Pediatric Asthma Severity Research Articles

Severe Asthma and Allergy: A Pediatric Perspective

Severe asthma in children is associated with significant morbidity and lung function decline. It represents a highly heterogeneous disorder with multiple clinical phenotypes. As its management is demanding, the social and economic burden are impressive. Several co-morbidities may contribute to worsen asthma control and complicate diagnostic and therapeutic management of severe asthmatic patients. Allergen sensitization and/or allergy symptoms may predict asthma onset and severity. A better framing of “allergen sensitization” and understanding of mechanisms underlying progression of atopic march could improve the management and the long-term outcomes of pediatric severe asthma. This review focuses on the current knowledge about interactions between severe asthma and allergies.

Implementation of a Modified Pediatric Asthma Severity Score (MPASS) to Reduce Length of Stay for Pediatric Asthma Patients: A Quality Improvement Study

Implementation of a Modified Pediatric Asthma Severity Score (MPASS) to Reduce Length of Stay for Pediatric Asthma Patients: A Quality Improvement Study

New Drugs for Pediatric Asthma.

Asthma is the most common chronic disease in children. As suggested by international guidelines, the main goals of asthma treatment are symptoms control and lung function preservation, through a stepwise and control-based approach. The first line therapy based on inhaled corticosteroids may fail to reach control in more than one third of patients, especially adolescents, and in these lung function and quality of life may progressively worsen. Treatment with omalizumab, the first anti-immunoglobulin E recombinant humanized monoclonal antibody, has been definitely approved in pediatric uncontrolled asthma. In this review, we discuss the mechanisms and potential roles of emerging therapies for pediatric severe asthma. Novel biologic drugs (i.e., dupilumab, mepolizumab, reslizumab, and benralizumab) seem to be promising in reducing annual exacerbation rates and steroid-use in glucocorticoid-dependent cases, but available data are few and limited to adolescents and adults. Evidences on the use of the muscarinic antagonist tiotropium as controller medication in pediatric settings are progressively growing, sustaining an application as asthma maintenance treatment in children aged >6 years and in preschool children with persistent asthmatic symptoms, but well powered trials are needed to confirm its safety and efficacy. New inhaled corticosteroids (i.e., ciclesonide and mometasone) are effective as once-daily controller therapy, but long-term studies in the different pediatric ages are needed to compare effectiveness and safety to usual treatments. At present, the role of macrolides in pediatric severe asthma is controversial and their administration is not recommended routinely, but may be considered in children with neutrophilic asthma for reducing daily oral steroids administration and improving lung function. Despite the availability of several novel therapeutic strategies for uncontrolled asthma, future trials targeted at specific pediatric age subgroups are needed to support evidences of safety and efficacy also in children.

Tobacco Control Laws and Pediatric Asthma

J Hatoun, K Davis-Plourde, B Penti, H Cabral, L Kazis. Pediatrics. 2018;141(suppl 1):S130–S136 To assess the impact of a tobacco tax policy on pediatric asthma severity. The study included an analysis of 12 860 interviews from the child Asthma Call-back Survey from 2006 to 2010, representing a total population of eligible subjects during this time period of >24 million children from 35 states. Patient-level data from the child Asthma Call-back Survey were merged with …

Variability of outcome measures in trials of intravenous therapy in acute severe paediatric asthma: a systematic review

ObjectiveTo determine the variability of primary and secondary outcomes used in trials of intravenous bronchodilators in children with acute severe paediatric asthma.MethodsSystematic search of MEDLINE, EMBASE, Cochrane CENTRAL and the...

Risk factors associated with severe asthma exacerbations in children attending Alexandria University Children’s Hospital, Egypt

Background: Severe asthma exacerbation is one of the common pediatric medical emergencies that necessitates hospital visits. The study aimed to identify risk factors associated with pediatric severe asthma exacerbations that might have the potential to guide the parents for early medical consultations and physicians at primary health care centers for proper management.Methods: A case-control study was conducted on over 100 asthmatic children below 12 years attending the Emergency Department of Alexandria University Children’s Hospital in acute exacerbation. Based on a modified pulmonary index score, the patients were allocated into 2 groups; study group (50 patients with severe asthma exacerbation) and control group (50 patients with mild asthma exacerbations). Demographic data, history of illness, alarming clinical signs, medications, and outcome of all participants were recorded.Results: Severe asthma exacerbations were more encountered among males, older age, and with a longer duration of asthma (X±SD=28.4±15.9 months) with significant differences when compared to controls. Comparing the studied groups revealed higher risk for severe asthma exacerbations mainly with; history of sudden onset of severe respiratory distress (Odds ratio “OR”=30.13, 95% CI, 13.78-66.69) and chronic steroid-dependent asthma (OR=14.46, 95% CI, 3.97-52.65). Cyanosis, lethargy, and inability to talk were alarming signs in patients with severe asthma exacerbation when compared to those with mild asthma exacerbation (p<0.05).Conclusions: Severe asthma exacerbation in children is still associated with many risk factors that may alert the patients’ caregivers and physicians prospectively for early proper management.

The Portuguese Severe Asthma Registry: Development, Features, and Data Sharing Policies.

The Portuguese Severe Asthma Registry (Registo de Asma Grave Portugal, RAG) was developed by an open collaborative network of asthma specialists. RAG collects data from adults and pediatric severe asthma patients that despite treatment optimization and adequate management of comorbidities require step 4/5 treatment according to GINA recommendations. In this paper, we describe the development and implementation of RAG, its features, and data sharing policies. The contents and structure of RAG were defined in a multistep consensus process. A pilot version was pretested and iteratively improved. The selection of data elements for RAG considered other severe asthma registries, aiming at characterizing the patient's clinical status whilst avoiding overloading the standard workflow of the clinical appointment. Features of RAG include automatic assessment of eligibility, easy data input, and exportable data in natural language that can be pasted directly in patients' electronic health record and security features to enable data sharing (among researchers and with other international databases) without compromising patients' confidentiality. RAG is a national web-based disease registry of severe asthma patients, available at asmagrave.pt. It allows prospective clinical data collection, promotes standardized care and collaborative clinical research, and may contribute to inform evidence-based healthcare policies for severe asthma.

Efficacy of Lactobacillus Administration in School-Age Children with Asthma: A Randomized, Placebo-Controlled Trial

Probiotics may have immunomodulatory effects. However, these effects in asthma remain unclear and warrant clinical trials. Here, we evaluated the effects of Lactobacillus paracasei (LP), Lactobacillus fermentum (LF), and their combination (LP + LF) on the clinical severity, immune biomarkers, and quality of life in children with asthma. This double-blind, prospective, randomized, placebo-controlled trial included 160 children with asthma aged 6–18 years (trial number: NCT01635738), randomized to receive LP, LF, LP + LF, or a placebo for 3 months. Their Global Initiative for Asthma–based asthma severity, Childhood Asthma Control Test (C-ACT) scores, Pediatric Asthma Severity Scores, Pediatric Asthma Quality of Life Questionnaire scores, peak expiratory flow rates (PEFRs), medication use, the levels of immune biomarkers (immunoglobulin E (IgE), interferon γ, interleukin 4, and tumor necrosis factor α) at different visits, and the associated changes were evaluated. Compared with the placebo group by generalized estimating equation model, children receiving LP, LF, and LP + LF had lower asthma severity (p = 0.024, 0.038, and 0.007, respectively) but higher C-ACT scores (p = 0.005, < 0.001, and < 0.001, respectively). The LP + LF group demonstrated increased PEFR (p < 0.01) and decreased IgE levels (p < 0.05). LP, LF, or their combination (LP + LF) can aid clinical improvement in children with asthma.

Management of Severe Asthma in Children

Severe asthma is a highly heterogeneous disorder associated with significant morbidity. The management of severe asthma in children is multifaceted and complicated by psychosocial factors, difficulties and barriers to medication adherence, difficulties of medication delivery, and comorbid diseases. This article aims to review the approach to the management of childhood severe asthma and examine the recent literature in the advances in phenotype-directed management of severe asthma in children. Recently, more focus has been placed on the development of multidisciplinary clinics, school medication management programs, home management programs, and other interventions in order to optimize asthma management and care. Furthermore, there has been a shift in the paradigm of asthma management in children towards phenotype-directed management, especially in children with severe difficult-to-control or treatment-resistant asthma. Current treatment of pediatric severe asthma includes three approved targeted biologic phenotype-directed therapies. There are some targeted therapies that are approved for adults which may prove to be beneficial in children with asthma as ongoing research continues. Further investigation into identifying predictors of treatment response and biomarkers that can lead to precision and personalized management for children with severe asthma is ongoing and will be imperative in determining the optimal treatment strategies for pediatric severe asthma.

Omalizumab in the Therapy of Pediatric Asthma.

Eosinophilic asthma is driven by Th2 immune response and is usually characterized by the increase of total serum IgE levels and/or specific IgE that express single or multiple allergen sensitization. In such an immuno-pathological background, the anti-IgE therapy, namely omalizumab, found its main clinical utility and recommendation to treat severe asthma. In this mini-review, we summarized the most relevant immuno-pathological and clinical evidences supporting the use of omalizumab in the therapy of pediatric asthma. Furthermore, we provided the main practical points for its use in the therapeutic management of asthmatic children. Through the binding of serum free IgE, omalizumab impairs not only the effector phase of IgE-mediated asthma, but also affects the IgE biology and the related immune response, globally. Here, the history of omalizaumab has been shortly reviewed from its preclinical development to its clinical validation in pediatric asthma. Thus, recent patents regarding anti-IgE therapy have been discussed. Omalizumab significantly improved the clinical management of severe and uncontrolled pediatric asthma; however, pre-treament IgE levels limited the use of omalizumab in some patients and the cost of the therapy is still relevant. Moreover, the optimal duration of the treatment with omalizumab in children has to be determined. Finally, the recent generation of a mutant IgE-Fc fragment being resistant to omalizumab binding might open further therapeutic applications, in addition to second generation anti-IgE antibodies.

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.

Safety of Terbutaline for Treatment of Acute Severe Pediatric Asthma.

The use of continuous intravenous terbutaline treatment in severe asthma attacks has been hampered by the lack of well-powered clinical trials where effects of such treatment are described in detail. Here, we aimed to provide a descriptive report on the largest cohort of severe pediatric asthma patients treated with terbutaline. The study was conducted in a pediatric intensive care unit in a large metropolitan tertiary care university hospital on 124 patients receiving terbutaline infusion. To stratify the effect of, and determine any age-related differences of, terbutaline, the patients were divided into 3 age groups (0-6 years, 7-12 years, and 13-18 years). Clinical response and the potential harmful effects of terbutaline infusion were determined. There were significant reductions in systolic (varying between 86% and 93% of the baseline) and diastolic blood pressures (varying between 74% and 86% of the baseline level). However, the values returned to baseline level shortly after discontinuation of infusion. Terbutaline increased heart rates in all groups shortly after initiation (9%-13% above baseline), which returned to below baseline levels 1 hour after discontinuation. Serum potassium levels were also reduced in all patients compared to their baseline values after initiation of terbutaline infusion. However, none of the subjects required potassium replacement. The results indicate that overall, terbutaline infusion was well tolerated without irreversible adverse effects of the treatment. Although hemodynamic and metabolic disturbances occurred, these were clinically easily managed and posed little risk in emergency department or pediatric intensive care unit.

Pediatric severe asthma: a case series report and perspectives on anti-IgE treatment

BackgroundThe primary goal of asthma management is to achieve disease control for reducing the risk of future exacerbations and progressive loss of lung function. Asthma not responding to treatment may result in significant morbidity. In many children with uncontrolled symptoms, the diagnosis of asthma may be wrong or adherence to treatment may be poor. It is then crucial to distinguish these cases from the truly “severe therapy-resistant” asthmatics by a proper filtering process. Herein we report on four cases diagnosed as difficult asthma, detail the workup that resulted in the ultimate diagnosis, and provide the process that led to the prescription of omalizumab.Case presentationAll children had been initially referred because of asthma not responding to long-term treatment with high-dose inhaled steroids, long-acting β2-agonists and leukotriene receptor antagonists. Definitive diagnosis was severe asthma. Three out four patients were treated with omalizumab, which improved asthma control and patients’ quality of life. We reviewed the current literature on the diagnostic approach to the disease and on the comorbidities associated with difficult asthma and presented the perspectives on omalizumab treatment in children and adolescents. Based on the evidence from the literature review, we also proposed an algorithm for the diagnosis of pediatric difficult-to-treat and severe asthma.ConclusionsThe management of asthma is becoming much more patient-specific, as more and more is learned about the biology behind the development and progression of asthma. The addition of omalizumab, the first targeted biological treatment approved for asthma, has led to renewed optimism in the management of children and adolescents with atopic severe asthma.

What Is the Role for Magnesium to Treat Severe Pediatric Asthma Exacerbations?

In this review, we explore the role for intravenous magnesium sulfate (IVMg) to treat children with acute exacerbations of asthma. Children who receive care for severe acute asthma in emergency departments are often hospitalized after inadequate response to standard asthma treatment. IVMg may have a role to decrease hospitalization of children with severe acute asthma, but is in need of further research. Future exploration of IVMg should include larger randomized controlled trials of IVMg versus standard treatment, administration of IVMg with enough time to have effect on hospitalization, exploration of the pharmacology of IVMg so that the most effective dosage regimens can be selected, and use of measures and criteria to select research participants reflective of the children likely to benefit from more effective asthma treatment in clinical practice.

Adolescent and caregivers' experiences of electronic adherence assessment in paediatric problematic severe asthma.

This study explored the experiences of adolescents and their caregivers regarding adherence to inhaled corticosteroids which are assessed through an electronic monitoring device (EMD). These devices are increasingly being used for assessing medication adherence, yet there is little information about patient's experience of these tools. Semi-structured interviews were conducted with eight adolescents with severe asthma, aged 11-15 years, who were electronically monitored as part of their care, along with their caregivers. Interviews were analysed using thematic analysis. Three themes were identified: 'they were trying to help me get better', 'checking up and catching out' and 'who is responsible?' The themes highlighted differences in priorities between participant groups, the impact of monitoring on the healthcare relationship and the dilemma of transferring responsibility for asthma management to adolescents. The findings suggest it is important for healthcare professionals to engage with patient's preferences and priorities when introducing EMDs.

Tobacco Control Laws and Pediatric Asthma.

Exposure to environmental tobacco smoke increases pediatric asthma severity. Strict, state-level tobacco control reduces smoking. The Child Asthma Call-Back Survey (Child ACBS) is a nationally representative survey of the guardians of children with asthma. The American Lung Association's annual State of Tobacco Control report grades tobacco control laws in each state including a tax grade (cigarette excise tax relative to the national mean), and a smoke-free air grade (number of locations where smoking is prohibited). We joined Child ACBS data from 2006 to 2010 with corresponding state and year tobacco grades. In the primary analysis, we investigated the effect of state tax grades on a child's asthma severity by using a logistic regression model adjusting for year. A secondary analysis assessed the impact of smoke-free air grades on in-home smoking. Our analysis included 12 860 Child ACBS interviews from 35 states over 5 years, representing over 24 million individuals. We merged 112 unique State of Tobacco Control grades with patient data by state and year. A higher tax grade was associated with reduced severity (adjusted odds ratio = 1.40; P = .007, 95% confidence interval: 1.10-1.80). A better smoke-free air grade was not associated with decreased in-home smoking after adjusting for confounding by income and type of residence. A stronger tobacco tax is associated with reduced asthma severity. Further study is needed to determine the effect of smoke-free air laws on in-home environmental. This work supports ongoing efforts to strengthen tobacco control through federal and state regulations.

Lung function in severe pediatric asthma: a longitudinal study in children and adolescents in Brazil

BackgroundIn severe asthma, high doses of inhaled corticosteroids (ICS) are used in order to achieve clinical and functional control. This study aimed to evaluate lung function in outpatients (children and adolescents) with severe asthma in Brazil, all of whom were treated with high doses of ICS. We evaluated all spirometry tests together and by ICS dose: 800 and > 800 µg/day.MethodsThis was a 3-year longitudinal study in which we analyzed 384 spirometry tests in 65 severe asthma patients (6–18 years of age), divided into two groups by the dose of ICS (budesonide or equivalent): 800 and > 800 µg/day.ResultsAt baseline, the forced expiratory volume in one second (FEV1) and the FEV1/forced vital capacity (FVC) ratio were both < 80% of the predicted values in 50.8% of the patients. The median age of the patients was 10.4 years (interquartile range 7.8–13.6 years). In the sample as a whole, there were significant increases in FEV1% and in the FEV1/FVC% ratio (p = 0.01 and p < 0.001, respectively) over the course of the study. In the > 800 µg/day group, there were no statistical increases or decreases in FEV1, the FEV1/FVC ratio, or forced expiratory flow between 25 and 75% of the FVC (FEF25–75%), when calculated as percentages of the predicted values. However, the z-score for FEF25–75% showed a statistically significant reduction, in the sample as a whole and in the > 800 µg/day group. Also in the > 800 µg/day group, there was a significant reduction in the post-bronchodilator FEV1% (p = 0.004).ConclusionsThe fact that the spirometric parameters (as percentages of the predicted values) remained constant in the > 800 µg/day group, whereas there was a gain in lung function in the sample as a whole, suggests an early plateau phase in the > 800 µg/day group. However, there was some loss of lung function in the > 800 µg/day group, as evidenced by a decrease in the z-score for FEF25–75%, suggesting irreversible small airway impairment, and by a reduction in the post-bronchodilator FEV1%, suggesting reduced reversibility of airway obstruction. Among children and adolescents with severe asthma, the use of ICS doses higher than those recommended for age does not appear to improve lung function.

Electronic monitoring of adherence to inhaled corticosteroids: an essential tool in identifying severe asthma in children.

International guidelines recommend that severe asthma can only be diagnosed after contributory factors, including adherence, have been addressed. Accurate assessment of adherence is difficult in clinical practice. We hypothesised that electronic monitoring in children would identify nonadherence, thus delineating the small number with true severe asthma.Asthmatic children already prescribed inhaled corticosteroids were prospectively recruited and persistence of adherence assessed using electronic monitoring devices. Spirometry, airway inflammation and asthma control were measured at the start and end of the monitoring period.93 children (62 male; median age 12.4 years) were monitored for a median of 92 days. Median (range) monitored adherence was 74% (21-99%). We identified four groups: 1) good adherence during monitoring with improved control, 24% (likely previous poor adherence); 2) good adherence with poor control, 18% (severe therapy-resistant asthma); 3) poor adherence with good control, 26% (likely overtreated); and 4) poor adherence with poor control, 32%. No clinical parameter prior to monitoring distinguished these groups.Electronic monitoring is a useful tool for identifying children in whom a step up in treatment is indicated. Different approaches are needed in those who are controlled when adherent or who are nonadherent. Electronic monitoring is essential in a paediatric severe asthma clinic.

The Effect of a Pediatric Intensive Care Severity-Tiered Pathway for Status Asthmaticus on Quality Measures and Outcomes.

Background: Patients with status asthmaticus admitted to the hospital contribute tremendous costs to the healthcare system. Treatment protocols directed at improving care to pediatric inpatients have improved both clinical and financial outcomes; however, there are limited data demonstrating the impact of goal-driven therapy for patients with status asthmaticus in the pediatric intensive care unit (PICU). The purpose of this initiative was to standardize care of children with status asthmaticus in the PICU to improve clinical outcomes. Materials and Methods: A goal-directed clinical pathway using a validated pediatric asthma severity score was developed. A pre-post intervention assessed patients 2-17 years of age admitted to the PICU with status asthmaticus. The effect of the protocol was measured from October 2015 to October 2016. The primary outcome was the transition time interval from continuous nebulized bronchodilator therapy to every 2 hourly intermittent treatments. Secondary outcomes related to treatment options and clinical complications were also assessed. Results: Postintervention patient (n = 124) demographics were similar to those in the preintervention group (n = 130). Compared with baseline, there was a 4.9-h decrease in the mean transition time from continuous to intermittent bronchodilator use (31.9 versus 27.0, P = 0.033) following the intervention. The mean and median hospital length of stay (LOS) was significantly decreased in the postintervention group by 14.76 h (P = 0.011) and 16.68 h (P = 0.003). There were no readmissions to the PICU in the postintervention group. The use of rescue BiPAP (Bi-level positive airway pressure ventilation) was significantly higher in the preintervention group compared with the postintervention group (42% versus 28%, P = 0.036). Conclusions: A severity-tiered, goal-driven treatment pathway for pediatric patients admitted to the PICU with status asthmaticus reduced the time required to transition from continuous to intermittent inhaled bronchodilator use. As a result, overall hospital LOS was significantly decreased with no increase in clinical complications.

Mechanisms Mediating Pediatric Severe Asthma and Potential Novel Therapies.

Although a rare disease, severe therapy-resistant asthma in children is a cause of significant morbidity and results in utilization of approximately 50% of health-care resources for asthma. Improving control for children with severe asthma is, therefore, an urgent unmet clinical need. As a group, children with severe asthma have severe and multiple allergies, steroid resistant airway eosinophilia, and significant structural changes of the airway wall (airway remodeling). Omalizumab is currently the only add-on therapy that is licensed for use in children with severe asthma. However, limitations of its use include ineligibility for approximately one-third of patients because of serum IgE levels outside the recommended range and lack of clinical efficacy in a further one-third. Pediatric severe asthma is thus markedly heterogeneous, but our current understanding of the different mechanisms underpinning various phenotypes is very limited. We know that there are distinctions between the factors that drive pediatric and adult disease since pediatric disease develops in the context of a maturing immune system and during lung growth and development. This review summarizes the current data that give insight into the pathophysiology of pediatric severe asthma and will highlight potential targets for novel therapies. It is apparent that in order to identify novel treatments for pediatric severe asthma, the challenge of undertaking mechanistic studies using age appropriate experimental models and airway samples from children needs to be accepted to allow a targeted approach of personalized medicine to be achieved.