Lung Function in School-age Children Who Had Mild Lower Respiratory Illnesses in Early Childhood 1- 3

GERALD L. STROPE, PAUL W. STEWART, FREDERICK W. HENDERSON, SALLY S. IVINS, HELEN C. STEDMAN, and MARIANNA M. HENRY

Introduction

Elementary schoolchildren with histories of hospitalization for viral lower respiratory illness (LRI) during early childhood have been found to have lower average levels of small airways function than children without such a history (1-7). Only 1 to 20/0 of children require hospitalization for treatment of LRI during infancy, whereas approximately 25 to 30% of infants experience an LRI of sufficient severity to warrant outpatient care (8-10). If the occurrence of LRI in early childhood has a substantial impact on the aggregate lung function of children, similar evidence of lower average lung function associated with mild LRI should be demonstrable. Characteristics of lung function of children who had experienced documented episodes of milder LRI requiring only outpatient care have not been studied extensively. To investigate the relationship between mild LRI in early childhood and later respiratory health, we studied 159children, 6 to 18 yr of age, who had prospective documentation of outpatient physician visits for LRI during the first 6 yr of life. We report here sex-specific analyses of associations between preschool wheezing and nonwheezing LRI experience and lung function in boys and girls. We have previously reported a follow-up investigation of 57 of these study boys (11). In that study, preschool wheezing LRI experience was associated with level of lung function at an average age of 15 yr, but not with degree of methacholine sensitivity. Methods Study Population Children who participated in this study were recruited from a larger group that had participated in an investigation of the etiology of acute LRI that was conducted in a private pediatric practice in Chapel Hill, North Carolina, between 1964 and 1975 (8, 12-15). In that study, practice physicians attempted to evaluate all LRI episodes experienced by children

SUMMARY We examined the relationship between patterns of mild lower respiratory illness (LRI) experienced in early childhood and lung function in 89 boys and 70 girls 6 to 18 yr of age. The children's histories of outpatient visits for wheezing and nonwheezing LRI during the first 6 yr of life had been documented by physicians In a single pediatric practice. Most children were reported by their parents to have been free of recurrent respiratory symptoms during the 2 yr prior to lung function testing. In sex-specific analyses, average lung function assessed by spirometry was similar in children who had made zero or one physician visit for wheezing LRI during the preschool years. Boys who had experienced two or more episodes of wheezing LRI during the preschool years had lower average FEV" FEV,IFVC, FEF 25-75' Vmax50, and Vmax75 than did boys who had zero or one preschool wheezing illness. The association between recurrent preschool wheezing LRI and later lung function remained after exclusion of data from seven boys who were reported to have wheezed in the 2 yr prior to study. Girls who had experienced two or more preschool wheezing LRI had lower average FEF 25- 75 and Vmax50 than girls with a history of zero or one such illness, but differences were not statistically significant. Recurrent nonwheezlng LRI during the preschool years was not significantly associated with subsequent lung function In either sex, regardless of preschool wheezing LRI history. Detailed information concerning early childhood LRI experience is valuable in epidemiologic studies of factors influencing lung function in children. AM REV RESPIR DIS 1991; 144:655-662

younger than 16 yr of age. For this investigation, the original study files were reviewed to identify all children who had made practice visits for LRI during the first 3 yr of life; 2,164 children were identified (12-15). At the time of initiation of this study, practice personnel thought that 308 (14%) of these children were active in the practice and at least 6 yr of age; however, local addresses could be identified for only 203 of these families. All 203 families were invited to participate. Parents of 158 children (78% of the 203 children who were found to still reside in the area) agreed to participate. Children without records of physician visits for LRI were identified by surveying consecutive, even-numbered files to identify families that had at least one school-age child who had been followed from birth by practice physicians. Thirty-four families of children who had made no visits to the practice for LRI during their preschool years were contacted. Twenty-five of these 34 families (74%) agreed to participate. Altogether, 183 children who had experienced varying patterns of LRI during early childhood were studied. The data of 24 children were subsequently excluded from analyses because of nonwhite race (13 children) or incomplete documentation of LRI histories because of family travel (11 children).

Preschool LRI History The medical records of the 159 study children were reviewed to characterize each child's LRI

experience during the first 6 yr of life (the preschool years). Diagnostic criteria for the clinical syndromes of childhood LRI that had been employed in the initial epidemiologic investigation were retained in the current study. These criteria were: (1) croup: hoarseness and barking cough with or without inspiratory stridor; (2) tracheobronchitis: cough and rhonchi without laryngeal obstruction or wheezing; (3) bronchiolitis: expiratory wheezing with or without tachypnea, air trapping, and substernal retractions; (4) pneumonia: crackles or other evidence of pulmonary consolidation on physical examination or chest radiograph (8, 12-15). For the current study, illness episodes with medical record entries of bronchiolitis, asthmatic bronchitis, asth-

(Received in originalform November 10, 1989 and in revised form March 25, 1991) 1 From the Department of Pediatrics, the School of Medicine and the Department of Biostatistics, the School of Public Health, The University of North Carolina, Chapel Hill, North Carolina. 2 Supported by Pediatric Pulmonary Specialized Center of Research Grant HL-19171 from the National Heart, Lung, and Blood Institute and by Cooperative Agreement CR 80739202 from the Environmental Protection Agency. J Correspondence and requests for reprints should be addressed to Marianna M. Henry, M.D., 635 Burnett-Womack CB 7220, University of North Carolina, Chapel Hill, NC 27599-7220.

655

656

ma, or wheezing were categorized as wheezing LRI. All other LRI episodes (i.e., those with medical record entries of croup, tracheobronchitis, pneumonia, croupy cough, stridor, rhonchi, crackles, or cough lasting longer than 1 wk) were categorized as nonwheezing LRI. If both types of medical record entries were recorded during a single illness episode, the illness was categorized as a wheezing LRI. Physician visits within 2 wk of initial LRI visits were considered to be follow-up visits for the same LRI episode. All wheezing LRI episodes were further classified according to their probable association with respiratory syncytial virus (RSV) infection. An illness was considered to be RSVrelated if culture-proved or if associated temporally with a documented RSV epidemic and not demonstrated to be of other etiology. All episodes of LRI, except two, were sufficiently mild to warrant only outpatient care; two boys had been hospitalized for single episodes of pneumonia. None of the children had been hospitalized for wheezing LRI. Respiratory health and confidential smoking questionnaires werecompleted by the parents and children, respectively. Information elicited included recent (in the 2 yr prior to testing) and earlier respiratory symptoms and diagnoses of the subjects and other family members and environmental exposures, including exposure to tobacco smoke. The respiratory health questionnaire was designed to meet the objectives of this study, but it resembled closely the ATS-NHLBI children's questionnaire (16).

STROPE, STEWART, HENDERSON, IVINS, STEDMAN, AND HENRY

potheses, and performance of selected exploratory analyses (20). All a priori hypotheses were sex-specific and formulated in terms of six categories of preschool LRI history. Specifically, children werecategorized by frequency of physician visits for wheezing LRI (0, 1, or ;;?; 2) and by frequency of visits for nonwheezing LRI « 2 or ;;?; 2) during the preschool years. These categories of LRI experience were chosen to facilitate comparison of lung function of children who had no or only minimal LRI experience with that of children who had more substantial, recurrent illness requiring repeated visits to physicians. Each pulmonary function test (PFT) measurement was transformed to the natural logarithmic scale; loge-PFT measurements were found to be distributed normally, with means linear in height and variances constant across height. The a priori linear models for logePFT measurements were conditional upon sex, the six LRI groups, and height. Measurements for boys and girls wereassumed to have different regression coefficients but the same variance. Within each sex, the slopes with respect to height were assumed initially to be the same across all six LRI groups (no height by LRI-group interaction). The assumptions for the models were examined by residual analysis and the fitting of alternative models. The normality assumption was also examined graphically by nonparametric density estimation (21). No substantial departures from the

assumptions were found. For purposes of comparing groups, these regression models were used to calculate mean logs-Pf'T at a height of 150em (the mean height of the study population) for each of the six LRI groups. Mean logs-Pf'T for each category of wheezing LRI experience (0, 1, or ;;?; 2) was then estimated by averaging group means across the two categories of nonwheezing LRI experience « 2 or ;;?; 2). An F test was used to evaluate the null hypothesis that the means for the three wheezing LRI categories were equal (for example, see table 5). Similarly, means for the two categories of nonwheezing LRI experience were estimated for F test comparison by averaging across the three categories of wheezing LRI experience. Finally, an F test for interaction (synergism) between the wheezing and nonwheezing factors was performed. In exploratory analyses and analyses designed to identify confounding variables, variations of this basic a priori model were used to study the relationship of pulmonary function to other measures. For example, environmental tobacco smoke exposure was evaluated as a possible confounding variable by adding appropriate indicator variables for smoke exposure to the basic model. A p value < 0.01 was considered to be indicative of significant differences in the data of children in the various preschool LRI groups. This more stringent criterion was used

TABLE 1

Pulmonary Function Test At the time of evaluation, the children had been free of upper respiratory illness for 4 wk and LRI for at least 6 wk. They had not used theophylline for 48 h or beta-2-agonists foir 12h prior to testing. Each child had standing height and weight recorded and was examined by a physician for signs of acute or chronic respiratory illness. Spirometry was performed in a standing position with noseclips using a rolling-seal spirometer (Model 840; Ohio Medical Products, Atlanta, GA) interfaced with an X-V recorder (Model 7045A; Hewlett-Packard, San Diego, CAl and microprocessor (Eagle I; Warren E. Collins, Braintree, MA). Children were instructed in the performance of FVC maneuvers, and data were collected until three consistent maneuvers with FVCvalues within 5070 of each other were recorded. The spirometric measurements used in statistical analyses were (1) the largest FVC, FEV l, and PEF from technically acceptable, but not necessarily the same, FVC maneuvers, and (2) FEF25-75, Vmax50 , and Ymax-, from the FVC maneuver with the largest sum of FVC and FEV l (11, 17, 18). Static lung volumes were measured using helium dilution as described previously (19).

DISTRIBUTION OF CHILDREN BY NUMBER OF EPISODES OF WHEEZING AND NONWHEEZING LRI DOCUMENTED BY PHYSICIAN VISITS DURING THE FIRST 6 YR OF LIFE Girls Number of Nonwheezing LRI Episodes

~2

0-1

Total

0-1

~2

Total

Number of wheezing LRI episodes

0 1 ~2

Total

22* 9 12

13 13 20

35 22 32

19 9 7

18 8 9

37 17 16

43

46

89

35

35

70

• Number of children in category.

TABLE 2 DISTRIBUTION OF CHILDREN BY NUMBER OF WHEEZING LRI EPISODES DURING AGE INTERVALS 0 TO 2 AND 2 TO 6 YR Boys

Girls

Number of Wheezing LRI Episodes in Yr 2-6

Number of Wheezing LRI Episodes in Yr 2-6

1

Total

5

3 4 5

40 19 10

57

12

69t

Total

0

42 25 19

37 15

8

7 8 11

60

26

86t

0

~

1

~

Number of wheezing LRI episodes in 2 yr 0-2

0 1 ~2

Analysis The analysis strategy consisted of the use of descriptive methods, testing of a priori hy-

Boys Number of Nonwheezing LRI Episodes

Total

35* 17

• Number of children in category. Insufficient data were available to classify three boys and one girl by wheezing illness experience in both age intervals.

t

657

WNG FUNCTION AFTER MILD PRESCHOOL RESPIRATORY ILLNESS

because of the observational rather than the experimental nature of the study, the multiple hypothesis tests performed, and the use of the data to fit statistical models for analyses.

TABLE 3 PERCENTAGE OF BOYS REPORTED BY THEIR PARENTS TO HAVE HAD RESPIRATORY SYMPTOMS IN THE 2 YR PRIOR TO LUNG FUNCTION TESTING OR A PHYSICIAN DIAGNOSIS OF ASTHMA Number of Preschool Nonwheezing LRI Episodes

Number of Preschool Wheezing LRI Episodes 0 Boys, n Cough or phlegm without colds Cough or phlegm ~ 4 days/wk for ~ 3 months/yr Chest colds; two or more lasting > 1 wk Wheezing Wheezing without colds Wheezing with exercise Asthma diagnosed by a physician (ever)

~2

0-1

~2

35 2.9*

22 22.7

31 25.8

43 11.9

45 19.6

2.9

13.6

3.2

7.1

4.4

8.6 2.9 0.0 0.0 2.9

13.6 9.1 4.6 4.6 13.6

9.7 12.9 12.9 9.7 25.8

4.8 9.5 7.1 4.8 11.9

15.2 6.5 4.4 4.4 15.2

Results

• Entry is percentage observed.

TABLE 4 PERCENTAGE OF GIRLS REPORTED BY THEIR PARENTS TO HAVE HAD RESPIRATORY SYMPTOMS IN THE 2 YR PRIOR TO LUNG FUNCTION TESTING OR A PHYSICIAN DIAGNOSIS OF ASTHMA Number of Preschool Nonwheezing LRI Episodes

Number of Preschool Wheezing LRI Episodes 0 Girls, n Cough or phlegm without colds Cough or phlegm ~ 4 days/wk for ~ 3 months/yr Chest colds; two or more lasting > 1 wk Wheezing Wheezing without colds Wheezing with exercise Asthma diagnosed by a physician (ever)

~2

0-1

~2

36 8.3*

17 17.7

16 18.8

35 5.7

34 20.6

8.3

5.9

0.0

5.7

5.9

16.7 8.3 2.8 2.8 5.6

11.8 29.4 5.9 5.9 0.0

12.5 25.0 6.3 0.0 37.5

8.6 20.0 2.9 2.9 14.3

20.6 14.7 5.9 2.9 8.8

• Entry is percentage observed.

TABLE 5 PRESCHOOL LOWER RESPIRATORY ILLNESS HISTORY AND LATER LUNG FUNCTION IN THE BOYS* Number of Nonwheezing LRI Episodes

Number of Wheezing LRI Episodes

Subjects

~2

P Value t

0-1

~2

2.92 (0.06)

2.94 (0.05)

0.0021

2.44 (0.05)

2.48 (0.05)

0.81 (0.01)

0.0011

0.84 (0.01)

0.85 (0.01)

2.72 (0.15)

2.18 (0.10)

0.0001

2.53 (0.10)

2.59 (0.10)

3.19 (0.14)

3.19 (0.17)

2.51 (0.11)

0.0001

2.94 (0.12)

2.97 (0.11)

87

1.49 (0.08)

1.51 (0.11)

1.13 (0.07)

0.0004

1.31 (0.07)

1.42 (0.07)

TLC, L

76

3.63 (0.09)

3.60 (0.10)

3.39 (0.08)

3.53 (0.07)

3.56 (0.08)

VRITLC

76

0.23 (0.01)

0.20 (0.01)

0.21 (0.01)

0.22 (0.01)

0.20 (0.01)

(n)

0

FVC, L

89

2.92 (0.06)

3.00 (0.08)

2.83 (0.06)

FEV1 , L

83

2.53 (0.05)

2.53 (0.07)

2.32 (0.05)

FEV1/FVC

83

0.87 (0.01)

0.86 (0.02)

FEF2s- 7s, LIs

83

2.80 (0.11)

Vmax so, LIs

87

Vmax 7S, LIs

P Value

0.0817

* Values are mean pulmonary function parameters evaluated at height = 150 em, with standard error shown in parentheses. p Values for test of null hypothesis Ho (no difference across groups) versus Ha (any difference among groups); p values greater than 0.1000 are not shown.

t

Eighty-nine white boys, 7 to 18 yr of age, and 70 white girls, 6 to 17 yr of age, were studied. They are categorized by numbers of physician visits made for wheezing- and non-wheezing-associated LRI during the first 6 yr of life in table 1. Sixtyone percent of boys and 470/0 of girls had been seen by a practice physician on at least one occasion for wheezing LRI during the first 6 yr; two or more visits with wheezing had been made by 36% of boys and 23 % of girls. Among children with recurrent wheezing LRI, nine boys and six girls had made four or more visits for wheezing LRI during the first 6 yr oflife. Of children who had ever experienced wheezing LRI in the first 6 yr, 44 of 51 boys (86070) and 29 of 32 girls (91 0/0) had made physician visits with wheezing before 2 yr of age (table 2). Episodes of wheezing LRI linked by virus culture or epidemiologic association with RSV infection had occurred in the first 2 yr of life in 33 of 51 (65070) boys and 19 of 32 (59%) girls who had preschool wheezing LRI. Recurrent visits for nonwheezing LRI had been made by 52% of boys and 50% of girls (table 1). Percentages of positive responses to questionnaire items concerning the occurrence of respiratory symptoms in the 2 yr prior to study and parental report of a physician's diagnosis of asthma at some time during the child's life are shown in tables 3 and 4 for boys and girls, respectively. Seven of 88 boys (8.0%) and 12 of 69 girls (17.4%) were reported to have had any wheezing in the 2 yr prior to study. A physician's diagnosis of asthma was reported to have been made in 12 of 88 boys (13.6%) and eight of 69 girls (11.50/0) The average spirometric lung function of children who had no physician visits for wheezing illness during the preschool years did not differ from that of children who had made one such visit (tables 5 and 6 for boys and girls, respectively). The occurrence of two or more wheezing LRI episodes during the first 6 yr of life was associated with significantly lower average FEV tt FEV1/FVC, FEF 2 5 - 7 5 , Vmax5 o, and Vmax-, in boys (table 5). Girls who had two or more episodes of preschool wheezing LRI had lower average FEF25-75 and Vmax., than did girls with zero or one preschool wheezing illness, although differences in average lung

658

STROPE, STEWART, HENDERSON, IVINS, STEDMAN, AND HENRY

TABLE 6 PRESCHOOL LOWER RESPIRATORY ILLNESS HISTORY AND LATER LUNG FUNCTION IN THE GIRLS· Number of Nonwheezing LRI Episodes

Number of Wheezing LRI Episodes

Subjects (n)

~2

0

P Value"

0-1

~2

FVC, L

70

2.77 (0.05)

2.66 (0.08)

2.72 (0.09)

2.66 (0.06)

2.80 (0.06)

FEV1 , L

68

2.51 (0.05)

2.41 (0.07)

2.41 (0.08)

2.39 (0.06)

2.51 (0.05)

FEV,IFVC

68

0.90 (0.01)

0.90 (0.02)

0.89 (0.02)

0.90 (0.01)

0.90 (0.01)

FEF2s- 7s, LIs

68

2.94 (0.11)

2.86 (0.17)

2.69 (0.19)

2.75 (0.13)

2.92 (0.13)

Vmax so, LIs

69

3.39 (0.14)

3.35 (0.29)

2.86 (0.25)

3.06 (0.15)

3.32 (0.15)

Vmax 7S' LIs

69

1.63 (0.09)

1.45 (0.12)

1.57 (0.14)

1.48 (0.10)

1.63 (0.10)

TLC, L

63

3.39 (0.07)

3.25 (0.11)

3.42 (0.13)

3.29 (0.09)

3.42 (0.08)

VRITLC

63

0.21 (0.01)

0.20 (0.01)

0.21 (0.02)

0.22 (0.01)

0.20 (0.01)

0.0646

P Value

• Values are mean pulmonary function parameters evaluated at height = 150 em, with standard error shown in parentheses. p Values for test of null hypothesis Ho (no difference across groups) versus Ha (any difference among groups); p values greater than 0.1000 are not shown.

t

TABLE 7 PRESCHOOL LOWER RESPIRATORY ILLNESS HISTORY AND LATER LUNG FUNCTION IN ASYMPTOMATIC BOYS·

Subjects (n)

Number of Wheezing LRI Episodes ~2

0

P Value t

FVC, L

81

2.94 (0.06)

3.00 (0.08)

2.82 (0.07)

FEV1 , L

75

2.56 (0.05)

2.52 (0.06)

2.31 (0.05)

0.0026

FEV 1/FVC

75

0.87 (0.01)

0.85 (0.01)

0.82 (0.01)

0.0110

FEF2s- 7s, LIs

75

2.82 (0.11)

2.69 (0.14)

2.23 (0.11)

0.0007

Vmax so, LIs

79

3.22 (0.14)

3.17 (0.18)

2.62 (0.13)

0.0043

Vmax 7S, LIs

79

1.51 (0.08)

1.51 (0.11)

1.18 (0.08)

0.0056

• Values are mean pulmonary function parameters evaluated at height = 150 em, with standard error shown in parentheses. Excluded from data were seven boys reported by their parents to have experienced wheezing in the 2 yr prior to lung function testing and from one boy who had recurrent preschool wheezing episodes whose parents did not answer the question concerning wheezing in the previous 2 yr. t p Values for test of null hypothesis Ho (no difference across groups) versus Ha (any difference among groups); p values greater than 0.1000 are not shown.

function were not significant (table 6). Exclusion of data from children who were reported to have wheezed in the 2 yr prior to study (table 7 for boys) or to have ever had a physician's diagnosis of asthma did not alter the conclusions concerning wheezing LRI and lung function. Average VR/TLC and TLC did not differ significantly across the three wheezing illness categories in boys or girls. The

differences in lung function related to early childhood wheezing illness history in boys were constant across height (figure 1: FEV! and FEF 2 S - 7 S for boys). Exploratory analyses included an investigation of the role of age at occurrence of wheezing LRI episodes in the association between preschool wheezing LRI experience and later lung function. No evidence was found to suggest that

an earlier age of occurrence of the first wheezing LRI was associated with lower average lung function in an analysis that included information concerning frequency of preschool wheezing LRI (figure 2: FEF 2 S - 7 S for boys and girls). In a separate analysis, differences in lung function were examined when children were categorized according to the number of wheezing LRI experienced during the age intervals from zero to 2 and 2 to 6 yr (table 2). No significant association was identified between the occurrence of wheezing LRI during the first 2 yr of life and subsequent lung function in boys or girls, although the eight boys who had histories of ~ 2 wheezing LRI episodes in the first 2 yr of life and had no further wheezing episodes between 2 and 6 yr of age had lower FEF2S-7S, Vmaxso, and Vmax7s than did the 52 boys who had zero to one such episode during this early age interval and no further preschool wheezing LRI (p values = 0.0585, 0.0975, and 0.0742, respectively) (table 8: FEF2S- 7S)' The 26 boys who experienced one or more wheezing LRI between 2 and 6 yr of age had lower average FEV h FEF 2 S - 7 S , Vmaxso, and Vmax7S, (p values = 0.0119, 0.0008, 0.0002, and 0.0018, respectively) than did the 60 boys who did not have wheezing LRI during this later interval (table 8: FEF2 S- 7S). The 12 girls who had wheezing LRI between 2 and 6 yr of age had lower average Vmax., (p value = 0.0453) than did the 57 girls who did not have wheezing LRI during this interval. We also investigated whether the occurrence of RSV-associated wheezing LRI during the first 2 yr of life (classic childhood bronchiolitis) was associated with differences in lung function. RSVwheezing LRI during the first 2 yr was not associated with differences in level of lung function in this small study population when information concerning frequency of wheezing LRI was included in the analysis. The frequency of occurrence of nonwheezing LRI episodes during the preschool years was not found to be associated with average level of lung function in boys or girls (tables 5 and 6). There was no evidence that a history of recurrent nonwheezing LRI had a differential impact on lung function in children with different histories of wheezing LRI. In analyses designed to investigate the potential confounding role of specific nonwheezing LRI episodes in the relationship between preschool wheezing illness and later lung function, no consistent evi-

659

WNG FUNCTION AFTER MILD PRESCHOOL RESPIRATORY ILLNESS

2.0

BOYS o

1.5

>-

w

LL 01 0

1.0

-.J

0.5

..

~/

Fig. 1. Mean loge FE'/, and FEF 25 - 75 by frequency of physician visits for wheezing LRI during the preschool years and standing height for boys. Open circles = 0; open squares = 1; closed triangles = ;.. 2.

0 100

140

120

160

180

2.0 o

o

no evidence was found to suggest that differences in lung function associated with preschool wheezing LRI were attributable to tobacco smoke exposure during early childhood or during the 2 yr prior to evaluation. There was an association between exposure to maternal cigarette smoke during the first 2 yr of life and preschool wheezing LRI (odds ratio = 2.41 concerning maternal smoke exposure in children who had two or more versus children who had zero to one preschool wheezing LRI; 950/0 confidence interval = 1.11 to 5.25).Nonwheezing LRI experience was not related to maternal cigarette smoke exposure. Paternal cigarette smoke exposure was not associated with preschool wheezing or nonwheezing LRI histories.

1.5

....,

LL'"

w

Discussion 1.0

LL 01 0

-.J

05

..

W'.

0

100

BOYS

2.0 0 0

1.5 II>

7

:CI.O

LL

w

LL

gO.5 ....J

cP

4

0

0

• ••

c.~.jJ

•

otJ

8

•

0.0 0

10

2.0

II>

7

II> N

LL

w

1.0

LL

C'

.3 0.5

•

0

t· •

1.5

•

0 0

.q "'•• Jil

f NA

0

c.

20

30

40

50

60

GIRLS

8

t ~ 0

0

0

·0 0

......0

o •

•

dlA,C

•

0

• • o•

cPo 0

•

c

•

6.

00 NA 0 10 20 30 40 50 60 AGE (mo) OF FIRST WHEEZING LRI

Fig. 2. Mean loge FEF 2s - 75 by frequency of physician visits for wheezing LRI during the preschool years and age of first wheezing LRI for boys and girls. NA = not applicable. Open circles = 0; open squares = 1;closed triangles = ;.. 2.

""

120

.

....

.. ..

140 HEIGHT (em)

160

180

dence of an association between the occurrence of croup, pneumonia, or tracheobronchitis and later lung function was identified. Exposure to tobacco smoke, another possible confounding factor in the relationship between LRI history and lung function, was assessed using estimates of exposure obtained by questionnaire. None of the children reported current active smoking. Exposure to environmental tobacco smoke was assessed as: (1) any maternal smoking during the first 2 yr of the child's life (positive responses for 29 of 89 boys and 22 of 67 girls), (2) any paternal smoking during the first 2 yr of the child's life (positive responses for 26 of 89 boys and 25 of 67 girls), (3) any smoking in the home during the first 2 yr of the child's life (positive responses for 44 of 89 boys and 33 of 70 girls), and (4) any smoking in the home in the 2 yr prior to pulmonary function testing (positive responses for 44 of 89 boys and 32 of 70 girls). In analyses designed to assess the potential confounding role of tobacco smoke exposure in the observed association between recurrent preschool wheezing LRI and later lung function,

Several studies of children who had been sufficiently ill to require hospitalization for viral LRI early in life have provided evidence of persistent airway dysfunction in a proportion of these children during middle childhood (1-7). In their study of 200 approximately 8-yr-old children who had been hospitalized for LRI during infancy, Mok and Simpson (3) found lower average FEVo.75, FEV h and FEF25-75 (by 4 to 5.6% predicted for FEV o.75 and FEV 1 and by 120/0 predicted for FEF25-75) in children who had been hospitalized with bronchiolitis than in children who had not been admitted for infant LRI. In another comprehensive study, Pullan and Hey (4) evaluated lung function in 130 children who had been hospitalized 10yr previously for RSV-associated LRI (predominantly bronchiolitis) during infancy. Children who had been hospitalized with RSV LRI had lower average FVC, FEV 1, PEF, FEF 25-75, Vmax50, and Vrnax-, (by 4 to 9% predicted for FVC, FEV 1, and PEF and by 13 to 25% predicted for FEF 25-75, Vmax50, and Vmax75) than did control children. There has been one previous report concerning lung function of schoolchildren who were documented to have had mild LRI during early childhood. MeConnochie and colleagues (22) studied 25 children, 8 to 12yr old, who had made a single outpatient visit for bronchiolitis during the first 24 months of life and 25 matched control children. No consistent differences in spirometry were found in the two groups of children, although children who had bronchiolitis had significantly lower average FEF25-75' We examined associations between

660

STROPE, STEWART, HENDERSON, IVINS, STEDMAN, AND HENRY

TABLE 8 NUMBER OF WHEEZING LRI EPISODES DURING AGE INTERVALS o TO 2 AND 2 TO 6 YR AND LATER FEF25 - 75 VALUES Boys

Girls

Number of Wheezing LRI Episodes in Yr 2-6

Number of Wheezing LRI Episodes in Yr 2-6

0

~

1

Means·

0

2.40* (0.14) 2.36 (0.13) 2.30 (0.16)

2.93 (0.15) 2.83 (0.21) 2.98 (0.36)

2.44 (0.38) 2.78 (0.36) 2.54 (0.27)

2.91 (0.17)

2.59 (0.22)

~

1

Means

Number of wheezing LRI episodes in yr 0-2

o

~2

Means§

2.nt (0.12) 2.78 (0.19) 2.32 (0.22)

2.08 (0.22) 2.00 (0.17) 2.29 (0.20)

2.6111 (0.12)

2.11 (0.12)

2.68 (0.23) 2.81 (0.22) 2.75 (0.24)

• For boys and for girls, variation in row means is not statistically significant (p value> 0.1000). Entry: mean FEF25- 15 in LIs calculated at height = 150 em, with standard errors shown in parentheses. Geometric mean of two means in row, with SE shown in parentheses. § For boys, column means are significantly different (p value = 0.0008). For girls, column means are not significantly different (p value> 0.1000). II Geometric mean of three means in column, with SE shown in parentheses.

t

*

patterns of mild LRI, manifested initially during the first 3 yr of life, and lung function in 159 children, 6 to 18 yr old, whose histories of mild LRI warranting outpatient care had been documented from birth to 6 yr of age in a single pediatric practice. An important potential limitation of this study population is the high nonparticipation rate of children who had been seen for LRI during the first 3 yr of life but who no longer resided in the area. It is not surprising that such a large proportion of children should be unavailable as the interval between initiation of the original study and planning of this investigation extended over 16 yr, particularly in a small university community whose student population, university support personnel, and faculty might be expected to relocate frequently. Although a large proportion of area children participated, we have no knowledge of the respiratory outcomes of children who moved from the area. We have no reason to believe that the children's LRI experience was associated with any factors that might have been influential in decisions concerning family relocation. The environmental and occupational milieu of the area would not be expected to be beneficial or detrimental to family members who have respiratory illness. Selective participation of area children who had more severe, and presumably ongoing, respiratory problems could also have been a source of bias. We performed analyses both with and without data from children who had wheezing in the 2 yr before lung func-

tion testing to minimize the influence of participation of currently symptomatic children. Utilization of medical chart review to document preschool LRI experience could have resulted in misclassification of children by LRI history, as severity of illness necessary to prompt parents to seek medical evaluation varies. Medical chart review, however, is highly likely to be superior to parental report of remote LRI for these children who had been followed while an epidemiologic investigation of LRI was being conducted. In this study population, there was no evidence that a single mild preschool wheezing LRI was associated with any persistent differences in spirometry. However, boys with histories of two or more outpatient visits for wheezing LRI during the preschool years had lower average FEV l, FEVl/FVC, FEF2S-7S, Vmaxso, and Vmax-, than did boys with histories of zero or one such illness. This association was not dependent on inclusion of data from boys who had wheezed in the 2 yr prior to study or from those who had a physician's diagnosis of asthma. Boys who had recurrent preschool wheezing LRI had lower lung function than did those who had zero or one illness throughout the range of heights, suggesting that average differences in lung function were not attributable to lower lung function in younger boys whose lung function might have been more highly influenced by more recent preschool respiratory events. Furthermore, in a follow-up study of a subset of these boys that has been published, the association

between preschool wheezing LRI and lung function was found to be persistent; specifically, reevaluation of 57 boys an average of 4 yr after their participation in this initial assessment again demonstrated lower average lung function in boys with histories of two or more preschool wheezing LRI (11). No significant association between preschool wheezing LRI and later lung function was identified in girls, although girls who had recurrent preschool wheezing LRI had slightly lower average FEF25-75 and Vmax., than did girls with histories of zero or one such illness. The absence of a significant association among girls could be attributable in part to the smaller number of girls who were evaluated. Power analysis indicated that probabilities of detecting differences in lung function among girls were smaller than for boys. For example, the probability of detecting a difference in FEF2s-7s between girls who had two or more versus a single preschool wheezing LRI of the same magnitude as that observed in boys was 0.59 for girls, using a test of alpha = 0.01, as compared with 0.78 for boys. Sex-related differences in small airway caliber (23, 24) or baseline airway tone may also contribute to this discrepancy in results of boys and girls. Age of occurrence of the first wheezing LRI was not associated with later level of lung function, although the range of ages of first wheezing LRI may be limited by the recruitment strategy that identified children who had made at least one practice visit for LRI by 3 yr of age. Wheezing LRI experience during the first 2 yr of life was not closely associated with later lung function. However, among boys who had no wheezing LRI between 2 and 6 yr of age, those who had two or more wheezing LRI in the first 2 yr tended to have lower small airways function than did those who had no or only a single wheezing LRI during the first 2 yr. The specific occurrence of mild RSVassociated wheezing LRI during the first 2 yr was not associated with differences in later lung function; however, this analysis was limited by small numbers of children with histories of recurrent wheezing LRI who had not experienced RSVassociated wheezing in the first 2 yr. These finding do not necessarily conflict with prevailing hypotheses that lower levels of small airways function during the first months of life are predictive of wheezing with viral LRI in early childhood (25) or that occurrence of wheezing LRI in early childhood is detrimental to subsequent airway growth or func-

661

WNG FUNCTION AFTER MILD PRESCHOOL RESPIRATORY ILLNESS

tion. The observed trend for boys who had recurrent wheezing LRI limited to the first 2 yr to have lower lung function during later childhood suggests that at least a subset of these boys have lower later lung function. The study of a larger group of children might reveal a more convincing association. Our data suggest a strong association between wheezing LRI experience between 2 and 6 yr of age and later lung function in boys. The findings of Gold and colleagues (26) in their study of a large cohort of East Boston children provide an interesting comparison. In that study, the combination of parental report of LRI before 2 yr of age and of two or more LRI during a specific study year when the children were 6 to 12 yr of age was associated with lower average small airways function; whereas, report of LRI in the first 2 yr alone was not predictive of later level of lung function. Dependence of these associations on inclusion of data concerning LRI experience after the first 2 yr of life may reflect continued expression of airway injury sustained principally during early childhood, particularly in a subset of children who may have been more severely affected and, therefore, continued to manifest symptomatic airway disease after the first several years of life. In analyses designed to evaluate environmental tobacco smoke exposure as a potential confounding variable, we found no evidence that the association between recurrent preschool wheezing LRI and lower average lung function was attributable to tobacco smoke exposure. Because of the requirement to retain preschool LRI history in analytic models as a recruitment criterion for study participation, it was not reasonable to test for an unconditional association (i.e., without LRI history in the model) between tobacco smoke exposure and lung function. Analyses concerning smoke exposure and lung function that include information concerning LRI history would be less likely to show independent association between both LRI history and smoke exposure and later lung function because of the observed colinearity between preschool wheezing LRI history and maternal tobacco smoke exposure. No evidence was found for an association between the frequency of mild, preschool nonwheezing LRI and later lung function. In analyses designed to evaluate the potential confounding role of specific nonwheezing LRI diagnoses in the relationship between wheezing LRI and later lung function, the specific diagnoses

of single or recurrent episodes of croup, pneumonia, or tracheobronchitis were not associated with consistent differences in lung function. Several population-based studies of school-age children have provided evidence that parental reports of recurrent episodes of bronchitis (27-30) or single/recurrent episodes of pneumonia (26, 28, 30) occurring during early childhood have been associated with lower average FEV1 (26), FEV o.7s/FVC (30), PEF (28), or Vmax., (27, 29). Differences in conclusions from investigations of nonwheezing LRI and later lung function may be accounted for in part by differences in study design or analysis, including illness identification (physician records versus parental recall and limitations of each method), illness categorization (wheeze- or non-wheeze-associated versus specific diagnoses), illness severity, and potential inclusion of data from children who have active asthma. The pathophysiologic mechanisms that underlie the association between recurrent wheezing LRI and later lung function are not well understood. We have examined previously the possibility that bronchial reactivity may contribute to this association in our follow-up assessment of study boys (11). In those analyses, preschool wheezing LRI experience was not related to methacholine sensitivity during adolescence, and differences in lung function associated with recurrent preschool wheezing LRI remained after adjustment for degree of methacholine sensitivity. In a separate report, we discuss the role of respiratory allergy, particularly to house dust mite antigens, as an important covariable in this association. Other factors that may contribute independently or by influencing the incidence of symptomatic wheezing LRI include individual differences in the susceptibili ty to severe viral-induced airway injury and its subsequent repair, cumulative damage resulting from repeated inflammatory insults related to infectious or to toxic environmental exposures, and inborn or acquired differences in airway caliber, tone, and other structural features. Acknowledgment The writers thank Margaret E. Burchinal, Myla S. Hunt, Christy S. Kleoudis, Margaret E. Martin, Penelope S. Pekow, Reid TatumMerritt, and Tarlough A. Wiggins for their technical and statistical assistance; Ronald W. Helms and Robert Chapman for their statistical and epidemiologic counsel; the children's pediatricians, R. M. Christian, Jr., W. G. Con-

ley III, R. J. Senior, and C. I. Sheaffer, for their many hours and diagnostic expertise; and the children and their families for their cheerful participation. This long-standing program of research reflects the leadership and enthusiasm of Floyd W. Denny, Jr. and Wallace A. Clyde, Jr. during the past 25 yr.

References 1. Kattan M, Keens TG, Lapierre J, Levison H, Bryan AC, Reilly BJ. Pulmonary function abnormalities in symptom-free children after bronchiolitis. Pediatrics 1977; 59:683-8. 2. Sims DG, Downham MAPS, Gardner PS, Webb JKG, Weightman D. Study of 8-year-old children with a history of respiratory syncytial virus bronchiolitis in infancy. Br Med J 1978; 1:11-4. 3. Mok JYQ, Simpson H. Outcome for acute bronchitis, bronchiolitis, and pneumonia in infancy. Arch Dis Child 1984; 59:306-9. 4. Pullan CR, Hey EN. Wheezing, asthma, and pulmonary dysfunction 10years after infection with respiratory syncytial virus in infancy. Br Med J 1982; 284:1665-9. 5. Hall CB, Hall WJ, Gala CL, MaGill FB, Leddy JP. Long-term prospective study in children after respiratory syncytial virus infection. J Pediatr 1984; 105:358-64. 6. Gurwitz D, Mindorif C, Levinson H. Increased incidence of bronchial reactivity in children with a history of bronchiolitis. J Pediatr 1981; 98:551-5. 7. Gurwitz D, Corey M, Levison H. Pulmonary function and bronchial reactivity in children after croup. Am Rev Respir Dis 1980; 122:95-9. 8. Denny FW, Clyde WA Jr. Acute lower respiratory tract infections in non hospitalized children. J Pediatr 1986; 108:635-46. 9. McConnochie KM, Hall CB, Barker WHo Lower respiratory tract illness in the first two years of life; epidemiologic patterns and costs in a suburban pediatric practice. Am J Public Health 1988; 78:34-9. 10. Wright AL, Taussig LM, Ray CG, Harrison HR, Holberg CJ. The Tucson children's respiratory study. II. Lower respiratory tract illness in the first year of life.Am J Epidemiol1989; 129:1232-46. 11. Voter KZ, Henry MM, Stewart PW, Henderson FW. Lower respiratory illness in early childhood and lung function and bronchial reactivity in adolescent males. Am Rev Respir Dis 1988; 137:302-7. 12. Henderson FW, Clyde WA, Collier AM, Denny FW. The etiologic and epidemiologic spectrum of bronchiolitis in pediatric practice. J Pediatr 1979; 95:183-90. 13. Chapman RS, Henderson FW, Clyde WA Jr, Collier AM, Denny FW. The epidemiology of tracheobronchitis in pediatric practice. Am J Epidemiol 1981; 114:786-97. 14. Murphy TF, Henderson FW, Clyde WA Jr, Collier AM, Denny FW. Pneumonia; an elevenyear study in a pediatric practice. Am J Epidemiol1981; 113:12-20. 15. Denny FW, Murphy TF, Clyde WA Jr, Collier AM, Henderson FW. Croup: an ll-year study in a pediatric practice. Pediatrics 1983; 71:871-6. 16. Ferris BG. Epidemiologic standardization project. Am Rev Respir Dis 1978; 118(Part 2):7-53. 17. American Thoracic Society. Snowbird workshop on standardization of spirometry. Am Rev Respir Dis 1979; 119:831-8. 18. American Thoracic Society. Standardization of spirometry: 1987 update. Am Rev Respir Dis 1987; 136:1285-307.

662 19. Collier AM, Pimmel RL, Hasselblad V,Clyde WA Jr, Knelson lH, Brooks lG. Spirometric changes in normal children with upper respiratory infections. Am Rev Respir Dis 1978; 117:47-53. 20. Klienbaum DG, Kupper LL, Muller KE. Applied regression analysis and other multivariable methods. 2nd ed. North Scituate, MA: Duxbury Press, 1988. 21. Silverman BW. Density estimation for statistics and data analysis. London: Chapman and Hall Ltd., 1986. 22. McConnochie KM, Mark lD, McBride rr, Hall W1, Brooks JG. Normal pulmonary function measurements and airway reactivity in childhood after mild bronchiolitis. J Pediatr 1985; 107:54-8. 23. Mead J. Dysanapsis in normal lungs assessed by the relationship between maximal flow, static

STROPE, STEWART, HENDERSON, IVINS, STEDMAN, AND HENRY

recoil, and vital capacity. Am Rev Respir Dis 1980; 121:339-42. 24. Tager IB, WeissST,Munoz A, WeltyC, Speizer FE. Determinants ofresponse to eucapneic hyperventilation with cold air in a population-based study. Am Rev Respir Dis 1986; 134:502-8. 25. Martinez FD, Morgan wr, Wright AL, Holberg Cl, Taussig LM. Diminished lung function as a predisposing factor for wheezing respiratory illness in infants. N Engl 1 Med 1988; 319:1112-7. 26. Gold DR, Tager lB, Weiss ST, Tosteson TO, Speizer FE. Acute lower respiratory illness in childhood as a predictor of lung function and chronic respiratory symptoms. Am Rev Respir Dis 1989; 140:877-84. 27. Leeder SR, Woolcock Al, Blackburn CRB. Prevalence and natural history of lung disease in

New South Wales schoolchildren. Int J Epidemiol 1974; 3:15-23. 28. Leeder SR, Corkhill RT, Wysocki MJ, Holland WW, Colley lRT. Influence of personal and family factors on ventilatory function of children. Br J Prevent Soc Med 1976; 30:219-24. 29. Woolcock AJ, Leeder ST, Peat JK, Blackburn CRB. The influence of lower respiratory illness in infancy and childhood and subsequent cigarette smoking on lung function in Sydney schoolchildren. Am Rev Respir Dis 1979; 120:5-14. 30. Yarnell lWG, St. Leger AS. Respiratory infectionsand their influence on lung function in children: a multiple regression analysis. Thorax 1981; 36:847-51.