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2002;109;362Pediatrics

Fernando D. MartinezDevelopment of Wheezing Disorders and Asthma in Preschool Children

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Development of Wheezing Disorders and Asthma in Preschool Children

Fernando D. Martinez, MD

ABSTRACT. Recent longitudinal studies have shedlight on the pathogenesis and progression of asthma. Thepatterns of expression of childhood asthma that persistinto adult life have been explored. Distinct asthma phe-notypes (transient wheezing, nonatopic wheezing, andatopy-associated asthma) have been identified. Definingwhich children are at risk for persistent asthma couldallow for better management and, potentially, for re-duced morbidity and mortality. Pediatrics 2002;109:362367;asthma expression, phenotypes, wheezing, atopy.

ABBREVIATIONS. IgE, immunoglobulin E; FEV1, forced expira-tory volume in 1 second; RSV, respiratory syncytial virus; IFN-,interferon-; IL, interleukin.

Much about the natural history of asthmaremains unknown; longitudinal studies,however, have shed some light on the

pathogenesis and progression of the disease. Asthmais a heterogeneous condition with variable signs andsymptoms in patient groups, as well as variabilitywithin each individual patient over time.1 Certainpatterns of asthma expression observed duringchildhood persist into adulthood.2,3 Although mildasthma during childhood may resolve, it seems thatasthma is a progressive condition in many children,especially those who have severe disease.4 Early al-lergic sensitization is an important risk factor forpersistent asthma,5 and the role of allergen exposureduring the early years of life in the course of thedisease, as well as the role of other factors, hasemerged as an important focus. Longitudinal studiesof wheezing disorders from childhood to adulthoodare necessary for understanding the true progressionand the risk factors of what is understood to beasthma.

PATTERNS OF ASTHMA EXPRESSION DURINGCHILDHOOD INTO ADULTHOOD

In some young children with mild asthma, wheez-

ing resolves spontaneously; in others, especiallythose with severe asthma, wheezing continues intoadulthood.6 Defining which children are at risk forpersistent asthma could allow for better manage-ment and, potentially, for reduced morbidity andmortality. In 1964, a longitudinal study was initiated

in Melbourne, Australia, to follow childhood asthmainto adulthood.2,3,7 Starting from a cohort of 30 000children, 401 were enrolled at age 7, based on theirparents responses to a questionnaire concerningtheir childs history of asthma, wheezing episodes,and bronchitis. The children were classified into 4categories: those who never wheezed (controls,n 106); those with fewer than 5 episodes associatedwith apparent respiratory infection (mild wheezy

bronchitis, n 75); those with 5 or more episodesassociated with apparent respiratory infection(wheezy bronchitis,n 107); and those with wheez-ing not associated with respiratory infection (asthma,

n 113). A fifth group of children with severeasthma (n 79) was selected from the same cohort atage 10.2 Evaluationsincluding physical examina-tions, patient questionnaires on symptoms and ther-apy, laboratory measurements such as eosinophiland immunoglobulin E (IgE) levels, pulmonary func-tion (with spirometry, lung volumes, and histaminechallenge), and skin reactivity testing have beenconducted every 7 years.2 At the evaluation con-ducted when patients were 35 years old, the partic-ipants were categorized as follows2: no recentasthma (not having wheezed for 3 or more yearsprevious to the evaluation); infrequent wheeze (hav-

ing wheezed in the previous 3 years but not in the 3months before evaluation); frequent asthma (havingwheezed less than once per week in the 3 previousmonths); or persistent asthma (having wheezed atleast once weekly in the previous 3 months).

Symptom assessment at age 35 was comparedwith the categorization established when partici-pants were 7 to 10 years of age (Table 1). Resultsshowed that of the 65 patients who had mild wheezy

bronchitis at 7 years of age, 77% (n 50) had nosymptoms at age 35, whereas only 23% (n 15) hadfrequent or persistent asthma.7 Of the 98 participantswith asthma at 7 years of age, 50% (n 49) had no

recent asthma or infrequent asthma as adults,whereas 50% (n 49) had frequent or persistentasthma. Importantly, 75% (n 50) of those who hadsevere asthma (n 67) at age 10 had frequent orpersistent asthma at age 35. According to these re-sults, many children do not remit from their asthma,and the more severe their asthma, the less likely theyare to remit. These data support the tracking conceptof the disease: children with mild disease had remis-sion or continued with mild disease in their adult-hood, whereas children with severe asthma sufferedpersistent severe asthma when they reached adult-hood.

Assessmentof the participants every 7 years over

From the University of Arizona, Tucson, Arizona.

Received for publication May 4, 2001; accepted Oct 22, 2001.

Reprint requests to (F.D.M.) Arizona Respiratory Center, Box 245030, 1501

N Campbell Ave, Room 2349, Tucson, AZ 85724. E-mail: fernando@resp-

sci.arizona.edu

PEDIATRICS (ISSN 0031 4005). Copyright 2002 by the American Acad-

emy of Pediatrics.

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age 28 showed that those with asthma and severeasthma at age 7 experienced abnormal pulmonaryfunction as adults,2 although in the participants withasthma, the abnormalities were relatively minor (Fig1). Participants who were classified at age 7 as hav-ing mild wheezy bronchitis and wheezy bronchitishad no evidence of airway obstruction at age 35.2 Thepatterns of wheezing and asthma expressed early inlife generally persisted into adulthood. Conversely,persistent airway obstruction in adulthood was as-sociated with more troublesome asthma during

childhood.2,7These patterns presented in Fig 1 suggest that no

significant additional loss of pulmonary function oc-curs after the age of 7 to 10 years and up to the ageof 35, even in individuals with severe disease. Thiswould imply that children are either born with thedeficit of pulmonary function or that there is a loss ofpulmonary function after birth, after which no addi-tional loss occurs. The studies from the Tucson Chil-drens Respiratory Study would argue that the latteris the case.

Children were categorized at age 6 based on thehistory of their wheezing from before age 3. The

categories included the following: nonwheezers(children who had never wheezed); transient wheezers(at least 1 lower respiratory tract illness with wheez-

ing during the first 3 years of life but who had nowheezing at 6 years); late-onset wheezers (no lowerrespiratory tract illness with wheezing during thefirst 3 years of life but who had wheezing at 6 years);and persistent wheezers (at least 1 lower respiratorytract illness with wheezing during the first 3 years oflife and wheezing at 6 years). Based on pulmonaryfunction measurements made before age 1, non-wheezers and persistent wheezers had no significantdifference in pulmonary function. At age 6, however,persistent wheezers and nonwheezers had a signifi-

cant difference in pulmonary function (Table 2),which was still measurable, using forced expiratoryvolume in 1 second (FEV1), at age 11.

8 Therefore,significant loss of pulmonary function seems to haveoccurred after age 1 but before age 6, and, conse-quently, the deficits in pulmonary function in wheez-ing are not significantly present early after birth, butseem to be acquired during the first years of life.

ASTHMA PHENOTYPES

Most epidemiologic studies have suggested thatthere are several different asthma phenotypes, re-flecting a heterogeneous group of conditions that

follow a common final pathway characterized byrecurrent airway obstruction. Three of these pheno-types are transient early wheezing (wheezing up toage 3 but not after), nonatopic wheezing of the tod-dler and early school years, and IgE-mediatedwheezing/asthma (Fig 2).1

Transient Early Wheezing

In most children, transient early wheezing charac-teristically resolves by age 3. Generally, transientwheezing in infants is not associated with a familyhistory of asthma or allergic sensitization.9 The pri-mary risk factor for this phenotype seems to be re-

duced pulmonary function.1,9

The lower level of pul-monary function seems to track along individualgrowth curves, and it remains low at age 6.10 Ofinterest, however, is that children younger than 3years of age with transient early wheezing had noincreased prevalence of methacholine hyperrespon-siveness or positive peak flow variability at age 11.1

These results suggest that mechanical pulmonarycharacteristics, such as reduced airway resistanceor increased dynamic compliance,11 play a role intransient wheezing, rather than increased airwaylability.1

Other risk factors for transient wheezing includeprematurity12 and exposure to siblings and other

Fig 1. FEV1as percentage of predicted values in different groupsof subjects enrolled in the Melbourne Longitudinal Study ofasthma. Subjects were classified according to their diagnosis attime of enrollment: control;fmild wheezy bronchitis; wheezy bronchitis; asthma; severe asthma. Assessmentof the participants every 7 years showed that those with asthmaand severe asthma at age 7/10 showed diminished lung functionas adults, those with asthma having relatively mild abnormalities.These abnormalities tracked with age. Adapted from Oswald etal.2 Used with permission.

TABLE 1. Distribution of Asthma in 401 Subjects Aged 35 According to Whether They Had Bronchitis or Asthma as Children

At Age 7* No RecentAsthma

Asthma at Age 35* N(%) Total

Infrequent Frequent Persistent

Mild wheezy bronchitis 42 (65) 8 (12) 10 (15) 5 (8) 65Wheezy bronchitis 54 (63) 10 (12) 9 (10) 13 (15) 86Asthma 29 (30) 20 (20) 18 (18) 31 (32) 98Severe asthma 7 (10) 10 (15) 8 (12) 42 (63) 67Total 132 48 45 91 401

* Values are numbers (percentages) of participants. Eighty-five controls are excluded.Patients entered study at age 10.

Adapted from Oswald et al.7

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children at day care centers.13 Maternal smokingduring pregnancy, as well as postnatal exposure totobacco smoke, increases the risk for transient

wheezing in children younger than 3 years ofage.14,15

Nonatopic Wheezing

Most school-aged asthmatic children have a his-tory of airway obstruction during the first 2 to 3years of life.16,17 The most common cause of airwayobstruction in infancy is viral infection, most fre-quently caused by the respiratory syncytial virus(RSV).18 Several studies have explored the relation-ship between RSV respiratory tract infection andwheezing. The objective of a recently reported lon-gitudinal study, the Tucson Childrens Respiratory

Study, was to determine whether RSV lower respi-ratory tract illness, by itself, and occurring during thefirst 3 years of life, was a risk factor for subsequentpersistent wheezing.19

A total of 472 children with lower respiratory tractillness underwent testing for the infecting organism.Of these, RSV was documented in 207 (43.9%) chil-dren, parainfluenza in 68 (14.4%), other agents (ad-enovirus, influenza,Chlamydia, cytomegalovirus, rhi-novirus, bacteria, mixed infection) in 68 (14.4%), andno infecting pathogen in 129 (27.3%). Analyses dem-onstrated that RSV infection significantly increasedthe risk for wheezing during the first 10 years of life;the risk decreased with age, however, and was no

longer significant by 13 years of age (Fig 3).19 Fur-thermore, RSV infection during the first 3 years of

life was not associated with increased risk for skintest positivity or higher IgE levels later in life com-pared with other causes of lower respiratory tractinfection (Table 3). No relationship of RSV lowerrespiratory tract infection to allergic sensitization,irrespective of family history of asthma, was identi-fied.

The effect of RSV lower respiratory tract infectionon pulmonary function was also assessed. Childrenwho had RSV infection before 3 years of age hadsignificantly lower FEV1, adjusted for length andgender than children who had not had lower respi-ratory tract illness. This difference remained inde-pendent of current wheezing at 11 years of age (P .001). The children with a history of RSV infectionwere also more likely to respond to bronchodilata-tion than their counterparts with no such history(P .05; Table 4). These findings may indicate thatthe children with lower levels of pulmonary functionwere either born with reduced function, or had aninteraction between the immune system and RSVinfection that altered lung growth, or both.19

Although additional research is needed to definealterations in airway function secondary to RSV re-spiratory tract infection, findings from the TucsonChildrens Respiratory Study provide important im-plications.19 First, although RSV infection is a risk for

subsequent wheeze during childhood, RSV-associ-ated wheezing resolves in most children by 13 yearsof age. Second, the relationship between persistentwheezing up to 13 years of age after RSV infectiondoes not seem to be associated with an increased riskfor allergic sensitization.

Atopic Wheezing/Asthma

More than half of all cases of persistent asthmastart before age 3, and 80% begin before age 6.Among school-aged children with persistent asthma,the onset of symptoms before age 3 is associated with

increased severity of the disease and increased bron-chial hyperresponsiveness. Patients with early-onsetasthma also have significant deficits in pulmonaryfunction growth. Thus, the decisive airway changesseem to begin early in life.5

Frequently, asthma that begins early in life is as-sociated with atopy, the genetic predisposition forsensitization to allergens (Fig 4).20 Early allergic sen-sitization seems to play an important role in persis-tent asthma.

The correlation between allergic sensitization andrespiratory symptoms of asthma was studied in 380Australian (Belmont, New South Wales) school chil-dren enrolled between 8 to 10 years of age.21 The

Fig 2. Hypothetical yearly peak prevalence of wheezing accord-ing to phenotype in childhood. Asthma phenotypes reflect a het-erogenous group of conditions characterized by recurrent airwayobstruction. Three of these phenotypes are shown. This classifica-tion of wheezing phenotypes should not imply that the groups areexclusive. Dashed lines suggest that wheezing can be represented

by different curve shapes resulting from many different factors,including overlap of groups. Adapted from Stein et al.1

TABLE 2. Maximal Expiratory Flow at Functional Residual Capacity (VmaxFRC in mL/sec)During the First Year of Life and at 6 Years of Age According to History of Wheezing

Nonwheezer Persistent Wheezer P

VmaxFRC* at 1 y 123.3 (110.0, 138.0) 104.6 (73.6, 144.5) NSVmaxFRC* at 6 y 1262.1 (1217.4, 1308.1) 1069.7 (906.9, 1146.5) .01

* mL/sec; mean (95% confidence interval).

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participants underwent skin prick testing to 13 aller-

gens at enrollment and 2 and 4 years later. Threegroups of children emerged: those who were sensi-tized at the time they entered the study, those who

became sensitized during the study, and those whonever became sensitized during the study. The prev-alence of persistent respiratory symptoms (wheeze,exercise wheeze, or night cough) was the same inchildren who became sensitized during the studyand children who did not become sensitized (11% to12%). The children who were sensitized at the begin-ning of the study, however, had a prevalence ofrespiratory symptoms that was significantly greater(approximately 40%) than the other groups, and theywere at significantly greater risk for the development

of asthma than the other groups.21These findings underscore the importance of early

allergic sensitization in the development of persis-tent asthma. Interestingly, specific factors have beenidentified that decrease the risk for persistent disease(Table 5). In these cases, increased exposure to otherchildren, pets, or farm animals in early life mayprotect against the development of asthma in chil-dren.

In 412 Swedish children, exposure to pets duringthe first year of life resulted in a lower incidence ofallergic rhinitis at 7 to 9 years of age and a decreasedfrequency of asthma at 12 to 13 years of age.22 An

increased number of siblings also showed an inverserelationship to subsequent development of allergic

rhinitis and asthma. Similarly, in a controlled study

of secondary school children in rural areas surround-ing Quebec City, Canada, children who had beenraised on a farm exhibited significantly less wheeze,airway hyperresponsiveness, and allergic skin testpositivity during adolescence than did children with-out exposure to a farming environment.23 The oddsratio among children raised on a farm for havingcurrent wheeze was 0.70; for having asthma, 0.59;and for atopy, 0.58. The number of siblings among

both groups did not affect the results. These findingshave been confirmed in other studies; some investi-gators, however, question whether heightened earlyexposure offers protection against airway inflamma-tion or whether increased urban pollutants cause

symptoms in children not raised on a farm.24The possible protective effects of increased early

exposure to other children were supported by astudy involving 1035 children followed since birth aspart of the Tucson Childrens Respiratory Study.13

The risk for asthma (children given a diagnosis ofasthma by a physician and who had an exacerbationof their asthma during the previous year) was com-pared between children with and without older sib-lings and between children who attended and didnot attend day care before 6 months of age.

In children with older siblings in the home andchildren who attended day care during the first 6

months of life, 12% developed asthma. In childrenwithout older siblings in the home and in children

Fig 3. Adjusted odds ratios (95% confidence in-tervals) for infrequent and frequent wheeze as-sociated with RSV lower respiratory tract infec-tions before 3 years of age. RSV infectionsignificantly increased the risk for wheezingduring the first 10 years of life. The risk de-creased with age and was no longer significantat 13 years of age. Results were adjusted forconfounding variables including family historyof asthma, positive skin test at 6 or 11 years ofage, gender, maternal education, birth weight,and current maternal smoking. Adapted fromStein et al.19 Used with permission.

TABLE 3. Skin Test Positivity and Serum IgE Concentrations at Different Ages in Children With Lower Respiratory Tract IllnessBefore 3 Years of Age

CausativeAgent

Positive Skin Test (%) Serum IgE Concentration (IU/L)

Age 6 Years Age 11 Years Age 9 Months Age 6 Years Age 11 Years

RSV 37.4 59.3 4.31 33.1 58.6Parainfluenza 40.7 52.9 3.25 26.0 78.5Other agents 39.2 56.5 4.29 30.3 69.4Negative tests 39.8 55.8 4.24 35.1 51.7None 39.7 58.9 4.25 39.5 64.8

Adapted from Stein et al.19

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who did not attend day care during the first 6months of life, however, 21% developed asthma.Similarly, children with older siblings and childrenwho attended day care during the first 6 months oflife were less likely to develop frequent wheezing(3 wheezing episodes during the previous year)when they were older.13 The adjusted relative risk

for frequent wheezing at 2 years of age among chil-dren with greater exposure was 1.4, but by 6 yearsold, the adjusted relative risk declined to 0.8, and atage 13 it declined even further to 0.3. Therefore, earlyexposure to older siblings in the home and day careattendance offers protective effects against frequentwheezing and asthma later in childhood.13

A preliminary investigation suggested that the ef-fects of early exposure to endotoxin in house-dust inearly life may protect against the later developmentof allergic sensitization.25 A total of 61 infants, aged9 to 24 months with at least 3 episodes of physician-documented wheezing, were included in this study

from Denver. The investigators measured the con-centrations of house-dust endotoxin and allergens inthe childrens homes. Allergic skin tests were per-formed in all children, and flow cytometry was usedto measure proportions of T-lymphocytes producinginterferon-(IFN-), and interleukin (IL)-4, IL-5, andIL-13. Children living in homes with significantlylower concentrations of house-dust endotoxin testedpositive on allergic skin testing more often than chil-dren living in homes with higher concentrations ofhouse-dust endotoxin. The children living in homeswith a greater concentration of house-dust endotoxinalso had increased proportions of T-lymphocytesthat produced IFN-but not IL-4, IL-5, andIL-13. It

was suggested that early exposure to house-dustendotoxin may protect against allergic sensitizationvia augmentation of TH1-type immunity.

ASTHMA AS A PROGRESSIVE DISEASE

As reviewed above, many longitudinal studies ofasthma have given us important insights into itsnatural history.18,1215,2125 There seem to be differ-ent forms of asthma, and one of these is a progressivedisease that begins mainly during the first years oflife. If interventions take place after the age of 6 to 7years, it seems to be too late to alter the natural

course of this form of the disease, and from then on,only symptoms can be controlled. Identifying thosechildren who are or will be affected by this form ofasthma before 6 years of age may allow us to treatthem by the critical time. The children with this formof the disease seem to be a minority of the childrenwho have asthma, and although they show symp-toms early in life and are sensitized early in life, thereis no clear way to identify them at present.

The Childhood Asthma Management Program ex-amined the relationships between disease severityand duration in 1041 children aged 5 to 12 years withmild-to-moderate chronic asthma, atopy, and well-

preserved pulmonary function.4

Pulmonary func-tion, as determined by PC20FEV1, pre- and postbron-chodilator percent predicted FEV1 and pre- andpostbronchodilator FEV1/forced vital capacity, de-clined significantly (P .001) with each years dura-tion of asthma; the strongest association was demon-strated in comparing function before bronchodilatoruse with that after bronchodilator use.4 Childrenwith a longer duration of asthma also had higherlevels of symptoms (P .001) and greater use ofalbuterol (P .064) during a prospective 28-dayscreening period. These findings are consistent withother ongoing studies showing that persistentasthma is associated with chronic airway inflamma-tion, reduced pulmonary function, and increasedasthma symptomatology.

The recently published results of The ChildhoodAsthma Management Program have shown that in-haled corticosteroids were effective in significantlyreducing the subjective measures of asthma, such assymptoms, in children during the 4 years of study,

but the course of asthma, as reflected in postbron-chodilator FEV1, the primary outcome of the study,was not altered.26 Therefore, if the adverse effects ofpersistent asthma are to be prevented, diagnosis andintervention would seem to be necessary before theage of 5 to 6years.

Fig 4. Pathogenesis of persistent childhood asthma: a hypothesis.In genetically predisposed children, exposure during early life toallergens induces an immune-mediated response that results inairway inflammation. In turn, chronic airway inflammation pro-duces bronchial hyperresponsiveness and persistent wheeze.

TABLE 4. Mean Baseline FEV1 at 11 Years of Age (95% Con-fidence Interval)

Causative Agent Baseline FEV1 AfterBronchodilator

RSV (n 110) 2.11 (2.052.15)* 2.26 (1.702.90)Parainfluenza (n 38) 2.16 (2.072.25) 2.29 (1.632.67)Other agents (n 32) 2.19 (2.092.24) 2.27 (1.692.60)Negative test (n 72) 2.14 (2.082.20) 2.25 (1.832.76)None (n 189) 2.22 (2.182.25) 2.31 (1.702.99)

*P .001 compared with subgroup having no illness.P .05 compared with subgroup having no illness.

Adapted from Stein et al.19

TABLE 5. Factors Associated With the Onset of PersistentAsthma

Increased Risk Decreased Risk

Early allergic sensitization Exposure to other childrenearly in life

Sensitization to certainaeroallergens (perennial?)

Exposure to pets

Eosinophilia Exposure to farm animals

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2002;109;362PediatricsFernando D. Martinez

Development of Wheezing Disorders and Asthma in Preschool Children

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