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Keywords:

  • allergic symptoms;
  • atopic dermatitis;
  • follow-up;
  • prognosis;
  • risk factors;
  • sensitization

Abstract

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Background: The prognosis of atopic dermatitis is usually good, but the risk of developing asthma and allergic rhinitis is very high. The aim of this study was to follow children with atopic eczema up to school age to chart the course of sensitization and development of clinical allergy, as well as to study risk factors of sensitization.

Methods: Ninety-four children with atopic dermatitis were followed up to 8 years of age. The children were examined twice a year up to 3 years of age, and thereafter once yearly. At each visit, a clinical examination was performed, and a blood sample was taken. After 3 years of age, skin prick tests (SPTs) with inhalation allergens were performed at each visit. Information was obtained about atopy in the family, feeding patterns during infancy, symptoms of atopic disease, infections, and environmental factors.

Results: During the follow-up, the eczema improved in 82 of the 94 children, but 43% developed asthma and 45% allergic rhinitis. The risk of developing asthma was higher in children with a heredity of eczema. Presence of severe eczema at the time of inclusion in the study was associated with an increased tendency to produce food-specific IgE. An early onset of eczema was associated with an increased risk of sensitization to inhalant allergens, and development of urticaria. Early allergic reactions to food were associated with later reactions to food, allergic rhinitis, urticaria, and sensitization to both food and inhalant allergens. Early feeding patterns, time of weaning, and introduction of solid food, did not influence the risk of development of allergic symptoms. A large number of periods or days with fever during the follow-up was associated with an increased risk of developing allergic rhinitis and urticaria.

Conclusions: Our results confirm the good prognosis for dermatitis and the increased risk of developing asthma and allergic rhinitis. Development of otherallergic symptoms or sensitization was associated withthe following factors: a family history of eczema, age at onset of eczema and its severity, early adverse reactions to foods, and proneness to infections.

Infants and young children with atopic dermatitis (AD) are at great risk of developing respiratory allergy later in life with rhinitis, eye symptoms, and sometimes asthma. The reported risks range between 50% and 75% ( 1–6). The risk is greater in children with severe eczema; in clinical experience, only a few children with severe eczema do not seem prone to develop IgE-mediated allergy. For unknown reasons, eczema and respiratory allergies are increasing in our society. It is not yet known whether the increasing prevalence of eczema is accompanied by a poorer long-term prognosis for eczema. The aim of our study was to follow a group of children with atopic eczema up to school age to determine the course of sensitization and development of clinical allergy, and study the risk factors of sensitization.

Material and methods

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

One hundred children with atopic dermatitis were recruited in Uppsala and Örebro, two middle-sized cities in Sweden. Most of them attended the allergy clinic, but a few were also referred by child welfare clinics when it became known that we wanted to do a prospective follow-up study. Ninety-four of these 100 children (Uppsala 45, Örebro 49), aged 4–35 (median 17.0) months at recruitment, completed the study. The inclusion criteria were pruritic eczema on an area of at least the size of the child's hand, and a duration of the disease of at least 3 months.

The children were examined every 6 months up to 3 years of age and thereafter once yearly up to 7 years of age. At each visit, the child was examined, and a blood sample was taken, and after 3 years of age, skin prick tests (SPTs) with inhalation allergens were performed every year. At the first visit, a questionnaire was filled in about background factors such as heredity of atopy and eczema, symptoms of bronchial obstruction and atopic dermatitis, feeding patterns during infancy, and development of eczema and other possibly allergic symptoms. On the follow-up visits, a written form, based on an interview, was filled in containing questions about exposures and events since the last visit: furry animals in the home; environmental tobacco smoke; number of days with fever (>38.5°C); number of febrile episodes; occurrence of bronchial obstruction, rhinoconjunctivitis, periods with snoring and coughing, and urticaria; severity of eczema, area involved, and treatment; and number of adverse reactions to food as well as the offending foods. All background factors are listed in Table 1. The children were seen at an interval of at least 36 months between the first and the last visit. Moreover, all children were at least 60 months old at the last visit. During the study, the children were examined on 632 occasions, with a mean of 6.7 visits per child.

Table 1.  Background factors on admission to study (explanatory factors). Frequencies as percentage (n=94 except for fx5)
Heredity
Family history of atopy, single or double69
Family history of atopic dermatitis, single or double58
Feeding patterns during infancy
Breast-feeding ended before 6 months of age53
Introduction of cow's milk-based formula
before 4 months of age44
Introduction of hen's egg before 12 months of age69
Introduction of fish before 7 months of age35
Eczema
Onset of eczema before 4 months of age51
Eczema score 6–8 on first examination52
Food reactions
Any adverse food reaction before 36 months of age63
Adverse reaction to cow's milk, soybean, hen’s egg, or fish
before 36 months of age42
Positive fx5 (n=87) before 36 months of age 61

In analysis of the data, the follow-up time was divided into three periods for simplification. One visit in each period was evaluated. These three index visits were as follows:

Period 1. The first index visit was the inclusion visit. The children were 4 months to 3 years old, mean age 18.3 months.

Period 2. The first visit as soon as possible after the age of 3 years. The children were 3–5 years old, mean age 42.0 months.

Period 3. The last visit in the study; on this occasion, the children were 5–8 years old, mean age 85.5 months.

Definitions and methods

Atopic dermatitis was defined as pruritic, chronic, or chronically relapsing dermatitis, with typical features and distribution, as suggested by Hanifin & Rajka ( 7). A score was used to evaluate the severity and extent of involvement (graded 0–3 each), and the treatment (grade 0–2), making a maximal score of 8 ( Table 2). The total eczema score at each visit was plotted, and an eczema coefficient was calculated with a regression line through each score value. Bronchial asthma was defined as three or more episodes of bronchial obstruction diagnosed by a physician. Allergic rhinoconjunctivitis was defined as development of rhinitis and conjunctivitis at least twice after exposure to a particular allergen and unrelated to infection. Urticaria was defined as a history of typical symptoms. Atopic heredity was regarded as present if at least one of the family members had shown symptoms of atopic dermatitis, bronchial asthma, or allergic rhinoconjunctivitis.

Table 2.  Sum of scores for severity, extent of involvement, and treatment was used as eczema score in this study
Severity (mean of worst area corresponding to size of child's hand)
0: healthy
1: superficial, pale, dry, no obvious itch
2: red, moderate itch
3: red with papulovesicles, sometimes oozing or infected; severe itch
Area
0: healthy
1: area less than child's hand
2: area corresponding to 1–4×size of hand of child
3: larger area
Treatment during last week
0: no treatment
1: daily treatment with emollients and/or group 1 steroid
2: at least five treatments with steroid stronger than group 1

SPTs were performed as single tests on the forearm of the child with the following allergens (Allergo-logic Laboratory, Copenhagen [ALK], Copenhagen Denmark, 10 SQ/ml): birch, timothy, and mugwort pollen; cat, dog, and horse epithelia; Dermatophagoides farinae and D. pteronyssinus; and Cladosporium herbarum. In addition, extracts of egg and fish (ALK) and commercial skimmed milk were used for SPT when needed. Histamine hydrochloride 10 mg/ml was used as a positive control. A mean wheal diameter of at least 3 mm after 15 min was regarded as a positive test.

After venepuncture and coagulation, blood serum was separated and stored at −20°C pending analysis. Determinations of allergen-specific IgE antibodies to individual allergens and to a panel of six food allergens (fx5 containing allergens from hen's egg, cow's milk, cod, wheat, peanut, and soybean) or a panel of inhalant allergens (Phadiatop) were performed with Pharmacia CAP-RAST, according to the manufacturer's instructions. In the presentation of data, explanatory and outcome parameters are used. As explanatory para-meters, the choice fell on family history of atopy and eczema, feeding pattern during infancy, age at onset of eczema and the severity of eczema at the first visit, food reactions before 36 months of age, a positive fx5 before 36 months of age, presence of furry animals at home, exposure to indoor tobacco smoke, 2 or more days with fever (≥38.5°) in the last month preceding at least two visits, and more than three febrile episodes 6 months before any visit. Theseparameters were chosen because they often are discussed asbeing allergy risk factors.

Our outcome parameters ( Table 3) included asthma, urticaria, allergic rhinoconjunctivitis, adverse food reaction after 36 months of age, less than average healing of the eczema, eczema score of ≥3 at the last visit, positive SPT or RAST for inhalation allergens after 36 months of age, and a positive fx5 after 36 months of age.

Table 3.  Outcome parameters
 (%)
Asthma47
Urticaria at least once51
Allergic rhinoconjunctivitis at least twice50
Adverse food reaction after 36 months of age56
Less than average healing of eczema,
 according to eczema coefficient50
Eczema score 3 or more at last visit49
Positive SPT or RAST for inhalation allergens
 after 36 months of age78
Positive fx5 after 36 months of age (n=84) 44

Statistics

All explanatory factors were analyzed against outcome parameters, using ORs with 95% confidence intervals. To identify the factors that best predicted the outcome parameter, asthma development logistic regression was used. The selection method was backward stepwise elimination with the likelihood ratio. The analyses were performed with the SPSS program for Windows, Release 8.0.

Ethics

All parents of the participating children gave their oral consent after receiving oral and written information. The ethics committee of the Medical Faculty in Uppsala and Örebro approved the study.

Results

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Initial findings

On admission to the study, the mean eczema score was 5.4±1.3 (range 2–8; median 6.0). Even at this early stage, 24 children had shown symptoms of bronchial obstruction (mean age 22.6 months at recruitment), 13 children had experienced symptoms of allergic rhinoconjunctivitis (mean age 22.9 months), and 59 children had reacted to foods (mean age 17.7 months) ( Table 4). Of these 59 children, 31 had reacted to cow's milk, hen's egg, fish, or soybean, and the remaining 28 children only to fruits and vegetables. The reactions were unspecified dermal reactions ( 19), airway symptoms ( 19), gastrointestinal symptoms ( 14), anaphylactic reactions ( 5), and worsening of the eczema ( 2). Adverse reactions to food were reported in 71% of children with severe eczema (score 6 or more) and in 51% of children who had less severe eczema initially (OR 2.6, 1.1–6.4). Furry animals occurred in 15 families, in 12.3% of the families with atopic heredity, and in 25.0% of families without such heredity.

Table 4.  Results of examinations and history on first visit ( 1), first visit after 3 years of age ( 2), and last visit ( 3)
Time at examination123
Age (months, mean±1 SD)18.3±8.542.0±5.085.5±6.3
Eczema score (mean±1 SD)5.4±1.33.5±2.22.4±2.3
Bronchial obstruction in last year (%)263343
Rhinoconjunctivitis in last year (%)143745
Adverse food reaction in last year (%)633931
Furry animals at home (%)16514
Exposure to environmental tobacco
 smoke (%)313026
Eczema score 6–8 (%)522113

Clinical course

Of the 94 children, all but 12 showed a decreasing eczema score during the study period ( Table 4). At the first visit after 3 years of age, 18 children no longer had eczema; 10 of the 24 children with a history of bronchial obstruction on the first examination were asymptomatic, but 17 other children now had obstructive symptoms. Of these 17 children, 13 had shown clinical signs of allergy, and a further three were sensitized to inhalants without clinical allergy symptoms. A total of 35 children had developed allergy symptoms of the nose and/or eyes.

At the last visit, 33 children had no eczema, six had a score of 1, and seven a score of 2.

The percentage of children with symptoms of bronchial obstruction the year before the visit increased from 26% at the onset of the study to 43% at the last visit. The corresponding figures for allergic rhinoconjunctivitis were 14% and 45%, respectively. Urticaria was reported to have occurred at least once in 51% of the children, and on two or more occasions in 27%.

At the end of the study, only 14 children had never experienced symptoms of asthma or allergic rhinoconjunctivitis, and in these children eczema had almost disappeared (eczema score 0–2). At all three index visits, about 20% of the children were reported to have had more than 2 days with fever during the last month, and about two out of three were reported to have had at least one febrile episode during the preceding 6 months.

Risk factors – asthma

When the 44 children who had asthma at the end of the study were compared to the 50 children who did not have it ( Table 5), we found that a positive heredity of eczema and an initially high eczema score were significantly associated with an increased risk of developing asthma. An even higher risk of developing asthma was found in children with a positive fx5 before 36 months of age. Only one out of 14 children who never became sensitized developed asthma symptoms.

Table 5.  Children with or without diagnosis of asthma in relation to some explanatory factors
 Asthma yes n=44 %Asthma no n=50 %Odds ratio
Heredity of atopy78642.0 (0.8–5.0)
Heredity of eczema71462.9 (1.2–6.9)
Breast-feeding ended before
 6 months of age51550.9 (0.4–1.9)
Onset of eczema before
 4 months of age53491.2 (0.5–2.7)
Eczema score 6–8 at visit one64412.6 (1.1–6.1)
Exposure to environmental
 tobacco smoke38351.1 (0.5–2.7)
Furry animals at home18350.4 (0.2–1.1)
Positive fx5 before 36 months
 of age79435.0 (1.9–12.8)
Adverse food reactions before
 36 months of age82652.5 (0.9–6.5)
Adverse reactions to cow’s milk,
 hen’s egg, fish, or soybean
 before 36 months of age47371.5 (0.7–3.4)

Heredity of atopy, feeding patterns during infancy, and time at onset of eczema did not significantly increase the risk of developing asthma. Among children with heredity of atopy, the OR for development of asthma was 2.0 (0.8–5.0) and for allergic rhinoconjunctivitis 1.4 (0.6–3.4). No influence of tobacco smoke or presence of furred animals at home was observed. Early adverse food reactions increased the risk of developing asthma, but not significantly. A multivariate analysis with relevant factors for asthma development showed that a heredity of eczema and a positive fx5 before 36 months of age were significant.

Risk factors – sensitization with or without respiratory allergic symptoms

A family history of atopy or eczema was associated with a high risk (86% and 87%, respectively) of becoming sensitized to inhalant allergens at 36 months of age or later; the risk of developing asthma or allergic rhinoconjunctivitis was lower (54%vs 59% and 52%vs 54%).

No feeding pattern during infancy was associated with an increased risk of becoming sensitized or developing clinical allergy. No increased risk was seen even in the group of 10 children who were breast-fed less than 1 month.

An onset of eczema before 4 months of age was associated with an increased risk of becoming sensitized to airborne allergens at 36 months of age or later, and of developing urticaria, but not of developing respiratory allergy symptoms. In the bivariate analysis, the severity of the eczema at the first visit was associated with the risk of developing asthma, but not with the risk of developing rhinoconjunctivitis (OR=1.3) or urticaria (OR=1.0).

A greater number of days with fever or febrile episodes was associated with nasal allergy and urticaria, but not with asthma (OR=1.7).

Adverse reactions to foods before 36 months of age were also associated with later adverse food reactions and increased risk of rhinoconjunctivitis, urticaria, and sensitization to airborne and food allergens. Children who had experienced an adverse food reaction when consuming cow’s milk, soybean, fish, or hen's egg before 36 months of age had a significantly higher risk of developing food reactions (72%), a positive fx5 after 36 months of age (72%), and increased risk of urticaria (72%).

A positive fx5 before 36 months of age was found in 53 of 87 children (61%), and 92% of these developed IgE antibodies against airborne allergens during the study. Among children with a negative fx5 before 36 months of age, the corresponding figure was 56%. A positive fx5 before 36 months of age was also associated with a high risk of developing allergic nose/eye symptoms (70%) and urticaria (70%).

Thirty-three children had no asthma or rhinoconjunctivitis after 36 months of age. In comparison with the other children, we found that they had less heredity of atopy (63%vs 75%) and eczema (49%vs 63%), and later onset of eczema (46%vs 54%). Significant correlations, with all explanatory and outcome factors analyzed, are presented in Table 6.

Table 6.  Significant findings in bivariate analyses with all explanatory and outcome parameters
Outcome factorExplanatory parameterOR (95% CI)
AsthmaHeredity of eczema2.9 1.2–6.9
 High eczema score at visit one2.6 1.1–6.1
 Positive fx5 before 36 months of age5.0 1.9–12.8
UrticariaOnset of eczema before 4 months of age2.6 1.1–6.0
 Environmental tobacco smoke0.4 0.2–0.9
 Increased number of days with fever
  (>2 days with fever last month)3.2 1.4–7.5
 Increased number of febrile episodes
  (at least one in last 6 months)2.9 1.2–7.1
 Adverse food reactions before 36
  months of age3.8 1.4–10.2
 Adverse reactions to cow’s milk, hen’s egg,
  fish, or soybean before 36 months of age4.5 1.5–10.8
 Positive fx5 before 36 months of age7.5 2.8–20.1
Allergic eye-
 nose symptomsFurry animals at home0.3 0.1–0.8
 Increased number of days with fever
  (>2 days with fever last month)2.9 1.2–6.7
 Increased number of febrile episodes
  (at least one in last 6 months)2.6 1.1–6.1
 Adverse food reactions before 36
  months of age3.6 1.3–9.6
 Positive fx5 before 36 months of age8.9 3.2–24.7
Adverse food reactions
 after 36 months of ageAdverse food reactions before 36
  months of age5.1 1.9–14.1
 Adverse reactions to cow’s milk, hen’s egg,
  fish, or soybean before 36 months of age3.1 1.3–7.3
 Positive fx5 before 36 months of age4.2 1.7–10.6
Positive SPT or RAST for
 inhalation allergens
 after 36 months of ageHeredity of atopy3.6 1.3–10.3
 Heredity of eczema3.3 1.2–9.3
 Onset of eczema before 4 months of age3.0 1.0–8.6
 Adverse food reactions before 36
  months of age3.9 1.4–11.0
 Positive fx5 before 36 months of age9.7 2.9–32.9
Positive fx5 after 36
 months of ageAdverse food reactions before 36
  months of age4.4 1.4–13.6
 Adverse reactions to cow’s milk, hen’s egg,
  fish, or soybean before 36 months of age4.7 1.9–12.1
 High eczema score (6–8) at visit 12.6 1.1–6.4

Discussion

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Our patient material was selected to include infants and young children with mild-to-severe eczema, in order to study the risk patterns of sensitization and development of clinical symptoms of allergy. These 94 children were followed until they were 5–8 years of age. We used our own eczema scoring system, since, at the time our study was planned, no such system was generally accepted. Our system, like most others, takes into consideration the extent and severity of eczema ( 8–11). Unlike most other systems, we also included the treatment of the eczema before each visit, since the type and intensity of treatment influence at least the severity of the eczema. Different grading systems are not interchangeable, and our scoring system therefore cannot easily be converted into other systems ( 12).

In our study, we confirmed that the prognosis of childhood eczema is usually good ( 6, 13).

Although not all infants with eczema who fulfill the criteria of atopic eczema have positive skin tests and/or RASTs, the eczema usually is a marker of an atopic disposition that is accompanied by a high risk of early sensitization to allergenic foods and of later sensitization to airborne allergens ( 5, 14–22). This high risk was confirmed by our study. Of 94 children with eczema, 50% developed allergic rhinitis and 47% developed asthma before 7 years of age. Moreover, a further 18% were sensitized to inhalant allergens, but had not yet developed clinical symptoms from the airways. Although we included no control group of children without eczema, these figures are six to eight times higher than those reported in Sweden for allergic rhinitis and asthma among children in this age group ( 4–6, 23). An early onset of IgE-mediated food allergy in an infant with atopic eczema indicates the presence of a Th2-dominant lymphocyte pattern with a cytokine profile facilitating an IgE response to environmental antigens. It is therefore not surprising that an early manifestation of IgE-mediated food allergy is accompanied by a very high risk of sensitization to airborne allergens and a high risk of developing asthma and allergic rhinitis ( 24). Only 17 of the 69 children (25%) with symptoms of food allergy before 36 months of age failed to develop asthma or allergic rhinitis during the study.

Atopic heredity was associated with a significantly increased risk of becoming sensitized to airborne allergens, but not of developing clinical allergy. This may seem remarkable, but the atopic trait affects the likelihood of producing allergen-specific IgE, and not necessarily organ or tissue sensitivity and reactivity, which are influenced by local factors. It is probable that some of the sensitized children in our study group will develop allergy symptoms later. As children with atopic heredity had ORs of >1 for asthma and allergic rhinoconjunctivitis, it is possible that a significant association could have been found if a larger number of children had been included.

Other risk factors included early onset of eczema and initially severe eczema. This has also been reported in other studies ( 24, 25). Severe eczema, but not an early onset, was associated with sensitization to food allergens. This is in agreement with other studies showing that food allergy occurs more often in children with severe eczema ( 25, 26). The increased frequency of urticaria was observed among children with food reactions but also among children with increased rate of infections, indicating that urticaria may be caused by both allergic and nonallergic mechanisms.

It may also seem remarkable that such environmental factors as keeping furred animals and exposure to tobacco smoke were not associated with an increased risk of developing allergy and asthma, since these factors in many other studies are regarded as major risk factors for asthma and allergy ( 16, 27–32). The most likely explanation is that families with severe atopic problems avoid keeping furred animals and smoke less than the population in general and probably also less than families with less severe atopic problems. The type of infant feeding seemed to influence very little the risk of developing allergy and asthma, but the design of our study is not optimal for evaluation of food as a risk factor since all children suffered from atopic eczema.

In conclusion, our study has confirmed the good prognosis of childhood eczema, but also the increased risk of developing respiratory allergy. This risk is especially high in children with early onset of food allergy. We found no characteristics other than mild eczema, and late onset of eczema in the children under study, who did not become sensitized to airborne allergens before school age. Sensitization to individual food and airborne allergens will be reported in a forthcoming paper.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

The excellent technical assistance of Charlotta Maherzi is gratefully acknowledged. Konsul TH C Bergs Stiftelse, Stockholm, Sweden, and Astma-Allergiförbundet Sweden supported this study.

References

  1. Top of page
  2. Abstract
  3. Material and methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References