Latest Asthma Research, September 24

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Toups, M.M., Press, V.G., and A. Volerman. National Analysis of State Health Policies on Students' Right to Self-Carry and Self-Administer Asthma Inhalers at School. Journal of School Health. Oct 2018; 88(10): 776-784. doi: 10.1111/josh.12681.

  • BACKGROUND: Asthma has no known cure, and though manageable, it disrupts the everyday lives of over 6 million US children. Because children spend more than half of their waking hours in school, students must be able to carry and administer their inhaler at school to manage their asthma.

  • METHODS: This policy paper is a comprehensive review of all 50 states and the District of Columbia's laws and policies for the self-carry and administration of quick-relief asthmainhalers among children in prekindergarten through 12th grade. RESULTS: All states permit students to carry and administer their inhalers at school, although each state differs in their development and implementation of policies for asthma self-management at school. This review examines how states regulate self-carry policies by looking at policy development, regulated school systems, relevant stakeholders, required medical records, and school liability.

  • CONCLUSIONS: Each state's laws have nuances that create gray areas, increasing the potential of misinterpreted or incorrectly implemented policies for asthma self-management at school. As a result, children may not have immediate access to their inhaler for symptom management or in an emergency. State policymakers should reform current laws to remove barriers for students to carry and use inhalers at school.

Teixeira, Samantha and Anita Zuberi. Neighborhood Social and Environmental Factors and Asthma Among Children Living in Low-Income Neighborhoods: The Importance of Informal Social Control. Family and Community Health. Oct/Dec 2018; 41(4): 214-224.  doi: 10.1097/FCH.0000000000000202.

  • Despite the knowledge that children in low-income neighborhoods are particularly vulnerable to asthma, few studies of child asthma focus on variation among low-income neighborhoods. We examined the relationship between child asthma and features associated with neighborhood poverty including safety, social cohesion, informal social control, collective efficacy, and disorder, across a sample of children from low-income neighborhoods (N = 3010; 2005-2007). Results show that the relationship between asthma and poverty is accounted for by family-level characteristics, but informal social control remains significantly and positively related to asthma after accounting for family-level characteristics. We discuss the importance of neighborhood environmental features for children's asthma.

Reynolds, K.C., et al. Featured Article: Multiple Comorbid Conditions, Sleep Quality and Duration, and Academic Performance in Urban Children With Asthma. Journal of Pediatric Psychology. Oct 2018; 43(9): 943-954. doi: 10.1093/jpepsy/jsy027.

  • OBJECTIVE: Common comorbid medical conditions including allergic rhinitis (AR), obesity, and sleep disordered breathing (SDB) have been linked with asthma exacerbations; however, these conditions also impact sleep and academic functioning. The current study sought to examine unique and combined associations of these common comorbidities on sleep and academic performance among urban minority children with persistent asthma. We expected additional comorbid diagnoses would be associated with poorer sleep and academic functioning.

  • METHOD: Urban children 7-9 years old (n = 249) with persistent asthma from African American, Latino, and non-Latino White backgrounds participated in this cross-sectional study. Asthma and AR were assessed using guidelines-based approaches. Overweight/obesity was assessed using body mass index and parents reported on SDB risk. Sleep quality (sleep efficiency) and sleep duration were assessed via 4 weeks of actigraphy. A cumulative risk index (CRI) score of asthma-related comorbidities (i.e., number of comorbidities for which each child met criteria) was calculated.

  • RESULTS: Comorbid conditions were prevalent (AR, 85%; overweight/obese, 39%; SDB risk, 44%). Lower SDB risk and better AR control were both associated with fewer school absences. A higher CRI score was associated with shorter sleep duration and more absences. For children with 1 comorbid condition, better lung function was associated with better sleep efficiency.

  • CONCLUSION: Findings suggest increased risk of shorter sleep and more frequent school absences among urban minority children with asthma and more comorbid conditions. Assessment and treatment of this high-risk group must consider how comorbid conditions exacerbate children's asthma and may affect sleep and daytime functioning.

Shaffo, F.C., et al. Mechanisms of organophosphorus pesticide toxicity in the context of airway hyperreactivity and asthma. American Journal of Physiology: Lung Cellular and Molecular Physiology. Oct 2018; 315(4): L485-L501. doi: 10.1152/ajplung.00211.2018.

  • Numerous epidemiologic studies have identified an association between occupational exposures to organophosphorus pesticides (OPs) and asthma or asthmatic symptoms in adults. Emerging epidemiologic data suggest that environmentally relevant levels of OPs may also be linked to respiratory dysfunction in the general population and that in utero and/or early life exposures to environmental OPs may increase risk for childhood asthma. In support of a causal link between OPs and asthma, experimental evidence demonstrates that occupationally and environmentally relevant OP exposures induce bronchospasm and airway hyperreactivity in preclinical models. Mechanistic studies have identified blockade of autoinhibitory M2 muscarinic receptors on parasympathetic nerves that innervate airway smooth muscle as one mechanism by which OPs induce airway hyperreactivity, but significant questions remain regarding the mechanism(s) by which OPs cause neuronal M2 receptor dysfunction and, more generally, how OPs cause persistent asthma, especially after developmental exposures. The goals of this review are to 1) summarize current understanding of OPs in asthma; 2) discuss mechanisms of OP neurotoxicity and immunotoxicity that warrant consideration in the context of OP-induced airway hyperreactivity and asthma, specifically, inflammatory responses, oxidative stress, neural plasticity, and neurogenic inflammation; and 3) identify critical data gaps that need to be addressed in order to better protect adults and children against the harmful respiratory effects of low-level OP exposures.

Di Cicco, M., et al. Does lung microbiome play a causal or casual role in asthma? Pediatric Pulmonolgy. Oct 2018; 53(1): 1340-1345.  doi: 10.1002/ppul.24086. 

  • Asthma is the most common chronic disease in childhood. The pathogenesis of asthma is multifactorial and is thought to include environmental factors interacting with genetics during pregnancy and in the first years of life. In the last decades, a possible role of gut microbiota in allergic disease pathogenesis has been demonstrated. Next generation sequencing techniques have allowed the identification of a distinct microbiome in the healthy lungs. The lung microbiome is characterized by the prevalence of bacteria belonging to the phylum Bacteroidetes (mostly Prevotella and Veilonella spp) in healthy subjects and to the phylum Proteobacteria in asthmatics (mostly Haemophilus, Moraxella, and Neisseria spp). In asthma, as well as in other diseases, the lung microbiome composition changes due to a disruption of the delicate balance between immigration and elimination of bacteria. The lung microbiome can interact with the immune system, thus influencing inflammation. Early infections with viruses, such as respiratory syncytial virus, may alter lung microbiome composition favoring the emergence of Proteobacteria, a phylum which is also linked to severity of asthma and bronchial hyperreactivity. Lastly, antibiotics may alter the gut and lung microbiota and potentially disturb the relationship between microbiota and host. Therefore, antibiotics should be prescribed with increasing awareness of their potential harmful effect on the microbiota in young children with and without asthma. The potential effects of probiotics and prebiotics on lung microbiome are unknown.

Han, Y.Y., et al. Exposure to polycyclic aromatic hydrocarbons, vitamin D, and lung function in children with asthma. Pediatric Pulmonolgy. Oct 2018; 53(10): 1362-1368. doi: 10.1002/ppul.24084. 

  • BACKGROUND: It is unclear whether exposure to polycyclic aromatic hydrocarbons (PAH) affects lung function in children with asthma. Whether vitamin D insufficiency enhances any detrimental effects of PAH on lung function in asthmatic children is also unknown.

  • METHODS: Cross-sectional study of 1,821 children (6-17 years) who participated in the 2007-2012 National Health and Nutrition Examination Survey. Multivariable linear regression was used to analyze the relation between molar mass of urinary PAH metabolites (sum of all PAH (ΣmolPAH), sum of PAH with 2 benzene rings (Σmol2-PAH), or sum of PAH with 3 or 4 benzene rings (Σmol3,4-PAH)) and lung function or exhaled fraction of nitric oxide (FeNO) in children with and without asthma. In this multivariable analysis, we tested whether vitamin D insufficiency (a serum 25(OH)D level <30 ng/mL) interacts with PAH exposure on lung function in children with asthma.

  • RESULTS: Children in the highest quartiles of urinary Σmol3,4-PAH had 2.3 times increased odds of asthma than those in the lowest quartile of Σmol3,4-PAH. Urinary PAH were not associated with lung function in children with or without asthma. Given a significant interaction between vitamin D insufficiency and PAH metabolites on lung function in asthmatic children, we stratified the analysis by vitamin D status. In this analysis, urinary PAH metabolites were significantly associated with 2.7-3.9% reduced %predicted FEV1 and %predicted FEV1/FVC in children with asthma and vitamin D insufficiency, but not in those with asthma and vitamin D sufficiency.

  • CONCLUSIONS: Vitamin D insufficiency and PAH exposure may have synergistic detrimental effects on lung function in asthmatic children.

Fazlollahi, Mina, et al. The nasal microbiome in asthma. Journal of Allergy and Clinical Immunology. Sept 2108; 142(3): 834-843.e2. https://doi.org/10.1016/j.jaci.2018.02.020

  • BACKGROUND: Nasal microbiota may influence asthma pathobiology.

  • OBJECTIVE: We sought to characterize the nasal microbiome of subjects with exacerbated asthma, nonexacerbated asthma, and healthy controls to identify nasal microbiota associated with asthma activity.

  • METHODS: We performed 16S ribosomal RNA sequencing on nasal swabs obtained from 72 primarily adult subjects with exacerbated asthma (n = 20), nonexacerbated asthma (n = 31), and healthy controls (n = 21). Analyses were performed using Quantitative Insights into Microbial (QIIME); linear discriminant analysis effect size (LEfSe); Phylogenetic Investigation of Communities by Reconstruction of Unobserved States; and Statistical Analysis of Metagenomic Profiles (PICRUSt); and Statistical Analysis of Metagenomic Profiles (STAMP). Species found to be associated with asthma activity were validated using quantitative PCR. Metabolic pathways associated with differentially abundant nasal taxa were inferred through metagenomic functional prediction.

  • RESULTS: Nasal bacterial composition significantly differed among subjects with exacerbated asthma, nonexacerbated asthma, and healthy controls (permutational multivariate ANOVA, P = 2.2 × 10 −2 ). Relative to controls, the nasal microbiota of subjects with asthma were enriched with taxa from Bacteroidetes (Wilcoxon-Mann-Whitney, r = 0.33, P = 5.1 × 10 −3 ) and Proteobacteria ( r = 0.29, P = 1.4 × 10 −2 ). Four species were differentially abundant based on asthma status after correction for multiple comparisons: Prevotella buccalis , P adj = 1.0 × 10 −2 ; Dialister invisus , P adj = 9.1 × 10 −3 ; Gardnerella vaginalis , P adj = 2.8 × 10 −3 ; Alkanindiges hongkongensis , P adj = 2.6 × 10 −3 . These phyla and species were also differentially abundant based on asthma activity (exacerbated asthma vs nonexacerbated asthma vs controls). Quantitative PCR confirmed species overrepresentation in asthma relative to controls for Prevotella buccalis (fold change = 130, P = 2.1 × 10 −4 ) and Gardnerella vaginalis (fold change = 160, P = 6.8 × 10 −4 ). Metagenomic inference revealed differential glycerolipid metabolism (Kruskal-Wallis, P = 1.9 × 10 −4 ) based on asthma activity. CONCLUSIONS: Nasal microbiome composition differs in subjects with exacerbated asthma, nonexacerbated asthma, and healthy controls. The identified nasal taxa could be further investigated for potential mechanistic roles in asthma and as possible biomarkers of asthma activity.

Holt, Patrick G., et al. Developmental regulation of type 1 and type 3 IFN production and risk for infant infections and asthma development. Journal of Allergy and Clinical Immunology. Sept 2018. doi: 10.1016/j.jaci.2018.08.035 [e-pub ahead of print].

  • Virus-associated febrile lower respiratory tract infections (fLRI) during infancy have been identified as risk factors for persistent wheeze development. We hypothesized that variations in innate immune defence capacity during this period, exemplified by production of types 1 and 3 interferons (T1/3IFNs), may be an underlying determinant of risk. To investigate relationships between postnatal development of innate interferon response capacity and susceptibility to early infections and persistent wheeze. We studied a subset of subjects from a birth cohort at high risk for asthma/allergy, and determined capacity of cord blood cells (n=151) to produce any of a panel of 17 T1/3IFNs in response to the viral mimic poly(I:C), employing a sensitive PCR assay. We investigated relationships between neonatal interferon responses and lower respiratory infection history during infancy, wheezing history to 5Yrs, and ensuing maturation of innate immune capacity by 4Yrs (n=160) and 10Yrs (n=125). While cohort subjects produced on average 2.6±0.3 of the 17 innate IFNs tested at birth, 24% showed no T1/3IFN production. This non-producer subgroup showed increased risk for infant fLRI (OR 2.62[1.14-6.06]p=0.024) and persistent wheeze (OR 4.24[1.60-11.24]p=0.004) at age 5Yrs relative to those producing ≥1 T1/3IFNs, whereas risk for infant wheezy LRI or "transient early wheeze" was unaffected. Moreover, infants who experienced fLRI subsequently demonstrated accelerated development of T1/3IFN response capacity between 1Yr and 4Yrs. T1/3IFN response capacity appears strongly developmentally constrained at birth. Infants in whom this negative regulation is strongest manifest increased risk for severe respiratory infections during infancy and subsequent persistent wheeze.

Martenies, Sheen E. and Stuart A. Batterman. Effectiveness of Using Enhanced Filters in Schools and Homes to Reduce Indoor Exposures to PM2.5 from Outdoor Sources and Subsequent Health Benefits for Children with Asthma. Environmental Science & Technology. Sept 2018; 52(18): 10767-10776. doi: 10.1021/acs.est.8b02053

  • Filters can reduce indoor concentrations of particulate matter (PM2.5), but their benefits have not been well-characterized. This study investigates exposure, health, and cost impacts of high efficiency filters in homes and schools, focusing on the asthma-related outcomes. Reductions in indoor exposures to PM2.5 from outdoor sources with enhanced filters (e.g., MERV 12) are estimated using probabilistic indoor air quality models, and avoided health impacts are quantified using health impact assessment. These methods are applied using data from Detroit, Michigan, an urban region with elevated asthma rates. Replacing inefficient filters with enhanced filters in schools would reduce the PM2.5-attributable asthma burden by 13% annually, with higher benefits for more efficient filters. Marginal costs average $63 per classroom or $32 per child with asthma per year. In homes, using efficient furnace filters or air cleaners yields 11 to 16% reductions in the asthma burden with an annualized marginal costs of $151-494 per household. Additional benefits include reductions in health risk for adults and lower exposures to other contaminants such as PM from indoor sources. On the basis of the included health outcomes, efficient filters in schools in particular is a potentially cost-efficient way to reduce the asthma-related health burden for children.

Bernstein, J.A. and L. Mansfield. Step-up and step-down treatments for optimal asthma control in children and adolescents. Journal of Asthma. Sept 2018: 1-13. doi: 10.1080/02770903.2018.1490752. [Epub ahead of print]

  • OBJECTIVE: To review therapeutic options for stepwise management of pediatric asthma in the context of this population's unique needs such as potential effects of asthma, treatments, or both on growth and psychosocial development, and caregiver involvement.

  • DATA SOURCES AND STUDY SELECTION: We conducted PubMed searches to identify relevant articles then reviewed resultant articles, guidelines for asthma management in children, and articles from personal files.

  • RESULTS: Stepwise management of asthma, similar to adults, is recommended for children in current global and US guidelines. Treatment may be stepped up or stepped down temporarily or long-term based on response over time. Inhaled corticosteroids remain the recommended treatment for persistent childhood asthma and any potential small effects on growth are considered relatively minor compared with their benefit. Controller medication options for patients <18 years old are limited, especially for Global Initiative for Asthma Steps 2-5. The long-acting antimuscarinic antagonist tiotropium (Steps 4/5, patients aged ≥12 years) and in certain circumstances (Step 5), anti-immunoglobulin E (aged ≥6 years) and interleukin-5 antibodies (aged ≥12 years) are newer treatment options. Tiotropium is indicated in the United States and Europe for patients ≥6 years old. Stepping down treatment, which is recommended but infrequently practiced, can maintain symptom control and minimize adverse events while substantially reducing costs. Patient education and better monitoring remain important for self-management and optimum outcomes.

  • CONCLUSION: A need exists to target individual treatment goals for children with asthma by using step-up and step-down approaches to maximize treatment benefits and minimize potential adverse effects.

Sonney, Jennifer, et al. Applying Human-Centered Design to the Development of an Asthma Essentials Kit for School-Aged Children and Their Parents. Journal of Pediatric Health Care. Sept 2018; pii: S0891-5245(18)30346-8. doi: 10.1016/j.pedhc.2018.07.008. [e-pub ahead of print]

  • This study aimed to design and test an asthma essentials kit to support parent-child shared asthma management. Fourteen children (age range = 7-11 years) with asthma and their parents participated in this study. Development of the asthma essentials kit involved a generative phase, focused on understanding and designing to meet user needs, and an evaluative phase, which entailed narrowing, evaluating, and refining the asthma essentials kit. As is typical in human-centered design, analysis was iterative throughout the design process such that findings informed each subsequent phase. The final asthma essentials kit concepts collectively addressed the three user-identified priorities: roles and responsibilities, desire for normalcy, and shared asthma management. Concept prototypes included a to-go bag, cue card, wearable device, and mobile health application. Usability and acceptability testing showed that the asthma essentials kit prototypes were highly useful, acceptable, and easy to navigate. Human-centered design holds promise in developing interventions to meet user needs.

Mensah, George A., Kiley, James P, and Gary H. Gibbons. Generating evidence to inform an update of asthma clinical practice guidelines: Perspectives from the National Heart, Lung, and Blood Institute. Journal of Asthma and Clinical Immunology. Sept 2018; 142(3): 744-748. https://doi.org/10.1016/j.jaci.2018.07.004

  • Asthma is the most prevalent chronic respiratory disease worldwide. Its increasing prevalence and evidence of suboptimal control require renewed efforts in the development and widespread implementation of clinical practice guidelines for prevention, treatment, and control. Given the rapidly changing landscape and evolving best practices for guideline development, the National Heart, Lung, and Blood Institute made a commitment to support rigorous systematic evidence reviews that frontline health care providers and stakeholders could use to create new or update existing guidelines. This article describes the protocols, key questions, methodology, and analytic framework to support the update of the 2007 National Asthma Education and Prevention Program Expert Panel Report 3 (EPR-3) on the diagnosis and management of asthma in adults and children. It also describes the expert panel's practical experience in managing asthmatic patients across the age and severity spectrum. The article explains the process for ensuring that the expert panel's deliberations are conducted in accordance with the Institute of Medicine's standards and recommendations for guideline development. The outcome of this ambitious effort will be an update of the EPR-3 asthma guidelines and publication of the key recommendations in the Journal of Allergy and Clinical Immunology. Importantly, several novel approaches will be explored and incorporated as appropriate to accelerate adoption and sustained implementation of the guidelines.

Stein, Michelle M., et al. A decade of research on the 17q12-21 asthma locus: Piecing together the puzzle. Journal of Allery and Clinical Immunology. Sept 2018; 142(3): 749-764.e3. https://doi.org/10.1016/j.jaci.2017.12.974

  • Chromosome 17q12-21 remains the most highly replicated and significant asthma locus. Genotypes in the core region defined by the first genome-wide association study correlate with expression of 2 genes, ORM1-like 3 (ORMDL3) and gasdermin B (GSDMB) , making these prime candidate asthma genes, although recent studies have implicated gasdermin A (GSDMA) distal to and post-GPI attachment to proteins 3 (PGAP3) proximal to the core region as independent loci. We review 10 years of studies on the 17q12-21 locus and suggest that genotype-specific risks for asthma at the proximal and distal loci are not specific to early-onset asthma and mediated by PGAP3 , ORMDL3 , and/or GSDMA expression. We propose that the weak and inconsistent associations of 17q single nucleotide polymorphisms with asthma in African Americans is due to the high frequency of some 17q alleles, the breakdown of linkage disequilibrium on African-derived chromosomes, and possibly different early-life asthma endotypes in these children. Finally, the inconsistent association between asthma and gene expression levels in blood or lung cells from older children and adults suggests that genotype effects may mediate asthma risk or protection during critical developmental windows and/or in response to relevant exposures in early life. Thus studies of young children and ethnically diverse populations are required to fully understand the relationship between genotype and asthma phenotype and the gene regulatory architecture at this locus.

Verma, Mukesh, et al. Experimental asthma persists in IL-33 receptor knockout mice because of the emergence of thymic stromal lymphopoietin–driven IL-9 + and IL-13 + type 2 innate lymphoid cell subpopulations. Journal of Allergy and Clinical Immunology. Sept 2018; 142(3): 793-803.e8.

  • BACKGROUND: IL-33 plays an important role in the development of experimental asthma. OBJECTIVE: We sought to study the role of the IL-33 receptor suppressor of tumorigenicity 2 (ST2) in the persistence of asthma in a mouse model.

  • METHODS: We studied allergen-induced experimental asthma in ST2 knockout (KO) and wild-type control mice. We measured airway hyperresponsiveness by using flexiVent; inflammatory indices by using ELISA, histology, and real-time PCR; and type 2 innate lymphoid cells (ILC2s) in lung single-cell preparations by using flow cytometry.

  • RESULTS: Airway hyperresponsiveness was increased in allergen-treated ST2 KO mice and comparable with that in allergen-treated wild-type control mice. Peribronchial and perivascular inflammation and mucus production were largely similar in both groups. Persistence of experimental asthma in ST2 KO mice was associated with an increase in levels of thymic stromal lymphopoietin (TSLP), IL-9, and IL-13, but not IL-5, in bronchoalveolar lavage fluid. Expectedly, ST2 deletion caused a reduction in IL-13 + CD4 T cells, forkhead box P3–positive regulatory T cells, and IL-5 + ILC2s. Unexpectedly, ST2 deletion led to an overall increase in innate lymphoid cells (CD45 + lin − CD25 + cells) and IL-13 + ILC2s, emergence of a TSLP receptor–positive IL-9 + ILC2 population, and an increase in intraepithelial mast cell numbers in the lung. An anti-TSLP antibody abrogated airway hyperresponsiveness, inflammation, and mucus production in allergen-treated ST2 KO mice. It also caused a reduction in innate lymphoid cell, ILC2, and IL-9 + and IL-13 + ILC2 numbers in the lung.

  • CONCLUSIONS: Genetic deletion of the IL-33 receptor paradoxically increases TSLP production, which stimulates the emergence of IL-9 + and IL-13 + ILC2s and mast cells and leads to development of chronic experimental asthma. An anti-TSLP antibody abrogates all pathologic features of asthma in this model.

Skevaki, Chysanthi, et al. Influenza-derived peptides cross-react with allergens and provide asthma protection. Journal of Allergy and Clinical Immunology. Sept 2018; 142(3): 804-814.

  • BACKGROUND: The hygiene hypothesis is the leading concept to explain the current asthma epidemic, which is built on the observation that a lack of bacterial contact early in life induces allergic T H 2 immune responses.

  • OBJECTIVE: Because little is known about the contribution of respiratory tract viruses in this context, we evaluated the effect of prior influenza infection on the development of allergic asthma.

  • METHODS: Mice were infected with influenza and, once recovered, subjected to an ovalbumin- or house dust mite–induced experimental asthma protocol. Influenza-polarized effector memory T (Tem) cells were transferred adoptively to allergen-sensitized animals before allergen challenge. A comprehensive in silico analysis assessed homologies between virus- and allergen-derived proteins. Influenza-polarized Tem cells were stimulated ex vivo with candidate peptides. Mice were immunized with a pool of virus-derived T-cell epitopes.

  • RESULTS: In 2 murine models we found a long-lasting preventive effect against experimental asthma features. Protection could be attributed about equally to CD4 + and CD8 + Tem cells from influenza-infected mice. An in silico bioinformatic analysis identified 4 influenza- and 3 allergen-derived MHC class I and MHC class II candidate T-cell epitopes with potential antigen-specific cross-reactivity between influenza and allergens. Lymphocytes from influenza-infected mice produced IFN-γ and IL-2 but not IL-5 on stimulation with the aforementioned peptides. Immunization with a mixture of the influenza peptides conferred asthma protection, and peptide-immunized mice transferred protection through CD4 + and CD8 + Tem cells.

  • CONCLUSION: For the first time, our results illustrate heterologous immunity of virus-infected animals toward allergens. This finding extends the original hygiene hypothesis.

Andre-Gregoire, Gwennan, et al. Targeting of Rac1 prevents bronchoconstriction and airway hyperresponsiveness. Journal of Allergy and Clinical Immunology. Sept 2018; 142(3): 824-833.e3. https://doi.org/10.1016/j.jaci.2017.09.049

  • BACKGROUND: The molecular mechanisms responsible for airway smooth muscle cells' (aSMCs) contraction and proliferation in airway hyperresponsiveness (AHR) associated with asthma are still largely unknown. The small GTPases of the Rho family (RhoA, Rac1, and Cdc42) play a central role in SMC functions including migration, proliferation, and contraction.

  • OBJECTIVE: The objective of this study was to identify the role of Rac1 in aSMC contraction and to investigate its involvement in AHR associated with allergic asthma.

  • METHODS: To define the role of Rac1 in aSMC, ex and in vitro analyses of bronchial reactivity were performed on bronchi from smooth muscle (SM)-specific Rac1 knockout mice and human individuals. In addition, this murine model was exposed to allergens (ovalbumin or house dust mite extract) to decipher in vivo the implication of Rac1 in AHR. RESULTS: The specific SMC deletion or pharmacological inhibition of Rac1 in mice prevented the bronchoconstrictor response to methacholine. In human bronchi, a similar role of Rac1 was observed during bronchoconstriction. We further demonstrated that Rac1 activation is responsible for bronchoconstrictor-induced increase in intracellular Ca2+ concentration and contraction both in murine and in human bronchial aSMCs, through its association with phospholipase C β2 and the stimulation of inositol 1,4,5-trisphosphate production. In vivo, Rac1 deletion in SMCs or pharmacological Rac1 inhibition by nebulization of NSC23766 prevented AHR in murine models of allergic asthma. Moreover, nebulization of NSC23766 decreased eosinophil and neutrophil populations in bronchoalveolar lavages from mice with asthma.

  • CONCLUSIONS: Our data reveal an unexpected and essential role of Rac1 in the regulation of intracellular Ca2+ and contraction of aSMCs, and the development of AHR. Rac1 thus appears as an attractive therapeutic target in asthma, with a combined beneficial action on both bronchoconstriction and pulmonary inflammation.

Lam, Phoebe H., et al. Family obligations and asthma in youth: The moderating role of socioeconomic status. Health Psychology. Sept 2018; 37(10): 968-978. http://dx.doi.org/10.1037/hea0000655

  • OBJECTIVE: Fulfilling family obligations—providing instrumental help to and spending time with family—is a common aspect of family relationships. However, whether fulfilling these obligations links with physical health remains unclear. In this study, we investigated whether fulfilling family obligations was associated with asthma outcomes among youth, and whether these associations differed depending on family socioeconomic status (SES).

  • METHOD: Participants were 172 youth, 8 to 17 years of age (Mage = 12.1; 54% boys) who had been physician-diagnosed with asthma and reported on family-obligation frequency; completed the Asthma Control Test (ACT; Nathan et al., 2004), a clinical measure of asthma control; and completed a measure of airway inflammation (i.e., fractional exhaled nitric oxide). Parents also completed the ACT in reference to their asthmatic children and reported on family income.

  • RESULTS: Fulfilling family obligations was not associated with asthma outcomes (βs< .14, ps >.075). However, SES (family income) interacted with family obligations, such that fulfilling family obligations was associated with greater airway inflammation (interaction term β = −.17, p = .023) and poorer parent-reported asthma control (interaction term β = .15, p = .039), only among youth from lower SES backgrounds. Exploratory analyses suggest that these interactions were robust against covariates and were largely consistent across age and the two dimensions of family-obligation behaviors.

  • CONCLUSION: Findings from this study suggest that among youth from lower SES backgrounds, engaging in more frequent family-obligation behaviors may have negative repercussions in terms of their asthma. 

Dumas, Orianne, et al. Severe Bronchiolitis Profiles and Risk of Developing Recurrent Wheezing by Age 3 Years. Journal of Allergy and Clinical Immunology. Sept 2018; pii: S0091-6749(18)31296-X. doi: 10.1016/j.jaci.2018.08.043. [e-pub ahead of print]

  • BACKGROUND: A better understanding of bronchiolitis heterogeneity may help clarify its relationship with the development of recurrent wheezing and asthma.

  • OBJECTIVES: To identify severe bronchiolitis profiles by a clustering approach, and to investigate for the first time their association with allergy/inflammatory biomarkers; nasopharyngeal microbiota; and development of recurrent wheezing by age 3 years.

  • METHODS: We analyzed data from a prospective, 17-center U.S. cohort study of 921 infants (age <1 year) hospitalized with bronchiolitis (2011-2014 winters) with post-hospitalization follow-up. Severe bronchiolitis profiles at baseline (hospitalization) were determined by latent class analysis, based on clinical factors and viral etiology. Blood biomarkers and nasopharyngeal microbiota profiles were determined using samples collected within 24h of hospitalization. Recurrent wheezing by age 3 years was defined based on parental report of breathing problem episodes post-discharge. RESULTS: Three severe bronchiolitis profiles were identified: profile A (15%), characterized by history of breathing problems/eczema during infancy and non-RSV (mostly rhinovirus) infection; profile B (49%) with the largest probability of RSV infection and which resembled classic RSV-bronchiolitis; and profile C (36%), the most severely ill group. Profile A infants had higher eosinophil counts, higher cathelicidin levels, and elevated proportions of Haemophilus-dominant or Moraxella-dominant microbiota profile. Compared to profile B, we observed significantly increased risk of developing recurrent wheezing in children with profile A (hazard ratio 2.64; 95% CI 1.90-3.68), and, to a lesser extent, with profile C (1.51; 1.14-2.01).

  • CONCLUSION: Although longer follow-up is needed, our results may help identify, among childrenhospitalized for bronchiolitis, subgroups with particularly elevated risk of developing asthma.

Rhinitis in Children and Adolescents with Asthma: Ubiquitous, Difficult to Control, and Associated with Asthma Outcomes. Journal of Asthma and Clinical Immunology. Sept 2018; ii: S0091-6749(18)31282-X. doi: 10.1016/j.jaci.2018.07.041. [Epub ahead of print]

  • BACKGROUND: Rhinitis and asthma are linked, but substantial knowledge gaps in this relationship exist.

  • OBJECTIVE: To determine the prevalence of rhinitis and its phenotypes in children and adolescents with asthma, assess symptom severity and medication requirements for rhinitis control, and investigate associations between rhinitis and asthma.

  • METHODS: 749 children with asthma participating in the Asthma Phenotypes in the Inner-City study received baseline evaluations and were managed for 1 year with algorithm-based treatments for rhinitis and asthma. Rhinitis was diagnosed by questionnaire focusing on individual symptoms, and pre-defined phenotypes were determined by combining symptom patterns with skin testing and serum specific IgE. RESULTS: Analyses were done on 619 children with asthma who completed at least 4 of 6 visits. Rhinitis was present in 93.5%, and phenotypes identified at baseline were confirmed during the observation/management year. Perennial allergic rhinitis with seasonal exacerbations (PARSE) was most common (34.2%) and severe. Nonallergic rhinitis was least common (11.2%) and least severe. The majority of children remained symptomatic despite the use of nasal corticosteroids ± oral antihistamines. Rhinitis was worse in difficult-to-control vs. easy-to-control asthma and its seasonal patterns partially corresponded to those of difficult-to-control asthma.

  • CONCLUSION: Rhinitis is almost ubiquitous in urban children with asthma, and its activity tracks that of lower airway disease. PARSE is the most severe phenotype and most likely to be associated with difficult-to-control asthma. This study offers strong support to the concept that rhinitis and asthma represent the manifestations of one disease in two parts of the airways.

Kuzeniewicz, M.W., et al. Hyperbilirubinemia, Phototherapy, and Childhood Asthma. Pediatrics. Sept 2018; pii: e20180662. doi: 10.1542/peds.2018-0662. [Epub ahead of print]

  • OBJECTIVES: Our aim was to quantify the associations of both hyperbilirubinemia and phototherapy with childhood asthma using a population-based cohort with total serum bilirubin (TSB) levels.

  • METHODS: Retrospective cohort study of infants born at ≥35 weeks' gestation in the Kaiser Permanente Northern California health system (n = 109 212) from 2010 to 2014. Cox models were used to estimate hazard ratios (HRs) for a diagnosis of asthma.

  • RESULTS: In the study, 16.7% of infants had a maximum TSB level of ≥15 mg/dL, 4.5% of infants had a maximum TSB level of ≥18 mg/dL, and 11.5% of infants received phototherapy. Compared with children with a maximum TSB level of 3 to 5.9 mg/L, children with a TSB level of 9 to 11.9 mg/dL, 12 to 14.9 mg/dL, and 15 to 17.9 mg/dL were at an increased risk for asthma (HR: 1.22 [95% confidence interval (CI): 1.11-1.3], HR: 1.18 [95% CI: 1.08-1.29], and HR: 1.30 [95% CI: 1.18-1.43], respectively). Children with a TSB level of ≥18 mg/dL were not at an increased risk for asthma (HR: 1.04; 95% CI: 0.90-1.20). In propensity-adjusted analyses, phototherapy was not associated with asthma (HR: 1.07; 95% CI: 0.96-1.20).

  • CONCLUSIONS: Modest levels of hyperbilirubinemia were associated with an increased risk of asthma, but an association was not seen at higher levels. No dose-response relationship was seen. Using phototherapy to prevent infants from reaching these modest TSB levels is unlikely to be protective against asthma.

Spear, M.L., et al. A genome-wide association and admixture mapping study of bronchodilator drug response in African Americans with asthma. Pharmacogenomics Journal. Sept 2018. doi: 10.1038/s41397-018-0042-4. [Epub ahead of print]

  • Short-acting β2-adrenergic receptor agonists (SABAs) are the most commonly prescribed asthma medications worldwide. Response to SABAs is measured as bronchodilator drug response (BDR), which varies among racial/ethnic groups in the United States. However, the genetic variation that contributes to BDR is largely undefined in African Americans with asthma. To identify genetic variants that may contribute to differences in BDR in African Americans with asthma, we performed a genome-wide association study (GWAS) of BDR in 949 African American children with asthma, genotyped with the Axiom World Array 4 (Affymetrix, Santa Clara, CA) followed by imputation using 1000 Genomes phase III genotypes. We used linear regression models adjusting for age, sex, body mass index (BMI) and genetic ancestry to test for an association between BDR and genotype at single-nucleotide polymorphisms (SNPs). To increase power and distinguish between shared vs. population-specific associations with BDR in children with asthma, we performed a meta-analysis across 949 African Americans and 1830 Latinos (total = 2779). Finally, we performed genome-wide admixture mapping to identify regions whereby local African or European ancestry is associated with BDR in African Americans. We identified a population-specific association with an intergenic SNP on chromosome 9q21 that was significantly associated with BDR (rs73650726, p = 7.69 × 10-9). A trans-ethnic meta-analysis across African Americans and Latinos identified three additional SNPs within the intron of PRKG1 that were significantly associated with BDR (rs7903366, rs7070958 and rs7081864, p ≤ 5 × 10-8). Our results failed to replicate in three additional populations of 416 Latinos and 1615 African Americans. Our findings indicate that both population-specific and shared genetic variation contributes to differences in BDR in minority children with asthma, and that the genetic underpinnings of BDR may differ between racial/ethnic groups.

Ochoa, K., Richman, J., an V. J. Wang. LA phonospirometry technique compared to pediatric respiratory assessment measure and peak expiratory flow measurement as a novel technique to assess the severity of an asthma exacerbation. 12:1-5. doi: 10.1080/02770903.2018.1514046. [Epub ahead of print]

  • OBJECTIVE: Asthma is a common chronic disease treated in emergency departments. The measurements of Peak Expiratory Flow (PEF) and Pediatric Respiratory Assessment Measure (PRAM) scores have been recommended as objective techniques in the assessment of acute asthma exacerbations, but have multiple barriers limiting their use. The Los Angeles phonospirometry technique is an easier, trans-cultural technique. The technique assesses dyspnea by measuring how many seconds a child is able to chant "LA LA LA" in a single breath. The objective of this study is to determine the correlation of this technique with PEF measurements and PRAM scores in children with acute asthma exacerbations, both before and after nebulized bronchodilator treatment.

  • METHODS: A convenient sample of children aged 5-17 years being treated for asthma in the ED was enrolled. Phonospirometry, PRAM, and PEF measurements were obtained through pre and post inhaled bronchodilator treatments. The highest values from each measurement were correlated using Spearman's correlation coefficient.

  • RESULTS: A total of 91 children were enrolled. The correlations at pre-treatment, after first, second, and third treatments between phonospirometry and PEF were 0.38 (p < 0.001), 0.60 (p < 0.001), 0.54 (p < 0.001), 0.52 (p < 0.01), respectively; between phonospirometry and PRAM were -0.37 (p < 0.001), -0.42 (p < 0.001), -0.26 (p < 0.05), and -0.06 (p > 0.05), respectively; and between PEF and PRAM were -0.6 (p < 0.01), -0.54 (p < 0.001), -0.38 (p < 0.01), and -0.36 (p - 0.05), respectively.

  • CONCLUSIONS: This novel technique correlates mild to moderately with PEF, and shows promising aide in the assessment of children with acute asthma exacerbations.