Pii: s0952-7915(01)00282-5

Why are allergies increasing?
Johannes Ring*, Ursula Krämer†, Torsten Schäfer* and Heidrun Behrendt‡
The incidence of atopic allergy is increasing in certain ‘Western’ programme have revealed dramatic differences in symptom countries but this remains unexplained. Various hypotheses with prevalence of the different diseases in various countries of differing amounts of evidence and/or relevance have been the world (156 study centres in 56 countries [11]). The assessed, including increased awareness of the diseases, highest asthma prevalence rates were found in Australia, improved diagnostics, genetic susceptibility, psycho-social New Zealand, the United Kingdom, the USA and some influences, allergen exposure, decreased immune-system cities in Latin America. Lower prevalence rates were found stimulation, underlying disease, anti-allergic therapy and pollution.
in non-industrialized countries and more-rural areas. Therewas no concordant pattern between prevalence rates of Addresses
atopic eczema and respiratory atopic diseases [12,13•,14].
*Department of Dermatology and Allergy Biederstein, Technical UniversityMunich, Biedersteiner Strasse 29, D-80802, Munich, Germany According to many authors, the most rapid increase in †Med. Institut für Umwelthygiene (MIU), Aufm Hennekamp 50, D-40225, prevalence of atopic diseases occurred in Western coun- Düsseldorf, Germany‡Division of Environmental Dermatology and Allergy, GSF-National tries in the years between 1960 and 1990 [15]. The reasons Research Center for Environment and Health, Neuherberg/Technical for this increase in prevalence of atopy are not known.
University Munich, Biedersteiner Strasse 29, D-80802 Munich, Germany There exist, however, a number of hypotheses which are controversially and often emotionally discussed (Table 2) Current Opinion in Immunology 2001, 13:701–708
[16]. In this review, the pros and cons of the varioushypotheses will be considered.
0952-7915/01/$ — see front matter 2001 Elsevier Science Ltd. All rights reserved.
Hypothetical concepts to explain the increase
Introduction
in prevalence of atopic diseases
The incidence of atopic allergic diseases is increasing
Increased awareness and improved diagnostics
Allergy is a major health problem in most modern societies Undoubtedly, allergic diseases are recognized more easily [1,2]. Although the allergic diseases per se are not new — today than 50 years ago. This may be due to increasing they were described in ancient Chinese and Greek litera- public interest in these diseases as well as to the development ture (reviewed in [3,4]) — there is broad consensus that of modern and more reliable diagnostic techniques. However, the prevalence of certain allergic diseases has increased in this improved diagnostic methodology and increased most industrialized countries of the world during the past awareness may only contribute to the explanation rather than few decades [5–9]. This phenomenon holds true for the so- totally explain the increased prevalence, which has been called type I (atopic) diseases, namely extrinsic bronchial documented in cross-sectional population-based studies.
asthma, allergic rhinoconjunctivitis (‘hay fever’) andatopic-eczema/dermatitis. A similar trend has not been Genetic susceptibility
found for other types of allergic diseases, namely type II Since the first description of ‘atopy’ [17], a genetic predis- (cytotoxic), type III (immune-complex) or type IV position determining the susceptibility to develop atopic (delayed-type) hypersensitivity reactions such as allergic It is also known that the three atopic diseases are inher- The increase in prevalence of atopic diseases is real
ently connected within families, showing a considerable Studies from different authors reporting an increase overlap (asthma plus atopic eczema, rhinoconjunctivitis in prevalence of asthma, allergic rhinoconjunctivitis and plus asthma, etc.). This has been shown by classical atopic eczema have to be interpreted carefully with regard genetics in family or twin studies [18]. Using modern to potential differences in methodology [10].
molecular biology techniques, segregation and geneticlinkage studies, several loci for specific atopy-associated Several studies by a few groups that used a similar method- genes have been determined on various chromosomes ology have also shown a significant increase in atopic diseases [19–21] (Table 3). Some authors have found genetic between 1960 and 1990 (Table 1; for references, see [2]).
polymorphisms in allergy-relevant gene products — forexample CD14, which is a receptor for endotoxin [22].
Until recently there were no standardized methods to compare prevalence rates of the different atopic diseases.
Of special interest is the obvious dominance of the mater- Therefore the International Study of Asthma and Allergies nal genetic influence over the paternal in many studies, in Childhood (ISAAC) [11•] was started, whereby symp- giving rise to speculations about the role of environ- toms were investigated with standardized questionnaires mental influences in utero. In the explanation of these and by implementation of a video showing an asthmatic findings, a possible role of genomic imprinting or of patient. The results of the first phase of the ISAAC mitochondrial DNA has been discussed [13•,20,21].
Allergy and hypersensitivity
Changes in prevalence of atopic diseases over the past few decades (reviewed in [2]).
Age group
Country
Children
*The year in which prevalence was assessed. †Self-reported. ‡Patients who had ever had asthma.
The more we know about the multiple genes involved in often is connected with higher parental educational level the development of atopy, the clearer it becomes that the and professional life. Several studies have found significant genetic background alone cannot explain the increase in inverse correlations between the parental educational level prevalence. This became particularly clear in studies com- and the prevalence of atopy in the offspring: children from paring East and West German populations after the fall of ‘academic’ parents have a significantly higher risk of devel- the Berlin Wall in 1989; these were populations of a simi- oping atopic sensitization — measured in skin-prick test or lar genetic and geographic background living under similar radio-allergo-sorbent test (RAST) — and disease [26,27].
climatic conditions yet under quite different lifestyles (seebelow) [23•,24,25] (Figure 1).
At the same time, family size has decreased; there seemsto be an inverse correlation between the number of Psycho-social influences
children or the number of people living within one One of the most characteristic features of a ‘Western society’ apartment and the frequency of atopy [28].
is the individual freedom within a more or less democraticcommunity trying to provide equal rights for all its mem-bers. This has led to increased mobility of individual people but also to increased social mobility within the society. One Gene-loci relevant for allergic diseases.
factor may be the increase during the past few decades inthe mean age at which women give birth to their first child (K Thesdrup-Pedersen, personal communication), which Hypothetical concepts to explain the increase in prevalence of
atopic diseases.
Increased awareness and improved diagnostics ADRB2 (β-adrenergic receptor)GLR (glucocorticoid receptor on Decreased stimulation of the immune system (‘jungle’ or ‘hygiene’ Why are allergies increasing? Ring et al.
Prevalence of allergies in East and WestGermany plotted against year of birth. Solidlines indicate no additional pollutant exposure; dotted lines indicate additional pollutant exposure. The circle indicates the years withthe most dramatic increase. Adapted, with The changes in living habits include also the increased trend homes with wall-to-wall carpeting has also increased. At of young women to smoke, increased psychologic stress, and the same time, there is an increasing tendency to keep altered living and entertainment habits of children, who sit pets, as shown in Germany (Table 4; [34]).
for many hours in front of the TV, thereby decreasing theirphysical activity and increasing the exposure to indoor The exposure to pollen allergens may also have changed allergens (T Platts-Mills, personal communication).
due to atmospheric pollution over the big cities leading tolonger-lasting elevated pollen counts even during the Allergen exposure
night as well as to altered allergen release from pollen by There is no allergy without exposure to allergen. This expo- interaction with pollutants (see below) [35•].
sure to allergens, both indoors and outdoors, has considerablychanged both quantitatively and qualitatively during the past Decreased stimulation of the immune system because
few decades. Eating habits show a tendency towards more of improved hygiene (‘jungle’ or ‘hygiene’ hypothesis)
and more exotic foods and spices already in early life There is no doubt that the immune system of people liv- followed by a trend towards more and more ‘fast food’.
ing in Western societies is no longer ‘trained’ or challengedas it used to be in the past by severe infectious diseases of Indoor exposure to house-dust-mite allergens [29•,30–34] viral, bacterial, fungal or parasitic origin. A major defense probably has increased during the past few years due to the mechanism for parasitic infestation — namely IgE anti- striving for insulation and energy saving. The number of bodies — is still present and may now be directed against Increasing prevalence of pet-keeping in East and West German homes (n = 19 090) [34].
East
City
West
City
Allergy and hypersensitivity
Arguments pro/contra the ‘hygiene’ hypothesis.
Early infections are inversely associated with atopyPopulations with high prevalence of parasitic infestation have low prevalence of hay fever and asthma Anthroposophic children have less allergies Gastrointestinal flora with high lactobacillus counts in Children raised in a farmhouse have less allergies than non-farmers’ children in the same living area Children from academic parents have increased atopy risk CD14 gene polymorphism may explain the variable Parasitic infestation associated with higher risk of urticaria Several microorganisms (B. pertussis, RSV) increase IgE Active tuberculosis does not decrease Th2 reactivity 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 Pertussis vaccination can protect children from atopy by High prevalence of allergy in poor areas of developing Outdoor NO2 concentration and prevalence of pollen sesitization and Modern (‘type II’) air pollution is associated with higher hay fever in schoolchildren in suburbs of Düsseldorf (Düsseltal and Friedrichstadt). It shows the association between exposure to traffic- Mouse models of atopic eczema are normal under SPF related outdoor NO2 levels, atopic sensitization against aeroallergens conditions and develop eczema only when kept and syptoms of hay fever in 306 nine-year-old German children.
Percentages were adjusted and regression lines plotted for equidistantexposure groups in urban areas. In Düsseltal, there were <40 351 RSV, respiratory syncytial virus; SPF, specific-pathogen-free.
vehicles per 24 hours; in Friedrichstadt, there were <50 914 vehiclesper 24 hours. Adapted, with permission, from [61].
innocent environmental substances such as pollen or otherparticles (i.e. the ‘jungle’ or ‘hygiene’ hypothesis) [36•].
the CD14 gene has been shown to be associated with Populations with a high degree of parasitic infestation usu- ally show increased values of total serum IgE but lowerprevalence rates of asthma and hay fever [16,36•]. In the It may be that the microbial stimulation in the gastroin- comparison of East and West German school children, testinal tract plays a more important role than respiratory serum concentrations of total IgE were strikingly higher in infections. Studies investigating Italian military men the East [37], which was not reflected by specific IgE anti- showed a much lower rate of gastrointestinal infection in bodies against common environmental allergens in RAST allergic recruits [45]. Studies from Northern Europe found assays, but was dependent upon the number of people characteristic differences in the intestinal microflora living in one apartment. There was a significantly higher regarding Lactobacillus species and anaerobic organisms in proportion of East German children with parasitic infesta- children with and without allergy [46].
tion compared with the West [37]. Children who grew upin early life in a day-care facility develop less allergies later Upper-respiratory-tract infections in the first year of life as well as herpesvirus-type infections seem to have an allergy-protective effect leading to decreased prevalence In almost all epidemiological studies comparing urban and rates of asthma, wheezing or hay fever at 7 years of age; rural areas, it was found that allergies are more prevalent in however, repeated lower-respiratory-tract infections, the city. Children who were raised in a farmhouse with especially with respiratory syncytial virus (RSV), showed a heavy exposure to farm animals and endotoxin had less positive association with asthma and wheezing [47,48].
allergies than children living in the same area but not in afarmhouse. These results have been shown for Swiss, The supporters of the ‘hygiene’ hypothesis also quote Austrian, Finnish and German children as well as studies from anthroposophic children with less atopic Aborigines in Australia [39•,40–42]. The exposure to diseases [49] or people who, after measles infection, various infectious agents and endotoxin may lead to stim- seemed to be protected against allergies [50]. This has led ulation of blood mononuclear cells, leading to production to practical recommendations against vaccination programs of IFN-γ and a Th1 cytokine secretion pattern [43,44].
in order to prevent allergy. Our own studies have shown Notably, a genetic polymorphism in the transcription of that pertussis vaccination is able to protect children from Why are allergies increasing? Ring et al.
atopic diseases by preventing pertussis infection characteristic for Eastern Germany and is still present in (U Krämer, J Ring, H Behrendt, unpublished data).
some Eastern European countries. It is associated with Furthermore, recent animal models of atopic eczema have adverse health effects, namely upper respiratory tract been described in which mutant mice kept under specific- pathogen-free (SPF) conditions were symptom-free;however, as soon as they were kept in normal cages, they Type II air pollution is characterized by the presence of pri- developed signs and symptoms of atopic eczema [51•].
mary and secondary pollutants being emitted from outdooras well as indoor sources. It is found in highly populated The interactions between infections and the development industrialized urban areas in the Western world. This type of allergy are complex and partly conflicting (Table 5): one of air pollution has been found to be associated with has to distinguish the different kinds of microbial allergic sensitization and disease in several studies [57].
organisms (parasites, fungi, bacteria and viruses), theatopic disease manifestation (respiratory atopy versus A large number of animal experimental studies in various atopic skin disease), the period of life, the nature of the species have shown that air pollutants can enhance IgE stimulus (vaccination or infection) and maybe other under- antibody formation [58•]. In vitro studies using different lying diseases (see below). Obviously, among different cell populations showed that several pollutants (especially kinds of bacterial infections, quite contrary effects can be diesel exhaust particles) are able to shift the T-cell observed: Bordetella pertussis is a strong enhancer of IgE response towards the Th2 secretion pattern [59]. Other formation, whereas Mycobacterium species may push the pollutants may have a dual effect: cadmium can induce immune system towards the Th1 pattern [52]. Active leukotriene synthesis from rat mast cells while at the same tuberculosis does not protect from Th2 reactivity [53].
time inhibiting histamine release (reviewed in [57]).
It is definitely too early to give practical recommendations Extracts from atmospheric pollutant particles collected such as “don’t vaccinate” or “don’t wash your children” on over large cities in Western Germany were able to induce histamine release from human basophils and prime anti-IgE-induced histamine and leukotriene release as well as IL-8 Underlying diseases
secretion from neutrophil leukocyctes [57]. These experi- Apart from the genetic background, there may be certain mental findings have been supported by epidemiological underlying diseases exerting a strong stimulus against a studies [60], especially the well-known comparison Th2-secretion pattern: recently an inverse association studies of East and West German schoolchildren with between the prevalence of type I diabetes mellitus and higher prevalences of respiratory atopic disease in type-I-pol- atopic sensitization and disease has been reported [54].
luted East Germany. Similarly, associations betweenexposure to vehicle exhaust and allergy prevalence have Anti-allergic therapy
been reported in West German children. In a recent study in Recent evidence suggests that, possibly through the city of Düsseldorf it was shown that NO2 (a marker of symptomatic anti-allergic medication (e.g. H1 antagonists), outdoor pollution) was significantly associated with increas- lymphocytes may be shifted towards a Th2 pattern — hist- ing rates of pollen sensitization and hay fever [61] (Figure 2).
amine playing a role as immuno-regulator [55•]. These dataare in conflict with the results of the multicentre study In the indoor environment, exposure to environmental tobacco ‘Early treatment of the atopic child’ (ETAC), where smoke has been shown in many studies to increase the risk of prophylactic use of an H1 antagonist (namely cetirizine) the development of atopic diseases, especially when mothers was able to reduce the risk of asthma in children with atopic were smoking during pregnancy and/or lactation [62,63].
eczema sensitized to house-dust-mite and pollen [56].
Little is known about the long-term effects of other phar- Pollen grains as the major source of outdoor aeroallergen macotherapeutic regimens at the immunoregulatory level.
have been shown to interact with pollutant particles, leading to agglomeration and changes in surface structure.
Environmental pollution
In a specially designed fluidized-bed reactor chamber, Environmental pollutants have been recognized to be exposure to different gaseous air pollutants was shown to harmful to human health, especially with respect to alter the allergen release from pollen into an aqueous cytotoxicity, mutagenicity and carcinogenicity. The role of milieu. Thus SO2 induced a decrease in allergen release, pollutants in allergy is still controversial. In studies whereas type-II pollutants such as volatile organic evaluating the role of pollutant exposure, it is crucial to compounds promoted pollen-grain activation [64].
distinguish between different qualities of air pollutants, atleast between two types, as detailed below.
Recently we found that, under humid conditions, pollengrains themselves secrete significant amounts of pro- Type I air pollution is characterized by primary pollutants inflammatory eicosanoid-like substances able to attract such as SO2, large particles and dust fall, emitted predom- neutrophil granulocytes and activate eosinophils. This inantly from outdoor sources. This type of air pollution was process of ‘initiation of allergy’ precedes the allergen−APC Allergy and hypersensitivity
Determinants influencing the development ofallergic diseases. Adapted, with permission, Adjuvant factors:air pollutants,for example diesel exhaust, ozoneand ETS Lack of protective factors:infections?vaccination? (antigen-presenting cell) interaction and may be the first Woolcock AJ: The burden of asthma. ACI Int Suppl 2000, 1:53-56.
step in the process of atopic sensitization (see the review Simons E (Ed): Ancestors of Allergy. New York: New York Global by Behrendt and Becker, this issue, pp 709−715).
Ring J: Erstbeschreibung einer atopischen Familienanamnese im
Conclusions
julisch-claudischen Kaiserhaus: Augustus, Claudius, Britannicus.
Hautarzt 1983, 36:470-474. [Title translation: First report of a family
Although there is no doubt that the prevalence of certain anamnesis of atopy in the House of the julian-claudian emperors: allergic, especially atopic, diseases has increased during the past few decades in many countries of the world, the caus- Burr ML (Ed): Epidemiology of Allergic Diseases. Basel: Karger; 1993.
es of this increase cannot be explained satisfactorily at the Wahn U, Wichmann H: Special Report on Allergies (in German). moment. There exist only hypothetical explanations with Federal Statistical Office FS. Stuttgart: Metzler-Poeschel; 2000.
higher or lower degrees of plausibility. It may well be that Taylor B, Wadsworth M, Wadsworth J, Peckham C: Changes in the
not only one, but several, factors act together in this reported prevalence of childhood eczema since the 1939–45 war.
Lancet 1984, 2:1255-1258.
respect. It becomes more and more obvious that factorscharacteristic of a ‘modern society’ (‘Western society’) that Varjonen E, Kalimo K, Lammintausta K, Terho P: Prevalence of atopic
disorders among adolescents in Turku, Finland. Allergy 1992,
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the process of a developing allergy — from genetic suscep- asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC.
The International Study of Asthma and Allergies in Childhood
tibility, via allergic sensitization, to airway and skin (ISAAC) Steering Committee. Lancet 1998, 351:1225-1232.
hyper-responsiveness and finally a manifest allergic disease This report of the ISAAC program shows a tremendous variation in allergyprevalence around the world.
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13. Schäfer T, Vieluf D, Behrendt H, Krämer U, Ring J: Atopic eczema
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