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.

Long-term evolution of neuroendocrine cell hyperplasia of infancy: the FRENCHI findings.

Only few studies report long-term evolution of patients with neuroendocrine cell hyperplasia of infancy (NEHI). We report data from a 54-patient cohort followed up in the French network for rare respiratory diseases (RespiRare). Demographic characteristics and respiratory and nutritional evolution were collected at the time of the patient's last scheduled visit. The mean duration of follow-up was 68 months (5 months to 18 years). Fifteen patients (27.8%) were considered clinically cured. During follow-up, hospitalizations for wheezy exacerbations were reported in 35 patients (55%), and asthma diagnosed in 20 (37%). Chest CT scan improvement was noted in 25/44 (56.8%). Spirometry showed a persistent obstructive syndrome in 8/27 (29.6%). A sleep disorder was rare (2/36, 5.5%). Oxygen weaning occurred in 28 of the 45 patients initially treated (62.2%) and was age-dependent (35.7% under 2 years, 70.5% between 2 and 6 years, and 100% after 7 years). Oxygen duration was linked to a biopsy-proven diagnosis (p = 0.02) and to the use of a nutritional support (p = 0.003). Corticosteroids were largely prescribed at diagnosis, with no evident respiratory or nutritional effect during follow-up. Among 23 patients with an initial failure to thrive, 12 (52.2%) had no weight recovery. Initial enteral feeding (17/54, 31.5%) was stopped at a mean age of 43 months (3 to 120), with no effect on cure and oxygen liberation at the last visit.  Conclusion: Our results show that NEHI has a globally positive, but unequal, improvement over time. Further prospective studies are needed to better clarify the different trajectories of patients with NEHI. What is Known: • Neuroendocrine cell hyperplasia of infancy (NEHI) is an interstitial lung disease whose long-term outcome is considered positive from very few studies including heterogeneous populations. What is New: • The 68-month follow-up of our 54-patient cohort showed respiratory/nutritional symptom persistence in 72.2%, oxygen requiring in 34%, and asthma in 37%. When controlled, radiological or functional improvement was noted in 56.8 and 40.7%. Further prospective studies are needed to better clarify the different trajectories of patients with NEHI.

French national cohort of neuroendocrine cell hyperplasia of infancy (FRENCHI) study: diagnosis and initial management.

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%). CONCLUSION: 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. WHAT IS KNOWN: •Neuroendocrine cell hyperplasia of infancy (NEHI) is an interstitial lung disease whose diagnosis is essential to limit corticosteroids therapy. WHAT IS NEW: •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.

Quality of life was similar in children with congenital diaphragmatic hernia and oesophageal atresia and related to respiratory morbidity.

AIM: To assess quality of life (QoL) in children with congenital diaphragmatic hernia (CDH) and to compare it with oesophageal atresia (OA). METHODS: A cross-sectional study in CDH children (≥7 years) was conducted in Lille University Hospital, France, from January 2013 to April 2014. History, lung function (rest, exercise) and Pediatric Quality of Life Inventory questionnaires (PedsQoL 4.0) were collected. Data of OA children were previously published. RESULTS: Fifty-four CDH patients (male: 53%, median age: 11 years, IQR 9-14) were compared to 54 OA patients (male: 61%, median age: 13 years, IQR: 11-15). CDH children had significantly more frequent history of pneumonia (30% vs 13%), exercise limitation (54% vs 35%) and chest deformity (39% vs 11%); 46% had an obstructive pattern and 66% an abnormal cardiopulmonary exercise test. The median PedsQoL total score in children was 81 (IQR 73-90) in CDH and 81 (IQR 72-91) in OA (P = .8). In CDH, duration of neonatal oxygen therapy, hospitalisation for respiratory disease, exercise limitation, inhaled corticosteroids treatment, chest deformity, abnormal cardiopulmonary exercise test and lower forced expiratory volume in one second were significantly associated with lower QoL scores. CONCLUSION: PedsQoL scores remained satisfactory in CDH children with CDH, with no difference compared to OA. Patients with respiratory morbidity and lung function impairment, who displayed lower scores, should be identified in order to optimise their management in reference centres.

Severe preschool asthmatics have altered cytokine and anti-viral responses during exacerbation.

BACKGROUND: Preschool asthma/recurrent wheeze is a heterogeneous condition. Different clinical phenotypes have been described, including episodic viral wheeze (EVW), severe intermittent wheeze (SIW), and multiple-trigger wheeze (MTW). OBJECTIVE: To compare clinical, viral, and inflammatory/immune profiling at exacerbation between MTW, SIW, and EVW phenotypes. METHODS: Multicenter, prospective, observational cohort (VIRASTHMA-2). Children (1-5 years) with preschool asthma were enrolled during hospitalization for a severe exacerbation. History and anamnestic data, plasma, and nasal samples were collected at exacerbation (T1) and at steady state, 8 weeks later (T2), and sputum samples were collected at T1. RESULTS: A total of 147 children were enrolled, 37 (25%) had SIW, 18 (12.2%) EVW, and 92 (63%) MTW. They were atopic (47%), exposed to mold (22%) and cigarette smoke (50%), and prone to exacerbations (≥2 in the previous year in 70%). At exacerbation, at least one virus was isolated in 94% and rhinovirus in 75%, with no difference between phenotypes. Children with MTW and SIW phenotypes displayed lower plasma concentrations of IFN-γ (P = .002), IL-5 (P = .020), TNF-α (P = .038), IL-10 (P = .002), IFN-ß (P = .036), and CXCL10 (P = .006) and lower levels of IFN-γ (P = .047) in sputum at exacerbation than children with EVW. At T2, they also displayed lower plasma levels of IFN-γ (P = .045) and CXCL10 (P = .013). CONCLUSION: Among preschool asthmatic children, MTW and SIW, prone to exacerbations, display lower systemic levels of Th1, Th2 cytokines, pro- and anti-inflammatory cytokines, and antiviral responses during severe virus-induced exacerbation.

Bronchopulmonary and vascular anomalies are frequent in children with oesophageal atresia.

AIM: Oesophageal atresia is frequently associated with other malformations, and our aim was to use computed tomography (CT) to explore intrathoracic malformations in patients with this condition. METHOD: This was retrospective study of children aged 0-16 with oesophageal atresia who were born in 1996-2013 and followed up at the French reference centre for rare oesophageal diseases at the University of Lille. Computed tomography scans were available for 48 of the 234 patients during follow-up visits, and these were reviewed by a thoracic radiologist. RESULTS: More than two-thirds of the scans were performed to explore persistent respiratory symptoms. We found that six patients had a pulmonary malformations: four lobar agenesis, one right pulmonary aplasia and one congenital cystic adenomatoid malformation. Computed tomography enabled us to diagnose unexpected thoracic malformations in 16 patients: four lobar agenesis, six arteria lusoria, five persistent left superior vena cava and one partial anomalous pulmonary venous return. It also confirmed the diagnoses of suspected malformations in five patients: one congenital cystic adenomatoid malformation, one pulmonary hypoplasia, two right-sided aortic arches and one communicating bronchopulmonary foregut malformation. CONCLUSION: Intrathoracic anomalies were frequently associated with oesophageal atresia, and contrast-enhanced chest CT scans should be performed on patients with persistent respiratory symptoms.

Toward the Standardization of Mycological Examination of Sputum Samples in Cystic Fibrosis: Results from a French Multicenter Prospective Study.

Fungal respiratory colonization of cystic fibrosis (CF) patients emerges as a new concern; however, the heterogeneity of mycological protocols limits investigations. We first aimed at setting up an efficient standardized protocol for mycological analysis of CF sputa that was assessed during a prospective, multicenter study: "MucoFong" program (PHRC-06/1902). Sputa from 243 CF patients from seven centers in France were collected over a 15-month period and submitted to a standardized protocol based on 6 semi-selective media. After mucolytic pretreatment, sputa were plated in parallel on cycloheximide-enriched (ACT37), erythritol-enriched (ERY37), benomyl dichloran-rose bengal (BENO37) and chromogenic (CAN37) media incubated at 37 °C and on Sabouraud-chloramphenicol (SAB27) and erythritol-enriched (ERY27) media incubated at 20-27 °C. Each plate was checked twice a week during 3 weeks. Fungi were conventionally identified; time for detection of fungal growth was noted for each species. Fungal prevalences and media performances were assessed; an optimal combination of media was determined using the Chi-squared automatic interaction detector method. At least one fungal species was isolated from 81% of sputa. Candida albicans was the most prevalent species (58.8%), followed by Aspergillus fumigatus (35.4%). Cultivation on CAN37, SAB27, ACT37 and ERY27 during 16 days provided an optimal combination, detecting C. albicans, A. fumigatus, Scedosporium apiospermum complex and Exophiala spp. with sensitivities of 96.5, 98.8, 100 and 100%. Combination of these four culture media is recommended to ensure the growth of key fungal pathogens in CF respiratory specimens. The use of such consensual protocol is of major interest for merging results from future epidemiological studies.

Virus-triggered exacerbation in allergic asthmatic children: neutrophilic airway inflammation and alteration of virus sensors characterize a subgroup of patients.

BACKGROUND: Viruses are important triggers of asthma exacerbations. They are also detected outside of exacerbation. Alteration of anti-viral response in asthmatic patients has been shown although the mechanisms responsible for this defect remain unclear. The objective of this study was to compare in virus-infected and not-infected allergic asthmatic children, aged 6 to 16 years, admitted to hospital for a severe exacerbation, the innate immune response and especially the expression of pattern recognition receptor (PRR) and their function. METHODS: Virus identification was performed both during the exacerbation and at steady state (eight weeks later). Data assessed at both periods included clinical features, anti-viral response and inflammation (in sputum and plasma), and PRR expression/function in blood mononuclear cells. RESULTS: Viruses were identified in 46 out of 72 children (median age 8.9 years) during exacerbation, and among them, in 17 at steady state. IFN-ß, IFN-γ and IL-29 levels in sputum and plasma were similar between infected and not infected patients at both times, as well as the expression of TLR3, RIG-I and MDA5 in blood monocytes and dendritic cells. Airway inflammation in infected patients was characterized by significantly higher IL-5 concentration and eosinophil count. Compared to patients only infected at exacerbation, the re-infected children significantly exhibited lower levels of IFN-γ in plasma and sputum at exacerbation associated with modifications in PRR expression and function in blood mononuclear cells. These re-infected patients also presented an airway neutrophilic inflammation at steady state. CONCLUSION: Our results reports in asthmatic children that impaired anti-viral response during virus-induced exacerbation is more pronounced in a subgroup of patients prone to re-infection by virus. This subgroup is characterized by altered PRR function and a different pattern of airway inflammation. TRIAL REGISTRATION: This multicenter prospective study was approved by the regional investigational review board (ref: 08/07).

Utility of measuring FEV0.75/FVC ratio in preschoolers with uncontrolled wheezing disorder.

Uncontrolled wheezing disorder is common in preschoolers and disease control assessment is challenging as parents frequently overestimate the extent to which their child's disease is controlled. This is the first study of forced expiratory volume in t s (FEVt)/forced vital capacity (FVC) ratio measurements (i.e. FEV1/FVC, FEV0.75/FVC and FEV0.5/FVC) in wheezy preschoolers in relation to disease control. Our objective was to evaluate whether FEVt/FVC ratios less than the lower limit of normal (LLN; z-score <-1.64) were associated with uncontrolled wheezing disorder in preschoolers.Valid FVC, FEV1, FEV0.75 and FEV0.5 values were obtained in 92 healthy and 125 wheezy (62% uncontrolled) children (3-5 years). Associations between spirometry value

Nonsteroidal Anti-Inflammatory Drug without Antibiotics for Acute Viral Infection Increases the Empyema Risk in Children: A Matched Case-Control Study.

OBJECTIVE: To investigate the risk factors of empyema after acute viral infection and to clarify the hypothesized association(s) between empyema and some viruses and/or the use of nonsteroidal anti-inflammatory drugs (NSAIDs). STUDY DESIGN: A case-control study was conducted in 15 centers. Cases and controls were enrolled for a source population of children 3-15 years of age with acute viral infections between 2006 and 2009. RESULTS: Among 215 empyemas, 83 cases (children with empyema and acute viral infection within the 15 preceding days) were included, and 83 controls (children with acute viral infection) were matched to cases. Considering the intake of any drug within 72 hours after acute viral infection onset and at least 6 consecutive days of antibiotic use and at least 1 day of NSAIDs exposure, the multivariable analysis retained an increased risk of empyema associated with NSAIDs exposure (aOR 2.79, 95% CI 1.4-5.58, P = .004), and a decreased risk associated with antibiotic use (aOR 0.32, 95% CI 0.11-0.97, P = .04). The risk of empyema associated with NSAIDs exposure was greater for children not prescribed an antibiotic and antibiotic intake diminished that risk for children given NSAIDs. CONCLUSIONS: NSAIDs use during acute viral infection is associated with an increased risk of empyema in children, and antibiotics are associated with a decreased risk. The presence of antibiotic-NSAIDs interaction with this risk is suggested. These findings suggest that NSAIDs should not be recommended as a first-line antipyretic treatment during acute viral infections in children.

Sweat test practice in pediatric pulmonology after introduction of cystic fibrosis newborn screening.

The influence of the generalization of cystic fibrosis newborn screening (CFNBS) in France on sweat test (ST) prescription is unknown. In this French retrospective, descriptive, and multicenter study, we studied the indications, number, methods, and results of STs prescribed by a pediatric pulmonologist in children who had a negative CFNBS and an ST for respiratory symptoms in 2012. We included 502 children with 523 STs, performed with four different methods. The main indication was asthma (71.3 %), then chronic cough (52.4 %), atypical lower airway infections (42.2 %), and bronchiectasis (7 %). Four children had a diagnosis of CF (0.8 %), all presenting with chronic productive cough and recurrent respiratory infections. CONCLUSION: Asthma is the most frequent indication of ST in our cohort. Because of the systematic CFNBS in France, some prescriptions should be avoided, particularly in case of severe or moderate asthma with no other associated symptom. Moreover, methods of STs often do not follow the guidelines and need standardization. WHAT IS KNOWN: • Newborn screening (NBS) has become the most frequent circumstance of the diagnosis of cystic fibrosis (CF) in France after its generalization. • The prescription of sweat test (ST) in children with respiratory symptoms who already had a negative NBS has not been studied. WHAT IS NEW: • In children with a negative CF NBS referred to a university hospital for respiratory diseases, despite important variations of ST methods, only 4 children among 502 have been diagnosed as CF. • Despite recommendations, ST prescription should be avoided in children with moderate to severe asthma and no other associated symptom.

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.

Delineation of CCDC39/CCDC40 mutation spectrum and associated phenotypes in primary ciliary dyskinesia.

BACKGROUND: CCDC39 and CCDC40 genes have recently been implicated in primary ciliary dyskinesia (PCD) with inner dynein arm (IDA) defects and axonemal disorganisation; their contribution to the disease is, however, unknown. Aiming to delineate the CCDC39/CCDC40 mutation spectrum and associated phenotypes, this study screened a large cohort of patients with IDA defects, in whom clinical and ciliary phenotypes were accurately described. METHODS: All CCDC39 and CCDC40 exons and intronic boundaries were sequenced in 43 patients from 40 unrelated families. The study recorded and compared clinical features (sex, origin, consanguinity, laterality defects, ages at first symptoms and at phenotype evaluation, neonatal respiratory distress, airway infections, nasal polyposis, otitis media, bronchiectasis, infertility), ciliary beat frequency, and quantitative ultrastructural analyses of cilia and sperm flagella. RESULTS: Biallelic CCDC39 or CCDC40 mutations were identified in 30/34 (88.2%) unrelated families with IDA defects associated with axonemal disorganisation (22 and eight families, respectively). Fourteen of the 28 identified mutations are novel. No mutation was found in the six families with isolated IDA defects. Patients with identified mutations shared a similar phenotype, in terms of both clinical features and ciliary structure and function. The sperm flagellar ultrastructure, analysed in 4/7 infertile males, showed evidence of abnormalities similar to the ciliary ones. CONCLUSIONS: CCDC39 and CCDC40 mutations represent the major cause of PCD with IDA defects and axonemal disorganisation. Patients carrying CCDC39 or CCDC40 mutations are phenotypically indistinguishable. CCDC39 and CCDC40 analyses in selected patients ensure mutations are found with high probability, even if clinical or ciliary phenotypes cannot prioritise one analysis over the other.

Fetal Lung Volume Appears to Predict Respiratory Morbidity in Congenital Diaphragmatic Hernia.

Congenital diaphragmatic hernia (CDH) is associated with pulmonary hypoplasia and respiratory morbidity. To assess whether respiratory morbidity during the first 2 years of life in infants with left-sided CDH is associated with fetal lung volume (FLV) evaluated by the observed-to-expected FLV ratio (o/e FLV) on antenatal magnetic resonance imaging (MRI). In this retrospective study, o/e FLV measures were collected. Respiratory morbidity in the first 2 years of life was studied according to two endpoints: treatment with inhaled corticosteroids for >3 consecutive months and hospitalization for any acute respiratory disease. The primary outcome was a favorable progression defined by the absence of either endpoint. Forty-seven patients were included. The median o/e FLV was 39% (interquartile range, 33-49). Sixteen (34%) infants were treated with inhaled corticosteroids and 13 (28%) were hospitalized. The most efficient threshold for a favorable outcome was an o/e FLV ≥ 44% with a sensitivity of 57%, specificity of 79%, negative predictive value of 56%, and positive predictive value of 80%. An o/e FLV ≥ 44% was associated with a favorable outcome in 80% of cases. These data suggest that lung volume measurement on fetal MRI may help to identify children at lower respiratory risk and improve information during pregnancy, patient characterization, decisions about treatment strategy and research, and personalized follow-up.

Primary ciliary dyskinesia and fungal infections: Two cases of allergic bronchopulmonary aspergillosis in children.

Primary ciliary dyskinesia (PCD) is a rare inherited disease that affects the movement of the respiratory cilia. The main clinical manifestations are chronic upper and lower respiratory symptoms and recurrent lung infections, particularly bacterial and viral infections. Fungal infections are not usually associated with PCD. Allergic bronchopulmonary aspergillosis (ABPA) is a rare complex immune hypersensitivity reaction to Aspergillus fumigatus reported in patients with asthma and cystic fibrosis. Only three cases of ABPA associated with adult PCD have been described in the literature. Herein, we reported on two cases of ABPA in two boys aged 10 and 13 years with PCD. Both had severe lung disease and chronic Pseudomonas aeruginosa infections. One patient was diagnosed according to the typical clinical features of ABPA, while the other was diagnosed during a scheduled visit with no clinical changes but worsening pulmonary function and radiologic anomalies. The diagnosis of ABPA was confirmed in the two patients who then improved after receiving specific treatment. These two cases were the first to describe the occurrence of ABPA in children with PCD. We recommend that physicians involved in the management of children with PCD be aware of this potential complication.

Diet and nutritional status of children with food allergies.

The aim of the present study was to assess the food intakes and nutritional status of children with food allergies following an elimination diet. We conducted a cross sectional study including 96 children (mean age 4.7 ± 2.5 years) with food allergies and 95 paired controls (mean age 4.7 ± 2.7 years) without food allergies. Nutritional status was assessed using measurements of weight and height and Z scores for weight-for-age, height-for-age and weight-for-height. Nutrient intakes assessment was based on a 3-day diet record. Children with food allergies had weight-for-age and height-for-age Z scores lower than controls (0.1 versus 0.6 and 0.2 versus 0.8 respectively). Children with 3 or more food allergies were smaller than those with 2 or less food allergies (p = 0.04). A total of 62 children with food allergies and 52 controls completed usable diet records. Energy, protein and calcium intakes were similar in the two groups. Children with food allergies were smaller for their age than controls even when they received similar nutrient intakes. Nutritional evaluation is essential for the follow up of children with food allergies.