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  • End of life care for patients with cystic fibrosis

    Dorota Sands, Teresa Repetto, Lieven J. Dupont, Aleksandra Korzeniewska-Eksterowicz, Paola Catastini, Susan Madge


    Palliative care is an approach that improves quality of life for patients and their families facing problems associated with a life-threatening illness. Care planning is particularly important in CF, where predicting a time of death is extremely difficult. The patient and family should receive realistic information about health status and further options of care. Particularly important is the explanation that treatment does not stop during the terminal phase of the disease, instead the primary aim is to alleviate unpleasant symptoms. More invasive end of life care is becoming the norm in patients awaiting lung transplantation. Terminal care should be organised in the place chosen by the patient and their family. Ideally terminal care should not end when the patient dies, instead psychological and spiritual support should continue to bereaved families.

    © 2011 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

    Keywords: Cystic fibrosis; End of life; Palliative care

  • Best practice guidance for the diagnosis and management of cystic fibrosis-associated liver disease

    Dominique Debray, Deirdre Kelly, Roderick Houwen, Birgitta Strandvik, Carla Colombo


    Approximately 5–10% of cystic fibrosis (CF) patients develop multilobular cirrhosis during the first decade of life. Most CF patients later develop signs of portal hypertension with complications, mainly variceal bleeding. Liver failure usually occurs later, after the paediatric age. Annual screening for liver disease is recommended to detect pre-symptomatic signs and initiate ursodeoxycholic acid therapy, which might halt disease progression. Liver disease should be considered if at least two of the following variables are present: abnormal physical examination, persistently abnormal liver function tests and pathological ultrasonography. If there is diagnostic doubt, a liver biopsy is indicated. All CF patients with liver disease need annual follow-up to evaluate the development of cirrhosis, portal hypertension or liver failure. Management should focus on nutrition, prevention of bleeding and variceal decompression. Deterioration of pulmonary function is an important consideration for liver transplantation, particularly in children with hepatic dysfunction or advanced portal hypertension.

    © 2011 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

    Keywords: Cystic fibrosis; Liver disease; Liver biopsy; Esophageal varices; Ultrasonography; Ursodeoxycholic acid

  • Guidelines for the diagnosis and management of distal intestinal obstruction syndrome in cystic fibrosis patients

    Carla Colombo, Helmut Ellemunter, Roderick Houwen, Anne Munck, Chris Taylor, Michael Wilschanski on behalf of the ECFS


    Complete or incomplete intestinal obstruction by viscid faecal material in the terminal ileum and proximal colon – distal intestinal obstruction syndrome (DIOS) – is a common complication in cystic fibrosis. Estimates of prevalence range from 5 to 12 episodes per 1000 patients per year in children, with higher rates reported in adults. DIOS is mainly seen in patients with pancreatic insufficiency, positive history of meconium ileus and previous episodes of DIOS. DIOS is being described with increasing frequency following organ transplantation. Diagnosis is based on suggestive symptoms with a right lower quadrant mass confirmed on X-ray. The main differential is chronic constipation. Treatment consists of rehydration combined with stool softening laxatives or gut lavage with balanced electrolyte solutions. Rapid fluid shifts have been described following osmotic agents. Avoiding dehydration and optimizing pancreatic enzyme dosage may reduce the chance of further episodes. Prophylactic laxative therapy is widely used, but is not evidence-based.

    © 2011 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

    Keywords: Cystic fibrosis; Intestinal obstruction; Diagnosis; Treatment

  • European cystic fibrosis bone mineralisation guidelines

    Isabelle Sermet-Gaudelus, Maria Luisa Bianchi, Michèle Garabédian, Robert M. Aris, Alison Morton, Dana S. Hardin, Sarah L. Elkin, Juliet E. Compston, Steven P. Conway, Mireille Castane, Susan Wolfe, Charles S. Haworth


    Patients with cystic fibrosis (CF) are at risk of developing low bone mineral density (BMD) and fragility fractures. This paper presents consensus statements that summarise current knowledge of the epidemiology and pathophysiology of CF-related skeletal deficits and provides guidance on its assessment, prevention and treatment. The statements were validated using a modified Delphi methodology.

    © 2011 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

    Keywords: Cystic fibrosis; Dual Energy X-ray Absorptiometry (DXA); Bone density; Fractures; Bisphosphonates; Calcium; Vitamin D; Puberty

  • The implementation of standards of care in Europe: State of the art

    Carla Colombo, James Littlewood


    The care and condition of people with cystic fibrosis (CF) in 34 European countries is reported using data obtained from publications, registries and professionals providing CF patient care. Care and outcomes differ markedly between countries. Although the 2005 European standards of patient care publication was widely known, in many countries there were no specialized CF centres. In only a minority of countries was funding considered adequate and in some countries costs covered by patients compromised care. Only 15 countries had a national CF patient registry. Neonatal screening was routine in only 10 countries, but this included 59% of European infants. The initiatives of EuroCareCF Workpackage 1 to form networks for professionals working with CF patients are described. Suggestions for the future include at least one adequately staffed CF Centre in each country, improved funding, neonatal screening, national patient registries and the formation of national CF parent and patient organisations.

    © 2011 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

    Keywords: Cystic fibrosis; Care; Demographics

  • A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial.

    Boyle MP, Bell SC, Konstan MW, McColley SA, Rowe SM, Rietschel E, Huang X, Waltz D, Patel NR, Rodman D; VX09-809-102 study group.




    The phe508del CFTR mutation causes cystic fibrosis by limiting the amount of CFTR protein that reaches the epithelial cell surface. We tested combination treatment with lumacaftor, an investigational CFTR corrector that increases trafficking of phe508del CFTR to the cell surface, and ivacaftor, a CFTR potentiator that enhances chloride transport of CFTR on the cell surface.


    In this phase 2 clinical trial, we assessed three successive cohorts, with the results of each cohort informing dose selection for the subsequent cohort. We recruited patients from 24 cystic fibrosis centres in Australia, Belgium, Germany, New Zealand, and the USA. Eligibility criteria were: confirmed diagnosis of cystic fibrosis, age at least 18 years, and a forced expiratory volume in 1 s (FEV1) of 40% or more than predicted. Cohort 1 included phe508del CFTR homozygous patients randomly assigned to either lumacaftor 200 mg once per day for 14 days followed by addition of ivacaftor 150 mg or 250 mg every 12 h for 7 days, or 21 days of placebo. Together, cohorts 2 and 3 included phe508del CFTR homozygous and heterozygous patients, randomly assigned to either 56 days of lumacaftor (cohort 2: 200 mg, 400 mg, or 600 mg once per day, cohort 3: 400 mg every 12 h) with ivacaftor 250 mg every 12 h added after 28 days, or 56 days of placebo. The primary outcomes for all cohorts were change in sweat chloride concentration during the combination treatment period in the intention-to-treat population and safety (laboratory measurements and adverse events). The study is registered with, number NCT01225211, and EudraCT, number 2010-020413-90.


    Cohort 1 included 64 participants. Cohort 2 and 3 combined contained 96 phe508del CFTR homozygous patients and 28 compound heterozygotes. Treatment with lumacaftor 200 mg once daily and ivacaftor 250 mg every 12 h decreased mean sweat chloride concentration by 9.1 mmol/L (p<0.001) during the combination treatment period in cohort 1. In cohorts 2 and 3, mean sweat chloride concentration did not decrease significantly during combination treatment in any group. Frequency and nature of adverse events were much the same in the treatment and placebo groups during the combination treatment period; the most commonly reported events were respiratory. 12 of 97 participants had chest tightness or dyspnoea during treatment with lumacaftor alone. In pre-planned secondary analyses, a significant decrease in sweat chloride concentration occurred in the treatment groups between day 1 and day 56 (lumacaftor 400 mg once per day group -9.1 mmol/L, p<0.001; lumacaftor 600 mg once per day group -8.9 mmol/L, p<0.001; lumacaftor 400 mg every 12 h group -10.3 mmol/L, p=0.002). These changes were significantly greater than the change in the placebo group. In cohort 2, the lumacaftor 600 mg once per day significantly improved FEV1 from day 1 to 56 (difference compared with placebo group: +5.6 percentage points, p=0.013), primarily during the combination period. In cohort 3, FEV1 did not change significantly across the entire study period compared with placebo (difference +4.2 percentage points, p=0.132), but did during the combination period (difference +7.7 percentage points, p=0·003). Phe508del CFTR heterozygous patients did not have a significant improvement in FEV1.


    We provide evidence that combination lumacaftor and ivacaftor improves FEV1 for patients with cystic fibrosis who are homozygous for phe508del CFTR, with a modest effect on sweat chloride concentration. These results support the further exploration of combination lumacaftor and ivacaftor as a treatment in this setting.


    Vertex Pharmaceuticals, Cystic Fibrosis Foundation Therapeutics Development Network.

  • Effects of ivacaftor in patients with cystic fibrosis who carry the G551D mutation and have severe lung disease.

    Barry PJ, Plant BJ, Nair A, Bicknell S, Simmonds NJ, Bell NJ, Shafi NT, Daniels T, Shelmerdine S, Felton I, Gunaratnam C, Jones AM, Horsley AR.




    The development of ivacaftor represents a significant advance in therapeutics for patients with cystic fibrosis (CF) who carry the G551D mutation. Patients with an FEV1 < 40% predicted represent a considerable proportion of eligible patients but were excluded from phase 3 clinical trials, and the effectiveness of the drug in this population is, therefore, unknown.


    Data were collected from adult CF centers in the United Kingdom and Ireland with patients enrolled in an ivacaftor compassionate use program (FEV1 < 40% or on lung transplant waiting list). Clinically recorded data were collated from patient records for 1 year prior and for a period of 90 to 270 days following ivacaftor commencement. Each patient was matched to two control subjects who would have met the requirements for the compassionate use program with the exception of genotype.


    Twenty-one patients received ivacaftor for a median of 237 days. Mean FEV1 improved from 26.5% to 30.7% predicted (P = .01), representing a 16.7% relative improvement. Median weight improved from 49.8 to 51.6 kg (P = .006). Median inpatient IV antibiotic days declined from 23 to 0 d/y (P = .001) and median total IV treatment days decreased from 74 to 38 d/y (P = .002) following ivacaftor. Changes in pulmonary function and IV antibiotic requirements were significant compared with control subjects.


    Ivacaftor was clinically effective in patients with CF who carry the G551D mutation and have severe pulmonary disease. The reductions in treatment requirements were clinically and statistically significant and have not been described in less severe populations.

  • Personalized medicine in advanced cystic fibrosis

    Edward F Mckone



    Clinical trials in patients with cystic fibrosis typically include patients with mild to moderate lung disease as determined by percent predicted FEV1 (ppFEV1). With improvements in ppFEV1 being the most common clinical trial primary endpoint, the rationale is that patients with very mild cystic fibrosis might not show a ppFEV1 change as disease burden is low and there might be a ceiling effect if lung function is in the normal range. Likewise, those with severe cystic fibrosis lung disease might not show a change in ppFEV1 because of irreversible lung fibrosis leading to fixed airflow obstruction.

  • Efficacy and Safety of Ivacaftor in Patients Aged 6 to 11 Years with Cystic Fibrosis with a G551D Mutation

    Jane C. Davies, Claire E. Wainwright, Gerard J. Canny, Mark A. Chilvers, Michelle S. Howenstine, Anne Munck, Jochen G. Mainz, Sally Rodriguez, Haihong Li, Karl Yen, Claudia L. Ordoñez, and Richard Ahrens, on behalf of the VX08-770-103(ENVISION) StudyGroup



    Rationale: Ivacaftor (VX-770), a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, has been shown to improve lung function, pulmonary exacerbation rate, respiratory symptoms, and weight gain compared with placebo in patients with cystic fibrosis aged 12 years or older with a G551D-CFTR mutation.

    Objectives: This randomized, double-blind, placebo-controlled trial evaluated ivacaftor in patients with cystic fibrosis aged 6–11 years with a G551D-CFTR mutation on at least one allele.

    Methods: Patients were randomly assigned to receive ivacaftor administered orally at 150 mg (n = 26) or placebo (n = 26) every 12 hours for 48 weeks in addition to existing prescribed cystic fibrosis therapies.

    Measurements and Main Results: Despite near-normal mean baseline values in FEV1, patients receiving ivacaftor had a significant increase in percent predicted FEV1 from baseline through Week 24 versus placebo group (treatment effect, 12.5 percentage points; P < 0.001). Effects on pulmonary function were evident by 2 weeks, and a significant treatment effect was maintained through Week 48. Patients treated with ivacaftor gained, on average, 2.8 kg more than those receiving placebo at Week 48 (P < 0.001). The change from baseline through Week 48 in the concentration of sweat chloride, a measure of CFTR activity, with ivacaftor was −53.5 mmol/L (P < 0.001) versus placebo. The incidence of adverse events was similar in the two groups.

    Conclusions: In patients who are younger and healthier than those in previously studied populations, ivacaftor demonstrated a significant improvement in pulmonary function, weight, and CFTR activity compared with placebo. Clinical trial registered with (NCT00909727).

    KEYWORDS: cystic fibrosis, cystic fibrosis transmembrane conductance regulator protein, cystic fibrosis, pulmonary, G551D-CFTR mutation, sweat test

  • Magnetic resonance imaging detects changes in structure and perfusion, and response to therapy in early cystic fibrosis lung disease.

    Wielpütz MO, Puderbach M, Kopp-Schneider A, Stahl M, Fritzsching E, Sommerburg O, Ley S, Sumkauskaite M, Biederer J, Kauczor HU,Eichinger M, Mall MA.




    Studies demonstrating early structural lung damage in infants and preschool children with cystic fibrosis (CF) suggest that noninvasive monitoring will be important to identify patients who may benefit from early therapeutic intervention. Previous studies demonstrated that magnetic resonance imaging (MRI) detects structural and functional abnormalities in lungs from older patients with CF without radiation exposure.


    To evaluate the potential of MRI to detect abnormal lung structure and perfusion in infants and preschool children with CF, and to monitor the response to therapy for pulmonary exacerbation.


    MRI studies were performed in 50 children with CF (age, 3.1 ± 2.1 yr; range, 0-6 yr) in stable clinical condition (n = 40) or pulmonary exacerbation before and after antibiotic treatment (n = 10), and in 26 non-CF control subjects (age, 2.9 ± 1.9 yr). T1- and T2-weighted sequences before and after intravenous contrast and first-pass perfusion imaging were acquired, and assessed on the basis of a dedicated morphofunctional score.


    MRI demonstrated bronchial wall thickening/bronchiectasis, mucus plugging, and perfusion deficits from the first year of life in most stable patients with CF (global score, 10.0 ± 4.0), but not in non-CF control subjects (score, 0.0 ± 0.0; P < 0.001). In patients with exacerbations, the global MRI score was increased to 18.0 ± 2.0 (P < 0.001), and was significantly reduced to 12.0 ± 3.0 (P < 0.05) after antibiotic therapy.


    MRI detected abnormalities in lung structure and perfusion, and response to therapy for exacerbations in infants and preschool children with CF. These results support the development of MRI for noninvasive monitoring and as an end point in interventional trials for early CF lung disease. Clinical trial registered with (NCT00760071).


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