Exposure to inorganic particles in paediatric sarcoidosis: the PEDIASARC study.

Inorganic antigens may contribute to paediatric sarcoidosis. Thirty-six patients matched with 36 healthy controls as well as a group of 21 sickle-cell disease (SCD) controls answered an environmental questionnaire. Patients' indirect exposure to inorganic particles, through coresidents' occupations, was higher than in healthy and SCD controls (median score: 2.5 (0.5-7) vs 0.5 (0-2), p=0.003 and 1 (0-2), p=0.012, respectively), especially for construction, exposures to metal dust, talc, abrasive reagents and scouring products. Wood or fossil energies heating were also linked to paediatric sarcoidosis. This study supports a link between mineral environmental exposure due to adult coresident occupations and paediatric sarcoidosis.

Pulmonary Alveolar Microlithiasis in Children Less than 5 Years of Age.

OBJECTIVE: To collect all published cases up to January 2019 of pulmonary alveolar microlithiasis (PAM) in patients age 5 years and under and to compare their characteristics with those of the 1022 cases in the most recent all-age cohort published in 2015. STUDY DESIGN: We identified 28 cases of PAM worldwide in children age 5 years and under, accounting for only 2%-3% of all cases. RESULTS: Children seem more frequently symptomatic, notably with more cough and severe acute respiratory failure, but had no reported extrapulmonary manifestation. Children with PAM evidenced less typical radiologic findings, with frequent ground glass opacities not reported in adult cases and milder calcifications as less frequent, smaller, and mainly restricted to the lower lobes. CONCLUSIONS: PAM remains an uncommon diagnosis in young children, as symptoms and radiologic findings are less specific. Physicians should be aware to look for calcifications in chest computed tomography at mediastinal window and avoid elution of the bronchoalveolar lavage to find microliths. Collecting longitudinal data through an international registry would help in characterizing PAM to predict disease progression and plan lung transplantation.

Reduced Intestinal Inflammation With Lumacaftor/Ivacaftor in Adolescents With Cystic Fibrosis.

A chronic intestinal inflammation may occur in patients with cystic fibrosis (CF), while no therapeutic management is proposed. Although Lumacaftor/Ivacaftor is well-known to modulate the defective cystic fibrosis transmembrane conductance regulator (CFTR) protein in lungs, no data are available on the impact of this treatment on CF intestinal disorders. We, therefore, investigated the evolution of intestinal inflammation after initiation of Lumacaftor/Ivacaftor in CF adolescents (median of follow-up: 336 days [IQR: 278;435]). Median fecal calprotectin concentrations decreased significantly after Lumacaftor/Ivacaftor initiation (102 µg/g [IQR: 69-210]) compared with the baseline (713 µg/g (IQR:148-852), P = 0.001). To our knowledge, this study showed for the first time that CF-related intestinal inflammation is improved by Lumacaftor/Ivacaftor treatment.

Management of initial colonisations with Burkholderia species in France, with retrospective analysis in five cystic fibrosis Centres: a pilot study.

BACKGROUND: Whereas Burkholderia infections are recognized to impair prognosis in cystic fibrosis (CF) patients, there is no recommendation to date for early eradication therapy. The aim of our study was to analyse the current management of initial colonisations with Burkholderia cepacia complex (BCC) or B. gladioli in French CF Centres and its impact on bacterial clearance and clinical outcome. METHODS: We performed a retrospective review of the primary colonisations (PC), defined as newly positive sputum cultures, observed between 2010 and 2018 in five CF Centres. Treatment regimens, microbiological and clinical data were collected. RESULTS: Seventeen patients (14 with BCC, and 3 with B. gladioli) were included. Eradication therapy, using heterogeneous combinations of intravenous, oral or nebulised antibiotics, was attempted in 11 patients. Six out of the 11 treated patients, and 4 out of the 6 untreated patients cleared the bacterium. Though not statistically significant, higher forced expiratory volume in 1 second and forced vital capacity at PC and consistency of treatment with in vitro antibiotic susceptibility tended to be associated with eradication. The management of PC was shown to be heterogeneous, thus impairing the statistical power of our study. Large prospective studies are needed to define whom to treat, when, and how. CONCLUSIONS: Pending these studies, we propose, due to possible spontaneous clearance, to check the presence of Burkholderia 1 month after PC before starting antibiotics, at least in the milder cases, and to evaluate a combination of intravenous beta-lactam + oral or intravenous fluoroquinolone + inhaled aminoglycoside.

Association between asthma and lung function in adolescents born very preterm: results of the EPIPAGE cohort study.

Prematurity and bronchopulmonary dysplasia (BPD) affect long-term lung function. We studied the respiratory outcome of adolescents born very preterm and controls from the Etude EPIdémiologique sur les Petits Ages Gestationnels cohort and analysed their current lung function in relation to asthma symptoms (categorised in three age groups) from birth. In models including BPD, asthma at each age and confounding factors in the preterm group, BPD and preschool wheeze were the only independent variables associated with FEV1 Preschool wheeze is an independent factor associated with FEV1 impairment in adolescents born very preterm. These results highlight the need for optimal management of early respiratory symptoms in preterm-born infants. TRIAL REGISTRATION NUMBER: Results, NCT01424553.

Lumacaftor/Ivacaftor Population Pharmacokinetics in Pediatric Patients with Cystic Fibrosis: A First Step Toward Personalized Therapy.

BACKGROUND: A major breakthrough in cystic fibrosis (CF) therapy was achievedAQ1 with CFTR modulators. The lumacaftor/ivacaftor combination is indicated for the treatment of CF in pediatric patients above 6 years old. Pharmacokinetic (PK) studies of lumacaftor/ivacaftor in these vulnerable pediatric populations are AQ2crucial to optimize treatment protocols. OBJECTIVES AND METHODS: The objectives of this study were to describe the population PK (PPK) of lumacaftor and ivacaftor in children with CF, and to identify factors associated with interindividual variability. The association between drug exposure and clinical response was also investigated. RESULTS: A total of 75 children were included in this PPK study, with 191 concentrations available for each compound and known metabolites (lumacaftor, ivacaftor, ivacaftor-M1, and ivacaftor-M6). PPK analysis was performed using Monolix software. A large interindividual variability was observed. The main sources of interpatient variability identified were patient bodyweight and hepatic function (aspartate aminotransferase). Forced expiratory volume in the first second (FEV1) was statistically associated with the level of exposure to ivacaftor after 48 weeks of treatment. CONCLUSIONS: This study is the first analysis of lumacaftor/ivacaftor PPK in children with CF. These data suggest that dose adjustment is required after identifying variability factors to optimize efficacy. The use of therapeutic drug monitoring as a basis for dose adjustment in children with CF may be useful.

Antioxidant potential is correlated to ω6 / ω3 ratio and Brasfield score in cystic fibrosis children.

OBJECTIVES: Oxidative stress is associated with the condition of cystic fibrosis (CF), but no guidelines exist for its assessment or treatment. Our aim was to evaluate a test that measures the blood antioxidant capability in CF children. METHODS: This antioxidant capability was assessed by the Kit Radicaux Libres (KRL) test in 44 CF children (24 boys). We recorded also anthropometric measures, pulmonary function, CF severity scores, and plasma nutritional and inflammatory parameters (proteins, vitamins, erythrocyte fatty acids, and micronutrients). We performed univariate and multivariate analyses with linear regression models. RESULTS: The mean age at the first KRL assessment was 12.2 ± 3.8 years. Factors that correlated with decreased antioxidant capacity were mostly related to the severity of pulmonary disease [ forced expiratory volume at 1 second (FEV1), acute exacerbation, and congestion. In multivariate analysis, the correlation between Brasfield score and erythrocyte antioxidant potential remained significant (ß = - 0.611, p < 0.001). Among nutritional factors, the ω6/ω3 ratio was significantly correlated to erythrocyte antioxidant potential (ß = - 1.213, p = 0.01). CONCLUSION: The blood antioxidant capability, measured by the KRL test, appears to be an interesting biomarker to evaluate oxidative stress in CF. This study suggests that the ω6/ω3 ratio should be regarded as a nutritional marker in antioxidant management in CF children.

[Transition from pediatric to adult care in chronic respiratory diseases: The cystic fibrosis model]. / Transition des patients atteints d'une maladie respiratoire chronique depuis la pédiatrie vers les services pour adultes - L'exemple de la mucoviscidose.

Increased life expectancy in cystic fibrosis has made transition from pediatric to adult cystic fibrosis centers a crucial step for patients, their families and caregivers. This transition must be gradual and carefully prepared. A formalized process, early discussion with patients and families about transition, patient's empowerment prior to transfer, and close links between pediatric and adult teams are key points to succeed. Therapeutic education, validated questionnaires, personalized action plans or connected tools can help. Transfer will take place at the appropriate time for each patient, ideally during a period of disease stability, in a progressive manner, with joint or alternating consultations between pediatric and adult cystic fibrosis center teams. Other chronic respiratory diseases with pediatric onset may benefit from similar transition processes.

Title: Transition des patients atteints d'une maladie respiratoire chronique depuis la pédiatrie vers les services pour adultes - L'exemple de la mucoviscidose. Abstract: Du fait de l'augmentation de l'espérance de vie des individus atteints de mucoviscidose, la transition de la pédiatrie vers les services de médecine pour adultes est devenue une étape essentielle pour les patients, les aidants et les soignants. Cette transition doit être progressive et longuement préparée. Avoir un processus établi et formalisé, aborder tôt le thème de la transition avec le patient et sa famille, autonomiser le patient avant le transfert et établir des liens étroits entre les structures médicales pédiatriques et pour adultes sont des éléments importants pour la réussite de cette étape. L'éducation thérapeutique ainsi que l'utilisation de questionnaires validés, d'un plan d'action personnalisé ou d'outils connectés peuvent aider. Le transfert se fera au moment le mieux adapté pour le patient, idéalement en période de stabilité de la maladie, de manière progressive, avec des consultations conjointes ou alternées entre les équipes de pédiatrie et de médecine pour adultes. D'autres maladies respiratoires chroniques débutant dans l'enfance ou à l'adolescence pourront bénéficier d'un processus de transition similaire.

Higher levels of Pseudomonas aeruginosa LasB elastase expression are associated with early-stage infection in cystic fibrosis patients.

Pseudomonas aeruginosa is a common pathogen in cystic fibrosis (CF) patients and a major contributor to progressive lung damage. P. aeruginosa elastase (LasB), a key virulence factor, has been identified as a potential target for anti-virulence therapy. Here, we sought to differentiate the P. aeruginosa isolates from early versus established stages of infection in CF patients and to determine if LasB was associated with either stage. The lasB gene was amplified from 255 P. aeruginosa clinical isolates from 70 CF patients from the Toulouse region (France). Nine LasB variants were identified and 69% of the isolates produced detectable levels of LasB activity. Hierarchical clustering using experimental and clinical data distinguished two classes of isolates, designated as 'Early' and 'Established' infection. Multivariate analysis revealed that the isolates from the Early infection class show higher LasB activity, fast growth, tobramycin susceptibility, non-mucoid, pigmented colonies and wild-type lasR genotype. These traits were associated with younger patients with polymicrobial infections and high pFEV1. Our findings show a correlation between elevated LasB activity in P. aeruginosa isolates and early-stage infection in CF patients. Hence, it is this patient group, prior to the onset of chronic disease, that may benefit most from novel therapies targeting LasB.

Exploration of the relationship between cumulative exposure to tobramycin and ototoxicity in patients with cystic fibrosis.

BACKGROUND: Aminoglycosides (AGs), such as tobramycin, are essential antibiotics in the management of pulmonary infections in patients with cystic fibrosis (CF). They induce ototoxicity without the relationship being clearly described in the literature. Our aim is to propose a mathematical and statistical model describing the relationship between the estimated cumulative exposure (Area Under the Curve, AUC) to tobramycin and ototoxicity with audiogram interpretation in young patients with CF. METHODS: Cumulative AUCs were estimated for each course of tobramycin, for the 106 individuals with CF (between 4 and 22 years of age) enrolled in this retrospective study (35 who had received IV tobramycin, 71 controls). Mean hearing loss was calculated for each audiogram and a statistical model was developed to predict hearing loss. RESULTS: The model confirms a significant relationship between cumulative tobramycin exposure and changes in hearing acuity: Meanhearingloss=2.7+(3×10-5)×AUC_tobramycin+individual_susceptibility However, the ototoxic effect is not clinically perceptible (mean hearing loss: 3.8 dB). The impact of AUC on hearing loss is minor in these subjects who received a limited number of courses of tobramycin (median: 5 courses). CONCLUSION: A significant relationship between cumulative exposure to tobramycin and ototoxicity was demonstrated. Individual treatment susceptibility should not be overlooked. As ototoxicity is not clinically perceptible in the study subjects, hearing tests should be continued during adulthood to provide individualized medical guidance and to obtain a lifetime analysis of the relationship between exposure and hearing loss.

Pediatrician intervention impacts parental smoking in cystic fibrosis, diabetes, and bronchiolitis.

BACKGROUND: Child exposure to cigarette smoke is harmful. It should be reduced through parental smoking cessation interventions. The aim of our study was to determine the impact of simple advice provided by the pediatrician on the smoking habits of parents of children with cystic fibrosis (CF), diabetes mellitus (DM), and infants hospitalized for bronchiolitis. METHODS: Parents were interviewed on their smoking habits. Smoking cessation advice was provided by the pediatrician. A new smoking habits assessment was done at 3 months by phone interviews. RESULTS: A total of 260 parents were interviewed (91 in the CF group, 136 in the DM group, and 33 in the bronchiolitis group). A total of 70 parents were active smokers: 33% of parents of children with CF, 23.5% of parents of children with DM, and 24.2% for those with infants hospitalized for bronchiolitis (p = .42). In the CF group, smoking cessation had been significantly more frequently discussed with the medical team previously. A total of 67 smoking parents (95.7%) answered the 3-month assessment: 29.8% reported having started a smoking cessation process; 10.4% had quit smoking. The quitting rate was significantly higher in the groups of patients followed for a respiratory disorder (37.5% for bronchiolitis, 15% for CF vs. 0% for DM, p = .005). CONCLUSION: This study shows the important role that information and simple advice from pediatricians can have in initiating smoking cessation in parents of patients followed in specialized clinics or who are hospitalized, with a greater efficiency in parents of patients suffering from lung disorders.

Long-Term Outcomes in Real Life of Lumacaftor-Ivacaftor Treatment in Adolescents With Cystic Fibrosis.

Background: The combination of the CFTR corrector lumacaftor (LUM) and potentiator ivacaftor (IVA) has been labeled in France since 2015 for F508del homozygote cystic fibrosis (CF) patients over 12 years. In this real-life study, we aimed (i) to compare the changes in lung function, clinical (e.g., body mass index and pulmonary exacerbations) and radiological parameters, and in sweat chloride concentration before and after initiation of LUM/IVA treatment; (ii) to identify factors associated with response to treatment; and (iii) to assess the tolerance to treatment. Materials and Methods: In this tri-center, non-interventional, and observational cohort study, children (12-18 years old) were assessed prospectively during the 2 years of therapy, and retrospectively during the 2 years preceding treatment. Data collected and analyzed for the study were exclusively extracted from the medical electronic system records of the patients. Results: Forty adolescents aged 12.0-17.4 years at LUM/IVA initiation were included. The lung function decreased significantly during and prior to treatment and increased after LUM/IVA initiation, becoming significant after 2 years of treatment. LUM/IVA significantly improved the BMI Z-score and sweat chloride concentration. By contrast, there was no significant change in exacerbation rates, antibiotic use, or CT scan scores. Age at LUM/IVA initiation was lower in good responders and associated with greater ppFEV1 change during the 2 years of treatment. LUM/IVA was well-tolerated. Conclusion: In F508del homozygote adolescents, real-life long-term LUM/IVA improved the ppFEV1 trajectory, particularly in the youngest patients, nutritional status, and sweat chloride concentration but not exacerbation rates or radiological scores. LUM/IVA was generally well-tolerated and safe.

Chest physiotherapy enhances detection of Pseudomonas aeruginosa in nonexpectorating children with cystic fibrosis.

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.

Increased Fecal Calprotectin Is Associated with Worse Gastrointestinal Symptoms and Quality of Life Scores in Children with Cystic Fibrosis.

In cystic fibrosis (CF), cystic fibrosis transmembrane regulator (CFTR) dysfunction leads to digestive disorders that promote intestinal inflammation and dysbiosis enhancing gastrointestinal symptoms. In pancreatic insufficiency CF patients, both intestinal inflammation and dysbiosis, are associated with an increase in the fecal calprotectin (FC) level. However, associations between the FC level, gastrointestinal symptoms, and quality of life (QoL) remain poorly studied. We aimed to assess such associations in pancreatic insufficiency CF children. The FC level was measured in pancreatic insufficiency CF children's stool samples. Children and their parents completed two questionnaires: The Gastrointestinal Symptoms Scales 3.0-PedsQLTM and the Quality of Life Pediatric Inventory 4.0-PedsQLTM. Lower scores indicated worse symptomatology or QoL. Thirty-seven CF children were included. A FC level above 250 µg/g was associated with worse gastrointestinal symptoms and QoL scores. The FC level was inversely correlated with several gastrointestinal scores assessed by children (i.e., Total, "Heart Burn Reflux", "Nausea and Vomiting", and "Gas and Bloating"). Several QoL scores were correlated with gastrointestinal scores. The FC level was weakly associated with clinical parameters. Some gastrointestinal and QoL scores were related to disease severity associated parameters. In CF, the FC level, biomarker previously related to intestinal inflammation and dysbiosis, was associated with worse digestive symptoms and QoL scores.

Nitric oxide and carbon monoxide lung transfer in patients with advanced liver cirrhosis.

In advanced cirrhosis, decreased lung transfer for carbon monoxide (TLCO) and increased alveolar-arterial oxygen tension difference (PA-aO(2) >or=15 mmHg while breathing ambient air) are frequently detected. Pulmonary membrane diffusion capacity for CO (DmCO) and pulmonary capillary blood volume (Vcap) can be derived from the simultaneous measurement of TLCO and lung transfer for nitric oxide (TLNO). Measurements of single-breath TLNO and TLCO were performed in 49 cirrhotic patients with advanced liver cirrhosis and in 35 healthy controls to derive Vcap, DmCO, and TLNO:TLCO ratio. Twenty-five patients had increased PA-aO(2), of whom 11 had hepatopulmonary syndrome (HPS). Compared with controls, non-HPS patients with normal PA-aO(2) had a significant approximately 10% decrease in TLCO, DmCO, and Vcap but similar TLNO:TLCO ratios. Compared with non-HPS patients with normal PA-aO(2), non-HPS patients with increased PA-aO(2) had lower Vcap and higher TLNO:TLCO ratio but similar DmCO. HPS patients had lower Vcap and higher TLNO:TLCO ratios than both subgroups of non-HPS patients. In cirrhotic patients, TLNO:TLCO ratios correlated positively, and TLCO (percentage of the predicted value) and Vcap (percentage of the predicted value) correlated negatively with PA-aO(2) (r(2) = 0.25, P = 0.0003, r(2) = 0.48, P < 0.0001 and r(2) = 0.57, P < 0.0001, respectively). We concluded that, in cirrhotic patients, lower TLCO and increased PA-aO(2) are associated with lower Vcap. In addition, high TLNO:TLCO ratios in patients with increased PA-aO(2) suggest a decreased thickness of the capillary blood layer in these patients.

Educational and health outcomes associated with bronchopulmonary dysplasia in 15-year-olds born preterm.

INTRODUCTION: To evaluate the consequences of bronchopulmonary dysplasia (BPD) on academic outcomes and healthcare use in adolescents born very preterm. METHODS: This cohort study included 15-year-old adolescents born very preterm (< 32 weeks) between 2011 and 2013, with and without BPD, and controls born full term. Data regarding academic performance, current medical follow-up, and family characteristics were collected. Multivariate logistic regression was used to quantify relationships between academic outcomes and BPD. RESULTS: From the 1341 children included in the initial cohort, 985 adolescents were eligible and 351 included (55 preterms with a history of BPD, 249 without, and 47 controls). Among adolescents born very preterm, a history of BPD was associated with a higher risk to attend a school for children with special needs (p < 0.05) and to have repeated a grade (p = 0.01). It was also associated with an increased number of medical and paramedical consultations. A history of BPD was not associated with the parents' employment status, family structure, or the presence of younger siblings. CONCLUSION: This study highlights that a history of BPD is associated with poorer academic outcomes and high healthcare use in adolescence.