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A significant increase in life expectancy in successive birth cohorts of people with cystic fibrosis (CF) is a result of more effective treatment for the disease. It is also now widely recognized that outcomes for patients cared for in specialist CF Centres are better than for those who are not. Key to the effectiveness of the specialist CF Centre is the multidisciplinary team (MDT), which should include consultants, clinical nurse specialist, microbiologist, physiotherapist, dietitian, pharmacist, clinical psychologist, social worker, clinical geneticist and allied healthcare professionals, all of whom should be experienced in CF care. Members of the MDT are also expected to keep up to date with developments in CF through continued professional development, attendance at conferences, auditing and involvement in research. Specialists CF Centres should also network with other Centres both nationally and internationally, and feed Centre data to registries in order to further the understanding of the disease. This paper provides a framework for the specialist CF Centre, including the organisation of the Centre and the individual roles of MDT members, as well as highlighting the value of CF organisations and disease registries.

Background Respiratory viruses have become increasingly recognised as important agents in pulmonary exacerbations in infants and children with CF. The aim of this study was to determine the prevalence of respiratory viruses during acute pulmonary exacerbations in adults and compare the severity of these exacerbations with non-viral associated exacerbations. Methods This was a retrospective case control study. Viral throat swabs were taken from all patients presenting with an acute pulmonary exacerbation requiring intravenous antibiotic treatment over a 12month period. Results There were 432 pulmonary exacerbations in 180 adults. A positive viral PCR in 42 exacerbations indicated a prevalence of 9.7%. The commonest virus isolated was rhinovirus ( n =29, 69%) with influenza A/H1N1 in seven patients (16.7%). Exacerbations associated with a positive viral PCR had a greater fall in lung function at presentation with higher levels of inflammatory markers. They received more days of intravenous antibiotics, showed less response to treatment and had a shorter time to next pulmonary exacerbation compared to matched controls. Conclusion Viral associated pulmonary exacerbations in adults with CF are associated with more severe pulmonary involvement and respond less well to standard treatment.

BackgroundEnteral tube feeding (ETF) has been evaluated in paediatric and mixed child and adult populations with cystic fibrosis, demonstrating positive outcomes from 6months to 2years post insertion. No studies have examined the longer term nutritional and clinical outcomes in an exclusively adult population with cystic fibrosis or compared the outcomes for those who meet standard criteria and opt to undertake or decline ETF.MethodsTwenty three out of 380 patients attending the Leeds Regional Adult CF unit fulfilled the standard criteria for commencing ETF (CF Trust, 2002) between 2004 and 2008. Weight, BMI, FEV1, FVC, CFRD, and number of intravenous antibiotic treatment days were collected at 1year pre baseline, at baseline, and at 1, 2, and 3years post baseline for all these patients whether they accepted or declined ETF.ResultsSeventeen of the 23 patients agreed to accept a programme of ETF, two of whom died within the first year of ETF. In the remaining patients (n=15), weight increased by 19.5% from baseline (p

Background:Once daily intravenous aminoglycoside dosing (ODD) is widely used to treat acute Pseudomonas aeruginosa exacerbations in patients with cystic fibrosis. Controversy exists as to what is the most appropriate method of therapeutic drug monitoring (TDM) of such therapy with recommendations including trough plasma concentrations of

Background Despite the importance of identifying and managing a pulmonary exacerbation, and its use as an outcome measure in interventions, there is no standardised definition in cystic fibrosis. In achieving standardised criteria it is important to identify patient-reported indicators. Methods Interviews were undertaken with 35 school aged children. They reported symptoms experienced during a pulmonary exacerbation in two ways: the first symptoms they become aware of, and how they recognised when they were improving. Interviews were taped, transcribed verbatim and the data analysed thematically. Results For many children, the onset of an exacerbation was characterised by ‘cold' symptoms, tiredness, and changes in cough. For those with moderate or severe disease, sleep disruption, activity induced breathlessness, changes in mood, sputum volume and lack of appetite were common. When describing improvement children focused initially on activities they were now able to perform accompanied by improvements in tiredness and cough. Those with moderate or severe disease also reported improvements in sleep and mood, breathlessness, sputum volume and colour. Conclusions Child-reported indicators of a pulmonary exacerbation tend to map onto those reported by adults. These results provide the rationale for the development of a single scale for school age children and adults that could be sensitive to progressive stages of CF disease.

Background Safety and toxicity data for nebulised tobramycin are mainly derived from use of the Pari LC® Plus nebuliser, yet many centres are now using advanced nebulisers, such as the eFlow®. Methods Ten children (ages 2–16years) receiving 300mg TOBI® via eFlow® for clinical reasons participated. Serum tobramycin levels were obtained 1h post nebulisation. Nine provided samples for urinary NAG, and 10 underwent audiology. Results Tobramycin levels were >1mg/L in 3 children (maximum 3.8, 2 children aged 2years). Urine NAG/creatinine levels were raised (>0.94μmol/min/mmol) in 5 children, 1 of these had a tobramycin level of >1mg/L. One patient had high frequency hearing loss. Conclusion Serum tobramycin levels over 1mg/L can occur 1h post 300mg TOBI® delivered by eFlow®. Raised urinary NAG levels suggest that some children may have some associated early renal toxicity.

In cystic fibrosis inhalation of drugs for the treatment of CF related lung disease has been proven to be highly effective. Consequently, an increasing number of drugs and devices have been developed for CF lung disease or are currently under development. In this European consensus document we review the current status of inhaled medication in CF, including the mechanisms of action of the various drugs, their modes of administration and indications, their effects on lung function, exacerbation rates, survival and quality of life, as well as side effects. Specifically we address antibiotics, mucolytics/mucous mobilizers, anti-inflammatory drugs, bronchodilators and combinations of solutions. Additionally, we review the current knowledge on devices for inhalation therapy with regard to optimal particle sizes and characteristics of wet nebulisers, dry powder and metered dose inhalers. Finally, we address the subject of testing new devices before market introduction.

Background Reports indicate that nutritional and respiratory decline occur up to four years prior to diagnosis of cystic fibrosis related diabetes (CFRD). Our aim was to establish whether intensive nutritional intervention prevents pre-diabetic nutritional decline in an adult population with CFRD. Methods 48 adult patients with CFRD were matched to 48 controls with CF, for age, gender and lung pathogen status. Nutritional and other clinical indices were recorded at annual intervals from six years before until two years after diagnosis. Data were also analysed to examine the impact of early and late acquisition of CFRD. Results No important differences in weight, height, body mass index (BMI), lung function or intravenous treatment were found between groups in the six years prior to diagnosis, nor any significant deviation over time. In those who developed diabetes, use of overnight enteral tube feeding (ETF) was four times as likely at the time of diagnosis, compared to controls [ETF 43.8% (CFRD) v 18.8% (CF Controls), OR 4.0, CI 1.3 to 16.4, p =0.01]. Age at onset of CFRD played a significant role in determining the pre-diabetic clinical course. Younger diabetics with continued growth at study onset ( n =17) had a lower BMI from 2 years prior to diagnosis compared to controls [BMI 18.9 kg/m 2 (CFRD) v 20.8 kg/m 2 (CF Controls), diff=1.9, CI −0.1 to 3.7 p =0.04]. The BMI of older diabetics (completed growth at study onset) was equal to that of controls throughout. Conclusion Pre-diabetic nutritional decline is not inevitable in adults with CFRD, but is influenced by age of onset. In the group overall, those with CFRD are more likely to require ETF from 2 years prior to diagnosis. Despite intensive nutritional intervention, patients who continue to grow throughout the pre-diabetic years, show a level of nutritional decline absent in older adults.

Background This study was designed to address the concern that intensive regimens to eradicate early Pseudomonas aeruginosa infection in patients with cystic fibrosis may lead to the emergence of antibiotic-resistant isolates. Methods Data was analysed retrospectively over a 10 year period at the Leeds Regional Paediatric Cystic Fibrosis Centre. All patients with first-ever isolation of P. aeruginosa who successfully completed an eradication regimen were included. Antibiotic sensitivities of P. aeruginosa were compared between initial and subsequent re-isolations in patients where eradication was successful and in those where treatment had failed. Results Forty one patients with first acquisitions for P. aeruginosa and who completed eradication treatment were identified. Eradication treatments consisted of oral, intravenous, nebulised antibiotics or a combination of these. The antibiotic sensitivity of P. aeruginosa in first growths was high and remained so on subsequent re-isolations. A repeated measures logistic model found no significant difference with time of isolation. There was no statistically significant difference in antibiotic sensitivity between P. aeruginosa isolated after successful and failed eradication. Conclusions Repeated intensive regimens for P. aeruginosa eradication did not result in a significant increase in overall antibiotic resistance between initial and subsequent growths of this organism over the period of this study.

Background Low bone mineral density is common in adults with cystic fibrosis. Children with good lung function compared to controls matched for body size have normal bone mineralisation. There are few data in large unselected populations of children. Methods All children between five and 16 years were invited to take part. Disease severity was assessed. Bone mineral measurements using a GE-Lunar Prodigy densitometer were expressed as age and gender matched Z -scores. Bone mineral apparent density for L2–L4 was estimated and data from UK Caucasian children used to create age and gender specific reference ranges for predicted values. Z -scores were calculated. Total body analysis utilised the Molgaard method. Blood was sampled for measurement of 25-hydroxyvitamin D, and parathyroid hormone levels. Results 107 children entered the study. 18 and 10 children had low areal and apparent bone mineral density respectively. Short, narrow bones were common. Fifteen children reported 22 fractures, 20 with associated trauma. The best predictors of bone status were ZBMI and percent predicted FEV 1 . Conclusions Bone mineral density corrected for body size was normal in over 90% of children. These results are similar to previously reported results in small studies of children with well preserved respiratory function.

BackgroundThis study aims to quantitatively and qualitatively assess microvascular complications and their risk factors in patients with cystic fibrosis-related diabetes (CFRD) compared to those with type 1 diabetes mellitus (DM1).Methods79 patients with CFRD were matched with 79 patients with DM1 according to sex, age and duration of insulin therapy. Retinopathy, peripheral neuropathy, nephropathy and microalbuminuria were the microvascular complications assessed. Risk factors studied were: smoking, BMI, HbA1c, cholesterol, cholesterol/HDL ratio, diastolic and systolic blood pressure.ResultsBoth groups had the same number of microvascular complications (29%). CFRD patients showed more microalbuminuria (21% versus 4.1%; p=0.003), while retinopathy was more common in patients with DM1 (24% versus 10%; p=0.044). The prevalences of peripheral neuropathy and nephropathy were similar. Patients with CFRD had lower BMI (p

Inadequate bone mineral accrual during growth and accelerated bone demineralisation in adulthood are recognised as additional and serious complications for patients with cystic fibrosis (CF). However, little attention has been given to preventative strategies for this population. Inadequate bone accrual during childhood and adolescence, and premature bone loss, lead to a failure to attain an optimal peak bone mass, osteoporosis and fracture in patients with CF. Pharmaceutical treatments may assist in the improvement of bone in patients with CF, but these are usually not preferable for use in children. Evidence indicates that regular, weight-bearing exercise significantly enhances bone accrual in healthy children. This paper reviews the literature concerning the potential for weight-bearing exercise to improve bone mineral accrual in children with CF. All relevant literature since 1979 was obtained and reviewed from the Medline, PubMed, Cochrane and PEDro data base. Evidence concerning the efficacy of exercise for bone health in CF is lacking. There have been no controlled trials investigating the value of weight-bearing exercise for bone accrual in children with CF. As exercise may offer an effective and enjoyable strategy to improve the bone development in children who have CF, exercise should be a high priority for randomised controlled trials in this population.

BackgroundPatients with cystic fibrosis (CF) are at high risk from the nephrotoxic effects of intravenous antibiotics due to repeated and prolonged courses of therapy. Routine methods of monitoring renal injury are insensitive. N-acetyl-b-d-glucosaminidase (NAG) is a lysosomal enzyme present in the renal proximal tubular cells, with increased excretion an indicator of renal tubular dysfunction.MethodsUrinary NAG, creatinine, serum creatinine, electrolytes and BUN were measured on days 1, 14 and at the first out-patient visit following treatment with tobramycin or colistin. Urinary NAG levels were corrected for urinary creatinine and expressed as a NAG ratio. Patients who received >1 course of intravenous antibiotics during the study period were included in a separate analysis of the cumulative effect of treatment.Results88 patients (44 female, 31 with CFRD) completed a single course of intravenous antibiotics. 71 patients had urinary NAG levels at follow-up. The median time to follow-up was 50 days. Serum electrolytes, creatinine and BUN were normal throughout. A 3.5-fold increase in urinary NAG excretion was observed between day 1 and 14 and 46% of patients had an elevated NAG level at follow-up. A highly significant difference in NAG excretion was observed on day 14 for tobramycin vs. colistin (median 2.24 vs. 0.98, p1 course of treatment during the study period, baseline NAG levels were significantly higher in subsequent courses (p

Background The disease progression of cystic fibrosis (CF) is marked by an increase in clinical conditions and therapeutic interventions, which have the potential to affect health-related quality of life (HRQoL). This cross-sectional study explored associations between clinical variables and HRQoL. Methods HRQoL was measured using the Cystic Fibrosis Quality of Life (CFQoL) questionnaire, which consists of nine domains: physical, social, treatment, chest symptoms, emotional functioning, concerns for the future, relationships, body image, and career concerns. The CFQoL was completed by 223 adults with CF. Clinical and demographic data collected were: age, gender, FEV 1 % predicted, BMI, Burkholderia cepacia status, lung transplant status, diabetic status, level of nutritional intervention, and presence of an intravenous access device. Multiple regression using forward selection was used to construct models relating these variables to each HRQoL domain. Results Despite many of the variables being inter-related, some variables were associated with CFQoL domains even in the presence of other important clinical factors. FEV 1 % predicted was weakly positively associated with all nine domains. Strong evidence emerged that patients who had received a lung transplant reported a higher HRQoL in physical and social functioning, chest symptoms, and treatment issues. Females tended to report a lower quality of life for chest symptoms and career issues, but higher values for body image. Patients with an access device expressed more career concerns. There was no evidence of an association between B. cepacia and any of the nine CFQoL domains. The model for the body image domain explained a high percentage of the variance ( R 2 =30%): negative body image was associated with lower BMI, having an access device, diabetes, and enteral feeding. Conclusions While important associations were identified, much of the variance in HRQoL remains unexplained. Other clinical and psychosocial variables merit investigation. A longitudinal study is required to investigate how the disease trajectory and associated treatments affect an individual's quality of life.

Background: Most patients with cystic fibrosis (CF) require a higher energy and protein intake than their healthy peer group. There are few data on dietary intakes of adult patients. The aim of this study was to determine nutritional intakes in an adult population with CF. The impact of nutritional intervention and disease on macronutrient intake was examined. Methods: Retrospective cross-sectional analysis of 94 unweighed food diaries at annual review (1995–2000). Energy and protein intakes were compared to the estimated average requirement (EAR) for energy and reference nutrient intake (RNI) for protein. The effect of diet alone, oral supplements, enteral tube feeding, and cystic fibrosis related diabetes (CFRD), on macronutrient intake was examined and impact of pancreatic sufficency (PS) and lung transplantation. Results: Mean energy and protein intakes approached recommended CF guidelines, but in 72% of assessments these values were not achieved. Mean energy and protein intakes for patients on diet alone and protein intake for those with CFRD failed to meet recommendations. Oral supplementation and enteral tube feeding regimens increased energy and protein intake above recommended levels. No group achieved 40% total energy from fat. Patients receiving enteral tube feeds had the highest mean energy and protein intakes but lowest body mass index (BMI) and lung function. Conclusion: Adequate mean energy and protein intakes in adult patients with CF mask subgroups of patients who fail to meet recommendations ie. diet alone, diabetic. Oral supplementation and enteral tube feeding increase energy and protein intake but fail to achieve an adequate BMI level in subjects with a decreased clinical status. Individual nutritional assessment remains essential.

Disease progression in cystic fibrosis (CF) is marked by deterioration across a number of physiological systems. In addition, there is evidence that females have a worse prognosis than males. The current work assesses the impact of both these factors on health related quality of life (HRQoL).Two hundred and twenty-three adolescents and adults completed the cystic fibrosis quality of life (CFQoL) questionnaire with a further 185 approached and not responding by non-completion of the questionnaire. The CFQoL is divided into nine domains: physical, social, treatment, chest symptoms, emotional functioning, concerns for the future, relationships, body image, and career. Measurement of objective clinical status included, body mass index (BMI), and percentage of predicted forced expiratory volume in one second (FEV1). General health perceptions (GHP) were also measured.Patients were sub-divided by gender and disease severity (mild70% FEV1, moderate 40-69% and severe40%). Factorial analysis of variance indicated significant main effects for FEV1 (F = 587.98, Por = 0.001) and BMI (F = 17.29, Por = 0.001) as a function of disease severity. Post hoc tests revealed significant two-group differences for FEV1 and BMI between disease severity groups. No differences were observed for gender across FEV1 or BMI. Differences emerged across most CFQoL domains for disease severity, with the exception of concerns for the future, which was consistently low throughout. Gender differences emerged for chest symptoms, emotional functioning, concerns for the future, body image and career. With the exception of body image, females exhibited poorer HRQoL. Pearson correlations indicated that females' perception of health was more closely related to clinical status than males.Disease severity has an impact on HRQoL in adolescents and adults with CF. Some differences emerged between males and females, with females generally reporting poorer HRQoL. Evidence indicated that males and females perceived their health status differently, with females having a more accurate perception of objective clinical health status.

Background: Patients were defined each successive month as either ‘chronic’ when more than 50% of the preceding 12 months were PA culture positive, ‘intermittent’ when ≤50% of the preceding 12 months were PA culture positive, ‘free of PA’, with no growth of PA for the previous 12 months, having previously been PA culture positive, or ‘never infected’, when PA had never been cultured. Methods: Cross-sectional analysis of 146 children attending the Leeds Regional Cystic Fibrosis Centre was performed to assess relationship between the new definition and clinical scores and investigations. The response variable was regressed on age and sex and the residuals analysed using the Kruskal–Wallis test. Results: The ‘chronic’ group (18% of patients) had significantly worse Shwachman–Kulczycki (SK) and Northern chest X-ray scores, and % predicted FEV1 values than the ‘free’ (28%) or ‘never’ (20%) categories (P

Background We report the aetiology and outcome of bloodstream infections (BSI) occurring at two regional cystic fibrosis (CF) centres (one adult, one paediatric) between 1998 and 2006. Methods A retrospective analysis of all positive blood cultures during the study period was performed. Results During the study period 1691 blood culture sets were taken. Fifty-seven clinically significant episodes of BSI in 48 people with CF (36 adult, 12 paediatric) were identified, along with 28 other episodes considered to be contamination or not clinically significant. The most common BSIs were caused by coagulase-negative staphylococci (13) Candida spp (10), and Stenotrophomonas maltophilia (8). The majority (82%) of significant BSIs were considered to originate from totally-implantable vascular access devices (TIVADs); only 9% were attributed to the lower respiratory tract. The TIVAD was removed in two-thirds of cases of TIVAD-associated BSI. There were three deaths (60% of cases) attributable to BSI originating from the lower respiratory tract but no deaths attributable to TIVAD-associated BSI. Conclusion Most significant BSIs in patients with CF originate from TIVADs. Targeted antimicrobial therapy and appropriate early device removal is associated with good clinical outcome. BSI originating from the lower respiratory tract is associated with poor clinical outcome.

Assessment of the potential risk of in flight hypoxaemia in patients with cystic fibrosis is often based on a hypoxic challenge where individuals have saturations and/or blood gases taken before and after inspiring 15% normobaric oxygen. The aim of this study was to see if routine clinical measurements could predict the outcome of this test. This was a prospective study comparing the modified 6-min walking test, lung function, body mass index, Northern (N) and Shwachman–Kulczycki (SK) scores with a hypoxic challenge (flight test) in 69 adults attending the Leeds regional CF Unit. Although, there was a significant correlation between post flight test PaO2 and N score (P=0.003), SK score (P=0.002), FVC % predicted (P=0.01), FEV1 % predicted (P=0.002), resting saturations (P13) or low baseline PaO2 (

Background: Generic health-related quality of life measures are often applied to disease groups without assessment of their psychometric properties. The current work assesses the properties of the Short Form 36-item (SF-36) questionnaire in a British sample of adolescents and adults with cystic fibrosis (CF). Methods: Two hundred and twenty-three adolescents and adults with CF completed the SF-36 with a further 185 approached and not responding by non-completion of the questionnaire. The structure and internal reliability of the instrument was assessed by principal components analysis, Cronbach alpha coefficients and item to domain correlations. Differences between disease severity groups were assessed by analysis of variance. Results: Factor analysis of the SF-36 scores broadly confirmed domain structures for the SF-36. Cronbach alpha coefficients were high (range 0.82–0.91) and item-to-same domain correlations were stronger than item-to-unrelated domain correlations. Examination of differences between mild, moderate and severe disease states revealed four significant main effects for: physical functioning, role limitation due to physical functioning, general health perceptions and energy and vitality. The analysis also revealed the presence of numerous ceiling effects across domains. Conclusions: The domain structure of the SF-36 was demonstrated to be robust. However, the discriminatory ability of the measure was disappointing. The presence of ceiling effects and the low frequency of differences between intermediate disease severity groups indicated that the SF-36 was not discriminatory with respect to mild disease states or progression of illness.