Wheezing in childhood: incidence, longitudinal patterns and factors predicting persistence

Study population

The German MAS recruited 1,314 infants born in 1990 in six German obstetric departments in five German cities (Dusseldorf, Mainz, Freiburg, Gaisach, Berlin). A detailed description of the stratified sampling scheme and study subjects is given elsewhere 8. Briefly, 499 newborns with presumed risk factors for atopy (cord blood immunoglobulin (Ig)E increased to ≥0.9 kU·L⁻¹, at least two atopic family members, or both) and 815 newborns with none of these risk factors were included in the cohort. All children were followed up at 1, 3, 6, 12, 18 and 24 months, and then annually, within 4 weeks of the child's birthday, up to the age of 13 yrs. The present study was approved by the hospital’s ethics committee (University Children's Hospital, Munich, Germany) and written informed consent, at the time of enrolment, was obtained from the child’s parents.

Parental questionnaires and interviews

At each follow-up visit, parents either gave structured interviews to a study physician or completed postal questionnaires (at age 8, 9, 11 and 12 yrs). The main topics of these interviews were asthmatic and atopic symptoms and disease; questions on diet, development and psychological aspects were also included. From age 5 yrs onwards, questions relating to wheeze corresponded to the International Study of Asthma and Allergies in Childhood core questions 9. Foremost interest was in atopic symptoms and diseases. Furthermore, symptoms and diagnoses of other illnesses were assessed at every follow-up, as were maternal breast-feeding and feeding practices up to age 2 yrs. Parental smoking habits were assessed at age 1 month and pet keeping was assessed at age 3 months. Furthermore, the use of medication was assessed at every follow-up. Children regularly visited a physician independent of the study team.

Definitions

Wheeze was defined as any parent-reported wheezing in the 12 months prior to any of the follow-ups. The definitions “early wheezers” and “late wheezers” were used to describe the children starting wheezing before 3 yrs of age and at 3–6 yrs of age, respectively 10. Children who started wheezing only after 6 yrs of age were defined as “very late wheezers”. Early wheezers were further classified on the basis of the recurrence of wheezing between 4 and 13 yrs of age; they were defined as: “early persistent wheezers” if they continued to wheeze every year up to the age of 13 yrs; “early intermittent wheezers” if they wheezed in some years but not in others between 3 and 13 yrs of age; and “early remittent wheezers” if they did not wheeze from 3 yrs up to the age of 13 yrs. For the purposes of the univariate and multivariate analyses, children not wheezing before the age of 3 yrs were defined as “early nonwheezers”. Parental atopy was defined as any reporting of asthma, hay fever or atopic dermatitis ever. Early atopic dermatitis was defined as present if the parents reported at least one of the following up to the age of 2 yrs: a reported diagnosis by the family physician; a parental reporting of symptoms of atopic dermatitis; or visible atopic dermatitis at the time of follow-up. In order to exclude very mild cases of atopic dermatitis, only children with parental reports of self-scratching were included in the definition of atopic dermatitis 11. Lower respiratory tract infections in the first 3 yrs of life were defined on the basis of parental reports of symptoms and diagnoses 12.

Cord blood, total and specific IgE

Serum samples were obtained from the children at birth and at 1, 2, 3, 5, 6, 7 and 10 yrs of age. Cord blood IgE, total IgE and specific IgE antibodies to food allergens (cow's milk, egg white, soy bean and wheat) and inhalant allergens (house dust mite (Dermatophagoides pteronyssinus), cat dander, mixed grass and birch pollen) were determined by using ImmunoCAP (Phadia, Freiburg, Germany). Sensitisation to a specific allergen was defined as a concentration ≥0.70 kU·L⁻¹ of the respective specific IgE (ImmunoCAP class 2). This cut-off was chosen to constitute a stronger atopic effect than would have been by merely choosing evidence of any detectable specific IgE, i.e. ImmunoCAP class 1. Increased cord blood IgE was defined as a concentration of ≥0.9 kU·L⁻¹, and increased total IgE at age 3 yrs was defined as a concentration ≥30.0 kU·L⁻¹. This cut-off was based on the upper standard deviation limit of an equivalent aged normal infant population 13.

Assessment of indoor allergen exposure

At the ages of 6 and 18 months and 3, 4 and 5 yrs, Der p 1, Der f 1, and Fel d 1 allergens were extracted from dust samples collected by parents from the carpet and analysed with a sandwich ELISA (ALK, Copenhagen, Denmark) 14, 15. High level of exposure to a specific allergen at a specific age was defined as a measured value above the third quartile of the respective distribution in the total population.

Statistical analysis

Chi-squared tests were used to compare prevalence between groups and Mantel–Haenszel tests were used for analysing trends over categories. Generalised estimation equation models were used in order to adjust for repeated measures in the analysis of the effect of early childhood factors on wheezing at age 11, 12 and 13 yrs. Data are presented as odds ratios (ORs) and 95% confidence intervals (CI). All factors significant in univariate analysis were included in a stepwise procedure to elicit a final model. In order to take the stratified sampling scheme and a possible participation bias into account, all multivariate models were adjusted for parental atopy. Furthermore, sensitivity, specificity, and positive and negative predictive values of various early life factors were calculated for the outcome of wheezing at the age of 11, 12 or 13 yrs. For analyses on the incidence and natural course of wheeze over time, all children with complete data on wheeze up to the respective time point of analysis were included in the analyses. For all other analyses, all children with data on early wheeze were included.

Study population and response rates

Of the 1,314 enrolled children, 441 (33.6%) had information on wheeze for every year of the follow-up until age 13 yrs (fig. 1⇓). For 391 (88.7%) of these children, data on specific IgE in the first 3 yrs of life were available. In order to assess potential participation bias, the study population of 441 children was compared with children with incomplete data on the course of wheeze based on data collected at birth (table 1⇓). No significant differences were found with respect to parental history of atopy, sex, cord-blood IgE, older siblings or parental education. However, children in the study population were more likely to have nonsmoking parents (p<0.001). Furthermore, the study population of 441 children was compared with children with complete data up to the age of 3 yrs and incomplete data thereafter, based on data collected in the first years of life. No significant differences were found with respect to early atopic dermatitis, early wheeze and early atopic sensitisation. However, children in the study population were more likely to be breastfed for at ≥4 weeks (p = 0.020). A detailed description of the population sample is reported elsewhere 14.

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Fig. 1—

Schematic of the Multicentre Allergy Study (MAS) cohort, including response rates, drop-out and longitudinal pattern of wheezing. Ig: immunoglobulin.

Incidence of first wheezing episode from birth to 13 yrs of age

In total, 80 (18%) children out of the study population of 441 wheezed in the first year of life. The incidence of new wheeze sharply declined in the second (33 (9%) out of 361) and third year of life (13 (4%) out of 328). Overall, 126 (29%) out of 441 of the children in the MAS cohort started wheezing in their first 3 yrs of life (early wheezers). The incidence of new wheezing disorders was stable thereafter up to 7 yrs of age at ∼4% (range 3.5–5.0%). Then the incidence further declined to <1% at 10–12 yrs and abruptly rose again at 13 yrs to about 4% (fig. 2⇓). Overall, 40 (9%) out of the population sample of 441 started wheezing between 3 and 6 yrs of age (late wheezers) and another 42 (9%) out of 441 started wheezing after 6 yrs of age (very late wheezers).

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Fig. 2—

Incidence of wheezing up to the age of 13 yrs in the German Multicentre Allergy Study cohort.

The natural course of wheezing

Six different longitudinal patterns of wheezing in the population sample were distinguished (fig. 1⇑). Among early wheezers, remission of symptoms after early childhood was very high: 79 (63%) out of 126 did not wheeze after the age of 3 yrs, (early remittent wheezers); 43 (34%) out of 126 continued to wheeze after the age of 3 yrs but not every year (early intermittent wheezers); and only 4 (3%) out of 126 of the early wheezers continued wheezing every single year from birth up to age 13 yrs. Among children who never wheezed before the age of 3 yrs: 233 (74%) out of 315 also did not wheeze up to the age of 13 yrs (never wheezers); 40 (13%) out of 315 started wheezing between 3 and 6 yrs of age (late wheezers); and 42 (13%) out of 315 started wheezing after the age of 6 yrs (very late wheezers). Overall, the prevalence of children wheezing at age 11, 12 or 13 yrs was 22% (28 out of 126) among early wheezers and only 10% (31 out of 315) among early nonwheezers. Among these 59 children wheezing at age 11–13 yrs, 28 (47%) of them were early wheezers, 6 (10%) were late wheezers and 25 (42%) were very late wheezers.

The frequency of an atopic family background, early sensitisation and current sensitisation was analysed in relation to the six different longitudinal patterns of wheezing (table 2⇓). The prevalence of atopy at 3 yrs of age was very low among never wheezers (12%), low among early remittent wheezers and very late wheezers (both 19%), intermediate among late and early intermittent wheezers (32 and 36%, respectively) and high among early persistent wheezers (75%). The prevalence of atopy at 10 yrs of age was low among never and early remittent wheezers (27 and 30%, respectively), intermediate among late and very late wheezers (45 and 53%, respectively) and highest among early intermittent and early persistent wheezers (69 and 75%, respectively). Interestingly, among very late onset wheezers, the prevalence of early sensitisation was relatively low (18.7%), whereas sensitisation at age 10 yrs was moderately high (53.1%; table 2⇓).

Different patterns of risk factors for wheezing at the age of 13 yrs

The association of early atopic sensitisation (and related risk factors) with wheezing at 11–13 yrs of age in children wheezing or not wheezing before 3 yrs of age was examined (table 3⇓). In the MAS cohort, cat and/or mite exposure and sensitisation were strongly linked 14 and their concurrence contributed to a reduced lung function at school age 16; therefore, in the present study, their interaction in the multivariate analysis was accounted for. In univariate analysis, the spectrum of early-life risk factors associated with wheezing at age 13 yrs was remarkably broader in early wheezers than in early nonwheezers; indeed, among early wheezers, wheezing at puberty was associated with parental asthma, hay fever and atopic dermatitis, allergic sensitisation against food or airborne allergens, elevated total IgE and early atopic dermatitis. In contrast, among early nonwheezers, wheezing at puberty was significantly associated with only parental hay fever and asthma, sensitisation to indoor allergens, and early atopic dermatitis. In addition, the strength of the associations observed and their statistical significance was much stronger among early wheezers than among early nonwheezers. This trend was maintained in the multivariate analyses; perennial sensitisation to indoor (mites, cat and dog) allergens persisted as a very strong predictor of wheezing at 11–13 yrs among early wheezers but no longer showed a significant association among early nonwheezers, and the association of wheezing at 11–13 yrs with parental atopy was three times stronger among early wheezers (adjusted OR 8.32, 95% CI 2.74–25.20) than among early nonwheezers (adjusted OR 2.48, 95% CI 1.01–6.09). However, whereas atopic dermatitis early in life remained a significant predictor for wheezing at 11–13 yrs among early nonwheezers, it was no longer significant in the group of children with early wheeze. In contrast, in the group of early wheezers, male sex emerged as a significant predictor for wheezing at 11–13 yrs. All other early life factors analysed (i.e. cord blood IgE, siblings, breast feeding, parental smoking, parental education, early pets, early allergen exposure and early infections) did not show a significant association with wheezing at 11–13 yrs in either groups (data not shown).

In a model including the whole population, wheezing at 11–13 yrs of age was best described by the following factors in early life: early wheeze (adjusted OR 1.87, 95% CI 0.98–3.54; p = 0.056) parental atopy (adjusted OR 3.22, 95% CI 1.54–6.72; p = 0.002), early indoor (mites, cat and dog) sensitisation (adjusted OR 4.04, 95% CI 1.87–8.73; p≤0.001) and early AD (adjusted OR 2.99, 95% CI 1.52–5.88; p = 0.002).

Prediction of wheezing at 11–13 yrs of age

Table 4⇓ shows the sensitivity, specificity, and positive and negative predictive values of early-life factors for wheezing at 11–13 yrs of age. Best overall values for all prediction parameters were observed for early sensitisation to indoor (mites, cat and dog) allergens (positive predicted value of 57%). When early wheeze was a factor, prediction was even improved to some extent, with a positive predicted value of 75%. Thus, a child with sensitisation to indoor (mites, cat and dog) allergens as well as at least one episode of wheezing before the age of 3 yrs had a probability as high as 75% of still having wheeze at 13 yrs. The positive predicted value increased to 83% when a child with early wheezing and early sensitisation against indoor allergens was also exposed to high concentrations of indoor allergens in the first 3 yrs of life.