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.

Methionine supplementation for multi-organ dysfunction in MetRS-related pulmonary alveolar proteinosis.

INTRODUCTION: Pulmonary alveolar proteinosis related to mutations in the methionine tRNA synthetase (MARS1) gene is a severe, early-onset disease that results in death before the age of 2 years in one-third of patients. It is associated with a liver disease, growth failure and systemic inflammation. As methionine supplementation in yeast models restored normal enzymatic activity of the synthetase, we studied the tolerance, safety and efficacy of daily oral methionine supplementation in patients with severe and early disease. METHODS: Four patients received methionine supplementation and were followed for respiratory, hepatic, growth and inflammation-related outcomes. Their course was compared to those of historical controls. Reactive oxygen species production by patient monocytes before and after methionine supplementation was also studied. RESULTS: Methionine supplementation was associated with respiratory improvement, clearance of the extracellular lipoproteinaceous material and discontinuation of whole-lung lavage in all patients. The three patients who required oxygen or noninvasive ventilation could be weaned off within 60 days. In addition, liver dysfunction, inflammation and growth delay improved or resolved. At a cellular level, methionine supplementation normalised the production of reactive oxygen species by peripheral monocytes. CONCLUSION: Methionine supplementation was associated with important improvements in children with pulmonary alveolar proteinosis related to mutations in the MARS1 gene. This study paves the way for similar strategies for other tRNA synthetase deficiencies.

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.

Nonsense mutations accelerate lung disease and decrease survival of cystic fibrosis children.

RATIONALE: Limited information is available on the clinical status of people with Cystic Fibrosis (pwCF) carrying 2 nonsense mutations (PTC/PTC). The main objective of this study was to compare disease severity between pwCF PTC/PTC, compound heterozygous for F508del and PTC (F508del/PTC) and homozygous for F508del (F508del+/+). METHODS: Based on the European CF Society Patient Registry clinical data of pwCF living in high and middle income European and neighboring countries, PTC/PTC (n = 657) were compared with F508del+/+ (n = 21,317) and F508del/PTC(n = 4254).CFTR mRNA and protein activity levels were assessed in primary human nasal epithelial (HNE) cells sampled from 22 PTC/PTC pwCF. MAIN RESULTS: As compared to F508del+/+ pwCF; both PTC/PTC and F508del/PTC pwCF exhibited a significantly faster rate of decline in Forced Expiratory Volume in 1 s (FEV1) from 7 years (-1.33 for F508del +/+, -1.59 for F508del/PTC; -1.65 for PTC/PTC, p < 0.001) until respectively 30 years (-1.05 for F508del +/+, -1.23 for PTC/PTC, p = 0.048) and 27 years (-1.12 for F508del +/+, -1.26 for F508del/PTC, p = 0.034). This resulted in lower FEV1 values in adulthood. Mortality of pediatric pwCF with one or two PTC alleles was significantly higher than their F508del homozygous pairs. Infection with Pseudomonas aeruginosa was more frequent in PTC/PTC versus F508del+/+ and F508del/PTC pwCF. CFTR activity in PTC/PTC pwCF's HNE cells ranged between 0% to 3% of the wild-type level. CONCLUSIONS: Nonsense mutations decrease the survival and accelerate the course of respiratory disease in children and adolescents with Cystic Fibrosis.

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.

High Prevalence of Nontuberculous Mycobacteria in Cystic Fibrosis Patients in Tropical French Reunion Island.

BACKGROUND: Reunion Island is a French overseas department located in a tropical area, where cystic fibrosis incidence is high. Cystic fibrosis (CF) patients are at risk of developing nontuberculous mycobacteria (NTM) infection. Epidemiologic studies are lacking in Reunion Island. METHODS: From 2002 to 2015, a retrospective review was performed in university hospitals on Reunion Island. All CF patients having at least 1 positive NTM isolate were included. Clinical, radiologic, and microbiologic data were collected from patient records. RESULTS: Fifty-one CF patients were included. The overall estimated prevalence of NTM was 26.4% in total CF population and 36.9% in patients over 12 years of age. Mycobacterium abscessus and Mycobacterium avium were the most frequently identified species found in 31 patients (60.8%) and 14 patients (27.4%), respectively. A rare NTM species: Mycobacterium simiae was found in 4 patients (7.8%). Twenty-nine patients (56.9%) met the American Thoracic Society (ATS) criteria for infection. They were more likely younger with a low body mass index and more frequently infected by Mycobacterium abscessus (22/29). CONCLUSION: The overall prevalence of NTM in tropical Reunion Island is 3 times higher than in metropolitan France. A different environmental exposure in a tropical climate or risk factors related to cystic fibrosis or its treatment in Reunion patients could explain it.

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.

A review of non-cystic fibrosis bronchiectasis in children with a focus on the role of long-term treatment with macrolides.

Bronchiectasis is a rare chronic airway disease arising from several respiratory and systemic diseases. The grade of evidence for specific treatment of childhood bronchiectasis unrelated to cystic fibrosis (CF) is low with very few randomized controlled trials. Treatment has been based mainly on evidence from studies in adults with non-cystic fibrosis bronchiectasis and patients with cystic fibrosis. Recently, long-term treatment with macrolides has been proposed. These molecules offer the advantage of anti-inflammatory and immunomodulatory properties in addition to their antibacterial properties. A total of three randomized double-blind placebo-controlled trials conducted in adults showed that macrolides taken for 6-12 months led to a significant reduction in exacerbation rates. Only one long-term, randomized double-blind placebo-controlled trial was conducted in the pediatric population. It showed that azithromycin administered weekly for up to 24 months reduced pulmonary exacerbations. Further randomized controlled studies are needed to determine the optimal dose and duration of treatment with macrolides. The clinical profile of children who would benefit from this treatment also needs to be determined.