Summary of main findings
In this study, we have investigated the diagnostic accuracy of IgE tests (RAST) to cat, dog, and house dust mites for the prediction of asthma at the age of 6 years in children under 5 years presenting with complaints of persistent coughing in primary care. After considering patient characteristics and clinical history, IgE testing improved the predictive accuracy, as indicated by an increase of the area under the curve by 11%. Furthermore, IgE testing improved patient differentiation as indicated by a change in the range of asthma probabilities from 6–75% pre-test to 1–95% post-test.
Comparison with existing literature
As was found in other studies,7,16 wheezing appears to be an important predictor of asthma. Children who did not wheeze had a less than 50% probability of developing asthma, even after a positive IgE test. For purposes of illustration, we used a 50% probability of asthma as a threshold for a GP to decide whether or not to start treatment. In reality, GPs' treatment thresholds may differ. Unfortunately, our study cannot answer the question of where a threshold should lie. Ultimately, that question can only be addressed by formal cost-effectiveness or cost-utility analyses. The current study may inform such analyses, which may then clarify the proper role of testing for IgE. Three other studies17-19 examined specific IgE as a diagnostic tool for asthma and found that it was important in predicting asthma. These results are in line with our study, although the children in these studies had wheezing as a presenting symptom and the studies were hospital based.
Strengths and limitations of the study
The fact that this study is based in general practice is a strength, but at the same time it can be considered as a limitation. Being based in general practice, the predictive function we constructed is likely to be valid for children who present at GPs' surgeries, and not necessarily for children in the general population. This is important as most research on asthma and allergy in children is either population-based or hospital-based; therefore, results from these studies cannot be applied straightforwardly to the primary care situation. As most children with allergy or asthma are diagnosed and treated in general practice, it is important to conduct research that can be applied straightforwardly to general practice.
Furthermore, most of the studies performed in the general population use wheezing as the inclusion criterion, whereas in this study, cough is used, because cough is the symptom most presented in general practice in this age group.
Although many researchers have studied asthma and allergy, this study is one of the few to construct a clinical prediction rule and to evaluate the added value of allergy tests for the diagnosis of asthma in young children in general practice. In other studies17-19 the value of IgE tests was examined in isolation, without reference to diagnostic information that is available in a diagnostic work-up in practice.
A limitation of this study is that some children may have received some form(s) of (intermittent) treatment. These were not included in the model. This implies that the predictive function we describe may be valid under current treatment practices according to international guidelines. If early treatments do not influence the probability of asthma at age 6 years, the function may have wider applicability. Currently, the impact of treatment is still controversial,5,20,21 although there is evidence that early treatment, such as inhaled corticosteroids, may improve lung function in the long run. In that case, in general practice, where most children with asthma are diagnosed, identifying those young children with a high enough probability of developing asthma is of clinical relevance.21,22
As data on wheezing was not collected at baseline, we reconstructed this variable from the retrospective review of the medical records and questionnaires completed after inclusion. If some random misclassification is assumed, wheezing may play even more of a differentiating role than reported here. There was no significant difference between reported wheeze in those children with an IgE-negative or IgE-positive status at inclusion. Thus, children in families with a heightened awareness of atopy were not more likely to have reported wheeze and therefore have it recorded.
Ideally speaking, all children at follow-up should have had the same diagnostic procedures. However, in this study, asthma was defined as the presence of asthma-related symptoms and/or use of asthma medication in the previous 12 months, together with a positive histamine test result from the lung function test. This means that children without asthma-related symptoms or medication in the previous 12 months would be diagnosed as not having asthma. Therefore, in symptom-free children a lung function test was not performed because it did not have any additional value for the diagnosis of asthma.
Implications for research and clinical practice
In diagnostic cohort studies, in contrast to aetiologic studies, the emphasis is not on some exposure of interest whose influence is to be quantified and adjusted for confounding factors. Rather, the contrasts in patients' test results (where ‘tests’ include clinical history items) are used to predict the likelihood of asthma at a later point in time. This also implies that the analysis is centred around efficiency, that is, optimal prediction using information that becomes available early in the diagnostic work-up and is often virtually free of charge (such as clinical history). Next, the diagnostic impact of added information that does not come free of charge (laboratory testing, imaging) is estimated as conditional on the information already available. So, the issue of confounding in aetiologic cohorts becomes an issue of redundancy of diagnostic information in studies such as the current one.23
Ideally, a prediction rule should be derived, and then validated prospectively on a separate population. Although we used bootstrapping techniques, the results are likely to be somewhat less robust when applied to a separate population.24 The prediction rule, therefore, should be validated in another primary care population.
Assessment of specific IgE to inhalants may be helpful in determining those children with persistent cough (≥5 days) who will and will not develop asthma at the age of 6 years. In particular, children who wheeze may be usefully categorised into low- and high-risk groups. A simple scoring formula using wheeze and a family history of pollen allergy in coughing children who are younger than 5 years of age may support GPs in selectively ordering an IgE test.