Characterization of chronic lung allograft dysfunction biomarkers in bronchoalveolar lavage fluid by SELDI-TOF proteomic analysis

Malgré les progrès récents réalisés en transplantation pulmonaire, le pronostic à long terme est compromis par la survenue d une dysfonction chronique du greffon dont le diagnostic est basé sur le déclin de la fonction respiratoire. Nous avons analysé les profils protéiques du liquide de lavage bronchiolo-alvéolaire (LBA) de patients transplantés pulmonaires par une technologie protéomique innovante afin de caractériser des biomarqueurs diagnostiques de dysfonction chronique du greffon. Nous avons comparé de façon transversale le protéome des LBA de 13 patients avec un syndrome de bronchiolite oblitérante (groupe BOS), 21 patients avec une fonction pulmonaire stable (groupe ST) et 8 patients avec rejet aigu (groupe AR) par analyse protéomique SELDI-TOF (Surface Enhanced Laser Desorption/Ionization Time-Of-Flight). 45 pics d intensité statistiquement différente ont été caractérisés entre le groupe BOS et ST, et 42 entre les groupes BOS et AR. Parmi les pics les plus discriminants, des biomarqueurs correspondant aux protéines S100 (10812Da, 10412Da et 13335Da, p<0,002) et aux alpha-défensines 1-3 (3354Da, 3424Da et 3470 Da, p<0,01) étaient surexprimés dans le groupe BOS. La protéine S100A8 (10812 Da) permet de différencier les patients BOS des patients stables avec une sensibilité de 92% et une spécificité de 72% (AUC=0.87) et les alpha-défensines présentent également une performance diagnostique importante. L analyse protéomique du LBA par technique SELDI-TOF a permis de caractériser plusieurs biomarqueurs d intérêt pour le diagnostic de dysfonction chronique du greffon et potentiellement impliqués dans sa physiopathologie : les protéines S100 et les alpha-défensines.Objective: Despite progresses in lung transplantation, long-term prognosis is compromised by chronic allograft rejection. Its diagnosis is based on a delayed functional criterion and its physiopathology is still unclear. We investigated proteomic profiles of bronchoalveolar lavage fluid (BALF) of lung transplanted patients by an innovative proteomic technology in order to characterize diagnostic biomarkers of chronic allograft rejection. Methods: In a cross sectional pilot study, protein profiles of 13 lung transplant recipients with bronchiolitis obliterans syndrome (BOS), 21 patients with lung function stability (ST) and 8 patients with acute rejection (AR) were studied by SELDI-TOF MS (Surface Enhanced Laser Desorption Ionization Time-Of-Flight Mass Spectrometry) analysis. Results: Forty five differentially expressed proteins were detected in BOS group vs. ST population and forty two in BOS group vs. AR set. Among the most discriminating peaks, biomarkers corresponding to S100 proteins (10,812 Da, 10,412 Da and 13,335 Da, p<0.002) and alpha-defensins (3,354 Da, 3,424 Da and 3,470 Da, p<0.01) were up regulated in BOS patients compared to ST or AR patients. S100A8 protein (10,812 Da) discriminate BOS patients from ST patients with a sensitivity of 92% and a specificity of 72% (AUC=0.87), while alpha-defensins offer a slightly weaker diagnostic accuracy. Conclusion: BALF SELDI-TOF analysis allows detection of relevant biomarkers linked to BOS diagnosis and potentially involved in its physiopathology: S100 proteins and alpha-defensins.GRENOBLE1-BU Médecine pharm. (385162101) / SudocSudocFranceF

Management of voriconazole hepatotoxicity in a lung transplant patient.

International audienceLung allograft airway colonization by Aspergillus species is common among lung transplant recipients. We report the case of a 46-year-old female lung transplant outpatient diagnosed with persistent pulmonary Aspergillus colonization (>50 colonies of Aspergillus terreus) 3 months after lung transplantation. Oral voriconazole 200 mg twice a day (b.i.d) was initiated shortly after diagnosis. Two days after voriconazole initiation, alkaline phosphatase (ALP), alanine transaminase (ALT), and aspartate transaminase (AST) were normal or slightly elevated (79, 37, and 21 UI/L, respectively). Ten days after the first voriconazole administration, these values started to increase. Maximum levels were reached after 20 days for ALP (369 UI/L) and at around 30 days for ALT and AST (223 and 188 UI/L, respectively). Instead of discontinuing antifungal therapy, it was decided to reduce the voriconazole dose to 100 mg b.i.d. This asymptomatic progressive cholestatic hepatitis resolved, and 10 days after dose reduction ALP, ALT, AST were at 136, 53, and 28 UI/L, respectively. Finally, therapeutic drug monitoring revealed adequate voriconazole plasma trough concentrations (0.98 mg/L) 30 days after dose reduction and no more colonies of Aspergillus were observed. Voriconazole-induced hepatotoxicity is a well known dose-dependent adverse drug reaction. This experience confirms the appropriateness of voriconazole dose reduction instead of therapy interruption in dose-dependent moderate liver toxicity. Voriconazole therapeutic drug monitoring before and after dose reduction may help to avoid drug accumulation and inappropriately low drug exposure, respectively

Unusual cystic presentation of pulmonary nodular amyloidosis associated with MALT-type lymphoma.

The case reported herein consists of nodular pulmonary amyloidosis presenting with unusual cystic radiological features which reveal a pulmonary localisation of an extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). The present case is the first to report a radiological presentation of nodular pulmonary amyloidosis in the absence of Sj?n's syndrome. Although transthoracic fine-needle biopsy was helpful for the diagnostic of amyloidosis, final diagnosis of associated MALT-type lymphoma required an open lung biopsy. This emphasises the importance of performing surgical investigations in pulmonary nodular amyloidosis in order to depict the presence of underlying lung tumours or lymphoproliferative disorders

Development of a pharmacist collaborative care program for pulmonary arterial hypertension.

International audiencePatients with Pulmonary Arterial Hypertension (PAH) require multidisciplinary care. Involving pharmacists in PAH multidisciplinary care teams may enhance patient education and improve medication use. We describe the implementation of a Pharmacist Collaborative Care Program (PCCP) in a PAH referral centre in Grenoble, France. Initiated in 2007, the PCCP program includes a pharmacist intervention whose goals are educational, psychosocial, and technical. During patient interviews, pharmacists make an 'educational diagnosis' and provide a patient-specific education session. Patient skills are evaluated at the end of the session. Pharmacists provide feedback to nurses and physicians through a standardized report form and discussion during medical rounds and PAH group meetings. Pharmacists re-evaluate patients' skills every 3-6 months during multidisciplinary clinical evaluations. The PCCP program for PAH is an established practice in Grenoble and may inform future patient education programs involving pharmacists in France, where legislation has recently been passed to standardize patient education

Nonspecific Immunoglobulin Replacement in Lung Transplantation Recipients With Hypogammaglobulinemia

International audienceBACKGROUND: After lung transplantation (LT), immunoglobulin (Ig) G plasma concentrations<6 g/L are common and correlate with an increased risk of chronic lung allograft dysfunction (CLAD) and a poorer survival.METHODS: We conducted an open substitution intervention with nonspecific intravenous Ig (IVIg), in all patients with IgG plasma less than 6 g/L post-LT in 54 of 84 consecutive recipients since 1998 who survived more than 3 months. Pre-LT and post-LT events were retrospectively analyzed

Lung transplantation for lymphangioleiomyomatosis : The French experience

International audienceBackground. 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

Glucose trajectories in cystic fibrosis and their association with pulmonary function

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Rituximab and mycophenolate mofetil combination in patients with interstitial lung disease (EVER-ILD): a double-blind, randomised, placebo-controlled trial

International audienceBackground Standard of care for interstitial lung disease (ILD) with a nonspecific interstitial pneumonia (NSIP) pattern proposes mycophenolate mofetil (MMF) as one of the first step therapies while rituximab is used as rescue therapy. Methods In a randomised, double blind, two-parallel group, placebo-controlled trial ( NCT02990286 ), patients with connective tissue disease-associated ILD or idiopathic interstitial pneumonia (with or without autoimmune feature) and a NSIP pattern (defined on NSIP pathological pattern or on integration of clinico-biological data and a NSIP-like HRCT pattern) were randomly assigned in a 1:1 ratio to receive rituximab (1000 mg) or placebo on day 1 and day 15 in addition to MMF (2 g daily) for six months. The primary endpoint was the change in percent of predicted forced vital capacity (FVC) from baseline to 6 months analysed by a linear mixed model for repeated measures analysis. Secondary endpoints included progression-free survival (PFS) up to 6 months and safety. Findings Between January 2017 and January 2019, 122 randomised patients received at least one dose of rituximab (n=63) or placebo (n=59). The least-squares mean change from baseline to 6 months in FVC (% predicted) was +1.60 ( se 1.13) in the rituximab+MMF group and −2.01 ( se 1.17) in the placebo+MMF group (between-group difference, 3.60 [95% CI 0.41 to 6.80]; p=0.0273). PFS was better in the rituximab+MMF group (crude HR 0.47 [95%CI 0.23 to 0.96]; p=0.03). Serious adverse events occurred in 26 patients of the rituximab+MMF group (41%) and in 23 of the placebo+MMF group (39%). Nine infections were reported in the rituximab+MMF group (five bacterial infections, 3 viral infections, 1 other) and four bacterial infections in the placebo+MMF group. Interpretation Combination of rituximab and MMF was superior to MMF alone in patients with ILD and a NSIP pattern. The use of this combination must consider the risk of viral infection

The N-Terminal Domain of cGAS Determines Preferential Association with Centromeric DNA and Innate Immune Activation in the Nucleus

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Rapid Improvement after Starting Elexacaftor–Tezacaftor–Ivacaftor in Patients with Cystic Fibrosis and Advanced Pulmonary Disease

International audienceRationale: 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) <40 who initiated elexacaftor-tezacaftor-ivacaftor from December 2019 to August 2020 in France was conducted. Clinical characteristics were collected at initiation and at 1 and 3 months. Safety and effectiveness were evaluated by September 2020. National-level transplantation and mortality figures for 2020 were obtained from the French CF and transplant centers and registries. Measurements and Main Results: Elexacaftor-tezacaftor- ivacaftor was initiated in 245 patients with a median (interquartile range) ppFEV1 = 29 (24-34). The mean (95% confidence interval) absolute increase in the ppFEV1 was +15.1 (+13.8 to +16.4; P < 0.0001), and the mean (95% confidence interval) in weight was +4.2 kg (+3.9 to +4.6; P < 0.0001). The number of patients requiring long-term oxygen, noninvasive ventilation, and/or enteral tube feeding decreased by 50%, 30%, and 50%, respectively (P < 0.01). Although 16 patients were on the transplant waiting list and 37 were undergoing transplantation evaluation at treatment initiation, only 2 received a transplant, and 1 died. By September 2020, only five patients were still on the transplantation path. Compared with the previous 2 years, a twofold decrease in the number of lung transplantations in patients with CF was observed in 2020, whereas the number of deaths without transplantation remained stable. Conclusions: In patients with advanced disease, elexacaftor-tezacaftor-ivacaftor is associated with rapid clinical improvement, often leading to the indication for lung transplantation being suspended