.
      • Bieber T.
      Allergic and nonallergic forms of atopic diseases.
      • Schmid-Grendelmeier P.
      • Simon D.
      • Simon H.U.
      • Akdis C.A.
      • Wuthrich B.
      Epidemiology, clinical features, and immunology of the “intrinsic” (non-IgE-mediated) type of atopic dermatitis (constitutional dermatitis).
      However, some of these patients might have IgE sensitization against microbial antigens, such as Staphylococcus aureus enterotoxins and Candida albicans or Malassezia sympodialis (formally known as Pityrosporum ovale).
      • Scheynius A.
      • Johansson C.
      • Buentke E.
      • Zagari A.
      • Linder M.T.
      Atopic eczema/dermatitis syndrome and Malassezia.
      • Novak N.
      • Allam J.P.
      • Bieber T.
      Allergic hyperreactivity to microbial components: a trigger factor of “intrinsic” atopic dermatitis?.
      In addition, some of these patients have positive reactions on the atopy patch test (APT).
      • Kerschenlohr K.
      • Decard S.
      • Darsow U.
      • Ollert M.
      • Wollenberg A.
      Clinical and immunologic reactivity to aeroallergens in “intrinsic” atopic dermatitis patients.
      In children a transient form of AD with low IgE serum levels and without any detectable sensitizations has been shown, which develops into the extrinsic variant of AD with increasing IgE serum levels and developing sensitizations against aeroallergens and food allergens later in life.
      • Novembre E.
      • Cianferoni A.
      • Lombardi E.
      • Bernardini R.
      • Pucci N.
      • Vierucci A.
      Natural history of “intrinsic” atopic dermatitis.
      Expression of IgE receptors (ie, the high-affinity receptor for IgE [FcεRI]) can be found in the epidermal skin lesions of patients with AD. The reason for a higher IgE-binding capacity of DCs in the skin and in the peripheral blood of patients with AD is that FcεRI is regulated distinctly on DCs of atopic and nonatopic subjects.
      • Novak N.
      • Tepel C.
      • Koch S.
      • Brix K.
      • Bieber T.
      • Kraft S.
      Evidence for a differential expression of the FcepsilonRIgamma chain in dendritic cells of atopic and nonatopic donors.

       Skin barrier dysfunction

      AD is characterized by dry skin, even involving nonlesional skin and increased transepidermal water loss. In particular, ceramides serve as the major water-retaining molecules in the extracellular space of the cornified envelope, and the barrier function of these complex structures is provided by a matrix of structural proteins, which are bound to ceramides.
      • Sator P.G.
      • Schmidt J.B.
      • Honigsmann H.
      Comparison of epidermal hydration and skin surface lipids in healthy individuals and in patients with atopic dermatitis.
      • Arikawa J.
      • Ishibashi M.
      • Kawashima M.
      • Takagi Y.
      • Ichikawa Y.
      • Imokawa G.
      Decreased levels of sphingosine, a natural antimicrobial agent, may be associated with vulnerability of the stratum corneum from patients with atopic dermatitis to colonization by Staphylococcus aureus.
      A reduced content of ceramides has been reported in the cornified envelope of both lesional and nonlesional skin in patients with AD. Changes in stratum corneum pH levels have been found in patients with AD and might impair lipid metabolism in the skin.
      • Rippke F.
      • Schreiner V.
      • Doering T.
      • Maibach H.I.
      Stratum corneum pH in atopic dermatitis: impact on skin barrier function and colonization with Staphylococcus aureus.
      Overexpression of stratum corneum chymotryptic enzyme is also likely to contribute to the breakdown of the AD epidermal barrier.
      • Vasilopoulos Y.
      • Cork M.J.
      • Murphy R.
      • Williams H.C.
      • Robinson D.A.
      • Duff G.W.
      • et al.
      Genetic association between an AACC insertion in the 3′UTR of the stratum corneum chymotryptic enzyme gene and atopic dermatitis.
      This would allow penetration of irritants and allergens, which trigger an inflammatory response, thus contributing to the cutaneous hyperreactivity characteristic of AD. The increased susceptibility to irritants in patients with AD might therefore represent a primary defect of epidermal differentiation compounded by the presence of inflammation-induced skin damage.

       Key cells in AD

       T cells

      The key role of immune effector T cells in AD is supported by the observation that primary T-cell immunodeficiency disorders frequently have increased serum IgE levels and eczematous skin lesions, which clear after successful bone marrow transplantation.
      • Novak N.
      • Bieber T.
      • Leung D.Y.
      Immune mechanisms leading to atopic dermatitis.
      • Baud O.
      • Goulet O.
      • Canioni D.
      • Le Deist F.
      • Radford I.
      • Rieu D.
      • et al.
      Treatment of the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) by allogeneic bone marrow transplantation.
      In animal models of AD, the eczematous rash does not occur in the absence of T cells.
      • Spergel J.M.
      • Mizoguchi E.
      • Oettgen H.
      • Bhan A.K.
      • Geha R.S.
      Roles of Th1 and Th2 cytokines in a murine model of allergic dermatitis.
      In addition, treatment with topical calcineurin inhibitors (TCIs), which specifically target activated T cells, significantly reduces the clinical skin rash present in AD.
      • Hoetzenecker W.
      • Ecker R.
      • Kopp T.
      • Stuetz A.
      • Stingl G.
      • Elbe-Burger A.
      Pimecrolimus leads to an apoptosis-induced depletion of T cells, but not Langerhans cells in patients with atopic dermatitis.
      The important role that TH1 and TH2 cytokines play in the skin's inflammatory response has been demonstrated in experimental models of allergen-induced allergic skin inflammation in mice with targeted deletions or overexpression of these cytokines. In this regard transgenic mice genetically engineered to overexpress IL-4 in their skin have inflammatory pruritic skin lesions similar to those seen in patients with AD, suggesting that local skin expression of TH2 cytokines plays a critical role in AD.
      • Chan L.S.
      • Robinson N.
      • Xu L.
      Expression of interleukin-4 in the epidermis of transgenic mice results in a pruritic inflammatory skin disease: an experimental animal model to study atopic dermatitis.
      Allergen-sensitized skin from IL-5–deficient mice has been found to have no detectable eosinophils and exhibits decreased thickening, whereas skin from IL-4–deficient mice displays normal thickening of the skin layers but has a reduction in eosinophil counts.
      • Spergel J.M.
      • Mizoguchi E.
      • Oettgen H.
      • Bhan A.K.
      • Geha R.S.
      Roles of Th1 and Th2 cytokines in a murine model of allergic dermatitis.
      In patients with AD, activated T cells with skin-homing properties, which express high levels of IFN-γ, predominantly undergo apoptosis in the circulation, skewing the immune response to surviving TH2 cells as a mechanism for TH2 predominance.
      • Akdis M.
      • Trautmann A.
      • Klunker S.
      • Daigle I.
      • Kucuksezer U.C.
      • Deglmann W.
      • et al.
      T helper (Th) 2 predominance in atopic diseases is due to preferential apoptosis of circulating memory/effector Th1 cells.
      In the affected skin these T cells switch on effector cytokines and induce the activation and apoptosis of keratinocytes.
      • Akdis C.A.
      • Blaser K.
      • Akdis M.
      Apoptosis in tissue inflammation and allergic disease.
      Recently, T regulatory (TReg) cells have been described as a further subtype of T cells, with immunosuppressive function and cytokine profiles distinct from those of either TH1 or TH2 cells.
      • Umetsu D.T.
      • Akbari O.
      • Dekruyff R.H.
      Regulatory T cells control the development of allergic disease and asthma.
      • Akdis M.
      • Verhagen J.
      • Taylor A.
      • Karamloo F.
      • Karagiannidis C.
      • Crameri R.
      • et al.
      Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells.
      • Carneiro R.
      • Reefer A.
      • Wilson B.
      • Hammer J.
      • Platts-Mills J.
      • Custis N.
      • et al.
      T cell epitope-specific defects in the immune response to cat allergen in patients with atopic dermatitis.
      TReg cells are able to inhibit the development of both TH1 and TH2 responses. Mutations in a nuclear factor expressed in TReg cells, Foxp3, result in immune dysregulation polyendocrinopathy enteropathy X-linked syndrome characterized by hyper-IgE, food allergy, and eczema.
      • Lin W.
      • Truong N.
      • Grossman W.J.
      • Haribhai D.
      • Williams C.B.
      • Wang J.
      • et al.
      Allergic dysregulation and hyperimmunoglobulinemia E in Foxp3 mutant mice.
      In addition, staphylococcal superantigens subvert TReg cell function and might thereby augment skin inflammation.
      • Ou L.S.
      • Goleva E.
      • Hall C.
      • Leung D.Y.
      T regulatory cells in atopic dermatitis and subversion of their activity by superantigens.

       DCs

      Two types of FcεRI-bearing myeloid DCs have been found in the lesional skin of patients with atopic eczema, namely LCs and IDECs. Both display a different function in the pathophysiologic network of AD. LCs play a predominant role in the initiation of the allergic immune response and prime naive T cells into T cells of the TH2 type with high IL-4–producing capacity, which predominate in the initial phase of AD.
      • Novak N.
      • Valenta R.
      • Bohle B.
      • Laffer S.
      • Haberstok J.
      • Kraft S.
      • et al.
      FcepsilonRI engagement of Langerhans cell-like dendritic cells and inflammatory dendritic epidermal cell-like dendritic cells induces chemotactic signals and different T-cell phenotypes in vitro.
      Further on, stimulation of FcεRI on the surface of LCs by allergens induces the release of chemotactic signals and recruitment of precursor cells of IDECs and T cells in vitro. Stimulation of FcγRI on IDECs leads to the release of high amounts of proinflammatory signals, which contribute to the amplification of the allergic immune response.
      In contrast to other inflammatory skin diseases, such as allergic contact dermatitis or psoriasis vulgaris, only very low numbers of plasmacytoid DCs (pDCs), which play a major role in the defense against viral infections, can be detected within the epidermal skin lesions of AD.
      • Wollenberg A.
      • Wagner M.
      • Gunther S.
      • Towarowski A.
      • Tuma E.
      • Moderer M.
      • et al.
      Plasmacytoid dendritic cells: a new cutaneous dendritic cell subset with distinct role in inflammatory skin diseases.
      pDCs in the peripheral blood of patients with AD have been shown to bear the trimeric variant of FcεRI on their cell surface, which is occupied with IgE molecules. The modified immune function of pDCs in patients with AD after FcεRI-mediated allergen stimulation might contribute to the deficiency of pDCs in patients with AD to produce type I IFNs and thereby contribute to the high susceptibility of patients with AD toward viral skin infections, such as herpes simplex–induced eczema herpeticum.
      • Novak N.
      • Allam J.P.
      • Hagemann T.
      • Jenneck C.
      • Laffer S.
      • Valenta R.
      • et al.
      Characterization of FcepsilonRI-bearing CD123 blood dendritic cell antigen-2 plasmacytoid dendritic cells in atopic dermatitis.

       Keratinocytes

      Keratinocytes play a role in innate immunity by expressing Toll-like receptors and producing antimicrobial peptides in response to invading microbes.
      • Sayama K.
      • Komatsuzawa H.
      • Yamasaki K.
      • Shirakata Y.
      • Hanakawa Y.
      • Ouhara K.
      • et al.
      New mechanisms of skin innate immunity: ASK1-mediated keratinocyte differentiation regulates the expression of beta-defensins, LL37, and TLR2.
      AD keratinocytes secrete a unique profile of chemokines and cytokines after exposure to proinflammatory cytokines. This includes high levels of RANTES after stimulation with TNF-α and IFN-γ.
      • Giustizieri M.L.
      • Mascia F.
      • Frezzolini A.
      • De Pita O.
      • Chinni L.M.
      • Giannetti A.
      • et al.
      Keratinocytes from patients with atopic dermatitis and psoriasis show a distinct chemokine production profile in response to T cell-derived cytokines.
      They are also an important source of thymic stromal lymphopoietin, which activates DCs to prime naive T cells to produce IL-4 and IL-13.
      • Yoo J.
      • Omori M.
      • Gyarmati D.
      • Zhou B.
      • Aye T.
      • Brewer A.
      • et al.
      Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin.
      There is growing evidence to incriminate the epidermis as both target and enhancer of the inflammatory response in AD.
      • Klunker S.
      • Trautmann A.
      • Akdis M.
      • Verhagen J.
      • Schmid-Grendelmeier P.
      • Blaser K.
      • et al.
      A second step of chemotaxis after transendothelial migration: keratinocytes undergoing apoptosis release IFN-gamma-inducible protein 10, monokine induced by IFN-gamma, and IFN-gamma-inducible alpha-chemoattractant for T cell chemotaxis toward epidermis in atopic dermatitis.
      • Trautmann A.
      • Akdis M.
      • Kleeman D.
      • Altznauer F.
      • Simon H.-U.
      • Graeve T.
      • et al.
      T cell-mediated Fas-induced keratinocyte apoptosis plays a key pathogenetic role in eczematous dermatitis.
      Apoptosis of keratinocytes induced by T cells and mediated by Fas is a crucial event in the formation of eczema/spongiosis in AD.
      • Trautmann A.
      • Akdis M.
      • Kleeman D.
      • Altznauer F.
      • Simon H.-U.
      • Graeve T.
      • et al.
      T cell-mediated Fas-induced keratinocyte apoptosis plays a key pathogenetic role in eczematous dermatitis.
      IFN-γ released from T cells upregulates Fas and several cytokines, such as IL-1α, IL-1 receptor agonist, TNF-α, and GM-CSF, and chemokines on keratinocytes.
      • Klunker S.
      • Trautmann A.
      • Akdis M.
      • Verhagen J.
      • Schmid-Grendelmeier P.
      • Blaser K.
      • et al.
      A second step of chemotaxis after transendothelial migration: keratinocytes undergoing apoptosis release IFN-gamma-inducible protein 10, monokine induced by IFN-gamma, and IFN-gamma-inducible alpha-chemoattractant for T cell chemotaxis toward epidermis in atopic dermatitis.
      • Pastore S.
      • Corinti S.
      • La Placa M.
      • Didona B.
      • Girolomoni G.
      Interferon-gamma promotes exaggerated cytokine production in keratinocytes cultured from patients with atopic dermatitis.
      There is evidence that cleavage of E-cadherin and sustained desmosomal cadherin contacts between keratinocytes that are undergoing apoptosis result in spongioform morphology in the epidermis as a hallmark of eczematous lesions.
      • Trautmann A.
      • Altznauer F.
      • Akdis M.
      • Simon H.-U.
      • Disch R.
      • Bröcker E.-B.
      • et al.
      The differential fate of cadherins during T cell-induced keratinocyte apoptosis leads to spongiosis in eczematous dermatitis.
      Suppression of keratinocyte activation and apoptosis remains a potential target for the treatment of AD.
      • Klunker S.
      • Trautmann A.
      • Akdis M.
      • Verhagen J.
      • Schmid-Grendelmeier P.
      • Blaser K.
      • et al.
      A second step of chemotaxis after transendothelial migration: keratinocytes undergoing apoptosis release IFN-gamma-inducible protein 10, monokine induced by IFN-gamma, and IFN-gamma-inducible alpha-chemoattractant for T cell chemotaxis toward epidermis in atopic dermatitis.
      • Yoo J.
      • Omori M.
      • Gyarmati D.
      • Zhou B.
      • Aye T.
      • Brewer A.
      • et al.
      Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin.
      • Trautmann A.
      • Akdis M.
      • Schmid-Grendelmeier P.
      • Disch R.
      • Bröcker E.-B.
      • Blaser K.
      • et al.
      Targeting keratinocyte apoptosis in the treatment of atopic dermatitis and allergic contact dermatitis.

       Eosinophils

      Studies over the past 2 decades have shown that eosinophils play a major role in AD, characterized by activated eosinophils in the peripheral blood and in the lesional skin.
      • Kapp A.
      The role of eosinophils in the pathogenesis of atopic dermatitis—eosinophil granule proteins as markers of disease activity.
      • Simon D.
      • Braathen L.R.
      • Simon H.U.
      Eosinophils and atopic dermatitis.
      Interestingly, psychosocial stress represents an important trigger for the increase of eosinophil counts in the peripheral blood.
      • Schmid-Ott G.
      • Jaeger B.
      • Adamek C.
      • Koch H.
      • Lamprecht F.
      • Kapp A.
      • et al.
      Levels of circulating CD8+ T-lymphocytes, natural killer cells and eosinophils increase upon acute psychosocial stress in patients with atopic dermatitis.
      Inhibition of eosinophil apoptosis in AD, probably mediated by an autocrine release of IL-5 and GM-CSF, appears to be a relevant mechanism for the eosinophil accumulation observed in AD.
      • Wedi B.
      • Raap U.
      • Lewrick H.
      • Kapp A.
      Delayed eosinophil programmed cell death in vitro: a common feature of inhalant allergy and extrinsic and intrinsic atopic dermatitis.
      Several lines of investigation indicate that eosinophils are recruited to, and activated at, tissue sites by TH2 cytokines, such as IL-5 and IL-13.
      • Simon D.
      • Braathen L.R.
      • Simon H.U.
      Eosinophils and atopic dermatitis.
      In addition, chemokines (eotaxin and RANTES) also contribute to eosinophil chemotaxis and activation. Moreover, interaction of eosinophil surface molecules and the endothelial cells vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 are important for eosinophil extravasation and activation. Eosinophils might also play a role in switching the TH1 response in AD through production of significant amounts of IL-12 on activation.
      • Grewe M.
      • Czech W.
      • Morita A.
      • Werfel T.
      • Klammer M.
      • Kapp A.
      • et al.
      Human eosinophils produce biologically active IL-12: Implications for control of T cell responses.
      Once activated, the eosinophil is capable of releasing an armory of potent cytotoxic granule proteins and chemical mediators contributing to tissue inflammation, as shown by the deposition of eosinophil products in the inflamed skin.
      • Kapp A.
      The role of eosinophils in the pathogenesis of atopic dermatitis—eosinophil granule proteins as markers of disease activity.
      • Simon D.
      • Braathen L.R.
      • Simon H.U.
      Eosinophils and atopic dermatitis.
      Moreover, eosinophils might have a relevant role in neuroimmunologic interactions.
      • Raap U.
      • Goltz C.
      • Deneka N.
      • Bruder M.
      • Renz H.
      • Kapp A.
      • et al.
      Brain-derived neurotrophic factor is increased in atopic eczema and modulates eosinophil functions compared with that seen in nonatopic subjects.

       Pathophysiology of pruritus in AD

      Patients with AD have a reduced threshold for pruritus manifested as cutaneous hyperreactivity and scratching after exposure to allergens, changes in humidity, excessive sweating, and low concentrations of irritants.
      • Leung D.Y.
      • Bieber T.
      Atopic dermatitis.
      Although pruritus can occur throughout the day, it is usually worse at night, frequently disrupting the patient's sleep and overall quality of life.
      • Leo H.L.
      • Bender B.G.
      • Leung S.B.
      • Tran Z.V.
      • Leung D.Y.
      Effect of pimecrolimus cream 1% on skin condition and sleep disturbance in children with atopic dermatitis.
      The mechanisms of pruritus in AD are complex and poorly understood. Allergen-induced release of histamine from skin mast cells is not an exclusive cause of pruritus in AD because antihistamines are not effective in controlling the itch of AD unless there is associated urticaria.
      • Klein P.A.
      • Clark R.A.
      An evidence-based review of the efficacy of antihistamines in relieving pruritus in atopic dermatitis.
      The observation that TCIs and corticosteroids are effective therapeutic agents at reducing pruritus suggests that the inflammatory cells play an important role in driving pruritus.
      • Eichenfield L.F.
      • Lucky A.W.
      • Boguniewicz M.
      • Langley R.G.
      • Cherill R.
      • Marshall K.
      • et al.
      Safety and efficacy of pimecrolimus (ASM 981) cream 1% in the treatment of mild and moderate atopic dermatitis in children and adolescents.
      • Van Der Meer J.B.
      • Glazenburg E.J.
      • Mulder P.G.
      • Eggink H.F.
      • Coenraads P.J.
      The management of moderate to severe atopic dermatitis in adults with topical fluticasone propionate. The Netherlands Adult Atopic Dermatitis Study Group.
      Other substances that have been implicated in pruritus include cytokines, neuropeptides, proteases, eicosanoids, and eosinophil-derived proteins.
      • Dillon S.R.
      • Sprecher C.
      • Hammond A.
      • Bilsborough J.
      • Rosenfeld-Franklin M.
      • Presnell S.R.
      • et al.
      Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice.
      • Takaoka A.
      • Arai I.
      • Sugimoto M.
      • Yamaguchi A.
      • Tanaka M.
      • Nakaike S.
      Expression of IL-31 gene transcripts in NC/Nga mice with atopic dermatitis.
      • Bilsborough J.
      • Leung D.Y.
      • Maurer M.
      • Howell M.
      • Boguniewcz M.
      • Yao L.
      • et al.
      IL-31 is associated with cutaneous lymphocyte antigen-positive skin homing T cells in patients with atopic dermatitis.
      • Sonkoly E.
      • Muller A.
      • Lauerma A.I.
      • Pivarcsi A.
      • Soto H.
      • Kemeny L.
      • et al.
      IL-31: a new link between T cells and pruritus in atopic skin inflammation.

       Triggers of AD

       Stress

      Stress-induced immunomodulation is altered in patients with AD, but the exact mechanisms are not well understood.
      • Schmid-Ott G.
      • Jaeger B.
      • Adamek C.
      • Koch H.
      • Lamprecht F.
      • Kapp A.
      • et al.
      Levels of circulating CD8+ T-lymphocytes, natural killer cells and eosinophils increase upon acute psychosocial stress in patients with atopic dermatitis.
      This phenomenon might be mediated by neuroimmunologic factors, such as neuropeptides, which can be found in the blood and within the epidermal nerve fibers in close association with epidermal LCs. Increased levels of nerve growth factor and substance P can be found in the plasma of patients with AD and correlate positively with the disease activity.
      • Toyoda M.
      • Nakamura M.
      • Makino T.
      • Hino T.
      • Kagoura M.
      • Morohashi M.
      Nerve growth factor and substance P are useful plasma markers of disease activity in atopic dermatitis.
      Enhanced levels of brain-derived growth factor can be detected in the sera and plasma of patients with AD. Brain-derived growth factor has been shown to reduce eosinophil apoptosis while enhancing chemotaxis of eosinophils in vitro.
      • Raap U.
      • Goltz C.
      • Deneka N.
      • Bruder M.
      • Renz H.
      • Kapp A.
      • et al.
      Brain-derived neurotrophic factor is increased in atopic eczema and modulates eosinophil functions compared with that seen in nonatopic subjects.

       Allergens

      Placebo-controlled food challenge studies have demonstrated that food allergens can induce eczematoid skin rashes in a subset of infants and children with AD.
      • Sampson H.A.
      Update on food allergy.
      • Werfel T.
      • Breuer K.
      Role of food allergy in atopic dermatitis.
      In some patients urticarial reactions can trigger the itch-scratch cycle that flares this skin condition. Children with food allergy have positive immediate skin test responses or serum IgE directed to various foods, particularly egg, milk, wheat, soy, and peanut. Food allergen–specific T cells have been cloned from the skin lesions of patients with AD, providing direct evidence that foods can contribute to skin immune responses. In addition, it is well established that food can exacerbate AD both through allergic and nonallergic hypersensitivity reactions. Furthermore, direct contact with the skin (eg, in the preparation of meals or when feeding infants) might be an important factor for the aggravation of eczema.
      Beyond the age of 3 years, food allergy is frequently outgrown, but sensitization to inhalant allergens is common. Pruritus and skin lesions can develop after intranasal or bronchial inhalation challenge with aeroallergens in patients with AD. Epicutaneous application of aeroallergens (eg, house dust mites, weeds, animal danders, and molds) by means of the APT on uninvolved skin of patients with AD elicits eczematoid reactions in a subset of patients with AD.
      • Darsow U.
      • Laifaoui J.
      • Kerschenlohr K.
      • Wollenberg A.
      • Przybilla B.
      • Wuthrich B.
      • et al.
      The prevalence of positive reactions in the atopy patch test with aeroallergens and food allergens in subjects with atopic eczema: a European multicenter study.
      A combination of effective house dust mite reduction measures has been reported to improve AD. The isolation from AD skin lesions and allergen patch test sites of T cells that selectively respond to Dermatophagoides pteronyssinus (Der p 1) and other aeroallergens supports the concept that immune responses in AD skin can be elicited by inhalant allergens.

       Microorganisms

      Most patients with AD are colonized with S aureus and experience exacerbation of their skin disease after infection with this organism.
      • Leung D.Y.
      Infection in atopic dermatitis.
      In patients with AD with bacterial infection, treatment with antistaphylococcal antibiotics can result in reduction of skin disease. An important strategy by which S aureus exacerbates AD is by secreting toxins called superantigens, which stimulate activation of T cells and macrophages. Most patients with AD make specific IgE antibodies directed against staphylococcal superantigens, which correlate with skin disease severity.
      • Leung D.Y.M.
      • Harbeck H.
      • Bina P.
      • Reiser R.F.
      • Yang E.
      • Norris A.D.
      • et al.
      Presence of IgE antibodies to staphylococcal enterotoxins on the skin of patients with atopic dermatitis: evidence for a new group of allergens.
      Superantigens also induce corticosteroid resistance, thereby complicating their response to therapy.
      • Hauk P.J.
      • Leung D.Y.M.
      Tacrolimus (FK506): new treatment approach in superantigen-associated diseases like atopic dermatitis?.
      Binding of S aureus to skin is enhanced by AD skin inflammation. This is supported by clinical studies demonstrating that treatment with topical corticosteroids or tacrolimus reduces S aureus counts in AD. AD skin has also been found to be deficient in antimicrobial peptides needed for host defense against bacteria, fungi, and viruses.
      • Ong P.Y.
      • Ohtake T.
      • Brandt C.
      • Strickland I.
      • Boguniewicz M.
      • Ganz T.
      • et al.
      Endogenous antimicrobial peptides and skin infections in atopic dermatitis.
      • Nomura I.
      • Goleva E.
      • Howell M.D.
      • Hamid Q.A.
      • Ong P.Y.
      • Hall C.F.
      • et al.
      Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes.
      This constellation of genes is underexpressed because of the significant upregulation of TH2 cytokines in AD. Along with lower levels of proinflammatory cytokines, such as TNF-α and IFN-γ, the decrease in antimicrobial defenses within patients with AD might explain their increased susceptibility to skin infections compared with that seen in patients with psoriasis.
      • Nomura I.
      • Goleva E.
      • Howell M.D.
      • Hamid Q.A.
      • Ong P.Y.
      • Hall C.F.
      • et al.
      Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes.
      Patients with AD have an increased propensity toward disseminated infections with herpes simplex or vaccinia virus. Susceptibility to severe viral infections, such as eczema herpeticum or eczema vaccinatum, might be linked to the severity of atopy.
      • Howell M.D.
      • Wollenberg A.
      • Gallo R.L.
      • Flaig M.
      • Streib J.E.
      • Wong C.
      • et al.
      Cathelicidin deficiency predisposes to eczema herpeticum.
      As such, smallpox vaccination is contraindicated in patients with AD unless there is imminent danger of exposure to smallpox.
      • Plaut M.
      • Tinkle S.S.
      Risks of smallpox vaccination: 200 years after Jenner.
      There is increasing evidence that the opportunistic yeast Malassezia species represents a contributing factor in AD.
      • Scheynius A.
      • Johansson C.
      • Buentke E.
      • Zagari A.
      • Linder M.T.
      Atopic eczema/dermatitis syndrome and Malassezia.
      • Faergemann J.
      Pityrosporum species as a cause of allergy and infection.
      Several studies have demonstrated the presence of specific serum IgE, a positive skin prick test (SPT) response, and a positive APT response against Malassezia species in adults with AD.
      • Scheynius A.
      • Johansson C.
      • Buentke E.
      • Zagari A.
      • Linder M.T.
      Atopic eczema/dermatitis syndrome and Malassezia.
      IgE sensitization to Malassezia species is specific for patients with AD but is not seen in patients with asthma or allergic rhinitis.
      • Scalabrin D.M.
      • Bavbek S.
      • Perzanowski M.S.
      • Wilson B.B.
      • Platts-Mills T.A.
      • Wheatley L.M.
      • et al.
      Use of specific IgE in assessing the relevance of fungal and dust mite allergens to atopic dermatitis: a comparison with asthmatic and nonasthmatic control subjects.
      • Schmid-Grendelmeier P.
      • Scheynius A.
      • Crameri R.
      The role of sensitization to Malassezia sympodialis in atopic eczema.

       Autoantigens

      Autoreactivity of patients with AD to human proteins might contribute to the pathophysiology of this condition.
      • Mothes N.
      • Niggemann B.
      • Jenneck C.
      • Hagemann T.
      • Weidinger S.
      • Bieber T.
      • et al.
      The cradle of IgE hyperreactivity in atopic eczema lies in infancy.
      • Natter S.
      • Seiberler S.
      • Hufnagl P.
      • Binder B.R.
      • Hirschl A.M.
      • Ring J.
      • et al.
      Isolation of cDNA clones coding for IgE autoantigens with serum IgE from atopic dermatitis patients.
      IgE against autoantigens could stimulate type 1 hypersensitivity reactions and DCs and induce the proliferation of autoreactive T cells.
      • Valenta R.
      • Seiberler S.
      • Natter S.
      • Mahler V.
      • Mossabeb R.
      • Ring J.
      • et al.
      Autoallergy—a pathogenetic factor in atopic dermatitis.
      Recently, it has been shown that IgE against manganese superoxide dismutase (MnSOD) from the skin-colonizing yeast M sympodialis cross-reacts with human MnSOD.
      • Schmid-Grendelmeier P.
      • Fluckiger S.
      • Disch R.
      • Trautmann A.
      • Wuthrich B.
      • Blaser K.
      • et al.
      IgE-mediated and T cell-mediated autoimmunity against manganese superoxide dismutase in atopic dermatitis.
      Because patients reacting to human MnSOD were sensitized against the M sympodialis MnSOD, sensitization most likely occurs primarily by exposure to the environmental fungal MnSOD.

       Irritant factors

      Frequently, rough or woolly clothing leads to mechanical irritation and exacerbation of AD and eczema. Chemical irritants like skin-cleansing agents should also be considered but can only be satisfactorily identified by means of avoidance.

      Diagnosis

       Symptoms and signs and diagnostic criteria

      The use of well-defined diagnostic criteria is important in the diagnosis of AD, especially for those patients who lack the typical phenotype of the disease, and the diagnostic criteria developed by Hanifin and Rajka are widely accepted (Fig 3).
      • Hanifin J.M.
      • Rajka G.
      Diagnostic features of atopic eczema.
      Other criteria have been developed
      • Johnke H.
      • Vach W.
      • Norberg L.A.
      • Bindslev-Jensen C.
      • Host A.
      • Andersen K.E.
      A comparison between criteria for diagnosing atopic eczema in infants.
      that correlate well with those of Hanifin and Rajka, although use of only visible eczema as a criterion might lead to overdiagnosis of the disease. Skin biopsies are not essential for the diagnosis but might be required to exclude other diagnoses, particularly in adults.
      Figure thumbnail gr3
      Fig 3Diagnostic approach to patients presenting with symptoms and signs of atopic dermatitis.

       Differential diagnosis

      The most important differential diagnoses are other forms of eczema. Especially in adulthood, combination forms are prevalent with components of atopic, contact, and irritative eczema. Atopic eczema of the hands and feet must be differentiated from psoriasis in the palms and soles and from tinea. Scabies infection must always be considered. The differential diagnosis of acute AD with intense erythema of the skin, together with exudation or blistering, for example, differs from differential diagnoses of the chronic lichenified forms. Other, more rare diseases should be suspected, especially in recalcitrant cases: in children genodermatoses, such as Netherton syndrome, including the recently described immune dysregulation polyendocrinopathy enteropathy X-linked syndrome,
      • Chatila T.A.
      Role of regulatory T cells in human diseases.
      should be considered, and in both children and adults vitamin deficiencies and malignancies, especially cutaneous T cell lymphoma/mycosis fungoides, should be considered.

       Diagnostic work-up

      The investigation of exacerbating factors in AD involves a patient history, specific skin and blood tests, and challenge tests, depending on the degree of the disease severity and on the suspected factors involved (Fig 4).
      Figure thumbnail gr4
      Fig 4Relative significance of complicating or exacerbating factors in patients with AD from infancy to adulthood.

       Food

      There is no universally recommended diet for patients with AD. Dietary restrictions should only be recommended in cases of an established diagnosis of food hypersensitivity. International guidelines for the diagnosis of food hypersensitivity have been published.
      • Sampson H.A.
      Update on food allergy.
      • Bindslev-Jensen C.
      • Ballmer-Weber B.K.
      • Bengtsson U.
      • Blanco C.
      • Ebner C.
      • Hourihane J.
      • et al.
      Standardization of food challenges in patients with immediate reactions to foods—position paper from the European Academy of Allergology and Clinical Immunology.
      As regards food-induced eczema, it is important to note that the predictive value of a positive case history is lower than that for food-induced immediate reactions.
      • Breuer K.
      • Heratizadeh A.
      • Wulf A.
      • Baumann U.
      • Constien A.
      • Tetau D.
      • et al.
      Late eczematous reactions to food in children with atopic dermatitis.
      Both SPTs and measurement of specific IgE can be used to assess for sensitization to a food at any age. Diagnostic sensitivity and specificity varies considerably among different foods, reading systems, and age groups. A decision point discriminating between clinical relevance of sensitization (with challenge as the gold standard) has been developed with regard to specific IgE and SPTs to egg, milk, peanut, and others foods in children.
      • Sampson H.A.
      Utility of food-specific IgE concentrations in predicting symptomatic food allergy.
      • Osterballe M.
      • Bindslev-Jensen C.
      Threshold levels in food challenge and specific IgE in patients with egg allergy: is there a relationship?.
      • Celik-Bilgili S.
      • Mehl A.
      • Verstege A.
      • Staden U.
      • Nocon M.
      • Beyer K.
      • et al.
      The predictive value of specific immunoglobulin E levels in serum for the outcome of oral food challenges.
      Decision points can be helpful in making the decision to perform oral challenges. However, the need for challenges has to be decided on an individual basis.
      Other invalidated tests, such as lymphocyte cytotoxicity tests, the basophil degranulation test, or measurement of serum IgG (or subclasses), should not be used.
      APT is primarily a tool to investigate the mechanisms of eczema in the skin. However, APT can also reveal sensitization in patients with AD and might identify a subgroup of such patients. An elimination diet should not be recommended for a patient solely on the basis of a positive APT response to a food.
      • Turjanmaa K.
      The role of atopy patch tests in the diagnosis of allergy in atopic dermatitis.
      All the abovementioned tests require specialist knowledge in their performance and interpretation.
      Standardized, physician-supervised food challenges provide the most accurate diagnostic tool.
      • Bindslev-Jensen C.
      • Ballmer-Weber B.K.
      • Bengtsson U.
      • Blanco C.
      • Ebner C.
      • Hourihane J.
      • et al.
      Standardization of food challenges in patients with immediate reactions to foods—position paper from the European Academy of Allergology and Clinical Immunology.
      However, it should be noted that patients can present with reactions at least 24 hours after a food challenge, and the challenge settings and protocol should be appropriately designed; for example, in case of a negative challenge response, the skin of the patient should be examined the following day.
      • Breuer K.
      • Heratizadeh A.
      • Wulf A.
      • Baumann U.
      • Constien A.
      • Tetau D.
      • et al.
      Late eczematous reactions to food in children with atopic dermatitis.
      After a diagnosis has been established, a tailor-made education program for the patient should be initiated.

       Inhalant allergy

      Sensitization to inhalant allergens is often seen in patients with AD. Allergens can exacerbate AD either by means of inhalation, direct contact with the skin, or ingestion. Sensitization can be detected by means of SPTs (if the skin is free from eczema) or by measurement of specific IgE antibodies. In addition, APTs can be used to assess the response in the skin. Most important allergens include dust mite, animal dander, and pollen confirmed by clinical trials and avoidance measures. The role of dust mite allergen exposure is supported by patch tests, avoidance studies, and the very high titers of IgE antibodies to mite proteins in a large proportion of adults, as well as children older than 7 years with AD.
      • Scalabrin D.M.
      • Bavbek S.
      • Perzanowski M.S.
      • Wilson B.B.
      • Platts-Mills T.A.
      • Wheatley L.M.
      • et al.
      Use of specific IgE in assessing the relevance of fungal and dust mite allergens to atopic dermatitis: a comparison with asthmatic and nonasthmatic control subjects.
      • Mitchell E.B.
      • Crow J.
      • Chapman M.D.
      • Jouhal S.S.
      • Pope F.M.
      • Platts-Mills T.A.
      Basophils in allergen-induced patch test sites in atopic dermatitis.
      • Tan B.B.
      • Weald D.
      • Strickland I.
      • Friedmann P.S.
      Double-blind controlled trial of effect of housedust-mite allergen avoidance on atopic dermatitis.
      • Platts-Mills T.A.
      • Mitchell E.B.
      • Rowntree S.
      • Chapman M.D.
      • Wilkins S.R.
      The role of dust mite allergens in atopic dermatitis.
      The positive effect of house dust mite avoidance with special encasings has been shown in various studies.
      • Tan B.B.
      • Weald D.
      • Strickland I.
      • Friedmann P.S.
      Double-blind controlled trial of effect of housedust-mite allergen avoidance on atopic dermatitis.

       Contact allergy

      In patients with AD, contact sensitization to topical medications frequently occurs, especially in adults. In cases of worsening eczema despite treatment, the possibility of contact dermatitis needs to be ruled out by means of patch testing. Patients with AD are no more likely to be sensitized than normal.

      Systemic and topical treatment

      The management of AD presents a clinical challenge.

       Basic treatment

      Basic therapy of AD should comprise optimal skin care, addressing the skin barrier defect with regular use of emollients and skin hydration, along with identification and avoidance of specific and nonspecific trigger factors. Nonspecific irritants include contactants, such as clothing made from occluding or irritating synthetic or wool material.
      • Morren M.A.
      • Przybilla B.
      • Bamelis M.
      • Heykants B.
      • Reynaers A.
      • Degreef H.
      Atopic dermatitis: triggering factors.
      Further irritating factors are soaps and hot water temperature during showering or bathing. Contacts with water should be minimized, moderately heated water should be used, and mild syndets with an adjusted pH value (acidified to pH 5.5-6.0 in order to protect the acid mantle of the skin) should be used for cleansing.
      • Subramanyan K.
      Role of mild cleansing in the management of patient skin.
      Other specific provocation factors and airborne and food allergens have to be considered (see the section on diagnosis for how to identify allergens).
      • Turjanmaa K.
      The role of atopy patch tests in the diagnosis of allergy in atopic dermatitis.
      • Sampson H.A.
      Food allergy-accurately identifying clinical reactivity.
      Further treatment, on the basis of disease severity, includes the addition of multiple therapeutic agents in a step-wise fashion (Fig 5). A combination of different topical agents might be indicated. In cases of severe AD that cannot be controlled with topical treatment, systemic treatment options might need to be considered. For optimal disease management, regular medical supervision, together with education of the patient or care providers and appropriate psychosocial support, is needed. In selected patients hospitalization might be of great benefit, especially in centers with a multidisciplinary team approach.
      Figure thumbnail gr5
      Fig 5Stepwise management of patients with AD.

       Topical treatment

       Emollients

      A key feature of AD is severe dryness of the skin caused by a dysfunction of the skin barrier with increased transepidermal water loss.
      • Seidenari S.
      • Giusti G.
      Objective assessment of the skin of children affected by atopic dermatitis: a study of pH, capacitance and TEWL in eczematous and clinically uninvolved skin.
      This is typically accompanied by intense pruritus and inflammation. The regular use of emollients is important for addressing this problem, and together with skin hydration, it represents the mainstay of the general management of AD.
      • Loden M.
      Role of topical emollients and moisturizers in the treatment of dry skin barrier disorders.
      • McHenry P.M.
      • Williams H.C.
      • Bingham E.A.
      Management of atopic eczema: Joint Workshop of the British Association of Dermatologists and the Research Unit of the Royal College of Physicians of London.
      Emollients should be applied continuously, even if no actual inflammatory skin lesions are obvious.
      • Ellis C.
      • Luger T.
      on behalf of the ICCAD II Faculty
      International consensus conference on atopic dermatitis II (ICCAD II): clinical update and current treatment strategies.
      Because different emollients are available, selection criteria, such as the individual skin status, seasonal and climatic conditions, and the time of day, should be considered for optimizing the patients' basic treatment. “Water-in-oil” or “oil-in-water” emulsions might be substituted to support the skin barrier function. Emollients containing polidocanol are effective in reducing pruritic symptoms. Adjuvant application of topical preparations with urea allows for intensive hydration of the skin, whereas salicyl acid can be added to an emollient for the treatment of chronic hyperkeratotic lesions.
      • Rudolph R.
      • Kownatzki E.
      Corneometric, sebumetric and TEWL measurements following the cleaning of atopic skin with a urea emulsion versus a detergent cleanser.

       Topical glucocorticosteroids

      Topical glucocorticosteroids are still an important tool for the treatment of acute flare-ups.
      • Darsow U.
      • Lubbe J.
      • Taieb A.
      • Seidenari S.
      • Wollenberg A.
      • Calza A.M.
      • et al.
      Position paper on diagnosis and treatment of atopic dermatitis.
      • Hanifin J.M.
      • Cooper K.D.
      • Ho V.C.
      • Kang S.
      • Krafchik B.R.
      • Margolis D.J.
      • et al.
      Guidelines of care for atopic dermatitis, developed in accordance with the American Academy of Dermatology (AAD)/American Academy of Dermatology Association “Administrative Regulations for Evidence-Based Clinical Practice Guidelines.”.
      Over recent years, the risk of adverse effects induced by topical steroids could effectively be reduced by optimizing application protocols and using new steroid preparations with improved risk/benefit ratios and lower atrophogenic potential, such as prednicarbate, mometasone furoate, fluticasone, and methylprednisolone aceponate.
      • Van Der Meer J.B.
      • Glazenburg E.J.
      • Mulder P.G.
      • Eggink H.F.
      • Coenraads P.J.
      The management of moderate to severe atopic dermatitis in adults with topical fluticasone propionate. The Netherlands Adult Atopic Dermatitis Study Group.
      • Korting H.C.
      • Kerscher M.J.
      • Schafer-Korting M.
      Topical glucocorticoids with improved benefit/risk ratio: do they exist?.
      • Kerscher M.J.
      • Hart H.
      • Korting H.C.
      • Stalleicken D.
      In vivo assessment of the atrophogenic potency of mometasone furoate, a newly developed chlorinated potent topical glucocorticoid as compared to other topical glucocorticoids old and new.
      For the topical use of glucocorticosteroids, different therapeutic schemes have been established: intermittent use might be as effective as an initial therapy with a high potent steroid followed by a time-dependent dose reduction or change over to a lower potent preparation.
      • Thomas K.S.
      • Armstrong S.
      • Avery A.
      • Po A.L.
      • O'Neill C.
      • Young S.
      • et al.
      Randomised controlled trial of short bursts of a potent topical corticosteroid versus prolonged use of a mild preparation for children with mild or moderate atopic eczema.
      The choice of an adequate vehicle is important to achieve the optimal therapeutic effect. Recent data indicate that in children and adults an application of corticosteroids (fluticasone) on unaffected skin twice weekly prevents further flare-ups of AD.
      • Berth-Jones J.
      • Damstra R.J.
      • Golsch S.
      • Livden J.K.
      • Van Hooteghem O.
      • Allegra F.
      • et al.
      Twice weekly fluticasone propionate added to emollient maintenance treatment to reduce risk of relapse in atopic dermatitis: randomised, double blind, parallel group study.
      Aside from an anti-inflammatory effect, treatment with topical steroids contributes to a reduction of skin colonization with S aureus and therefore might affect a further trigger factor of AD.
      • Stalder J.F.
      • Fleury M.
      • Sourisse M.
      • Rostin M.
      • Pheline F.
      • Litoux P.
      Local steroid therapy and bacterial skin flora in atopic dermatitis.
      • Nilsson E.J.
      • Henning C.G.
      • Magnusson J.
      Topical corticosteroids and Staphylococcus aureus in atopic dermatitis.
      The side effects of uncontrolled topical steroid use, particularly on delicate skin areas, are well documented, and therefore topical steroid preparations should be applied no more than twice daily as short-term therapy for acute eczematous lesions. Only mild to moderately potent preparations should be used on genital, facial, or intertriginous skin areas. In children only mild to moderately potent steroid preparations should be used.
      • Ainley-Walker P.F.
      • Patel L.
      • David T.J.
      Side to side comparison of topical treatment in atopic dermatitis.
      In general, during acute flares, steroids should be used in combination with baseline emollient skin care to avoid steroid overuse and steroid-related side effects.

       TCIs

      The TCIs pimecrolimus and tacrolimus allow a steroid-free, anti-inflammatory topical therapy of AD. In both animal and human studies, both molecules demonstrated an immunomodulatory activity.
      • Hultsch T.
      • Kapp A.
      • Spergel J.
      Immunomodulation and safety of topical calcineurin inhibitors for the treatment of atopic dermatitis.
      In the United States and Europe pimecrolimus cream (1%) and tacrolimus ointment (0.03%) are approved for the treatment of AD in children aged 2 years and older
      • Wahn U.
      • Bos J.D.
      • Goodfield M.
      • Caputo R.
      • Papp K.
      • Manjra A.
      • et al.
      Efficacy and safety of pimecrolimus cream in the long-term management of atopic dermatitis in children.
      and in adults.
      • Harper J.
      • Green A.
      • Scott G.
      • Gruendl E.
      • Dorobek B.
      • Cardno B.
      • et al.
      First experience of topical SDZ ASM 981 in children with atopic dermatitis.
      Tacrolimus ointment (0.1%) is only approved for use in adults.
      The anti-inflammatory potency of 0.1% tacrolimus ointment is similar to a corticosteroid with moderate potency,
      • Ashcroft D.M.
      • Dimmock P.
      • Garside R.
      • Stein K.
      • Williams H.C.
      Efficacy and tolerability of topical pimecrolimus and tacrolimus in the treatment of atopic dermatitis: meta-analysis of randomised controlled trials.
      whereas 1% pimecrolimus cream is less active.
      • Luger T.
      • Van Leent E.J.
      • Graeber M.
      • Hedgecock S.
      • Thurston M.
      • Kandra A.
      • et al.
      SDZ ASM 981: an emerging safe and effective treatment for atopic dermatitis.
      Thus far, no trials have been published comparing pimecrolimus 1% with a mild corticosteroid. Both agents proved to be effective, with a good safety profile for a treatment period of up to 2 years with pimecrolimus
      • Paul C.
      • Cork M.
      • Rossi A.B.
      • Papp K.A.
      • Barbier N.
      • de Prost Y.
      Safety and tolerability of 1% pimecrolimus cream among infants: experience with 1133 patients treated for up to 2 years.
      and up to 4 years with tacrolimus.
      • Breuer K.
      • Werfel T.
      • Kapp A.
      Safety and efficacy of topical calcineurin inhibitors in the treatment of childhood atopic dermatitis.
      A frequently observed side effect with TCIs is a transient burning sensation of the skin. In a comparative study of the local side effects of 0.03% tacrolimus ointment versus 1% pimecrolimus cream in children, pimecrolimus achieved better local tolerability than tacrolimus.
      • Kempers S.
      • Boguniewicz M.
      • Carter E.
      • Jarratt M.
      • Pariser D.
      • Stewart D.
      • et al.
      A randomized inverstigator-blinded study comparing pimecrolimus cream 1% with tacrolimus 0.03% in the treatment of pediatric patients with moderate atopic dermatitis.
      Preliminary studies indicate that treatment with TCIs is not associated with a risk of skin atrophy.
      • Queille-Roussel C.
      • Paul C.
      • Duteil L.
      • Lefebvre M.C.
      • Rapatz G.
      • Zagula M.
      • et al.
      The new topical ascomycin derivate SDZ ASM 981 does not induce skin atrophy when applied to normal skin for 4 weeks: a randomized, double-blind controlled study.
      Therefore they are a useful alternative for the treatment of sensitive skin areas, such as the face and intertriginous regions.
      Generalized viral infections, such as eczema herpeticum or eczema molluscatum, have been observed during TCI treatment.
      • Wollenberg A.
      • Zoch C.
      • Wetzel S.
      • Plewig G.
      • Przybilla B.
      Predisposing factors and clinical features of eczema herpeticum: a retrospective analysis of 100 cases.
      It is unclear whether a trend for increased frequency of viral superinfections with use of TCIs really exists.
      • Paul C.
      • Cork M.
      • Rossi A.B.
      • Papp K.A.
      • Barbier N.
      • de Prost Y.
      Safety and tolerability of 1% pimecrolimus cream among infants: experience with 1133 patients treated for up to 2 years.
      Although there is no evidence of a causal link of cancer and the use of TCIs, the United States Food and Drug Administration has issued a black-box warning for pimecrolimus (Elidel; Novartis, Basel, Switzerland) and tacrolimus (Protopic; Astellas, Deerfield, Ill) because of a lack of long-term safety data.
      Elidel.
      Protopic.
      Furthermore, the new labeling states that these drugs are recommended as second-line treatments and that their use in children younger than 2 years of age is currently not recommended. Long-term safety studies with TCIs in patients with AD, including infants and children, are ongoing.
      • Paul C.
      • Cork M.
      • Rossi A.B.
      • Papp K.A.
      • Barbier N.
      • de Prost Y.
      Safety and tolerability of 1% pimecrolimus cream among infants: experience with 1133 patients treated for up to 2 years.

       Wet-wrap therapy

      A wet layer of cotton dressing, which is then covered with tubular bandages applied over emollients
      • Mallon E.
      • Powell S.
      • Bridgman A.
      “Wet-wrap” dressings for the treatment of atopic eczema in the community.
      in combination with antiseptics or topical steroids,
      • Oranje A.P.
      • Wolkerstorfer A.
      • de Waard-van der Spek F.B.
      Treatment of erythrodermic atopic dermatitis with “wet-wrap” fluticasone propionate 0.05% cream/emollient 1:1 dressings.
      has been shown to be beneficial in cases of exacerbated AD skin lesions.
      • Foelster-Holst R.
      • Nagel F.
      • Zoellner P.
      • Spaeth D.
      Efficacy of crisis intervention treatment with topical corticosteroid prednicarbat with and without partial wet-wrap dressing in atopic dermatitis.
      A more practical alternative approach using clothing rather than bandages has also been described in detail.
      • Boguniewicz M.
      • Nicol N.
      Conventional therapy.

       Topical antimicrobial therapy

      The skin of patients with AD is heavily colonized with S aureus, even at uninvolved sites. Toxins secreted by the majority of S aureus on the skin behave as superantigens and, as discussed in the pathophysiology section, can directly influence the disease activity, although clinical signs of bacterial superinfection might be absent.
      • Breuer K.
      • Kapp A.
      • Werfel T.
      Bacterial infections and atopic dermatitis.
      • Breuer K.
      • HAussler S.
      • Kapp A.
      • Werfel T.
      Staphylococcus aureus: colonizing features and influence of an antibacterial treatment in adults with atopic dermatitis.
      Topical antiseptics, such as triclosan (2,4,4'-trichloro-2'-hydroxydiphenyl ether) or chlorhexidine, offer the advantage of a low sensitizing potential and low resistance rate. They can be used in emollients or as part of an additional wet-wrap dressing therapy.
      • Breuer K.
      • HAussler S.
      • Kapp A.
      • Werfel T.
      Staphylococcus aureus: colonizing features and influence of an antibacterial treatment in adults with atopic dermatitis.
      The topical use of triclosan has been shown to be effective in significantly reducing skin colonization with S aureus and skin symptoms.
      • Sporik R.
      • Kemp A.S.
      Topical triclosan treatment of atopic dermatitis.
      An irritative, photoallergenic, phototoxic, mutagenic, or carcinogenic potential of triclosan has not been observed.
      • Bhargava H.N.
      • Leonard P.A.
      Triclosan: application and safety.
      The use of silver-coated textiles and silk fabric with a durable antimicrobial finish can reduce S aureus colonization and eczema severity.
      • Gauger A.
      • Mempel M.
      • Schekatz A.
      • Schafer T.
      • Ring J.
      • Abeck D.
      Silver-coated textiles reduce Staphylococcus aureus colonization in patients with atopic eczema.
      • Ricci G.
      • Patrizi A.
      • Bendandi B.
      • Menna G.
      • Varotti E.
      • Masi M.
      Clinical effectiveness of a silk fabric in the treatment of atopic dermatitis.
      These new options are still under investigation.
      The addition of a topical antimicrobial agent to a topical steroid preparation has been shown to result in greater clinical improvement than a topical steroid alone.
      • Leyden J.J.
      • Kligman A.M.
      The case for steroid-antibiotic combination.
      Interestingly, AD seems not to be associated with a higher risk of sensitization against topical antimicrobials.
      • Jappe U.
      • Schnuch A.
      • Uter W.
      Frequency of sensitization to antimicrobials in patients with atopic eczema compared with nonatopic individuals: analysis of multicentre surveillance data, 1995-1999.
      Because of deficient skin barrier function, patients with AD are exposed to a higher risk of recurrent bacterial superinfections of the skin. For the treatment of mild and localized forms of this secondary infection, a topical antibiotic treatment might be beneficial.
      Although erythromycin and fusidic acid have been widely used in Europe, high resistance rates of S aureus to erythromycin have resulted in a preferential use of fusidic acid.
      • Abeck D.
      • Mempel M.
      Staphylococcus aureus colonisation in atopic dermatitis and its therapeutic implications.
      Topical fusidic acid has proved to be very effective against S aureus because of its low minimal inhibitory concentration and good tissue penetration.
      • Verbist I.
      The antimicrobial activity of fucidic acid.
      However, long-term therapy with fusidic acid is suspected to be responsible for increasing resistance.
      • Ravenscroft J.C.
      • Layton A.
      • Barnham M.
      Observations on high levels of fusidic acid resistant Staphylococcus aureus in Harrogate, North Yorkshire, UK.
      Therefore a restricted topical application for only short periods of about 2 weeks is advisable.
      • Peeters K.A.B.M.
      • Mascini E.M.
      • Sanders C.J.G.
      Resistance of Staphylococcus aureus to fusidic acid.
      For intranasal eradication of methicillin-resistant S aureus, topical mupirocin has been shown to be effective.
      • Ravenscroft J.C.
      • Layton A.M.
      • Eady E.A.
      • Murtagh M.S.
      • Coates P.
      • Walker M.
      • et al.
      Short-term effects of topical fusidic acid or mupirocin on the prevalence of fusidic acid resistant (FusR) Staphylococcus aureus in atopic eczema.
      Other secondary infections caused by yeasts, dermatophytes, or streptococci have also been implicated as trigger factors in AD.
      • Lubbe J.
      Secondary infections in patients with atopic dermatitis.
      In general, signs of secondary infections should only be treated if present.

      Systemic treatment

       Antimicrobial treatment

      Systemic antibiotic treatment is indicated for widespread bacterial secondary infection, (primarily S aureus). First- or second-generation cephalosporins or semisynthetic penicillins for 7 to 10 days are usually effective. Erythromycin-resistant organisms are fairly common, making macrolides less useful alternatives.
      • Hoeger P.H.
      Antimicrobial susceptibility of skin-colonizing S. aureus strains in children with atopic dermatitis.
      In cases of penicillin or cephalosporin allergy, clindamycin or oral fusidic acid are possible alternatives. Unfortunately, recolonization after a course of antistaphylococcal therapy occurs rapidly.
      • Boguniewicz M.
      • Sampson H.
      • Harbeck R.
      • Leung D.Y.M.
      Effects of cefuroxime axetil on S. aureus colonization and superantigen production in atopic dermatitis.
      Maintenance antibiotic therapy, however, should be avoided because it might result in colonization by methicillin-resistant organisms.
      Infection of the skin with the herpes simplex virus in the form of an eczema herpeticum (Kaposi's varicelliform eruption) represents a severe and possibly life-threatening complication of AD, requiring a systemic antiviral treatment with acyclovir or other antiviral agents (eg, valacyclovir).
      • Wollenberg A.
      • Zoch C.
      • Wetzel S.
      • Plewig G.
      • Przybilla B.
      Predisposing factors and clinical features of eczema herpeticum: a retrospective analysis of 100 cases.
      Recent findings underline the pathogenetic importance of a fungal colonization as a trigger factor.
      • Scheynius A.
      • Johansson C.
      • Buentke E.
      • Zagari A.
      • Linder M.T.
      Atopic eczema/dermatitis syndrome and Malassezia.
      • Mothes N.
      • Niggemann B.
      • Jenneck C.
      • Hagemann T.
      • Weidinger S.
      • Bieber T.
      • et al.
      The cradle of IgE hyperreactivity in atopic eczema lies in infancy.
      • Schmid-Grendelmeier P.
      • Fluckiger S.
      • Disch R.
      • Trautmann A.
      • Wuthrich B.
      • Blaser K.
      • et al.
      IgE-mediated and T cell-mediated autoimmunity against manganese superoxide dismutase in atopic dermatitis.
      Contradictory data have been published about the efficacy of a systemic treatment of AD with ketoconazole,
      • Lintu P.
      • Savolainen J.
      • Kortekangas-Savolainen O.
      • Kalimo K.
      Systemic ketoconazole is an effective treatment of atopic dermatitis with IgE-mediated hypersensitivity to yeasts.
      • Baeck O.
      • Bartosik J.
      Systemic ketoconazole for yeast allergic patients with atopic dermatitis.
      and although it is assumed that selected patients with AD might benefit from a topical or systemic antimycotic therapy,
      • Nikkels A.F.
      • Piérard G.E.
      Framing the future of antifungals in atopic dermatitis.
      the effect of a therapeutic intervention needs to be better defined by further studies.

       Systemic corticosteroids

      Although oral corticosteroids are commonly used for many different skin diseases, few randomized clinical trials have been performed in patients with AD thus far.
      • Aylett S.E.
      • Atherton D.J.
      • Preece M.A.
      The treatment of difficult atopic dermatitis in childhood with oral beclomethasone dipropionate.
      It is well known that relapse after the discontinuation of oral steroids is often observed. Corticosteroids in the form of a long-term oral therapy are associated with a series of well-documented side effects (eg, disturbance of growth, osteoporosis, cataracts, and development of lymphopenia). In cases of acute flare-up, patients might benefit from a short course of systemic therapy with corticosteroids, but long-term use and use in children should be avoided.

       Cyclosporin A

      As with TCIs, cyclosporin A (CyA) inhibits calcineurin-dependent pathways, resulting in reduced levels of proinflammatory cytokines, such as IL-2 and IFN-γ. Multiple clinical trials have shown CyA to be an effective treatment for adult and childhood AD, and although relapse after discontinuation of therapy is often observed, posttreatment disease severity often does not return to baseline levels.
      • Sowden J.M.
      • Berth-Jones J.
      • Ross J.S.
      • Motley R.J.
      • Marks R.
      • Finlay A.Y.
      • et al.
      Double-blind, controlled, crossover study of cyclosporin in adults with severe refractory atopic dermatitis.
      • Berth-Jones J.
      • Finlay A.Y.
      • Zaki I.
      • Tan B.
      • Goodyear H.
      • Lewis-Jones S.
      • et al.
      Cyclosporine in severe childhood atopic dermatitis: a multicenter study.
      • Zaki I.
      • Emerson R.
      • Allen B.R.
      Treatment of severe atopic dermatitis in childhood with cyclosporin.
      Despite the effectiveness of oral CyA in the treatment of AD, because of the possible side effects, particularly renal toxicity, the use of CyA should be limited to patients with severe refractory disease, contraindications must be excluded, and blood pressure and laboratory parameters must be monitored closely. The treatment can be performed in the form of a short- or long-term therapy with high-dose (3-5 mg/kg/d) or low-dose (2.5 mg/kg/d) administration, depending on the patients' individual medical conditions.
      • Berth-Jones J.
      • Graham-Brown R.A.
      • Marks R.
      • Camp R.D.
      • English J.S.
      • Freeman K.
      • et al.
      Long-term efficacy and safety of cyclosporin in severe adult atopic dermatitis.
      • Akhavan A.
      • Rudikoff D.
      The treatment of atopic dermatitis with systemic immunosuppressive agents.
      The principle of treatment should be to aim for the lowest effective dose and the shortest treatment period because toxicity is related to both of these factors. In children it should be considered that vaccinations might not be effective during immunosuppression.

       Azathioprine

      Azathioprine is a long-known systemic immunosuppressive agent affecting purine nucleotide synthesis and metabolism, which has been shown to be efficient for many dermatologic conditions.
      • Anstey A.V.
      • Wakelin S.
      • Reynolds N.J.
      • British Association of Dermatologists Therapy
      • Guidelines and Audit Subcommittee
      Guidelines for prescribing azathioprine in dermatology.
      It is also used quite frequently as monotherapy in nonlicensed indications, including AD.
      • Tan B.B.
      • Lear J.T.
      • Gwakrdger D.J.
      • English J.S.C.
      Azathioprine in dermatology: a survey of current practice in the UK.
      Although most reports on the use of azathioprine in AD have been uncontrolled, open, and retrospective studies, there is accumulating evidence for its efficacy in severe recalcitrant AD.
      • Meggitt S.J.
      • Reynolds N.J.
      Azathioprine for atopic dermatitis.
      • Berth-Jones J.
      • Takwale A.
      • Tan E.
      • Barclay G.
      • Agarwal S.
      • Ahmed I.
      • et al.
      Azathioprine in severe adult atopic dermatitis: a double-blind, placebo-controlled, crossover trial.
      • Lear J.T.
      • English J.S.C.
      • Jones P.
      • Smith A.G.
      Retrospective review of the use of azathioprine in severe atopic dermatitis.
      Azathioprine has a number of side effects, including myelosuppression, hepatotoxicity, gastrointestinal disturbances, increased susceptibility for infections, and possible development of skin cancer. Because azathioprine is metabolized by the thiopurine methyltransferase, a deficiency of this enzyme should be excluded before starting oral immunosuppression with azathioprine.
      • Lear J.T.
      • English J.S.C.
      • Jones P.
      • Smith A.G.
      Retrospective review of the use of azathioprine in severe atopic dermatitis.
      The recommended dosage of azathioprine for dermatologic indications is 1 to 3 mg/kg daily but should be determined based on thiopurine methyltransferase levels.
      • Snow J.L.
      • Gibson L.E.
      The role of genetic variation in thiopurine methyltransferase activity and the efficacy and/or side effects of azathioprine therapy in dermatologic patients.
      Regular blood tests must be performed throughout treatment with azathioprine.
      • Berth-Jones J.
      • Takwale A.
      • Tan E.
      • Barclay G.
      • Agarwal S.
      • Ahmed I.
      • et al.
      Azathioprine in severe adult atopic dermatitis: a double-blind, placebo-controlled, crossover trial.
      The onset of action is usually slow, and benefit might not be apparent until 2 to 3 months after starting treatment.
      • Wojnarowska F.
      • Kirtschig G.
      • Highet A.S.
      • Venning V.A.
      • Khumalo N.P.
      British Association of Dermatologists. Guidelines for the management of bullous pemphigoid.

       Antihistamines

      The therapeutic value of antihistamines seems to reside principally in their sedative properties, and they are useful as a short-term adjuvant to topical treatment during relapses associated with severe pruritus. Nonsedating antihistamines seem to have only very modest value in atopic eczema.
      • Wahlgren C.-F.
      • Hagermark O.
      • Bergstrom R.
      The antipruritic effect of a sedative and a non-sedative antihistamine in atopic dermatitis.
      • Diepgen T.L.
      • Early Treatment of the Atopic Child Study Group
      Long-term treatment with cetirizine of infants with atopic dermatitis: a multi-country, double-blind, randomized, placebo-controlled trial (the ETAC trial) over 18 months.
      Although there are no large controlled studies to date, newer nonsedating antihistamines seem to have little or no value in atopic eczema.
      • Wahlgren C.-F.
      • Hagermark O.
      • Bergstrom R.
      The antipruritic effect of a sedative and a non-sedative antihistamine in atopic dermatitis.

       Phototherapy

      The treatment of AD with phototherapy is well established and represents a standard second-line treatment for adults.
      • Scheinfeld N.S.
      • Tutrone W.D.
      • Weinberg J.M.
      • DeLeo V.A.
      Phototherapy of atopic dermatitis.
      In phases of acute flares, a combination with corticosteroids is often practiced.
      The following therapy options can be used for AD: broad-band UVB (280-320 nm), narrow-band UVB (311-313 nm), UVA (320-400 nm), UVA1 (340-400 nm), PUVA, and Balneo-PUVA. In addition, combinations of UVB and topical glucocorticosteroids and UVB with UVA, as well as UVA1 medium- and high-dose therapy, showed favorable results.
      • Abeck D.
      • Schmidt T.
      • Fesq H.
      • Strom K.
      • Mempel M.
      • Brockow K.
      • et al.
      Long-term efficacy of medium-dose UVA1 phototherapy in atopic dermatitis.
      • Krutmann J.
      • Diepgen T.L.
      • Luger T.A.
      • Grabbe S.
      • Meffert H.
      • Sonnichsen N.
      • et al.
      High-dose UVA1 therapy for atopic dermatitis: results of a multicenter trial.
      • Reynolds N.J.
      • Franklin V.
      • Gray J.C.
      • Diffey B.L.
      • Farr P.M.
      Narrow-band ultraviolet B and broad-band ultraviolet A phototherapy in adult atopic eczema: a randomised controlled trial.
      In children UV therapy should be restricted to adolescents older than 12 years, except in exceptional cases. It must be emphasized that to date, information about the long-term side effects of UV therapy is still not available.

       Immunotherapy

      To date, hyposensitization is not an established instrument for the treatment of AD. Although a number of case reports suggest clinical benefit from allergen-specific desensitization in AD, double-blinded controlled trials have failed to show consistent efficacy of immunotherapy in the treatment of AD.
      • Mastrandrea F.
      The potential role of allergen-specific sublingual immunotherapy in atopic dermatitis.
      A recent randomized multicenter trial investigated the efficacy of an allergen-specific immunotherapy of house dust mite preparations in patients with AD sensitized to house dust mite allergens for 1 year and revealed a dose-dependent effect on disease symptoms.
      • Werfel T.
      • Breuer K.
      • Rueff F.
      • Przybilla B.
      • Worm M.
      • Grewe M.
      • et al.
      Usefulness of specific immunotherapy in patients with atopic dermatitis and allergic sensitization to house dust mites: a multi-centre, randomized, dose-response study.
      However, further well-controlled studies are needed to determine the future role of immunotherapy for AD.

       Additional treatment options and future perspectives

      The development of new, targeted therapeutic approaches is based on an increasing knowledge of the cellular and molecular aspects in atopic diseases. Most of the new approaches aim at inhibiting components of the allergic inflammatory response, including cytokine modulation (eg, TNF inhibitors),
      • Jacobi A.
      • Antoni C.
      • Manger B.
      • Schuler G.
      • Hertl M.
      Infliximab in the treatment of moderate to severe atopic dermatitis.
      • Buka R.L.
      • Resh B.
      • Roberts B.
      • Cunningham B.B.
      • Friedlander S.
      Etanercept is minimally effective in 2 children with atopic dermatitis.
      blockade of inflammatory cell recruitment (chemokine receptor antagonists and cutaneous lymphocyte antigen inhibitors),
      • Dimitroff C.J.
      • Kupper T.S.
      • Sackstein R.
      Prevention of leukocyte migration to inflamed skin with a novel fluorosugar modifier of cutaneous lymphocyte-associated antigen.
      and inhibition of T-cell activation (alefacept and efalizumab).
      • Leung D.Y.
      Infection in atopic dermatitis.

      Education

      The goal of the patients' education should be living with atopic dermatitis by means of an empowered patient or, in the case of infants and young children, a caregiver who can work as a partner with the doctor in self-managing their own or their children's disease.
      Education to enhance disease knowledge, psychologic improvement in disease perception, and scratch control behavior modification, together with regular daily treatment, will lead to better skin care. This improvement in disease control will restore family dynamics, and the patient and family will cope better and have an overall improvement in quality of life. Additionally, education should be aimed at reducing doctor shopping, facilitating a better partnership between the doctor and the patient-parent, and decreasing the long-term costs of chronic disease treatment.
      Many preliminary studies have been single nurse-led interventions that were usually not controlled to assess outcomes.
      • Chinn D.J.
      • Poyner T.
      • Sibley G.
      Randomized controlled trial of a single dermatology nurse consultation in primary care on the quality of life of children with atopic eczema.
      From the recent controlled studies, there is the general impression that positive outcomes are dependant on the time spent with parents and the qualification of the trainer.
      • McSkimming J.
      • Gleeson L.
      • Sinclair M.
      A pilot study of a support group for parents of children with eczema.
      • Koblenzer C.S.
      • Koblenzer P.J.
      Chronic intractable atopic eczema.
      • Broberg A.
      • Kalimo K.
      • Lindblad B.
      • Swanbeck G.
      Parental education in the treatment of childhood atopic eczema.
      Sharing personal experiences in managing AD was helpful in 80% of those parents attending the program conducted by Staab et al.
      • Staab D.
      • Ruden U.
      • Kehrt R.
      • Wahn U.
      The impact of childhood atopic dermatitis on quality of life of family.
      A 12-lesson educational program
      • Staab D.
      • Ruden U.
      • Kehrt R.
      • Wahn U.
      The impact of childhood atopic dermatitis on quality of life of family.
      described positive outcomes after 1 year, including diminished fear of topical corticosteroid cream use. In a recent German multicenter study 820 children with AD were randomized into an intervention group (n = 443) and a control group (n = 377).
      • Staab D.
      • Diepgen T.
      • Fartasch M.
      • Kupfer J.
      • Lob-Corzilius T.
      • Ring J.
      • et al.
      Age-related, structured education programmes improve the management of atopic dermatitis in children and adolescents: Results of the German Atopic Dermatitis Intervention Study (GADIS).
      The intervention group underwent a 12-hour education program on an outpatient basis. After 1 year, the overall Severity Score for Atopic Dermatitis (SCORAD) measure, quality of life, scratching index, and adherence to treatment showed statistically significant improvement.
      Fundamentally, each patient with AD should be educated on various aspects of the disease. For economic and practical reasons, structured education will target patients with moderate and severe chronic AD and their parents. Structured patient education should enable both the patient and the parent to have realistic short-term goals, enter a process of problem solving, accept living with their disease, appropriately use available social support, and enhance their own motivation for therapy.

      Potential approaches for primary and secondary prevention of AD

      Based on the idea of diet as modulatory, a number of controlled interventions have tested this hypothesis of primary prevention through the nutritional route. Hydrolyzed cow's milk formula consists of predigested peptides of whey and casein. The formulas have equivalent nutritional values but a reduced capacity to induce IgE-mediated reactions.
      • Halken S.
      • Hansen K.S.
      • Jacobsen H.P.
      • Estmann A.
      • Faelling A.E.
      • Hansen L.G.
      • et al.
      Comparison of a partially hydrolyzed infant formula with two extensively hydrolyzed formulas for allergy prevention: a prospective, randomized study.
      • Halken S.
      Prevention of allergic disease in childhood: clinical and epidemiological aspects of primary and secondary allergy prevention.
      • Mimouni Bloch A.
      • Mimouni D.
      • Mimouni M.
      • Gdalevich M.
      Does breastfeeding protect against allergic rhinitis during childhood? A meta-analysis of prospective studies.
      • Muraro A.
      • Dreborg S.
      • Halken S.
      • Host A.
      • Niggemann B.
      • Aalberse R.
      • et al.
      Dietary prevention of allergic diseases in infants and small children. Part III: critical review of published peer-reviewed observational and interventional studies and final recommendations.
      A large controlled study in high-risk infants using different partially and extensively hydrolyzed formulas for the first 6 months of life demonstrated that extensively hydrolyzed casein formula has the capacity to reduce AD by 50% in the first year of life.
      • von Berg A.
      • Koletzko S.
      • Grubl A.
      • Filipiak-Pittroff B.
      • Wichmann H.E.
      • Bauer C.P.
      • 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.
      • Muraro A.
      • Dreborg S.
      • Halken S.
      • Host A.
      • Niggemann B.
      • Aalberse R.
      • et al.
      Dietary prevention of allergic diseases in infants and small children. Part II. Evaluation of methods in allergy prevention studies and sensitization markers. Definitions and diagnostic criteria of allergic diseases.
      A different approach for primary prevention is suggested by the introduction of probiotics (Lactobacillus GG) into the maternal and infantile diet. One study reported a decreased incidence of AD but had no effect on allergic sensitization.
      • Isolauri E.
      • Arvola T.
      • Sutas Y.
      • Moilanen E.
      • Salminen S.
      Probiotics in the management of atopic eczema.
      Elimination diets in the mother are not recommended because of their limited success. Other potential avenues that are being explored include adding bacterial, mycobacterial, and parasitic materials into the infant diet.
      A secondary prevention trial with cetirizine for infants with AD and a positive family history of asthma failed to demonstrate an effect for the whole group. In a subset of patients with dust mite or grass pollen sensitization, the incidence of asthma was reduced by 50%.
      • Warner J.O.
      • ETAC Study Group
      A double-blinded, randomized, placebo-controlled trial of cetirizine in preventing the onset of asthma in children with atopic dermatitis: 18 months' treatment and 18 months' posttreatment follow-up.
      This concept is currently being investigated in a second trial of 500 children.
      • Warner J.O.
      • ETAC Study Group
      A double-blinded, randomized, placebo-controlled trial of cetirizine in preventing the onset of asthma in children with atopic dermatitis: 18 months' treatment and 18 months' posttreatment follow-up.
      Trials using environmental control measures have shown potential effects in AD severity in children, although not in adults.
      • Capristo C.
      • Romei I.
      • Boner A.L.
      Environmental prevention in atopic eczema dermatitis syndrome (AEDS) and asthma: avoidance of indoor allergens.
      Another secondary prevention trial is under investigation based on the early treatment of AD with topical pimecrolimus to prevent the progression of AD to asthma based on the concept that the skin is the primary site of sensitization.
      This document represents a consensus of an international panel of experts from the European Academy of Allergology and Clinical Immunology and the American Academy of Allergy, Asthma and Immunology. These common proposals were developed to aid in the diagnosis and treatment of AD on both sides of the Atlantic.

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