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International audience; Rationale: Elexacaftor-tezacaftor-ivacaftor is a CFTR (cystic fibrosis [CF] transmembrane conductance regulator) modulator combination, developed for patients with CF with at least one Phe508del mutation. Objectives: To evaluate the effects of elexacaftor-tezacaftor- ivacaftor in patients with CF and advanced respiratory disease. Methods: A prospective observational study, including all patients aged ⩾12 years and with a percent-predicted FEV1 (ppFEV1)

INTRODUCTION The prognosis of people diagnosed with cystic fibrosis (CF) has dramatically improved over the past decade in France, largely due to advances in CF care management, including an emphasis on chronic maintenance medications. Currently, the majority of French CF patients are adults, which means that they went through a transition process from receiving care at a pediatric CF center to receiving care at an adult CF center. To determine the impact of the transfer on clinical evolution, we report the transition procedure of our CF center in Lyon. MATERIALS AND METHODS From January 2006 to December 2016, 97 CF patients underwent a standardized process of transitioning from the pediatric to the adult CF center in Lyon. We compared the clinical evolution of these patients during three periods, starting the year before transition and ending the year after transition. Clinical data taken into account were forced expiratory volume in 1 s (FEV1 in liters), body mass index (BMI in kg/m2 ), pulmonary colonization, number of antibiotic courses, number of days of hospitalization per year, and outpatient visits per year. RESULTS No significant differences were observed between respiratory and nutritional status, respiratory microbiome, number of antibiotic courses, or number of hospitalizations or visits when comparing the threeperiods of observation around transition (the year before, the first year after, and the second year after transfer). CONCLUSION The standardized transition procedure used in Lyon is associated with the clinical stability of our CF patients.

Iron deficiency (ID) diagnosis in cystic fibrosis (CF) is challenging because of frequent systemic inflammation. We aimed to determine the prevalence and risk factors of ID in adult patients with CF. We conducted a single-centre prospective study in a referral centre. ID was defined by transferrin saturation ≤16% or ferritin ≤20 (women) or 30 (men) μg/L, or ≤100 μg/L in the case of systemic inflammation. Apparent exacerbation was an exclusion criterion. We included 165 patients (78 women), mean age—31.1 ± 8.9 years. ID prevalence was 44.2%. ID was significantly associated with female gender (58.9% vs. 38%), lower age (29.4 ± 8.5 vs. 32.5 ± 9.1), lower body mass index (20.5 ± 2.2 vs. 21.3 ± 2.5), and Pseudomonas aeruginosa colonization (70.8% vs. 55.1%). Diabetes mellitus, antiacid drug use and low pulmonary function were more frequent in patients with ID with no statistical significance. The use of CFTR correctors was not associated with ID. In the multivariate analysis, ID was associated with female gender (OR 2.64, CI95% 1.31–5.31), age < 30 years (OR 2.30, CI95% 1.16–4.56), and P. aeruginosa (OR 2.09, CI95% 1.04–4.19).

BACKGROUND To better understand the mechanisms of infection with nontuberculous mycobacteria (NTM) in patients with cystic fibrosis (CF), we explore different risk factors associated with NTM positivity in a meta-analysis. METHODS Studies published before 31 July 2019 were selected from MEDLINE. Combined odds ratios (ORs) were calculated by pooling the ORs of each study. The weighted mean difference (WMD) was used for continuous numerical measurements. Summary data were pooled using fixed- or random-effects models according to the presence of heterogeneity (P 50%). RESULTS Nineteen studies with a total of 23 418 patients, of whom 1421 (6%) were diagnosed as NTM positive, were included. Older age was significantly associated with NTM positivity (WMD = 2.12, 95% confidence interval [CI]: 1.11-3.13; P

Therapeutic drug monitoring (TDM) of tobramycin is widely performed in patients with cystic fibrosis (CF), but little is known about the value of model-informed precision dosing (MIPD) in this setting. We aim at reporting our experience with tobramycin MIPD in adult patients with CF. We analyzed data from adult patients with CF who received IV tobramycin and had model-guided TDM during the first year of implementation of MIPD. The predictive performance of a pharmacokinetic (PK) model was assessed. Observed maximal (Cmax) and minimal (Cmin) concentrations after initial dosing were compared with target values. We compared the initial doses and adjusted doses after model-based TDM, as well as renal function at the beginning and end of therapy. A total of 78 tobramycin courses were administered in 61 patients. After initial dosing set by physicians (mean, 9.2 ± 1.4 mg/kg), 68.8% of patients did not achieve the target Cmax ≥ 30 mg/L. The PK model fit the data very well, with a median absolute percentage error of 4.9%. MIPD was associated with a significant increase in tobramycin doses (p < 0.001) without significant change in renal function. Model-based dose suggestions were wellaccepted by the physicians and the expected target attainment for Cmax was 83%. To conclude, the implementation of MIPD was effective in changing prescribing practice and was not associated with nephrotoxic events in adult patients with CF.

Background and Aims Cystic fibrosis patients are at high risk for chronic kidney disease (CKD), because of chronic aminoglycoside exposure, high protein and dietary salt intake, and Cystic Fibrosis Related Diabetes. Lung transplantation also entails a high renal burden in the long run because of calcineurin inhibitors exposure. We aimed at studying kidney function by gold standard glomerular filtration rate (mGFR) before and 1 year after lung transplantation, as well as identify risk factors for kidney function impairment. Method Patients from the Cystic Fibrosis reference center in Lyon, France were systematically referred to the nephrology department before lung transplantation. mGFR (iohexol or inulin clearance) was performed before and 12-18 months after lung transplantation. Risk factors for a worse nephrological outcome (i.e. post transplantation mGFR < 60mL/min/1.73m²) were searched for. Results 28 patients (10 males), mean age 32 yr, underwent pre transplantation mGFR. Three died following lung transplantation and two progressed to end stage renal disease rapidly thereafter. 23 patients benefited from both pre and post transplantation mGFR. Mean mGFR was 105±21mL/min/1.73m² and 67±19 mL/min/1.73m² before and after transplant respectively. Factors associated with a worse renal outcome in both univariate and multivariate analysis were age at transplantation (p=0.03) and the occurrence of acute kidney injury in the post-operative period (p=0.005). Cumulated aminoglycoside exposure and time spent under cardiopulmonary bypass were not associated with renal outcome. Conclusion Lung transplantation is associated with a high renal burden in adult Cystic Fibrosis patients. We advise a clinical referral to a nephrologist as part of the systematic evaluation in lung transplantation candidates even if GFR is in the normal range.

Objectives The use of thrombopoietin-receptor agonists (TPO-RAs) has increased as a second-line therapy in ITP, but the efficacy and safety of such drugs has not been evaluated in SLE-associated ITP. Methods This was a multicentre retrospective cohort study from 2009 to 2016. Participating centres (n = 11) were secondary- or tertiary-care hospitals belonging to the French national network for adult ITP. Results We included 18 patients with SLE-ITP treated with TPO-RAs; 10 (55%) had aPL, 5 (27%) showing definite APS. Except for one patient, all (94%) achieved response with TPO-RAs overall. After a median follow-up of 14.7 months with TPO-RAs, four arterial thrombosis events (including one catastrophic APS) occurred in four patients. Two venous thrombosis events occurred in a patient without APS or aPLs. Conclusion Our results suggest that aPLs should be systematically screened before TPO-RA initiation in patients with SLE. With aPL positivity, alternative therapy should be discussed (if possible), especially in patients with definite APS or suboptimal adherence to anti-coagulation therapy.

International audience; Rationale: Lumacaftor-ivacaftor is a CFTR (cystic fibrosis transmembrane conductance regulator) modulator combination recently approved for patients with cystic fibrosis (CF) homozygous for the Phe508del mutation.Objectives: To evaluate the safety and effectiveness of lumacaftor-ivacaftor in adolescents (≥12 yr) and adults (≥18 yr) in a real-life postapproval setting.Methods: The study was conducted in the 47 CF reference centers in France. All patients who initiated lumacaftor-ivacaftor from January 1 to December 31, 2016, were eligible. Patients were evaluated for lumacaftor-ivacaftor safety and effectiveness over the first year of treatment following the French CF Learning Society's recommendations.Measurements and Main Results: Among the 845 patients (292 adolescents and 553 adults) who initiated lumacaftor-ivacaftor, 18.2% (154 patients) discontinued treatment, often owing to respiratory (48.1%, 74 patients) or nonrespiratory (27.9%, 43 patients) adverse events. In multivariable logistic regression, factors associated with increased rates of discontinuation included adult age group, percent predicted FEV1 (ppFEV1) less than 40%, and numbers of intravenous antibiotic courses during the year before lumacaftor-ivacaftor initiation. Patients with continuous exposure to lumacaftor-ivacaftor showed an absolute increase in ppFEV1 (+3.67%), an increase in body mass index (+0.73 kg/m2), and a decrease in intravenous antibiotic courses by 35%. Patients who discontinued treatment had significant decrease in ppFEV1, without improvement in body mass index or decrease in intravenous antibiotic courses.Conclusions: Lumacaftor-ivacaftor was associated with improvement in lung disease and nutritional status in patients who tolerated treatment. Adults who discontinued lumacaftor-ivacaftor, often owing to adverse events, were found at high risk of clinical deterioration.

OBJECTIVE: To describe the prevalence of cystic fibrosis-related diabetes (CFRD) before and after lung transplantation (LT); to analyse the survival and renal function after LT according to the CFRD status before LT. METHODS: Sixty cystic fibrosis (CF) patients transplanted at the Lyon University Hospital between 2004 and 2014 were included. Genotype, pancreatic status, age at LT, survival were recorded. Glucose tolerance status, daily insulin dose requirement, glomerular filtration rate (GFR), and daily glucocorticoid (GC) dose were recorded before LT and until December 2016. RESULTS: The median follow-up was 5.6 (3.8-8.2) years, and nine patients died. Survival was poorest for patients with CFRD before LT compared with those without CFRD (P = 0.03) but was not correlated with the GFR before LT, with sex, age at LT, or CF genotype. The prevalence of CFRD was 68% at 2 years and 54% at 5 years. For persistent insulin-treated CFRD, the insulin requirement decreased (-2.1 IU/d/y; P \\textless 0.01) and was correlated with the daily GC dose (+0.4 IU/d for one additional milligram, P = 0.012). Seven (11%) patients who had insulin-treated CFRD before LT became nondiabetic after LT, with a median time of 2 (1-4) years. After LT, the GFR decreased (-5.3 ml/min/1.73 m (2) /y; P \\textless 0.001) and was not correlated with the CFRD status before LT. CONCLUSIONS: CFRD before LT is associated with poor survival after LT, which should lead to better management of diabetes. Some patients with pre-LT CFRD became nondiabetic after LT. CFRD is not associated with renal insufficiency after LT.

Background: Patients with cystic fibrosis (CF) are at risk of kidney injury even before undergoing lung transplantation, because of prolonged exposure to aminoglycosides (AGs), chronic dehydration and complications of diabetes mellitus. The usual equations estimating the glomerular filtration rate (GFR), such as Cockcroft-Gault and Modification of Diet in Renal Disease, are not adapted to the CF population due to patients' low body weight and reduced muscle mass. The aim of this study was to precisely measure GFR in adult CF patients and to see whether repeated AG treatment would impair renal function before lung transplantation. Methods: Inulin or iohexol clearances were performed in 25 adult CF patients when they entered the lung transplant waiting list. No patient was treated with AGs at the time of GFR measurement. Body mass index (BMI), history of diabetes mellitus and blood pressure were recorded. Exposure to intravenous (IV) AGs within 5 years prior to the GFR measurement was obtained from the patient's medical files. Urine samples were collected to check for albuminuria and proteinuria. Results: The population was predominantly female (67%). The mean age was 32 years, the mean BMI was 19 kg/m2 and 28% had CF-related diabetes. Median exposure to IV AG within 5 years before GFR measurement was 155 days with a mean dosage of 7.7mg/kg/day. The mean measured GFR was 106 mL/min/1.73 m2 and the mean estimated GFR according to the Chronic Kidney Disease Epidemiology Collaboration formula was 124 mL/min/1.73 m2. Conclusion: Despite prolonged exposure to high-dose IV AG, no decline in GFR was observed in these patients.

Allergic bronchopulmonary aspergillosis (ABPA) affects up to 15% of patients with cystic fibrosis (CF). Corticosteroids are used as first-line therapy, but relapse and adverse effects commonly occur. Case reports have suggested the efficacy of the anti-IgE recombinant humanized monoclonal antibody omalizumab. A retrospective multicenter observational French study retrieved 32 CF patients (11 children and 21 adults) who have received omalizumab for more than 3 months in the context of ABPA. Clinical characteristics, concomitant medications (inhaled and oral corticosteroids, antifungal drugs), lung function, body mass index (BMI), and serum IgE were compared at the start and during the first year of omalizumab therapy. Omalizumab-related adverse effects and costs were also evaluated. No significant difference with omalizumab could be demonstrated with regard to lung function, BMI, or the number of patients receiving oral corticosteroids. At the time of initiation of omalizumab, 56% of patients were receiving oral corticosteroids. Five patients were able to discontinue corticosteroids during follow-up and nine patients were able to reduce their daily dose. A total of 78% of the patients had received antifungal therapy at the time of the initiation of omalizumab. Treatment tolerance was good (12.5% of patients experienced side effects). The median cost of omalizumab treatment was €3,620 per patient per month. Omalizumab may represent a steroid-sparing therapy in CF patients with ABPA. A randomized-controlled trial is urgently required to provide higher level of evidence regarding the efficacy and cost-effectiveness of omalizumab in CF patients with ABPA. Pediatr Pulmonol. 2017;52:190-197. © 2016 Wiley Periodicals, Inc.

In our current adult CF population, low BMD prevalence was only 20 %, lower than that historically described. We found a mild increase of serum RANK-L levels, independent from the bone resorption level. The increased fracture risk in CF may be explained by a lower tibial cortical thickness and total vBMD. Bone disease is now well described in cystic fibrosis (CF) adult patients. CF bone disease is multifactorial but many studies suggested the crucial role of inflammation. The objectives of this study were, in a current adult CF population, to assess the prevalence of bone disease, to examine its relationship with infections and inflammation, and to characterize the bone microarchitecture using high resolution peripheral scanner (HR-pQCT). Fifty-six patients (52 % men, 26 ± 7 years) were assessed in clinically stable period, during a respiratory infection, and finally 14 days after the end of antibiotic therapy. At each time points, we performed a clinical evaluation, lung function tests, and biochemical tests. Absorptiometry and dorso-lumbar radiographs were also performed. A subgroup of 40 CF patients (63 % men, 29 ± 6 years) underwent bone microarchitecture assessment and was age- and gender-matched with 80 healthy controls. Among the 56 CF patients, the prevalence of low areal BMD (T-score

Background The prevalence of cystic fibrosis-related diabetes is increasing. This condition is potentially responsible for respiratory decline. Methods At inclusion, then yearly (over three years), 111 children and 117 adults with cystic fibrosis had oral glucose tolerance and insulin tests at one (G1) and 2h (G2). KmL analysis identified homogeneous G1 and G2 glucose trajectories. A linear mixed model quantified the relationships between trajectories and FEV1 changes. Results In children, there were three G1 and four G2 trajectories and FEV1 decrease was not significantly different between G1 or G2 trajectories. In adults, two G1 and four G2 trajectories were identified and FEV1 change was estimated at −0.85/year (95% CI: [−1.54; −0.17], p=0.01) whatever the G1 trajectory and found significantly faster in the high and increasing G2 trajectory (−2.1/year, [−3.9; −0.2], p=0.03). Conclusions In case of persistent G2 abnormality, physicians should be alert for clinical deterioration and intensify patient surveillance.

Background and Aims Catheter venous thrombosis may result in life-threatening embolic complications. Recently, a thrombophilic tendency was described in cystic fibrosis (CF), the significance of which remains unclear. The aims of this study were to (1) document the frequency of catheter venous thrombosis detected by colour-Doppler-ultrasound (Doppler-US), (2) assess genetic and acquired thrombophilia risk factors for catheter venous thrombosis and hypercoagulability status and (3) provide recommendations on laboratory screening when considering insertion of a totally implantable vascular access device (TIVAD) in CF patients. Methods We designed a multicentre prospective study in patients selected at the time of catheter insertion. Doppler-US was scheduled at 1 and 6months after insertion and before insertion in case of a previous central line. Blood samplings were drawn at insertion and at 1 and 6months later. Results One-hundred patients received a TIVAD and 90 completed the 6-month study. Prevalence of thrombophilia abnormalities and hypercoagulability was found in 50% of the cohorts. Conversely, catheter venous thrombosis frequency was low (6.6%). Conclusion Our data do not support biological screening at the time of a TIVAD insertion. We emphasise the contribution of a medical history of venous thromboembolism and prospective Doppler-US for identifying asymptomatic catheter venous thrombosis to select patients who may benefit from biological screening and possible anticoagulant therapy.

Common variable immunodeficiency (CVID) is characterized by infections and hypogammaglobulinemia. Neutropenia is rare during CVID. The French DEFI study enrolled patients with primary hypogammaglobulinemia. Patients with CVID and neutropenia were retrospectively analyzed. Among 473 patients with CVID, 16 patients displayed neutropenia (lowest count [0–1400]*106/L). Sex ratio (M/F) was 10/6. Five patients died during the follow-up (11 years) with an increased percentage of deaths compared to the whole DEFI group (31.3 vs 3.4%, P

Introduction Lung transplantation (LT) is the final therapeutic option for cystic fibrosis (CF) patients with end stage lung disease. Lung transplanted CF patients differ from other LT patients because of their younger age, better survival after LT, but also specific associated comorbidities related to their underlying disease, particularly CF related diabetes (CFRD). The objective was to describe the prevalence of CFRD before and after LT; and to analyse survival and renal function after LT according to CFRD status before LT. Methods CF patients treated in the Lyon CF reference centre and transplanted at the Lyon University Hospital (France) between 2004 and 2014 were retrospectively included. Genotype (classified in delF508 homozygous, delF508 heterozygous or other), pancreatic status, age at LT and survival were recorded. The following criteria were recorded three months before LT, between three and six months after LT, and at each year of follow-up until December 2016: glucose tolerance status (CFRD or others), daily insulin dose requirement; renal function, defined by the estimated glomerular filtration rate (GFR, calculated with the Modification of Diet in Renal Disease formula); and daily glucocorticoid (GC) dose. Analysis for repeated measures data was conducted by using linear mixed-effect regression models that included fixed and random effects. Results Sixty-three adult CF patients were transplanted. Thirty-two (53.3%) patients were delF508 homozygous. All were pancreatic insufficient, and 42 (70%) had CFRD before LT. The mean ± SD calculated GFR before LT was 109 ± 47 mL/min/1.73 m2, and did not differ according to CFRD status (P = 0.68). The mean ± SD age at LT was 27.6 ± 8.4 year. The median (IQR) time of follow-up was 5.6 (3.8–8.2) years and 12 (20%) patients died in the follow-up: three patients died in the first three post-operative months, seven patients in the five years following LT and the last two respectively at 6 and 8 years after the LT. The prevalence of CFRD was 68% (41/60) and 54% (20/37) respectively at two and five years after LT. For the 27 patients who had persistent insulin-treated CFRD, insulin requirement decreased with an estimated slope of −2.1 ± 2.9 IU/day per year (P Conclusions CFRD before LT was associated with a poor survival after LT in CF patients, which should conduct to a better management of diabetes control in the peri- and post-operative period after LT. Some patients with pre-LT CFRD get free of diabetes after LT. CFRD is not associated with renal insufficiency after LT. Others factors might participate to renal insufficiency after LT such as perioperative hemodynamic conditions and immunosuppressive drugs.

Background We evaluated the prevalence of non-tuberculous mycobacteria (NTM)-positive cultures among our cystic fibrosis (CF) center patients, reviewed risk factors for NTM positivity, and determined its impact on lung function evolution. Methods From 2009 to 2014, CF adults and children attending the CF center of Lyon (France) and having at least one positive NTM isolate were included. Each case was matched by age and gender with two CF patients with no NTM isolate (controls). Results 48 CF patients with NTM-positive isolates were matched to 96 controls. The age group for whom incident NTM was higher was young adolescents aged 13 to 17. A significant association for NTM positivity was found with Staphylococcus aureus in multivariate analysis and with allergic bronchopulmonary aspergillosis, corticosteroid and itraconazole in univariate analysis. Mean annual FEV1 decline was faster for NTM-positive patients compared to controls. Conclusion These data highlight the high incidence of NTM-positive cultures among young adolescents with CF.

Introduction With increasing life expectancy, more women with cystic fibrosis and diabetes mellitus become pregnant. We investigated how pre-gestational diabetes (cystic fibrosis-related diabetes) influenced pregnancy outcome and the clinical status of these women. Material and methods We analyzed all pregnancies reported to the French cystic fibrosis registry between 2001 and 2012, and compared forced expiratory volume (FEV1) and body mass index before and after pregnancy in women with and without pre-gestational diabetes having a first delivery. Results A total 249 women delivered 314 infants. Among these, 189 women had a first delivery and 29 of these had pre-gestational diabetes. There was a trend towards a higher rate of assisted conception among diabetic women (53.8%) than non-diabetic women (34.5%, p = 0.06), and the rate of cesarean section was significantly higher in diabetic women (48% vs. 21.4%, p = 0.005). The rate of preterm birth and mean infant birthweight did not differ significantly between diabetic and non-diabetic women. Forced expiratory volume before pregnancy was significantly lower in the diabetic group. The decline in forced expiratory volume and body mass index following pregnancy did not differ between the women with and those without pre-gestational diabetes. Conclusion Pre-gestational diabetes in women with cystic fibrosis is associated with a higher rate of cesarean section but does not seem to have a clinically significant impact on fetal growth or preterm delivery. The changes in maternal pulmonary and nutritional status following pregnancy in women with cystic fibrosis were not influenced by pre-gestational diabetes.

Pulmonary hypertension (PH) may affect survival in cystic fibrosis (CF) and can be assessed on echocardiographic measurement of the pulmonary acceleration time (PAT). The study aimed at evaluating PAT as a tool to optimize timing of lung transplant in CF patients. Prospective multicenter longitudinal study of patients with forced expiratory volume in 1 second (FEV1) ≤60% predicted. Echocardiography, spirometry and nocturnal oximetry were obtained as part of the routine evaluation. We included 67 patients (mean FEV1 42±12% predicted), among whom 8 underwent lung transplantation during the mean follow-up of 19±6 months. No patients died. PAT was determined in all patients and correlated negatively with systolic pulmonary artery pressure (sPAP, r=–0.36, P=0.01). Patients in the lowest PAT tertile (35 mmHg. By multivariate analysis, FEV1and nocturnal desaturation were the main determinants of reduced PAT. A PAT

Introduction To investigate how pre-gestational poor pulmonary function [forced expiratory volume (FEV1) Material and methods We analyzed pregnancies reported to the French cystic fibrosis registry between 2000 and 2012, in women without lung transplantation with a first delivery and a valid FEV1 measurement the year before pregnancy. We compared pregnancy outcome, clinical evolution (body mass index and pulmonary function) before and after pregnancy in women with and without pre-gestational poor pulmonary function. Results A total of 149 women had a first delivery and 36 (24.2%) of these had pre-gestational FEV1 50% (39.4%, P = 0.8), and the rate of cesarean section was significantly higher in women with FEV1 Conclusion Pre-gestational poor pulmonary function in women with cystic fibrosis is associated with a higher rate of cesarean section and a clinically significant impact on fetal growth. The changes in maternal pulmonary and nutritional status following pregnancy in women with cystic fibrosis were not influenced by pre-gestational pulmonary function status.

A 35-year-old woman with severe cystic fibrosis was admitted for sudden loss of strength in both legs, revealing a myelitis. The medullary lesion biopsy revealed phaeohyphomycosis caused by Cladophialophora species. Myelitis caused by Cladophialophora bantiana is a rare disease associated with high mortality.

Resume Objectif Les troubles du metabolisme glucidique (TMG) aggravent la morbimortalite au cours de la mucoviscidose. Au sein d’un reseau regroupant 4 centres de ressources et de competences de la mucoviscidose, une etude sur la conformite des pratiques de depistage et de prise en charge des TMG a ete realisee suite a l’implementation du referentiel reseau. Methodes En 2005 puis en 2007, 60 dossiers de patients de plus de 10 ans ont ete tires au sort. Le referentiel recommandait une glycemie aleatoire a chaque bilan standard, un dosage de l’hemoglobine glyquee (HbA1c) annuel et une hyperglycemie provoquee par voie orale (HGPO) a 10, 15 et 18 ans puis par 2 a 3 ans, a la recherche d’un diabete ou d’une intolerance aux hydrates de carbone. Resultats Le depistage par glycemie aleatoire etait realise de facon annuelle pour 82 % des patients en 2005 et 91,5 % en 2007. L’HbA1c etait realisee annuellement chez 77 % des patients en 2005 et 90 % en 2007 ( p Conclusion Nous observons une tendance a l’amelioration des pratiques de depistage entre 2005 et 2007 pouvant s’expliquer par l’appropriation des recommandations par les professionnels, cette etude ayant permis de les sensibiliser afin d’ameliorer leurs pratiques.

Aims To examine the efficacy and safety of pegfilgrastim in patients with congenital neutropenia (CN). Methods Seventeen patients enrolled in the French Severe CN Register received pegfilgrastim. Results Median age at pegfilgrastim introduction was 19.1 years (range 3.9–52.3 years). In 14 cases pegfilgrastim replaced GCSF (filgrastim or lenograstim), after a median of 6.9 years of GCSF therapy. The dose of pegfilgrastim was usually one full vial per injection (except in five children, who received 1/6 to 1/2 a vial), resulting in a dose of between 50 and 286 µg/kg. The pegfilgrastim schedule ranged from two injections every 7 days to one injection every 30 days, with treatment-free periods. The median interval between the first and last dose of pegfilgrastim was 0.8 years (0.01–4.1 years). The absolute neutrophil count tended to increase more strongly on pegfilgrastim than on GCSF, but the difference was not statistically significant. During pegfilgrastim therapy, a severe infection occurred in two patients and recurrent ENT infections in two other patients. Bone pain was reported by nine patients, anemia and thrombocytopenia occurred in one patient (WHO grade III), chronic urticaria occurred in one patient (WHO grade III), and a single pegfilgrastim injection was followed by respiratory distress and death 15 days later in a patient with GDSIb. At the last update, 10 patients had stopped receiving pegfilgrastim and seven patients were still receiving pegfilgrastim. Conclusion Compared to conventional GCSF, pegfilgrastim is more difficult to use in congenital neutropenia, with more frequent adverse events and sometimes poor efficacy. Pediatr Blood Cancer 2009;53:1068–1073. © 2009 Wiley-Liss, Inc.

International audience; Patients with cystic fibrosis (CF) experience repeated infectious respiratory exacerbations leading to a continuous decline in lung function. The exacerbations are treated in hospital or at home. Our aim was to compare the clinical outcome for patients undergoing intravenous antibiotic treatment either in hospital or at home. A retrospective 10-year study was performed in four regional CF Centers. The outcome measures were percentage changes in forced expiratory volume in 1 sec (FEV(1)), forced vital capacity (FVC) and weight for age z-score (WZS). FEV(1), FVC, and WZS changes were calculated for the entire study period and for each course. A total of 1,164 courses were analyzed. For each course, the mean improvement in FEV(1) and FVC was significantly higher when performed in hospital than when performed at home (P < 0.05). FEV(1) and FVC values were 10.2%, 9.5% respectively in the hospital group and 7.3%, 6.8% in the home group. A total of 153 patients were analyzed (51 inpatients matched to 102 patients treated at home). The two groups had no significant differences in any outcome variable at baseline. The mean variation per year in FEV(1) was greater in the hospital group versus the home group (-0.4% vs. -1.8%; P = 0.03). The mean variation per year in WZS was greater in the hospital group versus the home group (P < 0.01). Clinical outcome, as defined by spirometric parameters and body weight, was better after a course of treatment in hospital than after a home treatment. This benefit was maintained throughout of the study period.

A high prevalence of low bone mineralization is documented in adult patients with cystic fibrosis (CF). Osteopenia is present in as much as 85% of adult patients and osteoporosis in 13 to 57% of them. In children, studies are discordant probably because of different control database. Denutrition, inflammation, vitamin D and vitamin K deficiency, altered sex hormone production, glucocorticoid therapy, and physical inactivity are well known risk factors for poor bone health. Puberty is a critical period and requires a careful follow-up for an optimal bone peak mass. This review is a consensus statement established by the national working group of the French Federation of CF Centers to develop practice guidelines for optimizing bone health in patients with CF. Recommendations for screening and for calcium, vitamin D and K supplementation are given. Further work is needed to define indications for treatment with biphosphonates and anabolic agents.

International audience; BACKGROUND: An imbalance in the ratio of arachidonic acid and docosahexaenoic acid (DHA) was found in cystic fibrosis (CF) affected tissues and was suggested to promote inflammation. Several studies have shown that the long chain n-3 fatty acids reduced inflammatory activity while others have highlighted prooxidant activity of DHA at high concentrations. The aim of our study was to evaluate the effects of an intravenous fish-oil emulsion enriched with n-3 FA in patients with CF on plasma and platelet FA composition and peroxidation markers. METHODS: 13 patients with CF received one IV emulsion per week of 2 mL/kg fish-oil n-3 emulsion for 12 weeks. RESULTS: There was a significant increase in 20:5 n-3 and 22:6 n-3 platelet FA composition, no variation in 20:4 n-6, a decrease in n-9. There was no variation in plasma FA composition. Specific urinary markers of lipid peroxidation derived from n-3 and n-6 showed a very high level before infusion compared with usual values in healthy subjects which was not affected by treatment. A significant weight loss and a decrease in reduced glutathione were observed in adult patients. CONCLUSIONS: The intravenous administration of n-3 FA in CF patients induced a significant modification in platelet FA composition but no modification of oxidative markers. However, the weight loss and the decreased level in reduced glutathione observed in adult patients may suggest a potential deleterious activity for some patients. Further studies are necessary to determine the optimal dose and route for long chain FA administration required to reach a potential beneficial effect.

International audience; Some bacterial species recovered from the airways of cystic fibrosis (CF) patients are indisputably associated with lung infections, whereas the clinical relevance of others, such as Nocardia spp., remains unclear. Sixteen French CF cases of colonization/infection with Nocardia spp. were reviewed in order to evaluate the epidemiology, the clinical impact and the potential treatment of these bacteria, and results were compared to those of the literature. Five Nocardia species were identified, Nocardia cyriacigeorgica being the major species (50 % of cases). At first isolation, Nocardia was the sole pathogen recovered in six patients. Seven patients presented pulmonary exacerbation. For 12 patients, antimicrobial treatment against Nocardia was started immediately, mainly based on cotrimoxazole (6 of the 12 cases). In this study, we highlight the heterogeneity of the clinical management of Nocardia spp. in CF. Guidelines for the clinical management of Nocardia infections in CF patients are proposed.

STUDY QUESTION: Is gynaecological management of women with cystic fibrosis (CF) adequate? SUMMARY ANSWER: Gynaecological care (frequency of follow-up cervical screening and contraceptive use among sexually active women) in women with CF fails to reach the recommended level. WHAT IS KNOWN ALREADY: Little is known about gynaecological follow-up and cervical screening in CF. Only few studies have described contraceptive practices in cohorts of CF women. STUDY DESIGN SIZE DURATION: We did a cross-sectional study in a cohort of 155 CF women attending the Lyon adult centre. Women attending the CF adult centre in 2014 completed a written questionnaire about their contraceptive choices frequency of gynaecological follow-up and cervical screening. Other clinical data were collected from the CF adult centre registry. PARTICIPANTS/MATERIALS SETTING METHODS: One hundred and twenty women (100%) answered the questionnaire among whom two were post-menopausal (46 and 59 years of age) and five were pregnant. MAIN RESULTS AND THE ROLE OF CHANCE: Seventy-four per cent of the women declared they had undergone gynaecological follow-up (89% of the women with transplantation) and only 55% reported having at least one previous Pap smear test. Among the transplanted patients only 58% had had a Pap smear test despite immunosuppressive treatment. The overall rate of contraception was only 64% and in diabetic women it was 61%. Among contraception users; 65% used oral contraception predominantly combined estrogen-progestagen (47%); among diabetic patients 26% used progestin-only contraception. Intrauterine device accounted for 10% of patients using contraception and tubal ligation only 4%. LIMITATIONS REASONS FOR CAUTION: This study is limited by its cross-sectional design. Despite an internal validation of the questionnaire showing an almost perfect agreement the risk of recall bias has to be taken into account. WIDER IMPLICATIONS OF THE FINDINGS: This study of practices highlights the importance of improved information regarding sexuality fertility and reproductive health in young women with CF. A regular gynaecological follow-up and cervical screening is mandatory in this population. Better gynaecological care and contraceptive advice would help to avoid unplanned pregnancies and optimize contraceptive selection in relationship to specific clinical conditions. STUDY FUNDING/COMPETING INTERESTS: None. (c) The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions please email: journals.permissions@oup.com.

Objective Serum immunoglobulin (Ig) G4 elevation has been associated with several pathological conditions other than IgG4-related disease (IgG4-RD). In cystic fibrosis (CF), an elevation of specific IgG4 has been associated with colonization and infection by Pseudomonas aeruginosa. IgG4 elevation may be a marker of chronic infection or inflammatory stimulation. The aim of this study was to explore the prevalence of elevated IgG4 levels in CF and its correlation with the major clinical and microbiological features found in CF patients. Methods In a cross-sectional study, we analyzed data from a large cohort of adult CF patients attending the CF center of Lyon University Hospital. An elevated IgG4 level was defined as being above the cut-off value of 135 mg/dL. Results One hundred and sixty-five CF patients were analyzed. An IgG4 elevation was detected in 43 patients (26%). Compared with the control group (≤ 135 mg/dL), high IgG4 patients exhibited a greater prevalence of Staphylococcus aureus colonization and higher IgG, IgG1, IgG2 and IgE levels. No significant differences were observed in terms of pulmonary function, colonization with Pseudomonas aeruginosa, or the annual rate of bronchial exacerbations. Conclusion An elevated IgG4 serum level was frequently detected in adult CF patients and did not appear to be associated with poor lung function. We suggest that IgG4 elevation is a marker of the activation of tolerance. Its clinical significance remains to be demonstrated.

Introduction Systemic Lupus Erythematosus (SLE) is associated with thrombocytopenia in approximately 20 % of cases. Management of such cases has been similar to that of Immune ThrombocytoPenia (ITP) as an immune-mediated mechanism is inferred in the pathogenesis of SLE-associated thrombocytopenia. First line treatment is similar to primary ITP (corticosteroids, intravenous immunoglobulin), with the use of hydroxychloroquin in addition. Immunosuppressive agents, rituximab or splenectomy can be used as second line treatment. However, a significant number of patients will not respond to these treatments and will relapse afterward. More recently, Romiplostim and Eltrombopag, 2 agonists of thrombopoietin receptor (TPO-RA) have been approved for ITP as second line therapy resulting in sustained increment in platelet count in about 70-80 % of cases with reduction in bleeding. However, the experience with this class of agents in SLE is only anecdotal. Their effectiveness and side effects in SLE related ITP is unknown. Patients and Method This was a multicenter retrospective cohort study of patients with SLE related ITP diagnosed from 1998 to 2015 and treated with TPO-RA. All participating centers (n=13) were secondary or tertiary care hospitals belonging to the French national network for adult ITP. Clinical data were retrospectively collected from medical charts for each patient and completed by telephone interviews with patients and physicians by using a standardized questionnaire. ITP was defined according to the international working group definitions. SLE was defined according to the international guidelines (American College of Rheumatology for systemic lupus erythematosus, revised Sapporo criteria for antiphospholipid syndrome). Response (R) and complete response (CR) were defined according to standardized international criteria: platelet count > 30 × 109/L with at least a doubling of the baseline value or >100 × 109/L.2 Non-response (NR) was defined as the absence of platelet count increase >30 × 109/L with at least a doubling of the baseline count or the need for rescue therapy (IVIg and/or corticosteroids). Patient's characteristics (table 1&2) PS: PitiŽ Salptrire, F: female, M: male, HCQ: hydroxychloroquin, MMF: Mycophenolate mofetil, CTC: corticosteroid, RTX : rituximab, CYC: cyclophosphamide, IVIG : intravenous immunoglobulin, AZA: azathioprine, spm: splenectomy, Toci: tocilizumab, Aba: abatacept, Csa: ciclosporine, TPO-RA : thrombopoietin-receptor agonist, Elt : eltrombopag, Romipl : romiplostim, NS :non specified, CR: complete remission, R :responder, NR :non responder APLS: antiphospholipid syndrome, APL : antiphospholipid (presence of antibody without clinical symptoms) Results and Discussion A total of 16 patients (12 F/ 4M) received TPO-RA (Romiplostim 36%, eltrombopag 28 %, both 36%). Patients had received a median of 5.5 treatment lines for ITP. All but one patient responded at least to one of TPO-RA (93%). No SLE flare has been observed with these treatments. Unexpectedly, 3 patients (18,5%) developed thrombotic events as a side effect. Two arterial thrombosis occurred in patients receiving eltrombopag (both of them with a previous history of APL or APLS), and two venous thrombosis in the same patient (without antiphospholipid) treated with romiplostim. The same strategy was used in the 3 patients: TPO-RA was stopped but rechallenged promptly to increase platelet level, given that they were receiving anticoagulant or anti-aggregant therapy. No reoccurrence has been observed. The other side effects were similar to that observed with primary ITP. This study has some limitations due to its retrospective design, including some potential selection bias but the rapid and sustained response observed raises the possibility that in certain refractory cases of thrombocytopenia associated with SLE, TPO-RA might be a second line therapy to be considered in this patient population. Given the high rate of thrombotic events, we suggest that TPO-RA should be used with caution in patient with APL. Prospective systematic studies would help define the role of this class of agents in SLE and other rheumatic disease that progress with immune mediated thrombocytopenia. Table 1 Table 1. Table 2 Table 2. Disclosures Terriou: amgen: Consultancy; Novartis: Consultancy. Bussel:Prophylix Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Physicians Education Resource: Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Protalex: Membership on an entity's Board of Directors or advisory committees, Research Funding; UpToDate: Patents & Royalties; BiologicTx: Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; Genzyme: Research Funding; Sysmex: Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees; Momenta Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding.

Objective: CFRD is the most common comorbidity in CF. The recommended treatment of CFRD is Insulin, but other options are also in use. Only few data exist related to other treatment options. Therefore we analyzed the German CFregister for the documented therapy of CFRD. Methods: Data from the German CF-register were used from patients with CFRD in 2010 in a retrospective observational study. Delta FEV1% and delta BMI-Zscore from 2 year before diagnosis of CFRD to year of diagnosis and from year of diagnosis to 2 years after were calculated for each treatment group (Insulin, oral anti-diabetic drugs, no therapy with drugs) and compared using ANOVA-analysis. Results: 798 patients with CFRD were documented in 2010. 51.9%.were female; age (mean±SD) at diagnosis 23.8±9.3 years; CFRD duration 5.8±4.5 years. Treatment: 57.6% Insulin, 9.8% oral anti-diabetic drugs, 2.1% with both and 30.2% without any drug treatment. The mean (±SD) CFRD duration in the non-treated patients was 4.5±4.0 years. ANOVA tests showed no differences between treatment groups regarding changes in FEV1% and BMI-Z-score from 2 years before to the year of diagnosis and delta FEV1 and delta BMI-Z-score and from year of diagnosis to 2 years later. Conclusions: The percentage of patients treated with oral anti-diabetic drugs is in the international published range. We know the weakness of retrospective studies. Nevertheless the numbers are high and the observation time is long. Our data point to the question if insulin is the only successful initial treatment of CFRD in all CF patients. At least a part of patients with CFRD seems to be well treated with other regimes. Supported by German CF Foundation.

223 Infertility among women with cystic fibrosis: prevalence and risk factors M. Shteinberg, A. Ben Lulu, Z. Blumenfeld, M. Gur, L. Bentur, H. Mussaffi, H. Blau, I. Sarouk, O. Efrati, M. Cohen-Cymberknoh, E. Kerem, M. Aviram, E. Pickard, G. Livnat. Carmel Medical Center, Pulmonology and CF Center, Haifa, Israel; Technion-Israel Institute of Technology, The B. Rappaport Faculty of Medicine, Haifa, Israel; Rambam Health Care Campus, Obstetrics & Gynecology, Haifa, Israel; Rambam Health Care Campus, Ruth Rappaport Children’s Hospital, Haifa, Israel; Schneider Children’s Medical Center, Kathy and Lee Graub Cystic Fibrosis Center, Petach Tikva, Israel; Tel Aviv University, Sackler Faculty of Medicine, Tel Aviv, Israel; Sheba Medical Center, Cystic Fibrosis Center, Tel Aviv, Israel; Hadassah-Hebrew University Medical Center, Cystic Fibrosis Center, Jerusalem, Israel; Soroka Medical Center, Cystic Fibrosis Center, Beer Sheva, Israel; Shaare Zedek Medical Center, Cystic Fibrosis Center, Jerusalem, Israel; Carmel Medical Center, CF Center, Haifa, Israel Objectives: Women with cystic fibrosis frequently encounter difficulty conceiving; however, the incidence of subfertility among CF women has not been established. It is unknown whether CF severity is associated with subfertility. We aimed to determine the rate of subfertility in women with CF, and to explore risk factors for female subfertility. Methods: A retrospective study of all CF centers in Israel including women with CF aged 18 and older. Women were divided into four fertility categories: 1. Normal fertility (spontaneous pregnancy). 2. Subfertility (having required assisted reproduction after 1 year of infertility). 3. Infertile (remained infertile despite treatments). 4. Not attempted childbearing. Clinical characteristics were compared between the fertility groups. Chi or T-test were employed where appropriate. Results: 130 women were included. 32 women had normal fertility, 17 subfertility, 4 infertility, and 77 never attempted childbearing. For further analysis, groups 2 and 3 were combined. The following variables were associated with decreased fertility: presence of two class I–III mutations, 52% (groups 2&3) vs. 40% in group 1; Pancreatic insufficiency, 61% vs. 44% (p =0.196); and BMI, 22.2±3kg/m2 vs. 23.2±3kg/m2, respectively. Differences did not reach statistical significance. There were no differences in lung function, rate of exacerbations, or colonization with Pseudomonas between fertility groups. Conclusion: The rate of subfertility among CF women was 39.6%, much higher than in the general population (10–15%). No clear risk factors for infertility were identified, although a trend for pancreatic sufficiency was associated with less infertility.

ObjectivesThe aim of the study was to evaluate sleep quality and nocturnal gas exchange in patients with cystic fibrosis (CF) and to assess if sleep quality and daytime lung function could predict nocturnal hypoxaemia or hypercapnia.Study designDaytime sleepiness and objective sleep quality were evaluated by the Pittsburgh Sleep Quality Index (PSQI) and actigraphy in 25 children and 55 young adults (mean age 24±10 years, forced expiratory volume in 1 s (FEV1) 41±11% predicted). Nocturnal gas exchange was assessed by pulse oximetry (SpO2) and transcutaneous carbon dioxide (PtcCO2) recordings. Eleven patients underwent simultaneous polysomnography (PSG).ResultsPSQI was 6.3±3.4 with 51% of the patients having a score >5 corresponding to significant sleep complaints. On actigraphy, sleep efficiency was impaired at 79±11% with a fragmentation index at 41±18. Mean nocturnal SpO2 was 93±3% with 18% of the patients exhibiting >10% of night time spent with a value below 90%. Mean PtcCO2 was 44±6 mm Hg with 47% of the patients exhibiting >10% of night time with a value >45 mm Hg. Daytime arterial blood gases correlated with nocturnal gas exchange. FEV1 was the only lung function parameter that correlated with nocturnal SpO2 (p2 and PtcCO2 accurately identified rapid eye movement sleep hypoventilation.ConclusionsPatients with CF exhibit poor sleep quality that does not predict nocturnal gas exchange. Nocturnal hypoxaemia and hypercapnia can be identified by simple tools.

International audience; BACKGROUND: Primary immunoglobulin deficiencies lead to recurrent bacterial infections of the respiratory tract and bronchiectasis, even with adequate immunoglobulin replacement therapy. It is not known whether patients able to secrete IgM (eg, those with hyper-IgM [HIgM] syndrome) are as susceptible to these infections as patients who lack IgM production (eg, those with panhypogammaglobulinemia [PHG]). OBJECTIVE: This study is aimed at identifying specific microbiological and clinical (infections) characteristics that distinguish immunoglobulin-substituted patients with PHG from patients with HIgM syndrome. METHODS: A cohort of patients with HIgM syndrome (n = 25) and a cohort of patients with PHG (n = 86) were monitored prospectively for 2 years while receiving similar polyvalent immunoglobulin replacement therapies. Regular bacterial analyses of nasal swabs and sputum were performed, and clinical events were recorded. In parallel, serum and saliva IgM antibody concentrations were measured. RESULTS: When compared with patients with PHG, patients with HIgM syndrome were found to have a significantly lower risk of nontypeable Haemophilus influenzae carriage in particular (relative risk, 0.39; 95% CI, 0.21-0.63). Moreover, patients with HIgM syndrome (including those unable to generate somatic hypermutations of immunoglobulin genes) displayed anti-nontypeable H influenzae IgM antibodies in their serum and saliva. Also, patients with HIgM syndrome had a lower incidence of acute respiratory tract infections. CONCLUSIONS: IgM antibodies appear to be microbiologically and clinically protective and might thus attenuate the infectious consequences of a lack of production of other immunoglobulin isotypes in patients with HIgM syndrome. Polyvalent IgG replacement therapy might not fully compensate for IgM deficiency. It might thus be worth adapting long-term antimicrobial prophylactic regimens according to the underlying B-cell immunodeficiency phenotype.

Background: Although transplantation is known to impair glucose tolerance, evolution of pre-existing diabetes after lung transplantation (LT) in cystic fibrosis (CF) has never been described. Objectives: We aimed to assess the outcome of CF-related diabetes (CFRD) after LT, with the hypothesis that suppressing chronic inflammatory foci may improve glucose tolerance in some patients. Methods: In a retrospective study of 29 CF diabetic patients treated with insulin and undergoing LT, CFRD control was assessed 3 months before LT and 1 (n = 27) and 2 (n = 18) years after LT by measuring insulin dosage, fasting blood glucose and glycosylated hemoglobin (HbA1c) levels. Patients with HbA1c ≤7% and an insulin dose ≤1 UI/kg/day were defined as having controlled CFRD (group A). Other patients were assigned to group B. Results: Before LT, 19 (65.5%) patients were in group A. At 2 years, 6 of 10 (60%) patients who were in group B prior to LT had moved into group A, which then comprised 77.8% of all patients. Insulin could have been stopped in 5 patients. Uncontrolled CFRD before LT (OR = 16) and a long delay between the diagnosis of CFRD and LT (OR = 1.3) were significant predictors of uncontrolled CFRD at 1 year. Conclusions: LT does not seem to worsen CFRD in some patients, suggesting that in some cases, glucose tolerance may be improved by the suppression of chronic pulmonary infection.

Background: Cystic fibrosis (CF) is caused by compound heterozygosity or homozygosity of CF transmembrane conductance regulator gene (CFTR) mutations. Phenotypic variability associated with certain mutations makes genetic counselling difficult, notably for R117H, whose disease phenotype varies from asymptomatic to classical CF. The high frequency of R117H observed in CF newborn screening has also introduced diagnostic dilemmas. The aim of this study was to evaluate the disease penetrance for R117H in order to improve clinical practice. Methods: The phenotypes in all individuals identified in France as compound heterozygous for R117H and F508del, the most frequent CF mutation, were described. The allelic prevalences of R117H (p R117H), on either intron 8 T5 or T7 background, and F508del (p F508del) were determined in the French population, to permit an evaluation of the penetrance of CF for the [R117H]+[F508del] genotype. Results: Clinical details were documented for 184 [R117H]+[F508del] individuals, including 72 newborns. The disease phenotype was predominantly mild; one child had classical CF, and three adults' severe pulmonary symptoms. In 5245 healthy adults, p F508del was 1.06%, p R117H;T7 0.27% and p R117H;T5 ,0.01%. The theoretical number of [R117H;T7]+[F508del] individuals in the French population was estimated at 3650, whereas only 112 were known with CF related symptoms (3.1%). The penetrance of classical CF for [R117H;T7]+[F508del] was estimated at 0.03% and that of severe CF in adulthood at 0.06%. Conclusions: These results suggest that R117H should be withdrawn from CF mutation panels used for screening programmes. The real impact of so-called disease mutations should be assessed before including them in newborn or preconceptional carrier screening programmes .

To examine the efficacy and safety of pegfilgrastim in patients with congenital neutropenia (CN).Seventeen patients enrolled in the French Severe CN Register received pegfilgrastim.Median age at pegfilgrastim introduction was 19.1 years (range 3.9-52.3 years). In 14 cases pegfilgrastim replaced GCSF (filgrastim or lenograstim), after a median of 6.9 years of GCSF therapy. The dose of pegfilgrastim was usually one full vial per injection (except in five children, who received 1/6 to 1/2 a vial), resulting in a dose of between 50 and 286 microg/kg. The pegfilgrastim schedule ranged from two injections every 7 days to one injection every 30 days, with treatment-free periods. The median interval between the first and last dose of pegfilgrastim was 0.8 years (0.01-4.1 years). The absolute neutrophil count tended to increase more strongly on pegfilgrastim than on GCSF, but the difference was not statistically significant. During pegfilgrastim therapy, a severe infection occurred in two patients and recurrent ENT infections in two other patients. Bone pain was reported by nine patients, anemia and thrombocytopenia occurred in one patient (WHO grade III), chronic urticaria occurred in one patient (WHO grade III), and a single pegfilgrastim injection was followed by respiratory distress and death 15 days later in a patient with GDSIb. At the last update, 10 patients had stopped receiving pegfilgrastim and seven patients were still receiving pegfilgrastim.Compared to conventional GCSF, pegfilgrastim is more difficult to use in congenital neutropenia, with more frequent adverse events and sometimes poor efficacy.

No guidelines are available for noninvasive ventilation (NIV) for cystic fibrosis (CF).To survey and evaluate the use of NIV for CF in France.We surveyed the coordinator physicians of every accredited CF center in France.The respondents represented 36 centers (15 pediatric centers, 13 adult centers, and 8 centers that see both pediatric and adult patients), which had a total of 4,416 patients with CF at the time of the study, 168 (3.8%) of whom were using NIV. NIV was being used more often in the adults centers (7.6% of these patients) than in the pediatric centers (1.2% of these patients) or adult-and-pediatric centers (4.1% of these patients) (P= .01). All the respondent centers use NIV as first-line treatment for severe hypercapnic respiratory exacerbation and for stable diurnal hypercapnia, especially when associated with sleep disturbance. Bi-level pressure-targeted ventilation is the preferred ventilation mode. Settings are adjusted based on arterial blood gas values, noninvasive evaluation of patient-ventilator synchrony, patient comfort, and sometimes a sleep study. The surveyed centers reported a number of expected benefits from NIV, but few of those benefits have been proven. Problems with NIV are common and limit its use.We found a relative homogeneity in these French centers' stated indications for and use of NIV, which highlights their numerous expectations about the benefits of NIV, which contrasts with the few validated benefits. Studies of the benefits of NIV are needed.

Objectives Bone disease has been well described in cystic fibrosis (CF) adult patients. While DXA remains the gold standard method to assess bone, it has important limitations. High resolution peripheral QCT (HRpQCT) could provide useful information on geometry, volumetric density (vBMD) and microarchitecture of bone that may be impaired in CF. Our aims were to assess the prevalence of CF related low BMD in a current adult CF population and to characterize the bone geometry and microarchitecture with HRpQCT at the distal radius and tibia. Methods Fifty six CF patients had a clinical and biological evaluation, a DXA at the lumbar spine and hip and a spine radiograph. A subgroup of 43 CF and 86 age- and gender-matched healthy controls underwent HRpQCT measurements. Results Among the 56 CF (52% men, 26±7 yrs), the prevalence of low areal BMD defined by a T-score Conclusion In this study, bone disease seemed to be less severe than previously described with only 20% of CF patient with low areal BMD. Yet, the impaired cortical thickness leading to a lower total vBMD of the tibia, may explain the increased fracture risk in CF population.

Objectives To evaluate contraceptives practices and gynecological cares among the CF women attending Lyon University Adult CF centre. Methods A questionnaire was proposed to all of the 155 women attending the CF adult centre in 2014. Contraceptive methods and gynaecological health care were recorded. Other clinical records included diabetes mellitus, transplantation and previous pregnancy. Results 120 questionnaires were recorded. 2 were post menopausal; 5 were pregnant. The overall rate of contraception in the remaining 113 was 64%, 61% for diabetic women. Oral contraception (OC) represents 65%, predominantly estroprogestative (47%); diabetic patients used progestin-only pill in 26%. Among the 19 transplanted women, 7 didn't use any contraception; 5 were single and 2 want a child. 27 women had at least one previous pregnancy. 44% of them used OC, 19% intrauterine device, 11% tubal ligation or stent. 74% declared a regular gynaecological follow-up (89% in transplanted women), mainly by a gynaecologist. 55% had ever had a pap smear test, but some of there were above 25 years old. Only 42% of patients reported having had a pap smear test in the last 3 years. Among transplanted patients, 58% ever had a pap smear test despite immunosuppressive therapy. Conclusion This preliminary study of practices highlights the importance of a better information about sexuality, fertility and reproductive health in CF adolescents and young women in order to avoid unplanned pregnancy, to optimize contraceptives choice in relation to specific clinical conditions. The gynecological health care needs also to be optimize with better information of recommanded follow-up.

Objectives The aim of DIAMUCO study is to describe the natural history of the glucose tolerance (GT) and to identify predictive factors of the changes in GT in cystic fibrosis (CF) patients for a three-year period. Methods We used a cross-sectional study design and included a total of 228 patients, 111 children (between 10 and 18 years) and 117 adults between 2009 and 2011. All patients had an annual screening. Patients were classified as having normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or CF-related diabetes mellitus (CFRD) using the 2-h oral glucose tolerance test (OGTT). Results At baseline, 67.1% (n = 153) patients were classified as NGT, 25.4% (n = 58) as IGT and 7.4% (n = 17) as CFRD. Over half of patients changed at least once of glucose tolerance status during follow-up. The mean decline of FEV1 was 1.54 per year without difference between female and male. A decrease in FEV1 (p TableClinical characteristicsTotalCFRDIGTNTpAge20.1±8.124.3±9.319.3±7.420.0±8.20.1FEV172.4±24.165.0±22.173.8±23.972.6±24.50.4Weight z-score0.5±1.5−0.70±1.24−0.79±1.18−0.37±1.50.1 Conclusion We confirm the variability of glucose tolerance status over time. The impact of glucose tolerance status on respiratory deterioration seems to concern only patients with permanently CFRD status. The early treatment decision must therefore be careful.