Thorax 1996;51(Suppl 1):S7-S12

Prognostic factors for the outcome of childhoodasthma in adolescence

Ruurd Jan Roorda

The incidence of asthma, particularly in child-hood, is rising."1 Although the precise reasonsfor this increase are unknown, it is likely thata number of environmental factors are at leastpartly responsible. To date, the most likelyexplanation for the increased prevalence ofasthma is an increased allergen load in theenvironment causing increased airway res-ponsiveness in atopic children.5 The increasedprevalence of asthma in children may well haveserious implications for adults if patients con-tinue to have asthma symptoms in adulthood,although, as yet, only a small number of studieshave shown that the prevalence of asthma risesin young adults.6Over the past few decades the natural evol-

ution of asthma from childhood to adulthoodhas been the subject of many studies.7-5 It waslong believed that the prognosis for asthmaoriginating in infancy or childhood was good,and that in most patients the symptoms wouldresolve by the age ofpuberty. However, a reviewof the literature shows that not all patientsbecome asymptomatic in adulthood. In fact,asthma symptoms persist in 30-80% of adultpatients. Although epidemiological studieshave shown a fair chance of either "remission"or a reduction in asthma symptoms betweenthe ages of 10 and 20 years,5"I and mostpopulation based and clinical studies have alsoshown a reduction in asthma symptoms withage, the relapse rate after a symptom-free in-terval is known to be relatively high.6062 It hasalso been shown that, even in the absenceof asthma symptoms, subjects may still haveobstructed air flow limitation and increasedbronchial responsiveness.39636A number of questions therefore remain to

be answered:

1. Can childhood asthma really be outgrown?2. Do asthmatic children become asthmatic

adults?3. Will the rise in childhood asthma lead to a

further increase in the incidence of asthmain the adult population?

4. Which factors determine the prognosis ofasthma in individual children?Furthermore, certain risk factors which could

probably be recognised in childhood might beassociated with an unfavourable prognosis. Ifthis is the case, treatment and medical super-vision of children at risk should start at an earlyage. Can such treatment affect the prognosisof childhood asthma?Most published studies are retrospective in

design (questionnaire based studies) and havetherefore been subject to potential bias dueto missing data, loss to follow up, and recall

bias.6768 Relatively few prospective studies havefocused on childhood factors which may con-tribute to the prediction of outcome in adult-hood.

Definition of asthmaA review ofthe literature highlights the fact thatin most studies asthma is not clearly defined.Unfortunately, many physicians are reluctantto make a diagnosis of asthma in infants, pre-ferring to use terms such as "wheezy bronch-itis". Children who are classified as having"wheezy bronchitis" in one study may wellbe diagnosed asthmatic in another study. Theabsence of a uniform definition of asthmamakes the available data difficult to interpret.

Population under studyAnother problem is the selection and hetero-geneity of subjects for studies on the long termprognosis ofasthma. Most ofthese studies havebeen based on selected groups of patients withmoderate or severe asthma. However, popu-lation based cohort studies indicate that theprognosis of mild asthma is probably muchmore favourable. It is therefore important torealise that potential risk factors that mightaffect the outcome of childhood asthma aredirectly related to the population under studyand the severity of disease.

Length of follow upA further problem in the study of long termprognosis of asthma is the relatively short peri-ods of observation employed in many studies.Asthma may vary spontaneously over time andperiods of remission are often followed by re-lapses. An important problem, therefore, isthat of "complete remission" which has beendefined as complete freedom from asthmasymptoms during a period of between two andfive years, or the absence of symptoms at thetime of the final assessment. It is now wellknown that asthma symptoms may recur aftermuch longer periods of time. It is thereforelikely that a considerable number of patientsthought to be in complete remission remainlatent asthmatics until the symptoms aretriggered again.

Potential risk factorsNotwithstanding these limitations, it has beensuggested in the literature that a number offactors influence asthma prognosis includingfamily history of atopy, age of onset of symp-

Department ofPediatricPulmonology,'De Weezenianden'Hospital,Zwolle,The NetherlandsR J Roorda

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toms and asthma severity in childhood, child-hood respiratory infections, sex, presence ofother atopic conditions such as eczema or al-lergic rhinitis, and exposure to allergens andother environmental triggers such as tobaccosmoke and damp. Prospective studies that in-clude a measure of childhood pulmonary func-tion and bronchial responsiveness and data onallergy (as assessed by skin tests or radio-allergosorbent test (RAST)) are limited andhave only been published in recent years.

Clinical studiesONSET OF ASTHMA AND ITS SEVERITY INCHILDHOODThe majority of clinical studies do not show asignificant negative effect on the prognosis ofearly onset asthma although the disease maybe severe in these children.'2132127435' In somestudies early onset of symptoms has beenassociated with an unfavourable outcome.20 35 54This does not contradict the favourable prog-nosis for children with wheezing during theearly years of life found in epidemiologicalstudies since this group of patients includes anumber of children with wheezy illnesses otherthan asthma. A higher asthma symptom scorein childhood, which represents more severeasthma, is a well known risk factor for thepersistence of asthma in adulthood.'727435' Theclinical severity of asthma in childhood is there-fore an important predictor of asthma per-sistence in adulthood.

ATOPIC MANIFESTATIONSIn at least 75% of asthmatic children asthmais associated with allergy to inhaled allergensand a family history of allergy.Few long term studies have considered the

influence of family history on the long termprognosis of childhood asthma. Ryssing andFlensborg'8 and Martin et a13' agree that apositive family history for atopy is associatedwith an unfavourable asthma prognosis. How-ever, in other studies family history was foundnot to affect asthma prognosis adversely.253447

If family history does not determine in-dividual asthma prognosis the implication isthat the severity of asthma is not geneticallydetermined, even if the individual has a geneticpredisposition to the disease. Therefore, en-vironmental factors are probably the most im-portant factors in the clinical expression andprognosis of asthma.Due to cumulative exposure to allergens,

skin reactivity to inhaled allergens increaseswith age and peaks in young adults aged be-tween 25 and 34 years of age.69 Many studieshave shown that both the number of positiveskin tests and weal diameter increase with age.In most of the studies the increase in skinreactivity, as expressed by the number of posi-tive skin tests, appears to be independent ofthe progress ofasthma in children.24273070 Somestudies have shown a favourable prognosis inchildren with negative skin tests or positivetests to a small number of allergens.43 Thesefindings might, however, be influenced by se-

lection criteria, as almost all of the childrenincluded in these studies were allergic.

In our own study, in which the study popu-lation was stratified according to the degree ofskin reactivity in childhood (sum score of thesemiquantitative expression ofweal diameters),those subjects who had the lowest childhoodtotal skin test score were found to have thelowest incidence of asthma symptoms in adult-hood. Mean eosinophil count in childhood wasslightly but not significantly higher in subjectswith persistent symptoms in adulthood.4550Mazon et al55 studied the effects of sensitivity

to allergens (as assessed by skin testing orRAST) on the persistence of asthma. Althoughthe follow up interval was rather short (mean63 months) and the ages of the children in-cluded in the study were not given, a significantassociation with persistent symptoms and sens-itisation to house dust mite, moulds, pollen,and milk protein was demonstrated.No data are available to date on the value of

either total or specific serum IgE levels in theassessment of asthma prognosis. In some stud-ies children with normal or only slightly raisedIgE values ("intrinsic asthma") were labelledas having the most troublesome disease.3437Although epidemiological studies suggest

that the presence of allergic eczema and/orrhinitis with asthma has a negative effect onasthma prognosis,487' clinical studies haveproved to be inconclusive. Some studies foundno predictive effect,46 52 55 72 while others showeda significant negative effect of atopic eczemaon asthma prognosis." 18 19 26 27 44

BRONCHIAL HYPERRESPONSIVENESSA relationship exists between atopy or specific(allergic) bronchial hyperresponsiveness andnon-specific bronchial hyperresponsiveness to,for example, histamine or methacholine. How-ever, although atopy and bronchial hyper-responsiveness are interrelated, they appear toact independently with respect to asthma prog-nosis.

Gerritsen46 studied the prognostic value ofthe type of response to specific (house dust)inhalation provocation in childhood. The studyindicated that the prognosis for subjects whohad no response in childhood was better thanfor those subjects who did exhibit a response.However, there were no significant differencesin the prognosis for children with either anearly, late, or dual asthmatic response.

Non-specific bronchial hyperresponsivenessmay presage asthma.7374 The degree of non-specific bronchial hyperresponsiveness mayvary greatly from time to time within the asth-matic individual. As the asthmatic child ma-tures bronchial responsiveness may decrease.The cause of the decrease is not known butmay be due to a number of reasons such ashormonal and structural changes associatedwith growth.75 This has led to speculation thata natural decrease in bronchial responsivenessmay be responsible for the improvement ofasthma in adolescence.76 Although bronchialresponsiveness in asthmatic children decreaseswith age, in the majority of clinical studies

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Prognostic factors for the outcome of childhood asthma in adolescence

approximately half of symptomatic young ad-ults remained hyperresponsive. In subjects withno symptoms in adulthood the proportionwho remained hyperresponsive was muchlower.46 51 56 62

In prospective studies employing multipleregression techniques the degree of childhoodbronchial hyperresponsiveness was one of thefew significant variables that predicted per-sistent symptoms in adulthood.465' Fur-thermore, a strong association was foundbetween the presence and degree of bronchialhyperresponsiveness and the need for med-ication in adulthood. Treatment of airwayinflammation, reflected by bronchial hyper-responsiveness, is fundamental,77 and suchtreatment may also have a positive effect onthe long term prognosis of the disease.

It is a common belief that the airwaysobstruction of childhood asthma is

reversible.

PULMONARY FUNCTIONIt is a common belief that the airways ob-struction of childhood asthma is completelyreversible. However, in recent years numerousstudies have demonstrated persistent pul-monary abnormalities in both children andadults.39636 It therefore seems necessary notonly to treat symptomatic episodes of asthmain childhood but also to optimise pulmonaryfunction on a long term basis and to minimisethe process that may relate to irreversible air-ways obstruction.

Since pulmonary function in most childrenwith asthma is thought to be normal, it followsthat persistent abnormal pulmonary functionin childhood (measured either at rest or aftertreatment with bronchodilating agents, whichcompensate for the reversible part of the dis-turbance of pulmonary function) is probablyassociated with more severe asthma and an

unfavourable prognosis.A number of studies have shown that the

level ofchildhood pulmonary function is indeedpredictive of persistent asthma symptoms inadulthood.3840 Although other studies do notconfirm these findings they do demonstrate thepredictive value of a combination of airwayresponsiveness and levels of forced expiratoryvolume in one second (FEVI).5' Most of thestudies published to date do show a strongcorrelation between the level of pulmonaryfunction in childhood and adulthood.384052 Inasymptomatic adults the percentage predictedFEV, was in the normal range (or becamecloser to normal the longer the patient was freeof wheezing),526578 while their childhood levelwas normal or only mildly reduced. In anAustralian follow up study subjects who stillhad severe symptoms in adulthood had themost serious disturbance of pulmonary func-tion in childhood and the steepest decline ofpulmonary function towards adulthood. FEV,

levels below the fifth percentile at 10 or 14 yearsof age were associated with more troublesomeasthma at the age of 21 years.38

Studies in children consistently showa higher prevalence of asthma in

boys . . ., but in general the prognosisfor women is worse than it is for men.

DIFFERENCES IN SEX WITH RESPECT TO ASTHMAStudies in children consistently show a higherprevalence of asthma in boys, the prevalencebefore puberty being at least twice as high inboys than in girls. Symptoms may also start ata younger age in boys.The higher prevalence ofasthma in boys may

be caused by a combination of factors. "Hostsusceptibility" may be greater in boys, and ahigher incidence of respiratory distress syn-drome and other respiratory illnesses suggestthat boys may have more vulnerable airways.The absolute peripheral airway diameter issmaller in young boys than it is in young girls,especially in the first 18 months of life.7980Differences in the prevalence of asthma mayalso be influenced by differences in the size ofthe airways relative to size of the lungs. Theprevalence of allergic phenomena is also higherin boys.458' Furthermore, some studies havedemonstrated a higher prevalence of bronchialhyperresponsiveness in boys.82-84The predominance ofboys among asthmatic

subjects gradually diminishes until pubertywhen a higher incidence ofnew cases ofasthmais found in girls,28 and after the age of 20 yearsthe incidence of asthma is higher in womenthan in men. In most studies in young asthmaticadults the male:female ratio is about 1:1-5.Hospital admission rates and morbidity ratesafter the age of 40 years are also significantlyhigher in women than in men. Not only is theproportion of women with current complaintsin adulthood higher than in men, symptomscores are also increased. In general, therefore,the prognosis for women is worse than it is formen.'2 28404451 85 86 The cause of the differencesbetween the sexes is unknown and it is some-what surprising that this topic is not addressedmore fully in the literature.

In the 1960s it was postulated that hormonaldifferences might be responsible for the differ-ences in asthma severity between the sexes.87Hormones may influence airway inflammation,airway smooth muscle function, and vascularintegrity. The higher levels of morbidity dueto asthma in women may also be related todifferences in the rate of lung growth betweenthe sexes and a deterioration of pulmonaryfunction with age. Airway diameter and par-enchymal size may also affect morbidity due toasthma as airway responsiveness is related toairway size. Women possess smaller lungs thanmen and this may explain their increased airwayresponsiveness, although the higher level ofairway responsiveness cannot completely ex-plain the higher level of morbidity due toasthma among women.

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SMOKINGBoth active and passive smoking influence theoutcome of childhood asthma. However, fewlong term clinical studies have been carried outon the influence of passive smoking on theprognosis of asthma in children. There is evid-ence that a substantial proportion of childrenwith asthma, especially boys, have worseningsymptoms and reduced pulmonary functionwhen passively exposed to tobacco smoke.88The effects of passive smoking is likely to be

more significant in population based studiesthan in clinical studies. Tager89 demonstratedthat inhaled smoke, either actively or passively,renders asthmatic children more susceptible toirreversible limitation of the small airways.However, two prospective studies in young

adults in the Netherlands found no significanteffects on asthma symptoms among activesmokers,405' although in one of the studies thecigarette smoking (as measured by the numberofpack years) adversely affected the FEV, levelsin adult men.5' The lack of negative healtheffects may be explained by the so-called"healthy smoker" effect in which mildly asth-matic individuals with relatively few symptomsand limited bronchial responsiveness are ableto start cigarette smoking. The proportion ofasthmatics who were active smokers was sur-prisingly high compared with the proportion ofsmokers in the Dutch population as a whole.However, neither of these studies included asufficiently long follow up period and the num-ber of pack years was too small to demonstrateall of the potential effects of cigarette smokingon the prognosis for asthma sufferers.90 Thesame limitations may explain the lack of anegative effect of cigarette smoking found inthe Australian follow up study.38

TREATMENTAsthma is considered to be an inflammatorydisease of the airways and anti-inflammatoryagents are currently the mainstay of asthmatreatment. Few long term studies on the in-fluence of such treatment on asthma prognosishave been published. A large prospective multi-centre study in 116 children compared treat-ment for 22 months with either budesonidein combination with salbutamol (each 600 jtgdaily), or salbutamol and placebo. Childrenwho received inhaled corticosteroids showeda significant reduction in asthma symptomswithin the first few months of the study, aslight increase in pulmonary function, and areduction in airway responsiveness which stillhad not reached a plateau by the end of thestudy.9' In some of the children asthma symp-toms had resolved (clinical remission for atleast eight months). Lower symptom burdenat baseline seemed to be the only predictor ofpatients likely to enter remission.92 However,cessation of inhaled corticosteroid therapy ledto recurrence of symptoms and a rapid de-terioration of airway responsiveness.93 It maybe concluded, therefore, that inhaled cortico-steroid therapy cannot cure asthma, and that

the underlying inflammatory process remains,even after a long period of treatment.

In a retrospective study carried out in Den-mark maintenance prophylactic treatment withinhaled corticosteroids was compared withother treatment regimens in children. Thestudy indicated that the earlier treatment withcorticosteroids was begun following the diag-nosis of asthma, the greater was the increase inpulmonary function (FEV, ml/year).94 Konig95carried out a retrospective study to comparethe effects of sodium cromoglycate with thoseof inhaled corticosteroids. A significant clinicalimprovement and improvement in pulmonaryfunction were found in all of the childrentreated with anti-inflammatory agents, andthere were no differences between agents. Asproperly matched and controlled prospectivelong term studies have not yet been published,it is not possible to evaluate the effects of anyparticular treatment for asthma. Nevertheless,the above studies suggest that early use ofprophylactic asthma treatment may succeed inimproving the prognosis for asthmatic childrenand may favour optimal lung growth through-out adolescence.

... denial of symptoms ischaracteristic of adolescents with

asthma.

UNDER-DIAGNOSIS AND UNDER-TREATMENTAlthough the prevalence of asthma is risingworldwide, there is still evidence for under-diagnosis ofasthma in childhood.96 In addition,patients may frequently underestimate the se-verity of their disease and denial of symptomsis characteristic of adolescents with asthma.Both of these factors imply a risk of the diseasenot being appropriately treated.

Studies have shown that, although the pro-portion of young adults who continue to sufferfrom asthma symptoms is relatively high, thenumber of them who are under medical super-vision for their asthma is low. The majority(approximately 80%) do not receive regularmedical supervision, though these individualsmay have a high symptom score.49"' For-tunately, the more severe the asthma, thegreater the proportion of subjects who do re-ceive regular monitoring.Most adolescents included in these studies

exhibited poor compliance with their treatmentregimens and this may mean that they receivedeither inadequate treatment or no treatment atall. In the follow up cohort study carried outin Australia more than 75% of patients aged21 years who had frequent episodes of asthmaand 40% of those with persistent asthma werenot receiving adequate treatment.97 Despite thepresence of asthma symptoms, the majority ofpatients did not use any medication for theirasthma. Those who did used mainly broncho-dilator therapy, and only a minority receivedanti-inflammatory treatment.495156

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Prognostic factors for the outcome of childhood asthma in adolescence

ConclusionBy the second decade of life asthma symptomsoften abate and it may seem that patients withmild asthma have "outgrown" the disease. Un-fortunately this is likely to be the exceptionrather than the rule.Although the severity of asthma symptoms

fluctuates with time, the inherited tendencytowards respiratory symptoms never disappearsand many teenagers who seem to be free ofsymptoms do, in fact, have persistent asthma.During symptom-free periods subclinical, butnevertheless significant, airways obstructionand/or bronchial hyperresponsiveness may bepresent. It is not unusual for adults who havebeen asymptomatic for a number of years toredevelop asthma symptoms. Indeed, much ofthe so-called adult onset asthma has its rootsin childhood. Levison98 concluded that, in thesesubjects, it is often not the asthma that isoutgrown but the paediatrician.

... it is often not the asthma that isoutgrown but the paediatrician.

The more severe asthma is in childhood themore likely it is that the disease will persist inadulthood. A complete list ofthe characteristicsof the disease in childhood, and the potentialrisk factors associated with an unfavourableprognosis, such as pulmonary function andbronchial responsiveness and markers ofairwayinflammation, is therefore needed.As properly matched and controlled pro-

spective long term studies have not been pub-lished it has not been possible to evaluate theeffects on prognosis of any single class of anti-asthma agent. Such studies are needed to findout if it is possible to alter the natural historyof the disease. In theory modem asthma treat-ments, because they are able to improve symp-

toms and underlying disease phenomena, are

also beneficial in the long term prognosis ofchildhood asthma.

Since compliance ... is low,a monitoring system is needed toguarantee adequate follow up and

treatment during and beyondpuberty.

The majority of patients with persistentasthma included in the currently available stud-ies were not receiving adequate treatment.Since compliance with therapeutic regimens inasthma, especially in adolescence, is low, a

monitoring system is needed to guarantee ad-equate follow up and treatment during andbeyond puberty.

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