The Allergic March
Posted: September 2007
Ulrich Wahn, PhD MD
Figure 1. Allergic March
The term “allergic march” [also called atopic march] (Fig 1) refers to the natural history of atopic manifestations, which is characterized by a typical sequence of immunoglobulin E (IgE) antibody responses and clinical symptoms that appear early in life, persist over years or decades, and often remit spontaneously with age.
Although wide individual variations are observed, the onset of atopic diseases tends to be in the first decades of life and therefore may be related to the maturation of the immune system. In general, no clinical symptoms are detectable at birth and, although the production of IgE starts in the 11th week of gestation, no specific sensitization to food or inhalant allergens can be detected in cord blood with standard methods for measuring elevated serum IgE antibodies. Earlier findings describing elevated IgE concentrations in cord blood as a predictor of clinical manifestations of atopy have not been confirmed. After birth, total serum IgE concentrations increase with age but are distributed over a wide range. The 95th percentile at the age of 1 year in Caucasians is 80 kU/l, and at the age of 6 years is around 400 kU/l.
The first IgE responses directed to food proteins may be observed during the first months of life, and are most commonly directed to hen’s egg and cow’s milk. Even in completely breast-fed infants, high amounts of specific serum IgE antibodies to hen’s egg can be detected. It has been proposed that exposure to hen’s egg proteins occurs via mother’s milk, but this needs further clarification.
It has been demonstrated that strong infantile IgE antibody responses to food proteins are markers for atopic reactivity in general and are predictors of subsequent sensitization to aeroallergens.
Sensitization to environmental allergens from indoor and outdoor sources requires more time and is generally observed between the first and tenth years of life. The annual incidence of early sensitization depends on the amount of exposure. A longitudinal birth cohort study in Germany (Multicentre Atopy Study - MAS) found a dose-response relationship between early exposure to cat and mite allergens and the risk of sensitization during the first years of life.
In general, atopic dermatitis is the first clinical manifestation of the IgE response, with the highest incidence during the first three months of life and the highest period prevalence during the first three years of life.
Seasonal allergic rhinoconjunctivitis is generally not observed during the first two years of life, although a minority of children will develop specific IgE antibodies during this early period. Two seasons of exposure to pollen allergens are required before the typical symptoms of classical seasonal allergic rhinoconjunctivitis appear in association with specific serum IgE antibodies. Prevalence before the end of the first decade in children is around 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 in a minority the wheezing may persist throughout school age and adolescence. However, the understanding of the natural history of childhood asthma is still limited, and numerous data sets support the existence of various asthma phenotypes in childhood. During the first three years of life, the presence of wheezing 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 predictive value during the first two years 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 stronger.
It has been known for many years that atopic diseases run in families. The risk that neonates will develop atopic symptoms during the first two decades of life strongly depends on the manifestation of the same specific symptoms in their parents and siblings: there is a closer association between specific symptoms like asthma or atopic dermatitis in the child and the same symptoms in parents or siblings than with other atopic manifestations in the family. These clinical observations suggest the presence of phenotype-specific genes.
During the last two decades, molecular genetic studies have investigated the genes associated with various allergic diseases, including asthma. Two approaches are being applied to the identification of genes related to disease:
Positional cloning, in which the entire genome is screened using a panel of polymorphic DNA markers. This approach attempts to demonstrate a genetic linkage of a certain phenotype and genetic markers of known chromosomal localization.
Examination of candidate genes already known to be involved in the pathophysiology contributing to a certain phenotype. The role of candidate genes may be assessed by defining polymorphisms within the respective genes and testing for associations with the disease.
To date, a variety of markers within specific chromosomal regions have been linked to either atopic dermatitis or asthma, whereas other regions seem to be linked to other atopic phenotypes. If genetic studies turn out to be fruitful, they might help to identify candidate targets for primary prevention measures, as well as individuals who may respond to certain therapeutic interventions in the future.
During the last two decades, two general hypotheses have been proposed in the literature in connection with the observed increase of atopy and asthma in childhood.
New risk factors connected to nutrition, environmental exposure or lifestyle that were not known several decades ago have become relevant.
Protective factors related to a more traditional lifestyle in the past have been lost, leading to a greater susceptibility to atopic diseases.
The environmental factor studied most extensively as a potential risk for sensitization and manifestation of atopy and asthma is exposure to environmental allergens. A number of cross-sectional studies performed in children and adults have identified a close association between allergen exposure, particularly in the domestic environment, and sensitization to that specific allergen. Longitudinal studies like the MAS study in Germany have demonstrated that during the first years of life there is a dose-response relationship between exposure to indoor allergens such as dust mite and cat and the risk of sensitization to these allergens.
However, the situation is much less clear for atopic dermatitis and asthma. Earlier studies performed by Sporik et al. suggested that, in sensitized children, exposure to dust mite allergens not only determines the risk of asthma, but also the time of onset of the disease. More recent investigations by the same group, however, suggest that other factors besides allergen exposure are important in determining which children develop asthma.
In a comprehensive meta-analysis, Peat evaluated several environmental factors said to be responsible for the incidence and severity of atopic diseases, particularly asthma. Comparing the strength of the various effects reported in the literature, she concluded that indoor allergen exposure is the environmental component with by far the strongest impact on the manifestation of asthma.
One paradigm holds that exposure induces asthma with airway inflammation via sensitization; in recent years, however, this paradigm has been challenged because in several countries the prevalence of asthma in children has been increasing independent of allergen exposure. Data sets obtained from the birth-cohort study MAS 90 suggest that while domestic allergen exposure is a strong determinant for early sensitization in childhood it cannot be considered to be a primary cause of airway hyperresponsiveness or asthmatic symptoms.
A number of intervention studies are currently examining the effect of indoor allergen elimination on the incidence of asthma in cohorts followed prospectively from birth. The results will strongly impact public health policies, because they will clarify whether the elimination of indoor allergens is an important element of primary prevention of various atopic diseases. But even if it turns out that other factors play a major part in determining whether an atopic child will develop asthma, so that allergen elimination would be an inefficient measure of primary prevention, the reduction of allergen exposure (secondary prevention) will still remain a very important part of management.
Exposure to endotoxin
Endotoxin exposure is another possible protective factor against allergy in early life. Endotoxins consist of a family of molecules called lipopolysaccharides (LPS) and are an intrinsic part of the outer membrane of Gram-negative bacteria. It has been suggested that increased exposure to endotoxins on farms or in homes with animals could modify immune responses to reduce the prevalence of atopic diseases. LPS and other bacterial wall components engage with antigen presenting cells via CD14-ligation to produce strong IL-12 responses. IL-12, in turn, is an obligatory signal for the maturation of naive T cells into Th1-type cells. Endotoxin levels in samples of dust from children’s mattresses have recently been found to be inversely related to the occurrence of hay fever, atopic asthma, and atopic sensitization. LPS and other bacterial wall components can also be found abundantly in stables where pigs, cattle and poultry are kept. Endotoxin concentrations were found to be highest in the stables of farming families and also in dust samples from kitchen floors and mattresses in rural areas in Southern Germany and Switzerland, where the incidence of atopy is low. These findings support the hypothesis that environmental exposure to endotoxin and other bacterial wall components confers important protection against the development of atopic diseases.
Figure 2. Hygiene hypothesis
Can early exposure to infections be protective?
A hypothesis (“Hygiene Hypothesis – Fig 2) that has been attracting 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 contribute to the recent epidemic in atopic disease and asthma. Although this area of study is very complex, several pieces of information appear to support this hypothesis. Studies from several countries provide indirect evidence that early exposure to viral infections, although triggering symptoms in the lower airway during early life, may have long-lasting protective effects: children born into families with several siblings, particularly if these siblings are older, have been found to have a reduced risk of allergic sensitization and asthma at school age. Studies in children who had attended day care centres during infancy support this concept.
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 half that seen in vaccinated children. The induction of a systemic and nonspecific switch to Th1 activities by certain infections could be responsible for inhibiting the development of atopy during childhood.
Prenatal or perinatal bacterial infections should also be taken into account as potential modulators of the atopic march. Preterm birth in many cases is now understood to be the result of bacterial infections during pregnancy. The observation that infants with very low birth weight have a lower prevalence of atopic eczema and atopic sensitization could therefore fit with this hypothesis.
Although these observations on the relationship between immune responses to infectious agents and atopic sensitization and disease expression are stimulating and challenging, conclusions regarding their 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, 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?
The hygiene hypothesis originated from epidemiologic observations relating exposure to other children to a reduced risk of allergy. This provocative hypothesis prompted investigators to search for evidence that environmental exposures and genetic factors interact in childhood either to promote or protect against the development of atopic diseases. Knowledge regarding other environmental factors associated with this protection has blossomed and has led to a number of testable hypotheses related to mechanisms associated with modification of personal risk for allergy and asthma. Concurrent with this activity has been an expansion in knowledge about innate immune responses, T regulatory mechanisms, immune development in early childhood and the genetics that affect each of these processes. Studies are now in progress in a number of centres worldwide to incorporate these new advances in immunology into models linking environmental exposures to the induction of tolerance.
Pollutants and Tobacco Smoke as Adjuvant Factors
Several environmental factors, though not serving as allergens, are capable of upregulating existing IgE responses, leading either to disease manifestation or to an aggravation of symptoms. Guinea pig and mouse experiments have suggested that allergic sensitization to ovalbumin increases after experimental exposure to traffic- or industry-related pollutants, and a strong association between allergic rhinitis caused by cedar pollen allergy and exposure to heavy traffic was reported from Japan, although important sociodemographic confounders turned out to be a problem in the Japanese study. Other investigators were unable to identify any relationship between traffic exposure and the prevalence of hay fever or asthma. The role of tobacco smoke, a complex mixture of various particles and organic compounds, has been extensively studied. The studies, which have recently been reviewed, consistently demonstrate that the risk of lower airway diseases like bronchitis, recurrent wheezing in infants and pneumonia increases with exposure to tobacco smoke. Whether passive tobacco smoke exposure is causally related to the development of asthma is still disputed.
Until recently there was a lack of data about the risk of sensitization from tobacco smoke. The MAS prospective birth cohort study in Germany reported that an increased risk for sensitization was found only in children whose mothers smoked up to the end of pregnancy and continued to smoke after birth. This subgroup of the cohort had a significantly increased rate of sensitization to IgE antibodies to food proteins, particularly to hen´s egg and cow´s milk. This increase was only observed during infancy, and sensitization rates later on were not different from those in children who had never been exposed to tobacco smoke. These observations might be related to the fact that in children the highest urinary concentrations of cotinine, a metabolite of nicotine, are detected during the first years of life, when the child spends most of the time close to the mother.
Bowel flora, vaccinations, antibiotics and allergy
The intestinal microflora might well be the major source of microbial stimulation of the immune system in early childhood. The intestinal microflora can enhance Th1-type responses. The results of a comparative study of Estonian and Swedish children demonstrated that there are indeed differences in the intestinal microflora. In Estonia, the typical microflora includes more lactobacilli and fewer clostridia, a pattern that is associated with a lower presence of atopic disease.
Intervention studies are needed to demonstrate the relevance of these findings and to examine the effect of adding probiotics to infant formulas. In one published study from Finland, which was not blinded, infants with milk allergy and atopic dermatitis had milder symptoms and fewer markers of intestinal inflammation if their milk formula was fortified with lactobacilli.
Observations from Japan have suggested that positive tuberculin responses in children predict a lower incidence of asthma, lower serum IgE levels and a cytokine profile biased toward the Th1 type. This was supported by animal experiments that demonstrated that the IgE response to ovalbumin in mice could be downregulated by a previous infection with BCG. However, cohort studies form Europe did not find a protective effect of BCG vaccination.
A few reports have described an association between the use of antibiotics during the first two years of life and an increased risk of asthma. It seems too early to draw final conclusions from these publications. Immunizations do not seem to influence the risk of early sensitization or development of atopy. Pediatricians therefore should resist questioning most successful immunization programmes, like that for measles.
Lifestyle and the Development of Atopic Disease
The risk of atopic sensitization and disease manifestation early in life is particularly high in industrialized Western countries, and within these countries the prevalence of atopy correlates with socioeconomic status. What factor related to Western lifestyle might be responsible for increasing the susceptibility for atopic sensitization?
In a recent Swedish study, the prevalence of atopy in children from anthroposophic families was found to be lower than in children from other families, which led the authors to the conclusion that lifestyle factors associated with anthroposophy may lessen the risk of atopy in childhood. Several studies focusing on differences between the former socialist countries and Western European societies reported lower prevalence rates for atopy in the former East. This was particularly striking in areas with little genetic diversity, such as East and West Germany, where it was found that lifestyle mainly influences the development of atopy in the first years of life. These observations are consistent with the studies reporting lower prevalence rates for children coming from families with several siblings.
Observations from Germany suggest that within the population of an industrialized country with a Western lifestyle, high socioeconomic status is a risk factor for early sensitization and symptomatic manifestation of atopic dermatitis and allergic airway disease. The prevalence of atopy and asthma in Turkish migrants living in Germany increases as they assimilate culturally.
A long list of lifestyle-related factors might be associated with the apparent epidemic of atopy in the 21st century and might have relevance for the atopic march in children. Two of these factors relate to fats: obesity and a change in the use of dietary fatty acids. Obesity has been found in some studies in the USA to be associated with certain types of childhood asthma. If they really are associated, the question still remains whether asthma causes obesity or vice versa, or whether are they both explained by a common cause like immobility of the children. Another hypothesis is that the use of omega 3 versus omega 6 dietary fatty acids in certain populations might be responsible for an increased risk of allergic inflammation. Both hypotheses deserve attention, but at this stage preventive advice should not be based on them.
In many industrialized countries, the increase in the prevalence of atopy and asthma has become a serious public health issue. If preventive intervention is to be at all effective, it would have to be applied early in life, most probably in early infancy. Unfortunately, our understanding of the natural history of the process of atopic sensitization, atopic dermatitis and allergic airway disease is still very limited. The evaluation of risk factors and determinants is a necessary prerequisite for any effective intervention studies.
Interventions for primary prevention are aimed at a population that is still healthy, but is at risk of the disease. Unfortunately, all predictors investigated so far are insufficiently sensitive and specific. Therefore, possible preventive measures should be recommended only if they are applicable to the whole population, present no risk, and are low cost.
Although the extent to which breast feeding prevents atopy remains controversial, several other beneficial aspects of breast feeding justify the recommendation for exclusive breast feeding for at least four months. If breast milk is not sufficiently available during the first 3-4 days, water is recommended. Solid foods should be introduced to the diet after the fourth month. All exposure to tobacco smoke should be avoided, particularly during pregnancy and infancy, because maternal smoking during pregnancy is significantly associated with reduced respiratory function and recurrent wheezing in infancy and early childhood and the risk of developing IgE responses to food proteins early in life.
Since children with a positive family history for atopy in first-degree relatives are more susceptible to allergic sensitization, atopy and asthma, additional measures for primary prevention have been studied in this “high risk group” during the last decade.
The majority of the studies investigating prevention during pregnancy have found no real evidence for a protective effect of any maternal exclusion diet during that time. The protective effect of maternal avoidance of potential food allergens (milk, eggs and fish) during the breast-feeding period seems at best to be marginal. The use of hydrolysed formulas for atopy prevention has been extensively studied over the years in cases where the mother does not produce sufficient breast milk. Some studies indicate that in “high-risk” infants extensively hydrolysed formulas together with avoidance of cow’s milk proteins and solid foods for at least four months in children has some protective effect. However, protection may only be related to the food proteins that were avoided but not for prevention of disease such as atopic eczema or respiratory allergy. A recent, large randomized prospective study (the German Infant Nutrition Intervention Study) reported that extensively and partially hydrolyzed formulas (moderately reduced allergenicity); reduced the incidence of atopic dermatitis in infancy when compared to standard infant formulas.
The introduction of complementary food during the first four months of life has been associated with a higher risk of atopic eczema. It is still not clear to what extent 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.
The increasing prevalence of atopic diseases, particularly allergic asthma, has become a major challenge for allergists and public health authorities in many countries. The natural history of the atopic march, including which determinants are modifiable and might become candidates for preventive intervention, is still very poorly understood. Information provided by cross-sectional studies can only generate hypotheses, which need to be tested by prospective longitudinal cohort studies. As this work progresses, one can look forward to new strategies for the treatment and prevention of allergic diseases.
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.
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 6 years of life. J Allergy Clin Immunol; 1999;103 (6):1173-1179.
Martinez FD. Complexities of the genetics of asthma. Am J Respir Crit Care Med, 1997;156:117-22.
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.
Braun-Fährländer, 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 is 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.
Umetsu D T, McIntire J J, Akbari O, Macaubas C, DeKruyff R, Asthma: an epidemic of dysregulated immunity. Nature immunology, Vol. 3;No. 8:715-720.
Rook GAW, Stanford JL: Give us this day our daily germs. Immunology Today, 1999;19:113-117.
Kulig M, Luck W, Lau S, Niggemann B, Bergmann R, Klettke U, Guggenmoos-Holzmann I, Wahn U, MAS-Group. Effect of pre-and postnatal tobacco smoke exposure on specific sensitization to food and inhalant allergens during the first 3 years of life. Allergy, 1999;54:220–228.
Grüber C, Illi S, Plieth A, Sommerfeld C, Wahn U. Cultural adaptation is associated with atopy and wheezing among children of Turkish origin living in Germany. Clin Exp All, 2002;32:526-531
Björksten B. Allergy priming in early life. Lancet, 1999;353:167-168.
von Berg A, Koletzko S, Grübl, A, Filipiak-Pittroff B, Wichmann H-E, Bauer C P, Reinhardt D, Berdel D, for the GINI study group. The effect of hydrolyzed cow’s milk formula for allergy prevention in the first year of life: The German Infant Nutritional Intervention Studiy (GINI), a randomized double-blind trial. J Allergy Clin Immunol, 2003 Mar;111(3):533-540.