Pneumocystis jirovecii and Cystic Fibrosis in Brittany, France.

Pneumocystis jirovecii is a transmissible fungus with a high pulmonary tropism. The prevalence of P. jirovecii in patients with cystic fibrosis (CF) has been estimated in Germany at 7.4%, in Spain at 21.5% and in Brazil at 38.2%. Data on the prevalence of P. jirovecii in CF patients in France remain scarce, particularly in Brittany, where the prevalence of CF is high (from 1/1600 to 1/4500). Our objectives were to determine the prevalence of colonization of the airways by P. jirovecii in Brittany in CF patients monitored at the "Centre de Ressources et de Compétences de la Mucoviscidose (CRCM)" of Rennes compared to that previously observed at the CRCM of Roscoff-Brest. Sputa from 86 patients (178 specimens) followed in Rennes were analyzed retrospectively. The detection of P. jirovecii was performed using real-time PCR targeting the gene encoding the mitochondrial large subunit of ribosomal RNA. Pneumocystis jirovecii DNA was detected in 3/86 patients (3.5%) monitored at Rennes, whereas it had previously been detected in 1/76 patients (1.3%) monitored at Roscoff-Brest, thus showing an overall prevalence of 2.5% in Brittany. These results obtained from two Breton centers taken together show that P. jirovecii prevalence in patients with CF in Brittany is lower than those observed in Germany, Spain, Brazil or in other regions of France. This study is a preliminary step in determining the risk factors for P. jirovecii acquisition, its epidemiological and clinical significance in CF patients through a prospective multicenter study.

Pseudomonas aeruginosa and Periodontal Pathogens in the Oral Cavity and Lungs of Cystic Fibrosis Patients: a Case-Control Study.

Cystic fibrosis (CF) is the most frequent lethal genetic disease in the Caucasian population. Lung destruction is the principal cause of death by chronic Pseudomonas aeruginosa colonization. There is a high prevalence of oropharyngeal anaerobic bacteria in sputum of CF patients. This study was carried out due to the lack of results comparing subgingival periodontal pathogenic bacteria between the oral cavity and lungs in patients with CF in relation with P. aeruginosa presence. Our first goal was to detect P. aeruginosa in oral and sputum samples by culture and molecular methods and to determine clonality of isolates. In addition, subgingival periodontal anaerobic bacteria were searched for in sputum. A cross-sectional pilot case-control study was conducted in the CF Reference Center in Roscoff, France. Ten CF patients with a ΔF508 homozygous mutation (5 chronically colonized [CC] and 5 not colonized [NC]) were enrolled. P. aeruginosa was detected in saliva, sputum, and subgingival plaque samples by real-time quantitative PCR (qPCR). Subsequently, periodontal bacteria were also detected and quantified in subgingival plaque and sputum samples by qPCR. In CC patients, P. aeruginosa was recovered in saliva and subgingival plaque samples. Sixteen P. aeruginosa strains were isolated in saliva and sputum from this group and compared by pulsed-field gel electrophoresis (PFGE). Subgingival periodontal anaerobic bacteria were found in sputum samples. A lower diversity of these species was recovered in the CC patients than in the NC patients. The presence of the same P. aeruginosa clonal types in saliva and sputum samples underlines that the oral cavity is a possible reservoir for lung infection.

[Analysis of hospital outpatient care of a rare disease: cystic fibrosis]. / Analyse de la prise en charge hospitalière ambulatoire de la mucoviscidose.

INTRODUCTION: Following the generalization of neonatal screening, the French CF Care Network has become structured around 45 qualified centres, the French CF Society, 2 national expertise centres, the Patient Registry and the National Protocol of CF Care in collaboration with the Vaincre Ia Mucoviscidose patient association. This organization and progress in treatment have resulted in the outpatient follow-up of a growing number of patients. Since 2010, the CF Network representatives have been conducting an assessment of outpatient follow-up to identify difficulties in complying with national and international clinical practice guidelines. METHODS: Two complementary quantitative and qualitative approaches were used to characterize and quantify the activities carried out by professionals in 8 centres both for outpatient visits and patient care coordination. RESULTS: Two thirds of the 1,4 75 patients followed in the centres were managed over the period, less than half (40%) of them attended outpatient visits, but all of them were concerned by care coordination activities, whether or not they were related to the visit. The core team (doctor, nurse, physio-therapist) is not mobilized at each scheduled outpatient visit as recommended. Professionals devote 40% less time for follow-up in adult centres than in paediatric centres, all activities included. The multidisciplinary outpatient visit process is complicated by the lack of available resources and the unsuitability of certain premises. DISCUSSION: With a constantly growing number of patients, CF centres are struggling to comply with good clinical practice and meet the specific needs of adult patients and transplant recipients. An upgrade of professional resources and an update of the National Protocol appear to be necessary.

CFTR p.Arg117His associated with CBAVD and other CFTR-related disorders.

BACKGROUND: The high frequency of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene mutation p.Arg117His in patients with congenital bilateral absence of the vas deferens (CBAVD) and in newborns screened for CF has created a dilemma. METHODS: Phenotypic and genotypic data were retrospectively collected in 179 non-newborn French individuals carrying p.Arg117His and a second CFTR mutation referred for symptoms or family history, by all French molecular genetics laboratories, referring physicians, CF care centres and infertility clinics. RESULTS: 97% of the patients had the intronic T7 normal variant in cis with p.Arg117His. 89% patients were male, with CBAVD being the reason for referral in 76%. In 166/179 patients with available detailed clinical features, final diagnoses were: four late-onset marked pulmonary disease, 83 isolated CBAVD, 67 other CFTR-related phenotypes, including 44 CBAVD with pulmonary and/or pancreatic symptoms and 12 asymptomatic cases. Respiratory symptoms were observed in 30% of the patients, but the overall phenotype was mild. No correlation was observed between sweat chloride concentrations and disease severity. Five couples at risk of CF offspring were identified and four benefited from prenatal or preimplantation genetic diagnoses (PND or PGD). Eight children were born, including four who were compound heterozygous for p.Arg117His and one with a severe CF mutation. CONCLUSIONS: Patients with CBAVD carrying p.Arg117His and a severe CF mutation should benefit from a clinical evaluation and follow-up. Depending on the CBAVD patients' genotype, a CFTR analysis should be considered in their partners in order to identify CF carrier couples and offer PND or PGD.

Experiences Among Patients With Cystic Fibrosis in the MucoExocet Study of Using Connected Devices for the Management of Pulmonary Exacerbations: Grounded Theory Qualitative Research.

BACKGROUND: Early detection of pulmonary exacerbations (PEx) in patients with cystic fibrosis is important to quickly trigger treatment and reduce respiratory damage. An intervention was designed in the frame of the MucoExocet research study providing patients with cystic fibrosis with connected devices and educating them to detect and react to their early signs of PEx. OBJECTIVE: This study aims to identify the contributions and conditions of home monitoring in relation to their care teams from the users' point of view to detect PEx early and treat it. This study focused on the patients' experiences as the first and main users of home monitoring. METHODS: A qualitative study was conducted to explore patients' and professionals' experiences with the intervention. We interviewed patients who completed the 2-year study using semistructured guides and conducted focus groups with the care teams. All the interviews were recorded and transcribed verbatim. Their educational material was collected. A grounded analysis was conducted by 2 researchers. RESULTS: A total of 20 patients completed the study. Three main categories emerged from the patients' verbatim transcripts and were also found in those of the professionals: (1) task technology fit, reflecting reliability, ease of use, accuracy of data, and support of the technology; (2) patient empowerment through technology, grouping patients' learnings, validation of their perception of exacerbation, assessment of treatment efficacy, awareness of healthy behaviors, and ability to react to PEx signs in relation to their care team; (3) use, reflecting a continuous or intermittent use, the perceived usefulness balanced with cumbersome measurements, routinization and personalization of the measurement process, and the way data are shared with the care team. Furthermore, 3 relationships were highlighted between the categories that reflect the necessary conditions for patient empowerment through the use of technology. CONCLUSIONS: We discuss a theorization of the process of patient empowerment through the use of connected devices and call for further research to verify or amend it in the context of other technologies, illnesses, and care organizations. TRIAL REGISTRATION: ClinicalTrials.gov NCT03304028; https://clinicaltrials.gov/ct2/show/results/NCT03304028.

Early glucose abnormalities revealed by continuous glucose monitoring associate with lung function decline in cystic fibrosis: A five-year prospective study.

BACKGROUND: Cystic fibrosis related diabetes (CFRD) is commonly associated with declining lung function and nutritional status. We aimed to evaluate the pulmonary impact of early glucose abnormalities by using 2-h standard oral glucose tolerance testing (OGTT) and continuous glucose monitoring (CGM) in people with cystic fibrosis (PwCF). METHODS: PwCF aged ≥10 years old without known CFRD were included in a five-year prospective multicentre study. Annual evaluation of nutritional status, lung function, OGTT and CGM was set up. Associations between annual rate changes (Δ) in lung function, ΔFEV1 (forced expiratory volume in 1 s) percentage predicted (pp) and ΔFVC (forced vital capacity) pp., and annual rate changes in OGTT or CGM variables were estimated with a mixed model with a random effect for subject. RESULTS: From 2009 to 2016, 112 PwCF (age: 21 ± 11 years, BMI (body mass index) z-score: -0.55 ± 1.09, FEV1pp: 77 ± 24 %, 2-h OGTT glucose: 122 ± 44 mg/dL, AUC (area under curve) >140 mg/dL: 1 mg/dL/day (0.2, 3.0) were included. A total of 428 OGTTs and 480 CGMs were collected. The participants presented annual decline of FVCpp and FEV1pp at -1.0 % per year (-1.6, -0.4), p < 0.001 and - 1.9 % per year (-2.5, -1.3), p < 0.001 respectively without change in BMI z-score during the study. Variation of two-hour OGTT glucose was not associated with declining lung function, as measured by ΔFEV1pp (p = 0.94) and ΔFVCpp (p = 0.90). Among CGM variables, only increase in AUC >140 mg/dL between two annual visits was associated with a decrease in ΔFVCpp (p < 0.05) and ΔFEV1pp (p < 0.05). CONCLUSIONS: This prospective study supports the fact that early glucose abnormalities revealed by CGM predict pulmonary function decline in PwCF, while 2-h standard OGTT glucose is not associated with pulmonary impairment.

Proposal of a quantitative PCR-based protocol for an optimal Pseudomonas aeruginosa detection in patients with cystic fibrosis.

BACKGROUND: The lung of patients with cystic fibrosis (CF) is particularly sensitive to Pseudomonas aeruginosa. This bacterium plays an important role in the poor outcome of CF patients. During the disease progress, first acquisition of P. aeruginosa is the key-step in the management of CF patients. Quantitative PCR (qPCR) offers an opportunity to detect earlier the first acquisition of P. aeruginosa by CF patients. Given the lack of a validated protocol, our goal was to find an optimal molecular protocol for detection of P. aeruginosa in CF patients. METHODS: We compared two formerly described qPCR formats in early detection of P. aeruginosa in CF sputum samples: a qPCR targeting oprL gene, and a multiplex PCR targeting gyrB and ecfX genes. RESULTS: Tested in vitro on a large panel of P. aeruginosa isolates and others gram-negative bacilli, oprL qPCR exhibited a better sensitivity (threshold of 10 CFU/mL versus 730 CFU/mL), whereas the gyrB/ecfX qPCR exhibited a better specificity (90% versus 73%). These results were validated ex vivo on 46 CF sputum samples positive for P. aeruginosa in culture. Ex vivo assays revealed that qPCR detected 100 times more bacterial cells than culture-based method did. CONCLUSION: Based on these results, we proposed a reference molecular protocol combining the two qPCRs, which offers a sensitivity of 100% with a threshold of 10 CFU/mL and a specificity of 100%. This combined qPCR-based protocol can be adapted and used for other future prospective studies.

Safety and pharmacokinetics of Roscovitine (Seliciclib) in cystic fibrosis patients chronically infected with Pseudomonas aeruginosa, a randomized, placebo-controlled study.

BACKGROUND: The orally available kinase inhibitor R-roscovitine has undergone clinical trials against various cancers and is currently under clinical evaluation against Cushing disease and rheumatoid arthritis. Roscovitine displays biological properties suggesting potential benefits in CF: it partially corrects F508del-CFTR trafficking, stimulates the bactericidal properties of CF alveolar macrophages, and displays anti-inflammatory properties and analgesic effects. METHODS: A phase 2 trial study (ROSCO-CF) was launched to evaluate the safety and effects of roscovitine in Pseudomonas aeruginosa infected adult CF patients carrying two CF causing mutations (at least one F508del-CFTR mutation) and harboring a FEV1 ≥40%. ROSCO-CF was a multicenter, double-blind, placebo-controlled, dose-ranging study (200, 400, 800 mg roscovitine, orally administered daily for 4 days/week/4 weeks). RESULTS: Among the 34 volunteers enrolled, randomization assigned 11/8/8/7 to receive the 0 (placebo)/ 200/400/800 mg roscovitine doses, respectively. In these subjects with polypharmacy, roscovitine was relatively safe and well-tolerated, with no significant adverse effects (AEs) other than five serious AEs (SAEs) possibly related to roscovitine. Pharmacokinetics of roscovitine were rather variable among subjects. No significant efficacy, at the levels of inflammation, infection, spirometry, sweat chloride, pain and quality of life, was detected in roscovitine-treated groups compared to the placebo-treated group. CONCLUSION: Roscovitine was relatively safe and well-tolerated in CF patients especially at the 200 and 400 mg doses. However, there were 5 subject withdrawals due to SAEs in the roscovitine group and none in the placebo group. The lack of evidence for efficacy of roscovitine (despite encouraging cellular and animal results) may be due to high pharmacokinetics variability, short duration of treatment, and/or inappropriate dosing protocol.

Use of Home-Based Connected Devices in Patients With Cystic Fibrosis for the Early Detection and Treatment of Pulmonary Exacerbations: Protocol for a Qualitative Study.

BACKGROUND: Early detection of pulmonary exacerbations (PEx) in patients with cystic fibrosis (CF) is important to quickly trigger treatment and reduce respiratory damage. We hypothesized that using home-based and wearable connected devices (CDs) and educating patients to react in case of abnormal variations in a set of parameters would allow patients to detect and manage their PEx early with their care team. OBJECTIVE: This qualitative study aimed to assess the feasibility and appropriate conditions of a new PEx management process from the users' point of view by analyzing the experience of patients and of CF center teams regarding the education program, the use of CDs, and the relationship between the patient and the care team during PEx management. METHODS: We have been conducting a multicenter pilot study involving 36 patients with CF aged ≥12 years. The intervention was divided into 3 phases. In phase 1 (3 months), patients were equipped with CDs, and their parameters were collected on 3 nonconsecutive days each week. Phase 2 involved the development of a "React to PEx" educational program aimed at providing patients with a personalized action plan. A training session to the educational program was organized for the physicians. Physicians then determined the patients' personalized alert thresholds by reviewing the data collected during phase 1 and their patients' clinical history. In phase 3 (12 months), patients were educated by the physician during a clinic visit, and their action plan for reacting in timely fashion to their PEx signs was defined. Education and action plans were revised during clinic visits. At the end of the project, the patients' experience was collected during semistructured interviews with a researcher as part of the qualitative study. The experience of CF teams was collected during focus groups using a semistructured guide once all their patients had finished the study. The interviews and focus groups were recorded and transcribed verbatim to be analyzed. Data from educational sessions were collected throughout the educational program to be put into perspective with the learnings reported by patients. Analyses are being led by 2 researchers using NVivo (QSR International). RESULTS: The study received the favorable reception of the Committee for the Protection of Persons (CPP NORTH WEST III) on June 10, 2017 (#2017-A00723-50). Out of the 36 patients included in phase 1, 27 were educated and entered phase 3. We completed collection of all data from the patients and care providers. Qualitative analysis will provide a better understanding of users' experience on the conditions of data collection, how useful CDs are for detecting PEx, how useful the PEx action plan is for reacting quickly, what patients learned about PEx management, and the conditions for this PEx management to be sustainable in routine care. CONCLUSIONS: This study will open new perspectives for further research into the implementation of an optimal PEx care process in the organization of care teams in order to support patient self-management. TRIAL REGISTRATION: ClinicalTrials.gov NCT03304028; https://clinicaltrials.gov/ct2/show/results/NCT03304028. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/14552.

Psychological effects of false-positive results in cystic fibrosis newborn screening: a two-year follow-up.

OBJECTIVE: To evaluate parental stress after a false-positive result at the time of the cystic fibrosis (CF) newborn screening (NBS), attributable to heterozygotism or persistent hypertrypsinemia. STUDY DESIGN: A prospective study was conducted in 86 French families at 3, 12, and 24 months after NBS. A psychologist conducted interviews with a questionnaire, the Perceived Stress Scale, and the Vulnerable Child Scale. RESULTS: Overall, 96.5% of parents said they had been anxious at the time of the sweat test. However, 86% felt entirely reassured 3 months after the test. The mean Perceived Stress Scale score did not differ from that observed in the French population. Mean Vulnerable Child Scale scores were high, associated with a low Parental Perception of Child Vulnerability. These results did not differ significantly at 1 and 2 years. In total, 86% to 100% of families no longer worried about CF. All parents stated that they would have the test performed again for another child. CONCLUSIONS: CF NBS can lead to false-positive results, causing parental anxiety, which quickly decreases after a sweat test performed soon after the phone call.

Porphyromonas, a potential predictive biomarker of Pseudomonas aeruginosa pulmonary infection in cystic fibrosis.

Introduction: Pseudomonas aeruginosa pulmonary infections are the primary cause of morbi-mortality in patients with cystic fibrosis (CF). In this cohort study, the objective was to identify candidate biomarkers of P. aeruginosa infection within the airway microbiota. Methods: A 3-year prospective multicentre study (PYOMUCO study) was conducted in Western France and included patients initially P. aeruginosa free for at least 1 year. A 16S-targeted metagenomics approach was applied on iterative sputum samples of a first set of patients (n=33). The composition of airway microbiota was compared according to their P. aeruginosa status at the end of the follow-up (colonised vs non-colonised), and biomarkers associated with P. aeruginosa were screened. In a second step, the distribution of a candidate biomarker according to the two groups of patients was verified by qPCR on a second set of patients (n=52) coming from the same cohort and its load quantified throughout the follow-up. Results: Porphyromonas (mainly P. catoniae) was found to be an enriched phylotype in patients uninfected by P. aeruginosa (p<0.001). This result was confirmed by quantitative PCR. Conversely, in patients who became P. aeruginosa-positive, P. catoniae significantly decreased before P. aeruginosa acquisition (p=0.014). Discussion: Further studies on replication cohorts are needed to validate this potential predictive biomarker, which may be relevant for the follow-up in the early years of patients with CF. The identification of infection candidate biomarkers may offer new strategies for CF precision medicine.

Using registry data to improve quality of care.

Patient registries provide clinicians, patients and families with the ability to track important health outcomes at a population, cystic fibrosis (CF) center, and patient level. International quality improvement (QI) work driven by registries has been effective at improving the health and the care delivered to the individual patient. In this review, we examine the role CF registries have played in the QI process over the years and discuss the inherent strengths and limitations that exist when using registry data for this purpose.

Lessons from the on-site quality audit of data transmitted to the French cystic fibrosis registry.

BACKGROUND: The French Cystic Fibrosis Registry takes a census of the population of patients and records their annual data transmitted by Cystic Fibrosis Centers (CFCs). Quality of patient data has been a focus in the past years, with the implementation of automated controls before data integration. The objective was to assess, at the 14 CFCs trained in the quality improvement named Hospital Program to Improve Outcomes and Expertise in Cystic Fibrosis (PHARE-M), the quality of the 2012 and 2013 data transmitted to the French Registry with respect to the rules established to obtain forced expiratory volume in 1 second (FEV1%) and anthropometric data. METHODS: The clinical researcher selected 20 patients at each CFC from age ranges corresponding to different visit frequencies and measurement procedures in order to reach saturation of error causes. The control consisted in comparing source data, pulmonary function tests (PFTs), patient records, and data in the Registry. RESULTS: The audit focused on 242 patients, 2455 consultations and 1855 PFTs. Less than 5% of data concerning weight, height, or FEV1 (L) in the patient records files had discrepancies with source data. Discrepancies on patient height between patient records and PFT files were found in 11% of cases. For one hundred and ten patients (45%), anomalies were found between the patient record and the Registry for the FEV1% and the associated anthropometric measurements mainly related to the interpretation of the selection rule of the venue corresponding to the "best spirometry in the year" and the reference standard used (local standards versus Knudson reference equations). For the 33 children in the age range of 6-17 years old (27% out of 120 children records controlled), the FEV1% value in the Registry presented an average deviation of +4.25% (min. = -9.3%; max. = +16.9%; median = 4%) with the value from the Patient record. CONCLUSIONS: This first on-site quality audit of the data transmitted to the Registry pointed out variability in the measurement process at the CFCs. The rule for selecting the data for the Registry was applied differently at some CFCs, and various local References for the FEV1% calculation were used. Avenues for improvement have been identified.

Introduction of a collaborative quality improvement program in the French cystic fibrosis network: the PHARE-M initiative.

BACKGROUND: An agreement, signed in 2007 by the 49 French Cystic Fibrosis Centers, included a commitment to participate, within the next 5 years, in a care quality assessment and improvement program (QIP). The objective was to roll out in the French Cystic Fibrosis (CF) care network a QIP adapted from the US program for Accelerating Improvement in Cystic Fibrosis Care developed by The Dartmouth Institute Microsystem Academy (TDIMA) and customized by the US CF Foundation between 2002 and 2013. METHODS: The French national team at the Nantes-Roscoff CF Center of Expertise was trained at TDIMA and visited US CF centers involved in US Learning and Leadership Collaboratives (LLCs). It introduced the PHARE-M QIP in France by transposing the Action Guide and material. A PHARE-M LLC1 including seven centers, underwent two external assessments. Adjustments were made, then a PHARE-M LLC2 was rolled out at seven more centers in two regions. On-site coaching was strengthened. The teams' satisfaction was assessed and further adjustments were made. In 2014, the program sought recognition as a continuing education program for healthcare professionals. RESULTS: Ninety-six trainees including 14 patients/parents from the 14 CFCs volunteered to participate, test and adapt the program during LLC1 and LLC2 sessions. Comparison of patient outcomes collected in the Registry report by CF center, reflection on potential best practices, selection by each team of an improvement theme, implementation of improvement actions, and exchanges between teams fostered the adhesion of the teams. The program strengthened quality of care, interdisciplinary functioning and collaboration with patients/parents at the centers. The satisfaction expressed by the teams increased over time. A post-PHARE-M cycle maintains the focus on continuous quality improvement (CQI). In 2015, PHARE-M was recognized as a continuing professional development program in healthcare. CONCLUSIONS: The PHARE-M is a complex intervention in multidisciplinary teams working in a variety of hospital settings. A confluence of factors motivated teams to engage in the program. Involving Patient/Parent in quality improvement (QI) work and developing patient therapeutic education for self-management appeared to be complementary approaches to improve care. Incorporating the program into hospital continuing education insures its sustainability. Transparency of Patient Registry indicators per center published in a brief lapse of time is required to effectively support CQI. The impact of the PHARE-M on patient outcomes after 3 years is the subject of a research program funded by the French Ministry of Health whose results will be available in 2017.

Quality of care in cystic fibrosis: assessment protocol of the French QIP PHARE-M.

BACKGROUND: The PHARE-M care quality improvement program, modeled on the US Cystic Fibrosis Quality Improvement Program, was introduced at 14 cystic fibrosis centers (CFCs) in the French Cystic Fibrosis Network between 2011 and 2013. The pilot phase assessments attested the progressive adherence of the teams and improvements in care management. The PHARE-M Performance research project aims at assessing in 2015 the impact of the PHARE-M program on patient health indicators at trained versus untrained centers. It also sought to identify contextual factors that could account for variability in the performance of the PHARE-M among the trained centers. METHODS: A mixed methodology combining: a quantitative experimental study: a comparison, using a mixed model for repeated data (from 2011 to 2015), of the average changes over time in forced expiratory volume in 1 s (FEV1) and body mass index (BMI) between two groups of patients included in a closed cohort (non-transplant patients, continuous follow-up at one participating CFC, and a CF-causing mutation), one having benefitted from the PHARE-M program and the other not having done so, and a realistic study: a characterization of the impact on care management and an identification of mechanisms through which the PHARE-M intervention improved the team's effectiveness in different CFC contexts; this required modeling the intervention, context, and impact on care management with respect to the criteria of the chronic care model (CCM); this was done using a self-administered questionnaire given to professionals and patients/parents supplemented with focus groups. CONCLUSION: Although the study population was controlled, it may be difficult to establish a causal relationship between the differences in the changes over time in patient health indicators in the two groups of patients and the PHARE-M intervention as it is often the case in complex interventions rolled out in adaptive environments. The analysis of factors associated with variations in the impact of the PHARE-M at the different trained CFCs required the adoption of instruments validated in other contexts; these could be useful for assessing the performance of other interventions in healthcare practices at CFCs in France.

Cystic fibrosis mortality trends in France.

BACKGROUND: In 1992 France set up a national cystic fibrosis observatory (Observatoire national de la mucoviscidose, ONM) to monitor the state of health of patients on an annual basis. Using the ONM data, this study estimates the main indicators for life expectancy and assesses the total number of cystic fibrosis patients. METHODS: The data for the years 1994 to 2003 are divided into 3-year periods. Life tables are drawn up for these periods, from which mean and median lengths of life are determined. Using the most recent life table, the number of births in 2003 and the incidence of the disease, the total population of patients can be estimated, assuming a stationary population. RESULTS: In 2001-2003, life expectancy at birth of patients registered with the ONM was 39.1 years and median length of life was 36.4 years. These results, substantially better than those of 1994-1996, are linked to improved conditions of patient inclusion in the ONM database, to improvements in their healthcare, but also to the limitations of the life tables. Based on the 2003 data, the total theoretical number of patients is 6490, and coverage by the ONM database is thus 63.2%. CONCLUSIONS: These provisional results demonstrate the need to convert the ONM observatory into a registry providing exhaustive coverage of all patients.

Real-life initiation of lumacaftor/ivacaftor combination in adults with cystic fibrosis homozygous for the Phe508del CFTR mutation and severe lung disease.

OBJECTIVE: To investigate the short-term adverse events and effectiveness of lumacaftor/ivacaftor combination treatment in adults with cystic fibrosis (CF) and severe lung disease in a real life setting. METHODS: A multicentre observational study investigated adverse events, treatment discontinuation, FEV1 and body mass index (BMI) one month and three months after lumacaftor/ivacaftor initiation in adults with CF and FEV1 below 40% predicted. RESULTS: Respiratory adverse events (AEs) were reported by 27 of 53 subjects (51%) and 16 (30%) discontinued treatment. The mean absolute change in FEV1 was +2.06% after one month of treatment (P=0.086) and +3.19% after 3 months (P=0.009). BMI was unchanged. CONCLUSIONS: Treatment with lumacaftor/ivacaftor in patients with CF and severe lung disease was discontinued more frequently than reported in clinical trials, due to respiratory AEs. Nevertheless, the patients who continued treatment had an increase in lung function comparable to what was observed in pivotal trials.

Highlighting the impact of cascade carrier testing in cystic fibrosis families.

BACKGROUND: Cascade carrier testing within cystic fibrosis (CF) affected families offers relatives of CF patients the opportunity to know their status regarding the mutation that segregates within their family, and thus to make informed reproductive choices. As an Australian study has recently shown that this test seemed underused, we searched to assess uptake of this test in a European area where CF is common, and to report its public health implications. METHODS: This study relied on 40 CF-affected families from western Brittany, France. Investigations included drawing of family trees and registration of carrier tests performed in those families. RESULTS: Of the 459 relatives eligible for testing, 185 were tested, leading to an adjusted uptake rate of testing of 40.7% (95% CI: [34.1%; 47.3%]). The main predictors for having testing were being female (p=0.031) and having a high prior risk (p<0.001). Planning a pregnancy or expecting a child (reported in at least 38.4% of tested relatives) also appeared critical in choosing to be tested. Overall, carrier testing allowed to reassure more than 1/4 of the relatives and to detect five new 1-in-4 at-risk couples who then requested prenatal diagnosis. CONCLUSIONS: This observational study assesses, for first time in Europe, uptake of CF cascade carrier testing within CF families, which is a critical tool to reassure non-carriers and to detect early new at-risk couples.

Modulating Innate and Adaptive Immunity by (R)-Roscovitine: Potential Therapeutic Opportunity in Cystic Fibrosis.

(R)-Roscovitine, a pharmacological inhibitor of kinases, is currently in phase II clinical trial as a drug candidate for the treatment of cancers, Cushing's disease and rheumatoid arthritis. We here review the data that support the investigation of (R)-roscovitine as a potential therapeutic agent for the treatment of cystic fibrosis (CF). (R)-Roscovitine displays four independent properties that may favorably combine against CF: (1) it partially protects F508del-CFTR from proteolytic degradation and favors its trafficking to the plasma membrane; (2) by increasing membrane targeting of the TRPC6 ion channel, it rescues acidification in phagolysosomes of CF alveolar macrophages (which show abnormally high pH) and consequently restores their bactericidal activity; (3) its effects on neutrophils (induction of apoptosis), eosinophils (inhibition of degranulation/induction of apoptosis) and lymphocytes (modification of the Th17/Treg balance in favor of the differentiation of anti-inflammatory lymphocytes and reduced production of various interleukins, notably IL-17A) contribute to the resolution of inflammation and restoration of innate immunity, and (4) roscovitine displays analgesic properties in animal pain models. The fact that (R)-roscovitine has undergone extensive preclinical safety/pharmacology studies, and phase I and II clinical trials in cancer patients, encourages its repurposing as a CF drug candidate.

Costs and health-related quality of life of patients with cystic fibrosis and their carers in France.

BACKGROUND: Our goal was to provide data on the economic burden and health-related quality of life (HRQoL) associated with cystic fibrosis (CF) in France. METHODS: A retrospective cross-sectional study was carried out on adults and children with CF, who completed an anonymous questionnaire regarding their socio-demographic characteristics, healthcare consumption and presence of a carer. Costs were calculated with a bottom-up approach, and HRQoL was assessed using EQ-5D. RESULTS: 82 adults and 158 children were included. The total average annual cost of CF was €29,746 per patient. Total costs were higher in adults than in children and increased with disease duration. The average utility was lower in adults (0.667 vs. 0.783 in children, p=0.0015). The HRQoL of carers was also affected (0.742 and 0.765 for carers of adults and children with CF, respectively). CONCLUSIONS: Our study highlights the burden of CF in terms of costs and decreased HRQoL for both patients and carers.