Association of Radiologically Ascertained Pneumonia Before Age 3 yr with Asthmalike Symptoms and Pulmonary Function During Childhood
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Association of Radiologically Ascertained Pneumonia
Before Age 3 yr with Asthmalike Symptoms and
Pulmonary Function During Childhood
A Prospective Study
JOSÉ A. CASTRO-RODRÍGUEZ, CATHARINE J. HOLBERG, ANNE L. WRIGHT, MARILYN HALONEN,
LYNN M. TAUSSIG, WAYNE J. MORGAN, and FERNANDO D. MARTINEZ
Respiratory Sciences Center, The University of Arizona, College of Medicine, Tucson, Arizona
Epidemiologic evidence suggests an association between reports of pneumonia in early life and the
subsequent development of diminished lung function. However, no studies are available in which the
diagnosis of pneumonia was based on radiologic evidence. Lower respiratory illnesses with or with-
out a radiologically confirmed diagnosis of pneumonia were assessed in a study of 888 children en-
rolled at birth. Pulmonary function tests, markers of atopy, asthma diagnosis, and prevalence of respi-
ratory symptoms were assessed at different ages between birth and 11 yr. Incidence of pneumonia
during the first 3 yr of life was 7.4%. Respiratory syncytial virus was the most frequent agent identi-
fied both in children with pneumonia and in those with lower respiratory tract illness (LRI) without
pneumonia (36.4% versus 35.6%, respectively). Children with a diagnosis of pneumonia were more
likely to have physician-diagnosed asthma and current wheezing at ages 6 and 11 yr than were those
who had no LRIs. When compared with children without LRIs, those with a diagnosis of pneumonia
had lower levels of maximal flows at FRC at mean age of 2 mo (albeit not significantly) and at age 6 yr,
and lower levels of FEV1 and FEF25–75 at age 11 yr. These deficits were independent of known con-
founders, including wheezing at the time of study, and were partly and significantly reversed after
administration of a bronchodilator. We conclude that children with radiologically confirmed pneu-
monia have diminished airway function that is probably present shortly after birth. These deficits are
at least in part due to alterations in the regulation of airway muscle tone. Castro-Rodríguez JA, Hol-
berg CJ, Wright AL, Halonen M, Taussig LM, Morgan WJ, Martinez FD. Association of radio-
logically ascertained pneumonia before age 3 yr with asthmalike symptoms and pulmonary
function during childhood: a prospective study. AM J RESPIR CRIT CARE MED 1999;159:1891–1897.
The association between pneumonia in early life and the sub- tract illness (LRI) in early life and subsequently diminished
sequent development of chronic respiratory symptoms and lung function. We have reported that children with LRIs caus-
decreased levels of lung function has been a matter of consid- ing wheezing during the first year of life had significantly
erable attention (1–5). Results of several retrospective studies lower levels of lung function before any LRI occurred (9).
suggest that both infants (2, 3, 5) and young children (1, 4) Others have reported similar results (10). No attempt has
who are diagnosed as having pneumonia subsequently show been made to determine whether episodes of illness associ-
lower levels of several measures of maximal expiratory flow. ated with the diagnosis of pneumonia were also associated
A possible explanation for these findings is that severe respi- with lower premorbid lower levels of lung function.
ratory infections that occur at the time of rapid lung develop- Most epidemiologic studies of the association of pneumo-
ment may impair lung growth (1). This could then lead to in- nia in early life with subsequent respiratory function and mor-
creased risk for the development of chronic obstructive lung bidity have been based either on parental questionnaires ad-
disease later in life (6–8). ministered years after the episode of pneumonia occurred (1)
Explanations other than injury caused by respiratory infec- or on reports by home health visitors who obtained the rele-
tion are possible for the association between lower respiratory vant data from the parents at different times during the sub-
jects’ early lives (2–4). In none of these studies was the diagno-
sis of pneumonia based on radiologic evidence, despite the
(Received in original form November 10, 1998 and in revised form February 1, 1999)
frequent difficulty in distinguishing pneumonia clinically from
Supported by grants HL 14136, HL 56177, and HL 03154 from the National Heart,
Lung, and Blood Institute.
other LRIs occurring early in life (11–13). In these circum-
stances, a diagnosis of pneumonia that is not based on radio-
Correspondence and requests for reprints should be addressed to Fernando D.
Martinez, M.D., 1501 N. Campbell Avenue, Suite 2349, P.O. Box 245030, Tuc-
logic ascertainment may not be reliable, because signs and
son, AZ 85724. symptoms usually associated with pneumonia may overlap
Am J Respir Crit Care Med Vol 159. pp 1891–1897, 1999 those present in subjects who have other forms of LRI in
Internet address: www.atsjournals.org this age group. Only a few hospital-based follow-up studies,1892 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 159 1999
involving small numbers of children with LRI, are available, sis of asthma and one or more asthma episodes in the previous year.
but in none of these was pneumonia studied separately from Parents were also asked whether the child’s chest had sounded
other LRIs (14–17). wheezy or whistling during the past year, and how often this had oc-
In the present study we assessed respiratory symptoms, curred. Children were considered to have “current infrequent wheez-
ing” if they had had from one to three episodes of wheezing during
asthma diagnosis, and lung function at ages 6 and 11 yr in chil-
the previous year. Children were considered to have “current fre-
dren with and without a radiologic diagnosis of pneumonia as quent wheezing” if they had had more than three episodes of wheez-
ascertained directly by a physician during the first 3 yr of life. ing during the previous year.
Infant pulmonary function tests were also performed before
the development of any LRI in a subgroup of these children. Markers of Atopy
Skin prick tests were performed with extracts of allergens common in
METHODS the Tucson area. At age 6 yr, subjects were tested with house dust,
The children included in the study were part of a birth cohort of 1,246 Bermuda grass, olive, careless weed, Alternaria alternata, mesquite,
children enrolled from 1980 to 1984 in the Tucson Children’s Respira- and mulberry, and at age 11 yr Dermatophagoides farinae and cat dan-
tory Study, a large longitudinal study of respiratory illnesses in chil- der were added (allergens provided by Hollister-Stier Laboratories,
dren (18). Detailed information about the enrollment process and Everett, WA). Two perpendicular diameters of all wheals were mea-
study design have been published elsewhere (18, 19). Birth weight, sured at 20 min. Skin test-positive subjects were defined as those who
level of maternal education, maternal smoking, and data on family had at least one positive reaction (wheal size measuring 3 mm or more
history of asthma and allergies were obtained from questionnaires ad- after substraction of the control value).
ministered to parents shortly after their child’s birth. Blood for serum IgE analysis was obtained from subjects at a me-
The study was approved by the Human subjects Committee of The dian age of 9.3 mo (the “9 mo” sample), and again at ages 6 and 11 yr.
University of Arizona, and informed consent was obtained from the Total serum IgE levels were measured with a paper radioimmunosor-
subjects’ parents. bent test (Pharmacia, Diagnostics, Piscataway, NJ). All samples were
LRIs were diagnosed by the subjects’ pediatricians at the time of assayed in duplicate, and results were expressed as international units
the subjects’ acute illness during the first 3 yr of life (19). Parents were per milliliter.
requested to take their children to their pediatricians whenever the
Pulmonary Function Tests
children had any of the following symptoms: deep or “wet” chest
cough, wheezing, hoarseness, stridor, barking cough, or shortness of Pulmonary function testing was done on 176 children during the first
breath. The pediatricians obtained a detailed history at the time of year of life. A detailed description of the selection criteria and the
such illnesses, and recorded all relevant signs and symptoms (includ- medical and demographic characteristics of these infants, as compared
ing wheezing on auscultation) on a study form. with those who were not tested, has been reported (9); prevalence of a
Of the original 1,246 children enrolled in the study, 888 were fol- family history of asthma or allergies did not differ significantly for the
lowed for LRIs by the original study pediatricians for the entire first infants who underwent pulmonary function testing and those who
3 yr of life. A comparison between children followed for LRIs and were not tested. Partial expiratory flow–volume curves were obtained
those who dropped out of follow-up has been reported elsewhere by the chest compression technique (20, 21). Of the 176 children ini-
(20). Briefly, children not followed were of lower socioeconomic sta- tially tested, 133 were tested before any LRI occurred and were in-
tus and had mothers with a higher prevalence of maternal smoking cluded in the study. The subjects’ age (mean 6 SD) at the time of test-
(20). ing was 2.4 6 2.0 mo.
Children were classified as having had pneumonia if the pediatri- Partial expiratory flow–volume curves were also obtained at the
cian specified this diagnosis on the study form and if there was radio- time of the 6-yr survey (age: 6.4 yr 6 0.5 yr [mean 6 SD]). Voluntary
graphic evidence compatible with this diagnosis. Radiographic criteria maneuvers were used as described originally by Taussig (22). Maximal
·
considered compatible with the diagnosis of pneumonia were the expiratory flow at FRC ( VmaxFRC) was calculated as described pre-
presence of infiltrates and/or a radiologist’s diagnosis of bronchopneu- viously (20) both for tests performed during the first year of life and
monia or pneumonitis. Chest radiograms were not required in the for those obtained at age 6 yr.
study, and were ordered for clinical reasons only. Children who had At the time of the 11-yr survey (age 10.8 yr 6 0.5 yr), FVC, FEV1,
more than one LRI during the first 3 yr of life and had a diagnosis of and FEF25–75 were measured with standard spirometry. Baseline
pneumonia and radiologic evidence of pneumonia for one or more of values were first obtained, and the best curve was chosen according
these LRIs were included in the pneumonia group. Children with a to predefined criteria (23, 24). Subsequently, two puffs of albuterol
diagnosis of pneumonia but without radiologic evidence compatible (180 mg) were administered with a metered dose inhaler having an
with this diagnosis were included in a separate group (LRI/no pneu- Aerochamber spacing device (Monaghan Medical, Plattsburgh, NY).
monia). Children who had other LRIs but did not have either a diag- Postbronchodilator values were obtained 15 min after the albuterol
nosis of pneumonia or radiologic evidence of pneumonia were also in- inhalation.
cluded in the LRI/no pneumonia group. Only the first episode of
pneumonia or the first LRI (in the case of the LRI/no pneumonia Statistical Analysis
group) was used to describe LRI characteristics in this study. Total serum IgE values were log-normally distributed, and results were
At the time of a subject’s LRI, the study nurses who worked in the expressed as geometric mean and 95% confidence intervals (CIs).
pediatrician’s office obtained additional historical information and ·
Values for VmaxFRC were logarithmically transformed and ad-
nasopharyngeal swabs for isolation of pathogenic agents, including justed for length or height; results were standardized to the children’s
respiratory viruses (respiratory syncytial virus [RSV], parainfluenza average length (57.4 cm) before the age of 1 yr or to their average
virus, adenovirus, influenza virus, and others), mycoplasma, and chla- height (110.3 cm) at the age of 6 yr. Values for FVC, FEV1, and
mydia. Culture and immunofluorescence techniques used to identify FEF25–75 obtained at age 11 yr were also logarithmically transformed
pathogenic agents have been described in detail elsewhere (19). Not and adjusted for height. Results were standardized to the children’s
all children who developed LRIs had microbiologic tests, owing to average height (143.2 cm for boys and 144.9 cm for girls) at the age of
lack of nurse or laboratory availability at the time of the LRI. ·
11 yr. Results of transformed and adjusted VmaxFRC, FVC, FEV1,
and FEF25–75 were expressed as geometric means and 95% CIs.
Asthma and Wheezing Data Analysis of variance (ANOVA) and Duncan’s multiple-compari-
Questionnaires were completed when the subjects were aged 6 and 11 son test were used to compare means, and the chi-square test was used
yr (mean 6 SD: 6.3 6 0.9 yr and 10.9 6 0.6 yr, respectively). Parents to compare proportions (25). The 95% CIs for odds ratios (ORs) were
were asked whether they had ever been told by a doctor that their calculated with standard algorithms (26). Multiple regression models
child had asthma (“MD asthma”) and how many asthma attacks or were used to determine whether pneumonia and LRI/no pneumonia
episodes of asthma the child had had during the previous year. A child remained associated with the dependent variables (pulmonary func-
was considered to have “current MD asthma” if he/she had a diagno- tion test [PFT] parameters at ages 6 and 11 yr) after controlling forCastro-Rodríguez, Holberg, Wright, et al.: Pneumonia, Pulmomary Function, and Asthma 1893
gender, current wheezing at age 6 yr, maternal prenatal smoking, ma- TABLE 2
ternal education, and parental ethnicity; for lung function at age 11 yr, AGENTS IDENTIFIED (IN PERCENTAGES) FOR THE FIRST EPISODE
current wheezing at age 11 yr was also considered. Results of the mul- OF PNEUMONIA (PNEUMONIA GROUP) AND FOR THE FIRST
tiple regression analysis were expressed as differences between the no LOWER RESPIRATORY ILLNESS (LRI/NO PNEUMONIA
LRI group (assigned a value of zero) and the two LRI groups. Statisti- GROUP) DURING THE FIRST 3 yr OF LIFE*
cal significance was defined by a two-sided a level of 0.05.
Group RSV Parainfluenza Others Negative Total
RESULTS Pneumonia (n 5 55) †
36.4 7.3 12.7 43.6 100.0
LRI/no pneumonia (n 5 343) 35.6 15.2 11.7 37.6 100.0
Of the 888 eligible children who were followed for LRIs dur-
ing the first 3 yr of life, 613 (69.0%) had at least one PFT mea- Definition of abbreviations: LRI 5 lower respiratory illness; NS 5 not significant; RSV 5
respiratory syncytial virus.
surement. There were no significant differences between these * Not all children who developed LRIs had microbiologic test performed, due to lack
613 children with PFTs and 275 children without PFTs with re- of nurse or laboratory availability at the time of the LRI.
spect to prevalence of asthma or wheezing at age 6 or 11 yr †
p 5 0.64 (NS), when compared with LRI/no pneumonia for each identified agent.
(Table 1). However, the children with PFTs belonged to fami-
lies of a significantly higher socioeconomic status and with a
lower prevalence of maternal smoking (Table 1). Of the 888 pneumonia (51.1% males). The subjects’ ages (mean 6 SD) at
eligible children, 66 (7.4%) had pneumonia, 397 (44.7%) had the first episode of pneumonia (pneumonia group) and at the
LRI/no pneumonia, and 425 (47.9%) had no LRI. As with the first LRI (LRI/no pneumonia group) were 1.00 6 0.73 yr and
prevalence of asthma or wheezing, the cumulative incidence 1.00 6 0.74 yr, respectively. Reports of wheezing (by history
of pneumonia and of LRI/no pneumonia was also similar in or physical examination) during the first episode of pneumo-
children with and without PFT measurements (Table 1). Among nia or during the first LRI were very similar in the two groups
children with LRI/no pneumonia, a chest radiogram that (65.4% versus 69.8%, respectively). A report of tachypnea
showed no evidence of pneumonia (as described in METHODS) during the first LRI was significantly more prevalent in the
was obtained from 37 children. We found no differences in pneumonia group than in the LRI/no pneumonia group
any of the parameters studied between this group and children (62.0% versus 34.9%, respectively; OR: 3.0; 95% CI: 1.7 to 5.6;
classified as having LRI/no pneumonia but for whom no chest p , 0.001). Among 66 children with pneumonia, 42 had radio-
film was requested by the pediatrician. For this reason, these logic evidence of infiltrates, 22 had bronchopneumonia, and
two groups of subjects were combined in the LRI/no pneumo- two had pneumonitis. The proportion of children from whom
nia category. RSV, parainfluenza, or other agents were isolated for the first
Similar proportions of male and female children were found episode of pneumonia (pneumonia group) or for the first LRI
among subjects with pneumonia (54.5% males) and with LRI/no (LRI/no pneumonia group) was not significantly different for
the two groups (Table 2).
Among 66 children with pneumonia, 22 had only one epi-
TABLE 1 sode of LRI, 43 had two episodes (one of which was diagnosed
CHARACTERISTICS OF SUBJECTS WITH AND WITHOUT ANY as pneumonia and the other as either pneumonia [n 5 1] or
PULMONARY FUNCTION TEST AT AGE , 1, 6, OR 11 yr other LRI/no pneumonia [n 5 42]). One subject had three ep-
isodes of LRI (two diagnosed as pneumonia and the other as
Subjects with Subjects without
PFT PFT LRI/no pneumonia). Only two children with pneumonia re-
(n 5 613 ) (n 5 275 ) quired hospitalization.
Associated demographic, clinical, and Current MD Asthma and Current Wheezing
immune characteristic* at Ages 6 and 11 yr
Male sex 49.3 49.5
Current MD asthma at age 6 yr 8.0 7.0 Current MD asthma was significantly more likely at ages 6 and
Current MD asthma at age 11 yr 14.7 13.0 11 yr among children who had pneumonia or LRI/no pneumo-
Frequent wheezing at age 6 yr 7.9 9.3 nia in early life than in children with no LRI (Table 3). Cur-
Frequent wheezing at age 11 yr 10.4 10.3 rent infrequent wheezing (from one to three episodes during
Skin test reactivity at age 6 yr 41.1 34.8
the previous year) and current frequent wheezing (more than
Skin test reactivity at age 11 yr 63.6 50.5†
IgE at 9 mo, mean 6 SE 3.9 6 1.1 4.0 6 1.1
IgE at age 6 yr, mean 6 SE 35.7 6 1.1 26.6 6 1.3
IgE at age 11 yr, mean 6 SE 63.4 6 1.1 42.9 6 1.3 TABLE 3
Any parent with MD asthma 24.3 20.9
PREVALENCE (IN PERCENTAGE) OF CURRENT MD ASTHMA
Hispanic ethnicity mother 20.8 19.6
AT AGE 6 AND 11 yr BY PNEUMONIA AND LRI/NO
High maternal education, . 12 yr 74.4 63.5‡
PNEUMONIA DURING THE FIRST 3 yr OF LIFE
Maternal prenatal smoking 17.0 24.2§
Maternal smoking at age 1 yr 22.0 30.4§ At 6 yr At 11 yr
Proportion (%) of subjects in the three
study groups % OR % OR
Pneumonia 6.9 8.7 Group (n) (95% CI) (n) (95% CI)
LRI/no pneumonia 45.4 43.3
Pneumonia 13.6* 3.3 25.9* 2.8
No LRI 47.8 48.0
(59) (1.4–7.8) (54) (1.4–5.6)
Total 100.0 100.0
LRI/no pneumonia 10.2* 2.4 16.1† 1.6
Definition of abbreviations: LRI 5 lower respiratory illness; MD 5 physician; PFT 5 pul- (371) (1.3–4.2) (347) (1.0–2.4)
monary function test. No LRI 4.6 1 11.0 1
* All characteristics are expressed in percentage except for total serum IgE levels. In (394) (373)
some cases percentages were calculated from slightly smaller numbers of children be-
cause of missing values for some subjects. Definition of abbreviations: CI 5 confidence interval; LRI 5 lower respiratory illness;
†
p , 0.05. OR 5 odds ratio.
‡
p , 0.001. * p , 0.01.
§
p < 0.01 for subjects with PFT versus subjects without PFT. †
p , 0.05 for the comparison with no LRI.1894 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 159 1999
TABLE 4
ODDS RATIOS FOR CURRENT INFREQUENT (THREE OR FEWER EPISODES IN THE PREVIOUS YEAR)
AND CURRENT FREQUENT WHEEZING (MORE THAN THREE EPISODES IN THE PREVIOUS YEAR) AT
AGES 6 AND 11 yr BY PNEUMONIA AND LRI/NO PNEUMONIA DURING THE FIRST 3 yr OF LIFE
Infrequent Frequent
At 6 yr At 11 yr At 6 yr At 11 yr
Group n OR (95% CI) n OR (95% CI) n OR (95% CI) n OR (95% CI)
Pneumonia 59 3.2* (1.7–6.1) 54 1.6 (0.8–3.3) 59 3.9* (1.7–8.9) 54 2.3‡ (1.0–5.2)
LRI/no pneumonia 368 1.9* (1.3–2.8) 345 1.3 (0.9–1.9) 368 2.0† (1.1–3.4) 345 1.4 (0.9–2.3)
No LRI 393 1 373 1 393 1 373 1
Definition of abbreviations: CI 5 confidence interval; LRI 5 lower respiratory illness; OR 5 odds ratio.
* p < 0.001.
†
p < 0.01.
‡
p , 0.05 for the comparison with No LRI. All comparisons made with the no-wheezing group at each age.
three episodes during the previous year) at age 6 yr were also found between the different LRI groups and any individual al-
more likely in the two LRI groups than in the reference group lergen assessed at age 6 and 11 yr (data not shown). The geo-
(Table 4). Conversely, children with either pneumonia or metric mean (95%CI) for total serum IgE levels at 9 mo was
LRI/no pneumonia in early life were not at increased risk for 4.2 IU/ml (3.1 to 5.7) for the pneumonia, 3.8 IU/ml (3.3 to 4.4)
having infrequent wheezing at age 11 yr, although those with for the LRI/ no pneumonia, and 4.1 IU/ml (3.5 to 4.7) for the
pneumonia were significantly more likely to have frequent reference group (p 5 0.74). Likewise, there was no significant
wheezing at age 11 yr than was the reference group (Table 4). difference in total serum IgE levels among groups either at
age 6 yr (p 5 0.57) or at age 11 yr (p 5 0.55).
Markers of Atopy
There was no significant difference in prevalence of at least
one positive skin test at age 6 yr among the study groups PFTs
·
(34.7%, 40.1%, and 41.7% for the pneumonia, LRI/no pneu- Length-adjusted mean VmaxFRC values before any LRI (at
monia, and reference groups, respectively; p 5 0.65). Simi- age , 1 yr) were lower in children with pneumonia and with
larly, prevalence of at least one positive skin test at age 11 yr LRI/no pneumonia than in children with no LRI, although
did not differ among the groups (53.3%, 60.8%, and 63.7%, these results only reached statistical significance for the LRI/
respectively; p 5 0.38). Also, no significant association was no pneumonia group (Table 5). Significantly lower mean height-
TABLE 5
PULMONARY FUNCTION TESTS (GEOMETRIC MEAN AND 95% CONFIDENCE INTERVAL [CI])
AT AGES , 1, 6, AND 11 yr ACCORDING TO PNEUMONIA AND LRI/NO PNEUMONIA
DURING THE FIRST 3 yr OF LIFE, UNADJUSTED FOR OTHER FACTORS
Pulmonary Function Test Pneumonia LRI/No Pneumonia No LRI
At age , 1 yr (before any LRI)
Number of subjects 8 61 64
·
V maxFRC, ml/s* 109.1 91.8‡ 128.4
95% CI (69.3–171.7) (78.3–107.4) (115.2–143.0)
At age 6 yr
Number of subjects 40 241 247
·
V maxFRC, L/s† 1.09‡ 1.12‡ 1.27
95% CI (0.99–1.19) (1.08–1.16) (1.22–1.31)
At age 11 yr
Number of subjects 30 216 213
Before albuterol
FVC, L 2.59 2.53 2.58
95% CI (2.48–2.70) (2.49–2.56) (2.54–2.62)
FEV1, L* 2.10§ 2.14‡ 2.21
95% CI (2.00–2.19) (2.11–2.17) (2.18–2.25)
FEF25–75, L/s† 1.81‡i 2.12‡ 2.29
95% CI (1.63–2.01) (2.05–2.19) (2.20–2.38)
After albuterol
FVC, L 2.71 2.64 2.67
95% CI (2.62–2.80) (2.61–2.68) (2.63–2.71)
FEV1, L 2.29 2.26 2.30
95% CI (2.21–2.37) (2.23–2.29) (2.27–2.33)
FEF25–75, L/s 2.52 2.58 2.70
95% CI (2.31–2.73) (2.51–2.66) (2.62–2.78)
·
Definition of abbreviations: LRI 5 lower respiratory illness; V maxFRC 5 maximal expiratory flow at functional residual capacity.
* p , 0.01 for analysis of variance overall.
†
p , 0.00001 for analysis of variance overall.
Duncan’s multiple comparison: ‡ p , 0.01, § p , 0.05 as compared with no LRI; i p , 0.01 as compared with LRI/no pneumonia.Castro-Rodríguez, Holberg, Wright, et al.: Pneumonia, Pulmomary Function, and Asthma 1895
·
adjusted VmaxFRC values at age 6 yr were observed both in DISCUSSION
children in the pneumonia group and in those in the LRI/no
To our knowledge, this is the first study in which sequelae in
pneumonia group than in children in the no LRI group (Ta-
later childhood of radiologically confirmed pneumonia in the
ble 5). At age 11 yr, mean unadjusted values for FEV1 and
first 3 yr of life were assessed in a large population sample of
FEF25–75 before albuterol were significantly lower in children
children enrolled at birth. The great majority of these children
who had pneumonia and in children who had LRI/no pneu-
were seen by their pediatricians as outpatients, and did not re-
monia than in children who had no LRI. Children in the pneu-
quire hospitalization.
monia group also had a significantly lower mean FEF25–75
The cumulative incidence of pneumonia during the first 3 yr
value before albuterol than children in the LRI/no pneumonia
of life in this study (7.4%) was similar to that described by
group. Unadjusted mean values for FVC before albuterol
Murphy and associates (27) for a general pediatric practice in
were not significantly different among groups. After use of al-
North Carolina. The etiologic agents for episodes of pneumo-
buterol, mean unadjusted values for FVC, FEV1, and FEF25–75
nia were very similar to those of other LRIs without a diagno-
were not significantly different among groups (Table 5).
sis of pneumonia. Almost 60% of all such episodes were linked
Differences in lung function between groups at age 6 and at
to viral isolates, and the main agent detected was RSV, which
age 11 yr remained substantially unchanged after adjusting for
accounted for almost one-half of all isolated agents. This find-
possible confounders (Table 6). Although both children with a
ing is in agreement with several other epidemiologic studies in
history of pneumonia and those with a history ·
of LRI/no
which the etiologic agent associated with pneumonia was as-
pneumonia had significant deficits in baseline VmaxFRC at
sessed during the first 3 yr of life (28, 29).
age 6 yr and in baseline FEV1 and FEV25–75 at age 11 yr, these
The association between pneumonia in early life and the
deficits were considerably larger for subjects with a history of
subsequent development of asthma has not been extensively
pneumonia. However, after administration of albuterol, the
explored. The main findings of this study indicated that chil-
deficits observed for both groups at age 11 yr were markedly
dren with a diagnosis of pneumonia during the first 3 yr of life
reduced, and this was especially true for the group with a his-
were three times more likely to have current physician-diag-
tory of pneumonia. As a consequence, no significant deficits in
nosed asthma at ages 6 and 11 yr than were children who had
postbronchodilator lung function were observed for either
no LRIs during the same period. Similarly, children with a di-
children with a history of pneumonia or for those with a his-
agnosis of pneumonia were almost four times as likely to have
tory of LRI/no pneumonia.
frequent wheezing at age 6 yr and twice as likely to have fre-
None of the associations between type of LRI and the differ-
quent wheezing at age 11 yr than were children who had no
ent outcomes described here showed significant heterogeneity
LRIs during the first 3 yr of life. Conversely, children with a
after stratifying by the etiology of the LRI (data not shown).
history of LRI/no pneumonia during the first 3 yr of life were
twice as likely to have current asthma and frequent wheezing
TABLE 6 at age 6 yr but were only marginally more likely to have cur-
rent asthma (OR 5 1.6) and frequent wheezing (OR 5 1.4) at
ADJUSTED DIFFERENCES (GEOMETRIC MEAN AND 95%
CONFIDENCE INTERVAL) IN PULMONARY FUNCTION age 11 yr than were children who had no LRIs during the first
TESTS AT AGES 6 AND 11 yr BETWEEN PNEUMONIA 3 yr of life. More than 65% of all children who had pneumonia
AND LRI/NO PNEUMONIA GROUPS DURING were also found to have wheezing at the time of their first epi-
THE FIRST 3 yr OF LIFE AND NO LRI* sode of pneumonia, and the great majority of these episodes
Pulmonary Function Test Pneumonia LRI/No Pneumonia
were due to RSV. These results suggest that the factors that
determine the association between pneumonia early in life
At age 6 yr and asthma later in life are similar to those that determine the
Number of subjects 40 241
·
2165.9† 2119.8¶
association between bronchiolitis early in life and asthma later
V maxFRC, ml/s
(2267.5 to 239.3) (2178.3 to 258.1) in life. It is thus plausible to speculate that the same disease
At age 11 yr mechanisms that determine LRIs in children with pneumonia
Number of subjects 30 216 are also present in those who develop LRI/no pneumonia. As
Before albuterol in other studies (30–33), the diagnosis of pneumonia in this
FVC, ml 124.4 249.3‡ cohort was related to the degree of tachypnea, considered an
(274.3 to 1127.3) (297.6 to 20.0)
FEV1, ml 296.7‡ 268.8†
index of severity of LRI. Children who develop roentgeno-
(2182.9 to 26.8) (2112.8 to 223.7) graphic evidence of pneumonia during LRIs early in life may
FEF25–75, ml/s 2381.0§i 2142.6† be at the extreme of severity within the same basic mechanism
(2538.9 to 2206.5) (2235.1 to 245.4) of disease that causes most LRIs in this age group.
After albuterol We have previously shown (9) that a major determinant of
FVC, ml 242.0 234.3 LRIs in early life is the level of lung function prior to the
(270.9 to 1159.6) (289.7 to 122.3)
FEV1, ml 20.6 242.4
occurrence of LRI. Children with a history of pneumonia
(291.3 to 193.7) (287.3 to 12.0) might then be expected to have had lower levels of lung func-
FEF25–75, ml/s 2138.4 293.3 tion before any pneumonia occurred, if the hypothesis is
(2321.6 to 160.6) (2188.4 to 15.7) correct that pneumonia early in life represents a more severe
Definition of abbreviation: LRI 5 lower respiratory illness.
form of LRI. Unfortunately, only eight such children had their
* The no LRI group was assigned a value of 0. There were 247 subjects in the No LRI lung function measured during the first months of life in our
group who were tested at age 6 yr and 213 at age 11 yr. study.
·
These children tended to have lower mean levels of
†
p , 0.01 compared with no LRI. VmaxFRC, an index derived from partial flow–volume curves
‡
p , 0.05 compared with no LRI.
§
p < 0.0001 compared with no LRI. obtained through the chest rapid compression technique (21).
¶
p , 0.001 compared with no LRI. The levels of lung function in these eight children were similar
i
p , 0.01 compared with LRI/no pneumonia. to those observed in children who subsequently developed
Results were adjusted for gender, any wheezing at age 6 yr, maternal prenatal smok-
ing, maternal education, and mother ethnicity and father ethnicity; for lung function at LRI/no pneumonia, but difference did not reach statistical sig-
age 11 yr, any wheezing at age 11 yr was also considered. nificance when compared with lung function in the no LRI1896 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 159 1999
group, probably because of the small number of subjects significant extent, due to alterations in the regulation of air-
involved. When PFTs were done later in childhood in the way tone. The observed deficits (particularly for FEF25–75),
same group of children with a history of pneumonia during the were, however, not completely reversed by bronchodilator ad-
first
·
3 yr of life, significant reductions were observed for ministration (see Tables 5 and 6). In addition, we have no in-
VmaxFRC at age 6 yr and for both FEV1 and FEF25–75 at age formation about reversibility of lung function deficits ob-
11 yr. These reductions were particularly noticeable for served shortly after birth. Therefore, we cannot exclude the
FEF25–75 at age 11 yr, with children who had a history of pneu- possibility that both anomalies in the regulation of airway
monia having significantly lower levels for this index than tone and structural alterations of the lungs and airways may
those observed for children with a history of LRI/no pneumo- be present in subjects who will subsequently develop more se-
nia during the first 3 yr of life (Table 5). Interestingly, no sig- vere respiratory tract illnesses.
nificant differences between groups in either FEV1, or FEF25–75 In summary, our results suggest that pneumonia during the
were observed after administration of a bronchodilator (al- first 3 yr of life is part of a continuum of severity of viral LRIs
buterol). These results were independent of known confound- in this age group. These pneumonias are associated with a sig-
ers including wheezing at both ages 6 and 11 yr. nificant risk of subsequent persistent wheezing and with sig-
There are two possible explanations for these findings. It is nificant deficits in lung function. These deficits can already be
plausible that the lower levels of lung function observed both detected during the first months of life, before the develop-
in children with pneumonia and those with LRI/no pneumo- ment of any LRI. Elucidating the factors that determine di-
nia at ages 6 and 11 yr were the consequence of premorbid al- minished lung function early in life may be crucial to any strat-
terations in airway structure or in airway smooth-muscle tone. egy for preventing pneumonia and other LRIs in infancy and
This explanation is supported by the evidence of diminished early childhood.
lung function present before any LRI occurred both in chil-
Acknowledgment : The authors are indebted to the members of Group
dren with a subsequent history of pneumonia and in those Health Medical Associates: John Bean, M.D., Henry Bianchi, M.D., John Cur-
with a history of LRI/no pneumonia. That children
·
with a his- tiss, M.D., John Ey, M.D., Alejandro Sanguineti, M.D., Barbara Smith, M.D.,
tory of pneumonia had larger deficits in V maxFRC and in Terry Vondrak, M.D., Neil West, M.D., and Maureen McLellan, R.N., P.N.P.;
FEF25–75 at ages 6 and 11 yr, respectively, than those observed to Marilyn Smith, R.N., and Lydia De La Ossa, R.N., the study nurses; and
to Royce Robbins, M.S., and Bruce Saul, M.S., for technical assistance.
among children with a history of LRI/no pneumonia may offer
clues about why the diagnosis of pneumonia was ·
applied to
one group and not to the other. Since both VmaxFRC and References
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