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Objectives: To describe the development of atopic der- matitis) index. Predictive odds ratios of early skin lesions
matitis (AD) during the first 3 years of life and identify for those who developed AD vs those who did not were
the localization of the early skin lesions that predicts the calculated.
development of AD.
Results: The cumulative incidence of AD by age 3 years
Design: Prospective,longitudinal,birthcohortstudyofchil- was 44% (155/356). The prevalence rate peaked at age 2
dren born to mothers with a history of asthma, followed up years for boys and at age 2.5 years for girls, but there were
for 3 years with scheduled visits every 6 months as well as no other sex differences in the proportion of children de-
visits for onset or acute exacerbations of skin symptoms. velopingAD.SkininvolvementininfantswithADwasfound
to begin at the scalp, forehead, ear, and neck in a balaclava-
Setting: The cohort was recruited from greater Copenha- like pattern and continue to the extensor sides and trunk,
gen, Denmark, and followed up at a clinical research unit, finally affecting the flexor sides of the extremities. Early skin
whichcontrolledalldiagnosesandtreatmentofskindiseases. lesions of arms and joints best predicted AD at age 3 years.
Participants: A total of 411 infants were enrolled in the Conclusions: Atopic dermatitis begins at the scalp, fore-
cohort; 55 had incomplete follow-up and were excluded head, ear, and neck in a balaclava-like pattern. Eczema
from certain analyses. at the arms and joints provides the highest predictive value
for the development of AD at age 3 years. This may be
Main Outcome Measures: Atopic dermatitis was de- used for early prediction and intervention of AD.
fined based on the criteria of Hanifin and Rajka, and se-
verity was assessed by the SCORAD (Scoring Atopic Der- Arch Dermatol. 2006;142:561-566
A
TOPIC DERMATITIS (AD) IS A in the first years of life have been reported
chronically relapsing in- to be the head, the trunk, and the extensor
flammatory skin disease, surfaces of the extremities,9-12 although, to
which usually presents in our knowledge, the early presentation and
the first years of life1-3 and progression of eczema lesions have not been
is often associated with a family history of described prospectively in detail.
atopy.1,4,5 The cumulative incidence of AD
has increased in the previous 4 decades, CME course available at
especially in countries with a Western www.archdermatol.com
lifestyle.6-8
The primary aim of this study was to de-
Author Affiliations: Danish See also pages 555 and 633 scribe the progressively changing predilec-
Pediatric Asthma Centre, tion skin lesion pattern of AD during the first
Department of Pediatrics The diagnosis of AD is based on a syn- 3 years of life in a cohort of high-risk in-
(Drs Brydensholt Halkjær, drome of clinical criteria in which the ma- fants. Second, we aimed to identify an early
Loland, Buchvald, and jorfeaturesarepruritus,typicalmorphologic localization pattern of skin lesions that may
Bisgaard), and Danish Research features and distribution of the lesions, predict AD within 3 years of life.
Centre of Allergy, Department chronicrelapsingcourse,andpersonalorfam-
of Dermatology (Drs Agner and
ily history of atopy. The diagnosis is particu- METHODS
Skov), Copenhagen University
Hospital, Gentofte, Denmark;
larlyimpreciseinearlyinfancy,partlybecause
and Division of Biostatistics, itching, as one of the cardinal symptoms, is MATERIALS
National Medical Jewish and difficult to recognize. The morphologic fea- The Copenhagen Prospective Study on Asthma
Research Center, Denver, Colo tures are therefore instrumental to the diag- in Childhood (COPSAC) is a prospective lon-
(Dr Strand). nosis at this young age. The predilection sites gitudinal birth cohort study of 411 children (208
30
required identification by an ophthalmologist), delayed blanch
(because it required an injection of methacholine), and im-
paired cell-mediated immunity.
20 The severity of AD was scored using the SCORAD (Scoring
Atopic Dermatitis) index, ranging from 0 to 103 points,15 which
Boys
Girls includes the assessment of (1) extent, (2) intensity (erythema,
10 edema/papules, oozing/crust, excoriation, lichenification, and dry-
0.5 1.0 1.5 2.0 2.5 3.0
ness on a scale from 0 to 3), and (3) subjective symptoms (pru-
Age, y ritus and sleeplessness [using a scale from 0-10 of the parents’
subjective opinion of the child’s degree of pruritus and sleepless-
Figure 2. Atopic dermatitis prevalence rates, by age and sex, up to age 3
ness]). The severity of AD was subsequently categorized into mild
years. Subjects were included in calculations until time of withdrawal from (⬍15 SCORAD points), moderate (15-40 SCORAD points), and
the study. Prevalence rates began to decline slightly before age 3 years for severe (⬎40 SCORAD points) according to the objective com-
both boys and girls. ponents of the index (clinical signs and disease extent), ranging
Scheduled Visits, y
Abbreviations: AD, atopic dermatitis; SCORAD, the Scoring Atopic Dermatitis index.
*Data are given as mean percentage (male/female, %).
Standard operation procedures at the CRU outlined treatment Median Age at Onset, d No. of
recommendations as skin moisturizers and topical corticoste- Skin Region (25th-75th Percentiles) Infants
roids, mainly mild (hydrocortisone) for eczema located to the Scalp 108 (85-157) 16
head and genitals and mid-strength (hydrocortisone butyrate) Ear 113 (65-199.5) 20
for eczema located at the body and extremities. The amount of Forehead 116 (69-201) 26
treatment used was quantified as number, amount, and dura- Neck 153 (98-201) 37
tion of treatment courses. Elbow, ext 183 (125-368) 21
Wrist, flex 185 (123-369) 22
DATA ANALYSIS Cheek 197 (119-360) 106
Ankle, ext 198 (123-347) 33
Data were entered online into the cohort database. The central Knee, ext 198 (170-362) 25
tendency and dispersion are reported as the arithmetic mean±SD. Nose 198 (182-495) 5
Kaplan-Meier survival analysis methods were used to com- Back, upper 202 (121-370) 41
pute cumulative probabilities of AD diagnosis by age up to 3 Chest 203 (124-362.5) 48
years. Those censored in this analysis were children not com- Ankle, flex 208 (154-370) 14
pleting the study to age 3 years (censored at time of with- Forearm, ext 226 (151.5-381.5) 20
drawal) and those completing visits through age 3 years with- Abdomen 231 (120-462.5) 44
out an AD diagnosis (censored at age 3 years). This analysis Wrist, ext 238 (123-441) 31
was stratified by sex, and the log-rank test was used to com- Upper leg, ext 245 (155.5-424) 44
pare probabilities between sex across age. Upper arm, flex 251 (157-370) 19
The odds of AD diagnosis by age 3 years were computed for Chin 274 (122-475) 63
those with and without a skin lesion observed at the 18-month Foot, back 275 (183-397) 9
visit for each of 10 main body regions. Sample odds ratios (ORs) Lower leg, ext 278 (157.5-393) 32
Upper arm, ext 283 (157-397) 27
were calculated, including 95% confidence intervals (CIs) based
Back of neck 284 (102-414) 34
on asymptotic theory. For this analysis, subjects were restricted
Forearm, flex 320 (191.5-472.5) 20
to those who had had a skin lesion in at least 1 body region by Back, lower 325 (169-502) 39
the 18-month visit and completed the study through age 3 years. Perioral 339 (191-443) 39
Fisher exact and 2 tests were used to compare propor- Eye area 344 (157-441) 6
tions. P⬍.05 was considered significant. Diaper region 354 (218.5-476.5) 24
Knee, flex 367 (194-543) 57
RESULTS Upper leg, flex 370 (157-546) 24
Hand, back 370 (170-547) 19
Elbow, flex 397 (359-536) 37
The COPSAC study enrolled 411 neonates at age 1 month, Lower leg, flex 419 (195-549) 18
356 of whom provided complete follow-up data by age Hand, palm 557 (NA) 1
3 years. The earliest sign of dermatitis leading to the AD Foot, sole 576 (NA) 1
diagnosis was recorded at age 1 month, with the highest
incidence rate occurring during the second half-year of Abbreviations: AD, atopic dermatitis; ext, extensor surface; flex, flexure;
NA, not applicable.
life. For those with complete follow-up, the cumulative *Those not completing the study through 3 years of age were not
incidence of AD was 31% (109/356) at age 1 year, 41% included.
(147/356) at age 2 years, and 44% (155/356) at age 3 years
(Figure 1). The prevalence of AD peaked at age 2 years For those who completed 3 years of the study, the cu-
for boys and at age 2.5 years for girls (Figure 2). By age mulative incidence of AD was 43% (78/183) for girls and
18 months, the cumulative incidence of seborrheic der- 45% (77/173) for boys (P=.70 for difference). Kaplan-
matitis capitis was 24% in children with AD, 28% in chil- Meier estimates of the cumulative probability of AD di-
dren with skin lesions but not fulfilling AD diagnosis, agnosis by age 3 years were slightly lower (40% for both
and 21% in children without other dermatitis skin le- boys and girls). However, these estimates incorporated
sions. This mitigates against seborrheic dermatitis capi- all subjects in the cohort until they dropped out of the
tis being mistakenly diagnosed as AD. study. Differences in cumulative AD probabilities across
Most infants presented with mild AD, and only single age (0-3 years) between boys and girls were not signifi-
cases presented with severe AD. The severity of AD de- cant (P=.80). Girls and boys did not differ in AD sever-
clined with age, with an increased fraction of mild cases ity measured by the SCORAD index (objective compo-
and a reduced fraction of moderate severity and no ob- nents) (Figure 1 and Table 1).
vious sex difference (Table 1). Topical corticosteroid Skin involvement in infants who developed AD started
(mild, mid-strength, and potent) was prescribed in 7.6 at the scalp, forehead, ear, neck, and cheek and later spread
(2.9, 4.5, and 0.2, respectively) courses per child during to the extensor side of the extremities and the rest of the
the first 3 years of life, with a mean ± SD of 15 ±14 days face and trunk, finally affecting the flexor sides of the ex-
per treatment period. The non-AD lesions group re- tremities (Table 2). The most commonly involved re-
ceived a total of 4 courses (mean, 16.3 days). Systemic gions in children with AD seen at the scheduled visits
corticosteroid courses were given for respiratory symp- were the cheeks, the flexures of the knee, and the chin,
toms on 8 occasions in 7 children with AD. occurring in at least 1 in 4 infants, whereas the eye area,
60
50
40
Infants, %
30
20
10
0
Cheek
Knee, Flex
Chin
Chest
Perioral
Back, Upper
Back, Lower
Abdomen
Neck, Ext
Ankle, Ext
Neck, Flex
Wrist, Ext
Wrist, Flex
Knee, Ext
Diaper Region
Hand, Ext
Forearm, Flex
Ear
Forearm, Ext
Scalp
Forehead
Ankle, Flex
Foot, Ext
Nose
Hand, Palm
Foot, Sole
Eye Area
Elbow, Flex
Elbow, Ext
Skin Region
Figure 3. Affected skin regions at scheduled (6-, 12-, and 18-month) visits compared with visits for acute exacerbations of skin symptoms. The percentages are
based on 139 infants with skin lesions by 18 months and atopic dermatitis diagnosis by age 3 years. Ext indicates extensor surface; flex, flexure.
palm of hand, foot sole, and nose regions were very rarely the second half-year of life, with a declining incidence
affected. During the visits for acute exacerbations, the fore- rate thereafter (Figure 1). Such early onset concurs with
head, ear, neck, and eye area were more commonly af- previous reports.1,17,18
fected (Figure 3). Using survival analysis methods, the cumulative inci-
Table 3 shows the pattern of skin lesions that may dence of AD was 40% by 3 years of life in this cohort study
predict AD. Of the 356 subjects who completed 3 years of children born to mothers with a history of asthma. A re-
of the study, 139 (39%) had had a skin lesion in at least cent study based on posted questionnaires in the same geo-
1 body region by the 18-month visit and AD by age 3 years; graphic region reported that 38% of children with single
100 (28%) had a skin lesion by the 18-month visit but parental atopic history developed AD by age 4 years.5
no AD diagnosis by age 3 years; and 117 (33%) had not We used the diagnostic criteria defined by Hanifin and
had any skin lesions at any visit during these first 18 Rajka14 to identify children with AD. This classification
months of life. The risk of AD at age 3 years was esti- has been a matter of debate, especially with respect to
mated for 10 body regions, which were aggregated based the significance of some minor features in younger chil-
on anatomy and the progression seen in the children with dren.19-23 A recent study24 has demonstrated good agree-
AD (Table 2). Early lesions presenting on the arms and ment between Hanifin-Rajka criteria and other criteria
joints showed a strong correlation to later development used to diagnose AD at this young age.
of AD (OR, 7.5-11.8; maximum 95% CI, 2.7-50.9), The specificity of the AD diagnosis is probably high
whereas diaper area demonstrated no correlation to de- in our cohort because the diagnosis, detailed phenotyp-
velopment of AD (OR, 1.9; 95% CI, 0.9-4.1). The cheeks ing, and management of skin lesions was controlled solely
were affected in almost 80% of children with AD, but by the CRU physicians. This reduces the risk of misclas-
cheek involvement was likewise observed in more than sification. This reduced risk of misclassification is of par-
40% of children without AD, indicating that skin le- ticular importance in the clinical evaluation of AD, for
sions on the cheek are not specific for AD. Lesions in the which interobserver variation is a problem.25
children without AD were itchy, eczematous, and indis- The cumulative incidence of seborrheic dermatitis capi-
tinguishable from those in the children with AD. tis was not significantly different in children with AD and
in children with skin lesions not fulfilling AD diagnosis.
COMMENT This suggests that misclassification between AD and seb-
orrheic dermatitis capitis was not a major confounder.
The COPSAC prospective cohort study of high-risk in- The sensitivity of the AD diagnoses in the present study
fants provides new and precise information on the pro- was recently supported by comparing the COSPAC da-
gression of AD during the first 3 years of life. This gives tabase with the records of the family practitioner, which
new insight into early prediction of AD and improves the revealed no diagnoses of AD that was not recorded in the
ability to diagnose and intervene early. COPSAC database.
The first sign of AD was diagnosed from age 1 month. The severity of the disease was mild to moderate in most
The highest dermatitis incidence rate was found during cases (Table 1). This is in line with a recent study of a com-