Originally posted in Journal of Cystic Fibrosis

Abstract: Background: Cystic fibrosis (CF) is characterised by impaired mucociliary clearance (MCC), chronic inflammation and infection, and progressively deteriorating lung function. Inhaled mannitol (Bronchitol) has been shown to increase MCC and cough clearance and FEV1 in CF patients, contributing to better lung hygiene and consequently a slower decline in lung function. This study was designed to determine the dose relationship of mannitol treatment and improvement in FEV1 and FVC as well as safety.Methods: This was a randomised, open-label, crossover, dose response study. Following a 2-week treatment with mannitol 400mg b.i.d., 48 CF patients with a mean (SD) FEV1 % predicted of 64 (13.2), received a further 3 treatments with 40mg, 120mg or 240mg b.i.d. for 2weeks each, in random order.Results: The study demonstrated a dose dependent increase in FEV1 and FVC. The 400mg dose showed the greatest improvement and the 40mg dose had no discernible effect. The mean percent change in FEV1 was ?1.57%, 3.61%, 3.87% and 8.75% respectively for the 40mg, 120mg, 240mg and 400mg treatments. There was a statistically significant change in FEV1 for 400mg compared to 40mg (p<0.0001) but the difference with 120mg and 240mg did not reach significance.The mean % change in FVC was ?0.90, 1.74, 3.07 and 8.14, for the 40mg, 120mg, 240mg and 400mg treatment arms, with p=0.0001, p=0.0037 and p=0.0304 respectively when compared to 400mg. The highest tested dose of 400mg had a similar safety profile to the other doses tested.The change in FEV1 and FVC by dose in the paediatric age group (<18years) was similar to the results in the adult population.Conclusion: Based on these results the 400mg b.i.d. dose has been further studied in phase III trials.

Originally posted in Journal of Cystic Fibrosis

Abstract: Background: A meta-analysis was performed to examine differences in family mealtimes between families with and without a child with CF. Both global measures of family functioning during the mealtime and parent-child micro behaviors specific to feeding were compared to determine if one class of mealtime behaviors is more strongly affected.Methods: Of 41 studies identified, 10 studies across 4 independent samples met the criteria for study inclusion. All studies included observational methodology. The mean sample age ranged from 18.6months to 8years and 6months. The total aggregate sample size was 230 participants, 119 with CF and 111 comparison children.Results: Families with children with CF encounter more difficulties during mealtimes than comparison families, and the effects on overall family functioning are greater than for parent–child micro feeding behaviors.Conclusion: Findings suggest that future interventions should focus on the broader family context as well as behaviors specific to feeding.

Originally posted in Journal of Cystic Fibrosis

While the determination of exercise capacity is viewed as clinical best practice in cystic fibrosis (CF), its measurement using a cardiopulmonary exercise test (CPET) remains as somewhat of a mystery for many CF clinicians. Two studies in the current issue (of the Journal of Cystic Fibrosis) highlight the use of exercise testing in CF clinical practice. The role of retained exercise capacity (VO2max) and levels of physical activity in CF in maintaining health status is compelling. Using an accelerometer to determine levels of physical activity, Hebestreit et al. found that more physically active CF patients had best preserved VO2max, FEV1 and nutritional status. These results are supported by a more recent review by Wilkes and colleagues who reported that children with CF with increased activity demonstrated a reduced decline in pulmonary function.

Originally posted in Journal of Cystic Fibrosis

Abstract: Background: Mice with the cystic fibrosis transmembrane conductance regulator (Cftr) gene knocked out develop osteopenia. To determine whether this phenotype is present in cystic fibrosis mouse models with the ?F508 Cftr mutation we assessed the femora of adult FVB/N Cftrtm1Eur and C57BL/6 Cftrtm1Kth mice.Methods: Bone disease, relative to littermate controls, was measured using histology, densitometry and quantitative imaging.Results: C57BL/6 Cftrtm1Kth mice had shorter femurs and bones of lower volume due to thinner trabeculae, compared to wild type littermates. FVB/N Cftrtm1Eur mice also presented a lower bone volume which was due to significantly fewer trabeculae in this strain. Osteoblast and osteoclast numbers did not differ between CF and controls, for either of FVB/N Cftrtm1Eur or C57BL/6 Cftrtm1Kth mice. The bone architecture of FVB/N Cftrtm1Eur mice did not significantly differ from that of C57BL/6 Cftrtm1Kth mice.Conclusions: An osteopenic bone disease is evident in adult ?F508-Cftr cystic fibrosis mouse models.

Originally posted in Journal of Cystic Fibrosis

The Journal of Cystic Fibrosis is the official Journal of the European Cystic Fibrosis Society (ECFS). The ECFS is a professional organisation and has members that form a wide range of disciplines including scientists, physicians, nurses and allied health professionals. The mission of ECFS is to facilitate the acquisition and sharing of knowledge and the improvement of patient care in all aspects of CF. An important instrument for this mission is the Journal. After nearly a decade, the Journal is now a well established source of valuable scientific and clinical information for individuals all over the world, interested in this hereditary disease. Cystic Fibrosis is a very complex disease which is mirrored by the high diversity of topics which are covered in the Journal (). Articles are published online and in the six yearly issues of the Journal or supplements.

Originally posted in Journal of Cystic Fibrosis

Abstract: Background: This is the second article related to a review of the literature based on data from national cystic fibrosis (CF) registries up to June 2008 and covering a total of 115 studies. It focuses on two topics: neonatal screening (NS) and nutritional status, with particular reference to growth.Methods: Ten papers meeting the inclusion criteria were found on the topic of NS and its impact on the course of the disease, and were analyzed according to a dedicated grid. The issue of nutrition was addressed by 14 studies, analyzed according to similar criteria.Results: Most of the studies report benefits of early diagnosis by NS, albeit to variable degrees. The benefits were assessed in terms of better nutritional status and growth, but also in terms of lower overall morbidity rate as compared to subjects diagnosed by symptoms. The main biases of these studies, which partly undermine the validity of their results, are also analyzed.A part of our analysis on nutrition/growth is dedicated to the identification of the most suitable parameters to define malnutrition: in children older than two years the body mass index percentile (BMIp) appears to be the most sensitive and significantly associated with respiratory function. Better nutritional status and satisfactory growth appear to be associated with better lung function and lower risk of death. The relationship between nutritional status and socio-economic status is also of interest.Conclusions: CF registry studies support the outcome of cohort observational studies i.e. that pre-symptomatic early diagnosis is beneficial, especially in terms of nutritional status and growth. Studies on nutrition indicate that good nutritional status is associated with better respiratory function and prognosis. Regarding methods, the need emerged to manage potential biases of this kind of non randomized studies, resorting to suitable statistical techniques, such as matching and stratification and, above all, to multivariate methods able to provide estimates adjusted for the main covariates tested.

Originally posted in Journal of Cystic Fibrosis

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.

Originally posted in Journal of Cystic Fibrosis

Abstract: In patients with cystic fibrosis (CF), respiratory infections with the opportunistic bacterial pathogen Pseudomonas aeruginosa have a major impact on morbidity and mortality. Aminoglycosides, especially tobramycin, have been used successfully to combat these infections. Aminoglycoside penetration of bronchial secretions is poor when the antibiotic is administered intravenously. Nebulization allows direct delivery of the drug to the sites of infection within the airways, while avoiding systemic exposure. Published clinical data show that inhaled tobramycin reduces the bacterial load, improves lung function and reduces the number of hospital admissions. Inhaled tobramycin has been used successfully to eradicate P. aeruginosa in patients with early infection. Maintaining clinical benefits requires chronic tobramycin treatment, and the concept of chronic intermittent inhaled treatment (typically, alternating drug and drug-free periods of 28days) was introduced to minimize the emergence of aminoglycoside resistant P. aeruginosa strains. Other therapeutic advances include the development of different tobramycin formulations and nebulizers that reduce delivery time without compromising efficacy. An optimal treatment regimen for patients with CF with early or intermittent P. aeruginosa infections remains a high priority to maintain long-term lung health.

Originally posted in Journal of Cystic Fibrosis

Originally posted in Journal of Cystic Fibrosis

Abstract: Mutation epidemiology in each ethnic group is important for cystic fibrosis diagnosis and genetic counselling. To date, little has been reported on the prevalence of cystic fibrosis in the Ecuadorian population where the mutation distribution appears to differ from that of Europe. We present a series of four Ecuadorian patients homozygous for the H609R mutation in the CFTR gene. This is the first report of detection of this mutation in the Ecuadorian population. Taking advantage of the homozygous status of the patients, an evaluation of the most important clinical parameters is presented. From the diagnostic point of view, the information provided by our study is of relevance in designing an appropriate strategy for genetic testing of patients in Ecuador and in European countries where immigration from Ecuador is common.

Originally posted in Journal of Cystic Fibrosis

Abstract: Cystic fibrosis (CF; MIM# 219700) is the most frequent recessive disease in Caucasian patients. However, immigration from the Middle East and Africa to Europe is revealing different CFTR mutations.Here, we have described an 875+1G?A mutation, found for the first time in a homozygous state in an 8 yr old boy. He was the child of a couple of Egyptian first level cousins, both carriers of the mutation.The functional test revealed the 875+1G?A to be a severe mutation, leading to defective protein function as detected by nasal potential difference (NPD) measurements.

Originally posted in Journal of Cystic Fibrosis

Abstract: Patient registries are organized systems of data collection for scientific, clinical or health strategy purposes.Aims of our review were to document scientific literature based on data and information from cystic fibrosis (CF) registries; to understand which clinical problems have been addressed and for which of these the studies concerned have correctly answered the questions raised (i.e. a methodological critique) and to identify clinical issues in need of further investigation. The review included primary studies starting from a formally constituted CF registry of at least national level, using data from the registry to evaluate research hypotheses.This article is an overview of the research undertaken, focusing in detail on the issues of mortality and survival. The studies considered here focused mainly or secondarily on survival in CF, the aim being to ascertain an improving trend, identify any prognostic factors and, in some cases, attempt to provide a predictive model of survival.

Originally posted in Journal of Cystic Fibrosis

Abstract: Background: For the past decade, percentage of ideal body weight (%IBW) was recommended by European and US nutrition consensus reports as preferred clinical measure of nutritional status in children with cystic fibrosis (CF). We and others have demonstrated that the %IBW method underestimates the prevalence of nutritional failure in CF, but the underlying mechanism for this methodological flaw remains incompletely defined.Design: We performed model calculations from cross sectional growth data of healthy and CF-children to assess the methodological limitations of %IBW calculation.Results: Here we demonstrate that an intrinsic limitation of %IBW method is that it largely ignores the statistical principle of regression to the mean. The key assumption of %IBW is that ideal weight-for-age is on exactly the same percentile ranking as height-for-age. We show that this assumption is only valid if the individual’s height is close to the reference median. When the stature deviates from the median of the reference population, however, the increments of height-for-age and weight-for-age percentiles are not the same. In consequence, %IBW method systematically underestimates the ideal weight for smaller-than-average individuals, like CF-patients, which results in significant underestimation of the prevalence of malnutrition in this group of patients.Conclusion: There is increasing scientific evidence that calculation of %IBW as a measure of nutritional status in children with CF is flawed and should be discontinued. It is expected that future guidelines will recommend the use of alternative measures of weight-for-height proportion, e.g. BMI percentiles, to assess underweight and malnutrition in patients with CF.

Originally posted in Journal of Cystic Fibrosis

Abstract: Background: Cystic fibrosis (CF) specific patient-derived and reported symptom tools are critical steps toward evaluating the outcomes of new therapies for CF.Methods: We conducted 25 in-depth qualitative interviews using the Day Reconstruction Method and 9 cognitive interviews at two CF programs, the University of Washington and Seattle Children’s Hospital and Regional Medical Center. The interviews were audio-recorded and transcribed, and then coded and analyzed for themes relating to pulmonary symptoms and related psychosocial impacts.Results: Six pulmonary symptoms were identified as central to CF: cough, sputum production, wheeze, chest tightness, difficulty breathing/shortness of breath, and fever. Emotional impacts included frustration, sadness/depression, irritability, worry, difficulty sleeping; while activity impacts included time spent sitting or lying down, reduction of usual activities, and missing school or work. In all, 8 symptom items, 4 emotional impacts items, and 4 activity impacts were selected for inclusion on a new daily diary. We also assessed triggers for seeking care.Conclusions: Using a qualitative inductive methodology, we have obtained patient centered data regarding pulmonary symptoms and burdens and have created a novel patient reported outcome measure for CF. Future studies will assess the validity of the instruments.

Originally posted in Journal of Cystic Fibrosis

Abstract: Background: Allergic bronchopulmonary aspergillosis (ABPA) in patients with CF is associated with frequent exacerbations and deterioration of lung function. Oral corticosteroids are standard therapy for ABPA and are associated with severe side effects. Monthly pulses of high-dose intravenous methylprednisolone (HDIVPM) are an effective therapy for autoimmune diseases with fewer side effects compared to oral prednisone, implicating its use for patients with CF who suffer from ABPA.Methods: 9 patients with CF and ABPA (4 male, 5 female, ages 7–36 years) received HDIVPM (10–15 mg/kg/d), for 3 days per month, and itraconazole, until clinical and laboratory resolution of ABPA.Results: All patients showed clinical and laboratory improvement (FEV1 increase, serum IgE levels and total eosinophil counts decrease) and treatment was discontinued after 6–10 pulses. Adverse effects were minor and disappeared shortly after each IV pulse therapy.Conclusion: High-dose IV-pulse methylprednisolone is an effective treatment for ABPA in CF with minor side effects.

Originally posted in Journal of Cystic Fibrosis

Abstract: Background: Adaptive aerosol delivery (AAD) nebuliser devices can reduce treatment times whilst enabling adherence to be monitored using inbuilt data logs. Using one such device, we have monitored nebulised antibiotic adherence in children with Cystic Fibrosis (CF).Methods: In CF children infected with Pseudomonas aeruginosa, downloaded data from an AAD device was used to calculate morning, evening and overall monthly adherence to antibiotic therapy over a year.Results: Overall monthly adherence to nebulised antibiotic therapy in 28 children was maintained between 60 and 70% over the year. Considerable variation in adherence, both between and within patients, was evident (Mean [SD] coefficient of variation, 37[44]%). Evening adherence (75[37]%) was better than morning adherence (58[34]%: p=0.012). Treatment regimens were changed in 8/28 patients based on adherence data.Conclusions: Routine adherence monitoring can be implemented in an outpatient setting. Using this type of information it is possible to identify which aspects of treatment can be improved and to work together with families to individualise treatments.

Originally posted in Journal of Cystic Fibrosis

Abstract: Background: Sexual and reproductive health (SRH) is increasingly relevant for men with CF. However, the extent of similarities or differences in SRH clinical practices across different centres or states is unknown as single clinic studies are not informative about variations in male preferences or clinical practices. We wished to determine the variability of male SRH knowledge and preferences, and clinical practices across different CF clinics.Methods: Men attending 5 adult CF clinics in Australasia completed a survey of SRH knowledge, attitudes and behaviours.Results: 264 (64%) men participated, with a median age of 30 years (17–56). 65% knew of near universal infertility due to a transport problem. 43% heard about infertility from their preferred source, but significantly later than desired. Less than half had undergone semen analysis (SA), which, while varying by site, was consistently later than preferred. 57 men were fathers, of whom 29 had utilised ART.Conclusion: Men’s preferences around SRH were more consistent than clinical practices. Clinical practice guidelines and training for health professionals would help reduce the gap between men’s SRH preferences and clinical practice.

Originally posted in Journal of Cystic Fibrosis

Abstract: Approximately 10–80% of patients with Cystic Fibrosis (CF) have vitamin D deficiency. Obtaining therapeutic vitamin D levels has been a challenge for CF care providers using current recommended high-dose oral ergocalciferol (400,000 IU over 2 months). The objective of this study was to evaluate the safety and efficacy of a 2-week, very high dose ergocalciferol (700,000 IU over 14 days) repletion strategy in children and young adults with CF.As part of a quality improvement initiative, a prospective cohort study was performed from January through May 2007. Phase I included identifying individuals with CF who were subtherapeutic in 25-OH D. In phase II, 50,000 IU of ergocalciferol was prescribed for a 14 day term and administered daily. During phase III, a post treatment 25-OH D level was obtained to determine improvement. Baseline demographics and clinical characteristics were obtained at study entry. Stratification of the post 25-OHD levels was defined.Eighteen individuals with CF participated in the study. The mean age was 17±5 years (range 6–25 years). One hundred percent were pancreatic insufficient and required pancreatic enzyme replacement. All 18 had 25-OHD levels less than 30 ng/mL pre-treatment.Seventeen of the 18 (94%) participants became therapeutic in the 2-week interval. No patients had values considered high abnormal (100–150 ng/mL) or toxic (>150 ng/mL). Mean change was noted at an increase of 37.3±22 ng/mL in the 2-week period (p<0.001). Pre and peripubertal individuals had a significantly greater increase in 25-OH D levels.The results of this study demonstrate that very high dosing of vitamin D using oral ergocalciferol over a 14 day period is an effective strategy in achieving therapeutic levels of 25-OH vitamin D in children and young adults with CF. We believe this regimen deserves further study.

Originally posted in Journal of Cystic Fibrosis

Abstract: Introduction: Extra-pulmonary complications of Burkholderia cepacia complex (Bcc) infection in patients with cystic fibrosis are unusual. To the best of the authors’ knowledge no case of pyomyositis secondary to Bcc infection has been reported previously.Case presentation: We report a case of pyomyositis of the forearm caused by Bcc infection in a patient with CF. We also briefly discuss the management of pyomyositis.Conclusion: Pyomyositis is a potential extra-pulmonary complication of Bcc infection in patients with CF. A high index of clinical suspicion is required to make a prompt diagnosis. Final diagnosis may need MRI. An early diagnosis, aggressive medical therapy, multidisciplinary care and timely surgical intervention are all essential for proper management of this condition.

Originally posted in Journal of Cystic Fibrosis

Abstract: We investigated the prevalence of cystic fibrosis-related diabetes (CFRD) and its association with various demographic and clinical conditions in a Dutch child and adult cystic fibrosis (CF) population.Patients were classified as having either normal glucose tolerance (NGT), impaired glucose tolerance (IGT) or CFRD. Associations with the following parameters were studied: age, gender, BMI, mutations, pulmonary function, infection status, and hospitalization.In our patient population the prevalence of IGT and CFRD was 16% and 31% respectively. After excluding pancreatic sufficient patients, the prevalence of CFRD was 40% and in patients over 40 years 52%. Compared with patients with NGT, CFRD patients were older, had more in-hospital days and had worse pulmonary function. Women developed CFRD at a significantly younger age than men.CFRD is a frequently occurring co-morbidity in patients with CF. The prevalence of CFRD is increasing in ageing CF populations and deserves rising attention in CF management.

Originally posted in Journal of Cystic Fibrosis

Abstract: Many countries have introduced newborn screening for cystic fibrosis to facilitate diagnosis prior to the development of lung disease. Although most infants with cystic fibrosis are asymptomatic from a respiratory point of view at diagnosis, structural lung disease has been detected by computed tomography. We present a case of an asymptomatic infant with cystic fibrosis diagnosed following newborn screening who had endobronchial infection with Pseudomonas aeruginosa and radiological evidence of bronchiectasis at 3 months of age.

Originally posted in Journal of Cystic Fibrosis

Abstract: Early diagnosis and treatment of the respiratory and gastrointestinal complications of cystic fibrosis (CF) have led to improved survival with many patients living beyond the fourth decade. Along with this increased life expectancy is the risk of further disease associated with the chronic manifestations of their condition. We report a patient with documented CF related liver disease for which he was under routine surveillance that presented with histologically proven hepatocellular carcinoma (HCC). It is important that physicians are aware of this association as increased vigilance may lead to earlier diagnosis and perhaps, a better outcome.

Originally posted in Journal of Cystic Fibrosis

We were interested to read recently in the Journal of ‘cepacia syndrome’ being successfully treated by combined nebulised and intravenous (IV) therapy with both meropenem and tobramycin in a 31 year old woman with cystic fibrosis (CF) and an en-bloc liver–pancreas transplant . This reminded us of one of our current patients who survived the ‘cepacia syndrome’ following treatment with IV antibiotics, nebulised tobramycin and recombinant human deoxyribonuclease (rhDNase) and remains relatively well 8 years later.