Journal of Cystic Fibrosis 14 (2015) 285 – 286 www.elsevier.com/locate/jcf
Letter to the Editor
The Lung Clearance Index as a probe for the effectiveness of short-term therapies in cystic fibrosis lung disease To the Editor: In a recently published article in the Journal, Welsh et al. [1] suggested that the lung clearance index (LCI) derived from the Multiple Breath Washout (MBW), is not suitable to gauge the short-term response to intravenous antibiotic therapy in school-age children with cystic fibrosis. In the light of this work we reassessed our recently published data on the use of the MBW test for monitoring after therapeutic interventions in a study population of 15 adult CF patients; and aimed to add some potential interesting findings on the use of the parameters of ventilation distribution. Welsh et al. came to this conclusion on LCI based on the fact that LCI changes after treatment were found to be unpredictable and on average, small in a group eligible for this type of treatment. Indeed, LCI changes after intravenous antibiotic therapy can be heterogeneous, with mean LCI typically decreasing by ~ 0.5 across previous studies by us [2] and others [3,4] or LCI change not even reaching significance [5]. A possible explanation for this variable response can be found in the fact that LCI is a combined result of serial dead space (instrumental and anatomical), conductive and acinar ventilation heterogeneities [6]. The different components contributing to global ventilation heterogeneity represented by LCI, can be separated using a normalized phase III slope analysis of the MBW test. Welsh et al. [1] and Yammine et al. [5] performed this MBW slope analysis in children, distinguishing between conductive and acinar components of ventilation heterogeneity (represented by Scond and Sacin, respectively) and observed a significant [1] or a borderline significant decrease of Sacin [5], and no significant changes in Scond in either study [1,5]. This compares to our own findings in adult CF patients [2], where intravenous antibiotic therapy led to reduced LCI and reduced acinar ventilation heterogeneity. In our study [2] we used a set of modified parameters Sacin* and Scond* that have been validated by modeling for CF lung disease [7] where severity of ventilation heterogeneity can lead to considerable underestimation of actual conductive ventilation heterogeneity by Scond. Scond* is similar to Scond for normal subjects but markedly greater than Scond for severe CF lung disease (corresponding Sacin* and Sacin values are in fact very similar). We showed in our study that LCI decrease
(i.e., improvement) following intravenous antibiotic treatment was actually correlated to Sacin* decrease (i.e., improvement) [2]. It is not clear whether Welsh et al. [1] investigated this relationship or whether it was non-significant, but Yammine et al. [5] reported an absence of correlation between changes in LCI and in Sacin, and somewhat surprisingly an improvement in Scond was seen to correlate with a deterioration in LCI. Such paradoxical negative correlation could partly be explained by the use of Scond instead of Scond* (which would have been warranted in this group with moderate to severe CF lung disease, and would perhaps have led to other significant changes in the parameters of ventilation distribution). In our group of 15 adult CF patients, with very strict timing of measurements (within 24 h upon initiation of intravenous antibiotic therapy, and 8 days later, for all), 7 patients improved in terms of LCI, and 9 patients in terms of FEV1. This was in line with the 55% LCI and 67% FEV1 response rate in Welsh et al. [1]. We actually also showed that in responsive patients– for whom LCI and acinar ventilation heterogeneity could be improved after intravenous antibiotic treatment–and who were readmitted for an acute exacerbation within a one year observation window, the same peripheral response occurred on these different occasions. Similarly, non-responders did not respond on every single occasion. We contend that there can be a subgroup of patients that possibly does not benefit from intravenous antibiotic treatment in terms of lung function or parameters of ventilation distribution but this fact should not necessarily imply that LCI should be completely abandoned for monitoring the effect of therapeutic interventions. Yammine et al. [5] also suggested that intravenous antibiotic treatment induced LCI changes (whether positive or negative) were related to changes in FRCMBW − RV. In the light of this work, we have reassessed and recalculated our data to examine whether the effect of antibiotic therapy on acinar ventilation heterogeneity could be linked to this parameter or an alternative measure of gas trapping. We calculated correlations between Sacin*, parameter of acinar ventilation distribution that changed significantly in our study group, and parameters of gas trapping, also using the alternative parameter suggested by Yammine et al. In our adult patients (n = 15), we found a borderline relationship between change in Sacin* and in FRCMBW − RV
http://dx.doi.org/10.1016/j.jcf.2014.08.004 1569-1993© 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
286
Letter to the Editor
(rho = -0.49; P = 0.062), a significant relationship between changes in Sacin* and in RV/TLC (rho = + 0.64; P = 0.01) and no relationship at all between Sacin* and FRCPL − FRCMBW (P = 0.6). These combined observations could support the hypothesis that the peripheral effect of intravenous antibiotic treatment is due to conformational changes of very peripheral lung units, without them being actually closed off from ventilated air spaces at FRC, but generating changes in acinar ventilation heterogeneity. In conclusion–and in the light of the recently published data on this matter–we would like to challenge the idea that LCI should be dismissed to monitor the effect of therapeutic interventions, accepting that some patients will show a lung functional response, and others will not. The combination of standard lung function and ventilation distribution, with its peripheral acinar effect in particular, can help target therapy and could perhaps even identify a subgroup of CF patients who are more liable to benefit from intravenous antibiotic therapy. References [1] Welsh L, Nesci C, Tran H, Tomai M, Ranganathan S. Lung clearance index during hospital admission in school-age children with cystic fibrosis. J Cyst Fibros 2014;13:687–91. [2] Vanderhelst E, De Meirleir L, Schuermans D, Malfroot A, Vincken W, Verbanck S. Evidence of an acinar response following treatment for exacerbation in adult patients with cystic fibrosis. Respiration 2014;87: 492–8. [3] Robinson PD, Cooper P, Van Asperen P, Fitzgerald D, Selvadurai H. Using index of ventilation to assess response to treatment for acute pulmonary exacerbation in children with cystic fibrosis. Pediatr Pulmonol 2009;44: 733–42. [4] Horsley AR, Davies JC, Gray RD, Macleod KA, Donovan J, Aziz ZA, Bell NJ, Rainer M, Mt-Isa S, Voase N, Dewar MH, Saunders C, Gibson JS, Parra-Leiton J, Larsen MD, Jeswiet S, Soussi S, Bakar Y, Meister MG,
Tyler P, Doherty A, Hansell DM, Ashby D, Hyde SC, Gill DR, Greening AP, Porteous DJ, Innes JA, Boyd AC, Griesenbach U, Cunningham S, Alton EW. Changes in physiological, functional and structural markers of cystic fibrosis lung disease with treatment of a pulmonary exacerbation. Thorax 2013;68:532–9. [5] Yammine S, Bigler A, Casaulta C, Singer F, Latzin P. Reasons for heterogeneous change in LCI in children with cystic fibrosis after antibiotic treatment. Thorax 2014;69:183. [6] Verbanck S, Paiva M, Paeps E, Schuermans D, Malfroot A, Vincken W, Vanderhelst E. Lung clearance index in adult cystic fibrosis patients: the role of convection-dependent lung units. Eur Respir J 2013;42:380–8. [7] Verbanck S, Paiva M, Schuermans D, Malfroot A, Vincken W, Vanderhelst E. Acinar and conductive ventilation heterogeneity in severe CF lung disease: back to the model. Respir Physiol Neurobiol 2013;188:124–32.
Eef Vanderhelst* Liesbeth De Meirleir Respiratory Division, University Hospital UZ Brussel, Brussels, Belgium Cystic Fibrosis Center, University Hospital UZ Brussel, Brussels, Belgium ⁎ Corresponding author at: Respiratory Division, University Hospital UZ Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium. Tel : +32 2 477 4675; fax : +32 2 477 6352.
Daniel Schuermans Respiratory Division, University Hospital UZ Brussel, Brussels, Belgium Anne Malfroot Cystic Fibrosis Center, University Hospital UZ Brussel, Brussels, Belgium Walter Vincken Sylvia Verbanck Respiratory Division, University Hospital UZ Brussel, Brussels, Belgium 30 July 2014
Letter to the Editor
The Lung Clearance Index as a probe for the effectiveness of short-term therapies in cystic fibrosis lung disease To the Editor: In a recently published article in the Journal, Welsh et al. [1] suggested that the lung clearance index (LCI) derived from the Multiple Breath Washout (MBW), is not suitable to gauge the short-term response to intravenous antibiotic therapy in school-age children with cystic fibrosis. In the light of this work we reassessed our recently published data on the use of the MBW test for monitoring after therapeutic interventions in a study population of 15 adult CF patients; and aimed to add some potential interesting findings on the use of the parameters of ventilation distribution. Welsh et al. came to this conclusion on LCI based on the fact that LCI changes after treatment were found to be unpredictable and on average, small in a group eligible for this type of treatment. Indeed, LCI changes after intravenous antibiotic therapy can be heterogeneous, with mean LCI typically decreasing by ~ 0.5 across previous studies by us [2] and others [3,4] or LCI change not even reaching significance [5]. A possible explanation for this variable response can be found in the fact that LCI is a combined result of serial dead space (instrumental and anatomical), conductive and acinar ventilation heterogeneities [6]. The different components contributing to global ventilation heterogeneity represented by LCI, can be separated using a normalized phase III slope analysis of the MBW test. Welsh et al. [1] and Yammine et al. [5] performed this MBW slope analysis in children, distinguishing between conductive and acinar components of ventilation heterogeneity (represented by Scond and Sacin, respectively) and observed a significant [1] or a borderline significant decrease of Sacin [5], and no significant changes in Scond in either study [1,5]. This compares to our own findings in adult CF patients [2], where intravenous antibiotic therapy led to reduced LCI and reduced acinar ventilation heterogeneity. In our study [2] we used a set of modified parameters Sacin* and Scond* that have been validated by modeling for CF lung disease [7] where severity of ventilation heterogeneity can lead to considerable underestimation of actual conductive ventilation heterogeneity by Scond. Scond* is similar to Scond for normal subjects but markedly greater than Scond for severe CF lung disease (corresponding Sacin* and Sacin values are in fact very similar). We showed in our study that LCI decrease
(i.e., improvement) following intravenous antibiotic treatment was actually correlated to Sacin* decrease (i.e., improvement) [2]. It is not clear whether Welsh et al. [1] investigated this relationship or whether it was non-significant, but Yammine et al. [5] reported an absence of correlation between changes in LCI and in Sacin, and somewhat surprisingly an improvement in Scond was seen to correlate with a deterioration in LCI. Such paradoxical negative correlation could partly be explained by the use of Scond instead of Scond* (which would have been warranted in this group with moderate to severe CF lung disease, and would perhaps have led to other significant changes in the parameters of ventilation distribution). In our group of 15 adult CF patients, with very strict timing of measurements (within 24 h upon initiation of intravenous antibiotic therapy, and 8 days later, for all), 7 patients improved in terms of LCI, and 9 patients in terms of FEV1. This was in line with the 55% LCI and 67% FEV1 response rate in Welsh et al. [1]. We actually also showed that in responsive patients– for whom LCI and acinar ventilation heterogeneity could be improved after intravenous antibiotic treatment–and who were readmitted for an acute exacerbation within a one year observation window, the same peripheral response occurred on these different occasions. Similarly, non-responders did not respond on every single occasion. We contend that there can be a subgroup of patients that possibly does not benefit from intravenous antibiotic treatment in terms of lung function or parameters of ventilation distribution but this fact should not necessarily imply that LCI should be completely abandoned for monitoring the effect of therapeutic interventions. Yammine et al. [5] also suggested that intravenous antibiotic treatment induced LCI changes (whether positive or negative) were related to changes in FRCMBW − RV. In the light of this work, we have reassessed and recalculated our data to examine whether the effect of antibiotic therapy on acinar ventilation heterogeneity could be linked to this parameter or an alternative measure of gas trapping. We calculated correlations between Sacin*, parameter of acinar ventilation distribution that changed significantly in our study group, and parameters of gas trapping, also using the alternative parameter suggested by Yammine et al. In our adult patients (n = 15), we found a borderline relationship between change in Sacin* and in FRCMBW − RV
http://dx.doi.org/10.1016/j.jcf.2014.08.004 1569-1993© 2014 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
286
Letter to the Editor
(rho = -0.49; P = 0.062), a significant relationship between changes in Sacin* and in RV/TLC (rho = + 0.64; P = 0.01) and no relationship at all between Sacin* and FRCPL − FRCMBW (P = 0.6). These combined observations could support the hypothesis that the peripheral effect of intravenous antibiotic treatment is due to conformational changes of very peripheral lung units, without them being actually closed off from ventilated air spaces at FRC, but generating changes in acinar ventilation heterogeneity. In conclusion–and in the light of the recently published data on this matter–we would like to challenge the idea that LCI should be dismissed to monitor the effect of therapeutic interventions, accepting that some patients will show a lung functional response, and others will not. The combination of standard lung function and ventilation distribution, with its peripheral acinar effect in particular, can help target therapy and could perhaps even identify a subgroup of CF patients who are more liable to benefit from intravenous antibiotic therapy. References [1] Welsh L, Nesci C, Tran H, Tomai M, Ranganathan S. Lung clearance index during hospital admission in school-age children with cystic fibrosis. J Cyst Fibros 2014;13:687–91. [2] Vanderhelst E, De Meirleir L, Schuermans D, Malfroot A, Vincken W, Verbanck S. Evidence of an acinar response following treatment for exacerbation in adult patients with cystic fibrosis. Respiration 2014;87: 492–8. [3] Robinson PD, Cooper P, Van Asperen P, Fitzgerald D, Selvadurai H. Using index of ventilation to assess response to treatment for acute pulmonary exacerbation in children with cystic fibrosis. Pediatr Pulmonol 2009;44: 733–42. [4] Horsley AR, Davies JC, Gray RD, Macleod KA, Donovan J, Aziz ZA, Bell NJ, Rainer M, Mt-Isa S, Voase N, Dewar MH, Saunders C, Gibson JS, Parra-Leiton J, Larsen MD, Jeswiet S, Soussi S, Bakar Y, Meister MG,
Tyler P, Doherty A, Hansell DM, Ashby D, Hyde SC, Gill DR, Greening AP, Porteous DJ, Innes JA, Boyd AC, Griesenbach U, Cunningham S, Alton EW. Changes in physiological, functional and structural markers of cystic fibrosis lung disease with treatment of a pulmonary exacerbation. Thorax 2013;68:532–9. [5] Yammine S, Bigler A, Casaulta C, Singer F, Latzin P. Reasons for heterogeneous change in LCI in children with cystic fibrosis after antibiotic treatment. Thorax 2014;69:183. [6] Verbanck S, Paiva M, Paeps E, Schuermans D, Malfroot A, Vincken W, Vanderhelst E. Lung clearance index in adult cystic fibrosis patients: the role of convection-dependent lung units. Eur Respir J 2013;42:380–8. [7] Verbanck S, Paiva M, Schuermans D, Malfroot A, Vincken W, Vanderhelst E. Acinar and conductive ventilation heterogeneity in severe CF lung disease: back to the model. Respir Physiol Neurobiol 2013;188:124–32.
Eef Vanderhelst* Liesbeth De Meirleir Respiratory Division, University Hospital UZ Brussel, Brussels, Belgium Cystic Fibrosis Center, University Hospital UZ Brussel, Brussels, Belgium ⁎ Corresponding author at: Respiratory Division, University Hospital UZ Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium. Tel : +32 2 477 4675; fax : +32 2 477 6352.
Daniel Schuermans Respiratory Division, University Hospital UZ Brussel, Brussels, Belgium Anne Malfroot Cystic Fibrosis Center, University Hospital UZ Brussel, Brussels, Belgium Walter Vincken Sylvia Verbanck Respiratory Division, University Hospital UZ Brussel, Brussels, Belgium 30 July 2014
