Small airways disease in cystic fibrosis

Abstract Background Forced expiratory volume in 1 second (FEV 1 ) is the only parameter currently recognized as a surrogate endpoint in cystic fibrosis (CF) trials. However, FEV 1 is relatively insensitive to changes in the small airways of patients with milder lung disease. This pilot study aimed to evaluate the lung clearance index (LCI) as a marker for use in efficacy trials with inhaled antibiotics in CF. Methods This open-label, single-arm study enrolled CF patients with Pseudomonas aeruginosa infection, who were treated with tobramycin (28-day on/off regime). FEV 1 , LCI and bacterial load in sputum (CFU) were assessed at baseline, after 1, 4 and 8 weeks of treatment. Results All patients (n=17) showed elevated LCI of >11 despite 3 patients having normal FEV 1 (>90% predicted) at baseline. Overall, LCI improved in 8 (47%) patients and FEV 1 in 9 (53%) patients. At week 4, LCI improved by 0.88, FEV 1 increased by 0.52%, and P. aeruginosa reduced by 30481.3 CFU/mL. These changes were however statistically non-significant. Six adverse events occurred in 5/17 (29.4%) patients, most of which were mild-to-moderate in severity. Conclusions Due to the low evaluable sample size, no specific trend was observed related to the changes between LCI, FEV1 and CFU. Based on the individual data from this study and from recently published literature, LCI has been shown to be a more sensitive parameter than FEV1 for lung function. LCI can hypothesized to be an appropriate endpoint for efficacy trials in CF patients if the heterogeneity in lung function is limited by enrolling younger patients or patients with more milder lung disease and thus, limiting the ventilation inhomogeneities. Trial registration : The study is registered with ClinicalTrials.gov, identifier: NCT02248922

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EARLY DETECTION OF PULMONARY FUNCTION ABNORMALITIES IN CYSTIC FIBROSIS

PEDIATRICS ◽

10.1542/peds.50.2.291 ◽

1972 ◽

Vol 50 (2) ◽

pp. 291-298

Author(s):

Andre Lamarre ◽

Bernard J. Reilly ◽

A. Charles Bryan ◽

Henry Levison

Keyword(s):

Cystic Fibrosis ◽

Arterial Oxygen Tension ◽

Volume Ratio ◽

Arterial Oxygen ◽

Mixing Efficiency ◽

Small Airways ◽

Diffusing Capacity ◽

Blood Gas ◽

Physiologic Dead Space ◽

Airway Conductance

We studied gas exchange in 19 children with cystic fibrosis in whom measurement of lung volumes, flow rates and airway conductance, diffusing capacity and mixing efficiency were normal. A significant decrease in arterial oxygen tension was found together with a significant increase in alveolar-arterial difference for oxygen and physiologic dead space/tidal volume ratio. These findings are consistent with evidence that early in cystic fibrosis the site of obstruction is in the small airways. It is also suggested from these data that blood gas abnormalities occur before other parameters of lung function become abnormal.

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75* Small airways response to domase alfa improves using controlled inhalation: a randomized controlled trial in cystic fibrosis patients

Journal of Cystic Fibrosis ◽

10.1016/s1569-1993(11)60093-3 ◽

2011 ◽

Vol 10 ◽

pp. S19 ◽

Cited By ~ 5

Author(s):

M. van den Beukel-Bakker ◽

S. Volpi ◽

E. Salonini ◽

E.C. van der Wiel-Kooij ◽

C. Sintnicolaas ◽

...

Keyword(s):

Cystic Fibrosis ◽

Randomized Controlled Trial ◽

Controlled Trial ◽

Small Airways ◽

Randomized Controlled

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Primary inflammation in human cystic fibrosis small airways

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00419.2001 ◽

2002 ◽

Vol 283 (2) ◽

pp. L445-L451 ◽

Cited By ~ 44

Author(s):

Rabindra Tirouvanziam ◽

Ibrahim Khazaal ◽

Bruno Péault

Keyword(s):

Cystic Fibrosis ◽

Severe Combined Immunodeficiency ◽

In Vivo Model ◽

Small Airways ◽

Combined Immunodeficiency ◽

Tissue Destruction ◽

Primary Defect ◽

Clear Cut ◽

Lung Failure

Most cystic fibrosis (CF) patients die of lung failure, due to the combined effects of bacterial infection, neutrophil-mediated inflammation, and airway obstruction by hyperviscous mucus. To this day, it remains unclear where and how this pathological vicious circle is initiated in vivo. In particular, it has proven difficult to investigate whether inflammatory pathways are dysregulated in CF airways independently of infection. Also, the relative involvement of large (tracheobronchial) vs. small (bronchiolar) airways in CF pathophysiology is still unclear. To help address these issues, we used an in vivo model based on the maturation of human fetal CF and non-CF small airways in severe combined immunodeficiency mice. We show that uninfected mature CF small airway grafts, but not matched non-CF controls, undergo time-dependent neutrophil-mediated inflammation, leading to progressive lung tissue destruction. This model of mature human small airways provides the first clear-cut evidence that, in CF, inflammation may arise at least partly from a primary defect in the regulation of neutrophil recruitment, independently of infection.

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Electrolyte transport properties in distal small airways from cystic fibrosis pigs with implications for host defense

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00422.2015 ◽

2016 ◽

Vol 310 (7) ◽

pp. L670-L679 ◽

Cited By ~ 18

Author(s):

Xiaopeng Li ◽

Xiao Xiao Tang ◽

Luis G. Vargas Buonfiglio ◽

Alejandro P. Comellas ◽

Ian M. Thornell ◽

...

Keyword(s):

Cystic Fibrosis ◽

Transport Properties ◽

Host Defense ◽

Bacterial Colonization ◽

Short Circuit ◽

Airway Epithelial Cells ◽

Small Airway ◽

Small Airways ◽

Bacterial Killing ◽

Airway Epithelia

While pathological and clinical data suggest that small airways are involved in early cystic fibrosis (CF) lung disease development, little is known about how the lack of cystic fibrosis transmembrane conductance regulator (CFTR) function contributes to disease pathogenesis in these small airways. Large and small airway epithelia are exposed to different airflow velocities, temperatures, humidity, and CO2 concentrations. The cellular composition of these two regions is different, and small airways lack submucosal glands. To better understand the ion transport properties and impacts of lack of CFTR function on host defense function in small airways, we adapted a novel protocol to isolate small airway epithelial cells from CF and non-CF pigs and established an organotypic culture model. Compared with non-CF large airways, non-CF small airway epithelia cultures had higher Cl− and bicarbonate (HCO3−) short-circuit currents and higher airway surface liquid (ASL) pH under 5% CO2 conditions. CF small airway epithelia were characterized by minimal Cl− and HCO3− transport and decreased ASL pH, and had impaired bacterial killing compared with non-CF small airways. In addition, CF small airway epithelia had a higher ASL viscosity than non-CF small airways. Thus, the activity of CFTR is higher in the small airways, where it plays a role in alkalinization of ASL, enhancement of antimicrobial activity, and lowering of mucus viscosity. These data provide insight to explain why the small airways are a susceptible site for the bacterial colonization.

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An 8 week open-label interventional multicenter study to evaluate the lung clearance index as endpoint for clinical trials in cystic fibrosis patients ≥6 years of age, chronically infected with Pseudomonas aeruginosa

10.21203/rs.3.rs-15870/v1 ◽

2020 ◽

Author(s):

Sivagurunathan Sutharsan ◽

Susanne Naehrig ◽

Uwe Mellies ◽

Christian Sieder ◽

joerg Zeigler

Keyword(s):

Cystic Fibrosis ◽

Pseudomonas Aeruginosa ◽

Bacterial Load ◽

Surrogate Endpoint ◽

Forced Expiratory Volume ◽

Small Airways ◽

Open Label ◽

Lung Clearance ◽

Inhaled Antibiotics ◽

Lung Clearance Index

Abstract Background Forced expiratory volume in 1 second (FEV 1 ) is the only parameter currently recognized as a surrogate endpoint in cystic fibrosis (CF) trials. However, FEV 1 is relatively insensitive to changes in the small airways of patients with milder lung disease. This pilot study aimed to evaluate the lung clearance index (LCI) as a marker for use in efficacy trials with inhaled antibiotics in CF. Methods This open-label, single-arm study enrolled CF patients with Pseudomonas aeruginosa infection, who were treated with tobramycin (28-day on/off regime). FEV 1 , LCI and bacterial load in sputum (CFU) were assessed at baseline, after 1, 4 and 8 weeks of treatment. Results All patients (n=17) showed elevated LCI of >11 despite 3 patients having normal FEV 1 (>90% predicted) at baseline. Overall, LCI improved in 8 (47%) patients and FEV 1 in 9 (53%) patients. At week 4, LCI decreased by 0.88, FEV 1 increased by 0.52%, and P. aeruginosa reduced by 30481.3 CFU/mL. These changes were however statistically non-significant. Six adverse events occurred in 5/17 (29.4%) patients, most of which were mild-to-moderate in severity. Conclusions Due to the low evaluable sample size, no specific trend was observed related to the changes between LCI, FEV 1 and CFU. Based on the individual data from this study and from recently published literature, LCI has been shown to be a more sensitive parameter than FEV 1 for lung function. However, LCI alone does not seem to be the ideal clinical endpoint for efficacy studies with antibiotic treatment in small groups of CF patients.Trial registration : The study is registered with ClinicalTrials.gov, identifier: NCT02248922

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