Pediatric asthma comorbidities: Global impact and unmet needs.

Real-world data on the range and impact of comorbid health conditions that affect pediatric asthma are scant, especially from developing countries. Lack of data hinders effective diagnosis, treatment, and overall management of these complex cases. We, hereby, describe the common pediatric asthma comorbid conditions in terms of evidence for association, potential mechanisms of impact on asthma control, and treatment benefit. Obesity, upper airway allergies, dysfunctional breathing, multiple sensitizations, depressive disorders, food allergy, and gastro-esophageal reflux are common associations with difficult-to-treat asthma. On the other hand, asthma symptoms and/or management may negatively impact the well-being of children through drug adverse effects, worsening of anaphylaxis symptoms, and disturbing mental health. Awareness of these ailments may be crucial for designing the optimum care for each asthmatic child individually and may ultimately improve the quality of life of patients and their families. A multidisciplinary team of physicians is required to identify and manage such comorbidities aiming to mitigate the over-use of asthma pharmacotherapy. Asthma research should target relevant real-world difficulties encountered at clinical practice and focus on interventions that would mitigate the impact of such comorbidities. Finally, policymakers and global healthcare organizations are urged to recognize pediatric asthma control as a healthcare priority and allocate resources for research and clinical interventions. In other words, global asthma control needs support by compassionate scientific partnership.

A comparison of caregiver-reported snoring and objective snoring in children from urban neighborhoods.

OBJECTIVE: Sleep Disordered Breathing (SDB) is both prevalent and under-recognized in pediatric minority populations. Recognition of SDB is often triggered by symptoms of caregiver-reported snoring. However, the validity and utility of caregiver reports likely vary across populations. Our objective is to assess the association between caregiver-reported snoring and objectively recorded snoring in a low-income urban community and explore factors associated with agreement between objective and subjective snoring. METHODS: 169 6 to 12 year old participants underwent at-home sleep studies with a WatchPAT device as part of the Environmental Assessment of Sleep in Youth (EASY) cohort study. Differences in subjective snoring, objective snoring, and concordance between subjective and objective snoring based on socioeconomic and clinical characteristics were assessed. RESULTS: The sample had a high proportion of non-white (78.9 %) and low income (39.6 %) children. Caregivers reported snoring for 20.7 % of the children and snoring was measured objectively for 21.9 %. Of those with objective snoring, only 29.7 % were identified as snorers by caregiver report (sensitivity: 0.30; specificity: 0.82). Primary Spanish language and co-sleeping were associated with increased caregiver reported snoring, and allergy was associated with increased objective snoring. Older child age and normal range BMI percentile were associated with higher concordance between caregiver and objective snoring. CONCLUSIONS: Among a community-based, predominantly minority sample, caregiver-reported snoring resulted in under-estimation of prevalence of objectively assessed snoring. Reliance on caregiver report may poorly identify children with snoring or SDB in clinical practice.

Human Epidemiology and RespOnse to SARS-CoV-2 (HEROS): Objectives, Design and Enrollment Results of a 12-City Remote Observational Surveillance Study of Households with Children using Direct-to-Participant Methods.

The Human Epidemiology and Response to SARS-CoV-2 (HEROS) is a prospective multi-city 6-month incidence study which was conducted from May 2020-February 2021. The objectives were to identify risk factors for SARS-CoV-2 infection and household transmission among children and people with asthma and allergic diseases, and to use the host nasal transcriptome sampled longitudinally to understand infection risk and sequelae at the molecular level. To overcome challenges of clinical study implementation due to the coronavirus pandemic, this surveillance study used direct-to-participant methods to remotely enroll and prospectively follow eligible children who are participants in other NIH-funded pediatric research studies and their household members. Households participated in weekly surveys and biweekly nasal sampling regardless of symptoms. The aim of this report is to widely share the methods and study instruments and to describe the rationale, design, execution, logistics and characteristics of a large, observational, household-based, remote cohort study of SARS-CoV-2 infection and transmission in households with children. The study enrolled a total of 5,598 individuals, including 1,913 principal participants (children), 1,913 primary caregivers, 729 secondary caregivers and 1,043 other household children. This study was successfully implemented without necessitating any in-person research visits and provides an approach for rapid execution of clinical research.

Comparison of home-based spirometry and oscillometry measurements in school-age children with bronchopulmonary dysplasia.

INTRODUCTION: This study compares home-based oscillometry and spirometry for characterizing respiratory system disease in school-aged children with bronchopulmonary dysplasia (BPD) in clinical research. We hypothesized higher rates of successful completion and abnormal cases identified through oscillometry, with correlations between device measurements. METHODS: Participants 6-12 years old with BPD in the ongoing Air Quality, Environment and Respiratory Outcomes in BPD (AERO-BPD) study performed oscillometry followed by spirometry at two separate home visits. Parameters measured included airway resistance at 5 Hz(R5), resistance from 5 to 19 Hz(R5-19), resonance frequency(Fres), reactance at 5 Hz(X5), area under the curve between Fres and X5(AX), forced expiratory volume in 1 second(FEV1), forced vital capacity(FVC), and FEV1/FVC. Descriptive statistics identified the proportion of successful tests, correlation in measurements, and rate of lung disease for each device. RESULTS: Among 76 subjects with 120 paired observations, 95% and 71% of participants successfully performed oscillometry and spirometry, respectively, at home visit one. 98% and 77% successfully performed oscillometry and spirometry, respectively, at home visit two. Odds ratios favored oscillometry (range 5.31-10.13, p < 0.01). FEV1 correlated with AX (correlation coefficient r = -0.27, p = 0.03); FEV1/FVC with AX (r = -0.32, p = 0.02); and FEV1/FVC with R5 (r = -0.37, p = 0.01). AX exhibited the highest prevalence of abnormality at 25%; other oscillometry parameters ranged from 5%-22%. Forty-five to sixty-four percent of participants had abnormal spirometry. Oscillometry assessments had significantly lower odds of capturing lung disease (odds ratios 0.07-0.24, p < 0.0001). CONCLUSIONS: School-aged children with BPD demonstrated higher success rates in field-based oscillometry than spirometry. Spirometry exhibited higher rates of abnormality than oscillometry. Moderate correlation exists between device measurements.

Exploring the relationship between school-supervised asthma therapy and social determinants of health in pediatric asthma care.

BACKGROUND: Social determinants of health (SDoH), including access to care, economic stability, neighborhood factors, and social context, strongly influence pediatric asthma outcomes. School-supervised asthma therapy (SST) is an evidence-based strategy that improves asthma outcomes, particularly for historically marginalized children, by providing support for daily medication adherence in school. However, little is known about the relationship between these programs and the adverse SDoH commonly affecting underrepresented minority and marginalized children with asthma. METHODS: We examined qualitative data from interviews (n = 52) conducted between 2017 and 2020 with diverse multi-level partners involved in Asthma Link, a SST intervention. Participants included end-users (children and their parents), deliverers (school nurses and pediatric providers), and systems-level partners (e.g., insurers, legislators, and state officials). We used inductive coding to determine themes and subthemes and deductive coding using the Healthy People 2030 SDoH framework. RESULTS: Three themes emerged: (1) SST mitigates adverse SDoH (improves access to preventive healthcare and asthma health literacy), (2) SST benefits children experiencing specific adverse SDoH (provides a consistent medication routine to children with unstable family/housing situations) and (3) specific adverse SDoH impede SST implementation (economic instability, culture and language barriers). CONCLUSION: This study suggests an important relationship between SDoH and SST that warrants further evaluation in our future work on this community-based asthma intervention. Moreover, our findings underscore the importance of measuring SDoH in the implementation and evaluation of pediatric asthma interventions, particularly given the strong influence of these social factors on child health outcomes.

Recommendations for asthma monitoring in children: A PeARL document endorsed by APAPARI, EAACI, INTERASMA, REG, and WAO.

Monitoring is a major component of asthma management in children. Regular monitoring allows for diagnosis confirmation, treatment optimization, and natural history review. Numerous factors that may affect disease activity and patient well-being need to be monitored: response and adherence to treatment, disease control, disease progression, comorbidities, quality of life, medication side-effects, allergen and irritant exposures, diet and more. However, the prioritization of such factors and the selection of relevant assessment tools is an unmet need. Furthermore, rapidly developing technologies promise new opportunities for closer, or even "real-time," monitoring between visits. Following an approach that included needs assessment, evidence appraisal, and Delphi consensus, the PeARL Think Tank, in collaboration with major international professional and patient organizations, has developed a set of 24 recommendations on pediatric asthma monitoring, to support healthcare professionals in decision-making and care pathway design.

Utility of eosinophil peroxidase as a biomarker of eosinophilic inflammation in asthma.

BACKGROUND: The relative utility of eosinophil peroxidase (EPX) and blood and sputum eosinophil counts as disease biomarkers in asthma is uncertain. OBJECTIVE: We sought to determine the utility of EPX as a biomarker of systemic and airway eosinophilic inflammation in asthma. METHODS: EPX protein was measured by immunoassay in serum and sputum in 110 healthy controls to establish a normal reference range and in repeated samples of serum and sputum collected during 3 years of observation in 480 participants in the Severe Asthma Research Program 3. RESULTS: Over 3 years, EPX levels in patients with asthma were higher than normal in 27% to 31% of serum samples and 36% to 53% of sputum samples. Eosinophils and EPX correlated better in blood than in sputum (rs values of 0.74 and 0.43, respectively), and high sputum EPX levels occurred in 27% of participants with blood eosinophil counts less than 150 cells/µL and 42% of participants with blood eosinophil counts between 150 and 299 cells/µL. Patients with persistently high sputum EPX values for 3 years were characterized by severe airflow obstruction, frequent exacerbations, and high mucus plug scores. In 59 patients with asthma who started mepolizumab during observation, serum EPX levels normalized in 96% but sputum EPX normalized in only 49%. Lung function remained abnormal even when sputum EPX normalized. CONCLUSIONS: Serum EPX is a valid protein biomarker of systemic eosinophilic inflammation in asthma, and sputum EPX levels are a more sensitive biomarker of airway eosinophilic inflammation than sputum eosinophil counts. Eosinophil measures in blood frequently miss airway eosinophilic inflammation, and mepolizumab frequently fails to normalize airway eosinophilic inflammation even though it invariably normalizes systemic eosinophilic inflammation.

Impact of Exacerbation History on Dupilumab Efficacy in Children with Uncontrolled Moderate-to-Severe Asthma: LIBERTY ASTHMA VOYAGE Study.

Purpose: Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukins-4/-13, key and central drivers of type 2 inflammation in multiple diseases. This post hoc analysis of the Phase 3 LIBERTY ASTHMA VOYAGE study (NCT02948959) evaluated the efficacy of dupilumab in children aged 6 to 11 years with moderate-to-severe asthma with a type 2 inflammatory phenotype (blood eosinophil count ≥150 cells/µL or fractional exhaled nitric oxide [FeNO] ≥20 ppb) and a history of 1, 2, or ≥3 prior exacerbations. The impact of baseline type 2 biomarker levels on the efficacy of dupilumab in this population was also investigated. Patients and Methods: Patients were stratified by the number of exacerbations in the prior year (1, 2, or ≥3) and level of FeNO or blood eosinophil count at baseline. Endpoints included rate of severe exacerbations, percentage of non-exacerbators, and change from baseline in both lung function parameters (pre- and post-bronchodilator [BD] percent predicted forced expiratory volume in 1 s (ppFEV1) and ppFEV1/forced vital capacity [FVC] ratio) and Asthma Control Questionnaire 7 Interviewer-Administered (ACQ-7-IA) score. Results: A total of 350 patients were included in this analysis. Across patients with 1, 2, or ≥3 prior exacerbations and different levels of type 2 biomarkers, dupilumab reduced the risk of severe asthma exacerbations vs placebo by 53.0-96.0% and improved both pre-BD ppFEV1 and pre-BD FEV1/FVC ratio at Week 52. Dupilumab led to significant reductions in ACQ-7-IA scores in all groups of patients by Week 52. Conclusion: In children with uncontrolled, moderate-to-severe asthma with a type 2 phenotype, dupilumab consistently reduced the risk of asthma exacerbations, improved lung function, and reduced ACQ-7-IA scores, regardless of exacerbation history.

Basophils are important for development of allergic skin inflammation.

BACKGROUND: Atopic dermatitis skin lesions exhibit increased infiltration by basophils. Basophils produce IL-4, which plays an important role in the pathogenesis of atopic dermatitis. OBJECTIVE: We sought to determine the role of basophils in a mouse model of antigen-driven allergic skin inflammation. METHODS: Wild-type mice, mice with selective and inducible depletion of basophils, and mice expressing Il4-driven enhanced green fluorescent protein were subjected to epicutaneous sensitization with ovalbumin or saline. Sensitized skin was examined by histology for epidermal thickening. Cells were analyzed for surface markers and intracellular expression of enhanced green fluorescent protein by flow cytometry. Gene expression was evaluated by real-time reverse transcription-quantitative PCR. RESULTS: Basophils were important for epidermal hyperplasia, dermal infiltration by CD4+ T cells, mast cells, and eosinophils in ovalbumin-sensitized mouse skin and for the local and systemic TH2 response to epicutaneous sensitization. Moreover, basophils were the major source of IL-4 in epicutaneous-sensitized mouse skin and promote the ability of dendritic cells to drive TH2 polarization of naive T cells. CONCLUSION: Basophils play an important role in the development of allergic skin inflammation induced by cutaneous exposure to antigen in mice.

Lung function trajectories in a cohort of patients with moderate-to-severe asthma on mepolizumab, omalizumab, or dupilumab.

BACKGROUND: Lung function is an independent predictor of mortality. We evaluated the lung function trajectories of a cohort of patients with asthma receiving biologic therapy. METHODS: We identified 229 monoclonal antibody-naïve adult patients with moderate-to-severe asthma who initiated omalizumab, mepolizumab, or dupilumab between 2010 and 2022 in a large healthcare system in Boston, MA. Generalized additive mixed models were used to estimate the lung function trajectories during the 156 weeks following biologic initiation. Response was defined as an improvement in FEV1 or a decrease of ≤0.5% per year. The Kaplan-Meier estimator was used to assess time to no additional improvement in FEV1 in responders. All models were adjusted for age, sex, body mass index, smoking status, baseline exacerbation rate, and baseline blood eosinophil count. RESULTS: Eighty-eight patients initiated mepolizumab, 76 omalizumab, and 65 dupilumab. Baseline eosinophil count was highest in the mepolizumab group (405 cells/mcL) and lowest for omalizumab (250 cells/mcL). Both FEV1 and FVC improved in the mepolizumab group (FEV1 + 20 mL/year; FVC +43 mL/year). For omalizumab, there was an initial improvement in the first year followed by decline with an overall FEV1 loss of -44 mL/year and FVC -32 mL/year. For dupilumab, both FEV1 (+61 mL/year) and FVC (+74 mL/year) improved over time. Fifty percent of the mepolizumab group, 58% omalizumab, and 72% of dupilumab were responders. The median time to no additional FEV1 improvement in responders was 24 weeks for omalizumab, 48 weeks for mepolizumab, and 57 weeks for dupilumab. CONCLUSION: In this clinical cohort, mepolizumab, omalizumab, and dupilumab had beneficial effects on FEV1 and FVC with distinct post-initiation trajectories.

Protocol for the air purification for eosinophilic COPD study (APECS): a randomised controlled trial of home air filtration by HEPA.

INTRODUCTION: Exposure to particulate matter (PM) pollution has been associated with lower lung function in adults with chronic obstructive pulmonary disease (COPD). Patients with eosinophilic COPD have been found to have higher levels of airway inflammation, greater responsiveness to anti-inflammatory steroid inhalers and a greater lung function response to PM pollution exposure compared with those with lower eosinophil levels. This study will evaluate if reducing home PM exposure by high-efficiency particulate air (HEPA) air filtration improves respiratory health in eosinophilic COPD. METHODS AND ANALYSIS: The Air Purification for Eosinophilic COPD Study (APECS) is a double-blinded randomised placebo-controlled trial that will enrol 160 participants with eosinophilic COPD living in the area of Boston, Massachusetts. Real and sham air purifiers will be placed in the bedroom and living rooms of the participants in the intervention and control group, respectively, for 12 months. The primary trial outcome will be the change in forced expiratory volume in 1 s (FEV1). Lung function will be assessed twice preintervention and three times during the intervention phase (at 7 days, 6 months and 12 months postrandomisation). Secondary trial outcomes include changes in (1) health status by St. George's Respiratory Questionnaire; (2) respiratory symptoms by Breathlessness, Cough and Sputum Scale (BCSS); and (3) 6-Minute Walk Test (6MWT). Inflammatory mediators were measured in the nasal epithelial lining fluid (NELF). Indoor PM will be measured in the home for the week preceding each study visit. The data will be analysed to contrast changes in outcomes in the intervention and control groups using a repeated measures framework. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Institutional Review Board of Beth Israel Deaconess Medical Centre (protocol #2019P0001129). The results of the APECS trial will be presented at scientific conferences and published in peer-reviewed journals. TRIAL REGISTRATION: NCT04252235. Version: October 2023.

Future of biologics in pediatric asthma: Optimizing response, early introduction, and equitable access to treatment.

OBJECTIVE: To evaluate the current evidence, its limitations, and future research directions for the use of biologics in pediatric asthma, with a particular focus on the potential use of biologics to prevent pediatric asthma and equity issues in access to biologic treatment and research participation. DATA SOURCES: PubMed articles about the use of biologics in pediatric asthma were searched up to May 2023. STUDY SELECTIONS: Recent (2019-2023) original research articles and reviews were prioritized. RESULTS: Although there are now 5 U.S. Food and Drug Administration-approved biologics for use in pediatric asthma, there are important knowledge gaps that ongoing research seeks to address, which include (1) the long-term efficacy and safety of using biologics in children, (2) the comparative efficacy of different biologics, (3) multi-omics-based classification of asthma endotypes and phenotypes in children to find potential new therapeutic targets and enable identification and validation of new biomarkers that may predict and help monitor response to treatment, and (4) whether starting biologics in early childhood can modify the natural history of asthma and potentially prevent asthma development. SUMMARY: To promote equitable access to biologics and optimize asthma outcomes, future research should recruit patients across the full spectrum of socioeconomic and racial/ethnic backgrounds. Large-scale national and international collaborations between asthma researchers and clinicians are also necessary to fully understand the role of biologics in pediatric asthma.

Dupilumab Improves Lung Function Parameters in Pediatric Type 2 Asthma: VOYAGE Study.

BACKGROUND: Uncontrolled asthma in growing children can impair lung growth that may lead to adverse complications in later life. Dupilumab, a human monoclonal antibody, blocks the shared receptor for IL-4 and IL-13, key drivers of type 2 inflammation. OBJECTIVE: To extensively evaluate the effect of dupilumab on lung function in children (6-11 years) with moderate-to-severe asthma enrolled in phase 3 LIBERTY ASTHMA VOYAGE (NCT02948959). METHODS: Children with asthma were randomized 2:1 to add-on dupilumab 100/200 mg by bodyweight or placebo every 2 weeks, for 52 weeks. We analyzed spirometry parameters in children with type 2 asthma (blood eosinophils ≥150 cells/µL or fractional exhaled nitric oxide [FeNO] ≥20 parts per billion [ppb] at baseline) and within subgroups defined by baseline blood eosinophils or FeNO values. RESULTS: A total of 116 (49%) dupilumab-treated children and 59 (52%) on placebo had impaired lung function (prebronchodilator percent-predicted forced expiratory volume in 1 second [ppFEV1] <80%) at baseline. Dupilumab improved pre- and postbronchodilator ppFEV1 as early as week 2, sustained for up to 52 weeks (least-squares mean difference vs placebo at week 52: 7.79 percentage points; 95% confidence interval [CI]: 4.36-11.22; P < .001 and 4.37 points; 95% CI: 0.95-7.78; P = .01, respectively). Sustained improvements were also observed in other lung function parameters, including pre- and postbronchodilator forced vital capacity (FVC), prebronchodilator forced expiratory flow, and FEV1/FVC ratio across all populations. CONCLUSIONS: Dupilumab led to significant, sustained lung function improvements across a range of lung function measures in children (6-11 years) with uncontrolled, moderate-to-severe type 2 asthma.

Asthma morbidity measures across Black ethnic subgroups.

BACKGROUND: Black adults are disproportionately affected by asthma and are often considered a homogeneous group in research studies despite cultural and ancestral differences. OBJECTIVE: We sought to determine if asthma morbidity differs across adults in Black ethnic subgroups. METHODS: Adults with moderate-severe asthma were recruited across the continental United States and Puerto Rico for the PREPARE (PeRson EmPowered Asthma RElief) trial. Using self-identifications, we categorized multiethnic Black (ME/B) participants (n = 226) as Black Latinx participants (n = 146) or Caribbean, continental African, or other Black participants (n = 80). African American (AA/B) participants (n = 518) were categorized as Black participants who identified their ethnicity as being American. Baseline characteristics and retrospective asthma morbidity measures (self-reported exacerbations requiring systemic corticosteroids [SCs], emergency department/urgent care [ED/UC] visits, hospitalizations) were compared across subgroups using multivariable regression. RESULTS: Compared with AA/B participants, ME/B participants were more likely to be younger, residing in the US Northeast, and Spanish speaking and to have lower body mass index, health literacy, and <1 comorbidity, but higher blood eosinophil counts. In a multivariable analysis, ME/B participants were significantly more likely to have ED/UC visits (incidence rate ratio [IRR] = 1.34, 95% CI = 1.04-1.72) and SC use (IRR = 1.27, 95% CI = 1.00-1.62) for asthma than AA/B participants. Of the ME/B subgroups, Puerto Rican Black Latinx participants (n = 120) were significantly more likely to have ED/UC visits (IRR = 1.64, 95% CI = 1.22-2.21) and SC use for asthma (IRR = 1.43, 95% CI = 1.06-1.92) than AA/B participants. There were no significant differences in hospitalizations for asthma among subgroups. CONCLUSIONS: ME/B adults, specifically Puerto Rican Black Latinx adults, have higher risk of ED/UC visits and SC use for asthma than other Black subgroups.

Association of Sputum Eosinophilia With Easily Measured Type-2 Inflammatory Biomarkers in Untreated Mild Persistent Asthma.

BACKGROUND: A multicenter clinical trial in patients with mild persistent asthma indicated that response to inhaled corticosteroids (ICS) is limited to those with sputum eosinophilia. However, testing for sputum eosinophilia is impractical in most clinical settings. OBJECTIVE: We examined associations between sputum eosinophilia and type 2 inflammatory biomarkers in untreated mild persistent asthma. METHODS: Induced sputum, blood eosinophil count (BEC), fractional exhaled nitric oxide (FeNO), and serum periostin were obtained twice during the 6-week run-in period in a clinical trial that enrolled patients 12 years and older with symptomatic, mild persistent asthma without controller therapy. The optimal threshold for each biomarker was based on achieving 80% or greater sensitivity. Performance of biomarkers (area under the receiver operating characteristics curve [AUC], range 0.0-1.0) in predicting sputum eosinophilia 2% or greater was determined; AUCs of 0.8 to 0.9 and more than 0.9 define excellent and outstanding discrimination, respectively. RESULTS: Of 564 participants, 27% were sputum eosinophilic, 83% were atopic, 70% had BEC of 200/uL or higher or FeNO of 25 ppb or greater; 64% of participants without sputum eosinophilia had elevated BEC or FeNO. The AUCs for BEC, FeNO, and both together in predicting sputum eosinophilia were all below the threshold for excellent discrimination (AUC 0.75, 0.78, and 0.79, respectively). Periostin (in adults) had poor discrimination (AUC 0.59; P = .02). CONCLUSIONS: In untreated mild persistent asthma, there is substantial discordance between sputum eosinophilia, BEC, and FeNO. Until prospective trials test the ability of alternative biomarkers to predict ICS response, BEC or FeNO phenotyping may be an option to consider ICS through a shared decision-making process with consideration of other clinical features.