[Show abstract][Hide abstract] ABSTRACT: Asthma is a common chronic disease without cure. Our understanding of asthma onset, pathobiology, classification and management has evolved substantially over the past decade; however, significant asthma-related morbidity and excess healthcare utilization and cost persist. To address this important clinical condition, the National Heart, Lung, and Blood Institute (NHLBI) convened a group of extramural investigators for an Asthma Research Strategic Planning workshop on September 18-19, 2014 to accelerate discoveries and their translation to patients. The workshop focused on (1) in utero and early life origins of asthma, (2) the use of phenotypes and endotypes to classify disease, (3) defining disease modification, (4) disease management, and (5) implementation research. This report summarizes the workshop, producing recommendations to guide future research in asthma.
American Journal of Respiratory and Critical Care Medicine 08/2015; DOI:10.1164/rccm.201505-0963WS · 13.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Severe asthma occurs more often in older adult patients. We hypothesized that the greater risk for severe asthma in older individuals is due to aging, and is independent of asthma duration.
This is a cross-sectional study of prospectively collected data from adult participants (N=1130; 454 with severe asthma) enrolled from 2002 - 2011 in the Severe Asthma Research Program.
The association between age and the probability of severe asthma, which was performed by applying a Locally Weighted Scatterplot Smoother, revealed an inflection point at age 45 for risk of severe asthma. The probability of severe asthma increased with each year of life until 45 years and thereafter increased at a much slower rate. Asthma duration also increased the probability of severe asthma but had less effect than aging. After adjustment for most comorbidities of aging and for asthma duration using logistic regression, asthmatics older than 45 maintained the greater probability of severe asthma [OR: 2.73 (95 CI: 1.96; 3.81)]. After 45, the age-related risk of severe asthma continued to increase in men, but not in women.
Overall, the impact of age and asthma duration on risk for asthma severity in men and women is greatest over times of 18-45 years of age; age has a greater effect than asthma duration on risk of severe asthma.
PLoS ONE 07/2015; 10(7):e0133490. DOI:10.1371/journal.pone.0133490 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Oxidative stress is known to play a role in critical illness due to an imbalance in reactive oxygen species and reactive nitrogen species, and the body's ability to detoxify pro-oxidants using small molecule anti-oxidants and anti-oxidant enzymes.
To compare the concentrations of plasma redox metabolites and redox potentials for the Cys/CySS and GSH/GSSG thiol/disulfide pairs in critically ill children with healthy control children.
We performed a prospective clinical observational study of children ages ≤18 years and weight ≥6 kg, who were hospitalized between January 2010 and April 2012 in a 30-bed multidisciplinary medical-surgical pediatric intensive care unit (PICU). We measured the plasma concentrations of Cys, CySS, GSH, and GSSG within the first 24 h of PICU arrival, and we calculated the redox potential for the Cys/CySS (Eh Cys/CySS) and GSH/GSSG (Eh GSH/GSSG) thiol/disulfide pairs in the plasma of 61 critically ill children and 16 healthy control children.
Critically ill children have less Cys (p = 0.009), less CySS (p = 0.011), less Total Cys ([Cys] + 2[CySS], p = 0.01), more GSSG (p < 0.001), and more oxidized Eh GSH/GSSG (p < 0.001) compared to healthy children.
Our results demonstrate that in the presence of pediatric critical illness, the Total Cys/CySS thiol pool decreases while GSH is likely one component of the cellular redox system that reduces CySS back to Cys, thus maintaining Eh Cys/CySS. The Total Cys pool is more abundant than the Total GSH pool in the plasma of children. Further investigation is needed to elucidate the differences in redox potentials in subgroups of critically ill children, and to determine whether differences in redox metabolite concentrations and redox potentials correlate with severity of critical illness and clinical outcomes.
Frontiers in Pediatrics 05/2015; 3. DOI:10.3389/fped.2015.00046
[Show abstract][Hide abstract] ABSTRACT: Although the majority of children with asthma have a favorable clinical response to treatment with low to moderate doses of inhaled corticosteroids (ICS), a small subset of children have "severe" asthma characterized by ongoing symptoms and airway inflammation despite treatment with high doses of ICS and even oral corticosteroids. Although there is symptom heterogeneity in the affected children, children with severe asthma share the risk for adverse outcomes, including recurrent and potentially life-threatening exacerbations, which contribute to substantial economic burden. This article reviews current knowledge of severe asthma in school-age children (age 6-17 years) with a focus on recent literature published after January 2012. Clinical management approaches for children with severe asthma are discussed as well as current phenotyping efforts and emerging phenotypic-directed therapies that may be of benefit for subpopulations of children with severe asthma in the future.
Current Allergy and Asthma Reports 05/2015; 15(5):521. DOI:10.1007/s11882-015-0521-5 · 2.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
The mechanisms underlying glucocorticoid responsiveness are largely unknown. Although redox regulation of the glucocorticoid receptor (GR) has been reported, it has not been studied in asthmatic patients.
We characterized systemic cysteine oxidation and its association with inflammatory and clinical features in healthy children and children with difficult-to-treat asthma. We hypothesized that cysteine oxidation would be associated with increased markers of oxidative stress and inflammation, increased features of asthma severity, decreased clinically defined glucocorticoid responsiveness, and impaired GR function.
PBMCs were collected from healthy children (n = 16) and children with asthma (n = 118) aged 6 to 17 years. Children with difficult-to-treat asthma underwent glucocorticoid responsiveness testing with intramuscular triamcinolone. Cysteine, cystine, and inflammatory chemokines and reactive oxygen species generation were quantified, and expression and activity of the GR were assessed.
Cysteine oxidation was present in children with difficult-to-treat asthma and accompanied by increased reactive oxygen species generation and increased CCL3 and CXCL1 mRNA expression. Children with the greatest extent of cysteine oxidation had more features of asthma severity, including poorer symptom control, greater medication use, and less glucocorticoid responsiveness despite inhaled glucocorticoid therapy. Cysteine oxidation also modified the GR protein by decreasing available sulfhydryl groups and decreasing nuclear GR expression and activity.
A highly oxidized cysteine redox state promotes a posttranslational modification of the GR that might inhibit its function. Given that cysteine oxidation is prevalent in children with difficult-to-treat asthma, the cysteine redox state might represent a potential therapeutic target for restoration of glucocorticoid responsiveness in this population.
Journal of Allergy and Clinical Immunology 03/2015; 136(2). DOI:10.1016/j.jaci.2015.01.023 · 11.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: S-nitrosoglutathione is an endogenous airway smooth muscle relaxant. Increased airway S-nitrosoglutathione breakdown occurs in some asthma patients. We asked whether patients with increased airway catabolism of this molecule had clinical features that distinguished them from other asthma patients. We measured S-nitrosoglutathione reductase expression and activity in bronchoscopy samples taken from 66 subjects in the Severe Asthma Research Program. We also analysed phenotype and genotype data taken from the program as a whole. Airway S-nitrosoglutathione reductase activity was increased in asthma patients (p = 0.032). However, only a subpopulation was affected and this subpopulation was not defined by a "severe asthma" diagnosis. Subjects with increased activity were younger, had higher IgE and an earlier onset of symptoms. Consistent with a link between S-nitrosoglutathione biochemistry and atopy: 1) interleukin 13 increased S-nitrosoglutathione reductase expression and 2) subjects with an S-nitrosoglutathione reductase single nucleotide polymorphism previously associated with asthma had higher IgE than those without this single nucleotide polymorphism. Expression was higher in airway epithelium than in smooth muscle and was increased in regions of the asthmatic lung with decreased airflow. An early-onset, allergic phenotype characterises the asthma population with increased S-nitrosoglutathione reductase activity.
European Respiratory Journal 10/2014; 45(1). DOI:10.1183/09031936.00042414 · 7.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Rationale: Airway hyperresponsiveness (AHR) is classically found in asthma, and persistent AHR is associated with poor asthma control. Although airway smooth muscle (ASM) cells play a critical pathophysiologic role in AHR, the paracrine contributions of surrounding cells such as fibroblasts to the contractile phenotype of ASM cells have not been examined fully. This study addresses the hypothesis that nicotine promotes a contractile ASM cell phenotype by stimulating fibroblasts to increase nerve growth factor (NGF) secretion into the environment.
PLoS ONE 10/2014; 9(10):e109602. DOI:10.1371/journal.pone.0109602 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Severe asthma in children is characterized by sustained symptoms despite treatment with high doses of inhaled corticosteroids or oral corticosteroids. Children with severe asthma may fall into 2 categories, difficult-to-treat asthma or severe therapy-resistant asthma. Difficult-to-treat asthma is defined as poor control due to an incorrect diagnosis or comorbidities, or poor adherence due to adverse psychological or environmental factors. In contrast, treatment resistant is defined as difficult asthma despite management of these factors. It is increasingly recognized that severe asthma is a highly heterogeneous disorder associated with a number of clinical and inflammatory phenotypes that have been described in children with severe asthma. Guideline-based drug therapy of severe childhood asthma is based primarily on extrapolated data from adult studies. The recommendation is that children with severe asthma be treated with higher-dose inhaled or oral corticosteroids combined with long-acting β-agonists and other add-on therapies, such as antileukotrienes and methylxanthines. It is important to identify and address the influences that make asthma difficult to control, including reviewing the diagnosis and removing causal or aggravating factors. Better definition of the phenotypes and better targeting of therapy based upon individual patient phenotypes is likely to improve asthma treatment in the future.
[Show abstract][Hide abstract] ABSTRACT: Background
Although exhaled breath condensate (EBC) pH has been identified as an “emerging” biomarker of interest for asthma clinical trials, the clinical determinants of EBC pH remain poorly understood. Other studies have associated acid reflux–induced respiratory symptoms, for example, cough, with transient acidification of EBC.
We sought to determine the clinical and physiologic correlates of EBC acidification in a highly characterized sample of children with poorly controlled asthma. We hypothesized that (1) children with asymptomatic gastroesophageal reflux determined by 24-hour esophageal pH monitoring would have a lower EBC pH than children without gastroesophageal reflux, (2) treatment with lansoprazole would alter EBC pH in those children, and (3) EBC acidification would be associated with increased asthma symptoms, poorer asthma control and quality of life, and increased formation of breath nitrogen oxides (NOx).
A total of 110 children, age range 6 to 17 years, with poor asthma control and esophageal pH data enrolled in the Study of Acid Reflux in Children with Asthma (NCT00442013) were included. Children submitted EBC samples for pH and NOx measurement at randomization and at study weeks 8, 16, and 24.
Serial EBC pH measurements failed to distinguish asymptomatic gastroesophageal reflux and was not associated with breath NOx formation. EBC pH also did not discriminate asthma characteristics such as medication and health care utilization, pulmonary function, and asthma control and quality of life both at baseline and across the study period.
Despite the relative ease of EBC collection, EBC pH as a biomarker does not provide useful information of children with asthma who were enrolled in asthma clinical trials.
[Show abstract][Hide abstract] ABSTRACT: Importance
In asthma and other diseases, vitamin D insufficiency is associated with adverse outcomes. It is not known if supplementing inhaled corticosteroids with oral vitamin D3 improves outcomes in patients with asthma and vitamin D insufficiency.Objective
To evaluate if vitamin D supplementation would improve the clinical efficacy of inhaled corticosteroids in patients with symptomatic asthma and lower vitamin D levels.Design, Setting, and Participants
The VIDA (Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma) randomized, double-blind, parallel, placebo-controlled trial studying adult patients with symptomatic asthma and a serum 25-hydroxyvitamin D level of less than 30 ng/mL was conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institute’s AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by January 2014. After a run-in period that included treatment with an inhaled corticosteroid, 408 patients were randomized.Interventions
Oral vitamin D3 (100 000 IU once, then 4000 IU/d for 28 weeks; n = 201) or placebo (n = 207) was added to inhaled ciclesonide (320 µg/d). If asthma control was achieved after 12 weeks, ciclesonide was tapered to 160 µg/d for 8 weeks, then to 80 µg/d for 8 weeks if asthma control was maintained.Main Outcomes and Measures
The primary outcome was time to first asthma treatment failure (a composite outcome of decline in lung function and increases in use of β-agonists, systemic corticosteroids, and health care).Results
Treatment with vitamin D3 did not alter the rate of first treatment failure during 28 weeks (28% [95% CI, 21%-34%] with vitamin D3 vs 29% [95% CI, 23%-35%] with placebo; adjusted hazard ratio, 0.9 [95% CI, 0.6-1.3]). Of 14 prespecified secondary outcomes, 9 were analyzed, including asthma exacerbation; of those 9, the only statistically significant outcome was a small difference in the overall dose of ciclesonide required to maintain asthma control (111.3 µg/d [95% CI, 102.2-120.4 µg/d] in the vitamin D3 group vs 126.2 µg/d [95% CI, 117.2-135.3 µg/d] in the placebo group; difference of 14.9 µg/d [95% CI, 2.1-27.7 µg/d]).Conclusions and Relevance
Vitamin D3 did not reduce the rate of first treatment failure or exacerbation in adults with persistent asthma and vitamin D insufficiency. These findings do not support a strategy of therapeutic vitamin D3 supplementation in patients with symptomatic asthma.Trial Registration
clinicaltrials.gov Identifier: NCT01248065
JAMA The Journal of the American Medical Association 05/2014; 311(20):2083. DOI:10.1001/jama.2014.5052 · 35.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Anti-microbial peptide, LL-37, is produced in response to active vitamin D to exert immunomodulatory effects and inhibits HIV replication in vitro. To date, no studies have investigated LL-37 in HIV-infected patients. This study sought to investigate LL-37 and the relationship to 25-hydroxyvitamin D (25(OH)D) and HIV-related variables in this population. Methods: HIV-infected subjects and healthy controls ages 1-25 years old were prospectively enrolled in this cross-sectional study. Fasting plasma LL-37 and 25(OH)D concentrations were measured in duplicate with ELISA. Results: HIV+ subjects (36 antiretroviral therapy (ART)-experienced; 27 ART-naïve) and 31 healthy controls were enrolled. Overall, 93% were black and median age was 20 years. There was no difference in median (interquartile range) LL-37 between the HIV-infected group and controls (58.3 (46.4,69.5) vs. 51.3 (40.8,98.2) µg/mL, respectively; P=0.57); however, ART-experienced had higher concentrations than ART-naïve (66.2 (55.4,77.0) vs. 48.9 (38.9,57.9) µg/mL, respectively; P<0.001). LL-37 was positively correlated with 25(OH)D in controls, but not in HIV-infected groups, and was positively correlated with current CD4 and ∆CD4 (current-nadir) in ART-experienced. After adjustment for age, race, sex, and HIV duration, the association between LL-37 and CD4 remained significant. Conclusions: LL-37 was associated with 25(OH)D in healthy controls but not in HIV-infected subjects. LL-37 concentrations were higher in ART-experienced compared to ART-naïve, and were associated with CD4 counts and immune restoration after treatment. These findings suggest that HIV and/or HIV-related variables may alter the expected positive relationship between vitamin D and LL-37 and should be further investigated.
AIDS research and human retroviruses 05/2014; 30(7). DOI:10.1089/AID.2013.0279 · 2.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: AsthmaSESSION TYPE: Slide PresentationsPRESENTED ON: Saturday, March 22, 2014 at 12:15 PM - 01:15 PMPURPOSE: The progression and development of asthma across the menopausal transition has not been thoroughly addressed, or clearly separated from the effects of age. The present study evaluates the effects of menopause on asthma severity, quality of life and healthcare utilization using a propensity score model.
The analyses were conducted using data from participants enrolled in the Severe Asthma Research program (SARP). Ten sites enrolled asthmatics between 2002 to 2011, and contributed a standardized set of data to a central coordinating center [AJRCCM 2012;185:356-62]. Data on 166 menopausal and 538 non-menopausal asthmatic women, older than 18 years of age was available for analyses. The effect of menopause on asthma control, asthma quality of life, and all secondary endpoints was analyzed after conducting a Propensity Score matching with subsequent multivariate analysis using conditional logistic regression to adjust for the effect of the covariates that remained unbalanced after matching. Those unbalanced covariates were: the age at enrollment, gastroesophageal reflux disease, and hypertension.
Compared to non-menopaused women, menopaused women were older, reported more gastroesophageal reflux disease, sinusitis history and used more inhaled corticosteroids. They were less likely to have atopy or test positively on skin testing. Unadjusted analysis showed that menopaused women had an odds ratio of 5.62(95 CI: 3.83; 8.26) of severe asthma compared to non-menopaused women. They were more likely to require healthcare utilization. After Propensity Score matching with subsequent multivariate adjustment menopause was neither associated with greater incidence of severe asthma [OR:1.75 (95 CI: 0.52; 5.9)], or with a worse asthma quality of life [mean difference: 0.31 (95 CI: -0.30; 0.93)].
The increased unadjusted asthma severity, increased need for treatment and health care utilization in menopaused women are more likely due to other age associated co-morbidities and/or aging dependent conditions.
In elderly women, menopause is unlikely to be the reason for increased risk of severe asthma or worse quality of life.
Suzy Comhair: Grant monies (from sources other than industry): NIH (HL69170) The following authors have nothing to disclose: Joe Zein, Eugene Bleecker, William Busse, William Calhoun, Mario Castro, K. Fan Chung, Raed Dweik, Anne Fitzpatrick, Benjamin Gaston, Elliot Israel, Nizar Jarjour, Wendy Moore, Gerald Teague, Sally Wenzel, Serpil ErzurumNo Product/Research Disclosure Information.
[Show abstract][Hide abstract] ABSTRACT: The National Heart, Lung, and Blood Institute has sponsored several asthma clinical networks, but the Severe Asthma Research Program (SARP) is unique, because it is not a clinical trials network, and it includes both adults and children. Investigators in SARP have comprehensively characterized 1,644 patients with asthma over the past 10 years, including 583 individuals with severe asthma and 300 children below the age of 18 years. The diversity in clinical characteristics, physiologic measures, and biomarkers in a large number of subjects across the ages provides an ideal cohort in which to investigate asthma heterogeneity. Using both biased and unbiased approaches, multiple asthma phenotypes have been described in SARP. These phenotypic analyses have improved our understanding of heterogeneity in asthma, and may provide a starting point to transform clinical practice through the evidence-based classification of disease severity. Although these new phenotypes strive to make order out of a heterogeneous group of patients, they are limited by that heterogeneity. There may be large groups of patients, especially those with milder asthma, that can be grouped into a clinical phenotype to guide therapy, but there will always be patients on the "edge" of a phenotype who will not fit into these groupings. In the SARP cluster analysis, subjects on the "edge" of a phenotype frequently had lung function that was better or worse than other subjects in the same cluster, despite similar clinical characteristics. This suggests that different pathophysiologic mechanisms may be responsible for decrements in lung function in some subjects. This is extremely important for subjects with severe asthma who may be on the "edge" of two phenotypes that may be driven by different pathobiologic mechanisms that warrant different therapeutic approaches.
Annals of the American Thoracic Society 12/2013; 10(Supplement):S118-S124. DOI:10.1513/AnnalsATS.201309-307AW
[Show abstract][Hide abstract] ABSTRACT: The Eunice Kennedy Shriver National Institute of Child Health and Human Development convened an Asthma Group in response to the Best Pharmaceuticals for Children Act. The overall goal of the Best Pharmaceuticals for Children Act Program is to improve pediatric therapeutics through preclinical and clinical drug trials that lead to drug-labeling changes. Although significant advances have been made in the understanding and management of asthma in adults with appropriately labeled medications, less information is available on the management of asthma in children. Indeed, many medications are inadequately labeled for use in children. In general, the younger the child, the less information there is available to guide clinicians. Because asthma often begins in early childhood, it is incumbent on us to continue to address the primary questions raised in this review and carefully evaluate the medications used to manage asthma in children. Meanwhile, continued efforts should be made in defining effective strategies that reduce the risk of exacerbations. If the areas of defined need are addressed in the coming years, namely prevention of exacerbations and progression of disease, as well as primary intervention, we will see continuing reduction in asthma mortality and morbidity along with improved quality of life for children with asthma.
The Journal of allergy and clinical immunology 11/2013; 133(1). DOI:10.1016/j.jaci.2013.10.018 · 11.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Childhood asthma clusters, or subclasses, have been developed by computational methods without evaluation of clinical utility.
To replicate and determine whether childhood asthma clusters previously identified computationally in the Severe Asthma Research Program (SARP) are associated with treatment responses in Childhood Asthma Research and Education (CARE) Network clinical trials.
A cluster assignment model was determined by using SARP participant data. A total of 611 participants 6 to 18 years old from 3 CARE trials were assigned to SARP pediatric clusters. Primary and secondary outcomes were analyzed by cluster in each trial.
CARE participants were assigned to SARP clusters with high accuracy. Baseline characteristics were similar between SARP and CARE children of the same cluster. Treatment response in CARE trials was generally similar across clusters. However, with the caveat of a smaller sample size, children in the early-onset/severe-lung function cluster had best response with fluticasone/salmeterol (64% vs 23% 2.5× fluticasone and 13% fluticasone/montelukast in the Best ADd-on Therapy Giving Effective Responses trial; P = .011) and children in the early-onset/comorbidity cluster had the least clinical efficacy to treatments (eg, -0.076% change in FEV1 in the Characterizing Response to Leukotriene Receptor Antagonist and Inhaled Corticosteroid trial).
In this study, we replicated SARP pediatric asthma clusters by using a separate, large clinical trials network. Early-onset/severe-lung function and early-onset/comorbidity clusters were associated with differential and limited response to therapy, respectively. Further prospective study of therapeutic response by cluster could provide new insights into childhood asthma treatment.
The Journal of allergy and clinical immunology 10/2013; 133(2). DOI:10.1016/j.jaci.2013.09.002 · 11.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Food allergy affects 8% of preschool children, but factors responsible for food allergy in children are poorly understood. Use of antacid medication may be a contributing factor. The purpose of this study was to determine if parent-reported antacid medication use was associated with higher prevalence of food allergy in atopic children. In this cross-sectional study, parents of children with atopic diseases completed a questionnaire relating to a history of treatment with antacid medication and food allergy. Charts were independently reviewed for food-specific IgE and/or skin-prick test results. Food allergy was defined as a reaction to a food consistent with the anaphylaxis consensus statement and either an elevated food-specific IgE or a positive food skin-prick test. One hundred four questionnaires were completed. Mean age of the participating children was 7.0 ± 4.3 years (range, 5 months to 18 years of age). Forty-seven (45%) individuals were reported to have taken an antacid medication in the past. History of taking antacid medication was associated with an increased prevalence (57% (27)/47 versus 32% (18)/57) and higher prevalence of food allergy of having food allergy (aPR, 1.7 [1.1-2.5]). Mean peanut food-specific IgE was higher in those with a history of taking antacid medication (11.0 ± 5.0 versus 2.0 ± 5.5.; p = 0.01). History of treatment with antacid medication is associated with an increased prevalence of having food allergy.