A Longitudinal, Population-Based, Cohort Study of Childhood Asthma Followed to Adulthood
Malcolm R. Sears, M.B., Justina M. Greene, Andrew R. Willan, Ph.D., Elizabeth M. Wiecek, M.D., D. Robin Taylor, M.D., Erin M. Flannery, Jan O. Cowan, G. Peter Herbison, M.Sc., Phil A. Silva, Ph.D., and Richie Poulton, Ph.D.
Background The outcome of childhood asthma in adults has beendescribed in high-risk cohorts, but few population-based studieshave reported the risk factors for persistence and relapse.
Methods We assessed children born from April 1972 through March1973 in Dunedin, New Zealand, repeatedly from 9 to 26 yearsof age with questionnaires, pulmonary-function tests, bronchial-challengetesting, and allergy testing.
Results By the age of 26 years, 51.4 percent of 613 study memberswith complete respiratory data had reported wheezing at morethan one assessment. Eighty-nine study members (14.5 percent)had wheezing that persisted from childhood to 26 years of age,whereas 168 (27.4 percent) had remission, but 76 (12.4 percent)subsequently relapsed by the age of 26. Sensitization to housedust mites predicted the persistence of wheezing (odds ratio,2.41; P=0.001) and relapse (odds ratio, 2.18; P=0.01), as didairway hyperresponsiveness (odds ratio for persistence, 3.00;P<0.001; odds ratio for relapse, 3.03; P<0.001). Femalesex predicted the persistence of wheezing (odds ratio, 1.71;P=0.03), as did smoking at the age of 21 years (odds ratio,1.84; P=0.01). The earlier the age at onset, the greater therisk of relapse (odds ratio, 0.89 per year of increase in theage at onset; P<0.001). Pulmonary function was consistentlylower in those with persistent wheezing than in those withoutpersistent wheezing.
Conclusions In an unselected birth cohort, more than one infour children had wheezing that persisted from childhood toadulthood or that relapsed after remission. The factors predictingpersistence or relapse were sensitization to house dust mites,airway hyperresponsiveness, female sex, smoking, and early ageat onset. These findings, together with persistently low lungfunction, suggest that outcomes in adult asthma may be determinedprimarily in early childhood.
The increase in the prevalence of wheezing disorders, whetheror not they are labeled as asthma, could be related to an increasedincidence or an increased persistence of asthma.1,2 Studiesof the natural history of asthma have often focused on selectedpopulations. However, the outcomes in children referred to universityclinics3,4 or selected in high-risk cohorts5 may not reflectthe outcomes in the general population, since the initial selectioncriteria may predetermine the risk factors for persistence orrelapse.6
Most children attending asthma specialty clinics who have beenfollowed have had atopy, with frequent symptoms and airway hyperresponsiveness,indicating severe disease that is likely to persist. The effectsof sex, age at onset, and smoking on the outcome have been uncertainin such children7,8 and in high-risk cohorts selected accordingto the presence of parental atopy.5,9 The few population-basedepidemiologic studies of outcomes of childhood asthma differin the frequency of assessment, cohort-retention rates, andthe use of quantitative measurements.10,11,12,13 In particular,repeated lung-function measurements have been reported infrequently.14,15,16We report outcomes in an unselected, population-based birthcohort of over 1000 New Zealand children followed to adulthood.
Methods
Study Members
The Dunedin Multidisciplinary Health and Development Study isa longitudinal investigation of health and behavior in a completebirth cohort.17,18,19,20,21 The study members were born in Dunedin,New Zealand, between April 1972 and March 1973. Of 1139 childrenborn during that period and residing in the province of Otago,New Zealand, at the age of three years, 1037 (91 percent, 52percent of whom were boys) participated in the first follow-upassessment at three years of age. The cohort families representedthe full range of socioeconomic status in New Zealand's SouthIsland and were primarily of European extraction.
The children were seen every 2 years between 3 and 15 yearsof age and then were seen at 18, 21, and 26 years. Respiratoryquestionnaires were completed and lung-function measurementswere performed at the ages of 9, 11, 13, 15, 18, 21, and 26years; airway hyperresponsiveness to methacholine was determinedat the ages of 9, 11, 13, 15, and 21 years; atopy was determinedat 11 years (IgE levels only), 13 years (skin tests only), and21 years (IgE levels and skin tests); and responsiveness toa bronchodilator was determined at 18 and 26 years.
The research ethics committee of the Otago Hospital Board approvedeach assessment. The participants gave written informed consentfrom the age of 18 years; before that age, a parent or guardiangave written informed consent, and the child gave oral assent.
Follow-up
For accurate classification of remission, relapse, or persistenceof asthma, study members who completely missed any assessmentwere excluded from the analysis. For an assessment to be included,at least a respiratory questionnaire had to be completed. Thecharacteristics of the study members who were included werecompared with the characteristics of those not included. Theoutcome characteristics of those included and all study membersparticipating at the age of 26 years were also compared.
Questionnaires
When the child was nine years old, the accompanying adult (usuallythe mother) answered detailed questions about the child's symptomsand illnesses, providing a retrospective history of respiratoryevents between birth and the age of nine, including frequency,severity, trigger factors, and treatment (specifically, theuse of bronchodilator and corticosteroid medications).19 Subsequently,similar questions were answered by the study member. From theage of 18 years, the study member completed the self-administeredquestionnaire used in the European Community Respiratory HealthStudy22 and questions from the American Thoracic Society questionnaire23before answering the interviewer-administered questionnaire.
Skin Tests
Skin-prick testing was performed at the ages of 13 years (714participants) and 21 years (885 participants) to determine sensitivityto house dust mites (Dermatophagoides pteronyssinus) (Bencard),grass, cat dander, dog dander, horse dander, kapok, wool, Aspergillusfumigatus, alternaria, penicillium, and cladosporium (Hollister–Stier).20The positive and negative controls were 0.1 percent histamineand diluent, respectively. The response was measured as themean diameter of the resulting wheal.
Lung-Function Tests
Three measurements of forced vital capacity (FVC) and forcedexpiratory volume in one second (FEV1), obtained in the absenceof recent use (within six hours) of a bronchodilator, were recordedon a Godart water-sealed spirometer at the ages of 9, 11, 13,15 and 21 years (when methacholine challenges were also performed),a Morgan rolling-seal spirometer at the age of 18 years, anda SensorMedics body plethysmograph at the age of 26 years. Theinstruments were calibrated daily with a 3-liter syringe. Themeasurements were made between 1 p.m. and 4 p.m. The predictedvalues at 26 years of age were based on a study of New Zealandadults.24
Airway Responsiveness
Methacholine challenge was performed in all consenting studymembers at the ages of 9, 11, 13, 15, and 21 years with theuse of an abbreviated validated protocol21 modified from thatof Chai et al.25 Challenge was not performed in those with airflowobstruction (FEV1 of less than 75 percent of the FVC at 9 and11 years of age and of less than 70 percent of the FVC at olderages), but spirometry was repeated 10 minutes after they hadinhaled nebulized albuterol (5 mg per milliliter) for 2 minutes.At 18 and 26 years of age, bronchodilator responsiveness wasdetermined in all consenting study members.
Definitions
Figure 1 illustrates the definitions of different patterns ofwheezing. All wheezing, irrespective of causal factors, wasincluded except for wheezing occurring only once or twice annuallyand lasting less than one hour. Wheezing reported at every assessmentafter its first mention was classified as persistent wheezing.Remission was defined as the absence of wheezing after wheezinghad been reported at two or more successive prior assessments.Relapse was recorded if wheezing was reported at two or moresuccessive assessments, then was absent at one or more successiveassessments, and then was reported at all subsequent assessments.Intermittent wheezing was characterized by the presence of symptomsat some assessments but not others and not at two consecutiveassessments and not fitting the patterns described above. Wheezingreported at one assessment only was classified as transientwheezing.
Figure 1. Patterns of Wheezing (Shaded Bars) in Childhood Reported by Study Members or Their Parents, Illustrating Definitions of Persistent Wheezing, Remission, Relapse, Intermittent Wheezing, Transient Wheezing, and No Wheezing Ever.
Airway hyperresponsiveness was defined by a value for methacholinePC20 (the concentration of methacholine causing a 20 percentdecrease in the FEV1) of 8 mg per milliliter or less or an increasein the FEV1 of at least 10 percent from base line in responseto a bronchodilator. Atopy was defined by a wheal diameter atleast 2 mm greater than that of the wheal produced by the diluentcontrol.
Statistical Analysis
The data were analyzed with SAS software. The characteristicsof the study members and the prevalences of persistence, remission,and relapse were described with summary statistics. Logisticregression was used to estimate unadjusted and adjusted oddsratios, significance levels, and confidence intervals for factorsassociated with persistence or relapse. Trends and differencesbetween outcome groups in mean measures of pulmonary functionwere assessed with generalized estimating equations incorporatingthe repeated nature of these data.
Results
Study Sample
At the age of 9 years, 815 study members (78.6 percent of thecohort of 1037) completed respiratory questionnaires, as did802 (77.3 percent) at 11 years, 735 (70.9 percent) at 13 years,972 (93.7 percent) at 15 years, 868 (83.7 percent) at 18 years,957 (92.3 percent) at 21 years, and 954 (92.0 percent) at 26years. Because of the reduced numbers at 11 and 13 years, only613 study members (59.1 percent of the total, of whom 317 weremale) provided respiratory data at every assessment. These 613make up the sample for the analysis of persistence, remission,and relapse of wheezing, since those with missing data cannotbe accurately classified.
Representativeness of the Sample
There were no significant differences in sex ratio, family historyof asthma and hay fever, symptoms, proportion with atopy, lung-functionmeasurements, or prevalence of airway hyperresponsiveness betweenthe 613 study members with complete respiratory data and theoriginal cohort of 1037, or between the 613 study members andall study members undergoing these investigations at particularages. As compared with those not attending every assessment,the 613 were more likely to report current asthma or wheezingat 9 years and were more likely to be sensitive to house dustmites or to any allergen at 13 and 21 years. However, they werenot more likely to have airway hyperresponsiveness at 9 yearsand were less likely to have airway hyperresponsiveness at 21years (Table 1). At 26 years, there were no significant differencesin the prevalences of asthma, wheezing, asthma treatment, orsmoking or in lung-function measurements between those seenat every assessment and those not seen at every assessment (Table 1).Hence, the 613 with complete outcome data are generallyrepresentative of the base cohort.
Table 1. Characteristics of the 613 Study Members Who Provided Respiratory Data at All Assessments from 9 to 26 Years of Age, as Compared with the Characteristics of Those Not Providing Data at All Assessments.
Persistence of Wheezing
Of the study members, 72.6 percent had reported wheezing duringat least one assessment by the age of 26 years, and 51.4 percenthad reported such wheezing at more than one assessment. At thisage, 26.9 percent of the study members were currently wheezing.In 14.5 percent, wheezing had persisted from onset, whereas12.4 percent had had a remission followed by a relapse by theage of 26 years (Table 2). Another 15.0 percent remained inremission, 9.5 percent had intermittent symptoms, and 21.2 percenthad reported symptoms at only one assessment.
Table 2. Outcomes at Age 26 Years among 613 Study Members Who Provided Respiratory Data at Every Assessment, According to Sex.
Transient Wheezing
Wheezing at only one assessment (transient wheezing) was reportedby 130 of the 613 study members (21.2 percent) (Table 2), including28 (4.6 percent) who reported wheezing only at the age of 26years. As compared with the group of study members who neverreported wheezing, the group with transient wheezing had a significantlyhigher prevalence of atopy for house dust mites at the age of13 years (23.3 percent vs. 12.7 percent, P=0.02), and nonsignificanttrends toward an increased prevalence of atopy at 21 years ofage and toward smoking.
Relation of Persistence and Remission to Risk Factors
Table 3 shows the relations between outcomes at the age of 26years and atopy, airway hyperresponsiveness, parental and personalsmoking, birth order, and whether the study member had beenbreast-fed. At the age of 26 years, study members with persistentor relapsing wheezing had higher prevalences of sensitivityto house dust mites (P<0.001) and cat allergen (P<0.001)and of airway hyperresponsiveness (P<0.001) and lower lung-functionmeasurements (P<0.001) than those whose wheezing did notpersist or relapse.
Table 3. Characteristics of Study Members with Different Patterns of Wheezing.
Table 4 shows the odds ratios for persistence and relapse ofwheezing according to univariate and multivariate models. Thehighest odds ratios associated with either persistence or relapsewere for airway hyperresponsiveness (determined as either avalue for methacholine PC20 that was less than 8 mg per milliliteror an increase in the value for FEV1 of more than 10 percentfrom base line in response to a bronchodilator) between theages of 9 and 21 years and for a positive skin test for housedust mites at the age of 13 years. Female sex and smoking alsopredicted persistence, whereas an early age at onset predictedrelapse. Other factors that were significant in the univariateanalysis were not independently significant in multivariateanalyses.
Table 4. Odds Ratios for Factors Predicting Persistence of Wheezing from Onset to the Age of 26 Years or Relapse, by the Age of 26 Years.
Throughout childhood and into adulthood, study members withpersistent wheezing had consistently lower lung-function measurements,expressed as the ratio of FEV1 to FVC, than study members whonever reported wheezing (Figure 2). The slopes of change inthe FEV1:FVC ratio over time from the ages of 9 to 26 yearsin any outcome category for either sex were not significantlydifferent from those for study members who never reported wheezing.When generalized estimating equations incorporating the repeatednature of the data in the analysis were used, the mean FEV1:FVCratio for male study members with persistent wheezing was 6.8percent less than the mean for male study members who neverreported wheezing (P<0.001); for male study members who hada relapse, the difference was –6.5 percent (P<0.001).The differences in the mean FEV1:FVC ratio between those withremission, intermittent wheezing, or transient wheezing andthose who never reported wheezing were nonsignificant (–0.8percent, –1.9 percent, and –1.1 percent, respectively).Among female study members, the differences in the FEV1:FVCratio, as compared with those who never reported wheezing, were–4.7 percent for persistent wheezing (P<0.001), –2.7percent for relapse (P=0.003), –2.3 percent for remission(P=0.022), –1.8 percent for intermittent wheezing, and–0.1 percent for transient wheezing.
Figure 2. Mean (±SE) FEV1:FVC Ratios Measured at 9, 11, 13, 15, 18, 21, and 26 Years in Male (Panel A) and Female (Panel B) Study Members, According to the Pattern of Wheezing.
The lung-function measurements in study members with persistentwheezing who reported having used inhaled corticosteroids atany time were substantially lower at all ages and for both sexesthan they were in those with persistent wheezing who had neverused inhaled corticosteroids; the mean difference in the FEV1:FVCratio was –7.2 percent in male study members and –8.2percent in female study members. Similarly, in the group withpersistent wheezing, lung-function measurements were lower instudy members who had airway hyperresponsiveness on three ormore occasions than in those who had hyperresponsiveness lessoften (mean difference, –7.4 percent for male and femalestudy members combined).
Discussion
Our study of an unselected, population-based birth cohort withthe use of seven respiratory assessments from childhood intoadulthood provides insights into the risk factors for the persistenceand relapse of childhood asthma and for pulmonary-function outcomes.There were significant differences in the prevalences of childhoodasthma, wheezing, and atopy between the 613 study members forwhom respiratory data were available at all assessments (59.1percent) and those for whom respiratory data were not availableat all assessments, but there were no differences in outcomecharacteristics at the final assessment, at the age of 26 years.Because our multidisciplinary study evaluated many aspects ofhealth and development other than asthma and allergy, this approachreduced the likelihood that the decision to return for eachassessment was biased by the presence of these conditions, thusincreasing generalizability.
Wheezing was common in this cohort, reported at some time by72.6 percent of the 613 study members. This high cumulativeprevalence, which may be slightly biased upward for reasonsnoted above, includes the 21.2 percent of study members whoreported wheezing at only one assessment. The latter group differedfrom those who never reported wheezing in having almost doublethe prevalence of atopy to house dust mites, and therefore thisgroup could not be ignored. We have previously compared theresponses of 946 study members assessed at the age of 21 yearswith those of 991 subjects 20 to 22 years old who were enrolledin the cross-sectional European Community Respiratory HealthSurvey, performed elsewhere in New Zealand. This comparisonshowed no significant or systematic differences in the prevalenceof reported wheezing in the previous 12 months, waking withchest symptoms, attacks of asthma, and use of asthma medication,26thus providing evidence that our high prevalence rates are notbiased by the longitudinal design. In a birth cohort from theUnited Kingdom, 43 percent of the cohort members reported wheezingby the age of 33 years,12 a result suggesting, as does our study,that wheezing is very common but is often mild and transient.
As young adults, 26.9 percent of our cohort had continuing symptomsof asthma; 14.5 percent had persistent wheezing from onset withno remission, and 12.4 percent had relapsed after remission.These study members represent over one third of the 72.6 percentwho reported ever wheezing, a result consistent with Australianstudies in Tasmania10 and Melbourne,13 in which two thirds ofsubjects with asthma "outgrew" their disease.6
An early age at onset was a risk factor for relapse. The oddsratio of 0.89 indicates the protective effect per year of increasein the age at onset. According to this model, the risk for childrenwith a 10-year-later age at onset was 0.8910, or 0.31 —that is, a 10-year-later age at onset reduced the risk of relapseby 69 percent.
Assessing outcomes relatively early in adult life may overestimatethe number of remissions and underestimate the number of relapses,because symptoms may recur later. In a study in Tucson, Arizona,remission was most likely in adolescence and was uncommon inadulthood.27 Another limitation of our study is that historiesof wheezing in early childhood were obtained when the childrenwere already nine years old. Our study therefore indicates thelikelihood of persistence or relapse among children whose mothersrecalled that they wheezed in early childhood or in whom wheezingdeveloped subsequently. However, early-childhood wheezing notrecalled by the mother had probably been mild and had remitted,since otherwise one would expect these symptoms to be recalled.
Lung function was persistently impaired throughout childhoodin study members with persistent asthma in adulthood, a phenomenonknown as tracking. However, the slopes of change in FEV1:FVCwere similar in each group, indicating that impairment of lungfunction occurred in early childhood, before our first measurementsat the age of nine years. Children with atopy may have impairedlung function as early as three years of age.28 Lung functionin male study members with a relapse tracked closely with thatin male study members with persistent asthma, whereas femalestudy members with a relapse had lower lung function only asadults. This difference may be due to the greater severity ofdisease among young boys with asthma.
The impairment in lung function in the group with persistentasthma was greater in those with persistent airway hyperresponsivenessand in those treated with inhaled corticosteroids. This findingillustrates confounding by severity, since the use of inhaledcorticosteroids is an indicator of more severe disease, notthe cause of impaired lung function. In the Melbourne longitudinalstudy, adult lung function was impaired in subjects with currentsevere asthma, but not in those with milder asthma who werenot using inhaled corticosteroids, whereas those who were asymptomaticfor three years had normal lung function, even though they hadhad asthma throughout childhood.13,16 Our study extends thefindings of the birth-cohort study from the United Kingdom15by showing that reduced lung function in adulthood among thosewith persistent asthma is evident early in childhood and hasconsistently been at this lower level throughout childhood andadolescence into adulthood.
In the United Kingdom birth cohort, smoking was a risk factorfor the development of asthma between 17 and 33 years of ageand was a strong predictor of relapse of earlier asthma by theage of 33 years.12 In our study, smoking at 21 years of agewas predictive of persistent wheezing in both univariate andmultivariate analyses and of relapse of wheezing in univariatebut not in multivariate analysis. In studies based on asthma-clinicpopulations, the effect of smoking on the persistence of asthmahas been inconsistent, perhaps reflecting self-selection (the"healthy smoker" effect).7
In summary, in a population-based birth cohort of New Zealandchildren who were not selected because they had asthma or wereat high risk, the independent risk factors for persistent asthmain adulthood included allergy to house dust mites, smoking,airway hyperresponsiveness, and female sex. The independentrisk factors for relapse after remission included allergy tohouse dust mites, airway hyperresponsiveness, and early ageat onset. Those with persistent or relapsing asthma had substantiallyimpaired lung function at each assessment during childhood,adolescence, and adulthood, a result suggesting that these outcomesare determined early in childhood. The challenge is to developidentification and treatment strategies applicable to earlychildhood that will reduce these adverse outcomes.
Supported by funds from the Health Research Council of New Zealand,the Otago Medical Research Foundation, the New Zealand LotteryGrants Board, and the Asthma Foundation of New Zealand.
We are indebted to Air New Zealand; to the study members andtheir families for their ongoing commitment and support; toDr. Wendy Lou for statistical assistance; and to Mrs. PearlDavis and Mrs. Jan Kettink for secretarial and administrativeassistance.
Source Information
From the Departments of Medicine (M.R.S., J.M.G.), and Clinical Epidemiology and Biostatistics (A.R.W., E.M.W.), McMaster University, Hamilton, Ont., Canada; and the Department of Medicine (D.R.T., E.M.F., J.O.C.), the Department of Preventive and Social Medicine (G.P.H.), and the Dunedin Multidisciplinary Health and Development Research Unit (P.A.S., R.P.), University of Otago, Dunedin, New Zealand.
Address reprint requests to Dr. Sears at the Firestone Institute for Respiratory Health, McMaster University and St. Joseph's Healthcare, 50 Charlton Ave. E., Hamilton, ON L8N 4A6, Canada, or at searsm{at}mcmaster.ca.
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