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Early Life Risk Factors for Current Wheeze, Asthma, and Bronchial Hyperresponsiveness at 10 Years of Age^*

^* From the David Hide Asthma & Allergy Research Centre, St. Mary’s Hospital, Newport, Isle of Wight, UK.

Correspondence to: S. Hasan Arshad, DM, Department of Respiratory Medicine, University Hospital of North Staffordshire, Newcastle Rd, Stoke-on-Trent, ST4 6QG, UK; e-mail: sha{at}soton.ac.uk

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion Conclusions References

 
Study objectives: We sought to identify early life factors (ie, first 4 years) associated with wheeze, asthma, and bronchial hyperresponsiveness (BHR) at age 10 years, comparing their relative influence for these conditions.

Methods: Children were seen at birth, and at 1, 2, 4, and 10 years of age in a whole-population birth cohort study (1,456 subjects). Information was collected prospectively on genetic and environmental risk factors. Skin-prick testing was performed at 4 years of age. Current wheeze (in the last 12 months) and currently diagnosed asthma (CDA) [ie, current wheeze and ever-diagnosed asthmatic subject] were recorded at 10 years of age when BHR was measured at bronchial challenge. Independent significant risk factors for these outcomes were identified by logistic regression.

Results: Independent significance for current wheeze occurred with maternal asthma (odds ratio [OR], 2.08; 95% confidence interval [CI], 1.27 to 3.41) and paternal asthma (OR, 2.12; 95% CI 1.29 to 3.51), recurrent chest infections at 2 years (OR, 3.98; 95% CI, 2.36 to 6.70), atopy at 4 years of age (OR, 3.69; 95% CI, 2.36 to 5.76), eczema at 4 years of age (OR, 2.15; 95% CI, 1.24 to 3.73), and parental smoking at 4 years of age (OR, 2.18; 95% CI, 1.25 to 3.81). For CDA, significant factors were maternal asthma (OR, 2.26; 95% CI, 1.24 to 3.73), paternal asthma (OR, 2.30; 95% CI, 1.17 to 4.52), and sibling asthma (OR, 2.00; 95% CI, 1.16 to 3.43), recurrent chest infections at 1 year of age (OR, 2.67; 95% CI, 1.12 to 6.40) and 2 years of age (OR, 4.11; 95% CI, 2.06 to 8.18), atopy at 4 years of age (OR, 7.22; 95% CI, 4.13 to 12.62), parental smoking at 1 year of age (OR, 1.99; 95% CI, 1.15 to 3.45), and male gender (OR, 1.72; 95% CI, 1.01 to 2.95). For BHR, atopy at 4 years of age (OR, 5.38; 95% CI, 3.06 to 9.47) and high social class at birth (OR, 2.03; 95% CI, 1.16 to 3.53) proved to be significant.

Conclusions: Asthmatic heredity, predisposition to early life atopy, plus early passive smoke exposure and recurrent chest infections are important influences for the occurrence of wheeze and asthma at 10 years of age. BHR at 10 years of age has a narrower risk profile, suggesting that factors influencing wheezing symptom expression may differ from those predisposing the patient to BHR.

Key Words: atopy • bronchial hyperresponsiveness • childhood asthma • risk factors • wheezing

	Introduction

TOP Abstract Introduction Materials and Methods Results Discussion Conclusions References

 
The increasingly common occurrence of childhood wheeze and asthma,¹²³ particularly in affluent westernized society,⁴ is well-documented. Although genetic predisposition and environmental exposure are thought to lead to the development of these conditions,⁵ the nature of such associations remains unclear. While the scope of modifying genetic influences is still limited, attention has focused on environmental factors that might be amenable to interventions. Thus, interest has fallen on numerous influences as the potential causes for childhood asthma, including early allergen exposure,⁶⁷ method of infant feeding,⁸ viral respiratory infection,⁹ environmental tobacco smoke exposure,¹⁰¹¹ and pet contact.¹² However, the evolving "hygiene hypothesis"¹³ also has led to findings that large family size,¹⁴ rural living,¹⁵ anthroposophic lifestyle,¹⁶ and animal contact¹⁷ conversely protect against allergy and asthma development.

A major difficulty in studies of childhood asthma has been the imprecise definition for this condition. Studying wheezing symptoms provides a useful alternative but may not best represent children with true asthma. Nonspecific bronchial hyperresponsiveness (BHR) is an important feature of asthma, and its identification has been used in the research arena to strengthen the assessment of possible asthma. Comparing risk factor profiles for wheezing, asthma, and BHR could facilitate a better understanding of the mechanisms underlying these conditions as well as of their similarities and differences. Here, we describe early life risk factors (ie, from the first 4 years of life) for current wheeze, a questionnaire-based definition of currently diagnosed asthma (CDA), and objectively measured BHR among 10-year-old children from our unselected British whole-population birth cohort.

	Materials and Methods

TOP Abstract Introduction Materials and Methods Results Discussion Conclusions References

 
A whole-population birth cohort was established on the Isle of Wight in 1989 to prospectively study the natural history of childhood wheezing and to identify risk factors for the development of childhood wheezing and asthma. Approval for the study was obtained from the local research ethics committee. Of 1,536 children born between January 1, 1989, and February 28, 1990, informed consent was obtained for 1,456 subjects to be enrolled. Enrollment took place at birth, and information on family history of allergy (ie, parental or sibling), household pets, parental smoking, social class (Registrar General’s Classification), and birth weight were recorded. Children were followed up at the ages of 1 year (1,167 children; 80.2%), 2 years (1,174 children; 80.6%), 4 years (1,218 children; 83.7%), and 10 years (1,373 children; 94.3%). The results of cohort follow-up (at 1, 2, 4, and 10 years) have been reported previously.^18192021 At every follow-up visit, detailed questionnaires were completed with the parents for each child regarding asthma and allergy prevalence. "Current wheeze" was recorded as having occurred in the prior 12 months. Exposure to relevant environmental factors (eg, domestic pets and tobacco smoke) was noted. The method of feeding was obtained at 1 year and 2 years. A history of recurrent chest infections (ie, more than one in the past year) was assessed at 1 year and 2 years of age. Diagnoses of eczema (ie, chronic or chronically relapsing itchy dermatitis lasting > 6 weeks with characteristic morphology and distribution), recurrent nasal symptoms/rhinitis (ie, recurrent nasal discharge or blockage with attacks of sneezing and itchy eyes), and food allergy (ie, history of vomiting, diarrhea, colic, or rash within 4 h of the ingestion of a particular food on at least two occasions) were made at 1, 2, and 4 years. At age 10 years, purely questionnaire-derived asthma-related definitions were current wheezing (ie, wheezing in the last 12 months) and CDA (ie, a combination of current wheeze and ever having been diagnosed as having asthma).

Skin-prick testing (SPT) was performed with a panel of common inhaled and food allergens (ALK-Abelló; Hørsholm, Denmark). This comprised house dust mite (Dermatophagoides pteronyssinus), grass pollen mix, tree pollen mix, cat and dog epithelia, Alternaria alternata, Cladosporium herbarum, milk, hen’s egg, soya, cod, and peanut plus histamine to act as positive controls, and physiologic saline solution to act as a negative control. An allergen skin test reaction with a mean wheal diameter of at least 3 mm greater than that for the negative control was regarded as a positive result, and the subject was defined as being atopic.

All children with past or current wheezing were also invited to perform a methacholine bronchial challenge at 10 years of age to assess BHR using a dosimeter (Koko; PDS Instrumentation; Louisville, CO) with a compressed air source at 8 L/min and nebulizer output at 0.8 L/min. An initial inhalation of a 0.9% saline solution was followed 1 min later by spirometry recording to obtain a baseline value. Subsequently, incremental concentrations from 0.0625 to 16 mg/mL methacholine were serially administered. The provocative concentration of methacholine causing a 20% fall in FEV₁ (PC₂₀) from the post-saline solution inhalation value was interpolated. BHR was defined as being present when the PC₂₀ was < 4.0 mg/mL. To perform this test, children were required to be free from respiratory infection for 14 days, to not be receiving oral steroids, to not have received a ß₂-agonist for 6 h, and to have abstained from caffeine intake for at least 4 h. The intention was to perform a bronchial challenge whenever possible in all children with wheezing histories (484 children) plus in a control group of randomly selected children who had never wheezed (300 children). Testing was not conducted in all children owing to time constraints for the completion of the study.

Statistical Analysis
Data were double entered into a statistical software package (SPSS, version 10.0; SPSS; Chicago, IL). Univariate analysis of early life factors (ie, in the first 4 years of life) for current wheeze, CDA, and BHR was performed separately in comparison with children who did not have that respective condition. ² testing (with the Fisher exact test where indicated by low expected cell counts) was used for this purpose. To obtain the independent effect of risk factors showing univariate trends for significance (p < 0.2), logistic regression models were created for each outcome variable. Stepwise backward (likelihood ratio) logistic regression was used for this purpose.

	Results

TOP Abstract Introduction Materials and Methods Results Discussion Conclusions References

 
At 10 years of age, 1,373 of the original 1,456 children (94%) were reviewed again. Current wheeze was present in 18.9% (259 children), and CDA was present in 13.0% (178 children). The characteristics of these conditions have been detailed previously.²¹ Among children who were seen at 10 years of age, bronchial challenge was completed in 784 subjects with BHR, which was defined as a PC₂₀ of <4.0 mg/mL, present in 169 cases.

Risk Factors for Current Wheeze at 10 Years of Age
Factors showing statistical significance at univariate testing for current wheeze at 10 years of age are listed in Table 1 , with odds ratios (ORs) and 95% confidence intervals (CIs). Male gender was a significant risk factor in this regard. Significantly increased risk was also found with a personal history of allergic disease at 1 year of age (ie, eczema, food allergy), 2 years of age (ie, eczema), and 4 years of age (ie, eczema, rhinitis, and food allergy), plus atopic sensitization at 4 years of age. Family history in the form of maternal, paternal, and sibling asthma along with maternal urticaria proved to be another significant influence. Recurrent chest infections at 1 year and 2 years of age were further significant risk factors for current wheeze, as was parental smoking at 4 years of age plus exclusive formula feeding in the first 3 months of life. Social class at birth did not show any associations with current wheeze. A significant reduction in the risk of current wheeze at univariate analysis was found with cat ownership at birth. Cord IgE levels did not vary significantly with the presence of current wheeze (median, 0.1 vs 0.1 kilounits per liter, respectively; p = 0.257 [Mann-Whitney U test]).

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion Conclusions References

 
Understanding the etiology of childhood wheeze and asthma remains an area of extensive ongoing research. In this article, we sought to identify whether different early life influences underlie wheeze, asthma, and BHR at 10 years of age. We found that wheeze and asthma at 10 years of age, both defined by questionnaire responses requiring a history of recent wheeze, possess similar early life risk factors. Thus, the important roles of asthmatic heredity, as well as a predisposition for being atopic and having allergic comorbidity, in the development of wheeze and asthma readily emerges from our study. Significant independent associations of these conditions with early life tobacco smoke exposure and recurrent chest infections in infancy also suggest some causal influence of early life environmental exposures. The only factor to show significance for asthma but not wheeze was male gender. Our patients with CDA had received a physician diagnosis of asthma at some point that might crudely indicate greater disease morbidity and severity. In turn, our risk factor analysis would suggest that the more severe wheezing conditions in our 10-year-old children were likely to be seen in boys. A very different risk factor profile was identified for BHR at 10 years of age. It was associated with atopic sensitization at 4 years of age and higher social class at birth but was not related to either a family history of disease or other early environmental exposures.

The imprecise definition, particularly in childhood, of what constitutes a diagnosis of asthma has posed a major difficulty in the study of this disease. Attempts to provide a standard definition of current asthma by incorporating BHR measurement and current wheeze have shown some promise but have considerable resource implications dictated by the need to perform bronchial challenges. What best defines BHR also has not been firmly established. Precise cutoffs for PC₂₀ may vary by age, but traditionally values of < 8.0 mg/mL have been used in this regard. Here, we have defined BHR at a PC₂₀ of < 4.0 mg/mL, thus incorporating American Thoracic Society categories "mild-positive" and "moderate-severe" for BHR at the methacholine bronchial challenge.²² Previously,²¹ we demonstrated that CDA showed similar characteristics and morbidity in our 10-year-old population to that of symptomatic BHR. Indeed, the extent to which BHR measurement reflects symptomatic disease may not always be as accurate as is generally perceived. Thus, asymptomatic BHR was found in one third of a study of British children,²³ 13% of a New Zealand cohort,²⁴ and 6.7% of children in an Australian study.²⁵ Recently,²⁶ we demonstrated that among our children with BHR, symptom expression was associated with maternal asthma, parental smoking in the fourth year of life, and atopic sensitization at 4 years of age. Now, we show that if a diagnosis of BHR is considered, regardless of symptom expression, only atopic sensitization still shows independent significance. Thus, different mechanisms appear to underlie BHR per se compared to wheezing symptom expression, a fact substantiated by the risk factor profiles that we found for children with wheeze and asthma.

Of the early life influences that we found to be significant, atopic sensitization at age 4 years emerged as highly significant for wheeze, asthma, and BHR at 10 years of age. This is consistent with prior associations of such atopic sensitization with wheeze, asthma, and BHR at 7 years of age²⁷ and 10 years of age²⁸ in other populations. Work by Clifford et al²⁹ has suggested an intrinsically close relationship between atopy and BHR in children. This is supported by findings from the Dunedin cohort³⁰ of a link between BHR and total IgE levels even in the absence of allergic symptoms. Indeed, a close relationship³¹ between the inheritance of atopy and BHR has been proposed. Our results provide further evidence that atopic sensitization is of paramount significance when considering early life risk factors for BHR per se at 10 years of age. Interestingly, clinical allergic comorbidity in early life showed no significant association with BHR but did show an association, in the guise of eczema at 4 years of age, with wheeze and asthma at age 10 years. The association of early life eczema and later symptoms of allergic airways disease is certainly consistent with the notion of an allergic march in childhood. The different relationships of BHR at age 10 years with clinical allergy and atopic sensitization in earlier life may reflect the fact that by 4 years of age aeroallergen sensitization predominated.²⁰ Thus, one might speculate that clinical allergic comorbidity secondary to aeroallergen sensitivity, such as rhinitis, in later childhood is more relevant to the presence of BHR at 10 years of age than earlier childhood allergic manifestations.

Our data also suggested that environmental influences such as early tobacco smoke exposure and recurrent chest infections in infancy would appear to be more relevant to the presence of wheezing symptoms and asthma than the presence of BHR per se at 10 years of age. In this context, past work¹⁰³² has consistently identified a relationship between parental smoking and childhood wheeze and asthma. While early passive smoke exposure did not influence BHR in our 10-year-old children, it is possible that more recent passive smoke exposure might have shown some influence in this regard. This might in turn explain observations linking concurrent passive smoke exposure and childhood BHR in other populations.³³³⁴

The other environmental factor to show significance for both wheeze and asthma at 10 years was a history of recurrent chest infections in infancy. The possible role of such infections in childhood wheezing illnesses has been reported previously.⁹³⁵ However, whether they are a cause of wheeze and asthma or merely reflect an association by which childhood wheezing phenotypes more readily manifest lower respiratory tract symptoms when infected remains unclear.

The one environmental factor to show significance for BHR was high social class at birth. The reasons for this finding are open to speculation. No such association with wheeze or asthma was identified, further highlighting the notion that different factors influence wheezing symptom expression than BHR per se.

Genetic predisposition in terms of family history of asthma proved to be a major influence for both wheeze and asthma in our 10-year-old children. This confirms past findings of the importance of heredity to the occurrence of childhood wheeze and asthma.²⁹³² While previous work³²³⁶³⁷ has identified a stronger influence of maternal disease on such conditions, our study confirms an equally strong paternal association. It should be recognized that this finding arose despite the fact that in our study, the majority of questionnaire data were obtained by interviewing the mother in the family.

The potential candidate genes for BHR, atopy, and asthma are clustered together on chromosome 5. Confirming a previous report by von Mutius and Nicolai,³⁸ we found no association between family history of asthma and BHR, indicating different genes for these conditions. However, contrary to these findings, Peat et al³⁹ did find an association between asthma in either parent and BHR in Australian schoolchildren. Crane et al⁴⁰ suggested that BHR associated with atopy was influenced by a family history of asthma but not if BHR occurred in nonatopic children. We were unable to support the notion of a differential effect of family history of asthma on BHR depending on the atopic status.

	Conclusions

TOP Abstract Introduction Materials and Methods Results Discussion Conclusions References

 
Our study demonstrates that factors that are present in early life can have a bearing on wheeze, asthma, and BHR at 10 years of age. While atopic sensitization emerges as significant for all three conditions, we found that other factors, namely, asthmatic heredity, eczema at 4 years of age, early life passive smoking exposure, and infantile chest infections, are associated with asthma and wheezing but not with BHR. Thus, different influences may mediate the symptomatic wheezing or asthmatic state compared to BHR per se. Future work should explore this notion further.

	Acknowledgements

	Footnotes

 
Abbreviations: BHR = bronchial hyperresponsiveness; CDA = currently diagnosed asthma; CI = confidence interval; OR = odds ratio; PC₂₀ = provocative concentration of methacholine causing a 20% fall in FEV₁; SPT = skin-prick testing

Support for the 10-year follow-up of this study was funded by grant No. 364 from the National Asthma Campaign (United Kingdom).

Received for publication March 10, 2004. Accepted for publication August 13, 2004.

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This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via ISI Web of Science (38) Citing Articles via Google Scholar Google Scholar Articles by Arshad, S. H. Articles by Matthews, S. Search for Related Content PubMed PubMed Citation Articles by Arshad, S. H. Articles by Matthews, S.