Factors influencing the initiation of biologic therapy in children with severe asthma: Results of the pediatric asthma noninvasive diagnostic approaches (PANDA) study.

BACKGROUND & OBJECTIVES: Despite the availability of biologics for severe pediatric asthma, real-life studies reporting on drivers behind initiating biologics and their alignment with the Global Initiative for Asthma (GINA) recommendations are lacking. METHODS: We performed analysis within the pediatric asthma noninvasive diagnostic approaches study, a prospective cohort of 6- to 17-year-old children with severe asthma. Information was collected on demographic factors, symptom control, treatment, comorbidities, and diagnostic tests from medical records and questionnaires. We divided patients into "starters" or "nonstarters" based on the clinical decision to initiate biologics and performed multivariate logistic regression analysis to identify drivers behind initiating therapy. Additionally, we assessed patient suitability for biologics according to key factors in the GINA recommendations: Type 2 inflammation, frequency of exacerbations, and optimization of treatment adherence. RESULTS: In total, 72 children (mean age 11.5 ± 3.0 years, 65.3% male) were included (13 starters). Initiation of biologics was associated with a higher GINA treatment step (adjusted odds ratio's [aOR] = 5.0, 95%CI 1.33-18.76), steroid toxicity (aOR = 21.1, 95%CI 3.73-119.91), frequency of exacerbations (aOR = 1.6, 95%CI 1.10-2.39), improved therapy adherence (aOR = 1.7, 95%CI 1.10-2.46), Caucasian ethnicity (aOR = 0.20, 95%CI 0.05-0.80), ≥1 allergic sensitization (aOR = 0.06, 95%CI 0.004-0.97), and allergic rhinitis (aOR = 0.13, 95%CI 0.03-0.65). Furthermore, steroid toxicity was identified as an important factor for deviation from the current recommendations on biologic prescription. CONCLUSIONS: We identified multiple drivers and inhibitors for initiating biologics, and showed the clinical need for biologics in severe pediatric asthmatics suffering from steroid toxicity. These findings may help refine asthma management guidelines.

Intravenous magnesium sulphate in children with acute wheeze: a nationwide survey.

OBJECTIVE: Dutch guidelines recommend to consider intravenous magnesium sulfate (iv MgSO4) as a treatment option in case of failure of first line treatment in both children with exacerbations of acute episodic viral wheeze (AEVW) and acute asthma (AA). The implications on the actual use of iv MgSO4 iv in daily practice in both groups are unknown. Therefore, we conducted a cross-sectional nationwide survey to evaluate the use of iv MgSO4 in children with AEVW and AA. METHODS: A questionnaire was handed out to pediatricians and pediatric residents in one academic and six community teaching hospitals. RESULTS: In 111 respondents, 76% reported regular use of iv MgSO4 in children with AEVW and 96% in children with AA. In total 89% and 93% of users were convinced iv MgSO4 was effective in children with AEVW and AA, respectively. Adverse effects, mainly hypotension, were identified by 23% and 17% of users in AEVW and AA, respectively. Most common reasons not to give MgSO4 were lack of evidence and small amount of studies. CONCLUSIONS: IV MgSO4 is reported to be widely used in Dutch practice in both young children with AEVW and older children with AA by respondents, while the national guidelines advise only to consider this treatment option.

Risk factors for intensive care admission in children with severe acute asthma in the Netherlands: a prospective multicentre study.

RATIONALE: Severe acute asthma (SAA) can be fatal, but is often preventable. We previously observed in a retrospective cohort study, a three-fold increase in SAA paediatric intensive care (PICU) admissions between 2003 and 2013 in the Netherlands, with a significant increase during those years of numbers of children without treatment of inhaled corticosteroids (ICS). OBJECTIVES: To determine whether steroid-naïve children are at higher risk of PICU admission among those hospitalised for SAA. Furthermore, we included the secondary risk factors tobacco smoke exposure, allergic sensitisation, previous admissions and viral infections. METHODS: A prospective, nationwide multicentre study of children with SAA (2-18 years) admitted to all Dutch PICUs and four general wards between 2016 and 2018. Potential risk factors for PICU admission were assessed using logistic regression analyses. MEASUREMENTS AND MAIN RESULTS: 110 PICU and 111 general ward patients were included. The proportion of steroid-naïve children did not differ significantly between PICU and ward patients. PICU children were significantly older and more exposed to tobacco smoke, with symptoms >1 week prior to admission. Viral susceptibility was not a significant risk factor for PICU admission. CONCLUSIONS: Children with SAA admitted to a PICU were comparable to those admitted to a general ward with respect to ICS treatment prior to admission. Preventable risk factors for PICU admission were >7 days of symptoms without adjustment of therapy and exposure to tobacco smoke. Physicians who treat children with asthma must be aware of these risk factors.

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.

Multidisciplinary treatment in children with problematic severe asthma: A prospective evaluation.

OBJECTIVE: For children with problematic severe asthma, achieving adequate control of asthma is difficult. The aim of this prospective observational study was to evaluate the effects of intensive multidisciplinary inpatient treatment on multiple outcome variables in children with problematic severe asthma. METHODS: Participants were 89 children with problematic severe asthma (mean age 13.6 ± 2.5 years) treated in tertiary care clinics at high altitude (Switzerland) or sea level (Netherlands) and their parents (85 mothers, 55 fathers). The primary outcome variable was the Childhood Asthma Control Test (C-ACT). Other outcome variables were forced expiratory volume in 1 sec (FEV1 ), fractional concentration of exhaled nitric oxide (FeNO), quality of life [PAQLQ(S)], children's coping (UCL-A), parents' report of behavioral problems (CBCL), and parenting stress (PSI/NOSI). Evaluations were taken pre-treatment, post-treatment, and 3-6 months follow-up. Median [P25;P75] treatment duration 74 [56;80] days; Median follow-up interval 131 [103;177] days. RESULTS: The percentages of children showing controlled asthma (C-ACT) were 18% (pre-treatment), 69% (post-treatment), and 44% (follow-up). The vast majority of the children (80%) showed an improvement on C-ACT with 4% showing a deterioration. On C-ACT, FeNO, quality of life, and behavioral problems, improvements at post-treatment were highly significant. Improvements generally remained at a functional level at follow-up. Children's coping and parenting stress in parents did not change. CONCLUSIONS: The improvement in asthma control and other outcome variables suggests that multidisciplinary inpatient treatment is an effective approach for a heterogeneous group of children with asthma that remained uncontrolled in secondary care. Pediatr Pulmonol. 2017;52:588-597. © 2016 Wiley Periodicals, Inc.

Frequency and Duration of Rhinovirus Infections in Children With Cystic Fibrosis and Healthy Controls: A Longitudinal Cohort Study.

BACKGROUND: Respiratory viral infections are an important cause of morbidity in patients with chronic respiratory diseases, such as cystic fibrosis (CF). We hypothesized that patients with CF are more susceptible to human rhinovirus (HRV) infections than healthy controls. METHODS: In a 6-month winter period, 20 young children with CF (0-7 years) and 18 age-matched healthy controls were sampled biweekly for HRV-polymerase chain reaction using nasopharyngeal swabs, irrespective of respiratory symptoms. Respiratory symptoms were scored twice a week. If any symptom was present, an additional sample was obtained. All HRV-positive samples were genotyped to distinguish HRV subtypes. RESULTS: We analyzed 645 samples, with comparable total numbers of samples in both groups. HRV was detected in 40.8% of all analyzed samples. Children with CF had significantly more HRV-positive samples compared with healthy controls, with a mean number (± standard deviation) of 8.1 ± 2.3 versus 5.7 ± 2.9 positive samples per individual (P < 0.01). Prolonged detection (>2 weeks) with the same HRV subtype occurred more frequently in the CF patients (P < 0.01). The genetic distribution and pattern of phylogenetic diversity of the different HRV subtypes were similar in both groups. CONCLUSIONS: This is the first in vivo longitudinal study showing that HRV is detected more frequently and persists for longer periods in CF patients compared with healthy controls. This might indicate increased viral replication and/or decreased antiviral defense in patients with CF.

Respiratory tract infections and asthma control in children.

INTRODUCTION: Asthma control is considered the major goal of asthma management, while many determinants of control are difficult to modify. We studied the association between respiratory infection episodes (RTIs) of various types and asthma control. METHODS: Cross-sectional data were used from children aged 4-18 years with physician-diagnosed asthma who participated in a web-based electronic portal for children with asthma, allergies or infections. Asthma control was measured using the Childhood Asthma Control Test (C-ACT) or the Asthma Control Test (ACT). Linear regression was used to analyse the association between categories of numbers of various types of RTIs sustained in the preceding 12 months (categorized) and asthma control, adjusted for potential confounders. RESULTS: Asthma control was assessed in 654 children, and 68.5% were clinically well controlled (ACT ≥ 20). Higher total numbers of RTIs in the last 12 months were strongly associated with a lower level of asthma control (p(trend) < 0.001). Similarly strong statistically significant associations were found for subtypes of RTI: ≥4 vs. 0 otitis episodes: coefficient -1.7 (95% CI -3.3 to -0.2); ≥5 vs.0 colds: coefficient -2.3 (95% CI -3.0 to -1.6); ≥3 vs. 0 bronchitis episodes: coefficient -3.1 (95% CI -4.0 to -2.3), each with p(trend) < 0.05. CONCLUSION: Higher numbers of reported respiratory tract infections are associated with lower level of asthma control. The different type of respiratory tract infections contribute equally to less controlled asthma.

The expert network and electronic portal for children with respiratory and allergic symptoms: rationale and design.

Data on baseline characteristics of children with asthma to predict individual treatment responses are lacking. We aimed to set up a data-collection system which can easily fill this gap in clinical practice.A web-based application was developed, named 'Portal for children with respiratory and allergic symptoms', hereafter called Electronic Portal (EP). It contains health- and disease-related questionnaires on respiratory- and allergic diseases. All patients, 1-18 years of age, with respiratory- and/or allergic complaints are invited to enter the EP before their first visit. By using the EP large amounts of data, gathered during routine patient care can be used for research purposes. This may help to further investigate the different treatment related asthma phenotypes and will be helpful to monitor risk factors for other atopic diseases and respiratory infections.

Highly frequent infections with human rhinovirus in healthy young children: a longitudinal cohort study.

BACKGROUND: Human rhinoviruses (HRVs) are an important cause of respiratory tract infections. OBJECTIVES: We questioned whether the high prevalence rates of HRVs found in epidemiological studies is due to long-term individual continuity or a result of frequent infections with different HRV subtypes. STUDY DESIGN: In a 6-month winter period 18 healthy controls, aged 0-7 years, were at least sampled every two weeks for HRV-PCR, irrespective of respiratory symptoms. All HRV positive samples were genotyped to determine HRV diversity. RESULTS: In total 272 samples were collected. HRV was found in 101/272 (37%) samples. Genotyping revealed 27 different HRV subtypes. A median of 3.0 different HRV subtypes was found per child. Re-infections and continuity with identical HRV sequences were observed. The number of HRVs were higher in the youngest age group (p=0.01) and they had more different HRV subtypes (p=0.05) compared to oldest age group. CONCLUSIONS: We found a high HRV exposition with a considerable diverse population of HRV subtypes in young children. These results have major implications for future research into the pathogenic role of HRV in respiratory diseases. Characterisation of subtypes will be necessary to discriminate between prolonged continuity and re-infections in patients with respiratory diseases.

Respiratory pathogens in children with and without respiratory symptoms.

OBJECTIVES: To investigate the occurrence of respiratory pathogens in samples from children with and without respiratory symptoms and to identify whether age and/ or coinfections modify the impact of respiratory pathogens on symptoms. STUDY DESIGN: In a prospective longitudinal study, 18 children were sampled biweekly for respiratory pathogens, irrespective of respiratory symptoms. Polymerase chain reaction was performed for 13 respiratory pathogens. Episodes were defined "asymptomatic" if no symptoms of any respiratory tract illness were present between 1 week before and 1 week after sampling. RESULTS: A total of 230 samples were collected. In 56% of the symptomatic episodes, a pathogen was detected, compared with 40% of the asymptomatic episodes (P = .03). Rhinovirus and coronaviruses were most prevalent in both symptomatic and asymptomatic episodes. In the youngest children, 9% of the pathogen-positive episodes were asymptomatic, compared with 36% in the oldest children (P = .01). Multiple pathogens were found in 17% of the symptomatic episodes and in 3% of the asymptomatic episodes (P = .02). CONCLUSIONS: Respiratory pathogens are frequently detected in samples from children with no respiratory symptoms. Symptomatic cases occurred more often in younger children and with detections of more than 1 respiratory pathogen.

Prevalence and impact of respiratory viral infections in young children with cystic fibrosis: prospective cohort study.

OBJECTIVE: We aimed to investigate differences in upper and lower respiratory tract symptoms in relation to respiratory viral infections detected with polymerase chain reaction assays in young children with cystic fibrosis and healthy control subjects. METHODS: In a 6-month winter period, 20 young children with cystic fibrosis and 18 age-matched, healthy, control subjects were contacted twice per week for detection of symptoms of an acute respiratory illness. If any symptom was present, then a home visit was made for physical examination and collection of nasopharyngeal swabs for viral analysis. In addition, parents were instructed to collect nasopharyngeal swabs every 2 weeks. RESULTS: Children with cystic fibrosis and healthy control subjects had similar frequencies of acute respiratory illnesses (3.8+/-1.0 and 4.2+/-1.7 episodes, respectively). Although there were no significant differences in upper respiratory tract symptoms, the children with cystic fibrosis had longer periods of lower respiratory tract symptoms (22.4+/-22.2 vs 12.8+/-13.8 days) and a higher mean severity score per episode (2.35+/-0.64 vs 1.92+/-0.46). In addition, similar increases in upper respiratory tract symptom scores were associated with significantly greater increases in lower respiratory tract symptom scores in children with cystic fibrosis. No differences in the seasonal occurrences and distributions of respiratory viruses were observed, with picornaviruses and coronaviruses being the most prevalent. CONCLUSIONS: Although there were no differences in the seasonal occurrences and distributions of polymerase chain reaction-detected respiratory viruses, acute respiratory illnesses were frequently associated with increased lower respiratory tract morbidity in young children with cystic fibrosis.

Prevalence and pathogenicity of WU and KI polyomaviruses in children, the Netherlands.

A longitudinal study in 2004 and 2005 detected polyomaviruses WU and KI in 44% and 17% of children with and without respiratory symptoms, respectively, in the Netherlands. In some children both viruses were detected for long periods. In several symptomatic children no other respiratory pathogen was detected.

RSV mediates Pseudomonas aeruginosa binding to cystic fibrosis and normal epithelial cells.

Cystic fibrosis lung disease typically has a course of exacerbations and remissions, suggesting that external factors like viral infections can influence this course. Clinical data suggest synergism between respiratory syncytial virus (RSV) infections and Pseudomonas aeruginosa in cystic fibrosis (CF) lung disease. We studied the influence of RSV infection on adherence of P. aeruginosa to IB3-1, HEp-2, and A549 epithelial cell monolayers in vitro. RSV infection of epithelial cells as well as simultaneous addition of RSV and P. aeruginosa to noninfected cells both strongly enhanced the pseudomonal adherence to epithelial cells. The increased adherence varied from 1.2- to 8.2-fold in case of previous RSV infection, and from 1.7- to 16.1-fold in case of simultaneous addition. We observed direct binding of RSV to P. aeruginosa, and blocking of RSV with heparin eliminated the effect on increased adherence. This suggests that RSV possibly acts as a coupling agent between P. aeruginosa and epithelial cells. In conclusion, RSV enhances P. aeruginosa infection of respiratory epithelial cells. It suggests a role of specific viral-bacterial interactions in exacerbations of CF lung disease, which could have important implications on prevention and treatment.

Viral respiratory infections in cystic fibrosis.

Viral respiratory infections in CF patients are associated with an increase in morbidity at short and long term. Viral infections have a greater impact on CF patients compared to non-CF controls. They result in increased respiratory symptoms, deterioration of Shwachman and radiological scores, prolonged hospitalizations, a persistent decrease of pulmonary function, increased use of antibiotics and a higher frequency of exacerbations at follow-up. In addition, interaction between viruses and bacteria in CF is suggested. Some studies observe increased new bacterial colonization and raised antipseudomonal antibodies in episodes of viral respiratory infections. Experimental data suggest that increased virus replication, impaired specific anti-bacterial defense and increased adherence of bacteria play a role in the pathogenesis of viral respiratory infections in CF. Further knowledge about the role of viruses and interaction with bacteria in CF lung disease might result in new therapeutic strategies to improve prognosis of CF patients.