Introduction Les infections pulmonaires dues aux mycobactéries non tuberculeuses (ipMNT) nécessitent un traitement complexe et prolongé. Le maintien de l’observance au traitement est un enjeu important. MYCOCARE est un programme de suivi infirmier de 12 mois destiné à accompagner les patients atteints d’ipMNT. Méthodes Après inscription du patient au programme MYCOCARE par son médecin, une infirmière spécialisée dans la prise en charge des ipMNT réalise jusqu’à 5 entretiens téléphoniques sur 12 mois. Elle évalue l’observance (échelle de Morisky [EM8]), la tolérance (critères PRO-CTCAE : troubles gastro-intestinaux, toux, dyspnée, sommeil, fatigue, appétit) et la qualité de vie (EQ-5D-5L). Un numéro vert est à disposition pour répondre aux questions des patients. Le lien avec l’équipe médicale est maintenu via des comptes rendus adressés sur un extranet sécurisé.En cas de traitement par nébulisation, l’initiation se déroule à l’hôpital avec une séance d’éducation thérapeutique à la pratique et compréhension des traitements. L’autonomie du patient est évaluée à J7 et J21 du programme. Résultats Entre le 01/07/2021 et le 30/06/2024, 207 patients (âge moyen 61,2 ans ; 35 % H/F) suivis dans 88 hôpitaux ont été inclus. Au 30/06/2024, 58 patients (28 %) sont toujours accompagnés. Au total, 86 patients (41,6 %) ont suivi l’intégralité du programme et 63 (30,4 %) l’ont abandonné (28 à l’initiative du médecin, 14 à l’initiative du patient, 11 pour négativation des cultures, 10 sont décédés et 1 perdu de vue).Le score d’observance des traitements anti-infectieux est satisfaisant à M2 (score sur l’EM8 7,3±1,0 ; n=102), et ne varie pas significativement au cours du suivi (6,9±1,6 à M12 n=46, p=0,14, test post hoc). Le score de qualité de vie est acceptable et stable (7,4±3,2 à l’inscription (J0) et 7,2±2,9 à M12).Aucune variation significative du taux de déclarations des effets indésirables entre M2 et M12 n’a été remontée (3,2±2,2 à M2 vs 2,4±2,4 à M12, p=0,15). La fatigue, la toux et la dyspnée, les symptômes les plus rapportés, tendent à s’améliorer dans le temps. Conclusion Le programme MYCOCARE constitue un outil à la disposition des praticiens soignant des patients atteints d’ipMNT pouvant faciliter le suivi du traitement. Le taux faible de sorties du programme suggère une bonne acceptabilité des patients suivis. MYCOCARE pourrait contribuer à l’optimisation de l’observance thérapeutique et plus largement, contribuer à une meilleure coordination des acteurs de la prise en charge des ipMNT, favoriser le lien hôpital-ville, et contribuer à une meilleure compréhension de la maladie par les patients.

ABSTRACTAchromobacter spp. are opportunistic pathogens of environmental origin increasingly isolated in patients with underlying conditions like cystic fibrosis (CF). Despite recent advances, their virulence factors remain incompletely studied, and siderophore production has not yet been investigated in this genus. The aim of this study was to evaluate the production of siderophores in a large collection of Achromobacter spp. and evaluate the variability according to the origin of the strain and species. A total of 163 strains were studied, including 128 clinical strains (CF and non-CF patients) and 35 strains of environmental origin. Siderophores were quantified by the liquid chrome azurol-sulphonate assay. Species were identified by nrdA gene-based phylogeny. Strains were assigned to 20 species, with Achromobacter xylosoxidans being the most represented (51.5% of strains). Siderophore production was observed in 72.4% of the strains, with amounts ranging from 10.1% to 90% siderophore units. A significantly higher prevalence of siderophore-producing strains and greater production of siderophores were observed for clinical strains compared with strains of environmental origin. Highly variable observations were made according to species: A. xylosoxidans presented unique characteristics (one of the highest prevalence of producing strains and highest amounts produced, particularly by CF strains). Siderophores are important factors for bacterial growth commonly produced by members of the Achromobacter genus. The significance of the observations made during this study must be further investigated. Indeed, the differences observed according to species and the origin of strains suggest that siderophores may represent important determinants of the pathophysiology of Achromobacter spp. infections and also contribute to the particular epidemiological success of A. xylosoxidans in human infections.IMPORTANCEAchromobacter spp. are recognized as emerging opportunistic pathogens in humans with various underlying diseases, including cystic fibrosis (CF). Although their pathophysiological traits are increasingly studied, their virulence factors remain incompletely described. Particularly, siderophores that represent important factors of bacterial growth have not yet been studied in this genus. A population-based study was performed to explore the ability of members of the Achromobacter genus to produce siderophores, both overall and in relevant subgroups (Achromobacter species; strain origin, either clinical—from CF or non-CF patients—or environmental). This study provides original data showing that siderophore production is a common trait of Achromobacter strains, particularly observed among clinical strains. The major species, Achromobacter xylosoxidans, encompassed both one of the highest prevalence of siderophore-producing strains and strains producing the largest amounts of siderophores, particularly observed for CF strains. These observations may represent additional advantages accounting for the epidemiological success of this species.

Achromobacter spp. are emerging pathogens in CF. Based on intrinsic resistance and the report of multidrug resistant strains, Achromobacter spp. are considered as difficult-to-treat pathogens. Cefiderocol is a novel siderophore cephalosporin that has been infrequently used in the management of Achromobacter infections and for which susceptibility data are lacking. We evaluated the cefiderocol susceptibility of a collection of CF Achromobacter strains encompassing different airway colonization types, species and antimicrobial susceptibility patterns. A total of 110 clinically-documented Achromobacter strains from 70 CF patients were included. Strains were identified by nrdA gene sequencing. Antimicrobial susceptibility testing included a standard antibiogram and cefiderocol susceptibility testing using disk diffusion method and Minimal Inhibitory Concentration (MIC) determination by both Etest and ComASP™ microdilution performed according to CA-SFM/EUCAST guidelines. Isolates displayed a high nrdA allele diversity and belonged to 9 species and a group of unassigned isolates. Preliminary results showed: i) MIC values of 0.064 to 1 mg/mL, ii) a A. insuavis strain displaying a MIC of 4 mg/mL, above the resistance breakpoint, iii) an additional incubation time required for the ComASP™ MIC to be readable for some isolates. A full report of the distribution of MIC determined by microdilution will be presented and compared with the distribution of MIC and inhibition zone diameters determined by agar diffusion to evaluate the more accurate method to be used for Achromobacter spp. The study will provide original results on the distribution of MICs and inhibition zone diameters of cefiderocol for a large collection of CF Achromobacter strains with clinical and microbiological documentation allowing specific observations for A. xylosoxidans, the most frequently identified species in CF, and other clinically-relevant species.

Pseudomonas aeruginosa is the major environmental opportunistic pathogen in cystic fibrosis (CF), able to chronically colonize patient's airways. However, P. aeruginosa acquisition sources are poorly known. A patient attending the Montpellier CF center was sporadically colonized in 2010 by a strain of P. aeruginosa of sequence type (ST) 27 and strains of identical genotype were isolated from all water points in his home during environmental investigations in 2015 and 2020. Our objectives were: i) to compare characteristics of clinical and environmental strains to identify properties that could favor transmission to patient, ii) to study the environmental strains' evolution between 2015 and 2020 to search for features involved in environmental persistence. Genomic (whole genome MLST analysis, Single Nucleotide Polymorphism (SNP) searches and genomic content comparison) and phenotypic (motility, biofilm formation and antibiotic susceptibility) comparisons of clinical and environmental strains were performed. Strains were closely related since their genomes differed by 4 SNP maximum. The clinical strain presented all the characteristics of first colonization strain: planktonic lifestyle and low biofilm production, wildtype antibiotic susceptibility. This strain had significantly higher swimming and twitching motilities than environmental strains. At the genomic level, a prophage (45 kpb) absent from the genome of the clinical strain was present in all the environmental strains' genomes and its integration in the genome could have contributed to the environmental persistence. During this persistence, decreased motility and increased biofilm formation were the predominant adaptive traits. This study highlights a potential P. aeruginosa transmission from the domestic environment to the patient but also reports for the first time a persistence of P. aeruginosa for at least 5 years in a home water network.

Introduction: The French clinical research network is a platform called "Plateforme Nationale de Recherche Clinique" (PNRC), it was created in 2009 under the guidance of the patients' organisation Vaincre la Mucoviscidose and French investigators from the ECFS-CTN to promote CF clinical research in France. Objectives: We aim to describe 1) the most relevant actions carried out by the platform since 2009; 2) which pitfalls were encountered and how they've been managed; 3) which future plans could be addressed. Methods: An assessment of the platform activities has been led by the clinical research coordinators and the steering committee. Pitfalls and successes were identified after a SWOT analysis (Strengths, Weaknesses, Opportunities & Threats) and from clinical research data collected from the French and European research registries. Results: The most important actions performed to increase inclusions and improve the quality of clinical research were: creation of clinical research coordinator positions, a tool included in the French registry to monitor patients' inclusion in trials, assistance in carrying out studies and helping CF centres to organize their research activities, a clinical research brochure for patients and relatives, clinical research regional newsletters, an online clinical trial finder. This revealed that 245 CF studies (158 academic and 87 industrial) have taken place in France over the last 14 years and that more than 20% of French CF patients (1575) have at least participated in one clinical study. Conclusions: The PNRC is an efficient collaborative clinical research network, led by a dynamic group of clinical research coordinators allowing an increase of clinical projects to run in France and number of patients' inclusions. Today the platform has become a key player in national and international clinical research and is ready for future innovative trials.

Les Achromobacter spp. sont considérés comme des agents pathogènes émergents chez les patients atteints de mucoviscidose (CF) et les patients immunodéprimés. A. xylosoxidans est l'espèce la plus fréquemment identifiée mais d'autres espèces infectent également l'homme. Cependant, l'identification des différentes espèces reste difficile ce qui entraîne une description imprécise de la résistance aux antibiotiques de chaque taxon. En raison de leur résistance intrinsèque aux antibiotiques et de l'apparition de souches multirésistantes, les Achromobacter spp. sont considérés comme des bactéries difficiles à traiter. Le céfidérocol est une nouvelle céphalosporine sidérophore à large spectre qui n'a été que rarement utilisée dans le traitement des infections à Achromobacter chez les patients CF et pour laquelle il manque des données de sensibilité. Nous avons évalué la sensibilité au céfidérocol d'une collection d'espèces différentes d'Achromobacter provenant de patients atteints ou non de mucoviscidose. Un total de 160 souches d'Achromobacter cliniquement documentées ont été incluses: 110 provenant des voies respiratoires de 70 patients CF et 50 provenant de patients non atteints de mucoviscidose (NCF) (hémocultures, voies respiratoires...). Les souches ont été identifiées par séquençage du gène nrdA. Les tests de sensibilité au céfidérocol ont été réalisés par la méthode de diffusion sur disque (disques de 30 µg de céfidérocol testés sur des plaques de gélose Mueller-Hinton déplétées en fer) et la détermination de la concentration minimale inhibitrice (CMI) par microdilution Etest et par ComASP™ a été réalisée conformément aux directives du CA-SFM/EUCAST. Au total, les souches d'Achromobacter présentaient une grande diversité d'allèles nrdA et appartenaient à neuf espèces différentes. Les résultats préliminaires sur 38 souches ont montré: i) des valeurs de CMI allant de 0,064 à 1 µg/mL, ii) une souche de patient CF d'A. insuavis présentant une CMI de 4 µg/mL, supérieure aux concentrations critiques PK/PD, iii) un temps d'incubation supplémentaire nécessaire pour que la CMI ComASP™ soit lisible pour 13 % des isolats. Un rapport complet de la distribution des CMI déterminées par microdilution sera présenté et comparé à la distribution des CMI et des diamètres de zone d'inhibition déterminés par diffusion sur milieu gélosé, pour l'ensemble de la population et selon les espèces. En l'absence de données similaires dans la littérature, l'étude fournira des résultats originaux sur la distribution des CMI et des diamètres de zone d'inhibition du céfidérocol pour une large collection d'Achromobacter avec une documentation clinique et microbiologique permettant des observations spécifiques pour A. xylosoxidans et d'autres espèces cliniquement pertinentes. Aucun lien d'intérêt

Introduction: The S364P (c.1090T>C) is a rare variant of unknown clinical significance, eligible to ETI treatment according to the FDA approval only (not eligible for EMA). Currently, functional data to define the molecular consequences associated with this variant are missing and CF modulators efficacy in patients with this genotype is limited Objective: Compare the effect of ETI on CFTR protein amount and function on nasal epithelial cells with the clinical endpoints in a CF patient homozygous for the variant S364P. Methods: We studied prospectively a 27 years old patient homozygous for this variant who rapidly declined with the need to test new strategies. We first planned to carry out functional analyses to evaluate the benefit of ETI on an epithelium model cultured in Air Liquide Interface (28 days of differentiation) from samples of the patient's nasal cells. The ETI effect on the amount of CFTR mRNA (RT-PCR) and protein (Western Blot), as well as the Cl- secretion measurement (Ussing Chamber) were evaluated. In parallel, the patient initiated ETI thanks to the compassionate access authorized by the French Medicine Agency (for severe patients regardless of the genotype) and clinical parameters were evaluated at one (M1), 3 (M3) and 6 months (M6) of treatment Results: Ex vivo data did not demonstrate a significant improvement on CFTR protein amount or on Cl- secretion. On the other hand, we observed a rapid improvement of clinical parameters: reduction of symptoms and no need for antibiotics in this 6 months period; FEV1 improvement from 42% to 60% at M1, 66% at M3 and 68% at M6; weight gain +1.7 Kg at M1 and +2.5 kg at M3 and M6; decrease of sweat chloride (mmol/l) from 82 at the initiation to 24 at M1. Conclusion: These data demonstrate the limits of ex vivo tests on the nasal epithelial cell cultures to predict the therapeutic response in practice. Noncontributive in vitro or ex vivo study should not stop clinicians to keep trying medication for rare mutations.

Achromobacter are opportunistic pathogens increasingly isolated in patients with cystic fibrosis (CF). Despite recent advances, their virulence factors remain incompletely studied. Particularly, ironchelating molecules called siderophores have not yet been studied in CF Achromobacter isolates although being major bacterial virulence factors. The aims of our study were: I) to characterize the production of siderophores by Achromobacter spp. isolated from CF patients, II) to compare results to strains from non-CF patients to search for specific virulence characteristics that may be observed in the CF context. A total of 162 strains of Achromobacter were studied including 104 strains from 66 CF patients and 58 strains from non-CF patients (blood, bronchoalveolar lavage fluid, others). Achromobacter species were identified by nrdA gene sequencing. Siderophores were quantified by the liquid Chrome Azurol-Sulphonate assay. Results obtained for the different species and for CF versus non-CF strains were compared using the Mann-Whitney test. Siderophore production was observed for 91.4% of strains with I) 94% CF strains and 90% non-CF strains being siderophore producers, II) CF strains producing significantly higher quantity of siderophores than non-CF strains (sometimes as high as a Pseudomonas aeruginosa CF strain). Among the diversity of Achromobacter species identified, Achromobacter xylosoxidans is the species showing both the highest proportion of siderophore-producing strains and the highest siderophore quantity produced. Siderophores are widely produced in the genus Achromobacter. Strains from CF patients present specific siderophore production characteristics that could contribute to the overall virulence of these emerging pathogens. A. xylosoxidans, the species the most frequently identified in CF, displayed unique characteristics that might contribute to its epidemiological success in the CF lung.

Objective: The 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. Our objective was to evaluate ETI in pwCF with advance lung disease and no F508del variant. Methods: An 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)<40 and/or being under evaluation for lung transplantation) and enrolled in the French Compassionate Program were included. Participants initiated ETI at recommended doses and effectiveness was evaluated at 4–6 weeks in terms clinical manifestations, sweat chloride concentration and ppFEV1. Results: Among 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 a CFTR variant that is not currently approved by FDA for ETI eligibility. Important clinical benefits including withholding the indication for lung transplantation were observed in those for whom treatment was effective; a significant decrease in sweat chloride concentration by a median [IQR] –30 [–14; –43] (n = 42; P < 0.0001) and an improvement in ppFEV1 by +10.0 [6.0; 20.5] (n = 44, P < 0.0001) further occurred. Conclusion: Clinical benefit was observed in a large subset of pwCF with advanced lung disease and CFTR variants not currently approved for ETI.

Les infections au complexe Mycobacterium abscessus (Mabs) demeurent difficiles à traiter tant chez les patients atteints de mucoviscidose que chez ceux qui ne le sont pas. Les résultats cliniques rapportés sont largement insatisfaisants. Les données des essais cliniques sont limitées et aucun traitement approuvé n’est actuellement disponible pour le traitement des infections pulmonaires à Mabs. Les études de cohortes peuvent fournir des informations utiles sur la gestion de ces infections. Sur la base d’une étude de cohorte rétrospective, nous avons étudié l’efficacité et la sécurité clinique d’ALIS et la conversion microbiologique des patients ayant bénéficié d’un traitement par ALIS depuis sa mise à disposition dans le cadre de l’ATU en France (2015). Il s’agit d’un recueil de données cliniques et biologiques rétrospectives des patients inclus dans la cohorte des patients traités par ALIS au moins un mois entre mars 2016 et février 2020. Les critères d’infection à mycobactéries non tuberculeuses (MNT) étaient ceux de l’ATS/IDSA. L’observance du traitement nébulisé a été mesurée par l’indice de possession de médicament (délivrance par les pharmacies hospitalières). Les effets secondaires rapportés ont été décrits. La conversion microbiologique a été définie par l’analyse des expectorations négative et répétée. Vingt-six patients ayant bénéficié d’ALIS ont été inclus dans cette étude. La conversion des cultures a été obtenue chez 54 % (14/26) des patients, sans différence entre les patients atteints de mucoviscidose et les autres. La durée moyenne de traitement était de 11,1 mois. L’observance du traitement était significativement meilleure dans le groupe des patients avec conversion que dans celui sans conversion microbiologique, avec un OR de 47,8. Neuf patients (35 %) ont eu un événement indésirable conduisant à l’arrêt du traitement. ALIS semble bénéfique chez les patients ayant une infection pulmonaire à Mabs. Une étude randomisée et l’amélioration des stratégies antibiotiques associées restent nécessaires pour démontrer la place d’ALIS dans la prise en charge médicamenteuse des infections pulmonaires à Mabs.

Introduction: It remains unclear whether children with non-severe (NSA) or severe asthma (SA) display similar patterns of sensitization. Objectives: to assess sensitization patterns in children with SA and NSA. Methods: IgE to 112 components (c-sIgE) (ImmunoCAP® ISAC) were analyzed in preschoolers (3-6 years) with SA (n=84) and NSA (n=47) and school-age children (6-12 years) with SA (n=90) and NSA (n=108) from the COBRAPed study (Lezmi G et al, J Allergy Clin Immunol Pract 2021). Results: 48%/75% of preschool/school-age children had positive c-sIgE to any airborne, 21%/27% to any food, 21%/36% to any cross-reactive allergen (Fig). Sensitization patterns did not clearly discriminate SA from NSA. At school-age, sensitization to milk, fish, nuts, legumes were more frequent in children with SA: 7% vs 1% (p=0.05), 7% vs 1% (p=0.05), 20% vs 9% (p=0.03), 18% vs 7% (p=0.01). Among patients with positive c-sIgE, 6 clusters were identified: (1) preschool multiple, (2) preschool multiple predominantly grass pollen and PR-10, (3) preschool low predominantly HDM, (4) school-age multiple, (5) school-age multiple, low food and nsLTP, (6) school-age low predominantly HDM. Cluster (4) was associated with SA (p<0.01) and lower FEV1/FVC (p=0.05). Conclusions: Sensitization patterns are overall similar in children with SA and NSA. Figure: Patterns of sensitization to each allergen component (columns) for individual participants (rows) stratified by severity group

L’objectif de ce travail était d’obtenir parmi des pneumologues experts un consensus sur la conduite à tenir avant de traiter une infection pulmonaire à mycobactérie non tuberculeuse (MNT). Nous avons sollicité le groupe de travail « Mycobactéries » faisant partie du groupe de recherche et d’enseignement en pneumo-infectiologie (GREPI) de la SPLF (Société de Pneumologie de Langue Française), afin de réaliser une enquête delphi couvrant trois domaines pertinents pour le clinicien avant de décider d’initier une antibiothérapie prolongée: (1) affirmer le diagnostic d’infection; (2) définir le degré de gravité de l’infection et (3) identifier les comorbidités et freins au traitement antibiotique prolongé. Les résultats de cette enquête permettent de valider un algorithme décisionnel avant d’initier une antibiothérapie prolongée. Chaque assertion était notée et commentée par les experts via un questionnaire en ligne. Les notes ont été pondérées en fonction du nombre de patients suspects d’infection à MNT vus chaque année. Les assertions qui ont obtenu une moyenne pondérée supérieure à 9/10 et qui n’ont pas reçu de suggestion d’amélioration, ont été validées et n’ont pas fait l’objet d’une réévaluation au 2e tour (fort consensus). Trente sept experts ont répondu au total. Au premier tour, 9 assertions sur 38 ont obtenu un fort consensus. D’autres assertions, en particulier concernant le degré de sévérité, ont été revues et de nouvelles assertions ajoutées pour une évaluation au 2e tour. 51 assertions ont finalement été testées. 78% des assertions (40/51) ont obtenu un consensus fort et 22% (11/51) un consensus relatif. Il n’y a pas eu de désaccord. Le consensus obtenu sur la totalité des assertions après deux tours permet de développer un algorithme décisionnel pratique avant d’initier un traitement antibiotique prolongé. Cette enquête delphi a permis d’élaborer un premier consensus sur les critères diagnostiques, de gravité de l’infection ainsi que sur les points cliniques déterminants avant de décider d’initier ou non une antibiothérapie prolongée chez les patients ayant une infection pulmonaire à MNT.