Rostrum
How epidemiology has challenged 3 prevailing
concepts about atopic dermatitis
Hywel Williams, PhD, and Carsten Flohr, MRCPCH Nottingham, United Kingdom
We challenge 3 prevailing concepts in understanding atopic
dermatitis using data from epidemiologic studies. First, we
show that although atopy is associated with atopic dermatitis to
some degree, its importance is not likely to be a simple cause-
and-effect relationship, especially at a population level. Our
epidemiologic data do not exclude a contributory role for IgE-
mediated immunologic processes, especially in those with
existing and severe disease. Second, evidence is presented that
does not support a straightforward inverse relationship
between infections and atopic dermatitis risk. A link, if present,
is likely to be more complex, depending critically on the timing
and type of infectious exposure. Third, recent evidence suggests
that the risk of subsequent childhood asthma is not increased in
children with early atopic dermatitis who are not also early
wheezers, suggesting a comanifestation of phenotypes rather
than a progressive atopic march. Collectively, these
observations underline the importance of epidemiologic studies
conducted at a population level to gain a more balanced
understanding of the enigma of atopic dermatitis. (J Allergy
Clin Immunol 2006;118:209-13.)
Key words: Atopy, atopic march, eczema, hygiene
A number of ideas about atopic dermatitis have devel-
oped over the last 40 years, often based on clinician’s
experiences of persons with more severe disease who
present themselves for treatment. Some ideas have be-
come firmly embedded into the belief systems of practi-
tioners and researchers simply because the notions have
been promulgated many times in textbooks and at aller-
gology and dermatology meetings. Thus there is a com-
mon perception that atopic dermatitis is atopic (by atopy,
we mean demonstration of IgE sensitization in the serum
or a positive skin prick test response).1 Another popular
idea is that the increase in atopic dermatitis is mainly
due to a lack of infections: the so-called hygiene
From the Centre of Evidence-Based Dermatology, University of Nottingham
King’s Meadow Campus.
Disclosure of potential conflict of interest: C. Flohr receives grants/research
support from the Radcliffe Research Fellowship at University College,
University of Oxford, and is employed by the University of Nottingham.
H. Williams has declared that he has no conflict of interest.
Received for publication February 28, 2006; revised April 24, 2006; accepted
for publication April 25, 2006.
Available online June 8, 2006.
Reprint requests: Hywel Williams, PhD, Centre of Evidence-Based Dermatology,
Room A103, Lenton Lane, University of Nottingham King’s Meadow Cam-
pus, Nottingham NG7 2NR. E-mail: hywel.williams@nottingham.ac.uk.
0091-6749/$32.00
Ó 2006 American Academy of Allergy, Asthma and Immunology
doi:10.1016/j.jaci.2006.04.043
hypothesis. Then there is the notion that children with
atopic dermatitis progress from skin disease through to
asthma as the child becomes older: the atopic march.
Although generating ideas from hospital patients is
fine, rigorous epidemiologic studies are needed to relate
numerators to defined populations to test such ideas. The
purpose of this short rostrum article is to provide a brief
glimpse at what epidemiology has contributed to our
understanding of the following 3 themes: (1) How atopic
is atopic dermatitis? (2) Is atopic dermatitis caused by a
lack of infections? (3) Do children with atopic dermatitis
progress to asthma? Throughout the rest of the article,
we shall refer to atopic dermatitis as eczema in accordance
with the new World Allergy Organization nomenclature
committee’s recommendations published in this journal.1
We have based our material on systematic reviews of the
literature where possible, and in the tradition of Journal
of Allergy and Clinical Immunology rostrum articles,
we have allowed ourselves some space for debate and
research recommendations in our concluding section.
HOW ATOPIC IS ATOPIC ECZEMA?
There is continuing controversy as to whether allergic
sensitization (ie, skin prick test positivity or increase of
specific IgE levels to common environmental allergens) is
an essential feature of childhood eczema. Early studies
Food allergy, dermatologic
diseases, and anaphylaxis
demonstrated very high levels of total serum IgE in chil-
dren with eczema, and in vitro research has shown skin
from affected individuals to be rich in IgE-bearing anti-
gen-presenting dendritic cells, which are considered in-
strumental in the capture of environmental allergens.2
Further studies underlying the importance of sensitization
include the observation that inhalation of house dust mite
allergen can provoke eczematous skin lesions in predis-
posed patients and that IgE receptors can act as mediators
in the clinical expression of eczema after skin application
of aeroallergens in the atopy patch test.3 Therefore it is
not surprising that many regard allergic sensitization as
an integral part and important cause of childhood eczema.
Yet despite detailed knowledge of the underlying immuno-
logic mechanisms in childhood eczema, the causative role
of sensitization in childhood eczema remains uncertain.
Recent epidemiologic research suggests that although
sensitization to environmental allergens is clearly associ-
ated with the disease phenotype that is called eczema,
it does not seem to be an important causative factor.4
Indeed, the strength of the association between allergic
209
 210 Williams and Flohr J ALLERGY CLIN IMMUNOL
JULY 2006

TABLE I. Allergic sensitization and eczema in 12 population-based studies4,5

Study Study Age, Diagnostic No AD, % AD, % Odds ratio

Study (location) population size y criteria Atopic Atopic (95% CI)

Schäfer et al,5 Schoolchildren 1845 5-14 Physician 36% specific 75% 5.27 (2.54-11.15)
1999 (Germany) IgE (ae)
Schäfer et al,6 West German 2075 5-6 Physician 26% 50% 2.84 (1.97-4.10)
2000 (Germany) schoolchildren/
East German 1926 5-6 Physician 23% SPT (ae1f) 37% 1.97 (1.43-2.71)
schoolchildren
Möhrenschläger Schoolchildren 5476 5-7 Physician 25% specific IgE 40% 2.20 (1.80-2.70)
et al,7 2006 or SPT (ae)
(Germany)
Arshad et al,8 Unselected 981 4 Physician 16% SPT (ae1f) 43% 3.86 (2.59-5.75)
2001 (UK) birth cohort
Perkin et al,9 Unselected 614 5 Physician 12% SPT (ae1f) 33% 3.0 (1.78-4.92)
2003 (UK) birth cohort
Mortz et al,10 Schoolchildren 1501 12-16 Physician 19% specific IgE (ae1f) 30% 2.23 (1.65-3.25)
2003 (Denmark)
20% SPT (ae1f) 64% 1.25 (0.77-2.02)*
6.78 (3.54-12.98)
2.50 (1.09-5.74)*
Rönmark et al,11 Schoolchildren 3431 7-8 Questionnaire Not given SPT Not given 2.34 (1.92-2.86)
2003 (Sweden) (unvalidated) (ae) physician
diagnosed
1.41 (1.24-1.62)
‘‘itchy rash
past 12 mo’’
Hattevig et al,12 Schoolchildren 242 10-14 Physician 18% specific 27% Not given
1987 (Sweden) IgE (ae)
Soto-Quiros et al,13 Schoolchildren 170 10-13 Questionnaire 76% SPT (ae) 78% 1.1 (0.5-2.4)
2002 (Costa Rica) (validated)
Yemaneberhan Cross-sectional 12876 5-601 Questionnaire 8% SPT (ae) 15% 1.99 (0.93-4.26)
et al,14 2004 (Ethiopia) household survey (unvalidated)
Leung et al,15 1994 Schoolchildren 1062 13.9 Questionnaire 21% 23% 1.1 (0.7-1.8) 
(Southeast Asia) in Hong Kong (unvalidated)
China (San Bu) 737 16.4 9% 11% 1.1 (0.6-1.8) 
Malaysia 409 15.5 4% SPT (ae) 7% 1.9 (0.6-5.6) 
(Kota Kinabalu) (mean age)
Hesselmar et al,16 Schoolchildren 412 12 Questionnaire Not given SPT Not given 1.4 (0.84-2.36)
2001 (Sweden) (unvalidated) (ae)
Food allergy, dermatologic
diseases, and anaphylaxis

AD, Atopic dermatitis; ae, aeroallergen; SPT, skin prick test; f, food allergen.
*Excluding IgE-associated sensitization to inhalant allergens as part of diagnostic criteria.
 Age- and sex-adjusted odds ratios.

sensitization and childhood eczema varies widely between
studies. Up to 50% of patients with eczema in hospital set-
tings are not sensitized, and an even greater proportion are
not sensitized in cases ascertained from community stud-
ies, as shown in the 12 population-based studies summa-
rized in Table I.4-16 A recent systematic review found
good evidence to suggest that those with more severe
eczema are also more likely to be sensitized, thus partly
explaining the higher sensitization rates in hospital versus
community studies.4 The strength of the association be-
tween allergic sensitization and the eczema phenotype
also varies between developing and industrialized nations.
Population-based data collected from 31,000 children
aged 8 to 12 years from 22 countries as part of the Interna-
tional Study of Asthma and Allergies in Childhood, using
standardized diagnostic criteria that includes physical
examinations, has shown that the association between
allergic sensitization and flexural eczema is weaker in
low-than in high-income countries.17 The population-at-
tributable risk for allergic sensitization (ie, the proportion
of flexural eczema that is directly attributable to atopy at
the population level) varies from less than 50% in affluent
countries to almost zero in a number of nonaffluent study
centers.17 Taken together, these findings suggest that aller-
gic sensitization is neither a prerequisite for childhood ec-
zema nor a uniform cause of eczema and that other risk
factors linked to western lifestyle must be sought to ex-
plain the high prevalence of childhood eczema in industri-
alized countries. At the same time, these epidemiologic
data do not exclude a contributory role for IgE-mediated
immunologic processes, especially in those with existing
and severe disease.
It having been acknowledged that some persons with
eczema are atopic and some are not, does this mean than
J ALLERGY CLIN IMMUNOL
VOLUME 118, NUMBER 1
eczema can be conveniently divided into 2 distinct types:
an allergic (extrinsic) and a nonallergic (intrinsic) pheno-
type?18 We would caution against such a premature binary
classification based on easily measurable epiphenomena
that do not necessarily play an important causative role.
Perhaps there are 5 or more types of eczema, the defining
patterns of which will become clearer as we learn more
about the genetic and environmental causes of what is cur-
rently recognized as the common phenotype of eczema.19
For example, the recent discovery of 2 independent loss-
of-function genetic variants (R510X and 2282del4) in
the gene encoding filaggrin as very strong predisposing
factors for eczema might tempt us to start dividing eczema
into dry (or defective barrier) and nondry types.20 Other
important discoveries around the corner might help to
explain the variation of eczema phenotype, and therefore
it is premature to put all our eggs into the IgE basket.21
Cohort studies of 5 years’ duration or more that
assemble children with eczema defined by reliable diag-
nostic criteria22 in early life and who are also tested for at-
opy are needed to see whether those with genuine atopic
eczema differ from those with nonatopic eczema in terms
of incidence of subsequent asthma, eczema persistence,
and eczema severity over the following years. Those con-
ducting randomized controlled clinical trials of persons
with eczema should also consider measuring atopy as a
covariate so that exploratory subgroup analysis could be
done to see whether treatment response is different in
those with and without atopy.
IS ATOPIC DERMATITIS CAUSED BY
A LACK OF INFECTIONS?
Epidemiologic studies have shown that eczema is more
common among children growing up in smaller families
and in those with a higher socioeconomic status.23 It
seems plausible that reduced exposure to certain viral
and bacterial pathogens in early life could lead to an in-
crease in eczema incidence. Deprivation in stimulation
of the developing immune system from certain microbial
antigens in the gastrointestinal mucosa or other lymphoid
tissues might lead to immunologic deviations that could
increase the risk of sensitization to environmental aller-
gens and eczema.24 Microbial antigens can act as inducers
of regulatory T cell–mediated anti-inflammatory cyto-
kines, such as IL-10 and TGF-b, and a lack of stimulation
from such cytokines could promote skin inflammation,
as seen in eczema, especially in those with a genetic
predisposition.25
However, there is currently no clear epidemiologic
evidence to suggest that exposure to a specific infection
reduces the risk of childhood eczema. In fact, a recent
systematic review found that some childhood infections,
such as measles, are associated with an increased risk of
eczema development, as shown in Table II.26 In addition,
the decreased risk of eczema seen with increased number
of siblings appears to persist after adjustment for early
childhood infections, suggesting that early postnatal or
Williams and Flohr 211
even prenatal factors, such as an alteration of the gut mi-
croflora, play an important role in eczema development.
This might be why frequent antibiotic prescribing in in-
fants increases the risk of eczema development and could
also explain why probiotics have been shown to reduce the
risk of eczema development. The protective effect on ec-
zema development seen with day-care attendance during
infancy, endotoxin exposure, and being brought up with
a pet during early life could all be mediated by nonpatho-
logic microbial stimulation of the infant’s immune system
and warrant further study.26 Microbial stimulation or lack
thereof might be important for eczema development, but
the association is far from simple. It is important for future
work to carefully examine the effect of timing and the
degree of individual microbial and other infectious ex-
posures on eczema risk. It is also possible that other en-
demic infections, such as gut parasites, simply suppress
the expression of latent eczema in certain populations in
which allergic disease rates are very low,27 and a study
is currently underway in Vietnam by the authors to evalu-
ate the effects of wide-scale deworming programs on the
subsequent expression of allergic disease.
DO CHILDREN WITH ATOPIC DERMATITIS
PROGRESS TO ASTHMA?
Although eczema, asthma, and allergic rhinitis tend
to cluster in the same individuals and families, the exact
relationship between early eczema and subsequent asthma
over time is far from clear.28 The simple notion of the
atopic march (ie, a child who progresses from eczema to
asthma and hay fever as he or she becomes older) is a pop-
ular one.29,30 Indeed, the concept formed the very basis of
the Early Treatment of the Atopic Child study, one of the
largest randomized controlled trials in the field of eczema,
a study that failed to show any benefit from the antihista-
mine cetirizine in preventing subsequent asthma in chil-
Food allergy, dermatologic
diseases, and anaphylaxis
dren with early eczema.31 Cohort studies that compare
children with early eczema with those who do not have ec-
zema and who are then followed over time to estimate the
incidence of subsequent asthma are needed to evaluate the
role of preceding eczema in subsequent asthma develop-
ment. One recent such study is the Multi-Centre Allergy
Study, a German birth cohort study that followed 1314
children from birth to 7 years.32 The Multi-Centre
Allergy Study showed that early wheeze and a specific
sensitization pattern were significant predictors for wheez-
ing at school age, irrespective of early eczema. Early
eczema without these cofactors did not confer any in-
creased risk of subsequent asthma (adjusted odds ratio,
1.11; 95% CI, 0.56-2.20). The idea of a distinct subgroup
of children with early eczema and early wheeze is further
supported by the observation of a specific sensitization
pattern to wheat, cat, mite, soy, or birch (a less prevalent
sensitization pattern at age 2 years) in that group plus sig-
nificantly reduced lung function at age 7 years. Such an
important finding needs to be confirmed in other studies,
but if true, it spells the end of the idea of a simple atopic
 212 Williams and Flohr J ALLERGY CLIN IMMUNOL
JULY 2006

TABLE II. Summary of studies on eczema and the hygiene hypothesis

No. of studies No. of No. of studies No. of

Total no. of supporting prospective not supporting prospective
Hypotheses studies hypothesis studies hypothesis studies

Environment
Basic hygiene 1 1 1 — —
Day care 2 2 2 — —
Anthroposophic lifestyle 1 1 0 — —
Farming 6 0 0 6 2
Animals 7 4 4 3 0
Endotoxin 3 2 2 1 1
Infection
Childhood infections 9 0 — 9 2
Hepatitis A and B 1 0 — 1 0
Herpes simplex 1 0 — 1 0
Helicobacter pylori 2 1 0 1 0
Endoparasites 2 0 — 2 0
Tuberculosis and BCG 5 0 — 5 1
Tuberculin response 4 1 0 3 1
Prevention of infection
Vaccinations 6 2 1 4 1
Antibiotics 8 5 2 3 1
Treatment
Probiotics 4 4 4 0 —
Mycobacterium vaccae 2 1 1 1 1

Values in bold indicate where the evidence from longitudinal studies supports an association with childhood eczema.

march from eczema to asthma and instead points to an
early comanifestation of 2 phenotypes at an early age.33
The link between eczema and asthma is further challenged
by positional cloning studies that suggest a closer relation-
ship between eczema and psoriasis than between eczema
and asthma.34 It has also been noted previously that the
epidemiology of eczema seems to be much more aligned
to allergic rhinoconjunctivitis than asthma.35 Perhaps
eczema is not that close to asthma after all, and they cluster
together simply because they happen to share some caus-
ative risk factors. Let the cohort studies begin . . .
Food allergy, dermatologic
diseases, and anaphylaxis
disease.37 Children with eczema who do not exhibit early
wheezing are probably not at an increased risk of signif-
icant asthma compared with children who do not have
eczema, and such information could be quite useful in
the consultation of the family of a young child with
eczema.
Future research should adhere to the new World
Allergy Organisation nomenclature to assist in scientific
communication,1 and where possible, children with ec-
zema should be tested for atopy so that the role of atopy
in determining prognosis, disease associations, severity,

and responsiveness to treatment can be determined.

WHERE DO ALL THESE EPIDEMIOLOGIC
DATA LEAVE US?
We have challenged 3 prevailing concepts in the field of
eczema with epidemiologic research based on systematic
reviews of the literature. It is all very well challenging
prevailing concepts with epidemiologic evidence, but
where does that leave the practicing clinician and future
research agenda for eczema? In clinical terms the fact that
not all eczema is atopic is important to remember, so that
the consultation is not dominated by an obsession with
allergic factors: indeed, nonallergic factors, such as Staph-
ylococcus aureus, and physical factors, such as low hu-
midity, excessive heat, emotional stress, and addressing
the defective barrier function, might be just as important.36
Because the relationship between infections and eczema is
not a simple one, it is not surprising that therapeutic ram-
ifications, such as administration of probiotics for eczema,
has thus far been disappointing, at least for established
Infections probably play some part in regulating the de-
velopment of eczema, but future studies will need to dis-
sect the timing, magnitude, and type of such infectious
or macrobiotic stimulation to clarify those that are pro-
tective, neutral, or harmful. With regard to the natural
history of disease, we should look to more cohort studies
that evaluate the link between early wheezing in the
presence of eczema and also explore some of the ideas
suggested by Bieber38 on a new possible concept of an
atopic march from barrier dysfunction through early
sensitization to eventual autosensitization from skin
antigens.
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