Phenotypes of cough in children: A latent class analysis.

INTRODUCTION: Distinguishing phenotypes among children with cough helps understand underlying causes. Using a statistical data-driven approach, we aimed to identify and validate cough phenotypes based on measurable traits, physician diagnoses, and prognosis. METHODS: We used data from the Swiss Paediatric Airway Cohort and included 531 children aged 5-16 years seen in outpatient clinics since 2017. We included children with any parent-reported cough (i.e. cough without a cold, cough at night, cough more than other children, or cough longer than 4 weeks) without current wheeze. We applied latent class analysis to identify phenotypes using nine symptoms and characteristics and selected the best model using the Akaike information criterion. We assigned children to the most likely phenotype and compared the resulting groups for parental atopy history, comorbidities, spirometry, fractional exhaled nitric oxide (FeNO), skin prick tests and specific IgE, physician diagnoses, and 1-year prognosis. RESULTS: We identified four cough phenotypes: non-specific cough (26%); non-allergic infectious and night cough with snoring and otitis (4%); chronic allergic dry night cough with snoring (9%); and allergic non-infectious cough with rhino-conjunctivitis (61%). Children with the allergic phenotype often had family or personal history of atopy and asthma diagnosis. FeNO was highest for the allergic phenotype [median 17.9 parts per billion (ppb)] and lowest for the non-allergic infectious phenotype [median 7.0 parts per billion (ppb)]. Positive allergy test results differed across phenotypes (p < .001) and were most common among the allergic (70%) and least common among the non-specific cough (31%) phenotypes. Subsequent wheeze was more common among the allergic than the non-specific phenotype. CONCLUSION: We identified four clinically relevant cough phenotypes with different prognoses. Although we excluded children with current wheeze, most children with cough belonged to allergy-related phenotypes.

[Where we stand with asthma: optimized medical care and biologic therapy for children]. / Le point sur l'asthme en pédiatrie : optimisation de la prise en charge et thérapies biologiques.

Asthma recommendations are in constant evolution. Salbutamol exclusivity as the historical reference treatment for asthma exacerbations is now questioned. In case of light to moderate crisis, budesonide/formoterol, combining an inhaled corticosteroid and a fast acting long lasting beta2 agonist, can now be proposed as first line as needed treatment, for adolescents older than 12 years old. In addition, progress in fundamental research revealed the heterogeneous nature of asthma and allowed for the emergence of new-targeted therapies.

La prise en charge de l'asthme est en constante évolution. L'exclusivité du salbutamol, traitement historique de référence des exacerbations aiguës, même légères, est remise en question depuis plusieurs années. En cas de symptômes ou crise légère à modérée, le budésonide/formotérol, combiné de corticostéroïde inhalé et bronchodilatateur (ß2-agoniste) d'action rapide et prolongée, peut dorénavant être proposé en première intention, à la demande, y compris en pédiatrie, notamment à partir de 12 ans. De plus, les progrès en recherche fondamentale ont permis de révéler la nature hétérogène de l'asthme et de faire émerger de nouvelles cibles thérapeutiques. En particulier, les patients asthmatiques peuvent bénéficier de l'entrée des biologiques dans l'arsenal thérapeutique.

[Respiratory issues in children with severe neurological impairment]. / Atteinte respiratoire chez l'enfant en situation de polyhandicap sévère.

Respiratory problems have a significant impact on morbidity and mortality in children with severe neurological impairment. In particular, impaired airway clearance, recurrent respiratory infections, bronchial hyper reactivity can lead to acute decompensation and, with time, to chronic respiratory failure. Multiple coexisting and interacting factors that influence the respiratory status of these children should be recognized and effectively addressed to reduce respiratory morbidity and mortality. An accurate assessment involving a multidisciplinary approach and relatively simple interventions can lead to significant improvements in the quality of life of children as well as their parents and carers.

Les complications respiratoires ont un impact significatif sur la morbidité et la mortalité chez les enfants en situation de polyhandicap sévère. En particulier l'encombrement bronchique, les infections respiratoires récurrentes et l'hyperréactivité bronchique peuvent conduire à des décompensations aiguës et, avec le temps, à une insuffisance respiratoire chronique. De multiples facteurs coexistant et interagissant qui influencent l'état respiratoire de ces enfants doivent être reconnus et traités efficacement afin de réduire la morbidité et la mortalité respiratoires. Une évaluation précise impliquant une approche multidisciplinaire et des interventions relativement simples peuvent conduire à une amélioration significative de la qualité de vie de ces enfants ainsi que de leurs parents et tuteurs.

[Phage therapy for respiratory infections]. / Phagothérapie pour traiter les infections respiratoires.

The crisis of antibiotic resistance represents a global public health challenge, affecting particularly patients with respiratory infections. The use of (bacterio)phages for the treatment of bacterial infections (phage therapy) seems safe but its effectiveness has not yet been proven by controlled clinical trials. Nevertheless, phage therapy is regaining interest, encouraged by published cases treated successfully with personalized phage combinations as well as significant advances at a preclinical level. Standardized approaches in phage production and treatment administration, as well as future translational studies, are needed to improve our understanding and explore the potential of phage therapy.

La crise de l'antibiorésistance représente un enjeu considérable en santé publique, touchant particulièrement les patients avec des infections respiratoires. L'utilisation des (bactério)phages pour le traitement des infections bactériennes semble sécuritaire mais son efficacité n'a pas encore été formellement démontrée dans des essais cliniques contrôlés. La phagothérapie regagne de l'intérêt comme traitement personnalisé pour les patients qui ne répondent pas aux traitements standards, comme en témoignent les multiples cas publiés ainsi que des découvertes significatives au niveau préclinique. Des approches standardisées concernant la production et l'administration des phages ainsi que des études translationnelles sont nécessaires afin d'améliorer notre compréhension et d'explorer le potentiel de la phagothérapie.

Deep phenotyping, including quantitative ciliary beating parameters, and extensive genotyping in primary ciliary dyskinesia.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a rare genetic disorder resulting in abnormal ciliary motility/structure, extremely heterogeneous at genetic and ultrastructural levels. We aimed, in light of extensive genotyping, to identify specific and quantitative ciliary beating anomalies, according to the ultrastructural phenotype. METHODS: We prospectively included 75 patients with PCD exhibiting the main five ultrastructural phenotypes (n=15/group), screened all corresponding PCD genes and measured quantitative beating parameters by high-speed video-microscopy (HSV). RESULTS: Sixty-eight (91%) patients carried biallelic mutations. Combined outer/inner dynein arms (ODA/IDA) defect induces total ciliary immotility, regardless of the gene involved. ODA defect induces a residual beating with dramatically low ciliary beat frequency (CBF) related to increased recovery stroke and pause durations, especially in case of DNAI1 mutations. IDA defect with microtubular disorganisation induces a low percentage of beating cilia with decreased beating angle and, in case of CCDC39 mutations, a relatively conserved mean CBF with a high maximal CBF. Central complex defect induces nearly normal beating parameters, regardless of the gene involved, and a gyrating motion in a minority of ciliated edges, especially in case of RSPH1 mutations. PCD with normal ultrastructure exhibits heterogeneous HSV values, but mostly an increased CBF with an extremely high maximal CBF. CONCLUSION: Quantitative HSV analysis in PCD objectives beating anomalies associated with specific ciliary ultrastructures and genotypes. It represents a promising approach to guide the molecular analyses towards the best candidate gene(s) to be analysed or to assess the pathogenicity of the numerous sequence variants identified by next-generation-sequencing.

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.

[Cigarette smoke and nicotine during pregnancy : where are we today?] / Fumée de tabac, cigarette électronique et dérivés nicotiniques pendant la grossesse†: le point de la situation.

In Switzerland, about 13  % of pregnant women smoke, giving birth to more than 11'000 infants per year exposed to tobacco in utero. Although this proportion is stable since the 2000's, the users of nicotine with new devices (electronic cigarettes, inhaled heated tobacco, sniffed or chewed tobacco) are increasing. The literature is unanimous about deleterious effects of prenatal exposure to tobacco smoke on the fetus, with multiple short- and long-term consequences. Available data suggest that in utero exposure to e-cigarette could also expose the fetus to a similar profile of adverse effects. In this article, we review briefly the known epidemiological and mechanistic data on the short- and long-term effects of prenatal cigarette smoke and nicotine consumption.

En Suisse, environ 13 % des femmes enceintes fument, donnant naissance à plus de 11 000 nourrissons par an exposés au tabac in utero. Si cette proportion est stable depuis les années 2000, celle des nouveaux modes de consommation du tabac et de la nicotine (cigarette électronique, inhalation de tabac chauffé, tabac à priser ou à sucer) est en augmentation. La littérature est unanime sur les effets délétères de l'exposition anténatale au tabac sur le fœtus, avec de multiples conséquences à court et à long terme. Les études disponibles à ce jour suggèrent que l'exposition in utero à l'e-cigarette expose à un profil similaire d'effets secondaires indésirables. Dans cet article, nous revoyons brièvement les données épidémiologiques et mécanistiques connues des effets à court et à long terme de la fumée de tabac et de la nicotine en anténatal.

[Revolution in the treatment of cystic fibrosis]. / Révolution dans le traitement de la mucoviscidose.

Cystic Fibrosis is a genetic disorder resulting in the absence or dysfunction of the CFTR protein, a chloride channel present on the surface of epithelia, particularly respiratory. Until recently, treatments only concerned the consequences of the disease. But a new type of molecules called «â€…modulators ¼, is already available to some patients and targets the origin of the disease. «â€…Modulators ¼ are divided into «â€…potentiators ¼, which improve the transport of chloride by the CFTR protein, and «â€…correctors ¼, increasing the amount of CFTR proteins. An oral triple therapy combining a potentiator and two correctors has just been approved in the USA and will treat 85 % of patients. The clinical benefit of «â€…modulators ¼ is remarkable, and these drugs are revolutionizing the treatment of Cystic Fibrosis.

La mucoviscidose est une maladie génétique entraînant une absence ou des dysfonctions de la protéine Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), un canal chlore présent à la surface des épithélia, notamment respiratoire. Jusqu'à récemment, les traitements ne concernaient que les conséquences de la maladie. Mais un nouveau type de molécules appelées «â€…modulateurs ¼ est déjà à la disposition de certains patients et cible l'origine de la maladie. Les «â€…modulateurs ¼ sont divisés en «â€…potentiateurs ¼, permettant d'améliorer le transport du chlore par la protéine CFTR, et en «â€…correcteurs ¼, augmentant la quantité de protéines CFTR. Une trithérapie orale combinant un potentiateur et deux correcteurs vient d'être approuvée aux États-Unis et permettra de traiter 85 % des patients. Le bénéfice clinique des «â€…modulateurs ¼ est remarquable et ces médicaments bouleversent le traitement de la mucoviscidose.

Mutations in DNAJB13, Encoding an HSP40 Family Member, Cause Primary Ciliary Dyskinesia and Male Infertility.

Primary ciliary dyskinesia (PCD) is an autosomal-recessive disease due to functional or ultra-structural defects of motile cilia. Affected individuals display recurrent respiratory-tract infections; most males are infertile as a result of sperm flagellar dysfunction. The great majority of the PCD-associated genes identified so far encode either components of dynein arms (DAs), which are multiprotein-ATPase complexes essential for ciliary motility, or proteins involved in DA assembly. To identify the molecular basis of a PCD phenotype characterized by central complex (CC) defects but normal DA structure, a phenotype found in ∼15% of cases, we performed whole-exome sequencing in a male individual with PCD and unexplained CC defects. This analysis, combined with whole-genome SNP genotyping, identified a homozygous mutation in DNAJB13 (c.833T>G), a gene encoding a HSP40 co-chaperone whose ortholog in the flagellated alga Chlamydomonas localizes to the radial spokes. In vitro studies showed that this missense substitution (p.Met278Arg), which involves a highly conserved residue of several HSP40 family members, leads to protein instability and triggers proteasomal degradation, a result confirmed by the absence of endogenous DNAJB13 in cilia and sperm from this individual. Subsequent DNAJB13 analyses identified another homozygous mutation in a second family; the study of DNAJB13 transcripts obtained from airway cells showed that this mutation (c.68+1G>C) results in a splicing defect consistent with a loss-of-function mutation. Overall, this study, which establishes mutations in DNAJB13 as a cause of PCD, unveils the key role played by DNAJB13 in the proper formation and function of ciliary and flagellar axonemes in humans.

A new index for characterizing micro-bead motion in a flow induced by ciliary beating: Part I, experimental analysis.

Mucociliary clearance is one of the major lines of defense of the respiratory system. The mucus layer coating the pulmonary airways is moved along and out of the lung by the activity of motile cilia, thus expelling the particles trapped in it. Here we compare ex vivo measurements of a Newtonian flow induced by cilia beating (using micro-beads as tracers) and a mathematical model of this fluid flow, presented in greater detail in a second companion article. Samples of nasal epithelial cells placed in water are recorded by high-speed video-microscopy and ciliary beat pattern is inferred. Automatic tracking of micro-beads, used as markers of the flow generated by cilia motion, enables us also to assess the velocity profile as a function of the distance above the cilia. This profile is shown to be essentially parabolic. The obtained experimental data are used to feed a 2D mathematical and numerical model of the coupling between cilia, fluid, and micro-bead motion. From the model and the experimental measurements, the shear stress exerted by the cilia is deduced. Finally, this shear stress, which can easily be measured in the clinical setting, is proposed as a new index for characterizing the efficiency of ciliary beating.

Pulmonary complications after liver transplantation in children: risk factors and impact on early post-operative morbidity.

Liver transplantation (LT) is associated with high post-operative morbidity, despite excellent survival rates. With this retrospective study, we report the incidence of early and late pulmonary complications (PC) after LT, identify modifiable risk factors for PC and analyzed the role of PC in post-operative ventilation duration and hospital length of stay. In a series of 79 children (0-16 years) with LT over a 12 years period, early (<3 months post-LT) and/or late (>3 months post-LT) PC occurred in 68 patients (86%). Sixty-four percent (64%) developed early major complications such as pulmonary edema, atelectasis, or pleural effusion. Atelectasis requiring an intervention (P ≤ .02), pulmonary edema (P ≤ .02), or elevated PELD/MELD scores (P = .05) were associated with an increase in total ventilation duration and length of stay in the ICU. Risk factors for early PC included preoperative hypoxemia (P = .005), low serum albumin at LT admission (P = .003), or early rejection (P = .002). About 20% of patients experienced late PC of which 81% were infections. Risk factor assessment prior to LT may ultimately help reduce early PC thereby possibly minimizing post-operative morbidity and ICU length of stay.

Case Report: When cystic fibrosis, elexacaftor/tezacaftor/ivacaftor therapy, and alpha1 antitrypsin deficiency get together.

In the last 10 years, the care of patients with cystic fibrosis (CF) has been revolutionized with the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulator drugs, with a major impact on symptoms and life expectancy, especially considering the newest and highly effective elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) therapy. Conversely, adverse effects are relatively frequent, with some being life-threatening, such as severe hepatitis. Clinical trials on children starting CFTR modulators have reported transaminase elevations >3× upper limit of the norm in 10%-20% of patients, whereas real-life studies have reported discontinuation rates three times higher than those observed in phase 3 trials. We report the case of a 10-year-old boy with CF who developed severe acute hepatitis 2 weeks after starting ELX/TEZ/IVA therapy. An extensive screening for potential causes led to the identification of heterozygous alpha1-antitrypsin (AAT) deficiency with genotype MZ. The Z allele of SERPINA1 gene, encoding AAT, is known as a risk factor for CF liver disease. We hypothesized that it may act as a risk factor for drug-induced liver injury from CFTR modulators, notably ELX/TEZ/IVA. Therefore, checking AAT before starting CFTR modulator therapy can be suggested, in particular for children with previous, even transient, liver disease.

Lung structural and functional impairments in young children with cystic fibrosis diagnosed following newborn screening - A nationwide observational study.

BACKGROUND: Non-invasive and sensitive clinical endpoints are needed to monitor onset and progression of early lung disease in children with cystic fibrosis (CF). We compared lung clearance index (LCI), FEV1, functional and structural lung magnetic resonance imaging (MRI) outcomes in Swiss children with CF diagnosed following newborn screening. METHODS: Lung function (LCI, FEV1) and unsedated functional and structural lung MRI was performed in 79 clinically stable children with CF (3 - 8 years) and 75 age-matched healthy controls. Clinical information was collected throughout childhood. RESULTS: LCI, ventilation and perfusion defects, and structural MRI scores were significantly higher in children with CF compared with controls, but FEV1 was not different between groups. Lung MRI outcomes correlated significantly with LCI (morphology score (r = 0.56, p < 0.001); ventilation defects (r = 0.43, p = 0.001); perfusion defects (r = 0.64, p < 0.001), but not with FEV1. Lung MRI outcomes were more sensitive to detect impairments in children with CF (abnormal ventilation and perfusion outcomes in 47 %, morphology score in 30 %) compared with lung function (abnormal LCI in 21 % and FEV1 in 4.8 %). Pulmonary exacerbations, respiratory hospitalizations, and increase in patient-reported cough was associated with higher LCI and higher structural and functional MRI outcomes. CONCLUSIONS: The LCI and lung MRI outcomes non-invasively detect even mild early lung disease in young children with CF diagnosed following newborn screening. Pulmonary exacerbations and early respiratory symptoms were risk factors for structural and functional impairment in childhood.