Allergy Asthma Immunol Res.  2011 Apr;3(2):67-73. 10.4168/aair.2011.3.2.67.

The Atopic March: Progression from Atopic Dermatitis to Allergic Rhinitis and Asthma

• Zheng T
• Yu J
• Oh MH
• Zhu Z

• KMID: 2130356
• DOI: http://doi.org/10.4168/aair.2011.3.2.67

Abstract

Atopic dermatitis (AD) is an inflammatory disease characterized by pruritic skin lesions. The pathogenesis of AD may include disrupted epidermal barrier function, immunodysregulation, and IgE-mediated sensitization to food and environmental allergens. AD is also part of a process called the atopic march, a progression from AD to allergic rhinitis and asthma. This has been supported by multiple cross-sectional and longitudinal studies and experimental data. Research on the mechanisms of AD has been centered on the adaptive immune system with an emphasis on the T-helper 1 (Th1)-Th2 paradigm. Recently, the conceptual focus has largely shifted to include a primary defect in the epithelial barrier as an initial event in AD providing a significant insight into the disease initiation and pointing to a complex secondary interplay of environmental and immunological sequelae with barrier disruption. Further understanding of AD will help the development of more effective treatment for AD and ultimately, preventative algorithms for the atopic march. In this review we highlight recent advances in our understanding of the pathogenesis of AD and the atopic march.

Keyword

Eczema; atopic dermatitis; allergic rhinitis; asthma; atopic march

MeSH Terms

Allergens
Asthma
Dermatitis, Atopic
Eczema
Immune System
Longitudinal Studies
Rhinitis
Rhinitis, Allergic, Perennial
Skin
Allergens

Reference

1. Spergel JM, Paller AS. Atopic dermatitis and the atopic march. J Allergy Clin Immunol. 2003. 112:S118–S127.

2. Spergel JM. Epidemiology of atopic dermatitis and atopic march in children. Immunol Allergy Clin North Am. 2010. 30:269–280.

3. Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, Motala C, Ortega Martell JA, Platts-Mills TA, Ring J, Thien F, Van Cauwenberge P, Williams HC. Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003. J Allergy Clin Immunol. 2004. 113:832–836.

4. Spergel JM. Atopic march: link to upper airways. Curr Opin Allergy Clin Immunol. 2005. 5:17–21.

5. Ricci G, Patrizi A, Baldi E, Menna G, Tabanelli M, Masi M. Long-term follow-up of atopic dermatitis: retrospective analysis of related risk factors and association with concomitant allergic diseases. J Am Acad Dermatol. 2006. 55:765–771.

6. Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. The Group Health Medical Associates. Asthma and wheezing in the first six years of life. N Engl J Med. 1995. 332:133–138.

7. Kulig M, Bergmann R, Klettke U, Wahn V, Tacke U, Wahn U. Natural course of sensitization to food and inhalant allergens during the first 6 years of life. J Allergy Clin Immunol. 1999. 103:1173–1179.

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

9. Novembre E, Cianferoni A, Lombardi E, Bernardini R, Pucci N, Vierucci A. Natural history of "intrinsic" atopic dermatitis. Allergy. 2001. 56:452–453.

10. Ohshima Y, Yamada A, Hiraoka M, Katamura K, Ito S, Hirao T, Akutagawa H, Kondo N, Morikawa A, Mayumi M. Early sensitization to house dust mite is a major risk factor for subsequent development of bronchial asthma in Japanese infants with atopic dermatitis: results of a 4-year followup study. Ann Allergy Asthma Immunol. 2002. 89:265–270.

11. Wüthrich B, Schmid-Grendelmeier P. The atopic eczema/dermatitis syndrome. Epidemiology, natural course, and immunology of the IgE-associated ("extrinsic") and the nonallergic ("intrinsic") AEDS. J Investig Allergol Clin Immunol. 2003. 13:1–5.

12. van der Hulst AE, Klip H, Brand PL. Risk of developing asthma in young children with atopic eczema: a systematic review. J Allergy Clin Immunol. 2007. 120:565–569.

13. Kapoor R, Menon C, Hoffstad O, Bilker W, Leclerc P, Margolis DJ. The prevalence of atopic triad in children with physician-confirmed atopic dermatitis. J Am Acad Dermatol. 2008. 58:68–73.

14. Guilbert TW, Morgan WJ, Zeiger RS, Bacharier LB, Boehmer SJ, Krawiec M, Larsen G, Lemanske RF, Liu A, Mauger DT, Sorkness C, Szefler SJ, Strunk RC, Taussig LM, Martinez FD. Atopic characteristics of children with recurrent wheezing at high risk for the development of childhood asthma. J Allergy Clin Immunol. 2004. 114:1282–1287.

15. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. Lancet. 1998. 351:1225–1232.

16. Asher MI, Montefort S, Björkstén B, Lai CK, Strachan DP, Weiland SK, Williams H. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet. 2006. 368:733–743.

17. Laughter D, Istvan JA, Tofte SJ, Hanifin JM. The prevalence of atopic dermatitis in Oregon schoolchildren. J Am Acad Dermatol. 2000. 43:649–655.

18. Kay J, Gawkrodger DJ, Mortimer MJ, Jaron AG. The prevalence of childhood atopic eczema in a general population. J Am Acad Dermatol. 1994. 30:35–39.

19. Spergel JM. From atopic dermatitis to asthma: the atopic march. Ann Allergy Asthma Immunol. 2010. 105:99–106. quiz 107-9, 117.

20. Wuthrich B, Schmid-Grendelmeier P. Natural course of AEDS. Allergy. 2002. 57:267–268.

21. Stern DA, Morgan WJ, Halonen M, Wright AL, Martinez FD. Wheezing and bronchial hyper-responsiveness in early childhood as predictors of newly diagnosed asthma in early adulthood: a longitudinal birth-cohort study. Lancet. 2008. 372:1058–1064.

22. Illi S, von Mutius E, Lau S, Nickel R, Gruber C, Niggemann B, Wahn U. The natural course of atopic dermatitis from birth to age 7 years and the association with asthma. J Allergy Clin Immunol. 2004. 113:925–931.

23. Burgess JA, Dharmage SC, Byrnes GB, Matheson MC, Gurrin LC, Wharton CL, Johns DP, Abramson MJ, Hopper JL, Walters EH. Childhood eczema and asthma incidence and persistence: a cohort study from childhood to middle age. J Allergy Clin Immunol. 2008. 122:280–285.

24. Leynaert B, Neukirch C, Kony S, Guénégou A, Bousquet J, Aubier M, Neukirch F. Association between asthma and rhinitis according to atopic sensitization in a population-based study. J Allergy Clin Immunol. 2004. 113:86–93.

25. Burgess JA, Walters EH, Byrnes GB, Matheson MC, Jenkins MA, Wharton CL, Johns DP, Abramson MJ, Hopper JL, Dharmage SC. Childhood allergic rhinitis predicts asthma incidence and persistence to middle age: a longitudinal study. J Allergy Clin Immunol. 2007. 120:863–869.

26. Shaaban R, Zureik M, Soussan D, Neukirch C, Heinrich J, Sunyer J, Wjst M, Cerveri I, Pin I, Bousquet J, Jarvis D, Burney PG, Neukirch F, Leynaert B. Rhinitis and onset of asthma: a longitudinal population-based study. Lancet. 2008. 372:1049–1057.

27. Bugiani M, Carosso A, Migliore E, Piccioni P, Corsico A, Olivieri M, Ferrari M, Pirina P, de Marco R. Allergic rhinitis and asthma comorbidity in a survey of young adults in Italy. Allergy. 2005. 60:165–170.

28. Guerra S, Sherrill DL, Martinez FD, Barbee RA. Rhinitis as an independent risk factor for adult-onset asthma. J Allergy Clin Immunol. 2002. 109:419–425.

29. Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ, Togias A, Zuberbier T, Baena-Cagnani CE, Canonica GW, van Weel C, Agache I, Aït-Khaled N, Bachert C, Blaiss MS, Bonini S, Boulet LP, Bousquet PJ, Camargos P, Carlsen KH, Chen Y, Custovic A, Dahl R, Demoly P, Douagui H, Durham SR, van Wijk RG, Kalayci O, Kaliner MA, Kim YY, Kowalski ML, Kuna P, Le LT, Lemiere C, Li J, Lockey RF, Mavale-Manuel S, Meltzer EO, Mohammad Y, Mullol J, Naclerio R, O'Hehir RE, Ohta K, Ouedraogo S, Palkonen S, Papadopoulos N, Passalacqua G, Pawankar R, Popov TA, Rabe KF, Rosado-Pinto J, Scadding GK, Simons FE, Toskala E, Valovirta E, van Cauwenberge P, Wang DY, Wickman M, Yawn BP, Yorgancioglu A, Yusuf OM, Zar H, Annesi-Maesano I, Bateman ED, Ben Kheder A, Boakye DA, Bouchard J, Burney P, Busse WW, Chan-Yeung M, Chavannes NH, Chuchalin A, Dolen WK, Emuzyte R, Grouse L, Humbert M, Jackson C, Johnston SL, Keith PK, Kemp JP, Klossek JM, Larenas-Linnemann D, Lipworth B, Malo JL, Marshall GD, Naspitz C, Nekam K, Niggemann B, Nizankowska-Mogilnicka E, Okamoto Y, Orru MP, Potter P, Price D, Stoloff SW, Vandenplas O, Viegi G, Williams D. Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2) LEN and AllerGen). Allergy. 2008. 63:Suppl 86. 8–160.

30. Ciprandi G, Cirillo I, Vizzaccaro A, Milanese M, Tosca MA. Airway function and nasal inflammation in seasonal allergic rhinitis and asthma. Clin Exp Allergy. 2004. 34:891–896.

31. Liew WK, Williamson E, Tang ML. Anaphylaxis fatalities and admissions in Australia. J Allergy Clin Immunol. 2009. 123:434–442.

32. Poulos LM, Waters AM, Correll PK, Loblay RH, Marks GB. Trends in hospitalizations for anaphylaxis, angioedema, and urticaria in Australia, 1993-1994 to 2004-2005. J Allergy Clin Immunol. 2007. 120:878–884.

33. Eigenmann PA, Sicherer SH, Borkowski TA, Cohen BA, Sampson HA. Prevalence of IgE-mediated food allergy among children with atopic dermatitis. Pediatrics. 1998. 101:E8.

34. Malmberg LP, Saarinen KM, Pelkonen AS, Savilahti E, Mäkelä MJ. Cow's milk allergy as a predictor of bronchial hyperresponsiveness and airway inflammation at school age. Clin Exp Allergy. 2010. 40:1491–1497.

35. Saarinen KM, Pelkonen AS, Mäkelä MJ, Savilahti E. Clinical course and prognosis of cow's milk allergy are dependent on milk-specific IgE status. J Allergy Clin Immunol. 2005. 116:869–875.

36. Spergel JM, Mizoguchi E, Brewer JP, Martin TR, Bhan AK, Geha RS. Epicutaneous sensitization with protein antigen induces localized allergic dermatitis and hyperresponsiveness to methacholine after single exposure to aerosolized antigen in mice. J Clin Invest. 1998. 101:1614–1622.

37. He R, Kim HY, Yoon J, Oyoshi MK, MacGinnitie A, Goya S, Freyschmidt EJ, Bryce P, McKenzie AN, Umetsu DT, Oettgen HC, Geha RS. Exaggerated IL-17 response to epicutaneous sensitization mediates airway inflammation in the absence of IL-4 and IL-13. J Allergy Clin Immunol. 2009. 124:761–770.e1.

38. Akei HS, Brandt EB, Mishra A, Strait RT, Finkelman FD, Warrier MR, Hershey GK, Blanchard C, Rothenberg ME. Epicutaneous aeroallergen exposure induces systemic TH2 immunity that predisposes to allergic nasal responses. J Allergy Clin Immunol. 2006. 118:62–69.

39. Strid J, Hourihane J, Kimber I, Callard R, Strobel S. Disruption of the stratum corneum allows potent epicutaneous immunization with protein antigens resulting in a dominant systemic Th2 response. Eur J Immunol. 2004. 34:2100–2109.

40. Liu YJ. Thymic stromal lymphopoietin: master switch for allergic inflammation. J Exp Med. 2006. 203:269–273.

41. Lee EB, Kim KW, Hong JY, Jee HM, Sohn MH, Kim KE. Increased serum thymic stromal lymphopoietin in children with atopic dermatitis. Pediatr Allergy Immunol. 2010. 21:e457–e460.

42. Zheng T, Oh MH, Oh SY, Schroeder JT, Glick AB, Zhu Z. Transgenic expression of interleukin-13 in the skin induces a pruritic dermatitis and skin remodeling. J Invest Dermatol. 2009. 129:742–751.

43. Li M, Hener P, Zhang Z, Kato S, Metzger D, Chambon P. Topical vitamin D3 and low-calcemic analogs induce thymic stromal lymphopoietin in mouse keratinocytes and trigger an atopic dermatitis. Proc Natl Acad Sci U S A. 2006. 103:11736–11741.

44. Demehri S, Morimoto M, Holtzman MJ, Kopan R. Skin-derived TSLP triggers progression from epidermal-barrier defects to asthma. PLoS Biol. 2009. 7:e1000067.

45. Cork MJ, Robinson DA, Vasilopoulos Y, Ferguson A, Moustafa M, MacGowan A, Duff GW, Ward SJ, Tazi-Ahnini R. New perspectives on epidermal barrier dysfunction in atopic dermatitis: gene-environment interactions. J Allergy Clin Immunol. 2006. 118:3–21. quiz 22-3.

46. McGrath JA, Uitto J. The filaggrin story: novel insights into skin-barrier function and disease. Trends Mol Med. 2008. 14:20–27.

47. Kissling S, Wuthrich B. Follow-up of atopic dermatitis after early childhood. Hautarzt. 1993. 44:569–573.

48. Palmer CN, Irvine AD, Terron-Kwiatkowski A, Zhao Y, Liao H, Lee SP, Goudie DR, Sandilands A, Campbell LE, Smith FJ, O'Regan GM, Watson RM, Cecil JE, Bale SJ, Compton JG, DiGiovanna JJ, Fleckman P, Lewis-Jones S, Arseculeratne G, Sergeant A, Munro CS, El Houate B, McElreavey K, Halkjaer LB, Bisgaard H, Mukhopadhyay S, McLean WH. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat Genet. 2006. 38:441–446.

49. 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. J Invest Dermatol. 2002. 119:433–439.

50. Werner Y, Lindberg M. Transepidermal water loss in dry and clinically normal skin in patients with atopic dermatitis. Acta Derm Venereol. 1985. 65:102–105.

51. Grice K, Sattar H, Baker H, Sharratt M. The relationship of transepidermal water loss to skin temperature in psoriasis and eczema. J Invest Dermatol. 1975. 64:313–315.

52. 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. Acta Derm Venereol. 1995. 75:429–433.

53. Gupta J, Grube E, Ericksen MB, Stevenson MD, Lucky AW, Sheth AP, Assa'ad AH, Khurana Hershey GK. Intrinsically defective skin barrier function in children with atopic dermatitis correlates with disease severity. J Allergy Clin Immunol. 2008. 121:725–730.e2.

54. Leung DY, Boguniewicz M, Howell MD, Nomura I, Hamid QA. New insights into atopic dermatitis. J Clin Invest. 2004. 113:651–657.

55. Leyden JJ, Marples RR, Kligman AM. Staphylococcus aureus in the lesions of atopic dermatitis. Br J Dermatol. 1974. 90:525–530.

56. Nomura I, Tanaka K, Tomita H, Katsunuma T, Ohya Y, Ikeda N, Takeda T, Saito H, Akasawa A. Evaluation of the staphylococcal exotoxins and their specific IgE in childhood atopic dermatitis. J Allergy Clin Immunol. 1999. 104:441–446.

57. Allakhverdi Z, Comeau MR, Jessup HK, Yoon BR, Brewer A, Chartier S, Paquette N, Ziegler SF, Sarfati M, Delespesse G. Thymic stromal lymphopoietin is released by human epithelial cells in response to microbes, trauma, or inflammation and potently activates mast cells. J Exp Med. 2007. 204:253–258.

58. Bunikowski R, Mielke ME, Skarabis H, Worm M, Anagnostopoulos I, Kolde G, Wahn U, Renz H. Evidence for a disease-promoting effect of Staphylococcus aureus-derived exotoxins in atopic dermatitis. J Allergy Clin Immunol. 2000. 105:814–819.

59. Mischke D, Korge BP, Marenholz I, Volz A, Ziegler A. Genes encoding structural proteins of epidermal cornification and S100 calcium-binding proteins form a gene complex ("epidermal differentiation complex") on human chromosome 1q21. J Invest Dermatol. 1996. 106:989–992.

60. O'Regan GM, Sandilands A, McLean WH, Irvine AD. Filaggrin in atopic dermatitis. J Allergy Clin Immunol. 2009. 124:R2–R6.

61. Marenholz I, Nickel R, Rüschendorf F, Schulz F, Esparza-Gordillo J, Kerscher T, Grüber C, Lau S, Worm M, Keil T, Kurek M, Zaluga E, Wahn U, Lee YA. Filaggrin loss-of-function mutations predispose to phenotypes involved in the atopic march. J Allergy Clin Immunol. 2006. 118:866–871.

62. Stemmler S, Parwez Q, Petrasch-Parwez E, Epplen JT, Hoffjan S. Two common loss-of-function mutations within the filaggrin gene predispose for early onset of atopic dermatitis. J Invest Dermatol. 2007. 127:722–724.

63. Ying S, Meng Q, Corrigan CJ, Lee TH. Lack of filaggrin expression in the human bronchial mucosa. J Allergy Clin Immunol. 2006. 118:1386–1388.

64. Morar N, Cookson WO, Harper JI, Moffatt MF. Filaggrin mutations in children with severe atopic dermatitis. J Invest Dermatol. 2007. 127:1667–1672.

65. Barker JN, Palmer CN, Zhao Y, Liao H, Hull PR, Lee SP, Allen MH, Meggitt SJ, Reynolds NJ, Trembath RC, McLean WH. Null mutations in the filaggrin gene (FLG) determine major susceptibility to early-onset atopic dermatitis that persists into adulthood. J Invest Dermatol. 2007. 127:564–567.

66. Weidinger S, Rodríguez E, Stahl C, Wagenpfeil S, Klopp N, Illig T, Novak N. Filaggrin mutations strongly predispose to early-onset and extrinsic atopic dermatitis. J Invest Dermatol. 2007. 127:724–726.

67. Weidinger S, Illig T, Baurecht H, Irvine AD, Rodriguez E, Diaz-Lacava A, Klopp N, Wagenpfeil S, Zhao Y, Liao H, Lee SP, Palmer CN, Jenneck C, Maintz L, Hagemann T, Behrendt H, Ring J, Nothen MM, McLean WH, Novak N. Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations. J Allergy Clin Immunol. 2006. 118:214–219.

68. Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, Debenedetto A, Schneider L, Beck LA, Barnes KC, Leung DY. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol. 2007. 120:150–155.

69. Choi H, Kim S, Kim HJ, Kim KM, Lee CH, Shin JH, Noh M. Sphingosylphosphorylcholine down-regulates filaggrin gene transcription through NOX5-based NADPH oxidase and cyclooxygenase-2 in human keratinocytes. Biochem Pharmacol. 2010. 80:95–103.

70. Andoh T, Saito A, Kuraishi Y. Leukotriene B(4) mediates sphingosylphosphorylcholine-induced itch-associated responses in mouse skin. J Invest Dermatol. 2009. 129:2854–2860.

71. De Benedetto A, Agnihothri R, McGirt LY, Bankova LG, Beck LA. Atopic dermatitis: a disease caused by innate immune defects? J Invest Dermatol. 2009. 129:14–30.

72. Sugiura H, Ebise H, Tazawa T, Tanaka K, Sugiura Y, Uehara M, Kikuchi K, Kimura T. Large-scale DNA microarray analysis of atopic skin lesions shows overexpression of an epidermal differentiation gene cluster in the alternative pathway and lack of protective gene expression in the cornified envelope. Br J Dermatol. 2005. 152:146–149.

73. Kim BE, Leung DY, Boguniewicz M, Howell MD. Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6. Clin Immunol. 2008. 126:332–337.

74. Fallon PG, Sasaki T, Sandilands A, Campbell LE, Saunders SP, Mangan NE, Callanan JJ, Kawasaki H, Shiohama A, Kubo A, Sundberg JP, Presland RB, Fleckman P, Shimizu N, Kudoh J, Irvine AD, Amagai M, McLean WH. A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming. Nat Genet. 2009. 41:602–608.

75. Henderson J, Northstone K, Lee SP, Liao H, Zhao Y, Pembrey M, Mukhopadhyay S, Smith GD, Palmer CN, McLean WH, Irvine AD. The burden of disease associated with filaggrin mutations: a population-based, longitudinal birth cohort study. J Allergy Clin Immunol. 2008. 121:872–877.e9.

76. Smith FJ, Irvine AD, Terron-Kwiatkowski A, Sandilands A, Campbell LE, Zhao Y, Liao H, Evans AT, Goudie DR, Lewis-Jones S, Arseculeratne G, Munro CS, Sergeant A, O'Regan G, Bale SJ, Compton JG, DiGiovanna JJ, Presland RB, Fleckman P, McLean WH. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet. 2006. 38:337–342.