United States
Environmental Protection
Agency
Health Effects Research
Laboratory
Research Triangle Park NC 27711
Research and Development
EPA-600/S1-81-022  May 1981
Project Summary
Effects  of  Etiologically  Defined
Respiratory Infections on  Lung
Function  and  Its Growth  in an
Area of  Low Air  Pollution  -
Spirometry  in Young  Children
When  Illness-Free
Albert M. Collier, Gerald L. Strope, Ronald W. Helms, Lisa Morrisey Lavange,
Wallace A. Clyde,  Jr., Russel  Pimmel,  Floyd  W.  Denny, Frederick W.
Henderson, and Gerald W. Fernald
  This longitudinal study was per-
formed in a group of 3-12 year old
children to document normal lung
growth patterns as measured by spi-
rometry. By clinical and laboratory
parameters, these children were free
of illness at the time of study and had
been for the preceding 21 days. Spiro-
metry was performed prospectively
over a period of six years in 69 children
(27 black females, 23 black males, 10
white females, and 9 white males)
from a day care center. Eight-hundred
fifteen spirometric tests were made on
these children. Linear regres-
sion analyis by a method of weighted
least squares was found to adequately
describe the data over a height range
of 100-150 cm and was performed on
six spirometric parameters: forced
vital capacity (FVC), forced expiratory
volume in  one second (FEVi), peak
expiratory flow (PEF), forced expira-
tory flow during the middle half of the
FVC (FEF25-75%), and maximum expira-
ory flows after 50% and 75% of the
FVC have been exhaled (Vmax5o% and
Vmax75%, respectively). Ninety-five
percent confidence limits for the
regression lines and 95% prediction
intervals for individual observations
were also computed. There were sig-
nificant differences between the re-
gression lines (considering slope and
intercept) for all six parameters when
black females were compared to black
males, white females to white males,
black females to white females and
black males to white males, except for
Vmax75% for the comparison of black
females to black males and white
females to white males. These slopes
and intercepts  were similar to those
reported  by others for children of
similar age and height. The 95% confi-
dence limits and 95% prediction inter-
vals were proportional to height and
were similar to estimates of parameter
variability reported by others. This
study demonstrates that spirometry
can be performed reliably at an early
age in a day care center population,
that there are significant racial and
sexual differences in spirometric vol-
ume and flow parameters and that the
variability of these  measurements is

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proportional to height rather than
being a constant.
  This final report was submitted in
fulfillment of Grant #R-804577 by
the University of North Carolina under
the sponsorship of the U.S. Environ-
mental Protection Agency. This report
covers the period from August 1,
1978  to  April  30, 1980 and  was
completed as of April 30, 1980.
  This Project Summary was devel-
oped by EPA's Health Effects Research
Laboratory. Research Triangle Park,
NC. to announce key findings of the
research project that is fully docu-
mented in a separate report of the
same title (see Project Report ordering
information at back).

Introduction
  The growth of the lung in children isa
dynamic process characterized by an
increase in alveolar, number followed by
an increase in size of airways and air
spaces in  the lung. Other researchers
have shown that the total number of
airways is the same in children and
adults. The total complement of bronchi
al generations is present by the end of
the sixteenth week of gestation and the
spaces which will contain air begin to
change to an alveolar pattern during the
latter part of gestation. During the first
weeks of life, typical alveoli appear and
lung growth for the first four years of life
consists predominantly of an  increase
in alveolar number. At this point, increase
in lung size changes to  a pattern of
growth consisting of an increase in size
of airways and alveoli. The physiologic
importance of this growth pattern  has
been demonstrated by other researchers
who found that the conductance of
peripheral airways (beyond the fifteenth
bronchial  generation) increases dra-
matically  at about five years of  age,
while no change occurs  in the central
airways.
  Most reference data for pulmonary
function tests in children have been
generated on newborns and on children
over five or six years of age. Pulmonary
function tests from infancy to five years
of age have not been well documented
and  it  is not known what effect  the
relative  lower conductance of the pe-
ripheral airways might have on measure-
ments of lung function.  It is also  not
known what effects acute respiratory
illnesses might have on measurements
of pulmonary function  and if these
effects are more easily detected because
conductance of the peripheral airways
 is lower. Previous research has shown
 that the peripheral fraction  of total
 respiratory resistance measured by the
 forced  random  noise technique  in a
 group  of children, whose average age
 was 46 months, to be significantly
 greater than in a group of children
 whose average age was  61  months.
 (Conductance of the peripheral airways
 was less in younger children than in the
 older children.) Other researchers have
 demonstrated a greater number of
 significantly decreased spirometric
 parameters during acute upper respira-
 tory illness in a  group of children less
 than 84 months of age, as compared to a
 group of children greater than 84 months
 of age. These data suggest that there
 are differences in lung function during
 early life attributable to developmental
 phenomena  in the airways and  that
 these differences may be important in
 the manifestation of disease.
  Additionally, data of pulmonary func-
 tion in children have been collected in a
 cross-sectional fashion. No data exist
 which  have been systematically gener-
 ated in a  longitudinal fashion. These
 data are important to determine if lung
 function development in children  pro-
 gresses in a  predictable fashion much
 the same as height and weight develop-
 ment, or if the growth of the lung might
 progress in another as yet undetermined
 pattern.
  This report outlines theanalysisof the
 spirometry data collected over a six-year
 period at the Frank Porter Graham Child
 Development  Center. Only information
 gathered  on  the children when  they
 were well has been included in  this
 analysis. The  data have been analyzed
 in a cross-sectional fashion so that later
 analyses can beperformedtodetermine
 what the relationships of each individual
 child's growth pattern is to the overall
 growth  pattern. Because of the known
 effects of race and sex on lung function,
 the children have been separated  into
 four groups for these analyses: black
 females and males and white females
 and males.
Conclusions
  Over the six year study period, 69
children were followed for an average of
3.5 years each and had an average of
3.14 measurements made per year. The
children, in general, were 90 to 155cm.
tall and spanned an age range of 2'/2 to
12  years. Only data from the children
whose heights were between 100 and
 150 cm., however, were included in the
 regression analyses.
  The regression coefficients and stan-
 dard errors of the six spirometric param-
 eters computed by weighted least squares
 analysis  for  the four race/sex groups
 are shown in Table 1. The coefficients
 for the 95% confidence and 95% predic-
 tion limits are also  listed. Plots of each
 discrete data  point along with the
 regression lines and 95% confidence
 and prediction intervals for each param-
 eter in each of the four race/sex groups
 reveal an excellent  fit of the data to the
 regression lines. Comparisons of plots
 of the regressions for the four race/sex
 groups in general  reveal that, for any
 given  height, white  children have larger
 lung function  parameters than black
 children. The p-values for the tests of no
 difference comparing the regression
 lines (including slope and intercept)
 between the important race/sex group-
 ings are shown in Table 2.  All of these
 comparisons are significantly different
 except for v"max75% for black females
compared to black males and for white
females compared to white males. The
variability parameters (95% prediction
 limits) as computed in these analyses
are similar to variability as computed by
 more classical  methods (e.g.. Mean ±
 2SD).  This suggests that making mea-
surements in  a longitudinal fashion
does not reduce the expected variability,
as demonstrated below.
 1. The feasibility of  obtaining reproduc-
  ible spirometric tests of lung function
  in small children as young as three
  years of age.
 2. Significant racial and sexual differ-
  ences in most spirometric parameters
  of lung function  in young children.
 3. That regression  lines of spirometric
  parameters  of lung  function can be
  adequately described in  young chil-
  dren by a  linear  regression over the
  height range of 100-150 cm.
4. That parameters of variability are
  proportional to  height rather than
  being a constant over the region of
  interest.
Recommendations
  To ascertain the effects of acquired
inslut on  the  lung such as from air
pollution on infectious agents, additional
reference data from populations studied
in an area with minimal air pollution,
and from  populations whose illness
patterns have been closely documented,
are needed. Until  the  effects of  lower

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Table 1.    Weighted Regression Coefficients* for Spirometric Parameters
                                   Black Females
                                                                  Black Males
Parameter*
FVC. '
FEVi, '
PEF. '/sec
FEFzs-75%. '/sec
VmaxsoVo, '/sec
Vmax7s%, '/sec
b"
-1.966±0.084
-1.533±0.076
-3. 1 12±0.290
-0.493±0.211
-0.820±0.245
0.243±0.177
m{
0.0267±0.0008
0.0222±0.0007
0.0531 ±0.0026
0.0195±0.0019
0.0245±0.0022
0.007 3±0.00 16
K*
(xlO3)
0.415
0.378
1.477
1.041
1.213
0.865
Lc
(xlO2)
0.371
0.334
1.281
0.931
1.084
0.781
b
-2.601 ±0.1 00
-2. 191 ±0.090
-4.913±0.343
-1.650±0.246
-1.888±0.291
-0.297±0.209
m
0.0324±0.0009
0.0281 ±0.0008
0.0685±0.0031
0.0292±0.0022
0.0330±0.0026
0.0119±0.0019
K
(xlO3)
0.485
0.437
1.692
1.231
1.478
1.032
L
(x102)
0.372
0.335
1.284
0.933
1.087
0.783
                                   White Females
                                                                  White Males
   Parameter
                                   K
                                 (xlO3)
  L
fx102)
                                                                                         m
  K
(xlO2)
                                  L
                                (x103)
 FVC, '
 FEI/,, '
 PEF. '/sec
 FEFZ5-7s%, '/sec
 VmaxsoVo, '/sec
 1/073*75%, '/sec
-2.969±0.165   0.0365±0.0013   0.708   0.374  -2.442±0.152
-2.469±0.148   0.0313±0.0012   0.639   0.336  -1.676±0.136
-3.846±0.569   0.0611 ±0.0046   2.393   1.288  -1.378±0.523
-1.644±0.414   0.0316±0.0033   1.739   0.936  -0.077±0.380
-2.111 ±0.482   0.0380±0.0039   2.026   1.090  -0.287 ±0.443
-0.256±0.347   0.0130±0.0028   1.485   0.786   0.466±0.319
                        0.0331±0.0013   0.663   0.374
                        0.0256±0.0011   0.581   0.336
                        0.0402±0.0043   2.227   1.288
                        0.0174±0.0032   1.618   0.937
                        0.0209±O.O037   1.885   1.091
                        0.0067±O.O026   1.390   0.786
"Regression equations have the form y=mx + b, where y represents the parameters; m. the slope with units equal to those of the
 parameter divided by cm; b, the intercept with units identical to the parameter; and x, the height in cm.
"Ninety-five percent confidence limits (for the regression line) for any height between 100 and 150 cm can be computed using the
 form (mx + b) ± Kx. where K represents the 95% confidence coefficient.
cNinety-five percent prediction limits (for an individual observation) for any height between 100 and 150 cm can be computed using
 the form (mx + b) ± Lx, where L represents the 95% prediction coefficient.
"Parameters are FVC (forced vital capacity). FEVi (forced expiratory volume in one second), PEF (peak expiratory flow). FEFzs-7s°/o
 (forced expiratory flow during the middle half of the FVC), Vmax50%, (maximum expiratory flow after 50% of the FVC has been
 exhaled), and Vmax7s% (maximum expiratory  flow after 75% of the FVC has been exhaled).
"b - intercept ± S.E.
'm = slope ± S.E.
respiratory illnesses during infancy on
lung growth and development are better
understood, populations whose entire
life  history of  respiratory illness is
known should be studied. Since lower
respiratory illnesses during infancy may
be related to altered lung function later
in life, these illnesses need to be docu-
mented. Documentation should not only
include determination of the etiology of
the illness and  other clinical data but
should also include attempts to charac-
terize changes in lung function during
these illnesses, as well as when illness
free. This will necessitate the continued
effort in developing tests of lung function
which can be utilized in very young
children. Also, reference data for tests
of pulmonary function are needed which
have been collected in a longitudinal
fashion  in illness-free,  non-smoking
individuals 13-25 years of age who are
living in an area relatively free of
atmospheric pollution.
                     Table 2.    P- Values for Tests of No Differences Between the Indicated
                                Regression Lines
                      Comparisons"
FVC    FEV,
PEF     FEF25-75%
       Vmax75%
BF vs BM*
WF vs WM
BF vs WF
BM vs WM
Oc
0
0
0
0
0
0
0
<0.001
<0.003
<0.002
0
<0.001
<0.001
0
0

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