Ratio Between Forced Expiratory Flow
Between 25% and 75% of Vital Capacity
and FVC Is a Determinant of Airway
Reactivity and Sensitivity to
Methacholine*
Annie Lin Parker, MD, FCCP; Muhanned Abu-Hijleh, MD; and
F. Dennis McCool, MD, FCCP
Study objective: The ratio between forced expiratory flow between 25% and 75% of vital capacity
(FEF25–75) and FVC is thought to reflect dysanapsis between airway size and lung size. A low
FEF25–75/FVC ratio is associated with airway responsiveness to methacholine in middle-aged and
older men. The current study was designed to assess this relationship in both male and female
subjects over a broader range of ages.
Study design: Data analysis of consecutive subjects who had a > 20% reduction in FEV1 after
< 189 cumulative units of methacholine over a 7-year period.
Setting: Pulmonary function laboratory in a university-affiliated hospital.
Patients: A total of 764 consecutive subjects aged 4 to 91 years (mean ⴞ SD age, 40.8 ⴞ 19.6
years). There were 223 male (29.3%) and 540 female (70.7%) subjects.
Measurements and results: Airway reactivity was assessed as the dose-response slope of the
reduction in FEV1 from baseline vs the cumulative dose of inhaled methacholine. The cumulative
dose of methacholine causing 20% reduction in FEV1 (PD20) was used as the indicator of airway
sensitivity. In a linear regression model that included age, height, and percentage of predicted
FEV1, the FEF25–75/FVC ratio accounted for 7.6% of variability in airway reactivity (p < 0.0001,
r2 ⴝ 0.076). Subjects with higher airway sensitivity, indicated by lower PD20, also had a lower
FEF25–75/FVC ratio.
Conclusions: A low FEF25–75/FVC ratio, indicating small airway size relative to lung size, is
associated with higher airway sensitivity and reactivity to methacholine in susceptible subjects.
(CHEST 2003; 124:63– 69)
Key words: airway reactivity; airway sensitivity; dysanapsis; methacholine
Abbreviations: cu ⫽ cumulative units; DRS ⫽ dose-response slope; FEF25–75 ⫽ forced expiratory flow between 25%
and 75% of vital capacity; PD20 ⫽ cumulative dose of methacholine causing 20% reduction in FEV1; PFT ⫽ pulmonary
function test; Pst[L]50 ⫽ static recoil pressure of the lung at 50% of vital capacity; VC ⫽ vital capacity;
V̇max50 ⫽ maximal flow at 50% of vital capacity
presence of airway hyperresponsiveness to
T hevariable
stimuli is considered one of the characteristics of asthma.1 Airway size is one factor that
may determine the presence of airway hyperrespon*From the Department of Pulmonary and Critical Care Medicine, Memorial Hospital of Rhode Island and Brown Medical
School, Providence, RI.
Manuscript received November 28, 2001; revision accepted
January 6, 2003.
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail:
[email protected]).
Correspondence to: Annie Lin Parker, MD, FCCP, Department of
Pulmonary and Critical Care Medicine, Memorial Hospital of
Rhode Island, 111 Brewster St, Pawtucket, RI 02860; e-mail:
[email protected]
siveness to bronchoprovocative agents such as
methacholine. Airway size varies from one individual
to another, and some of this variability cannot be
accounted for by differences in lung size among
individuals.2,3 The term dysanapsis has been used to
describe this disproportionate but physiologically
normal growth between the airways and the lung
parenchyma. Since direct measures of airway and
lung size are often not feasible in vivo, the ratio of
forced expiratory flow between 25% and 75% of vital
capacity (FEF25–75) and FVC (FEF25–75/FVC ratio)
has been used as a surrogate measure of dysanapsis.4 – 6 Individuals with low FEF25–75/FVC ratios will
have small airway size relative to their lung size and
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CHEST / 124 / 1 / JULY, 2003
63
may be more likely to acquire expiratory flow limitation
than individuals with higher ratios. In a study of
subjects 7 to 29 years of age, a low ratio was found to be
a significant predictor of airway hyperresponsiveness to
eucapneic hyperventilation of cold air.6 More recently,
in a study of 929 middle-aged and older men, Litonjua
et al7 found a negative association between this ratio
and the degree of methacholine airway responsiveness.
An epidemiologic study8 from Europe has also suggested that the size of airway may play an important
role in the incidence of asthma.
The current study was designed to assess the
relationship of FEF25–75/FVC ratio and methacholine airway responsiveness over a broader range of
ages and in a group that included women and
children. The airway responsiveness to methacholine
was characterized by the following: (1) reactivity, as
assessed by the slopes of the methacholine doseresponse curve; and (2) sensitivity, expressed by the
cumulative dose of methacholine required to cause
20% reduction in FEV1 (PD20).9
Materials and Methods
Study Design
Consecutive subjects who had a ⱖ 20% reduction in FEV1
after ⱕ 189 cumulative units (cu) of methacholine between
January 1993 and September 2000 were included in the study.
Only subjects with known interstitial lung diseases, neuromuscular diseases, and diaphragm paralysis were excluded. All studies
were performed in the Pulmonary Function Laboratory of
Memorial Hospital of Rhode Island.
Pulmonary Function Testing
Spirometry was performed using standard techniques on the
spirometer (Transfer Test Model C Apparatus; Morgan Scientific; Haverhill, MA). At least three spirograms were performed
until the American Thoracic Society standard for acceptability
and reproducibility of the FVC maneuver was met.10 The
spirogram with the highest value for FVC was used as the
baseline FVC, and the spirogram with the highest FEV1 was used
as the baseline FEV1. All other baseline measurement were
obtained from the spirogram with the highest sum of FVC and
FEV1.10 Following spirometry, lung volumes and specific airways
conductance were determined by variable-pressure body plethysmography (Warren E. Collins; Braintree, MA).10,11 The pulmonary function test (PFT) data were expressed as a percentage of
predicted normal values.12,13
Methacholine Bronchoprovocation Protocol
Serial dilutions of methacholine chloride (Provocholine;
Methapharm; Branford, ON, Canada) were prepared in normal
saline solution containing 0.4% phenol (pH 7.0) and passed
through bacterial-retentive filters with 0.2 ␮m porosity. Methacholine aerosol was delivered using a Rosenthal French Nebulization Dosimeter (Laboratory for Applied Immunology; Baltimore, MD) and a DeVilbiss Nebulizer (DeVilbiss; Somerset, PA)
set for a 0.6-s delivery time with an output of 7.4 L per actuation.
All testing was done with the same equipment by the same two
technicians. Following a control inhalation of diluent, each
patient took five slow inhalations from functional residual capacity to total lung capacity from the dosimeter starting at a
concentration of 0.025 mg/mL. A FVC maneuver was performed
within 5 min of methacholine inhalation. If the reduction in
FEV1 was ⬍ 20% from baseline, five inhalations of increasing
concentrations of methacholine, 0.25 mg/mL, 2.5 mg/mL, 10
mg/mL, and 25 mg/mL, were administered. The time between
administration of different concentrations was ⬍ 3 min. The
corresponding totals were 0.125 cu, 1.4 cu, 14 cu, 64 cu, and 189
cu, with one dose unit being one inhalation of 1 mg/mL. The
study was terminated when FEV1 fell by ⱖ 20% at any concentration or when the maximum dose of methacholine (189 cu) had
been administered.
Data Analysis
Airway reactivity was analyzed as a continuous variable using
the slope of the dose-response curve. The dose-response slope
(DRS) was defined as the reduction in FEV1 from baseline after
the final dose of methacholine inhaled divided by the cumulative
dose inhaled. The DRS was expressed in units of the percentage
reduction in FEV1 per micromole methacholine. Because of their
highly skewed distribution, DRS was logarithmically transformed
(log10) for all analysis. A small constant (0.3) was added to each
value of DRS to eliminate zero and slightly negative values.7,14 A
simple linear regression model was constructed for FEF25–75/
FVC ratio and airway reactivity (log10DRS) with log10DRS as the
dependent variable.
In another analysis, a multiple linear regression model with
log10DRS as the dependent variable was created to include age,
height, and FEV1 percentage predicted and a coefficient of
determination (r2) was obtained. The FEF25–75/FVC ratio was
then added to this model, and a new r2 was obtained. The
difference in these two coefficients (r2) was considered the
explaining power of the FEF25–75/FVC ratio for the variability in
methacholine airway reactivity, independent of age, height, and
FEV1. The analyses were then repeated for both genders
and four different age groups (ⱕ 25, ⬎ 25 to ⱕ 45, ⬎ 45 to ⱕ 65,
and ⬎ 65 years).
Airway sensitivity was assessed by the PD20. Subjects were
classified into four groups based on PD20: ⱕ 1.4 cu, ⬎ 1.4 to
ⱕ 14 cu, ⬎ 14 to ⱕ 64 cu, and ⬎ 64 to ⱕ 189 cu. The cumulative
unit cut-off for each group corresponded to the increments of
methacholine concentration used in our protocol. Differences in
FEF25–75/FVC ratio among groups were determined by using
analysis of variance and the Fisher least-significant difference
multiple-comparison test. Differences were considered significant for p ⬍ 0.05. All analyses were performed using Statview
(SAS Institute; Cary, NC).
Results
A total of 764 subjects were included in this
analysis. Sixty-one of the subjects performed only
spirometry, and the remaining 703 subjects had both
spirometry and lung volume data. The ages of the
subjects ranged from 4 to 91 years (mean ⫾ SD,
40.8 ⫾ 19.6 years). There were 224 male (29%) and
540 female (71%) patients. Baseline PFT results of
the group were all within normal limits (Table 1).
There was a significant association between
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Clinical Investigations
Table 1—Subject Characteristics and Baseline
PFT Data*
Variables
Mean ⫾ SD
Range
No.
Age, yr
Height, inches
Weight, lb
TLC, % predicted
FRC, % predicted
RV, % predicted
FVC, % predicted
FEV1, % predicted
FEF25–75, % predicted
sGaw, % predicted
FEV1/FVC
FEF25–75/FVC
40.8 ⫾ 19.6
63.6 ⫾ 4.6
164.4 ⫾ 49.4
103.9 ⫾ 14.5
98.1 ⫾ 22.9
104.1 ⫾ 33.4
98.4 ⫾ 14.1
93.9 ⫾ 15.1
81.6 ⫾ 26.3
85.8 ⫾ 26.2
79.4 ⫾ 8.0
0.77 ⫾ 0.27
4–91
43–75
38–460
60–169
45–260
27–269
49–142
44–136
16–185
20–201
50–99
0.14–1.79
764
764
764
703
703
703
764
764
764
761
764
764
*TLC ⫽ total lung capacity; FRC ⫽ functional residual capacity;
RV ⫽ residual volume; sGaw ⫽ specific airway conductance.
FEF25–75/FVC ratio and airway reactivity as assessed
by a simple linear regression with log10DRS as the
dependent variable (p ⬍ 0.0001, coefficient of determination r2 ⫽ 0.058). When a multiple linear regression model with log10DRS as the dependent variable
was created to include age, height, and FEV1 percentage of predicted, the r2 was 0.073 (p ⬍ 0.0001).
The r2 went from 0.073 to 0.149 with an increase of
0.076 when FEF25–75/FVC ratio was added to this
model; therefore, the FEF25–75/FVC ratio explained
7.6% of the variability in methacholine airway reactivity, independent of age, height, and FEV1. The
analysis was repeated after removing subjects with
spirometry data suggestive of overt baseline airway
obstruction (FEV1/FVC ⬍ 70%). The association
between FEF25–75/FVC ratio and log10DRS remained highly significant in the 679 subjects who
had an FEV1/FVC ⱖ 0.70 (Table 2).
When the group was divided according to gender,
male subjects had a lower FEF25–75/FVC ratio compared to female subjects (0.70 ⫾ 0.25 vs 0.80 ⫾ 0.27).
The association between FEF25–75/FVC ratio and
log10DRS was significant in both male and female
subjects (Table 2). The r2 was higher in male subjects
(0.146 vs 0.049), but this was most likely due to the
smaller sample size (224 male vs 540 female subjects).
The subject groups were then divided into four age
groups, and the FEF25–75/FVC ratios were lower in the
older age groups (0.94 ⫾ 0.27 for age ⱕ 25 years,
0.80 ⫾ 0.23 for age ⬎ 25 to ⱕ 45 years, 0.68 ⫾ 0.24 for
age ⬎ 45 and to ⱕ 65 years, and 0.55 ⫾ 0.23 for age
⬎ 65 years). Male subjects consistently had a lower
FEF25–75/FVC ratio than female subjects in every age
group. The association between FEF25–75/FVC ratio
and airway reactivity remained significant in all age
groups, with r2 ranging from 0.052 to 0.136 (Table 3).
Because the smoking status of the subjects was not
available, the analysis was not done for smokers vs
nonsmokers.
When the analysis was repeated for FEV1 percentage of predicted and log10DRS with log10DRS as the
dependent variable, significant association was again
noted but with a lower r2 (0.038; p ⬍ 0.0001). There
was a moderate correlation between FEF25–75/FVC
ratio and FEV1 percentage of predicted (r ⫽ 0.47,
p ⬍ 0.0001). As expected, there was a much stronger
correlation between FEF25–75 and FEF25–75/FVC ratio
(r ⫽ 0.84). Both had significant association with
log10DRS in simple linear regression models (r2 ⫽ 0.10
for FEF25–75); however, when a multiple regression
model was constructed to include age, height, FEV1,
FEF25–75, and FEF25–75/FVC ratio with log10DRS as
the dependent variable, only FEF25–75/FVC ratio had
significant p value (p ⫽ 0.02), but not FEV1 (p ⫽ 0.21)
or FEF25–75 (p ⫽ 0.61).
When subjects were grouped according to their
airway sensitivity as measured by PD20, there were
significant differences in FEF25–75/FVC ratios among
the groups (Table 4). Subjects with lower PD20 values,
indicating higher airway sensitivity to methacholine,
had lower FEF25–75/FVC ratios. When subjects
were classified into four quartiles according to their
FEF25–75/FVC ratios with similar numbers of patients
in each quartile, subjects in the quartile with the lowest
FEF25–75/FVC ratio had significantly lower PD20 values compared to subjects in the other three quartiles
(all p ⱕ 0.0001) [Fig 1]. There was a significant correlation between airway reactivity and sensitivity to
methacholine when analysis was made of log10DRS
and PD20 (r ⫽ 0.79, p ⬍ 0.0001).
Table 2—Relationship of FEF25–75/FVC Ratio to Airway Reactivity (Log10DRS)*
Variables
Patients, No.
Age, yr
Height, inches
FEV1, % predicted
FEF25–75/FVC
r2†
All subjects
FEV1/FVC ⱖ 0.70
Male subjects
Female subjects
764
679
224
540
40.8 ⫾ 19.6
38.5 ⫾ 18.7
38.4 ⫾ 19.7
41.8 ⫾ 19.5
63.6 ⫾ 4.6
63.5 ⫾ 4.7
67.0 ⫾ 5.4
62.3 ⫾ 3.4
93.9 ⫾ 15.1
95.9 ⫾ 13.8
91.1 ⫾ 15.3
95.0 ⫾ 14.9
0.77 ⫾ 0.27
0.82 ⫾ 0.23
0.70 ⫾ 0.25
0.80 ⫾ 0.27
0.076
0.042
0.146
0.049
*Data are presented as mean ⫾ SD.
†The difference in r2 when the FEF25–75/FVC ratio was added to the baseline linear regression models including age, height, and FEV1
percentage of predicted in the analysis. All p ⬍ 0.0001.
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65
Table 3—Relationship of FEF25–75/FVC Ratio to Airway Reactivity (Log10DRS) by Age and Gender Groups*
Age Groups, yr
Patients, No.
Age, yr
Height, inches
FEV1, % predicted
FEF25–75/FVC
r2 †
187
61
126
289
92
197
182
43
139
106
28
78
16.4 ⫾ 5.5
15.4 ⫾ 5.7
16.9 ⫾ 5.4
35.9 ⫾ 5.5
35.9 ⫾ 5.5
35.9 ⫾ 6.1
54.5 ⫾ 5.7
53.1 ⫾ 6.1
55.0 ⫾ 5.6
73.9 ⫾ 5.8
74.8 ⫾ 6.3
73.6 ⫾ 5.6
62.0 ⫾ 6.3
63.4 ⫾ 8.1
61.4 ⫾ 5.1
65.1 ⫾ 3.7
69.0 ⫾ 2.8
63.3 ⫾ 2.6
63.6 ⫾ 3.7
68.3 ⫾ 3.4
62.2 ⫾ 2.3
62.4 ⫾ 3.1
65.8 ⫾ 2.4
61.1 ⫾ 2.3
101.4 ⫾ 12.4
99.1 ⫾ 12.5
102.5 ⫾ 12.3
94.1 ⫾ 13.0
94.0 ⫾ 12.4
94.2 ⫾ 13.4
89.0 ⫾ 14.4
83.4 ⫾ 14.4
90.7 ⫾ 14.0
88.3 ⫾ 19.6
75.8 ⫾ 15.0
92.8 ⫾ 19.1
0.94 ⫾ 0.27
0.86 ⫾ 0.25
0.98 ⫾ 0.24
0.80 ⫾ 0.23
0.72 ⫾ 0.18
0.84 ⫾ 0.24
0.68 ⫾ 0.24
0.60 ⫾ 0.22
0.70 ⫾ 0.24
0.55 ⫾ 0.23
0.43 ⫾ 0.20
0.59 ⫾ 0.22
0.052
0.049
0.043
0.083
0.245
0.044
0.064
0.195
0.038
0.136
0.132
0.147
ⱕ 25
Male
Female
⬎ 25 to ⱕ 45
Male
Female
⬎ 45 to ⱕ 65
Male
Female
⬎ 65
Male
Female
*Data are presented as mean ⫾ SD.
†The difference in r2 when the FEF25–75/FVC ratio was added to the baseline linear regression models including age, height, and FEV1
percentage of predicted in the analysis. All p ⬍ 0.05 except for male subjects ⱕ 25 yr old (p ⫽ 0.055).
Discussion
Analysis of this group of 764 subjects showed
significant association between FEF25–75/FVC ratio
and airway reactivity and sensitivity. Subjects with
lower FEF25–75/FVC ratios had higher airway reactivity and sensitivity to methacholine as assessed by
the DRS and PD20. This association existed for both
male and female subjects, subjects of various age
groups and remained significant after excluding subjects with evidence of overt airway obstruction.
Airway hyperresponsiveness is considered one of
the characteristics of asthma.1 Even though it can be
demonstrated in asymptomatic, nonasthmatic subjects, there is evidence that airway hyperresponsiveness may precede the symptoms and clinical diagnosis of asthma in both children and adults.15–17 These
findings suggest that airway hyperresponsiveness
may play a role in the pathogenesis of asthma.
Identifying pulmonary function characteristics that
are associated with airway hyperresponsiveness may
provide a better understanding of mechanisms that
predispose an individual to asthma. Our findings that
the FEF25–75/FVC ratio was significantly associated
with airway reactivity and sensitivity suggest that
small airways relative to lung size may be a feature
that promotes asthma.
Table 4 —Relationship of FEF25–75/FVC to Airway
Sensitivity (PD20)*
PD20, cu
Patients,
No.
Age, yr
Height,
inches
FEF25–75/
FVC†
ⱕ 1.4
⬎ 1.4 to ⱕ 14
⬎ 14 to ⱕ 64
⬎ 64 to ⱕ 189
52
226
233
253
43.5 ⫾ 19.6
38.9 ⫾ 20.7
40.7 ⫾ 19.0
42.1 ⫾ 19.1
63.5 ⫾ 4.5
63.0 ⫾ 5.0
63.7 ⫾ 4.6
64.2 ⫾ 4.1
0.61 ⫾ 0.24
0.71 ⫾ 0.29
0.79 ⫾ 0.24
0.84 ⫾ 0.26
*Data are presented as mean ⫾ SD.
†All p ⬍ 0.05.
Airway responsiveness to methacholine is often
analyzed in the construct of airway sensitivity and
reactivity. Airway sensitivity can be quantified by the
threshold dose of methacholine that leads to a
predetermined level of airway narrowing. Factors
that can affect airway sensitivity may include intrinsic
properties of the airway smooth muscle, the sympathetic and parasympathetic tones, and the level of
airway inflammation. Once airway narrowing has
been triggered, further airway narrowing may occur
in response to a higher dose of methacholine. Airway
reactivity represents the degree of further narrowing
and can be quantified as the slope of the relationship
between the cumulative dose of methacholine and
the decrement of FEV1. Airway reactivity may depend on factors such as synthesis of prostaglandins18
and stimulation of airway irritant receptors19 and
may be independent of factors that affect airway
sensitivity. For example, ␤-adrenergic blockade
changes the threshold, but not the slope of the
dose-response curves to acetylcholine.20
The association between airway size and hyperresponsiveness has been explored.7,21–22 Britton and
colleagues21 measured airway reactivity to methacholine in a large, random population sample of
adults between the ages of 18 years and 70 years.
They demonstrated that at any given age, airway
caliber as indicated by the baseline FEV1, in absolute
terms or as percentage of predicted, and atopy were
the major determinants of airway hyperreactivity in
the general population. Kanner et al22 found a
similar association between FEV1 and airway hyperresponsiveness to methacholine in a group of smokers between ages of 35 years and 60 years with mild
COPD. The positive association between FEV1 percentage of predicted and log10DRS in our study is
consistent with these findings.
We chose to further analyze the association be-
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Clinical Investigations
Figure 1. Relationship of FEF25–75/FVC ratio to airway sensitivity (PD20). All subjects were classified
into four groups according to their FEF25–75/FVC ratio with equal number of subjects in each group
(quartiles). The mean PD20 measurements for each quartile were 30.7 cu, 50.5 cu, 58.7 cu, and
54.7 cu. Subjects who had an FEF25–75/FVC ratio in the lowest quartile had significantly lower
PD20 compared to subjects in the other three quartiles (all p ⱕ 0.0001).
tween airway size and reactivity by considering airway size relative to lung size. Green and colleagues4
proposed that there were substantial betweenindividual differences in airway size independent of
lung parenchymal size. These differences may have an
embryologic basis reflecting physiologically normal but
disproportionate growth of the airways and parenchyma within the lung. They termed this phenomenon dysanapsis and speculated that differences in the
airway-parenchymal relationship might influence the
pathogenesis of airway diseases. Mead5 subsequently
showed that dysanapsis manifested itself by an inverse
relationship between vital capacity (VC) and the product of the ratio of maximal flow at 50% of VC (V̇max50)
divided by VC and the static recoil pressure of the lung
at 50% of VC (Pst[L]50) [V̇max50/VC ⫻ Pst[L]50]. A
low (V̇max50/VC ⫻ Pst[L]50)/VC ratio would indicate
smaller airways relative to the lung parenchyma. A less
invasive measure of dysanapsis is the FEF25–75/FVC
ratio.4 – 6 A major advantage of using the FEF25–75/FVC
ratio is that both parameters can be derived from a
maximal expiratory flow-volume loop.
The relationship between the FEF25–75/FVC ratio
and airway reactivity has been investigated. Litonjua
et al7 found that the FEF25–75/FVC ratio was negatively associated with the degree of methacholine
airway responsiveness (as assessed by the slope of the
log10 dose and FEV1 relationship) in a group of 929
middle-aged and older men (average age, 60.5 ⫾ 7.7
years; range, 41 to 86 years). In their study, FEF25–75/
FVC ratio explained approximately 5.1% of the variability of log10DRS. They concluded that individuals
with small airways relative to lung size may be more
likely to have hyperresponsive airways than those without dysanapsis.
We extended the findings of Litonjua et al7 to a
group of subjects that included female subjects and
younger adults. We confirmed their findings that the
FEF25–75/FVC ratio is a determinant of airway reactivity to methacholine. In both studies, despite the
difference in subject population, the coefficients of
determination were in the similar range (5.1% vs
7.6%). We also found that the FEF25–75/FVC ratio is
a stronger determinant of airway reactivity than
FEV1. The r2 value for FEF25–75/FVC ratio was
greater than the r2 for FEV1 in simple regression
models (0.058 vs 0.038). Given the expected strong
correlation between FEF25–75 and FEF25–75/FVC
ratio, one may expect the same result for FEF25–75.
Indeed, a significant association was also noted between FEF25–75 and airway reactivity. However, in a
multiple linear regression model that included age,
height, FEV1, FEF25–75, and FEF25–75/FVC ratio
with log10DRS as the dependent variable, only
FEF25–75/FVC ratio had a significant p value. These
findings suggest that the airway size relative to lung
size is a more important determinant of airway
reactivity than the absolute size of the airway.
Another characteristic of the airway response to
various triggers is airway sensitivity. We assessed
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CHEST / 124 / 1 / JULY, 2003
67
airway sensitivity as the PD20. When subjects were
classified into four groups according to their PD20,
those with lower PD20 had lower FEF25–75/FVC
ratio. Similarly, when subjects were classified into
four groups according to their FEF25–75/FVC ratio,
subjects with the lowest ratio also had the lowest
PD20. Both findings support the notion that subjects
who were more sensitive to methacholine have
smaller airway size relative to their lung size.
Dysanapsis between airway size and lung size may
have an embryologic basis,4 but acquired factors
such as smoking or inflammation that affect the
airway wall thickness may alter the relationship between airway and lung size and lower the FEF25–75/
FVC ratio. We did not control for the history of
smoking or the level of airway inflammation because
these data were not available; however, Litonjua and
colleagues7 have found that the association between
FEF25–75/FVC ratio and methacholine airway responsiveness was not affected by the pack-years of smoking,
eosinophil counts, or IgE measurements. These findings suggest that dysanapsis in the form of small airway
size relative to lung size, either intrinsic or acquired,
will lead to higher airway reactivity and sensitivity to
methacholine.
Epidemiologic data on asthma prevalence have
demonstrated a gender difference that varies with
age. Asthma and wheezing are more prevalent in
boys than in girls.23,24 During puberty, there is a
gender reversal in the prevalence25,26; after puberty,
women have a higher prevalence and morbidity rate
of asthma than men.8,27 Gender differences in the
rate of lung growth and in airway size have been
suggested as one of the potential explanations for this
phenomenon.28 Female infants have proportionately
larger airways relative to their lung size than do male
infants.29 During childhood and adolescence, the
growth of airway, relative to lung parenchyma, occurs faster in teenage boys than in teenage girls.30,31
These findings suggest that smaller airways may have
a role in the higher prevalence of asthma and
wheezing in prepubertal boys; the subsequent faster
growth of airways in adolescent male compared to
female subjects may partly explain the gender reversal of asthma prevalence after puberty. Male subjects
in our study had a lower FEF25–75/FVC ratio than
female subjects in all age groups. Our subjects were
a preselected group who were symptomatic with
airway hyperresponsiveness; therefore, the results of
persistently lower FEF25–75/FVC ratio in male subjects cannot be generalized to a general population.
However, the fact that the association of lower
FEF25–75/FVC ratios with higher airway reactivity
and sensitivity exist in both genders and in all age
groups suggests that the association between dys-
anapsis and airway hyperreactivity may be the potential link between anatomic variations and the clinical
development of asthma.
We conclude that FEF25–75/FVC ratio is a determinant of airway responsiveness to methacholine. A
low FEF25–75/FVC ratio, indicating small airway size
relative to lung size, is associated with higher airway
sensitivity and reactivity to methacholine in susceptible subjects.
ACKNOWLEDGMENT: The authors thank Gail Dusseault and
Laureen Sheehan for technical support.
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