Published ahead of print on November 19, 2004, doi:10.1164/rccm.200406-791OC
© 2005 American Thoracic Society doi: 10.1164/rccm.200406-791OC
Behavior Problems Antecede the Development of Wheeze in ChildhoodA Birth Cohort StudyAcademic Division of Clinical Psychology, Education and Research Centre, and Academic Division of Medicine and Surgery South, North West Lung Centre, University of Manchester, Wythenshawe Hospital, Manchester, United Kingdom Correspondence and requests for reprints should be addressed to Rachel Calam, Ph.D., Academic Division of Clinical Psychology, 2nd Floor, Education and Research Centre, Wythenshawe Hospital, Manchester M23 9LT, UK. E-mail: rachel.calam{at}man.ac.uk
Rationale: It is not clear to what extent behavior problems observed in children with asthma antecede asthma development, or are a consequence of the disease. Objectives: We investigated psychologic factors at age 3 years and subsequent development of wheeze by age 5 in an unselected birth cohort study. Children were recruited prenatally, followed prospectively, and reviewed at age 3 and 5 years. The rate of significant behavior problems at age 3 (above the clinically relevant cut-off on the Eyberg Child Behavior Inventory) was compared between children who had never wheezed (n = 397) and those developing late-onset wheezing (after age 3 years; n = 39). Late-onset wheezers were more likely to be above cut-offs for behavior problems at 3 years (before wheeze onset), compared with children who never wheezed, on Intensity (23.1% vs. 6.0%, p < 0.001) and Problem scores (10.8% vs. 1.3%, p < 0.001). Families of late-onset wheezers had poorer scores on family functioning variables, but we found no evidence of increased anxiety or depression scores in parents. In the multivariate analysis, significant and independent associates of late-onset wheeze were as follows: maternal asthma (odds ratio [OR] 5.4, 95% confidence intervals [CI] 2.1–13.8, p < 0.001), maternal smoking when child was 3 years (OR 3.3, CI 1.2–8.7, p = 0.02), expressiveness (OR 0.71, CI 0.55–0.9, p = 0.005), and significant behavior problems at age 3 years (OR 3.5, CI 1.2–9.9, p = 0.02). Conclusions: Behavior problems in early life are associated with increased risk of subsequent development of wheeze.
Key Words: asthma • child • child behavior • family There is now a substantial body of evidence indicating that children with asthma have higher levels of behavior problems compared with children without asthma (1). However, it is unclear to what extent behavior problems antecede asthma development or are a consequence of the disease. To date, the few studies examining prospectively the contribution of psychologic factors have been performed exclusively in children at high risk for the development of asthma (2–6). These studies have shown that psychosocial factors may have some predictive value in identifying children at risk for the development of symptoms. A large-scale prospective study of children with atopic dermatitis showed ratings of problem behavior predicted subsequent development of asthma symptoms (4). In a whole population–based birth cohort study that included children at low risk for the development of asthma (the National Asthma Campaign Manchester Asthma and Allergy Study [NACMAAS]), we recently have shown that at age 3 years the occurrence of recurrent wheeze was significantly positively correlated with elevated behavior problems ratings (7). However, we were unable to provide any evidence for the direction of causality in relationships between behavior ratings and development of wheeze. Further follow-up of the children to age 5 years enabled us to test the hypothesis that behavior problems and psychosocial factors measured at age 3 antecede the development of respiratory symptoms. Some of the results of this study were reported in the form of an abstract (8).
The NACMAAS is an unselected, population-based birth cohort study (9–12). Ethical approval for the study was granted by the local research ethics committee. Informed consent was obtained from all parents.
Study Population
Allergic sensitization was determined by skin-prick testing (mite, cat, dog, grasses, milk, egg; sensitization defined as a wheal 3 mm or larger than the negative control).
Psychosocial Assessment The Eyberg Child Behavior Inventory (ECBI; measure of child problem behavior) (15) is made up of a list of 36 common behavioral problems. Parents respond yes or no to each item to record whether each of these is currently a problem with their child (Problem) and rate how often the specific behavior currently occurs (Intensity; 1–7, "never" to "always," respectively). Scores are totaled for each scale, yielding separate Problem and Intensity scores. Reliability and validity was confirmed in the pediatric population (16). Clinically relevant cut-offs of a score of 131 or more for Intensity and 15 or more for Problem (17) may indicate significant psychopathology requiring intervention and parental concerns about the child's behavior. The Family Relationships Index (FRI; measure describing the family) (18) is derived from the Family Environment Scale and measures expressiveness, cohesion, and conflict. The Hospital Anxiety and Depression Scale (HAD; measure of parental psychologic adjustment) (19) is a 10-item questionnaire often used to screen anxiety and depression. The General Health Questionnaire (GHQ) (20, 21) is widely used to identify psychiatric disorder in community settings and indicates level of disturbance in the parent.
Statistical Analysis
Figure 1 shows the study profile. Of the 963 questionnaires distributed, 771 (80.1%) were returned at the 3-year follow-up visit. Parents who returned the psychosocial questionnaires were more likely to be employed than those who did not (p = 0.02). There were no differences in terms of family history, parental smoking, maternal age, gestational age, birth weight, history of wheeze, and allergic sensitization between children of parents who returned the psychosocial questionnaires compared with those who did not (data available on request). The parents of 37 children completed the ECBI Intensity but not the ECBI Problem scale. A total of 721 children (392 boys) attended the follow-up visit at age 5 years (93.5% follow-up rate). Of those, 397 never wheezed, 163 had transient early wheeze, 39 developed late-onset wheezing and 84 had persistent wheezing. A further 38 children could not fit into a wheeze phenotype classification (e.g., no reported wheeze, but receiving asthma medication at age 3 or 5 years).
Demographic Data Socioeconomic status (SES) was derived using the National Statistics Socio-Economic Classification (data missing in five children). For the purpose of analysis, groups were reduced to four SES categories: managerial/professional, intermediate, routine/manual, and not working. We found significant differences between SES categories in cohesion, with nonsignificant trends for expressiveness and ECBI intensity (Table 1). There were no significant differences in SES for sex and family size.
Behavior Ratings and Wheeze Table 2 shows the number of children above and below the clinically relevant cut-offs for ECBI Intensity and Problem scores for each of the four phenotypes of wheeze. To test the hypothesis that behavior problems precede the development of wheeze, we compared children with late-onset wheezing to those who had never wheezed, excluding transient and persistent wheezers from the analysis. We used both actual scores and clinical cut-offs for ECBI Intensity and Problem scales. There were no significant differences between children who had never wheezed and late-onset wheezers in actual scores on the ECBI Intensity (mean, 95% confidence intervals [CI] 97.4, 95.3–99.5 vs. 102.5, 92.6–112.1, respectively; p = 0.3) or Problem scales (median, interquartile range: 1, 0–5 vs.2, 0–7.5, respectively; p = 0.3). However, late-onset wheezers were significantly more likely to have Intensity and Problem scores on the ECBI above clinically relevant cut-offs at age 3 years (both p < 0.001; Table 2).
To examine this finding further, we compared individual items on the ECBI between children who had never wheezed and late-onset wheezers (see Table E1 in the online supplement). Of the eight items for which a significantly higher proportion of late wheezers were reported as showing difficulties, six related to problems of inattention/concentration or overactivity. Because of the small numbers and the problem of assessing results of multiple statistical testing (36 ECBI items), these findings should be interpreted with caution.
Family Psychosocial Factors and Wheeze
Families of children with late-onset wheeze had significantly lower scores for FRI expressiveness, and we observed a trend that failed to reach statistical significance on the FRI Cohesion and Conflict scales. However, we found no differences in parental anxiety or depression, analyzed by either actual scores or whether they were above or below the clinically relevant cut-off of 11. There was a significant correlation between all but one of the psychosocial measures (Table E2).
Other Associates of Late-Onset Wheeze
Multivariate Analysis Multivariate logistic regression analysis included factors significant at p  0.1 in the univariate analyses and parental atopic status, which was found to be associated with late-onset wheeze in previous studies (although no significant association was observed in the current study; p = 0.29). Separate models were used for Intensity and Problem scores, because these variables were highly interrelated (r = 0.49, p < 0.001, Spearman correlation; Table E2). In the analysis using ECBI Intensity, the following risk factors remained significant and independent associates of late-onset wheeze: maternal asthma (odds ratio [OR] 5.4, 95% CI 2.1–13.8, p < 0.001), maternal smoking when child was 3 years (OR 3.3, CI 1.2–8.7, p = 0.02), expressiveness (OR 0.71, CI 0.55–0.9, p = 0.005), and ECBI Intensity above the clinically relevant cut-off (OR 3.5, CI 1.2–9.9, p = 0.02). The remaining variables were not significant associates of the late-onset wheeze (parental atopic status, p = 0.94; child atopic status, p = 0.47; child gender, p = 0.29; conflict, p = 0.29; cohesion, p = 0.27). A trend was observed for an overall effect for SES (p = 0.07). When we repeated the analysis using ECBI Problem scores, this trend was not found to be an independent predictor of late-onset wheeze (p = 0.26).
Our data suggest that behavior problems in early life may be associated with subsequent development of wheeze. Our finding that behavioral disturbance anteceded the development of wheeze and was not a secondary psychological reaction to disease is consistent with another recently published prospective study of a high-risk population (4). Although we must treat our analysis of ECBI individual items with caution, it appears that the specific problems that parents reported related particularly to attention problems and overactivity. With the exception of two items involving teasing or arguing with peers or siblings, the remaining six items corresponded exactly to a factor of Inattentive Behavior identified and confirmed in major factor analyses of the ECBI on large samples of children (17). This is a potentially important finding, because this specific constellation of inattentive, overactive behavior problems may have a physiologic component (22). To pursue this further, it would be necessary to undertake behavioral observation of children, because parental report is not a particularly sensitive index of hyperactivity. An adequate discussion of this issue goes beyond the scope of this article, but the consistency of our finding highlights the potential value of studying interactions between specific behavioral patterns, physiologic systems, and health variables. Cross-sectional studies have suggested a link between oral medication for asthma and hyperactivity (23–25). The present article excluded children who had received asthma medication before behavior rating; behavioral problems thus anteceded both the development of wheeze and use of asthma medication. Behavioral problems may not be caused by or attributable to wheezing illness or asthma medication but may antecede the development of symptoms. The scores for family relationship variables in our study indicated that the families of children who developed late-onset wheeze showed significantly lower expressiveness and trends toward lower levels of cohesion and higher levels of conflict. In multivariate analysis, however, cohesion and conflict were no longer significant, leaving maternal asthma, maternal smoking, ECBI Intensity above cut-off, and expressiveness associated with late-onset wheeze. It is important to note that we found no differences in parental mental health scores between children who had never wheezed and those with late-onset wheezing. In interpreting our findings, it is important to note that all the data were obtained from parental (usually maternal) report, which raises the possibility that some of the findings arise from common method variance and response tendencies in the parent. If this were primarily the case, however, it would be expected that anxiety and depression would also be elevated. One important methodologic point that has clear clinical relevance is that preliminary analyses did not show significant differences in mean scores for the ECBI between children who had never wheezed and those who developed late-onset wheeze. However, when we looked at the number of children with scores above the clinically relevant cut-off on the ECBI, which would represent parents who perceive their child's behavior to present a considerable challenge, the difference in distribution became striking. The implication of our finding is that it is the children with marked behavior problems who are at increased risk of subsequent wheeze, and that more modest elevations in perceived behavioral difficulty at age 3 are not so strongly associated with late-onset wheeze. This implication is consistent with findings of meta-analysis in this area (1). We do not suggest that behavior problems per se cause wheeze or predict specific aspects of asthma onset. They are likely to show dynamic, reciprocal relationships with other causal factors, which are intertwined and contribute to the development of both behavior and wheeze. Parents who report behavior problems tend to have other psychosocial stressors; studies have identified several linked psychosocial and environmental factors that contribute to the development of asthma (26). For example, maternal smoking during pregnancy increases risk of attention deficit and hyperactivity disorder (27, 28) and behavior problems (29) and respiratory symptoms. Smoking is, in turn, related to a range of other variables (30). SES was related to late-onset wheeze in the univariate analysis, but after adjusting for other risk factors, this association was no longer significant. However, behavior scores above clinically relevant cut-offs remained a substantial and significant predictor of late-onset wheeze in the multivariate analysis. Other studies have shown links between stressors in early childhood and wheeze or asthma (26, 31, 32), although the processes of mediation of inflammatory responses in the presence of stressors require further elucidation (33). Caregiver stress is associated with the modification of infant immune functioning and cytokine production, and may lead to enhanced responses to allergens (34). In our study, family relationship dysfunction showed trends in the predicted direction, with reduced expressiveness at 3 years remaining a significant associate of late-onset wheeze in the multivariate model. Again, these variables are not independent; parental capacity to express difficulties and problem-solve will be associated with successful management of child behavior. Parental anxiety and depression, which might be expected to be proxy measures of stress, were not associated with late-onset wheeze. It is possible that our measure was not sufficiently sensitive. In addition, different environmental stressors may have different degrees of impact, or operate with different levels of intensity, at different stages in the development of the immune system. Further longitudinal exploration of relationships between physiologic factors and psychosocial variables would be valuable. We are aware that even within this large-scale prospective cohort, the numbers are relatively small and our comments can therefore only be tentative. However, given the increasing prevalence of asthma, the prediction of onset of symptoms and strategies for prevention are important issues. Identifying pathways for the development of asthma across childhood has the potential to enable crafting of tailored interventions addressing both biological and psychosocial factors. It is an empiric question whether interventions to enhance parenting from infancy, and to prevent the development of behavior problems in very young children (35), have the potential to reduce asthma prevalence and severity.
The authors thank all the parents and children who took part in the study, all members of NACMAAS study group, and Julie Morris, M.Sc., for statistical advice.
Supported by Asthma UK grant 01/012 and the Moulton Charitable Trust. This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org Conflict of Interest Statement: R.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; L.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; B.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Received in original form June 22, 2004; accepted in final form November 11, 2004
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ABSTRACT
METHODS
2 test was used to investigate the differences between children above and below the cut-off on the ECBI. Appropriate univariate tests for parametric (analysis of variance, t test) and nonparametric data (Kruskal-Wallis, Mann-Whitney U test) were used to assess relationships between wheeze and psychosocial variables. Other risk factors of late-onset wheeze were evaluated using logistic regression analysis. Variables found to be associated with late-onset wheeze at a significance level of p 
