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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)

Immunocompromised patients have an increased risk of a severe form of COVID-19. The clinical efficacy of the tixagevimab/cilgavimab monoclonal antibody combination as pre-exposure prophylaxis against BA.1 and BA.2 SARS-CoV-2 Omicron sublineages is unknown. We aimed to describe the incidence and outcomes of COVID-19 among immunocompromised patients receiving tixagevimab/cilgavimab as preexposure prophylaxis during the Omicron wave in France.This was an observational multicentre cohort study of immunocompromised patients receiving tixagevimab/cilgavimab as preexposure prophylaxis between December 28, 2021 and March 31, 2022. Patients received tixagevimab/cilgavimab 150/150 mg intramuscularly if they had impaired vaccine response and a high risk of severe form of COVID-19.Tixagevimab/cilgavimab was administered to 1112 immunocompromised patients. After a median (range) follow-up of 63 (49-73) days, COVID-19 was confirmed in 49/1112 (4.4%) ≥5 days after treatment. During the study period, mean weekly incidence rate was 1669 in 100 000 inhabitants in Ile-de-France and 530 in 100 000 among patients who received tixagevimab/cilgavimab prophylaxis. Among infected patients, 43/49 (88%) had a mild-to-moderate form and 6/49 (12%) had a moderate-to-severe form of COVID-19. Patients with moderate-to-severe illnesses were less likely to have received early therapies than patients with mild forms (53.5% vs. 16.7% respectively) and 2/49 (4%) patients died from COVID-19.Our study reported a low rate of infections and severe illnesses among immunocompromised patients treated with tixagevimab/cilgavimab. A global preventive strategy including vaccines, preexposure prophylaxis with monoclonal antibodies, and early therapies might be effective to prevent severe forms of COVID-19 among severely immunocompromised patients.

Chronic lung allograft dysfunction (CLAD) remains the leading cause of morbidity and mortality after lung transplantation. The term encompasses both obstructive and restrictive phenotypes, as well as mixed and undefined phenotypes. Imaging, in addition to pulmonary function tests, plays a major role in identifying the CLAD phenotype and is essential for follow-up after lung transplantation. Quantitative imaging allows for the performing of reader-independent precise evaluation of CT examinations. In this review article, we will discuss the role of quantitative imaging methods for evaluating the airways and the lung parenchyma on computed tomography (CT) images, for an early identification of CLAD and for prognostic estimation. We will also discuss their limits and the need for novel approaches to predict, understand, and identify CLAD in its early stages.

International audience; BACKGROUND: A concern about the susceptibility of immunocompromised patients to the worldwide pandemic of coronavirus disease 2019 (COVID-19) has been raised. We aimed at describing COVID-19 infections in the French cohort of lung transplant (LT) patients. METHODS: Multicenter nationwide cohort study of all LT recipients with COVID-19 diagnosed from March 1 to May 19, 2020. Recipient main characteristics and their management were retrieved. Hospitalization characteristics, occurrence of complications and survival were analyzed. RESULTS: Thirty-five LT patients with a COVID-19 infection were included. Median age was 50.4 (40.6-62.9) years, 16 (45.7%) were female, and 80% were double-LT recipients. Infection was community-acquired in 25 (71.4%). Thirty-one (88.6%) required hospitalization, including 13 (41.9%) in the intensive care unit. The main symptoms of COVID-19 were fever, cough, and diarrhea, present in 71.4%, 54.3%, and 31.4% of cases, respectively. Extension of pneumonia on chest CT was moderate to severe in 51.4% of cases. Among the 13 critically ill patients, 7 (53.9%) received invasive mechanical ventilation. Thrombotic events occurred in 4 patients. Overall survival rate was 85.7% after a median follow-up of 50 days (41.0-56.5). Four of 5 nonsurvivors had had bronchial complications or intensification of immunosuppression in the previous weeks. On univariate analysis, overweight was significantly associated with risk of death (odds ratio, 16.0; 95% confidence interval, 1.5-170.6; P = 0.02). CONCLUSIONS: For the 35 LT recipients with COVID-19, the presentation was severe, requiring hospitalization in most cases, with a survival rate of 85.7%. Copyright

Purpose The purpose of this study was first to evaluate the imaging-related cumulative post-transplantation radiation dose in cystic fibrosis (CF) lung transplantation (LT) recipients and second, to identify the occurrence and type of malignancies observed after LT. Materials and methods A total of 52 patients with CF who underwent LT at our institution between January 2001 and December 2006 with at least 3 years of survival were retrospectively included. There were 27 men and 25 women with a mean age of 24.4 ± 9.2 (SD) years (range: 7.6–52.9 years) at the time of LT. Calculation of cumulative effective and organ doses after LT were based on dosimetry information and acquisition parameters of each examination. Cumulative radiation doses were calculated until June 2016, but stopped at the time of de novomalignancy diagnosis, for patients developing the condition. Results Patients received a mean cumulative effective dose of 110.0 ± 51.6 (SD) mSv (range: 13–261.3 mSv) over a mean follow-up of 8.1 ± 3.6 (SD) years (range: 0.5–13.5 years), with more than 100mSv in 5 years in 19/52 patients (37%). Chest CT accounted for 73% of the cumulative effective dose. Mean doses to the lung, breast and thyroid were 152.8 ± 61.1 (SD) mGy (range: 21.2–331.6 mGy), 106.5 ± 43.2 (SD) mGy (range: 11.9–221.4 mGy) and 72.7 ± 31.8 (SD) mGy (range: 9.5–165.0 mGy), respectively. Nine out of 52 patients (17%) developed a total of 10 de novo malignancies, all but one attributable to immunosuppression after a mean post-transplantation follow-up period of 11.1 ± 3.5 (SD) years (range: 3.7–16.3 years). Six-month cumulative effective dose was not greater in patients with de novomalignancies than in those without de novomalignancies (28.9 ± 14.5 (SD) mGy (range: 13.0–53.4) vs 25.6 ± 15.3 (range: 5.0–69.7), respectively, P > 0.05). Conclusion The cumulative effective dose exceeded 100 mSv in 5 years in 37% of LT recipients, the reason why continuous efforts should be made to optimize chest CT acquisitions accounting for 73% of the radiation dose.

We report for the first time in literature an exceptional case of a third-time lung transplantations (LTx) done on a single lung because of previous pneumonectomy in a cystic fibrosis 22-year-old female. Several hypotheses were advocate to explain the need of persistent continuous noninvasive ventilation occurred after left pneumectomy. Finally, chronic lung allograft dysfunction (CLAD) associated with near- diaphragmatic palsy secondary to lung distension was the retained diagnosis. Twenty-three months after third-time single lung retransplantation she is still alive, in good condition, with a Forced Expiratory Volume in 1 second (FEV1) measured at 47%, justifying the accepted risk and the technical difficulties of an exceptional procedure.

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.

OBJECTIVES: Lung transplantation (LTx) is an accepted therapy for selected infants, children and adolescents with end-stage lung and pulmonary vascular disease. It remains a challenge for a selected group of patients. In 2011, the number of paediatric lung transplantations (PLTxs) worldwide was 107. In France, a total of 131 PLTxs have been performed since 2000 (data from ABM: Agence de biomedecine), 65 of which were conducted at our institution. METHODS: All patients under 18 (4.8–17.11) years of age matching inclusion and exclusion criteria, who underwent LTx at our institution were included in this study (n= 58). We analysed the outcomes of these patients in terms of survival rates, controlling for indications for transplantations and surgical procedures. Secondary outcomes were analysis of surgical and medical complications and identification of prognostic factors in the field of LTx in these categories of ages. RESULTS: The 30-day mortality rate was 10%. Kaplan–Meier survival rates at 1 month, 1, 3, 5 and 10 years were 90, 81, 66, 60 and 57%, respectively; the median survival was 91 months. Reduced-size transplantation was performed in 33% of double-lung transplantation (DLTx) patients without negatively impacting survival. In our series, female sex, the presence of a sex mismatching and, in particular, the occurrence of a male donor to a female recipient (F/M group) have been poor prognostic factors after PLTx. CONCLUSIONS: The overall survival after PLTx was encouraging (57% at 10 years). A PLTx should be offered to the small number of patients with end-stage pulmonary disease. The limited number of paediatric donor organs can be overcome by using reduced-size organs without a survival disadvantage to the patients. In our series, male sex and sex matching seemed to be positive predictive prognostic factors after PLTx but further studies are required to confirm these results and to also clarify the role of age of donor, time of cold ischaemia and body mass index in PLTx.

Resume Introduction La transplantation pulmonaire pediatrique (TP) reste une petite partie des TP effectuees dans le monde. La majorite de ces TP concerne les jeunes adolescents, les transplantations chez les nourrissons restant anecdotiques. Nous avons mene une etude retrospective de TP chez les enfants et les adolescents dans un centre a Paris depuis le debut des annees 90 a 2013. Methodes Les donnees de l’hopital Broussais puis celles de l’HEGP ont ete recueillies retrospectivement de 1990 a 2013 : 380 TP ont ete rapportees chez 368 patients, dont 111 TP realisees chez des enfants de 5 a 18 ans (30 %). Resultats Cent onze patients ont recu 121 TP : 86 greffes bipulmonaires, 13 greffes combinees poumons-foie, 3 greffes monopulmonaires, 5 greffes cœur-poumons et 4 greffes combinees cœur-poumons-foie. Quatre-vingt-huit pour cent des patients etaient greffes pour mucoviscidose. L’âge median etait de 14 ans, le poids de 34 kg et la taille de 144 cm. L’âge median des donneurs etait de 27 ans, le poids de 60 kg et la taille de 167 cm. Les courbes de survie conditionnelle pour les enfants n’etaient pas differentes de celles des adultes : 72 % a un an, 42 % a 5 ans, 37 % a 10 ans et de 26 % a 15 ans. Il n’y avait pas de surmortalite precoce apres transplantation. La survie selon la periode de greffe etait significativement plus elevee apres l’annee 2000 (53 % a 5 ans vs 32 %, p = 0,03). Conclusion La transplantation pulmonaire chez les enfants de moins de 18 ans a des resultats similaires a ceux des adultes.

Background Fungi of the genus Scedosporium are emerging pathogens responsible for severe infections in lung transplant recipients. These infections are associated with poor prognosis and some centers consider now Scedosporium species colonization as a contraindication to lung transplantation (LT) even though no published evidence demonstrates that Scedosporium species colonization is associated with higher morbidity or mortality after LT. Methods Here, we aim to describe characteristics and outcome of cystic fibrosis (CF) lung transplant recipients colonized with Scedosporium species in a single center over a 15-year period. Results During the study period, 14 patients had scedosporial colonization reported. Only one patient, colonized before transplantation by Lomentospora prolificans, developed scedosporial disease. Among the eight patients colonized before transplantation by Scedosporium apiospermum complex, the median survival was 1.92 year (range 0.21-12.5). All these patients except one became free of fungal colonization after transplantation with antifungal prophylaxis including voriconazole or posaconazole. For the five patients colonized after LT, including two with L. prolificans, the median survival was 1.75 years (range 0.1-13); three of them are still alive. Conclusions It appears to us that scedosporial colonization may not be a contraindication for LT in CF patients, as long as S. apiospermum complex is involved and a life-long azole prophylaxis prescribed.

Oral posaconazole (PSZ), an azole antifungal drug, was recently introduced for the treatment of invasive fungal infections. The prescription of PSZ together with the immunosuppressant tacrolimus (TRL) was evaluated in 14 lung transplant patients with cystic fibrosis. PSZ inhibited CYP3A4 TRL metabolism, resulting in a decrease of TRL dose by a factor of 3, with tapering to a mean of 2 mg/d. Previous studies with itraconazole and voriconazole showed that TRL dose could be decreased by factors of 5 and 4, respectively. Joint therapeutic drug monitoring of TRL and PSZ was carried out to investigate the high risk of interindividual variability associated with this coprescription in such patients.

Il prelievo polmonare, che inizia con l’accettazione dell’organo e termina immediatamente prima dell’impianto nel ricevente, implica una successione di tappe ciascuna delle quali gioca un ruolo importante nell’ottica del successo del trapianto sia a breve sia a lungo termine. I prelievi sono soprattutto da donatori cadaveri ma, in qualche caso molto selezionato, sono possibili prelievi lobari da donatori viventi. Altre branche di ricerca si orientano attualmente verso donatori a cuore non battente, permettendo di sperare in un maggior numero di innesti. L’appaiamento tra donatore e ricevente, che si fonda essenzialmente su parametri quali la compatibilita immunologica e il grado di urgenza, comprende anche la qualita dell’organo scelto, che puo essere ottimale o meno quando prelevati da donatori limite. L’equipe che si occupa del prelievo gioca un ruolo essenziale nell’accettazione definitiva dell’organo mediante esame in situ del polmone, nella coordinazione con l’equipe che effettuera il trapianto e per l’aspetto tecnico chirurgico del prelievo (preservazione e dissezione del mediastino). La qualita della conservazione e legata a una ipotermia stabile che inizia con la perfusione di soluzione elettrolitica extracellulare raffreddata, un’insufflazione moderata dell’organo senza iperossia e un breve periodo di ischemia fredda che consentono di ridurre il rischio di edema da riperfusione e alcune disfunzioni primarie dell’organo. La collaborazione delle equipe che lavorano sul donatore ha in questo tutta la sua importanza.

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.

The present study was conducted to confirm the presence of severe lymphocytic alveolitis and to determine the factors responsible for the very different alveolar CD4 to CD8 T-cell ratios (CD4/ CD8) described in methotrexate-induced pneumonitis (MTX-pneumonitis). Clinical and radiologic findings, as well as bronchoalveolar lavage (BAL) data, including CD4 and CD8 subset analysis, were retrospectively reviewed for patients hospitalized between 1985 and 2000 for MTX-pneumonitis. BAL cell counts from patients with MTX-pneumonitis (cases) were compared with those from patients receiving MTX but who did not have evidence of MTX toxicity (MTX-exposed patients) and those from healthy subjects (control subjects). Nineteen BAL were performed in 14 consecutive cases of MTX-pneumonitis. MTX was given for various underlying diseases. All cases presented a subacute diffuse interstitial pneumonitis that recovered, with MTX discontinuation and/or initiation of adjunctive steroid therapy. At the time of diagnosis, BAL cell counts in MTX-pneumonitis indicated severe lymphocytic alveolitis when compared with MTX-exposed patients and control subjects and moderate neutrophil alveolitis compared with control subjects. The lymphocytic alveolitis resulted from an increase in both CD4 and CD8 lymphocyte cell counts. Nevertheless, alveolar CD4/ CD8 T-cell ratios ranged from 0.4 to 9.6. CD4/CD8 values correlated positively with lymphocyte counts but negatively with time elapsed between last MTX administration and BAL and with steroid cumulative dose received by the patients. Severe lymphocytic alveolitis was confirmed in our series of MTX-pneumonitis. The between-patient variation in CD4/CD8 T-cell ratios may reflect the large range of time intervals between last MTX administration and BAL evaluation and the use of adjunctive steroid therapy.

We report 4 cases of acute lobar torsion in patients who had undergone bilateral lung transplantation. Bronchoscopy showed complete obstruction in only 2 of them. Torsion was confirmed by computed tomography in coronal minimal and maximal intensity projections with reconstruction. At operation, 1 detorsion and 3 lobectomies were carried out. Early diagnosis and rapid surgical intervention can save the affected lobe.

Massive hemoptysis in patients with severe leptospirosis is often resistant to conventional therapies and can rapidly become fatal. Desmopressin is a fast-acting blood-saving agent used in various hereditary and acquired clotting disorders. We used desmopressin infusions to treat massive pulmonary hemorrhage in six leptospirosis patients with respiratory failure, shock, and multiple organ dysfunction. Hemoptysis ceased rapidly in every case, and five patients finally recovered. Two additional patients with less severe hemoptysis were also successfully treated.