Lung clearance index short-term variability in cystic fibrosis. A pre-post pulmonary exacerbation study.

Lung clearance index short-term variability in cystic fibrosis. 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A pre-post pulmonary exacerbation study. Matteo De Marchis, Enza Montemitro, Alessandra Boni, Alessandra Federici, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3136515/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 17 Jan, 2024 Read the published version in Italian Journal of Pediatrics → Version 1 posted 4 You are reading this latest preprint version Abstract Background: Multiple Breath washout (MBW) represents an important tool to detect early a possible pulmonary exacerbation especially in Cystic Fibrosis (CF) disease. Lung clearance index (LCI) is the most commonly reported multiple breath washout (MBW) index and in the last years was used as management measure for evaluation. Our aim was to analyze clinical utility of LCI index variability in pulmonary exacerbation in CF after intravenous (IV) antibiotic therapy. Methods: A single-center study was conducted at CF Unit of Bambino Gesù Children’s Hospital among hospitalized > 3 years patients for pulmonary exacerbations and treated with antibiotic IV treatment for 14 days. MBW and spirometry were evaluated within 72 hours of admission to hospital and at the end of hospitalization. Descriptive analysis was conducted and correlations between quantitative variables were investigated. Results: Fifty-seven patients (M22/F35) with an average age 18.56 (± 8.54) years were enrolled. LCI2.5 was significantly reduced at the end of antibiotic treatment in both pediatric and adult populations with an average reduction of -6,99%; 37/57 patients denoted an improvement, 20/57 are stable or worsened in LCI2.5 values and 4/57 (7.02%) had a significant deterioration (>15%) at end of treatment. On the contrary a significative elevation of FEV1% and FVC% were found, respectively of +7,30% and of +5,46%. A positive good correlection among LCI 2.5 and Scond (rho= +0,615, p=0.000) and LCI 2.5 and Sacin (rho=+0,649, p=0.000) and a negative strong correlation between FEV1% and LCI 2.5 were found in post treatment period. A similar modification of LCI 2.5 and FEV1 was noticed in both adult and pediatric population. Conclusions: LCI may have a role in the routine clinical care of both adult and pediatric CF patients as a good tool to assess response to IV antibiotic end-therapy in the same way as FEV1. cystic fibrosis lung clearance index multiple breath washout spirometry pulmonary exacerbation intravenous antibiotic therapy Background CF is the most common life-limiting autosomal recessive disease in Caucasian population, and is a complex multisystemic disorder caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), an ion channel which primarily regulates anion transport through cell surface. To date, more than 2000 mutations have been identified 1 . Functional failure of CFTR leads to multisystemic dysfunction, involving lungs, gastrointestinal tract, liver and pancreatic gland. Impaired mucociliary clearance and dense secretions primarily result in chronic pulmonary inflammation and infections, irreversible lung architecture modification, respiratory failure and death 2 . In the last decade, LCI started to be used in CF management as an efficacy endpoint in interventional trials thanks to its ability to effectively assess small airways disease both in preschool and middle-age children, when forced expiratory volume in 1 second (FEV1) is generally within normal range and CF lung disease still mild 3–5 . LCI is the most commonly reported MBW index in the pediatric literature and it is defined as the number of functional residual capacity lung turnovers required to reduce the alveolar concentration of a tracer-gas to a given fraction of its starting value, historically 1/40 (2.5%). A particular advantage of LCI in pediatric population is feasibility by passive cooperation and minimal coordination across all the pediatric age ranges 6 . Horsley et al. described Lung clearance index as a sensitive, repeatable and practical measure of airways disease also in adults with cystic fibrosis 7 . Despite being the gold standard for the assessment of pulmonary function in CF lung disease, FEV1 measurement through spirometry has been shown to be less sensitive than LCI in detecting early abnormalities and peripheral airways disease in CF 8 . LCI is an early marker of ventilation inhomogeneity, reflecting initial airways dysfunction in CF population with normal pulmonary function tests 9–10 and it is being recognized as a useful surrogate pulmonary outcome measure, especially in the new era of CFTR modulators, where new disease trajectories will require adequate clinical markers to characterize clinical phenotypes and monitor the efficacy of treatments 11–14 . LCI is a sensitive and feasible measures index (LCI) with strong intra-test and inter-test repeatability 15 . In CF, pulmonary exacerbations are crucial events which progressively determine a loss of respiratory function, worsening of the quality of life and negatively impact overall survival. According to studies, lung function fails to return to baseline value in up to 25% of CF pulmonary exacerbations, despite a prompt antibiotic treatment 16–17 . In contrast to studies in which FEV1 was used as primary outcome, consistently showing a positive treatment effect 18–21 , studies addressing LCI as outcome measure obtained heterogeneous results 22–24 . LCI significantly increases in patients with a pulmonary exacerbation, but LCI response to therapy for pulmonary exacerbations is heterogeneous and not completely clear in literature 25 . Our primary aim was to evaluate LCI index short-term delta-variability response in pulmonary exacerbation at end of antibiotic IV therapy. We also aimed to analyze the possible correlations between spirometry and LCI values post therapy course to support treatment variability. Methods Study design A pre-post single-center retrospective study according to STROBE statement checklist was conducted at the CF Centre of Bambino Gesù Pediatric Hospital, from September 2020 to February 2021. Fifty-eight consecutive CF patients eligible for antibiotic IV treatment with a Pulmonary exacerbation (PE) according to standard Fuchs’ criteria 26 , were enrolled. We included patients starting from 3 years of age. Exclusion criteria were FEV1 ≤ 40 %of predicted and chronic Burkholderia cepacia complex and Non-Tuberculous mycobateria airways infection to reduce cross infections and to reduce bias of advanced lung disease with possible reduced modifications. All study participants performed primarily multiple breath washout test and subsequently spirometric assessment within 72-hours from hospital admission for pulmonary exacerbation and at the end of IV antibiotic course. IV treatment was conducted entirely in hospital, according to the CF guidelines, providing 14 days of intravenous processing with standard chest daily physiotherapy pulmonary rehabilitation 27 . The study protocol was approved by the local ethics committee of Bambino Gesù Children’s Hospital (2819_OPBG_2022). A written informed consent was obtained from all eligible subjects or from their parents/guardians when necessary. Sample Size We conducted sample size calculations starting from previous study of Sonneveld N. et al 25 . To detect a difference of 0.3, considering 0.8 SD of differences, given a type I error of 0.05% and 80% power, 58 subjects were required for the analysis. Considering that pediatric population has proportionally milder disease and with FEV1 generally in the normal range, we decided to divide the population into pediatric and pre-adult age (PPaa) with 18 years age. Multiple-breath-washout MBW measurements were performed with a flow, volume and molecular mass measurement analyzer (EXHALYZER D, Ecomedics, Switzerland), according to ERS/ATS Consensus Guidelines by healthcare professional. A minimum of two acceptable MBW trials for each patient at each test evaluation. Washout repeats were excluded if there was evidence of a leak or a large difference between the LCI or functional residual capacity (FRC) measurements (> 25% from the median) 31 . Normal cut-off value of LCI was set at 7.1 according 3.3.1 software (ULN for LCI) 28,29 . Scond and Sacin, two MBW test secondary indexes of conductive airways and acinar zone respectively, collected during the measurements, were included in the analysis. Spirometry FEV1, forced vital capacity (FVC) and forced expiratory flow 25–75% (FEF25-75) were measured using standard spirometry following the ATS/ERS guidelines 30 with an ultrasound spirometer (Ecomedics, EXHALIZER-D software 3.3.1). Data were expressed in % predicted using the normative data from the Global Lung Function Initiative software (GLI 2012, Global Lung Function Initiative Task Force). Statistical analysis The collected data, related to demographic and clinical characteristics of patients, were presented as counts and proportions (categorical data) or mean, median, standard deviation (continuous data). The t-Student paired test was used to compare normally distributed continuous data and Wilcoxon signed-rank tests for data that are not normally distributed. In line with the secondary objectives of the study, correlations between quantitative variables were investigated using Pearson’s (parametric) or Spearman’s (non parametric) correlation coefficient. Considering a significance level of 0,05 Bonferroni corrected P-value has been determined on the basis of number of tests performed. The statistical elaboration of the data was performed using IBM SPSS Statistics (version 25). Results Fifty-seven patients with CF (M/F 22/35) were recruited; their mean age (± SD) was 18.56 ± 8.7 years for females and 18.57 ± 8.5 years for males. PPaa patients were 28/57 with a median age of 11,23 ± 3.95 years, and adult patients were 29/57 with a median age of 25,65 ± 5.01 years. The majority of the subjects in the sample were pancreatic insufficient and ΔF508 homozygous. Pseudomonas colonization was present in 44% of patients and 17% of sample subjects were treated by CFTR modulators. The demographic and anthropometric characteristics of the entire study sample are shown in Table 1 . Considering respiratory function at baseline, within the sample subjects had a moderate impairment with mean FEV1% of 73.48 (± 21,19) and mean LCI 2.5 of 12.85 (± 3.86) as shown in Table 2 . Modification after antibiotic IV therapy was statistically significative for FEV1% (p = 0.000), FVC% (p = 0.000) and for LCI 2.5 (p = 0.001); no differences were found for Sacin (p = 0.33) and Scond (p = 0.38). In particular, FEV1% + 7,30% and FVC % +5,46% variations instead a -6,99% reduction of LCI2.5 were found at end of antibiotic IV treatment. Regarding LCI 2.5, 37/57 patients showed an increase in LCI after therapy with an average of -8.41% while in 20/57 remained stable or worsened. Among total sample, 4/57 patients showed a significant deterioration > 15% in LCI 2.5 after antibiotic therapy. All differences in the measured pre and post antibiotic IV therapy respiratory parameters are shown in Table 2 . Table 1 Demographic and clinical characteristics of the study sample (57 patients). Demographic / clinical characteristic. . Value Sex (M/F) 22/35 ΔF508 homozygous (%) 15 ΔF508 heterozygous (%) 85 Age (yrs) ± SD 18.56 (8.54) Height (cm) ± SD 150.16 (20.63) Weight ± SD 46.11 (16.87) BMI ± SD 19.69 (3.49) Chronic pseudomonas aeruginosa colonization (%) 44% Pancreatic insufficiency (%) 96.5% Patients on CFTR modulator (%) 17% Table 2 Spirometry and multiple breath washout parameters of the study sample (mean value ± SD ); statistically significant changes in bold. Multiple Breath washout average values Pre (mean ± SD) Post (mean ± SD) Variation pre-post (%) LCI 2.5 12.85 (3.86) 12.01 (4.05) -6,99 LCI 5 7.72 (1.98) 7.34 (2.03) -5,18 Scond 0.08 (0.10) 0.07 (0.04) -14,29 Sacin 0.223 (0.16) 0.246 (0.20) + 9,35 Spirometric parameters Pre (mean ± SD) Post (mean ± SD) FEV1 (liters) 2.08 (0.85) 2.23 (0.89) + 6,73 FEV1% 73.48 (21,19) 79.27 (20.21) + 7,30 FVC (liters) 2.70 (1.06) 2.83 (1.13) + 4,59 FVC % 81.83 (16.67) 86.56 (16.43) + 5,46 FEF 25–75 (Liters/second) 1.99 (1.14) 2.07 (1.12) + 3,86 FEF 25–75% 62.3 (33.0) 67.2 (31.5) + 7,29 Regarding sub-classification of the sample, we noticed a similar modification after IV antibiotic treatment for PPaa and adult subjects in FEV1% (-6,36% vs -5,25%) and in LCI 2.5 (+ 1,06 vs + 0,62). Considering correlation, we noticed a positive good correlation among LCI 2.5 and Scond (rho = + 0.615, p = 0.000) and Sacin (rho = + 0.649, p = 0.000) in post treatment period, instead FEV1% and LCI 2.5 showed a negative strong correlation (rho= -0.78 with p = 0.000) after IV antibiotic therapy. Discussion According to our results, LCI values appear to significantly vary during the course of a PE in people with CF as an important tool to monitor response to end of antibiotic therapy as the same of spirometry. In particular, we demonstrate a significant correlation between the gold standard CF lung function parameter FEV1% and a small airways inhomogeneity index such as LCI 2.5. Also Hatziagorou et al. investigated the use of LCI to assess IV antibiotic treatment response with a significant improvement in most lung function parameters: LCI (p = 0.0001), FEV1% (p = 0.05), FEV1 z-score (p = 0.033) and FEF25-75 (p = 0.046). LCI decreased by a mean of 1.77 lung turnovers with an average decrease in LCI of 26% (p = 0.001) and average increase in FEV1% of 10.36% (p = 0.05) post IV therapy for PE 31 . These data are more encouraging than ours but the caseload is much smaller (32 patients) and the evaluation was performed one month after IV antibiotic therapy 30 . We may hypothesize that a more distant evaluation time from initiation of antibiotic therapy may better stabilize lung function. Our data are more in line with Robinson et al. that reported a LCI2.5 mean decrement of 0.48 lung turnovers with a 3.8% change and with Eef Vanderhelst that had described a significant decrease of 4.5% among only CF adult patients 22 . As reported in literature, we might hypothesize that in the pre-school population there is a greater variation in LCI post antibiotic treatment, with an average treatment effect of − 15.5% (95% CI − 25.4 to − 5.6) but in this data no distinction was made between acute PE and scheduled admission for IV therapy 30 . As reported in literature, under clinical stability conditions, the inter-individual variability of LCI was of 16%. Our data suggest the hypothesis that this variability during PE is reduced for the presence of inflammation, mucus and increased broncostriction 32,33 . Sacin and Scond are two values that are becoming more studied in literature, especially Sacin that reflects alveolar functionality, starting point of lung damage in CF disease. In contrast to Vanderhelst, our data demonstrate that LCI 2.5 correlates with both Sacin and Scond emphasizing how much in CF-PE both proximal and distal airways are affected 23 . In our setting, LCI2.5 and FEV1 are concordant in showing a statistically significant amelioration of lung function after an IV antibiotic therapy. Despite its limits, we suggest that LCI 2.5 may be adopted as an additional biomarker to assess lung function response to antibiotic therapy, at the end of PE. According our experience, we focused attention on 4 patients who showed a greater drop in LCI 2.5 (> 15%) and analyzing their clinical conditions we try to explain this anomalous trend. One of these patients had Allergic Bronchopulmonary Aspergillosis, spirometric indexes improved but LCI value did not respond; one pediatric patient did not respond probably for her severe anatomic compromission, with computed tomography confirming severe atelectasis in upper lobe of the right lung. Two adult women patients from starting to the end of hospitalization preserved more or less the same spirometric values, including FEF 25–75% for small airways, despite primary value of LCI 2.5 and secondary inhomogeneity parameters had a severe worsening. About our experience and expertise on administration of MBW we tried to explain this no response; one of the possibilities was performing hypertonic solution or Dornase alfa shortly before the execution of test with an increased mobilization of mucus and poor compliance of some patients with daily respiratory physiotherapy. A major limitation to our study is the lack of a baseline LCI 2.5 value in well-being due to SARS-CoV-2 pandemic with reduction of outpatient evalutations and of the routine availability of Exhalyzer –D in our center only after March, 2020. Among limitations were the lack of knowledge about aerosol therapy treatment (Dornase alfa, hypertonic solution, bronchodilators) performed during the hospitalization for IV antibiotic treatment, and the typology of chest physiotherapy administered by respiratory therapists. Sovrainfections could represent another possible bias factor that prevented improvements of LCI 2.5 values. The variability of LCI response for each patient (improvement vs stability vs worsening) could be explained by the precence of hypothetical different clusters of PE in CF, as recently reported in the literature for adult patients, but further studies are needed to prove this hypothesis 34 . Conclusions In conclusion, our study shows that LCI is a valid tool to monitor antibiotic responses in PE in CF in the same way as the FEV1%, with the advantages of being easy to perform especially in pediatric population. We can assume that LCI will be used in conjunction with the clinic, to be evaluated end of antibiotic cycle to make any treatment implementations or total changes. Future long-term studies are needed to confirm these findings and to identify an agreed change to monitor response to therapy. Declarations Ethics approval and consent to participate Local ethics committees of Bambino Gesù Children’s Hospital approved the study (n° 2819_OPBG_2022). Parental consent was not required because this is a retrospective study and data were anonymized. Written infomed consents were obtained by parents of patients (all under the age of 16). All methods of this study were carried out in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Consent for publication Written informed consents for publication of the data in an anonymous and aggregated form were obtained. Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding This work was supported also by the Italian Ministry of Health with current research funds. Authors’ contributions MDM, EM and LC conceived the study. MDM and AB wrote the manuscript. MDM, LC and AF collected data. DDG analyzed all data with statical analysis. RC and AGF conceived and directed the work thanks to their knowledge of the subject matter. All authors analyzed and interpreted patients’ data, read and approved the final manuscript. Acknowledgements Thanks in particular to Carla Viscomi and Nicoleta Popa for the organization of the management of patients to be evaluated especially for the attention of cross-infection considering microbiology segregations in our day-hospital References Cystic fibrosis mutation database. 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Svedberg M, Gustafsson PM, Robinson PD, Rosberg M, Lindblad A. Variability of lung clearance index in clinically stable cystic fibrosis lung disease in school age children. J Cyst Fibros. 2018 Mar;17(2):236–41. Dong K, Huh SM, Lam GY, Jang J, Franciosi AN, Wilcox PG et al. Pulmonary exacerbation inflammatory phenotypes in adults with cystic fibrosis. J Cyst Fibros 2022 Dec 24:S1569-1993(22)01433-3. Cite Share Download PDF Status: Published Journal Publication published 17 Jan, 2024 Read the published version in Italian Journal of Pediatrics → Version 1 posted Reviewers agreed at journal 12 Jul, 2023 Reviewers invited by journal 12 Jul, 2023 Editor assigned by journal 12 Jul, 2023 First submitted to journal 07 Jul, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3136515","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":217987223,"identity":"f9798c07-b672-479a-84a7-9cc529c35324","order_by":0,"name":"Matteo De Marchis","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEUlEQVRIiWNgGAWjYBADxgYIKcHAz8DARkAxM1g1QotkA1QLD5FaGBgMDhDQott+/viDDxUMsv1ih599+LnDwt74eO+xh18Y7sjZ49BidiaZsXHGGQbjmbPTjGf2npFI3HbmXLqxDMMzY1y2mB1IZmzmbWNI3HA7wZiZsU0iwexGjpm0BMPhxB5cWs4/Zmz+C9Sy/3b6Z5AWe+MZEC31OLXcANrCCLJFOgdsC+MGiRwzyQ8MhxNwOuzGY8OZPWckjGfczilm7G2TSJwB8guDwWHDngO4HJb44MOPChvZ/tnpmxl+ttXZ87cDQ+xHxWF59gYc1kCABDKHh4GZxwCvcgzAw8D4gzQdo2AUjIJRMLwBAOCaXPg0j/HRAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-7527-9964","institution":"Bambino Gesu Pediatric Hospital: Ospedale Pediatrico Bambino Gesu","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Matteo","middleName":"","lastName":"De Marchis","suffix":""},{"id":217987224,"identity":"cee524b6-9617-417d-9090-63c2ef712939","order_by":1,"name":"Enza Montemitro","email":"","orcid":"","institution":"Bambino Gesu Pediatric Hospital: Ospedale Pediatrico Bambino Gesu","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Enza","middleName":"","lastName":"Montemitro","suffix":""},{"id":217987225,"identity":"8b0a8969-f79d-43af-8f3e-62ed250b4348","order_by":2,"name":"Alessandra Boni","email":"","orcid":"","institution":"Bambino Gesu Pediatric Hospital: Ospedale Pediatrico Bambino Gesu","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Alessandra","middleName":"","lastName":"Boni","suffix":""},{"id":217987226,"identity":"2e51e4be-adab-4a40-8cbe-6fb8fe7a0a5b","order_by":3,"name":"Alessandra Federici","email":"","orcid":"","institution":"Bambino Gesu Pediatric Hospital: Ospedale Pediatrico Bambino Gesu","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Alessandra","middleName":"","lastName":"Federici","suffix":""},{"id":217987227,"identity":"69320bb2-17e5-4acd-aed3-7f1c264bbf56","order_by":4,"name":"Daniele Di Giovanni","email":"","orcid":"","institution":"University of Rome Tor Vergata Department of Industrial Engineering: Universita degli Studi di Roma Tor Vergata Dipartimento di Ingegneria Industriale","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Daniele","middleName":"Di","lastName":"Giovanni","suffix":""},{"id":217987228,"identity":"a5a60cc3-5bd8-40a2-9146-488c7c6394b2","order_by":5,"name":"Luca Cristiani","email":"","orcid":"","institution":"Bambino Gesu Pediatric Hospital: Ospedale Pediatrico Bambino Gesu","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Luca","middleName":"","lastName":"Cristiani","suffix":""},{"id":217987229,"identity":"c4b322a4-dac8-43d9-ada4-b925d64d7e78","order_by":6,"name":"Renato Cutrera","email":"","orcid":"","institution":"Bambino Gesu Pediatric Hospital: Ospedale Pediatrico Bambino Gesu","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Renato","middleName":"","lastName":"Cutrera","suffix":""},{"id":217987230,"identity":"2f6e8546-234e-4359-bb83-6228458a8708","order_by":7,"name":"Alessandro G. Fiocchi","email":"","orcid":"","institution":"Bambino Gesu Pediatric Hospital: Ospedale Pediatrico Bambino Gesu","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Alessandro","middleName":"G.","lastName":"Fiocchi","suffix":""}],"badges":[],"createdAt":"2023-07-03 17:52:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3136515/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3136515/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13052-023-01574-w","type":"published","date":"2024-01-17T15:01:40+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":49979074,"identity":"b319c1b5-0116-4938-98a6-e01e889ce610","added_by":"auto","created_at":"2024-01-22 15:10:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":326639,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3136515/v1/7e1c602d-1b82-4347-9be8-1fa4635996d8.pdf"}],"financialInterests":"","formattedTitle":"Lung clearance index short-term variability in cystic fibrosis. A pre-post pulmonary exacerbation study.","fulltext":[{"header":"Background","content":"\u003cp\u003eCF is the most common life-limiting autosomal recessive disease in Caucasian population, and is a complex multisystemic disorder caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), an ion channel which primarily regulates anion transport through cell surface. To date, more than 2000 mutations have been identified \u003csup\u003e1\u003c/sup\u003e. Functional failure of CFTR leads to multisystemic dysfunction, involving lungs, gastrointestinal tract, liver and pancreatic gland. Impaired mucociliary clearance and dense secretions primarily result in chronic pulmonary inflammation and infections, irreversible lung architecture modification, respiratory failure and death \u003csup\u003e2\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn the last decade, LCI started to be used in CF management as an efficacy endpoint in interventional trials thanks to its ability to effectively assess small airways disease both in preschool and middle-age children, when forced expiratory volume in 1 second (FEV1) is generally within normal range and CF lung disease still mild \u003csup\u003e3\u0026ndash;5\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eLCI is the most commonly reported MBW index in the pediatric literature and it is defined as the number of functional residual capacity lung turnovers required to reduce the alveolar concentration of a tracer-gas to a given fraction of its starting value, historically 1/40 (2.5%). A particular advantage of LCI in pediatric population is feasibility by passive cooperation and minimal coordination across all the pediatric age ranges \u003csup\u003e6\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHorsley et al. described Lung clearance index as a sensitive, repeatable and practical measure of airways disease also in adults with cystic fibrosis\u003csup\u003e7\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eDespite being the gold standard for the assessment of pulmonary function in CF lung disease, FEV1 measurement through spirometry has been shown to be less sensitive than LCI in detecting early abnormalities and peripheral airways disease in CF \u003csup\u003e8\u003c/sup\u003e. LCI is an early marker of ventilation inhomogeneity, reflecting initial airways dysfunction in CF population with normal pulmonary function tests \u003csup\u003e9\u0026ndash;10\u003c/sup\u003e and it is being recognized as a useful surrogate pulmonary outcome measure, especially in the new era of CFTR modulators, where new disease trajectories will require adequate clinical markers to characterize clinical phenotypes and monitor the efficacy of treatments \u003csup\u003e11\u0026ndash;14\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eLCI is a sensitive and feasible measures index (LCI) with strong intra-test and inter-test repeatability \u003csup\u003e15\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn CF, pulmonary exacerbations are crucial events which progressively determine a loss of respiratory function, worsening of the quality of life and negatively impact overall survival. According to studies, lung function fails to return to baseline value in up to 25% of CF pulmonary exacerbations, despite a prompt antibiotic treatment \u003csup\u003e16\u0026ndash;17\u003c/sup\u003e. In contrast to studies in which FEV1 was used as primary outcome, consistently showing a positive treatment effect \u003csup\u003e18\u0026ndash;21\u003c/sup\u003e, studies addressing LCI as outcome measure obtained heterogeneous results \u003csup\u003e22\u0026ndash;24\u003c/sup\u003e. LCI significantly increases in patients with a pulmonary exacerbation, but LCI response to therapy for pulmonary exacerbations is heterogeneous and not completely clear in literature\u003csup\u003e25\u003c/sup\u003e .\u003c/p\u003e \u003cp\u003eOur primary aim was to evaluate LCI index short-term delta-variability response in pulmonary exacerbation at end of antibiotic IV therapy. We also aimed to analyze the possible correlations between spirometry and LCI values post therapy course to support treatment variability.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003e A pre-post single-center retrospective study according to STROBE statement checklist was conducted at the CF Centre of Bambino Ges\u0026ugrave; Pediatric Hospital, from September 2020 to February 2021. Fifty-eight consecutive CF patients eligible for antibiotic IV treatment with a Pulmonary exacerbation (PE) according to standard Fuchs\u0026rsquo; criteria \u003csup\u003e26\u003c/sup\u003e, were enrolled. We included patients starting from 3 years of age. Exclusion criteria were FEV1\u0026thinsp;\u0026le;\u0026thinsp;40 %of predicted and chronic Burkholderia cepacia complex and Non-Tuberculous mycobateria airways infection to reduce cross infections and to reduce bias of advanced lung disease with possible reduced modifications. All study participants performed primarily multiple breath washout test and subsequently spirometric assessment within 72-hours from hospital admission for pulmonary exacerbation and at the end of IV antibiotic course. IV treatment was conducted entirely in hospital, according to the CF guidelines, providing 14 days of intravenous processing with standard chest daily physiotherapy pulmonary rehabilitation \u003csup\u003e27\u003c/sup\u003e. The study protocol was approved by the local ethics committee of Bambino Ges\u0026ugrave; Children\u0026rsquo;s Hospital (2819_OPBG_2022). A written informed consent was obtained from all eligible subjects or from their parents/guardians when necessary.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eSample Size\u003c/h2\u003e \u003cp\u003eWe conducted sample size calculations starting from previous study of Sonneveld N. et al \u003csup\u003e25\u003c/sup\u003e. To detect a difference of 0.3, considering 0.8 SD of differences, given a type I error of 0.05% and 80% power, 58 subjects were required for the analysis. Considering that pediatric population has proportionally milder disease and with FEV1 generally in the normal range, we decided to divide the population into pediatric and pre-adult age (PPaa) with \u0026lt;\u0026thinsp;18 years and adult population with \u0026gt;\u0026thinsp;18 years age.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eMultiple-breath-washout\u003c/h2\u003e \u003cp\u003e MBW measurements were performed with a flow, volume and molecular mass measurement analyzer (EXHALYZER D, Ecomedics, Switzerland), according to ERS/ATS Consensus Guidelines by healthcare professional. A minimum of two acceptable MBW trials for each patient at each test evaluation. Washout repeats were excluded if there was evidence of a leak or a large difference between the LCI or functional residual capacity (FRC) measurements (\u0026gt;\u0026thinsp;25% from the median) \u003csup\u003e31\u003c/sup\u003e. Normal cut-off value of LCI was set at 7.1 according 3.3.1 software (ULN for LCI) \u003csup\u003e28,29\u003c/sup\u003e. Scond and Sacin, two MBW test secondary indexes of conductive airways and acinar zone respectively, collected during the measurements, were included in the analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eSpirometry\u003c/h2\u003e \u003cp\u003eFEV1, forced vital capacity (FVC) and forced expiratory flow 25\u0026ndash;75% (FEF25-75) were measured using standard spirometry following the ATS/ERS guidelines\u003csup\u003e30\u003c/sup\u003e with an ultrasound spirometer (Ecomedics, EXHALIZER-D software 3.3.1). Data were expressed in % predicted using the normative data from the Global Lung Function Initiative software (GLI 2012, Global Lung Function Initiative Task Force).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe collected data, related to demographic and clinical characteristics of patients, were presented as counts and proportions (categorical data) or mean, median, standard deviation (continuous data). The t-Student paired test was used to compare normally distributed continuous data and Wilcoxon signed-rank tests for data that are not normally distributed. In line with the secondary objectives of the study, correlations between quantitative variables were investigated using Pearson\u0026rsquo;s (parametric) or Spearman\u0026rsquo;s (non parametric) correlation coefficient. Considering a significance level of 0,05 Bonferroni corrected P-value has been determined on the basis of number of tests performed. The statistical elaboration of the data was performed using IBM SPSS Statistics (version 25).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eFifty-seven patients with CF (M/F 22/35) were recruited; their mean age (\u0026plusmn;\u0026thinsp;SD) was 18.56\u0026thinsp;\u0026plusmn;\u0026thinsp;8.7 years for females and 18.57\u0026thinsp;\u0026plusmn;\u0026thinsp;8.5 years for males. PPaa patients were 28/57 with a median age of 11,23\u0026thinsp;\u0026plusmn;\u0026thinsp;3.95 years, and adult patients were 29/57 with a median age of 25,65\u0026thinsp;\u0026plusmn;\u0026thinsp;5.01 years. The majority of the subjects in the sample were pancreatic insufficient and ΔF508 homozygous. Pseudomonas colonization was present in 44% of patients and 17% of sample subjects were treated by CFTR modulators. The demographic and anthropometric characteristics of the entire study sample are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eConsidering respiratory function at baseline, within the sample subjects had a moderate impairment with mean FEV1% of 73.48 (\u0026plusmn;\u0026thinsp;21,19) and mean LCI 2.5 of 12.85 (\u0026plusmn;\u0026thinsp;3.86) as shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Modification after antibiotic IV therapy was statistically significative for FEV1% (p\u0026thinsp;=\u0026thinsp;0.000), FVC% (p\u0026thinsp;=\u0026thinsp;0.000) and for LCI 2.5 (p\u0026thinsp;=\u0026thinsp;0.001); no differences were found for Sacin (p\u0026thinsp;=\u0026thinsp;0.33) and Scond (p\u0026thinsp;=\u0026thinsp;0.38). In particular, FEV1% + 7,30% and FVC % +5,46% variations instead a -6,99% reduction of LCI2.5 were found at end of antibiotic IV treatment.\u003c/p\u003e \u003cp\u003eRegarding LCI 2.5, 37/57 patients showed an increase in LCI after therapy with an average of -8.41% while in 20/57 remained stable or worsened. Among total sample, 4/57 patients showed a significant deterioration\u0026thinsp;\u0026gt;\u0026thinsp;15% in LCI 2.5 after antibiotic therapy.\u003c/p\u003e \u003cp\u003eAll differences in the measured pre and post antibiotic IV therapy respiratory parameters are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eDemographic and clinical characteristics of the study sample (57 patients).\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDemographic / clinical characteristic. .\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eValue\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (M/F)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22/35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eΔF508 homozygous (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eΔF508 heterozygous (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e85\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (yrs)\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18.56 (8.54)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeight (cm)\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e150.16 (20.63)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46.11 (16.87)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19.69 (3.49)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic pseudomonas aeruginosa colonization (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e44%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePancreatic insufficiency (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e96.5%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePatients on CFTR modulator (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSpirometry and multiple breath washout parameters of the study sample (mean value\u0026thinsp;\u0026plusmn;\u0026thinsp;SD ); statistically significant changes in bold.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultiple Breath washout average values\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePre (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePost (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eVariation pre-post (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLCI 2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12.85 (3.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12.01 (4.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e-6,99\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLCI 5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.72 (1.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.34 (2.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-5,18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eScond\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.08 (0.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.07 (0.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-14,29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSacin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.223 (0.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.246 (0.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;9,35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSpirometric parameters\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003ePre (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003ePost (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFEV1 (liters)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.08 (0.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.23 (0.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;6,73\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFEV1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e73.48 (21,19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e79.27 (20.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e+\u0026thinsp;7,30\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFVC (liters)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.70 (1.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.83 (1.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;4,59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFVC %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e81.83 (16.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e86.56 (16.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e+\u0026thinsp;5,46\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFEF 25\u0026ndash;75 (Liters/second)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.99 (1.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.07 (1.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;3,86\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFEF 25\u0026ndash;75%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62.3 (33.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67.2 (31.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e+\u0026thinsp;7,29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eRegarding sub-classification of the sample, we noticed a similar modification after IV antibiotic treatment for PPaa and adult subjects in FEV1% (-6,36% vs -5,25%) and in LCI 2.5 (+\u0026thinsp;1,06 vs\u0026thinsp;+\u0026thinsp;0,62).\u003c/p\u003e \u003cp\u003eConsidering correlation, we noticed a positive good correlation among LCI 2.5 and Scond (rho\u0026thinsp;=\u0026thinsp;+\u0026thinsp;0.615, p\u0026thinsp;=\u0026thinsp;0.000) and Sacin (rho\u0026thinsp;=\u0026thinsp;+\u0026thinsp;0.649, p\u0026thinsp;=\u0026thinsp;0.000) in post treatment period, instead FEV1% and LCI 2.5 showed a negative strong correlation (rho= -0.78 with p\u0026thinsp;=\u0026thinsp;0.000) after IV antibiotic therapy.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAccording to our results, LCI values appear to significantly vary during the course of a PE in people with CF as an important tool to monitor response to end of antibiotic therapy as the same of spirometry. In particular, we demonstrate a significant correlation between the gold standard CF lung function parameter FEV1% and a small airways inhomogeneity index such as LCI 2.5.\u003c/p\u003e \u003cp\u003eAlso Hatziagorou et al. investigated the use of LCI to assess IV antibiotic treatment response with a significant improvement in most lung function parameters: LCI (p\u0026thinsp;=\u0026thinsp;0.0001), FEV1% (p\u0026thinsp;=\u0026thinsp;0.05), FEV1 z-score (p\u0026thinsp;=\u0026thinsp;0.033) and FEF25-75 (p\u0026thinsp;=\u0026thinsp;0.046). LCI decreased by a mean of 1.77 lung turnovers with an average decrease in LCI of 26% (p\u0026thinsp;=\u0026thinsp;0.001) and average increase in FEV1% of 10.36% (p\u0026thinsp;=\u0026thinsp;0.05) post IV therapy for PE\u003csup\u003e31\u003c/sup\u003e. These data are more encouraging than ours but the caseload is much smaller (32 patients) and the evaluation was performed one month after IV antibiotic therapy\u003csup\u003e30\u003c/sup\u003e. We may hypothesize that a more distant evaluation time from initiation of antibiotic therapy may better stabilize lung function.\u003c/p\u003e \u003cp\u003eOur data are more in line with Robinson et al. that reported a LCI2.5 mean decrement of 0.48 lung turnovers with a 3.8% change and with Eef Vanderhelst that had described a significant decrease of 4.5% among only CF adult patients \u003csup\u003e22\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAs reported in literature, we might hypothesize that in the pre-school population there is a greater variation in LCI post antibiotic treatment, with an average treatment effect of \u0026minus;\u0026thinsp;15.5% (95% CI \u0026minus;\u0026thinsp;25.4 to \u0026minus;\u0026thinsp;5.6) but in this data no distinction was made between acute PE and scheduled admission for IV therapy\u003csup\u003e30\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAs reported in literature, under clinical stability conditions, the inter-individual variability of LCI was of 16%. Our data suggest the hypothesis that this variability during PE is reduced for the presence of inflammation, mucus and increased broncostriction \u003csup\u003e32,33\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSacin and Scond are two values that are becoming more studied in literature, especially Sacin that reflects alveolar functionality, starting point of lung damage in CF disease. In contrast to Vanderhelst, our data demonstrate that LCI 2.5 correlates with both Sacin and Scond emphasizing how much in CF-PE both proximal and distal airways are affected \u003csup\u003e23\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn our setting, LCI2.5 and FEV1 are concordant in showing a statistically significant amelioration of lung function after an IV antibiotic therapy. Despite its limits, we suggest that LCI 2.5 may be adopted as an additional biomarker to assess lung function response to antibiotic therapy, at the end of PE.\u003c/p\u003e \u003cp\u003eAccording our experience, we focused attention on 4 patients who showed a greater drop in LCI 2.5 (\u0026gt;\u0026thinsp;15%) and analyzing their clinical conditions we try to explain this anomalous trend. One of these patients had Allergic Bronchopulmonary Aspergillosis, spirometric indexes improved but LCI value did not respond; one pediatric patient did not respond probably for her severe anatomic compromission, with computed tomography confirming severe atelectasis in upper lobe of the right lung. Two adult women patients from starting to the end of hospitalization preserved more or less the same spirometric values, including FEF 25\u0026ndash;75% for small airways, despite primary value of LCI 2.5 and secondary inhomogeneity parameters had a severe worsening.\u003c/p\u003e \u003cp\u003eAbout our experience and expertise on administration of MBW we tried to explain this no response; one of the possibilities was performing hypertonic solution or Dornase alfa shortly before the execution of test with an increased mobilization of mucus and poor compliance of some patients with daily respiratory physiotherapy.\u003c/p\u003e \u003cp\u003eA major limitation to our study is the lack of a baseline LCI 2.5 value in well-being due to SARS-CoV-2 pandemic with reduction of outpatient evalutations and of the routine availability of Exhalyzer \u0026ndash;D in our center only after March, 2020. Among limitations were the lack of knowledge about aerosol therapy treatment (Dornase alfa, hypertonic solution, bronchodilators) performed during the hospitalization for IV antibiotic treatment, and the typology of chest physiotherapy administered by respiratory therapists. Sovrainfections could represent another possible bias factor that prevented improvements of LCI 2.5 values.\u003c/p\u003e \u003cp\u003eThe variability of LCI response for each patient (improvement vs stability vs worsening) could be explained by the precence of hypothetical different clusters of PE in CF, as recently reported in the literature for adult patients, but further studies are needed to prove this hypothesis \u003csup\u003e34\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, our study shows that LCI is a valid tool to monitor antibiotic responses in PE in CF in the same way as the FEV1%, with the advantages of being easy to perform especially in pediatric population. We can assume that LCI will be used in conjunction with the clinic, to be evaluated end of antibiotic cycle to make any treatment implementations or total changes. Future long-term studies are needed to confirm these findings and to identify an agreed change to monitor response to therapy.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e Local ethics committees of Bambino Gesù Children’s Hospital approved the study (n° 2819_OPBG_2022). Parental consent was not required because this is a retrospective study and data were anonymized. Written infomed consents were obtained by parents of patients (all under the age of 16). All methods of this study were carried out in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e Written informed consents for publication of the data in an anonymous and aggregated form were obtained.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003eThis work was supported also by the Italian Ministry of Health with current research funds.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions\u0026nbsp;\u003c/strong\u003eMDM, EM and LC conceived the study. MDM and AB wrote the manuscript. MDM, LC and AF collected data. DDG analyzed all data with statical analysis.\u0026nbsp;RC and AGF conceived and directed the work thanks to their knowledge of the subject matter.\u0026nbsp;All authors analyzed and interpreted patients’ data, read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003eThanks in particular to Carla Viscomi and Nicoleta Popa for the organization of the management of patients to be evaluated especially for the attention of cross-infection considering microbiology segregations in our day-hospital\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCystic fibrosis mutation database. Hospital for Sick Children, Toronto. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003c/span\u003e\u003cspan address=\"http://www.genet.sickkids.on.ca\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed September 29, 2018.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStoltz A, Meyerholz DA, Welsh DKJ. MJ, Origins of cystic fibrosis lung disease N Engl J Med 2015 Jan 22;372(4):351 \u0026ndash; 62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBouhuys A, van Lennep H. Effect of body posture on gas distribution in the lungs. J Appl Physiol. 1962 Jan;17:38\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSutharsan S, Edward F, McKone,Downey DG, Duckers J, MacGregor G, Tullis E, et al. 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Chest. 2012 Feb;141(2):485\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCollaco JM, Green DM, Cutting GR, Naughton KM, Peter J, Mogayzel Jr. Location and duration of treatment of cystic fibrosis respiratory exacerbations do not affect outcomes. Am J Respir Crit Care Med. 010 Nov 1;182(9):1137-43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOrdo\u0026ntilde;ez 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 Dec 15; 168(12):1471\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSanders DB, Bittner RCL, Rosenfeld M, Hoffman LR, Redding J, Goss GJ. CH. Failure to recover to baseline pulmonary function after cystic fibrosis pulmonary exacerbation. Am J Respir Crit Care Med. 2010 Sep 1;182(5):627 \u0026ndash; 32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVanDevanter DR, O'Riordan MA, Blumer JL, Michael W, Konstan MW. Assessing time to pulmonary function benefit following antibiotic treatment of acute cystic fibrosis exacerbations. Respir Res. 2010 Oct;6(1):137.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRobinson 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 Aug;44(8):733\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVanderhelst 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(6):492\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWelsh 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 Dec;13(6):687\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYammine 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 Feb;69(2):183.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSonneveld N, Stanojevic S, Amin R, Aurora P, Davies J, Elborn JS, et al. Lung clearance index in cystic fibrosis subjects treated for pulmonary exacerbations. Eur Respir J. 2015 Oct;46(4):1055\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFuchs HJ, Borowitz DS, Christiansen DH, Morris M, Nash EM, Ramsey ML. Effect of Aerosolized Recombinant Human DNase on Exacerbations of Respiratory Symptoms and on Pulmonary Function in Patients with Cystic Fibrosis. N Engl J Med. 1994;331:637\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eButton BM, Wilson C, Dentice R, Cox NS, Middleton A, Tannenbaum E, Bishop J, Cobb R, Burton K, Wood M. Physiotherapy for cystic fibrosis in Australia and New Zealand: A clinical practice guideline. Respirol 2016 May;21(4):656\u0026ndash;67. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/resp.12764\u003c/span\u003e\u003cspan address=\"10.1111/resp.12764\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Epub 2016 Apr 18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRobinson PD, Latzin P, Verbanck S, Hall GL, Horsley A, Gappa M. al. Consensus statement for inert gas washout measurement using multiple- and single- breath tests European Respiratory Journal 2013 41: 507\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAnagnostopoulou P, Latzin P, Jensen R, Stahl M, Harper A, Yammine S, et al. Normative data for multiple breath washout outcomes in school-aged Caucasian children. Eur Respir J. 2020 Apr;3(4):1901302.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQuanjer H, Stanojevic PH, Cole S, Baur TJ, Hall X, Culver GL. Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur Respir J. 2012 Dec;40(6):1324\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHatziagorou E, Avramidou V, Kirvassilis F, Tsanakas J. Use of lung clearance index to assess the response to intravenous treatment in cystic fibrosis. Hippokratia 2015 Jan-Mar;19(1):47\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRayment H, Stanojevic JH, Davis S, George Retsch-Bogart SD, Ratjen G. Lung clearance index to monitor treatment response in pulmonary exacerbations in preschool children with cystic fibrosis. Thorax. 2018 May;73(5):451\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSvedberg M, Gustafsson PM, Robinson PD, Rosberg M, Lindblad A. Variability of lung clearance index in clinically stable cystic fibrosis lung disease in school age children. J Cyst Fibros. 2018 Mar;17(2):236\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDong K, Huh SM, Lam GY, Jang J, Franciosi AN, Wilcox PG et al. Pulmonary exacerbation inflammatory phenotypes in adults with cystic fibrosis. J Cyst Fibros 2022 Dec 24:S1569-1993(22)01433-3.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"italian-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"itjp","sideBox":"Learn more about [Italian Journal of Pediatrics](http://ijponline.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ITJP/default.aspx","title":"Italian Journal of Pediatrics","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"cystic fibrosis, lung clearance index, multiple breath washout, spirometry pulmonary exacerbation, intravenous antibiotic therapy","lastPublishedDoi":"10.21203/rs.3.rs-3136515/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3136515/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Multiple Breath washout (MBW) represents an important tool to detect early a possible pulmonary exacerbation especially in Cystic Fibrosis (CF) disease. Lung clearance index (LCI) is the most commonly reported multiple breath washout (MBW) index and in the last years was used as management measure for evaluation. Our aim was to analyze clinical utility of LCI index variability in pulmonary exacerbation in CF after intravenous (IV) antibiotic therapy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e A single-center study was conducted at CF Unit of Bambino Gesù Children’s Hospital among hospitalized \u0026gt; 3 years patients for pulmonary exacerbations and treated with antibiotic IV treatment for 14 days. MBW and spirometry were evaluated within 72 hours of admission to hospital and at the end of hospitalization. Descriptive analysis was conducted and correlations between quantitative variables were investigated.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eFifty-seven patients (M22/F35) with an average age 18.56 (± 8.54) years were enrolled. LCI2.5 was significantly reduced at the end of antibiotic treatment in both pediatric and adult populations with an average reduction of -6,99%; 37/57 patients denoted an improvement, 20/57 are stable or worsened in LCI2.5 values and 4/57 (7.02%) had a significant deterioration (\u0026gt;15%) at end of treatment. On the contrary a significative elevation of FEV1% and FVC% were found, respectively of +7,30% and of +5,46%. A positive good correlection among LCI 2.5 and Scond (rho= +0,615, p=0.000) and LCI 2.5 and Sacin (rho=+0,649, p=0.000) and a negative strong correlation between FEV1% and LCI 2.5 were found in post treatment period. A similar modification of LCI 2.5 and FEV1 was noticed in both adult and pediatric population.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e LCI may have a role in the routine clinical care of both adult and pediatric CF patients as a good tool to assess response to IV antibiotic end-therapy in the same way as FEV1.\u003c/p\u003e","manuscriptTitle":"Lung clearance index short-term variability in cystic fibrosis. A pre-post pulmonary exacerbation study.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-07-17 10:49:28","doi":"10.21203/rs.3.rs-3136515/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2023-07-12T15:41:36+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-07-12T12:34:47+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-07-12T09:47:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"Italian Journal of Pediatrics","date":"2023-07-08T03:09:34+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"italian-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"itjp","sideBox":"Learn more about [Italian Journal of Pediatrics](http://ijponline.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ITJP/default.aspx","title":"Italian Journal of Pediatrics","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c0a67a90-8fad-4599-b6c8-dd8fa4fe1650","owner":[],"postedDate":"July 17th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-01-22T15:08:56+00:00","versionOfRecord":{"articleIdentity":"rs-3136515","link":"https://doi.org/10.1186/s13052-023-01574-w","journal":{"identity":"italian-journal-of-pediatrics","isVorOnly":false,"title":"Italian Journal of Pediatrics"},"publishedOn":"2024-01-17 15:01:40","publishedOnDateReadable":"January 17th, 2024"},"versionCreatedAt":"2023-07-17 10:49:28","video":"","vorDoi":"10.1186/s13052-023-01574-w","vorDoiUrl":"https://doi.org/10.1186/s13052-023-01574-w","workflowStages":[]},"version":"v1","identity":"rs-3136515","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3136515","identity":"rs-3136515","version":["v1"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}