Abstract
Background/Aim: Bronchiectasis has long been neglected, unlike chronic obstructive pulmonary disease (COPD) and asthma. Recent clinical trials have shown that long-term use of azithromycin or erythromycin reduce exacerbations of non-cystic fibrosis (non-CF) bronchiectasis. Because of this, we should actively try to treat patients susceptible to severe status. Patients and Methods: We enrolled patients who had been diagnosed with bronchiectasis at five branches of the Catholic Medical Center between January 2015 to December 2017. We retrospectively analyzed these patients for demographic characteristics such as sex, age, body mass index (BMI), history of smoking and tuberculosis, bacterial colonization, pulmonary function, hospitalizations, and other exacerbations. Results: Colonization was shown to have a statistically significant association with hospitalization. A three-year follow up period showed that the mean frequency of hospitalization in patients without colonization was 0.8 times, compared to 0.7 times and 1.9 times, respectively in patients with NTM colonization and with other bacterial colonization (p-value=0.03). Patients with a lower BMI also had an increased risk of hospitalization (p-value=0.024). Current smokers had increased risk of mortality as compared to those who had never smoked (HR=11.29, p-value 0.015). Patients with a high BMI also had low risk of mortality as compared to patients with a low BMI (HR=0.76, p-value 0.005). Conclusion: Patients with bronchiectasis having chronic colonization, low BMI, or who are current smokers tend to be at greater risk for severe illness. Therefore, physicians should actively treat these patients to prevent exacerbations and mortality.
Bronchiectasis is a chronic respiratory disease characterized by a clinical syndrome of cough, sputum production, and bronchial infection. Radiologic findings show abnormal and permanent dilatation of the bronchi (1). Bronchiectasis is usually divided into either cystic fibrosis (CF) or non-cystic fibrosis (non-CF) bronchiectasis. CF is an autosomal recessive genetic disorder resulting from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). CF mainly occurs in Caucasians, rarely in Asian races (2). Therefore, in the present study, we only dealt with non-CF bronchiectasis. Usually, in real world practice, patients with bronchiectasis are treated when they develop exacerbations. The treatment of bronchiectasis should mainly be to prevent exacerbations, like other chronic pulmonary diseases. Unlike chronic obstructive pulmonary disease (COPD) and asthma, bronchiectasis has long been neglected. The average overall annual prevalence of patients aged 65 years or older diagnosed with bronchiectasis among US Medicare enrollees numbered 701 per 100,000 persons (3). The overall prevalence of bronchiectasis in 100,000 persons was 464 in South Korea, which is higher than 67 in Germany and 138 in the USA (4). This is probably because there are many patients in Asia who have bronchiectasis owing to previous tuberculosis or infection (5, 6). There are many causative factors for bronchiectasis (7). The most common causes are postinfectious, such as pneumonia, whooping cough, measles, or mycobacterial infection. There are other etiologic factors such as muco-ciliary disorder, obstructive causes such as foreign body and cancer, immune disorders, COPD, and miscellaneous. Bronchiectasis has been known to be the final common pathway for a number of diseases, many of which require specific treatment (8). The British Thoracic Society (BTS) guidelines suggest identifying relevant and possibly causative diseases such as rheumatoid arthritis, COPD, asthma, gastroesophageal reflux disease, or inflammatory bowel disease (9).
We should be as concerned about bronchiectasis as we are of COPD and asthma. In South Korea, physicians usually prescribe just muco-active drugs to patients with bronchiectasis. In addition, they add bronchodilators to patients with airflow limitation. To date, antibiotics have been limited to patients who are in state of acute exacerbation. According to European Respiratory Society (ERS) or BTS guidelines, physiotherapy such as airway clearance and pulmonary rehabilitation is highlighted in the management of bronchiectasis in adults. However, educational intervention is not much established in our nation. Recent clinical trials have shown that long-term use of azithromycin or erythromycin reduce exacerbations of non-CF bronchiectasis (10, 11). Inhaled antibiotics are also effective in treatment (12, 13). Therefore, we should actively try to treat patients with bronchiectasis susceptible to severe illness. In Europe, the bronchiectasis severity index and FACED score have been proposed to predict prognosis (7, 14). The bronchiectasis severity index includes age, body mass index (BMI), Medical Research Council (MRC) breathlessness score, forced expiratory volume in 1 second (FEV1), previous hospitalizations, exacerbation frequency, colonization, and radiologic appearance, predicting future exacerbations and hospitalization, health status, and death. Similarly, FACED scores include age, modified MRC dyspnea scale, FEV1, colonization of P. aeruginosa, and radiological extension of bronchiectasis. However, geographic variation exists in the etiology, epidemiology, and microbiology of patients with bronchiectasis (15). In the United States, immune-related mechanisms including autoimmune diseases, immunodeficiencies, and hematologic malignancies were identified as predominant etiologies of bronchiectasis (16). In contrast, post-infection and post-tuberculosis was predominant causes for bronchiectasis in Asia (6, 17). In the present study, we aimed to explore factors predicting worse outcomes in patients with bronchiectasis reflecting our country’s practices.
Patients and Methods
Patient selection. We enrolled patients diagnosed with bronchiectasis at five branches of the Catholic Medical Center (Seoul St. Mary’s Hospital, Eunpyeong St. Mary’s Hospital, Uijeongbu St. Mary’s Hospital, Bucheon St. Mary’s Hospital, and St. Vincent’s Hospital) between January 2015 and December 2017. We enrolled patients with bronchiectasis who were coded with the International Classification of Diseases 10th revision (ICD-10) diagnosis code J47 (bronchiectasis). According to BTS guideline for bronchiectasis in adults, to confirm a diagnosis of bronchiectasis, a thin section computed tomography (CT) is recommended. Bronchiectasis is defined by bronchial dilatation, where the broncho-arterial ratio exceeds one. In our country, physicians usually diagnose bronchiectasis with chest CT scan. Patients with severe diseases, such as malignancy, pulmonary fibrosis, or heart failure were excluded because of possible misinterpretation in prognosis. We also excluded patients who were not in follow-up. The enrolled patients regularly visited the out-patient clinic of the Pulmonary Department. We retrospectively analyzed the patients for demographic characteristics such as sex, age, BMI, history of smoking and tuberculosis, bacterial colonization, pulmonary function, hospitalizations, and other exacerbations.
Definition of clinical factors
History of smoking and tuberculosis. History of smoking was recorded based on the patients’ statements. Non-smokers were defined as those who had never smoked or had smoked fewer than 100 cigarettes in their lifetime. Current smokers were defined as those who reported that they continued to smoke or who had stopped smoking fewer than 6 months prior to their diagnosis of bronchiectasis. We also investigated a history of tuberculosis based on the patients’ statement. Patients who had never been diagnosed with tuberculosis were defined as “tuberculosis negative”. Patients who had been diagnosed with tuberculosis in the past were defined as “tuberculosis positive”.
Colonization. Chronic colonization was defined by isolation of possible pathogenic bacteria in sputum culture on more than two examinations, at least three months apart in a one-year period (7, 18, 19). We divided patients into three groups, patients colonized with nontuberculous mycobacteria (NTM), with other bacteria, and patients without colonization.
Pulmonary function. The post-bronchodilator FEV1/FVC (forced expiratory volume in 1 s/forced vital capacity) ratio was investigated. This is used for the diagnosis of COPD, reflecting airflow limitations according to Global Initiative for chronic Obstructive Lung Disease (GOLD) report.
Hospitalization. Usually, severe exacerbations result in hospitalization. We calculated the frequency of hospital admissions during a three-year follow-up period.
Exacerbations. According to BTS guidelines for bronchiectasis in adults, antibiotics are used to treat patients with exacerbations presenting with worsening symptoms (cough, increased sputum volume or purulence with viscosity changes, breathlessness, or hemoptysis) with or without systemic involvement. We calculated the number of times that patients received antibiotic treatment in outpatient clinics over a three-year follow-up period. The frequency of total exacerbations was calculated by the sum of the frequency of hospitalizations and exacerbations in the outpatient clinic.
Statistical analysis
We analyzed the association between clinical variables and the frequency of hospitalizations with the Wilcoxon rank sum test or the Kruskal–Wallis test for categorical variables, and we used the Spearman’s rank correlation analysis for continuous variables. To investigate significant factors leading to hospitalization, simple and multiple linear regression analyses were used. Also, univariable Cox proportional hazard regression analysis was performed to identify factors associated with mortality. Statistical consultation was supported by the Department of Biostatistics of the Catholic Research Coordinating Center.
Results
Patient characteristics. A total of 301 patients were enrolled. Baseline characteristics are shown in Table I. The mean age of patients was 69.6 years old. Among them, 204 patients were female (67.8%) and 97 male (32.2%). The majority of patients had never smoked (246, 81.7%), as compared to former and current smokers (55, 18.3%). In addition, 89 patients (29.6%) had been diagnosed with tuberculosis in the past. Patients with chronic colonization were 31.6%, including NTM and other bacteria. Among them, patients with NTM colonization were 81 (27.2%), compared to 13 patients (4.4%) with other bacteria colonization. Among the patients with other bacteria colonization, 10 patients (76.9%) were colonized with Pseudomonas aeruginosa. The others were two patients (15.4%) with Klebsiella pneumoniae and one patient (0.1%) with Enterobacter aerogenes. The post-bronchodilator mean FEV1/FVC was 68.5%, which means there were many patients who were co-diagnosed with COPD. The mean frequency of hospitalization was 0.8 times during the three-year follow-up period. The mean frequency of exacerbations in out-patient clinics was 4.5 times during a three-year follow-up period. The mean frequency of total exacerbations was 2.3 times per year.
Baseline characteristics of study patients with bronchiectasis.
Hospitalization. There was no statistically significant relationship between age, sex, smoking status, FEV1/FVC (post-bronchodilator), and hospitalization as shown in Table II and Table III. Colonization was shown to have a statistically significant association with hospitalization. The mean frequency of hospitalization in patients without colonization was 0.8 times during a three-year follow period, as compared to 0.7 times in patients with NTM colonization, and 1.9 times in patients with other bacterial colonization (p-value=0.03). Additionally, patients with a lower BMI had an increased risk of hospitalization (p-value=0.024).
Association between factors and hospitalization.
Spearman rank correlations between factors and hospitalizations.
In univariate analysis, no history of tuberculosis, chronic colonization, and low BMI were significantly related to hospitalization (Table IV). Patients with a history of tuberculosis had a lower risk of hospitalization, as compared to patients without a history of tuberculosis (β=−0.14, p-value=0.045). Patients with other bacteria colonization had a higher risk of hospitalization, as compared to patients without colonization (β=0.37, p-value=0.019). Also, patients with high BMI had a lower risk of hospitalization, as compared to patients with a low BMI (β=−0.02, p-value=0.01). In multivariate analysis, patients colonized with other bacteria had a higher risk of hospitalization, as compared to patients without colonization (adjusted β=0.33, p-value=0.034).
Simple and multiple linear regressions.
Mortality. There were nine deaths among a total of 301 patients. Current smoking and low BMI were significant factors associated with mortality. There was no strong relationship of age, sex, history of tuberculosis, colonization, or FEV1/FVC with death (Table V). Current smokers had an increased risk of death as compared to non-smokers (HR=11.29, p-value=0.015). Also, patients with a high BMI had a lower risk of death as compared to patients with a low BMI (HR=0.76, p-value=0.005).
Univariate Cox proportional hazard regression.
Discussion
In the present study, bronchiectasis with chronic colonization or low BMI posed a greater risk of hospitalization. Additionally, patients with bronchiectasis who currently smoke or had a low BMI had an increased risk of mortality. According to research of the FACED score, chronic colonization by P. aeruginosa was statistically associated with a five-year mortality in all cases following diagnosis (14). In studying the bronchiectasis severity index, patients with chronic colonization also had a higher risk of mortality as compared to non-colonized patients (7). Bronchiectasis patients are often colonized with bacterial species, even in a stable state, regardless of etiology (20).
This is probably because bronchiectasis patients have impaired host defenses to maintain sterility of the respiratory tract. The failure of host defenses leads to chronic inflammation resulting in a vicious cycle of new or further impairment of muco-ciliary clearance and host defenses. Therefore, bronchiectasis patients with chronic colonization have more exacerbations that lead to hospitalization.
The incidence of NTM-pulmonary disease (PD) is increasing worldwide. NTM colonization is common among patients with chronic lung diseases. In a previous study, growth of NTM was associated with high socioeconomic status (SES), never smoking, and younger age (21). This could be a surveillance bias, as these patients undergo intensive follow up, leading to detection of NTM. In our study, patients with NTM colonization had low risk of hospitalization. This is probably because patients with NTM colonization might be more conscious about health. Bronchiectasis patients with a lower BMI tend to have a poor prognosis. Low BMI is associated with poor pulmonary function in chronic respiratory disease. This mechanism could be an impaired immune response to respiratory muscle weakness in patients with a lower BMI (22). As a result, bronchiectasis patients with a lower BMI had a greater risk of hospitalization and mortality. A similar result was reported in a Korean nationwide population-based study, which focused only on the association between BMI and mortality (23). In the present study, current smokers with bronchiectasis had an increased mortality. This was also demonstrated in a previous study (24).
The strengths of the present study are as follows: This was the first multicenter study in South Korea to evaluate factors associated with worse outcomes in bronchiectasis. In European countries, there are many on-going studies, reflecting increased concerns about bronchiectasis. In contrast, in Asian countries, studies about bronchiectasis are relatively scarce despite the higher prevalence as compared to western countries. This study could be a reference for Asian bronchiectasis studies. In addition, to date, studies about exacerbations of bronchiectasis have not been published. While researchers have been interested in exacerbations of chronic pulmonary diseases like COPD and asthma, bronchiectasis has long been neglected. Considering the increased interest in bronchiectasis, the strength of this study is that it provides guidelines to diagnose bronchiectasis patients and identify factors predicting worse outcomes. However, this study has some limitations. First, it was a retrospective study with a relatively small sample size. Nevertheless, this study could represent a real-world bronchiectasis population by enrolling consecutive patients. Secondly, there could be more patients with moderate-to-severe bronchiectasis in the enrolled group. This is probably because bronchiectasis patients with no or mild symptoms do not usually visit hospitals.
Also, we did not have data on radiological finding details. Therefore, we could not calculate bronchiectasis severity score. Regarding comorbidities, we just excluded patients with severe diseases, such as malignancy, pulmonary fibrosis, or heart failure because of possible misinterpretation in prognosis. Further studies are needed to investigate comorbidities that patients may have beyond bronchiectasis.
Conclusion
In conclusion, this study showed that bronchiectasis patients with chronic colonization, low BMI, or who currently smoke tend to be susceptible to severe illness. Therefore, physicians should actively treat these patients to prevent exacerbations or mortality.
Footnotes
Authors’ Contributions
KYK: Conception and design, collection of data, data analysis, and interpretation; HYL: administrative support, provision of study materials or patients; CDY: administrative support, provision of study materials or patients; EGL: administrative support, provision of study materials or patients; SHK: administrative support, provision of study materials or patients; JWK: conception and design, collection of data, data analysis and interpretation.
Conflicts of Interest
The Authors have no conflicts of interest to declare in relation to this study.
- Received September 28, 2022.
- Revision received October 10, 2022.
- Accepted October 11, 2022.
- Copyright © 2022, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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