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(Chest. 2003;124:63-69.)
© 2003 American College of Chest Physicians

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

* From the Department of Pulmonary and Critical Care Medicine, Memorial Hospital of Rhode Island and Brown Medical School, Providence, RI.

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: Annie_Parker{at}brown.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
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 ± SD age, 40.8 ± 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 = 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.

Key Words: airway reactivity • airway sensitivity • dysanapsis • methacholine


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The presence of airway hyperresponsiveness to variable stimuli is considered one of the characteristics of asthma.1 Airway size is one factor that may determine the presence of airway hyperresponsiveness 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 5 6 Individuals with low FEF25–75/FVC ratios will have small airway size relative to their lung size and 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 dose-response curve; and (2) sensitivity, expressed by the cumulative dose of methacholine required to cause 20% reduction in FEV1 (PD20).9


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Design
Consecutive subjects who had a >= 20% reduction in FEV1 after <= 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 µm 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 >= 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 (<= 25, > 25 to <= 45, > 45 to <= 65, and > 65 years).

Airway sensitivity was assessed by the PD20. Subjects were classified into four groups based on PD20: <= 1.4 cu, > 1.4 to <= 14 cu, > 14 to <= 64 cu, and > 64 to <= 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
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
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 ).


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  		Table 1. Subject Characteristics and Baseline PFT Data*

 
There was a significant association between 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 >= 0.70 (Table 2 ).


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  		Table 2. Relationship of FEF25–75/FVC Ratio to Airway Reactivity (Log10DRS)*

 
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 <= 25 years, 0.80 ± 0.23 for age > 25 to <= 45 years, 0.68 ± 0.24 for age > 45 and to <= 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.


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  		Table 3. Relationship of FEF25–75/FVC Ratio to Airway Reactivity (Log10DRS) by Age and Gender Groups*

 
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 <= 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).


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  		Table 4. Relationship of FEF25–75/FVC to Airway Sensitivity (PD20)*

 


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  		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 <= 0.0001).

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
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 16 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.

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, ß-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 between airway size and reactivity by considering airway size relative to lung size. Green and colleagues4 proposed that there were substantial between-individual 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 (max50) divided by VC and the static recoil pressure of the lung at 50% of VC (Pst[L]50) [max50/VC x Pst[L]50]. A low (max50/VC x 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 5 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 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 dysanapsis 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.


   Acknowledgements
 
The authors thank Gail Dusseault and Laureen Sheehan for technical support.


   Footnotes
 
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; max50 = maximal flow at 50% of vital capacity

Received for publication November 28, 2001. Accepted for publication January 6, 2003.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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