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 ). 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
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 . 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
. 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
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
found for other types of allergic diseases, namely type II
Since the first description of ‘atopy’ , 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 . Using modern
to potential differences in methodology .
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 ).
polymorphisms in allergy-relevant gene products — forexample CD14, which is a receptor for endotoxin .
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 ).
*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
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 .
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
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; ).
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
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) .
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 .
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 , 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 . 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
species and anaerobic organisms in
proportion of East German children with parasitic infesta-
children with and without allergy .
tion compared with the West . 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  or people who, after measles infection,
various infectious agents and endotoxin may lead to stim-
seemed to be protected against allergies . 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 .
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 . Other
formation, whereas Mycobacterium
species may push the
pollutants may have a dual effect: cadmium can induce
immune system towards the Th1 pattern . Active
leukotriene synthesis from rat mast cells while at the same
tuberculosis does not protect from Th2 reactivity .
time inhibiting histamine release (reviewed in ).
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
secretion from neutrophil leukocyctes . 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 , 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 .
luted East Germany. Similarly, associations betweenexposure to vehicle exhaust and allergy prevalence have
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  (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 .
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.
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 .
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
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
julisch-claudischen Kaiserhaus: Augustus, Claudius, Britannicus.
: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.
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
may originate from the physical, chemical, biological or psy-
cho-social environment play a role in the development of
Wüthrich B: Epidemiology of the allergic diseases: are they really
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on the increase? Int Arch Allergy Appl Immunol
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10. Diepgen Th L: Is the prevalence of atopic dermatitis increasing?
chemical) as well protective inhibitory factors that may be
Edited by Williams W. Cambridge, UK: Cambridge
lost. At the same time it is important to distinguish between
the different levels at which these factors may interfere in
11. Anonymous: Worldwide variation in prevalence of symptoms of
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
hyper-responsiveness and finally a manifest allergic disease
This report of the ISAAC program shows a tremendous variation in allergyprevalence around the world.
(Figure 3). Only when there is reliable knowledge aboutwhich factor or substance is responsible for what, and to
12. Williams H (Ed): Atopic Dermatitis: the Epidemiology, Causes and
Prevention of Atopic Eczema.
Cambridge, UK: Cambridge University
what degree, may rational consequences be drawn for
primary prevention of allergic diseases.
13. Schäfer T, Vieluf D, Behrendt H, Krämer U, Ring J: Atopic eczema
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Optimization in Multi-implant Placement for Immediate Loading in Edentulous Arches Using a Modified Surgical Template and Prototyping: A Case Report Sérgio J. Jayme, DDS, MScD1/Valdir A. Muglia, DDS, MScD, DSc2/Rafael R. de Oliveira, DDS, MScD3/Arthur B. Novaes Jr, DDS, MScD, DSc4 Immediate loading of dental implants shortens the treatment time and makes it possible to give thepa
Leitlinien der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Halschirurgie Otorhinolaryngol Nova 2002–03;12:161–174Erhalten: 13. Juni 2003Angenommen: 27. Juni 2003 Antibiotikatherapie der Infektionen an Kopf und Hals (Konsensusbericht)1, 2 Im Auftrag des Präsidiums herausgegeben von P. Federspil, Homburg/Saar Mitglieder der Konsensuskonferenz:3 P. Federspil, Hom