Journal of Cystic Fibrosis

Measuring and improving respiratory outcomes in cystic fibrosis lung disease: Opportunities and challenges to therapy

2010-01-01

Abstract: Cystic fibrosis (CF) is a life-shortening disease with significant morbidity. Despite overall improvements in survival, patients with CF experience frequent pulmonary exacerbations and declining lung function, which often accelerates during adolescence. New treatments target steps in the pathogenesis of lung disease, such as the basic defect in CF (CF Transmembrane Conductance Regulator [CFTR]), pulmonary infections, inflammation, and mucociliary clearance. These treatments offer hope but also present challenges to patients, clinicians, and researchers. Comprehensive assessment of efficacy is critical to identify potentially beneficial treatments. Lung function and pulmonary exacerbation are the most commonly used outcome measures in CF clinical research. Other outcome measures under investigation include measures of CFTR function; biomarkers of infection, inflammation, lung injury and repair; and patient-reported outcomes. Molecular diagnostics may help elucidate the complex CF airway microbiome. As new treatments are developed for patients with CF, efforts should be made to balance treatment burden with quality of life. This review highlights emerging treatments, obstacles to optimizing outcomes, and key future directions for research.

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

2010-01-01

Abstract: Background: Long-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.Methods: A randomized controlled trial was conducted to compare the effect of two doses of azithromycin (5mg/kg/day and 15mg/kg/day) on FEV1 and pulmonary exacerbations in children with cystic fibrosis. Enrolled children were randomly allocated to receive daily azithromycin (5mg/kg/day or 15mg/kg/day) for 6months. Clinical assessment and FEV1 measurement were performed monthly.Results: 56 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 12months of follow up. There was no difference in clinical scores, FEV1, pulmonary exacerbation rates between two groups at baseline, 6months and at 12months. Per protocol analysis revealed that pulmonary exacerbation increased after discontinuing AZM and there was significantly more increase after 12months 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 6months. There was no significant side effect of azithromycin.Conclusion: In this randomized controlled trial, we did not find differences in the effect of 2 doses (5mg/kg/day or 15mg/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 6months after discontinuing azithromycin.

Prevalence of dyslipidemia in adults with cystic fibrosis

2010-01-01

Abstract: Background: A high fat calorie diet is advocated for patients with cystic fibrosis (CF) however the lipid profiles of individuals with CF, including those with CF-related diabetes (CFRD), are not well studied.Methods: We conducted a retrospective review of adult CF patients attending St Michael's Hospital between January 2005 and December 2007.Results: 334 patients (77% pancreatic insufficient (PI)) were included in the study. Mean HDL cholesterol was significantly lower in males (p<0.0001) with 44% of males having HDL cholesterol <38.7mg/dL(1mmol/L). Pancreatic sufficient patients were more likely than PI subjects to have total cholesterol >201mg/dL(5.2mmol/L) (p<0.01). 5% of subjects had triglyceride concentrations >195mg/dL(2.2mmol/L). Diabetes was diagnosed in 23% of subjects. Lipid profiles were similar between diabetics and non-diabetics. Total cholesterol and triglycerides both increased with increasing age and increasing BMI (p<0.01).Conclusion: Dyslipidemia occurs in CF patients however no differences in lipid profiles were seen between those with diabetes and those without. Fasting lipids should be monitored in CF patients, particularly those with PS, older age, and high BMI. As survival in CF increases, the prevalence of dyslipidemia may increase resulting in clinically important complications.

A 10-year large-scale cystic fibrosis carrier screening in the Italian population

2010-01-01

Abstract: Background: Cystic Fibrosis (CF) is one of the most common autosomal recessive genetic disorders, with the majority of patients born to couples unaware of their carrier status. Carrier screenings might help reducing the incidence of CF.Methods: We used a semi-automated reverse-dot blot assay identifying the 47 most common CFTR gene mutations followed by DGGE/dHPLC analysis.Results: Results of a 10-year (1996–2006) CF carrier screening on 57,999 individuals with no prior family history of CF are reported. Of these, 25,104 were couples and 7791 singles, with 77.9% from the Italian Veneto region. CFTR mutations were found in 1879 carriers (frequency 1/31), with ΔF508 being the most common (42.6%). Subjects undergoing medically assisted reproduction (MAR) had significantly (p<0.0001) higher CF carrier frequency (1/22 vs 1/32) compared to non-MAR subjects.Conclusions: If coupled to counselling programmes, CF carrier screening tests might help reducing the CF incidence.

Entry of Burkholderia organisms into respiratory epithelium: CFTR, microfilament and microtubule dependence

2010-01-01

Abstract: Background: The pathogenesis of infection with Burkholderia cepacia complex (Bcc) organisms may be linked to its capacity to invade respiratory epithelium.Methods: An antibiotic exclusion assay was used to study B. dolosa AU4459 and B. cenocepacia J2315 invasion into wild-type (WT) and CFTR-deficient respiratory epithelial cells. Inhibitors were used to evaluate Bcc invasion dependency on host microtubule (mt) and microfilament (mf) systems.Results: B. dolosa entered WT-CFTR cells with 5-fold greater efficiency than CFTR deficient cells (25% vs 5%, respectively). Invasion dropped to <0.5% after either mf or mt inhibition. B. cenocepacia entered WT (0.05%) and CFTR-deficient cells (0.07%) with similarly low efficiencies, which significantly decreased with either mf or mt inhibition (0.008% and 0.002%, respectively).Conclusion: B. dolosa and B. cenocepacia enter respiratory epithelial cells in a mf and mt dependent fashion. Mutated CFTR leads to less internalization of B. dolosa, but not B. cenocepacia.

Pulmonary outcome differences in U.S. and French cystic fibrosis cohorts diagnosed through newborn screening

2010-01-01

Abstract: Background: A comparison of the longitudinal progression of lung disease in cystic fibrosis patients identified through newborn screening (NBS) in cohorts located in two different countries has never been performed and was the primary objective of this study.Methods: The study included 56 patients in Brittany diagnosed through NBS between 1989 and 1994 and 69 similar patients in Wisconsin between 1985 and 1994. The onset and progression of lung disease was radiographically quantified using the Wisconsin Chest X-ray (WCXR) scoring system. A single pediatric pulmonologist blinded to all identifiers scored the films.Results: Generalized estimating equation analyses adjusted for age, genotype, sex, pancreatic insufficiency, and meconium ileus showed worse WCXR scores in Brittany patients compared to Wisconsin patients (average score difference=4.48; p<0.001). Percent predicted FEV1 was also worse among Brittany patients (p<0.001).Conclusions: The finding of milder radiographically-quantified lung disease using the WCXR scoring system, as well as better FEV1 values, may be explained by variations in nutrition, environmental exposures, or healthcare delivery.

Inflammation in Achromobacter xylosoxidans infected cystic fibrosis patients

C.R. Hansen, T. Pressler, K.G. Nielsen, P.Ø. Jensen, T. Bjarnsholt, N. Høiby — 2010-01-01

Abstract: Background: Achromobacter xylosoxidans infection may cause conspicuous chronic pulmonary inflammation in cystic fibrosis (CF) patients similar to Pseudomonas aeruginosa and the Burkholderia cepacia complex (Bcc). Evolution in lung function was compared in chronically infected patients. Cytokine concentrations in CF patients with and without chronic infection were compared to healthy controls.Methods: Cytokines in serum and sputum were measured using multiplex bead based immunoassay.Results: Sixty CF patients, 11 with A. xylosoxidans, 11 with Bcc, 21 with P. aeruginosa and 17 non-infected CF patients were compared to 11 healthy controls. A. xylosoxidans patients were younger, but had a FEV1 decline similar to P. aeruginosa patients. Bcc patients had the steepest decline in FEV1.Serum levels of G-CSF, IL-6 and TNF-α were significantly higher in CF patients compared to healthy controls. Chronically infected CF patients had significantly higher serum levels of IFN-γ and IL-6 compared to non-infected CF patients. Bcc patients had significantly lower serum G-CSF and A. xylosoxidans patients had significantly higher sputum TNF-α compared to the other groups of chronically infected patients.Conclusion: A. xylosoxidans can cause a level of inflammation similar to P. aeruginosa in chronically infected CF patients. A. xylosoxidans is a clinically important pathogen in CF and should be treated accordingly.

Constipation in pediatric Cystic Fibrosis patients: An underestimated medical condition

2010-01-01

Abstract: Background: The aims of this study were to determine prevalence, risk factors and treatment of constipation in patients with Cystic Fibrosis (CF), as well as the diagnostic value of abdominal radiography.Methods: A cohort of 214 pediatric CF patients was investigated. Furthermore, 106 abdominal radiographs of CF patients with or without constipation were independently assessed by three observers on two separate occasions using the Barr and Leech scores.Results: The prevalence of constipation was 47%. Low total fat absorption and meconium ileus were independent risk factors for constipation in CF, while fiber and fluid intake were not associated. In CF patients the inter and intraobserver variabilities of the Barr and Leech scores were poor to moderate.Conclusion: Constipation is a significant medical issue in CF and was associated with low total fat absorption and a history of meconium ileus. Finally, abdominal radiography seems of little value in the regular follow-up of CF patients.

An aerobiological model of aerosol survival of different strains of Pseudomonas aeruginosa isolated from people with cystic fibrosis

I.J. Clifton, L.A. Fletcher, C.B. Beggs, M. Denton, S.P. Conway, D.G. Peckham — 2010-01-01

Abstract: Pseudomonas aeruginosa is a common and important pathogen in people with cystic fibrosis (CF). Recently epidemic strains of P. aeruginosa associated with increased morbidity, have been identified. The method of transmission is not clear, but there is evidence of a potential airborne route. The aim of this study was to determine whether different strains of P. aeruginosa isolated from people with CF were able to survive within artificially generated aerosols in an aerobiological chamber.Viable P. aeruginosa could still be detected up to 45min after halting generation of the aerosols. All of the strains of P. aeruginosa expressing a non-mucoid phenotype isolated from people with CF had a reduced ability to survive within aerosols compared to an environmental strain. Expression of a mucoid phenotype by the strains of P. aeruginosa isolated from people with CF promoted survival in the aerosol model compared to strains expressing a non-mucoid phenotype.

Cystic fibrosis transmembrane conductance regulator (CFTR) regulates the production of osteoprotegerin (OPG) and prostaglandin (PG) E2 in human bone

2010-01-01

Abstract: Bone loss is an important clinical issue in patients with cystic fibrosis (CF). Whether the cystic fibrosis transmembrane conductance regulator (CFTR) plays a direct role in bone cell function is yet unknown. In this study, we provide evidence that inhibition of CFTR-Cl− channel function results in a significant decrease of osteoprotegerin (OPG) secretion accompanied with a concomitant increase of prostaglandin (PG) E2 secretion of primary human osteoblast cultures (n=5). Our data therefore suggest that in bone cells of CF patients, the loss of CFTR activity may result in an increased inflammation-driven bone resorption (through both the reduced OPG and increased PGE2 production), and thus might contribute to the early bone loss reported in young children with CF.

Can Burkholderia cepacia complex be eradicated with nebulised Amiloride and TOBI®?

R. Ball, K.G. Brownlee, A.J.A. Duff, M. Denton, S.P. Conway, T.W.R. Lee — 2010-01-01

Burkholderia cepacia complex (Bcc) is an important gram-negative pathogen for people with cystic fibrosis (CF). Burkholderia multivorans (genomovar II), is the most prevalent species in the United Kingdom and thought to be mainly acquired from the environment. Burkholderia cenocepacia (particularly IIIA) is more commonly associated with Cepacia syndrome, and is highly transmissible, usually acquired by cross-infection from other patients with CF . Bcc is often inherently resistant to multiple antibiotics and is associated with accelerated decline in lung function and nutritional status . Retrospective data from a large United Kingdom adult CF Centre reported that once Bcc was acquired chronic infection developed in approximately 50% of cases of B. multivorans infection and 94% of B. cenocepacia infection, despite treatment .