Skewed X-chromosome inactivation drives the proportion of DNAAF6-defective airway motile cilia and variable expressivity in primary ciliary dyskinesia.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a rare airway disorder caused by defective motile cilia. Only male patients have been reported with pathogenic mutations in X-linked DNAAF6, which result in the absence of ciliary dynein arms, whereas their heterozygous mothers are supposedly healthy. Our objective was to assess the possible clinical and ciliary consequences of X-chromosome inactivation (XCI) in these mothers. METHODS: XCI patterns of six mothers of male patients with DNAAF6-related PCD were determined by DNA-methylation studies and compared with their clinical phenotype (6/6 mothers), as well as their ciliary phenotype (4/6 mothers), as assessed by immunofluorescence and high-speed videomicroscopy analyses. The mutated X chromosome was tracked to assess the percentage of cells with a normal inactivated DNAAF6 allele. RESULTS: The mothers' phenotypes ranged from absence of symptoms to mild/moderate or severe airway phenotypes, closely reflecting their XCI pattern. Analyses of the symptomatic mothers' airway ciliated cells revealed the coexistence of normal cells and cells with immotile cilia lacking dynein arms, whose ratio closely mirrored their XCI pattern. CONCLUSION: This study highlights the importance of searching for heterozygous pathogenic DNAAF6 mutations in all female relatives of male PCD patients with a DNAAF6 defect, as well as in females consulting for mild chronic respiratory symptoms. Our results also demonstrate that about one-third-ranging from 20% to 50%-normal ciliated airway cells sufficed to avoid severe PCD, a result paving the way for gene therapy.

Objectives for algorithmic decision-making systems in childhood asthma: Perspectives of children, parents, and physicians.

Objectives: To identify with children, parents and physicians the objectives to be used as parameters for algorithmic decision-making systems (ADMSs) adapting treatments in childhood asthma. Methods: We first conducted a qualitative study based on semi-structured interviews to explore the objectives that children aged 8-17 years, their parents, and their physicians seek to achieve when taking/giving/prescribing a treatment for asthma. Following the grounded theory approach, each interview was independently coded by two researchers; reconciled codes were used to assess code frequency, categories were defined, and the main objectives identified. We then conducted a quantitative study based on questionnaires using these objectives to determine how children/parents/physicians ranked these objectives and whether their responses were aligned. Results: We interviewed 71 participants (31 children, 30 parents and 10 physicians) in the qualitative study and identified seven objectives associated with treatment uptake and five objectives associated with treatment modalities. We included 291 participants (137 children, 137 parents, and 17 physicians) in the quantitative study. We found little correlation between child, parent, and physician scores for each of the objectives. Each child's asthma history influenced the choice of scores assigned to each objective by the child, parents, and physician. Conclusion: The identified objectives are quantifiable and relevant to the management of asthma in the short and long term. They can therefore be incorporated as parameters for future ADMS. Shared decision-making seems essential to achieve consensus among children, parents, and physicians when choosing the weight to assign to each of these objectives.

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.

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.

Biologicals in childhood severe asthma: the European PERMEABLE survey on the status quo.

INTRODUCTION: Severe asthma is a rare disease in children, for which three biologicals, anti-immunoglobulin E, anti-interleukin-5 and anti-IL4RA antibodies, are available in European countries. While global guidelines exist on who should receive biologicals, knowledge is lacking on how those guidelines are implemented in real life and which unmet needs exist in the field. In this survey, we aimed to investigate the status quo and identify open questions in biological therapy of childhood asthma across Europe. METHODS: Structured interviews regarding experience with biologicals, regulations on access to the different treatment options, drug selection, therapy success and discontinuation of therapy were performed. Content analysis was used to analyse data. RESULTS: We interviewed 37 experts from 25 European countries and Turkey and found a considerable range in the number of children treated with biologicals per centre. All participating countries provide public access to at least one biological. Most countries allow different medical disciplines to prescribe biologicals to children with asthma, and only a few restrict therapy to specialised centres. We observed significant variation in the time point at which treatment success is assessed, in therapy duration and in the success rate of discontinuation. Most participating centres intend to apply a personalised medicine approach in the future to match patients a priori to available biologicals. CONCLUSION: Substantial differences exist in the management of childhood severe asthma across Europe, and the need for further studies on biomarkers supporting selection of biologicals, on criteria to assess therapy response and on how/when to end therapy in stable patients is evident.

A Comprehensive Analysis of Immune Constituents in Blood and Bronchoalveolar Lavage Allows Identification of an Immune Signature of Severe Asthma in Children.

Background: Targeted approaches may not account for the complexity of inflammation involved in children with severe asthma (SA), highlighting the need to consider more global analyses. We aimed to identify sets of immune constituents that distinguish children with SA from disease-control subjects through a comprehensive analysis of cells and immune constituents measured in bronchoalveolar lavage (BAL) and blood. Methods: Twenty children with SA and 10 age-matched control subjects with chronic respiratory disorders other than asthma were included. Paired blood and BAL samples were collected and analyzed for a large set of cellular (eosinophils, neutrophils, and subsets of lymphocytes and innate lymphoid cells) and soluble (chemokines, cytokines, and total antibodies) immune constituents. First, correlations of all immune constituents between BAL and blood and with demographic and clinical data were assessed (Spearman correlations). Then, all data were modelled using supervised multivariate analyses (partial least squares discriminant analysis, PLS-DA) to identify immune constituents that significantly discriminate between SA and control subjects. Univariate analyses were performed (Mann-Whitney tests) and then PLS-DA and univariate analyses were combined to identify the most discriminative and significant constituents. Results: Concentrations of soluble immune constituents poorly correlated between BAL and blood. Certain constituents correlated with age or body mass index and, in asthmatics, with clinical symptoms, such as the number of exacerbations in the previous year, asthma control test score, or forced expiratory volume. Multivariate supervised analysis allowed construction of a model capable of distinguishing children with SA from control subjects with 80% specificity and 100% sensitivity. All immune constituents contributed to the model but some, identified by variable-important-in-projection values > 1 and p < 0.1, contributed more strongly, including BAL Th1 and Th2 cells and eosinophilia, CCL26 (Eotaxin 3), IgA and IL-19 concentrations in blood. Blood concentrations of IL-26, CCL13, APRIL, and Pentraxin-3 may also help in the characterization of SA. Conclusions: The analysis of a large set of immune constituents may allow the identification of a biological immune signature of SA. Such an approach may provide new leads for delineating the pathogenesis of SA in children and identifying new targets for its diagnosis, prediction, and personalized treatment.

Childhood asthma outcomes during the COVID-19 pandemic: Findings from the PeARL multi-national cohort.

BACKGROUND: The interplay between COVID-19 pandemic and asthma in children is still unclear. We evaluated the impact of COVID-19 pandemic on childhood asthma outcomes. METHODS: The PeARL multinational cohort included 1,054 children with asthma and 505 non-asthmatic children aged between 4 and 18 years from 25 pediatric departments, from 15 countries globally. We compared the frequency of acute respiratory and febrile presentations during the first wave of the COVID-19 pandemic between groups and with data available from the previous year. In children with asthma, we also compared current and historical disease control. RESULTS: During the pandemic, children with asthma experienced fewer upper respiratory tract infections, episodes of pyrexia, emergency visits, hospital admissions, asthma attacks, and hospitalizations due to asthma, in comparison with the preceding year. Sixty-six percent of asthmatic children had improved asthma control while in 33% the improvement exceeded the minimal clinically important difference. Pre-bronchodilatation FEV1 and peak expiratory flow rate were improved during the pandemic. When compared to non-asthmatic controls, children with asthma were not at increased risk of LRTIs, episodes of pyrexia, emergency visits, or hospitalizations during the pandemic. However, an increased risk of URTIs emerged. CONCLUSION: Childhood asthma outcomes, including control, were improved during the first wave of the COVID-19 pandemic, probably because of reduced exposure to asthma triggers and increased treatment adherence. The decreased frequency of acute episodes does not support the notion that childhood asthma may be a risk factor for COVID-19. Furthermore, the potential for improving childhood asthma outcomes through environmental control becomes apparent.

Sleep in children and young adults with interstitial and diffuse lung disease.

OBJECTIVE: Obstructive sleep apnea (OSA) is common in adult patients with interstitial lung disease (ILD). The aim of the study was to evaluate the prevalence of OSA and sleep quality in children and young adults with children's interstitial and diffuse lung disease (chILD). METHODS: A polysomnography (PSG) was performed in room air in all consecutive patients followed at a national reference centre between June 2018 and September 2019. Clinical and PSG data were collected. RESULTS: The PSG data of 20 patients (12 girls, median age 9 (range 0.5-20) years), were analyzed. Seven (35%) patients had pulmonary alveolar proteinosis (PAP), 5 (25%) a disorder of surfactant metabolism, 3 (15%) diffuse pulmonary hemorrhage, 4 (20%) chILD of unknown etiology and one patient had laryngeal and pulmonary sarcoidosis. The median obstructive apnea-hypnea index (OAHI) was normal at 0 events/hour, with a value > 4 events/hour being observed in 2 young adults: an 18-year-old male with PAP and a vital capacity of 27% predicted who had an OAHI of 10.7 events/hour, and a 20-year-old male with laryngeal and pulmonary sarcoidosis who had positional OSA with an OAHI of 19.5 events/hour. The median total sleep time, sleep efficiency, % of wake after sleep onset, and sleep stages were moderately disturbed. CONCLUSIONS: Moderate or severe OSA was not observed in children <18 years with chILD. Mild or moderate OSA was observed in 2 young adults with PAP and sarcoidosis. As opposed to adults, OSA seems uncommon in children with chILD.

The economic burden of severe asthma in children: a comprehensive study.

OBJECTIVE: The economic burden of severe asthma (SA) in children is poorly described. We aimed to determine the healthcare costs of SA in children for the French national health insurance (NHI). METHODS: Children (6-18 years of age) with physician-confirmed diagnoses of SA or non-SA (NSA) were identified. Direct and indirect expenditures related to asthma and associated co-morbidities in the previous six months were determined, based on a physician-guided parental questionnaire and confirmed by medical records. The costs for the French NHI were assessed per child over a six month period. RESULTS: Data from 74 children, including 48 with SA (22 requiring omalizumab) and 26 with NSA, were analyzed. The global cost of SA was €3,982 per child over a six-month period, including €3,821 direct costs and €161.9 indirect costs. The global cost was €6,716 (4,220) for those requiring omalizumab vs. €1,669 (3,108) for those who did not (p < 0.01). For children with SA, 65% of direct costs were attributed to medication. Among those on omalizumab, such treatment accounted for 93% of medication costs. The global cost was 10 times higher for children with SA than those with NSA (€3,982 (4,422) vs. €363.2 (352.6), p < 0.01), and 20 times higher for children with SA on omalizumab than those with NSA (p < 0.01). CONCLUSION: The economic burden of SA in children for the French NHI is substantial and mainly driven by the most severe children requiring biologics.

Alveolar proteinosis of genetic origins.

Pulmonary alveolar proteinosis (PAP) is a rare form of chronic interstitial lung disease, characterised by the intra-alveolar accumulation of lipoproteinaceous material. Numerous conditions can lead to its development. Whereas the autoimmune type is the main cause in adults, genetic defects account for a large part of cases in infants and children. Even if associated extra-respiratory signs may guide the clinician during diagnostic work-up, next-generation sequencing panels represent an efficient diagnostic tool. Exome sequencing also allowed the discovery of new variants and genes involved in PAP. The aim of this article is to summarise our current knowledge of genetic causes of PAP.

Health-related quality of life in infants and children with interstitial lung disease.

INTRODUCTION: Interstitial lung disease in children (chILD) is a highly heterogeneous group of rare and severe respiratory disorders. The disease by itself, the burden of the treatments (oxygen therapy, corticosteroid pulses, nutritional support) and recurrent hospitalizations may impair the quality of life (QoL) of these children. The aim of the study was to compare the health-related QoL (HR-QoL) in chILD compared to a healthy population and to find out the predictive factors of an altered QoL. METHODS: Patients aged 1 month to 18 years with ILD of known or unknown etiology were prospectively included. Parents and children over 8 years old were asked to fill the PedsQL 4.0 Generic Core Scale ranging from 0 to 100 points. RESULTS: A total of 78 children were recruited in 13 French pediatric centers. Total scores were 11.94 points (P = 0.0003) less for child self-report and 14.08 points ( P < 0.0001) less for parent proxy-report with respect to the healthy population. The clinical factors associated with a lower total score were: extrapulmonary expression of the disease, higher Fan severity score, long-term oxygen therapy, nutritional support, and a number of oral treatments. CONCLUSION: Using a validated quality of life (QoL) scale, we showed that health-related-QoL is significantly impaired in chILD compared with a healthy population. Factors altering QoL score are easy to recognize and could help identify children at a heightened risk of low QoL.

Cartoons to improve young children's cooperation with inhaled corticosteroids: A preliminary study.

INTRODUCTION: The objective of this pilot study was to evaluate if animated cartoons could increase the cooperation of young children with asthma during the delivery of their inhaled corticosteroids (ICS). METHODS: Subjects were children aged 6-47 months having a physician diagnosis of asthma, who required an ICS therapy delivered through a pMDI/spacer twice a day for at least 2 months. Families who reported on a questionnaire that their child was frequently crying or moving during treatment delivery were asked to participate in a prospective, cross-over, randomized study. After a first week of run-in, children watched alternatively, during the delivery of ICS, either an animated cartoon for 7 days and a black screen video for another 7 days. The main outcome was the median percentage of time of non-cooperation, defined by the length of time the child was crying and/or moving divided by the length of time required for delivering ICS. RESULTS: Parents of 50 children out of 113 (44%) reported that their child was frequently crying or moving during treatment delivery. Among these 50 children, 11 (22%) completed the study. The median percentages of time of non-cooperation (IQR 1-3) were 0% (0-3) and 56% (40-97) during the distraction and control periods, respectively, in the first group, and 100% (98-100) and 0% (0-5) during the control and distraction periods, respectively, in the second group. Animated cartoons increased cooperation up to 97% (55-100%) (P = 0.008). CONCLUSIONS: Bad cooperation among young children with asthma during the delivery of their treatment can be dramatically improved by the use of animated cartoons.

Pulmonary hemosiderosis in children with Down syndrome: a national experience.

BACKGROUND: Pulmonary hemosiderosis is a rare and complex disease in children. A previous study from the French RespiRare® network led to two important findings: 20% of the children presented with both pulmonary hemosiderosis and Down syndrome (DS), and at least one tested autoantibody was found positive in 50%. This study investigates the relationships between pulmonary hemosiderosis and DS. METHODS: Patients younger than 20 years old and followed for pulmonary hemosiderosis were retrieved from the RespiRare® database. Clinical, biological, functional, and radiological findings were collected, and DS and non-DS patients' data were compared. RESULTS: A total of 34 patients (22 girls and 12 boys) were included, among whom nine (26%) presented with DS. The mean age at diagnosis was 4.1 ± 3.27 years old for non-DS and 2.9 ± 3.45 years old for DS patients. DS patients tended to present a more severe form of the disease with an earlier onset, more dyspnoea at diagnosis, more frequent secondary pulmonary hypertension, and an increased risk of fatal evolution. CONCLUSIONS: DS patients have a higher risk of developing pulmonary hemosiderosis, and the disease seems to be more severe in this population. This could be due to the combination of an abnormal lung capillary bed with fragile vessels, a higher susceptibility to autoimmune lesions, and a higher risk of evolution toward pulmonary hypertension. A better screening for pulmonary hemosiderosis and a better prevention of hypoxia in DS paediatric patients may prevent a severe evolution of the disease.