Epidemiology of childhood interstitial lung disease in France: the RespiRare cohort.

INTRODUCTION: Interstitial lung disease in children (chILD) are rare and mostly severe lung diseases. Very few epidemiological data are available in limited series of patients. The aim of this study was to assess the prevalence and incidence of chILD in France. METHODS: We performed within the RespiRare network a multicentre retrospective observational study in patients with chILD from 2000 to 2022 and a prospective evaluation of chILD's incidence between February 2022 and 2023. RESULTS: chILD was reported in 790 patients in 42 centres. The estimated 2022 prevalence in France was 44 /million children (95% CI 40.76 to 47.46) and the computed incidence was 4.4 /million children (95% CI 3.44 to 5.56). The median age at diagnosis was 3 months with 16.9% of familial forms. Lung biopsy and genetic analyses were performed in 23.4% and 76.9%, respectively. The most frequent chILD aetiologies in the <2 years group were surfactant metabolism disorders (16.3%) and neuroendocrine cell hyperplasia of infancy (11.8%), and in the 2-18 years group diffuse alveolar haemorrhage (12.2%), connective tissue diseases (11.4%), hypersensitivity pneumonitis (8.8%) and sarcoidosis (8.8%). The management included mainly oxygen therapy (52%), corticosteroid pulses (56%), oral corticosteroids (44%), azithromycin (27.2%), enteral nutrition (26.9%), immunosuppressants (20.3%) and hydroxychloroquine (15.9%). The 5-year survival rate was 57.3% for the patients diagnosed before 2 years and 86% between 2 and 18 years. CONCLUSION: This large and systematic epidemiological study confirms a higher incidence and prevalence of chILD than previously described. In order to develop international studies, efforts are still needed to optimise the case collection and to harmonise diagnostic and management practices.

High risk of lung cancer in surfactant-related gene variant carriers.

BACKGROUND: Several rare surfactant-related gene (SRG) variants associated with interstitial lung disease are suspected to be associated with lung cancer, but data are missing. We aimed to study the epidemiology and phenotype of lung cancer in an international cohort of SRG variant carriers. METHODS: We conducted a cross-sectional study of all adults with SRG variants in the OrphaLung network and compared lung cancer risk with telomere-related gene (TRG) variant carriers. RESULTS: We identified 99 SRG adult variant carriers (SFTPA1 (n=18), SFTPA2 (n=31), SFTPC (n=24), ABCA3 (n=14) and NKX2-1 (n=12)), including 20 (20.2%) with lung cancer (SFTPA1 (n=7), SFTPA2 (n=8), SFTPC (n=3), NKX2-1 (n=2) and ABCA3 (n=0)). Among SRG variant carriers, the odds of lung cancer was associated with age (OR 1.04, 95% CI 1.01-1.08), smoking (OR 20.7, 95% CI 6.60-76.2) and SFTPA1/SFTPA2 variants (OR 3.97, 95% CI 1.39-13.2). Adenocarcinoma was the only histological type reported, with programmed death ligand-1 expression ≥1% in tumour cells in three samples. Cancer staging was localised (I/II) in eight (40%) individuals, locally advanced (III) in two (10%) and metastatic (IV) in 10 (50%). We found no somatic variant eligible for targeted therapy. Seven cancers were surgically removed, 10 received systemic therapy, and three received the best supportive care according to their stage and performance status. The median overall survival was 24 months, with stage I/II cancers showing better survival. We identified 233 TRG variant carriers. The comparative risk (subdistribution hazard ratio) for lung cancer in SRG patients versus TRG patients was 18.1 (95% CI 7.1-44.7). CONCLUSIONS: The high risk of lung cancer among SRG variant carriers suggests specific screening and diagnostic and therapeutic challenges. The benefit of regular computed tomography scan follow-up should be evaluated.

Non-invasive respiratory support in children and young adults with complex medical conditions in pediatric palliative care.

OBJECTIVE: Dyspnoea and sleep-disordered breathing (SDB) are common in children with life-limiting conditions but studies on treatment with non-invasive ventilation (NIV) or continuous positive airway pressure (CPAP) are scarce. The aim of the study was to describe children treated with long-term NIV/CPAP within a paediatric palliative care programme in France. METHODS: Cross-sectional survey on children and young adults with complex medical conditions treated within the French paediatric NIV network with long-term NIV/CPAP. Characteristics of the patients were analysed and patient-related outcome measures of NIV/CPAP benefit were reported. RESULTS: The data of 50 patients (68% boys), median age 12 (0.4-21) years were analysed. Twenty-three (46%) patients had a disorder of the central nervous system and 5 (10%) a chromosomal anomaly. Thirty-two (64%) patients were treated with NIV and 18 (36%) with CPAP. NIV/CPAP was initiated on an abnormal Apnoea-Hypopnoea Index in 18 (36%) of the patients, an abnormal nocturnal gas exchange alone in 28 (56%), and after an acute respiratory failure in 11 (22%) of the patients. Mean objective NIV/CPAP adherence was 9.3±3.7 hours/night. NIV/CPAP was associated with a decrease in dyspnoea in 60% of patients, an increase in sleep duration in 60% and in sleep quality in 74%, and an improvement in parents' sleep in 40%. CONCLUSIONS: In children with life-limiting conditions, long-term NIV/CPAP may be associated with relief of dyspnoea, an improvement of SDB and an improvement in parents' sleep.

Lung volume recruitment and airway clearance for children at home in France.

BACKGROUND: Airway clearance (ACT) and lung volume recruitment (LVR) techniques are used to manage bronchial secretions, increase cough efficiency and lung/chest wall recruitment, to prevent and treat respiratory tract infections. The aim of the study was to review the prescription of ACT/LVR techniques for home use in children in France. METHODS: All the centers of the national pediatric noninvasive ventilation (NIV) network were invited to fill in an anonymous questionnaire for every child aged ≤20 years who started a treatment with an ACT/LVR device between 2022 and 2023. The devices comprised mechanical in-exsufflation (MI-E), intermittent positive pressure breathing (IPPB), intrapulmonary percussive ventilation (IPV), and/or invasive mechanical ventilation (IMV)/NIV for ACT/LVR. RESULTS: One hundred and thirty-nine patients were included by 13 centers. IPPB was started in 83 (60 %) patients, MI-E in 43 (31 %) and IPV in 30 (22 %). No patient used IMV/NIV for ACT/LVR. The devices were prescribed mainly by pediatric pulmonologists (103, 74 %). Mean age at initiation was 8.9 ± 5.6 (0.4-18.5) years old. The ACT/LVR devices were prescribed mainly in patients with neuromuscular disorders (n = 66, 47 %) and neurodisability (n = 37, 27 %). The main initiation criteria were cough assistance (81 %) and airway clearance (60 %) for MI-E, thoracic mobilization (63 %) and vital capacity (47 %) for IPPB, and airway clearance (73 %) and repeated respiratory exacerbations (57 %) for IPV. The parents were the main carers performing the treatment at home. CONCLUSIONS: IPPB was the most prescribed technique. Diseases and initiation criteria are heterogeneous, underlining the need for studies validating the indications and settings of these techniques.

Pediatric long-term noninvasive respiratory support in children with central nervous system disorders.

RATIONALE: The use of long-term noninvasive respiratory support is increasing in children along with an extension of indications, in particular in children with central nervous system (CNS) disorders. OBJECTIVE: The aim of this study was to describe the characteristics of children with CNS disorders treated with long-term noninvasive respiratory support in France. METHODS: Data were collected from 27 French pediatric university centers through an anonymous questionnaire filled for every child treated with noninvasive ventilatory support ≥3 months on 1st June 2019. MAIN RESULTS: The data of 182 patients (55% boys, median age: 10.2 [5.4;14.8] years old [range: 0.3-25]) were collected: 35 (19%) patients had nontumoral spinal cord injury, 22 (12%) CNS tumors, 63 (35%) multiple disabilities, 26 (14%) central alveolar hypoventilation and 36 (20%) other CNS disorders. Seventy five percent of the patients were treated with noninvasive ventilation (NIV) and 25% with continuous positive airway pressure (CPAP). The main investigations performed before CPAP/NIV initiation were nocturnal gas exchange recordings, alone or coupled with poly(somno)graphy (in 29% and 34% of the patients, respectively). CPAP/NIV was started in an acute setting in 10% of the patients. Median adherence was 8 [6;10] hours/night, with 12% of patients using treatment <4 h/day. Nasal mask was the most common interface (70%). Airway clearance techniques were used by 31% of patients. CONCLUSION: CPAP/NIV may be a therapeutic option in children with CNS disorders. Future studies should assess treatment efficacy and patient reported outcome measures.

Prevalence and Determinants of Wheezing and Bronchodilatation in Children With Cystic Fibrosis: A Retrospective Cohort Study.

Background: Many patients with cystic fibrosis (CF) wheeze, and are dubbed as having CF-asthma. Understanding the determinants of such wheezing may avoid unnecessary treatments and open newer treatment avenues. Objectives: Main: To evaluate the prevalence and characteristics of wheezing and a positive bronchodilatory response (BDR) in children with CF. Secondary: To identify the predictive markers and the impact of current wheezing a positive BDR. Methods: A retrospective single-center study in children with CF. We determined the characteristics of physician-reported wheeze in patients <6 years, and a BDR in patients aged 6-17 years. Anthropometric, lung function, laboratory, genetic and microbiological data were recorded in all groups. Variables were compared using the Chi2 and Student t-tests, and ANOVA. Results: 125 preschool and 69 school-aged children and adolescents with CF were included in the study. 71.2% of patients <6 years of age had had at least one episode of wheezing: 26.3% of patients were Transient Early Wheezers, 12.6% Late Onset Wheezers and 37.9% were Persistent Wheezers. The prevalence of a positive BDR was 73.5, 48.5, and 52.9% in the 6-8 years, 10-12 years, and 15-17 years age groups, respectively. Allergic factors were not predictive of wheezing in preschoolers. In the 6-8 years age group, the sum of wheal diameters of allergic skin prick tests (SPT, house dust mite + cat + dog dander) was greater in those with a BDR vs. no BDR (4 [2.0-8.8] vs. 1 [0-7.0] mm, p = 0.01). The presence of Pseudomonas aeruginosa in the bronchial secretions before 3 years of age was not significantly associated with either the presence of wheezing at the age of 6 years or a BDR in school-aged children and adolescents. The proportion of homozygous p.F508del patients was significantly lower in the group of patients who had wheezed by 6 years of age (60% vs. 72.7%, p = 0.009), but higher in the 6-8 years old group with a BDR vs. no BDR (64% vs. 36%, p = 0.04). Current wheezers at 6 years had a lower mean FEV1 vs. the non-current wheezers (91.5 ± 4.4% vs. 100.9 ± 2.4%; p = 0.047). Similarly, forced vital capacity (FVC) was significantly lower in the 6-8 years old group with BDR vs. no BDR (85 ± 19 vs. 101 ± 21%, p = 0.015). Conclusion: Wheezing and BDR are very frequent findings in children with CF. Current wheeze at the age of 6 years was associated with worse lung function. Labeling wheezing in CF as "CF-Asthma" is misleading since the determinants are different, and may lead to inappropriate prescriptions of inhaled steroids.

Telehome Monitoring of Symptoms and Lung Function in Children with Asthma.

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

Long term noninvasive ventilation and continuous positive airway pressure in children with neuromuscular diseases in France.

The aim of the study was to describe the characteristics of children with neuromuscular diseases treated with long term noninvasive ventilation or continuous positive airway pressure in France. On June 1st 2019, 387 patients (63% boys, mean age 11.2 ± 5.5 years) were treated with long term noninvasive ventilation/continuous positive airway pressure. Thirty three percent of patients had spinal muscular atrophy, 30% congenital myopathy/dystrophy, 20% Duchenne muscular dystrophy, 7% Steinert myotonic dystrophy, and 9% other neuromuscular diseases. Ninety-four percent of patients were treated with long term noninvasive ventilation and 6% with continuous positive airway pressure. Treatment was initiated electively for 85% of patients, mainly on an abnormal overnight gas exchange recording (38% of patients). Noninvasive ventilation/continuous positive airway pressure was initiated during a respiratory exacerbation in 15% of patients. Mean duration of noninvasive ventilation/continuous positive airway pressure was 3.3 ± 3.1 years. Mean objective long term noninvasive ventilation/continuous positive airway pressure use was 8.0 ± 3.1 h/24. Spinal muscular atrophy, congenital myopathy/dystrophy, and Duchenne muscular dystrophy represented 83% of children with neuromuscular diseases treated with long term noninvasive ventilation in France. Screening for nocturnal hypoventilation was satisfactory as noninvasive ventilation /continuous positive airway pressure was predominantly initiated electively.

The First 1000 Days: Impact of Prenatal Tobacco Smoke Exposure on Hospitalization Due to Preschool Wheezing.

Preschool wheezing and related hospitalization rates are increasing. Prenatal tobacco smoke exposure (PTSE) increases the risk of wheezing, yet >20% of French women smoke during pregnancy. In this observational retrospective monocentric study, we assessed the link between PTSE and hospital admissions. We included infants <2 years of age admitted for acute wheezing. A phone interview with mothers was completed by electronic records. The primary endpoint was the ratio of cumulative duration of the hospitalization stays (days)/age (months). 129 children were included (36.4% exposed to PTSE vs. 63.6% unexposed). There was a significant difference in the duration of hospitalization/age: 0.9 days/month (exposed) vs. 0.58 days/month (unexposed) (p = 0.008). Smoking one cigarette/day during pregnancy was associated with an increase in hospitalization duration of 0.055 days/month (r = 0.238, p = 0.006). In the multi-variable analysis, this positive association persisted (ß = 0.04, p = 0.04; standardized ß = 0.27, p = 0.03). There was a trend towards a dose-effect relationship between PTSE and other important parameters associated with hospital admissions. We have demonstrated a dose-effect relationship, without a threshold effect, between PTSE and duration of hospitalization for wheezing in non-premature infants during the first 2 years of life. Prevention campaigns for future mothers should be enforced.

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.

Paediatric long term continuous positive airway pressure and noninvasive ventilation in France: A cross-sectional study.

OBJECTIVE: To describe the characteristics of children treated with long term continuous positive airway pressure (CPAP) or noninvasive ventilation (NIV) in France. DESIGN: Cross-sectional national survey. SETTING: Paediatric CPAP/NIV teams of 28 tertiary university hospitals in France. PATIENTS: Children aged <20 years treated with CPAP/NIV since at least 3 months on June 1st, 2019. INTERVENTION: An anonymous questionnaire was filled in for every patient. RESULTS: The data of 1447 patients (60% boys), mean age 9.8 ± 5.8 years were analysed. The most frequent underlying disorders were: upper airway obstruction (46%), neuromuscular disease (28%), disorder of the central nervous system (13%), cardiorespiratory disorder (7%), and congenital bone disease (4%). Forty-five percent of the patients were treated with CPAP and 55% with NIV. Treatment was initiated electively for 92% of children, while 8% started during an acute illness. A poly(somno)graphy (P(S)G) was performed prior to treatment initiation in 26%, 36% had a P(S)G with transcutaneous carbon dioxide monitoring (PtcCO2), while 23% had only a pulse oximetry (SpO2) with PtcCO2 recording. The decision of CPAP/NIV initiation during an elective setting was based on the apnea-hypopnea index (AHI) in 41% of patients, SpO2 and PtcCO2 in 25% of patients, and AHI with PtcCO2 in 25% of patients. Objective adherence was excellent with a mean use of 7.6 ± 3.2 h/night. Duration of CPAP/NIV was 2.7 ± 2.9 years at the time of the survey. CONCLUSION: This survey shows the large number of children treated with long term CPAP/NIV in France with numerous children having disorders other than neuromuscular diseases.

Impact at school age of early chronic methicillin-sensitive Staphylococcus aureus infection in children with cystic fibrosis.

BACKGROUND: Bacterial infection early in life may increase structural lung lesions in children with cystic fibrosis (CF). METHODS: A 9-year monocentric (Bordeaux University Hospital, France) retrospective study in children with CF to evaluate the impact of the early-onset (at 1 year of age, Y1) of chronic meticillin-sensitive Staphylococcus aureus (MSSA) infection on the severity of bronchiectasis and Bhalla score on CT scan, clinical status, lung function tests, and serum immunoglobulins (IgG) at the age of 6 years (Y6). RESULTS: A total of 37 children were included: 10 had contracted chronic MSSA infection at Y1 and 27 at a later date. Children with MSSA infection at Y1 showed increased Y6 CT scan bronchiectasis severity scores vs late MSSA infection (mean ± SD: 4.7 ± 0.8 vs 2.5 ± 0.5, P < .05) and Bhalla scores (7.3 ± 1.1 vs 4.7 ± 0.8, P < .05), but no significant decrease in lung function ([% reference values] FEV1: 83.7 ± 6 vs 90.6 ± 2.2, P = .21; FEF25-75: 67.8 ± 8.9 vs 76.3 ± 3.9, P = .18). In addition, Y6 serum IgG was greater in the early chronic Y1 MSSA group (11.3 ± 0.7 vs 8.9 ± 0.7 g/L, P < .05). Clinical symptoms or nutritional status were similar in both infection groups. CONCLUSION: Early chronic MSSA infection may enhance the progression of structural lung disease in CF at 6 years.

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.