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.

Effects of Allergen Exposure and Environmental Risk Factors in Schools on Childhood Asthma.

PURPOSE OF REVIEW: This review aims to assess the prevalence of common allergen exposures and environmental risk factors for asthma in schools, examine the underlying mechanisms of these environmental risk factors, and explore possible prevention strategies. RECENT FINDINGS: Cockroach, mouse, dust mites, fungi, viral infections, ozone pollution, and cleaning products are common allergen exposures and environmental risk factors in schools which may affect asthma morbidity. Novel modifiable environmental risk factors in schools are also being investigated to identify potential associations with increased asthma morbidity. While several studies have investigated the benefit of environmental remediation strategies in schools and their impact on asthma morbidity, future studies are warranted to further define the effects of modifiable risk factors in schools and determine whether school mitigation strategies may help improve asthma symptoms in students with asthma.

Environmental Interventions for Asthma.

Exposure and sensitization to environmental factors play a fundamental role in asthma development and is strongly associated with asthma morbidity. While hereditary factors are critical determinants of asthma, exposures to environmental factors are implicated in the phenotypic expression of asthma and have been strongly associated in the risk of its development. Significant interest has thus been geared toward potentially modifiable environmental exposures which may lead to the development of asthma. Allergen exposure, in particular indoor allergens, plays a significant role in the pathogenesis of asthma, and remediation is a primary component of asthma management. In the home, multifaceted and multitargeted environmental control strategies have been shown to reduce home exposures and improve asthma outcomes. In addition to the home environment, assessment of the school, daycare, and workplace environments of patients with asthma is necessary to ensure appropriate environmental control measures in conjunction with medical care. This article will discuss the role of the environment on asthma, review targeted environmental therapy, and examine environmental control measures to suppress environmental exposures in the home and school setting.

Factors to Consider in Prescribing Asthma Biologic Therapies to Children.

The increasing availability of biologics, both by expanding age indications and by development of new therapies, provides additional options to treat children and adolescents with severe asthma. However, the evidence for these biologics in these populations is limited compared with that for adult studies. As such, before initiation of therapy, possible alternative therapies that can also provide asthma control, confirmation of the diagnosis of asthma, management of comorbidities, and assessment of adherence should be explored. The choice of a biologic should be a shared decision-making process between providers and families, balancing biologic efficacy, goals of care, administration, and ability to treat multiple conditions. Response to treatment should be periodically evaluated not only to ensure an ineffective treatment is not continued but also to consider when to potentially discontinue therapy should it be beneficial. The utilization of biologics in children and adolescents with severe asthma also leads to unanswered questions on their role in disease remission and long-term outcomes.

The Coronavirus Disease 2019 Pandemic and Mental Health-Related School-Nurse Visits in United States Schools.

OBJECTIVE: No studies have examined school-nurse visits related to mental health (MH) during the coronavirus disease 2019 (COVID-19) pandemic. We examined changes in the rate of MH-related school-nurse visits before and during the COVID-19 pandemic. METHODS: We analyzed school-nurse visit data (n = 3,445,240) for subjects Grade K-12 in US public schools using electronic health record software (SchoolCare, Ramsey, NJ). Data between January 1 and December 31 in 2019 (pre-COVID-19 pandemic) versus January 1 to December 31 in 2020 (during COVID-19 pandemic) were compared. For each year, total visits to a school-nurse were calculated for general MH, anxiety, and self-harm. The exposure was number of school-nurse visits in each time period (2019 vs 2020). The main outcome was change in the rate of general MH, anxiety, and self-harm visits in 2019 versus 2020. RESULTS: There were 2,302,239 total school-nurse visits in 2019 versus 1,143,001 in 2020. During the COVID-19 pandemic, the rate of visits for general MH increased by 30% (4.7-6.1 per 10,000 visits, 95% confidence interval [CI] {18%, 43%}; P < .001), and visits for anxiety increased by 25% (24.8-31 per 10,000 visits, 95% CI [20%,30%]; P < .001). There was no significant difference in self-harm visits across all ages during the COVID-19 pandemic. CONCLUSIONS: Our study found a significant increase in the rate of school-nurse visits for MH and anxiety during the COVID-19 pandemic, suggesting the pediatric population is at-risk for increased negative MH-effects associated with the pandemic and highlights a critical role of school-nurses in identifying youth with potential MH-needs.

Effect of radon exposure on asthma morbidity in the School Inner-City Asthma study.

BACKGROUND: Radon may have a role in obstructive lung disease outside its known carcinogenicity. Little is known about radon's effects on asthma morbidity. OBJECTIVE: To determine the effect of radon on fractional exhaled nitric oxide (FE NO), asthma symptom-days, and lung function in inner-city asthmatic school children. METHODS: Two hundred ninety-nine school-aged asthmatic children enrolled in the School Inner-City Asthma Study (SICAS-1) were followed. One and two-month averaged radon was assessed using a spatiotemporal model predicting zip code-specific monthly exposures. FE NO and spirometry were measured twice during the academic year. Asthma symptoms were assessed four times during the academic year. The interaction between indoor radon exposure (Bq/m3 ) and seasonality predicting log-transformed FE NO, forced expiratory volume in 1 s (FEV1 ) % predicted, forced vital capacity (FVC) % predicted, FEV1 /FVC, and asthma symptom-days was evaluated. RESULTS: Participants with high radon exposure had greater change in FE NO from warm to cold periods compared to low radon exposure (interaction p = 0.0013). Participants with >50th percentile radon exposure experience significant FE NO increase from warm to cold weather ( ß $\beta $ = 0.29 [95% confidence interval [CI]: 0.04-0.54], p = 0.0240). We report a positive association between radon 1-month moving average (incidence rate ratio [IRR] = 1.01, p = 0.0273) and 2-month moving average (IRR = 1.01, p = 0.0286) with maximum asthma symptom-days (n = 299, obs = 1167). CONCLUSIONS: In asthmatic children, radon may be associated with increased asthma morbidity, suggesting radon may be a modifiable environmental risk factor for airway inflammation.

Environmental Exposures Impact Pediatric Asthma Within the School Environment.

The school is a microenvironment well-known to host many indoor allergens and pollutants, with a strong association between school allergen exposure and childhood asthma morbidity. Despite advances in therapies, asthma continues to be one of the most common chronic conditions among children, associated with significant morbidity, health care utilization, and productivity loss. Asthma prevalence is also disproportionately high among children in minority communities. This review will focus on environmental exposures associated with asthma morbidity (cockroach, mouse, cat and dog, dust mite, fungus, air pollution). This review will also discuss recent school-based interventions to improve allergy morbidity among school-aged children. Understanding the multifaceted environmental factors which may contribute to asthma pathogenesis is necessary to help guide potential school-based interventions.

Atopic Dermatitis Mediates the Association Between an IL4RA Variant and Food Allergy in School-Aged Children.

BACKGROUND: Atopic dermatitis (AD) and food allergy (FA) may share genetic risk factors. It is unknown whether genetic factors directly cause FA or are mediated through AD, as the dual-allergen hypothesis suggests. OBJECTIVE: To test the hypothesis that AD mediates the relationship between an IL-4 receptor alpha chain gene (IL4RA) variant, the human IL-4 receptor alpha chain protein-R576 polymorphism, and FA. METHODS: A total of 433 children with asthma enrolled in the School Inner-City Asthma Study underwent genotyping for the IL4RA576 allele. Surveys were administered to determine FA, AD, and associated allergic responses. Mediation analysis was performed adjusting for race and ethnicity, age, sex, and household income. Multivariate models were used to determine the association between genotype and FA severity. RESULTS: AD was reported in 193 (45%) and FA in 80 children (19%). Each risk allele increased odds of AD 1.39-fold ([1.03-1.87], P = .03), and AD increased odds of FA 3.67-fold ([2.05- 6.57], P < .01). There was an indirect effect of genotype, mediated by AD, predicting FA; each risk allele increased the odds of FA by 1.13 (odds ratio [95% CI], Q/R = 1.13 [1.02-1.24], R/R = 1.28 [1.04-1.51]; P < .01). Each risk allele increased the odds of severe FA symptoms 2.68-fold ([1.26-5.71], P = .01). CONCLUSIONS: In a cohort of children with asthma, AD is part of the causal pathway between an IL4RA variant and FA. This variant is associated with increased risk of severe FA reactions. Addressing AD in children with an IL4RA polymorphism may modulate the risk of FA.

Biologics for Treatment of Atopic Dermatitis: Current Status and Future Prospect.

Atopic dermatitis (AD) is a common inflammatory skin disease characterized by intense pruritus and recurrent eczematous lesions that significantly impair quality of life. It is a heterogeneous disease affecting both children and adults. The treatment of moderate-to-severe forms of AD is challenging, as topical corticosteroids are often insufficient to achieve disease control or inappropriate and off-label use of immunosuppressants may have significant undesirable side effects. The development of targeted biologic therapies specifically for AD is thus highly desirable. Dupilumab is the only biologic therapy that is Food and Drug Administration approved for the treatment of moderate-to-severe AD in patients 6 years and older, with consistent long-term efficacy and safety trial data. In this article, we review the mechanisms, safety, and efficacy of dupilumab from recent clinical trials, and we review the current data, mechanism of action, clinical efficacy, and limitations of new biologics currently in phase 2 and 3 clinical trials (lebrikizumab, tralokinumab, nemolizumab, tezepelumab, and ISB 830).

Distinct clinical and immunological features of SARS-CoV-2-induced multisystem inflammatory syndrome in children.

BACKGROUNDPediatric SARS-CoV-2 infection can be complicated by a dangerous hyperinflammatory condition termed multisystem inflammatory syndrome in children (MIS-C). The clinical and immunologic spectrum of MIS-C and its relationship to other inflammatory conditions of childhood have not been studied in detail.METHODSWe retrospectively studied confirmed cases of MIS-C at our institution from March to June 2020. The clinical characteristics, laboratory studies, and treatment response were collected. Data were compared with historic cohorts of Kawasaki disease (KD) and macrophage activation syndrome (MAS).RESULTSTwenty-eight patients fulfilled the case definition of MIS-C. Median age at presentation was 9 years (range: 1 month to 17 years); 50% of patients had preexisting conditions. All patients had laboratory confirmation of SARS-CoV-2 infection. Seventeen patients (61%) required intensive care, including 7 patients (25%) who required inotrope support. Seven patients (25%) met criteria for complete or incomplete KD, and coronary abnormalities were found in 6 cases. Lymphopenia, thrombocytopenia, and elevation in inflammatory markers, D-dimer, B-type natriuretic peptide, IL-6, and IL-10 levels were common but not ubiquitous. Cytopenias distinguished MIS-C from KD and the degree of hyperferritinemia and pattern of cytokine production differed between MIS-C and MAS. Immunomodulatory therapy given to patients with MIS-C included intravenous immune globulin (IVIG) (71%), corticosteroids (61%), and anakinra (18%). Clinical and laboratory improvement were observed in all cases, including 6 cases that did not require immunomodulatory therapy. No mortality was recorded in this cohort.CONCLUSIONMIS-C encompasses a broad phenotypic spectrum with clinical and laboratory features distinct from KD and MAS.FUNDINGThis work was supported by the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Institute of Allergy and Infectious Diseases; Rheumatology Research Foundation Investigator Awards and Medical Education Award; Boston Children's Hospital Faculty Career Development Awards; the McCance Family Foundation; and the Samara Jan Turkel Center.

IFN{gamma} regulates retinal pigment epithelial fluid transport.

The present experiments show that IFNgamma receptors are mainly localized to the basolateral membrane of human retinal pigment epithelium (RPE). Activation of these receptors in primary cultures of human fetal RPE inhibited cell proliferation and migration, decreased RPE mitochondrial membrane potential, altered transepithelial potential and resistance, and significantly increased transepithelial fluid absorption. These effects are mediated through JAK-STAT and p38 MAPK signaling pathways. Second messenger signaling through cAMP-PKA pathway- and interferon regulatory factor-1-dependent production of nitric oxide/cGMP stimulated the CFTR at the basolateral membrane and increased transepithelial fluid absorption. In vivo experiments using a rat model of retinal reattachment showed that IFNgamma applied to the anterior surface of the eye can remove extra fluid deposited in the extracellular or subretinal space between the retinal photoreceptors and RPE. Removal of this extra fluid was blocked by a combination of PKA and JAK-STAT pathway inhibitors injected into the subretinal space. These results demonstrate a protective role for IFNgamma in regulating retinal hydration across the outer blood-retinal barrier in inflammatory disease processes and provide the basis for possible therapeutic interventions.

Confluent monolayers of cultured human fetal retinal pigment epithelium exhibit morphology and physiology of native tissue.

PURPOSE: Provide a reproducible method for culturing confluent monolayers of hfRPE cells that exhibit morphology, physiology, polarity, and protein expression patterns similar to native tissue. METHODS: Human fetal eyes were dissected on arrival, and RPE cell sheets were mechanically separated from the choroid and cultured in a specifically designed medium comprised entirely of commercially available components. Physiology experiments were performed with previously described techniques. Standard techniques were used for immunohistochemistry, electron microscopy, and cytokine measurement by ELISA. RESULTS: Confluent monolayers of RPE cell cultures exhibited epithelial morphology and heavy pigmentation, and electron microscopy showed extensive apical membrane microvilli. The junctional complexes were identified with immunofluorescence labeling of various tight junction proteins. The mean transepithelial potential (TEP) was 2.6 +/- 0.8 mV, apical positive, and the mean transepithelial resistance (R(T)) was 501 +/- 138 Omega . cm(2) (mean +/- SD; n = 35). Addition of 100 microM adenosine triphosphate (ATP) to the apical bath increased net fluid absorption from 13.6 +/- 2.6 to 18.8 +/- 4.6 microL . cm(-2) per hour (mean +/- SD; n = 4). In other experiments, VEGF was mainly secreted into the basal bath (n = 10), whereas PEDF was mainly secreted into the apical bath (n = 10). CONCLUSIONS: A new cell culture procedure has been developed that produces confluent primary hfRPE cultures with morphological and physiological characteristics of the native tissue. Epithelial polarity and function of these easily reproducible primary cultures closely resemble previously studied native human fetal and bovine RPE-choroid explants.

Human Adult Retinal Pigment Epithelial Stem Cell-Derived RPE Monolayers Exhibit Key Physiological Characteristics of Native Tissue.

PURPOSE: We tested what native features have been preserved with a new culture protocol for adult human RPE. METHODS: We cultured RPE from adult human eyes. Standard protocols for immunohistochemistry, electron microscopy, electrophysiology, fluid transport, and ELISA were used. RESULTS: Confluent monolayers of adult human RPE cultures exhibit characteristics of native RPE. Immunohistochemistry demonstrated polarized expression of RPE markers. Electron microscopy illustrated characteristics of native RPE. The mean transepithelial potential (TEP) was 1.19 ± 0.24 mV (mean ± SEM, n = 31), apical positive, and the mean transepithelial resistance (RT) was 178.7 ± 9.9 Ω·cm2 (mean ± SEM, n = 31). Application of 100 µM adenosine triphosphate (ATP) apically increased net fluid absorption (Jv) by 6.11 ± 0.53 µL·cm2·h-1 (mean ± SEM, n = 6) and TEP by 0.33 ± 0.048 mV (mean ± SEM, n = 25). Gene expression of cultured RPE was comparable to native adult RPE (n = 5); however, native RPE RNA was harvested between 24 and 40 hours after death and, therefore, may not accurately reflect healthy native RPE. Vascular endothelial growth factor secreted preferentially basally 2582 ± 146 pg/mL/d, compared to an apical secretion of 1548 ± 162 pg/mL/d (n = 14, P < 0.01), while PEDF preferentially secreted apically 1487 ± 280 ng/mL/d compared to a basolateral secretion of 864 ± 132 ng/mL/d (n = 14, P < 0.01). CONCLUSIONS: The new culture model preserves native RPE morphology, electrophysiology, and gene and protein expression patterns, and may be a useful model to study RPE physiology, disease, and transplantation.

CNTF mediates neurotrophic factor secretion and fluid absorption in human retinal pigment epithelium.

Ciliary neurotrophic factor (CNTF) protects photoreceptors and regulates their phototransduction machinery, but little is known about CNTF's effects on retinal pigment epithelial (RPE) physiology. Therefore, we determined the expression and localization of CNTF receptors and the physiological consequence of their activation in primary cultures of human fetal RPE (hfRPE). Cultured hfRPE express CNTF, CT1, and OsM and their receptors, including CNTFRα, LIFRß, gp130, and OsMRß, all localized mainly at the apical membrane. Exogenous CNTF, CT1, or OsM induces STAT3 phosphorylation, and OsM also induces the phosphorylation of ERK1/2 (p44/42 MAP kinase). CNTF increases RPE survivability, but not rates of phagocytosis. CNTF increases secretion of NT3 to the apical bath and decreases that of VEGF, IL8, and TGFß2. It also significantly increases fluid absorption (J(V)) across intact monolayers of hfRPE by activating CFTR chloride channels at the basolateral membrane. CNTF induces profound changes in RPE cell biology, biochemistry, and physiology, including the increase in cell survival, polarized secretion of cytokines/neurotrophic factors, and the increase in steady-state fluid absorption mediated by JAK/STAT3 signaling. In vivo, these changes, taken together, could serve to regulate the microenvironment around the distal retinal/RPE/Bruch's membrane complex and provide protection against neurodegenerative disease.