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Introduction: Interstitial lung disease in children (chILD) are rare and mostly severe lung diseases. Very few epidemiological data are available in limited series of patients. The aim of this study was to assess the prevalence and incidence of chILD in France., Methods: We performed within the RespiRare network a multicentre retrospective observational study in patients with chILD from 2000 to 2022 and a prospective evaluation of chILD's incidence between February 2022 and 2023., Results: chILD was reported in 790 patients in 42 centres. The estimated 2022 prevalence in France was 44 /million children (95% CI 40.76 to 47.46) and the computed incidence was 4.4 /million children (95% CI 3.44 to 5.56). The median age at diagnosis was 3 months with 16.9% of familial forms. Lung biopsy and genetic analyses were performed in 23.4% and 76.9%, respectively. The most frequent chILD aetiologies in the <2 years group were surfactant metabolism disorders (16.3%) and neuroendocrine cell hyperplasia of infancy (11.8%), and in the 2-18 years group diffuse alveolar haemorrhage (12.2%), connective tissue diseases (11.4%), hypersensitivity pneumonitis (8.8%) and sarcoidosis (8.8%). The management included mainly oxygen therapy (52%), corticosteroid pulses (56%), oral corticosteroids (44%), azithromycin (27.2%), enteral nutrition (26.9%), immunosuppressants (20.3%) and hydroxychloroquine (15.9%). The 5-year survival rate was 57.3% for the patients diagnosed before 2 years and 86% between 2 and 18 years., Conclusion: This large and systematic epidemiological study confirms a higher incidence and prevalence of chILD than previously described. In order to develop international studies, efforts are still needed to optimise the case collection and to harmonise diagnostic and management practices., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Chimeric antigen receptor (CAR) T-cell therapy for multiple myeloma targeting B-cell maturation antigen (BCMA) induces high overall response rates. However, relapse still occurs and novel strategies for targeting multiple myeloma cells using CAR T-cell therapy are needed. SLAMF7 (also known as CS1) and CD38 on tumor plasma cells represent potential alternative targets for CAR T-cell therapy in multiple myeloma, but their expression on activated T cells and other hematopoietic cells raises concerns about the efficacy and safety of such treatments. Here, we used CRISPR/Cas9 deletion of the CD38 gene in T cells and developed DCAR, a double CAR system targeting CD38 and CS1 through activation and costimulation receptors, respectively. Inactivation of CD38 enhanced the anti-multiple myeloma activity of DCAR T in vitro. Edited DCAR T cells showed strong in vitro and in vivo responses specifically against target cells expressing both CD38 and CS1. Furthermore, we provide evidence that, unlike anti-CD38 CAR T-cell therapy, which elicited a rapid immune reaction against hematopoietic cells in a humanized mouse model, DCAR T cells showed no signs of toxicity. Thus, DCAR T cells could provide a safe and efficient alternative to anti-BCMA CAR T-cell therapy to treat patients with multiple myeloma., (©2024 American Association for Cancer Research.)

Background: Pulmonary exacerbations (PEx) are strong predictors of respiratory disease progression in children with cystic fibrosis (CwCF) and may be associated with persistent decreased lung function after acute management. Telemonitoring devices can be used for early detection and monitoring of PEx, but its utility is debated., Research Question: Which symptoms and telemonitoring spirometry characterics are related to outcome dynamics following initial PEx management?, Methods: This retrospective study included CwCF followed at Bordeaux University Hospital, France. All severe PEx episodes treated with intravenous (IV) antibiotics (ATB) between 1 January 2017 and 31 December 2021 in CwCF using home telemonitoring were analyzed. Symptoms and home spirometry data were collected 45 days before and up to 60 days after each IV ATB course. We defined three response profiles based on terciles of baseline forced expiratory volume in 1 s (FEV 1 ) recovery., Results: A total of 346 IV ATB courses for PEx were administered to 65 CwCF during the study period. The drop in FEV 1 became significant 8 days before IV ATB initiation. Forty-one percent of IV ATB courses failed to restore baseline FEV 1 . The magnitude of FEV 1 drop and a greater delay in the initiation of treatment correlated with a low response level. On the 14th day of the IV treatment, a FEV 1 recovery less than 94% of baseline was associated with a nonresponder profile., Interpretation: Home spirometry may facilitate the early recognition of PEx to implement earlier interventions. This study also provides an outcome lung function threshold which identifies low responders to IV ATB., (© 2023 Wiley Periodicals LLC.)

Background: It is unclear whether sensitization patterns differentiate children with severe recurrent wheeze (SRW)/severe asthma (SA) from those with non-severe recurrent wheeze (NSRW)/non-severe asthma (NSA). Our objective was to determine whether sensitization patterns can discriminate between children from the French COBRAPed cohort with NSRW/NSA and those with SRW/SA., Methods: IgE to 112 components (c-sIgE) (ImmunoCAP® ISAC) were analyzed in 125 preschools (3-6 years) and 170 school-age children (7-12 years). Supervised analyses and clustering methods were applied to identify patterns of sensitization among children with positive c-sIgE., Results: We observed c-sIgE sensitization in 51% of preschool and 75% of school-age children. Sensitization to house dust mite (HDM) components was more frequent among NSRW than SRW (53% vs. 24%, p < .01). Sensitization to non-specific lipid transfer protein (nsLTP) components was more frequent among SA than NSA (16% vs. 4%, p < .01) and associated with an FEV1/FVC < -1.64 z-score. Among sensitized children, seven clusters with varying patterns were identified. The two broader clusters identified in each age group were characterized by "few sensitizations, mainly to HDM." One cluster (n = 4) with "multiple sensitizations, mainly to grass pollen, HDM, PR-10, and nsLTP" was associated with SA in school-age children., Conclusions: Although children with wheeze/asthma display frequent occurrences and high levels of sensitization, sensitization patterns did not provide strong signals to discriminate children with severe disease from those with milder disease. These results suggest that the severity of wheeze/asthma may depend on both IgE- and non-IgE-mediated mechanisms., (© 2024 The Authors. Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

The advent of CFTR modulators represents a turning point in the history of cystic fibrosis (CF) management, changing profoundly the disease's clinical course by improving mucosal hydration. Assessing changes in airway and digestive tract microbiomes is of great interest to better understand the mechanisms and to predict disease evolution. Bacterial and fungal dysbiosis have been well documented in patients with CF; yet the impact of CFTR modulators on microbial communities has only been partially deciphered to date. In this review, we aim to summarize the current state of knowledge regarding the impact of CFTR modulators on both pulmonary and digestive microbiomes. Our analysis also covers the inter-organ connections between lung and gut communities, in order to highlight the gut-lung axis involvement in CF pathophysiology and its evolution in the era of novel modulators therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lussac-Sorton, Charpentier, Imbert, Lefranc, Bui, Fayon, Berger, Enaud and Delhaes.)

In vertebrates, the embryonic olfactory epithelium contains progenitors that will give rise to distinct classes of neurons, including olfactory sensory neurons (OSNs; involved in odor detection), vomeronasal sensory neurons (VSNs; responsible for pheromone sensing), and gonadotropin-releasing hormone (GnRH) neurons that control the hypothalamic-pituitary-gonadal axis. Currently, these three neuronal lineages are usually believed to emerge from uniform pools of progenitors. Here, we found that the homeodomain transcription factor Dbx1 is expressed by neurogenic progenitors in the developing and adult mouse olfactory epithelium. We demonstrate that Dbx1 itself is dispensable for neuronal fate specification and global organization of the olfactory sensory system. Using lineage tracing, we characterize the contribution of Dbx1 lineages to OSN, VSN, and GnRH neuron populations and reveal an unexpected degree of diversity. Furthermore, we demonstrate that Dbx1-expressing progenitors remain neurogenic in the absence of the proneural gene Ascl1. Our work therefore points to the existence of distinct neurogenic programs in Dbx1-derived and other olfactory lineages., (© 2023 Wiley Periodicals LLC.)

Respiratory syncytial virus (RSV) infection is the leading cause of infant hospitalizations and mortality. Lumicitabine, an oral nucleoside analog was studied for the treatment of RSV. The phase 1b and phase 2b studies reported here assessed the safety, pharmacokinetics, and pharmacodynamics of lumicitabine in infants/neonates hospitalized with RSV. In the phase 1b study, infants (≥1 to ≤12 months) and neonates (<28 days) received a single-ascending or multiple-ascending doses (single loading dose [LD] then 9 maintenance doses [MD] of lumicitabine, or placebo [3:1]). In the phase 2b study, infants/children (28 days to ≤36 months old) received lumicitabine 40/20 mg/kg, 60/40 mg/kg LD/MD twice-daily or placebo (1:1:1) for 5 days. Safety, pharmacokinetics, and efficacy parameters were assessed over 28 days. Lumicitabine was associated with a dose-related increase in the incidence and severity of reversible neutropenia. Plasma levels of ALS-008112, the active nucleoside analog, were dose-proportional with comparable mean exposure levels at the highest doses in both studies. There were no significant differences between the lumicitabine groups and placebo in reducing viral load, time to viral non-detectability, and symptom resolution. No emergent resistance-associated substitutions were observed at the RSV L-gene positions of interest. In summary, lumicitabine was associated with a dose-related increase in the incidence and severity of reversible neutropenia and failed to demonstrate antiviral activity in RSV-infected hospitalized infants. This contrasts with the findings of the previous RSV-A adult challenge study where significant antiviral activity was noted, without incidence of neutropenia. Trial registration ClinicalTrials.gov Identifier: NCT02202356 (phase 1b); NCT03333317 (phase 2b)., Competing Interests: Abbie Oey, Matthew McClure, Julian A. Symons, Sushmita Chanda, John Fry, Dymphy Huntjens, and James Witek are current or former employees of Janssen Research & Development and may own stock/stock options in Johnson & Johnson. Patrick Smith works for Certara, a consulting firm in integrated drug development and has directly consulted with a variety of not‐for‐profit global health organizations, biotechnology, and pharmaceutical companies and governments with an interest in medical countermeasures against respiratory virus infections. Kathia Luciani, Michael Fayon, Kulkanya Chokephaibulkit, Rattapon Uppala, Jolanta Bernatoniene, Kenji Furuno, and Thorsten Stanley have no potential conflicts of interest to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Oey et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Malnutrition is both a feature and major cause of morbidity in cystic fibrosis (CF). Therefore, nutritional management is an essential element of patient care. In 2016, an international guideline for nutritional management in patients with CF was published. In light of these recommendations, the aim of this study was to investigate the dietary intake of children with CF at the University Hospital of Bordeaux., Methods: We conducted a retrospective study at the Paediatric CF Centre of the University Hospital of Bordeaux. Patients aged 2-18 years with CF who completed a 3-day food diary at home between January 2015 and December 2020 were included., Results: A total of 130 patients, with a median age of 11.8 [interquartile range (IQR): 8.3; 13.4] years, were included. The median Z-score for BMI was -0.35 (IQR: -0.9; 0.2) and 20% of the patients had a Z -score for BMI < -1. Recommended total energy intakes were achieved in 53% of the patients, particularly those with nutritional support. Recommended protein intake was met in 28% of the cases, while fat and carbohydrate intakes were met in 54%. Vitamin and micronutrient levels were normal in 80% of the patients, with the exception of vitamin K, which was within the therapeutic range in only 42% of the cases., Conclusion: Recommended nutritional targets are difficult to achieve in patients with CF, and providing nutritional support during follow-up remains a challenge., Competing Interests: MG, PG, HC, JM, AC, LN, CT and TL report no conflict of interest. FB has received a research grant from AstraZeneca and reports personal fees and non-financial support from Novartis, Chiesi and AstraZeneca. LD and RE are the co-coordinators of the French national cohort “Lum Iva Biota”, which received grants from Vertex. RE also reports a grant from Biocodex, personal fees from Biocodex and Menarini, and non-financial supports from Pfizer, Vertex, MSD, Nutricia, Nestle, Abbvie, Mayoly Spindler, Gilead sciences, Hospira and Aptalis Pharma. MF has received a research and educational grant from Novartis, and reports personal fees as a speaker from GlaxoSmithKine. In addition, MF has 1 co-patent (N°; FR 19/14751: i.e., New in situ pulmonary treatment device in premature babies). SB has received fees for expertise and boards for Zambon and Vertex., (© 2023 Gaschignard, Beaufils, Gallet, Clouzeau, Menard, Costanzo, Nouard, Delhaes, Tetard, Lamireau, Fayon, Bui and Enaud.)

Background: Paediatric diffuse alveolar haemorrhage (DAH) is a rare heterogeneous condition with limited knowledge on clinical presentation, treatment and outcome., Methods: A retrospective, descriptive multicentre follow-up study initiated from the European network for translational research in children's and adult interstitial lung disease (Cost Action CA16125) and chILD-EU CRC (the European Research Collaboration for Children's Interstitial Lung Disease). Inclusion criteria were DAH of any cause diagnosed before the age of 18 years., Results: Data of 124 patients from 26 centres (15 counties) were submitted, of whom 117 patients fulfilled the inclusion criteria. Diagnoses were idiopathic pulmonary haemosiderosis (n=35), DAH associated with autoimmune features (n=20), systemic and collagen disorders (n=18), immuno-allergic conditions (n=10), other childhood interstitial lung diseases (chILD) (n=5), autoinflammatory diseases (n=3), DAH secondary to other conditions (n=21) and nonspecified DAH (n=5). Median (IQR) age at onset was 5 (2.0-12.9) years. Most frequent clinical presentations were anaemia (87%), haemoptysis (42%), dyspnoea (35%) and cough (32%). Respiratory symptoms were absent in 23%. The most frequent medical treatment was systemic corticosteroids (93%), hydroxychloroquine (35%) and azathioprine (27%). Overall mortality was 13%. Long-term data demonstrated persistent abnormal radiology and a limited improvement in lung function., Conclusions: Paediatric DAH is highly heterogeneous regarding underlying causes and clinical presentation. The high mortality rate and number of patients with ongoing treatment years after onset of disease underline that DAH is a severe and often chronic condition. This large international study paves the way for further prospective clinical trials that will in the long term allow evidence-based treatment and follow-up recommendations to be determined., Competing Interests: Conflicts of interest: T. Bandeira reports personal fees from Sanofi and other support from Boehringer Ingelheim, outside the submitted work. Conflicts of interest: E.D. Manali reports other from Boehringer Ingelheim, other from Bering, other from Hoffman la Roche, outside the submitted work. Conflicts of interest: S. Papiris reports grants and other support from Boehringer Ingelheim and Hoffman la Roche, and other support from Savara, outside the submitted work. Conflicts of interest: M. Griese reports grants, personal fees and nonfinancial support from Boehringer Ingelheim for an advisory board on nintedanib, outside the submitted work. Conflicts of interest: The remaining authors have nothing to disclose., (Copyright ©The authors 2023.)

Background: Nutritional status is a major prognostic factor for breathing and the survival of patients with cystic fibrosis (CF). Since 2012, the development of CFTR modulators has considerably transformed the outcome of this disease. Indeed, both lung function and body mass index are improved by CFTR modulators, such as Lumacaftor/Ivacaftor. However, few data exist regarding the outcome of nutritional intakes under Lumacaftor/Ivacaftor., Methods: We conducted a prospective single-center study in children with CF treated with Lumacaftor/Ivacaftor to evaluate their nutritional intake before and after treatment., Results: Thirty-four children were included in this study, with a median age of 12.4 years [11.9; 14.7]. There was no significant improvement in weight, height or BMI. Patients' total energy intake was not significantly changed with Lumacaftor/Ivacaftor, while carbohydrate intakes decreased significantly. We found that blood levels of vitamin E and Selenium were significantly increased under Lumacaftor/Ivacaftor, without a significant increase in supplementation. In patients with a BMI Z-score < 0 at treatment initiation, there was a significant improvement in weight and BMI Z-score, while TEI and carbohydrate intakes were significantly lower., Conclusion: We showed that treatment with Lumacaftor/Ivacaftor improved the nutritional status of patients without necessarily being associated with an increase in nutritional intake. Although these data need to be confirmed in larger cohorts, they support the hypothesis that weight gain under modulators is multifactorial, and may be related to a decrease in energy expenditure or an improvement in absorption., Competing Interests: MG, FLS, PG, HC, JM, AC, LN, CT and TL report no conflict of interest. FB has received a research grant from AstraZeneca and reports personal fees and non-financial support from Novartis, Chiesi and AstraZeneca. LD and RE are the co-coordinators of the French national cohort “Lum Iva Biota”, which received grants from Vertex. RE also reports a grant from Biocodex, personal fees from Biocodex and Menarini, and non-financial supports from Pfizer, Vertex, MSD, Nutricia, Nestle, Abbvie, Mayoly Spindler, Gilead sciences, Hospira and Aptalis Pharma. MF has received a research and educational grant from Novartis, and reports personal fees as a speaker from GlaxoSmithKine. In addition, MF has 1 co-patent (N° 176; FR 19/14751: i.e., New in situ pulmonary treatment device in premature babies). SB has received fees for expertise and boards for Zambon and Vertex., (© 2023 Gaschignard, Beaufils, Lussac-Sorton, Gallet, Clouzeau, Menard, Costanzo, Nouard, Delhaes, Tetard, Lamireau, Fayon, Bui and Enaud.)

Lumacaftor-ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination approved for patients with cystic fibrosis (CF) who are homozygous for the F508del allele. This treatment showed significant clinical improvement; however, few studies have addressed the evolution of the airway microbiota-mycobiota and inflammation in patients receiving lumacaftor-ivacaftor treatment. Seventy-five patients with CF aged 12 years or older were enrolled at the initiation of lumacaftor-ivacaftor therapy. Among them, 41 had spontaneously produced sputa collected before and 6 months after treatment initiation. Airway microbiota and mycobiota analyses were performed via high-throughput sequencing. Airway inflammation was assessed by measuring the calprotectin levels in sputum; the microbial biomass was evaluated via quantitative PCR (qPCR). At baseline ( n  = 75), bacterial alpha-diversity was correlated with pulmonary function. After 6 months of lumacaftor-ivacaftor treatment, a significant improvement in the body mass index and a decreased number of intravenous antibiotic courses were noted. No significant changes in bacterial and fungal alpha- and beta-diversities, pathogen abundances, or calprotectin levels were observed. However, for patients not chronically colonized with Pseudomonas aeruginosa at treatment initiation, calprotectin levels were lower, and a significant increase in bacterial alpha-diversity was observed at 6 months. This study shows that the evolution of the airway microbiota-mycobiota in CF patients depends on the patient's characteristics at lumacaftor-ivacaftor treatment initiation, notably chronic colonization with P. aeruginosa. IMPORTANCE The management of cystic fibrosis has been transformed recently by the advent of CFTR modulators, including lumacaftor-ivacaftor. However, the effects of such therapies on the airway ecosystem, particularly on the microbiota-mycobiota and local inflammation, which are involved in the evolution of pulmonary damage, are unclear. This multicenter study of the evolution of the microbiota under protein therapy supports the notion that CFTR modulators should be started as soon as possible, ideally before the patient is chronically colonized with P. aeruginosa. (This study has been registered at ClinicalTrials.gov under identifier NCT03565692).

Introduction: Forced spirometry is the gold standard to assess lung function, but its accessibility may be limited. By contrast, home spirometry telemonitoring allows a multi-weekly lung function follow-up but its real-life adherence, reliability, and variability according to age have been poorly studied in patients with CF (PwCF). We aimed to compare real-life adherence, reliability and variability of home spirometry between children, teenagers and adults with CF., Methods: This real-life observational study included PwCF followed for six months in whom lung function ( i.e , forced expiratory volume maximum in 1 s (FEV1), forced vital capacity (FVC), forced mid-expiratory flow (FEF) and FEV1/FVC ratio) was monitored by both conventional and home spirometry between July 2015 and December 2021. The adherence, reliability and variability of home spirometry was assessed in all PwCF and compared between children (<12years old), teenagers (12-18 years old) and adults., Results: 174 PwCF were included (74 children, 43 teenagers and 57 adults). Home spirometry was used at least one time per week by 64.1 ± 4.9% PwCF, more frequently in children and teenagers than in adults (79.4 ± 2.9%, 69.2 ± 5.5% and 40.4 ± 11.5% respectively). The reliability to conventional lung function testing was good for all assessed parameters ( e.g. , FEV1: r = 0.91, p  < 0.01) and the variability over the 6 months of observation was low (FEV1 coefficient of variation = 11.5%). For each parameter, reliability was better, and the variability was lower in adults than in teenagers than in children., Conclusion: Home spirometry telemonitoring appears to be a reliable tool for multi-weekly lung function follow-up of PwCF., Competing Interests: FB has received a research grant from AstraZeneca and reports personal fees and non-financial support from Novartis, Chiesi and AstraZeneca. RE is the co-coordinator of the French national cohort “Lum Iva Biota”, which received grants from Vertex. RE also reports a grant from Biocodex, personal fees from Biocodex and Menarini, and non-financial supports from Pfizer, Vertex, MSD, Nutricia, Nestle, Abbvie, Mayoly Spindler, Gilead sciences, Hospira and Aptalis Pharma. FG, GB and JM report no conflict of interest. PB is the medical coordinator of the French national cohort (i.e., COBRA), which received grants from AstraZeneca, GlaxoSmithKine, Roche, Chiesi, Novartis and Legs Poix fundation. Moreover, PB reports grants and personal fees from Novartis, personal fees and non-financial support from Chiesi, grants, personal fees and non-financial support from Boehringer Ingelheim, personal fees and non-financial support from AstraZeneca, personal fees and non-financial support from Sanofi, personal fees from Menarini, personal fees from TEVA, outside the submitted work; In addition, PB has 3 patents (i) (EP N&#176;15152886.6 i.e., New compositions and methods of treating and/or preventing Chronic Obstructive Pulmonary Disease), pending; (ii) (EP N&#176;3050574 i.e., Use of plerixafor for treating and/or preventing acute exacerbations of chronic obstructive pulmonary disease), delivered; (iii) (EP N&#176;20173595.8 i.e., New compositions and methods of treating COVID-19 Disease), pending. MF has received a research and educational grant from Novartis, and reports personal fees as a speaker from GlaxoSmithKine. In addition, MF has 1 co-patent (N&#176; FR 19/14751: i.e., New in situ pulmonary treatment device in premature babies). SB has received fees for expertise and boards for Zambon and Vertex., (© 2023 Beaufils, Enaud, Gallode, Boucher, Macey, Berger, Fayon and Bui.)

Rationale: Children with preschool wheezing represent a very heterogeneous population with wide variability regarding their clinical, inflammatory, obstructive, and/or remodeling patterns. We hypothesized that assessing bronchial remodeling would help clinicians to better characterize severe preschool wheezers. Objectives: The main objective was to identify bronchial remodeling-based latent classes of severe preschool wheezers. Secondary objectives were to compare cross-sectional and longitudinal clinical and biological data between classes and to assess the safety of bronchoscopy. Methods: This double-center prospective study (NCT02806466) included severe preschool wheezers (1-5 yr old) requiring fiberoptic bronchoscopy. Bronchial remodeling parameters (i.e., epithelial integrity, reticular basement membrane [RBM] thickness, mucus gland, fibrosis and bronchial smooth muscle [BSM] areas, the density of blood vessels, and RBM-BSM distance) were assessed and evaluated by latent class analysis. An independent cohort of severe preschool wheezers (NCT04558671) was used to validate our results. Measurements and Main Results: Fiberoptic bronchoscopy procedures were well tolerated. A two-class model was identified: Class BR1 was characterized by increased RBM thickness, normalized BSM area, the density of blood vessels, decreased mucus gland area, fibrosis, and RBM-BSM distance compared with Class BR2. No significant differences were found between classes in the year before fiberoptic bronchoscopy. By contrast, Class BR1 was associated with a shorter time to first exacerbation and an increased risk of both frequent (3 or more) and severe exacerbations during the year after bronchoscopy in the two cohorts. Conclusions: Assessing bronchial remodeling identified severe preschool wheezers at risk of frequent and severe subsequent exacerbations with a favorable benefit to risk ratio.

Rationale: Sputum biomarkers hold promise as a direct measure of inflammation within the cystic fibrosis (CF) lung, but variability in study design and sampling methodology have limited their use. A full evaluation of the reliability, validity and clinical relevance of individual biomarkers is required to optimise their use within CF clinical research., Objectives: A biomarker Special Interest Working Group was established within the European Cystic Fibrosis Society-Clinical Trials Network Standardisation Committee, to perform a review of the evidence regarding sputum biomarkers in CF., Methods: From the 139 included articles, we identified 71 sputum biomarkers to undergo evaluation of their clinimetric properties, responsiveness, discriminant, concurrent and convergent validity., Results: Current evidence confirms the potential of sputum biomarkers as outcome measures in clinical trials. Inconsistency in responsiveness, concurrent and convergent validity require further research into these markers and processing standardisation before translation into wider use. Of the 71 biomarkers identified, Neutrophil Elastase (NE), IL-8, TNF-α and IL-1β, demonstrated validity and responsiveness to be currently considered for use in clinical trials. Other biomarkers show future promise, including IL-6, calprotectin, HMGB-1 and YKL-40., Conclusion: A concerted international effort across the cystic fibrosis community is needed to promote high quality biomarker trial design, establish large population-based biomarker studies, and work together to create standards for collection, storage and analysis of sputum biomarkers., Competing Interests: Conflict of Interest Statement AL, KH, LD, MF, OE, TL, CL, & DGD have no conflicts of interest to declare; CA has received honoraria from Gilead & is Member of the British Thoracic Society Board; P-RB has received grants from Vertex and GSK and consulting fees from Astra-Zeneca, Boehringer Ingelheim, Chiese, Insmed, Novartis, Pfizer, Teva, Vertex and Zambon; SN is currently an employee of Vertex Pharmaceuticals Inc. and, as such, may own stock or stock options in that company, the submitted work was performed by SN whilst a research fellow at the French Institute for Health and Medical Research (INSERM, Paris, France) and had no affiliation with any organization with a direct or indirect financial interest in the subject matter discussed in the manuscript; SB has received consulting fees from Vertex and Zambon; IS has received grant and consulting fees from Vertex pharmaceuticals., (Copyright © 2021 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Chimeric antigen receptor T cells (CAR-T) have provided promising results in multiple myeloma (MM). However, many patients still relapse, pointing toward the need of improving this therapy. Here, we analyzed peripheral blood T cells from MM patients at different stages of the disease and investigated their phenotype and capacity to generate functional CAR-T directed against CS1 or B Cell Maturation antigen. We found a decrease in naive T cells and elevated frequencies of exhaustion markers in T cells from treated MM patients. Interestingly, individuals treated with daratumumab display elevated ratios of central memory T cells. CAR-T derived from patients at relapse show reduced in vitro expansion and cytotoxic capacities in response to MM cells compared to those produced at diagnosis. Of note, CAR-T from daratumumab treated patients display intermediate defects. Reduced anti-myeloma activity of CAR T cells from treated patients was also observed in a mouse model. Our findings suggest that T cell defects in MM patients, specifically during relapse, have a major impact on their capacity to generate efficient therapeutic CAR-T. Selecting naive or central memory T cell subsets to generate therapeutic T cells could improve the CAR-T therapy for MM., Competing Interests: The authors declare no competing financial interests and have no conflict of interest to disclose., (© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: The ability to perceive bronchial obstruction is variable in asthma. This is one of the main causes of inaccurate asthma control assessment, on which therapeutic strategies are based. Objective: Primary: To evaluate the ability of physicians to characterize the bronchial obstruction perception profile in asthmatic children using a clinical and spiro-metric telemonitoring device. Secondary: To evaluate its impact on asthma management (control, treatment, respiratory function variability) and the acceptability of this telemonitoring system. Methods: 26 asthmatic children aged 6−18 years equipped with a portable spirometer and a smartphone application were home-monitored remotely for 3 months. Clinical and spiro-metric data were automatically transmitted to a secure internet platform. By analyzing these data, three physicians blindly and independently classified the patients according to their perception profile. The impact of telemonitoring on the quantitative data was assessed at the beginning (T0) and end (T3 months) of telemonitoring, using matched statistical tests. Results: Patients could initially be classified according to their perception profile, with a concordance between the three observers of 64% (kappa coefficient: 0.55, 95%CI [0.39; 0.71]). After discussion among the observers, consensus was reached for all patients but one. There was a significant >40% decrease in FEV1 and PEF variability, with good acceptance of the device. Conclusions: Clinical and spiro-metric tele-home monitoring is applicable and can help define the perception profile of bronchial obstruction in asthmatic children. The device was generally well accepted.

Background: Many patients with cystic fibrosis (CF) wheeze, and are dubbed as having CF-asthma. Understanding the determinants of such wheezing may avoid unnecessary treatments and open newer treatment avenues., Objectives: Main: To evaluate the prevalence and characteristics of wheezing and a positive bronchodilatory response (BDR) in children with CF. Secondary: To identify the predictive markers and the impact of current wheezing a positive BDR., Methods: A retrospective single-center study in children with CF. We determined the characteristics of physician-reported wheeze in patients <6 years, and a BDR in patients aged 6-17 years. Anthropometric, lung function, laboratory, genetic and microbiological data were recorded in all groups. Variables were compared using the Chi 2 and Student t -tests, and ANOVA., Results: 125 preschool and 69 school-aged children and adolescents with CF were included in the study. 71.2% of patients <6 years of age had had at least one episode of wheezing: 26.3% of patients were Transient Early Wheezers, 12.6% Late Onset Wheezers and 37.9% were Persistent Wheezers. The prevalence of a positive BDR was 73.5, 48.5, and 52.9% in the 6-8 years, 10-12 years, and 15-17 years age groups, respectively. Allergic factors were not predictive of wheezing in preschoolers. In the 6-8 years age group, the sum of wheal diameters of allergic skin prick tests (SPT, house dust mite + cat + dog dander) was greater in those with a BDR vs. no BDR (4 [2.0-8.8] vs. 1 [0-7.0] mm, p = 0.01). The presence of Pseudomonas aeruginosa in the bronchial secretions before 3 years of age was not significantly associated with either the presence of wheezing at the age of 6 years or a BDR in school-aged children and adolescents. The proportion of homozygous p.F508del patients was significantly lower in the group of patients who had wheezed by 6 years of age (60% vs. 72.7%, p = 0.009), but higher in the 6-8 years old group with a BDR vs. no BDR (64% vs. 36%, p = 0.04). Current wheezers at 6 years had a lower mean FEV 1 vs. the non-current wheezers (91.5 ± 4.4% vs. 100.9 ± 2.4%; p = 0.047). Similarly, forced vital capacity (FVC) was significantly lower in the 6-8 years old group with BDR vs. no BDR (85 ± 19 vs. 101 ± 21%, p = 0.015)., Conclusion: Wheezing and BDR are very frequent findings in children with CF. Current wheeze at the age of 6 years was associated with worse lung function. Labeling wheezing in CF as "CF-Asthma" is misleading since the determinants are different, and may lead to inappropriate prescriptions of inhaled steroids., Competing Interests: MF is affiliated (but not employed) by the INSERM, CIC 1401. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Galodé, Ladipo, Andrieux, Feghali, Bui and Fayon.)

Background: Noninvasive assessments of liver fibrosis are currently used to evaluate cystic fibrosis (CF)-related liver disease. However, there is scarce data regarding their repeatability and reproducibility, especially in children with CF. The present study aimed to evaluate the repeatability and reproducibility of transient elastography (TE) (FibroScan®) and point shear-wave elastography using virtual touch quantification (pSWE VTQ) in children with CF., Methods: TE and pSWE VTQ were performed in 56 children with CF by two different operators. Analysis of repeatability and reproducibility was available in 33 patients for TE and 46 patients for pSWE VTQ. Intra- and interobserver agreement were assessed using the intraclass correlation coefficient (ICC) and their 95% confidence interval (CI), and Bland and Altman graphs., Results: For TE, ICC was 0.91 (0.83-0.95) for intraobserver agreement and 0.92 (95% CI: 0.86-0.96) for interobserver agreement. For pSWE VTQ, ICC was 0.83 (0.72-0.90) for intraobserver agreement and 0.67 (0.48-0.80) for interobserver agreement., Conclusions: Both technics can be proposed in the follow-up of patients, according to their availability in CF centers., Impact: This study shows that TE and pSWE VTQ are reliable methods to evaluate liver fibrosis in children with CF. This study shows for the first time that TE and pSWE VTQ are both repeatable and reproducible in children with CF. These data indicate that both TE and pSWE VTQ can be proposed for the follow-up of patients with CF, according to their availability in each CF center., (© 2021. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: The combination of the CFTR corrector lumacaftor (LUM) and potentiator ivacaftor (IVA) has been labeled in France since 2015 for F508del homozygote cystic fibrosis (CF) patients over 12 years. In this real-life study, we aimed (i) to compare the changes in lung function, clinical (e.g., body mass index and pulmonary exacerbations) and radiological parameters, and in sweat chloride concentration before and after initiation of LUM/IVA treatment; (ii) to identify factors associated with response to treatment; and (iii) to assess the tolerance to treatment. Materials and Methods: In this tri-center, non-interventional, and observational cohort study, children (12-18 years old) were assessed prospectively during the 2 years of therapy, and retrospectively during the 2 years preceding treatment. Data collected and analyzed for the study were exclusively extracted from the medical electronic system records of the patients. Results: Forty adolescents aged 12.0-17.4 years at LUM/IVA initiation were included. The lung function decreased significantly during and prior to treatment and increased after LUM/IVA initiation, becoming significant after 2 years of treatment. LUM/IVA significantly improved the BMI Z -score and sweat chloride concentration. By contrast, there was no significant change in exacerbation rates, antibiotic use, or CT scan scores. Age at LUM/IVA initiation was lower in good responders and associated with greater ppFEV1 change during the 2 years of treatment. LUM/IVA was well-tolerated. Conclusion: In F508del homozygote adolescents, real-life long-term LUM/IVA improved the ppFEV1 trajectory, particularly in the youngest patients, nutritional status, and sweat chloride concentration but not exacerbation rates or radiological scores. LUM/IVA was generally well-tolerated and safe., Competing Interests: SB, FG, CC, RE, FB, and MF conducted clinical trials with Vertex pharmacological agents, on behalf of the European Cystic Fibrosis Society-Clinical Trials Network (ECFS-CTN) and within the scope of ECFS-CTN activities. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bui, Masson, Enaud, Roditis, Dournes, Galode, Collet, Mas, Languepin, Fayon, Beaufils and Mittaine.)