The effects of the COVID-19 pandemic on PICU admissions for severe asthma exacerbations: A single-center experience.

BACKGROUND: The incidence of severe asthma exacerbations (SAE) requiring a pediatric intensive care unit (PICU) admission during the coronavirus disease 2019 (COVID-19) pandemic (and its association with public restrictions) is largely unknown. We examined the trend of SAE requiring PICU admission before, during, and after COVID-19 restrictions in Amsterdam, the Netherlands, and its relationship with features such as environmental triggers and changes in COVID-19 restriction measures. METHODS: In this single-center, retrospective cohort study, all PICU admissions of children aged ≥2 years for severe asthma at the Amsterdam UMC between 2018 and 2022 were included. The concentrations of ambient fine particulate matter (PM2.5 ) and pollen were obtained from official monitoring stations. RESULTS: Between January 2018 and December 2022, 228 children were admitted to the PICU of the Amsterdam UMC for SAE. While we observed a decrease in admissions during periods of more stringent restriction, there was an increase in the PICU admission rate for SAE in some periods following the lifting of restrictions. In particular, following the COVID-19 restrictions in 2021, we observed a peak incidence of admissions from August to November, which was higher than any other peak during the indicated years. No association with air pollution or pollen was observed. CONCLUSION: We hypothesize that an increase in clinically diagnosed viral infections after lockdown periods was the reason for the altered incidence of SAE at the PICU in late 2021, rather than air pollution and pollen concentrations.

Developments in the Management of Severe Asthma in Children and Adolescents: Focus on Dupilumab and Tezepelumab.

Severe asthma in children and adolescents exerts a substantial health, financial, and societal burden. Severe asthma is a heterogeneous condition with multiple clinical phenotypes and underlying inflammatory patterns that might be different in individual patients. Various add-on treatments have been developed to treat severe asthma, including monoclonal antibodies (biologics) targeting inflammatory mediators. Biologics that are currently approved to treat children (≥ 6 years of age) or adolescents (≥ 12 years of age) with severe asthma include: anti-immunoglobulin E (omalizumab), anti-interleukin (IL)-5 (mepolizumab), anti-IL5 receptor (benralizumab), anti-IL4/IL13 receptor (dupilumab), and antithymic stromal lymphopoietin (TSLP) (tezepelumab). However, access to these targeted treatments varies across countries and relies on few and crude indicators. There is a need for better treatment stratification to guide which children might benefit from these treatments. In this narrative review we will assess the most recent developments in the treatment of severe pediatric asthma, as well as potential biomarkers to assess treatment efficacy for this patient population.

Rituximab in Idiopathic Pulmonary Hemosiderosis in Children: A Novel and Less Toxic Treatment Option.

Idiopathic pulmonary hemosiderosis (IPH) is a rare, potentially life-threatening chronic disease. Steroids are the cornerstone of treatment, even though toxicity and side-effects are very common. Recently, rituximab (RTX) has been suggested as a treatment option, although evidence for its efficacy and long-term safety is lacking. We describe the disease course of two pediatric patients with IPH that were treated with RTX for over 4 years. Demographics, treatments, and clinical variables such as growth, infections, imaging follow-up by CT, and data from pulmonary function tests were retrospectively described. These are the first two cases described with a long-term follow-up of pediatric IPH patients treated with RTX. RTX was well-tolerated and prevented outbreaks of bleeding. In addition, RTX had a robust steroid-sparing effect resulting in the improvement of growth, pulmonary function, and CT abnormalities.

Biologicals in childhood severe asthma: the European PERMEABLE survey on the status quo.

INTRODUCTION: Severe asthma is a rare disease in children, for which three biologicals, anti-immunoglobulin E, anti-interleukin-5 and anti-IL4RA antibodies, are available in European countries. While global guidelines exist on who should receive biologicals, knowledge is lacking on how those guidelines are implemented in real life and which unmet needs exist in the field. In this survey, we aimed to investigate the status quo and identify open questions in biological therapy of childhood asthma across Europe. METHODS: Structured interviews regarding experience with biologicals, regulations on access to the different treatment options, drug selection, therapy success and discontinuation of therapy were performed. Content analysis was used to analyse data. RESULTS: We interviewed 37 experts from 25 European countries and Turkey and found a considerable range in the number of children treated with biologicals per centre. All participating countries provide public access to at least one biological. Most countries allow different medical disciplines to prescribe biologicals to children with asthma, and only a few restrict therapy to specialised centres. We observed significant variation in the time point at which treatment success is assessed, in therapy duration and in the success rate of discontinuation. Most participating centres intend to apply a personalised medicine approach in the future to match patients a priori to available biologicals. CONCLUSION: Substantial differences exist in the management of childhood severe asthma across Europe, and the need for further studies on biomarkers supporting selection of biologicals, on criteria to assess therapy response and on how/when to end therapy in stable patients is evident.

First analysis of the Severe Paediatric Asthma Collaborative in Europe registry.

New biologics are being continually developed for paediatric asthma, but it is unclear whether there are sufficient numbers of children in Europe with severe asthma and poor control to recruit to trials needed for registration. To address these questions, the European Respiratory Society funded the Severe Paediatric Asthma Collaborative in Europe (SPACE), a severe asthma registry. We report the first analysis of the SPACE registry, which includes data from 10 paediatric respiratory centres across Europe. Data from 80 children with a clinical diagnosis of severe asthma who were receiving both high-dose inhaled corticosteroid and long-acting ß2-agonist were entered into the registry between January 2019 and January 2020. Suboptimal control was defined by either asthma control test, or Global Initiative for Asthma criteria, or ≥2 severe exacerbations in the previous 12 months, or a combination. Overall, 62 out of 80 (77%) children had suboptimal asthma control, of whom 29 were not prescribed a biologic. However, in 24 there was an option for starting a licensed biologic. 33 children with suboptimal control were prescribed a biologic (omalizumab (n=24), or mepolizumab (n=7), or dupilumab (n=2)), and for 29 there was an option to switch to a different biologic. We conclude that the SPACE registry provides data that will support the planning of studies of asthma biologics. Not all children on biologics achieve good asthma control, and there is need for new trial designs addressing biologic switching.

Precision medicine in severe pediatric asthma: opportunities and challenges.

PURPOSE OF REVIEW: Severe pediatric asthma exerts a substantial burden on patients, their families and society. This review provides an update on the latest insights and needs regarding the implementation of precision medicine in severe pediatric asthma. RECENT FINDINGS: Biologicals targeting underlying inflammatory pathways are increasingly available to treat children with severe asthma, holding the promise to enable precision medicine in this heterogeneous patient population with high unmet clinical needs. However, the current understanding of which child would benefit from which type or combination of biologicals is still limited, as most evidence comes from adult studies and might not be generalizable to the pediatric population. Studies in pediatric severe asthma are scarce due to the time-consuming effort to diagnose severe asthma and the challenge to recruit sufficient study participants. The application of innovative systems medicine approaches in international consortia might provide novel leads for - preferably noninvasive - new biomarkers to guide precision medicine in severe pediatric asthma. SUMMARY: Despite the increased availability of targeted treatments for severe pediatric asthma, clinical decision-making tools to guide these therapies are still lacking for the individual pediatric patient.

Controlled evaluation of a transition clinic for Dutch young people with cystic fibrosis.

BACKGROUND: Transition clinics (TCs) are advocated as best practice to support young people with cystic fibrosis (CF) during transition to adulthood and adult care. We aimed to research the functioning of a TC for young people with CF compared with direct hand-over care and to evaluate whether those treated at the TC have better transfer experiences and outcomes compared with the control group. METHODS: Mixed-methods retrospective controlled design, including interviews with professionals, observations of clinics, chart reviews (at four measurement moments), and patient surveys. Qualitative data analysis focused on organization and daily routines, and barriers and facilitators experienced. Young people's transfer experiences, self-management, health care use, and clinical outcomes were assessed quantitatively. RESULTS: The most notable feature distinguishing the TC and direct hand-over care comprised joint consultations between pediatric and adult care professionals in the former. A transition coordinator was considered essential for the success of the TC. The main barriers were lack of time, planning, and reimbursement issues. Young people treated at the TC tended to have better transfer experiences and were more satisfied. They reported significantly more trust in their adult care professionals. Their self-management-related outcomes were less favorable. CONCLUSIONS: The TC had several perceived benefits and showed positive trends in transfer experiences and satisfaction, but no differences in health-related outcomes. Structured preparation of young people, joint consultations with pediatric and adult care professionals, and better coordination were perceived as facilitating elements. Further improvement demands solutions for organizational and financial barriers, and better embedding of self-management interventions in CF care.

Young children experience little emotional burden during invasive procedures in asthma research.

Research in children should strike the right balance between protecting underage study subjects and advancing the medical field. This study gives insight into the emotional burden that common invasive research procedures in asthma research have on young children, both from the child and parent perspective. Puppetry was used to stimulate children (age 5-6 years) to explain their emotional burden prior to and after the research procedures. We operationalised emotional burden as willingness to participate in future research and reluctance towards participation. Parents filled out a questionnaire on this topic. Symptomatic patients as well as healthy controls were analysed. Forty-one children were included. Children's anticipatory fear for future research showed a clear decrease of 0.7 ± 1.6 on a 5-point Likert scale as a consequence of participation (p = 0.02). Sixty percent of all participating children explicitly indicated willingness to undergo identical research procedures again. Children uninformed by their parents about the venipuncture were significantly more reluctant to the venipuncture after the procedure (p < 0.01), compared to children who had been informed (4.0 ± 0.9 resp. 2.8 ± 1.2).Conclusion: This study suggests that the emotional burden of participation in asthma research for underage children can be prevented when they are properly informed and decreases as a consequence of participations. We believe increased emphasis should be placed on informing children and evaluating the emotional impact of research to help caretakers and research ethics committees make informed decisions about participation of children in medical research. What is Known: • Medical professionals and parents are likely to overestimate children's discomfort undergoing (invasive) research procedures. • Two thirds of children (age 6-18 years) participating in medical research indicated that they would participate in the same research study again. What is New: • Pre-school children experience little emotional burden during invasive procedures in asthma research. • Proper communication about (invasive) research procedures in pre-school children helps to reduce the anticipatory fear of these procedures in the future.

Noncystic Fibrosis Bronchiectasis: Evaluation of an Extensive Diagnostic Protocol in Determining Pediatric Lung Disease Etiology.

Introduction: Pediatric noncystic fibrosis (CF) bronchiectasis has a variety of causes. An early and accurate diagnosis may prevent disease progression and complications. Current diagnostics and yield regarding etiology are evaluated in a pediatric cohort at a tertiary referral center. Methods: Available data, including high-resolution computed tomography (HRCT) characteristics, microbiological testing, and immunological screening of all children diagnosed with non-CF bronchiectasis between 2003 and 2017, were evaluated. Results: In 91% of patients [n = 69; median age 9 (3-18 years)] etiology was established in the diagnostic process. Postinfection (29%) and immunodeficiency (29%) were most common, followed by congenital anomalies (10%), aspiration (7%), asthma (6%), and primary ciliary dyskinesia (1%). HRCT predominantly showed bilateral involvement in immunodeficient patients (85%) and those with idiopathic bronchiectasis (83%). Congenital malformations (71%) were associated with unilateral disease. Completion of the diagnostic process often led to a change of treatment as started after initial diagnosis. Conclusion: Using a comprehensive diagnostic protocol, the etiology of pediatric non-CF bronchiectasis was established in more than 90% of patients. HRCT provides additional diagnostic information as it points to either a more systemic or a more localized etiology. Adequate diagnostics and data analysis allow treatment to be specifically adapted to prevent disease progression.

Severe Paediatric Asthma Collaborative in Europe (SPACE): protocol for a European registry.

The development of new asthma biologics and receptor blockers for the treatment of paediatric severe asthma raises challenges. It is unclear whether there are sufficient children in Europe to recruit into randomised placebo-controlled trials to establish efficacy and safety in this age group. In February 2016, the European Respiratory Society funded a clinical research collaboration entitled "Severe Paediatric Asthma Collaborative in Europe" (SPACE). We now report the SPACE protocol for a prospective pan-European observational study of paediatric severe asthma. Inclusion criteria are: 1) age 6-17 years, 2) severe asthma managed at a specialised centre for ≥6 months, 3)clinical and spirometry evidence of asthma, and 4) reaching a pre-defined treatment threshold. The exclusion criterion is the presence of conditions which mimic asthma symptoms. Eligible children will be prospectively recruited into a registry, recording demographics, comorbidities, quality of life, family history, neonatal history, smoking history, asthma background, investigations, and treatment. Follow-up will provide longitudinal data on asthma control and treatment changes. The SPACE registry, by identifying well-phenotyped children eligible for clinical trials, and the amount of overlap in eligibility criteria, will inform the design of European trials in paediatric severe asthma, and facilitate observational research where data from single centres are limited.

Subendothelial heparan sulfate proteoglycans become major L-selectin and monocyte chemoattractant protein-1 ligands upon renal ischemia/reperfusion.

Leukocyte infiltration into inflamed tissues is considered to involve sequential steps of rolling over the endothelium, adhesion, and transmigration. In this model, the leukocyte adhesion molecule L-selectin and its ligands expressed on inflamed endothelial cells are involved in leukocyte rolling. We show that upon experimental and human renal ischemia/reperfusion, associated with severe endothelial damage, microvascular basement membrane (BM) heparan sulfate proteoglycans (HSPGs) are modified to bind L-selectin and monocyte chemoattractant protein-1. In an in vitro rolling and adhesion assay, L-selectin-binding HSPGs in artificial BM induced monocytic cell adhesion under reduced flow. We examined the in vivo relevance of BM HSPGs in renal ischemia/reperfusion using mice mutated for BM HSPGs perlecan (Hspg2(Delta3/Delta3)), collagen type XVIII (Col18a1(-/-)), or both (cross-bred Hspg2(Delta3/Delta3)xCol18a1(-/-)) and found that early monocyte/macrophage influx was impaired in Hspg2(Delta3/Delta3)xCol18a1(-/-) mice. Finally, we confirmed our observations in human renal allograft biopsies, showing that loss of endothelial expression of the extracellular endosulfatase HSulf-1 may be a likely mechanism underlying the induction of L-selectin- and monocyte chemoattractant protein-1-binding HSPGs associated with peritubular capillaries in human renal allograft rejection. Our results provide evidence for the concept that not only endothelial but also (microvascular) BM HSPGs can influence inflammatory responses.

Differential tissue targeting and pathogenesis of verotoxins 1 and 2 in the mouse animal model.

BACKGROUND: Both verotoxin (VT)1 and VT2 share the same receptor, globotriaosyl ceramide (Gb(3)). Although VT1 is slightly more cytotoxic in vitro and binds Gb(3) with higher affinity, VT2 is more toxic in mice and may be associated with greater pathology in human infections. In this study we have compared the biodistribution of iodine 125 ((125)I)-VT1 and (125)I-VT2 versus pathology in the mouse. METHODS: (125)I-VT1 whole-body autoradiography defined the tissues targeted. VT1 and VT2 tissue distribution, clearance, and tissue binding sites were compared. The effect of a soluble receptor analogue, adamantylGb(3), on VT2/Gb3 binding and in vivo pathology was assessed. RESULTS: (125)I-VT1 autoradiography identified the lungs and nasal turbinates as major, previously unrecognized, targets, while kidney cortex and the bone marrow of the spine, long bones, and ribs were also significant targets. VT2 did not target the lung, but accumulated in the kidney to a greater extent than VT1. The serum half-life of VT1 was 2.7 minutes with 90% clearance at 5 minutes, while that of VT2 was 3.9 minutes with only 40% clearance at 5 minutes. The extensive binding of VT1, but not VT2, within the lung correlated with induced lung disease. Extensive hemorrhage into alveoli, edema, alveolitis and neutrophil margination was seen only after VT1 treatment. VT1 targeted lung capillary endothelial cells. Identical tissue binding sites (subsets of proximal/distal tubules and collecting ducts) for VT1 and VT2 were detected by toxin overlay of serial frozen kidney sections. Glucosuria was found to be a new marker of VT1- and VT2-induced renal pathology and positive predictor of outcome in the mouse, consistent with VT-staining of proximal tubules. Lung Gb3 migrated on thin-layer chromatography (TLC) faster than kidney Gb(3), suggesting a different lipid composition. AdamantylGb(3), a soluble Gb(3) analogue, competed effectively for Gb3 binding by VT1 and VT2 in vitro. However, the effect in the mouse model (only measured against VT2, due to the lower LD(50), a concentration required for 50% lethality) was to increase, rather than reduce, pathology and further reduce the VT2 serum clearance rate. Additional renal pathology was seen in VT2 + adamantylGb(3)-treated mice. CONCLUSIONS: The lung is a preferential (Gb(3)) "sink" for VT1, which explains the relatively slower clearance of VT2 and subsequent increased VT2 renal targeting and VT2 mortality in this animal model.