Laura Viviani

Longitudinal study of infectious intestinal disease in the UK (IID2 study): incidence in the community and presenting to general practice

Objectives To estimate, overall and by organism, the incidence of infectious intestinal disease (IID) in the community, presenting to general practice (GP) and reported to national surveillance. Design Prospective, community cohort study and prospective study of GP presentation conducted between April 2008 and August 2009. Setting Eighty-eight GPs across the UK recruited from the Medical Research Council General Practice Research Framework and the Primary Care Research Networks. Participants 6836 participants registered with the 88 participating practices in the community study; 991 patients with UK-acquired IID presenting to one of 37 practices taking part in the GP presentation study. Main outcome measures IID rates in the community, presenting to GP and reported to national surveillance, overall and by organism; annual IID cases and GP consultations by organism. Results The overall rate of IID in the community was 274 cases per 1000 person-years (95% CI 254 to 296); the rate of GP consultations was 17.7 per 1000 person-years (95% CI 14.4 to 21.8). There were 147 community cases and 10 GP consultations for every case reported to national surveillance. Norovirus was the most common organism, with incidence rates of 47 community cases per 1000 person-years and 2.1 GP consultations per 1000 person-years. Campylobacter was the most common bacterial pathogen, with a rate of 9.3 cases per 1000 person-years in the community, and 1.3 GP consultations per 1000 person-years. We estimate that there are up to 17 million sporadic, community cases of IID and 1 million GP consultations annually in the UK. Of these, norovirus accounts for 3 million cases and 130 000 GP consultations, and Campylobacter is responsible for 500 000 cases and 80 000 GP consultations. Conclusions IID poses a substantial community and healthcare burden in the UK. Control efforts must focus particularly on reducing the burden due to Campylobacter and enteric viruses.

Factors associated with FEV1 decline in cystic fibrosis: analysis of the ECFS Patient Registry

Pulmonary insufficiency is the main cause of death in cystic fibrosis (CF). We analysed forced expiratory volume in 1 s (FEV1) data of 14 732 patients registered in the European Cystic Fibrosis Society Patient Registry (ECFSPR) database in 2007. We used linear and logistic regressions to investigate associations between FEV1 % predicted and clinical outcomes. Body mass index (BMI), chronic infection by Pseudomonas aeruginosa, pancreatic status and CF-related diabetes (CFRD) showed a statistically significant (all p<0.0001) and clinically relevant effect on FEV1 % pred after adjusting for age. Patients with a lower BMI experience a six-fold increased odds ratio (95% CI 5.0–7.3) of having severe lung disease (FEV1 <40% pred) compared to patients with normal BMI. Being chronically infected with P. aeruginosa increases the odds ratio of severe lung disease by 2.4 (95% CI 2.0–2.7), and patients with pancreatic insufficiency experience a 2.0-fold increased odds ratio (95% CI 1.6–2.5) of severe lung disease compared to pancreatic sufficient patients. Patients with CFRD have a 1.8-fold increased odds ratio (95% CI 1.6–2.2) compared to patients not affected. These potential risk factors for pulmonary disease in patients with CF are to some degree preventable or treatable. We emphasise the importance of their early identification through frequent routine tests, the implementation of infection control measures, and a timely initiation of relevant therapies. Independent effect of nutrition, chronic Pseudomonas aeruginosa infection and CF-related diabetes on FEV1 in CF patients http://ow.ly/qhAXJ

Future trends in cystic fibrosis demography in 34 European countries

Median survival has increased in people with cystic fibrosis (CF) during the past six decades, which has led to an increased number of adults with CF. The future impact of changes in CF demographics has not been evaluated. The aim of this study was to estimate the number of children and adults with CF in 34 European countries by 2025. Data were obtained from the European Cystic Fibrosis Society Patient Registry. Population forecasts were performed for countries that have extensive CF population coverage and at least 4 years of longitudinal data by modelling future entering and exiting flows in registry cohorts. For the other countries, population projections were performed based on assumptions from knowledge of current CF epidemiology. Western European countries’ forecasts indicate that an increase in the overall number of CF patients by 2025, by approximately 50%, corresponds to an increase by 20% and by 75% in children and adults, respectively. In Eastern European countries the projections suggest a predominant increase in the CF child population, although the CF adult population would also increase. It was concluded that a large increase in the adult CF population is expected in the next decade. A significant increase in adult CF services throughout Europe is urgently required. A large increase in the number of CF adults is expected by 2025 that will require increase in adult CF care services http://ow.ly/INkvb

The relative frequency of CFTR mutation classes in European patients with cystic fibrosis

More than 1900 different mutations in the CFTR gene have been reported. These are grouped into classes according to their effect on the synthesis and/or function of the CFTR protein. CFTR repair therapies that are mutation or mutation class specific are under development. To progress efficiently in the clinical phase of drug development, knowledge of the relative frequency of CFTR mutation classes in different populations is useful. Therefore, we describe the mutation class spectrum in 25,394 subjects with CF from 23 European countries. In 18/23 countries, 80% or more of the patients had at least one class II mutation, explained by F508del being by far the most frequent mutation. Overall 16.4% of European patients had at least one class I mutation but this varied from 3 countries with more than 30% to 4 countries with less than 10% of subjects. Overall only respectively 3.9, 3.3 and 3.0% of European subjects had at least one mutation of classes III, IV and V with again great variability: 14% of Irish patients had at least one class III mutation, 7% of Portuguese patients had at least one class IV mutation, and in 6 countries more than 5% of patients had at least one class V mutation.

Report of the European respiratory society/European cystic fibrosis society task force on the care of adults with cystic fibrosis

The improved survival in people with cystic fibrosis has led to an increasing number of patients reaching adulthood. This trend is likely to be maintained over the next decades, suggesting a need to increase the number of centres with expertise in the management of adult patients with cystic fibrosis. These centres should be capable of delivering multidisciplinary care addressing the complexity of the disease, in addition to addressing the psychological burden on patients and their families. Further issues that require attention are organ transplantation and end of life management. Lung disease in adults with cystic fibrosis drives most of the clinical care requirements, and major life-threatening complications, such as respiratory infection, respiratory failure, pneumothorax and haemoptysis, and the management of lung transplantation require expertise from trained respiratory physicians. The taskforce therefore strongly reccommends that medical leadership in multidisciplinary adult teams should be attributed to a respiratory physician adequately trained in cystic fibrosis management. The task force suggests the implementation of a core curriculum for trainees in adult respiratory medicine and the selection and accreditation of training centres that deliver postgraduate training to the standards of the HERMES programme. Respiratory physicians, trained in adult CF management, should lead multidisciplinary teams taking care of patients http://ow.ly/SgRgj

Defective CFTR Expression and Function Are Detectable in Blood Monocytes: Development of a New Blood Test for Cystic Fibrosis

Background Evaluation of cystic fibrosis transmembrane conductance regulator (CFTR) functional activity to assess new therapies and define diagnosis of cystic fibrosis (CF) is cumbersome. It is known that leukocytes express detectable levels of CFTR but the molecule has not been characterized in these cells. In this study we aim at setting up and validating a blood test to evaluate CFTR expression and function in leukocytes. Description Western blot, PCR, immunofluorescence and cell membrane depolarization analysis by single-cell fluorescence imaging, using the potential-sensitive DiSBAC2(3) probe were utilized. Expression of PKA phosphorylated, cell membrane-localized CFTR was detected in non-CF monocytes, being undetectable or present in truncated form in monocytes derived from CF patients presenting with nonsense mutations. CFTR agonist administration induced membrane depolarization in monocytes isolated from non-CF donors (31 subjects) and, to a lesser extent, obligate CFTR heterozygous carriers (HTZ: 15 subjects), but it failed in monocytes from CF patients (44 subjects). We propose an index, which values in CF patients are significantly (p<0.001) lower than in the other two groups. Nasal Potential Difference, measured in selected subjects had concordant results with monocytes assay (Kappa statistic 0.93, 95%CI: 0.80–1.00). Results and Significance CFTR is detectable and is functional in human monocytes. We also showed that CFTR-associated activity can be evaluated in 5 ml of peripheral blood and devise an index potentially applicable for diagnostic purposes and both basic and translational research: from drug development to evaluation of functional outcomes in clinical trials.

European Cystic Fibrosis Society Standards of Care: Quality Management in cystic fibrosis

Since the earliest days of cystic fibrosis (CF) treatment, patient data have been recorded and reviewed in order to identify the factors that lead to more favourable outcomes. Large data repositories, such as the US Cystic Fibrosis Registry, which was established in the 1960s, enabled successful treatments and patient outcomes to be recognized and improvement programmes to be implemented in specialist CF centres. Over the past decades, the greater volumes of data becoming available through Centre databases and patient registries led to the possibility of making comparisons between different therapies, approaches to care and indeed data recording. The quality of care for individuals with CF has become a focus at several levels: patient, centre, regional, national and international. This paper reviews the quality management and improvement issues at each of these levels with particular reference to indicators of health, the role of CF Centres, regional networks, national health policy, and international data registration and comparisons.

The European Cystic Fibrosis Society Patient Registry: valuable lessons learned on how to sustain a disease registry

BackgroundDisease registries have the invaluable potential to provide an insight into the natural history of the disease under investigation, to provide useful information (e.g. through health indicators) for planning health care services and to identify suitable groups of patients for clinical trials enrolment. However, the establishment and maintenance of disease registries is a burdensome initiative from economical and organisational points of view and experience sharing on registries management is important to avoid waste of resources. The aim of this paper is to discuss the problems embedded in the institution and management of an international disease registry to warn against common mistakes that can derail the best of intentions: we share the experience of the European Cystic Fibrosis Society Patient Registry, which collects data on almost 30,000 patients from 23 countries.MethodsWe discuss the major problems that researchers often encounter in the creation and management of disease registries: definition of the aims the registry has to reach, definition of the criteria for patients referral to the registry, definition of the information to record, set up of a data quality process, handling of missing data, maintenance of data confidentiality, regulation of data use and dissemination of research results.ResultsWe give examples on how many crucial aspects were solved by the European Cystic Fibrosis Society Patient Registry regarding objectives, inclusion criteria and variables definition, data management, data quality controls, missing data handling, confidentiality maintenance, data use and results dissemination.ConclusionsWe suggest an extensive literature research and discussions in working groups with different stake holders, including patient representatives, on the objectives, inclusion criteria and the information to record. We propose to pilot the recording of few variables and test the applicability of their definition first. The use of a shared electronic platform for data collection that automatically computes derived variables, and automatically performs basic data quality controls is a good data management practice, that also helps in reducing missing data. We found crucial for success the collaboration with existing national and international registries, cystic fibrosis organisations and patients’ associations.

Impact of the A (H1N1) pandemic influenza (season 2009–2010) on patients with cystic fibrosis

BACKGROUND Influenza, like other respiratory viral infections, can cause acute deterioration of lung function in patients with cystic fibrosis (CF). Previous studies on a small number of patients reported that most people with CF infected with A (H1N1) influenza experienced a mild course of disease. AIM To characterise the impact of A (H1N1) infection on CF in a large number of patients from different centres and countries. METHODS CF centres accessing the web-site of the European Cystic Fibrosis Society (ECFS) were asked to report clinical data on patients with an ascertained diagnosis of influenza caused by the A (H1N1) virus. The study was web-based and data were collected through an electronic data sheet on the ECFS website. RESULTS Twenty-five centres from 10 countries caring for 4698 patients with CF reported data on 110 patients (2.3%), median age 13 years (range 1-39 years). The prevalence of infection in each centre ranged from 0% to 9.4%. Only 8.8% of the patients had been vaccinated. The main symptoms were fever and respiratory exacerbation requiring IV antibiotics in 53% of the patients; 48% of the patients were hospitalised for an average of 12.9 days (range 2-56) and 31% required oxygen treatment during the time of the infection. Most of the patients recovered and FEV(1) 1 month after the infection was similar to that before the infection. However, 6 patients were admitted to ICU, 5 with mechanical ventilation. Three patients with severe respiratory disease died. CONCLUSIONS A (H1N1) influenza infection caused transient but significant morbidity in most of the patients with CF. However, in a small number of patients with severe lung disease, A (H1N1) influenza was associated with respiratory deterioration, mechanical ventilation and even death.

Reference percentiles for FEV1 and BMI in European children and adults with cystic fibrosis

BackgroundThe clinical course of Cystic Fibrosis (CF) is usually measured using the percent predicted FEV1 and BMI Z-score referenced against a healthy population, since achieving normality is the ultimate goal of CF care. Referencing against age and sex matched CF peers may provide valuable information for patients and for comparison between CF centers or populations. Here, we used a large database of European CF patients to compute CF specific reference equations for FEV1 and BMI, derived CF-specific percentile charts and compared these European data to their nearest international equivalents.Methods34859 FEV1 and 40947 BMI observations were used to compute European CF specific percentiles. Quantile regression was applied to raw measurements as a function of sex, age and height. Results were compared with the North American equivalent for FEV1 and with the WHO 2007 normative values for BMI.ResultsFEV1 and BMI percentiles illustrated the large variability between CF patients receiving the best current care. The European CF specific percentiles for FEV1 were significantly different from those in the USA from an earlier era, with higher lung function in Europe. The CF specific percentiles for BMI declined relative to the WHO standard in older children. Lung function and BMI were similar in the two largest contributing European Countries (France and Germany).ConclusionThe CF specific percentile approach applied to FEV1 and BMI allows referencing patients with respect to their peers. These data allow peer to peer and population comparisons in CF patients.