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1 The David Hide Asthma & Allergy Research Centre, St Mary's Hospital, Newport, Isle of Wight and 2 Respiratory Cell and Molecular Biology, School of Medicine, Southampton General Hospital, Southampton, UK
CORRESPONDENCE: S.H. Arshad, The DavidHide Asthma & Allergy Research Centre, St Mary's Hospital, Newport, Isle of Wight, PO30 5TG, UK. Fax: 44 1983822928. E-mail: sha@soton.ac.uk
Keywords: atopy, childhood asthma, persistent wheezing, risk factors, risk score
Received: January 16, 2003
Accepted May 28, 2003
This study was funded by the National Asthma Campaign, UK, grant number 364. The 10-yr follow-up was also funded with their assistance.
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Abstract |
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Children were seen at birth, 1, 2, 4 and 10 yrs in a whole population birth cohort study (n=1,456). Information was collected prospectively on wheeze prevalence and subjects were classified into wheezing phenotypes. Early life genetic and environmental risk factors were recorded and skin-prick testing (SPT) was performed at 4 yrs. Independently significant factors for persisting wheeze were identified at logistic regression and used to create a score for persistence.
Wheezing persistence from the first 4 yrs to the age of 10 yrs occurred in 37% of early life wheezers. Independent significance for persistence was associated with asthmatic family history, atopic SPT at 4 yrs and recurrent chest infections at 2 yrs, whilst recurrent nasal symptoms at 1 yr conferred reduced risk. A cumulative risk score using these factors identified wheezing persistence in 83% scoring 4 and transience in 80% scoring 0.
Thus, a combination of genetic predisposition, early life atopy and recurrent chest infections favours the persistence of early life wheezing. Risk scores using such knowledge could provide prognostic guidance on the outcome of early wheeze.
Over the past decade it has been increasingly recognised that childhood wheezing is a heterogeneous condition 1 rather than a single disease entity. While the common lay perception is that wheezing in early life follows a benign transient course, several cohort studies suggest otherwise. Thus, Martinez et al. 2 demonstrated persistent wheezing up to the age of 6 yrs in 38% of early life wheezers; a similar proportion to that identified by Brooke et al. 3 in their English cohort. The landmark Tucson study 2, 4 has shown that such persistent wheezers closely resemble the typical childhood asthmatic possessing high levels of personal atopy, impaired lung function and bronchial hyperresponsiveness (BHR). Stevenson et al. 5 showed that ongoing "persistent inflammation" exists in the airways of typically asthmatic children even when asymptomatic. Persistent wheezers would therefore have the greatest scope for development of uninterrupted airway inflammation with possible long-term sequelae. Given the findings from the Childhood Asthma Management Program study 6 that showed a longer duration of wheezing to be associated with greater disease severity, such persistent wheezers therefore harbour significant potential for troublesome disease. Conversely, transient wheezers who constituted the remainder of early life wheezers in the Tucson study were found to show little atopy and BHR. In clinical practice, however, it is often difficult to accurately identify children who are likely to continue wheezing. Given the close parallels between most persistent wheezers and those diagnosed with childhood asthma, identification of factors in early life distinguishing persistent disease from a large body of coexistent transient wheeze is vital in improving childhood asthma management. Here, the findings from an unselected whole population birth cohort study, which provide a simple tool tohelp in the early identification of persistent childhood wheezing, are described.
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Methods |
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3 mm greater than the negative control was regarded as a positive reaction.
Analysis
To improve accuracy, data double entry was performed with subsequent file comparison and reference to paper records to resolve any queries. Children were categorised at 10 yrs into four groups by presence of current wheeze at each follow-up: 1) nonwheezers (children who never wheezed during the first decade of life); 2) early transient wheezers (wheezing onset during the first 4 yrs of life that ceased and was not present within 12 months of assessment at 10 yrs); 3) persistent wheezers (children with wheezing onset during the first 4 yrs of life who still wheezed at 10 yrs); and 4) late-onset wheezers (children with wheezing onset from 5 yrs onwards who still wheezed at 10 yrs). To improve accuracy and minimise recall bias, the phenotypic analysis was restricted to 1,034 (71%) of the original 1,456 cohort recruits who were seen prospectively with information available from all study visits, 1 or 2, 4 and 10 yrs. These 1,034 children did not differ significantly in a range of demographic parameters or relevant risk factors from 339 children seen at 10 yrs who were excluded from phenotypic analysis because of missing prior follow-up (table 1
). Children included in the phenotypic analysis did experience significantly more breastfeeding (p=0.033) and less exposure to parental smoking at birth (p<0.001) than those excluded from analysis. This probably reflected the nonsignificant trend for higher social class in those included in the phenotypic analysis, since this factor was previously characterised as being associated with such findings in this cohort 7.
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Results |
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Factors showing trends for significance (p<0.2) at univariate analysis for persistence of early life wheezing are shown in table 2. Personal histories of eczema at 1 yr, recurrent chest infections at 2 yrs plus eczema, and rhinitis at 4 yrs all conferred significant risk of wheezing persistence. Atopic sensitisation at 4 yrs also significantly increased the risk of persistent wheezing. A nonsignificant trend in favour of transient wheezing was found with recurrent nasal symptoms at 1 yr. Family history of asthma (defined as present in parent or sibling) carried a significantly increased risk of wheezing persistence while paternal eczema gave a nonsignificant effect in the same direction. Wheezing persistence was significantly associated with maternal smoking at birth and parental smoking at 4 yrs at univariate testing. Neither sex nor social class at birth had significant influence upon wheezing persistence whilst cord IgE did not differ significantly between persistent and early transient wheezers (median 0.1 versus 0.1, respectively; p=0.298 Mann Whitney U-test).
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) identified independent significance for wheezing persistence with a family history of asthma, recurrent chest infections at 2 yrs and atopic SPT at 4 yrs. A similar but nonsignificant trend for wheezing persistence was observed with formula feeding (p=0.094, odds ratio (OR) 1.67, 95% confidence interval (CI) 0.92–3.06). Conversely, a significantly reduced risk of wheezing persistence was found with recurrent nasal symptoms at 1 yr. Similar nonsignificant trends in favour of transient wheezing were found for cat ownership at birth (p=0.091, OR 0.58, 95% CI 0.30–1.09) and sibling eczema (p=0.074, OR 0.56, 95% CI 0.29–1.06).
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. Risk scores of 3 and 4 were both associated with significantly increased risk of symptom persistence with 83% of those scoring 4 having persistent disease. Scores of 0, 1 or 2 were associated with either a trend for or statistical significance for transient disease. Among children with a zero risk score, 80% had a transient wheezing outcome. Sensitivity, specificity, positive predictive values, negative predictive values and likelihood ratios for successive strata of the risk score are given in table 5. A risk score of 3 or 4 was three times as likely to occur in a wheezing child destined to suffer persistent disease than one who would outgrow their condition.
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Discussion |
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In this context genetic predisposition towards being atopic and asthmatic would appear to be a crucial feature of wheezing persistence, confirming results such as those of Koeppen-Schomerus et al. 11 who, in a recent study of twin pairs, showed that heritable factors predominate over shared environmental influences in asthma development. The present findings add to those of Csonka et al. 12 who retrospectively looked at risk factors for wheezing persistence in their study group, and confirm the importance of heredity towards the persistent asthmatic phenotype suggested by London et al. 13. These results are also consistent with findings emerging from the Multicentre Asthma Study (MAS) 14 that identified an interaction of persistent atopic sensitisation in childhood and parental atopy/asthma as being associated with childhood asthma development. However, it is also worth considering whether some degree of such familial disease clustering may arise not only from genetic influences, but also partly from shared environment in early life.
One drawback of a study like this is of not being able to provide an unequivocal answer in this regard. Certainly it is unlikely that heredity alone can explain the development of wheezing persistence. The present findings suggest that in addition to genetic predisposition exposures like recurrent chest infections in infancy also significantly influence wheezing persistence. Stein et al. 15 demonstrated an association between respiratory syncytial virus infection in early life with both frequent and infrequent early life wheezing illnesses. However, the influence of such early life infection was seen to wane with age in that study. In this study, a continued influence for early life chest infection was identified for wheezing persistence as far as 10 yrs. This finding may be consistent with past speculation over the consequences 15, 16 of such infections upon bronchial epithelium and may be one reason for wheezing persistence at a structural level.
An alternative interpretation may be that asthmatic childhood phenotypes more readily manifest lower respiratory tract symptoms when infected. Therefore, rather than causing persistent wheeze, such infections may simply be a reflection of its presence. Recurrent nasal symptoms in the first year of life (probably reflecting upper respiratory tract viral infections) were found to favour a transient wheezing outcome. This would be consistent with findings from the MAS 17 that 1-yr-olds with recurrent nasal symptoms were less likely to suffer subsequent asthma and atopy. These data did not demonstrate a significant independent effect of other environmental exposures such as parental smoking, social class, pet exposure or method of infant feeding upon persistence of early life wheezing. However, nonsignificant trends were seen for increased wheezing persistence with exclusive formula feeding and a transient wheezing outcome with cat ownership at birth.
Previously, Castro-Rodriguez et al. 18 created a clinical index to identify asthma risk among recurrently wheezing young children in the Tucson cohort study. Using that system, cases identified with a positive stringent index carried a prevalence of 76% for active asthma while 95% of those with a negative stringent index never had active asthma. Here, the authors attempted to create a clinical risk score that could be used to predict the risk of symptom persistence in early wheezers using risk factors that were demonstrated to have independent significance for this outcome. Thus, attention was focused upon what were felt to be the most relevant genetic and environmental factors that may influence wheezing persistence in the population. Such an approach may be usefully augmented by addition of data concerning severity and morbidity of wheezing in early life. Unfortunately such data was not prospectively available in early life to be included in the prospectively determined risk score.
The information needed to calculate the score is easily obtainable by a clinician in an outpatient setting. The emphasis is on an accurate history in combination with SPT at 4 yrs. In this context it is worth considering whether atopic status in earlier childhood rather than at 4 yrs may be more informative in differentiating wheezing outcome. Insufficient SPT in infancy was available in this study to allow meaningful analysis of significance and thus inclusion in the scoring system but this point is worth considering in future work. Some may advocate a clinical definition of atopy rather than including SPT in such a scoring system. However, it should be remembered that SPT is safe, reproducible and relatively simple to perform even in a small child. It is a test that certainly could be incorporated into most paediatric outpatient settings and may even find usage in a general practitioner-run asthma clinic. Importantly, its presence in the score permits an objective measure to be included.
With this risk score, a maximum score of 4 was associated with prevalence for wheezing persistence of 83% while a zero score was associated with prevalence for transient wheezing of 80%. However, such scores at either extreme were present in only a few subjects. Rather than attempting to devise a composite dichotomous system of high or low score (i.e. negative or positive test), the authors have simply described the risk at successive strata of the score. The advantage of this is that the parent and physician can easily estimate the risk of persistence for a child with early onset wheeze. For instance, a score of 3 or more was found to be three times as likely in a child with wheezing persistence than a transient disease outcome. Such a scoring system may provide a simple but useful guide in the clinical setting to improve early identification of those children most at risk of wheezing persistence. Thus clinicians may consider a lower threshold for use of regular prophylactic therapy such as inhaled corticosteroids in children with early life wheezing possessing persistence scores of 3 or 4 bythe age of 4 yrs. This score may also help prevent inappropriate use of unnecessary medication in wheezing children who actually have a low risk of disease persistence. Clinicians should find it helpful to be able to quantify the degree of persistence risk as outlined by this score when discussing issues like commencement of regular therapy with the parent. This in turn may lead to better compliance with regular treatment when it is really needed.
Finally, it is worth reflecting that the tools in this risk score permit its effective use at 4 yrs of age. However, even earlier identification of wheezing persistence may ultimately prove more useful, since this may provide even further clarity and perhaps permit earlier intervention. The need to focus on very early life in this context should therefore be a matter of priority in future work of this kind.
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Footnotes |
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