Is There a Correlation between New Scoring Systems and Systemic Inflammation in Stable Bronchiectasis?

Aim The present study aimed to investigate the relation between FACED and BSI scores, which were developed to measure the severity of bronchiectasis, and systemic inflammation in patients with stable bronchiectasis. Methods FACED and BSI scores of 117 patients with stable bronchiectasis were calculated. The correlations between mean scores and CRP levels, leukocyte count, and neutrophil/lymphocyte ratio were investigated. Findings Mean BSI and FACED scores were 7.2 ± 5.2 and 2.1 ± 1.8, respectively. The severity of bronchiectasis as determined based on BSI and FACED increased significantly with increasing levels of CRP in patients with stable bronchiectasis (p=0.001 and p=0.027, resp.). No significant changes were found in leukocyte count (p=0.72 and p=0.09, resp.) and N/L ratio (p=0.45 and p=0.71, resp.). BSI and FACED scores were significantly correlated with CRP but not with leukocyte count or N/L ratio. Conclusion In patients with stable bronchiectasis who are evaluated based on FACED and BSI scores, CRP can be a useful biomarker as a direct indicator of the severity of systemic inflammation.


Introduction
Bronchiectasis is a chronic airway disease associated with symptoms such as cough, sputum production, and hemoptysis, and it may develop as a result of various etiologies [1]. A vicious cycle, based predominantly on airway infections, airway in ammation, and structural damage, plays a role in progression and pathogenesis of bronchiectasis [2]. It is disappointing that there are a limited number of e ective treatment strategies and evidence-based management recommendations for assessment and follow-up of bronchiectasis. e severity of bronchiectasis should be determined to obtain better treatment outcomes. Assessment of bronchiectasis may be a challenge since there is actually no simple measurement method that has been su ciently validated. Conventionally, previous reports measured the severity of disease based on FEV1 (forced expiratory volume in 1 s) [3], while Rei and Bhalla scores in HRCT were also used in some studies to measure disease severity [4,5]. However, FEV1 was not e ective in terms of clinical decision-making, and HRCT (high-resolution computed tomography) scores had a poor correlation with lung functions [6]. erefore, it became an obligation to create a new scoring system to assess the severity of bronchiectasis. FACED score (F: FEV1, A: age, C: colonization, E: number of a ected lobes, and D: dyspnea) [7] and Bronchiectasis Severity Index (BSI) [8] were recently designed as two multidimensional severity grading scales to assess the prognosis of bronchiectasis. FACED score is a ve-item grading system that predicts mortality in patients who had been monitored for 5 years. BSI is a seven-item scale that describes future risk of death, hospitalization, and exacerbations. Elevation of systemic in ammatory markers such as C-reactive protein (CRP) and total white blood cell count is known to be associated with the extent of the disease and poor lung functions [9]. e relation between CRP or total white blood cell count and the novel scoring systems used to assess bronchiectasis severity, namely, BSI and FACED, has not been investigated before.
Bronchiectasis is characterized by airway in ammation accompanied by continuous predominance of neutrophils. Proin ammatory cytokines such as IL-1, IL-6, and TNF-a increase, while anti-in ammatory cytokines such as IL-10 decrease in patients with bronchiectasis [10]. As a result of a series of complex interactions between various cells including the neutrophils and lymphocytes, in ammation may eventually cause permanent tissue damage [11]. e ratio of in ammatory cells in blood has a potential to re ect chronic in ammation and pathologic conditions, and the neutrophil/ lymphocyte ratio was recently shown to be increased during COPD exacerbations compared to stable disease conditions [12]. In the presence of various chronic conditions such as disorders of the cardiovascular and renal systems, it was shown that increased N/L ratio can be used as a marker of in ammation, and a higher N/L ratio was associated with disease severity, mortality, and hospitalization [13][14][15]. Since the lungs of patients with bronchiectasis are characterized by neutrophilic in ammation, N/L ratio can also be a useful marker to assess the clinical status of patients with bronchiectasis. e neutrophil/lymphocyte ratio is an in ammation marker that has not been previously investigated in patients with stable bronchiectasis. N/L ratio is an easily accessible marker that can be calculated from the total blood count, and it does not require any special equipment or speci c method of measurement. N/L ratio can become an easy-to-use method and a useful marker in patients with bronchiectasis if it proves to be useful as a biological marker in this patient group. e present study aimed to investigate the relation of CRP, total white blood cell count, and neutrophil/ lymphocyte ratio with BSI and FACED scores.

Methods
Patients who had been followed up by Pulmonology Clinics of Sakarya Training and Research Hospital and had a denitive diagnosis of bronchiectasis based on HRCT and BTS guidelines were included to the study [16]. e diagnosis of bronchiectasis with HRCT is based on radiology reports. BTS guideline mentions investigation and management of patients with bronchiectasis. BTS guideline does not include bronchiectasis caused by cystic brosis [16]. Patients with immunode ciency, allergic pulmonary aspergillosis, bronchiectasis secondary to primary ciliary dyskinesia, heart failure, malignancy or chronic renal failure; patients who had used antibiotics or steroids within the last one month; patients who described an acute exacerbation; and pregnant patients were excluded from the study. A total number of 117 patients who met the above-described criteria were included to the study. ese patients were followed between 2014 and 2016. e patients who had a history of steroid and antibiotic use in the last month were evaluated in the stabilization period of bronchiectasis. All patients performed spirometry, and peripheral venous blood samples were obtained from all patients on the day of spirometry. Total blood count and CRP levels were analyzed. In patients who were following up for two years, at least two measurements of CRP, WBC, and N/L were taken in the stabilization period, and the averages of these measurements were calculated. For the measurement of serum CRP levels, 3 cc of venous blood samples were collected in biochemistry test tubes. Blood samples were transferred to the analyzing laboratory at most 2 hours after sampling, and the analyses were performed on the same day. CRP levels were quantitatively analyzed by the nephelometric method using the BN 200 device. e reference range in healthy humans for the preferred method of analyses was 0.00-5.00 mg/L.

FACED and BSI Scoring and
Grading. FACED score consists of 5 variables: FEV 1%, age, Pseudomonas aeruginosa colonization, radiological extent of the disease, and dyspnea as assessed by the Medical Research Council (MRC) scale. e total score is calculated by adding up the scores for each variable and varies between 0 and 7 points. Based on the total score, bronchiectasis is evaluated in three groups as mild (0-2), moderate [3,4], and severe [5][6][7] bronchiectasis. BSI score consists of 9 variables: age, body mass index, FEV1%, hospitalizations within the last two years, number of exacerbations within the last one year, dyspnea as assessed by MRC scale, Pseudomonas aeruginosa colonization, colonization by other microorganisms, radiological extent of the disease, and/or presence of cystic bronchiectasis. Total score varies between 0 and 26 points. In BSI, scores of 0-4 points indicate mild, 5-8 indicate moderate, and 9 or above indicate severe bronchiectasis.

Statistical
Methods. SPSS for Windows 18.0 (Chicago, IL) software package was used for statistical analyses. Continuous variables were presented as mean values and standard deviations. Di erences between two groups were tested by t-test for normally distributed variables and by Mann-Whitney test for nonnormally distributed variables. For analysis of more than two groups, ANOVA test was used for normally distributed variables and Kruskal-Wallis test was used for nonnormally distributed variables.
Correlations were evaluated by means of Spearman's rank correlation test. A p value less than 0.05 was considered as signi cant. Table 1 shows the characteristics of 117 patients with stable bronchiectasis who were included in this study. Mean FACED and BSI scores and numbers of patients with mild, moderate, and severe bronchiectasis based on both scoring systems are shown in Tables 2 and 3.

Results
When the patients were classi ed as those with mild, moderate, and severe bronchiectasis according to BSI and FACED scores, signi cant relations were found between FVC %, FEV1%, FEV1/FVC, CRP, BMI, number of exacerbations, and number of hospitalizations according to both scoring systems. WBC and N/L ratio were not signi cantly related to disease severity based on neither of the scoring systems (Tables 2 and 3). A signi cant positive correlation was found between FACED and BSI scores and CRP levels (Figure 1), and a signi cant negative correlation was noted between pulmonary function test parameters and BMI index. No signi cant correlation was demonstrated between FACED and BSI scores and N/L ratio or leukocyte count (Table 4). Table 5. ere was no signi cant di erence between the groups.

Discussion
In the present study, the severity of bronchiectasis was assessed based on the recently developed FACED and BSI scoring systems, while systemic in ammation was evaluated by CRP levels, leukocyte count, and N/L ratio. Analyses of the correlations between FACED and BSI scores and markers of systemic in ammation in patients with stable bronchiectasis demonstrated a signi cant relation only with CRP levels, whereas no signi cant correlation was found with leukocyte count or N/L ratio (Table 4).
A study assessing the severity of bronchiectasis based on HRCT score reported a signi cant correlation between HRCT score and markers of systemic in ammation such as WBC and CRP [9]. In a study involving patients with diseases that result in respiratory failure, patients with bronchiectasis were shown to have higher CRP levels compared to the other patient groups, and CRP levels were associated with mortality in that study [17]. Patients with bronchiectasis and elevated CRP levels showed rapid FEV1 declines in another study [18]. All these ndings suggest that, as long as bronchiectasis is accompanied by systemic inammation, systemic in ammation should presumably be associated with disease severity. Previous studies assessed the severity of bronchiectasis based on FEV1 or HRCT scores. No previous study demonstrated a correlation between CRP and the recently developed BSI or FACED scoring systems. In the present study, CRP had a signi cant positive correlation both with BSI (r � 0.30, p � 0.001) and FACED (r � 0.30, p � 0.001) scores. Contrary to our ndings, a previous study comparing patients with bronchiectasis to a control group did not identify any nding indicative of systemic in ammation in the bronchiectasis group, and the authors highlighted that increased WBC count and CRP levels in patients with colonization might suggest presence of an in ammatory response [19].
It has been emphasized that increased bronchial inammation may be present even during periods of clinical   stability. During exacerbations, neutrophils migrate to the airways and proteolytic activity increases. Proteolytic agents destroy the lung matrix and contribute to the development of bronchiectasis [20]. In patients with stable bronchiectasis, presence of neutrophilic in ammation in sputum was suggested to be a good biomarker of disease severity. In that study, disease severity was assessed based on lung functions and BSI [21]. Considering there is an in ammation in the lungs with neutrophil predominance, demonstration of this condition in systemic circulation can be a useful parameter to grade the disease severity. N/L ratio was assessed as a marker of systemic in ammation in the presence of chronic diseases involving cardiovascular and renal systems [13][14][15].
Since bronchiectasis is also a chronic disease, one might expect that the increased neutrophilic in ammation in the lungs might be associated with an elevated N/L ratio in systemic circulation with increasing disease severity. No previous study in the literature investigated N/L ratio in patients with stable bronchiectasis. In the present study, a signi cant correlation was not found between N/L ratio and FACED or BSI scores in patients with stable bronchiectasis. In a study performed on patients with last-stage respiratory disorders, including 33 patients with bronchiectasis, a clear relation was demonstrated between decreased BMI and increased mortality [18]. Similarly, a Turkish study suggested that higher BMI values could be bene cial on expected survival time in patients with bronchiectasis [22]. BMI was associated with the ndings that re ect disease severity. Patients with low BMI values were shown to more frequently experience acute exacerbations, have poor lung functions, have increased systemic in ammation, and more commonly have chronic P. aeruginosa colonization. BMI was emphasized to be one of the factors with the most signi cant e ects on the risk of hospitalization and death [18,22]. A positive correlation was demonstrated between high BMI and survival [23]. A recent study reported a relation between radiological progression and low BMI [24]. In the present study, signi cant relations were found between BMI and both BSI and FACED severity classi cations re ecting the severity of bronchiectasis. Both scoring systems had signi cant negative correlations with BMI, while the correlation with FACED (r � −0.32, p � 0.002) score was more evident than the correlation with BSI (r � −0.21, p � 0.047) score.
A recently published study reported that low FVC values represented a risk factor for bacterial colonization [25]. Both BSI and FACED scorings take into account the FEV1 values. 20   Since both scoring systems had signi cant negative correlations with FVC in the present study (FACED (r � −0.70, p < 0.0001), BSI (r � −0.62, p < 0.0001)), it should be considered that the risk of bacterial colonization may increase with numeric increases in both scores, in other words, with increasing disease severity. Patient distribution was di erent when the disease severity was classi ed as mild, moderate, or severe based on the two scoring systems in the present study. On the contrary, Minov et al. [26] reported similar patient distribution rates based on both scoring systems (Tables 2 and 3). To explain this, in a recently published study, Guan et al. emphasized that the di erence in FEV1 distribution and the scoring for previous hospitalizations resulted in overall higher BSI scores; therefore, some patients were given a higher severity grade. e authors underlined the need for additional studies comparing e ectiveness of grading systems in bronchiectasis [27].
is study has some limitations. Since the study was performed as a single-center study with a small sample size, study results can only be generalized to a limited extent. Moreover, the groups were not homogenous in terms of severity grading based on the two scoring systems.

Conclusion
In patients with bronchiectasis, CRP can be a useful biomarker that directly re ects the level of systemic inammation. WBC and N/L ratio failed to capture systemic in ammation in patients with stable bronchiectasis whose severity grading was done based on FACED and BSI scoring systems. Additional studies are required to elucidate the clinical signi cance of the role of CRP in the assessment of treatment response and progression of bronchiectasis after anti-in ammatory therapy.