JCF-01062; No of Pages 5

Journal of Cystic Fibrosis xx (2014) xxx – xxx www.elsevier.com/locate/jcf

Original Article

Lung clearance index during hospital admission in school-age children with cystic fibrosis Liam Welsh a,b,⁎, Christopher Nesci a , Haily Tran a , Marisol Tomai a , Sarath Ranganathan a,b,c a

Department of Respiratory Medicine, Royal Children's Hospital, Melbourne, Australia b Murdoch Children's Research Institute, Melbourne, Australia c Department of Paediatrics, University of Melbourne, Australia

Received 22 January 2014; received in revised form 13 May 2014; accepted 13 May 2014 Available online xxxx

Abstract Background: There is currently limited information regarding lung clearance index (LCI) and its response to treatment of pulmonary exacerbations in CF. We aimed to examine the utility of LCI for assessing short term clinical response to IV antibiotic therapy in school-age children with CF. Methods: Subjects experiencing exacerbations and hospitalised for IV antibiotics performed both multiple breath nitrogen washout (MBNW) and spirometry on admission to hospital and prior to discharge. Results: 27 patients (aged 6–20 years) had paired data for MBNW and spirometry. Mean LCI reduced from 12.18 to 11.65 (4.4%) by time of discharge and FEV1 z-score improved from − 3.05 to − 2.86 (6.2%). Overall, LCI improved in n = 15 (55%) patients compared with n = 18 (67%) where FEV1 improved. Conclusions: In summary, these findings do not support the use of LCI (or indeed, FEV1) to gauge the short term clinical response to IV antibiotic therapy in school-age children with cystic fibrosis. Crown Copyright © 2014 Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society. All rights reserved. Keywords: Cystic fibrosis; Lung function; Multiple breath washout; Pulmonary exacerbation

1. Introduction Pulmonary disease in children with cystic fibrosis (CF) begins early in life with lung function abnormalities and bronchiectasis detected as soon as 3 months [1,2]. Traditional measures of lung function such as spirometry are often insensitive to the inhomogeneous nature of primary lung disease, with forced expiratory volume in 1 s (FEV1) commonly preserved in the normal range for the first decade [3]. Despite this, spirometry is still used as the mainstay of lung function testing to monitor disease progression and response to therapy in outpatient and inpatient settings. ⁎ Corresponding author at: Respiratory Medicine, Royal Children's Hospital, Melbourne, Flemington Road, Parkville 3052, Australia. Tel.: +61 3 9345 5842; fax: + 61 3 9345 9154. E-mail address: [email protected] (L. Welsh).

Multiple breath washout is now regarded as a more suitable method to gauge the subtle changes seen in early lung disease [4] and has the advantage of being applicable to all age-groups. Though it is well established that lung clearance index (LCI) is often abnormal in CF, it remains unclear what constitutes a clinically significant change. This is certainly an important question for those in the early stages of the disease process, which may be the optimal time to intervene, but it is also pertinent for those with established disease. There is currently limited information regarding LCI and its response to treatment. To date, just three studies have examined the usefulness of LCI to gauge clinical improvement during hospital admission following a course of intravenous (IV) antibiotic therapy [5–7] and a heterogeneous response has been reported in each. Importantly, only one of these studies has reported on alveolar phase III indices. Evidently, further data are

http://dx.doi.org/10.1016/j.jcf.2014.05.012 1569-1993/Crown Copyright © 2014 Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society. All rights reserved. Please cite this article as: Welsh L, et al, Lung clearance index during hospital admission in school-age children with cystic fibrosis, J Cyst Fibros (2014), http:// dx.doi.org/10.1016/j.jcf.2014.05.012

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L. Welsh et al. / Journal of Cystic Fibrosis xx (2014) xxx–xxx

required to better define the role of LCI and its concomitant indices in monitoring acute response to treatment. The primary aim of this study was to examine the utility of LCI for assessing short term clinical response to IV antibiotic therapy in school-age children with CF. Firstly, we hypothesized that LCI would improve during the admission and secondly, that LCI would be a clinically useful tool for assessing the therapeutic benefit of IV antibiotics. Preliminary results of this study have previously been reported in the form of an abstract [8].

2. Methods Between January and December 2013, consecutive patients with CF who were admitted to the Royal Children's Hospital (RCH), Melbourne requiring IV therapy were invited to participate. A pulmonary exacerbation was defined as any change in symptoms from baseline such as increase or development of cough, increase in purulent sputum production, or decrease in exercise tolerance, not responding to outpatient therapy. A clinical determination was made by the treating physician to administer IV antibiotics. Patients performed multiple breath nitrogen washout (MBNW) and spirometry on admission and prior to discharge. This study was approved by our local human research ethics committee. Informed consent was obtained from all patients and/or their parents. Prior to testing, height was recorded without shoes to the nearest 0.1 cm using a fixed stadiometer (Harpenden Stadiometer, Holtain Ltd, Dyfed, UK) and weight was measured in minimal clothing, without shoes, to the nearest 0.1 kg using digital scales (Tanita BWB 600, Tanita Corporation, Tokyo). Height, weight and body mass index (BMI, i.e. weight/height2), were reported in both raw form and as z-scores [9]. MBNW was performed using an Exhalyzer D (EcoMedics AG, Switzerland) running Spiroware version 3.1 software with the child sitting upright and wearing a nose clip. In brief, each test consisted of two phases. Following a period of tidal breathing of ambient air, participants were instructed to maintain their respiratory rate while breathing 100% oxygen. Each MBNW test finished when there were three consecutive breaths b 1/40th of the starting nitrogen concentration. A minimum of two satisfactory LCI results were obtained for each patient. A satisfactory trial was defined as a regular breathing pattern throughout the test, with no signs of mouth leak, and functional residual capacity (FRC) values within 10%. The minimum interval between tests was equal to washout time. Tests were performed before or at least 2 h after physiotherapy to avoid any confounding effects on FRC and thereby LCI. This methodology adheres to the most recently published consensus statement [10]. LCI was calculated as the cumulative expired volume required to dilute the end-tidal nitrogen concentration to 1/40th of the starting concentration divided by FRC. LCI results were expressed in absolute terms and also as z-scores [11]. Spirometry was performed using an MS Pneumo spirometer (Care Fusion, Germany) running SentrySuite version 2.7 software according to ATS/ERS standards [12] with results expressed as percent predicted and z-scores [13].

The Australian Cystic Fibrosis Data Registry was used to collect clinical information regarding genotype, newborn screening status, pancreatic insufficiency, CF related diabetes mellitus, and Pseudomonas aeruginosa (PsA) infection. Hospital records were used to determine the length of stay in hospital. 3. Statistics Statistical analysis was performed using Stata Version 12.0 (Stata Corporation, Texas, USA). Paired t-tests were used to assess the change in lung function parameters over the course of the hospital admission. To determine whether changes in lung function outcomes during admission could be explained by factors other than IV antibiotic therapy, a stepwise regression model was developed to determine the influence of: sex, age, genotype (categorized as homozygous ΔF508 versus other/ unknown), newborn screening, body mass index, pancreatic insufficiency, and PsA infection. Pearson's correlation was used to measure the magnitude and statistical significance of the relationship between change in LCI and FEV1 z-scores between admission and discharge. Significance levels were set at p b 0.05. LCI z-scores were generated using healthy control data (n = 57) from Vermeulen et al. [11] which used the same equipment and included children of a similar age range to our study (i.e. 4–18 years). The mean (SD) for LCI in their control group was 7.30 (0.50). 4. Results Throughout 2013, we invited 48 children to participate in this study (4 declined). We collected paired MBNW and spirometry data from 27 patients (age 6–20 years) with CF on admission and prior to discharge during their hospital admission. Seventeen children completed baseline measurements only and were therefore not included in the analysis, however, they were similar in terms of sex (59% female), age (14.8 years), LCI z-score (8.7) and FEV1 z-score (−3.16) when compared to the study group. Clinical demographics are shown in Table 1 and lung function results are shown in Table 2. Plots of spirometry and lung clearance index on admission and discharge are shown in Figs. 1 and 2. The mean (SD) time to test on admission was 1.2 (0.9) days and mean time of test before discharge was 1.7 (2.5) days. The

Table 1 Clinical demographics of patients. Subjects Female (%) Age (years) ΔF508 homozygous (%) Pseudomonas aeruginosa colonised (%) Pancreatic insufficiency (%) Diagnosis by newborn screening (%) Height z-score Weight z-score BMI z-score

27 15 (56%) 14.7 (6.2; 19.9) 13 (48%) 9 (33%) 22 (81%) 17 (63%) − 0.05 (0.97) − 0.31 (0.91) − 0.25 (0.83)

Data presented as n, n (%), mean (range) or mean (SD).

Please cite this article as: Welsh L, et al, Lung clearance index during hospital admission in school-age children with cystic fibrosis, J Cyst Fibros (2014), http:// dx.doi.org/10.1016/j.jcf.2014.05.012

L. Welsh et al. / Journal of Cystic Fibrosis xx (2014) xxx–xxx

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Table 2 Lung function on admission and discharge. Parameter

On admission On discharge Actual change (95% CI)

FEV1 (L) FEV1 % predicted FEV1 z-score FVC (L) FVC % predicted FVC z-score FEV1/FVC ratio FEV1/FVC z-score FEF25–75 (L/s) FEF25–75 z-score Lung clearance index LCI z-score Scond Sacin

1.88 (0.80) 63.1 (20.1) − 3.05 (1.58) 2.60 (0.84) 76.5 (15.7) − 2.02 (1.35) 70.8 (14.6) − 2.00 (1.46) 1.53 (1.19) − 3.12 (1.69) 12.18 (2.98)

1.99 (0.89) 65.5 (20.0) − 2.86 (1.60) 2.73 (0.94) 79.6 (16.5) − 1.75 (1.42) 71.2 (15.7) − 1.91 (1.61) 1.73 (1.24) − 2.83 (1.80) 11.65 (2.67)

9.80 (5.97) 0.043 (0.03) 0.117 (0.09)

8.70 (5.3) − 1.10 (− 2.32; 0.18) 0.035 (0.02) − 0.008 (− 0.18; 0.002) 0.084 (0.06) − 0.033 (− 0.063; − 0.003) a

0.11 (0.01; 0.22) a 2.4 (− 1.43; 6.21) 0.19 (− 0.12; 0.50) 0.13 (0.03; 0.23) a 3.1 (− 0.05; 6.34) 0.27 (0.01; 0.55) a 0.40 (− 2.27; 3.10) 0.09 (− 0.19; 0.39) 0.20 (0.05; 0.35) a 0.32 (0.04; 0.55) a − 0.53 (− 1.16; 0.09)

Data are displayed as mean (SD) or mean difference (95% confidence interval). a p b 0.05.

Fig. 2. Lung clearance index on admission and discharge (p = 0.14). Mean (SD) was 12.18 (2.98) versus 11.65 (2.67).

5. Discussion

mean (SD) length of hospital admission was 11.9 (3.2) days with a mean test interval between admission and discharge of 8.9 (2.9) days. Overall, n = 15 (55%) patients had a reduction in LCI and n = 18 (67%) had an improvement in FEV1. However, there was no significant association between change in LCI z-score and change in FEV1 z-score (p = 0.84) during the admission (Fig. 3). FEF25–75 improved significantly throughout the course of the admission when expressed in absolute terms and as z-scores (Table 2). None of sex, age, genotype, newborn screening, body mass index, pancreatic insufficiency or PsA infection was associated with the change in LCI during the admission (data not shown). All patients except one had LCI values that were above the upper limit of normal for children (i.e. N 8.3) at both admission and discharge [11]. Seven patients (27%) had normal spirometry (i.e. N− 2 z-scores) at admission and eight patients (30%) had normal spirometry on discharge.

The findings of our study echo those reported previously with regard to the heterogeneous response of LCI to antibiotic therapy during pulmonary exacerbations [5–7]. While there was a dramatic reduction in LCI for some, in many LCI remained relatively unchanged or even worsened. Overall, there was only a modest reduction in LCI by 0.53 (4.4%) across the group. This in is keeping with Horsley et al. who showed a 5.5% reduction in LCI, Robinson et al. (4.8%) and Yammine et al. (2.2%) [5–7]. Taken together, these results suggest that using LCI alone to gauge the short term clinical response to IV antibiotic therapy is inappropriate. Though the jury may still be out regarding the usefulness of alveolar phase III indices due to a lack of data, the limited evidence suggests a similar pattern of heterogeneity. While we were able to show than Sacin improved significantly and had a much larger reduction (28%) than LCI, this was primarily driven by a few significant responders. To further cloud the issue, Yammine et al. reported no significant difference in Sacin but that 47% of patients had worsened Scond by the end of their tune-up. Perhaps some other influential factors may be at play such as age,

Fig. 1. FEV1 z-score on admission and discharge (p = 0.21). Mean (SD) was −3.05 (1.58) versus −2.86 (1.60).

Fig. 3. Change in lung clearance index z-score versus change in FEV1 z-score (r = 0.04, p = 0.84).

Please cite this article as: Welsh L, et al, Lung clearance index during hospital admission in school-age children with cystic fibrosis, J Cyst Fibros (2014), http:// dx.doi.org/10.1016/j.jcf.2014.05.012

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L. Welsh et al. / Journal of Cystic Fibrosis xx (2014) xxx–xxx

disease severity and microbiological infection, but without further longitudinal study this question will remain unanswered. There are also several other plausible reasons which may help to explain the heterogeneous response seen in LCI, and indeed Sacin. In the presence of established lung disease, treatment with IV antibiotics and intense physiotherapy can lead to the recruitment of additional lung units not previously involved in LCI measurement. This may result in an increase in ventilation inhomogeneity if the time constants of the additional units are slower, when compared to those previously assessed. This premise has been neatly demonstrated by noting decreased gas trapping in patients with significant increases in LCI [5]. In further support of this, Yammine et al. reported that 58% of the variability associated with change in LCI could be explained by changes in gas trapping [7]. Additionally, it is also important to consider what a patient's LCI may have been like prior to hospitalisation. Given that LCI is not measured routinely in the outpatient setting, we do not have longitudinal data to determine the degree of change in the lead up to admission, or whether any change was acute or gradual. This type of information would provide valuable insight with regard to the state of the disease before hospitalisation. Importantly, a recent study showed that baseline LCI in children and adolescents with CF predicted the time to first exacerbation in 12 months after initial assessment. This may be where the utility of LCI actually sits rather than in the acute setting [11]. In a similar fashion to LCI, there was also a varied treatment response observed in FEV1. This is in keeping with several previous studies which have reported either a lack of improvement or worsening of FEV1 following IV antibiotic treatment [14–17]. Previous pulmonary exacerbations requiring hospitalisation, female gender, pancreatic insufficiency, persistent infection with PsA, and a greater drop from baseline before treatment initiation have all been associated with a poor response to therapy [14–17]. A third of our patients had PsA infection, and though we did not find it to significantly influence LCI or FEV outcomes in our group, this may be a reflection of the study power. Much of the literature has shown LCI to be a more sensitive measure of lung disease than spirometry [4,18–21] and our findings support this. All of our study patients (except one) had abnormal LCI values throughout their admission, while 27% and 30% were still considered to have normal spirometry at admission and discharge, respectively. Though our findings do not support the use of LCI during treatment of exacerbations, it may be a useful adjunct in those with mild disease who have normal spirometry for monitoring progression. This makes physiological sense when considering what LCI and FEV1 are actually measuring. FEV1 is more a measure of predominantly large airway function that can be masked by inhomogeneity of lung disease, whereas LCI provides information about global ventilation including the peripheral airways, which is where early, heterogeneous lung disease begins. While considering the periphery of the lung, it is important to note that of all the pulmonary function outcomes we examined, FEF25–75 was the most responsive to treatment. Both in absolute terms and when converted to z-scores, FEF25–75 improved significantly by the time of discharge. It is well recognised that

FEF25–75 is a more sensitive index than FEV1 for detecting small airway obstruction, however it is often overlooked because it has a higher degree of variability. Despite the inherent variability associated with flows versus lung volumes, it does appear to be better suited to monitoring response to treatment of exacerbations than even LCI. While we made every effort in our study to exclude any such treatment-effect, the influence that physiotherapy has on LCI measurement remains controversial. While Fuchs et al., concluded that there was no need to schedule LCI measurements in relation to physiotherapy sessions in children with CF [22], other reports have suggested that LCI can change remarkably following physiotherapy [23]. Importantly, these studies have been performed in a small number of patients with varying degrees of CF lung disease. We acknowledge that our study has several limitations. Our cohort encompassed a broad spectrum of severity which included patients with mild lung disease through to those in the end-stages. Though this approach was designed to reveal which classes of severity were more likely to be responders, the study was probably underpowered, given the relatively few participants, to adequately perform such sub-analysis. In addition, we do not have any data regarding the severity of the admission. Aside from mean length of stay (range 7–18 days), we are unable to speculate about the influence that admission severity may have had on treatment response. As more aggressive treatment generally becomes the norm, and specific knowledge regarding the detrimental effect of exacerbations accumulates, decisions to utilize intravenous antibiotics in their treatment are probably made for relatively mild exacerbations compared with the past, with resulting diminished opportunity to detect improvement in lung function. The interval between admission and discharge testing may also have been insufficient to realise the optimal benefit from therapy. A recent investigation showed that 25% patients never recovered their baseline lung function following a pulmonary exacerbation and that it took up to 3 months for some to regain their pre-admission levels [15]. In view of these findings, perhaps the benefit of IV antibiotics may not be fully appreciated until a month or more after discharge. This question requires further exploration. Finally, we need to acknowledge the 17 children who did not perform discharge testing. We recognise these data would have benefited the strength of our study but do not believe it harms the validity, as the characteristics of these children (including sex, age and lung function) were similar to the study group. Several children objected to the length of testing and voiced discomfort regarding a dry mouth. We believe these were the two key reasons for children not returning for their discharge appointment. Despite these shortcomings, our study also has several notable strengths. Nearly all baseline testing was performed within the first two days of hospital admission and therefore in sequence with treatment initiation. As a standard, all testing was performed either before or at least 2 h after physiotherapy to avoid any confounding effects on FRC and thereby LCI. Moreover, follow-up testing was performed just 1.7 days before discharge to maximize the potential response to therapy. In summary, although relative change in LCI was slightly greater than that for FEV when expressed as z-scores, our findings do not support the use of either to gauge the short term

Please cite this article as: Welsh L, et al, Lung clearance index during hospital admission in school-age children with cystic fibrosis, J Cyst Fibros (2014), http:// dx.doi.org/10.1016/j.jcf.2014.05.012

L. Welsh et al. / Journal of Cystic Fibrosis xx (2014) xxx–xxx

clinical response to IV antibiotic therapy in school-age children with cystic fibrosis. Of spirometry measurements, closer attention should be paid to forced mid-expiratory flow measurements. There appears to be an urgent need to collect longitudinal data in both inpatient and outpatient settings to better describe the role of LCI for monitoring response to treatment in relation to baseline. Acknowledgements The authors wish to thank the patients and families who participated in this research and would also like to acknowledge Ms Anna Wight who assisted with some data entries on this project. References [1] Hoo AF, Thia LP, Nguyen TT, Bush A, Chudleigh J, Lum S, London Cystic Fibrosis C., et al. Lung function is abnormal in 3-month-old infants with cystic fibrosis diagnosed by newborn screening. Thorax 2012;67:874–81. [2] Stick SM, Brennan S, Murray C, Douglas T, von Ungern-Sternberg BS, Garratt LW, Australian Respiratory Early Surveillance Team for Cystic F., et al. Bronchiectasis in infants and preschool children diagnosed with cystic fibrosis after newborn screening. J Pediatr 2009;155(e621):623–8. [3] Welsh L, Robertson CF, Ranganathan SC. Increased rate of lung function decline in Australian adolescents with cystic fibrosis. Pediatr Pulmonol 2013. http://dx.doi.org/10.1002/ppul.22946 (in press). [4] Aurora P, Stanojevic S, Wade A, Oliver C, Kozlowska W, Lum S, London Cystic Fibrosis C., et al. Lung clearance index at 4 years predicts subsequent lung function in children with cystic fibrosis. Am J Respir Crit Care Med 2011;183:752–8. [5] 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. [6] Horsley AR, Davies JC, Gray RD, Macleod KA, Donovan J, Aziz ZA, et al. Changes in physiological, functional and structural markers of cystic fibrosis lung disease with treatment of a pulmonary exacerbation. Thorax 2013;68:532–9. [7] 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. [8] Welsh L, Tomai M, Tran H, Ranganathan S. Lung clearance index during pulmonary exacerbation in school-age children with cystic fibrosis. European Respiratory Society Annual Congress. Barcelona, Spain: European Respiratory Journal; 2013.

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[9] Cole TJ, Freeman JV, Preece MA. British 1990 growth reference centiles for weight, height, body mass index and head circumference fitted by maximum penalized likelihood. Stat Med 1998;17:407–29. [10] Robinson PD, Latzin P, Verbanck S, Hall GL, Horsley A, Gappa M, et al. Consensus statement for inert gas washout measurement using multipleand single-breath tests. Eur Respir J 2013;41:507–22. [11] Vermeulen F, Proesmans M, Boon M, Havermans T, De Boeck K. Lung clearance index predicts pulmonary exacerbations in young patients with cystic fibrosis. Thorax 2014;69:39–45. [12] Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation of spirometry. Eur Respir J 2005;26:319–38. [13] Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, et al. Multi-ethnic reference values for spirometry for the 3–95-yr age range: the global lung function 2012 equations. Eur Respir J 2012;40:1324–43. [14] Ordonez CL, Henig NR, Mayer-Hamblett N, Accurso FJ, Burns JL, Chmiel JF, et al. Inflammatory and microbiologic markers in induced sputum after intravenous antibiotics in cystic fibrosis. Am J Respir Crit Care Med 2003;168:1471–5. [15] Sanders DB, Bittner RC, Rosenfeld M, Hoffman LR, Redding GJ, Goss CH. Failure to recover to baseline pulmonary function after cystic fibrosis pulmonary exacerbation. Am J Respir Crit Care Med 2010;182:627–32. [16] Sanders DB, Hoffman LR, Emerson J, Gibson RL, Rosenfeld M, Redding GJ, et al. Return of FEV1 after pulmonary exacerbation in children with cystic fibrosis. Pediatr Pulmonol 2010;45:127–34. [17] Smith AL, Fiel SB, Mayer-Hamblett N, Ramsey B, Burns JL. Susceptibility testing of Pseudomonas aeruginosa isolates and clinical response to parenteral antibiotic administration: lack of association in cystic fibrosis. Chest 2003;123:1495–502. [18] Aurora P, Bush A, Gustafsson P, Oliver C, Wallis C, Price J, London Cystic Fibrosis C., et al. Multiple-breath washout as a marker of lung disease in preschool children with cystic fibrosis. Am J Respir Crit Care Med 2005;171:249–56. [19] Aurora P, Gustafsson P, Bush A, Lindblad A, Oliver C, Wallis CE, et al. Multiple breath inert gas washout as a measure of ventilation distribution in children with cystic fibrosis. Thorax 2004;59:1068–73. [20] Gustafsson PM, Aurora P, Lindblad A. Evaluation of ventilation maldistribution as an early indicator of lung disease in children with cystic fibrosis. Eur Respir J 2003;22:972–9. [21] Horsley AR, Gustafsson PM, Macleod KA, Saunders C, Greening AP, Porteous DJ, et al. Lung clearance index is a sensitive, repeatable and practical measure of airways disease in adults with cystic fibrosis. Thorax 2008;63:135–40. [22] Fuchs SI, Toussaint S, Edlhaimb B, Ballmann M, Gappa M. Short-term effect of physiotherapy on variability of the lung clearance index in children with cystic fibrosis. Pediatr Pulmonol 2010;45:301–6. [23] Pfleger A, Steinbacher E, Weinhandl M, Wagner E, Eber E. Short-term effects of physiotherapy on ventilation inhomogeneity in cystic fibrosis patients with moderate to severe lung disease. European Respiratory Society Annual Congress. Barcelona, Spain: European Respiratory Journal; 2013.

Please cite this article as: Welsh L, et al, Lung clearance index during hospital admission in school-age children with cystic fibrosis, J Cyst Fibros (2014), http:// dx.doi.org/10.1016/j.jcf.2014.05.012

Lung clearance index during hospital admission in school-age children with cystic fibrosis.

There is currently limited information regarding lung clearance index (LCI) and its response to treatment of pulmonary exacerbations in CF. We aimed t...
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