Airway remodelling and its relationship to inflammation in cystic fibrosis

Pulmonary disease is the most important cause of morbidity and mortality in cystic fibrosis (CF). Most patients with CF die from respiratory failure with extensive airway destruction. Airway remodelling, defined as structural airway wall changes, begins early in life in CF but the sequence of remodelling events in the disease process is poorly understood. Airway remodelling in CF has traditionally been thought to be solely the consequence of repeated cycles of inflammation and infection. However, new evidence obtained from developmental, physiological and histopathological studies suggests that there might instead be multiple mechanisms leading to airway remodelling in CF including (1) changes related to infection and inflammation; (2) changes specific to CF as a result of CF transmembrane conductance regulator (CFTR) dysfunction in the airway wall, independent of infection and inflammation; and (3) protective responses to (1) and/or (2). Recent advances in bronchoscopic techniques have allowed airway mucosal (endobronchial) biopsies to be taken in children and even infants. Endobronchial biopsy studies may provide insight into the role and relative contribution of the different mechanisms of airway remodelling in CF, with the main limitation that they assess only changes in proximal large airways and not in peripheral small airways from where CF disease is thought to originate. Findings from biopsy studies could encourage the development of novel therapeutic strategies targeting structural changes in addition to infection and inflammation.     

Developing a measure of eating attitudes and behaviours in cystic fibrosis

BackgroundEating disorders or disturbed eating attitudes and behaviours (EABs) may contribute to poor nutritional status in Cystic Fibrosis (CF). Existing measures of disturbed EABs can have different meanings in this population and do not assess CF-related EABs. A self-report measure of EABs in CF was developed to highlight areas of eating disturbance.MethodsThe content validity of a draft measure was evaluated via expert evaluation and literature review and an amended measure piloted with 8 CF patients using cognitive interviewing. A further amended measure was administered to 155 CF patients (11–62 years) attending CF clinics.ResultsPrincipal components analyses revealed a three-factor structure (‘Desire for thinness and weight loss’, ‘Disturbed EABs’, and ‘Appetite’) with good internal consistencies for subscales and the 21-item whole measure.ConclusionsThe measure looks promising as a tool to highlight EAB disturbance in CF. Further work will establish its construct validity and clarify interpretation of subscales.     

Exploring provider attitudes and perspectives related to men's health in cystic fibrosis

BackgroundNew modulator therapies have markedly improved the health of people with cystic fibrosis (CF), allowing an increased focus on quality-of-life improvements for men with CF, including those related to sexual and reproductive health (SRH). This study explored CF providers’ attitudes and experiences with addressing men's health in CF.MethodsWe interviewed geographically diverse adult and pediatric United States (U.S.) CF program directors via semi-structured telephone interviews exploring their perspectives and practices related to men's SRH in CF. Two coders analyzed transcribed interviews and created a codebook to identify key themes.ResultsWe interviewed 20 providers and identified the following themes: 1) Men's SRH is important to address within CF care, but there is no standardization around this aspect of care; 2) There is no consensus about the recommendation or utilization of semen analysis to assess men's infertility; 3) There are many barriers to men's SRH care provision in CF centers, including the low priority of SRH concerns and provider discomfort and lack of expertise in SRH; 4) Providers desire clear evidence-based guidelines and patient resources related to men's SRH in CF; and 5) Providers believe future research should focus on testosterone and the impact of modulators on men's SRH.ConclusionsCF center directors acknowledge the importance of addressing SRH with men with CF, but there is a lack of standardization and research in this aspect of care. Existing barriers to optimal SRH care and identified facilitators in this study can serve as targets for interventions in the CF care model.     

Smoking prevention and cessation programme in cystic fibrosis: integrating an environmental health approach

BackgroundThere have been several studies assessing the epidemiology and effects of tobacco smoke in the cystic fibrosis (CF) population, but few address the efforts of smoking cessation interventions. Our objective is to present one tobacco prevention and cessation programme targeting patients with CF in the Mediterranean region of Murcia (Spain).MethodsAll registered patients in the Regional CF unit (n = 105) in 2008 were included in a cross-sectional and prospective uncontrolled study of tobacco use and exposure in CF patients using a baseline and 1-year follow-up. Target population includes both patients and other family members living at home. The study included an initial telephone questionnaire, measurement of lung function, urinary cotinine levels, and several telephone counselling calls and/or personalised smoking cessation services.ResultsOf the 97 contacted patients, 59.8% (n = 58) were exposed to environmental tobacco smoke (ETS), 12.4% (n = 12) had smoked at one time, and 14.3% (n = 8) of patients over the age of 15 actively smoked. The mean age was 31.13 (range: 19–45). Of the non-smokers (n = 89), 56.2% reported ETS and 26.9% live with at least one smoker at home. 49.2% had urinary cotinine levels > 10 ng/ml. The correlation found between patients' cotinine levels and their reported tobacco exposure was (0.77, p < 0.0001). Active smoking by mothers during pregnancy was associated with significantly lower lung function in young CF patients (− 0.385, p = 0.04). At the 1-year follow-up, 13 individuals made attempts to stop smoking, 6 of which are now ex-smokers (12.5% of all smokers).ConclusionsSmoking during pregnancy adversely affects lung function in individuals with CF. Tobacco prevention and cessation programmes are an effective and vital component for CF disease management. The trained professionals in prevention and smoking cessation services could provide patients with adequate follow-up, integrating an environmental health approach into CF patients' healthcare.     

Development of a disease specific health related quality of life measure for adults and adolescents with cystic fibrosis

BACKGROUND: Health related quality of life (HRQoL) measurement is important in determining the impact of disease on daily functioning and subsequently informing interventions. In cystic fibrosis (CF) generic HRQoL measures have been employed but these may not be sufficiently specific. The aim of the current work was to develop and validate a disease specific HRQoL measure for adults and adolescents with cystic fibrosis. METHODS: Areas of concern to adults and adolescents with CF were identified by unstructured interviews, self-administered questionnaires, consultation with multidisciplinary specialist staff, a review of the relevant literature, and examination of other HRQoL measures. Items for the questionnaire were generated on the basis of this process. Continued evaluation and development of the Cystic Fibrosis Quality of Life (CFQoL) questionnaire was undertaken by a process of statistical analysis and continued feedback from patients. The full testing and validation of the CFQoL questionnaire took place over four phases: (1) initial item generation and testing of a preliminary questionnaire, (2) testing and validation of the second version of the questionnaire, (3) test-retest reliability of a third and final version of the questionnaire, and (4) sensitivity testing of the final version of the questionnaire. RESULTS: Nine domains of functioning were identified using principal components analysis with varimax rotation. Internal reliability of the identified domains was demonstrated using Cronbach alpha coefficients (range 0.72-0.92) and item to total domain score correlations. Concurrent validity (range r = 0.64-0.74), discriminatory ability between different levels of disease severity, sensitivity across transient changes in health (effect size range, moderate d = 0.56 to large d = 1.95), and test-retest reliability (r = 0.74-0.96) were also found to be robust. CONCLUSIONS: The CFQoL questionnaire is a fully validated disease specific measure consisting of 52 items across nine domains of functioning which have been identified by, and are of importance to, adolescents and adults with cystic fibrosis. This measure will be useful in clinical trials and longitudinal studies.     

Population pharmacokinetics of tobramycin administered thrice daily and once daily in children and adults with cystic fibrosis.

BACKGROUND: Tobramycin pharmacokinetics have not been evaluated previously in a large series of data collected in children and adults with CF receiving once (OD) or three times daily (TD) tobramycin. METHODS: Therapeutic drug monitoring data in children and adults with CF who participated in a randomised clinical trial evaluating efficacy and toxicity of OD versus TD tobramycin (TOPIC study) were analysed retrospectively. Population pharmacokinetic models stratified to treatment schedule were created, and individual pharmacokinetic parameters were calculated. RESULTS: In paediatric patients, volume of distribution per kg body weight (V1) was greater with OD treatment compared to TD (0.401+/-0.092 versus 0.354+/-0.041, p=0.003). Elimination rate was reduced in all patients receiving OD tobramycin compared to TD (children: 0.00197+/-0.00027 versus 0.00291+/-0.00041, p<0.001, adults: 0.00252+/-0.00008 versus 0.00322+/-0.00050, p<0.001). Tobramycin V1 decreased with increasing age (R(2)=0.3, p<0.001). CONCLUSIONS: The reduced elimination rate in OD may either be caused by circadian pharmacokinetic behaviour of tobramycin or indicates early renal damage caused by high tobramycin doses not detected by biochemical measurements. However, results of our previous work suggest that OD tobramycin may be less nephrotoxic. The higher V1 in children implies that a relative higher tobramycin dose in these patients is needed for the same target peak serum concentration.     

Comparison of ex vivo and in vitro intestinal cystic fibrosis models to measure CFTR-dependent ion channel activity

Background

New functional assays using primary human intestinal adult stem cell cultures can be valuable tools to study epithelial defects in human diseases such as cystic fibrosis.

Barrier to using APRI and GPR as identifiers of cystic fibrosis liver disease

Cystic fibrosis-associated liver disease (CFLD) is the third most common cause of death in cystic fibrosis (CF). Poor ability to identify early, non-cirrhotic liver disease hampers interventions to mitigate complications associated with CFLD and potential early therapies that may halt the progression of cirrhosis. Liver fibrosis indices, such as APRI, FIB-4, and GPR, are minimally invasive biomarkers that may be useful for the detection and monitoring of CFLD. However, variability in the upper limit of normal values used in these calculations makes it difficult to compare results across research studies and identify appropriate indices cutoffs. Previously published APRI and GPR values are re-calculated using the same upper limit of normal values as recently published data on APRI and GPR, highlighting the importance of standardized upper limit of normal values for calculating liver fibrosis indices in CFLD detection and monitoring.     

Exhaled molecular profiles in the assessment of cystic fibrosis and primary ciliary dyskinesia

BackgroundEarly diagnosis and monitoring of disease activity are essential in cystic fibrosis (CF) and primary ciliary dyskinesia (PCD). We aimed to establish exhaled molecular profiles as the first step in assessing the potential of breath analysis.MethodsExhaled breath was analyzed by electronic nose in 25 children with CF, 25 with PCD and 23 controls. Principle component reduction and canonical discriminant analysis were used to construct internally cross-validated ROC curves.ResultsCF and PCD patients had significantly different breath profiles when compared to healthy controls (CF: sensitivity 84%, specificity 65%; PCD: sensitivity 88%, specificity 52%) and from each other (sensitivity 84%, specificity 60%). Patients with and without exacerbations had significantly different breath profiles (CF: sensitivity 89%, specificity 56%; PCD: sensitivity 100%, specificity 90%).ConclusionExhaled molecular profiles significantly differ between patients with CF, PCD and controls. The eNose may have potential in disease monitoring based on the influence of exacerbations on the VOC-profile.     

Design and powering of cystic fibrosis clinical trials using pulmonary exacerbation as an efficacy endpoint

Background

Reduction in pulmonary exacerbations is an important efficacy endpoint for CF clinical studies. Powering exacerbation endpoints requires estimation of the future exacerbation incidence in CF study populations, but rates differ across the population.

Methods

We have estimated exacerbation rates for Epidemiologic Study of CF subpopulations stratified by age, FEV₁% predicted, sex, weight-for-age percentile, respiratory signs and symptoms, and history of exacerbation and bacterial culture. Sample sizes required to attain 80% power to detect exacerbation reductions of 20% to 80% in 1:1 randomized studies of 3 to 12 month duration were determined. Exacerbation treatments with “any” antibiotic (new oral quinolone, new inhaled antibiotic, or intravenous (IV) antibiotic) and with IV antibiotics were studied.

Results

At all ages, decreased FEV₁, female sex, exacerbation history, and Pseudomonas aeruginosa culture history were associated with increased treatment for exacerbation.

Conclusions

These data should assist investigators in the design of future CF exacerbation studies.     

Work disability in adults with cystic fibrosis and its relationship to quality of life.

With increasing numbers of cystic fibrosis (CF) patients surviving to adulthood, issues related to vocation inevitably arise and warrant specific attention. We examined the percentage of participants with CF currently working and explored risk factors for work disability among adults with CF. METHOD: We recruited 50 consecutive patients from an adult cystic fibrosis service. Demographic, employment history, illness severity indicators and CF-attributed work disability factors were evaluated. Demographic risk factors for work disability using the illness severity measures of FEV(1), S-K score, CRDQ, and recent hospitalisation as independent variables were determined. RESULTS: Factorial analysis of a disability index (DI) indicated no dependency on FEV(1) or S-K score, but dependency on quality of life indices (p<0.05), age (p<0.05) and hospital admission rate (p<0.05). Hours worked per week were dependent on quality of life (p<0.01) (mastery of disease domain), fewer hospital admissions (p<0.01) and age (p<0.05). Sixty-eight percent of the sample reported that CF resulted in significant impediments to employment. However, few had sought vocational guidance (6%). CONCLUSION: Determinants of workforce participation shows that hours worked and perceived disability are more dependent on mastery of disease, age, and time in hospital, than on clinical severity scores. Health professionals may assist productivity through career counselling or tailored programs.     

Real-world assessment of LCI following lumacaftor-ivacaftor initiation in adolescents and adults with cystic fibrosis

Lung clearance index (LCI) is a biomarker of ventilation inhomogeneity. Data are scarce on its usefulness in daily practice for monitoring the effects of treatments in older children and adults with CF. In this French observational study of lumacaftor-ivacaftor, 63 of 845 patients (7.5%) had available LCI performed at baseline and at six (M6; n=34) or 12 months (M12; n=46) after lumacaftor-ivacaftor initiation. At inclusion, median [IQR] age was 16 years [13-17], ppFEV₁ was 72.8 [59.6-80.7], and LCI was 12.3 [10.3-15.0]. At both M6 and M12, no statistically significant LCI increases of 0.13 units or 1.34% (95% CI: -4.85-7.53) and 0.6 units or 6.66% (95% CI: -0.03-13.5) were observed. Discordant results between LCI and ppFEV₁ were observed in one-third of the patients. In daily practice, LCI monitoring in adolescents and young adults with moderate lung disease gives results that are more heterogenous than those reported in children with milder disease.     

Long-term daily high and low doses of azithromycin in children with cystic fibrosis: A randomized controlled trial

BackgroundLong-term administration of azithromycin (AZM) in children with cystic fibrosis (CF) has improved outcomes. However, the doses and schedule of administration are not very well studied in children with CF.MethodsA randomized controlled trial was conducted to compare the effect of two doses of azithromycin (5 mg/kg/day and 15 mg/kg/day) on FEV₁ and pulmonary exacerbations in children with cystic fibrosis. Enrolled children were randomly allocated to receive daily azithromycin (5 mg/kg/day or 15 mg/kg/day) for 6 months. Clinical assessment and FEV₁ measurement were performed monthly.Results56 children (28 in high dose group and 28 in low dose group) were enrolled. 47 (24 and 23 children in low and high dose groups) completed 12 months of follow up. There was no difference in clinical scores, FEV₁, pulmonary exacerbation rates between two groups at baseline, 6 months and at 12 months. Per protocol analysis revealed that pulmonary exacerbation increased after discontinuing AZM and there was significantly more increase after 12 months of enrolment in children getting high dose azithromycin. There was no improvement in FEV₁ in either group at the end of treatment period. Children tolerated daily low as well as high dose AZM well for 6 months. There was no significant side effect of azithromycin.ConclusionIn this randomized controlled trial, we did not find differences in the effect of 2 doses (5 mg/kg/day or 15 mg/kg/day) of AZM on change in percentage predicted FEV₁, clinical scores, Pseudomonas colonization rates, pulmonary exacerbations and need for antibiotics. There was increase in exacerbations after stopping azithromycin in both the groups. Our results also suggest that the decrease in the incidence of LRTI persists only till 6 months after discontinuing azithromycin.     

Design and powering of cystic fibrosis clinical trials using rate of FEV1 decline as an efficacy endpoint

BackgroundRate of lung function decline (RLFD) (as FEV₁ percent predicted/yr) is a robust measure of CF therapeutic efficacy rarely used as a study endpoint, in part due to uncertainty of sample size requirements.MethodsSample size requirements for 1:1 randomizations to detect RLFD treatment effects from 20% to 80% were assessed in Epidemiologic Study of CF (ESCF) patients. Effects of measuring FEV₁ 1–4 times per year in studies of 1- to 4-year durations were assessed in 399 patients age ≥ 6 years with FEV₁ ≥ 70%. Impacts of inclusion/exclusion based on risk factors in 2369 ESCF patients were assessed over 1.5 years using semi-annual FEV₁ measures.ResultsIncreasing study duration and exclusion of lower risk patients (e.g., no P. aeruginosa infection) both substantially reduced requirements.ConclusionsCF RLFD studies of 1.5 years in duration appear feasible provided that investigators account for the beneficial effects of subject inclusion/exclusion based on risk factors in power estimates.     

Evaluation of bronchial responsiveness to exercise in children as an objective measure of asthma in epidemiological surveys.

BACKGROUND: Exercise has been proposed as a useful challenge test for the measurement of bronchial responsiveness in community surveys of the prevalence of childhood asthma. This study aimed to develop a standardised exercise challenge in which the sensitivity to detect asthma was increased by inhalation of dry air. METHODS: Sixty four children aged 12-13 years who had reported wheeze in the past 12 months and 70 control subjects were invited to participate in an exercise challenge at school. Subjects performed eight minutes of cycle exercise while breathing dry air at a workload calculated to produce a minute ventilation of 60% maximum voluntary ventilation during the final three minutes. A fall in forced expiratory volume in one second (FEV1) of 10% or more from baseline was considered a positive test. Data on recent asthma symptoms, asthma morbidity, and use of medication were collected by parent completed questionnaires in those subjects who reported wheeze in the past 12 months. Repeatability of the exercise test was determined in a further 13 children with known asthma. RESULTS: Fifty five children (88%) who reported wheeze in the previous 12 months and 54 control subjects (77%) were studied. Nine subjects in whom baseline FEV1 was less than 75% predicted did not perform the exercise test. Technically unsatisfactory tests were obtained in five subjects. Twenty six (57%) subjects who reported wheeze and three controls (6%) had a positive exercise test, giving a sensitivity of 57% (26 of 46) and specificity of 94% (47 of 50). Estimates of the repeatability of the exercise test showed a mean difference in percentage fall in FEV1 for patients with asthma of 3.08% (95% limits of agreement -7.76% to 13.92%). CONCLUSIONS: Despite attempts to maximise the stimulus to bronchoconstriction in this exercise challenge test, its sensitivity and specificity were not improved in comparison with previous epidemiological studies of the prevalence of asthma.     

Evidence for eosinophil activation in bronchiectasis unrelated to cystic fibrosis and bronchopulmonary aspergillosis: discrepancy between blood eosinophil counts and serum eosinophil cationic protein levels

BACKGROUND—Increased serum levelsof eosinophil cationic protein (ECP) have been detected in adolescentpatients with cystic fibrosis. However, ECP concentrations in adultpatients with bronchiectasis unrelated to cystic fibrosis have not been studied.
METHODS—Eosinophil numbers and serumconcentrations of ECP were determined in 14 patients with known ornewly diagnosed bronchiectasis and compared with age and sex matchedpatients with allergic bronchial asthma, chronic obstructive pulmonarydisease (COPD), and controls in whom bronchiectasis or obstructivepulmonary disease could be excluded.
RESULTS—Serum ECP levels were significantlyraised both in patients with bronchiectasis (median (range) 22.5 µg/l(7-85)) and allergic asthma (35.0 µg/l (7-128)) compared with thesex and age matched subjects suffering from COPD (6.7 µg/l (1.5-28);p<0.006) and non-obstructive normal controls (7.5 µg/l (3.5-19);p<0.003). In contrast, significantly increased peripheral eosinophilnumbers were observed in patients with bronchial asthma (305 × 10⁶/l; p<0.01) but not in those with bronchiectasis(10² × 10⁶/l), COPD (117 × 10⁶/l), and healthy controls (101 × 10⁶/l).
CONCLUSIONS—The discrepancy betweeneosinophil counts and eosinophil numbers in patients withbronchiectasis suggests that serum ECP levels may be more relevant inassessing local eosinophil involvement than blood eosinophil numbers.