The Allergic March
Updated: September 2015
Originally Posted: September 2007
Ulrich Wahn PhD, MD
The term “Allergic March” (also called “Atopic March”) refers to the natural history of atopic manifestations, which is characterized by a typical sequence of immunoglobulin E (IgE) antibody responses and clinical symptoms which may appear early in life, persist over years or decades and often remit spontaneously with age.
It is frequently misunderstood as the development from minor symptoms over a mild disease expression towards more severe chronic manifestations. It also has been misinterpreted as the exclusive development from atopic dermatitis in infancy to airway disease, particularly asthma in school-age. These interpretations have been shown to underestimate the variations and heterogeneity of atopy development during the first decade of life.
Multiple epidemiological surveys including non interventional birth cohort studies, which have been performed over the last two to three decades have elucidated the natural history of atopic disease early in life (1,2). This first decade of life turns out to be special and unique compared to later ages, since the annual incidence of manifestations and disease related immune responses is clearly much higher than in any other period of life.
The Natural History
In general no clinical symptoms except a dry skin are detectable at birth. Although the production of IgE starts in the 11th week of possibly gestation, no specific sensitization to food or inhalant allergens can be detected in cord blood with standard methods for measuring elevated serum IgE antibodies (3).
The process of allergic sensitization
The first IgE responses directed to food proteins may be observed during the first weeks or months of life. In all parts of the world they are most commonly directed to proteins from hen’s egg and cow’s milk, independent of the mode of feeding (breastfeeding versus formula feeding). These strong infantile IgE antibody responses to food proteins can be considered as markers for atopic reactivity in general, since they have been demonstrated to be predictors of subsequent sensitization to other food proteins (peanuts, tree nuts) or aeroallergens from the indoor or outdoor environment (Fig 1).
Sensitization to environmental allergens requires more time and is generally observed during the pre-school or early school-age period. The annual incidence of sensitization to indoor allergens depends on the amount of domestic allergen exposure: The German birth cohort study MAS as well as other studies found a dose response relationship between early exposure to cat and mite allergens and the risk of sensitization during the first years of life. Sensitization to outdoor allergens like proteins from pollen require exposure as well: Seasonal birch pollen exposure which is common in Central and Northern Europe may lead to sensitization, whereas in Southern Europe like in other parts of the world where birch pollen exposure is extremely low, sensitization is rare (4).
In most atopic individuals atopic dermatitis is the first clinical manifestation with the highest incidence during the first months of life, and the highest period prevalence during the first three years of life (Fig 2). There are remarkable gender differences with a higher incidence of boys early in life and a higher risk for persistence of the disease into adulthood in girls. The fact, that the majority of infants and young children show elevated total IgE levels and a high degree of sensitization to food protein, which is obviously related to the severity of the disease, has led to the misunderstanding, that eczema should be considered to be a manifestation of food allergy. More recent studies have clearly demonstrated, that food sensitization is closely associated to moderate and severe atopic dermatitis in the first years of life; however, in most cases this sensitization should be understood as a complication of the disease which is not causally responsible for the manifestation of eczema (5).
After many years of controversy regarding diagnosis and treatment of food allergy in children fortunately the last two decades have clarified complex issues and has led to stringent criteria for terminology particularly regarding disease definition: Allergic sensitization to food protein can be followed by both, skin test as well as in vitro IgE-testing. A great advantage of in vitro test is the good reproducibility, as well as the option to quantify IgE-levels and describe with the help of modern molecular techniques differences in qualitative IgE-responses to major and minor allergens. Qualitative and quantitative differences in IgE-responses to food proteins may be highly relevant for the development of clinical allergy, as demonstrated by double blind placebo controlled food challenge studies.
It has recently been convincingly demonstrated , that in a variety of models (peanuts, tree nuts, fruits, vegetables) the IgE-responses allow a risk assessment and in several cases prediction of anaphylactic reactions to food. So far the only treatment of clinically relevant food allergy in children is elimination diet, which should be limited for a few years in the case of hen’s egg or cow’s milk allergy, if the IgE-responses are relatively low (6). Very high IgE levels to these proteins are related to a less favourable outcome and a longer persistence of the disease (Fig 3).
In the case of nuts, fruits and vegetables the spectrum of IgE-responses to certain proteins has been shown to be linked to the risk for anaphylaxis, whereas IgE-responses to other allergens (so-called pan-allergens) suggest, that this response represents pollen-associated food allergy to proteins which were originally encountered in the environment. In most of these cases dietary elimination is not necessary.
Seasonal allergic rhinoconjunctivitis is generally not observed during the first two years of life. Children, however, may develop specific IgE-antibodies years before they become manifest. This so-called “Allergen March” has been carefully studied recently. An early sensitization in young children to grass or birch pollen allergens indicate a highly elevated risk for rhinitis manifestation in the subsequent years (odds ratio = 11 – 13). The prevalence of seasonal rhinoconjunctivitis in Europe before the end of the first decade is around 15 % (6,7).
In most cases rhinitis is observed together with comorbidity of the lower airways (seasonal asthma), atopic dermatitis and pollen-associated food-allergy (Fig 2). In children with seasonal allergic rhinitis it has been shown, that this particular manifestation unlike all others is associated with a high risk for future asthma manifestation (Fig 4).
Asthmatic wheeze may already be observed during early infancy. A majority of these “early wheezers” turn out to be transiently symptomatic whereas in a minority the symptoms may persist throughout school-age and adolescence. While the presence of wheezing is not related to allergen specific sensitization and is clearly associated to virus infections (RSV, rhinovirus) the pattern may change towards school-age: Persistent wheezing shows an association with early sensitization particularly to indoor allergens like house dust mites and cats (9, 10, 11, 12).
Determinants for atopic manifestations
With novel genetic tools becoming available over the last two decades many researchers have tried to identify gene polymorphisms which may be responsible for the different disease manifestations.
It has been known for decades that allergies run in families (Fig 5). In order to identify relevant genes many genetic studies used positional cloning, in which the entire genome is screened using a panel of polymorphic DNA-markers. Others focused on the examination of candidate genes already suspected to be involved in the pathophysiology contributing to a certain phenotype. Today it can be concluded, that there is not a single chromosomal region or gene which is linked to all atopic phenotypes.
The most convincing genetic data have been reported for atopic dermatitis where several gene polymorphisms which have been characterized can be assumed to be directly responsible for at least a relevant percentage of all manifestations. Mutations in the genes for filaggrin, a molecule which is responsible for skin hydration, have been repeatedly described as highly relevant. They may also be of importance for associated food allergies or even asthmatic manifestations (5, 13).
Environment and lifestyle factors
A number of phenotype specific risk factors have been identified. The role of tobacco smoke, a complex mixture of various particles and organic compound has consistently been demonstrated as a risk for lower airway disease like bronchitis recurrent wheezing in infants and pneumonia. Passive tobacco smoke exposure after birth and even during the gestational period could be demonstrated as one of the stronger risk factors which are causally related to the development of asthma in children. Mothers who smoked up to the end of pregnancy and continued to smoke after birth turned out to have children with a significantly increased risk for allergic sensitization to food proteins from hen’s egg and cow’s milk. Compared to other determinants which are related to early exposure or life style, tobacco smoke exposure turns out to be the one factor which has the most consistence and robust effect described in a large number of studies.
A long list of lifestyle related factors with possible relevance for the “Atopic March” in Children has been studied. Obesity has been found in a variety of studies not only to be associated but to be preceding certain types of childhood asthma. A variety factors related to the diet like the change in the use of dietary fatty acids, the supplementation of vitamins like vitamin D are still being studied but at this stage do not provide a sufficient basis for possible consequences of prevention.
Options for prevention
It has also been suggested that early exposure to certain infections agents or microbial components may have protective effects (14, 15, 16).
With regards to atopy prevention the following definitions can be applied:
- Primary prevention: Prevention of the development of an atopic disease and/or abnormal allergic immune responses in healthy children without any evidence of abnormal allergic immune responses (target group general population, high risk or low risk neonates).
- Secondary prevention: Prevention of the development of new atopic disease and/or new abnormal allergic immune responses in children with already established clinical symptoms and/or abnormal allergic immune responses (target group infants with atopic dermatitis or early sensitization to hen’s egg or cow’s milk).
- Tertiary prevention: Prevention of the progression of the severity and exacerbations of the already established allergic disease.
For primary prevention a majority of studies tried to intervene on the level of infantile diet. In general all possible preventive measures should be recommended only if they are applicable to the whole population, if they present no risk and if they are available at low cost. The extent to which breastfeeding prevents atopy remains controversial, several other beneficial aspects of breastfeeding, however, justify the recommendation for exclusive breastfeeding for at least four to six months.
The use of hydrolyzed formulas for atopy prevention in high risk children is recommended in some European countries, after a large randomized prospective study (German infant nutrition intervention study) reported, that extensively and partially hydrolyzed formulas reduced the incidence of atopic dermatitis in infancy, when compared to standard infant formulas. In the meantime a longtime follow up of this study has found that the intervention effect which occurs in the first month of life is stable up to the age of ten, however, it is exclusively related to eczema development and is not affecting IgE-responses in childhood nor the development of airway disease.
Other dietary studies have been investigating the role of various probiotic bacteria as well as prebiotic oligosaccharides. Overall the effect of interventions in specific high risk or low risk populations was at best modest. Not always the study results were reproducible by other investigators.
A role for immunotherapy the use of allergen specific immunotherapy, particularly via the sublingual route, offering allergens which are particularly relevant for asthma development (cats, house dust mites, grass pollen) has been studied in smaller controlled trials. So far the results have not been conclusive yet, however, ongoing trials with sublingual application of grass pollen and dust mites will provide evidence for a potential role of allergen specific immunotherapy as a measure of secondary prevention in high risk children.
Unfortunately pediatric cohort studies suggest, that for allergic rhinitis no single preventable risk factor has been identified. This therefore underlines a need for allergen specific approaches early in the disease process which has the potential to modify long-term outcomes.
The most asthma preventable risk factor for asthma is probably tobacco smoke exposure. Recent studies suggest, that even during pregnancy the offspring of smoking mothers have a significantly increased risk for asthma during childhood. Unfortunately avoidance studies aiming at house dust mite or cat elimination have not led to conclusive results. Therefore current guidelines do not give a strong recommendation in this area.
Specific prevention for food allergy
The role of solid food is still under investigation, since it turned out, that strict elimination in infancy was of no benefit for the child. Currently a variety of “early introduction trial” are being performed and one single study with early introduction of peanut protein as a measure of second prevention for infants with early risk markers turned out to give highly encouraging results (18). Another approach which is followed by several groups of researchers is to provide possibly protective factors like bacterial cell wall compounds (LPS etc.). Currently there is no final conclusion coming from these trials.
The philosophy of avoiding exposure to food proteins with a high potential for early sensitization turned out to be not effective. Therefore recent studies on defined exposure to allergenic food proteins early in infancy were performed. Some trials with peanut allergens indeed suggest, that exposure in the first months of life may result in long-term tolerance development. Other trials focusing on cow’s milk and hen’s egg are ongoing. Prevention for atopic dermatitis, aggressive topical treatment with avoidance in high risk infants of atopic mothers has resulted in a remarkable reduction of the incidence of eczema during infancy. Therefore mothers of high risk babies should be educated in prophylactic skin care.
- The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. World-wide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. Lancet 1998, 351:1225-1232.
- Bergmann RL, Bergmann KE, Lau-Schadendorf S, Wahn U. Atopic diseases in infancy. The German multicenter atopy study (MAS-90). Pediatr Allergy Immunol 1994; 5 Suppl 1:19-25.
- Lockett, Gabrielle et al. Does Allergy Begin In Utero? Pediatric Allergy and Immunology, 2015; 1:21.
- Kulig M., Bergmann R, Klettke U, Wahn V, Tacke U, Wahn U and the Multicenter Allergy Study Group. Natural course of sensitization to food and inhalant allergens during the first six years of life. J Allergy Clin Immunol; 1999;103(6):1173-1179.
- Cole, Christian et al. Filaggrin-stratified transcriptomic analysis of pediatric skin identifies mechanistic pathways in patients with atopic dermatitis. J Allergy Clin Immunol Volume 134; 2014;82.91.
- Wood; Robert A. et al. The natural history of milk allergy in an observational cohort. J Allergy Clin Immunol, Volume 131, 2013; 805:812.
- Hatzler, Laura et al. Molecular spreading and predictive value of preclinical IgE response to Phleum pratense in children with hay fever. J Allergy Clin Immunol 2012;1:8e5
- Hatzler, Laura et al. Parental hay fever reinforces IgE to pollen as pre-clinical biomarker of hay fever in childhood. Ped. Allergy and Immunology 25; 2014:366-373
- Illi, Sabina et al. Perennial allergen sensitization early in life and chronic asthma in children: a birth cohort study. Lancet.com, 2006, 763:770
- Lau S, Illi S, Sommerfeld C, Niggemann B, Bergmann R, von Mutius E, Wahn U and the Multicentre Allergy Study Group. Early exposure to house-dust mite and cat allergens and development of childhood asthma: a cohort study. Lancet, 2000;356:1392-1397.
- Jackson, Daniel J. et al. Evidence for a Causal Relationship between Allergic Sensitization and Rhinovirus Wheezing in Early Life. Am J Respir Crit Care Med, 2012; 281:285.
- Grabenhenrich, Linus B. et al. Early-life determinants of asthma from birth to age 20 years: A German birth cohort study. Am Academy of Allergy, Asthma & Immunology, 2013; 979:988.
- Hopper, John L. et al. Does eczema in infancy cause hay fever, asthma, or both in childhood? Insights from a novel regression model of sibling data. J Allergy Clin Immunol, November 2012;1117:1122.
- Braun-Fahrländer, Riedler J, Herz U, Eder W, Waser M, Grize L, Maisch S, Carr D, Gerlach F, Nowak D, Mutius v E, for the Allergy and Endotoxin study team. C Environmental Exposure to Endotoxin and its relation to asthma in school-age children. N Engl J Med; 347:869-877.
- Matricardi PM, Rosmini F, Ferrigno L, et al. Cross sectional retrospective study of prevalence of atopy among Italian military students with antibodies against hepatitis A virus. BMJ, 1997;314:999-1003.
- Rook GAW, Stanford JL: Give us this day our daily germs. Immunology Today, 1999;19:113-117.
- Ege, Markus J. et al. Exposure to Environmental Microorganisms and Childhood Asthma. The New England Journal of Medicine 2011;364:8,
- Du Toit, George et al. Randomized Trial of Peanut Consumption in Infants at Risk for Peanut Allergy. The New England Journal of Medicine, 2015; 803:813.
Legends for figures
|Fig 1||Prevalence of specific allergic sensitization during the first two decades of life MAS-birth cohort study, unpublished|
|Fig 2||Comorbidity of Asthma, Rhinitis and Eczema over 20 years in the German birth cohort MAS
Gough. H. PAI, 2015
|Fig 3||The natural history of milk allergy in an observational cohort
Robert A. Wood, Scott H. Sicherer, Brian P. Vickery et al.
J Allergy Clin Immunol 2013;131:85-12
|Fig 4||Stratification at age 5 years
Rochat et al., JACI 2010
|Fig 5||Age dependent/ cumulative Asthma during the first 20 years of life in relation to a family history of allergy|