JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2006, 57, Supp 4, 263–271
www.jpp.krakow.pl
S. OSTROWSKI, W. BARUD
FACTORS INFLUENCING LUNG FUNCTION: ARE THE PREDICTED
VALUES FOR SPIROMETRY RELIABLE ENOUGH?
Department of Medicine, Lublin University Medical School, Lublin, Poland
Spirometric lung function parameters are used as a diagnostic tool and to monitor
therapy effectiveness or the course of disease. On the other hand, forced expiratory
volume
in
one
second
(FEV1)
and
forced
vital
capacity
(FVC)
are
important
predictors of morbidity and mortality in elderly persons. In clinical use, FEV1 and
FVC are measured in liters and usually each is expressed as a percentage of the
predicted value. Reference values used for the prediction of lung function should be
reliable. It seems crucial that the reference cohort be representative. There is no
doubt that gender and height are the most important predictors of lung function. The
third
predictor,
age,
may
be
a
confounding
factor.
The
study
of
age-dependent
changes in lung function through the lifespan reveals distinctive differences. The
FEV1 and FVC in adults are related to the maximum level attained, the plateau
period, and the rate of lung function decline. A non-linear dependence between age
and lung function parameters is more complex. The maximum level of lung function,
possible to attain, is influenced by a genetic factor. The plateau and decline phases
are closely connected with several independent predictors. In the last decade, some
new factors influencing lung function have been established. A relation between lung
function and hyperglycemia of diabetes mellitus is a novel field of interest. Also, the
influence on lung function of waist size, weight, and body composition or muscle
strength are underscored. These, previously not full well unrecognized, factors make
it difficult to get accurate norms with regression equations, traditionally using sex,
height, and age as predictors.
Key
w o r d s : diabetes mellitus, lung function, predicted values, spirometry
INTRODUCTION
Spirometric lung function parameters are used as a diagnostic tool and to
monitor therapy efficacy or course of the disease. On the other hand, lung
264
function parameters including forced expiratory volume in one second (FEV1)
and
forced
vital
capacity
(FVC)
are
important
predictors
of
morbidity
and
mortality in elderly persons. In practical use, the FEV1 and FVC are measured in
liters and usually each expressed as a percentage of predicted values. The Global
Initiative for Chronic Obstructive Lung Disease (GOLD) and Global Initiative for
Asthma
(GINA)
both
established
criteria
classifying
patients
with
COPD
or
asthma into categories according to FEV1/FVC and FEV1 expressed as a percent
of predicted values (1, 2). Conventional assessments of obstructive lung disease
course are based on the severity of symptoms, amount of
β2-agonist used to treat
the symptoms, and lung function rated as % of predicted values. Moreover, the
FEV1 predicted values are used as a selective or outcome variable in research.
Predicted values are calculated from the measurements performed in reference
groups,
according to height, age, and gender. The reference values used for the
prediction of lung function should be reliable. It seems, therefore, crucial that the
reference cohort be representative and free of factors interfering with the results.
The question arises of whether the predicted values for the FEV1 and FVC are
reliable enough for all the purposes they are used for.
There is no doubt that gender and height are the most important predictors of
lung function. Height linearly correlates with lung size (3). The third predictor,
age, seems likely a confounding factor. Studying age-dependent changes of lung
function through the lifespan reveals distinct differences: FEV1 and FVC keep
increasing from birth to the age of 25 years, then remain stable for 5-10 years or
more, and start declining in later adulthood. Population studies have revealed that
pulmonary function, following the adolescent growth phase, appears in a steadystate, where there is little or no growth occurring up to the age of 40 years. Robins
at al (4) concede that in young adult males lung function is not in a steady-state
and that as many as 40% of them have a significant slope, either positive or
negative. Our previous observations made in a male cohort of active coal miners,
professionally exposed to dust, indicated lack of changes in FEV1 and FVC up to
the age of 34-40 years in 20% of the investigated subjects (5). The FEV1 and FVC
in adults are related to the maximum level attained, the plateau period, and the
subsequent rate of decline with age. A non-linear dependence between age and
lung function is complex. The maximum level of lung function being attained is
influenced by a genetic factor. There is some evidence for the possible link
between higher levels of FEV1 and FVC and chromosome 4, 6, and 18. The
plateau phase and the rate of decline of lung function are closely connected with
several independent predictors of FEV1 decline, including cigarette smoking,
occupational
productive
and
cough,
environmental
or
exposures,
malnutrition.
In
the
airways
last
hyperresponsiveness,
decade,
some
new
factors
influencing lung function have been established. Some of them, such as dyspnea
on exertion, asthma, or pneumonia pertain to a lung disease, but others such as
hypertension
or
chronic
heart
failure
indicate
a
heart
disease.
The
relation
between lung function and diabetes mellitus and hyperglycemia is a novel field
265
of interest. Patients with type 2 diabetes present a lower lung function. Moreover,
impaired lung function is considered a risk factor for glucose intolerance, insulin
resistance, and type 2 diabetes mellitus. Finally, the influence of waist size,
weight,
body
composition,
or
muscle
strength
on
lung
function
should
be
considered as sources of variation in FEV1 and FVC. A spate of confounding
factors make it difficult to get accurate norms for lung function with regression
equations, traditionally using sex, height, and age as predictors.
Genetic factors and lung function
The influence of genetic factors on pulmonary function, as represented mostly
by FEV1 and FVC, has been investigated in several studies. FVC is taken as a
measure of lung size and FEV1 as that of both lung size and rate of airflow.
Schilling et al (6) studied respiratory symptoms and lung function in 376 families
having 816 children. They presented a highly significant association between the
prevalence of wheeze in parents and their younger children. Wheeze in children
also was significantly associated with a parental history of asthma, and lung
function
was
accounting
lower
for
in
height,
children
weight,
with
age,
a
family
sex,
history
and
race,
of
asthma.
children’s
Even
lung
after
function
correlated significantly with parents’ lung function. In 271 pairs of parent and
natural children
Lebowitz et al (7) found a family aggregation of lung function
and body habitus, the major determinant of pulmonary function, suggesting an
important genetic influence on lung function measurements. Astemborski et al
(8), using statistical procedures, were able to separate the relative importance of
genetic and non-genetic factors influencing familial aggregation of pulmonary
function among adults. The familial aggregation of ventilatory function has been
described
in
a
Hispanic
population
of
New
Mexico
(9).
The
estimates
of
heritability were 0.43 for FVC and 0.42 for FEV1 if neither parent smoked and
0.65 for FVC and 0.44 for FEV1 if both parents smoked. The study concludes that
there is a moderate degree of heritability of FVC and FEV1 (9). The findings of
correlation between lung function and genetic factors were the basis for further
investigations. The National Heart, Lung, and Blood Institute Family Heart Study
data
showed
a
high
heritability
of
pulmonary
function.
The
next
step
was
identification of chromosomal regions influencing FEV1, FVC, and FEV1/FVC.
The genome scan identified regions on chromosomes 4 and 18, with a logarithm
of
the
odds
chromosomes
genotyping.
favoring
were
The
linkage
further
FEV1/FVC
(LOD)
scores
evaluated
by
ratio
linked
was
above
2.5,
incorporating
to
and
these
additional
chromosome
4
two
marker
around
28
centimorgans (cM; D4S1511) with a LOD score of 3.5, and the transformed ratio
was
linked
to
the
same
region
with
a
LOD
of
2.0.
FEV1
and
FVC
were
suggestively linked to regions on chromosome 18 with multipoint LOD scores of
2.4 for FEV1 and 1.5 for FVC at 31 cM and a LOD of 2.9 for FVC at 79 cM (10).
A
next
genome
scan
of
pulmonary
traits
in
the
Framingham
Heart
Study
266
identified a region on chromosome 6qter with evidence for linkage to FEV1 and
the FEV1/FVC ratio. For this study, additional markers were genotyped in the
region
to
refine
the
location
of
linkage
and
test
for
the
relationship.
The
chromosome 6 telomeric region provided significant evidence of linkage with the
additional markers, resulting in a maximum multipoint LOD score of 5.0 for
FEV1 at 184.5 cM. LOD scores for FVC and the FEV1/FVC ratio were above 1.0
in this region. Evidence for the association with FEV1 and FVC was observed
with D6S281 at 190 cM. The strongest effect was seen with the 224 allele, which
was associated with higher levels of FEV1 and FVC in allele carriers compared
with those carrying other alleles. This study supports the presence of a gene
influencing pulmonary function on the q-terminus of chromosome 6 in the region
of 184 cM (D6S503) to 190 cM (D6S281) (11). Using segregation analysis,
Malhorta et al (12) analyzed data of 264 members of 26 Utah Genetic Reference
pedigrees and inferred major locus inheritance of the FEV1/FVC ratio, but they
could not distinguish between a dominant or recessive mode of inheritance.
Suggestive evidence of linkage for FEV1/FVC was found on chromosome 2 and
chromosome 5.
Dietary antioxidants and lung function
The relationship between lung function, respiratory symptoms, and diet has
recently
received
considerable
attention.
Antioxidants
may
protect
the
lungs
against oxidant attack from harmful irritants, such as ozone, nitrogen dioxide, and
cigarette smoke (13-15). Positive associations between lung function in adults
and antioxidant vitamins have been demonstrated in several epidemiological
studies (16-18). These associations relate mainly to vitamin C but some studies
have reported associations with vitamin E and
β-carotene
(19). In the analysis
carried out in a sample of 1616 randomly selected adults, aged 35-79, free of
respiratory disease, Schunemann et al (20) showed that antioxidant vitamins may
play a role in respiratory health and that vitamin E and
β-cryptoxanthine
appear
to be stronger correlates of lung function than other antioxidant vitamins.
Hyperglycemia, diabetes mellitus, and lung function
A
number
of
cross-sectional
studies
have
reported
negative
correlations
between ventilatory function and the markers of glucose intolerance. Lange et al
(21) analyzed data of 11763 subjects from the population of Copenhagen City,
aged 20 or more, to assess possible associations between diabetes mellitus (DM),
plasma
glucose,
FVC
and
FEV1.
They
noticed
a
slight
impairment
of
lung
function in all age groups of diabetic subjects. It was more prominent in insulintreated diabetic than in subjects treated with oral hypoglycemic agents and/or
diet. Also, subjects in whom diabetes was not diagnosed presented a significant
relationship between the decline in lung function and raised plasma glucose
concentration. FVC and FEV1 was reduced by 334 ml and 239 ml in diabetic
267
subjects treated with insulin and by 184 ml and 117 ml in diabetic subjects treated
with
hypoglycemic
agents
and/or
diet,
respectively,
compared
with
control
subjects. The association between lung function, on the one side, and insulin
resistance and Type 2 diabetes, on the other side, was found in a cross-sectional
analysis made by Lawlor et al (22). Data were obtained from 3911 women aged
60-79. The FEV1 and FVC were inversely associated with insulin resistance and
prevalence of Type 2 diabetes mellitus (22). In another work, Lange et al (23)
studied more than 9000 subjects. During a 5-year observation period, declines in
FVC
and
FEV1
were
investigated
in
subjects
with
diabetes,
subjects
who
developed diabetes during that period, and non-diabetic subjects. The subjects
who developed diabetes during the observation period had the average annual
declines
in
FVC
and
FEV1
of
29
ml
and
25
ml,
respectively,
which
was
appreciable more than those in the non-diabetic subjects. By contrast, the subjects
who had had diabetes before the enrollment into the study had a decline of
ventilatory function that was not significantly greater than that the non-diabetic
subjects. The results suggest that diabetes, at its onset, is associated with a
significantly accelerated decline of ventilatory function, but later its impact on
ventilatory function abates (22). Tricia et al (24) analyzing data from the Third
National Health and Nutrition Examination Survey looked for the relationship
between lung function and glucose tolerance in adults without a clinical diagnosis
of
diabetes.
They
found
that
the
plasma
glucose
level
2
hours
after
oral
administration of 75 g of glucose was inversely related to FEV1, with a difference
of
-144.7
ml
for
persons
in
the
highest
quintile
of
post-challenge
glucose
compared with the lowest one. Similar associations were seen for FVC, but not
for the FEV1/FVC ratio. In the whole study population, persons with previously
diagnosed diabetes had an average FEV1 of 119.1 ml lower than that in persons
without diabetes. Additionally, patients with poorer control of diabetes had a
lower FEV1 (24).
Coronary events, hypertension, heart failure, and lung function
The relationship between an increased risk of cardiovascular mortality and low
levels of ventilatory function has long been recognized and reported in prospective
population studies. Diminished vital capacity deserves continued attention as a
possible coronary risk factor. Its relation to subsequent coronary events is not well
explained. In 1976, Friedman et al (25) published a paper about risk factors for
myocardial infarction and sudden cardiac death. They found a lower FVC level in
persons who later had a first myocardial infarction. The results were compared
with the matched-risk and non-risk factor groups for cardiovascular events. The
mean vital capacity, as measured at health checkups, was lower in persons who had
myocardial infarction than in risk factor matched controls: 3.17 vs. 3.29 liters
(P<0.05) and non-risk factor matched controls: 3.16 vs. 3.41 liters (P<0.001). The
FEV1 was also inversely related to the later development of myocardial infarction
268
or sudden deaths, but the FEV1/FVC was not. Heavy smoking, productive cough,
and
exertional
dyspnea
were
associated
with
diminished
total
vital
capacity.
However, exclusion of persons presenting with these complaints and those with
cardiac enlargement did not reduce the predictive value of total vital capacity. In a
longitudinal population study of 1462 women, aged 38-60, the peak expiratory
flow showed a significant negative correlation with the 12-year incidence of
myocardial infarction, electrocardiographic changes suggesting ischemic heart
disease, stroke, and death (26).
Table 1. Factors influencing or related to lung function.
gender
height
age
weight (obesity, fat distribution, free fatty mass)
smoking (active, passive)
race
genetic factor
generation acceleration of growth
air pollution (occupational and/or environmental exposure)
asthma
bronchial hyperresponsivenes
chronic obstructive pulmonary disease
chronic cough
dyspnea on exertion
heart failure, coronary artery disease,
β-mimetics,
hypertension
diet (malnutrition, dietary antioxidants)
impaired glucose tolerance,
diabetes mellitus
muscular disorders
hormonal disorders
equipment and technique of measurement
others
DISCUSSION
The overview of studies concerning different relationships of lung function
and various factors that take part in shaping this function revealed a complicated
structure of FEV1 and FVC conditioning. Beyond gender, height, and age, there
are a lot of other factors significantly influencing lung function. These factors are
listed in Table 1. The complexity of factors influencing lung function uncovers
difficulties in establishing the proper, reliable predicted values for FEV1 and
269
FVC. The majority of equations used for the estimation of normal values contain
at least four elements: first, the mean value in early adulthood reflecting the
maximum level of FEV1 or FVC attained; second, relation to height, imitating
dependence between height and lung volume; third, relation to age, imitating the
mean annual decrease from the age of 25 years until senility; and fourth, a free
factor of regression. Recently, Chinn et al (27) presented different sources of
FEV1 and FVC variability, but, first of all showed, significant differences of the
measured FEV1 in different populations of young adults. Ipso facto, they indicate
the weakness of the first element of regression equations. The other elements also
have many shortcomings, of which some were presented above. The sum of
shortcomings is reflected in low regression coefficients in most of the used
reference equations (28).
In
conclusion,
in
my
opinion,
the
currently
used
reference
equations
approximate lung function changes insufficiently. The weakest points of these
equations are that they are not well fit for different populations and not well
reflecting age-changes of FEV1 and FVC. Thus, the time perhaps has come to
change the philosophy of the predicted values for lung function tests and to
introduce
personalized
values
for
spirometry.
Spirometric
indices
should
be
obtained at the age of 20 and 40 or 20, 30, and 40 years of an individual. Such
values would then become a reference for individual changes of lung function
with further progressing age.
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Author’s address: S. Ostrowski, Department of Medicine, Lublin University Medical School,
Lublin, Staszica 16 St., 20-081 Poland; phone: + 48 81 5327717. E-mail: sjost@op.pl