Study objectives: First, to determine the relationships among chronic sputum expectoration (CSE), exacerbations, airflow obstruction, and emphysema in patients with [[alpha].sub.1]-antitrypsin deficiency ([[alpha].sub.1]-ATD) [PiZ]. Second, to use multivariate analysis to determine how these factors influence health status.
Design: Cross-sectional, single-center.
Setting: UK center for [[alpha].sub.1]-ATD, university teaching hospital.
Patients: One hundred seventeen nonsmoking patients underwent lung function testing, high-resolution CT (HRCT) scanning with density mask analysis, and health status assessment using the St. George's Respiratory Questionnaire (SGRQ) and short form 36 (SF-36) health survey questionnaire.
Results: Patients with CSE (n = 50) had worse postbronchodilator airflow obstruction than those who did not (p = 0.03), with a median FE[V.sub.1] of 1.15 L (interquartile range [IQR], 0.76 to 1.82) vs 1.44 L (IQR, 0.99 to 2.93), respectively, and higher HRCT scan voxel index (VI) values indicating more extensive emphysema (patients with CSE: median lower zone VI, 50; IQR, 28 to 61; patients without CSE: median lower zone VI, 41; IQR, 5 to 53; p = 0.04). Patients with CSE also had worse health status, as assessed by the SGRQ (p < 0.01 for all domains) and SF-36 questionnaire (p < 0.05 for seven of nine domains). Exacerbation frequency was greater in those patients with CSE (p < 0.001), with a median of two episodes per year (IQR, 1 to 3) vs 0.66 episodes per year (IQR, 0 to 2) for those without CSE. Stepwise linear regression analysis revealed FE[V.sub.1], exacerbation frequency, and lower zone VI to be the most important predictors of health status.
Conclusions: Among patients with [[alpha].sub.1]-ATD, those with CSE expectoration exhibit greater physiologic impairment and more extensive emphysema than those without. This is reflected in an inferior health status, which is also influenced independently by an increased exacerbation frequency in those with CSE.
Key words: COPD; CT; obstructive lung diseases; quality of life
Abbreviations: [[alpha].sub.1]-AT = [[alpha].sub.1]-antitrypsin; [[alpha].sub.1]-ATD = [[alpha].sub.1]-antitrypsin deficiency; CSE = chronic sputum expectoration; DLCO = diffusing capacity of the lung for carbon monoxide; HRCT = high-resolution CT; IQR = interquartile range; SF-36 = short form 36; SGRQ = St. George's Respiratory Questionnaire; VA = alveolar volume; VI = voxel index
Chronic cough and chronic sputum expectoration (CSE) represent important clinical symptoms that affect approximately 40% of patients with COPD. Sputum production is thought to reflect inflammatory processes in the major airways, (1,2) especially the presence of neutrophils and their products. (3,4) Inflammation has been implicated in the pathogenesis of emphysema and, hence, in the development and progression of airflow obstruction in patients with COPD. (4) It might be expected therefore that CSE would be an indicator not only of the severity and extent of inflammation, but also of the rate of disease progression. However, the most widely quoted epidemiologic study (5) failed to confirm this association. Nevertheless, the issue is being reassessed by several investigators because of the biochemical and pathologic data relating inflammation to disease severity. Moreover, some data have suggested that CSE may indeed be associated with the progression of airflow obstruction (4,6) and mortality (7) in patients with COPD.
Poor health status is another feature of COPD, and it reflects many features of the disease, including airflow obstruction, (8) reduced exercise capacity, (8) and the presence and frequency of exacerbations. (9) However, the strength of these associations is at best poor, perhaps reflecting the heterogeneous nature of COPD and the presence of the comorbid conditions that occur with increased frequency in late middle age when COPD becomes overt clinically. In addition, although sputum production has been shown to relate to health status, this association was limited to a single domain that included sputum production as a criterion. (10)
Patients with [[alpha].sub.1]-antitrypsin deficiency ([[alpha].sub.1]-ATD) usually have lower zone panlobular emphysema, with or without CSE, which develops at a relatively early age compared to the usual development of COPD. Thus, they are less likely to suffer from the age-related comorbidity that confounds the measurement of health status in patients with the usual form of COPD and provide a more ideal group in which to study the relationships among respiratory symptoms, pathophysiology, and health status. The current study was established to assess this relationship, including the severity of emphysema as demonstrated by CT scanning, in a well-defined group of patients. In particular, we used multivariate analysis to assess any independent health status burden conferred by chronic sputum production and any relationship to exacerbation frequency.
MATERIALS AND METHODS
The group of study subjects consisted of the first 127 patients attending our department for assessment. All patients had a serum [[alpha].sub.1]-antitrypsin ([[alpha].sub.1]-AT) concentration of < 10 [micro]M, and the phenotype was confirmed as PiZ (inferring a genotype PiZZ or PiZnull) by isoelectric focusing in a central US laboratory (Salt Lake City, UT). Augmentation therapy with ([[alpha].sub.1]-AT is not licensed within the United Kingdom and, therefore, was not received by any of the study participants. Investigations and data collection were undertaken at an annual assessment, occurring at least 4 weeks after any exacerbation. All subjects gave written informed consent to the study, which was approved by the University of Birmingham Hospital NHS Trust Research Ethics Committee.
All subjects performed dynamic spirometry before and after dual bronchodilatation with a nebulized [[beta].sub.2]-agonist and ipratropium bromide, as described previously. (11) Lung volumes were measured by helium dilution (Morgan Medical; Kent, UK) and gas transfer (ie, diffusing capacity of the lung for carbon monoxide [DLCO]), as measured by the single-breath carbon monoxide method and corrected for effective alveolar volume (ie, DLCO/ alveolar volume [VA] ratio). An arterialized earlobe capillary blood sample was obtained to estimate arterial Pa[O.sub.2]. (12) All tests were performed according to the guidelines of the British Thoracic Society/Association of Respiratory Technicians and Physiologists. (13)
The high-resolution CT (HRCT) scanning protocol has been described in detail in a previous publication. (11) Briefly, 1-mm thick slices were obtained at 10-mm intervals at full inspiration and expiration. The inspiratory scans were examined for the macroscopic changes of emphysema and bronchiectasis. (14) Density mask analysis using a threshold of -910 Hounsfield units was performed on single slices through the upper zone (at the level of the aortic arch) and the lower zone (at the level of the inferior pulmonary vein) in order to quantify the extent of emphysematous tissue. (15) The results were expressed as the voxel index (VI; ie, the number of low-density voxels [[less than or equal to] -910 Hounsfield units], expressed as a percentage of the total number of voxels representing lung tissue).
Disease-specific health status was assessed using the St. George's Respiratory Questionnaire (SGRQ) (10) and generic health status using the short form 36 (SF-36) health survey questionnaire, (16) as described previously. (11) Each of the domains is scored from 0 to 100, with a high score indicating worse impairment for the SGRQ and the converse for the SF-36.
CSE was defined as sputum expectoration on most days for at least 3 consecutive months of the year for [greater than or equal to] 2 consecutive years. (17) Eight of the 10 current smokers had CSE, and it was decided therefore to omit the current smokers from further analysis to exclude current smoking as a confounding factor. Of the remaining subjects, 85 were ex-smokers (median, 22 pack-years; interquartile range [IQR], 13 to 30 pack-years) and 32 were never smokers.
An exacerbation was defined as an episode associated with at least two of the three major criteria described by Anthonisen and colleagues, (18) namely, increased sputum volume, increased sputum purulence, and increased breathlessness lasting for > 24 h. These data were obtained retrospectively for 3 years and then prospectively every 3 to 6 months for up to 2 years. From these data, the average number of exacerbations per year was calculated and used for the subsequent analysis.
Descriptive statistics are displayed as the median and IQR, correlations between paired variables were examined using the Spearman [rho], and subgroup comparisons were made using the Mann-Whitney U test for continuous data and the [chi square] test or Fisher exact test, as appropriate for nominal data. Stepwise linear regression analysis was used in order to determine independent factors associated with changes in health status. The standardized residuals from these analyses conformed to a normal distribution, making this a valid test despite the nonparametric nature of some of the data. A p value of < 0.05 was taken as statistically significant for all analyses.
The 117 nonsmoking PiZ patients displayed a wide range of lung function, although the median data indicated severe airflow obstruction (median FE[V.sub.1], 32% predicted; total range, 10 to 130% predicted) and reduced gas transfer (median DLCO/VA ratio, 71% predicted; total range, 4 to 148% predicted), which are conditions that are consistent with the presence of emphysema. This was confirmed by HRCT scan, and the VI values demonstrated lower zone predominance (p < 0.001), which is characteristic of [[alpha].sub.1]-ATD. The absolute values for these measurements are summarized in Table 1. Health status also ranged from normal to severe impairment (Fig 1 and Table 2), although, again, as a group the data suggested marked disability with a median SGRQ total score of 48 (total range, 0 to 84; normal range, 5 to 7). Coexistent cardiovascular morbidity was rare with only nine of the patients (7.5%) having "received treatment for a heart complaint" and three patients (2.5%) having "received treatment for high BP."
[FIGURE 1 OMITTED]
Fifty of the patients (43%) had CSE. There was radiologic evidence of bronchiectasis in 31 patients (26%), and, although chronic sputum production was more common in these patients (61% vs 36% of those without bronchiectasis, p < 0.02), the association between these two features was not particularly strong. CSE was neither a specific indicator of radiologic bronchiectasis (specificity, 64%) nor sensitive to the diagnosis (sensitivity, 61%). In addition, the presence or absence of radiologic bronchiectasis did not relate to lung function (p > 0.13 for all comparisons).
The patients with CSE had worse lung function and had more emphysema visualized on HRCT scans compared to those without CSE, despite having a similar age range and smoking history (Table 1). They also displayed worse health status, as determined by the SGRQ (Fig 1), on which the median value for each domain was significantly worse for the sputum producers. The SGRQ values for those with CSE were 75.6 for symptoms (IQR, 68.0 to 83.7), 82.9 for activity (IQR, 60.4 to 100), 49.9 for impacts (IQR, 33.0 to 62.7), and 64.4 for the total score (IQR, 48.3 to 74.4). The corresponding SGRQ results for those patients without CSE were 47.6 (IQR, 28.9 to 66.7), 59.5 (IQR, 32.7 to 86.3), 28.9 (IQR, 11.7 to 47.6), and 42.0 (IQR, 23.9 to 59.5), respectively (p [less than or equal to] 0.001 for all comparisons). The data presented in Table 2 show that generic health status, as assessed by the SF-36, was also worse in those patients with CSE.
The patients with CSE reported significantly more exacerbations (p < 0.001), with a median of two episodes per year (IQR, one to three episodes per year) compared to 0.66 episodes per year (IQR, zero to two episodes per year) for the patients without CSE (Fig 2). Thirty-eight percent of those patients with CSE had complained of three or more exacerbations compared to only 6% of those without CSE. Furthermore, both the FE[V.sub.1] and SGRQ total score correlated significantly with the frequency of exacerbations ([rho] = 0.36 and [rho] = 0.56, respectively; p < 0.001). Data for the relationship between exacerbation frequency and SGRQ total score are summarized in Figure 3.
[FIGURES 2-3 OMITTED]
There was no difference in health status or exacerbation frequency (p > 0.05 for all comparisons [data not shown]) between those attending for baseline assessment (where episodes Were collected retrospectively) and those attending follow-up (where additional prospective data were available), suggesting that patient recall of exacerbations was reasonably accurate.
In order to investigate further the effect of CSE on health status, we performed a stepwise linear regression analysis examining both the disease-specific and generic health status scores in turn as dependent variables for the 106 patients with a complete data set. Independent variables included all demographic data, assessment type (ie, baseline or follow-up), patient acquisition (ie, index or nonindex case), corticosteroid use, smoking status, and previous cigarette consumption. All lung function variables (ie, Pa[O.sub.2], upper and lower zone VI values, and the presence of bronchiectasis and CSE) also were included.
Initially, in addition to FE[V.sub.1] and lower zone HRCT scan VI values, chronic sputum production appeared as an important independent predictor of health status for three of four domains of the SGRQ and for several of the domains of the SF-36. When exacerbation frequency also was added as an independent variable, it invariably replaced CSE and improved the predictive value of the models. However, in order to emphasize the relationships among CSE, exacerbations, and health status, the original results (excluding exacerbation data) are displayed in Table 3. The results following the addition of the exacerbation data are summarized in Table 4 and indicate that postbronchodilator FE[V.sub.1], exacerbation frequency, and lower zone emphysema were responsible for most of the identifiable variation in both disease-specific and generic health status. For example, in the case of the SGRQ total score these three variables accounted for 50% of the variability seen. Importantly, these findings were not related to demographic characteristics, corticosteroid treatment, or previous cigarette consumption.
In this group of patients with [[alpha].sub.1]-ATD, CSE was associated with more severe airflow obstruction and emphysema. In addition, these patients demonstrated worse health status, as assessed by both disease-specific and generic instruments, and the initial analysis indicated that this relationship was independent of the degree of physiologic impairment, smoking history, and age.
Of importance in our study, sputum expectoration was neither sensitive nor specific for the presence of bronchiectasis on HRCT scans. Sputum production always has been considered to be a consistent feature of bronchiectasis, Nevertheless, the bronchiectasis identified here is based on modern radiologic techniques that are likely to detect milder (or even a different) disease to that recognized clinically in the past. Clearly, further studies will be needed to explore the implications of this radiologic diagnosis and its relationship to chronic sputum production.
The evidence regarding the importance of CSE in the pathogenesis of COPD remains conflicting. The landmark epidemiologic study by Fletcher and Peto (5) failed to find a relationship between "chronic bronchitis" and the progression of airflow obstruction. This led to the belief that chronic bronchitis was an innocent "bystander" sharing a common etiology (usually cigarette smoke) with the airflow obstruction. However, more recently pathologic studies have indicated that chronic sputum production is associated with inflammation in the central airways. (1,2) In addition, bronchial washings from patients with chronic bronchitis and airways obstruction contain a greater proportion of neutrophils compared to samples obtained from asymptomatic smokers. (19) Furthermore, neutrophil chemoattractants such as interleukin-8 are found in relatively high concentrations in spontaneous sputum samples from patients with COPD and relate to the degree of airflow obstruction (20) and current smoking. (21) All these data suggest that chronic sputum production reflects airway inflammation and, by inference, the pathophysiologic factors believed to be associated with progressive airflow obstruction. Indeed, longitudinal data (6) from a large group of adults selected at random has demonstrated a relationship between chronic mucus hypersecretion and FE[V.sub.1] decline that is independent of age, sex, smoking history, and baseline airflow obstruction. The results presented here indicate that patients with CSE have worse lung function when stratified for age, sex, and smoking habit. These findings are consistent, therefore, with a link between chronic sputum production and FE[V.sub.1] decline, although firm conclusions are limited at present by the cross-sectional nature of the study.
The patients who regularly produced sputum also experienced more frequent exacerbations. Each such episode increases the inflammatory burden in the lungs further, (22) and, since inflammation is thought to be central to the progression of lung disease in patients with COPD, these episodes might lead theoretically to small but stepwise deteriorations in lung function. Nevertheless, this has never been demonstrated clearly, (5,22) although we did find a significant correlation between exacerbation frequency and FE[V.sub.1] ([rho] = 0.36; p < 0.001). However, the cross-sectional nature of the current study does not enable us to determine a causal relationship but does provide supportive data, which are clearly worthy of further study.
In the current study, both disease-specific and generic health status were worse than those of the UK population at large. (10,16) Dividing the patients into those with and without CSE, the former demonstrated worse health status for all the disease-specific domains and for many domains of the generic SF-36. The patient group in the current study included cases of both index patients (n = 89) who presented with respiratory problems and nonindex patients who were identified by family screening. The latter group was younger, had smoked less, and consequently had better lung function and health status (data not shown), as demonstrated in previous studies. (23) In addition, the prevalence of chronic sputum production was also less in this group (25%), and it is possible that this group might bias the comparisons of disease severity and health status between the patients with and without CSE. However, in the initial multivariate analysis (which excluded data on exacerbation frequency) age, patient acquisition, previous cigarette consumption, and lung function are all taken into account, and chronic sputum production remained an independent predictor of health status.
Seemungal and colleagues, (9) who studied a group of nondeficient patients with moderate COPD also found that daily sputum production and bronchitic symptoms (ie, cough and sputum production) were associated with a worse SGRQ symptom score. However, they did not find an association between daily sputum production and other health status domains. (9) The symptom of CSE is an integral part of the symptoms domain and understandably influences the score obtained. CSE did not influence the activity domain of the SGRQ in the current study but was related to the impact domain and, hence, to the overall score for the SGRQ. The mechanism by which CSE affects the impact domain and other domains of the SF-36 are not clear at present.
The data for the SF-36 are presented in Table 2 and indicate that the group as a whole experienced difficulty in performing physical activity (in terms of a reduction in physical functioning and role physical scores compared to the UK average). However, while the degree of impairment in those patients with CSE was associated with a significant reduction in social functioning and vitality, those patients without CSE had similar values to that of the UK population. Furthermore, although those patients with CSE had worse generic health status for the pain and role emotional domains, both groups exhibited scores that were similar to the population in general. With the SF-36, CSE acted as an independent predictor of physical functioning and perceived general health and vitality, but not of the other domains. Certainly an extra symptom (ie, CSE) can be expected to influence the patient's perception of general health and hence physical functioning and vitality. It is possible that sputum production causes discomfort and increased breathlessness due to mucus plugging, sleep disturbance, and psychological problems. (24,25) In support of this, there is some evidence that mucolytic therapy may lead to symptomatic improvement in COPD. (26)
As part of our study, we also collected information regarding the number of exacerbations. At the initial visit, these data were collected retrospectively, but for subsequent visits these data were supported by information from further contact episodes (at least every 6 months). Whereas the retrospective data collection is a potential weakness of the study, reassuringly, the exacerbation frequency was similar to the data collected prospectively in the patients who had been observed for several years. These additional contacts enabled chronic sputum production to be clearly documented. Furthermore, the postponement of assessments until the patient was clinically stable ensured that CSE was clearly distinct from intermittent expectoration that is associated with exacerbations. When exacerbation frequency was added to the multivariate analysis, it invariably replaced CSE as a significant independent predictor of health status. This finding suggests that the main mechanism by which CSE has a deleterious effect on health status is by increasing, or being associated with, the patient's susceptibility to exacerbations. This finding is consistent with that of Seemungal and colleagues, (9) who found a weaker but significant association between bronchitic symptoms and exacerbation frequency but, more importantly, that exacerbation frequency was associated with worse health status for all SGRQ domains. The patients studied by Seemungal et al (9) experienced more exacerbations (median, three exacerbations per year) than those in the current study, although this may reflect the less strict criteria that were used to define the episodes. In the current study, we included only exacerbations fulfilling at least two of the three major criteria that were defined by Anthonisen and colleagues, (18) which are more likely to represent significant illness and bacterial infections. However, despite the difference in data acquisition between our study and that of Seemungal et al, (9) the conclusions are similar, indicating the importance of exacerbation frequency as a determinant of health status. The clinical importance of exacerbation frequency is supported further by a recent controlled trial (27) in patients with COPD demonstrating that inhaled fluticasone propionate reduced exacerbation frequency, and this was accompanied by a lesser decline in health status.
Exacerbations in patients with [[alpha].sub.1]-ATD are episodes in which the proteinase load in the airway is clearly increased. (28) A retrospective study suggested that patients who had been receiving [[alpha].sub.1]-AT augmentation therapy had a reduction in the number of exacerbations, (29) and that this may be one mechanism by which augmentation therapy might stabilize lung function. (30) This indirect evidence suggests that treatment and prevention of these acute exacerbations should become a major therapeutic strategy that may not only improve symptoms, but may also influence long-term FE[V.sub.1] decline. Clearly, prospective studies are necessary to confirm this hypothesis, but the current data add strength to this concept.
In summary, chronic bronchitis is associated with more severe airflow obstruction and emphysema in patients with [[alpha].sub.1]-ATD (PiZ). The current study demonstrates that patients with chronic bronchitis have worse health-related quality of life compared to similar patients who do not produce sputum. The main mechanism for this disadvantage appears to be increased susceptibility to exacerbations in the former group. Whether the increased frequency of exacerbations or the underlying bronchial inflammation increases the rate of decline of lung function is uncertain and requires prospective longitudinal studies. The study of patients with [[alpha].sub.1]-ATD may facilitate such studies because of the age, rapidity of progression, and lack of comorbidity in this group.
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* From the Lung Investigation Unit, Nuffield House, Queen Elizabeth University Hospital, Birmingham, UK.
The Antitrypsin Deficiency Assessment and Programme for Treatment (ADAPT) project is supported by a noncommercial grant from Bayer plc. Dr. Stockley is a member of the [[alpha].sub.1] International Registry (AIR).
Manuscript received October 24, 2001; revision accepted April 9, 2002.
Correspondence to: Robert A. Stockley, DSc, Department of Medicine, Queen Elizabeth University Hospital, Birmingham, B15 2TH, United Kingdom; e-mail: firstname.lastname@example.org
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