The prevalence of atopic triad in children with

physician-confirmed atopic dermatitis

Roger Kapoor, MD, MBA,a Chandrakala Menon, PhD,b Ole Hoffstad, MA,b Warren Bilker, PhD,b,c
Patricia Leclerc, MA,e and David J. Margolis, MD, PhDb,d
Washington, District of Columbia; Philadelphia, Pennsylvania; and East Hanover, New Jersey

Background: Atopic dermatitis (AD) is often associated with comorbidities such as allergic rhinitis and
asthma.

Objective: We sought to describe the frequency of these comorbidities in children with AD.

Methods: We conducted a cross-sectional study of the first 2270 children with physician-confirmed AD
enrolled in a large postmarketing cohort. All were queried for information on comorbidities using a
questionnaire from the International Study of Asthma and Allergies in Childhood.

Results: In all, 71.3% reported at least one additional form of atopy (symptoms of asthma or allergic
rhinitis). A total of 33.3% reported only symptoms of asthma or allergic rhinitis whereas 38.0% reported
symptoms of asthma and allergic rhinitis. By age 3 years, nearly 66% reported at least one additional form of
atopy. A statistically significant trend toward poorer disease control was observed for those with additional
atopic illnesses (P \ .001).

Limitations: This is a cross-sectional study.

Conclusion: Individuals with AD exhibit a predisposition to additional atopic illnesses by age 3 years
and in turn the presence of these illnesses correlates with poor disease control. ( J Am Acad Dermatol
2008;58:68-73.)

T he term ‘‘atopy’’ was first introduced in 1923

and was used to describe asthma and allergic
rhinitis. Ten years later, atopic dermatitis
(AD) was added as part of the definition, giving rise
to the atopic triad. AD is a highly pruritic chronic
inflammatory skin disease that may present
From the George Washington University School of Medicine,
Washingtona; Departments of Biostatistics and Epidemiology,b
Psychiatry,c and Dermatology,d University of Pennsylvania
School of Medicine; and Novartis Pharmaceutical Corporation,
East Hanover.e
Supported by an unrestricted grant from Novartis to Trustees of
the University of Pennsylvania to conduct the design, data
management, and analysis aspects of the PEER study.
Disclosure: Ms Leclerc is an employee of Novartis. Dr Margolis has
a consulting relationship with Astellas Pharmaceuticals but not
with Novartis. Drs Kapoor, Menon, and Bilker, and Mr Hoffstad,
have no conflicts of interest to declare.
Accepted for publication June 17, 2007.
Reprint requests: David J. Margolis, MD, PhD, University of
Pennsylvania School of Medicine, 815 Blockley Hall, 423 Guardian
Dr, Philadelphia PA 19104. E-mail: margo@med.mail.upenn.edu.
Published online August 10, 2007.
0190-9622/$34.00
ª 2008 by the American Academy of Dermatology, Inc.
doi:10.1016/j.jaad.2007.06.041
Abbreviations used:
AD:
CI:
FDA:
atopic dermatitis
confidence interval
Food and Drug Administration
ISAAC: International Study of Asthma and
Allergies in Childhood
OR: odds ratio
PEER: Pediatric Eczema Elective Registry
predominantly during early infancy but may also
present during childhood or adulthood.1,2 Although
the true pathogenesis of AD remains elusive, an
association was recently noted between AD and
mutations of the filaggrin gene.1,3-8 It likely, how-
ever, has a polygenic mode of inheritance with the
clinical expression of AD being determined by many
factors such as environmental, immunologic, and
genetic.8-11 AD is a worldwide problem that con-
tinues to remain a common and agonizing illness to
patients and their families.9,12,13
The Pediatric Eczema Elective Registry (PEER)
(www.thepeerprogram.com) is an ongoing pro-
spective 10-year observational registry, which is part
of a manufacturer postmarketing commitment to the
Food and Drug Administration (FDA) and the

68
J AM ACAD DERMATOL
VOLUME 58, NUMBER 1
European Drug Agency. This long-term safety study
has the objective of examining the long-term conse-
quences of the use of pimecrolimus cream 1% in a
real-world setting. The parent of the enrolled partic-
ipant is asked to complete a biannual questionnaire
during a 10-year observation period about whether
the child’s AD is active or in remission regardless of
medication use.
The population of children enrolled in the registry
represents an uncommon opportunity to evaluate
the natural history of AD in a group of children with a
physician-confirmed diagnosis of AD. Furthermore,
one of the prerequisites for enrollment in the study is
that children must have used pimecrolimus cream
1% for at least 6 weeks for the treatment of their AD
within 6 months before entry into the study. We
undertook this study to describe the relationship
between AD and other atopic illnesses such as
asthma and allergic rhinitis in approximately the first
2000 individuals enrolled in PEER.
METHODS
Study design and population
Children for this study were selected from what is
planned to be a larger and ongoing 10-year prospec-
tive observational cohort study (registry) of children
with AD who have used pimecrolimus cream 1%. We
report here on the first 2270 children consecutively
enrolled in the study. All children were between the
ages of 2 and 17 years at the time of enrollment.
Children were recruited nationwide (United States)
through the physician’s office (dermatologists, pedi-
atric dermatologists, pediatricians, allergists, other
treating physicians, or a combination of these). The
primary diagnostic criterion is a physician’s clinical
diagnosis of AD. Per agreement with the FDA, all
individuals enrolled in this registry must have re-
ceived at least 6 total weeks of exposure to pime-
crolimus cream 1%. The exposure could be for 6
continuous weeks or 6 total weeks of intermittent
exposure within 6 months before enrollment.
Exclusion criteria for this study included history of
lymphoproliferative disease, systemic malignancy,
skin malignancy, or the use of systemic immunosup-
pression (ie, cyclosporine, tacrolimus, and metho-
trexate.). The goal of PEER is to report on systemic
and cutaneous malignancies in this pediatric popu-
lation. This report is only from data collected on
entry into PEER (those with previous systemic or
cutaneous malignancy were excluded).
Definitions of variables used in this study
The atopic triad was defined as patients with
symptoms of asthma and allergic rhinitis in addition
to AD. A family history of atopy was defined as a
Kapoor et al 69
mother, father, or sibling reporting a history of
illnesses from the atopic triad. The level of disease
control was labeled ‘‘bad’’ if the patient noted limited
disease control or uncontrolled disease in the previ-
ous 6 months.
Survey development, administration,
and sampling techniques
A questionnaire was created to survey the epide-
miologic and clinical characteristics of AD in the US
pediatric population. Items included AD status and
severity; medication use; related illnesses such as
asthma and allergic rhinitis; sociodemographic var-
iables; risk factors including pollen, fumes, dust,
pets, wool clothing, colds, cigarettes, foods, soaps,
emotion, and weather; and familial trends of atopy in
the mother, father, or siblings. With respect to
asthma, allergic rhinitis, and other allergic illnesses,
we used questions from the International Study of
Asthma and Allergies in Childhood (ISAAC).9,11,12,14-16
These questions have been used and tested world-
wide to ascertain the prevalence of asthma, allergic
rhinitis, and other allergic manifestations. ISAAC
has been used in more than 200 publications that
are listed on the ISAAC World Wide Web site (http://
isaac.auckland.ac.nz/). The questions are available
on their World Wide Web site and directly query
about symptoms of these illnesses. For example, the
ISAAC question for asthma is, ‘‘Has your child
had wheezing or whistling in the chest in the past
6 months?.’’
Analyses
For this cross-sectional study, we described our
variables using simple percentages or means with
SD. To assess the magnitude of the associations
between our AD cohort and related variables (in-
cluding familial characteristics and associated risk
factors), we used logistic regression models with a
single independent variable (unadjusted) and when
appropriate with multiple variables (adjusted) for
each model expressed as prevalence odds ratio
(OR), which is the ratio of odds of the prevalence
of an allergy versus the odds of not having the
allergy, with 95% confidence interval (CI). If rele-
vant, a test for trend for categorical data was used
to determine whether a significant trend existed.
Statistical analyses were conducted using software
(Stata, Version 9.2, Stata Corp, College Station, Tex).
This study was approved by our institutional
review board.
RESULTS
As of July 31, 2006, 2270 children with AD enrolled
in the PEER program. Of these children, 53.1% were
70 Kapoor et al J AM ACAD DERMATOL
JANUARY 2008

Table I. Demographic characteristics of our reported symptoms of both asthma and allergic
study population rhinitis. Among children 3 years and younger,
Demographic characteristic No. Percent
65.8% reported symptoms of asthma, allergic rhinitis,
or both (ie, the atopic triad). The prevalence of at
Sex
least one additional aspect of the atopic triad, apart
Male 1065 46.9
Female 1205 53.1 from AD, varied little with increasing age (65.8% # 3
Total 2270 100 years, 70.8% [ 3-6 years, 74.6% [ 6-9 years, 73.0% [
Ethnicity 9-12 years, and 74.0% [ 12-18 years). Furthermore,
Caucasian 1088 47.9 individuals who had more than one component of
African American 917 40.4 the atopic triad also demonstrated worse disease
American Indian 31 1.4 control (P \ .001 test of trend) and an increased
Asian 182 8.0 probability of a family history of asthma, allergic
Hawaiian 15 0.7 rhinitis, or AD as compared with an individual with
Unknown 37 1.6 one component of the atopic triad (Table II).
Total 2270 100
Having AD and asthma or allergic rhinitis was
Age, y
usually associated with having both (ie, all 3 compo-
#3 339 14.9
[3 and # 6 808 35.6 nents of atopic triad) and other forms of allergy. For
[6 and # 9 464 20.4 example, for those who reported having symptoms
[9 and # 12 303 13.3 of asthma, 80.3% reported a history of allergic rhinitis
[12 356 15.7 or a prevalence OR of 4.8 (95% CI: 4.0, 5.8). In
Total 2270 100 addition, individuals with symptoms of asthma also
Geographic distribution had a 3.3 (95% CI: 2.7, 4.1) increased prevalence odds
New England 43 1.9 of having an animal allergy, a 2.1 (95% CI: 1.7, 2.5)
Middle Atlantic 243 10.7 increased prevalence odds of having a food allergy,
East North Central 397 17.5 and 1.8 (95% CI: 1.4, 2.3) increased prevalence odds
West North Central 129 5.7
of having a drug allergy. A similar pattern was noted
South Atlantic 607 26.7
for an individual who reported a history of allergic
East South Central 270 11.9
West South Central 401 17.6 rhinitis along with their AD (Table III). These unad-
Mountain 75 3.3 justed estimates were not confounded by age, sex,
Pacific 98 4.3 race, or family history of the dependent variable.17
Unknown 7 0.3 A family history of atopy raised the odds of having
Total 2270 100 additional forms of atopy for children with AD. For
example, the prevalence OR of having asthma
among individuals whose mother, father, or sibling
also had asthma was 2.5 (95% CI: 2.1, 3.0), 2.3 (95%
female, 47.9% were Caucasian, and 40.4% were CI: 1.8, 2.9), and 2.2 (95% CI: 1.9, 2.6), respectively.
African American. At enrollment the mean age The odds of having allergies were also increased if
(6SD) was 7.0 6 4.1 years, the median age was 5.9 a mother (OR 3.4; 95% CI: 2.7, 4.6), father (OR 2.8;
years, and quartile range was 3.8 (25th percentile) to 95% CI: 2.2, 3.7), or sibling (OR 3.2; 95% CI: 2.5, 4.2)
9.7 (75th percentile) years. The onset of AD had a had seasonal allergies. As before, the unadjusted
mean age of 4.6 6 3.6 years and a median age of 3 estimates were not confounded by age, sex, or race.
(2,6) years. Additional demographic characteristics
are included in Table I. Approximately 46.6% of the DISCUSSION
enrolled participants reported they had either un- To our knowledge, this represents the largest
controlled disease or limited disease control during study of children in the United States that have a
the 6 months before study entry. Approximately 80% diagnosis of AD confirmed by a physician and
of the participants reported a family history (sibling, require a minimum of 6 weeks’ treatment with a
mother, or father) of atopic illnesses. topical prescription product. In this cross-sectional
Among the 2270 individuals currently enrolled study, we describe a high rate of additional atopic
in this registry, at study enrollment only 79.2% (473 illness associated with AD. For the predominant
of 2270) reported they had AD and another form number of participants in our study, we show that
of allergy including symptoms of asthma, allergic they generally presented with symptoms of an addi-
rhinitis, animal allergies, food allergies, and drug tional component of the atopic triad as early as
allergies. In addition to AD, 33.3% reported either 3 years of age. In fact, the prevalence of an additional
symptoms of asthma or allergic rhinitis and 38.0% form of atopy was the same in our study for those
J AM ACAD DERMATOL Kapoor et al 71
VOLUME 58, NUMBER 1

Table II. Number with atopic dermatitis and no Table III. Odds ratios with 95% confidence
other forms of allergy (eg, asthma, allergic rhinitis, intervals of a participant in the Pediatric Eczema
food allergies, animal allergies, and drug allergies) Elective Registry with either asthma or allergic
who had symptoms associated with asthma, rhinitis having other forms of allergy
seasonal allergies, or both among the 2270 Variable Odds ratio (95% CI)
individuals within the registry
Asthma
Additional forms of atopy Allergic rhinitis 4.8 (4.0, 5.8)
AD no history Animal allergies 3.3 (2.7, 4.1)
of asthma or Asthma or Asthma and Food allergies 2.1 (1.7, 2.5)
allergic allergic allergic Drug allergies 1.8 (1.4, 2.3)
rhinitis rhinitis rhinitis
Variable (N = 652) (N = 756) (N = 862)
Allergic rhinitis
Asthma 12.9 (10.5, 15.9)
AD, N, % 652, 28.7 756, 33.3 862, 38.0 Animal allergies 4.9 (3.8, 6.3)
Current age, 7.2 6 4.0 6.9 6 4.2 7.4 6 3.9 Food allergies 2.0 (1.7, 2.5)
y (mean 6 SD) Drug allergies 2.4 (1.8, 3.2)
Disease control
Good*, N, % 385, 59.0 398, 52.6 430, 49.9 CI, Confidence interval.
Family asthmay, N, % 141, 21.6 276, 36.5 514, 59.6
Family allergic 193, 29.6 414, 54.8 576, 66.8
rhinitisy, N, % diagnosis of AD by a physician. We may, however,
Family ADz, N, % 310, 47.5 365, 48.3 470, 54.5 have also selected children with AD who are more
likely to have additional related illnesses. Finally, we
All percentages are ratios comparing the total number with the
variable attribute as compared with the total number of
did not study those who were not determined by a
individuals in a given column. physician to have AD. Therefore, our results do not
AD, Atopic dermatitis. generalize to all individuals who have AD or to those
*P \ .001 for test of trend relating number of atopic disorders to who do not have AD.
level of disease control. The idea that individuals with AD might be
y
P \ .001 for test of trend relating number of atopic disorders to
family history of asthma or seasonal allergies.
entrapped in an atopic triad, consisting of AD,
z
P \ .001 for test of trend relating number of atopic disorders to allergic rhinitis, and asthma, has been postulated
family history of atopic dermatitis. and supported for many years, but our findings
suggest a much broader dilemma.26,27 Among our
study population, nearly 66% had at least symptoms
3 years and older. The finding that individuals with of asthma or allergic rhinitis and 38% had both
AD are more likely to develop asthma or allergic symptoms associated with their AD. In fact, nearly
rhinitis has been advanced in previous studies.9 Our 80% reported some additional form of allergic illness
results differ from previous studies in that our prev- (asthma, allergic rhinitis, seasonal allergy, food al-
alence rates of asthma and allergic rhinitis are higher lergy, animal allergy, or drug allergy) by the third
and the onset is earlier. An increasing rate of allergic year of life. Previous studies show the ratio of pure to
illnesses has been noted in recent worldwide prev- mixed AD to roughly be equal. However, these
alence estimates.4-6,18,19 In addition, several genetic studies were limited in size and scope and have
linkage studies have shown that AD and other atopic studied populations outside the United States.16
disorders share a common pathogenesis and genetic As a result of the cross-sectional design of our
basis.20,21 study, we do not know exactly when additional
As discussed in recent articles, definitions for AD diseases occurred or whether the onset of these
in previous studies have been inconsistent.22-24 diseases was modified by the patient’s control of
Some reports have defined an AD population as their AD or their use of pimecrolimus. However,
individuals who respond with a ‘‘yes’’ to the ques- because the percentage of individuals who remained
tion, ‘‘Have you had AD?’’ Others use the presence of free of both asthma and seasonal allergies after age
an itchy rash in the past 12 months, which is based on 3 years was relatively constant across all older age
clinical care as well as components of the United groups in our study, it seems likely that if an
Kingdom diagnostic criteria.7,10,15,25 We believe our additional illness is to be noted, it will be by the
criterion, a diagnosis of AD confirmed by a physician age of 3 years. This represents the possibility of a
and treated for a minimum of 6 weeks with a topical rather rapid onset of other atopic illnesses. Given
prescription product for their AD, allows for confi- that the PEER study is longitudinal, future analyses of
dent conclusions to be drawn regarding our rela- those younger than 3 years should be able to help us
tively homogeneous cohort of children given a determine exactly when individuals with AD are
72 Kapoor et al
most susceptible to developing the other atopic or
allergic illnesses.
Our findings differ from earlier findings of 100
infants from atopic families followed up during a
22-year period in the United Kingdom.28 This study
showed that the number of children with allergic
rhinitis increased throughout childhood from ap-
proximately 8% at year 1 to 69% at year 22, whereas
the annual prevalence of wheezing increased during
the course of the study from approximately 6% at
year 1 to nearly 40% by year 22.
Our data also suggest that patients who had both
asthma and allergic rhinitis had worse control of their
AD. This is consistent with data from the ISAAC
study, which suggested that the prognosis of
individuals with asthma was worse for those who
also had AD. Indeed, 41% of children with asthma,
but without AD, reported being ‘‘well’’ compared
with 34% of children with asthma and AD.27
Furthermore, our study demonstrates the relevance
of a family history for a child presenting with AD.
Approximately 85% of individuals in our study who
presented with AD and two additional forms of atopy
also reported a family history of AD, atopies, or both.
Our findings were more dramatic than previous
studies. Diepgen et al27 demonstrated that if a patient
had AD, then 42% of first-degree relatives had AD,
and 28% had a respiratory atopy. Our study suggests
that 50% and 41% of first-degree relatives of children
with AD also had AD or seasonal allergies, respec-
tively. Furthermore, a family history of asthma in a
mother, father, or sibling increased the odds of a
child with AD having asthma: OR 2.5 (95% CI: 2.1,
3.0), 2.3 (95% CI: 1.8, 2.9), and 2.2 (95% CI: 1.9, 2.6),
respectively. There was a similar pattern noted for a
history of seasonal allergies in the mother, father, or
sibling of a child with AD having seasonal allergies
with OR 3.4 (95% CI: 2.7, 4.6), 2.8 (95% CI: 2.2, 3.7),
and 3.2 (95% CI: 2.5, 4.2), respectively. This finding is
consistent with previous findings that a family history
of atopy leads to higher odds of having atopy in a
child.29 In addition, and very interesting, is our
observation that atopy is not limited to asthma and
seasonal allergy. In our study, patients also reported
a high rate of animal, drug, and food allergies.
This study has a few limitations. First, our study is a
cross-sectional report from what is planned to be a
longitudinal study. As such, we are reporting preva-
lent and not incident findings. However, future anal-
ysis from this ongoing 10-year prospective study will
allow an exact determination of when individuals
with AD are most susceptible to developing addi-
tional atopic illnesses. Second, although the diagnosis
of AD was confirmed by a physician, all other data are
reported by a parent or primary caregiver (or patient
J AM ACAD DERMATOL
JANUARY 2008
after age 18 years). However, the basis for these
reports is ISAAC survey questions. It is possible that
these questions do not properly ascertain symptoms
of asthma and allergic rhinitis. However, it is impor-
tant to note that these questions have been studied
worldwide and are the source for prevalence data
worldwide. Therefore, our results can be compared
with a large, diverse set of publications. Third, the
generalizability of our findings may be limited given
that all of our study population had AD and more
specifically had a form of AD that required treatment
with pimecrolimus cream 1% for greater than 6
weeks. It is true for our study, and for other epidemi-
ologic studies on AD, that the study population is not
a random sample from the population at large. The
enrollment criteria may imply a severity that may be
different from many of the other studies that we
discuss. Our study, therefore, may not generalize to
everyone who has AD, rather only to those given a
diagnosis by a physician and who required at least 6
weeks of treatment. These results do not generalize to
those who do not have AD. However, our population
does represent a group of those with AD who receive
medical care for AD. Also, our study population, as
noted in Table I, is large and geographically, demo-
graphically, and economically diverse.
Finally, participation in our study was entirely
voluntary and this may also play some role in the
results observed in that patients with more symp-
toms of allergic diseases may be more willing to
provide information regarding their illness, and be
more likely to recall an illness. This potential recall
bias has been described and is seen in many epide-
miologic studies. As a result, our study may over-
represent those with AD who have asthma and
allergic rhinitis. However, because all of our patients
were treated by a physician, our population does
represent those likely to seek medical care and,
therefore, includes those individuals more likely to
receive a diagnoses and treatment for AD.
AD is a substantial burden to individuals not only
because of its chronic nature but also because of the
comorbidities associated with the illness. When a
clinician speaks with a patient who has mild to
moderate AD and their family about illnesses asso-
ciated with AD, they should report that it is likely that
at least one additional component of the atopic triad
will appear by the age of 3 years. Patients with mild
to moderate AD also demonstrate a predisposition to
other forms of atopy such as animal, food, and drug
allergies. Finally, those with additional atopic illness
have worse control of their disease and a more
challenging clinical picture. As the PEER study con-
tinues to enroll and follow up children with AD
during their growing years, we will be able to refine
J AM ACAD DERMATOL
VOLUME 58, NUMBER 1
our findings and report on other medical events
associated with AD and the treatment or treatments
for this distressing illness.
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