Bronchiectasis

Study objective: To determine the most important variables influencing health-related quality of life (HRQL) in patients with clinically stable bronchiectasis (SB).

Design: Cross-sectional study.

Patients and interventions: A total of 86 patients (mean age, 69.5 years; SD, 8.9 years; 64% male) with SB were included. Data were collected on general patient characteristics, symptoms, laboratory findings, the extent of bronchiectasis, functional variables, medication in acute or stable phases, and the number of exacerbations. All patients completed the St. George Respiratory Questionnaire (SGRQ). Univariate and multivariate analyses were performed to identify the variables significantly influencing HRQL in these patients.

Results: Different clinical parameters (sputum, dyspnea, cough, and wheezing), spirometric variables, and laboratory parameters (fibrinogen), as well as the extent of bronchiectasis, medication, and the number of exacerbations were significantly correlated to the total questionnaire score, although only dyspnea (r = 0.43, p 0.0001), FE[V.sub.1] ([r.sup.2] = 0.33, p < 0.0001), and daily sputum production ([r.sup.2] = 0.2, p < 0.004) were independently correlated to the total score, globally explaining 55% of the total score variability. Systemic steroid treatment of exacerbations ([r.sup.2] = 0.17, p < 0.028) and the habitual presence of coughing ([r.sup.2] = 0.22, p < 0.004) and wheezing ([r.sup.2]= 0.16, p < 0.013) were in turn independently correlated to the activity and symptoms subscales, respectively.

Conclusion: Dyspnea, FE[V.sub.1], and sputum production are the strongest conditioning factors of HRQL in patients with clinically SB.

Key words: bronchiectasis; health-related quality of life; St. George Respiratory Questionnaire; sputum production

Abbreviations: CF = cystic fibrosis; CH = clinical history; HRCT = high-resolution CT; HRQL = health-related quality of life; SB = clinically stable bronchiectasis; SGRQ = St. George Respiratory Questionnaire

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Bronchiectasis, defined as the airway disorder caused by irreversible bronchial dilatation secondary to chronic bacterial colonization and inflammation, has drawn little attention to date, possibly because it has been regarded as a scantly prevalent disease. (1,2) Nevertheless, studies (3,4) show that even in the industrialized world, a relevant percentage of patients with difficult-to-control COPD or asthma present with bronchiectasis that at least partially accounts for the observed symptoms. This underscores the importance of identifying possible bronchiectasis, since the management approach differs from other airways diseases.

Bronchiectasis is characterized by chronic expectoration, progressive dyspnea that may become incapacitating, pulmonary functional deterioration, and multiple infectious exacerbations. (1) Very few studies have quantified the impact of bronchiectasis on patient health-related quality of life (HRQL) based on conveniently validated questionnaires. The few studies (4-6) found in the literature mainly refer to the influence of the type of microorganism found in sputum, particularly with Pseudomonas aeruginosa colonization. Only the St. George Respiratory Questionnaire (SGRQ) (7) has been validated in its English versions and recently by our group in Spanish (9) for use in patients with clinically stable bronchiectasis (SB). The present study uses this instrument to analyze the variables exerting the greatest and independent influence on quality of life in patients with SB.

MATERIALS AND METHODS

Study Population

The present study comprised all patients with bronchiectasis involving more than one lobe or cystic bronchiectasis not attributable to cystic fibrosis (CF) in our center during the period between 1990 and June 2003. Patients with traction bronchiectasis due to severe emphysema or advanced fibrosis were excluded, as were those presenting with surgically treated bronchiectasis or chronic background diseases sufficiently serious to interfere with patient quality of life to a greater extent than bronchiectasis itself. Patients unable to follow the study protocol because of severe physical or mental health problems were likewise excluded from the study, together with those individuals who failed to give informed consent. Clinical stability was required of all patients, and was defined as the absence of clinical worsening beyond normal daily variations, with no need for increasing habitual or rescue medication during at least the 4 weeks prior to evaluation. The study was approved by the local Clinical Research Ethics Committee.

Diagnosis of Bronchiectasis

In all cases, bronchiectasis was diagnosed by high-resolution CT (HRCT) of the chest, with the use of a 1- to 1.5-min window every 10 mm with acquisition times of 1 s during full inspiration, following the criteria of Naidich et al. (10) HRCT was repeated if the last exploration had been performed > 24 months before the start of the study, to update the extent of bronchiectasis. The extent of the disease was evaluated using a modification of the scoring system developed by Bhalla et al (11): each lung lobe (considering lingula and middle lobe as independent) was scored as 0 (no bronchiectasis), 1 (cylindrical bronchiectasis in a single lung segment), 2 (cylindrical bronchiectasis in more than one lung segment), or 3 (cystic bronchiectasis). The maximum score was 18 points. All HRCT images were independently evaluated by a radiologist and a clinician with extensive experience with these patients.

CF was excluded by the presence of a negative sweat chloride test result (< 60 mmol/L) or mutational analysis in patients with a compatible clinical picture. The following etiologies of bronchiectasis were considered: (1) posttuberculosis origin: past presence along with bronchiectasis of clear documented tuberculosis in a similar location. This etiology was also considered in the presence of indirect HRCT findings of past tuberculosis (apical fibrous tracts, calcified adenopathies or granulomas) together with a positive Mantoux test result, provided bronchiectasis could not be explained by other causes and the clinical manifestations appeared after the tuberculous process. (2) Postinfection origin: documented evidence of one or more nontuberculous pneumonic processes in the current location of bronchiectasis, or the past presence of necrotizing pneumonia, provided onset of the clinical manifestations was posterior to the infectious process. This etiology was also considered in the presence of primary immune deficiencies, provided bronchiectasis could not be explained by other causes. The rest of diagnoses (collagenosis, allergic bronchopulmonary aspergillosis, collagenosis, inflammatory diseases, ciliary dyskinesia, other congenital disorders) were assessed according to clinician criterion, based on the required complementary tests. If no compatible etiologic diagnosis was established following all the opportune complementary studies, bronchiectasis was classified as idiopathic.

Study Protocol

A complete clinical history (CH) was compiled of all patents (CH visit), including general parameters (age and sex), disease antecedents of interest, smoking history, and bronchodilator therapy. Dyspnea was assessed at the CH visit based on the scale proposed by the Medical Research Council, modified by the American Thoracic Society. (12) Likewise, HRQL was analyzed with the SGRQ, which was completed by all patients on occasion of the CH visit. All patients were instructed to daily record coughing, wheezing, hemoptysis, and the number of inhaled short-acting [[beta].sub.2]-agonist doses administered as a relief medication under clinically stable conditions in the month prior to the CH visit. Habitual coughing or wheezing were evaluated as dichotomic variables, designating a value of 1 when occurring on > 50% of days. However, daily sputum production (in milliliters) was evaluated, instructing the patients to collect the amount of sputum during the last 3 days in three graded sterile containers (one per day), and marking the amount reached each day on the container. Instructions were given to ensure that sputum collection was as correct as possible. The average of the three measures was taken to be the valid sputum output. Three fresh sputum samples were likewise collected at 15-day intervals for microbiological study during the clinically stable phase. Gram staining and culture in habitual or special media (in the event a specific microorganism was clinically suspected) were carried out. Chronic colonization was considered when the valid sputum sample (< 10 epithelial cells and > 25 leukocytes per field) yielded > 1 x [10.sup.5] cfu/mL in at least two samples spaced 15 days apart outside exacerbation periods. Data were collected on the number of exacerbations, the use of antibiotics, oral steroids, hospitalizations, or emergency department admissions in the 6 months prior to the CH visit. Exacerbation was defined by significant changes in sputum color or amount, increased dyspnea or wheezing, or an increase in basal or rescue medication not attributable to other causes and with an evolution of > 24 h.

Laboratory tests were performed with a CBC count and general biochemistry, including acute-phase reactants (fibrinogen concentration, erythrocyte sedimentation rate, and C-reactive protein). The functional indexes measured were as follows: FE[V.sub.1], FVC, and peak expiratory flow. They were expressed as absolute value in milliliters, and percentages of values predicted for patient age, sex, and height, as well as after the administration of 200 [micro]g of salbutamol. (13) Total lung capacity and residual volume were measured by the helium dilution technique. Indexes of gas transfer were measured using a carbon monoxide single-breath test adjusted for alveolar volume; gas transfer results were adjusted for hemoglobin. All maneuvers were performed at the same time in the morning. Both laboratory tests and functional assessments were performed at the CH visit. All measurements were performed in a clinical stable phase.

Assessment of HRQL

Quantification of HRQL was based on the SGRQ, a specific questionnaire for patients with respiratory disorders consisting of 50 items assessed by means of three subscales. The symptoms subscale refers to the frequency and severity of cough, wheezing, expectoration, or exacerbation. The systems subscale comprises eight items, corresponding to eight multiple choice questions (except question No. 8, which is dichotomic). The activity subscale in turn refers to the limitations in patient activity due to dyspnea, and involves 16 dichotomic response items. The impact subscale summarizes the alterations in the psychological, occupational, and social spheres, based on the way in which the patient perceives his or her disease. It consists of 26 items addressed by eight questions. The total questionnaire score and score corresponding to each of the three subscales are calculated as a function of the item scores, based on a range from 0 (best possible score) to 100 points (worst possible score). The questionnaire was designed for self-administration in 10 min, though there appear to be no significant differences when the instrument is delivered by personal interview. (14) In the present study, the questionnaires were completed by the patients, and only if the latter requested help did we resort to personal interviewing, without influencing the answers in any way.

Statistical Analysis

The data were tabulated as the mean (SD) in the case of quantitative variables, and as the absolute value (percentage) for qualitative variables. The normal distribution of the variables was confirmed by the Kolgomorov-Smirnov-Lilieford test. In the event of a nonnormal distribution, the corresponding logarithmic transformation was carried out. Such transformation proved necessary in relation to the number of disease exacerbations, oral steroid doses, emergency department admissions, antibiotic use, and hospitalizations in the previous 6 months; due to the existence of a left asymmetrical nonnormal distribution. Interobserver variation for the extent of SB was quantified as the [kappa] coefficient of agreement. (15) A correlation matrix (Pearson coefficient r) was developed to identify the variables significantly related to each quality-of-life subscale and to the global quality-of-life score. In order to identify the variables independently related to each subscale and to the total quality-of-life score, use was made of a multiple linear regression analysis for each subscale and for the total questionnaire score, with the dependent variables of each analysis being the scores of each subscale and the total score, respectively, while the independent variables were the parameters significantly correlated to the scores of each subscale and the total score in the corresponding correlation matrixes. The contribution and specific weight of each variable separately in accounting for the total variance of each subscale and total questionnaire score was determined by means of the corresponding correlation coefficients: multiple coefficient ([R.sup.2]), squared of simple correlation coefficient or determination coefficient ([r.sup.2]), and semipartial correlation coefficient. Verifications were made of linearity, homoscedasticity, normality, the absence of multilinearity (Dubin-Watson test, tolerance test, or variance inflation factor), and the absence of interdependence or autocorrelation of the explanatory variables, based on the corresponding study of residues. Statistical significance was considered for p < 0.05.

RESULTS

A total of 132 patients had bronchiectasis involving more than one lobe or cystic bronchiectasis not attributable to CF during the prospective study period. Fifteen patients with traction bronchiectasis were excluded, along with 14 patients with severe pathology causing greater quality-of-life deterioration than the actual bronchial disease, 13 subjects with manifest physical or psychological incapacity to follow the study protocol, 2 patients with surgically treated bronchiectasis, and 2 patients who refused to participate in the study. A total of 86 patients were thus finally included (mean age, 69.5 years; SD, 8.9; range, 38 to 84 years; 64% male). The general characteristics of these individuals are shown in Table 1. The finally identified etiologies were idiopathic in 37 cases (43%), after infection in 27 cases (31.4%), after tuberculosis in 16 cases (18.6%), and other causes in 6 cases (7%). Twelve patients (14%) presented with respiratory failure, 61 patients (71%) were receiving long-acting [[beta].sub.2]-agonists, and 21 patients (24.4%) were receiving anticholinergic agents. All patients were allowed to use short-acting [[beta].sub.2]-agonists as a relief medication for dyspnea, coughing episodes, or wheezing sensation. Eighteen patients (21%) had chronic colonization by P aeruginosa and 19 patients (22%) had chronic colonization by Haemophilus influenzae. Other identified microorganisms were Streptococcus pneumoniae (n = 9); Aspergillus niger (n = 1); Haemophilus parainfluenzae (n = 1); Klebsiella pneumoniae (n = 1); Stenotrophomonas malthophilia (n = 1); Moraxella catarrhalis (n = 1); Mycobacterium abscessus (n = 1); Mycobacterium fortuitum (n = 1); Serratia marcescens (n = 2); and Nocardia asteroides (n = 1). Interobserver agreement for the extent of SB was excellent ([kappa] = 0.81).

Table 2 reflects the statistically significant simple (Pearson) correlations found with respect to each quality-of-life subscale and the global score. Dyspnea and the forced spirometry functional variables showed the greatest simple correlation coefficients, although other variables such as short-acting [[beta].sub.2]-agonist dosage, daily sputum production, or the use of systemic steroids to treat the exacerbations all exhibited significant correlation coefficients of > 0.4. Lastly, a significant positive correlation was observed between the HRCT score and both the total SGRQ score (r = 0.27, p = 0.01) and the activity scale score (r = 0.30, p = 0.01).

Table 3 summarizes the results obtained by the multiple regression analysis. As a consequence of intercorrelation among several of the explanatory variables, only dyspnea (which explained 42.5% of the total variance), FE[V.sub.1] value (percentage of predicted) after bronchodilation (adding 9.2% to the explanation of variance afforded by dyspnea), and daily sputum production (adding 4.6% to the explanation of variance afforded by dyspnea and FE[V.sub.1]) were identified as independent variables, globally explaining 55% of the variability of the questionnaire total score. Dyspnea was the variable that independently accounted for the largest percentage of variance in the activity ([r.sup.2] = 0.38, p < 0.0001) and impact ([r.sup.2] = 0.31, p < 00001) subscales, whereas daily sputum production was the variable that independently accounted for the largest percentage of variance in the symptoms subscale ([r.sup.2] = 0.27, p < 0.0001). This was followed by FE[V.sub.1], particularly in the activity subscale (where it added 12.7% to the explanation of variance afforded by dyspnea) and, to a lesser degree, in the impact subscale (an additional 6.3%). No significant independent relation to the symptoms subscale was recorded.

Lastly, the number of steroid cycles administered in the previous 6 months ([r.sup.2] = 0.17, p < 0.028), and the presence of habitual cough ([r.sup.2] = 0.22, p = 0.004) or wheezing (re = 0.16, p = 0.013) were likewise significantly and independently related to the activity and symptoms subscales, respectively.

DISCUSSION

In our series, dyspnea, the FE[V.sub.1] value following bronchodilation, and daily sputum production were the most relevant HRQL-conditioning variables among the patients with non-CF SB, although other symptoms such as the presence of habitual coughing or wheezing also exerted a relative influence.

The SGRQ was designed by Jones et al (7) a little over a decade ago for specific application to COPD and other obstructive pulmonary diseases. (16-20) In 1997, Wilson et al (8) validated the English version of the SGRQ for use in patients with SB. Posteriorly, our group validated the Spanish language version for application to the same type of patients. (9) Very few studies to date have adequately analyzed the factors influencing HRQL in patients with SB not attributable to CF. Chan et al (21) in Hong Kong, and Wilson et al (8) in London found the total score, or scores of some of the subscales of the SGRQ, to be significantly correlated to certain clinical (dyspnea, daily sputum production, and wheezing) or functional parameters (oxygen saturation, FE[V.sub.1], FVC, and the 6-min walking test), the extent of SB, the number of exacerbations, and measures of anxiety and depression. However, only the study published by Wilson et al (8) involved a multivariate study, with the observation that the number of exacerbations in the previous year is the independent variable exerting the greatest influence on total HRQL score. However, the model, which moreover included P[O.sub.2] and the presence of bacteria in sputum, explained < 30% of the total variance, probably due to the absence in the analysis of some important variables such as dyspnea or the amount of sputum produced. In that same study, functional variables, the extent of SB, and the number of hospital patient admissions due to exacerbation of the disease were only weakly related to HRQL.

Our SGRQ-based results in the univariate study were similar to those reported by the above authors, since we identified different clinical, functional, treatment, evolutive, and analytic variables that were significantly related to some of the subscales or to the global questionnaire score. However, on performing the multivariate study, the only variables found to contribute an independent explanation of HRQL in our patients were dyspnea, the functional variables (FE[V.sub.1]), and daily sputum production. The impact of these variables in terms of the percentage variance explained was seen to change according to the questionnaire subscale examined. Moreover, other variables such as the habitual coughing or wheezing, or the use of systemic steroid cycles during exacerbations, also appeared as independent variables in the symptoms and activity scales, respectively.

Although some of these explanatory variables are basically the same as those described in the HRQL study of other airways disorders such as COPD or asthma (particularly as regards the key importance of dyspnea), other variables seem to be more characteristic of SB, such as the daily amount of sputum produced. Thus, on carrying out a detailed analysis of our results relating to the variables influencing the different questionnaire subseales, an interesting finding is that daily sputum production explains a greater percentage of the variance of the symptoms subscale than dyspnea proper. Undoubtedly, the important amount of sputum produced by these patients (usually greater than in other diseases of the airways) is a fundamental symptom that interferes decisively with HRQL. Thus, as can be seen in Table 3, the amount of sputum produced per se accounts for over one fourth of the variance of the symptoms subscale (27%), while on adding dyspnea to the analysis the explanation of variance increases by only 11%, ie both variables (sputum production and dyspnea) jointly account for 38% of the variance of the symptoms scale. However, it should be stressed that the functional variables did not afford relevant explanatory information in relation to the symptoms subscale. This would support the fact that--in the same way as has recently been postulated for COPD (22)--FE[V.sub.1] should not be used as the sole severity marker of SB.

In the case of the activity subscale, dyspnea is the principal explanatory variable (in the same way as in COPD), followed by the functional variables. However, a variable usually missing in studies of HRQL and which appears in our own series as an independent explanatory variable is a poorer activity score among patients who have received more steroid cycles for treatment of the exacerbations. The explanation for this appears to involve a number of factors, including probably a greater baseline disease severity in these individuals, a larger number (or greater severity) of exacerbations, the presence of latent steroid myopathy, or even a negative effect of steroid medication on chronic bacterial colonization of the airways. However, it should be mentioned that because of the small mean number of steroid cycles administered in 6 months to our patients (0.3; SD, 0.6), this relation, while statistically significant, may lack clinical significance.

In a way similar to the situation observed for the activity subscale, the functional variables show the greatest capacity to account for the variance of the subscale corresponding to the impact of dyspnea, although they jointly account for only 36% of the mentioned variability. This low percentage is probably due to the fact that the impact subscale is designed to quantify particularly the psychological and social dimensions of the disease, these variables being scantly considered in the present study. In this context, some studies (7,20) have shown that variables dependent on the psychological sphere, usually assessed by means of anxiety or depression questionnaires, exert a decisive influence on the way in which patients live their disease and hence on HRQL. Lastly, the multiple regression analysis performed, using the SGRQ total score as dependent variable, shows that dyspnea determined by the modified Medical Research Council scale, FE[V.sub.1] predicted value following bronchodilation, and daily sputum production are able to account for 55% of the variance of the SGRQ total score.

It should be pointed out that our study failed to analyze some variables that could reduce the percentage of unexplained variance, including (in the same was as published for other disorders of the airways) the influence of possible dynamic hyperinflation, (23) exercise testing, (17) or the already mentioned assessment of patient psychological condition. (7,20) However, there are some variables, usually described as exerting an influence in different studies of SB, that showed no significant and independent explanatory capacity for HRQL variance in our study, but which nevertheless deserve being mentioned, such as the number of previous exacerbations, the extent of SB, or P aeruginosa colonization of sputum. Wilson et al (8) found the number of previous disease exacerbations to be the independent variable most related to HRQL in bronchiectasic patients. In our own series this variable was weakly (though significantly) related to the total quality-of-life score ([r.sup.2] = 0.22, p < 0.05). This discrepancy is mainly explained by the fact that Wilson et al (8) failed to measure certain key variables such as dyspnea, sputum production, or the prior administration of antibiotics and steroids. These variables, which have been examined in the present study, usually exhibit a close correlation to the number of exacerbations, and this may be the reason why the variable "number of exacerbations" was displaced from the multivariate analysis in our study. In any case, an important variation among studies in the number of exacerbations is to be expected, since such information is collected retrospectively and is sometimes dependent on patient memory. Furthermore, based on the results of our study and on the absence of information regarding the severity of exacerbations, we could postulate that only the more serious or clinically unstable exacerbations (ie, those in which systemic steroids are usually administered) would exert a more determinant influence on HRQL. In this context, it should be taken into account that systemic corticotherapy during disease exacerbation effectively supplied independent information for the analysis of HRQL in our patients.

Other variables habitually studied in the literature in patients with SB are the extent of the latter and chronic P aeruginosa colonization of sputum. Some authors (24) have reported a positive correlation between HRCT and pulmonary function or sputum production. Consequently, HRCT contribution to the explanation of HRQL in patients with SB could be accounted for in part by these two variables. Similar considerations apply to chronic P aeruginosa colonization of sputum, which we and other authors have found to be related to poorer pulmonary function, increased sputum production, increased dyspnea, and poorer HRQL. (4-6,9)

In conclusion, in our series of patients with stable bronchiectasis, dyspnea, FE[V.sub.1] following bronchodilation, and daily sputum production were the factors that best explained patient HRQL, although other symptoms such as habitual coughing or wheezing, or the administration of systemic steroids during disease exacerbations also intervened significantly (albeit to a lesser extent). We therefore consider that ideal management of such patients should aim to improve the impact of these variables on patient HRQL.

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* From the Pneumology Unit (Drs. Martinez-Garcia and Soler-Cataluna) and Service of Internal Medicine (Dr. Roman-Sanchez), Requena General Hospital; and Service of Pneumology (Dr. Perpina-Tordera), La Fe University Hospital, Valencia, Spain.

This study was supported in party by the grant RedRespiraISCiii-TRIC-03/11 from the Ministerio de Sanidad y Consumo, Spain.

Manuscript received July 21, 2004; revision accepted January 7, 2005.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml).

Correspondence to: Miguel Angel Martinez-Garcia, MD, Unidad de Neumologia, Servicio de Medicina Interna, Hospital General de Requena (Valencia), Paraje Casa Blanca s/n, 43230, Requena, Valencia, Spain; e-mail: med013413@nacom.es

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