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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Resting lung function is only weakly related to health status in
chronic obstructive pulmonary disease, reflecting the multifactorial causes of impairment and the heterogeneous nature of the condition. The current study examined whether density mask analysis
of high-resolution computed tomography (HRCT) or exercise capacity were better surrogates for health status in a well-defined,
homogeneous group of patients with 
1-antitrypsin deficiency
(PiZ). Twenty-nine patients with predominantly lower zone emphysema on HRCT were studied. Exercise was assessed by incremental treadmill (
O2 peak) and shuttle walking tests (ISWT) and
health status by the St. George's Respiratory Questionnaire (SGRQ)
and SF-36. Although lower zone expiratory HRCT was related to
exercise capacity (rho = 
0.64 and 0.63 for O2 peak and ISWT,
respectively, p < 0.001), multiple regression analysis suggested
that FEV1 was a marginally better predictor (rho = 0.64 and
0.65, p < 0.001). HRCT also related significantly to health status
(rho = 0.37 for SGRQ activity, p < 0.05), although again FEV1
showed a stronger relationship (rho = 0.43, p = 0.01). However,
exercise capacity was the best predictor of health status with the
ISWT accounting for up to 55% of the variability seen in SGRQ total and up to 53% of the SF-36 domain scores (physical functioning). Although both HRCT and lung function relate to health status, exercise capacity is the best predictor of patients disability in
these patients with predominantly lower zone emphysema.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Characterization of patients with chronic obstructive pulmonary disease (COPD) includes conventional physiological assessment together with routine X-rays and more recently computed tomography. Of these, spirometry has been used traditionally to define disease severity (1), however it provides only limited information about disability and handicap as assessed by health status questionnaires (2). This is likely to reflect the heterogeneous nature of COPD and the variability of pathological and physiological abnormalities present within this group of patients. In addition, FEV1 is relatively insensitive to disease progression (5) and may not reflect all of the measurable benefits of intervention therapy, particularly with relation to health status (6). For instance, in this latter study involving more than 700 patients, the intervention had no effect on the decline in FEV1 after an initial improvement, although it did retard the deterioration in health status.
Quantitative analysis of high-resolution computed tomography (HRCT) provides an objective measure of the presence
and degree of emphysema in patients with COPD (7) and
correlates well with physiological status (11, 12). Moreover,
HRCT has been suggested as a more sensitive indicator of progression than spirometry in patients in whom emphysema is the
dominant factor (13, 14). In our previous studies in patients
with 1-antitrypsin deficiency (1-ATD) HRCT was shown to
be related not only to lung function, but also to health status (15).
Both lung function and HRCT assess the patient at rest when they are relatively asymptomatic. However, for most patients with COPD, exertional dyspnea is a prominent symptom and cause of disability. Furthermore, lung function is only weakly related to exercise tolerance (16) and this may account, in part, for the poor correlation between lung function and health status. In contrast, exercise capacity is related not only to pulmonary physiology but also to cardiovascular fitness and skeletal muscle function (17) and therefore may be expected to show a stronger relationship with impairment and disability than other investigations performed at rest.
The current study was therefore designed to investigate the
relationship between exercise capacity, emphysema as quantified by HRCT, physiological impairment, and health status in
a homogeneous group of patients with 1-ATD and predominantly lower zone emphysema. In particular, we wished to determine whether exercise capacity provided a better guide to
disability and handicap than other investigations and could
therefore be used prospectively as a better objective measure
to determine the effect of intervention therapy.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
Twenty-nine patients with 1-ATD (PiZ) and macroscopic emphysema on HRCT were selected consecutively from those attending the
Antitrypsin Deficiency Assessment and Programme for Treatment (ADAPT) center. The 1-AT concentration and phenotype were confirmed by analysis of finger prick blood spot in the central U.S. laboratory (Heredilab, Salt Lake City, UT). To ensure a homogeneous
group to assess factors influencing health status and exercise capacity, patients with a primary diagnosis of asthma or bronchiectasis (without
HRCT evidence of emphysema), liver disease, or other medical problems likely to limit exercise or alter health status were excluded.
The program was approved by the local ethics committee and all patients gave informed consent.
Exercise Testing
Patients performed a symptom-limited exercise test on a treadmill
(Morgan Medical, Kent, UK) according to the modified version of the
Naughton protocol (18). The workload was increased incrementally every 2 min by a combination of changes in speed and gradient. A
two-way nonrebreathable valve was used and ventilation was measured by a Fleisch pneumotachograph. Expired gases passed through
a mixing chamber where they were continuously sampled and the
fractional expired oxygen and carbon dioxide concentrations were
measured by rapid response zirconium and infrared analyzers, respectively (Morgan Medical). Oxygen uptake was calculated every 30 s
and the peak oxygen consumption achieved was recorded (O2 peak). For the purposes of group characterization, the results were compared to normal reference values (19).
An incremental shuttle walking test (ISWT) was also performed with each shuttle (approximately 10 m) being completed in a time period determined by an audio signal that decreased in interval progressively through the test (20). The test continued until the patient stopped due to dyspnea or was unable to complete a shuttle in the time allowed and the end point was taken as the total number of completed shuttles in meters. The patient performed two separate tests at least 30 min apart and the best result was taken for analysis.
All patients took their usual medication, including bronchodilators, prior to exercise testing.
Computed Tomography
HRCT scanning was performed using a GE Pro Speed Scanner. One millimeter slices were taken at 10-mm intervals throughout the thorax during breath holding at full inspiration with the subjects in the supine position and similar slices were also taken at 30-mm intervals at full expiration. Scans were examined for the presence of macroscopic changes of emphysema (21) and other pulmonary pathology. Objective quantification of the extent of emphysema was performed for single slices at the level of the aortic arch (upper zone) and inferior pulmonary vein (lower zone). The relative area of pixels representing lung tissue with a density < 910 HU (pixel index) (12) was determined using the scanner's software.
Resting Lung Function
Lung function testing was carried out on the same day as the clinical
assessment after the administration of nebulized 
2-agonist (salbutamol 5 mg or terbutaline 5 mg) and ipratropium bromide (500 µg). Simple spirometry measurements were obtained using a wedge bellows
spirometer. Mid-expiratory flow (MEF) was derived using a Fleisch
pneumotachograph with timing facility (Autolink; Morgan Medical) to
estimate small airway function and collapse. Lung volumes were determined by helium dilution and inspiratory capacity (IC) was measured
from the kymograph trace. Gas transfer (DLCO, DLCO/VA) was determined by the single breath carbon monoxide method. The majority of
subjects (n = 21) also had airway resistance measured by constant volume plethysmography from which specific airways conductance
(sGaw) was derived (Autolink; Morgan Medical). A resting arterialized capillary blood sample was obtained from the earlobe to determine PaO2 and PaCO2 (22). All lung function tests were performed and
expressed according to the national guidelines (23).
Health Status
Indices of health status were obtained using both disease-specific and generic questionnaires administered by a member of the research team with the patient well rested. The data were collected directly onto a computerized database from which the patient was able to select one of the permitted responses for each item.
The St. George's Respiratory Questionnaire (SGRQ) was used as a disease-specific measure (2) divided into three domains: symptoms, activity, and impacts from which a summary score (total) was derived. These domains are scored 0 to 100, with the higher figures indicating worse impairment.
The SF-36 assesses general health concepts (24) divided into eight domains: physical functioning, role limitations due to physical health problems, bodily pain, general health, vitality, social functioning, role limitations due to emotional problems, and mental health. The final scores again range from 0 to 100, however with this questionnaire a score of 0 indicates severe disability.
Statistical Analysis
The data were analyzed using a computerized statistical package (SPSS version 8.0). The frequency distribution of most of the variables analyzed was not normal and hence the descriptive statistics are displayed as median and interquartile ranges. Correlations between paired variables were examined using Spearman's rho.
To identify independent factors predicting exercise capacity, demographic, lung function, and HRCT parameters showing significant bivariate correlations with exercise capacity were entered as independent variables into a stepwise multiple regression analysis, with ISWT
distance covered and O2 peak as dependent variables. Similarly, to
identify independent predictors of health status, demographic data,
lung function, HRCT, and exercise tests were entered as independent
variables into stepwise multiple regression analysis with the components of the SGRQ and SF-36 being examined in turn as dependent variables.
A p value < 0.05 was taken as significant for all analyses.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Subject Characteristics
The baseline characteristics of the 29 PiZ subjects (19 male) are summarized in Table 1. Four patients had never smoked and the remainder were ex-smokers with a median cigarette consumption of 26 pack-years (range 6.75-62.5). As a group, the patients had moderate to severe airflow obstruction, significant air trapping, and impaired gas transfer. The HRCT pixel indices indicated varying degrees of emphysema in all lung zones with the lower zones displaying the most extensive disease (p < 0.001). Eight patients had radiological evidence of bronchiectasis (25), which was invariably cylindrical and limited in distribution. Fourteen of the patients had chronic cough and sputum production consistent with a diagnosis of chronic bronchitis (26), but this was independent of the presence of the mild bronchiectatic changes (2p = 1.00).
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Exercise Capacity
All patients were able to complete a satisfactory incremental
treadmill exercise test. Five patients completed the 15-min protocol but only two of these patients reached an anaerobic
threshold (the remainder were symptom limited before the
threshold was reached). The resulting O2 peak measurements ranged from 6.1 to 27.2 ml/min/kg. A wide range of exercise capacity was also demonstrated on the ISWT with the
distance covered ranging from 100 to 790 m. The medians and
the interquartile ranges for the treadmill test and ISWT are
shown in Table 1. There was a good correlation between both
forms of exercise test (rho = 0.70, p < 0.001). A scatter plot of
the individual data points is available as Figure E1 in the online data supplement to this article.
HRCT Relationships
The lower zone expiratory phase pixel indices showed a strong
relationship with traditional physiological assessment of emphysema (FEV1; rho = 0.75, residual volume/total lung capacity [RV/TLC]; rho = 0.51, DLCO; rho = 0.55: p < 0.01 for
all comparisons). However, other physiological tests also correlated with lower zone expiratory HRCT including slow vital
capacity (VC) (rho = 0.49, p < 0.01), mid expiratory flow
(MEF) (rho = 0.74, p < 0.001), and PaO2 (rho = 0.39, p < 0.05). The upper zone expiratory scans showed significant but
weaker correlations with airways obstruction, gas trapping,
and gas transfer (data not shown).
Abnormalities seen on HRCT showed a good correlation with exercise capacity, which was demonstrated best for the lower zone expiratory scans as shown in Figure 1. Finally, lower zone expiratory HRCT showed a significant correlation with the activity domain of the SGRQ (rho = 0.37, p < 0.05) and the vitality domain of the SF-36 questionnaire (rho = 0.33, p < 0.05).
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Lung Function Relationships
All lung function indices with the exception of DLCO/VA and
sGaw showed a significant correlation with exercise capacity
determined both by O2 peak and ISWT distance covered.
FEV1, MEF, RV/TLC, DLCO, and PaO2 demonstrated the strongest correlations and are displayed in Table 2 along with the remainder of the lung function variables. The individual data for
the relationship between both FEV1 and RV/TLC and the
ISWT are displayed in Figure E2 in the online data supplement.
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Predictors of Exercise Capacity
Expiratory HRCT pixel index (upper and lower zone), FEV1,
MEF, VC, RV/TLC, DLCO, and PaO2 were entered as independent variables into the multiple regression analysis. Of these
measures, FEV1 was the best predictor of both O2 peak and
ISWT distance covered (r2 = 0.44 and 0.62, respectively, p < 0.001) with additional predictive value from DLCO for O2
peak (combined r2 = 0.55, p < 0.001) and DLCO and RV/TLC
for ISWT (combined r2 = 0.74, p < 0.001). There was no additional predictive value from sex, age, or HRCT.
Health Status
The patients showed a wide range of health status in keeping with the variable degree of disease severity indicated by the HRCT and physiological impairment. HRCT and lung function indices were entered as independent variables into a multiple regression analysis, with each of the health status domains examined in turn as the dependent variable. FEV1 remained the best lung function predictor of many of the health status domains, including activity, impacts, and total scores for the SGRQ (r2 = 0.48, 0.25, and 0.38, respectively, p < 0.01) and physical functioning and general health for the SF-36 (r2 = 0.49 and 0.35, respectively, p < 0.01).
However, exercise capacity also related well to health status as shown in Table 3. All domains of the disease-specific
SGRQ were significantly related to both the O2 peak (p < 0.005) and ISWT distance covered (p < 0.05) with the highest
correlation coefficients seen for the activity and impacts domains. The relationships between the activity domain of the
SGRQ and both exercise tests are shown in Figure 2.
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The majority of the domains of the generic SF-36 questionnaire were also significantly correlated with both measures of exercise capacity (Table 3). There was not only a strong correlation between exercise and the physical functioning domain, but also relatively good correlations between exercise and general health, social functioning, and vitality.
In view of this, age, sex, the presence of chronic bronchitis, exercise capacity, and the lung function indices that correlated best with health status were entered as independent variables into a multiple regression analysis with the individual health status domains as dependent variables. The results indicated that the ISWT distance covered was the best predictor of many of the health status domains, with little or no additional predictive value from the other variables. The models and corresponding contribution to variability (r2) are shown in Table 4.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The current study demonstrates that exercise capacity is significantly related to HRCT pixel index and lung function in
this relatively homogeneous group of patients with predominantly lower lobe pan-lobular emphysema related to 1-ATD.
In addition, both HRCT and lung function relate to health status; however exercise capacity predicts this better than the degree of emphysema seen on HRCT or the degree of physiological impairment.
The correlations demonstrated here are better than those previously reported for patients with COPD, which may reflect several unique features of the present group. The patients had a single recognized genetic cause for their disease and all had clear evidence of emphysema demonstrated on HRCT scan. They were also younger than most patient groups with COPD and were therefore less likely to have the comorbidities that accompany aging and may also influence health status and exercise capacity. In addition, although the patients were recruited on the basis of the date of their annual ADAPT assessment, patients with comorbidity that might adversely influence health status were excluded. Nevertheless the patients studied here were representative of all PiZ patients with emphysema attending the ADAPT program (2p > 0.45 for comparisons of FEV1%, DLCO/VA%, pixel indices, and SGRQ total; data not shown). Finally, because of genetic family screening, the current study included some patients identified with early, milder disease providing a wider range of disease severity, which is likely to have improved the correlations observed.
The quantitative analysis of HRCT employed in the current study is a direct, objective method for the assessment of the presence and extent of emphysema. We chose to analyze a single slice through fixed anatomical structures in the upper and lower zones in expiration and, as in previous studies (11, 12), HRCT pixel index was related to many measures of lung function. The lower zone expiratory scans showed the strongest correlations, especially with airflow obstruction and gas trapping.
Lower zone HRCT also related well to exercise capacity.
The correlations observed were similar to those seen between
FEV1 and exercise capacity suggesting that FEV1 and expiratory HRCT are surrogates for the same pathophysiological
process in this group of patients. This is further substantiated
by the stepwise multiple regression analysis, which indicated
that FEV1 was the best single predictor of exercise tolerance
and no additional information was provided by HRCT, despite their similar bivariate correlations. These results provide
further evidence that expiratory CT is a good indicator of the
degree of airflow obstruction and gas trapping (27). The relationship observed between HRCT and exercise in the current
study broadly agrees with the previous study by Wakayama
and coworkers (28). These workers demonstrated significant
correlations between o2 max and both FEV1 and inspiratory HRCT (r = 0.47 and 0.77, respectively) in patients with COPD.
However, the strong relationship between HRCT and FEV1
observed in our current study was not present in that reported
by Wakayama and coworkers (28). This inconsistency may be
due to the homogeneous nature of our patient group and the
observation that lower zone emphysema (a predominant feature of 1-ATD) is responsible for proportionally greater
physiological impairment than the equivalent degree of upper
zone disease (29).
Lower zone expiratory HRCT was the only scan that correlated significantly with health status in this small group of patients, again suggesting that emphysema and air trapping in
this region is more important clinically. However, lung function was more closely related, especially FEV1, VC, and RV/
TLC, to the activity and physical functioning domains of the
SGRQ and SF-36, respectively. Of importance, exercise capacity showed the strongest relationship with health status,
with O2 peak demonstrating the best bivariate correlation.
Despite this, multiple regression analysis applied to the 22 patients who had undergone both forms of exercise testing indicated that the distance covered on the ISWT was the best independent predictor of most of the domains of the SGRQ and
SF-36 accounting for up to 69% of the variation (SGRQ activity). With the exception of the role emotional domain of the
SF-36, these findings were independent of age and sex (Table
4). Thus, when predicting the variation in health status in the
patients described here, exercise capacity accounted for both
the physiological and pathological data obtained from lung
function and HRCT.
It has been shown previously that the activity domain of the SGRQ is related to exercise capacity and, additionally, that this domain relates to breathlessness as assessed by tools such as the MRC questionnaire, Oxygen Cost Diagram, and Baseline Dyspnoea Index (30). In the current study, the ISWT was also strongly related to activity accounting for 69% of the variation seen, emphasizing the impact of breathlessness on the activities of daily living of these patients.
Not all workers have found an association between exercise capacity and subjective measures of health. For instance,
Wijkstra and coworkers found no correlation between exercise testing and quality of life in 40 patients with COPD (31)
using the Chronic Respiratory Questionnaire, the 6 min walk
test, and cycle ergometry to assess O2 peak. However, these
exercise measures are more dependent on muscle strength and
metabolism in contrast to the methods employed in the current study, which are more closely related to the everyday activity and hence are likely to be responsible for the clearer association seen here.
In summary, patients with lower zone emphysema associated with 1-ATD show a clear relationship between expiratory HRCT, resting lung function, exercise capacity, and
health status. These relationships are generally stronger than
those seen in previous studies involving patients with a general diagnosis of COPD, which probably reflects its heterogeneous nature. Exercise testing, by either formal treadmill testing or ISWT, provides the best objective estimate of limitations in health status caused by emphysema in our patients.
The ISWT, however, is a reliable, simple to perform field test
for this purpose and requires no complex equipment. In view
of its strong predictive power for health status it should be
considered appropriate as an alternative or secondary outcome measure to determine the efficacy of intervention trials
in 1-ATD in particular and COPD in general.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Professor R. A. Stockley, Department of Medicine, Queen Elizabeth University Hospital, Birmingham B15 2TH, UK. E-mail: r.a.stockley{at}bham.ac.uk
(Received in original form July 10, 2000 and in revised form November 8, 2000).
The ADAPT project is supported by a noncommercial grant from Bayer plc.This article has an online data supplement, which is accessible from this issue's table of contents online at www.atsjournals.org
Acknowledgments:
The authors would like to thank Sister Barbara Leung for
her assistance in patient care and data collection; ADAPT project coordinators, Mrs Carol Seymour and Miss Rebecca Lewis; and the pulmonary function technicians at the Lung Investigation Unit, Queen Elizabeth Hospital, Birmingham.
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References |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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M. Needham and R. A. Stockley Exacerbations in {alpha}1-antitrypsin deficiency Eur. Respir. J., June 1, 2005; 25(6): 992 - 1000. [Abstract] [Full Text] [PDF]
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D. G. Parr, B. C. Stoel, J. Stolk, and R. A. Stockley Pattern of Emphysema Distribution in {alpha}1-Antitrypsin Deficiency Influences Lung Function Impairment Am. J. Respir. Crit. Care Med., December 1, 2004; 170(11): 1172 - 1178. [Abstract] [Full Text] [PDF]
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D. G. Parr, B. C. Stoel, J. Stolk, P. G. Nightingale, and R. A. Stockley Influence of Calibration on Densitometric Studies of Emphysema Progression Using Computed Tomography Am. J. Respir. Crit. Care Med., October 15, 2004; 170(8): 883 - 890. [Abstract] [Full Text] [PDF]
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N J Stevenson and P M A Calverley Effect of oxygen on recovery from maximal exercise in patients with chronic obstructive pulmonary disease Thorax, August 1, 2004; 59(8): 668 - 672. [Abstract] [Full Text] [PDF]
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J.D. Newell Jr, J.C. Hogg, and G.L. Snider Report of a workshop: quantitative computed tomography scanning in longitudinal studies of emphysema Eur. Respir. J., May 1, 2004; 23(5): 769 - 775. [Abstract] [Full Text] [PDF]
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P A Dawkins, L J Dowson, P J Guest, and R A Stockley Predictors of mortality in {alpha}1-antitrypsin deficiency Thorax, December 1, 2003; 58(12): 1020 - 1026. [Abstract] [Full Text] [PDF]
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 L. J. Dowson, P. J. Guest, and R. A. Stockley The Relationship of Chronic Sputum Expectoration to Physiologic, Radiologic, and Health Status Characteristics in {alpha}1-Antitrypsin Deficiency (PiZ) Chest, October 1, 2002; 122(4): 1247 - 1255. [Abstract] [Full Text] [PDF]
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M. J. TOBIN Chronic Obstructive Pulmonary Disease, Pollution, Pulmonary Vascular Disease, Transplantation, Pleural Disease, and Lung Cancer in AJRCCM 2001 Am. J. Respir. Crit. Care Med., March 1, 2002; 165(5): 642 - 662. [Full Text] [PDF]
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L. J. DOWSON, P. J. GUEST, and R. A. STOCKLEY Longitudinal Changes in Physiological, Radiological, and Health Status Measurements in alpha 1-Antitrypsin Deficiency and Factors Associated with Decline Am. J. Respir. Crit. Care Med., November 15, 2001; 164(10): 1805 - 1809. [Abstract] [Full Text] [PDF]
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