EDITORIALS
Lung Clearance Index A Potential Quantitative Tool to Assess Treatment Response in Bronchiectasis? Bronchiectasis is a chronic condition characterized by permanently damaged and dilated airways with excess neutrophilic airway inflammation, and despite this host response, there is frequent chronic infection of the airways. This leads to patients having chronic cough and sputum production, and recurrent exacerbations leading to acute intervention. There are no currently approved medications with the indication for the treatment of bronchiectasis, excluding that due to cystic fibrosis (CF) (1). A major factor limiting progression in this field is a lack of satisfying clinical endpoints that are sensitive to detect changes in a clinical trial (2). This may be due to fact that bronchiectasis is a heterogeneous disease with a number of etiologies. Past infection is the commonest association in the literature to date, but often no cause is found (1). The reality is that independent of the cause, in postinfective and idiopathic bronchiectasis, patients have the same final endpoint, which is permanently damaged airways. It is accepted, however, that the course and treatment options may be different in certain etiologies such as active allergic bronchopulmonary aspergillosis (ABPA), active nontuberculous mycobacteria infection, and patients with immunodeficiency. CF is one of the diagnoses associated with bronchiectasis. There are a number of medications that have been approved for the treatment of patients with CF based on an improvement in lung function, specifically FEV1 (3). Some of these medications have been studied in patients with bronchiectasis for reasons other than CF (i.e., non-CF bronchiectasis), but they were unable to demonstrate a clinical response similar to that seen in patients with CF (4–8). It has puzzled researchers why FEV1 is not useful in patients with non-CF bronchiectasis, whereas it is useful as a marker of treatment response in patients with CF. The field, therefore, has been struggling to identify quantifiable endpoints in patients with non-CF bronchiectasis to assess treatment response (2). Whereas the FEV1 has been a key endpoint in studies of patients with CF, it should be noted that it is not a useful measure in patients who are very young or who have normal lung function, yet have active disease destined to progress to significant bronchiectasis. There is great interest in earlier intervention in CF, and therefore a need for a sensitive diagnostic test that can assess treatment response. Greater interest in the smaller airways has been proposed, looking for evidence of airway obstruction even in the absence of bronchiectasis. This can be seen using computed tomography (CT) of the chest where air trapping can be appreciated at end expiration (9). Serial CT scanning offers a potential marker to assess treatment response, although the repeated radiation associated with serial CT scanning is a potential limitation to using this as an endpoint. The lung clearance index (LCI) has seen a resurgence of interest in CF as a means of assessing ventilatory inhomogeneity by measuring multiple breath washouts using sulfur hexafluoride; patients with airway obstruction will take longer to wash out the gas, measured as a greater lung volume relative to their FRC, and, therefore, a greater 510
LCI (10, 11). The LCI has performed well in patients with CF with normal to mild airways impairment (10, 11). Because the FEV1 has not proven to be responsive to therapies in studies of patients with non-CF bronchiectasis, it is reasonable to evaluate the role of the smaller airways. Bilton and colleagues performed a study of inhaled mannitol compared with placebo in 343 patients over a 12-week period (8). A subanalysis of 82 patients found that inhaled mannitol reduced small airway mucus plugging seen on serial CT scanning. Again, serial CT scanning could be a potential marker to assess treatment response, but much like in the patients with CF, repeated radiation exposure is a potential limitation. The article by Rowan and colleagues (pp. 586–592) in this issue of the Journal comes very timely to assess whether the LCI could prove to be a more sensitive measure than FEV1 in patients with non-CF bronchiectasis (12). They studied 30 patients with stable non-CF bronchiectasis over a 2-week period and found the LCI to be reproducible with a high intraclass correlation coefficient of 0.94, showing it is reproducible over a 2-week period. The authors then studied 60 patients with stable non-CF bronchiectasis and compared LCI with FEV1 and midexpiratory flows (FEF25–75) in assessing bronchiectasis severity on the basis of CT scores. Eighty-one point six percent of patients had either had idiopathic or postinfectious bronchiectasis. The authors found that LCI correlated reasonably with overall CT severity scores (r = 0.55) and correlated better with CT severity than either FEV1 or FEF25–75. LCI correlated inversely with both FEV1 and FEF25–75, but the correlation was stronger for FEF25–75 (r = 20.58). The authors’ impression is that the LCI was useful particularly in patients with preserved lung function or those with mildly impaired FEV1, and the study findings do support this. This study, however, excluded patients with very severe bronchiectasis with an FEV1 less than 40% predicted, so it is not known how useful the LCI is in such patients. A limitation of the LCI is that the multiple breath washout uses sulfur hexafluoride, which is a greenhouse gas and is not approved for use in the United States and France. Alternative gases such as nitrogen could be used but would need validation studies to check that the results still hold. Another issue is whether the distribution of bronchiectasis can influence the utility of the LCI. For example, would the LCI in patients with advanced ABPA that causes proximal bronchiectasis differ from patients with postinfective distal bronchiectasis? Is the LCI affected whether there is an upper lobe predominance in those with posttuberculosis bronchiectasis or burnt-out sarcoidosis compared with the lower lobe predominance in postinfective bronchiectasis? Further studies are needed to explore these issues. Irving and colleagues did not find LCI a sensitive test in patients with advanced primary ciliary dyskinesia (PCD) with a lack of relationship between LCI, FEV1, and CT scores (13). All patients, however, had advanced PCD despite all having an FEV1 greater than 40% predicted. The study by Rowan and
American Journal of Respiratory and Critical Care Medicine Volume 189 Number 5 | March 1 2014
EDITORIALS colleagues was not powered for a subgroup analysis in patients with PCD, and further studies are needed to assess the clinical utility of LCI in less severe PCD. Overall, the LCI offers a promising tool to be more sensitive than FEV1 and FEF25–75 in patients with postinfective and idiopathic bronchiectasis. Both internal and external validation studies are needed in particular to determine whether LCI can assess treatment response to known effective therapies to determine whether LCI could be useful as a quantitative tool to assess existing and new therapies. n Author disclosures are available with the text of this article at www.atsjournals.org. Adam T. Hill, M.D. Department of Respiratory Medicine Royal Infirmary and University of Edinburgh Edinburgh, United Kingdom Patrick A. Flume, M.D. Department of Medicine and Pediatrics Medical University of South Carolina Charleston, South Carolina
References 1. Pasteur MC, Bilton D, Hill AT; British Thoracic Society Bronchiectasis non-CF Guideline Group. British Thoracic Society guideline for non-CF bronchiectasis. Thorax 2010;65:i1–i58. 2. Smith MP, Hill AT. Evaluating success of therapy for bronchiectasis: what end points to use? Clin Chest Med 2012;33: 329–349. 3. Mogayzel PJ Jr, Naureckas ET, Robinson KA, Mueller G, Hadjiliadis D, Hoag JB, Lubsch L, Hazle L, Sabadosa K, Marshall B; Pulmonary Clinical Practice Guidelines Committee. Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health. Am J Respir Crit Care Med 2013;187:680–689.
Editorials
4. Murray MP, Turnbull K, Macquarrie S, Hill AT. Assessing response to treatment of exacerbations of bronchiectasis in adults. Eur Respir J 2009;33:312–318. 5. Murray MP, Govan JR, Doherty CJ, Simpson AJ, Wilkinson TS, Chalmers JD, Greening AP, Haslett C, Hill AT. A randomized controlled trial of nebulized gentamicin in non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med 2011;183:491–499. 6. Scheinberg P, Shore E. A pilot study of the safety and efficacy of tobramycin solution for inhalation in patients with severe bronchiectasis. Chest 2005;127:1420–1426. 7. Wong C, Jayaram L, Karalus N, Eaton T, Tong C, Hockey H, Milne D, Fergusson W, Tuffery C, Sexton P, et al. Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial. Lancet 2012; 380:660–667. 8. Bilton D, Daviskas E, Anderson SD, Kolbe J, King G, Stirling RG, Thompson BR, Milne D, Charlton B; B301 Investigators. Phase 3 randomized study of the efficacy and safety of inhaled dry powder mannitol for the symptomatic treatment of non-cystic fibrosis bronchiectasis. Chest 2013;144:215–225 10.1378/chest.12–1763. 9. Bhalla M, Turcios N, Aponte V, Jenkins M, Leitman BS, McCauley DI, Naidich DP. Cystic fibrosis: scoring system with thin-section CT. Radiology 1991;179:783–788. 10. Horsley AR, Gustafsson PM, Macleod KA, Saunders C, Greening AP, Porteous DJ, Davies JC, Cunningham S, Alton EW, Innes JA. Lung clearance index is a sensitive, repeatable and practical measure of airways disease in adults with cystic fibrosis. Thorax 2008;63:135–140. 11. Gustafsson PM, De Jong PA, Tiddens HA, Lindblad A. Multiple-breath inert gas washout and spirometry versus structural lung disease in cystic fibrosis. Thorax 2008;63:129–134. 12. Rowan SA, Bradley JM, Bradbury I, Lawson J, Lynch T, Gustafsson P, Horsley A, O’Neill K, Ennis M, Elborn JS. Lung clearance index is a repeatable and sensitive indicator of radiological changes in bronchiectasis. Am J Respir Crit Care Med 2014;189:586–592. 13. Irving SJ, Ives A, Davies G, Donovan J, Edey AJ, Gill SS, Nair A, Saunders C, Wijesekera NT, Alton EW, et al. Lung clearance index and high-resolution computed tomography scores in primary ciliary dyskinesia. Am J Respir Crit Care Med 2013;188:545–549.
Copyright © 2014 by the American Thoracic Society
511
Lung Clearance Index A Potential Quantitative Tool to Assess Treatment Response in Bronchiectasis? Bronchiectasis is a chronic condition characterized by permanently damaged and dilated airways with excess neutrophilic airway inflammation, and despite this host response, there is frequent chronic infection of the airways. This leads to patients having chronic cough and sputum production, and recurrent exacerbations leading to acute intervention. There are no currently approved medications with the indication for the treatment of bronchiectasis, excluding that due to cystic fibrosis (CF) (1). A major factor limiting progression in this field is a lack of satisfying clinical endpoints that are sensitive to detect changes in a clinical trial (2). This may be due to fact that bronchiectasis is a heterogeneous disease with a number of etiologies. Past infection is the commonest association in the literature to date, but often no cause is found (1). The reality is that independent of the cause, in postinfective and idiopathic bronchiectasis, patients have the same final endpoint, which is permanently damaged airways. It is accepted, however, that the course and treatment options may be different in certain etiologies such as active allergic bronchopulmonary aspergillosis (ABPA), active nontuberculous mycobacteria infection, and patients with immunodeficiency. CF is one of the diagnoses associated with bronchiectasis. There are a number of medications that have been approved for the treatment of patients with CF based on an improvement in lung function, specifically FEV1 (3). Some of these medications have been studied in patients with bronchiectasis for reasons other than CF (i.e., non-CF bronchiectasis), but they were unable to demonstrate a clinical response similar to that seen in patients with CF (4–8). It has puzzled researchers why FEV1 is not useful in patients with non-CF bronchiectasis, whereas it is useful as a marker of treatment response in patients with CF. The field, therefore, has been struggling to identify quantifiable endpoints in patients with non-CF bronchiectasis to assess treatment response (2). Whereas the FEV1 has been a key endpoint in studies of patients with CF, it should be noted that it is not a useful measure in patients who are very young or who have normal lung function, yet have active disease destined to progress to significant bronchiectasis. There is great interest in earlier intervention in CF, and therefore a need for a sensitive diagnostic test that can assess treatment response. Greater interest in the smaller airways has been proposed, looking for evidence of airway obstruction even in the absence of bronchiectasis. This can be seen using computed tomography (CT) of the chest where air trapping can be appreciated at end expiration (9). Serial CT scanning offers a potential marker to assess treatment response, although the repeated radiation associated with serial CT scanning is a potential limitation to using this as an endpoint. The lung clearance index (LCI) has seen a resurgence of interest in CF as a means of assessing ventilatory inhomogeneity by measuring multiple breath washouts using sulfur hexafluoride; patients with airway obstruction will take longer to wash out the gas, measured as a greater lung volume relative to their FRC, and, therefore, a greater 510
LCI (10, 11). The LCI has performed well in patients with CF with normal to mild airways impairment (10, 11). Because the FEV1 has not proven to be responsive to therapies in studies of patients with non-CF bronchiectasis, it is reasonable to evaluate the role of the smaller airways. Bilton and colleagues performed a study of inhaled mannitol compared with placebo in 343 patients over a 12-week period (8). A subanalysis of 82 patients found that inhaled mannitol reduced small airway mucus plugging seen on serial CT scanning. Again, serial CT scanning could be a potential marker to assess treatment response, but much like in the patients with CF, repeated radiation exposure is a potential limitation. The article by Rowan and colleagues (pp. 586–592) in this issue of the Journal comes very timely to assess whether the LCI could prove to be a more sensitive measure than FEV1 in patients with non-CF bronchiectasis (12). They studied 30 patients with stable non-CF bronchiectasis over a 2-week period and found the LCI to be reproducible with a high intraclass correlation coefficient of 0.94, showing it is reproducible over a 2-week period. The authors then studied 60 patients with stable non-CF bronchiectasis and compared LCI with FEV1 and midexpiratory flows (FEF25–75) in assessing bronchiectasis severity on the basis of CT scores. Eighty-one point six percent of patients had either had idiopathic or postinfectious bronchiectasis. The authors found that LCI correlated reasonably with overall CT severity scores (r = 0.55) and correlated better with CT severity than either FEV1 or FEF25–75. LCI correlated inversely with both FEV1 and FEF25–75, but the correlation was stronger for FEF25–75 (r = 20.58). The authors’ impression is that the LCI was useful particularly in patients with preserved lung function or those with mildly impaired FEV1, and the study findings do support this. This study, however, excluded patients with very severe bronchiectasis with an FEV1 less than 40% predicted, so it is not known how useful the LCI is in such patients. A limitation of the LCI is that the multiple breath washout uses sulfur hexafluoride, which is a greenhouse gas and is not approved for use in the United States and France. Alternative gases such as nitrogen could be used but would need validation studies to check that the results still hold. Another issue is whether the distribution of bronchiectasis can influence the utility of the LCI. For example, would the LCI in patients with advanced ABPA that causes proximal bronchiectasis differ from patients with postinfective distal bronchiectasis? Is the LCI affected whether there is an upper lobe predominance in those with posttuberculosis bronchiectasis or burnt-out sarcoidosis compared with the lower lobe predominance in postinfective bronchiectasis? Further studies are needed to explore these issues. Irving and colleagues did not find LCI a sensitive test in patients with advanced primary ciliary dyskinesia (PCD) with a lack of relationship between LCI, FEV1, and CT scores (13). All patients, however, had advanced PCD despite all having an FEV1 greater than 40% predicted. The study by Rowan and
American Journal of Respiratory and Critical Care Medicine Volume 189 Number 5 | March 1 2014
EDITORIALS colleagues was not powered for a subgroup analysis in patients with PCD, and further studies are needed to assess the clinical utility of LCI in less severe PCD. Overall, the LCI offers a promising tool to be more sensitive than FEV1 and FEF25–75 in patients with postinfective and idiopathic bronchiectasis. Both internal and external validation studies are needed in particular to determine whether LCI can assess treatment response to known effective therapies to determine whether LCI could be useful as a quantitative tool to assess existing and new therapies. n Author disclosures are available with the text of this article at www.atsjournals.org. Adam T. Hill, M.D. Department of Respiratory Medicine Royal Infirmary and University of Edinburgh Edinburgh, United Kingdom Patrick A. Flume, M.D. Department of Medicine and Pediatrics Medical University of South Carolina Charleston, South Carolina
References 1. Pasteur MC, Bilton D, Hill AT; British Thoracic Society Bronchiectasis non-CF Guideline Group. British Thoracic Society guideline for non-CF bronchiectasis. Thorax 2010;65:i1–i58. 2. Smith MP, Hill AT. Evaluating success of therapy for bronchiectasis: what end points to use? Clin Chest Med 2012;33: 329–349. 3. Mogayzel PJ Jr, Naureckas ET, Robinson KA, Mueller G, Hadjiliadis D, Hoag JB, Lubsch L, Hazle L, Sabadosa K, Marshall B; Pulmonary Clinical Practice Guidelines Committee. Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health. Am J Respir Crit Care Med 2013;187:680–689.
Editorials
4. Murray MP, Turnbull K, Macquarrie S, Hill AT. Assessing response to treatment of exacerbations of bronchiectasis in adults. Eur Respir J 2009;33:312–318. 5. Murray MP, Govan JR, Doherty CJ, Simpson AJ, Wilkinson TS, Chalmers JD, Greening AP, Haslett C, Hill AT. A randomized controlled trial of nebulized gentamicin in non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med 2011;183:491–499. 6. Scheinberg P, Shore E. A pilot study of the safety and efficacy of tobramycin solution for inhalation in patients with severe bronchiectasis. Chest 2005;127:1420–1426. 7. Wong C, Jayaram L, Karalus N, Eaton T, Tong C, Hockey H, Milne D, Fergusson W, Tuffery C, Sexton P, et al. Azithromycin for prevention of exacerbations in non-cystic fibrosis bronchiectasis (EMBRACE): a randomised, double-blind, placebo-controlled trial. Lancet 2012; 380:660–667. 8. Bilton D, Daviskas E, Anderson SD, Kolbe J, King G, Stirling RG, Thompson BR, Milne D, Charlton B; B301 Investigators. Phase 3 randomized study of the efficacy and safety of inhaled dry powder mannitol for the symptomatic treatment of non-cystic fibrosis bronchiectasis. Chest 2013;144:215–225 10.1378/chest.12–1763. 9. Bhalla M, Turcios N, Aponte V, Jenkins M, Leitman BS, McCauley DI, Naidich DP. Cystic fibrosis: scoring system with thin-section CT. Radiology 1991;179:783–788. 10. Horsley AR, Gustafsson PM, Macleod KA, Saunders C, Greening AP, Porteous DJ, Davies JC, Cunningham S, Alton EW, Innes JA. Lung clearance index is a sensitive, repeatable and practical measure of airways disease in adults with cystic fibrosis. Thorax 2008;63:135–140. 11. Gustafsson PM, De Jong PA, Tiddens HA, Lindblad A. Multiple-breath inert gas washout and spirometry versus structural lung disease in cystic fibrosis. Thorax 2008;63:129–134. 12. Rowan SA, Bradley JM, Bradbury I, Lawson J, Lynch T, Gustafsson P, Horsley A, O’Neill K, Ennis M, Elborn JS. Lung clearance index is a repeatable and sensitive indicator of radiological changes in bronchiectasis. Am J Respir Crit Care Med 2014;189:586–592. 13. Irving SJ, Ives A, Davies G, Donovan J, Edey AJ, Gill SS, Nair A, Saunders C, Wijesekera NT, Alton EW, et al. Lung clearance index and high-resolution computed tomography scores in primary ciliary dyskinesia. Am J Respir Crit Care Med 2013;188:545–549.
Copyright © 2014 by the American Thoracic Society
511
