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International audience; Nonsense mutations are responsible for around 10% of cases of genetic diseases, including cystic fibrosis. 2,6-diaminopurine (DAP) has recently been shown to promote efficient readthrough of UGA premature stop codons. In this study, we show that DAP can correct a nonsense mutation in the Cftr gene in vivo in a new CF mouse model, in utero, and through breastfeeding, thanks, notably, to adequate pharmacokinetic properties. DAP turns out to be very stable in plasma and is distributed throughout the body. The ability of DAP to correct various endogenous UGA nonsense mutations in the CFTR gene and to restore its function in mice, in organoids derived from murine or patient cells, and in cells from patients with cystic fibrosis reveals the potential of such readthrough-stimulating molecules in developing a therapeutic approach. The fact that correction by DAP of certain nonsense mutations reaches a clinically relevant level, as judged from previous studies, makes the use of this compound all the more attractive.

Clinical trials for CFTR modulators consider mean changes of clinical status at the cohort level, and thus fail to assess the heterogeneity of the response. We aimed to study the different response profiles to lumacaftor-ivacaftor according to age in children with cystic fibrosis (CF).A mathematical framework, including principal component analysis, data clustering, and data completion, was applied to a multicenter cohort of 112 children aged 6-18 years, treated with lumacaftor-ivacaftor. Studied parameters at baseline and 6 months included body mass index (BMI), number of days of antibiotics (ATB), Sweat test (ST), forced expiratory volume in 1 s expressed in percentage predicted (ppFEVChange in ppFEVChange in ppFEV

Study Objective To describe human papilloma virus (HPV) vaccination practice among adolescent girls with cystic fibrosis (CF) and to identify reasons for non-vaccination. Design Cross-sectional multicentric study. Setting and Participants Girls aged 9-17 years, attending 7 French pediatric CF centers, and their accompanying adult. Interventions Administration of a self-report questionnaire. Main Outcome Measures The proportion of girls having received or receiving HPV vaccination, compliance with the vaccination schedule, factors associated with vaccination, and reasons for vaccination and for non-vaccination. Results A total of 113 girls and 104 accompanying adults participated. The mean age was 13.6 years (standard deviation 2.5; range 9-17). A total of 34 (30.9%) patients reported having received HPV vaccination. Among the 34 girls aged 15 years or older, 15 (44.1%) were vaccinated. Most patients (58.8%) started vaccination between 11 and 14 years of age (mean age 13.9). Most vaccine prescriptions (67.6%) were made by a CF center health care provider. Factors associated with vaccination were older age (odds ratio [OR] = 1.27, 95% confidence interval [CI] = 1.01-1.6, P = .037 for each year older), previous vaccination by the accompanying parent of one of their children for hepatitis B (OR = 8.01, 95% CI = 0.96-67.02), P = .055), and parental influence on decision-making (OR = 2.77, 95% CI = 0.97-7.95, P = .058). Health care providers’ positive advice and fear of HPV-related disease were the main reasons given to justify vaccination decisions. Insufficient knowledge and concerns about potential side effects were the main barriers. Conclusion HPV vaccination remains insufficient among girls with CF. CF health care providers may play a crucial role in HPV vaccination acceptance, and their sensitization to cervical cancer prevention is mandatory.

Introduction: Biological disease-modifying anti-rheumatic drugs (bDMARDs) targeting interleukin (IL)-6 and IL-1β represent a steroid-sparing first-line therapy used in systemic-onset juvenile idiopathic arthritis (sJIA). Recently, the occurrence of pulmonary alveolar proteinosis (PAP) in sJIA patients was reported with early-onset and exposure to bDMARDs as potential risk factors. We report on a new case with longitudinal immunomonitoring successfully treated by Janus Kinase inhibitors (JAKi) and review past clinical descriptions of this new entity. Methods: We report one case of pulmonary alveolar proteinosis and macrophage activation syndrome (PAP-MAS) with longitudinal immunomonitoring. We then conducted a review of the literature of seven publications reporting 107 cases of PAP-MAS sJIA, and included the main characteristics and evolution under treatment. Results: Of the seven articles analyzed, the incidence of PAP-MAS among sJIA patients varied from 1.28% to 12.9%. We report here a single case among a cohort of 537 sJIA patients followed in the pediatric department of the Hospices Civils de Lyon over the last 15 years. This child presented with all clinical and immunological characteristics of PAP-MAS. After several lines of treatment, he benefited from JAKi and improved with respect to both systemic symptoms and lung disease. In the literature, strategies with monoclonal antibodies targeting either INF-γ or IL-1β/IL-18 have been tested with variable results. Orally taken JAKi presents the advantage of targeting multiple cytokines and avoiding parenteral injections of monoclonal antibodies that may contribute to the pathogenesis. Conclusions: JAKi represent a promising option in the treatment of lung disease associated with sJIA.

INTRODUCTION The prognosis of people diagnosed with cystic fibrosis (CF) has dramatically improved over the past decade in France, largely due to advances in CF care management, including an emphasis on chronic maintenance medications. Currently, the majority of French CF patients are adults, which means that they went through a transition process from receiving care at a pediatric CF center to receiving care at an adult CF center. To determine the impact of the transfer on clinical evolution, we report the transition procedure of our CF center in Lyon. MATERIALS AND METHODS From January 2006 to December 2016, 97 CF patients underwent a standardized process of transitioning from the pediatric to the adult CF center in Lyon. We compared the clinical evolution of these patients during three periods, starting the year before transition and ending the year after transition. Clinical data taken into account were forced expiratory volume in 1 s (FEV1 in liters), body mass index (BMI in kg/m2 ), pulmonary colonization, number of antibiotic courses, number of days of hospitalization per year, and outpatient visits per year. RESULTS No significant differences were observed between respiratory and nutritional status, respiratory microbiome, number of antibiotic courses, or number of hospitalizations or visits when comparing the threeperiods of observation around transition (the year before, the first year after, and the second year after transfer). CONCLUSION The standardized transition procedure used in Lyon is associated with the clinical stability of our CF patients.

Background:To inform rational dosing of antibiotics, traditional Therapeutic Drug Monitoring (TDM) with empiric dose adjustment of has been increasingly supplanted by the use of Model-Informed Precision Dosing (MIPD) software.Our objective was to evaluate a model-informed precision dosing approach specifically designed to individualize empiric tobramycin dosing in adults with cystic fibrosis, and to compare target attainment between both the model-based and the empiric dosing approaches. Methods:The BestDose MIPD-software has been used with a published population pharmacokinetic model of tobramycin. To evaluate the MIPD strategy, we used retrospective data from CF adults treated with tobramycin at our local CF center. Empiric dose adjustments from the clinical staff were examined.Using a simulation-based methodology, individualized tobramycin doses that maximize the probability of attaining a Cmax/MIC ratio of 32 mg/L were retrospectively calculated, and compared with empiric dose adjustments. Results:Overall, 101 CF adults were evaluated. Tobramycin Cmax in patients were low (mean of 25.7 ± 5.6 mg/L). The percentage of patients predicted to achieve a Cmax/MIC of ≥ 32 mg/L was low (12.0 %, mean dose of 8.8 ± 1.3 mg/kg) with empiric dose adjustment. TDM with retrospective PK/PD modelling suggest increasing tobramycin dosing in a much larger number of patients (88.0 %, mean dose of 11.6 ± 2.5 mg/kg). Conclusions:Tobramycin doses empirically corrected by clinicians after TDM were predicted to be still insufficient to achieve the efficacy target in most CF patients. Meanwhile a model-based dosing approach that individualizes the tobramycin dosing led to significantly improved achievement of expected target exposure levels in CF adults. Prospective clinical evaluation is warranted.

BACKGROUND To better understand the mechanisms of infection with nontuberculous mycobacteria (NTM) in patients with cystic fibrosis (CF), we explore different risk factors associated with NTM positivity in a meta-analysis. METHODS Studies published before 31 July 2019 were selected from MEDLINE. Combined odds ratios (ORs) were calculated by pooling the ORs of each study. The weighted mean difference (WMD) was used for continuous numerical measurements. Summary data were pooled using fixed- or random-effects models according to the presence of heterogeneity (P 50%). RESULTS Nineteen studies with a total of 23 418 patients, of whom 1421 (6%) were diagnosed as NTM positive, were included. Older age was significantly associated with NTM positivity (WMD = 2.12, 95% confidence interval [CI]: 1.11-3.13; P

Early diagnosis of neuroendocrine cell hyperplasia of infancy (NEHI) is crucial as, conversely to the other causes of intersititial lung disease, corticosteroids are not recommended. Diagnosis is historically based on lung biopsy (NEHI), but in current practice, a clinical and radiological approach is more and more preferred (NEHI syndrome). This national study aimed to address diagnosis and initial management of patients followed up for a NEHI pattern in pediatric centers for rare lung diseases (RespiRare, France). Data on neonatal and familial events, symptoms at diagnosis, explorations performed and results, and therapeutic management were collected by questionnaire. Fifty-four children were included (boys 63%). The mean onset of symptoms was 3.8 ± 2.6 months. The most frequent symptoms at diagnosis were tachypnea (100%), retraction (79.6%), crackles (66.7%), and hypoxemia (59.3%). The mean NEHI clinical score, evocative when ≥ 7/10, was 7.9 ± 1.4 (76% with a score ≥ 7). All chest CT-scans showed ground glass opacities evolving at least the middle lobe and the lingula. Lung biopsy was performed in 38.9% of the cases and was typical of NEHI in only 52.4%, even when the clinical presentation was typical. Initial treatments were oxygen (83.6%) and more curiously intravenous pulses of steroids (83.3%) and azithromycin (70.2%).This national cohort of patients underlines diagnosis difficulties of NEHI. A composite clinical and radiological score should help clinicians for limiting the use of anti-inflammatory drugs.•Neuroendocrine cell hyperplasia of infancy (NEHI) is an interstitial lung disease whose diagnosis is essential to limit corticosteroids therapy.•In this national cohort of 54 patients with a NEHI pattern, diagnosis is mainly based on clinical symptoms and chest CT-scan results. The newly proposed clinical score and, when performed, the lung biopsies are faulted in 25 and 50% of the cases, respectively. •Corticosteroids are widely used. Such results plead for a new composite score to formally diagnose NEHI.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are closely monitored in people with cystic fibrosis (pwCF), with a special emphasis on severe cases. Previous studies used hospitalization rates as proxy for severity.We evaluated data from coronavirus disease 2019 (COVID-19) cases diagnosed in French pwCF followed in one of the 47 French CF center over the first year of the pandemic.criteria were applied for defining severity (e.g., respiratory failure and/or death). Data were compared to those from all French pwCF using the French CF Registry.As of April 30, 2021, 223 pwCF were diagnosed with COVID-19, with higher risks in adults (≥18 years, odds ratio [OR] = 2.52, 95% confidence interval [CI] = 1.82-3.48) and post-transplant individuals (OR = 2.68, 95% CI = 1.98-3.63). Sixty (26.9%) patients were hospitalized, with an increased risk in post-transplant individuals (OR = 4.74, 95% CI = 2.49-9.02). In 34 (15%) cases, COVID-19 was considered severe; 28/60 (46.7%) hospitalizations occurred in patients without objective criteria of severity. Severe cases occurred mostly in adults (85.3%) and post-transplant pwCF (61.8%, OR = 6.02, 95% CI = 2.77-13.06). In non-transplanted pwCF, risk factors for severity included low lung function (median ppFEV1 54.6% vs. 75.1%, OR = 1.04, 95% CI = 1.01-1.08) and CF-associated diabetes (OR = 3.26, 95% CI = 1.02-10.4). While most cases recovered without sequelae (n = 204, 91.5%), 16 (13%) were followed for possible sequelae, and three post-transplant females died.Severe COVID-19 cases occurred infrequently during the first year of the pandemic in French pwCF. Non-transplanted adults with severe respiratory disease or diabetes and post-transplant individuals were at risk for severe COVID-19. Thus, specific preventive measures should be proposed.

Initial dosing and dose adjustment of intravenous tobramycin in children with cystic fibrosis (CF) is challenging. The objectives of this study were to develop nonparametric population pharmacokinetic (PK) models of tobramycin in children with CF to be used for dosage design and model-guided therapeutic drug monitoring. We performed a retrospective analysis of tobramycin PK data in our children’s CF center. The Pmetrics package was used for nonparametric population PK analysis and dosing simulations. Both the ratios of maximal concentration to the MIC (C(max)/MIC) and daily area under the concentration-time curve to the MIC (AUC(24)/MIC) were considered efficacy targets. Trough concentration (C(min)) was considered the safety target. A total of 2,884 tobramycin concentrations collected in 195 patients over 9 years were analyzed. A two-compartment model including total body weight, body surface area, and creatinine clearance as covariates best described the data. A simpler model was also derived for implementation in the BestDose software to perform Bayesian dose adjustment. Both models were externally validated. PK/pharmacodynamics (PD) simulations with the final model suggest that an initial dose of tobramycin of 15 to 17.5 mg/kg/day was necessary to achieve C(max)/MICs of ≥10 for MICs up to 2 mg/liter in most patients. The AUC(24)/MIC target was associated with higher dosage requirements and higher C(min). A daily dose of 12.5 mg/kg would optimize both efficacy and safety target attainment. We recommend performing tobramycin therapeutic drug monitoring (TDM), model-based dose adjustment, and MIC determination to individualize intravenous tobramycin therapy in children with CF.

Summary Background Tezacaftor–ivacaftor is an approved cystic fibrosis transmembrane conductance regulator (CFTR) modulator shown to be efficacious and generally safe and well tolerated over 8–24 weeks in phase 3 clinical studies in participants aged 12 years or older with cystic fibrosis homozygous for the Phe508del CFTR mutation (F/F; study 661-106 [EVOLVE]) or heterozygous for the Phe508del CFTR mutation and a residual function mutation (F/RF; study 661-108 [EXPAND]). Longer-term (>24 weeks) safety and efficacy of tezacaftor–ivacaftor has not been assessed in clinical studies. Here, we present results of study 661-110 (EXTEND), a 96-week open-label extension study that assessed long-term safety, tolerability, and efficacy of tezacaftor–ivacaftor in participants aged 12 years or older with cystic fibrosis who were homozygous or heterozygous for the Phe508del CFTR mutation. Methods Study 661-110 was a 96-week, phase 3, multicentre, open-label study at 170 clinical research sites in Australia, Europe, Israel, and North America. Participants were aged 12 years or older, had cystic fibrosis, were homozygous or heterozygous for Phe508del CFTR, and completed one of six parent studies of tezacaftor–ivacaftor: studies 661-103, 661-106, 661-107, 661-108, 661-109, and 661-111. Participants received oral tezacaftor 100 mg once daily and oral ivacaftor 150 mg once every 12 h for up to 96 weeks. The primary endpoint was safety and tolerability. Secondary endpoints were changes in lung function, nutritional parameters, and respiratory symptom scores; pulmonary exacerbations; and pharmacokinetic parameters. A post-hoc analysis assessed the rate of lung function decline in F/F participants who received up to 120 weeks of tezacaftor–ivacaftor in studies 661-106 (F/F) and/or 661-110 compared with a matched cohort of CFTR modulator-untreated historical F/F controls from the Cystic Fibrosis Foundation Patient Registry. Primary safety analyses were done in all participants from all six parent studies who received at least one dose of study drug during this study. This study was registered at ClinicalTrials.gov ( NCT02565914 ). Findings Between Aug 31, 2015, to May 31, 2019, 1044 participants were enrolled in study 661-110 from the six parent studies of whom 1042 participants received at least one dose of study drug and were included in the safety set. 995 (95%) participants had at least one TEAE; 22 (2%) had TEAEs leading to discontinuation; and 351 (34%) had serious TEAEs. No deaths occurred during the treatment-emergent period; after the treatment-emergent period, two deaths occurred, which were both deemed unrelated to study drug. F/F (106/110; n=459) and F/RF (108/110; n=226) participants beginning tezacaftor–ivacaftor in study 661-110 had improvements in efficacy endpoints consistent with parent studies; improvements in lung function and nutritional parameters and reductions in pulmonary exacerbations observed in the tezacaftor–ivacaftor groups in the parent studies were generally maintained in study 661-110 for an additional 96 weeks. Pharmacokinetic parameters were also similar to those in the parent studies. The annualised rate of lung function decline was 61·5% (95% CI 35·8 to 86·1) lower in tezacaftor–ivacaftor-treated F/F participants versus untreated matched historical controls. Interpretation Tezacaftor–ivacaftor was generally safe, well tolerated, and efficacious for up to 120 weeks, and the safety profile of tezacaftor–ivacaftor in study 661-110 was consistent with cystic fibrosis manifestations and with the safety profiles of the parent studies. The rate of lung function decline was significantly reduced in F/F participants, consistent with cystic fibrosis disease modification. Our results support the clinical benefit of long-term tezacaftor–ivacaftor treatment for people aged 12 years or older with cystic fibrosis with F/F or F/RF genotypes. Funding Vertex Pharmaceuticals Incorporated.

ObjectivesLumacaftor-ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) modulator known to improve clinical status in people with cystic fibrosis (CF). This study aimed to assess lung structural changes after one year of lumacaftor-ivacaftor treatment, and to use unsupervised machine learning to identify morphological phenotypes of lung disease that are associated with response to lumacaftor-ivacaftor.MethodsAdolescents and adults with CF from the French multicenter real-world prospective observational study evaluating the first year of treatment with lumacaftor-ivacaftor were included if they had pretherapeutic and follow-up chest computed tomography (CT)-scans available. CT scans were visually scored using a modified Bhalla score. A k-mean clustering method was performed based on 120 radiomics features extracted from unenhanced pretherapeutic chest CT scans.ResultsA total of 283 patients were included. The Bhalla score significantly decreased after 1 year of lumacaftor-ivacaftor (−1.40±1.53 points compared with pretherapeutic CT; p1) ≥5 under lumacaftor–ivacaftor than those in the other clusters (54% of responders versus 32% and 33%; p=0.01).ConclusionOne year treatment with lumacaftor-ivacaftor was associated with a significant visual improvement of bronchial disease on chest CT. Radiomics features on pretherapeutic CT scan may help in predicting lung function response under lumacaftor-ivacaftor.

Background Severe asthma (SA) in children is a complex, heterogeneous disease, associated with a considerable burden. However, factors influencing asthma severity are poorly described and may differ according to age. Objective To determine whether factors associated with asthma severity differ between preschoolers with severe recurrent wheeze (SRW) and school-age children with SA. Methods Data from the French multicenter prospective observational cohort of preschool (3-6 years) children with SRW and nonsevere recurrent wheeze (NSRW) and school-age (7-11 years) children with SA and nonsevere asthma (NSA) (Pediatric Cohort of Bronchial Obstruction and Asthma) were analyzed. Results A total of 131 preschool children (92 SRW and 49 NSRW) and 207 school-age children (92 SA and 115 NSA) were included. In both univariable and multivariable analysis, SRW was associated with second-hand smoke exposure (multivariable analysis: odds ratio [95% CI], 29.8 [3.57-3910]) and exposure to mold/dampness at home (multivariable analysis: odds ratio [95% CI], 4.22 [1.25-18.2]) compared with NSRW. At school-age, history of atopic dermatitis and food allergy was more frequent in children with SA than in those with NSA. Multivariable analysis confirmed that SA was associated with a history of food allergy (odds ratio [95% CI], 5.01 [2.23-11.9]). Conclusions Our data suggest that factors influencing asthma severity may differ according to age. In preschool children with SRW, second-hand smoke and exposure to mold are predominant, whereas associated allergic disorders are mainly involved in SA at school-age.

Resistance of Aspergillus fumigatus to triazoles has been reported increasingly in Europe. As few data are available from Southern France, the objectives of this study were to assess the burden of A. fumigatus isolates with azole resistance from clinical specimens in Lyon, and explore the resistance mechanisms involved. In this retrospective cross-sectional study, 221 consecutive A. fumigatus isolates from respiratory samples were identified from an 8-month period from 195 patients attending the Pulmonary Medicine Departments of Lyon University Hospitals. Morphological identification was confirmed by sequence analysis of the β-tubulin gene. All samples were tested for susceptibilities to itraconazole, voriconazole, posaconazole and isavuconazole using concentration gradient strips, and the results were confirmed using the EUCAST broth microdilution method. Resistance mechanisms were investigated by sequencing the cyp51A gene and its promoter, and by expression analysis of cyp51 and genes encoding several efflux transporters. Four isolates exhibited azole resistance. Three isolates presented with polymorphisms in an intronic region of cyp51A, and one isolate had F46Y, M172V and E427K polymorphisms. No mutations were identified in the cyp51A promoter, but significant induction of cyp51A and cyp51B gene expression was observed for all four and three isolates, respectively. Significant induction of atrF and cdr1B gene expression was observed for two and three isolates, respectively. No significant induction of MDR1/2/3/4, MFS56 and M85 gene expression was observed. To conclude, the observed prevalence of azole resistance was 2.1%. Significant induction of expression of the cyp51 genes and two genes encoding efflux transporters was evidenced, underlying the diversity of resistance mechanisms to be explored.

Lung clearance index (LCI) is a biomarker of ventilation inhomogeneity. Data are scarce on its usefulness in daily practice for monitoring the effects of treatments in older children and adults with CF. In this French observational study of lumacaftor-ivacaftor, 63 of 845 patients (7.5%) had available LCI performed at baseline and at six (M6; n=34) or 12 months (M12; n=46) after lumacaftor-ivacaftor initiation. At inclusion, median [IQR] age was 16 years [13-17], ppFEV1 was 72.8 [59.6-80.7], and LCI was 12.3 [10.3-15.0]. At both M6 and M12, no statistically significant LCI increases of 0.13 units or 1.34% (95% CI: -4.85-7.53) and 0.6 units or 6.66% (95% CI: -0.03-13.5) were observed. Discordant results between LCI and ppFEV1 were observed in one-third of the patients. In daily practice, LCI monitoring in adolescents and young adults with moderate lung disease gives results that are more heterogenous than those reported in children with milder disease.

Lung damage in cystic fibrosis (CF) is strongly associated with lower airway infections. Early treatment of Pseudomonas aeruginosa is recommended. Pathogen detection requires sampling of lower airway secretions, which remains a challenge in nonexpectorating patients. Our hypothesis was that chest physiotherapy would improve the quality of airway secretion samples and increase the rates of pathogens detected in nonexpectorating patients.This prospective multicentre study compared three successive methods for sampling airway secretions applied through the same session: 1) an oropharyngeal swab (OP), 2) a chest physiotherapy session followed by a provoked cough to obtain sputum (CP-SP) and 3) a second oropharyngeal swab collected after chest physiotherapy (CP-OP). Haemophilus influenzae, Staphylococcus aureus and P. aeruginosa growth cultures were assessed. Accuracy tests and an equivalence test were performed to compare the three successive methods of collection.300 nonexpectorating children with CF were included. P. aeruginosa was detected cumulatively in 56 (18.9%) children, and according to the different collection methods in 28 (9.8%), 37 (12.4%) and 44 (14.7%) children by using OP, CP-OP and CP-SP, respectively. Compared with OP, the increased detection rate was +22% for CP-OP (p=0.029) and +57% for CP-SP (p=0.003). CP-SP had the best positive predictive value (86.3%) and negative predictive value (96.0%) for P. aeruginosa compared with the overall detection.The results of this adequately powered study show differences in the rates of pathogens detected according to the sampling method used. Chest physiotherapy enhanced detection of P. aeruginosa in nonexpectorating children with CF.

We assessed the diagnostic performances of homeostasis model assessment indices (HOMA) of β-cell function (HOMA-%β) and of insulin resistance (HOMA-IR) for cystic fibrosis related diabetes (CFRD) screening.Data were collected from a prospective cohort of 228 patients with CF (117 adults and 111 children). Fasting insulin and glucose levels were measured to calculate HOMA-%β and HOMA-IR. HOMA-%β100 indicated insulin secretion deficiency and HOMA-IR1 insulin resistance. Both were used to calculate sensitivity, specificity, and positive and negative predictive values (PPV and NPV). Two-hour oral glucose tolerance tests (2h-OGTT) defined CFRD. Analyses were conducted separately for children and adults. Performances of HOMA-%β and HOMA-IR were calculated at inclusion, for each year of follow-up and for pooled data over the follow-up period.Sensitivity, specificity, NPV and PPV were respectively: 88%, 45%, 98% and 11% for HOMA-%β and 42%, 48%, 91% and 6% for HOMA-IR in the pooled data of children; and 83%, 18%, 90% and 10% for HOMA-%β, and 39%, 80%, 92% and 18% for HOMA-IR in the pooled data of adults. Combining HOMA-%β and HOMA-IR did not improve performances.Within both age groups, HOMA-%β100 provided good sensitivity and NPV. HOMA-IR1 had low sensitivity. Calculation of the HOMA-%β could be an interesting first-line screening approach to exclude CFRD and thus avoid unnecessary OGTT in patients for whom value is ≥100. However, HOMA-%β100 does not support the diagnosis of CFRD and should be complemented by OGTT.

Lung damage in cystic fibrosis (CF) is strongly associated with lower airway infections. Early treatment of Pseudomonas aeruginosa is recommended. Pathogen detection requires sampling of lower airway secretions, which remains a challenge in nonexpectorating patients. Our hypothesis was that chest physiotherapy would improve the quality of airway secretion samples and increase the rates of pathogens detected in nonexpectorating patients. This prospective multicentre study compared three successive methods for sampling airway secretions applied through the same session: 1) an oropharyngeal swab (OP), 2) a chest physiotherapy session followed by a provoked cough to obtain sputum (CP-SP) and 3) a second oropharyngeal swab collected after chest physiotherapy (CP-OP). Haemophilus influenzae, Staphylococcus aureus and P. aeruginosa growth cultures were assessed. Accuracy tests and an equivalence test were performed to compare the three successive methods of collection. 300 nonexpectorating children with CF were included. P. aeruginosa was detected cumulatively in 56 (18.9%) children, and according to the different collection methods in 28 (9.8%), 37 (12.4%) and 44 (14.7%) children by using OP, CP-OP and CP-SP, respectively. Compared with OP, the increased detection rate was +22% for CP-OP (p=0.029) and +57% for CP-SP (p=0.003). CP-SP had the best positive predictive value (86.3%) and negative predictive value (96.0%) for P. aeruginosa compared with the overall detection. The results of this adequately powered study show differences in the rates of pathogens detected according to the sampling method used. Chest physiotherapy enhanced detection of P. aeruginosa in nonexpectorating children with CF., Sputum collection after a chest physiotherapy session strongly enhances the detection of P. aeruginosa in nonexpectorating CF children compared with the commonly used oropharyngeal swab method. Oropharyngeal swab after physiotherapy may be an acceptable alternative. https://bit.ly/3757ewq

International audience; Background: Phase 3 trials have demonstrated the safety and efficacy of lumacaftor-ivacaftor (LUMA-IVA) in patients with cystic fibrosis (CF) homozygous for the Phe508del CFTR mutation and percent predicted forced expiratory volume in 1 s (ppFEV1) between 40 and 90. Marketing authorizations have been granted for patients at all levels of ppFEV1.Methods: To evaluate the safety and effectiveness of LUMA-IVA over the first year of treatment in patients with ppFEV1

The combination of lumacaftor and ivacaftor (LUM/IVA) has been reported to induce a mean acute absolute drop of -4.1% predicted forced expiratory volume in 1s (FEV1) after a unique administration in healthy subjects. The aim of the present study was to assess acute FEV1 changes after the first dose of LUM/IVA in CF patients. A total of 32 pediatric patients were included. Respiratory manifestations occurred in only 3 patients (9.4%), but FEV1 consistently decreased (-10.4±4.6%, range: -1.5; -21.8%). FEV1 only partially resumed after salbutamol inhalation. Patients with previously known significant reversible airway obstruction and low FEV1 were more at risk of FEV1 decrease.

Respiratory syncytial virus (RSV) infections may worsen cystic fibrosis (CF) lung disease and favor Pseudomonas aeruginosa (Pa) or Staphylococcus aureus (Sa) acquisition, which is of particular importance in the youngest patients. We aimed to determine the effectiveness of PVZ on microbiological outcomes in young children with CF. We conducted a retrospective case-control study to compare these outcomes in children who systematically received PVZ (PVZ+; n = 40) or not (PVZ-; n = 140). One case was matched with at least three same-gender controls born the same year and month. Median (range) age at first Pa isolation was not statistically different between PVZ- (12.3 [3.8-32.6] months) and PVZ+ (10.4 [1.2-33.0] months; p = 0.953) patients. A similar trend was found for Sa (PVZ+: 6.4 [2.0-59.0] months; PVZ-: 3.8 [0.1-74.1] months; p = 0.191). The proportion of Pa isolations by 3 years of age did not differ between groups (PVZ+ 40% vs. PVZ- 41.4%), but this proportion was higher for Sa in the PVZ+ group (97%) than in the PVZ- group (85%; p = 0.001). Healthcare consumption and growth outcomes did not significantly differ between groups.Systematic PVZ use did not delay key pathogen acquisition in young children with CF. What is known: • Palivizumab is the only available monoclonal antibody against respiratory syncytial virus infection. • Whether or not it is useful in infants with cystic fibrosis remains controversial. What is new: • Palivizumab does not delay key pathogens (Pseudomonas aeruginosa, Staphylococcus aureus) first isolation in young children with cystic fibrosis. • Palivizumab does not reduce healthcare consumption or improve growth during the first 3 years of life of young children with cystic fibrosis.

Actinomycosis is a rare bacterial disease caused by Actinomyces spp., an anaerobic bacteria from the oropharynx, digestive, and female genital tracts. Initial clinical presentation often mimics malignancy, which can lead to a delay in diagnosis. Cervico-facial, genitourinary, digestive, and respiratory features are the most frequent. Few cases are reported in children and risk factors are not well known in this population. We report on the case of an 8-year-old boy with disseminated actinomycosis with cervico-facial, pulmonary, and bone involvement caused by Actinomyces israelii. The infiltrative appearance initially suggested malignancy and the patient was started on chemotherapy for presumed histiocytosis. Evaluation of subsequent tissue samples demonstrated the presence of filamentous structures consistent with fungal or filamentous bacterial infection. Prolonged culture yielded the correct diagnosis. The patient had a severe allergic reaction to piperacillin/tazobactam and was therefore transitioned to clindamycin to complete a 9-month course. This treatment, which has not been reported in children, led to a favorable clinical, biological, and radiological response, with a good clinical tolerance.

International audience; Rationale: Lumacaftor-ivacaftor is a CFTR (cystic fibrosis transmembrane conductance regulator) modulator combination recently approved for patients with cystic fibrosis (CF) homozygous for the Phe508del mutation.Objectives: To evaluate the safety and effectiveness of lumacaftor-ivacaftor in adolescents (≥12 yr) and adults (≥18 yr) in a real-life postapproval setting.Methods: The study was conducted in the 47 CF reference centers in France. All patients who initiated lumacaftor-ivacaftor from January 1 to December 31, 2016, were eligible. Patients were evaluated for lumacaftor-ivacaftor safety and effectiveness over the first year of treatment following the French CF Learning Society's recommendations.Measurements and Main Results: Among the 845 patients (292 adolescents and 553 adults) who initiated lumacaftor-ivacaftor, 18.2% (154 patients) discontinued treatment, often owing to respiratory (48.1%, 74 patients) or nonrespiratory (27.9%, 43 patients) adverse events. In multivariable logistic regression, factors associated with increased rates of discontinuation included adult age group, percent predicted FEV1 (ppFEV1) less than 40%, and numbers of intravenous antibiotic courses during the year before lumacaftor-ivacaftor initiation. Patients with continuous exposure to lumacaftor-ivacaftor showed an absolute increase in ppFEV1 (+3.67%), an increase in body mass index (+0.73 kg/m2), and a decrease in intravenous antibiotic courses by 35%. Patients who discontinued treatment had significant decrease in ppFEV1, without improvement in body mass index or decrease in intravenous antibiotic courses.Conclusions: Lumacaftor-ivacaftor was associated with improvement in lung disease and nutritional status in patients who tolerated treatment. Adults who discontinued lumacaftor-ivacaftor, often owing to adverse events, were found at high risk of clinical deterioration.

Introduction: Health-related quality of life (HR-QoL) is an understudied area in rare diseases. Interstitial lung diseases in children (chILD) are heterogeneous disorders that are associated with a high morbidity and mortality. The impaired lung function, the nutritional impact and the burden of the treatments can impair the HR-QoL of these children. The aim of this study was to compare the HR-QoL in chILD to an aged-matched healthy population and to identify the factors that were associated to an altered QoL. Methods: Patients were recruited in the French RespiRare network. Patients with chILD of all causes, aged 1 month to 18 years were prospectively included. The children over 8 years old and the 2 parents of all children were asked to complete the PedsQLTM 4.0 Generic Core Scale (0 to 100 points). Results: A total of 78 children were included in the RespiRare centres. Total mean scores appeared to be significantly reduced in child self-report and in parent proxy-report (11.94 points (p=0.0003) and 14.08 points (p Conclusion: The study shows that HR-QoL is significantly impaired in chILD compared to a healthy population, using a validated generic QoL scale. Factors altering QoL score are easy to recognize and could help identify children at a heightened risk of low QoL. A longitudinal follow-up of HR-QoL in chILD is necessary to follow the impact of the disease and the treatments. To better appreciate chILD QoL, a specific scale is currently under study by the chILD-EU group.

Viral respiratory tract infections are common during early childhood. How they impact cystic fibrosis lung disease history in young children is poorly known. The principal aim of our study was to determinate respiratory tract infections frequency in this cystic fibrosis young population. Secondary outcomes were nature of viral agents recovered and impact of such infections. We conducted a prospective cohort study of 25 children affected by cystic fibrosis and aged less than 2 years. Nasal samplings were taken systematically monthly or bimonthly with additional samples taken during respiratory tract infections episodes. Ten pathogens were tested by a combination of five duplex RT-PCRs or PCRs: influenza A and B, respiratory syncytial virus (RSV), metapneumovirus (MPV), rhinovirus/enterovirus (RV/EV)), coronavirus (HKU1, NL63, 229E and OC43), parainfluenza virus (1–4), adenovirus and bocavirus (Respiratory Multi-Well System MWS r-gene®, BioMerieux, Marcy l’Etoile, France). Cycle thresholds (CTs) were reported for all positive samples and considered positive for values below 40. Quantitative variables were compared using a nonparametric statistical test (Wilcoxon signed rank for paired comparisons). Pearson’s correlation coefficient (r) was used to assess relationships between two variables. Statistical analyses were performed using SAS v9.4 (SAS Institute, Cary, NC, USA) or GraphPad Prism V6.00 (GraphPad Software, La Jolla, CA, USA). The significance level was set at 0.05. The mean age at inclusion was 9.6 ± 6.7 months. The patients had 3.4 ± 1.7 respiratory tract infections episodes per child per year. Forty-four respiratory tract infections (69%) were associated with virus: rhinovirus and enterovirus (RV/EV) were implied in 61% of them and respiratory syncytial virus (RSV) in 14%. Only one patient required hospitalization for lower respiratory tract infections. 86% of the patients were treated by antibiotics for a mean of 13.8 ± 6.2 days. RSV infections (n = 6) were usually of mild severity. Respiratory tract infections in young children with cystic fibrosis were of mild severity, rarely requiring hospitalization. Unsurprisingly, RV/EV were the most frequent agents. RSV-related morbidity seems low in this population. This raises the question of the usefulness of RSV preventive medication in this young population.

Background Hypersensitivity pneumonitis (HP) is a rare interstitial lung disease in children, and very little data are available on the frequency, diagnosis, and outcomes of HP. In a pediatric cohort with HP, the characteristics of the CD4/CD8 lymphocyte ratio are often described as nonspecific. Methods We used the National French Database (RespiRare) to collect data from the last decade on HP. The diagnosis of HP was defined by the presence of a relevant exposure, clinical symptoms, and compatible lung imaging radiology and was usually defined by positive precipitins antibodies. Results A total of 16 children with a mean age of 10 years (4-13) presented with HP. All children presented with dyspnea on exertion. Diffuse ground-glass opacity was present in all computed tomography (CT) scans. Research guided by a questionnaire and precipitins antibodies against the corresponding antigens showed that patients were positive for contact with birds with or without fungi. Bronchoalveolar lavage (BAL) was performed in 12 children. The total cell counts were elevated in BAL fluid, with a mean value of 36% lymphocytes. The CD4/CD8 lymphocyte ratio was below one for all children. Conclusion BAL in our pediatric cohort with HP had the same characteristics as that of adults with HP. An HP diagnosis must be considered when dyspnea on exertion and diffuse ground-glass opacity are observed. Carrying out BAL and serological tests can help diagnose and avoid lung biopsy.

Background Shortcomings of inhaled antibiotic treatments for Pseudomonas aeruginosa infection in patients with cystic fibrosis (CF) include poor drug penetration, inactivation by sputum, poor efficiency due to protective biofilm, and short residence in the lung. Methods Eligible patients with forced expiratory volume in 1 s (FEV1) ≥25% of predicted value at screening and CF with chronic P. aeruginosa infection were randomly assigned to receive 3 treatment cycles (28 days on, 28 days off) of amikacin liposome inhalation suspension (ALIS, 590 mg QD) or tobramycin inhalation solution (TIS, 300 mg BID). The primary endpoint was noninferiority of ALIS vs TIS in change from baseline to day 168 in FEV1 (per-protocol population). Secondary endpoints included change in respiratory symptoms by Cystic Fibrosis Questionnaire-Revised (CFQ-R). Results The study was conducted February 2012 to September 2013. ALIS was noninferior to TIS (95% CI, −4.95 to 2.34) for relative change in FEV1 (L) from baseline. The mean increases in CFQ-R score from baseline on the Respiratory Symptoms scale suggested clinically meaningful improvement in both arms at the end of treatment in cycle 1 and in the ALIS arm at the end of treatment in cycles 2 and 3; however, the changes were not statistically significant between the 2 treatment arms. Treatment-emergent adverse events (TEAEs) were reported in most patients (ALIS, 84.5%; TIS, 78.8%). Serious TEAEs occurred in 17.6% and 19.9% of patients, respectively; most were hospitalisations for infective pulmonary exacerbation of CF. Conclusions Cyclical dosing of once-daily ALIS was noninferior to cyclical twice-daily TIS in improving lung function. ClinicalTrials.gov Identifier: NCT01315678