Nasopharyngeal microbiota in children is associated with severe asthma exacerbations.

BACKGROUND: The respiratory microbiome has been associated with the etiology and disease course of asthma. OBJECTIVE: We sought to assess the nasopharyngeal microbiota in children with a severe asthma exacerbation and their associations with medication, air quality, and viral infection. METHODS: A cross-sectional study was performed among children aged 2 to 18 years admitted to the medium care unit (MCU; n = 84) or intensive care unit (ICU; n = 78) with an asthma exacerbation. For case-control analyses, we matched all cases aged 2 to 6 years (n = 87) to controls in a 1:2 ratio. Controls were participants of either a prospective case-control study or a longitudinal birth cohort (n = 182). The nasopharyngeal microbiota was characterized by 16S-rRNA-gene sequencing. RESULTS: Cases showed higher Shannon diversity index (ICU and MCU combined; P = .002) and a distinct microbial community composition when compared with controls (permutational multivariate ANOVA R2 = 1.9%; P < .001). We observed significantly higher abundance of Staphylococcus and "oral" taxa, including Neisseria, Veillonella, and Streptococcus spp. and a lower abundance of Dolosigranulum pigrum, Corynebacterium, and Moraxella spp. (MaAsLin2; q < 0.25) in cases versus controls. Furthermore, Neisseria abundance was associated with more severe disease (ICU vs MCU MaAslin2, P = .03; q = 0.30). Neisseria spp. abundance was also related with fine particulate matter exposure, whereas Haemophilus and Streptococcus abundances were related with recent inhaled corticosteroid use. We observed no correlations with viral infection. CONCLUSIONS: Our results demonstrate that children admitted with asthma exacerbations harbor a microbiome characterized by overgrowth of Staphylococcus and "oral" microbes and an underrepresentation of beneficial niche-appropriate commensals. Several of these associations may be explained by (environmental or medical) exposures, although cause-consequence relationships remain unclear and require further investigations.

The ADEM2 project: early pathogenic mechanisms of preschool wheeze and a randomised controlled trial assessing the gain in health and cost-effectiveness by application of the breath test for the diagnosis of asthma in wheezing preschool children.

BACKGROUND: The prevalence of asthma-like symptoms in preschool children is high. Despite numerous efforts, there still is no clinically available diagnostic tool to discriminate asthmatic children from children with transient wheeze at preschool age. This leads to potential overtreatment of children outgrowing their symptoms, and to potential undertreatment of children who turn out to have asthma. Our research group developed a breath test (using GC-tof-MS for VOC-analysis in exhaled breath) that is able to predict a diagnosis of asthma at preschool age. The ADEM2 study assesses the improvement in health gain and costs of care with the application of this breath test in wheezing preschool children. METHODS: This study is a combination of a multi-centre, parallel group, two arm, randomised controlled trial and a multi-centre longitudinal observational cohort study. The preschool children randomised into the treatment arm of the RCT receive a probability diagnosis (and corresponding treatment recommendations) of either asthma or transient wheeze based on the exhaled breath test. Children in the usual care arm do not receive a probability diagnosis. Participants are longitudinally followed up until the age of 6 years. The primary outcome is disease control after 1 and 2 years of follow-up. Participants of the RCT, together with a group of healthy preschool children, also contribute to the parallel observational cohort study developed to assess the validity of alternative VOC-sensing techniques and to explore numerous other potential discriminating biological parameters (such as allergic sensitisation, immunological markers, epigenetics, transcriptomics, microbiomics) and the subsequent identification of underlying disease pathways and relation to the discriminative VOCs in exhaled breath. DISCUSSION: The potential societal and clinical impact of the diagnostic tool for wheezing preschool children is substantial. By means of the breath test, it will become possible to deliver customized and high qualitative care to the large group of vulnerable preschool children with asthma-like symptoms. By applying a multi-omics approach to an extensive set of biological parameters we aim to explore (new) pathogenic mechanisms in the early development of asthma, creating potentially interesting targets for the development of new therapies. TRIAL REGISTRATION: Netherlands Trial Register, NL7336, Date registered 11-10-2018.

Recognising symptoms of congenital myasthenic syndromes in children: A guide for paediatricians.

AIM: Congenital myasthenic syndromes (CMS) are a rare and diverse group of treatable neuromuscular transmission disorders. Diagnosis is often substantially delayed. This study aimed to identify common symptoms of CMS in children and their manifestation to aid diagnosis and early intervention. METHODS: We performed a retrospective cohort study, including 18 children (median age 13 years, range 9 years 5 months-18 years 0 month) with CMS. Data on CMS symptoms and their manifestation were extracted from patients' charts and supplemented with parental telephone interviews. Descriptive analyses were used to identify common symptoms. RESULTS: A median diagnostic delay of 4 years and 7 months (interquartile range: 51 months) was observed. Proximal muscle weakness (100%), ptosis (89%), clumsy gait (82%), difficulty eating solid foods (78%) and recurrent respiratory tract infections (72%) were most common in these patients. Symptoms mostly co-occurred and frequently had a fluctuating character, aggravated by infections or fatigue. CONCLUSION: Early referral to diagnose CMS is crucial to enable timely initiation of treatment. Heightened attention to a combination of symptoms related to muscle weakness, rather than individual symptoms, should support paediatricians in flagging these neuromuscular disorders. Medical history taking should be tailored to parents' perceptions, asking questions about recognisable symptoms of muscle weakness.

Respiratory insufficiency as a presenting symptom of congenital myasthenic syndromes.

AIM: Respiratory insufficiency can be a presenting symptom of congenital myasthenic syndromes (CMS) but is rarely recognised as such. In this study, we aim to raise awareness of CMS to paediatricians. METHODS: We performed a retrospective case study of infants and preschool children treated in the past 5 years in Amalia Children's Hospital, Radboud University Medical Center in Nijmegen, the Netherlands for respiratory insufficiency as presenting symptom of CMS. RESULTS: Five children aged 2 weeks to 5 years experienced severe to life-threatening episodes of respiratory insufficiency, especially during viral infections, due to respiratory muscle weakness. During infections, they often also had progression of their otherwise mild ocular, facial, and limb muscle weakness. They were eventually diagnosed with genetically proven CMS. In these five children, treatment with pyridostigmine, an acetylcholinesterase inhibitor, resulted in clinical improvement. CONCLUSION: CMS should be considered in every patient with unexplained recurrent respiratory insufficiency, or with an unusually severe course of a normally mild respiratory infection, especially in combination with mild muscle weakness outside periods of illness. Early diagnosis of CMS is crucial for early treatment, which may help avoiding sudden infant death, severe respiratory insufficiency and further deterioration of the muscle strength.

Exploring professionals' views regarding prenatal counselling in congenital diaphragmatic hernia.

OBJECTIVES: Congenital diaphragmatic hernia (CDH) is a congenital malformation in which the diaphragm and lungs are underdeveloped, leading to cardiorespiratory and other problems. This study aimed to explore professionals' views regarding prenatal counselling in CDH. METHODS: A qualitative study was performed among healthcare professionals involved in the care of CDH patients in Radboud university medical center Amalia Children's Hospital. Semi-structured interviews were conducted until saturation was achieved. Transcripts were qualitatively analysed to gain insight into professionals' views regarding counselling. RESULTS: Eighteen professionals with various backgrounds were included. The professionals agreed that the first counselling session should be soon after diagnosis and additional sessions should be offered. Concerning counselling content, participants considered explanation of the diagnosis, prognosis, short- and long-term consequences, treatment options and practical aspects important. As for decision-making about possible termination of pregnancy, all professionals emphasised the importance of the parental role, but the preferred parental involvement varied. Regarding practical aspects, preferred counsellors were a neonatologist, obstetrician, paediatric surgeon and/or medical social worker. Participants emphasised that the counselling should be adjusted to parents' needs. CONCLUSIONS: This study gained insight into professionals' views regarding the timeline, content, decision-making process, and practical aspects of prenatal counselling in CDH.

It Is Not Just the FEV1 That Matters, but the Personal Goals We Reach Along the Way: Qualitative, Multicenter, Prospective, Observational Study.

BACKGROUND: The COVID-19 pandemic has boosted the use of forced expiratory volume in 1 second (FEV1) telemonitoring in pediatric asthma, but a consensus on its most efficient and effective implementation is still lacking. To find answers, it is important to study how such an intervention is perceived, experienced, and used by both patients and health care professionals (HCPs). OBJECTIVE: The aim of this study was to provide perspectives on how FEV1 home monitoring should be used in pediatric asthma. METHODS: This is a qualitative, multicenter, prospective, observational study which included patients with asthma aged 6-16 and HCPs. Primary outcomes were results of 2 surveys that were sent to all participants at study start and after 3-4 months. Secondary outcomes consisted of FEV1 device usage during 4 months after receiving the FEV1 device. RESULTS: A total of 39 participants (26 patients and 13 HCPs) were included in this study. Survey response rates were 97% (38/39) at the start and 87% (34/39) at the end of the study. Both patients and HCPs were receptive toward online FEV1 home monitoring and found it contributive to asthma control, self-management, and disease perception. The main concerns were about reliability of the FEV1 device and validity of home-performed lung function maneuvers. FEV1 devices were used with a median frequency of 7.5 (IQR 3.3-25.5) during the 4-month study period. CONCLUSIONS: Patients and HCPs are receptive toward online FEV1 home monitoring. Frequency of measurements varied largely among individuals, yet perceived benefits remained similar. This emphasizes that online FEV1 home monitoring strategies should be used as a means to reach individual goals, rather than being a goal on their own.

The PRIDE Study: Evaluation of online methods of data collection.

BACKGROUND: Large birth cohort studies are extremely valuable in assessing associations between early life exposures and long-term outcomes. Establishing new birth cohorts is challenging due to declining participation rates. Online methods of data collection may increase feasibility, but have not been evaluated thoroughly. OBJECTIVE: The primary objective of the ongoing PRegnancy and Infant DEvelopment (PRIDE) Study is to identify exposures during pregnancy and in early life that may affect short-term or long-term health of mother and/or child. In this manuscript, we aimed to evaluate methods of recruitment and online data collection applied. POPULATION: Dutch women aged ≥18 years in early pregnancy. DESIGN: Prospective cohort study. METHODS: Initially, only prenatal care providers recruited participants, but alternative recruitment methods were added as a result of disappointing participation rates, including collaboration with "Moeders voor Moeders" (organisation that visits women in early pregnancy) and Facebook advertisements. Data on demographic characteristics, obstetric history, maternal health, life style factors, occupational exposures, nutrition, pregnancy complications, and infant outcomes are primarily collected through Web-based questionnaires at multiple time points during and after pregnancy. Additional data collection components include paternal questionnaires, blood and saliva sampling, and linkage to medical records. PRELIMINARY RESULTS: By September 2019, 9573 women were included in the PRIDE Study, of which 1.3% completed paper-based questionnaires. Mean age of the women analysed was 30.6 years, 71.1% had a high level of education, 57.2% were primiparae, and mean gestational age at enrolment was 9.9 (range 3, 37) weeks, with slight differences between recruitment methods. Pregnancy outcome was known for 89.8%. Retention rate at 6 months after the estimated date of delivery was estimated at 70%. Multiple validation studies conducted within the PRIDE Study indicated high data quality. CONCLUSION(S): Although challenging and time-consuming, online methods for recruitment and data collection may enable the establishment of new birth cohort studies.

Current practices in children with severe acute asthma across European PICUs: an ESPNIC survey.

Most pediatric asthma guidelines offer evidence-based or best practice approaches to the management of asthma exacerbations but struggle with evidence-based approaches for severe acute asthma (SAA). We aimed to investigate current practices in children with SAA admitted to European pediatric intensive care units (PICUs), in particular, adjunct therapies, use of an asthma severity score, and availability of a SAA guideline. We designed a cross-sectional electronic survey across European PICUs. Thirty-seven PICUs from 11 European countries responded. In 8 PICUs (22%), a guideline for SAA management was unavailable. Inhaled beta-agonists and anticholinergics, combined with systemic steroids and IV MgSO4 was central in SAA treatment. Seven PICUs (30%) used a loading dose of a short-acting beta-agonist. Eighteen PICUs (49%) used an asthma severity score, with 8 different scores applied. Seventeen PICUs (46%) observed an increasing trend in SAA admissions.Conclusion: Variations in the treatment of children with SAA mainly existed in the use of adjunct therapies and asthma severity scores. Importantly, in 22% of the PICUs, a SAA guideline was unavailable. Standardizing SAA guidelines across PICUs in Europe may improve quality of care. However, the limited number of PICUs represented and the data compilation method are constraining our findings.What is Known:• Recent reports demonstrate increasing numbers of children with SAA requiring PICU admission in several countries across the world.• Most pediatric guidelines offer evidence-based approaches to the management of asthma exacerbations, but struggle with evidence-based approaches for SAA beyond these initial steps.What is New:• A large arsenal of adjunct therapies and 8 different asthma scores were used.• In a large number of PICUs, a written guideline for SAA management is lacking.

Aerosol Transmission of Aspergillus fumigatus in Cystic Fibrosis Patients in the Netherlands.

We collected sputum samples and cough plates from 15 cystic fibrosis patients in the Netherlands who were colonized with Aspergillus fumigatus; we recovered A. fumigatus of the same genotype in cough aerosols and sputum samples from 2 patients. The belief that transmission of A. fumigatus from cystic fibrosis patients does not occur should be reconsidered.

Depression and anxiety during pregnancy: The influence of maternal characteristics.

BACKGROUND: Depression and anxiety during pregnancy are associated with adverse health outcomes for both mother and child. This study aims to investigate the occurrence of symptoms of depression and anxiety in early and late pregnancy, the longitudinal changes from early to late pregnancy, and factors associated with symptoms of depression and anxiety in pregnant women in the Netherlands. METHODS: We studied 2897 women participating in the PRegnancy and Infant DEvelopment (PRIDE) Study. To assess symptoms of depression and anxiety, web-based questionnaires including the Hospital Anxiety and Depression Scale (HADS) and multiple questions on maternal characteristics were completed in early and late pregnancy. Cross-sectional and longitudinal multivariable linear regression analyses were conducted. RESULTS: The depressive symptoms in our population increased, with a prevalence of probable depression from 5.4% in early pregnancy to 10.0% in late pregnancy (P < .001), whereas the anxiety symptoms decreased, with a prevalence of probable anxiety from 17.9% to 14.2% (P < .001). Characteristics associated with depressive or anxiety symptoms included low level of education, multiparity, a history of depression, severe nausea, extreme fatigue, lack of physical exercise, and negative life events. Being non-Dutch, not living with a partner, and having an unplanned pregnancy or a long time to pregnancy were associated with the depressive and/or anxiety symptoms in early pregnancy only. DISCUSSION: Symptoms of depression and anxiety are common in both early and late pregnancy. Screening for risk factors in early pregnancy is important, since prenatal depression and anxiety may be related to adverse maternal and child health outcomes.

Barriers and Facilitators When Implementing Web-Based Disease Monitoring and Management as a Substitution for Regular Outpatient Care in Pediatric Asthma: Qualitative Survey Study.

BACKGROUND: Despite their potential benefits, many electronic health (eHealth) innovations evaluated in major studies fail to integrate into organizational routines, and the implementation of these innovations remains problematic. OBJECTIVE: The purpose of this study was to describe health care professionals' self-identified perceived barriers and facilitators for the implementation of a Web-based portal to monitor asthmatic children as a substitution for routine outpatient care. Also, we assessed patients' (or their parents) satisfaction with this eHealth innovation. METHODS: Between April and November 2015, we recruited 76 health care professionals (from 14 hospitals). During a period of 6 months, participants received 3 questionnaires to identify factors that facilitated or impeded the use of this eHealth innovation. Questionnaires for patients (or parents) were completed after the 6-month virtual asthma clinic (VAC) implementation period. RESULTS: Major perceived barriers included concerns about the lack of structural financial reimbursement for Web-based monitoring, lack of integration of this eHealth innovation with electronic medical records, the burden of Web-based portal use on clinician workload, and altered patient-professional relationship (due to fewer face-to-face contacts). Major perceived facilitators included enthusiastic and active initiators, a positive attitude of professionals toward eHealth, the possibility to tailor care to individual patients ("personalized eHealth"), easily deliverable care according to current guidelines using the VAC, and long-term profit and efficiency. CONCLUSIONS: The implementation of Web-based disease monitoring and management in children is complex and dynamic and is influenced by multiple factors at the levels of the innovation itself, individual professionals, patients, social context, organizational context, and economic and political context. Understanding and defining the barriers and facilitators that influence the context is crucial for the successful implementation and sustainability of eHealth innovations.

A virtual asthma clinic for children: fewer routine outpatient visits, same asthma control.

eHealth is an appealing medium to improve healthcare and its value (in addition to standard care) has been assessed in previous studies. We aimed to assess whether an eHealth intervention could improve asthma control while reducing 50% of routine outpatient visits.In a multicentre, randomised controlled trial with a 16-month follow-up, asthmatic children (6-16 years) treated in eight Dutch hospitals were randomised to usual care (4-monthly outpatient visits) and online care using a virtual asthma clinic (VAC) (8-monthly outpatient visits with monthly web-based monitoring). Outcome measures were the number of symptom-free days in the last 4 weeks of the study, asthma control, forced expiratory volume in 1 s, exhaled nitric oxide fraction, asthma exacerbations, unscheduled outpatient visits, hospital admissions, daily dose of inhaled corticosteroids and courses of systemic corticosteroids.We included 210 children. After follow-up, symptom-free days differed statistically between the usual care and VAC groups (difference of 1.23 days, 95% CI 0.42-2.04; p=0.003) in favour of the VAC. In terms of asthma control, the Childhood Asthma Control Test improved more in the VAC group (difference of 1.17 points, 95% CI 0.09-2.25; p=0.03). No differences were found for other outcome measures.Routine outpatient visits can partly be replaced by monitoring asthmatic children via eHealth.

Ataxia-telangiectasia: recommendations for multidisciplinary treatment.

Ataxia-telangiectasia is a rare, neurodegenerative, and multisystem disease, characterized by cerebellar ataxia, oculocutaneous telangiectasia, immunodeficiency, progressive respiratory failure, and an increased risk of malignancies. It demands specialized care tailored to the individual patient's needs. Besides the classic ataxia-telangiectasia phenotype, a variant phenotype exists with partly overlapping but some distinctive disease characteristics. This guideline summarizes frequently encountered medical problems in the disease course of patients with classic and variant ataxia-telangiectasia, in the domains of neurology, immunology and infectious diseases, pulmonology, anaesthetic and perioperative risk, oncology, endocrinology, and nutrition. Furthermore, it provides a practical guide with evidence- and expert-based recommendations for the follow-up and treatment of all these different clinical topics.

Cost-effectiveness of FENO-based and web-based monitoring in paediatric asthma management: a randomised controlled trial.

BACKGROUND: In children with asthma, web-based monitoring and inflammation-driven therapy may lead to improved asthma control and reduction in medications. However, the cost-effectiveness of these monitoring strategies is yet unknown. OBJECTIVE: We assessed the cost-effectiveness of web-based monthly monitoring and of 4-monthly monitoring of FENO as compared with standard care. METHODS: An economic evaluation was performed alongside a randomised controlled multicentre trial with a 1-year follow-up. Two hundred and seventy-two children with asthma, aged 4-18 years, were randomised to one of three strategies. In standard care, treatment was adapted according to Asthma Control Test (ACT) at 4-monthly visits, in the web-based strategy also according to web-ACT at 1 month intervals, and in the FENO-based strategy according to ACT and FENO at 4-monthly visits. Outcome measures were patient utilities, healthcare costs, societal costs and incremental cost per quality-adjusted life year (QALY) gained. RESULTS: No statistically significant differences were found in QALYs and costs between the three strategies. The web-based strategy had 77% chance of being most cost-effective from a healthcare perspective at a willingness to pay a generally accepted €40 000/QALY. The FENO-based strategy had 83% chance of being most cost-effective at €40 000/QALY from a societal perspective. CONCLUSIONS: Economically, web-based monitoring was preferred from a healthcare perspective, while the FENO-based strategy was preferred from a societal perspective, although in QALYs and costs no statistically significant changes were found as compared with standard care. As clinical outcomes also favoured the web-based and FENO-based strategies, these strategies may be useful additions to standard care. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NTR1995).

Prenatal maternal psychological stress and childhood asthma and wheezing: a meta-analysis.

The aim of this study was to systematically review and meta-analyse observational studies on prenatal maternal psychological stress and the subsequent development of asthma and wheezing in early childhood.All available published literature from 1960 until November 2013 was systematically searched through electronic databases (PubMed, Embase, PsycInfo and Web of Science). All observational studies assessing associations between any form of prenatal maternal psychological stress and respiratory morbidity in the child were included. Data extraction, quality assessment and meta-analyses were performed.The overall meta-analysis included 10 studies and showed that the prevalence of wheezing, asthma and other respiratory symptoms is higher in children of mothers who were exposed to or experienced some form of psychological stress during pregnancy than in mothers who did not (pooled OR 1.56 (95% CI 1.36-1.80)). Comparable results were observed in subgroup analyses of stress exposure, perceived stress, asthma and wheezing.This study demonstrates that prenatal maternal psychological stress is associated with respiratory morbidity, including asthma and wheezing in the child. Future studies examining the early origins of asthma and wheezing need to account for the impact of prenatal maternal stress.

Monitoring strategies in children with asthma: a randomised controlled trial.

BACKGROUND: Asthma guidelines recommend monitoring of asthma control. However, in a substantial proportion of children, asthma is poorly controlled and the best monitoring strategy is not known. OBJECTIVES: We studied two monitoring strategies for their ability to improve asthma outcomes in comparison with standard care (SC): web-based monthly monitoring with the (Childhood) Asthma Control Test (ACT or C-ACT) and 4-monthly monitoring of FENO. METHODS: In this randomised controlled, partly blinded, parallel group multicentre trial with a 1-year follow-up, children aged 4-18 with a doctor's diagnosis of asthma treated in seven hospitals were randomised to one of the three groups. In the web group, treatment was adapted according to ACT obtained via a website at 1-month intervals; in the FENO group according to ACT and FENO, and in the SC group according to the ACT at 4-monthly visits. The primary endpoint was the change from baseline in the proportion of symptom-free days (SFD). RESULTS: Two-hundred and eighty children (mean age 10.4 years, 66% boys) were included; 268 completed the study. Mean changes from baseline in SFD were similar between the groups: -2.1% (web group, n=90), +8.9% (FENO group, n=91) versus 0.15% (SC, n=87), p=0.15 and p=0.78. Daily dose of inhaled corticosteroids (ICS) decreased more in the web-based group compared with both other groups (-200 µg/day, p<0.01), while ACT and SFD remained similar. CONCLUSIONS: The change from baseline in SFD did not differ between monitoring strategies. With web-based ACT monitoring, ICS could be reduced substantially while control was maintained. TRIAL REGISTRATION NUMBER: NTR 1995.

PELICAN: a cluster-randomized controlled trial in Dutch general practices to assess a self-management support intervention based on individual goals for children with asthma.

OBJECTIVE: Insufficient asthma management leads to impaired health-related quality of life (HRQL). The aim of this study is to assess whether individualized self-management (ISM) support will improve HRQL in children with asthma compared to enhanced usual care (EUC) in Dutch general practices. METHODS: A cluster-randomized controlled trial with 9-month follow-up. ISM is a nurse-led intervention that is optimized to the needs of children, leading to a written action plan. Power calculation demanded inclusion of 170 children (aged 6-11 years) diagnosed with asthma and active medication use. RESULTS: Outcomes were HRQL of the child (Paediatric Asthma Quality of Life Questionnaire, PAQLQ-s) and several secondary outcomes. Data of 29 children (mean age 8.6 years, SD 1.7) were analyzed; ISM (n = 15) or EUC (n = 14). Logistic regression analysis (minimal clinical important difference; MCID ≥ 0.5) and descriptive analyses were performed. Despite high PAQLQ-s score at baseline (median ISM 6.35, EUC 6.02), a substantial number of subjects from both groups showed MCID of HRQL (ISM 33%, EUC 57%). Treatment differences on HRQL were not significant (OR 0.38, 95% CI 0.08, 1.69). Secondary outcomes did not show significant differences either, with exception of PAQLQ-s symptoms domain score in favor of EUC. CONCLUSION: Due to recruitment problems and underpowered analyses, no firm conclusions on the effectiveness of ISM support for childhood asthma in primary care could be drawn. Still, this study can be considered a valuable pilot study and in the future, there might be better capacity in general practices to commit to such treatment.