Archives of Disease in Childhood 1995; 72: 16-24

Lung function, airway responsiveness, andrespiratory symptoms before and afterbronchiolitis

Sally Young, P T O'Keeffe, Jacqueline Arnott, L I Landau

Department ofRespiratory Medicine,Princess MargaretHospital for Children,PerthP T O'Keeffe

Department ofPaediatrics, UniversityofWestern Australia,Perth, WesternAustralia, AustraliaS YoungJ ArnottL I Landau

Correspondence to:Professor Louis I Landau,University Department ofPaediatrics, PrincessMargaret Hospital forChildren, Box D 184 GPO,Perth, Western Australia6001, Australia.

Accepted 13 September1994

AbstractAcute viral respiratory illness duringinfancy has been implicated as a pre-cursor for subsequent lower respiratorymorbidity in childhood. A prospective,longitudinal study ofrespiratory function,airway responsiveness, and lower res-piratory illness during early childhoodwas performed in a cohort of 253 healthyinfants to characterise those who experi-enced bronchiolitis. Seventeen infants(7% of the cohort), were given a diagnosisof bronchiolitis during the first two yearsof life with two (1%) requiring hospitaladmission. Seventy one per cent of thoseinfants with bronchiolitis had a familyhistory of atopy, 53% of asthma, and 29%had a mother who smoked cigarettes.These family history characteristics inthis group with bronchiolitis were notdifferent from the rest of the cohort.There were also no differences in thenumber of older siblings, the numberbreast fed, the duration of breast feeding,or socioeconomic status of the familiesbetween those that did and did not getbronchiolitis. Respiratory function wasassessed at 1, 6, and 12 months of age.Maximum flow at functional residualcapacity (VmaxFRC) was measured using therapid thoracic compression technique.Resistance (Rrs) and size correctedcompliance (Crslkg) were obtained from asingle brief occlusion at end inspiration.Airway responsiveness was assessed byhistamine inhalation challenge and theprovocation concentration of histamineresulting in a 40% fall on VmaFRCfrom baseline (PC40) was determined.Respiratory measurements were rankedinto terciles to assess the distribution ofinfants who developed bronchiolitisthrough the cohort. At the age of 5 weeks,a significant trend was observed forinfants who subsequently developed bron-chiolitis during the first year oflife to havebaseline Vmax,FRC values in the lowesttercile (odds ratio 3-16, 95% confidenceinterval 087 to 11-6). Rrs, Crs/kg, andPC40 were not different at any age betweenthe bronchiolitics and the cohort. Coughand wheeze were noted to be frequentbefore the episode of bronchiolitis. Thisstudy has demonstrated that infants whodevelop bronchiolitis have evidence ofpre-existing reduced respiratory functionand lower respiratory symptoms. It isproposed that bronchiolitis, although

potentially contributory, is not usuallycausative of subsequent lower respiratorymorbidity.(Arch Dis Child 1995; 72: 16-24)

Keywords: bronchiolitis, respiratory function,histamine inhalation challenge, lower respiratorysymptoms.

Acute viral respiratory infection during infancyis common, with symptoms ranging from thosethat are mild and restricted to the upper airwayto those that indicate involvement of the lowerrespiratory system, and in some, the develop-ment of features characteristic of the clinicalentity described as bronchiolitis. Bronchiolitishas received particular attention as it has beensuggested that an episode of bronchiolitis inthe first two years of life causes subsequentlower respiratory morbidity or that bronchiolitisidentifies those infants predisposed to developasthma.' Studies have documented abnormalpulmonary function, increased airway respon-siveness, increased lower respiratory symptoms,and impaired oxygenation in children with ahistory of bronchiolitis.2-18 Some have docu-mented an increased incidence of atopy andraised concentrations of IgE,2 5712 14-19 whileothers have not."l 20

Environmental factors, such as passivetobacco smoke exposure, have also beensuggested to predispose an infant exposed torespiratory syncytial virus for increased lowerrespiratory disease, particularly bronchiolitis.21Breast feeding, the number of older siblings,and socioeconomic status have also beenimplicated to influence whether an infant willdevelop bronchiolitis,3 4 8 while others have notidentified such associations.10-13 15 17 20 22The ability to test each of these hypotheses is

reliant on documenting those factors believedto be important in the development of andpotentially resulting from bronchiolitis beforeand after infection. The majority of studies inthe literature are based on infants hospitalisedfor bronchiolitis,5 7 8 10-3 17 19 20 who are thenfollowed up prospectively from the time ofhospitalisation.9 14-16 23 These study popula-tions represent the most severe end of thedisease spectrum. Children have been studiedmany years after bronchiolitis so that it is notpossible to differentiate between effects due tothe bronchiolitis or ongoing environmentalinsults encountered during the interveningperiod from initial infection to assessment.

During our longitudinal study of geneticand environmental influences on lung

16

on January 24, 2022 by guest. Protected by copyright.

http://adc.bmj.com

/A

rch Dis C

hild: first published as 10.1136/adc.72.1.16 on 1 January 1995. Dow

nloaded from

Lungfunction, airway responsiveness, and respiratory symptoms before and after bronchiolitis

function, airway responsiveness, and lower res-piratory illness in a cohort of healthy infants,7% were diagnosed as having bronchiolitisduring the first two years of life. We assessedthe natural history of the cohort throughoutthe first two years of life to test the hypothesisthat pre-existing lower respiratory functionabnormalities in early life predispose infants tobronchiolitis.

Subjects and methodsSUBJECTSThe infants in this study were part of a

prospective, longitudinal study of lungfunction, airway responsiveness, and lowerrespiratory illness during the first two years oflife. The inclusion criteria were full termgestation, an absence of perinatal problems,and no major congenital anomalies.The families of all the infants were recruited

at the antenatal clinic at Osborne Park Hospital,Perth, Western Australia. Total cohort recruit-ment spanned May 1987-December 1991during which time 1011 mothers were inter-viewed and 253 (25%) consented to partici-pation. The recruitment process has beendocumented previously.24 In brief: the motherwas interviewed during a routine antenatal visitand given an information sheet detailinginvolvement over the study period. Telephonecontact was made subsequent to the interviewto determine willingness to participate. Thestudy was performed with the approval of themedical ethics committees of Princess MargaretHospital for Children and the University ofWestern Australia.Two hundred and forty six infants (135

boys) were initially studied at a mean age of5 weeks (range 2-10). At the initial lungfunction assessment, no infant had previouslyhad a lower respiratory illness or any clinicallyimportant non-respiratory illness. Repeatmeasurements were made at 6 and 12 monthsof age and at each assessment all the infantswere well, with no upper or lower respiratorytract infection in the preceding three weeks.

FAMILY HISTORYThe family history of asthma, atopy in primaryrelatives (mother, father, siblings) and/orsecondary relatives (grandparents, aunts,uncles), and parental smoking habits duringthe pregnancy, the number of older siblings,and socioeconomic status (based on paternaloccupation) were obtained using a modifiedAmerican Thoracic Society questionnaire25administered by one of two investigators(SY, JA) at the first infant assessment.

INFANT LUNG FUNCTIONRespiratory function was assessed at 1, 6, and12 months of age using the rapid thoraciccompression technique.26 This technique asused in our laboratory has been describedpreviously.27 In summary: an inflatable jacketwas wrapped around the ribcage and abdomenof the infant. The jacket was rapidly inflated at

end inspiration and flow measured at functionresidual capacity from the resulting partialexpiratory flow-volume curve. The jacket pres-sure was gradually increased (10-80 cm H20)over a series of forced expirations until nofurther increase in flow occurred with anincrease in pressure and it was assumedmaximum flow at functional residual capacity(VmaxFRC) was reached.

Infants were studied while asleep afterreceiving chloral hydrate (60-80 mg/kg).Baseline VmaxFRC was established after theadministration of nebulised normal saline withan Airlife nebuliser (American Pharmaseal)run at 6 I/min from a compressed air source.The mean of five forced expirations was usedas the baseline VmaxFRc reference value.

Compliance (Crs) and resistance (Rrs) ofthe total respiratory system were measuredfrom a passive flow-volume slope after a singlebrief occlusion at end inspiration inducing theHering-Breuer reflux.28 Crs was size correctedby dividing by the infant's weight.The pattern of tidal breathing was assessed

by measuring the ratio of time to maximumexpiratory flow/total expiratory flow(Tme/Te)29 from a tidal flow-volume loop.Tme/Te was averaged from 10 consecutivetidal breaths recorded at baseline.

INFANT AIRWAY RESPONSIVENESSThe histamine inhalation challenge was carriedout using doubling concentrations of nebulisedhistamine from 0-125 g/l to a maximum con-centration of 8&0 g/l, as previously described.27A new concentration was delivered every fiveminutes and respiratory function assessed aftereach concentration, with a minimum of fiveforced expirations being performed. The chal-lenge ceased when a response to histamine wasrecorded or the maximum concentrationreached. A response was defined as a fall inVmaxFRc of at least 40% from baseline. Theprovocative concentration producing a 40%fall in VmaxFRC (PC40) was derived by linearinterpolation from the plot of log histamineconcentration against per cent fall in VmaxFRCfrom baseline.

ARTERIAL OXYGEN SATURATION MONITORINGArterial oxygen saturation (Sao2) wasmonitored throughout the study using aNellcor N-200 E pulse oximeter (Nellcor) inbeat to beat mode. The Sao2 level aftersaline nebulisation was taken as the baselinereference value. For each nebulisation, Sao2was recorded immediately before and afteradministration. Sao2 was monitored through-out forced partial expiratory manoeuvresand no effect of forced expiration on Sao2was observed. Supplemental oxygen wasadministered if Sao2 fell below 90%.

INFANT SKIN ALLERGEN ASSESSMENTSkin allergen testing was performed at the timeof but before the lung function assessmentusing the previously described skin prick

17

on January 24, 2022 by guest. Protected by copyright.

http://adc.bmj.com

/A

rch Dis C

hild: first published as 10.1136/adc.72.1.16 on 1 January 1995. Dow

nloaded from

Young, O'Keeffe, Arnott, Landau

method,30 on the volar aspect of the forearm.The following solutions were used: 0O9% saline(negative control), 10 mg/ml histamine acidphosphate (positive control), whole cows' milk(1:20 w/v), egg albumen (1:20 w/v), Derma-tophagoides pteronyssinus (dust mite) (1:50 w/v),and Lolium perenne (rye grass) (1:20 w/v)(Hollister-Stier, Miles Inc, PharmaceuticalDivision). Skin tests were read after 15minutes and a wheal equal to or greater than2 mm in diameter was recorded as a positiveresponse. All skin allergen testing was

completed by two investigators (SY, JA).

CORD BLOOD TOTAL CONCENTRATIONSCord blood total IgE concentrations were

analysed by macroprist assay.31 Samples were

assayed in duplicate and results reported as

international units (IU)/ml of serum. Thelower limit of detection was 0-01 IU/ml andthe interassay coefficient of variation was

16-9% (unpublished).

INFANT RESPIRATORY HEALTH

During the first year of life a weekly infantdiary record was completed by the parentsand included information on breast or bottlefeeding, the presence of cough and/or wheeze,and the occurrence of any doctor diagnosedrespiratory and/or atopic illness. At the age of 2years the modified American Thoracic Societyquestionnaire25 detailing the child's healthover the last year was completed by the parentsfor the 153 families who were still contactable.

DIAGNOSING BRONCHIOLITIS

From the weekly diary records and twoyear follow up questionnaire, an infant was

identified as having had bronchiolitis on thebasis of a doctor diagnosis (community basedgeneral practitioner, private paediatrician, or

hospital based paediatrician). Where available,hospital inpatient records were examinedto confirm the diary report and ascertainwhether per nasal aspirates had been takento determine the presence or absence ofrespiratory syncytial virus. In addition, themonth of diagnosis was recorded to enhancethe accuracy of the diary record information.

INFANT GROUP COMPARISONSTo assess whether infants who developedbronchiolitis during the first two years of life(B-All) had characteristics which differentiatedthem from other infants, they were prospec-tively compared to the whole study population(cohort), excluding those with a diagnosisof bronchiolitis. The B-All group were sub-divided into those that acquired bronchiolitisin the first (B-1) or second year (B-2) of lifeand were prospectively compared with each

other, as well as to the cohort. Of the 10 whodeveloped bronchiolitis in the first year, six hadthe episode before the 6 months' study andfour between the 6 and 12 month study. Nonehad bronchiolitis in the first two months. To

determine the incidence of respiratorysymptoms during the first year of life, exclud-ing symptoms associated with the episode ofbronchiolitis, a control group of infantsmatched for those confounders known to beassociated with lower respiratory symptomssuch as age, gender, and family history ofasthma, atopy, and parental smoking (matchedcontrols) were compared with the B-1group. The subjects were selected randomlywithout any knowledge of lung functionmeasurements.

STATISTICSDescriptive anthropometric data at each infantassessment was compared between the groupsusing the Student's unpaired t test. TheKruskal-Wallis test was used to determine ifthere was a difference between groups at eachage for lung function measures, IgE concentra-tions, duration of cough and wheeze, durationof breast feeding, number of older siblings, andSao2 levels. Where differences were indicated,the Mann-Whitney U test was used to identifycomparisons of significance. PC40 levelswere normalised by log transformation andbetween group comparisons made by para-metric analysis of variance and the Student'sunpaired t test. To determine the distributionof the bronchiolitic infants throughout thewhole study population, VmaxFRC, Tme/Te,and PC40 levels were divided into terciles andx2 and odds ratio analyses were used to com-pare subjects in the lower tercile with those inthe upper two terciles. The x2 test for trendwas used to compare groups for family historyof asthma, atopy, and parental smoking habit,socioeconomic status, and the incidence ofcough, wheeze, asthma, and eczema. Oddsratios were calculated to identify associationsbetween family history and risk for bronchi-olitis. Statistical significance was accepted if ap value less than 0'05 was obtained.

ResultsOf the 253 infants studied during the firstyear of life, 17 (10 girls) reported a doctordiagnosed episode of bronchiolitis (B-All).This represented 7%/o of the study population.Of these 17, 10 (six girls) were diagnosed intheir first year of life (B-1) and seven (fourgirls) in their second year (B-2). Hospitaladmission was required for two B-1 infants,that is, 1% of infants. Virology resultswere available only for those admitted tohospital and both were confirmed positive for

Table 1 Number of infants with positive family history(% of study group)

B-Al B-l B-2 Cohort(n=17) (n=10) (n=7) (n=236)

Atopy* 12 (70) 7 (70) 5 (71). 166 (71)Asthma* 9 (53) 4 (40) 5 (71)t 93 (40)Parents smoke (either

orboth) 7 (41) 4 (40) 3 (43) 116 (51)Mother smokes 5 (29) 3 (30) 2 (29) 71 (32)

*Atopy history in primary relatives (parents and siblings).tB-2 v cohort 0-05<p<0-10.

18

on January 24, 2022 by guest. Protected by copyright.

http://adc.bmj.com

/A

rch Dis C

hild: first published as 10.1136/adc.72.1.16 on 1 January 1995. Dow

nloaded from

Lung function, airway responsiveness, and respiratory symptoms before and after bronchiolitis

300

250

200-

4,E

150

co

B-i

-----B-2

50 --- B-All

Cohort

1 6 12Time (months)

Figure I Mean (SE) baseline VmaxFRc during the firstyear of life.

respiratory syncytial virus. No infant with a

diagnosis of bronchiolitis in the second year oflife was admitted. In all but one infant,where diagnosis was made during a summer

month, the reported episode occurred duringthe winter months between May andSeptember in Australia, demonstrating thewinter cluster pattem extensively describedfor bronchiolitis.32

B-All, B-1, B-2, and the cohort were

compared:

FAMILY HISTORYA description of the family history of asthmaand atopy in primary relatives and parentalsmoking habit during the pregnancy for infantswith a report of bronchiolitis and the wholestudy population is presented in table 1.Seventy one per cent of the cohort had a familyhistory of atopy, 40% a history of asthma, and

Table 2 Passive respiratory mechanics during the firstyear of life; mean (SE)

B-All B-i B-2 Cohort

Crs (mi/cm H20/kg)5 Weeks 1-5 (0-1) 1-4 (0-1) 1-5 (0-2) 1-4 (0 03)

27 Weeks 1-3 (0-1) 1-2 (0-1) 1-4 (0-4) 1-3 (0-03)55 Weeks 1-5 (0-2) 1-4 (0-1) 1-7 (0.5) 1-5 (0.04)

Rrs (cm H20 (ml/sec))5 Weeks 0-058 (0 004) 0-060 (0 005) 0-056 (0-004) 0-056 (0-001)

27 Weeks 0-040 (0-001) 0-042 (0-002) 0-038 (0 002) 0-056 (0 002)55 Weeks 0-034 (0 002) 0-031 (0 002) 0-042 (0-004) 0-034 (0-001)

No significant differences among study groups at any age.

Table 3 Tme/Te and Sao2 duing thefirstyear of life

B-All B-I B-2 Cohort

Mean (SE) Tme/Te5 Weeks 0-329 (0 029) 0-304 (0-035) 0-365 (0-050) 0-337 (0-010)27 Weeks 0-278 (0-031) 0-298 (0-036) 0-213 (0 052) 0-271 (0-010)55 Weeks 0-272 (0 023) 0-242 (0-012) 0-342 (0 060) 0-261 (0-010)

Median (range) Sao2 (%)5 Weeks 99 (96-100) 98 (97-100) 99 (96-100) 99 (90-100)

27 Weeks 97 (90-100) 97 (90-99) 98 (93-100) 97 (89-100)55 Weeks 97 (95-100) 96 (95-99) 98 (96-100) 97 (90-100)

No significant differences between study groups at any age.

32% had mothers who smoked cigarettes. Nodifferences were observed for the prevalence ofasthma, atopy, or parental smoking betweenB-All and the cohort. However, a trend waspresent for B-2 infants to have an increasedincidence of a family history of asthma incomparison to the cohort (0 05<p<010).This was not observed for B-1 infants.

Descriptive data showed no differencesamong the groups for birth weight, study age,or weight at any assessment (data not shown).At 27 weeks of age the B-All infantswere shorter (mean (SD) 65-4 (3 0) cm) incomparison with the cohort 67X3 (3 0) cm(p<005) but this difference was not present atany other age.

RESPIRATORY FUNCTIONAt the age of 5 weeks, before any lower respira-tory illness, B-All infants had a trend towardsa reduced mean baseline lung function withmean (SE) VmaxFRC of 75 (8) ml/sec in com-parison to the cohort with 95 (3) mllsec(p<0O08) (fig 1). Three infants had flowlimitation during tidal expiration with a mean(SE) baseline VmaxFRC of 32 (5) ml/sec. Thetwo infants subsequently requiring hospitalisa-tion had baseline VmaFRC values of 66and 68 ml/sec, respectively. There was nodifference in mean (SE) baseline lung functionbetween B-1 infants and the B-2 group (78( 11) v 70 (10) ml/sec). Although mean base-line VmaxFRc in the bronchiolitics remainedlower than the cohort at 27 and 55 weeks ofage this was not statistically significant.Standardising VmaxFRC for length did not affectthe results.

Baseline VmaxFRC values for the whole studypopulation at the age of 5 weeks were rankedinto terciles and the odds of subsequentlydeveloping bronchiolitis with a VmaxFRC inthe lower tercile compared with the upper twoterciles were determined. There was a trend forinfants in the lower tercile at 5 weeks of age tobe at increased risk of bronchiolitis duringthe first year of life (odds ratio 3-16, 95%confidence interval 0-87 to 11-6; p<006), butthere was no association between baselineVmaxFRc and bronchiolitis during the secondyear of life.

Assessment of passive lung mechanics of thetotal respiratory system during the first year oflife (table 2) showed no differences betweenany of the infant groups at any age for eithersize corrected Crs or Rrs. Tme/Te and Sao2levels were also not different between any ofthe infant groups at any study age (table 3).Tercile analysis of Tme/Te at the age of 5weeks showed no difference in tercile distribu-tion between those that did or did not subse-quently develop bronchiolitis or those thatexperienced bronchiolitis during the first orsecond year of life.

AIRWAY RESPONSIVENESSAlthough mean values of PC40 were lower inthe bronchiolitis group than the cohort at 27weeks, there were no significant differences in

19

on January 24, 2022 by guest. Protected by copyright.

http://adc.bmj.com

/A

rch Dis C

hild: first published as 10.1136/adc.72.1.16 on 1 January 1995. Dow

nloaded from

Young, O'Keeffe, Arnott, Landau

10

0,

40a-a.

1 6 12Time (months)

Figure 2 Geometric mean (SE) airway responsiveness toinhaled histamine during the firstyear of life.

the level of histamine responsiveness amongthe infant groups at any age (fig 2). Tercileanalysis of PC40 values at the age of 5 weeksshowed no association between tercile distrib-ution and subsequent bronchiolitis.

CORD IgE AND SKIN ALLERGEN SENSITIVITYNo differences were found for the mediancord blood IgE concentrations among any ofthe infant groups (table 4). The incidence ofskin allergen responsiveness for each infantgroup is also presented in table 4. For allinfant groups the peak incidence of skin testpositivity occurred at the age of 27 weeks.Throughout the first year of life, cows' milkand egg white were the allergens that mostfrequently elicited a response in each of theinfant groups, with house dust mite beingthe least frequent. B-All had an increasedincidence of skin test positivity in comparisonwith the cohort (p<0 05; table 4). Ondividing B-All into B- 1 and B-2, it was

observed that the B-2 infants had an

increased incidence of skin test positivity(570/o) in comparison with the cohort (22%)(p<0 05). B-1 infants were not different fromthe cohort. Incidence of skin test positivitybetween the B- 1 and B-2 groups did notdiffer, although it was noted that only B-2infants were sensitive to house dust mite.

LOWER RESPIRATORY SYMPTOMS DURING THEFIRST YEAR OF LIFEInformation detailing the duration of coughand wheeze during the episode of bronchiolitiswas only available for B-1 infants due to thefirst year diary being a weekly record while thetwo year questionnaire was an overview of thechild's respiratory health from age 1 to 2 years.

Six of the 10 B-1 infants had a report ofcough and wheeze with bronchiolitis, threereported cough only, and one wheeze only.The episode of bronchiolitis was associatedwith a minimum symptom duration of twoweeks in all infants.

Before diagnosis, 40% of the B- 1 infants hadreports of wheeze during 2-5 of the weeks(range 2-16) and 60% had coughed during 9-5of the weeks (range 1-25). Each B-1 infant wasmatched to a control infant for age, gender,and family history of asthma, atopy, andparental smoking to determine symptom fre-quency in relation to the timing of the episodeof bronchiolitis. For the same time period, no

matched control infant wheezed and 40% hadcoughed during five of the weeks (range 1-8).From the end of the episode of bronchiolitis tothe end of their first year of life, 60% of theB-1 infants had wheeze reported during threeof the weeks (range 1-25) and 50% coughed12 of the weeks (range 4-17). In comparison,for the same time period, Qnly two of thematched controls wheezed, one infant for one

week only and the other for 15 of the weeks,and 40% had a record of cough during six ofthe weeks (range 1-21).

LOWER RESPIRATORY SYMPTOMS AND ATOPICDISORDERS AT AGE 2 YEARSOne hundred and fifty three of the original 236families were reviewed at two years. There was

no difference in family history or initial testresults between this group and the others whowere unable to be followed up.Cough was the most frequently reported

symptom in the whole cohort (66%), while42% wheezed (table 5). No differences were

observed among the groups for the incidenceof cough. Wheeze was reported in 42% of thecohort and 56% of the bronchiolitis. Furtheranalysis indicated that while 100% of the B-2infants had reports of wheeze in the secondyear of life (by definition), only 22% of the B-1group reported wheeze in the second year(table 5).An increased incidence of diagnosed asthma

by the age of 2 years was observed in the B-All

Table 4 Cord IgE concentrations and infant skin allergen responses during thefirstyear of life

B-All B-i B-2 Cohort

n=11 n=7 n=4 n=158Median (range) IgE (IU/ml) 0-20 (0-03-0-66) 0-10 (0-03-0 66) 0-22 (0-9-0-57) 0-20 (0-01-3-4)

n=17 n=10 n=7 n=236No (%) with positive skin test reaction 8 (47)* 4 (40) 4 (57)* 51 (22)Total No positive responses to all allergens 14 7 7 87No of positive responses (% of all positive responses)

Dermatophagoides pteronyssinus 2 (14) 0 2 (28) 0Lolium perenne 2 (14) 1 (14) 1 (14) 16 (18)Cows' milk 6 (43) 4 (57) 2 (28) 32 (37)Egg white 4 (28) 2 (28) 2 (28) 39 (45)

Cord IgE: no significant differences between infant groups.Skin reactivity: *B-All v cohort, p<0 05; B-2 v cohort, p<005.

20

on January 24, 2022 by guest. Protected by copyright.

http://adc.bmj.com

/A

rch Dis C

hild: first published as 10.1136/adc.72.1.16 on 1 January 1995. Dow

nloaded from

Lungfunction, ainvay responsiveness, and respiratory symptoms before and after bronchiolitis

Table S Incidence oflower respiratory symptoms andatopic disorders reported at the age of 2 years; number (%)

B-All B-l B-2 Cohort(n= 16) (n=9) (n=7) (n=153)

Cough 11 (69) 5 (56) 6 (86) 101 (66)Wheeze 9 (56) 2 (22) 7 (100)t 64 (42)Asthma 7 (44)* 2 (22) 5 (71)t 28 (18)Eczema 7 (44) 4 (44) 3 (43) 63 (41)

Cough: no significant differences among infant groups.Wheeze: tB-2 v cohort, p<001.Astima: *B-AI1 v cohort, p<005; tB-2 v cohort, p<005.Eczema: no significant differences among infant groups.

group (44%) in comparison to the cohort(18%). Division of the B-All group showedthat 71% of the B-2 infants had asthma incomparison to 22% of B-1 infants (table 5).Eczema was diagnosed in 41% of the studycohort by the age of 2 years and 44% of thebronchiolitis. No differences were observedamong any of the infant groups (table 5).

Ninety per cent of the cohort were breast fedfor a duration range of 2-52 weeks and 100%of the B-All group for a duration of 13-52weeks. No differences were observed for eitherthe proportion of infants breast fed or theduration of breast feeding among the infantgroups. No differences were observed betweenthe infant groups for number of older siblingsor the socioeconomic status of the family (datanot shown).

DiscussionThe uniqueness of this study lies with theprospective, longitudinal documentation ofrespiratory function, airway responsiveness,and incidence of lower respiratory symptomsbefore and after an episode of bronchiolitisduring the first two years of life. This is alsoone of only a small number of studies in theliterature which is based on a communityrather than a hospital based cohort. Therefore,this study more clearly describes the predispos-ing factors for and outcome of bronchiolitis inthe general community than does a hospitalbased cohort which represents only thoseinfants with the more severe form of diseasewho may have different predisposing charac-teristics and sequelae than the majority thatdevelop bronchiolitis not requiring hospitaladmission. A previous study hypothesised thatbronchiolitis in infancy led to lower respiratorymorbidity in later childhood,3 but no physio-logical data on the state of the infantrespiratory system before bronchiolitis hadbeen reported, thereby preventing the testingof the proposed hypothesis. Our study wouldsuggest that the episode of bronchiolitis is notthe sole cause of subsequent respiratorymorbidity as pre-existing abnormalities inlung function and frequent lower respiratorysymptoms have been documented before thebronchiolitis.

Diverse diagnostic criteria have been usedto define bronchiolitis. In general, hospital basedstudies characterise bronchiolitis as coryzalsymptoms followed by rapid onset of fever,wheeze, tachypnoea, chest recession, crepita-tions and wheeze on auscultation, with radio-

graphic evidence of hyperinflation.2 6 8 10 12 13 Inaddition, some require a positive identificationof respiratory syncytial virus by per nasalaspirate7 11-13 while others do not, acceptingthe occurrence of infection at a time whenrespiratory syncytial virus is prevalent in thecommunity as indirect evidence of the probableviral causative agent.'4 While some investigatorsdiagnose bronchiolitis up to the age of 2years,5 8 10 others limit the diagnosis to the first12 months of age.32 In previously reportedcommunity based studies, the criteria fordefining bronchiolitis have included a physiciandiagnosis and the first episode of wheezing in achild less than 2 years of age.5Due to study design, the criteria used in our

study to identify bronchiolitis was limited tophysician diagnosis in a child under the age of2 years. To enhance the accuracy of thereported diagnosis, the infant diaries wereexamined to confirm that lower respiratorysymptoms were present in association withthe diagnosis. Also, the month in whichthe diagnosis was made was noted and, in allbut one infant, the episode was reported inthe period of peak incidence of respiratorysyncytial virus bronchiolitis documented forAustralia.32 Although a diagnosis of bronchi-olitis in a summer month is unusual it is notunknown,32 and therefore we did not excludethe infant from analysis. Using these criteria,17 infants were diagnosed with bronchiolitisduring the first two years of life, that is, 7% ofthe study population, and of these, two (1%)required hospitalisation. These figures are inconcordance with the documented incidenceof bronchiolitis in the literature.2 3 33One of the contentious issues regarding

the definition of bronchiolitis is the age of thediagnosis - under 1 year or 2 years of age?In this study bronchiolitis was reportedthroughout the first two years of life; however,we were interested in whether (a) there werepredisposing and/or outcome differencesbetween infants with a diagnosis in the first orsecond year and (b) whether the entity labelledbronchiolitis in the second year of life was thesame as that being reported in the first year.The data suggest that the episode of lowerrespiratory illness labelled bronchiolitis in thesecond year of life is more likely to be asthma.Those infants with a diagnosis of bronchiolitisin the second year of life had a particularly highgenetic risk of developing asthma (71%primary family history), all wheeze, had higherrates of positive skin allergen tests, and 71%of the infants had a subsequent diagnosis ofasthma. This outcome differs from those thathad bronchiolitis in the first year in whom only22% had a diagnosis of asthma at the age of2 years. It may be possible that those infantswith asthma who wheezed for the first timewith a viral respiratory infection in the secondyear of life initially received a diagnosis ofbronchiolitis.The relative contributory roles of genetic

and environmental factors to predisposinginfants for bronchiolitis is another con-tentious issue. A number of follow up studieshave identified an association between a

21

on January 24, 2022 by guest. Protected by copyright.

http://adc.bmj.com

/A

rch Dis C

hild: first published as 10.1136/adc.72.1.16 on 1 January 1995. Dow

nloaded from

Young, O'Keeffe, Arnott, Landau

family history of asthma and/or atopy andan episode of bronchiolitis.4 5 8 Other investi-gators, however, have not observed thisassociation,7 10-13 15 17 20 22 and in particular,a prospective longitudinal study of a group ofinfants believed to be at high risk for lowerrespiratory illness, defined by family history,observed that no infant had an episode ofbronchiolitis during the first year of life.22Our study was unable to show significantdifferences in family history between thosethat did and did not get bronchiolitis duringthe first year of life, however, it should benoted that our study population is biasedtowards those with an 'at risk' history dueto the increased willingness of members of thegeneral population with histories of asthmaand allergic disease to participate in thestudy in comparison with those with no suchhistories. Of interest is that those with adiagnosis of bronchiolitis during the secondyear of life, had an increased family history ofasthma 4n primary relatives.

Environmental factors suggested in previousstudies as important predisposing influencesfor bronchiolitis include parental tobaccosmoking (particularly maternal), number ofolder siblings, breast feeding, and socio-economic status of the family.3-5 21 34 We didnot observe any differences for these para-meters between infants who did and did notdevelop bronchiolitis. This may be due to oursmall sample size and the lack of variation insocioeconomic status within the study popula-tion. These environmental factors do seemimportant agents contributing to increasedseverity of lower respiratory symptoms andadmission to hospital. Exposure to maternaltobacco smoke has been documented to resultin reduced infant lung function in this andother cohorts.24 35One of the most pressing questions arising

from the literature to date is whether thelung function abnormalities documented inchildhood were caused by bronchiolitis duringinfancy or were in fact present before theinfection. Martinez and colleagues have shownthat decreased pulmonary function in early lifewas predictive of subsequent wheeze,36 37 andtherefore they have proposed that early lifelung function predisposes certain infants forwheezing respiratory illnesses. We observedthat at the age of 5 weeks, infants that weredestined to develop bronchiolitis tended tohave reduced respiratory function as deter-mined by VmaxFRC, an indicator of small airwaycalibre. At 6 and 12 months of age therewere no differences in respiratory functionbetween those that did and did not developbronchiolitis.

Several authors have shown marked changesin respiratory mechanics during the acutephase of bronchiolitis with persistence ofabnormality for a period of time after the acutephase.23 38 In this study we measured passivemechanics of the total respiratory systemand found no differences in size correctedcompliance and resistance before or afterinfection, or between those that did and didnot develop bronchiolitis. If we had measured

passive mechanics during the acute phase ofthe infection, changes may possibly have beenobserved, however, our results do indicate thatpassive lung mechanics do not identify thosepredisposed for bronchiolitis or are affectedadversely subsequent to the episode. Thisinability of Tme/Te ratio to predict those whodeveloped bronchiolitis, as reported byMartinez et al,37 was probably due to thesmall number in this cohort. Differences inoxygenation levels many years after bronchi-olitis have also been described,'0 18 however wedid not observe any differences in Sao2 levelsbefore or after bronchiolitis. These otherstudies were based on cohorts of infants withmore severe bronchiolitis requiring hospitaladmission.

Several studies have shown that airwayresponsiveness to cold dry air,39 metha-choline,40 and histamine24 27 is present innormal infants and that the level of airwayresponsiveness in early life is influenced bythe family history of asthma and parentalsmoking.24 The relationship between the levelof airway responsiveness and lower respiratoryillness during infancy is unclear, as evidencedin a study by Stick and colleagues where thedegree of airway sensitivity in recurrentlywheezy infants was found not to be differentfrom that of normal healthy individuals.4'Many studies in the literature document anincrease in airway responsiveness in infants14and older children3 6 7 12 13 16 17 after bronchi-olitis. Once again the dilemma that has arisenfrom these observations is whether increasedairway sensitivity was present before theinfection or was a result of infection. Althoughthere appeared to be increased airwayresponsiveness at 27 weeks in those thatdeveloped bronchiolitis, our study could notdemonstrate that an episode of bronchiolitiswas related to or caused increased airwayresponsiveness. This tendency to increasedresponsiveness at 27 weeks which followed theepisode of bronchiolitis in six infants concurswith the data available from a study in adultswhere airway reactivity was shown to beincreased for a short period after respiratorysyncytial virus infection.42Even allowing for the genetic bias in our

study population, it would appear that theoccurrence of lower respiratory symptomsduring the first two years of life is a commonphenomenon. During the first year of life 90%of the cohort reported cough and 30% wheeze.This high incidence of lower respiratorysymptoms continued into the second year oflife with 66% of infants experiencing coughand 42% wheeze. For all infants, coughwas the predominant symptom experiencedwhereas wheeze was the more discriminatorysymptom. Infants with an at risk family historytended to have an increased incidence ofwheeze in comparison with those without sucha history. Those that developed bronchiolitisreported a higher incidence of symptomsthroughout the first two years of life. Aswith respiratory function and airway respon-siveness, an association has been demonstratedbetween an episode of bronchiolitis and

22

on January 24, 2022 by guest. Protected by copyright.

http://adc.bmj.com

/A

rch Dis C

hild: first published as 10.1136/adc.72.1.16 on 1 January 1995. Dow

nloaded from

Lungfunction, airway responsiveness, and respiratory-symptoms before and after bronchiolitis 23

subsequent incidence of wheeze.3 6-8 12 15 16 20Our study indicates that those who developbronchiolitis experienced an increased inci-dence of lower respiratory symptoms, usuallyof minor significance and not requiringmedical attention, before the reported episodeof infection. This would again suggest thatbronchiolitis itself is not inducing lowerrespiratory symptoms in previously asympto-matic infants. From our data the bronchioliticsymptom scenario appears to be cough andwheeze before, during, and after infection.

Controversy exists as to whether an episodeof bronchiolitis is the first manifestation ofasthma. In our study, by the age of 2 years,those with a history of bronchiolitis had anincreased incidence of asthma (44%) incomparison with the cohort (18%). However,bronchiolitis alone does not appear to becausative of asthma, as only 22% of those witha diagnosis in the first year of life had asthmaby age 2 years. Seventy one per cent of infantswith a diagnosis of bronchiolitis between yearone and two received a diagnosis of asthmawhich would tend to suggest that bronchiolitisis causative; however, this group of infants hada significant genetic risk for asthma and it ismore probable that the episode diagnosed asbronchiolitis in this age bracket was asthma.

In conclusion we suggest that the abnormalpulmonary function and increased incidence oflower respiratory symptoms documented inolder children after an episode of bronchiolitisin infancy represents differences present fromearly life in these individuals. This study hasdemonstrated reduced pulmonary functionand increased symptom incidence in infantsbefore bronchiolitis. Therefore, we proposethat bronchiolitis, although potentially contri-butory, is not the sole cause of the lowerrespiratory morbidity described in older child-ren. Evidence of pre-existing lung functionabnormality does not exclude bronchiolitisthen causing further damage. Due to the dis-tinct differences observed between those whoget bronchiolitis during their first and secondyear of life, with those in the second year morelikely to be part of the asthma spectrum, thediagnosis should be restricted to those underthe age of 1 year.The authors wish to thank the families involved, for theirgenerous and long term participation, the staff of the antenatalclinical and State Health Pathology Laboratory at Osborne ParkHospital, Karen Krska for initial cord blood IgE analysis, andPeter LeSouef, Gary Geelhoed, Amanda Reese, DebbieTurner, Stephen Stick, John Henderson, and Dean Diepeveenfor contributions made during the course of this study.

Supported by the National Health and Medical ResearchCouncil (Project Nos 880910 and 910160).

1 Stark JM, Busse WW. Respiratory virus infection andairway hyperreactivity in children. Pediatric Allergy andImmunology 1991; 2: 95-100.

2 Wohl MEB, Chernick V. State of the art: bronchiolitis. AmRev Respir Dis 1978; 118: 759-81.

3 McConnochie KM, Roghmann KJ. Bronchiolitis as apossible cause of wheezing in childhood: new evidence.Pediatrics 1984; 74: 1-10.

4 McGonnochie KM, Roghmann KJ. Parental smoking,presence of older siblings, and family history of asthmaincrease risk of bronchiolitis. Am Jf Dis Child 1986; 140:806-12.

5 McConnochie KM, Roghmann KJ. Wheezing at 8 and 13years: changing importance of bronchiolitis and passivesmoking. Pediazr Pulmnonol 1989; 6: 138-46.

6 Duiverman EJ, Neijens HJ, van Strik R, et al. Lung functionand bronchial responsiveness in children who hadinfantile bronchiolitis. Pediatr Pulmonol 1987; 3: 38-44.

7 Welliver RC, Duffy L. The relationship of RSV specificimmunoglobulin IgE antibody responses in infancy,recurrent wheezing and pulmonary function at 7-8 years.PediatrPulmonol 1993; 15: 19-27.

8 Rooney JC, Williams HE. The relationship between provedviral bronchiolitis and subsequent wheezing. J Pediatr1971; 79: 744-7.

9 Caswell SJ, Thomson AH, Ashmore SP, Beardsmore CS.Latent sensitisation to respiratory syncitial virus duringacute bronchiolitis and lung function after recovery. ArchDis Child 1990; 65: 946-52.

10 Kattan M, Keens TG, Lapierre J-G, Levison H, Bryan AC,Reilly BJ. Pulmonary function abnormalities in symptom-free children after bronchiolitis. Pediatrics 1977; 59:683-8.

11 Pullan CR, Hey EN. Wheezing, asthma, and pulmonarydysfunction 10 years after infection with respiratorysyncytial virus in infancy. BMJ 1982; 284: 1665-9.

12 Sims DG, Downham MAPS, Gardner PS, Webb JKG,Weightman D. Study of 8-year-old children with a historyof respiratory syncytial virus bronchiolitis in infancy. BMJ1978; i: 11-4.

13 Sims DG, Gardner PS, Weightmnan D, Turner MW,Soothill JF. Atopy does not predispose to RSV bronchioli-tis or post bronchiolitis wheezing. BMY 1981; 282:2086-8.

14 Tepper RS, Rosenberg D, Eigen H. Airway responsivenessin infants following bronchiolitis. Pediatr Pulmonol 1992;13: 6-10.

15 Stokes GM, Milner AD, Hodges IGC, Groggins RC. Lungfunction abnormalities after acute bronchiolitis. J Pediatr1981; 98: 871-4.

16 Gurwitz D, Mindorff C, Levison H. Increased incidence ofbronchial reactivity in children with a history of bronchi-olitis. JPediatr 1981; 98: 551-5.

17 Mok JYQ, Simpson H. Symptoms, atopy, and bronchialreactivity after respiratory infection in infancy. Arch DisChild 1984; 59: 299-305.

18 Hall CB, Hall WI, Gala CL, MaGill FB, Leddy JB.Long-term prospective study in children after respira-tory syncytial virus infection. Jf Pediatr 1984; 105:358-64.

19 Welliver RC, Sun M, Rinaldo D, Ogra PL. Predictive valueof respiratory syncytial virus-specific IgE responses forrecurrent wheezing following bronchiolitis. JPediatr 1986;109: 776-80.

20 Webb MSC, Henry RL, Milner AD, Stokes GM, SwarbrickAS. Continuing respiratory problems three and a halfyears after acute viral bronchiolitis. Arch Dis Child 1985;60: 1064-7.

21 McConnochie KM, Roghmann KJ. Breastfeeding andmaternal smoking as predictors of wheezing in childrenage 6 to 10 years. PediatrPulmonol 1986; 2: 260-8.

22 Cogswell J, Halliday DF, Alexander JR. Respiratoryinfections in the first year of life in children at risk ofdeveloping atopy. BM3t 1982; 284: 1011-3.

23 Wohl MEB, Stigol LC, Mead J. Resistance of the totalrespiratory system in healthy infants and infants withbronchiolitis. Pediatrics 1969; 43: 495-509.

24 Young S, LeSouef PN, Geelhoed GC, Stick SM, LandauLI. The influence of a family history of asthma andparental smoking on the level of airway responsiveness ininfants soon after birth. N Engl J Med 1991; 324:1168-73.

25 Ferris BG. Epidemiology standardization project: II.Recommended respiratory disease questionnaires for usewith adults and children in epidemiological research. AmRev Respir Dis 1978; 118 (suppl): 7-53.

26 Taussig LM, Landau LI, Godfrey S, Arad I. Determinantsof forced expiratory flow in newborn infants. J7 ApplPhysiol 1982; 53: 1270-7.

27 LeSouef PN, Geelhoed GC, Turner DJ, Morgan SEG,Landau LI. Response of normal infants to inhaled hista-mine. Am Rev Respir Dis 1989; 139: 62-6.

28 Le Souef PN, England SJ, Bryan AC. Passive respiratorymechanics in newborns and children. Am Rev Respir Dis1984; 129: 552-6.

29 Morris MJ, Lane DJ. Tidal expiratory flow patterns in air-flow obstruction. Thorax 1981; 36: 135-42.

30 Pepys J. Laboratory methods in clinical allergy. Proc R SocMed 1972; 65: 271-2.

31 Turner KJ, Siemeisma NP, Kryska K, Cameron KJ.Seasonal variation in in-vitro synthesis of rye pollenspecific IgE by human peripheral mononuclear cells.Functional heterogeneity within the age pool. InternationalArchives of Allergy and Applied Immunology 1987; 82:398-401.

32 Phelan PD, Landau LI, Olinsky A. Clinical patterns ofacute respiratory infections. Respiratory illness in children.Oxford: Blackwell Scientific Publications, 1982: 76-8.

33 Denny FW, Collier AM, Henderson FW, Clyde WA. Theepidemiology of bronchiolitis. Pediatr Res 1977; 11:234-6.

34 Harlap S, Davies AM. Infant admissions to hospital andmaternal smoking. Lancet 1974; i: 529-32.

35 Hanrahan JP, Tasger IB, Segal MR, Weiss ST, Speizer FE.The effect of maternal smoking during pregnancy onearly lung function. Am Rev Respir Dis 1992; 145:1129-35.

36 Martinez FD, Morgan WJ, Wright AL, Holberg CJ, TaussigLM. Diminished lung function as a predisposing factor forwheezing respiratory illness in infants. NEnglJtMed 1988;319: 1112-7.

37 Martinez FD, Morgan WJ, Wright AL, et al. Initial airwayfunction is a risk factor for recurrent wheezing respiratory

on January 24, 2022 by guest. Protected by copyright.

http://adc.bmj.com

/A

rch Dis C

hild: first published as 10.1136/adc.72.1.16 on 1 January 1995. Dow

nloaded from

24 Young, O'Keeffe, Arnott, Landau

illness during the first 3 years of life. Am Rev Respir Dis1991; 143: 312-6.

38 Seidenberg J, Masters IB, Hudson I, Olinsky A, Phelan PD.Disturbance in respiratory mechanics in infants withbronchiolitis. Thorax 1989; 44: 660-7.

39 Geller DE, Morgan WJ, Cota AC, Taussig LM. Airwayresponsiveness to cold dry air in normal infants. PediatrPulmonol 1988; 4: 90-7.

40 Tepper R. Airway reactivity in infants: a positive response to

methacholine and metaproteranol. J Appl Physiol 1987;62: 1155-9.

41 Stick SM, Arnott J, Turner DJ, Young S, LeSouef PN,Landau LI. Bronchial responsiveness and lung function inrecurrently wheezy infants. Am Rev Respir Dis 1991; 144:1012-5.

42 Hall WJ, Hall CB, Speers DM. Respiratory syncitial virusinfection in adults: virological and serial pulmonaryfunction studies. Ann Intern Med 1978; 88: 203-5.

Herpesvirus 7

It pays to be circumspect. In 1992 (page 500) I wrote 'Unlessanother one has been discovered fairly recently there are sixknown human herpesviruses'. What I did not know at that timewas that human herpesvirus 7 (HHV-7) had been described in1990.Now further work in Japan (Keiko Tanaka and colleagues,

Journal ofPediatrics 1994; 125: 1-5) has shown that both humanherpesvirus-6 (HHV-6) and HHV-7 may cause the clinicalpicture of roseola infantum (exanthem subitum). Seventeenchildren with a clinical diagnosis of roseola were studied. Twohad blood taken for virus isolation and HHV-7 was isolated inboth cases. In all, seven children showed seroconversion toHHV-7. Only one of these had not previously seroconverted toHHV-6. Seven patients with roseola seroconverted to HHV-6with the illness and three patients showed no serologicalevidence of recent infection with either HHV-6 or HHV-7.

It seems, therefore, that roseola infantum may be caused byeither HHV-6 or HHV-7 but children are usually infected withHHV-6 first. Infection with one virus does not confer immunityto the other. Some children have two episodes of roseola, thefirst due to HHV-6 and the second to HHV-7 but in others thesecond (HHV-7) infection gives rise to non-specific symptoms ofupper respiratory tract infection. A few cases of roseola may becaused by other agents.

I have commented before (1992; 67: 500) about the Japanesecontribution to medicine. One hundred years agoJAMA (1894;23: 286) quoted from an editorial in an English publication,Medical Press, to the following effect: 'The mere fact of such adiscovery (isolation of the bacillus of bubonic plague) ... is itselfan eloquent testimony to the intellectual powers of a versatileand capable nation'.' How do I come up with such originalthoughts? You may well ask.

ARCHIVIST

1 Flanagin A, Sullivan-Fowler M. Kitasato's discovery. JAMA 100 years ago. JAMA1994; 272: 413.

on January 24, 2022 by guest. Protected by copyright.

http://adc.bmj.com

/A

rch Dis C

hild: first published as 10.1136/adc.72.1.16 on 1 January 1995. Dow

nloaded from