EPA-600/1-77-044
September 1977
Environmental Health Effects Research Series
LUNG FUNCTION AND ITS GROWTH
Health Effects Research Laboratory
Office of Research and Development
U.S. Environmental Protection Agency
Research Triangle Park, North Carolina 27711
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RESEARCH REPORTING SERIES
Research reports of the Office of Research and Development, U.S. Environmental
Protection Agency, have been grouped into nine series. These nine broad cate-
gories were established to facilitate further development and application of en-
vironmental technology. Elimination of traditional grouping was consciously
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The nine series are:
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3. Ecological Research
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This report has been assigned to the ENVIRONMENTAL HEALTH EFFECTS RE-
SEARCH series. This series describes projects and studies relating to the toler-
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clude biomedical instrumentation and health research techniques utilizing ani-
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This document is available to the public through the National Technical Informa-
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EPA-600/1-77-044
September 1977
LUNG FUNCTION AND ITS GROWTH
by
Albert M. Collier, Wallace A. Clyde, Jr.,
Floyd W. Denny, Gerald W. Fernald, W. Pau Glezen,
Frank A. Loda and Dwight A. Powell
Frank Porter Graham Child Development Center
and
Department of Pediatrics
University of North Carolina School of Medicine
Chapel Hill, North Carolina 27514
E.P.A. Grant R-902233
Project Officer
Brock Ketcham
Health Effects Research Laboratory
Clinical Studies Division
Environmental Protection Agency
Research Triangle Park, North Carolina
U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
HEALTH EFFECTS RESEARCH LABORATORY
RESEARCH TRIANGLE PARK, N.C. 27711
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DISCLAIMER
This report has been reviewed by the Health Effects Research Laboratory,
U.S. Environmental Protection Agency, and approved for publication. Approval
does not signify that the contents necessarily reflect the views and policies
of the U.S. Environmental Protection Agency, nor does mention of trade names
or commercial products constitute endorsement or recommendation for use.
ii
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FOREWORD
The many benefits of our modern, developing, industrial society are
accompanied by certain hazards. Careful assessment of the relative risk
of existing and new manmade environmental hazards is necessary for the
establishment of sound regulatory policy. These regulations serve to
enhance the quality of our environment in order to promote the public
health and welfare and the productive capacity of our Nation's population.
The Health Effects Research Laboratory, Research Triangle Park,
conducts a coordinated environmental health research program in toxicology,
epidemiology, and clinical studies using human volunteer subjects. These
studies address problems in air pollution, nonionizing radiation,
environmental carcinogenesis, and the toxicology of pesticides as well as
other chemical pollutants. .The Laboratory develops and revises air quality
criteria documents on pollutants for which national ambient air quality
standards exist or are proposed, provides the data for registration of new
pesticides or proposed suspension of those already in use, conducts research
on hazardous and toxic materials, and is preparing the health basis for
nonionizaing radiation standards. Direct support to the regulatory function
of the Agency is provided in the form of expert testimony and preparation of
affidavits as well as expert advice to the Administrator to assure the
adequacy of health care and surveillance of persons having suffered imminent
and substantial endangerment of their health.
This study provides baseline pulmonary function data on children living
in atn area of low environmental pollution. Children are studied longitudinally
to characterize pulmonary function changes associated with physical growth and
documented upper respiratory infections. This information will enable the
design of further studies to assess the growth of lung function.
Tohn H. Knelson, M.D.
Director,
Health Effects Research Labortory
iii
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ABSTRACT
Recent evidence that certain uncomplicated upper respiratory infections
(URI) induce pulmonary function abnormalities in adults prompted a prospec-
tive study in children where such infections occur more frequently. In a
longitudinal study, 55 children aged 2.5-9 years were observed for a
mean duration of 2 years. Spirometry and lung volume studies were obtained
routinely every 3 months, with each URI and 4 weeks post-illness, providing
data on 636 well and 260 illness observations. After grouping of data by
sex and age (< or > 84 mos), each spirometric parameter was analyzed using
linear regression with individual identification, height, and clinical
status (normal/URI) as independent variables. Adjusted mean values of
forced vital capacity (FVC), one-second forced expiratory volume (FEVj), peak
expiratory,flow rate (PEFR), midmaximal expiratory flow rate (MMEF) and
expiratory flow rate at 50 percent FVC (VSQ) all decreased during URI; 35
percent of these changes were significant with P _<_ 0.05 and 60 percent
with P ^ 0.1. The data suggest that lower respiratory tract involvement
without signs or symptoms of lower airways or alveolar disease occurs with
URI of varied etiology in childhood.
The most prevelant respiratory infectious agent of early childhood
causing both upper and lower respiratory infections is the respiratory
syncytial virus. With evidence that RSV may cause repeated infections
in children, studies of the immune responsiveness to recurrent RSV infections
were initiated in the longitudinal population. Following each of two docu-
mented infections, most children developed an elevation of serum virus neutra-
lizing antibody titer but less than 50% of children possessed detectable cir-
culating antigen responsive T lymphocytes even after the second infection.
These findings raise doubt as to the significance of cell-mediated immunity
in disease pathogenesis and support the need to investigate other areas of
the immune system such as local antibody responses to explain the recurrent
nature of infections.
This final report was submitted in fulfillment of Grant R802233 by the
University of North Carolina under the sponsorship of the U.S. Environmental
Protection Agency. This report covers the period June 1, 1973 to July 31,
1976, and work was completed as of July 31, 1976.
IV
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CONTENTS
Foreword ill
Abstract iv
Figures vi
Tables vii
Abbreviations viii
Acknowledgment ix
1. Introduction 1
2. Conclusions 2
3. Recommendations 3
4. Methods 4
5. Results 6
6. Discussion 8
7. Studies Initiated in Terminal Year of Grant 11
Figures vi
Tables . . . . vii
References 21
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FIGURES
Number
1 Serum Neutralizing Antibody for RSV in Day-Care Children
Observed Through Two Wintertime RSV Epidemics 13
2 Peripheral Lymphocyte Responses To RSV Antigen In Vitro in
Day Care Children Following Documented RSV Infection ... 14
vi
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TABLES
Num'ber
1 Reproducibility of Spirometric Measurements in Children:
Standard Error of the Estimates (SEE) for FVC 15
2 Regression Coefficents Using Height as Independent Variable ... 16
3 Population Statistics for Subjects Less Than 84 Months Old ... 17
A Statistic Showing Difference Between Normal and Symptomatic
Subjects 19
vii
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LIST OF ABBREVIATIONS
CMI cell-mediated immune response
CO carbon monoxide
FEVi forced expiratory volume (one second)
FRC functional residual capacity
FVC forced vital capacity
He helium
He-02 helium - oxygen gas mixture
Hz hertz (cycles per second)
ml/s millilters per second
MMEF midmaxlmal expiratory flow (rate)
PEFR peak expiratory flow rate
RSV respiratory syncytial virus
SEBC standard error between children
SEE standard error of the estimates
TLC total lung capacity
URI upper respiratory infection
vital capacity 50 percent (V25 25 percent, etc.)
viii
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ACKNOWLEDGEMENTS
The cooperation of the children, families, staff and teachers of the
Frank Porter Graham Child Development Center is gratefully acknowledged.
ix
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SECTION 1
INTRODUCTION
There is increasing evidence that upper respiratory infections (URI)
can induce pulmonary function abnormalities generally attributed to alterations
in the lower airways. Picken et al. (1) first reported frequency dependence
of dynamic compliance 4 to 8 weeks after a URI in otherwise normal subjects.
With mild viral infections, others have described a decrease in CO-diffusing
capacity (2), an increase in closing volume in smokers (3), a decrease in
maximal expiratory flow rates with He-02 gas mixture at low lung volumes
(3) ., and an increase in the frequency dependence of resistance in the range
of 3 to 9 hertz (4). Blair et al. (5) also found an increase incidence of
frequency dependent dynamic compliance with induced rhinovirus respiratory
tract infections. In all instances several other measures of pulmonary
function including spirometry were unchanged. Studies using nasally admin-
istered live attenuated influenza A vaccine showed small but consistent
decreases in flow rates at low lung volumes (which were not observed after
the second exposure) (6) and a decrease in the one-second forced expiratory
volume (7).
In general, changes associated with URI are suggestive of peripheral
airway obstruction. This is further supported by the fact that pulmonary
function abnormalities seem to be more pronounced in smokers (2,3) and in
patients with chronic obstructive respiratory diseases (7). These more pro-
nounced effects are attributed to the superposition of two disease processes
which compromise the small airways thereby causing significant decreases in
effective airway radius with a much larger change in resistance. Hogg (8)
has provided some evidence that a sharp increase in small airway conductance
occurs around age four to five years; thus, in younger children small com-
promises in airway diameter may produce a marked effect on resistance, pro-
viding a situation similar to the adult subject with established disease.
To further clarify this point we undertook a longitudinal study using small
children in whom spontaneous upper respiratory infections are very common.
A secondary objective of the study was to obtain regression equations
for predicting normal pulmonary function parameter values in children.
There are consideralbe data for children older than six or seven years of
age (9-12), but there is a paucity of data for younger children. Because
of the longitudinal nature of our study we were able to train younger children
and obtain sufficiently reproducible data to establish predictive equations.
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SECTION 2
CONCLUSIONS
The results of these studies on immune responsiveness and Lung growth,
as measured by pulmonary function testing in a longitudinal population of
children in an area of low environmental pollution, have demonstrated:
1. The feasibility of obtaining reproducible pulmonary function test
results in small children down to the age of three years.
2. The presence of upper respiratory tract infections at the time of
pulmonary function testing in young children may alter the test
results.
3. Cell-mediated immune responsiveness plays a minimal role in patho-
genesis of illness accompanying respiratory syncytial virus infec-
tions in young children.
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SECTION 3
RECOMMENDATIONS
1. In studies examining the effects of environmental pollution on pulmonary
function in children it is imperative that the children be free of respi-
ratory tract infections at the time of testing.
2. Methods should be developed to perform pulmonary function testing on
children below three years of age in order to evaluate the effects of
pollution on the lungs during this period of rapid development.
3. More information is needed on the immunological response of the respira-
tory tract in order that the effects of pollution on defense mechanisms
may be better evaluated.
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SECTION 4
METHODS
Subjects were 55 normal children (2.5 - 12 years old) who were studied
longitudinally in a program previously described (13). Informed consent
was obtained from the parents, and older children were informed of the value
and intent of the study. Duration in the pulmonary-function study ranged
from one to four years with a mean observation period of two years. Before
being incorporated into the study, all children were thoroughly trained in
pulmonary function maneuvers. Spirometry and the measurement of static lung
volumes were performed on a scheduled basis every three months, at the onset
of every respiratory infection, with the development of any complications,
and at one month after the onset of illness.
Spirometry was performed in a standing position using a 10-liter wedge
spirometer (Med. Science, Model 465). The flow signal was sampled 80 times
per second, and stored in a Digital Equipment Corp. PDP-12/40. The digitized
flow signal was integrated numerically to provide a volume signal. These
data were analyzed using the program of Domizi, Earle and associates (14,15)
to obtain forced vital capacity (FVC), one-second forced expiratory volume
(FEVi), peak expiratory flow rate (PEFR), midmaximum expiratory flow rate
(MMEF), flow rate with 50 and 25 percent of the vital capacity remaining
(Vso and ^25). The spirogram, the flow-volume curve, and the computed pulmonary
function parameters were displayed immediately for evaluation of technical
perfection. Results of repeated trials and of previous test session were
compared to insure a representative maximum effort. Flow and volume signals
obtained on that day were stored on computer tape in the PDP-12/40 computer.
Electronic calibrations were performed before each test. A one-liter syringe
was used to calibrate the system weekly, and the flow signal was calibrated
periodically with a rotometer.
Static lung volumes were measured in the seated position using helium
dilution with the water-sealed spirometer (Collins nine-liter respirometer),
modified to diminish dead space, and a helium (He) analyzer (Collins, helium
meter). The volume of the system was maintained constant by addition of
oxygen. No correction was made for absorption of helium. After three
minutes, a .maximum inspiratory effort was performed and the final He con-
centration measured. Functional residual capacity (FRC) and total lung
capacity (TLC) were calculated. Generally, the child's mouth was held to
the spirometer mouthpiece to avoid leaks, and if a leak was detected the
entire procedure was repeated. These data were punched on computer cards
and entered into the data file.
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In addition to pulmonary function data, sitting and standing height,
weight, age and clinical findings were also entered. The last included
coding for: no disease; rhinitis; sore throat, sneeze, cough or earache;
fever; asthma; pneumonia; and bronchiolitis.
During the analysis, data sets entered with findings of asthma, pneumonia
and bronchiolitis (9 cases) and data from subjects with a history of asthma
(3 subjects) were excluded. The data were further refined by eliminating
all sets of pulmonaryafunction data in which FEVj/FVC was less than 0.7, or
if VSQ was less than V25 (less than four percent of observations). Remaining
data were divided in four groups by sex and age with a separation at 84
months. The data were processed on the IBM 370/165 using SAS (18), to fit
the variation in each pulmonary function parameter with a linear model. Age
in months, individual identification and clinical status (asymptomatic or
symptomatic) were used as independent variables. The analysis was repeated
using height instead of age as an independent variable and again using both
variables. The population means, the standard error of the estimate (SEE)
and the standard error between children (SEBC) were calculated for each
parameter in the four age-sex groups. Differences between asymptomatic and
symptomatic subjects were evaluated by computing adjusted means for each
parameter in these two subgroups within the four age-sex groups; F and P
values were computed for intergroup comparisons.
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SECTION 5
RESULTS
The study included 896 observations, of which 260 were obtained during
expisodes of URI. In this section results of the regression analysis are
presented first and then used to evaluate the effect of URI on pulmonary
function parameters. Using both age and height as independent variables in
the regression analysis produced the smallest SEE and SEBC. Generally,
using height without age caused a small increase in these measures of vari-
ability, while using age without height produced a larger increase. This is
illustrated by Table 1 which shows the SEE for FVC for the four age-sex groups
computed for these three combinations of independent variables. This indi-
cates that including age as an independent variable contributes little to the
fit between the regression equation and the data because age and height are
so closely related. As a result of this, the remainder of the results were
derived using regression analyses that did not include age.
Regression equation coefficents for the eight pulmonary function para-
meters for the four age-sex groups are shown in Table 2. Slope values in-
dicate lung function development relative to overall growth. For example,
in males who were less than 84 months old, FVC increased 35.0 ml/cm of growth,
while in females of the same age the corresponding value was 31.0 ml/cm.
Comparing slopes in the two male age groups showed that five of eight were
in the younger group; in contrast, all slopes in the older female group were
greater or equal to those in younger females. When the comparison is made
between sex groups, in the younger subjects, seven of eight slopes are greater
in males while in the older population six of eight are greater in females.
Thus in comparison to overall growth, lung function appeared to develop more
rapidly in our younger male and older female subjects.
Tables 3 shows mean values, SEE and SEBC derived from the regression
analysis of the eight parameters for each age-sex group. The SEE's define
confidence limits on parameter values predicted from the regression equations
for subjects in the population studied. Typical values are 100 to 200 ml
for volume measurements (FVC, FEVi, FRC and TLC) and 300 to 500 milliliters
per second (ml/s) for flow measurements. These values provide a measure of
the variability in repeated measurements in the same subject. The SEBC's
define confidence limits on predicted values derived from the regression
equation for the general population. These values are typically 50 to 150
ml or ml/s greater than the corresponding values for the SEE.
From the regression analysis, adjusted mean values for well subjects
and for those with URI were computed and are shown in Table 4. This table
also shows the statistical significance (F and P values) of the differences
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between these two groups. In the symptomatic subjects the adjusted mean
valxies of the spirometric parameters FVC, FEVi, PEFR, MMEF and VSQ show a
decrease for all four age-sex groups. For FVC and PEFR, the difference was
significant (P £ 0.1) in three groups; for FEVi and MMEF, the difference was
significant in two of the four groups, and for VSQ the difference was signif-
icant in only one group. With P <_ 0.05, 35 percent of the changes were signif-
icant. Typically, the differences are 50 ml or ml/s for FVC, MMEF and VSQ with
a slightly larger difference in PEFR and smaller differences in FEVi> Differ-
ences in V25, FRC and TLC do not follow any pattern.
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SECTION 6
DISCUSSION
Although limited in number, studies evaluating pulmonary function
during upper respiratory infection suggest a component of pulmonary involve-
ment. Alterations in pulmonary function with either natural or experimental
upper respiratory infection have been detected with dynamic measurements at
elevated frequencies (1,5,4), or by measurement of closing volume (3) and CO-
diffusing capacity (2). Spirometric changes have been found only with the
use of a He-02 gas mixture in spontaneous disease (3) but routine spirometry
has shown some differences after intranasal administration of influenza A
vaccine (6,7). In general the changes in pulmonary function are subtle and
inconsistent within and among groups, but the abnormalities detected are
generally attributed to acute peripheral airways obstruction. The more
pronounced effect in the presence of preexisting small airway disease supports
this hypothesis (2,3,7). Our data fit this interpretation.
In the children with URI, the changes in pulmonary function parameters
were not all statistically significant. However, we believe the changes
were real since FVC, FEVi, PEFR, MMEF and VSQ decrease in all four age-sex
groups: 35 percent of these changes were significant with P <_ 0.05; and 60
percent were significant with P j^ 0.10. We found a reduction in FVC without
a change in TLC and a reduction of the flow rates at most lung volumes
suggesting earlier airway closure. The reported small caliber of peripheral
airways in young children (8) may enhance changes in pulmonary function
parameters with URI. This could explain the more pronounced changes observed
in the younger children. The flow rate measured at low lung volume, V.25,
which for theoretical reasons (17,18) should be most sensitive to changes
in peripheral airways, was not detectably altered. However, Knudson et al.
(19) in an epidemiological study showed that FEVi was superior to flow at
low lung volume for detecting abnormalities in younger subjects.
This study also provides data to establish predictive,equations for
pulmonary function parameters in children younger than previously reported.
In our study, we found that standing height was a more reliable predictor of
pulmonary function than age, and that using both age and height provided
only a slight improvement as measured by the reduction in the SEE and the
SEBC. This is consistent with the finding of Dickman et al. (11) that
pulmonary function parameters are most highly correlated with height.
Polgar et al. (9) and Zapletal et al. (10) described a nonlinear relation-
ship between pulmonary function parameters and height but their prediction
equation spanned a wider range of heights than represented by either of the
two age groups in our study population. In their recent report Knudson et
al. (12) used both age and height in a regression equation but the relation-
8
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ship was established with data from subjects over a much wider age range
than is generally used. In difference to these studies, our data indicate
that over a limited age range pulmonary function parameters can be related
to height with a linear relationship.
The height range in our older group coincides with that of younger
groups in most other studies (9-12). Regression equations for our older
group fall below the mean but within +2 S.D. of those shown in Polgar et
al. (9), which represents the compilation of all acceptable published data
available at that time. Since adult blacks generally fall below the predic-
tion curves established with a predominantly white population (20), we
partially attribute our lower mean values to the large fraction of blacks in
our study (66 percent).
The SEBC values represent the variability about the regression line
established without including adjustments for individual variations in the
analysis. These values provide confidence limits on predicted pulmonary
function parameters for the general population and may be used in establishing
normal ranges. Dividing the SEBC by the mean value provides a normalized
estimate of the variability analogous to the coefficient of variation. For
our four age-sex groups, this normalized measure of variability expressed as a
percentage ranged as follows: 12 - 18 percent for FVC and FEVi; 16-21
percent for PEFR; 24 - 30 percent for MMEF and V50; 33 - 41 percent for
V255 18 - 26 percent for FRC; and 10 - 13 percent for TLC. This variability
appears similar to that reported by Zapletal et al. (10) and Dickman et
al. (11). The variability described in the review by Polgar et al. (9) is
about one-half of ours but their analysis included considerably more data.
The apparent linear relationship between the measured parameters and
height suggests that pulmonary function growthand presumably lung matura-
tionis simply a reflection of overall growth within relatively narrow age
ranges. However, others (9-12) have found that over a more extensive age
range, the relationship is clearly nonlinear. In our study the slope
coefficent in the regression equation provides a measure of the relative
growth of pulmonary function in our four age-sex groups. In the older group,
both the actual values for the pulmonary function parameters and the slopes
of the regression lines were similar for males and females. In younger
females, all slopes appear to be lower than corresponding values in the
other three groups. These results can be explain by hypothesizing a lower
overall slope in female prior to puberty, and a rapid acceleration in pul-
monary function growth near puberty. Our older female group could contain
data from both the prepubertal linear growth period and the accelerated
adolescent period. Since males mature later, their rapid acceleration in
pulmonary function growth may not have occured in the age groups studied.
As a result, the slope in the older female population would be larger than
that in younger females and similar to that seen in males
In terms of growth, Zapletal et al. (10) suggested that increases in
pulmonary function related to height are highly correlated with growth of
TLC and that normalization of pulmonary function parameters with TLC makes
them independent of height. Green et al. (21) and Black et al (22) did
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not find this effect in adults. From calculations using our regression
equations we found that increases in FVC, FEV^ and PEFR appeared to be
closely correlated with increases in TLC. In contrast, variations in MMEF,
VSQ and V25 showed less correlation with TLC suggesting that processes other
than increasing TLC play a role in growth of the maximal expiratory flow.
In conclusion, we believe that reliable measurements of pulmonary func-
tion have been obtained in children over a period of several years. The
data provide a basis for predicting pulmonary function parameters for children
younger than previously reported. The nature of this prospective, longitudi-
nal study made it possible to test the same children when well and at the
time of intercurrent URI. These data strongly suggest pulmonary function
changes in the absence of clinical evidence of lung involvement. These
changes could be explained by subclinical pulmonary disease, reflex changes
in peripheral airways due to upper tract inflammantion, or reduced subject
effort during illness. The last possibility is considered unlikely since
careful attention was given to the reproducibility of each test session.
The impact of pulmonary function alterations on the growing lung cannot be
assessed presently, but it appears that these abnormalities are frequent and
occur with otherwise uncomplicated acute respiratory infections.
Comprehensive microbiologic and serologic studies to define the etiology
of URI episodes in the study population are being analyzed and will be
reported separately. Preliminary examination of the data reveals the full
spectrum of common respiratory agents which have been associated with child-
hood URI. In addition, continued study at this population should provide
data describing prospectively the growth of lung function in early childhood.
10
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SECTION 7
STUDIES INITIATED IN TERMINAL YEAR OF GRANT
Immune responsiveness against the respiratory syncytial virus (RSV) was
assessed in the study population because of increasing evidence that this
agent causes repeated infections at yearly intervals. In a review of the
past 10 years, Dr. Fred Henderson in our lab has documented RSV infections
in 89 children occurring 176 times as demonstrated either by virus isolation
(90) or seroconversion (86). In the entire population, 51 children have had
from one to four reinfections. There were 61 primary RSV infections in
children followed from birth, of whom 35 have had at least one recurrence.
For consequative annual infections, the recurrence rate was as high as 94%.
Against this background was assessed the serum antibody response and
the antigen specific reactivity of circulating thymus-derived lymphocytes.
Blood samples were obtained from children in the Frank Porter Graham Day
Care Center in the spring and fall of each year. Serum neutralizing anti-
body assay against RSV was performed by the plaque reduction method (27).
Peripheral blood lymphocyte transformation was measured by tritiated thymidine
incorporation after five day incubation of heparinized whole blood samples
with RSV infected Hep cells as antigen or noninfected Hep cell controls. As
shown in figure one, greater than 90% of children over four months of age
responded to a primary RSV infection with a significant rise in the titer of
serum neutralizing antibody. Within nine months there was a marked decline
in the geometric mean titer. In the subsequent spring, there was another
antibody titer rise following the second RSV infection in these children.
The response of circulating T-lymphocytes followed a somewhat different
course as shown in figure 2. While all children demonstrated a capacity
for T-cell reactivity as manifested by response to phytohemagglutinin, none
of 13 children tested after primary RSV infection demonstrated antigen
specific T-cell stimulation. In contrast, seven of seventeen (41%) children
demonstrated a significant response following their second RSV infection.
The observations on the immune response of day care children incurring
repeated infections with RSV provide data for speculation on several import-
ant points. First, it has recently been suggested that the host cell-
mediated immune response (CMI) may be an important pathogenetic mechanism in
RSV disease (23). This theory stems from knowledge that previous exposure
to parenteral-killed RSV vaccine rendered children vulnerable to severe
clinical illness upon natural infection (24). In such vaccinated children,
all who were tested prior to natural infection had developed CMI as measured
by circulating antigen responsive lymphocytes (25). Despite this, these
children suffered more severe RSV disease than did nonvaccinated controls.
11
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Further, there is precedence for a detrimental rate of CMI in respiratory
infections through study of M. Pneumoniae infections in day-care children
(26). This agent produces lower respiratory tract illness most commonly in
school-age children and adolescents, and uncommonly in the very young child.
Yet evidence now exists that asymptomatic M. Pneumoniae infection may be fre-
quent in the early years of life, but only during the ages when M. Pneimoniae
illness becomes more common do increasing numbers of children with M. Pneumoniae
infection mainifest a positive peripheral lymphocyte response to M. pneiffnoniae
antigen. In current study of the day care population, none of the children
infected a single time with RSV, and less than 50% of those infected two times,
developed peripherial lymphocyte reactivity to the RSV antigen. Since lympho-
cytes from seropositive adults manifested transformation under the same in
vitro conditions, these negative results seem very significant. When these
data are correlated with the fact that RSV illness is most prevalent among
very young children, presumably after the initial RSV infection, it would
seem doubtful that CMI is a crucial element in RSV disease pathogenesis.
A second important point of interest in these studies was the finding
that with one exception infants and young children could mount a brisk
systemic antibody response following primary RSV infection. Previous studies
by Parrott et al. (27) had demonstrated that the serum complement-fixation
antibody response to RSV was impaired in very young children, raising specu-
lation that a delayed or decreased immune response could contribute to the
increased severity of RSV disease during early infancy. Data from children
at the day care center demonstrates a comparable serologic rise after first
and second RSV infections, suggesting that at least in the age groups studied,
impaired development of circulating RSV-neutralizing antibody is not a major
contributor to disease pathogenesis. Of possibly more significance was the
observed decline in serum antibody levels after the primary infection. With-
in a nine-month period, there was more than a four-fold fall in the geometric
mean titer of serum-neutralizing antibody activity. In contrast to this
pattern, Wright et al (28) have recently shown that seronegative children
incurring influenza A infection respond with a hemagglutination inhibition
antibody response which remains stable over a two-year period and correlates
with complete protection against a second influenza A infection. Repeat RSV
infection in the day-care population was the rule rather than the exception.
Whether differences in these two respiratory viral agents is due to anti-
genicity, invasiveness, or differences in other aspects of the host immune
response, remain important questions for future study. Of particular interest
is the role of local immune antibody response. While it has been demonstrated
that a significant proportion of infants and young children develop secretory
antibody after natural or vaccine-induced RSV infection (23), the ability
to link local respiratory tract antibody with disease resistance or to de-
fine the protective levels of antibody remain difficult because of a non-
antibody inhibitor of RSV present in nasal washings of young children. This
problem is being addressed in ongoing EPA supported research through develop-
ment of alternative methods for measuring secretory antibody activity.
12
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o
PQ
Pd
W
1280
640-
320-
160
80
40-
20-
10-
(5.9)
(123.4)
(27.6)
(103.1)
*
IFALL 1974
SPRING 1975
FALL 1975.
SPRING 1976
Figure 1. Serum-neutrailzing antibody for RSV in day-care children observed through
two wintertime RSV epidemics. Geometric mean titer in parenthesis.
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25
0
i
O
a
0
O
J25
M
W
H
0
1
s
I
O
M
H
^
O
Pi
S5
O
53
O
M
H
>
S
12
11
10
9
8
7
6 -
5 -
4 -
3
2 -
1 -
'
_ ^
*
* i
1 1
1 2
NUMBER OF DOCUMENTED RSV INFECTIONS
Figure 2. Peripheral lymphocyte responses to RSV antigen in vitro in day-care
children following documented RSV infection. All lymphocyte cultures
were performed during the same month following a single RSV epidemic.
Only values above a ratio of three are considered to represent antigen
reactivity.
-------
TABLE 1. REPRODUCIBILITY OF SPIROMETRIC MEASUREMENTS IN CHILDREN:
STANDARD ERROR OF THE ESTIMATES (SEE)* FOR FVC
Variables
Included
Age and height
Height
Age
Males
<84 mo.
176
176
262
Males
>84 mo.
204
208
323
Females
<84 mo.
147
151
185
Females
>84 mo.
325
325
363
*SEE are given in milliliters.
15
-------
TABLE 2. REGRESSION COEFFICIENTS USING HEIGHT AS INDEPENDENT VARIABLE
Parameter
FVC
(ml)
FEVi (ml)
PEFR
MMEF
V50
V25
FRC
TLC
(ml/s)
(ml/s)
(ml/s)
(ml/s)
(ml)
(ml)
Male*
<84 mo.
INT.
-2781
-2351
-5201
-2154
-1704
-788
-2864
-3712
SLOPE
35.0
30.4
72.3
34.5
31.9
17.1
32.8
48.6
Malet
>84 mo.
INT.
-2873
-2549
-4244
-1984
-2179
-458
-2425
-3372
SLOPE
35
31
66
32
36
13
27
43
.4
.7
.2
.8
.4
.5
.9
.9
Female**
<84 mo.
INT.
-2418
-2109
-4374
-1792
-2835
-146
-1869
-2508
SLOPE
31.0
27.6
63.8
30.6
42.0
10.3
22.5
35.5
Femalett
>84 mo.
INT.
-2740
-2358
-6827
-2574
-2805
-527
-2696
-3665
SLOPE
34
30
84
37
42
14
29
45
.4
.0
.2
.3
.0
.1
.0
.3
* Based on 211 spirometric and 104 lung volume measurements in 17 subjects.
t Based on 106 spirometric and 90 lung volume measurements in 12 subjects.
** Based on 339 spirometric and 162 lung volume measurements in 29 subjects.
tt Based on 192 spirometric and 177 lung volume measurements in 15 subjects.
16
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TABLE 3. POPULATION STATISTICS FOR SUBJECTS LESS THAN 84 MONTHS OLD
Parameters
FVC (ml)
FEVi (ml)
PEFR (ml/s)
MMEF (ml/s)
V50 (ml/s)
V25 (ml/s)
FRC (ml)
TLC (ml)
Male
Adjusted
population
mean
1035
962
2648
1570
1747
1047
820
1769
(<84 mo.)*
SEE
118
108
388
351
362
335
175
199
SEBC
176
168
492
452
477
426
202
233
Female
Adjusted
population
mean
994
928
2709
1629
1860
1031
769
1638
(<84 mo.)t
SEE
110
108
449
362
417
353
174
165
SEBC
151
140
581
465
522
414
196
191
(continued)
-------
TABLE 3 (continued)
Parameters
FVC (ml)
FEVi (ml)
PEFR (ml/s)
MMEF (ml/s)
£ V50 (ml/s)
V25 (ml/s)
FRC (ml)
TLC (ml)
Male
Adjusted
population
mean
1749
1563
4328
2260
2618
1262
1241
2367
(>84 mo.)**
SEE
150
151
550
440
504
359
169
186
SEBC
208
184
698
544
641
415
219
240
Female
Adjusted
population
mean
1770
1575
4304
2315
2689
1274
1070
2241
(>84 mo.)tt
SEE
139
139
529
481
444
316
174
171
SEBC
325
281
874
548
800
440
231
397
* Includes 211 spirometric and 104 lung volume measurements in 17 subjects.
t Includes 339 spirometric and 162 lung volume measurements in 29 subjects.
** Includes 106 spirometric and 90 lung volume measurements in 12 subjects.
tt Includes 192 spirometric and 177 lung volume measurements in 15 subjects.
*** SEE (standard error of the estimate) characterizes the variability about the regression line obtained
by correcting for individual variation. SEBC (standard error between children) characterizes the
variability about the regression line obtained without correcting for individual variations.
-------
TABLE 4. STATISTIC SHOWING DIFFERENCE BETWEEN NORMAL AND SYMPTOMATIC SUBJECTS
Parameters
FVC (ml)
FEV'i (ml)
PEFR (ml/s)
MMEF (ml/s)
V50 (ml/s)
V25 (ml/s)
FRC (ml)
TLC (ml)
Normal
adjusted
mean
1051
970
2683
1573
1758
1046
812
1759
Male (<84 mo
Symptomatic
adjusted
mean
998
939
2549
1559
1717
1052
849
1807
.)*
F value
9.99
2.94
4.16
0.05
0.44
0.01
0.65
0.80
P
.003
.088
.043
.818
.507
.906
.421
.372
Normal
adjusted
mean
1014
946
2754
1658
1903
1036
768
1635
Female (<84
Symptomatic
adjusted
mean
957
895
2624
1575
1777
1023
773
1645
mo.)t
F value
17.80
15.23
5.72
3.57
6.17
0.09
0.03
0.11
P
.0001
.0001
.0170
.0600
.0140
.7690
.8580
.7410
(continued)
-------
Table 4 (continued)
ISJ
O
Male (>8A mo.)**
FVC (ml)
FEVi (ml)
PEFR (ml/s)
MMEF (ml/s)
V50 (ml/s)
V25 (ml/s)
FRC (ml)
TLC (ml)
Normal
adjusted
mean
1766
1574
4406
2266
2637
1249
1234
2362
Symptomatic
adjusted
mean
1691
1527
4063
2235
2552
1302
1267
2384
F value
3.39
1.35
5.28
0.67
0.39
0.35
0.43
0.18
P
.069
.248
.024
.796
.536
.553
.513
.675
Normal
adjusted
mean
1777
1575
4340
2348
2715
1270
1072
2254
Female (>84
Symptomatic
adjusted
mean
1744
1573
4170
2194
2594
1286
1063
2191
mo . ) tt
F value
1.58
0.01
2.97
2.95
2.14
0.06
0.06
3.35
P
.2100
.9180
.0870
.0880
.1450
.8010
.8130
.0690
* Includes 156 spirometric and 82 lung volume measurements while asymptomatic and 55 spirometric
and 22 lung volume measurements while symptomatic. Data were obtained for 17 subjects.
t Includes 222 spirometric and 113 lung volume measurements while asymptomatic and 117 spirometric
and 49 lung volume measurements while symptomatic. Data were obtained from 29 subjects.
** Includes 82 spirometric and 70 lung volume measurements while asymptomatic and 24 spirometric
and 20 lung volume measurements while symptomatic. Data were obtained from 12 subjects.
tt Includes 151 spirometric and 141 lung volume measurements while asymptomatic and 41 spirometric
and 36 lung volume measurements while symptomatic. Data were obtained from 15 subjects.
-------
REFERENCES
1. Picken, J. J., D. E. Niewoehner and E. H. Chester. Prolonged Effects of
Viral Infections of the Upper Respiratory Tract Upon Small Airways. Am.
J. Med. 52(6):738-746, 1972.
2. Gate, T. R., J. S. Roberts, M. A. Russ and J. A. Pierce. Effects of
Common Colds on Pulmonary Function. Am. Rev. Respir. Dis. 108(4):858-
865, 1973.
3. Fridy, W. W., Jr., R. H. Ingram, Jr., J. C. Hierholzer and M. T. Coleman.
Airways Function During Mild Viral Respiratory Illnesses: The Effect of
Rhinovirus Infection in Cigarette Smokers. Ann. Intern. Med. 80(2):150-
155, 1974.
4. Hall, W. J., R. Douglas, Jr., R. W. Hyde, F. K. Roth, A. S. Cross and
D. M. Speers. Pulmonary Mechanics after Uncomplicated Influenza A
Infection. Am. Rev. Respir. Dis. 113(20):141-147, 1976.
5. Blair, H. T., S. B. Greenberg, P. M. Stevens, P. A. Bilunos and R. B.
Couch. Effects of Rhinovirus Infection on Pulmonary Function of Healthy
Human Volunteers. Am. Rev. Respir. Dis. 114(1):95-102, 1976.
6. Rosenzweig, D. Y., D. J. Dwyer, J. E. Ferstenfeld and M. W. Rytel.
Changes in Small Airway Function after Live Attenuated Influenza Vac-
cination. Am. Rev. Respir. Dis. 111(4):399-403, 1975.
7. Zeck, R., N. Solliday, T. Kehoe and B. Berlin. Respiratory Effects of
Live Influenza Virus Vaccine: Healthy Older Subjects and Patients with
Chronic Respiratory Disease. Am. Rev. Respir. Dis. 114(6):1061-1067,
1976,
8. Hogg, J. C., J. Williams, J. B. Richardson, P. T. Macklem and W. M.
Thurlbeck. Age As A Factor In The Distribution Of Lower-Airway Con-
ductance And In The Pathologic Anatomy Of Obstructive Lung Disease.
Obstructive Lung Disease. 232(23):1283-1287.
9. Polgar, G. and V. Promadhat. Pulmonary Function Testing in Children:
Techniques and Standards, W. B. Saunders, Philadelphia, Pa., 1971.
273 pp.
10. Zapletal, A., E. K. Motoyama, K. P. Van De Woestijne, V. R. Hunt and A.
Bouhuys. Maximum Expiratory Flow-Volume Curves and Airway Conductance
in Children and Adolescents. J. Appl. Physiol. 26(3):308-316, 1969.
21
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11. Dickman, M. L., C. D. Schmidt and R. M. Gardner. Spirometric Standards
for Normal Children and Adolescents (Age 5 Years through 18 Years). Am.
Rev. Respir. Dis. 104(5):680-687, 1974.
12. Knudson, R. J., R. C. Slatin, M. D. Lebowitz and B. Burrows. The Maximal
Expiratory Flow-Volume. Am. Rev. Respir. Dis. 113(5):587-600. 1976.
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14. D. B. Domizi and R. H. Earle. On Line Pulmonary Function Analysis:
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Pulmonary Function Tests Using a Small Digital Computer (POP-12). In:
DECUS Proceedings, 1970. p. 23.
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22. Black, L. R. K. Offord and R. E. Hyatt. Variability in the Maximal
Expiratory Flow Volume Curve in Asymptomatic Smokers and In Nonsmokers.
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23. Parrott, R. H. Respiratory Syncytial Virus. In: Immunolgic and
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24. Kim, H. W., J. G. Conchola, C. D. Brandt, G. Pryles, R. M. Chanock, K. E.
Jensen and R. H. Parrott. Respiratory Syncytial Virus Disease in Infants
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Epidemiol. 80(3):422-434, 1969.
25. Kim, H. W., S. L. Leikin, J. Arrobio, C. D. Brandt, R. M. Chanock and
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Brandt, E. Comargo and R. M. Chanock. Epidemiology of Respiratory Syn-
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28. Wright, P. F., K. B. Ross, J. Thompson, D. T. Karzon. Influenza A Infec-
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23
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TECHNICAL REPORT DATA
(Please read Instructions on the reverse before completing)
1. REPORT NO.
EPA-600/1-77-044
4. TITLE AND SUBTITLE
Lung Function and Its Growth
6. PERFORMING ORGANIZATION CODE
3. RECIPIENT'S ACCESSION" NO.
5. REPORT DATE
September 1977
7. AUTHOR(S)
A.M. Collier, W.A. Clyde, Jr., F.W. Denny, G.W. Fernald,
W. Pau Glezen, F.A. Loda and D.A. Powell
8. PERFORMING ORGANIZATION REPORT NO.
9. PERFORMING ORGANIZATION NAME AND ADDRESS
Frank Porter Graham Child Development Center and
Department of Pediatrics
University of N.C. School of Medicine
Chapel Hill, N.C. 27514
10. PROGRAM ELEMENT NO.
1AA601
11. CONTRACT/GRANT NO.
R-902233
12. SPONSORING AGENCY NAME AND ADDRESS
Health Effects Research Laboratory
Office of Research and Development
U.S. Environmental Protection Agency
RpQoa-rr-Vi T-r-ianolp PavV N f 97711
13. TYPE OF REPORT AND PERIOD COVERED
RTP.NC
14. SPONSORING AGENCY CODE"
EPA 600/11
LA^J
NO1
15. SUPPLEMENTARY NOTES
16. A8STgAjTjence t^at Certain uncomplicated upper respiratory infections (URI) induce
pulmonary function abnormalities in adults prompted a study in children where such
infections occur more frequently. In a longitudinal study, 55 chilren aged 2.5 -
9 years were observed for a mean duration of 2 years. Spirometry and lung volume
studies were obtained routinely every 3 months, with each URI and 4 weeks post-illness
providing data on 636 well and 260 illness observations. Adjusted mean values of
forced vital capacity (FVC), 1 sec forced expiratory volume (FEV^), peak expiratory
sn^wrVT?' mldTfmal exPiratory flow rate (MMEF) and expiratory flow rate at
50^ FVC (V5 ) decreased during URI. The data suggest lower respiratory tract involvL
without slgns or symptoms of lower airways or alveolar disease occurs with URI of '
varied etiology in childhood.
Respiratory Suncytial virus is the most common cause of severe lower respiratory
illness in infants and recurrent infections occur commonly. To evaluate the immune
response to primary and secondary RSV infection serial determinations of serum
neutralizing antibody and circulating antigen reactive lymphocytes were performed.
Although a brisk serum antibody response was seen after both infections, antigen
reactive lymphocytes were only detected after the second episode.
nt
17.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.lDENTIFIERS/OPEN ENDED TERMS
c. COSATI Field/Group
respiratory infections
children
air pollution
immunity
lung
06 E, F, P
18. DISTRIBUTION STATEMENT
RELEASE TO PUBLIC
19. SECURITY CLASS (This Report)
UNCLASSIFIED
20. SECURITY CLASS (This page)
UNCLASSIFIED
21. NO. OF PAGES
33
22. PRICE
EPA Form 2220-1 (9-73)
24
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