Lung Function in Adults with Stable but Severe Asthma: Air Trapping
and Incomplete Reversal of Obstruction with Bronchodilation
Ronald L. Sorkness1, Eugene R. Bleecker2, William W. Busse1, William J. Calhoun3, Mario
Castro4, Kian Fan Chung5, Douglas Curran-Everett6, Serpil C. Erzurum7, Benjamin M. Gaston8,
Elliot Israel9, Nizar N. Jarjour1, Wendy C. Moore2, Stephen P. Peters2, W. Gerald Teague10,
Sally E. Wenzel6, for the National Heart Lung and Blood Institute Severe Asthma Research
1University of Wisconsin, Madison, WI; 2Wake Forest University, Winston-Salem, NC;
3University of Pittsburgh, Pittsburgh, PA, and University of Texas Medical Branch, Galveston,
TX; 4Washington University, St. Louis, MO; 5Imperial College, London, UK; 6National Jewish
Medical and Research Center, Denver, CO; 7Cleveland Clinic, Cleveland, OH; 8University of
Virginia, Charlottesville, VA; 9Brigham & Women’ s Hospital, Boston, MA; 10Emory University,
Running Head: Physiological Characteristics of Severe Asthma
Ronald L. Sorkness, PhD
University of Wisconsin
777 Highland Ave
Madison, WI 53705
phone: 608 263-6672
fax: 608 263-3104
Page 1 of 37Articles in PresS. J Appl Physiol (November 8, 2007). doi:10.1152/japplphysiol.00329.2007
Copyright © 2007 by the American Physiological Society.
5-10% of asthma cases are poorly controlled chronically and refractory to treatment, and these
severe cases account for disproportionate asthma-associated morbidity, mortality, and health
care utilization. While persons with severe asthma tend to have more airway obstruction, it is
not known whether they represent the severe tail of a unimodal asthma population, or a severe
asthma phenotype. We hypothesized that severe asthma has a characteristic physiology of
airway obstruction, and we evaluated spirometry, lung volumes, and reversibility during a stable
interval in 287 severe and 382 non-severe asthma subjects from the Severe Asthma Research
Program. We partitioned airway obstruction into components of air trapping (indicated by FVC)
and airflow limitation (indicated by FEV1/FVC). Severe asthma had prominent air trapping,
evident as reduced FVC over the entire range of FEV1/FVC. This pattern was confirmed with
measures of RV/TLC in a subgroup. In contrast, non-severe asthma did not exhibit prominent
air trapping, even at FEV1/FVC<75% predicted. Air trapping also was associated with increases
in total lung capacity and functional reserve capacity. After maximal bronchodilation, FEV1
reversed similarly from baseline in severe and non-severe asthma, but the severe asthma
classification was an independent predictor of residual reduction in FEV1after maximal
bronchodilation. An increase in FVC accounted for most of the reversal of FEV1when baseline
FEV1was <60% predicted. We conclude that air trapping is a characteristic feature of the
severe asthma population, suggesting that there is a pathological process associated with
severe asthma that makes airways more vulnerable to this component.
airway closure; difficult asthma; fixed obstruction
Page 2 of 37
Severe asthma, broadly defined as asthma that is poorly controlled chronically and refractory to treatment,
includes only 5-10% of persons with asthma, but accounts for disproportionate asthma-related morbidity,
mortality, and utilization of health care resources (31; 34; 39; 48). Although those classified as severe
asthma may have more airway obstruction as measured by spirometric variables when compared with
asthma subjects not classified as severe (10; 33; 41), it is not clear whether the severe group has a
distinguishing physiological profile, versus representing a sampling from the more severe tail of the inclusive
asthma population. Moore and colleagues (33) compared subjects classified as having severe asthma with
subjects having moderate asthma, defined as those with forced expiratory volume in 1 s (FEV1)<80%
predicted and treated with inhaled corticosteroids, but not meeting the criteria for severe asthma. These
groups were not statistically different with regard to FEV1, but the forced vital capacity (FVC) was
significantly lower in the severe group compared with the moderate group (33), suggesting that the pattern
of airway obstruction might be different in severe asthma.
Asthma patients with a history of frequent exacerbations have more airway closure, as measured by
elevated closing capacities during stable periods (17) and by relatively greater changes in FVC in response
to inhaled histamine challenge (13). Gibbons and colleagues (13) presented the concept that the FEV1is
sensitive to both airway narrowing and airway closure, and that the airway closure component can be
evaluated from changes in the FVC, while FEV1/FVC ratio evaluates the airway narrowing component.
They argued that airway closure is a more dangerous type of airway obstruction, and that evaluating
changes in FVC may reveal information about the underlying asthma pathophysiology that is not apparent
from the changes in FEV1.
We hypothesized that airway closure/near closure is a distinguishing physiological characteristic of
severe asthma. Developing further the concept of Gibbons (13), we show that alterations in FEV1can be
partitioned quantitatively into components of airflow limitation and air trapping, and we evaluate the relative
contributions of these components to the airway obstruction of severe versus non-severe asthma.
Page 3 of 37
Study Subjects. The Severe Asthma Research Program (SARP) is a multicenter asthma research group
funded by the National Heart, Blood and Lung Institute (49). Ten SARP sites enrolled subjects for the
purpose of investigating severe asthma, and contributed a standardized set of data to a central data
coordinating center, with the goal of creating a database of characteristics of a large number of subjects
with severe asthma during a period of stable disease. All procedures were approved by site-specific
institutional review boards, as well as an independent data safety monitoring board. After providing written
informed consent, subjects with physician-diagnosed asthma or with normal airways completed clinical
questionnaires and baseline spirometry that were used to determine the severity group classifications.
Exclusion criteria: current smoker or >5 pack-year previous smoking; diagnosis of vocal cord dysfunction,
chronic obstructive pulmonary disease, cystic fibrosis, or congestive heart failure. General characteristics of
the SARP cohort have been summarized previously for the asthma subjects in the age < 18 subgroup (10),
and for the initial 438 asthma subjects > 12 years of age (33). The current study includes 669 subjects with
asthma and 85 subjects with normal airways, all age ≥ 18 years and included in the SARP database as of
Severity group classification. The consensus definition for refractory asthma (Table 1) from the ATS
Workshop on Refractory Asthma (2) was used to determine the severity classifications. Subjects who met
at least 1 of the major criteria and 2 of the minor criteria were classified as Severe Asthma. All the subjects
with asthma who did not meet the criteria for Severe Asthma were classified as Non-severe Asthma for this
study. Subjects were classified as No Asthma if they reported no asthma symptoms or diagnosis, had
<20% decrease in FEV1with aerosolized methacholine challenge up to 25 µg/ml, and had no other
significant health problems.
Physiological measurements. Spirometry, plethysmographic lung volumes, methacholine
challenges, and maximum bronchodilation procedures were conducted among the SARP sites according to
a SARP Manual of Procedures, which conformed with ATS guidelines for spirometry (32), methacholine
challenge (7), and lung volumes measurements (46). For plethysmographic lung volumes, a pant rate of <1
Hz was used during the mouthpiece occlusion, which was activated after the subject had attained a stable
Page 4 of 37
end-expiratory volume for at least 4 breaths; after the brief occlusion, subjects exhaled maximally to
residual lung volume (RV), and then inhaled maximally to total lung capacity (TLC). Subjects withheld
short-acting beta agonist treatments for 4 hours, long-acting beta agonist treatments for 12 hours, and other
medications (theophylline, anticholinergics, leukotriene modifiers, antihistamines, caffeine, alcohol) for an
appropriate length of time to avoid interference with the spirometry, methacholine or lung volumes
measurements, unless required to manage asthma symptoms. Subjects were questioned regarding
adherence to medication holds, and regarding current asthma symptoms and recent respiratory infections
or systemic corticosteroid use, and the studies were delayed or rescheduled if necessary to ensure that the
subjects were in a stable state, and that the measurements were obtained with safety and validity.
Methacholine challenges were administered using the 5-breath dosimeter method, and the concentration
associated with a 20% decrease in FEV1(PC20) was computed by interpolation of the FEV1versus log
methacholine concentration plot (7). Methacholine was not administered if the pre-challenge FEV1was
<50% predicted (Prd). Maximal bronchodilation was induced with albuterol via metered dose inhaler
equipped with a spacer chamber, measuring FEV1before and 15 minutes after 4, 6, and a maximum of 8
total puffs (720 µg). The final 2 puffs of albuterol were excluded if the incremental change in FEV1after 6
puffs was ≤5% higher than the FEV1after 4 puffs. Maximal FEV1, FVC and FEV1/FVC were recorded as
%Prd, and as the fractional changes relative to the baseline spirometry values obtained after bronchodilator
medications had been withheld for an appropriate time. Predicted values for FEV1, FVC, FEV1/FVC ratio,
forced expiratory flow rate at 25-75% FVC (FEF25-75), and peak expiratory flow rate (PEF) were computed
using the equations of Hankinson, et al (15). Predicted values for TLC, functional residual capacity (FRC),
FRC/TLC ratio, RV, RV/TLC ratio, and the 95th percentile for RV/TLC were computed using the equations of
Stocks and Quanjer (38), with adjustments for African Americans per ATS recommendations (1).
Partitioning FEV1into volume and airflow components. The FEV1is a highly reproducible
measurement that is sensitive to changes in vital capacity or maximal expired airflow. While of considerable
value as an independent variable for diagnosis and monitoring of lung disease, FEV1is a nonspecific
measure. We suggest that FEV1may be treated as a dependent variable, partitioned quantitatively into its
Page 5 of 37
components of vital capacity and airflow. By evaluating these components individually, additional
information regarding the underlying mechanisms of airway obstruction may be gained (13).
FEV1= FVC •FEV1/FVC (1)
Dividing both sides of the equation by FEV1Prd and FVCPrd and multiplying both sides by 100 yields:
100 (FEV1/FEV1Prd) / FVCPrd = 100 (FVC/FVCPrd) •(FEV1/FVC) / (FEV1Prd) (2)
Expressing FEV1and FVC as percentages of their predicted values, and rearranging:
FEV1%Prd = FVC%Prd •(FEV1/FVC) / (FEV1Prd/FVCPrd) (3)
We assume that the predicted value for FEV1/FVC ratio is approximately equal to the ratio of the individual
predicted values for FEV1and FVC, in that the predictive equations were all derived from the same data set
(15). The validity of this assumption is supported by the high concordance between (FEV1/FVC)Prd and
FEV1Prd/FVCPrd computed for subjects in the current study using the Hankinson predictive equations (R2>
0.9999). Substituting (FEV1/FVC)Prd for FEV1Prd/FVCPrd, multiplying both sides by 100, and expressing
FEV1/FVC as a percentage of its predicted value:
FEV1%Prd = FVC%Prd •[(FEV1/FVC)%Prd] / 100 (4)
Equation (4) shows that FEV1%Prd is described by the product of FVC%Prd and (FEV1/FVC)%Prd, and is
therefore a dependent variable based on these 2 components. Figure 1 is a representation of equation (4),
illustrating that a given value of FEV1%Prd may result from a range of combinations of (FEV1/FVC)%Prd
and FVC%Prd, as a hyperbolic function of the 2 components. It follows that a fractional deviation of
FEV1%Prd from a reference value of FEV1%Prd also may be described by the relative fractional deviations
of FVC%Prd and (FEV1/FVC)%Prd from their respective reference values.
Placing reference values in equation (4):
FEV1%Prdref = FVC%Prdref •[(FEV1/FVC)%Prdref] / 100 (5)
Dividing equation (4) by equation (5):
FEV1%Prd / FEV1%Prdref =
FVC%Prd / FVC%Prdref •[(FEV1/FVC)%Prd] / [(FEV1/FVC)%Prdref] (6)
Page 6 of 37
FEV1/ FEV1ref = FVC / FVCref •[(FEV1/FVC) / (FEV1/FVC)ref] (7)
Equations (6) and (7) show that a fractional change in FEV1is the product of the fractional changes in FVC
and FEV1/FVC. Therefore, a reduction in FEV1%Prd relative to normal (i.e. 100% Prd) may be partitioned
into reductions in FVC%Prd and FEV1/FVC %Prd from their respective normals of 100% Prd. If TLC is not
reduced, a decrease in FVC%Prd implies the presence of air trapping during the forced expiratory
maneuver. The FEV1/FVC ratio is the proportion of available FVC that is exhaled in the first second, and
thus is a measure of relative maximal airflow, and it follows that a decrease in the (FEV1/FVC)%Prd
indicates airflow limitation. Thus, a reduction in FEV1%Prd may be partitioned into components that reflect
relative contributions of air trapping and airflow limitation. Similarly, fractional changes in FEV1associated
with bronchoconstriction or bronchodilation may be partitioned into the respective fractional changes in FVC
and FEV1/FVC, with the attendant implications regarding air trapping and airflow limitation (13).
Data analysis. The general linear model was used in least squares regression, ANOVA, and
ANCOVA contexts for data that conformed to parametric assumptions. Residuals from each analysis were
confirmed to be normally distributed, and randomly associated with regard to the model estimates and to
the independent variables, using visual inspection of normal probability plots and scatterplots. When non-
linearities or inhomogeneous slopes precluded using a continuous independent variable as a covariant, the
continuous independent variable was converted to intervals, each having a width of 20 %Prd units, and only
those intervals containing ≥10 subjects from both severity groups were included in the analyses. The
intervals were used as a categorical independent variable in an ANOVA model, along with the appropriate
interactive terms. The maximum bronchodilated:baseline ratios and the methacholine responsiveness data
were log-transformed for analyses. Linear correlations were tested using the Pearson correlation coefficient
(r) and the coefficient of determination (R2), and non-linear correlations with the Spearman rank order
correlation coefficient (rs). Pairwise group comparisons were done with the least significant difference test
or with the Mann-Whitney test. The Wilcoxon signed-rank test was used to evaluate relative contributions of
FVC%Prd and FEV1/FVC%Prd to reversibility and to persistent airway obstruction after maximal
bronchodilation. All analyses were performed with SYSTAT v.12 software (SYSTAT Software, Richmond,
Page 7 of 37
Group summaries. Table 2 compares subjects with Severe Asthma, Non-severe Asthma, and No Asthma
classifications with regard to demographic characteristics, spirometry variables, and lung volumes. The
subjects classified as Severe Asthma differed significantly from the Non-severe Asthma group with regard
to higher age, longer duration of asthma, and lower %Prd values for all the spirometric variables. In the
subgroup with plethysmographic lung volume measurements, the Severe Asthma subjects had significantly
higher residual lung volumes compared with the other two groups. Demographic data and some of the
spirometric data from SARP subjects were reported previously (33). Although the data in Table 2 include
additional adult SARP subjects enrolled after the previous report, and exclude subjects of age<18 years, the
group summaries for demographics, FEV1and FVC are consistent with those reported earlier (33).
Subjects in the No Asthma group were excluded from the subsequent analyses, in order to focus on
comparisons of Severe vs Non-severe asthma groups.
Air trapping relative to airflow limitation. Although the Severe Asthma group had significantly greater
airway obstruction by measures of spirometry (Table 2), there was considerable overlap between Severe
and Non-severe Asthma groups for each of the variables. We reasoned that, by evaluating FVC and
FEV1/FVC as components of FEV1relating to relative changes in air trapping vs airflow limitation (Fig. 1), it
might be possible to discern whether air trapping and airflow limitation were related similarly in Severe vs
Non-severe groups. Comparing FVC%Prd relative to FEV1/FVC%Prd, it was found that FVC%Prd was
significantly lower in the Severe Asthma group compared with the Non-severe group (P < 0.0001, ANOVA
R2= 0.26), over the range of FEV1/FVC 55-115%Prd (Fig. 2A). Subjects with FEV1/FVC <55%Prd were not
included in the group comparison, due to the lack of Non-severe subjects in this range; however, the Severe
group subjects in this range showed a further decrease in FVC%Prd (Fig. 2A). Comparisons within each of
the intervals for FEV1/FVC%Prd confirmed that FVC%Prd was significantly lower in the Severe Asthma
group within each interval of the overlapping range (Fig. 2A). These results indicate that subjects in the
Severe Asthma group have a greater component of air trapping, relative to the airflow limitation component,
contributing to their airway obstruction. Further, the lower FVC%Prd over the entire range of
FEV1/FVC%Prd in the Severe group suggests that air trapping is a characteristic broadly associated with
Page 8 of 37
severe asthma, even when severe airflow limitation is not present. To confirm this finding, we repeated
the analysis using RV/TLC%Prd as an alternative indicator of air trapping for the subgroup of subjects with
lung volume data, with similar conclusions (Fig. 2B): RV/TLC%Prd was significantly higher in the Severe
group (P = 0.0001, ANOVA R2= 0.33) over the 55-115%Prd range of FEV1/FVC, and significantly higher in
each of the individual intervals between 55 and 95%Prd (Fig. 2B). Because changes in FVC may affect
FEV1/FVC under some conditions, we also confirmed that substituting intervals of PEF%Prd for the
FEV1/FVC%Prd intervals as the indicator of airflow in the analyses resulted in the same conclusions: both
FVC%Prd (P < 0.0001, ANOVA R2= 0.40) and RV/TLC%Prd (P =0.009, ANOVA R2= 0.27) were altered
more prominently in the Severe Asthma group, indicating more air trapping relative to the decrease in
PEF%Prd, compared with the Non-severe group.
Corticosteroid treatment. Corticosteroid treatment intensity was the major criterion for the severity
classification (Table 1), but within the Severe classification there were 92 subjects on systemic steroids and
195 on high-dose inhaled steroid therapy, and within the Non-severe group there were 213 subjects on
inhaled steroids (8 of these high-dose), one subject on systemic steroids, and 160 subjects receiving no
steroid therapy. To test whether the type of corticosteroid therapy affected the patterns of air trapping vs
airflow limitation, the ANOVA analyses were repeated, including inhaled and systemic steroid subgroupings
of the Severe group and inhaled vs no steroid subgroupings within the Non-severe group as nested
variables. The FVC%Prd relative to the level of FEV1/FVC%Prd was significantly associated with the
intensity of corticosteroid therapy within the severity groups (P < 0.0001 for the nested treatment
categories), such that in the Non-severe group the FVC%Prd was lower in the subgroup receiving inhaled
steroids compared with those receiving no steroid therapy (least square means 91 vs 95%Prd) and in the
Severe group the FVC%Prd was lower in the subgroup receiving systemic steroids (71 vs 80%Prd).
Including the treatment subgroups in the analysis did not alter the difference in FVC%Prd attributed to the
severity group classification (P < 0.0001). These results suggest that within the severity classifications
determined with the ATS Workshop criteria, the intensity of corticosteroid therapy may serve as a further
indicator of asthma severity.
Page 9 of 37
Lung volumes. Plethysmographic lung volumes were measured at some of the SARP sites,
providing data for 75 Non-severe and 84 Severe Asthma group subjects. Demographic and spirometric
variables in the subjects with lung volume data were comparable in ranges and means to those of their
respective inclusive groups shown in Table 2.
Total lung capacity %Prd varied directly with RV/TLC%Prd (r = 0.31, P = 0.004; Fig. 3); this
association was not different in Severe vs Non-Severe asthma groups (P > 0.9 for differences in regression
slopes between the groups). This indicates that air trapping in stable asthma is associated with increased
TLC. The FRC/TLC%Prd varied in parallel with RV/TLC%Prd, and had a similar association with TLC%Prd
(r = 0.29, P =0.0006 for the pooled regression; P = 0.7 for differences in regression slopes between the
If TLC increases with air trapping, there may be an incremental increase in FVC, which would make
FVC%Prd a less sensitive indicator of air trapping (3). FVC%Prd correlated well with RV/TLC%Prd (r = -
0.64, R2= 0.41, P <0.0001; Fig. 4), and the slopes were not different for Non-severe vs Severe (P = 0.1),
indicating that FVC%Prd was adequate to assess air trapping for group comparisons. We also compared
the absolute volume differences between measured and predicted values for FVC versus RV (which would
be expected to be equal if the TLC were unaltered) in 45 subjects (39 Severe, 6 Non-severe) who had
RV/TLC higher than the 95th percentile. The FVC was lower than its predicted value in parallel with the RV
being higher than its predicted value (R2= 0.63, P < 0.0001), but not in a 1:1 ratio. The slope of the linear
regression was 0.67, suggesting that elevation in TLC associated with air trapping served to limit the
deviation of FVC from its predicted value to about two-thirds of the concomitant deviation of RV from its
Reversibility of obstruction with bronchodilator treatment. As shown by equation (7) (Methods), the
fractional change in FEV1is the product of the fractional changes in FVC and FEV1/FVC, and so the
reversibility of obstruction after maximal bronchodilation may be assessed as relative changes in the air
trapping and airflow limitation components of obstruction. A Max:Baseline ratio was computed for FEV1,
FVC, and FEV1/FVC as the values measured after maximal bronchodilation divided by the baseline values
measured after an appropriate period of withheld asthma medications. Figure 5 illustrates the relationship
Page 10 of 37
of each of the Max:Baseline ratios with the baseline FEV1%Prd for 244 Severe and 348 Non-severe
Asthma group subjects in whom maximal bronchodilation procedures were completed. Per equation (7),
the ratio for FEV1reversal (Fig. 5A) is the product of the reversal ratios for FVC (Fig. 5B) and for FEV1/FVC
(Fig. 5C). Both severity groups were adequately represented in the intervals of baseline FEV1%Prd within
the 40-120%Prd range for comparative analysis, and the Severe group with baseline FEV1<40%Prd is
included on Fig. 5 to illustrate the continuation of the data patterns. The reversal of FEV1with
bronchodilation was related nonlinearly to the baseline FEV1%Prd (Fig. 5A). While the magnitude of
reversal for FEV1/FVC increased by small increments for each decrease in baseline FEV1%Prd (Fig. 5C),
the reversal of FVC contributed largely to the marked increases in bronchodilator reversibility that occurred
at baseline FEV1below 60%Prd. There was no significant difference between Severe and Non-severe
groups with regard to the reversal of FEV1when compared at the same levels of baseline FEV1%Prd.
However, the severity groups exhibited small differences in the relative reversals of the FVC and FEV1/FVC:
when compared at equal levels of baseline FVC%Prd, the Severe group averaged about 2% more reversal
of FVC than the Non-severe group (P = 0.049), and when compared at equal levels of baseline
FEV1/FVC%Prd, the Non-severe group averaged about 2% more reversal of FEV1/FVC than the Severe
group (P < 0.003).
Residual obstruction after maximal bronchodilation. The non-reversible portion of reduced FEV1had
components of both air trapping (reduced FVC%Prd) and airflow limitation (reduced FEV1/FVC%Prd), with
the airflow limitation component contributing relatively more to the residual reduced FEV1(maximal
FEV1/FVC%Prd < maximal FVC%Prd; P < 0.01) in both the Severe and Non-severe Asthma groups (Table
2). Using a multivariate general linear model, 3 variables (the Severe Asthma classification, male sex, and
age) were identified as independent predictors of residual reduction in FEV1%Prd after maximal
bronchodilation (Table 3).
Responsiveness to inhaled methacholine. Methacholine challenge and computation of a PC20 FEV1
were completed for 113 Severe and 321 Non-severe Asthma subjects, all of whom had a pre-challenge
FEV1≥ 50%Prd. Within this subgroup of subjects without severe obstruction at baseline there was no
significant difference in PC20 between the Severe and Non-severe Asthma classifications (P > 0.16).
Page 11 of 37
Methacholine PC20 correlated weakly with most of the other measures of airway physiology, the best
correlation being with the reversibility of FEV1(rs= -0.40; Fig. 6). Of the 434 asthma subjects who
completed methacholine challenge, 50 (12%) had PC20 > 16mg/ml; of those 50 subjects, 15 met the criteria
for Severe Asthma, and 29 had at least one baseline spirometric variable <80%Prd. Compared with the
more responsive subjects, those having PC20 > 16 mg/ml were significantly older, both at their onset of
asthma (median ages 19 vs 10 years; P = 0.0003) and at the time of enrollment (median ages 42 vs 34
years; P = 0.016). The subjects with PC20 > 16mg/ml also had significantly higher baseline FEV1%Prd (P =
0.003), but did not differ from the more responsive subjects in the FEV1%Prd measured after maximal
bronchodilation (P > 0.7). We repeated the analyses of air trapping, lung volumes, reversibility, and residual
obstruction with the subjects having PC20 > 16 mg/ml excluded from the models, confirming that inclusion of
these subjects had no influence on the results or conclusions of those analyses.
We evaluated a large cohort of subjects classified as having Severe or Non-severe Asthma, applying the
concept of partitioning airway obstruction, as measured by FEV1, into components of airflow limitation
(measured as reduced FEV1/FVC) and air trapping (measured as reduced FVC). We found that air trapping
is a prominent group characteristic in Severe Asthma during a period of stable disease, not only in those
subjects exhibiting severe airflow limitation, but throughout the range of airflow limitation. In contrast, the
Non-severe Asthma group had less prominent air trapping, even when FEV1/FVC was <75%Prd. Although
elevated RV/TLC has been reported previously as a group characteristic of adults with severe asthma (41),
and associated with persistent airway obstruction in severe asthma (4; 40), this is the first study to show the
predilection of severe asthma for air trapping over the entire range of airflow limitation. In the current study,
had the air trapping occurred only in the presence of moderate-severe airflow limitation, or in a pattern
relative to airflow limitation that was consistent in Severe and Non-severe asthma classifications, we would
interpret that as evidence that Severe Asthma represents a more severe manifestation of the general
pathophysiology that causes airway obstruction in the population of Asthma. However, the data instead
show a statistically and physiologically significant shift of the study population classified as Severe Asthma
Page 12 of 37
toward more air trapping at all levels of airflow limitation-- these results suggest that there may be a
pathophysiological process present commonly in severe asthma that contributes to air trapping.
A strength of this study is the large number of subjects with severe asthma. Lacking distinguishing
biomarkers or other precise definitions of asthma phenotypes, the consensus definition of refractory asthma
employed for this study focused on identifying asthma that is incompletely controlled despite intensive
treatment. While the definition may result in the inclusion of multiple phenotypes of difficult asthma, as well
as some subjects who are misclassified due to inaccuracies of reported treatments, histories or diagnoses,
the Severe Asthma cohort does include a large number of subjects with difficult asthma that will ensure a
group analysis that is meaningful even in the presence of a small number of misclassified subjects and
outliers. The current study found strong associations of the Severe Asthma classification with some
physiological variables, illustrating that, though imprecise, the definition was sufficient to identify an asthma
subgroup with an identifiable pattern of airway obstruction.
Partitioning FEV1. Central to our analysis of spirometry measurements is the concept of partitioning
the FEV1into components of airflow limitation and air trapping, and we have presented a novel approach for
doing this in a quantitative manner. Equation (4) and Figure 1 show that FEV1%Prd is linked quantitatively
to the product of FVC%Prd and FEV1/FVC%Prd, and may be treated as a dependent variable based on
those quantities. Equation (7) further shows that any fractional change measured in FEV1may be
partitioned quantitatively into the concomitant fractional changes of FVC and FEV1/FVC ratio. The
significance of these relationships is that FVC and FEV1/FVC may be altered differentially, and a systematic
change in one of these quantities relative to the other could discern an underlying difference in
pathophysiology that would not be apparent from the FEV1.
FVC is determined by TLC and by the fraction of TLC that can be exhaled forcibly, so FEV1%Prd will
be reduced if either TLC is reduced (smaller than predicted lung size or restrictive disease), or if exhaled
volume is reduced (air trapping). Air trapping in this context is inclusive of all causes of reduced exhaled
volume, including airway premature closure/near-closure, dynamic airway compression, and reduced
expiratory muscle strength. The spirometry procedures evoked maximal inspiratory and expiratory efforts
from the subjects, with ATS standard end-of-test criteria (at least 6 s maximal expiratory effort). While
Page 13 of 37
severely obstructed subjects often did not meet the zero-flow criterion within the time that they could
sustain a maximal expiratory effort, the reduced FVC was accepted as an indicator of air trapping, as the
subjects were indeed unable to exhale more volume voluntarily. The random variability of TLC%Prd within
the cohort (Fig. 3) probably accounts for some of the random variability in FVC%Prd as a function of
RV/TLC%Prd (Fig. 4), and in addition, we have shown that there is a nonrandom increase in TLC
associated with air trapping (Fig. 3) that reduces the magnitude of the deviation from predicted FVC relative
to the deviation from predicted RV. However, as shown in Fig. 4, FVC%Prd does correlate well with
RV/TLC%Prd despite the variability in TLC, and thus is valid as an indicator for air trapping in an asthma
From equation (4) it can be reasoned that any change in FEV1%Prd not associated with a change in
FVC%Prd (air trapping or alterations in TLC) must be associated with a change in FEV1/FVC%Prd. This
ratio represents the fraction of the total forced expired volume that is exhaled in the first second of the
maneuver, and thus is sensitive to pathology that reduces maximal airflow, and is an indicator of airflow
limitation. A high correlation between FEV1/FVC ratio and large airway diameter measured with high
resolution computed tomography suggests that this variable is sensitive to changes in the caliber of central
airways (3). Because FVC is the denominator of FEV1/FVC, the ratio is affected by variability in FVC; for
example, the ratio may be increased artifactually if the FVC measurement is terminated prior to achieving a
true RV (35), and thus partitioning of FEV1requires a maximal expiratory effort in order to be interpretable.
However, we would argue that an FVC obtained with a maximal effort represents the available expiratory
volume, and the fraction of that volume expired in the first second can reveal meaningful information about
airflow limitation. FVC%Prd and FEV1/FVC%Prd have considerable independence with one another within
the asthma population (R2= 0.10 for the SARP subjects) , and Fig. 5 shows that marked increases in FVC
with bronchodilation typically are accompanied by increases, not decreases, in the FEV1/FVC ratio. These
data suggest that the two variables are affected differentially by underlying pathophysiology, despite having
some predictable dependencies. Thus, for the purposes of partitioning the FEV1%Prd into components that
may reflect different aspects of asthma pathophysiology, the use of FVC%Prd and FEV1/FVC%Prd is
Page 14 of 37
mathematically sound, and the physiological interpretation of these variables as broad indicators of air
trapping and airflow limitation is valid.
Air trapping. The RV is determined primarily by expiratory muscle strength relative to chest wall
recoil in young persons with healthy airways, and by airway closure in older persons and in persons having
airway pathology or reduced lung elastic recoil (24). The air trapping in asthma is associated with airway
closure or near-closure (17; 22; 25), but the mechanisms and the sites of airway closure are not well
understood. Small airways appear to be the location of ventilatory heterogeneity in asthma (42), and exhibit
increases in peripheral airflow resistance of several fold even in asymptomatic asthma subjects who have
normal FEV1(45). Using the wedged bronchoscope method, subjects with non-severe asthma were noted
to have slightly elevated plateau pressures during cessation of airflow, indicating that there was complete
closure of collateral pathways distal to the bronchoscope occurring at higher pressures than those
measured in subjects with normal airways (20; 23), and in subjects with nocturnal asthma, there was a
marked increase in plateau pressures at 4:00 AM compared with 4:00 PM (23)— these studies provide
direct evidence that closure occurs in the distal airways during baseline conditions in subjects with asthma,
and worsening during nocturnal asthma. It follows that severe asthma with measurable air trapping could
be a manifestation of a pathophysiological process that increases closure of collateral pathways or of more
proximal sites in the airways, either by exacerbating the tendency to closure that is already present in non-
severe asthma, or by introducing additional pathology that is additive or interactive with that found in non-
Airway closure occurs as a fluid meniscus that forms over the lumen when a critical airway diameter
relative to the volume of fluid lining the lumen is reached (16; 21; 27; 43); thus, any process that increases
intraluminal fluid volume or that favors airway narrowing would promote closure. Airway smooth muscle
contraction favors airway narrowing and closure, and the marked improvement in FVC after beta agonist
treatment in the Severe Asthma group in the current study suggests a contribution of this mechanism. An
inflammatory process in the small airways (51) also could contribute to airway closure, both by interfering
with surfactant activity (19; 44), resulting in airway narrowing due to increased surface tension, and by
increasing the volume of intraluminal material (16). The marked heterogeneity in airway obstruction
Page 15 of 37
observed in severe asthma (8; 25) suggests a patchy pattern of pathology that would be consistent with
foci of inflammation. A force that opposes small airway narrowing and closure is airway-parenchymal
coupling, which is a bronchodilating force obtained from the tethering effect of lung elastic recoil transmitted
to the airway adventitial walls (9; 26). Reduction of airway-parenchymal coupling, due either to reduced lung
elastic recoil or to an uncoupling of the tethering force from the airway lumen, could be a contributing factor
to air trapping in asthma (11; 14; 18; 28; 52). One consequence of reduced airway-parenchymal coupling
may be dynamic airway closure during a forced expiration, which has been observed as a reduced
FVC:slow vital capacity ratio in some persons with severe asthma (50).
We observed increases in TLC and FRC associated with increases in RV, consistent with the
studies of Brown and colleagues (3). Analogous to the fractional changes in FVC relative to changes in RV
with bronchodilation that were reported in the Brown paper (3), we found that the volume differences
between measured baseline FVC and predicted FVC were, on average, only about two-thirds the volume
differences between measured baseline and predicted RV, supporting their argument that an increase in
TLC helps to preserve vital capacity in the presence of air trapping. However, in contrast to the Brown
paper (3), we found no association between the post-maximal bronchodilation FEV1/FVC ratio and the
deviation in baseline FVC from its predicted value relative to the deviation in baseline RV from its predicted
value. Although the Severe Asthma group in our study had more air trapping (both reduced FVC and
increased RV) compared with the Non-severe Asthma group, the associated increases in TLC were similar
for the 2 groups for a given level of air trapping (Fig. 3).
Reversibility and hyperresponsiveness. In addition to the strong association with air trapping, the
Severe Asthma classification also was an independent predictor of persistent airway obstruction after
maximal bronchodilation with beta agonist. Age and male sex also were identified as independent
predictors of persistent obstruction, in agreement with previous studies of subjects with severe asthma (4;
40). In addition to age, long duration of asthma in an elderly population has been identified as a risk factor
for persistent airflow limitation after bronchodilation (5). If maximal expiratory airflow is determined by
airway conductance and lung elastic recoil (30; 36), then persistent airflow limitation after relaxing smooth
muscle must be related to other factors causing airway narrowing/closure and/or reduced elastic recoil. The
Page 16 of 37
post-bronchodilator FEV1/FVC correlates strongly with large airway luminal diameter measured with high
resolution computed tomography (3), suggesting that airway narrowing due to thickening of the airway wall
via inflammation or remodeling may contribute to post-bronchodilator airflow limitation. Reduction of luminal
area due to accumulation of mucous secretions or inflammatory exudates also would be expected to cause
reduced airway conductance that would not be reversed rapidly with bronchodilators. Reduced lung elastic
recoil has been observed commonly in persons with stable asthma, including young adults with relatively
short durations of asthma diagnosis, and in the absence of emphysema that could be detected by high
resolution computed tomography or by reduced carbon monoxide diffusion capacity (11; 12; 29; 52). In
these subjects a large proportion of the airflow limitation could be attributed to reduced lung elastic recoil
(11; 12; 29). Thus, the persistent airflow limitation after maximal bronchodilation is more prominent in the
Severe Asthma group, and likely is associated with both reduced lung elastic recoil and reduced airway
Responsiveness of FEV1to inhaled methacholine correlated with the change in FEV1after maximal
bronchodilation, but responsiveness correlated only weakly with other measures of airway physiology, and
12% of the subjects with asthma who completed methacholine challenge had a PC20 >16 µg/ml, which is
generally considered to be in the non-asthma range (7). One reason for the weak correlation with other
physiology variables is that subjects with more severe baseline airway obstruction were excluded from
methacholine challenge, thus truncating the range of physiologic variables available for comparison.
Although subjects withheld bronchodilator therapy prior to methacholine challenge, their maintenance
inhaled corticosteroid therapy would be expected to increase methacholine PC20 by 1-2 doubling
concentrations (37; 47), which could reverse mild hyperresponsiveness. Also, the dosimeter method (7)
used in SARP for methacholine challenge involves repeated deep breaths, which may reduce
responsiveness to methacholine compared with the tidal breathing method in some subjects with asthma
(6), potentially shifting the PC20 of a subject with mild hyperresponsiveness into the normal range. It is
possible that some of the non-hyperresponsive subjects did not have asthma, although more than half had
at least one spirometric variable <80% predicted, suggesting baseline airflow limitation. Further evaluation
of methacholine responsiveness relative to other characteristics and biomarkers being measured in the
Page 17 of 37
SARP cohort may provide insight regarding the utility of methacholine PC20 for the identification of asthma
In conclusion, the group of persons meeting the consensus definition criteria for Severe Asthma was
distinguished physiologically by more prominent air trapping relative to the level of airflow limitation, and
more prominently reduced FEV1after maximal bronchodilation, compared with subjects with Non-severe
Asthma. The presence of these differences over the ranges of FEV1/FVC%Prd and age suggest that they
reflect an underlying pathology that is present in persons with severe asthma, and not simply the extremes
of the general asthma population.
Page 18 of 37
The Severe Asthma Research Program (SARP) is a multicenter asthma research group funded by the
NHLBI and consisting of the following contributors (Steering Committee Members are marked with an
asterisk): Brigham & Women's Hospital- Elliot Israel*, Bruce D. Levy, Gautham Marigowda; Cleveland
Clinic Foundation-Serpil C. Erzurum*, Raed A. Dweik, Suzy A.A. Comhair, Abigail R. Lara, Marcelle
Baaklini, Daniel Laskowski, Jacqueline Pyle; Emory University- W. Gerald Teague*, Anne M. Fitzpatrick,
Eric Hunter; Imperial College School of Medicine- Kian F. Chung*, Mark Hew, Alfonso Torrego, Sally Meah,
Mun Lim; National Jewish Medical and Research Center- Sally E. Wenzel (currently at University of
Pittsburgh)*, Diane Rhodes; University of Pittsburgh- William J. Calhoun*, Melissa P. Clark, Renee Folger,
Rebecca Z. Wade; University of Texas-Medical Branch- William J. Calhoun*, Bill T. Ameredes, Dori Smith;
University of Virginia- Benjamin Gaston*, Peter Urban; University of Wisconsin- William W. Busse*, Nizar
Jarjour, Ronald Sorkness, Erin Billmeyer, Cheri Swenson, Gina Crisafi; Wake Forest University- Eugene R.
Bleecker*, Deborah Meyers, Wendy Moore, Stephen Peters, Annette Hastie, Gregory Hawkins, Jeffrey
Krings, Regina Smith; Washington University in St Louis- Mario Castro* , Leonard Bacharier, Iftikhar
Hussain, Jaime Tarsi; Data Coordinating Center- James R. Murphy*, Douglas Curran-Everett; NHLBI-
Patricia Noel *
Page 19 of 37
HL69116, HL69130, HL69149, HL69155, HL69167, HL69170, HL69174, HL69349, M01 RR018390, M01
RR007122-14, M01 RR03186
Page 20 of 37
Page 21 of 37
1. Lung function testing: selection of reference values and interpretative strategies. American Thoracic
Society. Am Rev Respir Dis 144: 1202-1218, 1991.
2. Proceedings of the ATS workshop on refractory asthma: current understanding, recommendations,
and unanswered questions. American Thoracic Society. Am J Respir Crit Care Med 162: 2341-2351,
3. Brown RH, Pearse DB, Pyrgos G, Liu MC, Togias A and Permutt S. The structural basis of
airways hyperresponsiveness in asthma. J Appl Physiol 101: 30-39, 2006.
4. Bumbacea D, Campbell D, Nguyen L, Carr D, Barnes PJ, Robinson D and Chung KF.
Parameters associated with persistent airflow obstruction in chronic severe asthma. Eur Respir J 24:
5. Cassino C, Berger KI, Goldring RM, Norman RG, Kammerman S, Ciotoli C and Reibman J.
Duration of asthma and physiologic outcomes in elderly nonsmokers. Am J Respir Crit Care Med
162: 1423-1428, 2000.
6. Cockcroft DW and Davis BE. The bronchoprotective effect of inhaling methacholine by using total
lung capacity inspirations has a marked influence on the interpretation of the test result. J Allergy
Clin Immunol 117: 1244-1248, 2006.
7. Crapo RO, Casaburi R, Coates AL, Enright PL, Hankinson JL, Irvin CG, MacIntyre NR, McKay
RT, Wanger JS, Anderson SD, Cockcroft DW, Fish JE and Sterk PJ. Guidelines for
methacholine and exercise challenge testing-1999. Am J Respir Crit Care Med 161: 309-329, 2000.
8. de Lange EE, Altes TA, Patrie JT, Gaare JD, Knake JJ, Mugler JP, III and Platts-Mills TA.
Evaluation of asthma with hyperpolarized helium-3 MRI: correlation with clinical severity and
spirometry. Chest 130: 1055-1062, 2006.
Page 22 of 37
9. Ding DJ, Martin JG and Macklem PT. Effects of lung volume on maximal methacholine-induced
bronchoconstriction in normal humans. J Appl Physiol 62: 1324-1330, 1987.
10. Fitzpatrick AM, Gaston BM, Erzurum SC and Teague WG. Features of severe asthma in school-
age children: Atopy and increased exhaled nitric oxide. J Allergy Clin Immunol 118: 1218-1225,
11. Gelb AF, Licuanan J, Shinar CM and Zamel N. Unsuspected loss of lung elastic recoil in chronic
persistent asthma. Chest 121: 715-721, 2002.
12. Gelb AF and Zamel N. Unsuspected pseudophysiologic emphysema in chronic persistent asthma.
Am J Respir Crit Care Med 162: 1778-1782, 2000.
13. Gibbons WJ, Sharma A, Lougheed D and Macklem PT. Detection of excessive
bronchoconstriction in asthma. Am J Respir Crit Care Med 153: 582-589, 1996.
14. Gold WM, Kaufman HS and Nadel JA. Elastic recoil of the lungs in chronic asthmatic patients
before and after therapy. J Appl Physiol 23: 433-438, 1967.
15. Hankinson JL, Odencrantz JR and Fedan KB. Spirometric reference values from a sample of the
general U.S. population. Am J Respir Crit Care Med 159: 179-187, 1999.
16. Hill MJ, Wilson TA and Lambert RK. Effects of surface tension and intraluminal fluid on mechanics
of small airways. J Appl Physiol 82: 233-239, 1997.
17. in 't Veen CCM, Beekman AJ, Bel EH and Sterk PJ. Recurrent exacerbations in severe asthma
are associated with enhanced airway closure during stable episodes. Am J Respir Crit Care Med
161: 1902-1906, 2000.
18. Irvin CG, Pak J and Martin RJ. Airway-parenchyma uncoupling in nocturnal asthma. Am J Respir
Crit Care Med 161: 50-56, 2000.
Page 23 of 37
19. Jarjour NN and Enhorning G. Antigen-induced airway inflammation in atopic subjects generates
dysfunction of pulmonary surfactant. Am J Respir Crit Care Med 160: 336-341, 1999.
20. Kaminsky DA, Bates JH and Irvin CG. Effects of cool, dry air stimulation on peripheral lung
mechanics in asthma. Am J Respir Crit Care Med 162: 179-186, 2000.
21. Kamm RD and Schroter RC. Is airway closure caused by a liquid film instability? Respir Physiol 75:
22. King GG, Eberl S, Salome CM, Young IH and Woolcock AJ. Differences in airway closure
between normal and asthmatic subjects measured with single-photon emission computed
tomography and Technegas. Am J Respir Crit Care Med 158: 1900-1906, 1998.
23. Kraft M, Pak J, Martin RJ, Kaminsky D and Irvin CG. Distal lung dysfunction at night in nocturnal
asthma. Am J Respir Crit Care Med 163: 1551-1556, 2001.
24. Leith DE and Mead J. Mechanisms determining residual volume of the lungs in normal subjects. J
Appl Physiol 23: 221-227, 1967.
25. Lutchen KR, Jensen A, Atileh H, Kaczka DW, Israel E, Suki B and Ingenito EP. Airway
constriction pattern is a central component of asthma severity. The role of deep inspirations. Am J
Respir Crit Care Med 164: 207-215, 2001.
26. Macklem PT. A theoretical analysis of the effect of airway smooth muscle load on airway narrowing.
Am J Respir Crit Care Med 153: 83-89, 1996.
27. Macklem PT, Proctor DF and Hogg JC. The stability of peripheral airways. Respir Physiol 8: 191-
28. Mauad T, Silva LF, Santos MA, Grinberg L, Bernardi FD, Martins MA, Saldiva PH and
Dolhnikoff M. Abnormal alveolar attachments with decreased elastic fiber content in distal lung in
fatal asthma. Am J Respir Crit Care Med 170: 857-862, 2004.
Page 24 of 37
29. McCarthy DS and Sigurdson M. Lung elastic recoil and reduced airflow in clinically stable
asthma. Thorax 35: 298-302, 1980.
30. Mead J, Turner JM, Macklem PT and Little JB. Significance of the relationship between lung recoil
and maximum expiratory flow. J Appl Physiol 22: 95-108, 1967.
31. Miller MK, Johnson C, Miller DP, Deniz Y, Bleecker ER and Wenzel SE. Severity assessment in
asthma: An evolving concept. J Allergy Clin Immunol 116: 990-995, 2005.
32. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van
der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D,
Pedersen OF, Pellegrino R, Viegi G and Wanger J. Standardisation of spirometry. Eur Respir J
26: 319-338, 2005.
33. Moore WC, Bleecker ER, Curran-Everett D, Erzurum SC, Ameredes BT, Bacharier L, Calhoun
WJ, Castro M, Chung KF, Clark MP, Dweik RA, Fitzpatrick AM, Gaston BM, Hew M, Hussain I,
Jarjour NN, Israel E, Levy BD, Murphy JR, Peters SP, Teague WG, Meyers DA, Busse WW and
Wenzel SE. Characteristics of the severe asthma phenotype by the National Heart, Lung, and Blood
Institute's Severe Asthma Research Program. J Allergy Clin Immunol 119: 405-413, 2007.
34. Moore WC and Peters SP. Severe asthma: an overview. J Allergy Clin Immunol 117: 487-494,
35. Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, Coates A, van der
Grinten CP, Gustafsson P, Hankinson J, Jensen R, Johnson DC, MacIntyre N, McKay R, Miller
MR, Navajas D, Pedersen OF and Wanger J. Interpretative strategies for lung function tests. Eur
Respir J 26: 948-968, 2005.
36. Pride NB, Permutt S, Riley RL and Bromberger-Barnea B. Determinants of maximal expiratory
flow from the lungs. J Appl Physiol 23: 646-662, 1967.
Page 25 of 37
37. Sont JK, Willems LN, Bel EH, van Krieken JH, Vandenbroucke JP and Sterk PJ. Clinical
control and histopathologic outcome of asthma when using airway hyperresponsiveness as an
additional guide to long-term treatment. The AMPUL Study Group. Am J Respir Crit Care Med 159:
38. Stocks J and Quanjer PH. Reference values for residual volume, functional residual capacity and
total lung capacity. ATS Workshop on Lung Volume Measurements. Official Statement of The
European Respiratory Society. Eur Respir J 8: 492-506, 1995.
39. Strek ME. Difficult asthma. Proc Am Thorac Soc 3: 116-123, 2006.
40. ten Brinke A, Zwinderman AH, Sterk PJ, Rabe KF and Bel EH. Factors associated with persistent
airflow limitation in severe asthma. Am J Respir Crit Care Med 164: 744-748, 2001.
41. The ENFUMOSA Study Group. The ENFUMOSA cross-sectional European multicentre study of
the clinical phenotype of chronic severe asthma. Eur Respir J 22: 470-477, 2003.
42. Verbanck S, Schuermans D, Paiva M and Vincken W. Nonreversible conductive airway ventilation
heterogeneity in mild asthma. J Appl Physiol 94: 1380-1386, 2003.
43. Wagers S, Lundblad LK, Ekman M, Irvin CG and Bates JH. The allergic mouse model of asthma:
normal smooth muscle in an abnormal lung? J Appl Physiol 96: 2019-2027, 2004.
44. Wagers SS, Norton RJ, Rinaldi LM, Bates JH, Sobel BE and Irvin CG. Extravascular fibrin,
plasminogen activator, plasminogen activator inhibitors, and airway hyperresponsiveness. J Clin
Invest 114: 104-111, 2004.
45. Wagner EM, Liu MC, Weinmann GG, Permutt S and Bleecker ER. Peripheral lung resistance in
normal and asthmatic subjects. Am Rev Respir Dis 141: 584-588, 1990.
46. Wanger J, Clausen JL, Coates A, Pedersen OF, Brusasco V, Burgos F, Casaburi R, Crapo R,
Enright P, van der Grinten CP, Gustafsson P, Hankinson J, Jensen R, Johnson D, MacIntyre
Page 26 of 37
N, McKay R, Miller MR, Navajas D, Pellegrino R and Viegi G. Standardisation of the
measurement of lung volumes. Eur Respir J 26: 511-522, 2005.
47. Wempe JB, Postma DS, Breederveld N, ting-Hebing D, van der Mark TW and Koeter GH.
Separate and combined effects of corticosteroids and bronchodilators on airflow obstruction and
airway hyperresponsiveness in asthma. J Allergy Clin Immunol 89: 679-687, 1992.
48. Wenzel S. Severe asthma in adults. Am J Respir Crit Care Med 172: 149-160, 2005.
49. Wenzel SE and Busse WW. Severe asthma: Lessons from the Severe Asthma Research Program.
J Allergy Clin Immunol 119: 14-21, 2007.
50. Wenzel SE, Schwartz LB, Langmack EL, Halliday JL, Trudeau JB, Gibbs RL and Chu HW.
Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with
distinct physiologic and clinical characteristics. Am J Respir Crit Care Med 160: 1001-1008, 1999.
51. Wenzel SE, Szefler SJ, Leung DY, Sloan SI, Rex MD and Martin RJ. Bronchoscopic evaluation of
severe asthma. Persistent inflammation associated with high dose glucocorticoids. Am J Respir Crit
Care Med 156: 737-743, 1997.
52. Woolcock AJ and Read J. The static elastic properties of the lungs in asthma. Am Rev Respir Dis
98: 788-794, 1968.
Page 27 of 37
Figure 1. Graphical representation of Equation (4), showing the relationship of FEV1%Prd to FVC%Prd and
Figure 2. Air trapping, as indicated by FVC (A) and RV/TLC (B), relative to FEV1/FVC in subjects with
Severe and Non-severe Asthma classifications. Each symbol is the mean ± SE for the subjects of each
severity group in each interval of FEV1/FVC %Predicted, and the numbers of subjects in each interval are
indicated. *P < 0.01; **P < 0.0001 for Severe vs Non-severe groups in the same interval of FEV1/FVC.
Figure 3. Association between TLC and RV/TLC. Linear regression line is for the pooled Severe and Non-
severe Asthma subjects.
Figure 4. Correlation between FVC and RV/TLC. Linear regression line is for the pooled Severe and Non-
severe Asthma subjects.
Figure 5. Reversibility of airway obstruction after maximal bronchodilation with albuterol, expressed as a
fractional change relative to baseline FEV1(A), FVC (B), and FEV1/FVC (C) in Severe and Non-severe
Asthma subjects, plotted against baseline FEV1%Predicted. Each symbol is the group median for subjects
in that range of baseline FEV1; numbers of subjects represented by each symbol are indicated.
Figure 6. Methacholine PC20 versus fractional change in FEV1with maximal bronchodilation in Severe and
Non-severe Asthma subjects. The ordinate is scaled as the log for PC20.
Page 28 of 37
Table 1. American Thoracic Society workshop consensus for
definition of severe/refractory asthma*
Major Criteria (need ≥ 1)
1. Treatment with continuous or near continuous (≥ 50% of year) oral corticosteroids
2. Requirement for treatment with high-dose inhaled corticosteroids
Minor Criteria (need ≥ 2)
1. Requirement for additional daily treatment with a controller medication (e.g. long-acting
beta-agonist, theophylline or leukotriene antagonist)
2. Asthma symptoms requiring short-acting beta-agonist use on a daily or near-daily basis
3. Persistent airway obstruction (FEV1 < 80% predicted, diurnal PEF variability > 20%)
4. One or more urgent care visits for asthma per year
5. Three or more oral steroid “bursts” per year
6. Prompt deterioration with a ≤ 25% reduction in oral or inhaled corticosteroid dose
7. Near-fatal asthma event in the past
*Requires that other conditions have been excluded, exacerbating factors have been treated,
and patient to be generally adherent.
Page 29 of 37
Table 2. Group Characteristics
Group No AsthmaNon-Severe AsthmaSevere Asthma
% Female Sex
32 ± 10.1 34 ± 11.6 43 ± 12.9*
Age of Asthma Onset
15 ± 13.0 17 ± 15.6
Years Asthma Duration
20 ± 12.7 26 ± 14.1*
Baseline Spirometry‡ (n)
102 ± 10.684 ± 16.8†
61 ± 22.0*†
103 ± 11.6 94 ± 15.3†
75 ± 19.2*†
99 ± 7.1 89 ± 11.3†
79 ± 15.4*†
101 ± 23.267 ± 26.9†
42 ± 28.8*†
103 ± 18.388 ± 19.7†
67 ± 23.7*†
Lung Volumes‡ (n)
107 ± 11.3108 ± 12.7 112 ± 18.9
107 ± 25.4114 ± 36.8 153 ± 51.3*†
97 ± 19.7102 ± 25.1 131 ± 31.0*†
Post Max Bronchodilation (n)
FEV1 Max %Predicted
106 ± 12.194 ± 14.5†
75 ± 20.0*†
FVC Max %Predicted
105 ± 13.5 99 ± 13.8†
88 ± 17.3*†
101 ± 7.295 ± 10.0†
84 ± 14.4*†
Group mean ± SD; *P <0.0001 vs Non-severe group; †P <0.004 vs No Asthma group; NA- not applicable;
‡measured after withdrawal of bronchodilator medications
Page 30 of 37
Table 3. Predictors of persistently reduced FEV1 %Predicted after maximal
bronchodilation with inhaled albuterol in subjects with asthma
VariableEffect on FEV1%PrdP-value
Severe (vs Non-severe) Asthma Classification -14.9%Prd <0.0001
Male (vs Female) Sex-4.6%Prd0.0015
Age-0.46%Prd / year <0.0001
Effects (least squares mean) and P-values determined using the multiple general linear model
Page 31 of 37
Page 32 of 37
Page 33 of 37
Page 34 of 37
Page 35 of 37
Page 36 of 37
Page 37 of 37 Download full-text