ABSTRACT
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.
ABSTRACT
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.
ABSTRACT
BACKGROUND: Good data quality is essential when rare disease registries are used as a data source for pharmacovigilance studies. This study investigated data quality of the Swiss cystic fibrosis (CF) registry in the frame of a European Cystic Fibrosis Society Patient Registry (ECFSPR) project aiming to implement measures to increase data reliability for registry-based research. METHODS: All 20 pediatric and adult Swiss CF centers participated in a data quality audit between 2018 and 2020, and in a re-audit in 2022. Accuracy, consistency and completeness of variables and definitions were evaluated, and missing source data and informed consents (ICs) were assessed. RESULTS: The first audit included 601 out of 997 Swiss people with CF (60.3 %). Data quality, as defined by data correctness ≥95 %, was high for most of the variables. Inconsistencies of specific variables were observed because of an incorrect application of the variable definition. The proportion of missing data was low with <5 % for almost all variables. A considerable number of missing source data occurred for CFTR variants. Availability of ICs varied largely between centers (10 centers had >5 % of missing documents). After providing feedback to the centers, availability of genetic source data and ICs improved. CONCLUSIONS: Data audits demonstrated an overall good data quality in the Swiss CF registry. Specific measures such as support of the participating sites, training of data managers and centralized data collection should be implemented in rare disease registries to optimize data quality and provide robust data for registry-based scientific research.
ABSTRACT
Patients with autosomal dominant (AD) hyper-IgE syndrome (HIES) suffer from a constellation of manifestations including recurrent bacterial and fungal infections, severe atopy, and skeletal abnormalities. This condition is typically caused by monoallelic dominant-negative (DN) STAT3 variants. In 2020, we described 12 patients from eight kindreds with DN IL6ST variants resulting in a new form of AD HIES. These variants encoded truncated GP130 receptors, with intact extracellular and transmembrane domains, but lacking the intracellular recycling motif and the four STAT3-binding residues, resulting in an inability to recycle and activate STAT3. We report here two new DN variants of IL6ST in three unrelated families with HIES-AD. The biochemical and clinical impacts of these variants are different from those of the previously reported variants. The p.(Ser731Valfs*8) variant, identified in seven patients from two families, lacks the recycling motif and all the STAT3-binding residues, but its levels on the cell surface are only slightly increased and it underlies mild biological phenotypes with variable clinical expressivity. The p.(Arg768*) variant, identified in a single patient, lacks the recycling motif and the three most distal STAT3-binding residues. This variant accumulates at the cell surface and underlies severe biological and clinical phenotypes. The p.(Ser731Valfs*8) variant shows that a DN GP130 expressed at near normal levels on the cell surface can underlie heterogeneous clinical presentations, ranging from mild to severe. The p.(Arg768*) variant demonstrates that a truncated GP130 protein retaining one STAT3-binding residue can underlie severe HIES.
Subject(s)
Hypersensitivity, Immediate , Job Syndrome , Humans , Job Syndrome/diagnosis , Job Syndrome/genetics , Cytokine Receptor gp130/genetics , Cytokine Receptor gp130/metabolism , Phenotype , STAT3 Transcription Factor , Hypersensitivity, Immediate/complications , Mutation/geneticsABSTRACT
AIM: To summarise lung function characteristics of athletic swimmers and discuss mechanisms explaining these changes while putting forward the lack of a clear understanding of the precise physiological factors implicated. METHODS: Literature search until 07.2021 on Medline and EMBASE using keywords swimming, athletes, respiratory physiology, lung development, lung function tests. Relevant articles in French and English were reviewed. RESULTS: We found insufficient data to perform a meta-analysis. However, there is evidence that swimmers have better expiratory flows and increased baseline lung volumes than non-athletes or non-swimmers. Although these features can result from changes in lung development following intense training over the years, the contribution of a genetic predisposition and positive selection cannot be totally excluded. CONCLUSION: Disentangling the participation of constitutional factors and years of hard training to explain the larger lung volumes of athletic swimmers is in favour of an adaptative response of the lungs to early swim training through modification of the pathway of lung development. There seems to be an optimal window of opportunity before the end of growth for these adaptational changes to occur. Precise mechanisms, and contribution of adaptative change on lung physiology, remain to be further studied.
Subject(s)
Adaptation, Physiological , Swimming , Humans , Lung , Respiratory Function Tests , Respiratory Physiological PhenomenaABSTRACT
BACKGROUND: Lung disease can develop within the first year of life in infants with cystic fibrosis (CF). However, the frequency and severity of respiratory symptoms in infancy are not known. METHODS: We assessed respiratory symptoms in 50 infants with CF and 50 healthy matched controls from two prospective birth cohort studies. Respiratory symptoms and respiratory rate were documented by standardized weekly interviews throughout the first year. Infants performed multiple breath washout in the first weeks of life. RESULTS: We analyzed 4552 data points (2217 in CF). Respiratory symptoms (either mild or severe) were not more frequent in infants with CF (OR:1.1;95% CI:[0.76, 1.59]; p=0.6). Higher lung clearance index and higher respiratory rate in infants with CF were not associated with respiratory symptoms. CONCLUSIONS: We found no difference in respiratory symptoms between healthy and CF infants. These data indicate that early CF lung disease may not be captured by clinical presentation alone.
Subject(s)
Cystic Fibrosis/physiopathology , Case-Control Studies , Female , Humans , Infant , Male , Predictive Value of Tests , Prospective Studies , Respiratory Function Tests , Respiratory RateABSTRACT
BACKGROUND: Increased (abnormal) ventilation inhomogeneity in individuals with mild Cystic Fibrosis (CF) lung disease may become a treatable trait for small-molecule therapeutics improving Cystic Fibrosis Transmembrane Regulator (CFTR) function. The relationship between CFTR function and ventilation inhomogeneity is unknown. We aimed to identify and quantify increased ventilation inhomogeneity in relation to CFTR function. METHODS: This was an international, multi-center, cross-sectional study. We collated data from individuals aged 3-25 years with minimal (CFTR-MF) or residual (CFTR-RF) function of a variety of CFTR genotypes and FEV1 ≥ 70% predicted. We measured lung function using nitrogen multiple-breath washout and spirometry. We compared lung clearance index (LCI) and FEV1 between individuals with CFTR-MF vs CFTR-RF using a mixed effects multi-variable linear regression model to account for study differences and a logistic model based on propensity-score matching to adjust for possible confounding. RESULTS: We included 141 with CFTR-MF and 35 with CFTR-RF. LCI (> 1.96 z-score) was elevated in 71.6% individuals with CFTR-MF and in 40.0% with CFTR-RF. FEV1 (< -1.96 z-score) was reduced in 11.3% individuals with CFTR-MF and in 5.7% with CFTR-RF. The mean difference (95% CI) of LCI and FEV1 between CFTR-MF and CFTR-RF was 3.71 (1.63 to 5.79) and -0.40 (-0.83 to 0.02) z-score. The LCI differences were similar after adjustment for confounders and in individuals with normal FEV1. CONCLUSION: Increased ventilation inhomogeneity is associated with less CFTR function. In individuals with mild CF lung disease, LCI can identify and quantify increased ventilation inhomogeneity, a candidate treatable trait.
Subject(s)
Cystic Fibrosis Transmembrane Conductance Regulator/physiology , Cystic Fibrosis/physiopathology , Adolescent , Child , Child, Preschool , Cross-Sectional Studies , Female , Humans , Male , Pulmonary Ventilation , Respiratory Function Tests , Retrospective StudiesABSTRACT
OBJECTIVES: The contribution of intracellular and fastidious bacteria in Cystic fibrosis (CF) pulmonary exacerbations, and progressive lung function decline remains unknown. This project aimed to explore their impact on bacterial microbiota diversity over time in CF children. METHODS: Sixty-one children enrolled in the MUCOVIB multicentre prospective cohort provided 746 samples, mostly nasopharyngeal swabs, throat swabs and sputa which were analysed using culture, specific real-time qPCRs and 16S rRNA amplicon metagenomics. RESULTS: Chlamydia pneumoniae (n = 3) and Mycoplasma pneumoniae (n = 1) were prospectively documented in 6.6% of CF children. Microbiota alpha-diversity in children with a documented C. pneumoniae was highly variable, similarly to children infected with Staphylococcus aureus or Pseudomonas aeruginosa. The transition from routine follow-up visits to pulmonary exacerbation (n = 17) yielded variable changes in diversity indexes with some extreme loss of diversity. CONCLUSIONS: The high rate of C. pneumoniae detection supports the need for regular screenings in CF patients. A minor impact of C. pneumoniae on the microbial community structure was documented. Although detected in a single patient, M. pneumoniae should also be considered as a possible aetiology of lung infection in CF subjects.
Subject(s)
Chlamydophila pneumoniae/isolation & purification , Cystic Fibrosis/microbiology , Microbiota , Mycoplasma pneumoniae/isolation & purification , Respiratory System/microbiology , Biodiversity , Child , Child, Preschool , Chlamydophila Infections/microbiology , Chlamydophila pneumoniae/genetics , DNA, Bacterial , Humans , Metagenomics , Mycoplasma pneumoniae/genetics , Pneumonia, Mycoplasma/microbiology , Prospective Studies , RNA, Ribosomal, 16S , Sputum/microbiologyABSTRACT
AIMS: Since 2016, Swiss guidelines recommend screening of all migrant children <5 years of age for tuberculosis (TB) and to screen older children only if they have risk factors for TB. Our goals were to describe the epidemiology of latent tuberculosis (LTBI) in migrant children at the Lausanne University Hospital, to identify determinants of LTBI and tuberculosis disease (TBD), and to evaluate the risk of a false-positive tuberculin skin test (TST) when using a positivity limit of 5 mm. METHODS: Newly arrived migrant children 0–18 years of age were prospectively enrolled from 31 August 2015 to 31 August 2017. Every migrant child was assessed for the risk of TB exposure and TBD and was administered a TST. A TB-spot test was performed in children ≥5 years of age when the TST was positive. Children with clinical and/or radiological signs of TBD were further investigated. Children ≥5 years of age with a positive TB-spot test and children <5 years of age with a positive TST, without clinico-radiological signs of TBD received a diagnosis of LTBI. A false-positive TST result was diagnosed in children ≥5 years of age when the TB-spot test was negative. Potential determinants of TB (LTBI and TBD) and of false-positive TSTs were identified. Student’s t-test or the Kruskal-Wallis test were used for continuous variables and the chi-square test or Fisher’s exact test for categorical variables. All variables with a p-value <0.05 were included in a multivariate logistic regression model. RESULTS: Two hundred and fifty-three patients were eligible for the study. The median age of the patients was 8.1 years (interquartile range [IQR] 4.5–12.8) and 104 (41%) were female. Twenty-four percent of the patients (62/253) came from a country with a moderate–high incidence of TBD (≥80 cases per 100,000 individuals). Twenty-eight patients (11%) had positive TSTs, and TB was confirmed in 17 (6.7%) of these patients (16 with LTBI and 1 with TBD). On multivariate analysis, moderate–high incidence of TBD in the country of origin (adjusted odds ratio [aOR] 18.8, 95% confidence interval [CI] 5.1–68.6; p <0.001), older age (aOR 1.1, 95% CI 1.0–1.3; p = 0.025), and contact with a TBD patient (aOR 8, 95% CI 1.8–36.2; p = 0.007) were associated with a diagnosis of TB. Among the 23 children over 5 years of age who had a positive TST with measurement available, a measure between 5–9 mm was more frequent in case of a false-positive TST (5/9, 56% vs 0/14, 0%, p = 0.002). BCG vaccination was the only predictor of a false-positive TST (p = 0.03). CONCLUSION: Screening migrant children ≥5 years of age for TB could confer a public health benefit even in the absence of other risk factors. The limit of TST positivity could be raised from ≥5 mm to ≥10 mm to decrease the rate of false-positive results. A national assessment of migrant children between the ages of 5 and 15 should be carried out to confirm our findings.
Subject(s)
Latent Tuberculosis , Transients and Migrants , Tuberculosis , Adolescent , Aged , Child , Child, Preschool , Female , Humans , Interferon-gamma Release Tests , Latent Tuberculosis/diagnosis , Latent Tuberculosis/epidemiology , Prevalence , Switzerland/epidemiology , Tuberculin Test , Tuberculosis/diagnosis , Tuberculosis/epidemiologySubject(s)
Coronavirus , Cystic Fibrosis , Betacoronavirus , COVID-19 , Child , Coronavirus Infections , Female , Humans , Pandemics , Pneumonia, Viral , SARS-CoV-2 , SpainABSTRACT
Numerous benefits are attributed to omega-3 fatty acids (OM3) especially in cardiovascular health. However, bioavailability and clinical efficacy depend on numerous factors, including OM3 form, food matrix effects (especially the lipid content of the diet), and metabolic capacity. Here, we show in humans that a "pre-digested" OM3-sn-1(3)-monoacylglycerol lipid structure (OM3-MAG) has a significantly greater absorption at high therapeutic doses (2.9 g/day) than the most commonly OM3-ethyl ester (3.1 g/day) form (used for the treatment of hypertriglyceridemia), and a comparable profile to other pre-digested OM3 free fatty acids (OM3-FFA) structure (3.2 g/day). Nutritional supplement doses of MAG resulted in similar increases in OM3 blood level, compared to OM3 triacylglycerols (OM3-TAG) supplements in obese subjects (1.2 g/day) under low fat diet, and in children with cystic fibrosis (1.0 g/day). These results suggest that both forms of pre-digested OM3-MAG and OM3-FFA are effectively absorbed and re-incorporated effectively into triacylglycerols inside the enterocytes, before being exported into the chylomicrons lipid transport system. The pre-digested OM3-MAG might provide a more effective therapy in severe cardiovascular conditions where high doses of OM3 are required and a low-fat diet is indicated, which limited digestive lipase activity.
Subject(s)
Cystic Fibrosis/drug therapy , Dietary Supplements , Fatty Acids, Omega-3 , Hypertriglyceridemia/drug therapy , Monoglycerides , Obesity/drug therapy , Adult , Biological Availability , Chylomicrons/metabolism , Cystic Fibrosis/blood , Cystic Fibrosis/pathology , Enterocytes/metabolism , Fatty Acids, Omega-3/administration & dosage , Fatty Acids, Omega-3/pharmacokinetics , Female , Humans , Hypertriglyceridemia/blood , Hypertriglyceridemia/pathology , Male , Middle Aged , Monoglycerides/administration & dosage , Monoglycerides/pharmacokinetics , Obesity/blood , Obesity/pathology , Triglycerides/bloodABSTRACT
Exercise induced dyspnea is a common complaint among adolescents, whether sedentary or competitive athletes. This complaint may be associated with reduced athletic performance and general fatigue. It can be caused by various etiologies, sometimes concomitant. It is important for clinicians to obtain a specific history and then perform the appropriate additional tests. The three most common diagnostic entities are exercise-induced asthma/bronchoconstriction, exercise-induced laryngeal obstruction, and physical deconditioning, each with distinctive characteristics. Therapeutic management, including environmental measures and appropriate drug treatment, must be individualized and depends on the etiology.
La dyspnée d'effort est une plainte fréquente chez l'adolescent, qu'il soit sédentaire ou sportif de compétition. Cette plainte peut être associée à une baisse des performances sportives et à une fatigue générale. Elle peut être causée par diverses étiologies, parfois concomitantes. Il est important pour les cliniciens d'obtenir une anamnèse spécifique pour ensuite réaliser les examens complémentaires appropriés. Les trois entités diagnostiques les plus fréquentes sont l'asthme/bronchoconstriction induite par l'effort, l'obstruction laryngée induite par l'exercice, et le déconditionnement physique, présentant chacune des caractéristiques distinctives. La prise en charge thérapeutique doit être individualisée et dépend de l'étiologie retrouvée, incluant des mesures environnementales et un traitement médicamenteux approprié.
Subject(s)
Asthma, Exercise-Induced , Athletic Performance , Laryngeal Diseases , Adolescent , Bronchoconstriction , Dyspnea , HumansSubject(s)
Pneumocystis carinii/isolation & purification , Pneumonia, Pneumocystis/immunology , Severe Combined Immunodeficiency/diagnosis , Female , Humans , Infant , Pneumonia, Pneumocystis/diagnosis , Pneumonia, Pneumocystis/etiology , Severe Combined Immunodeficiency/complications , Severe Combined Immunodeficiency/microbiologyABSTRACT
INTRODUCTION: Normalized phase III slope (SnIII ) indices from multiple breath washout (MBW) estimate ventilation inhomogeneity. Alternate (*) protocols for SnIII indices exist, however the utility of these outcomes in children with mild-to-moderate cystic fibrosis (CF) is unknown. METHODS: We measured nitrogen MBW and spirometry in 135 children (43 controls) aged 4-18 years. We assessed validity, practicability, and reliability of SnIII protocols. Outcomes included the ability to detect abnormal lung function, test agreement, measurement duration, intra-test repeatability, and quality. RESULTS: Lung clearance index (LCI) was abnormal in 80 (87%), Scond in 55 (60%), Scond* in 17 (19%), Sacin in 10 (11%), Sacin* in 11 (12%), and FEV1 in 28 (30%). Alternate protocols reduced measurement duration. Agreement of indices to detect abnormal lung function was poor. The quality of analysis and repeatability deteriorated with the alternate technique compared to standard. CONCLUSION: In children with mild-to-moderate CF lung disease, alternate protocols seem practical but clinimetric properties of standard SnIII protocols are preferable.
Subject(s)
Cystic Fibrosis/physiopathology , Lung/physiopathology , Respiration , Adolescent , Child , Child, Preschool , Female , Humans , Male , Reproducibility of Results , Respiratory Function Tests/methodsABSTRACT
Drowning is a significant and neglected public health problem mostly affecting young children. The definition of drowning has recently been modified and the notions of « dry drowning ¼, « secondary drowning ¼ and « near drowning ¼ are no longer accepted or used. However, recent articles in the media describing dry drowning of children have been reported. This entity seems to be absent of the actual scientific literature and worried parents can be reassured. Increased vigilance is the key as prevention is the most efficient intervention to reduce drowning mortality. To provide more guidance to the pediatrician and the general practitioner we are reviewing the most recent literature on the subject, as well as facts in the mater of drowning prevention.
La noyade est un problème de santé publique grave et négligé touchant principalement les enfants en bas âge. La définition de la noyade a été revue récemment et les notions de noyade « sèche ¼, « secondaire ¼ ou « presque-noyade ¼ ne sont plus reconnues ou utilisées. On observe néanmoins la mention récente dans les médias de noyades sèches d'enfants. L'entité décrite semble absente de la littérature médicale actuelle et les parents inquiets peuvent être rassurés. La vigilance reste toutefois de mise, car la prévention est l'intervention la plus efficace pour réduire la mortalité par noyade. Pour guider au mieux le pédiatre et le médecin de premier recours, nous revoyons les connaissances actuelles sur le sujet ainsi que les preuves en matière de prévention de la noyade.
Subject(s)
Drowning , Water , Child , Humans , Parents , Physicians , Public HealthABSTRACT
Exhaled nitric oxide (FENO) is a well-known, non-invasive airway biomarker. In patients with Cystic Fibrosis (CF) FENO is decreased. To understand if reduced FENO is primary related to Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) dysfunction or an epiphenomenon of chronic inflammation, we measured FENO in 34 infants with CF prior to clinical symptoms and in 68 healthy controls. FENO was lower in CF compared to controls (p=0.0006) and the effect was more pronounced in CF infants without residual CFTR function (p<0.0001). This suggests that FENO is reduced in CF early in life, possibly associated with underlying CFTR dysfunction.
Subject(s)
Breath Tests/methods , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Cystic Fibrosis , Nitric Oxide , Asymptomatic Diseases , Biomarkers/analysis , Biomarkers/metabolism , Cohort Studies , Cystic Fibrosis/diagnosis , Cystic Fibrosis/metabolism , Exhalation , Female , Humans , Infant , Inflammation/metabolism , Male , Nitric Oxide/analysis , Nitric Oxide/metabolism , SwitzerlandABSTRACT
It is not known at what age lung function impairment may arise in children with cystic fibrosis (CF). We assessed lung function shortly after birth in infants with CF diagnosed by newborn screening.We performed infant lung function measurements in a prospective cohort of infants with CF and healthy controls. We assessed lung clearance index (LCI), functional residual capacity (FRC) and tidal breathing parameters. The primary outcome was prevalence and severity of abnormal lung function (±1.64 z-scores) in CF.We enrolled 53 infants with CF (mean age 7.8â weeks) and 57 controls (mean age 5.2â weeks). Compared to controls, LCI and FRC were elevated (mean difference 0.30, 95% CI 0.02-0.60; p=0.034 and 14.5â mL, 95% CI 7.7-21.3â mL; p<0.001, respectively), while ratio of time to peak tidal expiratory flow to expiratory time was decreased in infants with CF. In 22 (41.5%) infants with CF, either LCI or FRC exceeded 1.64 z-scores; three infants had both elevated LCI and FRC.Shortly after birth, abnormal lung function is prevalent in CF infants. Ventilation inhomogeneity or hyperinflation may serve as noninvasive markers to monitor CF lung disease and specific treatment effects, and could thus be used as outcome parameters for future intervention studies in this age group.