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Department of Pneumology and Immunology, Charité Berlin, Virchow-Klinikum, 13353 Berlin, Germany
* To whom correspondence should be addressed. Email: ulrich.wahn{at}charite.de.
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ABSTRACT |
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 TOP ABSTRACT Introduction and DefinitionLITERATURE CITED |
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Introduction and Definition |
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TOPABSTRACTIntroduction and DefinitionLITERATURE CITED |
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The term "atopic march" refers to the natural history of atopic manifestations, which is characterized by a typical sequence of IgE antibody responses and clinical symptoms that appear during a certain age period, persist over years and decades, and often show a tendency for spontaneous remission with age.
To identify potential modifiable determinants, cross-sectional as well as longitudinal epidemiological studies of the development of atopic diseases have received much attention over the past decade. The number of interventional studies, however, which provide the most useful information is still limited. It is obvious that a prerequisite for any intervention aimed at the prevention of atopic manifestations is the identification of nongenetic determinants like exposure to environmental factors, food, or lifestyle-related factors that are modifiable on an individual basis or as a result of public health measures.
The natural history of atopic manifestations
During the first months of life, the first IgE responses directed to food proteins may be observed, particularly to chicken eggs and cow milk. Even in completely breast-fed infants, high amounts of specific serum IgE antibodies to chicken eggs can be detected. It has been proposed that exposure to chicken egg proteins occurs via the mother's milk, but this needs further clarification.
Sensitization to environmental allergens from indoor and outdoor sources requires more time and is generally observed between the first and 10th y of life. The annual incidence of early sensitization depends on the amount of exposure. In a longitudinal birth cohort study in Germany (Multicenter Allergy Study), a dose-response relationship could be shown between early exposure to cat and mite allergens and the risk of sensitization during the first years of life (1).
It has recently been demonstrated that strong infantile IgE antibody responses to food proteins must be considered as markers for atopic reactivity in general and are predictors of subsequent sensitization to aeroallergens (2).
As far as clinical symptoms are concerned, atopic dermatitis in general is the first manifestation, with the highest incidence during the first 3 mo of life and the highest period of prevalence during the first 3 y of life.
Seasonal allergic rhinoconjunctivitis is generally not observed during the first 2 y of life, although a minority of children will develop specific IgE antibodies during this early period. Obviously, 2 seasons of pollen allergen exposure are required before a classical seasonal allergic rhinoconjunctivitis with typical symptoms in association with specific serum IgE antibodies becomes manifest. Prevalence before the end of the first decade in children is 
15% in Central Europe.
Asthmatic wheezing may already be observed during early infancy. The majority of early wheezers turn out to be transiently symptomatic, whereas a minority may persist throughout school age and adolescence. Numerous data sets support the existence of various asthma subtypes in childhood. During the first 3 y of life, the manifestation of wheeze is not related to elevated serum IgE levels or specific sensitization and a positive parental history of atopy and asthma seems to be of minor importance during the first 2 y of life. Those who have persistent wheezing show an association with early sensitization to food and subsequent sensitization to aeroallergens. In addition, the association with a positive family history for atopy and asthma in first degree relatives becomes more and more obvious (3).
Can early exposure to infections be protective?
One of the hypotheses that has attracted much interest is that a decline in certain childhood infections or a lack of exposure to infectious agents during the first years of life, which is associated with smaller families in the middle-class environment of industrialized countries, could be causal for the recent epidemic in atopic disease and asthma (4). Although this area is obviously very complex, several pieces of information appear to support this hypothesis.
Studies from several countries provide indirect evidence for the hypothesis that early exposure to viral or mycobacterial (5) infections, although triggering lower airway symptoms during early life (6–9), may have long-lasting protective effects; children who were born into families with several, particularly older, siblings have been found to have a reduced risk of allergic sensitization and asthma at school age (10). Studies in children who had attended daycare centers during infancy support this concept (11).
Infections have long-lasting, nonspecific, systemic effects on the nature of the immune response to antigens and allergens. For example, recovery from natural measles infection reduces the incidence of atopy and allergic responses to house dust mites to one-half that in vaccinated children. Obviously, the fact that certain infections are inducing a systemic and nonspecific switch to T-helper cell 1 (Th1) activities could be responsible for an inhibition of the development of atopy during childhood.
Although these observations on the relationship between immune responses to infectious agents and atopic sensitization and disease expression are stimulating and challenging, conclusions regarding the relevance for the atopic march should be drawn with care. In different parts of the world, completely different infectious agents have been addressed in different study settings. It appears to be quite fashionable to join Rook and Stanford (12), who in a recent review article in Immunology Today pleaded "give us this day our daily germs," but which germ at what time under which circumstances and what is the price we have to pay?
Exposure to endotoxin
The role of endotoxin exposure as a possible element of atopy prevention in early life has recently been discussed (13,14). Endotoxins consist of a family of molecules called lipopolysaccharides and are an intrinsic part of the outer membrane of gram-negative bacteria. Lipopolysaccharides and other bacterial wall components, which can also be found abundantly in stables where pigs, cattle, and poultry are kept, engage with antigen presenting cells via cluster of differentiation-legation strong interleukin 12 responses. Interleukin 12, in turn, is regarded as an obligatory signal for the maturation of naive T cells into TH2-type cells. Endotoxin concentrations were recently found to be highest in stables of farming families and also in dust samples from kitchen floors and mattresses in rural areas in Southern Germany and Switzerland. These findings support the hypothesis that environmental exposure to endotoxin and other bacterial wall components is an important protective determinant regarding the development of atopic diseases. Indeed, endotoxin levels in samples of dust from children's mattress have recently been found to be inversely related to the occurrence of hay fever, atopic asthma, and atopic sensitization (8).
Options for alimentary prevention
Measures for primary prevention are aimed at a population that is still healthy but at risk of the disease. Unfortunately, all predictors investigated so far are insufficient in sensitivity and specificity.
Although the extent of a preventive effect of breast-feeding remains controversial, several other beneficial aspects justify the recommendation for exclusive breast-feeding for at least 4 mo. If breast milk is not sufficiently available during the first 3–4 d, water is recommended. Solid foods should be introduced to the diet after mo 4. An avoidance of exposure to tobacco smoke should be guaranteed, particularly during pregnancy and infancy.
Because children with a positive family history for atopy in first degree relatives have been shown to be more susceptible for allergic sensitization and the manifestation of atopy and asthma, additional measures for primary prevention have been studied during the last decade for this high-risk group.
The majority of studies aimed at prevention during pregnancy indicate that there is no real evidence for a protective effect of any maternal exclusion diet during that time. The effect of maternal avoidance of potential food allergens (milk, eggs, and fish) while breast-feeding seems at best to be marginal.
If maternal breast milk is not sufficient, the use of hydrolyzed infant formulas for atopy prevention has been extensively studied over the years. Some studies indicate that extensively hydrolyzed formulas in combination with avoidance of cow milk proteins and solid foods for at least 4 mo in children with a positive family history of atopy have some preventive effect (15), but this is related to the food proteins that were avoided and cannot be considered as a long-lasting prevention of atopic manifestations of the skin or the airways in general. Recently, extensively and partially hydrolyzed formulas with moderately reduced allergenicity have been investigated in a large randomized prospective study (German Infant Nutrition Intervention Study). Compared with standard infant formulas, hydrolyzed feeding resulted in reduced incidence of atopic dermatitis in infancy (16).
Another option for alimentary prevention that was proposed more recently is the supplementation of infant formula with probiotics such as lactobacilli (17). Initial studies from Finland suggested that the supplementation with certain lactobacilli strains to the diet of high-risk infants might not only modulate the intestinal flora but also reduce the incidence of atopic dermatitis during the first years of life. Unfortunately, this interesting observation was not consistently confirmed by follow-up studies; therefore, further trials will be necessary to clarify whether there are long-term clinical effects that are possibly associated with a downregulation of IgE responses in infants.
Even more recently, it was proposed that the supplementation of oligosaccharides to an infant formula might have more consistent immunomodulatory effects. In experimental animals, the so-called prebiotics have been demonstrated to result in an upregulation of TH1 and downregulation of TH2 responses together with IgE antibody responses. In humans, the addition of prebiotic oligosaccharides has been shown to result in remarkable changes of the intestinal flora. One study suggests that the incidence of early atopic phenotypes can be reduced by this intervention; however, further careful immunological studies will be necessary to clarify whether these clinical findings are associated with immunomodulatory effects.
The introduction of complementary food during the first 4 mo of life has been associated with a higher risk of atopic dermatitis. It is still not clear how much the risk for atopic sensitization and disease manifestation may be decreased by dietary intervention in early infancy. The majority of studies seem to indicate that the effects are transient and that the development of asthma later in childhood will not be prevented.
Because maternal smoking during pregnancy is significantly associated with reduced respiratory function and recurrent wheezing in infancy and early childhood (18) and the risk to develop IgE responses to food proteins early in life, smoking should be avoided in any case.
Perspectives and challenges
Because allergen avoidance as a measure of primary prevention is either not practicable (avoidance of pollen allergens) or has been shown to be of limited efficacy, novel strategies must be delineated to achieve tolerance induction and succeed with primary prevention of allergic diseases (8,15). Tolerance is defined as an antigen-induced state of specific unresponsiveness acquired either during fetal development or later in life.
Several approaches could be considered that should be targeted at young children with a high risk to develop allergic diseases: 1) application of microbial products and/or probiotics via the oral or intranasal route; 2) mucosal application of allergens; 3) application of allergens together with microbial products; and 4) application of allergens with anti-IgE.
It can be expected that the change of paradigms for allergy prevention from avoidance of risk factors to the active induction of tolerance might lead to more effective interventions that hopefully contribute to reversing the epidemiologic trends of the last decades.
Other articles in this supplement include references (19–28).
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FOOTNOTES |
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2 Author disclosures: H. U. Wahn, no conflicts of interest.
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LITERATURE CITED |
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TOPABSTRACTIntroduction and DefinitionLITERATURE CITED |
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1. Lau S, Illi S, Sommefeld C, Niggemann B, Bergmann R, von Mutius E, Wahn U. Early exposure to house-dust mite and cat allergens and development of childhood asthma: a cohort study. Lancet. 2000;356:1392–7.[CrossRef][Medline]
2. Nickel R, Kulig M, Forster J, Bergmann R, Bauer CP, Lau S, Guggenmoos-Holzmann I, Wahn U. Sensitization to hen's egg at the age of twelve months is predictive for allergic sensitization to common indoor and outdoor allergens at the age of three years. J Allergy Clin Immunol. 1997;99:613–7.[CrossRef][Medline]
3. Illi S, von Mutius E, Lau S, Niggemann B, Grüber C, Wahn U. The MAS Study Group: perennial allergen sensitization early in life and chronic asthma in children: a birth cohort study. Lancet. 2006;368:763–70.[CrossRef][Medline]
4. Alm JS, Swartz J, Lilja G, Scheyius A, Pershaben G. Atopy in children of families with an anthroposophic lifestyle. Lancet. 1999;353:1485–8.[CrossRef][Medline]
5. Shirakawa T, Enomoto T, Shimazu S, Hopkin JM. The inverse association between tuberkulin responses and atopic disorder. Science. 1997;275:77–9.
6. Krämer U, Heinrich J, Wjst M, Wichmann HE. Age of entry to day nursery and allergy in later childhood. Lancet. 1999;353:450–4.[CrossRef][Medline]
7. Murosaki S, Yamamoto Y, Ito K, Inokuchi T, Kusaka H, Ikeda H, Yoshikai Y. Heat-killed Lactobacillus plantarum L-137 suppresses naturally fed antigen-specific IgE production by stimulation of IL-12 production. J Allergy Clin Immunol. 1998;102:57–64.[CrossRef][Medline]
8. von Mutius E, Braun-Fahrländer C, Schierl R, Riedler J, Ehlermann S, Maisch S, Waser M, Nowak D. Exposure to endotoxin or other bacterial components might protect against the development of atopy. Clin Exp Allergy. 2000;30:1230–4.[CrossRef][Medline]
9. Shaheen SO, Aaby P, Hall AJ, Baker DJ, Heyes CB, Shiell AW, Goudiaby A. Measles and atopy in Guinea-Bissau. Lancet. 1996;347:1792–6.[CrossRef][Medline]
10. Illi S, Mutius EV, Bergmann R, Niggemann B, Sommerfeld C, Wahn U. The MAS Group: early childhood infectious diseases and the development of asthma up to school age: a birth cohort study. BMJ. 2001;322:390–5.
11. Matricardi PM, Rosmini F, Ferrigno L, Nisini R, Rapicetta M, Chionne P, Stroffolini T, Pasquini P, D'Amelio R. Cross-sectional retrospective study of prevalence of atopy among Italian military students with antibodies against hepatitis A virus. BMJ. 1997;314:999–1003.
12. Rook GAW, Stanford JL. Give us this day our daily germs. Immunol Today. 1998;19:113–6.[CrossRef][Medline]
13. Braun-Fährländer C, Riedler J, Herz U, Eder W, Waser M, Grize L, Maisch S, Carr D, Gerlach F, et al. Environmental exposure to endotoxin and its relation to asthma in school-age children. N Engl J Med. 2002;347:869–77.
14. Farooqi IS, Hopkin JM. Early childhood infection and atopic disorder. Thorax. 1998;53:927–32.
15. Zeiger R, Heller S, Mellon M, Halsey F, Hamburger RN, Sampson HA. Genetic and environmental factors affecting the development of atopy through age 4 in children of atopic parents: a prospective randomized study of food allergen avoidance. Pediatr Allergy Immunol. 1992;3:110–27.[CrossRef]
16. von Berg A, Koletzko S, Grübl A, Filipiak-Pittroff B, Wichmann HE, Bauer CP, Reinhardt D, Berdel D. The effect of hydrolyzed cow's milk formula for allergy prevention in the first year of life: the German Infant Nutritional Intervention Study, a randomized double-blind trial. J Allergy Clin Immunol. 2003;111:533–40.[CrossRef][Medline]
17. Shida K, Makino K, Morishita A, Takamizawa K, Hachimura S, Ametani A, Takehito S, Kumagai Y, Habu S, et al. Lactobacillus casei inhibits antigen-induced IgE secretion through regulation of cytokine production in murine splenocyte cultures. Int Arch Allergy Immunol. 1998;115:278–87.[CrossRef][Medline]
18. Keil T, Kulig M, Roll S, Grüber C, Nickel R, Niggemann B, Wahn U, Willich S, Lau S. The risk for sensitization and asthma by pre- and postnatal maternal smoking is confined to children with atopic parents. Allergy. In press 2008.
19. Visser HKA. Dietary influences on infection and allergy in infants: Introduction. J Nutr. 2008;138:1768S–9S.
20. Szépfalusi Z. The maturation of the fetal and neonatal immune system and allergy. J Nutr. 2008;138:1773S–81S.
21. M'Rabet L, Vos AP, Boehm G, Garssen J. Breast-feeding and its role in early development of the immune system in infants: consequences for health later in life. J Nutr. 2008;138:1782S–90S.
22. Morelli L. Postnatal development of interstinal microflora as influenced by infant nutrition. J Nutr. 2008;138:1791S–5S.
23. Biasucci G, Benenati B, Morelli L, Bessi E, Boehm G. Cesarean delivery may affect the early biodiversity of intestinal bacteria. J Nutr. 2008;138:1796S–800S.
24. Chirico G, Marzollo R, Cortinovis S, Fonte C, Gasparoni A. Antiinfective properties of human milk. J Nutr. 2008;138:1801S–6S.
25. Gottrand F. Long-chain polyunsaturated fatty acids influence the immune system of infants. J Nutr. 2008;138:1807S–12S.
26. Lafeber HN, Westerbeek EAM, van den Berg A, Fetter WPF, van Elburg RM. Nutritional factors influencing infections in preterm infants. J Nutr. 2008;138:1813S–7S.
27. Boehm G, Moro, G. Structural and functional aspects of prebiotics used in infant nutrition. J Nutr. 2008;138:1818S–28S.
28. van Goudoever J, Corpeleijn W, Riedijk M, Schaart M, Renes I, van der Schoor S. The impact of enteral IGF-1 and nutrition on gut permeability and amino acid utilization. J Nutr. 2008;138:1829S–33S.
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