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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.

Revue du rhumatisme - In Press.Proof corrected by the author Available online since mercredi 15 fevrier 2017

Extracorporeal membrane oxygenation (ECMO) is increasingly used as a bridge to lung transplantation (LTx). However, data concerning this approach remain limited.We retrospectively reviewed the medical records of all patients in France who received ECMO as a bridge to LTx from 2007 to 2011. Post-transplant survival and associated factors were assessed by the Kaplan-Meier method and the Cox model.Included were 36 patients from 11 centers. Indications for LTx were cystic fibrosis (CF) in 20 (56%), pulmonary fibrosis (PF) in 11 (30%), and other diagnoses in 5 (14%). ECMO was venovenous for 27 patients (75%) and venoarterial for 9 (25%). Mean follow-up was 17 months. Bridging to LTx was achieved in 30 patients (83%); however, only 27 patients (75%) survived the LTx procedure, and 20 (56%) were discharged from hospital. From ECMO initiation, 2-year survival rates were 50.4% overall, 71.0% for CF patients, 27.3% for PF patients, and 20.0% for other patients (p0.001). From LTx, 2-year survival rates were 60.5% overall, 71.0% for CF patients, 42.9% for PF patients, and 33.0% for other patients (p = 0.04).Our study confirms that the use of ECMO as a bridge to LTx in France could provide a medium-term survival benefit for LTx recipients with critical conditions. Survival differed by underlying respiratory disease. Larger studies are needed to further define the optimal use of ECMO.

Single (S) or bilateral (B) lung transplantation (LT) is offered for end stage, life-threatening pulmonary fibrosis (PF). Currently, no strong recommendation helps transplantation teams for choosing optimal total lung capacity (TLC) for size matching. We conducted a retrospective analysis of all LT performed in PF patients from 1988 to 2015 in Nantes University hospital, France, in order to study donor vs. recipient TLC. We defined transplanted BLT-TLC as follows: theoretic donor TLC minus lung volume surgical reduction, divided by theoretic recipient TLC. Transplanted SLT-TLC was similarly calculated, taking into account measured TLC of the remaining lung. 24 patients (46 ± 9 years, 10 SLT and 14 BLT) were included. Survival after transplantation for BLT, SLT and both was respectively 35.7%, 50% and 41.7% at 1 year, 21.5%, 10% and 16.7% at 5 years, with a median survival of 347 days for BLT and 272 days for SLT (p=0.38). Mean transplanted TLC was higher in BLT (86.4 ± 20.2% pred.) than in SLT (65.1 ± 7.2% pred.) (p = 0.007) and higher than recipient TLC measured / theoretic in BLT (54 ± 22%) and SLT (48 ± 10%) (p=0.038). Average lung volume reduction was 12.3% in BLT and was performed in 35.7% of BLT and 20% of SLT. When classifying patients according to different thresholds of transplanted TLC percentage (70% or 80% pred.), no mortality difference was observed in SLT, BLT or both groups. Taking into account surgical lung volume reduction, we report a lower transplanted TLC in BLT and SLT than the one suggested by Barnard et al. (Barnard J.B, J Heart Tranplant 2013;32:849-860). The best TLC size matching appears to be somewhere between measured and theoretic TLC recipient but has to be further explored.

Part of this work has been presented at the Fifth Congress on Trends in Medical Mycology, Valencia, Spain, 2011 (Abstract no. 308); International audience; OBJECTIVES:Triazole resistance in Aspergillus fumigatus due to a single azole resistance mechanism (TR/L98H) is increasingly reported in European countries. Data from patients with cystic fibrosis (CF) are limited. Our study aimed to investigate the prevalence and molecular mechanisms of azole resistance in A. fumigatus in a cohort of patients with CF.METHODS:Eighty-five A. fumigatus isolates from 50 CF patients, collected between January 2010 and April 2011, were retrospectively analysed for azole resistance using agar plates containing 4 mg/L itraconazole. MICs of itraconazole, voriconazole and posaconazole were determined according to EUCAST methodology for each isolate able to grow on this medium. Species identification was performed by sequencing of the β-tubulin gene. Sequencing analysis of the cyp51A gene and its promoter region was conducted.RESULTS:Nine isolates (four patients, 8% prevalence) were able to grow on itraconazole-containing agar plates. Itraconazole resistance was confirmed by EUCAST methodology (MICs >2 mg/L). All isolates had mutations in the cyp51A gene at residues previously involved in azole resistance: L98H (n = 5), M220T (n = 4) and G54R (n = 1). One patient had three genetically distinct azole-resistant isolates identified during the study. The isolates with L98H that were recovered from three patients (6% prevalence) also had the 34 bp tandem repeat in the promoter region of cyp51A (TR/L98H) and displayed multiazole resistance.CONCLUSIONS:We report an 8% prevalence of itraconazole resistance in CF patients in our centre, mostly driven by TR/L98H (6%). Our data confirm that TR/L98H occurs in France and can be highly prevalent in CF patients.

Joint Bone Spine - In Press.Proof corrected by the author Available online since lundi 25 avril 2016

Scopulariopsis species are rarely but increasingly recognized as opportunistic pathogens in immunocompromised patients. We report on a patient suffering from cystic fibrosis who developed disseminated fungal infection due to a rare Scopulariopsis species, Microascus cirrosus , after heart and lung transplantation. Despite antifungal combination therapy with voriconazole and caspofungin, the patient died 4 weeks after transplantation. Diagnostic difficulties and optimal management of disseminated Scopulariopsis / Microascus infections are discussed.

Dans notre specialite, les conditions d’apparition d’une crise d’asthme sont multiples. Le stress, la douleur, l’utilisation d’anesthesiques locaux, l’infection, la prescription medicamenteuse et l’exposition a certains pneumallergenes comme le latex et les poussieres de fraisage peuvent favoriser celle-ci. L’asthme est responsable d’environ 2000 deces par an en France et justifie 40 000 hospitalisations par an. Le tiers des deces survient dans la premiere demi-heure apres le debut des signes et 60 % en dehors de l’hopital. La pathologie asthmatique semble en constante augmentation ; nombreux sont les patients sous-medicalises et sous-traites ; l’observance des traitements est souvent partielle. L’application du principe de prudence se justifie afin de conduire de facon rationnelle et en toute securite un acte de chirurgie buccale chez ces patients. L’objet de notre article est de systematiser la conduite a tenir et de proposer une strategie pre, per- et post-operatoire. (Med Buccale Chir Buccale 2003; 9: 37-48)

Introduction La proportion d’adultes parmi les patients suivis pour une mucoviscidose ne cesse de croitre, depassant aujourd’hui 50 %. L’atteinte pulmonaire represente la premiere cause de morbi-mortalite dans cette population. Le VEMS est actuellement l’indice de reference utilise dans l’evaluation diagnostique et pronostique de la maladie mais il implique la realisation d’une expiration forcee, parfois difficile a effectuer chez ces patients. Des outils simples evaluant le systeme respiratoire au repos, seraient donc opportuns. Parmi eux, l’oscillometrie d’impulsion (IOS) permet de mesurer facilement la resistance et la reactance pulmonaires, cette derniere etant liee notamment a la compliance. L’objectif de cette etude est de caracteriser l’alteration fonctionnelle respiratoire dans la mucoviscidose de l’adulte en utilisant l’IOS, un examen rapide, non invasif, qui se deroule en ventilation courante avec une cooperation minimale. Methodes Etude monocentrique transversale menee au CHU de Nantes. Dans le cadre de leur suivi habituel au centre de ressources et de competences de la mucoviscidose, des mesures de resistance et de reactance par IOS ont ete effectuees chez tous les patients adultes non transplantes. Les correlations avec certaines donnees cliniques et paracliniques ont ete analysees. Resultats Quatre-vingt-huit patients (58 % d’hommes ; âge : 29 ± 8,5 ans) ont ete inclus. Les manœuvres ont toutes ete realisees sans difficulte. Les resistances pulmonaires totales etaient elevees (R5Hz = 0,47 ± 0,17 kPa.L/s) et la reactance diminuee (X5Hz = –0,23 ± 0,14 kPa.L/s). La reactance etait fortement correlee avec le VEMS (r = 0,88 ; p Conclusion A notre connaissance, cette etude est la premiere a utiliser l’oscillometrie d’impulsion pour decrire les anomalies de la fonction respiratoire des adultes atteints de mucoviscidose. La simplicite de realisation des mesures est le point fort de cette technique. Malgre un VEMS similaire, les patients les plus severes presentent des profils IOS differents dont la signification pronostique reste a preciser. D’autres etudes sont necessaires, notamment pour determiner l’interet de l’IOS dans la selection des patients eligibles a une transplantation pulmonaire.

We describe the first case of bacteremia due to Gallibacterium anatis . The patient, a 26-year-old woman, developed bacteremia and diarrhea. The origin of infection was possibly due to a diet contaminated by G. anatis in this highly immunocompromised patient.

International audience; 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

To the Editors: Pulmonary tumour embolism is considered to be a rare cause of pulmonary hypertension. The incidence, studied in autopsy series, varies from 3 to 26% of patients with solid tumour [1]. It occurs most frequently in breast, stomach, lung, liver, prostate and pancreas adenocarcinoma [1]. The literature shows a male predominance and an average age of 52.4 yrs [2]. The signs are those of any pulmonary hypertension, occurring either during the history of a known neoplasia or as the first manifestation of malignancy. Pre-mortem diagnosis is difficult to confirm and definitive diagnosis is usually made on an autopsy study. Several studies have reported pulmonary wedge aspiration cytology performed during a right heart catheterisation as a useful pre-mortem diagnostic tool [3]. Treatment consists of treating the neoplasia. Specific treatment for pulmonary hypertension has not been evaluated. Most frequently, evolution leads to refractory right cardiac failure and death [4]. In rare cases improvement has been reported after chemotherapy [5] or endarterectomy [6]. Two mechanisms can be involved in the development of pulmonary hypertension in tumour pulmonary embolism: the first one is by mechanical occlusion of the small pulmonary arteries by multiple neoplastic microemboli, the second one is through development of pulmonary tumour thrombotic microangiopathy (PTTM) as a result of …

We report a case of colchicine-induced rhabdomyolysis in a heart/lung-transplanted man treated with cyclosporin. A treatment was to resolve an acute gouty arthritis and was started with 3 mg of colchicine the first day, then 2 mg the second and the third day, and finally 1 mg/d during 6 days. Eight days later, the patient developed multiple organ failure and rhabdomyolysis. The concentration of colchicine analyzed was greater than the standard 153 hours after his last intake. Pharmacokinetic interactions are responsible of this toxicity. Cyclosporin, pravastatin, and azithromycin are known to inhibit P-glycoprotein, which will enhance the intracellular colchicine level by acting in its bioavailability and moderating hepatic and renal excretion. Moreover, long-term treatment by cyclosporin generates chronic renal failure that will, in the same time, decrease colchicine elimination. Even short-term administration of therapeutic colchicine dose may cause colchicine-related toxicity, especially in the setting of a renal failure and/or polymedicinal treatment.

Background— Novel therapies have recently become available for pulmonary arterial hypertension. We conducted a study to characterize mortality in a multicenter prospective cohort of patients diagnosed with idiopathic, familial, or anorexigen-associated pulmonary arterial hypertension in the modern management era. Methods and Results— Between October 2002 and October 2003, 354 consecutive adult patients with idiopathic, familial, or anorexigen-associated pulmonary arterial hypertension (56 incident and 298 prevalent cases) were prospectively enrolled. Patients were followed up for 3 years, and survival rates were analyzed. For incident cases, estimated survival (95% confidence intervals [CIs]) at 1, 2, and 3 years was 85.7% (95% CI, 76.5 to 94.9), 69.6% (95% CI, 57.6 to 81.6), and 54.9% (95% CI, 41.8 to 68.0), respectively. In a combined analysis population (incident patients and prevalent patients diagnosed within 3 years before study entry; n=190), 1-, 2-, and 3-year survival estimates were 82.9% (95% CI, 72.4 to 95.0), 67.1% (95% CI, 57.1 to 78.8), and 58.2% (95% CI, 49.0 to 69.3), respectively. Individual survival analysis identified the following as significantly and positively associated with survival: female gender, New York Heart Association functional class I/II, greater 6-minute walk distance, lower right atrial pressure, and higher cardiac output. Multivariable analysis showed that being female, having a greater 6-minute walk distance, and exhibiting higher cardiac output were jointly significantly associated with improved survival. Conclusions— In the modern management era, idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension remains a progressive, fatal disease. Mortality is most closely associated with male gender, right ventricular hemodynamic function, and exercise limitation.

We report a case of disseminated Scedosporium / Pseudallescheria infection due to P seudallescheria boydii sensu stricto after lung transplantation in a patient with cystic fibrosis. Dissemination occurred under voriconazole. Despite surgery and combination therapy with voriconazole, caspofungin, and terbinafine, the patient died 8 months after transplantation. Previously reported cases are reviewed.

Pulmonary arterial hypertension (PAH) is an orphan disease for which the trend is for management in designated centers with multidisciplinary teams working in a shared-care approach.To describe clinical and hemodynamic parameters and to provide estimates for the prevalence of patients diagnosed for PAH according to a standardized definition.The registry was initiated in 17 university hospitals following at least five newly diagnosed patients per year. All consecutive adult (or = 18 yr) patients seen between October 2002 and October 2003 were to be included.A total of 674 patients (mean +/- SD age, 50 +/- 15 yr; range, 18-85 yr) were entered in the registry. Idiopathic, familial, anorexigen, connective tissue diseases, congenital heart diseases, portal hypertension, and HIV-associated PAH accounted for 39.2, 3.9, 9.5, 15.3, 11.3, 10.4, and 6.2% of the population, respectively. At diagnosis, 75% of patients were in New York Heart Association functional class III or IV. Six-minute walk test was 329 +/- 109 m. Mean pulmonary artery pressure, cardiac index, and pulmonary vascular resistance index were 55 +/- 15 mm Hg, 2.5 +/- 0.8 L/min/m(2), and 20.5 +/- 10.2 mm Hg/L/min/m(2), respectively. The low estimates of prevalence and incidence of PAH in France were 15.0 cases/million of adult inhabitants and 2.4 cases/million of adult inhabitants/yr. One-year survival was 88% in the incident cohort.This contemporary registry highlights current practice and shows that PAH is detected late in the course of the disease, with a majority of patients displaying severe functional and hemodynamic compromise.

The effect of graft ischemic time on early graft function and long-term survival of patients who underwent lung transplantation remains controversial. Consequently, graft ischemic time has not been incorporated in the decision-making process at the time of graft acceptance.To investigate the relationship between graft ischemic time and (1) early graft function and (2) long-term survival after lung transplantation.The data from 752 patients who underwent single lung transplantation (n = 258), bilateral lung transplantation (n = 247), and heart-lung transplantation (n = 247) in seven French transplantation centers during a 12-year period were reviewed. Independent data quality control was done to ensure the quality of the collected variables. Mean graft ischemic time was 245.8 +/- 96.4 minutes (range 50-660). After adjustment on 11 potential confounders, graft ischemic time was associated with the recipient Pa(O2)/FI(O2) ratio recorded within the first 6 hours and with long-term survival in patients undergoing single or double lung transplantation but not in patients undergoing heart-lung transplantation. The relationship between graft ischemic time and survival appears to be of cubic form with a cutoff value of 330 minutes. These results were unaffected by the preservation fluid employed.The results of this large cohort of patients suggest a close relationship between graft ischemic time and both early gas exchange and long-term survival after single and double lung transplantation. Such relationship was not found in patients undergoing heart-lung transplantation. The expected graft ischemic time should be incorporated in the decision-making process at the time of graft acceptance.

International audience; Background: The liberalization of lung-donor criteria and the use of marginal donors have been advocated to face the current shortage of donors in lung transplantation. However, the impact of donor characteristics on the outcome of lung transplantation is still largely unknown. We aimed to determine, on a large cohort of patients, the effect of donors characteristics on short- and long-term outcome of lung transplantation. Methods: Between 1988 and 1998, a total of 785 adult patients underwent single-lung transplantation (n 270), bilateral-lung transplantation (n = 251), and heart-lung transplantation (n = 264) in 7 centers in France. We constructed several multivariate models to assess the relationship between donor characteristics and early gas exchange, duration of mechanical ventilation, and long-term survival after lung transplantation. Results: Among donor characteristics, donor gas exchange before harvest was found to be significantly associated with recipient early gas exchange, duration of mechanical ventilation, and long-term survival after adjustment for potential confounding variables. Moreover, nonlinear modeling showed a steep increase in the relative risk of death when donor Pao(2)/Fio(2) before harvest was below 350 (hazard ratio 1.43; 95% confidence interval 1.10 - 1.85; p = 0.01). Donor and recipient sex mismatch were also found to be significantly associated with long-term survival. Conclusions: Although liberalization of lung-donor criteria may be considered to overcome the shortage of lung donors, our data suggest that the violation of the gas-exchange criterion should be avoided.

Lung transplantation is a valid treatment in cystic fibrosis patients at end stage of the disease. It is decided when the vital prognosis seems to be engaged within two years. Patients are put on the waiting list after they have been checked out according to their individual potential risks and difficulties. The waiting time on list may be prolonged and should be used to optimize nutritional status (gastrostomy) and to take into account the psychological aspect of the project. The choice between double lung transplantation and heart lung transplantation depends on teams experience. Survival rate is increasing (until 90% and 78% survival rate at 1 and 5 years). Contra-indications are represented by a dependence on invasive assisted ventilation before referral to transplant, and adhesions after surgical pleurectomy. Long term results depend on bronchiolitis obliterans which is for some teams an opportunity to discuss the possibility of retransplantation.

The purpose of this study was to report a single center's experience of 5 new pregnancies following heart-lung transplantation. These 5 pregnancies gave rise to 4 live births. Vaginal delivery occurred at a mean of 38 ± 1 weeks of amenorrhea (range, 37–39 weeks) and the mean birth weight was 3,143 ± 757 grams (range, 2,270–3,990 grams). Mean maternal forced expiratory volume in 1 second (%) before, during (sixth month), and after (1 year) pregnancy was 87 ± 18, 87 ± 22, and 88 ± 17, respectively ( p = NS). In conclusion, pregnancy after heart-lung transplantation can be associated with a good prognosis for mother and child.

The purpose of this study was to assess the rate of gastric emptying (GE) in cystic fibrosis patients scheduled for lung transplantation.Thirty patients (20 males, 10 females, 22.6 +/- 6.4 years) were evaluated by GE scintigraphy before (1.58 +/- 1.11 years) and early after (5.8 +/- 2.6 weeks) heart-lung transplantation (n = 13) or lung transplantation (n = 17). Solid retention rates at 2 hours (RR2) and 3 hours (RR3) and half-emptying times (T50) of solids and liquids obtained before transplantation were compared with those after transplantation. Data were also compared with those obtained from a control group of 53 healthy volunteers.Before surgery, 20 patients (67%) showed a delayed GE (T50 of solids: patients 160.86 +/- 59.21 minutes vs controls 75.43 +/- 15.13 minutes, p0.0001), and 4 of them also had a delayed T50 of liquids. After surgery, the T50 of solids was considered unreliable (too much stasis) in 24 patients. Thus, analyses were done on the basis of solid retention rates. Twenty-nine patients (97%) showed very delayed GE compared with controls (p0.0001), 20 of whom also had a delayed T50 of liquids. RR2 and RR3 were significantly higher after surgery than before (RR2 = 86 +/- 17% and RR3 = 77 +/- 22% vs 50 +/- 24% and 27 +/- 24% after and before surgery, respectively, p0.0001). However, there was no correlation between pre- and post-transplantation scintigraphy results.Delayed GE of solids was a frequent abnormality in patients with end-stage cystic fibrosis, with a dramatic delay after surgery in almost all patients. These results emphasize the need for early management of such patients by dietary manipulation or prokinetic medications.