Rationale: In bronchiectasis there is a need for improved markers of lung function to determine disease severity and response to therapy.
Objectives: To assess whether the lung clearance index is a repeatable and more sensitive indicator of computed tomography (CT) scan abnormalities than spirometry in bronchiectasis.
Methods: Thirty patients with stable bronchiectasis were recruited and lung clearance index, spirometry, and health-related quality of life measures were assessed on two occasions, 2 weeks apart when stable (study 1). A separate group of 60 patients with stable bronchiectasis was studied on a single visit with the same measurements and a CT scan (study 2).
Measurements and Main Results: In study 1, the intervisit intraclass correlation coefficient for the lung clearance index was 0.94 (95% confidence interval, 0.89 to 0.97; P < 0.001). In study 2, the mean age was 62 (10) years, FEV1 76.5% predicted (18.9), lung clearance index 9.1 (2.0), and total CT score 14.1 (10.2)%. The lung clearance index was abnormal in 53 of 60 patients (88%) and FEV1 was abnormal in 37 of 60 patients (62%). FEV1 negatively correlated with the lung clearance index (r = –0.51, P < 0.0001). Across CT scores, there was a relationship with the lung clearance index, with little evidence of an effect of FEV1. There were no significant associations between the lung clearance index or FEV1 and health-related quality of life.
Conclusions: The lung clearance index is repeatable and a more sensitive measure than FEV1 in the detection of abnormalities demonstrated on CT scan. The lung clearance index has the potential to be a useful clinical and research tool in patients with bronchiectasis.
The lung clearance index has been shown to be a more sensitive marker of lung function, particularly in early disease, in cystic fibrosis. There are no published data on the use of the lung clearance index (LCI) in bronchiectasis.
LCI offers the potential to be a more useful measure of lung function than spirometry to monitor disease and responsiveness to interventions in clinical trials.
Bronchiectasis (BE) not caused by cystic fibrosis (CF) is a debilitating illness with symptoms of recurrent cough, daily sputum production, recurrent chest infections, and a poor health-related quality of life (HRQoL) (1). The estimated prevalence of BE in the United States ranges from 4 per 100,000 young adults to almost 300 per 100,000 in those more than 75 years old (2–5). British Thoracic Society guidelines indicate that management should be focused on improving or maintaining lung function, reducing exacerbations, and improving HRQoL (1, 6). FEV1 is commonly used as the primary method of monitoring patients with BE. However, there is an increasing body of evidence that FEV1 is insensitive to early lung disease, and the majority of clinical trials in BE have been unable to demonstrate a treatment effect using FEV1 (7–9). This highlights the need for other, sensitive and responsive markers of lung function in BE (7, 10).
The lung clearance index (LCI) measured by multiple breath washout (MBW) is a measure of ventilation inhomogeneity and has been shown to be a sensitive lung function test in early lung disease. Its usefulness has been demonstrated in CF, particularly in children and adults with mild disease (11–14). There are no studies published assessing LCI in BE.
In this study we tested the hypothesis that LCI measured by MBW is a better predictor of structural lung changes seen on computed tomography (CT) scan compared with FEV1.
The primary aim of this study was to assess whether LCI in patients with BE was (1) repeatable and (2) a more sensitive indicator of CT scan abnormalities than spirometry. Secondary aims were to explore the relationships of LCI with high-resolution CT (HRCT) changes and HRQoL, and to assess the practicalities of MBW testing and patient comfort.
This project consisted of two studies. Study 1 included 30 patients with BE who attended for two visits, 2 weeks apart, to assess the repeatability of LCI. The second study was a single visit including 60 patients with BE to compare the LCI measurement with CT scores performed at that visit.
Adults with a radiological diagnosis of BE by HRCT were recruited from the regional BE clinic at Belfast City Hospital, Belfast Health and Social Care Trust. Written informed consent was obtained. Patients were included if (1) they were 18–80 years of age; (2) a diagnosis of BE was confirmed, based on a CT report in the clinical notes, which described any evidence of BE. BE only was included. If only bronchial wall thickening was present, the patient was excluded. Traction BE was not included; (3) they were nonsmokers or ex-smokers with a less than 10–pack year smoking history; and (4) they were free of exacerbation symptoms (as defined by British Thoracic Society guidelines) for at least 4 weeks before taking part in the study (1). Patients were excluded if significant comorbidity was present (e.g., congestive cardiac failure, neoplasm). Full exclusion/inclusion criteria are given in the online supplement. In study 2, patients performed all investigations at a single visit, with the HRCT scan performed within 24 hours of each study visit. The study was approved by the Office of Research Ethics Committee for Northern Ireland (ORECNI-10/NIR03/44).
MBW tests were performed in the seated position with a nose clip applied, using the Innocor gas analyzer (Innovision A/S, Odense, Denmark), modified as previously described to use an open circuit wash-in protocol (14). LCI was performed before spirometry in all patient visits. Three MBW tests were performed with the mean result of at least two acceptable tests recorded. A test was excluded if functional residual capacity differed by more than 10% from the median of recordings or there was evidence of a leak or irregular breathing pattern. Analysis of washout data was performed with custom software. Two trained personnel only were responsible for the accrual of data and calibration (S.A.R. and K.O’N.). Detailed methods are described further in the online supplement.
After washout testing was completed, a visual analog score (VAS) was recorded to assess ease and comfort (0 representing very difficult to perform/very uncomfortable and 10 very easy to perform/very comfortable).
The normal range of LCI mean (SD), 6.5 (0.5), was taken from a cohort of healthy normal control subjects (n = 30; age, 21–44 yr). LCI represents the number of lung turnovers required to wash out the inert gas from an initial to final value. The normal range in this study was taken to be 2 SD above the mean. An abnormal value was therefore greater than 7.5. Published control data collected using identical apparatus, procedures, and software were compared and the same normal range was achieved (14).
Spirometry was performed in accordance with American Thoracic Society/European Respiratory Society guidelines on a MicroLab 3500 spirometer (CareFusion, Basingstoke, UK) (15). Percent predicted values were calculated from the all ages reference data published by Stanojevic and colleagues (16).
Expiratory and inspiratory HRCT scans of the chest were performed on a 64-slice CT scanner (Siemens AG, Munich, Germany) in the supine position. Two thoracic radiologists (T.L. and J.L.) reviewed each scan independently, using a standardized scoring method (17). This result gives a global CT score of BE and, in addition, scores each lobe on type of BE, extent, mucus plugging, air trapping, and emphysema. The complete scoring system can be seen in the online supplement. A score for each lobe was recorded, which was then converted to a total score for each of the parameters assessed: total BE score, average bronchiectatic bronchus size, degree of mucus plugging, degree of peribronchial thickening, parenchymal score, and degree of air trapping (hyperinflation score). The higher the number, the more severe the abnormality. Scores can also be converted into a percent score for comparison and to account for those who have had previous surgery. Further information on the HRCT scoring methods is found in the online supplement.
HRQoL was assessed with the St. George’s Respiratory Questionnaire (SGRQ) (18, 19). Questionnaires were completed independently by the patient at each study visit, with an investigator present for any queries.
A blood sample was collected and processed in the routine hospital laboratory for white cell count and C-reactive protein. A 24-hour sputum sample was collected in a dedicated preweighed collection tube from which volume (ml) and weight (g) were recorded. Frequency of pulmonary exacerbations requiring intravenous antibiotics over the last 12 months was determined from the clinical record.
Statistical analysis was performed with Prism (version 5.01; GraphPad Software Inc., La Jolla, CA) and SPSS (version 18 PASW Statistics 18; IBM, Armonk, NY).
The definition of repeatability was taken from previously published guidance on the investigation and interpretation of repeatability (20). To assess repeatability, the Lin concordance correlation coefficient (CCC) was used to calculate sample size. To obtain 95% confidence limits for the CCC with a lower limit no smaller than 0.65, 28 patients were required. Thirty patients were recruited to allow for dropouts or technical errors.
The sample size calculation to determine the relationship between HRCT changes and LCI used the correlation coefficient. For the lower limit of the 95% confidence interval (CI) of the true correlation to be no lower than 0.7, the required sample size was 54. Sixty patients were recruited to allow for dropouts or technical errors. Descriptive statistics were used to describe the population characteristics (mean [SD]). Subject demographics and characteristics were summarized using mean (SD) and frequencies. Intervisit repeatability of LCI was assessed by two methods: the intraclass correlation coefficient (ICC) and Bland–Altman test. The ICC was interpreted as follows: 0–0.2, poor agreement; 0.2–0.4, fair agreement; 0.4–0.6, moderate agreement; 0.6–0.8, strong agreement; 0.8–1.0, almost perfect agreement. Pearson’s r correlation coefficient was used for the assessment of reliability of LCI. Intravisit repeatability of triplicate washout repeats performed at each visit was expressed as the coefficient of variation of those measurements. Subjects with only two washout repeats were excluded from this analysis.
Associations were assessed using Pearson’s correlation coefficient between variables of interest. Sensitivity and specificity were assessed by calculating the percentage of subjects with less than the 80% predicted value for spirometry and a score for LCI greater than +1.96 SD score (i.e., >7.5). Receiver-operator characteristic (ROC) curves were used to assess sensitivity and specificity across all measures of interest.
Regression models were selected on the basis of the model with the smallest area under the curve (AUC) value as this has the best predictive performance. All models included age and sex in the analysis.
A paired t test was used to compare results between visits. For tertile groups, analysis of variance, using the Dunnett correction for multiple comparisons, was used. A two-tailed P value less than 0.05 was considered statistically significant.
Thirty patients were recruited (15 male) with a mean (SD) age of 56.7 (14.1) years, FEV1 (% predicted) 84.8 (20.7), and LCI 9.2 (1.8). A full outline of demographics and methods and further results for this are included in the online supplement. The intervisit ICC for LCI was 0.94 (95% CI, 0.89 to 0.97; P < 0.001). ICC between visits for FEV1 (% predicted) was 0.99 (95% CI, 0.97 to 0.99; P < 0.001) and for forced expiratory flow between 25 and 75% of FVC (FEF25–75%) (% predicted) it was 0.95 (95% CI, 0.90 to 0.98; P < 0.001). In subjects with a change in values between visits, there was no difference in bronchodilator therapy, time of airway clearance, or breathing pattern during the test to explain the variability. The coefficient of variation between LCI measurements for visit 1 was 4.4% and for visit 2 it was 4.8%.
Sixty patients were recruited and all patients completed this study with no dropouts. A summary of demographic data, lung function, and HRQoL measures is given in Table 1. The majority of patients were female and the mean FEV1 (% predicted) was 76.5, reflecting overall mild to moderate airflow obstruction. The most common etiologies for BE were idiopathic (43.3%) and postinfectious (38.3%).
|Age, yr||62.4 (10.7)|
|Etiology of bronchiectasis|
|FEV1, %||76.5 (18.9)|
|FEV1, z-score||−1.7 (1.4)|
|FVC, %||82.3 (16.6)|
|FVC, z-score||−1.3 (1.2)|
|Ratio, z-score||−0.7 (1.0)|
|LCI, lung turnovers||9.1 (2.0)|
|LCI, CV %||4.0 (2.9)|
|WCC, × 109/L||7.0 (1.9)|
|CRP, mg/L||4.5 (6.7)|
|24-h sputum volume, ml||11.4 (8.0)|
|24-h sputum weight, g||10.8 (8.2)|
There was no evidence of a reader effect between the two independent CT scorers. LCI was abnormal in 53 of 60 patients (88%). On the basis of conventional upper limits of normality (>80% predicted), FEV1 was abnormal in 37 (62%) and FEF25–75% in 41 (68%). Using z-scores, abnormal FEV1 and FEF25–75% values were 26 (43%) and 15 (25%), respectively. LCI increased with declining lung function (Figure 1).
An ROC analysis confirmed that LCI is more sensitive than spirometric measures when compared between patients with BE and healthy control subjects (Figure 2 and Table 2). This showed a differentiation between health and disease, and assumes that healthy control subjects have no abnormal CT findings, although this was not specifically addressed in this study.
|Variable||Area||SE||P Value||95% Confidence Interval|
|Inverse FEV1 (100 – value)||0.82||0.04||<0.0001||0.74||0.90|
|Inverse FEF25–75% (100 − value)||0.76||0.05||<0.0001||0.67||0.86|
Table 3 shows the relationship between LCI and spirometric/lung function measures with CT abnormalities.
|Percent Bronchiectasis||Percent Airway Thickening||Percent Mucus Plugging||Percent Parenchymal||Percent Air Trapping||Percent Total|
With the exception of airway thickening, which was consistent across all subscales, there is clear evidence of a relationship with LCI. The addition of FEV1 to the model was nonsignificant. There was no relationship between any measure of lung function to airway thickening; however, LCI had a stronger relationship with all scores in comparison with FEV1 and FEF25–75%.
In Figure 3, the data were divided into tertiles based on the severity of BE on CT scan. This shows that LCI has a clearer gradient and less variation in comparison with FEV1.
LCI by MBW has not been used in this population, and therefore we assessed the impact of this test on patient experience. VAS scores for ease and comfort of the test were 9.3 (0.8) and 8.9 (1.2), respectively, out of a maximal score of 10.
The mean time for a single LCI test (inclusive of wash-in and washout) was 7.4 minutes. There was no significant difference between visits for ease, comfort, or time of test. It was a safe procedure with no patients reporting adverse events.
There was evidence of a relationship between LCI and the symptom domain of SGRQ, showing an increase in symptoms with increasing LCI (R2 = 0.18, P = 0.03). This effect appeared to level off at higher LCI values. There was no evidence of a relationship with the subscales of activity, impact, and total score.
This study is the first report of LCI in adults with BE and provides evidence that LCI is a useful measure of lung function in this common condition. LCI in this study has been shown to be repeatable between visits, and has good inter- and intravisit reproducibility. Repeatability was not affected by disease severity and compares well with data seen in CF (14).
Many studies in patients with CF have shown that LCI by MBW is a more sensitive indicator of impaired lung function than FEV1 (21). In this study LCI also demonstrated improved sensitivity to abnormalities demonstrated on HRCT scan compared with FEV1 and FEF25–75% (% predicted). Although the patients studied here exhibited a wide range of airflow obstruction, 38% of them had an FEV1 within the normal range. Despite this, LCI was markedly abnormal in the majority of patients with BE (88%). The AUC data from ROC analysis confirm the improved sensitivity of LCI over FEV1. The data on repeatability of this measure compare well with the ranges of coefficient of variation (3–9%) in the European Cystic Fibrosis Society consensus document on the use of LCI in CF (22).
The correlation of structural abnormalities on CT and pulmonary function tests in BE has been linked primarily to evidence of intrinsic disease of small and medium-sized airways (23). The dominant finding in patients with BE at presentation is mild or no airflow obstruction (24). In this study, LCI correlates more strongly with quantitative radiological assessment of structural changes on CT scan compared with FEV1. The possibility of using LCI as a surrogate marker of lung damage is promising, based on these data. In CF, this apparent normal lung function based on spirometry in the early stages of the disease process has been termed the “silent zone” or “silent years” of lung function decline (25, 26). Monitoring disease progression and response to interventions in these subjects requires measurements that are both sensitive and repeatable. In this regard, the enhanced sensitivity of LCI assessing ventilation inhomogeneity over FEV1 represents a significant advantage. The box plots in Figure 3 indicate that LCI is a better discriminator of severity of structural disease on CT than conventional spirometry. Further studies are needed to determine the usefulness of LCI in the diagnosis and management of people with BE.
In a study assessing the role of LCI in a small group of patients (n = 21) with primary ciliary dyskinesia (PCD) and CF, the authors hypothesized that LCI and FEV1 were not related and that there was a poor relationship between LCI and disease severity on HRCT scan, with a particular lack of sensitivity in advanced PCD (27). In contrast to CF, HRCT imaging studies have shown that a decreased attenuation pattern on expiratory CT scan is common in severe BE, and may also be detected in lobes without bronchiectatic airways visible on HRCT (28). The lack of a relationship between LCI, FEV1, and HRCT scores in patients with PCD may be explained by the population size studied. In this study, 21 patients with PCD were included, which is less than the number required to power a study for an association. In addition, when comparing the LCI values, the CF group and our population of BE had an LCI greater than 12 in about 10% of the participants. The PCD group had about 30% with an LCI greater than 12. In patients with this level of LCI, there is a loss of the linear relationship between FEV1 and LCI. This supports our observation that LCI is a more discriminatory measurement in mild to moderate disease compared with those with more severe disease.
In addition, the assessment of acceptability and feasibility of LCI shows that this measure of lung function is simple to perform, with a high degree of comfort and no major adverse effects seen in this group. Feasibility has been reported in numerous studies in CF; however, as patients with BE are older, it is important to establish feasibility and acceptability in this population (14, 29). Despite taking a longer time to perform than spirometry, ease of use and comfort scores are good. Ease of use and comfort of the test for spirometry were not measured in this study or compared with MBW measurements. It is an inexpensive test, with the consumables costing less than €10 per triplicate of tests per patient.
The limitations of this study are that these data are cross-sectional taken during clinical stability, with no longitudinal data comparing HRCT findings in stable disease. To further validate the use of LCI, it will be important to measure the response of LCI during an intervention such as intravenous antibiotics, antiinflammatory therapy, or physiotherapy. In addition, serial CT scans would be ideal during these measures to correlate lung function parameters with structural changes on CT. This, however, is limited from an ethical perspective because of the exposure to radiation that would be required. Also, this study included patients with relatively good lung function measured by FEV1 and excluded those with an FEV1 less than 40% predicted. In advanced disease the benefit of LCI over FEV1 in terms of sensitivity may be reduced and the practicalities of LCI testing are complicated by the longer wash-in and washout times seen with higher LCI. A further limitation is that MBW methods used in this study are not commercially available, and sulfur hexafluoride is a greenhouse gas that is not approved for medical use in the United States and France. A more recently available nitrogen washout system can be used without further modification and does not require an inert gas (30). A study in this area has shown a small increase in LCI with age of 0.22 unit/decade (31). The healthy control data used to define a normal LCI were not age-matched and represent a limitation of this study. Although this data set involves an older population than in many other LCI studies, this should not impact the interpretation of the data.
LCI by MBW has been identified as a key clinical and research tool in children with CF and has been used to be a primary outcome measure in clinical trials (32, 33). It has also been proposed to be a predictor of subsequent future lung function in preschool children (34). In BE, LCI has the potential to be used as an outcome measure either in association with, or as an alternative to, conventional spirometry. It may be most valuable in patients with preserved lung function and normal FEV1, where it is a better predictor of structural changes on CT. In many studies in BE the lack of responsiveness of FEV1 to therapy makes LCI attractive as an outcome measure in clinical trials.
In conclusion, LCI is a repeatable and highly sensitive measure of lung function in BE, particularly in those with preserved spirometric lung function, and has the potential to play a key role in future assessment of lung function in BE and in clinical trials as an outcome measure in clinical trials.
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Supported by a fellowship grant from the Health and Social Care Research and Development, Public Health Agency, Northern Ireland (S.A.R.).
Author Contributions: S.A.R. performed data collection and manuscript preparation. This study was designed by J.S.E., J.M.B., and S.A.R. I.B. performed statistical analysis and review of data for manuscript preparation. J.L. and T.L. scored CT scans and assisted in manuscript preparation. J.M.B. and J.S.E. assisted with data interpretation and preparation of manuscript. P.G., A.H., K.O’N., and M.E. assisted in manuscript preparation.
This article has an online supplement, which is accessible from this issue’s table of contents online at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.201310-1747OC on January 15, 2014