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.
Chronic alcohol abuse is a systemic disorder and a risk factor for acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD). A significant amount of ingested alcohol reaches airway passages in the lungs and can be metabolized via oxidative and non-oxidative pathways. About 90% of the ingested alcohol is metabolized via hepatic alcohol dehydrogenase (ADH)-catalyzed oxidative pathway. Alcohol can also be metabolized by cytochrome P450 2E1 (CYP2E1), particularly during chronic alcohol abuse. Both the oxidative pathways, however, are associated with oxidative stress due to the formation of acetaldehyde and/or reactive oxygen species (ROS). Alcohol ingestion is also known to cause endoplasmic reticulum (ER) stress, which can be mediated by oxidative and/or non-oxidative metabolites of ethanol. An acute as well as chronic alcohol ingestions impair protective antioxidants, oxidize reduced glutathione (GSH, cellular antioxidant against ROS and oxidative stress), and suppress innate and adaptive immunity in the lungs. Oxidative stress and suppressed immunity in the lungs of chronic alcohol abusers collectively are considered to be major risk factors for infection and development of pneumonia, and such diseases as ARDS and COPD. Prior human and experimental studies attempted to identify common mechanisms by which alcohol abuse directly causes toxicity to alveolar epithelium and respiratory tract, particularly lungs. In this review, the metabolic basis of lung injury, oxidative and ER stress and immunosuppression in experimental models and alcoholic patients, as well as potential immunomodulatory therapeutic strategies for improving host defenses against alcohol-induced pulmonary infections are discussed.
Appropriate management of persistent asthma, according to US and international guidelines, requires daily use of controller medications, most generally, inhaled corticosteroids (ICS). This approach, although effective and well established, imposes burdens of treatment and side effects onto asthma patients. A growing body of evidence suggests that patients with persistent asthma need not be managed with daily ICS, but rather can use them on an intermittent basis, occasioned by the occurrence of symptoms sufficient to warrant treatment with a rescue inhaler. Large, randomized, controlled studies, over a range of asthma severity, and in a range of ages from pediatrics to adults, suggest that in well-selected patients, a symptom based approach to administering controller therapy may produce equivalent outcomes, while reducing exposure to ICS. The concept of providing anti-inflammatory treatment to the patient, at the time inflammation is developing, is termed ‘temporal personalization’. The evidence to date suggests that symptom-based controller therapy is broadly useful in selected asthma patients, and is a management approach that could be incorporated into US and international guidelines for asthma.
Asthma; Inhaled corticosteroids; Symptom-based controller therapy; Management; Treatment
Consumption and over-consumption of alcoholic beverages are well-recognized contributors to a variety of pulmonary disorders, even in the absence of intoxication. The mechanisms by which alcohol (ethanol) may produce disease include oxidative stress and prolonged endoplasmic reticulum (ER) stress. Many aspects of these processes remain incompletely understood due to a lack of a suitable animal model. Chronic alcohol over-consumption reduces hepatic alcohol dehydrogenase (ADH), the principal canonical metabolic pathway of ethanol oxidation. We therefore modeled this situation using hepatic ADH-deficient deer mice fed 3.5% ethanol daily for 3 months. Blood ethanol concentration was 180 mg% in ethanol fed mice, compared to <0.2% in the controls. Acetaldehyde (oxidative metabolite of ethanol) was minimally, but significantly increased in ethanol-fed vs. pair-fed control mice. Total fatty acid ethyl esters (FAEEs, nonoxidative metabolites of ethanol) were 47.6 μg/g in the lungs of ethanol-fed mice as compared to 1.5 μg/g in pair-fed controls. Histological and immunohistological evaluation showed perivascular and peribronchiolar lymphocytic infiltration, and significant oxidative injury, in the lungs of ethanol-fed mice compared to pair-fed controls. Several fold increases for cytochrome P450 2E1, caspase 8 and caspase 3 found in the lungs of ethanol-fed mice as compared to pair-fed controls suggest role of oxidative stress in ethanol-induced lung injury. ER stress and unfolded protein response signaling were also significantly increased in the lungs of ethanol-fed mice. Surprisingly, no significant activation of inositol-requiring enzyme-1α and spliced XBP1 were observed indicating a lack of activation of corrective mechanisms to reinstate ER homeostasis. The data suggest that oxidative stress and prolonged ER stress, coupled with formation and accumulation of cytotoxic FAEEs may contribute to the pathogenesis of alcoholic lung disease.
Previous studies have identified asthma phenotypes based on small
numbers of clinical, physiologic or inflammatory characteristics. However,
no studies have utilized a wide range of variables using machine learning
To identify subphenotypes of asthma utilizing blood, bronchoscopic,
exhaled nitric oxide and clinical data from the Severe Asthma Research
Program using unsupervised clustering, and then characterize them using
supervised learning approaches.
Unsupervised clustering approaches were applied to 112 clinical,
physiologic and inflammatory variables from 378 subjects. Variable selection
and supervised learning techniques were employed to select relevant and
nonredundant variables, address their predictive values, as well as the
predictive value of the full variable set.
Ten variable clusters and six subject clusters were identified, which
differed and overlapped with previous clusters. Traditionally defined severe
asthmatics distributed through subject Clusters 3–6. Cluster 4
identified early onset allergic asthmatics with low lung function and
eosinophilic inflammation. Later onset, mostly severe asthmatics with nasal
polyps and eosinophilia characterized Cluster 5. Cluster 6 asthmatics
manifested persistent inflammation in blood and bronchoalveolar lavage and
exacerbations despite high systemic corticosteroid use and side effects. Age
of asthma onset, quality of life, symptoms, medications and health care
utilization were some of the 51 nonredundant variables distinguishing
subject clusters. These 51 variables classified test cases with 88%
accuracy, compared to 93% accuracy with all 112 variables.
The unsupervised machine learning approaches used here provide unique
insights into disease, confirming other approaches while revealing novel
asthma phenotyping; variable analysis; unsupervised approaches; supervised machine learning approaches
Determining the cellular and molecular phenotypes of inflammation in asthma can identify patient populations that may best benefit from targeted therapies. Although elevated IL-6 and polymorphisms in IL-6 signalling are associated with lung dysfunction in asthma, it remains unknown if elevated IL-6 levels are associated with a specific cellular inflammatory phenotype, and how IL-6 blockade might impact such inflammatory responses.
Patients undergoing exacerbations of asthma were phenotyped according to their airway inflammatory characteristics (normal cell count, eosinophilic, neutrophilic, mixed granulocytic), sputum cytokine profiles, and lung function. Mice were exposed to the common allergen, house dust-mite (HDM), in the presence or absence of endogenous IL-6. The intensity and nature of lung inflammation, and levels of pro-granulocytic cytokines and chemokines under these conditions were analyzed.
Elevated IL-6 was associated with a lower FEV1 in patients with mixed eosinophilic-neutrophilic bronchitis. In mice, allergen exposure increased lung IL-6 and IL-6 was produced by dendritic cells and alveolar macrophages. Loss-of-function of IL-6 signalling (knockout or antibody-mediated neutralization) abrogated elevations of eosinophil and neutrophil recruiting cytokines/chemokines and allergen-induced airway inflammation in mice.
We demonstrate the association of pleiotropic cellular airway inflammation with IL-6 using human and animal data. These data suggest that exacerbations of asthma, particularly those with a combined eosinophilic and neutrophilic bronchitis, may respond to therapies targeting the IL-6 pathway and therefore, provide a rational basis for initiation of clinical trials to evaluate this.
Airway inflammation; Asthma; Allergy; Bronchitis; Eosinophil; Neutrophil; Granulocyte; IL-6; IL-6R; House dust-mite (HDM)
No consensus exists for adjusting inhaled corticosteroid therapy in patients with asthma. Approaches include adjustment at outpatient visits guided by physician assessment of asthma control (symptoms, rescue therapy, pulmonary function), based on exhaled nitric oxide, or on a day-to-day basis guided by symptoms.
To determine if adjustment of inhaled corticosteroid therapy based on exhaled nitric oxide or day-to-day symptoms is superior to guideline-informed, physician assessment–based adjustment in preventing treatment failure in adults with mild to moderate asthma.
Design, Setting, and Participants
A randomized, parallel, 3-group, placebo-controlled, multiply-blinded trial of 342 adults with mild to moderate asthma controlled by low-dose inhaled corticosteroid therapy (n=114 assigned to physician assessment–based adjustment [101 completed], n=115 to biomarker-based [exhaled nitric oxide] adjustment [92 completed], and n=113 to symptom-based adjustment [97 completed]), the Best Adjustment Strategy for Asthma in the Long Term (BASALT) trial was conducted by the Asthma Clinical Research Network at 10 academic medical centers in the United States for 9 months between June 2007 and July 2010.
For physician assessment–based adjustment and biomarker-based (exhaled nitric oxide) adjustment, the dose of inhaled corticosteroids was adjusted every 6 weeks; for symptom-based adjustment, inhaled corticosteroids were taken with each albuterol rescue use.
Main Outcome Measure
The primary outcome was time to treatment failure.
There were no significant differences in time to treatment failure. The 9-month Kaplan-Meier failure rates were 22% (97.5% CI, 14%-33%; 24 events) for physician assessment–based adjustment, 20% (97.5% CI, 13%-30%; 21 events) for biomarker-based adjustment, and 15% (97.5% CI, 9%-25%; 16 events) for symptom-based adjustment. The hazard ratio for physician assessment–based adjustment vs biomarker-based adjustment was 1.2 (97.5% CI, 0.6-2.3). The hazard ratio for physician assessment–based adjustment vs symptom-based adjustment was 1.6 (97.5% CI, 0.8-3.3).
Among adults with mild to moderate persistent asthma controlled with low-dose inhaled corticosteroid therapy, the use of either biomarker-based or symptom-based adjustment of inhaled corticosteroids was not superior to physician assessment–based adjustment of inhaled corticosteroids in time to treatment failure.
clinicaltrials.gov Identifier: NCT00495157
Tiotropium has activity as an asthma controller. However, predictors of a positive response to tiotropium have not been described.
To describe individual and differential response of patients with asthma to salmeterol and tiotropium, when added to an ICS, as well as predictors of a positive clinical response.
Data from the double-blind, three-way crossover NHLBI Asthma Clinical Research Network’s TALC trial (ClinicalTrials.gov number, NCT00565266) were analyzed for individual and differential treatment responses to salmeterol and tiotropium, and predictors of a positive response to the endpoints FEV1, morning peak expiratory flow (AM PEF), and asthma control days (ACDs).
While approximately equal numbers of patients showed a differential response to salmeterol and tiotropium in terms of AM PEF (90 and 78, respectively), and ACDs (49 and 53, respectively), more showed a differential response to tiotropium for FEV1 (104) than salmeterol (62). An acute response to a short-acting bronchodilator, especially albuterol, predicted a positive clinical response to tiotropium for FEV1 (OR 4.08 [CI 2.00–8.31], P < 0.001) and AM PEF (OR 2.12 [CI 1.12–4.01], P = 0.021), as did a decreased FEV1/FVC ratio (FEV1 response increased 0.39% of baseline for every 1% decrease in the FEV1/FVC ratio). Higher cholinergic tone was also a predictor, while ethnicity, gender, atopy, IgE Level, sputum eosinophils, FENO, asthma duration, and BMI were not.
While these results need confirmation, predictors of a positive clinical response to tiotropium include a positive response to albuterol and airway obstruction, factors which could help identify appropriate patients for this therapy.
asthma; tiotropium; salmeterol; responder analysis; predictor of response
A case report illustrates how multidisciplinary translational teams can be assessed using outcome, process, and developmental types of evaluation using a mixed methods approach. Types of evaluation appropriate for teams are considered in relation to relevant research questions and assessment methods. Logic models are applied to scientific projects and team development to inform choices between methods within a mixed methods design. Use of an expert panel is reviewed, culminating in consensus ratings of 11 multidisciplinary teams and a final evaluation within a team type taxonomy. Based on team maturation and scientific progress, teams were designated as: a) early in development, b) traditional, c) process focused, or d) exemplary. Lessons learned from data reduction, use of mixed methods, and use of expert panels are explored.
team science; logic models; process evaluation; translational teams; mixed methods
Severe asthma causes the majority of asthma morbidity. Understanding mechanisms that contribute to the development of severe disease is important.
The goal of the Severe Asthma Research Program is to identify and characterize subjects with severe asthma to understand pathophysiologic mechanisms in severe asthma.
We performed a comprehensive phenotypic characterization (questionnaires, atopy and pulmonary function testing, phlebotomy, exhaled nitric oxide) in subjects with severe and not severe asthma.
A total of 438 subjects with asthma were studied (204 severe, 70 moderate, 164 mild). Severe subjects with asthma were older with longer disease duration (P < .0001), more daily symptoms, intense urgent health care utilization, sinusitis, and pneumonia (P ≤ .0001). Lung function was lower in severe asthma with marked bronchodilator reversibility (P < .001). The severe group had less atopy by skin tests (P = .0007), but blood eosinophils, IgE, and exhaled nitric oxide levels did not differentiate disease severity. A reduced FEV1, history of pneumonia, and fewer positive skin tests were risk factors for severe disease. Early disease onset (age < 12 years) in severe asthma was associated with longer disease duration (P < .0001) and more urgent health care, especially intensive care (P = .002). Later disease onset (age ≥ 12 years) was associated with lower lung function and sinopulmonary infections (P ≤ .02).
Severe asthma is characterized by abnormal lung function that is responsive to bronchodilators, a history of sinopulmonary infections, persistent symptoms, and increased health care utilization.
Lung function abnormalities in severe asthma are reversible in most patients, and pneumonia is a risk factor for the development of severe disease.
Severe asthma; definition; bronchodilator response; pathophysiology; phenotype; pneumonia
Recent meta-analyses of genome-wide association studies in general populations of European descent have identified 28 loci for lung function.
We sought to identify novel lung function loci specifically for asthma and to confirm lung function loci identified in general populations.
Genome-wide association studies of lung function (percent predicted FEV1 [ppFEV1], percent predicted forced vital capacity, and FEV1/forced vital capacity ratio) were performed in 4 white populations of European descent (n = 1544), followed by meta-analyses.
Seven of 28 previously identified lung function loci (HHIP, FAM13A, THSD4, GSTCD, NOTCH4-AGER, RARB, and ZNF323) identified in general populations were confirmed at single nucleotide polymorphism (SNP) levels (P < .05). Four of 32 loci (IL12A, IL12RB1, STAT4, and IRF2) associated with ppFEV1 (P < 10−4) belong to the TH1 or IL-12 cytokine family pathway. By using a linear additive model, these 4 TH1 pathway SNPs cumulatively explained 2.9% to 7.8% of the variance in ppFEV1 values in 4 populations (P = 3 × 10−11). Genetic scores of these 4 SNPs were associated with ppFEV1 values (P = 2 × 10−7) and the American Thoracic Society severe asthma classification (P = .005) in the Severe Asthma Research Program population. TH2 pathway genes (IL13, TSLP, IL33, and IL1RL1) conferring asthma susceptibility were not associated with lung function.
Genes involved in airway structure/remodeling are associated with lung function in both general populations and asthmatic subjects. TH1 pathway genes involved in anti-virus/bacterial infection and inflammation modify lung function in asthmatic subjects. Genes associated with lung function that might affect asthma severity are distinct from those genes associated with asthma susceptibility.
Lung function; FEV1; asthma; TH1; IL12A; IL12RB1; STAT4; IRF2
Investigative bronchoscopy was performed in a subset of participants in the Severe Asthma Research Program (SARP) to gain insights into the pathobiology of severe disease. We evaluated the safety aspects of this procedure in this cohort with specific focus on patients with severe asthma.
To prospectively evaluate changes in lung function and the frequency of adverse events related to investigative bronchoscopy.
Bronchoscopy was performed using a common Manual of Procedures. A subset of very severe asthma was defined by severe airflow obstruction, chronic oral corticosteroid use and recent asthma exacerbations. Subjects were monitored for changes in lung function and contacted by telephone for 3 days after the procedure.
436 subjects underwent bronchoscopy (97 normal, 196 not severe, 102 severe and 41 very severe asthma). Nine subjects were evaluated in hospital settings after bronchoscopy; seven of these were respiratory related events. Recent Emergency Department visits, chronic oral corticosteroid use and a history of pneumonia were more frequent in subjects who had asthma exacerbations after bronchoscopy. The fall in FEV1 following bronchoscopy was similar in the severe compared to milder asthma group. Pre-bronchodilator FEV1 was the strongest predictor of change in FEV1 after bronchoscopy with larger decreases observed in subjects with better lung function.
Bronchoscopy in severe asthma subjects was well tolerated. Asthma exacerbations were rare and reduction in pulmonary function after the procedure was similar to subjects with less severe asthma. With proper precautions, investigative bronchoscopy can be performed safely in severe asthma.
investigative bronchoscopy; safety; severe asthma; exacerbation
Translational science requires that scientists from multiple disciplines work together to improve the prevention, diagnosis, and treatment of human disease. Although a literature exists on the design and management of multidisciplinary teams, little has been written on multidisciplinary translational teams (MTTs). MTTs are distinct hybrid entities, with goals taken from both industry and academic models. We identified 30 design factors in 10 domains from a literature survey relevant to our MTT model: specific goals, structures, and processes. These dimensions were adapted to our own institutional environment in the selection and management of 11 MTTs that exploited resources of University of Texas Medical Branch (UTMB) Clinical and Translational Sciences Awards (CTSA). Case illustrations of two specific MTTs illustrate some of the challenges encountered and opportunities realized in terms of education and scientific advances. Network depiction of disciplinarity indicated that CTSA KRs and CTSA leadership contributed to discipline diversity especially in small (or nascent) MTTs. A separate depiction of MTT-KR utilization indicated that data analysis, translational technologies, and novel methods were heavily utilized by MTTs, whereas other KRs contributed significant effort to infrastructure development. We conclude that the CTSA can provide a rich infrastructural framework and scientific environment for the development of successful MTTs.
team science; multidisciplinary teams; translational research
Rationale: Increasing body mass index (BMI) has been associated with less fractional exhaled nitric oxide (FeNO). This may be explained by an increase in the concentration of asymmetric dimethyl arginine (ADMA) relative to l-arginine, which can lead to greater nitric oxide synthase uncoupling.
Objectives: To compare this mechanism across age of asthma onset groups and determine its association with asthma morbidity and lung function.
Methods: Cross-sectional study of participants from the Severe Asthma Research Program, across early- (<12 yr) and late- (>12 yr) onset asthma phenotypes.
Measurements and Main Results: Subjects with late-onset asthma had a higher median plasma ADMA level (0.48 μM, [interquartile range (IQR), 0.35–0.7] compared with early onset, 0.37 μM [IQR, 0.29–0.59], P = 0.01) and lower median plasma l-arginine (late onset, 52.3 [IQR, 43–61] compared with early onset, 51 μM [IQR 39–66]; P = 0.02). The log of plasma l-arginine/ADMA was inversely correlated with BMI in the late- (r = −0.4, P = 0.0006) in contrast to the early-onset phenotype (r = −0.2, P = 0.07). Although FeNO was inversely associated with BMI in the late-onset phenotype (P = 0.02), the relationship was lost after adjusting for l-arginine/ADMA. Also in this phenotype, a reduced l-arginine/ADMA was associated with less IgE, increased respiratory symptoms, lower lung volumes, and worse asthma quality of life.
Conclusions: In late-onset asthma phenotype, plasma ratios of l-arginine to ADMA may explain the inverse relationship of BMI to FeNO. In addition, these lower l-arginine/ADMA ratios are associated with reduced lung function and increased respiratory symptom frequency, suggesting a role in the pathobiology of the late-onset phenotype.
asthma; obesity; age of asthma onset; ADMA; arginine
Rationale: The function of the P2X7 nucleotide receptor protects against exacerbation in people with mild-intermittent asthma during viral illnesses, but the impact of disease severity and maintenance therapy has not been studied.
Objectives: To evaluate the association between P2X7, asthma exacerbations, and incomplete symptom control in a more diverse population.
Methods: A matched P2RX7 genetic case-control was performed with samples from Asthma Clinical Research Network trial participants enrolled before July 2006, and P2X7 pore activity was determined in whole blood samples as an ancillary study to two trials completed subsequently.
Measurements and Main Results: A total of 187 exacerbations were studied in 742 subjects, and the change in asthma symptom burden was studied in an additional 110 subjects during a trial of inhaled corticosteroids (ICS) dose optimization. African American carriers of the minor G allele of the rs2230911 loss-of-function single nucleotide polymorphism were more likely to have a history of prednisone use in the previous 12 months, with adjustment for ICS and long-acting β2-agonists use (odds ratio, 2.7; 95% confidence interval, 1.2–6.2; P = 0.018). Despite medium-dose ICS, attenuated pore function predicted earlier exacerbations in incompletely controlled patients with moderate asthma (hazard ratio, 3.2; confidence interval, 1.1–9.3; P = 0.033). After establishing control with low-dose ICS in patients with mild asthma, those with attenuated pore function had more asthma symptoms, rescue albuterol use, and FEV1 reversal (P < 0.001, 0.03, and 0.03, respectively) during the ICS adjustment phase.
Conclusions: P2X7 pore function protects against exacerbations of asthma and loss of control, independent of baseline severity and the maintenance therapy.
asthma; P2X7; exacerbation; Asthma Clinical Research Network; corticosteroids
Rationale: Exhaled nitric oxide (FeNO) is a biomarker of airway inflammation in mild to moderate asthma. However, whether FeNO levels are informative regarding airway inflammation in patients with severe asthma, who are refractory to conventional treatment, is unknown. Here, we hypothesized that classification of severe asthma based on airway inflammation as defined by FeNO levels would identify a more reactive, at-risk asthma phenotype.
Methods: FeNO and major features of asthma, including airway inflammation, airflow limitation, hyperinflation, hyperresponsiveness, and atopy, were determined in 446 individuals with various degrees of asthma severity (175 severe, 271 nonsevere) and 49 healthy subjects enrolled in the Severe Asthma Research Program.
Measurements and Main Results: FeNO levels were similar among patients with severe and nonsevere asthma. The proportion of individuals with high FeNO levels (>35 ppb) was the same (40%) among groups despite greater corticosteroid therapy in severe asthma. All patients with asthma and high FeNO had more airway reactivity (maximal reversal in response to bronchodilator administration and by methacholine challenge), more evidence of allergic airway inflammation (sputum eosinophils), more evidence of atopy (positive skin tests, higher serum IgE and blood eosinophils), and more hyperinflation, but decreased awareness of their symptoms. High FeNO identified those patients with severe asthma characterized by the greatest airflow obstruction and hyperinflation and most frequent use of emergency care.
Conclusions: Grouping of asthma by FeNO provides an independent classification of asthma severity, and among patients with severe asthma identifies the most reactive and worrisome asthma phenotype.
nitric oxide; severe asthma; phenotype; airway reactivity; exhaled breath
Asthma is a chronic inflammatory disease of the airways that leads to various degrees of recurrent respiratory symptoms affecting patients globally. Specific subgroups of asthma patients have severe disease leading to increased healthcare costs and socioeconomic burden. Despite the overwhelming prevalence of the asthma, there are limitations in predicting response to therapy and identifying patients who are at increased risk of morbidity. This syndrome presents with common clinical signs and symptoms; however, awareness of subgroups of asthma patients with distinct characteristics has surfaced in recent years. Investigators attempt to describe the phenotypes of asthma to ultimately assist with diagnostic and therapeutic applications. Approaches to asthma phenotyping are multifold; however, it can be partitioned into 2 essential groups, clinical phenotyping and molecular phenotyping. Innovative techniques such as bipartite network analysis and visual analytics introduce a new dimension of data analysis to identify underlying mechanistic pathways.
Asthma; Allergic; Exercise induced; Molecular; Bipartite; Phenotype; Network; Logistic regression; Multivariate adaptive regression splines (MARS); Cytokines; Cluster analysis; Classification regression trees (CART); Heterogeneous; Airway; Inflammation
Benralizumab is a monoclonal antibody that binds the α subunit of the receptor to IL-5. As IL-5 is implicated in disease states that are mediated by eosinophils, benralizumab is an attractive option for use in the management of asthma. As a result of enhanced antibody-directed cell cytotoxicity, it has enhanced eosinophil-depleting activity as compared with neutralizing monoclonal antibody directed against IL-5.
This review presents the available data on benralizumab, including pharmacodynamics, pharmacokinetics, preclinical data and relevant clinical studies.
Our review indicates that although further investigation is necessary to demonstrate clinical benefit, benralizumab remains a promising treatment modality.
asthma; benralizumab; IL-5; IL-5Rα; MEDI-563
Long-term and unresolved airway inflammation and airway remodeling, characteristic features of chronic asthma, if not treated could lead to permanent structural changes in the airways. Aldose reductase (AR), an aldo-sugar and lipid aldehyde metabolizing enzyme, mediates allergen-induced airway inflammation in mice, but its role in the airway remodeling is not known. In the present study, we have examined the role of AR on airway remodeling using ovalbumin (OVA)-induced chronic asthma mouse model and cultured human primary airway epithelial cells (SAECs) and mouse lung fibroblasts (mLFs).
Airway remodeling in chronic asthma model was established in mice sensitized and challenged twice a week with OVA for 6 weeks. AR inhibitor, fidarestat, was administered orally in drinking water after first challenge. Inflammatory cells infiltration in the lungs and goblet cell metaplasia, airway thickening, collagen deposition and airway hyper-responsiveness (AHR) in response to increasing doses of methacholine were assessed. The TGFβ1-induced epithelial-mesenchymal transition (EMT) in SAECs and changes in mLFs were examined to investigate AR-mediated molecular mechanism(s) of airway remodeling.
In the OVA-exposed mice for 6 wks inflammatory cells infiltration, levels of inflammatory cytokines and chemokines, goblet cell metaplasia, collagen deposition and AHR were significantly decreased by treatment with AR inhibitor, fidarestat. Further, inhibition of AR prevented TGFβ1-induced altered expression of E-cadherin, Vimentin, Occludin, and MMP-2 in SAECs, and alpha-smooth muscle actin and fibronectin in mLFs. Further, in SAECs, AR inhibition prevented TGFβ1- induced activation of PI3K/AKT/GSK3β pathway but not the phosphorylation of Smad2/3.
Our results demonstrate that allergen-induced airway remodeling is mediated by AR and its inhibition blocks the progression of remodeling via inhibiting TGFβ1-induced Smad-independent and PI3K/AKT/GSK3β-dependent pathway.
The National Heart, Lung, and Blood Institute Severe Asthma Research Program (SARP) has characterized over the past 10 years 1,644 patients with asthma, including 583 individuals with severe asthma. SARP collaboration has led to a rapid recruitment of subjects and efficient sharing of samples among participating sites to conduct independent mechanistic investigations of severe asthma. Enrolled SARP subjects underwent detailed clinical, physiologic, genomic, and radiological evaluations. In addition, SARP investigators developed safe procedures for bronchoscopy in participants with asthma, including those with severe disease. SARP studies revealed that severe asthma is a heterogeneous disease with varying molecular, biochemical, and cellular inflammatory features and unique structure–function abnormalities. Priorities for future studies include recruitment of a larger number of subjects with severe asthma, including children, to allow further characterization of anatomic, physiologic, biochemical, and genetic factors related to severe disease in a longitudinal assessment to identify factors that modulate the natural history of severe asthma and provide mechanistic rationale for management strategies.
asthma; remodeling; inflammation; bronchoscopy; imaging
Asthmatic patients are currently classified as either severe or non-severe based primarily on their response to glucocorticoids. However, because this classification is based on a post-hoc assessment of treatment response, it does not inform the rational staging of disease or therapy. Recent studies in other diseases suggest that a classification which includes molecular information could lead to more accurate diagnoses and prediction of treatment response. We therefore measured cytokine values in bronchoalveolar lavage (BAL) samples of the lower respiratory tract obtained from 83 asthma patients, and used bipartite network visualizations with associated quantitative measures to conduct an exploratory analysis of the co-occurrence of cytokines across patients. The analysis helped to identify three clusters of patients which had a complex but understandable interaction with three clusters of cytokines, leading to insights for a state-based classification of asthma patients. Furthermore, while the patient clusters were significantly different based on key pulmonary functions, they appeared to have no significant relationship to the current classification of asthma patients. These results suggest the need to define a molecular-based classification of asthma patients, which could improve the diagnosis and treatment of this disease.
Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies (GWAS) of asthma in 5,416 asthma cases representing European Americans, African Americans/African Caribbeans, and Latinos, and replicated five regions among the most significant signals in 12,649 individuals from the same ethnic groups. Four were at previously reported loci on 17q21, and near the IL1RL1, TSLP, and IL33, genes, but we report for the first time that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a novel association with asthma in the PYHIN1, gene that was specific to individuals of African descent (p=3.9×10−9). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma.
Two recent large meta-analyses of genome-wide association studies of lung function in general populations of European descent identified 11 candidate genes/regions. The importance of these genes in lung function in whites and African Americans with asthma is unknown.
To determine if genes that regulate lung function in general populations are associated with lung function abnormalities in subjects with asthma from different racial groups.
SNPs were tested in five asthma populations (n = 1,441) for association with pulmonary function and meta-analysis was performed across populations. The SNPs with the highest significance were then tested for association with bronchodilator reversibility and bronchial hyperresponsiveness to methacholine (BHR). A joint analysis of consistently replicated SNPs was performed to predict lung function in asthma.
Hedgehog interacting protein (HHIP) on chromosome 4q31 was associated with lung function in all five populations, rs1512288: Pmeta = 9.62E-05 and 3.23E-05 for ppFEV1 and ppFVC, respectively. The SNPs in HHIP were also associated with reversibility (P < 0.05) but not BHR. Because of differences in linkage disequilibrium in the African-American subjects, the most relevant SNPs in HHIP were identified. A subset of normal lung function genes, including HHIP, family with sequence similarity 13, member A (FAM13A), and patched homolog 1 (PTCH1), together predict lung function abnormalities, a measure of severity in whites and African Americans with asthma.
A subset of the genes, including HHIP, which regulate lung function in general populations are associated with abnormal lung function in asthma in non-Hispanic whites and African Americans.
Asthma; Genetics; Asthma severity; Meta-analysis; FEV1; FVC; FEV1/FVC; HHIP; FAM13A; PTCH1
Studies of asthma phenotypes have identified obesity as a component of a group characterized by a high proportion of adult-onset asthmatics. However, whether age of asthma onset modifies the association between obesity and asthma is unknown.
From the Severe Asthma Project (SARP), we defined age of asthma onset as early (before 12 years of age) and late-onset (12 and higher). Comparisons of body mass index (BMI) categories were done within age of onset groups and obesity was also compared across these groups. Multivariable logistic regression analysis was done to evaluate the association between BMI categories with healthcare utilization and respiratory symptoms and multivariable linear regression for the association between duration of asthma and weight gain (BMI change/yr). An interaction between obesity and age of asthma onset was included in the multivariable analyses.
The study population consisted on 1,049 subjects of which the median age for asthma onset was 10 years (IQR 4 – 25); 48% were late-onset (≥ 12) and 52% were early-onset (<12). Compared to late-onset obese asthmatics, early-onset obese asthmatics had more airway obstruction, bronchial hyperresponsiveness, and higher OR of ever having 3 or more oral steroid tapers preceding/year or ICU admissions for asthma/preceding year (Interactions between obesity and age of asthma onset were respectively p=0.055 and p=0.02). In early-onset, but not in late-onset asthmatics, there was a significant association between increasing BMI and duration of asthma, after adjusting for confounders. The interaction between asthma duration and age of asthma onset was p < 0.01.
Asthmatics are differentially affected by obesity, based on whether they developed asthma early (<12 years) or later in life. These results highlight the need to understand obesity as a comorbidity that affects specific clinical phenotypes and not all asthma subjects alike.
Severe; asthma; obesity; SARP
Improvement in lung function following macrolide antibiotic therapy has been attributed to reduction in bronchial infection due to specific bacteria. However, the airway may be populated by a more diverse microbiota, and clinical features of asthma may be associated with characteristics of the airway microbiota present.
To determine if relationships exist between the composition of the airway bacterial microbiota and clinical features of asthma, using culture-independent tools capable of detecting the presence and relative abundance of most known bacteria.
In this pilot study, bronchial epithelial brushings were collected from sixty-five adults with sub-optimally controlled asthma participating in a multicenter study of the effects of clarithromycin on asthma control, and ten healthy subjects. A combination of high-density 16S rRNA microarray and parallel clone library-sequencing analysis was used to profile the microbiota and examine relationships with clinical measurements.
Compared to controls, 16S rRNA amplicon concentrations (a proxy for bacterial burden) and bacterial diversity were significantly higher among asthmatic patients. In multivariate analyses, airway microbiota composition and diversity were significantly correlated with bronchial hyperresponsiveness. Specifically, the relative abundance of particular phylotypes, including members of the Comamonadaceae, Sphingomonadaceae, Oxalobacteraceae and other bacterial families, were highly correlated with the degree of bronchial hyperresponsiveness.
The composition of bronchial airway microbiota is associated with the degree of bronchial hyperresponsiveness among patients with sub-optimally controlled asthma. These findings support the need for further functional studies to examine the potential contribution of members of the airway microbiota in asthma pathogenesis.
microbiome; bacteria; asthma; 16S rRNA; PhyloChip