BACKGROUND:Fatigue is a commonly reported clinical symptom, yet research on fatigue in children with severe asthma is missing. We aimed to explore the extent of fatigue in severe pediatric asthma and identify associated factors. METHOD:This study was conducted within the Pediatric Asthma Non-Invasive Diagnostic Approaches (PANDA), an observational cohort of 6- to 17-year-old Dutch children with severe asthma. The Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (PedsQL™-MFS) was used to measure self-reported fatigue. Fatigue levels were compared with a general pediatric Dutch population using linear regression, and quantifying the prevalence of "fatigued" (-2 < Standard deviations [SD] ≤ -1) and "severely fatigued" (SD ≤ -2) children. Secondly, we performed linear regression analyses to explore whether fatigue levels were independently associated with asthma attacks, comorbidities, medication, pulmonary function, symptom control, and asthma-related quality of life (QoL). RESULTS:Severe pediatric asthma patients (n = 78, mean age 11.8 ± 3.1 years) reported significantly more fatigue than Dutch peers (n = 328, mean age 11.8 ± 3.2 years) mean difference in z-score: -0.68; 95%CI -0.96, -0.40. In the severe asthma group, 28.2% scored as "fatigued" and 15.4% as "severely fatigued," compared with 14.0% and 3.4% in the general population. In pediatric asthma patients, asthma-related QoL (β = 0.77, p < .01, ΔR2 = .43), symptom control (β = 0.56, p < .01, ΔR2 = .24) and a dysfunctional breathing pattern (β = -0.36, p < .01, ΔR2 = .12) were most strongly associated with fatigue scores. CONCLUSION:Fatigue is a common symptom in children with severe asthma and is associated with multiple clinical factors and patient-reported outcomes. It should be considered as an important treatment target.

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.

BACKGROUND:Long-acting beta2-agonists (LABA) in combination with inhaled corticosteroids (ICS) are commonly used to treat asthma, however, some children lack response to the addition of LABA. This might be partially due to the presence of the Arg16Gly polymorphism, encoded by rs1042713 G>A in the ADRB2 gene. Carrying the A allele (Arg16) at this variant has been associated with an increased risk of exacerbations despite LABA treatment. We investigated whether genotype-guided treatment improved asthma-related outcomes. METHODS:We conducted an individual participant data meta-analysis of two randomised controlled trials: PUFFIN (Dutch and Swiss 6-18 year-olds) and PACT (English and Scottish 12-18 year-olds). Children with uncontrolled asthma despite ICS who required a step-up in treatment were included. Participants were randomised to genotype-guided treatment or the control group with a follow-up of at least 6 months. Genotype-guided treatment consisted of adding LABA for children with ADRB2 Gly16/Gly16, whilst children with ADRB2 Arg16/Arg16 or Arg16/Gly16 were treated with double dose ICS (PUFFIN) or add-on montelukast (PACT). The primary outcome was a change in asthma control; secondary outcomes included exacerbation rate and time to exacerbation. Repeated measures mixed models and Cox regression were used. RESULTS:Fifty-nine out of 102 (PUFFIN) and 59 out of 91 (PACT) children had at least one Arg (A allele). Amongst all 193 children, no difference was observed in asthma control between the study groups. However, genotype-guided treatment resulted in lower asthma exacerbation rates (-0.08 (95%CI -0.16 to -0.00, p = 0.04)) compared to the control group. CONCLUSION:Genotype-guided step-up treatment for children with uncontrolled asthma on ICS may lower asthma exacerbation rates and may be useful for personalising asthma care.

The addition of concanavalin A to mouse spleen cell suspensions can either inhibit or stimulate the immune response to heterologous erythrocytes according to the experimental conditions. Evidence is presented which is incompatible with the hypothesis that these two effects are mediated by a single cell and which favors the hypothesis of separate inhibitor and stimulatory cells.

RationaleSevere 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).ObjectivesTo 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.MethodsA 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 results110 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.ConclusionsChildren 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.

Background: Uncontrolled asthma in children is still highly prevalent despite the availability of effective asthma treatment. We investigated 1) the prevalence of uncontrolled asthma among children referred for asthma and referred for atopic diseases other than asthma (ie food allergy, allergic rhinitis or atopic dermatitis) to secondary care; and 2) the predictors associated with uncontrolled asthma. Methods: All children (4 to 18 years) referred for asthma or atopic diseases other than asthma to 8 secondary care centers in The Netherlands were invited to an electronic portal (EP). The EP is a web-based application with several validated questionnaires including the ISAAC questionnaires and the Asthma Control Test (ACT). Children were eligible for inclusion in this study when their parents reported in the EP that their child had asthma diagnosed by a physician. The ACT was used to assess asthma control. Multiple predictors of asthma control (patient, asthma and atopic characteristics) were evaluated by univariable and multivariable logistic regression analyses. Results: We included 408 children: 259 children (63%) with asthma referred for asthma and 149 children (37%) with asthma referred for atopic diseases other than asthma. Thirty-nine percent of all children had uncontrolled asthma: 47% of the children referred for asthma and 26% of the children referred for atopic diseases other than asthma. Predictors associated with uncontrolled asthma were a family history of asthma (odds ratio [OR] 2.08; 95% confidence interval [95% CI] 1.34 to 3.24), and recurrent upper and lower respiratory tract infections in the past year (OR 2.40; 95% CI 1.52 to 3.81 and OR 2.00; 95% CI 1.25 to 3.23, respectively). Conclusion: Uncontrolled asthma is highly prevalent in children with asthma referred to secondary care, even if children are primarily referred for atopic diseases other than asthma. Thus, attention should be paid to asthma control in this population.

Background: Many eHealth innovations fail to integrate into organizational routines and implementation remains problematic. Objective: To describe healthcare professionals’ perceived barriers and facilitators when implementing online monitoring and management as a substitution for outpatient care in children with asthma. Also, patient satisfaction with this innovation was assessed. Methods: During a period of six months, healthcare professionals received two-monthly questionnaires to identify factors that facilitate or impede the use of this innovation. Questionnaires for patients (and/or parents) were sent once after a period of 6 months. Results: Major barriers included concerns about the lack of financial reimbursement for online monitoring, lack of integration with electronic medical records, the burden of web-based portal use on clinician workload and altered patient-professional relationship. Major facilitators included enthusiastic and active initiators, a positive professionals’ attitude towards eHealth, the possibility to tailor care to individual patients (‘personalized eHealth’) and to easily deliver care according to current guidelines by using the innovation and long-term profit and efficiency. Conclusions: Implementation of an eHealth innovation is complex, dynamic and 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 important for successful implementation and sustainability of eHealth

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.

Summary 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 (FEV 1 ), 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.

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% Cl -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% Cl -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. (C) 2014 Elsevier Ltd. All rights reserved.

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.

The performance of a multiplex real-time PCR for the detection of Blastocystis, Dientamoeba fragilis, Giardia lamblia, Cryptosporidium species and Entamoeba species in faecal samples was evaluated in an observational prospective study. Paediatric patients (0-18 years) presenting with gastrointestinal symptoms and suspected of having enteroparasitic disease were included. A questionnaire on gastrointestinal symptoms and the chosen treatment was completed at the start of the study and after 6 weeks. Of 163 paediatric patients (mean age, 7.8 years), 114 (70%) had a PCR-positive faecal sample. D. fragilis was detected most frequently, in 101 patients, followed by Blastocystis in 49. In faecal samples of 47 patients, more than one protozoan was detected, mainly the combination of D. fragilis and Blastocystis. Reported gastrointestinal symptoms were abdominal pain (78%), nausea (30%), and altered bowel habits (28%). Eighty-nine of the PCR-positive patients were treated with antibiotics. A significant reduction in abdominal pain was observed both in treated and in untreated patients. This study demonstrated that multiplex real-time PCR detects a high percentage of intestinal protozoa in paediatric patients with gastrointestinal symptoms. However, interpretation and determination of the clinical relevance of a positive PCR result in this population are still difficult.

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. (C) 2011 Elsevier B.V. All rights reserved.

Alloimmune lung syndromes (allo-LS), including idiopathic pneumonia syndrome, bronchiolitis obliterans syndrome, and bronchiolitis obliterans organizing pneumonia, are severe complications after hematopoietic stem cell transplantation (HSCT). In our cohort of 110 pediatric patients, 30 had allo-LS (27.3%), 18 with ideopathic pneumonia syndrome and 12 with bronchiolitis obliterans syndrome. Multivariate analysis showed that respiratory viral infection early after HSCT is an important predictor for the development of allo-LS (P < .0001). This was true for all viruses tested. In multivariate analysis, allo-LS was the only predictor for higher mortality (P = .04). Paradoxically, prolonged administration of immunosuppressive agents because of acute graft-versus-host disease had a protective effect on the development of allo-LS (P = .004). We hypothesize that early infection of the respiratory tract with a common cold virus makes the lungs a target for alloimmunity. Biol Blood Marrow Transplant 16: 782-791 (2010) (C) 2010 Published by Elsevier Inc.

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 it 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 my 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 I respiratory pathogen. (J Pediatr 2009;154:396-400)

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.

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.

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.

Chronic colonisation of the lungs with Pseudomonas aeruginosa in patients with cystic fibrosis (CF) is associated with reduced lung function and life expectancy. Prevention of chronic colonisation might be achieved by avoidance of, or early and aggressive treatment of, primary P aeruginosa acquisition.1 Segregation of uninfected indivduals from chronically P aeruginosa colonised CF patients is advocated to prevent cross infection.2 As surveillance studies suggest that the airways of healthy children are rarely colonised with P aeruginosa ,3 healthy individuals are not regarded as a potential source of P aeruginosa acquisition. In addition, it has been shown that acquisition of P aeruginosa in CF patients is often preceded by a viral respiratory infection.4 We hypothesised that the incidence of P aeruginosa acquisition during periods of acute respiratory infections (ARI) is equal in both healthy and CF individuals, and considerably exceeds the prevalence in …

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.