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Abstract Background Interstitial lung diseases (ILDs) in children represent a heterogeneous group of rare respiratory disorders that affect the lung parenchyma. After the launch of the French Reference Centre for Rare Lung Diseases (RespiRare®), we created a national network and a web-linked database to collect data on pediatric ILD. Methods Since 2008, the database has been set up in all RespiRare® centres. After patient's parents' oral consent is obtained, physicians enter the data of children with ILD: identity, social data and environmental data; specific aetiological diagnosis of the ILD if known, genetics, patient visits to the centre, and all medical examinations and tests done for the diagnosis and/or during follow up. Each participating centre has a free access to his own patients' data only, and cross-centre studies require mutual agreement. Physicians may use the system as a daily aid for patient care through a web-linked medical file, backed on this database. Results Data was collected for 205 cases of ILD. The M/F sex ratio was 0.9. Median age at diagnosis was 1.5 years old [0–16.9]. A specific aetiology was identified in 149 (72.7%) patients while 56 (27.3%) cases remain undiagnosed. Surfactant deficiencies and alveolar proteinosis, haemosiderosis, and sarcoidosis represent almost half of the diagnoses. Median length of follow-up is 2.9 years [0–17.2]. Conclusions We introduce here the French network and the largest national database in pediatric ILDs. The diagnosis spectrum and the estimated incidence are consistent with other European databases. An important challenge will be to reduce the proportion of unclassified ILDs by a standardized diagnosis work-up. This database is a great opportunity to improve patient care and disease pathogenesis knowledge. A European network including physicians and European foundations is now emerging with the initial aim of devising a simplified European database/register as a first step to larger European studies.

Abstract Interstitial lung disease (ILD) in infants and children comprises a large spectrum of rare respiratory disorders that are mostly chronic and associated with high morbidity and mortality. These disorders are characterized by inflammatory and fibrotic changes that affect alveolar walls. Typical features of ILD include dyspnea, diffuse infiltrates on chest radiographs, and abnormal pulmonary function tests with restrictive ventilatory defect and/or impaired gas exchange. Many pathological situations can impair gas exchange and, therefore, may contribute to progressive lung damage and ILD. Consequently, diagnosis approach needs to be structured with a clinical evaluation requiring a careful history paying attention to exposures and systemic diseases. Several classifications for ILD have been proposed but none is entirely satisfactory especially in children. The present article reviews current concepts of pathophysiological mechanisms, etiology and diagnostic approaches, as well as therapeutic strategies. The following diagnostic grouping is used to discuss the various causes of pediatric ILD: 1) exposure-related ILD; 2) systemic disease-associated ILD; 3) alveolar structure disorder-associated ILD; and 4) ILD specific to infancy. Therapeutic options include mainly anti-inflammatory, immunosuppressive, and/or anti-fibrotic drugs. The outcome is highly variable with a mortality rate around 15%. An overall favorable response to corticosteroid therapy is observed in around 50% of cases, often associated with sequelae such as limited exercise tolerance or the need for long-term oxygen therapy.

Abstract Objective To document the epidemiological, clinical, histological and radiological characteristics of aggressive vascular abnormalities of bone in children. Study design Correspondents of the French Society of Childhood Malignancies were asked to notify all cases of aggressive vascular abnormalities of bone diagnosed between January 1988 and September 2009. Results 21 cases were identified; 62% of the patients were boys. No familial cases were observed, and the disease appeared to be sporadic. Mean age at diagnosis was 8.0 years [0.8-16.9 years]. Median follow-up was 3 years [0.3-17 years]. The main presenting signs were bone fracture (n = 4) and respiratory distress (n = 7), but more indolent onset was observed in 8 cases. Lung involvement, with lymphangiectasies and pleural effusion, was the most frequent form of extraosseous involvement (10/21). Bisphosphonates, alpha interferon and radiotherapy were used as potentially curative treatments. High-dose radiotherapy appeared to be effective on pleural effusion but caused major late sequelae, whereas antiangiogenic drugs like alpha interferon and zoledrenate have had a limited impact on the course of pulmonary complications. The impact of bisphosphonates and alpha interferon on bone lesions was also difficult to assess, owing to insufficient follow-up in most cases, but it was occasionally positive. Six deaths were observed and the overall 10-year mortality rate was about 30%. The prognosis depended mainly on pulmonary and spinal complications. Conclusion Aggressive vascular abnormalities of bone are extremely rare in childhood but are lifethreatening. The impact of anti-angiogenic drugs on pulmonary complications seems to be limited, but they may improve bone lesions.

Abstract Background Cellular responses to aging and oxidative stress are regulated by type 1 insulin-like growth factor receptor (IGF-1R). Oxidant injury, which is implicated in the pathophysiology of a number of respiratory diseases, acutely upregulates IGF-1R expression in the lung. This led us to suspect that reduction of IGF-1R levels in lung tissue could prevent deleterious effects of oxygen exposure. Methods Since IGF-1R null mutant mice die at birth from respiratory failure, we generated compound heterozygous mice harboring a hypomorphic (Igf-1rneo) and a knockout (Igf-1r-) receptor allele. These IGF-1Rneo/- mice, strongly deficient in IGF-1R, were subjected to hyperoxia and analyzed for survival time, ventilatory control, pulmonary histopathology, morphometry, lung edema and vascular permeability. Results Strikingly, after 72 h of exposure to 90% O2, IGF-1Rneo/- mice had a significantly better survival rate during recovery than IGF-1R+/+ mice (77% versus 53%, P < 0.05). The pulmonary injury was consistently, and significantly, milder in IGF-1Rneo/- mice which developed conspicuously less edema and vascular extravasation than controls. Also, hyperoxia-induced abnormal pattern of breathing which precipitated respiratory failure was elicited less frequently in the IGF-1Rneo/- mice. Conclusion Together, these data demonstrate that a decrease in IGF-1R signaling in mice protects against oxidant-induced lung injury.

Uncertainty remains regarding the effects of outdoor air pollution in rural areas on childhood asthma, rhinitis, and eczema. Although these diseases often coexist, few studies have examined the effects of air pollution on their multimorbidity. The objective of this study was to investigate the associations of pregnancy exposure to outdoor fine particulate matter (PM 2.5 ) and nitrogen dioxide (NO 2 ) with childhood asthma, rhinitis, eczema, and their multimorbidity. We included children from the 6-year (n = 1322) and 12-year (n = 1118) follow-up of the Pélagie mother-child cohort in Brittany, France where 64% of the participants lived in rural areas. Asthma, rhinitis, eczema, and a multimorbidity phenotype (concomitant presence of ≥2 diseases) were defined by validated questionnaires. PM 2.5 and NO 2 concentrations during pregnancy were modeled at residential address using land use regression. We assessed associations using logistic regressions per interquartile range (PM 2.5 : 3 μg/m 3 ; NO 2 : 10 μg/m 3 ). We also performed stratification by type of area (urban and rural). Asthma, rhinitis, eczema, and the multimorbidity phenotype prevalence were 12%, 20%, 22% and 12% at 6-years, and 10%, 23%, 19% and 11% at 12-years of follow-up. At 6-years, for eczema, a tendency of an association was observed with NO 2 (OR = 1.15, 95% CI = 0.97-1.36, p-value = 0.10), and stratification by type of area showed statistically significant associations for PM 2.5 (1.49 (1.03-2.13), p = 0.03) and NO 2 (1.40 (1.08-1.82), p = 0.01) in the urban stratum. At 12-years, main analyses showed a tendency of associations of PM 2.5 (1.38 (0.98-1.93), p = 0.07) and NO 2 (1.25 (0.98-1.59), p = 0.07) with asthma, and of NO 2 with the multimorbidity phenotype (1.23 (0.97-1.56), p = 0.09). While overall results were not statistically significant, associations in urban settings were stronger than in rural ones at 6-years suggesting that possible differences between the effects in urban and rural areas should be further explored., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To assess the feasibility and effectiveness of a pediatric asthma education program delivered in the context of a French suburban general hospital., Design: Monocentric retrospective study including children with asthma in Melun, Île-de-France, from January to December 2019. Data collected concerned asthma management, symptoms, education, and knowledge., Results: We included 262 patients with a median age of 4.5 years. Asthma education (AE) was taught to 226 (86 %) children, 36 with minimal education (ME), 155 (69 %) with an unstructured asthma education program (USEP) and 71 (31 %) a structured asthma education program (SEP). Patients with an SEP had better knowledge of the disease and its treatment as compared with those with a USEP or ME (p < 0.05). Lung function was evaluated for 70 % of children with ME, 90 % with a USEP (p = 0.144) and 77 % an SEP (p = 0.455). Allergy testing was assessed for 42 % of children with ME, 69 % a USEP (p = 0.020) and 57 % an SEP (p = 0.185). Almost all children with USEP (93 %) and SEP (94 %) also had a written asthma action plan as compared with 49 % of the children with ME (p < 0.001). Also, 76 % of children with ME did not have an asthma follow-up as compared with 37 % with a USEP and 52 % an SEP. Overall, 69 % of children with ME had at least one hospitalization within the year as compared with 32 % with a USEP (p = 0.001) and 59 % an SEP (p = 0.506)., Conclusions: An asthma education program delivered in a general hospital resulted in increased disease knowledge for children and their caregivers, together with reduced acute interventions., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Epaud reports a relationship with 10.13039/501100014088AstraZeneca Pharmaceuticals LP that includes: board membership, speaking and lecture fees, and travel reimbursement. Epaud reports a relationship with 10.13039/100031283Sanofi that includes: board membership and speaking and lecture fees. Epaud reports a relationship with GSK that includes: board membership, speaking and lecture fees, and travel reimbursement. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Even in the absence of liver disease, MARS1 screening should be considered in severe lung fibrosis of young individuals. Interpretation of the genetic variants can evolve with improvement of knowledge (databases, bioinformatic tools) over time. https://bit.ly/45OxF5E., Competing Interests: Conflict of interest: V. Cottin reports grants or contracts from Boehringer Ingelheim, outside the submitted work, consulting fees from AstraZeneca, Boehringer Ingelheim, Celgene/BMS, CSL Behring, Ferrer/United Therapeutics, GSK, Pliant, Pure Tech, RedX, Roche, Sanofi and Shionogi, outside the submitted work, fees for lectures and consulting from Boehringer Ingelheim, Ferrer/United Therapeutics and Roche, outside the submitted work, support for attending meetings from Boehringer Ingelheim, outside the submitted work, participation on a data and safety monitoring board for Galapagos, Galecto and GSK, outside the submitted work, and participation on an adjudication committee for Fibrogen, outside the submitted work. R. Epaud reports consulting fees from AstraZeneca, outside the submitted work, fees for lectures and consulting from AstraZeneca and GSK, fees for lectures from Chiesi, outside the submitted work, and support for attending meetings from AstraZeneca and GSK, outside the submitted work. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2023.)

Background: The MELODY system allows for performing ultrasonography on a patient remotely and has been proposed to assess disease characteristics in the context of the coronavirus disease 2019 (COVID-19) pandemic. The aim of this interventional crossover study was to address the feasibility of the system in children aged 1 to 10 years old., Methods: Children underwent ultrasonography with a telerobotic ultrasound system followed by a second conventional examination by a different sonographer., Results: In total, 38 children were enrolled, and 76 examinations were performed, with 76 scans analyzed. The mean [standard deviation (SD)] age of participants was 5.7 (2.7) years (range, 1-10 years). We found substantial agreement between telerobotic and conventional ultrasonography [κ=0.74 (95% CI: 0.53-0.94), P<0.005]. The mean (SD) duration was longer for telerobotic than conventional examinations [26.0 (2.5) vs. 13.9 (11.2) min, P<0.0001]. Abdominal organs and abnormalities were similarly visualized on telerobotic and conventional ultrasonography. Cardiac echocardiography provided reliable diagnoses, with non-significantly different measurements with both techniques, although the visualization score was significantly higher with conventional than telerobotic ultrasonography (P<0.05). On lung analysis, both examinations identified consolidations and pleural effusion, whereas visualization and total lung score were similar with the 2 techniques. Overall, 45% of parents reported that their children felt less pressure with the telerobotic system., Conclusions: Telerobotic ultrasonography may be effective, feasible, and well-tolerated in children., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-22-569/coif). The authors have no conflicts of interest to declare., (2023 Translational Pediatrics. All rights reserved.)

Childhood interstitial lung diseases (chILDs) are rare and heterogeneous diseases with significant morbidity and mortality. An accurate and quick aetiological diagnosis may contribute to better management and personalised treatment. On behalf of the European Respiratory Society Clinical Research Collaboration for chILD (ERS CRC chILD-EU), this review summarises the roles of the general paediatrician, paediatric pulmonologists and expert centres in the complex diagnostic workup. Each patient's aetiological chILD diagnosis must be reached without prolonged delays in a stepwise approach from medical history, signs, symptoms, clinical tests and imaging, to advanced genetic analysis and specialised procedures including bronchoalveolar lavage and biopsy, if necessary. Finally, as medical progress is fast, the need to revisit a diagnosis of "undefined chILD" is stressed., Competing Interests: Conflict of interest: None declared., (Copyright ©The authors 2023.)

Background: to perform a functional analysis of a new NK2 homeobox 1 (NKX2-1) variant (c.85&#95;86del denominated NKX2-1 DEL ) identified in a family presenting with isolated respiratory disease, in comparison to another frameshift variant (c.254dup denominated NKX2-1 DUP ) identified in a subject with classical brain-lung-thyroid syndrome., Methods: pathogenic variants were introduced into the pcDNA3-1(+)-wt-TTF1 plasmid. The proteins obtained were analyzed by western blot assay. Subcellular localization was assessed by confocal microscopy in A549 and Nthy cells. Transactivation of SFTPA , SFTPB , SFTPC , and ABCA3 promoters was assessed in A549 cells. Thyroglobulin promoter activity was measured with the paired box gene 8 (PAX8) cofactor in Nthy cells., Results: The two sequence variants were predicted to produce aberrant proteins identical from the 86th amino acid, with deletion of their functional homeodomain, including the nuclear localization signal. However, 3D conformation prediction of the conformation prediction of the mutant protein assumed the presence of a nuclear localization signal, a bipartite sequence, confirmed by confocal microscopy showing both mutant proteins localized in the nucleus and cytoplasm. Transcriptional activity with SFTPA, SFTPB, SFTPC, ABCA3 and thyroglobulin promoters was significantly decreased with both variants. However, with NKX2-1 DEL , thyroglobulin transcriptional activity was maintained with the addition of PAX8., Conclusion: These results provide novel insights into understanding the molecular mechanism of phenotypes associated with NKX2-1 pathogenic variants., 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., (© 2023 Delestrain, Aissat, Nattes, Gibertini, Lacroze, Simon, Decrouy, de Becdelièvre, Fanen and Epaud.)

Background: Most of the studies on cystic fibrosis (CF) focused on SARS-CoV-2 prevalence and suggested a low incidence of infection in this population. We aimed to assess the impact of the pandemic and related lockdown measures implemented in May 2020 in response to the first wave of SARS-CoV-2 infection on healthcare access, health, and behavior in CF patients., Methods: A national questionnaire opened online from May 15th, 2020 to June 11 th , 2020 was completed by 751 CF-patients, aged 14 years and over. It comprised questions about access to healthcare, anxiety and depression, smoking, alcohol, drug and psychotropic drug consumption, adherence to CF treatment, and constraints. A semi-structured comprehensive interview was performed no later than 1 month after the end of the lockdown in 16 CF-patients., Results: The mean age of the population was 28.0 [interquartile range (IQR) 20.0-37.0] years old. More than 75% of in-person consultations scheduled during the lockdown were canceled. Alternatively, 27% were postponed, and telehealth consultations were proposed and accepted in almost 40% of cases. More than 75% of the scheduled physiotherapy sessions were canceled and replaced mainly by self-drainage. Annual follow-up clinic visits were consistently postponed whereas required hospitalizations at CF centers for exacerbation were maintained in most cases. While 43.2% CF-patients had signs of anxiety, 51.0% presented symptoms of depression, both associated with increased use of psychotic medications and inversely correlated to COVID-19 prevalence. Among the lower and lower middle classes, very little medical information was obtained or requested by the patient, participation to sports or other activities was low, while excessive home confinement and isolation were more frequent. In contrast, in the upper middle and upper classes, individuals solicitated help to their CF centre, had more physical activities, and maintained contact with friends or families., Conclusion: The first lockdown in France had only minimal impact on the management care of CF-patients but was associated with increased symptoms of anxiety and depression, together with behavioral changes that varied with social class., Trial Registration: NCT04463628., 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 © 2022 Oubaya, Pombet, Delestrain, Remus, Douvry, Grenet, Corvol, Thouvenin, Prulière-Escabasse, Mounir, Argoud, Fretigne, Costes, Mackiewicz, Jung, Ahamada, Lanone, Maitre, Bégot and Epaud.)

The risk of stroke in children with sickle cell disease (SCD) is detected by abnormal intracranial arterial time-averaged mean of maximum velocities (TAMVs ≥200 cm/s). Recently, extracranial internal carotid artery (eICA) arteriopathy has been reported, and a cross-sectional study showed that eICA-TAMVs ≥160 cm/s are significantly associated with eICA kinkings and stenosis. The cumulative incidence of and predictive risk factors for intracranial arteriopathy are well described in sickle cell anemia (SCA=SS/Sβ0) but are lacking for SC/Sβ+ children, as is the cumulative incidence of eICA arteriopathy. We report a prospective longitudinal cohort study including 493 children with SCD (398 SCA, 95 SC/Sβ+), all assessed by transcranial and cervical color Doppler ultrasound. Cerebral MRI/MRA data were available in 375 children with SCD and neck MRA in 365 children. eICA kinkings were defined as eICA tortuosities on neck MRA, with an internal acute angle between the two adjacent segments <90°. The median follow-up was 10.6 years. The cumulative incidence of kinkings was significantly lower in SC/Sβ+ children than in children with SCA, and no SC/Sβ+ child developed intra- or extracranial stenotic arteriopathy. The 10-year KM estimate of cumulative incidence (95% CI) for eICA-TAMVs ≥160 cm/s revealed its development in the 2nd year of life in children with SCA, reaching a plateau of 17.4% (13.2-21.6%) by about 10 years of age, while the plateau for eICA stenosis was 12.3% (8.3-16.3%). eICA assessment identified 13.5% (9.3-17.7%) patients at risk of stroke who were not detected by transcranial color Doppler ultrasound. We also show, for the first time, that in addition to a congenital origin, eICA kinkings sin patients with SCD can develop progressively with aging as a function of eICA-TAMVs, themselves related to anemia severity. Ongoing hydroxyurea treatment was significantly associated with a lower risk of abnormal intracranial arteriopathy and eICA kinkings. After adjustment with hydroxyurea, baseline low hemoglobin, high reticulocyte, and WBC counts remained independent risk factors for intracranial arteriopathy, while low hemoglobin and SEN β-haplotype number were independent risk factors for extracranial arteriopathy. The association between extracranial arteriopathy and SEN β-haplotype number suggested a genetic link between the ethnic origin and incidence of eICA kinkings. This prospective cohort study shows the importance of systematically assessing the eICA and of recording biological parameters during the 2nd year of life before any intensive therapy to predict the risk of cerebral arteriopathy and treat patients with severe baseline anemia., 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 © 2022 Bernaudin, Arnaud, Kamdem, Hau, Madhi, Jung, Epaud and Verlhac.)

COPD is a progressive and debilitating disease often diagnosed after 50 years of age, but more recent evidence suggests that its onset could originate very early on in life. In this context, exposure to air pollution appears to be a potential contributor. Although the potential role of air pollution as an early determinant of COPD is emerging, knowledge gaps still remain, including an accurate qualification of air pollutants (number of pollutants quantified and exact composition) or the "one exposure-one disease" concept, which might limit the current understanding. To fill these gaps, improvements in the field are needed, such as the use of atmosphere simulation chambers able to realistically reproduce the complexity of air pollution, consideration of the exposome, as well as improving exchanges between paediatricians and adult lung specialists to take advantage of reciprocal expertise. This review should lead to a better understanding of the current knowledge on air pollution as an early determinant of COPD, as well as identify the existing knowledge gaps and opportunities to fill them. Hopefully, this will lead to better prevention strategies to scale down the development of COPD in future generations., Competing Interests: Conflict of interest: None of the authors have any conflict of interest to declare., (Copyright ©The authors 2022.)

Specialized pro-resolving lipid mediators (SPMs) as lipoxins (LX), resolvins (Rv), protectins (PD) and maresins (MaR) promote the resolution of inflammation. We and others previously reported reduced levels of LXA4 in bronchoalveolar lavages from cystic fibrosis (CF) patients. Here, we investigated the role of CF airway epithelium in SPMs biosynthesis, and we evaluated its sex specificity. Human nasal epithelial cells (hNEC) were obtained from women and men with or without CF. Lipids were quantified by mass spectrometry in the culture medium of hNEC grown at air-liquid interface and the expression level and localization of the main enzymes of SPMs biosynthesis were assessed. The 5-HETE, LXA4, LXB4, RvD2, RvD5, PD1 and RvE3 levels were significantly lower in samples derived from CF patients compared with non-CF subjects. Within CF samples, the 12-HETE, 15-HETE, RvD3, RvD4, 17-HODHE and PD1 were significantly lower in samples derived from females. While the mean expression levels of 15-LO, 5-LO and 12-LO do not significantly differ either between CF and non-CF or between female and male samples, the SPMs content correlates with the level of expression of several enzymes involved in SPMs metabolism. In addition, the 5-LO localization significantly differed from cytoplasmic in non-CF to nucleic (or nuclear envelope) in CF hNEC. Our studies provided evidence for lower abilities of airway epithelial cells derived from CF patients and more markedly, females to produce SPMs. These data are consistent with a contribution of CF airway epithelium in the abnormal resolution of inflammation and with worse pulmonary outcomes in women., Competing Interests: Authors VB and MD were employed by Ambiotis. 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 Shum, London, Briottet, Sy, Baillif, Philippe, Zare, Ghorbani-Dalini, Remus, Tarze, Escabasse, Epaud, Dubourdeau and Urbach.)

Cystic fibrosis (CF) is a lethal and widespread autosomal recessive disorder affecting over 80,000 people worldwide. It is caused by mutations of the CFTR gene, which encodes an epithelial anion channel. CF is characterized by a great phenotypic variability which is currently not fully understood. Although CF is genetically determined, the course of the disease might also depend on multiple other factors. Air pollution, whose effects on health and contribution to respiratory diseases are well established, is one environmental factor suspected to modulate the disease severity and influence the lung phenotype of CF patients. This is of particular interest as pulmonary failure is the primary cause of death in CF. The present review discusses current knowledge on the impact of air pollution on CF pathogenesis and aims to explore the underlying cellular and biological mechanisms involved in these effects., 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 © 2022 Blayac, Coll, Urbach, Fanen, Epaud and Lanone.)

Germline surfactant-associated genes mutations are associated with ILD and increased risk of lung cancer https://bit.ly/3CkkXgD., Competing Interests: Conflict of interest: R. Borie reports grants and personal fees from Boehringer Ingelheim and Roche, personal fees from Sanofi, and participation on a data safety monitoring/advisory board for Savara. Conflict of interest: B. Funalot has nothing to disclose. Conflict of interest: R. Epaud has nothing to disclose. Conflict of interest: C. Delestrain has nothing to disclose. Conflict of interest: A. Cazes has nothing to disclose. Conflict of interest: V. Gounant reports support for attending meetings and/or travel from AstraZeneca, BMS, Takeda and Pfizer, and participation on a data safety monitoring/advisory board for MSD, Chugai, Novartis, Boehringer and Takeda. Conflict of interest: J. Frija reports personal fees from Withings and Hinlab, and support for attending meetings and/or travel from Boehringer Ingelheim, Oxyvie, ADEP Assistance and Vitalaire, outside the submitted work. Conflict of interest: M.P. Debray reports personal fees from Boehringer Ingelheim and Roche outside the submitted work. Conflict of interest: G. Zalcman reports a research grant for a PhD thesis in his laboratory from Fondation Roche; consulting fees from BMS, AstraZeneca and Da Volterra; and support for attending meetings and/or travel from BMS, Abbvie, AstraZeneca and Pfizer. Conflict of interest: B. Crestani has nothing to disclose., (Copyright ©The authors 2021.)

Because of the direct interaction of lungs with the environment, respiratory diseases are among the leading causes of environment-related deaths in the world. Chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) are two highly debilitating diseases that are of particular interest in the context of environmental studies; they both are characterized by a similar progressive loss of lung function with small bronchi alterations, and a high phenotypic variability of unknown origin, which prevents a good therapeutic efficacy. In the last years, there has been an evolution in the apprehension of the study of diseases going from a restricted "one exposure, one disease" approach to a broader concept with other associating factors, the exposome. The overall objective of the REMEDIA project is to extend the understanding of the contribution of the exposome to COPD and CF diseases. To achieve our aim, we will (1) exploit data from existing cohorts and population registries to create a unified global database gathering phenotype and exposome information; (2) develop a flexible individual sensor device combining environmental and biomarker toolkits; (3) use a versatile atmospheric simulation chamber to simulate the health effects of complex exposomes; (4) use machine learning supervised analyses and causal inference models to identify relevant risk factors; and (5) develop econometric and cost-effectiveness models to assess the costs, performance, and cost-effectiveness of a selection of prevention strategies. The results will be used to develop guidelines to better predict disease risks and constitute the elements of the REMEDIA toolbox. The multidisciplinary approach carried out by the REMEDIA European project should represent a major breakthrough in reducing the morbidity and mortality associated with COPD and CF diseases., Competing Interests: The authors declare that they have no conflicts of interest with regard to the content of this report., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The Environmental Epidemiology. All rights reserved.)

Mutations in the gene encoding surfactant protein C (SP-C) cause interstitial lung disease (ILD), and glucocorticosteroid (GC) treatment is the most recognized therapy in children. We aimed to decipher the mechanisms behind successful GC treatment in twins carrying a BRICHOS c.566G > A (p.Cys189Tyr) mutation in the SP-C gene (SFTPC). METHODS: The twins underwent bronchoscopy before and after GC treatment and immunoblotting analysis of SP-C proprotein (proSP-C) and SP-C mature in bronchoalveolar fluid (BALF). Total RNA was extracted and analysed using quantitative real-time PCR assays. In A549 cells, the processing of mutated protein C189Y was studied by immunofluorescence and immunoblotting after heterologous expression of eukaryotic vectors containing wild type or C189Y mutant cDNA. RESULTS: Before treatment, BALF analysis identified an alteration of the proSP-C maturation process. Functional study of C189Y mutation in alveolar A549 cells showed that pro-SP-C C189Y was retained within the endoplasmic reticulum together with ABCA3. After 5 months of GC treatment with clinical benefit, the BALF analysis showed an improvement of proSP-C processing. SFTPC mRNA analysis in twins revealed a decrease in the expression of total SFTPC mRNA and a change in its splicing, leading to the expression of a second shorter proSP-C isoform. In A549 cells, the processing and the stability of this shorter wild-type proSP-C isoform was similar to that of the longer isoform, but the half-life of the mutated shorter isoform was decreased. These results suggest a direct effect of GC on proSP-C metabolism through reducing the SFTPC mRNA level and favouring the expression of a less stable protein isoform., (© 2020 British Pharmacological Society.)

Background: Increased rates of respiratory adverse events have been observed in people ≥12 years of age with cystic fibrosis homozygous for the Phe508del-CFTR mutation treated with lumacaftor/ivacaftor, particularly in those with percent predicted forced expiratory volume in 1 s (ppFEV 1 ) of <40%. We evaluated the safety, tolerability, and efficacy of tezacaftor/ivacaftor in people with cystic fibrosis homozygous for Phe508del-CFTR who discontinued lumacaftor/ivacaftor due to treatment-related respiratory signs or symptoms., Methods: Participants ≥12 years of age with cystic fibrosis homozygous for Phe508del-CFTR with ppFEV 1 of ≥25% and ≤90% were randomized 1:1 and treated with tezacaftor/ivacaftor or placebo for 56 days., Results: Of 97 participants, 94 (96.9%) completed the study. The primary endpoint was incidence of predefined respiratory adverse events of special interest (chest discomfort, dyspnea, respiration abnormal, asthma, bronchial hyperreactivity, bronchospasm, and wheezing): tezacaftor/ivacaftor, 14.0%; placebo, 21.3%. The adverse events were mild or moderate in severity. None were serious or led to treatment interruption or discontinuation. Overall, the discontinuation rate was similar between groups. The mean (SD) ppFEV 1 at baseline was 44.6% (16.1%) with tezacaftor/ivacaftor and 48.0% (18.1%) with placebo. The posterior mean difference in absolute change in ppFEV 1 from baseline to the average value of days 28 and 56 was 2.7 percentage points with tezacaftor/ivacaftor vs placebo., Conclusions: Tezacaftor/ivacaftor was generally safe, well tolerated, and efficacious in people ≥12 years of age with cystic fibrosis homozygous for Phe508del-CFTR with ppFEV 1 of ≥25% and ≤90% who previously discontinued lumacaftor/ivacaftor due to treatment-related respiratory signs or symptoms., Competing Interests: Declaration of Competing Interests All authors received nonfinancial support (assistance with manuscript preparation) from ArticulateScience LLC, which received funding from Vertex. Additional disclosures are as follows. BGB, MED, and NA are employees of Vertex and may own stock or stock options in Vertex. PKA, TJF and XY are former employees of Vertex and may own stock or stock options in Vertex. CS received a grant from Vertex and personal fees from Vertex, PTI, Chiesi, and Teva outside the submitted work. RF received an honorarium from Vertex during the conduct of the study. SMR received grants, personal fees, and nonfinancial support from Vertex during the conduct of the study; grants from Bayer, Forest Research Institute, AstraZeneca, Nivalis, Novartis, Galapagos/AbbVie, Proteostasis, Eloxx, Celtaxsys, PTC, and Vertex; personal fees from Bayer, Celtaxsys, Novartis, and Vertex; and nonfinancial support from Vertex outside the submitted work. SS received personal fees from Proteostasis, Novartis and Vertex outside the submitted work; has served as an investigator in clinical trials for Galapagos, Proteostasis, Celtaxsys, Flatley, Novartis, and Vertex; and has consulted for Proteostasis and Vertex. RCK and RE have no additional disclosures., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Lung involvement in childhood Langerhans cell histiocytosis (LCH) is infrequent and rarely life threatening, but occasionally, severe presentations are observed., Methods: Among 1482 children (< 15 years) registered in the French LCH registry (1994-2018), 111 (7.4%) had lung involvement. This retrospective study included data for 17 (1.1%) patients that required one or more intensive care unit (ICU) admissions for respiratory failure., Results: The median age was 1.3 years at the first ICU hospitalization. Of the 17 patients, 14 presented with lung involvement at the LCH diagnosis, and 7 patients (41%) had concomitant involvement of risk-organ (hematologic, spleen, or liver). Thirty-five ICU hospitalizations were analysed. Among these, 22 (63%) were secondary to a pneumothorax, 5 (14%) were associated with important cystic lesions without pneumothorax, and 8 (23%) included a diffuse micronodular lung infiltration in the context of multisystem disease. First-line vinblastine-corticosteroid combination therapy was administered to 16 patients; 12 patients required a second-line therapy (cladribine: n = 7; etoposide-aracytine: n = 3; targeted therapy n = 2). A total of 6 children (35%) died (repeated pneumothorax: n = 3; diffuse micronodular lung infiltration in the context of multisystem disease: n = 2; following lung transplantation: n = 1). For survivors, the median follow-up after ICU was 11.2 years. Among these, 9 patients remain asymptomatic despite abnormal chest imaging., Conclusions: Severe lung involvement is unusual in childhood LCH, but it is associated with high mortality. Treatment guidelines should be improved for this group of patients: viral infection prophylaxis and early administration of a new LCH therapy, such as targeted therapy.

Background: The objective was to determine whether high-flow nasal cannula (HFNC), a promising respiratory support in infant bronchiolitis, could reduce the proportion of treatment failure requiring escalation of care., Methods: In this randomised controlled trial, we assigned infants aged <6 months who had moderate bronchiolitis to receive either HFNC at 3 L·kg -1 ·min -1 or standard oxygen therapy. Crossover was not allowed. The primary outcome was the proportion of patients in treatment failure requiring escalation of care (mostly noninvasive ventilation) within 7 days following randomisation. Secondary outcomes included rates of transfer to the paediatric intensive care unit (PICU), oxygen, number of artificial nutritional support-free days and adverse events., Results: The analyses included 268 patients among the 2621 infants assessed for inclusion during two consecutive seasons in 17 French paediatric emergency departments. The percentage of infants in treatment failure was 14% (19 out of 133) in the study group, compared to 20% (27 out of 135) in the control group (OR 0.66, 95% CI 0.35-1.26; p=0.21). HFNC did not reduce the risk of admission to PICU (21 (15%) out of 133 in the study group versus 26 (19%) out of 135 in the control group) (OR 0.78, 95% CI 0.41-1.41; p=0.45). The main reason for treatment failure was the worsening of modified Wood clinical asthma score (m-WCAS). Short-term assessment of respiratory status showed a significant difference for m-WCAS and respiratory rate in favour of HFNC. Three pneumothoraces were reported in the study group., Conclusions: In patients with moderate bronchiolitis, there was no evidence of lower rate of escalating respiratory support among those receiving HFNC therapy., Competing Interests: Conflict of interest: P. Durand has nothing to disclose. Conflict of interest: T. Guiddir has nothing to disclose. Conflict of interest: C. Kyheng has nothing to disclose. Conflict of interest: F. Blanc has nothing to disclose. Conflict of interest: O. Vignaud has nothing to disclose. Conflict of interest: R. Epaud has nothing to disclose. Conflict of interest: F. Dugelay has nothing to disclose. Conflict of interest: I. Breant has nothing to disclose. Conflict of interest: I. Badier has nothing to disclose. Conflict of interest: V. Degas-Bussière has nothing to disclose. Conflict of interest: F. Phan has nothing to disclose. Conflict of interest: V. Soussan-Banini has nothing to disclose. Conflict of interest: A. Lehnert has nothing to disclose. Conflict of interest: C. Mbamba has nothing to disclose. Conflict of interest: C. Barrey has nothing to disclose. Conflict of interest: C. Tahiri has nothing to disclose. Conflict of interest: M. Decobert has nothing to disclose. Conflict of interest: M. Saunier-Pernaudet has nothing to disclose. Conflict of interest: I. Craiu has nothing to disclose. Conflict of interest: M. Taveira has nothing to disclose. Conflict of interest: V. Gajdos has nothing to disclose., (Copyright ©ERS 2020.)

Understanding the clinical presentation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and prognosis in children is a major issue. Children often present mild symptoms, and some severe forms require paediatric intensive care, with in some cases a fatal prognosis. Our aim was to identify the epidemiological characteristics, clinical presentation, and prognosis of children with coronavirus disease 2019 (Covid-19) hospitalized in Paris suburb hospitals. In this prospective, observational, multicentre study, we included children hospitalized in paediatric departments of Paris suburb hospitals from 23 March 2020 to 10 May 2020, during the national lockdown in France with confirmed SARS-CoV-2 infection (positive RNA test on a nasopharyngeal swab) or highly suspected infection (clinical, biological, and/or radiological data features suggestive for SARS-CoV-2 infection). A total of 192 children were included for confirmed ( n = 157) or highly suspected ( n = 35) SARS-CoV-2 infection. The median age was one year old (interquartile range 0.125-11) with a sex ratio 1.3:1. Fever was recorded in 147 (76.6%) children and considered poorly tolerated in 29 (15.1%). The symptoms ranged from rhinorrhoea (34.4%) and gastrointestinal (35.5%) to respiratory distress (25%). Only 10 (5.2%) children had anosmia and five (2.6%) had chest pain. An underlying condition was identified in almost 30% of the children in our study. Overall, 24 (12.5%) children were admitted to paediatric intensive care units, 12 required mechanical ventilation, and three died. For children in Paris suburbs, most cases of Covid-19 showed mild or moderate clinical expression. However, one-eighth of children were admitted to paediatric intensive care units and three died., Competing Interests: The authors have no potential conflicts of interest related to this article.

(1) Background: Pediatric sarcoidosis is a rare and mostly severe disease. Very few pediatric series with a prolonged follow-up are reported. We aimed to evaluate the evolution of pediatric sarcoidosis in adulthood. (2) Material and methods: Patients over 18-years-old with a pediatric-onset sarcoidosis (≤15-year-old) who completed at least a three-year follow-up in French expert centers were included. Clinical information at presentation and outcome in adulthood were studied. (3) Results: A total of 52 patients were included (34 prospectively in childhood and 18 retrospectively in adulthood), with a mean age of 12 (±2.7) at diagnosis. The median duration time of follow-up was 11.5 years (range 3-44.5). Relapses mostly occurred during treatment decrease (84.5%), others within the three years after treatment interruption (9.1%), and rarely when the disease was stable for more than three years (6.4%). Sarcoidosis was severe in 11 (21.2%) in adulthood. Patients received a high corticosteroid cumulative dose (median 17,900 mg) for a median duration of five years (range 0-32), resulting in mostly mild (18; 35.3%) and rarely severe (2; 3.8%) adverse events. (4) Conclusions: Pediatric-onset sarcoidosis needed a long-term treatment in almost half of the patients. Around one fifth of pediatric-onset sarcoidosis patients had severe sarcoidosis consequences in adulthood., Competing Interests: F.C.-A. is the PI of an academic study of the efficacy of infliximab in extrapulmonary sarcoidosis. T.A. reports personal fees from Chiesi, other from Vital Aire, other from Astrazeneca, other from Boehringer Ingelheim, outside the submitted work. D.V. reports personal fees from Roche, personal fees from Boehringer Ingelheim, outside the submitted work. N.N. reports grants from Société de pneumologie pédiatrique et d’allergologie (France), outside the submitted work. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. All others authors declared no direct conflict of interest related to the present work.

Background: Genetic testing is proposed for suspected cases of monogenic pulmonary fibrosis, but clinicians and patients need specific information and recommendation about the related diagnosis and management issues. Because multidisciplinary discussion (MDD) has been shown to improve accuracy of interstitial lung disease (ILD) diagnosis, we evaluated the feasibility of a genetic MDD (geneMDD) dedicated to the indication for and interpretation of genetic testing. The geneMDD group met monthly and included pediatric and adult lung specialists with ILD expertise, molecular and clinical geneticists, and one radiologist. Hematologists, rheumatologists, dermatologists, hepatologists, and pathologists were also invited to attend., Results: Since 2016, physicians from 34 different centers in 7 countries have participated in the geneMDD. The medical files of 95 patients (53 males) have been discussed. The median age of patients was 43 years [range 0-77], 10 were ≤ 15 years old, and 6 were deceased at the time of the discussion. Among 85 analyses available, the geneMDD considered the rare gene variants pathogenic for 61: 37 variants in telomere-related genes, 23 variants in surfactant-related genes and 1 variant in MARS. Genetic counseling was offered for relatives of these patients. The geneMDD therapeutic proposals were as follows: antifibrotic drugs (n = 25), steroids or immunomodulatory therapy (n = 18), organ transplantation (n = 21), watch and wait (n = 21), or best supportive care (n = 4)., Conclusion: Our experience shows that a dedicated geneMDD is feasible regardless of a patient's age and provides a unique opportunity to adapt patient management and therapy in this very rare condition.

This prospective observational study sought to ascertain clinical and laboratory parameters associated with the development of acute chest syndrome (ACS) during vaso-occlusive episodes (VOE) in children with sickle cell disease (SCD). It was performed at the pediatric department of the university Intercommunal Créteil hospital. All children with SCD (all sickle genotypes) consecutively admitted from November 2013 to December 2016 for painful VOEs and no evidence of ACS were included. Clinical and laboratory parameters collected at admission and within 48 h after admission were compared for children in whom ACS developed or not. Variables that were statistically significant on univariate analysis or considered to be clinically relevant were included in a multivariable model to ascertain the risk factors associated with the development of ACS during a VOE. The variables retained in the multivariate model were used to construct a predictive score for ACS. For each included child and during the study period, only data from the first VOE and/or the first ACS were analyzed. Among 191 hospitalizations for painful VOEs, for 176 children with SCD, ACS developed in 35 during hospitalization. Mean hospital stay was longer for children with ACS versus VOEs alone (7.6 (±2.3) vs. 3.3 (±1.8) days, p < 0.0001), and all children with ACS versus 28/156 (17.9%) with VOEs alone received red blood cell transfusion ( p < 0.0001). The multivariate model retained pain score (≥9/10), pain localization (abdominal or spinal pain or involving more than two limbs), and high reticulocyte (≥260 × 10 9 /L) and neutrophil (>10 × 10 9 /L) counts, at admission, as independently associated with ACS development. The area under the receiver operating characteristic curve for the ACS predictive score was 0.82 (95% CI: 0.74-0.89), and the negative predictive value was 97.7%. The evolution profiles during the first 48 h differed between children with ACS and VOEs alone, with a more rapid decline of pain score and leucocytosis in children with VOEs. Clinical and laboratory measurements at admission may be simple parameters to identify children with increased risk of ACS development during VOEs and to facilitate early diagnosis of this respiratory complication. Also, the persistent elevation of leukocyte count on day 2 may be considered a sign of evolving ACS., Competing Interests: The authors declare no conflict of interest.

Over the past 3 decades, the pediatric department of the university Intercommunal Créteil hospital, a referral center for sickle cell disease (SCD), has prospectively evaluated immunoglobulin (Ig) levels in a cohort of 888 children with SCD, including 731 with severe sickle genotypes (HbSS and HbSβ 0 thalassemia) and 157 with milder genotypes (HbSC and HbSβ + thalassemia). We found consistent sickle genotype differences in levels of IgG and IgA, with increased levels of IgA and IgG in the severe versus milder genotype, from early childhood to late adolescence. Additionally, our results revealed a low serum IgM level, irrespective of sickle genotype. Finally, we found that IgA and IgG levels were significantly increased after therapeutic intensification with hydroxyurea but were stabilized in children receiving a transfusion program. The mechanisms contributing to these changes in Ig levels are unclear as is their clinical significance. We believe they should be further investigated.

Background: Pulmonary hemosiderosis is a rare and complex disease in children. A previous study from the French RespiRare® network led to two important findings: 20% of the children presented with both pulmonary hemosiderosis and Down syndrome (DS), and at least one tested autoantibody was found positive in 50%. This study investigates the relationships between pulmonary hemosiderosis and DS., Methods: Patients younger than 20 years old and followed for pulmonary hemosiderosis were retrieved from the RespiRare® database. Clinical, biological, functional, and radiological findings were collected, and DS and non-DS patients' data were compared., Results: A total of 34 patients (22 girls and 12 boys) were included, among whom nine (26%) presented with DS. The mean age at diagnosis was 4.1 ± 3.27 years old for non-DS and 2.9 ± 3.45 years old for DS patients. DS patients tended to present a more severe form of the disease with an earlier onset, more dyspnoea at diagnosis, more frequent secondary pulmonary hypertension, and an increased risk of fatal evolution., Conclusions: DS patients have a higher risk of developing pulmonary hemosiderosis, and the disease seems to be more severe in this population. This could be due to the combination of an abnormal lung capillary bed with fragile vessels, a higher susceptibility to autoimmune lesions, and a higher risk of evolution toward pulmonary hypertension. A better screening for pulmonary hemosiderosis and a better prevention of hypoxia in DS paediatric patients may prevent a severe evolution of the disease.

Sickle cell anemia (SCA), albeit monogenic, has heterogeneous phenotypic expression, mainly related to the level of hemoglobin F (HbF). No large cohort studies have ever compared biological parameters in patients with major β-globin haplotypes; ie, Senegal (SEN), Benin (BEN), and Bantu/Central African Republic (CAR). The aim of this study was to evaluate the biological impact of α genes, β haplotypes, and glucose-6-phosphate dehydrogenase (G6PD) activity at baseline and with hydroxyurea (HU). Homozygous HbS patients from the Créteil pediatric cohort with available α-gene and β-haplotype data were included (n = 580; 301 females and 279 males) in this retrospective study. Homozygous β-haplotype patients represented 74% of cases (37.4% CAR/CAR, 24.3% BEN/BEN, and 12.1% SEN/SEN). HU was given to 168 cohort SCA children. Hematological parameters were recorded when HbF was maximal, and changes ( Δ HU-T0) were calculated. At baseline, CAR-haplotype and α-gene numbers were independently and negatively correlated with Hb and positively correlated with lactate dehydrogenase. HbF was negatively correlated with CAR-haplotype numbers and positively with BEN- and SEN-haplotype numbers. The BCL11A /rs1427407 "T" allele, which is favorable for HbF expression, was positively correlated with BEN- and negatively correlated with CAR-haplotype numbers. With HU treatment, Δ and HbF values were positively correlated with the BEN-haplotype number. BEN/BEN patients had higher HbF and Hb levels than CAR/CAR and SEN/SEN patients. In conclusion, we show that BEN/BEN patients have the best response on HU and suggest that this could be related to the higher prevalence of the favorable BCL11A /rs1427407/T/allele for HbF expression in these patients., (© 2018 by The American Society of Hematology.)

We retrospectively studied the clinical presentation, treatment modalities and outcome in 16 patients with heterozygous NKX2-1 mutation associated with chronic lung disease. Twelve different NKX2-1 mutations, including 4 novel mutations, were identified in the 16 patients. Nine patients presented with brain-lung-thyroid syndrome, 3 had neurological and lung symptoms and 4 had only pulmonary symptoms. Ten patients had neonatal respiratory distress, and 6 of them developed infiltrative lung disease (ILD). The other patients were diagnosed with ILD in childhood (n = 3) or in adulthood (n = 3). The median age at diagnosis was 36 months (IQ 3.5-95). Patient testing included HRCT (n = 13), BALF analysis (n = 6), lung biopsies (n = 3) and lung function tests (n = 6). Six patients required supplemental oxygen support with a median duration of 18 months (IQ 2.5-29). All symptomatic ILD patients (n = 12) benefited from a treatment consisting of steroids, azithromycin (n = 9), and/or hydroxychloroquine (n = 4). The median follow-up was 36 months (IQ 24-71.5). One patient died of respiratory failure at 18 months and another is waiting for lung transplantation. In summary, the initial diagnosis was based on clinical presentation and radiological features, but the presentation was heterogeneous. Definitive diagnosis required genetic analysis, which should be performed, even in absence of neurological or thyroid symptoms., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Mutations in the gene encoding surfactant protein C (SFTPC) have led to a broad range of phenotypes from neonatal respiratory distress syndrome to adult interstitial lung disease. We previously identified the c.435G>C variant in the SFTPC gene associated with fatal neonatal respiratory distress syndrome in an infant girl. Although this variation is predicted to change glutamine (Q) at position 145 to histidine (H), its position at the last base of exon 4 and the severity of the phenotype suggested that it might also induce a splicing defect. To test this hypothesis, we used hybrid minigene, biochemical and immunofluorescence tools to decipher the molecular mechanism of the mutation. Immunoblotting and confocal imaging showed similar maturation and localization of wild-type and Q145H proteins, but hybrid minigene analysis showed complete exon 4 skipping. Since the exon 4 is in frame, a putative truncated protein of 160 amino acids would be produced. We have shown that this truncated protein had an altered intracellular trafficking and maturation. The c.435G>C mutation is deleterious not because of its amino acid substitution but because of its subsequent splicing defect and should be referred to as r.325&#95;435del and p.Leu109&#95;Gln145del. The absence of residual full-length transcripts fully explained the severity of the phenotype we observed in the infant.

Background and Purpose: Pulmonary disease is the main cause of morbidity and mortality in cystic fibrosis (CF) patients due to exacerbated inflammation. To date, the only anti-inflammatory drug available to CF patients is high-dose ibuprofen, which can slow pulmonary disease progression, but whose cyclooxygenase-dependent digestive adverse effects limit its clinical use. Here we have tested sulindac, another non-steroidal anti-inflammatory drug with an undefined anti-inflammatory effect in CF airway epithelial cells., Experimental Approach: Using in vitro and in vivo models, we NF-κB activity and IL-8 secretion. In HeLa-F508del cells, we performed luciferase reporter gene assays in order to measure i) IL-8 promoter activity, and ii) the activity of synthetic promoter containing NF-κB responsive elements. We quantified IL-8 secretion in airway epithelial CFBE cells cultured at an air-liquid interface and in a mouse model of CF., Key Results: Sulindac inhibited the transcriptional activity of NF-κB and decreased IL-8 transcription and secretion in TNF-α stimulated CF cells via a cyclooxygenase-independent mechanism. This effect was confirmed in vivo in a mouse model of CF induced by intra-tracheal instillation of LPS, with a significant decrease of the induction of mRNA for MIP-2, following treatment with sulindac., Conclusion and Implications: Overall, sulindac decrease lung inflammation by a mechanism independent of cycolooxygenase. This drug could be beneficially employed in CF., (© 2016 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Stroke risk in sickle cell anemia (SCA), predicted by high transcranial Doppler (TCD) velocities, is prevented by transfusions. We present the long-term follow-up of SCA children from the Créteil newborn cohort (1992-2012) detected at risk by TCD and placed on chronic transfusions. Patients with normalized velocities and no stenosis were treated with hydroxyurea, known to decrease anemia and hemolytic rate. Trimestrial Doppler was performed and transfusions restarted immediately in the case of reversion to abnormal velocities. Patients with a genoidentical donor underwent transplant. Abnormal time-averaged maximum mean velocities (TAMMV) ≥200 cm/s were detected in 92 SCA children at a mean age of 3.7 years (range, 1.3-8.3 years). No stroke occurred posttransfusion after a mean follow-up of 6.1 years. Normalization of velocities (TAMMV < 170 cm/s) was observed in 83.5% of patients. Stenosis, present in 27.5% of patients, was associated with the risk of non-normalization (P< .001). Switch from transfusions to hydroxyurea was prescribed for 45 patients, with a mean follow-up of 3.4 years. Reversion, predicted by baseline reticulocyte count ≥400 × 10(9)/L (P< .001), occurred in 28.9% (13/45) patients at the mean age of 7.1 years (range, 4.3-9.5 years). Transplant, performed in 24 patients, allowed transfusions to be safely stopped in all patients and velocities to be normalized in 4 patients who still had abnormal velocities on transfusions. This long-term cohort study shows that transfusions can be stopped not only in transplanted patients but also in a subset of patients switched to hydroxyurea, provided trimestrial Doppler follow-up and immediate restart of transfusions in the case of reversion., (© 2016 by The American Society of Hematology.)

Early transcranial Doppler (TCD) screening of the Créteil sickle cell anemia (SCA)-newborn cohort, and rapid initiation of transfusion programs, resulted in successful prevention of overt strokes, but a high cumulative risk of silent cerebral infarcts (SCI) remained, suggesting that TCD screening does not identify all patients with SCA at risk for SCI. We hypothesized that episodes of hypoperfusion/hypoxia, as observed during acute chest syndromes or acute anemic events (AAE), and extracranial internal carotid artery (eICA) stenoses, detectable via submandibular Doppler sonography and cervical magnetic resonance angiography (MRA), could also be risk factors for SCI. This study includes 189 stroke-free patients with SCA from the Créteil newborn cohort (1992-2010) followed longitudinally by magnetic resonance imaging/MRA, including cervical MRA at the last assessment. All patients with abnormal TCD and/or intracranial stenoses were placed on a transfusion program. Mean follow-up was 9.9 years (range, 2.2-19.9 years; 1844 patient-years). Annual rates of clinical events were calculated. The cumulative risk for SCI was 39.1% (95% confidence interval [CI], 23.5%-54.7%) by age 18 years, with no plateau. We confirm that baseline hemoglobin level lower than 7 g/dL before age 3 years is a highly significant predictive risk factor for SCI (hazard ratio, 2.97; 95% CI, 1.43-6.17; P = .004). Furthermore, we show that AAE rate (odds ratio, 2.64 per unit increase; 95% CI, 1.09-6.38; P = .031) and isolated eICA stenosis (odds ratio, 3.19; 95% CI, 1.18-8.70; P = .023) are significant and independent risk factors for SCI., (© 2015 by The American Society of Hematology.)