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Elexacaftor-tezacaftor-ivacaftor induces rapid clinical improvement in patients with cystic fibrosis (CF) and advanced pulmonary disease, often leading to suspend the indication for lung transplantation. Yet no long-term data is available in lung transplant candidates.Lung transplant candidates (defined as being waitlisted for lung transplantation or considered for listing within 3 months) who have initiated elexacaftor-tezacaftor-ivacaftor were identified in the French cohort of patients with CF and advanced pulmonary disease. Patients were prospectively followed to evaluate treatment safety and effectiveness from initiation to July 20th, 2021.Among the 331 patients with advanced CF pulmonary disease who initiated elexacaftor-tezacaftor-ivacaftor, 65 were lung transplant candidates (17 listed for transplantation, 48 considered for listing within 3 months). Median [IQR] follow-up time was 363 [329; 377] days. At the end of the follow-up period, two patients were transplanted five and 11 days following treatment initiation, two were listed for transplantation, and 61 no longer met transplantation criteria. Improvement in percent predicted forced expiratory volume in 1 s (ppFEVIn lung transplant candidates eligible for elexacaftor-tezacaftor-ivacaftor, the rapid improvement following initiation of treatment persisted over one year with a reduction in treatment burden and lung transplantation could be safely deferred in most patients.

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)

Background People with cystic fibrosis (pwCF) are central in the development of patient-led assessment tools. Qualitative analysis of a frequently used CF-specific patient-reported outcome measure (PROM) sought patient recommendations for development of a new quality of life (QoL) tool. Methods We performed an inventory of PROMs, symptom-report and QoL tools used in clinical trials within the European Cystic Fibrosis Society Clinical Trial Network (ECFS-CTN) and in routine clinical practice among Cystic Fibrosis Europe and ECFS members. A qualitative study using cognitive interviews with pwCF and their caregivers reviewed the Cystic Fibrosis Questionnaire (CFQ), the French initial form of the Cystic Fibrosis Questionnaire-Revised (CFQ-R). Results Survey results from 33 countries revealed over 70 tools used in routine clinical practice, utilized by clinical specialists (n=124), pwCF/parents/carers (n=49) and other allied health professionals (n=60). The CFQ-R was the main PROM used in clinical trials. The qualitative study enrolled 99 pwCF, 6 to 11 years (n=31); 12 to 18 years (n=38); >18 years (n=30) and 26 parents. Inductive thematic analysis based on the CFQ, revealed 19 key themes. Themes common across all cohorts included burden of treatment, impact of disease on day-to-day life, relationships/family, stress/mood, and nutrition. Themes unique to individual groups included, treatment when not symptomatic for the paediatric group; education/studies and planning for the future for adolescents, impact of anxiety and depression on day-to-day life for adults, and for parents, questions addressing anxiety and their role as carers. Conclusions Patient-centeredness is paramount in development of an up-to-date PROM in the era of novel therapies.

Highlights • First feasibility study of respiratory viral detection in Cystic Fibrosis sputum. • High concordance between sputum and nasopharyngeal samples in viral. • Multiplex-PCR performed in 30 paired samples: 83% viral congruency. • Sputum: an optimal non-invasive sample for viral diagnosis in cystic fibrosis., Viruses are important agents in lung function deterioration in Cystic Fibrosis (CF). To date, no standard operating procedures (SOPs) have been established to determine which sampling method is the most effective for an optimal virological diagnosis of respiratory viral infections in CF. Here we investigated the performances of two sampling sites, sputum samples versus nasopharyngeal (NP) swabs, for thirty participants from three CF centres presenting an acute respiratory infection. Sputum and NP samples were simultaneously collected and multiplex PCR targeting 16 to 18 viruses were performed. Viruses were detected for 18/30 patients (60%). A high concordance between the sputum and NP samples was observed in 25 (83%) paired samples of which 13 tested positive and 12 tested negative. These results highlighted the relevance of sputum sampling for diagnostic of respiratory viruses in CF, which is less invasive and better accepted by CF patients than NP, and allows accurate bacterial detection.

International audience; Lung transplantation (LTx) is a steadily expanding field. The considerable developments have been driven over the years by indefatigable work conducted at LTx centers to improve donor and recipient selection, combined with multifaceted efforts to overcome challenges raised by the surgical procedure, perioperative care, and long-term medical complications. One consequence has been a pruning away of contraindications over time, which has, in some ways, complicated the patient selection process. The Francophone Pulmonology Society (Société de Pneumology de Langue Française, SPLF) set up a task force to produce up-to-date working guidelines designed to assist pulmonologists in managing end-stage respiratory insufficiency, determining which patients may be eligible for LTx, and appropriately timing LTx-center referral. The task force examined the most recent literature and evaluated the risk factors that limit patient survival after LTx. Ideally, the objectives of LTx are to prolong life while also improving quality of life. The guidelines developed by the task force apply to a limited resource and are consistent with the ethical principles described below.

Cystic fibrosis-related diabetes (CFRD) is a common complication of cystic fibrosis (CF), and restoring metabolic control in these patients may improve their management after lung transplantation. In this multicenter, prospective, phase 1-2 trial, we evaluate the feasibility and metabolic efficacy of combined pancreatic islet-lung transplantation from a single donor in patients with CFRD, terminal respiratory failure, and poorly controlled diabetes. Islets were infused via the portal vein under local anesthesia, 1 week after lung transplantation. At 1 year, the primary outcome was transplant success as evaluated by a composite score including four parameters (weight, fasting glycemia, HbA1c, and insulin requirements). Ten participants (age: 24 years [17-31], diabetes duration: 8 years [4-12]) received a combined islet-lung transplant with 2892 IEQ/kg [2293-6185]. Transplant success was achieved in 7 out of 10 participants at 1-year post transplant. Fasting plasma C-peptide increased from 0.91 μg/L [0.56-1.29] to 1.15 μg/L [0.77-2.2], HbA1c decreased from 7.8% [6.5-8.3] (62 mmol/mol [48-67]) to 6.7% [5.5-8.0] (50 mmol/mol [37-64]), with 38% decrease in daily insulin doses. No complications related to the islet injection procedure were reported. In this pilot study, combined pancreatic islet-lung transplantation restored satisfactory metabolic control and pulmonary function in patients with CF, without increasing the morbidity of lung transplantation.

Background Mycobacterium abscessus infections remain difficult to manage in both cystic fibrosis (CF) and non-CF patients and reported clinical outcomes are largely unsatisfactory. Clinical trial data are limited and no approved therapies are currently available for the management of M abscessus lung diseases. As an alternative, cohort studies may provide insightful information into the management of M abscessus pulmonary disease. Methods Based on a retrospective observational cohort study, we investigated the safety and efficacy of amikacin liposome inhaled suspension (ALIS) as an adjunct to a standard antibiotic regimen for M abscessus lung infection in both CF and non-CF patients. We also assessed the association of patient drug compliance with culture conversion and clinical outcomes. Results Twenty-six patients had long-term follow-up data available. Culture conversion was achieved in 54% (14/26) of the patients with no difference between CF and non-CF patients after an average treatment duration of 10 months. Patient treatment compliance was significantly better in the converter group compared to nonconverters with an odds ratio of 44.78 associated with good compared to poor patient compliance. Overall, 9 patients (35%) experienced an adverse event that led to treatment discontinuation. Conclusions ALIS appears beneficial in both CF and non-CF populations with M abscessus lung disease.

BackgroundThe European Medicines Agency has approved the cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination elexacaftor-tezacaftor-ivacaftor (ETI) for people with cystic fibrosis (pwCF) carrying at least one F508del variant. The United States Food and Drug Administration (FDA) also approved ETI for pwCF carrying one of 177 rare variants.MethodsAn observational study was conducted to evaluate the effectiveness of ETI in pwCF with advanced lung disease that were not eligible to ETI in Europe. All patients with no F508del variant and advanced lung disease (defined as having a percent predicted forced expiratory volume (ppFEV1)1.ResultsAmong the first 84 pwCF included in the program, ETI was effective in 45 (54%) and 39 (46%) were considered to be non-responders. Among the responders 22/45 (49%) carried aCFTRvariant that is not currently approved by FDA for ETI eligibility. Important clinical benefits, including suspending the indication for lung transplantation, a significant decrease in sweat chloride concentration by a median [IQR] −30 [-14;-43]mmol·l−1(n=42;p1by+10.0 [6.0; 20.5] (n=44,pConclusionClinical benefits were observed in a large subset of pwCF with advanced lung disease andCFTRvariants not currently approved for ETI.

BackgroundPre-formed donor-specific antibodies (DSAs) are associated with worse outcome after lung transplantation (LTx) and might limit access to LTx. A virtual crossmatch-based strategy for perioperative desensitisation protocol has been used for immunised LTx candidates since 2012 at Foch Hospital (Suresnes, France). We compared the outcome of desensitised LTx candidates with high DSA mean fluorescence intensity and those with low or no pre-formed DSAs, not desensitised.MethodsFor all consecutive LTx recipients (January 2012 to March 2018), freedom from chronic lung allograft dysfunction (CLAD) and graft survival were assessed using Kaplan–Meier analysis and Cox multivariate analysis.ResultsWe compared outcomes for desensitised patients with high pre-formed DSAs (n=39) and those with no (n=216) or low pre-formed DSAs (n=66). The desensitisation protocol decreased the level of immunodominant DSA (class I/II) at 1, 3 and 6 months post-LTx (pversus no DSAs; p=0.035) and CLAD with persistent DSAs (3.04, 1.02–9.17 versus no pre-formed DSAs; p=0.048).ConclusionThe desensitisation protocol in LTx recipients with high pre-formed DSAs was associated with satisfactory outcome, with cleared high pre-formed DSAs after desensitisation identified as an independent predictor of graft survival.

Purpose Pre-formed donor-specific antibodies (pf-DSA) are associated with worse outcome after lung transplantation (LTx) and might limit access to LTx. A virtual crossmatch (CXM)-based strategy for perioperative desensitization protocol has been used for immunized LTx candidates since 2012 at Foch hospital. We compared the outcome of desensitized LTx candidates with high pf-DSA mean fluorescence intensity (MFI) and those with low or no pf-DSA, not desensitized. Methods For all consecutive LTx recipients (January 2012-March 2018), freedom from CLAD and graft survival were assessed by Kaplan-Meier analysis and Cox proportional-hazards multivariate analysis. Results We compared outcomes for desensitized patients with high pf-DSA (n=39) and those with no (n=216) or low pf-DSAs (n=66). The desensitization protocol decreased the level of immunodominant pf-DSA (class I/II) at 1, 3, and 6 month post-LTx (p Conclusion The desensitization protocol in LTx recipients with high pf-DSAs was associated with satisfactory outcome, with cleared high pf-DSAs after desensitization identified as an independent predictor of graft survival.

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, FEV 1 and body mass index (BMI) one month and three months after lumacaftor/ivacaftor initiation in adults with CF and FEV 1 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 FEV 1 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.

Cystic fibrosis-related diabetes (CFRD) is a major determinant of morbi-mortality in all stages of the disease, especially following lung transplantation. CF patients with end-stage respiratory failure and severe CFRD may thus benefit from beta-cell replacement. Combined pancreatic islet-lung transplantation bears the advantage of grafting autoregulated islets from the same donor using percutaneous transhepatic puncture. Islet post-lung transplantation proves to be a good therapeutic option for patients unable to undergo simultaneous islet-lung allotransplantation, whilst enabling a sufficient amount of pancreatic islets to be grafted. Current pilot studies involving a small number of CF patients suggest pancreatic islet graft to be feasible, with metabolic and nutritional parameter improvement 1-year post-lung islet transplantation, yet without additional morbidity. Further studies are needed to determine the procedure’s long-term benefits and enable us to select the best candidates for this procedure so as to ensure an optimal outcome.

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.

In the context of lung transplant (LT), because of diagnostic difficulties, antibody-mediated rejection (AMR) remains a matter of debate. We retrospectively analyzed an LT cohort at Foch Hospital to demonstrate the impact of AMR on LT prognosis. AMR diagnosis requires association of clinical symptoms, donor-specific antibodies (DSAs), and C4d(+) staining and/or histological patterns consistent with AMR. Prospective categorization split patients into four groups: (i) DSA positive, AMR positive (DSA(pos) AMR(pos) ); (ii) DSA positive, AMR negative (DSA(pos) AMR(neg) ); (iii) DSA limited, AMR negative (DSA(Lim) ; equal to one specificity, with mean fluorescence intensity of 500-1000 once); and (iv) DSA negative, AMR negative (DSA(neg) ). AMR treatment consisted of a combination of plasmapheresis, intravenous immunoglobulin and rituximab. Among 206 transplanted patients, 10.7% were DSA(pos) AMR(pos) (n = 22), 40.3% were DSA(pos) AMR(neg) (n = 84), 6% were DSA(Lim) (n = 13) and 43% were DSA(neg) (n = 88). Analysis of acute cellular rejection at month 12 showed higher cumulative numbers (mean plus or minus standard deviation) in the DSA(pos) AMR(pos) group (2.1 ± 1.7) compared with DSA(pos) AMR(neg) (1 ± 1.2), DSA(Lim) (0.75 ± 1), and DSA(neg) (0.7 ± 1.23) groups. Multivariate analysis demonstrated AMR as a risk factor for chronic lung allograft dysfunction (hazard ratio [HR] 8.7) and graft loss (HR 7.56) for DSA(pos) AMR(pos) patients. Our results show a negative impact of AMR on LT clinical course and advocate for an early active diagnostic approach and evaluation of therapeutic strategies to improve prognosis.

Purpose Lung transplantation (LT) is limited by the shortage of suitable donors. To overcome this problem, many programs have begun to use extended criteria donors. However, the use lung donors over 65 years old is rarely reported especially among a population of young cystic fibrosis (CF) recipient. Methods We report a single center experience of lung transplantations for CF recipients between January 2005 and september 2019. Two cohorts were built and compared according to lung donor age Results Among this period, 378 bilateral lung transplantations (BLT) for CF were performed. 344 BLT were done with donors aged Conclusion Use of donor lungs over 65 years for CF recipients allows donor pool extension without compromising early and midterm results. However, longer follow up is needed to appreciate long term results.

Appropriate exposure to posaconazole (PSZ) has been limited until the recent approval of the delayed-release oral tablet formulation. Our goal was to determine the exposure obtained by using the standard dose of 300 mg once a day in lung transplant (LT) patients, including patients with cystic fibrosis (CF). PSZ trough concentrations ( C 0 ) were determined using a liquid chromatography-tandem mass spectrometry assay. Indicative thresholds of interest were C 0 measured during PSZ exposure were also collected. The interaction with proton-pump inhibitors (PPI) was evaluated. We recorded the results for 21 CF patients with LT (CFLT patients), 11 non-CF patients with LT (NCFLT patients), and 27 nontransplant (NT) patients in pneumology departments. The weights of the NCFLT, CFLT, and NT patients were 59.2 ± 8.4, 48.8 ± 8.4, and 63.7 ± 16.6 kg, respectively ( P = 0.001* [asterisk means that statistical test is significant]), and the PSZ C 0 exposures for these patients were 1.9 ± 1.5, 1.1 ± 0.8, and 2.4 ± 1.8 mg/liter, respectively ( P < 0.00001*). More than 60% of the concentrations were in the therapeutic range. In CFLT patients, the administration of one 300-mg PSZ tablet quickly achieved an exposure similar to that achieved with the PSZ oral suspension formulation (OSF) administered 3 or 4 times a day for several months. The TRL C 0 /dose ratio ( C 0 / D ) was 7.4 ± 4.4 mg/liter with PSZ tablets, whereas it was 4.6 ± 0.8 mg/liter with the PSZ oral solution ( P = 0.034*). The ERL C 0 / D was similar with both formulations. PPI had no impact on the PSZ concentration (1.49 ± 1.07 mg/liter without PPI versus 1.33 ± 1.17 mg/liter with PPI; P = 0.4134*). Despite the high levels of exposure, PSZ remained well tolerated (one case of diarrhea and one case of fatigue were reported). PSZ tablet administration allows satisfactory exposure, even in CFLT patients, with a dosage lower than that of the PSZ OSF. This once-a-day formulation was not impacted by PPI, which are extensively used in CF patients.

RésuméIntroductionLa transplantation pulmonaire (TP) accroît le risque d’infection, de cancer, d’insuffisance rénale, de complication cardiovasculaire, d’ostéoporose, souvent en continuité avec la situation clinique pré-existante.Patients et méthodeLes comorbidités et leur prise en charge à la première consultation pré-TP ont été recensées chez 157 patients ayant subi une TP entre 2008 et 2011.RésultatsL’âge médian était de 37ans [25 ; 51]. L’index de masse corporel médian était inférieur à 19kg/m2 chez 56 % des patients. Parmi les bronchopneumopathies chroniques obstructives (BPCO), seulement 50 % avaient réalisé une réhabilitation respiratoire au cours des deux années précédentes. Une ostéoporose était présente chez 42 % des patients dont 36 % étaient traités par biphosphonates. Une carence en vitamine D était présente chez 65 % des patients. Au plan cardiovasculaire, le bilan d’évaluation pré-TP révélait une HTA méconnue dans un cas, une hypercholestérolémie méconnue chez 6 % des patients et un diabète méconnu chez 4 % des patients. Des soins dentaires étaient nécessaires chez 41 % des patients. Des taux protecteurs d’anticorps anti-HB étaient acquis chez 50 % des patients.Discussion et conclusionLa prise en charge des troubles nutritionnels, de l’ostéoporose, des facteurs de risque infectieux et des facteurs de risque cardiovasculaires est perfectible. Il serait bénéfique d’intégrer précocement la notion de TP ultérieure à la gestion des insuffisants respiratoires chroniques.SummaryIntroductionLung transplantation (LT) is associated with an increased risk of infection, cancer, chronic renal failure, cardiovascular disease and osteoporosis. Some risk factors precede transplantation and could benefit for early diagnosis and optimised care.MethodsThe incidence of comorbidities and their treatment before referral were assessed in 157 consecutive lung transplant candidates between 2008 and 2011.ResultsThe median age was 37years [25; 51]. Fifty-six percent had a body mass index below 19kg/m2. In the COPD group, only 50 % had undergone a pulmonary rehabilitation program in the preceding 2 years. Osteoporosis was present in 42 %, of whom 36 % were on bisphophonate therapy. Vitamin D deficiency was present in 65 %. Previously undiagnosed cardiovascular risk factors were discovered during LT assessment: hypertension in one patient, hypercholesterolemia in 6 % and diabetes in 4 %. Poor dental condition necessitating extractions were found in 41 % of patients. Protective anti-HBs antibodies levels were present in 50 % of the patients at the time of referral.ConclusionThe assessment and early treatment of nutritional disorders, osteoporosis and risk factors for infection as well as addressing associated cardiovascular risk factors should be optimised in the care of patients with chronic respiratory insufficiency. The potential for becoming a lung transplant candidate in the future should be kept in mind early in the global management of those patients.

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.

Background Allergic bronchopulmonary aspergillosis (ABPA) is a severe lung disease complication caused by an Aspergillus fumigatus-induced hypersensitivity that affects 2–15% of patients with cystic fibrosis (CF). The mainstay treatment consists of a combination of corticosteroids and antifungals. However, repeated or long-term corticosteroid therapies can lead to serious side effects. The monoclonal anti-IgE antibody, omalizumab, has demonstrated its efficacy in allergic asthma. As ABPA results from a hypersensitivity to a specific allergen, omalizumab might benefit CF patients with ABPA. Therefore, we conducted a retrospective study to investigate the effects of omalizumab on ABPA in CF patients. Methods We retrospectively analyzed the clinical records of young patients with CF treated with omalizumab for an ABPA in several French CF centers. The clinical data were collected 3 months before the start of omalizumab treatment, at initiation, and every 3 months up to 12 following initiation. These data comprised clinical, biological, nutritional, and functional parameters. Results Eighteen patients were included (mean age: 17.1 ± 5.2 yrs). Under omalizumab was observed a stabilization of the lung function decline associated with a significant decrease in the corticosteroid daily dose (p = 0.0007) and an improvement in the nutritional status (p = 0.01). No serious side effect of omalizumab was reported. Conclusions This study suggests that omalizumab might be an interesting therapeutic strategy in ABPA, associated with less side effects compared to long-term corticosteroids. Further randomized-controlled trials are needed to ascertain the efficacy of omalizumab in CF patients with ABPA.

To define the characteristics of CF patients developing AA amyloidosis.A 30-year retrospective survey conducted within the national French CF network to identify cases of CF associated with AA amyloidosis.Nine cases of AA amyloidosis were identified (CF prevalence in France is approximately 6000 patients) and sufficient data were collected in six. The clinical presentation was renal disease in four cases, a compressive goiter in one case, and epigastric pain in one case. Organ involvement included kidney disease in all cases (proteinuria, with a median age at onset of 24 years, 4 cases with nephrotic syndrome, 5 with renal failure); gastrointestinal (4 cases with duodenal ulcer); thyroid (2 cases); and hepatobiliary system (3 cases). The median age at diagnosis of CF was 6.5 years. Five patients had pancreatic insufficiency. All patients had chronic respiratory infections requiring intravenous antibiotics several times a year. Five patients have died, at a median age of 29 years and a median duration of 6 years after the onset of proteinuria.AA amyloidosis is a rare but morbid complication of CF. Renal involvement is predominant.

Introduction: The incidence of venous thrombotic event (VTE ) after lung tansplantation was recently evaluated to approximately 44 % in a large series of patients (Neto et al., Transplantation. 2018; 102: 681). Cystic fibrosis (CF) is a devastating chronic inflammatory disease caused by a mutation in the gene encoding cystic fibrosis transmembrane regulator (CFTR), which is a chloride channel in epithelia cell membranes. Coagulation balance in patient with CF is complexed since there is both a decrease in vitamin K-dependent factor but also an excess of physiological inhibitors deficiencies. Lung fibrosis was also sometimes associated to a higher thrombotic risk. Aim: To analyse whether thrombin generation assay (TGA), which takes in account both pro-and anticoagulant factors, or the activity of soluble tissue factor (TFa) are able to discriminate the thrombotic risk of patients after bipulmonary lung transplantation (BLT) and are better discriminant than classical thrombophilia screening test [prothrombin time (PT), activated partial thromboplastin time (APTT), antithrombin (AT), protein C (PC) S (PS), Z (PZ) fibrinogen (FG) and FVIII levels (FVIIIc) measurements]. Methods: Thrombophilia screening (including TGT in the presence or absence of thrombomodulin (TM) and TFa quantification) was performed for 166 consecutive patients before BLT. Patients were divided in 3 categories : 100 with CF, 43 with chronic obstructive pulmonary disease (COPD) and 23 with idiopathic pulmonary fibrosis (IPF). Among them, 91 (51 with CF, 28 with COPD and 12 with IF) were transplanted. Proven VTE (positive duplex ultrasound) during the first trimester was registered. Results: Because of a defect in lipophilic vitamin absorption, prothrombin time below 70 % and a significant higher proportion of PZ deficiency was observed in patients with CF, in comparison to COPD. The frequency of AT, PC and PS were not significantly different between the 3 groups of patients. Because the chronic pulmonary contamination of the lung by bacteria, the frequency of elevated fibrinogen levels were significantly higher in patients with CF as compared to COPD and IPF groups (table 1). Median TFa values were significantly higher (p < 0.05) in patients with CF (median 0.24 pg/mL, range 0.1 - 7.7) than in patients with COPD (median 0.1 pg/ml, range 0.1 - 0.63). FTa was also elevated (median 0.24, range 0.1 - 6.15) in patients with IPF. Time to Peak (tt-Peak) was significantly shorter in patients with CF as compared to COPD or IPF, even in the presence of thrombomodulin (TM). MRI were higher in patients with CF than in patients with COPD or IPF, even in the presence of TM. Peak was higher in patients with CF as compared to patients with COPD (p < 0.05). In the presence of TM, Endogenous prothrombin potential (ETP) was significantly higher in patients with CF as compared to patients with COPD, and the ratio ETP/ETP with TM was higher in patients with CF as compared to patients with COPD or IPF, indicating a defective PC pathway in patients with CF (table 2). Among the 91 patients with BLT, a VTE was evidenced in 25 (27.5%) patients, with a similar frequency between the 3 groups (33.3 % in CF, 14.7 in COPD, 33.3 % in IPF, not significant). We analysed separately patients with CF from patients with COPD or IPF, since there were differences between coagulation parameters tested in patients with CF. Only APTT ratio was significantly lower (p < 0.01) in patients with CF who had a VTE (1.04) than in patients without VTE (1.12). No difference in the different parameters tested was evidenced in patients with COPD and IPF Conclusion: Even if TGA and TFa clearly evidence a more prothrombotic phenotype in patients with CF than in patients with COPD or IPF, thrombophilia screening before BLT fail to identify patients with a high post-operative thrombotic risk. Disclosures No relevant conflicts of interest to declare.

Objective: To study the advances in the management of lung-transplanted patients for cystic fibrosis in our centre and their impact on the outcome. Methods: A retrospective study has included 100 patients who underwent lung transplantation for cystic fibrosis between 1 January 1990 and 15 January 2007. There were 78 sequential double-lung transplantations and 22 lobar transplantations. This series has been equally divided in two groups according to the date of transplantation: group I, before September 2003 and, group II, after September 2003. Results: Recipient characteristics were similar in both groups. In group II, donors were older (40 vs 33 years, respectively, P = 0.013), with lower partial pressure of oxygen in arterial blood (PaO2)/fractional inspired oxygen (FiO2) ratios (372 vs 427 mm Hg,P = 0.022). In group II, recipients received, more often, thoracic epidural analgesia (n =3 5 vsn = 13, P < 0.001), the surgical approach was mostly a sternum-sparing bilateral anterior thoracotomy (n =4 2 vsn =9 ,P < 0.001), and lobar transplantations were performed more frequently (n =1 5 vsn =7 ,P = 0.30). Early tracheal extubation was more frequent in group II (P = 0.005). The overall median survival time was 52 months. In the first group, 1-, 2- and 3-year survival rates were 75%, 65% and 55%, respectively, whereas in the second group, these survival rates were 88%, 78% and 69%, respectively (P = 0.09). Conclusions: The acceptance of marginal donors and the frequent practice of lobar transplantations allowed an increasing number of lung transplantations for cystic fibrosis over time. Concomitantly, the extensive use of thoracic epidural analgesia has increased the rate of early extubation and contributed to a trend towards a survival improvement. # 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

Introduction L’incidence de l’insuffisance renale chronique (IRC) en post-transplantation pulmonaire chez le patient ayant une mucoviscidose est tres elevee. Les facteurs de risque sont multiples, l’impact d’une hyperoxalurie et la presence de cristaux d’oxalate de calcium sur la survenue et severite de l’insuffisance renale chronique (IRC) n’a jamais ete evalue. Patients/Materiels et methodes Il s’agit d’une etude monocentrique, prospective, menee entre 2008 et 2014. Les patients inclus devaient avoir une mucoviscidose, etre transplante pulmonaire et beneficier d’une analyse biochimique des urines ainsi que d’une cristallurie. Les patients ayant une IRC pre transplantation etaient exclus. Les analyses etaient centralisees dans le laboratoire d’exploration fonctionnelles de l’hopital Tenon. Deux analyses ont ete realisees : une analyse descriptive s’interessant a la prevalence des cristaux et des facteurs de risque associes chez tous les malades ; une analyse pronostique evaluant l’impact de la presence de cristaux sur la fonction renale post transplantation chez les patients ayant eu une cristallurie preoperatoire. Le critere de jugement etait la survenue d’une IRC durant le suivi post-transplantation definie par 2 mesures consecutives de DFG Observation/Resultats Quatre-vingt-sept patients ont ete inclus dans l’analyse descriptive et 45 patients dans l’analyse pronostique. Des cristaux s’observaient chez 32/87 (36 %) et 16/45 (35 %) patients. Les variables associees a leur presence etaient une augmentation significative de l’oxalurie (430 [315–635] vs 290 [175–437] μmol/L, p = 0,005), de calciurie (3,2 [1,4–5,20] vs 1,8 [1,1–2,7] mmol/L, p = 0,006) et de phosphaturie (26,5 [19,1–43,9] vs 20,2 [10,1–29,2] mmol/L, p = 0,008). L’IRC survenait chez 18/45 (40 %) des patients. L’âge (p = 0,05) et une proteinurie preoperatoire plus elevee (p = 0,007) etaient les seuls facteurs de risque identifies. La presence de cristaux urinaire n’etait pas associee a la survenue d’une IRC (p = 0,9). Dix-neuf biopsies chez 16 patients ont ete realisees durant le suivi. Les anomalies observees etaient principalement des lesions d’arteriosclerose, de glomerulosclerose et des calcifications intra-tubulaire. L’analyse par spectro-infrarouge n’a pas mis en evidence de cristaux oxalate de calcium. Discussion/Conclusion L’IRC est une complication frequemment observee chez le patient atteint de mucoviscidose. Malgre une prevalence importante de cristaux urinaire, ces derniers ne sont pas associes a la presence de cristaux intra-tissulaire et leur impact sur la fonction renale a moyen terme semble non contributive.

We report the case of a patient with cystic ¢brosis who underwent lung transplant and developed Aspergillus endocarditis and cutaneous relapse. Long-term survival was achieved with surgical and prolonged antifungal treatment. This case report emphasizes the recommendation of life-long antifungal treatment in transplant recipients who survive an episode of fungal endocarditis. Invasive aspergillosis is constantly increasing with the growing population of patients at risk for developing As- pergillus infections. Most of these patients are immunosup- pressed patients with malignant hematological diseases or solid organ transplant recipients (1). The increasing num- ber of patients at risk for developing invasive aspergillosis is associated with a higher prevalence of the disease and also with more severe clinical presentations. Pulmonary as- pergillosis probably has a better prognosis because of the availability of new antifungal drugs and therefore even some patients with extremely severe disease can be ex- pected to survive (2). Pulmonary aspergillosis remains the most common site of invasive infection, but Aspergillus can disseminate to other organs. This disseminated clinical presentation, especially endocarditis (3), often has a poor prognosis. We report a case ofAspergillusendocarditis with embolic complications in a young lung transplant recipient with multiple predisposing factors who survived with antifun- gal therapy and surgical treatment with a follow-up of 60 months, without discontinuation of treatment.

Background and objectives: Clinically relevant kidney involvement is uncommonly described in adult patients with cystic fibrosis (CF). We sought to report on a series of patients with CF and kidney biopsy–documented renal involvement. Design, setting, participants, & measurements: A retrospective study was undertaken in two referral centers for adult patients with CF in Paris, France. Patients who had undergone a biopsy of native kidneys between 1992 and 2008 were identified, and their medical records were reviewed. Results: We identified 13 adult patients with CF and renal disease. Proteinuria was present in all but two cases and was associated with progressive renal impairment in four patients (median serum creatinine 85 μmol/L; range 53 to 144 μmol/L). Renal biopsy disclosed a heterogeneous spectrum of nephropathies including AA amyloidosis ( n = 3), diabetic glomerulopathy ( n = 3), FSGS ( n = 2), minimal-change disease ( n = 1), postinfectious glomerulonephritis ( n = 1), IgA nephropathy related to Henoch-Schonlein purpura ( n = 1), membranous nephropathy ( n = 1), and chronic interstitial nephropathy ( n = 1). Chronic renal failure occurred in five patients, and one patient reached ESRD. Conclusions: Although rare, clinically significant renal disease may arise in young adult patients with CF. Given the wide spectrum of diseases that may be encountered, definite diagnosis by kidney biopsy is mandatory to optimize clinical treatment of these complex patients, particularly in the perspective of organ transplantation.

International audience; Background. Lymphangioleiomyomatosis (LAM) is a rare disease, leading in some cases to end-stage respiratory failure. Lung transplantation (LT) represents a therapeutic option in advanced pulmonary LAM. Methods. We conducted a retrospective multicenter study of 44 patients who underwent LT for LAM at 9 centers in France between 1988 and 2006. Results. All patients were women with a mean age of 41 +/- 10 years at LT. There were 34 single-lung transplants and 11 bilateral transplants (one retransplantation). Prior clinical events related to LAM were present in 75% of the patients and previous thoracic surgical procedures were noted in 86.6% of cases. At the latest preoperative evaluation, 30 patients had an obstructive pattern (mean forced expiratory volume in 1 second: 26% 14% of predicted) and 15 had a combined restrictive and obstructive pattern, with a mean KCO=27%+/- 8.8% of predicted, PaO2=52.8 +/- 10.4 and PaCO2=42.6 +/- 9.8 mm Hg. Intraoperative cardiopulmonary bypass was required in 13 cases. The length of mechanical ventilation was 7.5 +/- 12.8 days. The median duration of follow-up was 37 months. The 1, 2, 5, and 10 years survival rates were 79.6%, 74.4%, 64.7%, and 52.4%, respectively. Extensive pleural adhesions were found in 21 patients leading to severe intraoperative hemorrhage. Postoperative LAM-related complications were pneumothorax in the native lung in five patients, chylothorax in six, bronchial dehiscence or stenosis in seven. There were two cases of recurrence of LAM. Conclusion. Despite a high morbidity mainly caused by previous surgical interventions and disease-related complications, LT is a satisfactory therapeutic option for end-stage respiratory failure in LAM.

Background: Infection with Burkholderia cepacia complex (BCC) is a life-threatening complication of cystic fibrosis (CF) often seen as a contraindication for lung transplantation. Methods: We conducted a long-term retrospective study of all CF patients undergoing lung transplants from January 1990 to October 2006 in two French centers allowing transplantation in BCC-colonized patients. Results: Twenty-two of the 247 lung transplant patients with CF were infected with BCC (B. cenocepacia genomovar III n=8, B. multivorans genomovar II n=11, B. vietnamiensis genomovar V n=2 and B. stabilis genomovar IV n=1). BCC colonization was not associated with any significant excess mortality (HR 1.5, 95% CI 0.7 to 3.2, p=0.58). However, early mortality rates tended to be higher in the BCC group than in the non BCC group (3-month survival: 85% vs 95%, respectively; log rank p=0.05). Univariate analysis showed that the risk of death was significantly higher for the eight patients infected with B. cenocepacia than for the other 14 colonized patients (HR 3.2, 95% CI 1.1 to 5.9, p=0.04). None of the other risk factors tested - primary graft failure, late extubation, septicemia - had a significant effect. The five-year cumulative incidence rate of bronchiolitis obliterans syndrome was not significantly higher in the BCC group than in the non BCC group (38% vs 24%, respectively, p=0.35). Conclusion: Our results suggest that BCC infection with a non genomovar III organism may not be associated with excess mortality after lung transplantation in CF patients and should not been seen as sufficient reason to exclude lung transplantation. However, colonization with B. cenocepacia remains potentially detrimental.

Background Little data exist on causes of death in cystic fibrosis (CF) patients in the era of lung transplantation. Methods Deaths in CF patients in France (2007–2010) were identified using the French CF Registry and causes of deaths were determined based on medical files by a mortality adjudication committee. Results Of 256 deaths, half occurred after lung transplantation and were related to early or late complications of transplantation, whereas half occurred in patients who did not receive lung transplantation and were primarily related to respiratory failure or massive hemoptysis. Among patients who did not receive lung transplantation, only 19% died while waiting on a lung transplantation list. Lack of listing for lung transplantation was primarily related to late, or to lack of transplantation referral, rather than to contraindication to transplantation. Conclusions These data suggest that improvement in transplantation referral strategies may result in transplantation-related survival benefits.

Background Viral infections such as influenza are thought to impact respiratory parameters and to promote infection with Pseudomonas aeruginosa in patients with cystic fibrosis (CF). However, the real morbidity of the influenza virus in CF needs to be further investigated because previous studies were only observational. Methods CF patients were included in a case–control study (n = 44 cases and n = 371 controls) during the 2009 pandemic A/H1N1 influenza. Cases were patients with polymerase reaction chain-confirmed influenza A/H1N1 infection. Controls did not report any influenza symptoms during the same period. Sputum colonization and lung function were monitored during 1 year after inclusion. Results Cases were significantly younger than controls (mean(SD) 14.9 years(11) versus 20.1 years (13.2) and significantly less frequently colonized with P. aeruginosa (34 % versus 53 %). During influenza infection, 74 % of cases had pulmonary exacerbation, 92 % had antibiotics adapted to their usual sputum colonization and 82 % were treated with oseltamivir. Two cases required lung transplantation after A/H1N1 infection (one had not received oseltamivir and the other one had been treated late). The cases received a mean number of antibiotic treatments significantly higher during the year after the influenza infection (mean(SD) 2.8 (2.4) for cases versus 1.8(2.1) for controls; p = 0.002). An age-matched comparison did not demonstrate any significant modification of bronchopulmonary bacterial colonization during the year after influenza infection nor any significant change in FEV1 at months 1, 3 and 12 after A/H1N1 infection. Conclusions Our results do not demonstrate any change in sputum colonization nor significant lung disease progression after pandemic A/H1N1 influenza. Trial registration Clinical Trials.gov registration number: NCT01499914

Bronchial carcinoma, usually of the non-small-cell type, is uncommon after lung transplantation and occurs predominantly in single-lung transplant ex-smoker recipients on their native lung. Bronchial carcinoma of donor origin is much rarer. We report the case of a small-cell lung carcinoma of recipient origin that occurred 12 months after a bilateral lung transplantation for cystic fibrosis in a 25-year-old woman who was a non-smoker. The tumor was of recipient origin, due to a gender mismatch between donor and recipient. This unusual observation corroborates the hypothesis of chimerism of the bronchial epithelium after lung transplantation.

Nowdays adults with cystic fibrosis are no more attended in pediatric centers. Transition from pediatric to adult care centers must be anticipated. It requires the preparation of patients and families and a cooperation between both teams. Now, there are more patients and they are healthier. Adults centers caregivers have to pay particular attention to new young patients, to manage cystic fibrosis adult issues and to deal with more frequent comorbidities and severe complications. Adults centers will need better resources to maintain good quality of cares and improved life expectancy.

Study objective In patients with proven acute pulmonary embolism (PE), a systematic search for “residual” deep vein thrombosis (DVT) using venography or compression duplex ultrasonography (CDUS) of the lower limbs is negative in 20 to 50% of patients. We hypothesized that undetectable pelvic vein thrombosis (from the external iliac vein to the inferior vena cava) could account for a substantial proportion of patients with negative CDUS findings. Using a noninvasive test, magnetic resonance angiography (MRA), the objective of the study was to assess the prevalence of pelvic DVT in patients with acute PEs and normal findings on lower limb CDUS. Design Prospective study. Setting: A 35-bed respiratory unit in a 680-bed Parisian teaching hospital. Patients From June 1995 to October 1996, 24 patients (mean age, 49 years; age range, 18 to 83 years) with acute PEs and normal findings on lower limb CDUS underwent pelvic MRA. Measurements and results MRA disclosed pelvic DVT in seven patients (29%). The common iliac vein was involved in five patients. Internal iliac vein (hypogastric) thrombosis was imaged in two patients, but no patients had DVT limited to this vein. Three patients underwent subsequent venography studies that confirmed the MRA findings. In three other patients, a new MRA at the end of anticoagulant therapy showed the resolution of the DVT. Conclusions Our data support the view that, among patients with negative findings on CDUS, a substantial proportion of the DVTs that are responsible for PE originates in the pelvic veins. This study provides additional arguments to suggest that MRA might become the reference test for the exploration of pelvic DVT.

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.