Introduction

Epidemiological surveys have shown asthma-like symptoms to be far more prevalent than physician diagnosed asthma,¹ and underdiagnosis of asthma has repeatedly been suspected during the past two decades, especially in children and young adults. ^{2 3} Screening studies that used a combination of symptoms and objective indicators of asthma have confirmed this view.^4-6 In the present cohort children who reported asthma-like symptoms but not asthma at age 10 had impaired lung function.⁷

Some risk factors for the underdiagnosis of asthma have recently been proposed, including female sex, ^{6 8} low socioeconomic status,⁹ or belonging to an ethnic minority,¹⁰ whereas the diagnostic process seems to be facilitated if previous episodes of acute bronchitis or a family history of asthma are reported.⁶

This population based study examined a broad selection of potential risk factors for underdiagnosis of asthma among adolescents with coexisting asthma-like symptoms and obstructive airway abnormalities.

Subjects and methods

The Odense schoolchild study is a prospective multidisciplinary epidemiological study in a community based cohort of 1369 schoolchildren first investigated during their third school year in 1985-6.¹¹ The present analysis is based on data from 495 children aged 12 to 15 years and of Danish origin recruited from the original cohort for an extensive asthma and allergy screening programme. Subjects were selected either at random (n=292) or on the basis of a history indicating asthma, allergy, or related symptoms or a family history of asthma or allergic rhinitis (n=203).¹² Subjects completed a comprehensive questionnaire and monitored their peak expiratory flow twice daily for 2 weeks. Laboratory examinations included anthropometric measurements, puberty staging, spirometry, treadmill exercise testing, and provocation with inhaled methacholine. Subjects were asked to stop taking bronchodilators (but not inhaled steroids) before testing. Informed consent was obtained from all children and parents or guardians before participation. The study was approved by the local research ethics committee, the local school board, and the Danish Data Surveillance Authority.

For the present analysis, currently symptomatic subjects were grouped according to the presence or absence of physician diagnosed asthma and positive test results. The variables analysed are listed in the box. Current asthma-like symptoms (ongoing or within the previous year) were identified by questionnaire as previously reported.¹² Symptoms accepted included non-infectious cough, wheezing, and trouble breathing. Physician diagnosed asthma was identified by an affirmative answer to the question, "Is it your doctor's opinion, that you have asthma?" or the use of prescribed asthma medication, or both. Subjects with no previous diagnosis of asthma but asthma-like symptoms and at least one positive test result (hypervariability in peak expiratory flow, hyperresponsiveness to exercise or inhaled methacholine, or low ratio of forced expiratory volume in 1 second (FEV₁) to forced vital capacity (FVC)) were labelled as having undiagnosed asthma.

Details of test procedures have been reported previously.¹² The body mass index (weight (kg)/(height (m)²)) was also calculated. Puberty staging was done according to Tanner and Whitehouse¹³ and corrected for age by sex. Forced expiratory volumes were measured according to European recommendations.¹⁴ For the 6 minute treadmill provocation test results were expressed as the lowest FEV₁ obtained during the first 10 minutes after exercise in percentage of the best value before exercise. Bronchoprovocation with methacholine was performed according to Yan et al¹⁵ and expressed as the methacholine dose response slope.¹⁶ It was ensured that all subjects regained their baseline FEV₁ (within 10%) either spontaneously or aided by inhaled terbutaline (Bricanyl Turbohaler). Peak expiratory flow was recorded twice daily for 14 consecutive days with a Mini-Wright adult type peak flow meter. Variability in peak expiratory flow was expressed as the average of the two lowest values as a percentage of the period mean, after the first three recording days were discarded (the two lowest % mean index).¹⁷ Test results were considered abnormal if they were beyond the value delimiting the 5% "most asthmatic" part of the test distribution in 150 asymptomatic, non-smoking, and non-asthmatic reference subjects from the randomly selected part of the present cohort. The association of a range of medical, environmental, social, school, and activity related factors (see box) with undiagnosed versus diagnosed asthma and with asthma versus asthma-like symptoms only was assessed by logistic regression with SPSS.¹⁸

Variables that seemed to be differently distributed (P<0.15) between the groups compared were included in the logistic regression analysis by using backward selection (final removal criterion P>0.05). Questionnaire information and test results directly related to grouping criteria were not included in the regression models but were analysed separately. The Medstat program (Astra Denmark, Copenhagen) was used to calculate 95% confidence intervals on proportions. Proportions were compared with ² statistics with Yates's correction.

Results

Among 495 subjects investigated, 128 had current asthma-like symptoms. Of these, 15 (12%) were excluded from analysis because of missing data for group allocation. Forty five had physician diagnosed asthma, and 26 were considered as having undiagnosed asthma. The 42 remaining subjects had "symptoms only" (negative test results and not diagnosed with asthma). Despite the "normalising" effect of treatment with inhaled steroids on test results,¹² the sensitivity of the test battery for symptomatic physician diagnosed asthma was high (87%). The proportion of undiagnosed asthmatic subjects among all asthmatic subjects (36.6%) did not differ significantly between subjects selected randomly or by history. The prevalence of any positive test result among 256 non-asthmatic subjects in the random group was 16.0% (not significantly different from the expected value 1(0.95)⁴=18.5% for four independent tests), and the symptom prevalence was 12.1%. Thus, about eight subjects (16% of 12% (1.9%) of 435 subjects with no previous diagnosis of asthma) may have been misclassified as having asthma by chance. After correction for this the proportion of asthmatic patients not previously diagnosed was 29% (18/(18+45)).

Undiagnosed versus diagnosed asthma
Individual regression data for the 21 variables selected for logistic regression are shown in table 1. Adjusted odds ratios for independently contributing risk factors are given in table 2. Undiagnosed asthma was independently associated with self reported problems in the family ("we have very stressful problems in our family" (highest of three levels)), daily exposure to environmental tobacco smoke ("for how many hours a day are you usually exposed to indoor tobacco smoking"), low physical activity ("state average number of hours a week spent with physical activities"), high body mass index, and the absence of serial sneezing ("attacks of more than three consecutive sneezes")). No significant interactions between these factors were found.

Undiagnosed asthma versus symptoms only
Among symptomatic subjects not previously diagnosed with asthma, independent risk factors (see box) for having undiagnosed asthma as opposed to asthma-like "symptoms only" were bronchitis at age 10 (odds ratio 7.35 (1.52 to 35.4), ²=6.2, df=1, P=0.01), signs of humidity in home (0.28 (0.08 to 1.00), ²=3.81, df=1, P=0.05), and physical activity (0.89 (0.79 to 1.00), ²=3.80, df=1, P=0.05). The odds ratios stated were adjusted for all contributing variables (n=66, two missing). No significant interactions were found between the variables contributing to model.

Discussion

Few studies have investigated the characteristics of previously undiagnosed asthmatic patients, probably in part because of the lack of an accepted definition of this condition and the need for objective measurements to confirm the diagnosis to avoid overestimation.¹⁹ For epidemiology a pragmatic definition of asthma as the coexistence of recent wheeze and methacholine hyperresponsiveness has been proposed.²⁰ Cough, however, may be the sole expression of asthma,²¹ and various tests of airway responsiveness may identify different types of abnormalities of the airways.¹² Therefore, we extended our definition of asthma to comprise non-infectious cough or any breathing trouble, or both, in combination with any test result confirming abnormal variations in airway calibre including monitoring of peak expiratory flow, airway responsiveness to methacholine or exercise, and resting spirometry. By this definition subjects with previously undiagnosed asthma made up about one third of all asthmatic patients identified. True asthmatic patients were unlikely to hide in the "symptoms only" group because test results did not differ between those with symptoms but negative test results and reference subjects without symptoms.

Undiagnosed versus diagnosed asthma
Independent risk factors for undiagnosed as opposed to previously diagnosed asthma were serious family problems, low physical activity, high body mass index, high exposure to environmental tobacco smoke, and no history of serial sneezing, a characteristic symptom of allergic rhinitis. The first two of these risk factors were significantly associated with female sex, which, in accordance with previous reports, ^{6 8} comprised two thirds of the undiagnosed but only one third of the diagnosed patients with asthma.

Why is asthma overlooked?
The presence of one or more of the five independent risk factors could in several ways lead to misinterpretation or neglect of asthma-like symptoms by patients, parents, or medical professionals. A low level of physical activity is relatively unlikely to provoke symptoms of asthma induced by exercise and may serve as a means of self "treatment" in childhood asthma. Furthermore, low activity promotes weight gain (high body mass index) which in turn may lead to misinterpretation of asthma symptoms as due to lack of physical fitness. Social status, previously associated with underdiagnosis of asthma,⁹ was not directly measured but may be related to parents' smoking habits as well as problems in the family. Family problems may reduce focus on a child's symptoms, and parents who smoke may be disinclined to get a doctor's advice regarding symptoms related to smoking in the family. Environmental tobacco smoke has previously been shown to be a risk factor for childhood wheeze²² and is likely to be strongly advised against and thus probably reduced when a child is diagnosed with asthma.

In accordance with previous reports,⁶ symptoms were rarely reported to a physician by undiagnosed subjects with asthma, who thereby effectively avoided getting diagnosed and properly treated. Cough seemed to be particularly overlooked as an expression of asthma. Even though the more severely affected patients with asthma (in terms of airway responsiveness and symptoms) were also the most likely to get diagnosed, several moderately to severely affected subjects were first identified as a result of the present study.

The role of atopy as a risk factor for asthma has been established by population based studies with physician independent markers of asthma such as lung function impairment, bronchial responsiveness to methacholine, or typical asthma symptoms.^23-25 We speculate, however, that the traditional emphasis on two associated risk factors²⁶ for asthmanamely, atopy and male sexmay have led to the underrecognition of non-atopic girls with asthma suggested by our data. It seems likely that allergy affecting nose or eyes facilitates a diagnosis of asthma, both by promoting contact with a doctor and by increasing the doctor's awareness towards this diagnosis.

Undiagnosed asthma versus symptoms only
Undiagnosed patients with asthma also differed from those with symptoms but with no evidence of asthma. In this context, previously undiagnosed asthma at age 13 was positively associated with symptoms of bronchitisthat is, periodic cough for many days or weeksat age 10, confirming earlier reports on misclassification of asthma as bronchitis⁴ and suggesting that the asthma had been unrecognised for several years. The negative association between undiagnosed asthma and the level of physical activity suggests that exercise induced symptoms limit the activity level in undiagnosed subjects more than in subjects with respiratory symptoms unrelated to asthma. The independent association of indicators of high humidity in the home with non-asthmatic respiratory symptoms was unexpected but may be related to indoor microbial factors.²⁷

Summary
Substantial underdiagnosis of asthma in the adolescent population was confirmed by combined subjective and objective criteria. Underdiagnosis was independently associated with low physical activity, high body mass, serious family problems, passive smoking, and the absence of rhinitis symptoms. Girls were overrepresented among subjects with undiagnosed asthma and equally underrepresented among those with diagnosed asthma, indicating sex bias in the diagnostic process. Most patients with undiagnosed asthma had not reported their symptoms to a physician, suggesting a need for targeted asthma campaigns in the community.