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1.  Coexisting chronic conditions associated with mortality and morbidity in adult patients with asthma 
Objective
Many asthma patients suffer from chronic conditions other than asthma. We investigated the specific contribution of common comorbidities on mortality and morbidity in adult asthma.
Methods
In an observational study of adults with incident asthma identified between 1999 and 2003 using National Veterans Affairs and Centers for Medicare and Medicaid Services encounter databases (n=25,975, follow-up 3.0±1.7 years), association between 13 most prevalent comorbidities (hypertension, ischemic heart disease (IHD), osteoarthritis, rheumatoid arthritis, diabetes, mental disorders, substance/drug abuse, enlarged prostate, depression, cancer, alcoholism, HIV, and heart failure) and 4 conditions previously associated with asthma (sleep apnea, gastroesophageal reflux disease (GERD), rhinitis, and sinusitis) and mortality, hospitalizations and asthma exacerbations were assessed using multivariate regression analyses adjusted for other clinically important covariates.
Results
HIV followed by alcoholism and mental disorders among 18–45 years old, and heart failure, diabetes, IHD, and cancer among those ≥65 years old were associated with an increased risk of all-cause mortality. Many conditions were associated with increased risk for all-cause hospitalizations, but the increased risk was consistent across all ages for mental disorders. For asthma exacerbations, mental disorder followed by substance abuse and IHD were associated with increased risk among those 18–45 years old, and chronic sinusitis, mental disorder, and IHD among those ≥65 years old. GERD was associated with decreased risk for asthma exacerbation in all ages.
Conclusions
Many comorbidities are associated with poor outcome in adult asthmatics and their effect differs by age. Mental disorders are associated with increased risk of mortality and morbidity across ages.
doi:10.3109/02770903.2013.879881
PMCID: PMC4067514  PMID: 24432868
observational study; Veterans; outcome research; comorbidities; mental disorders
2.  An Association between l-Arginine/Asymmetric Dimethyl Arginine Balance, Obesity, and the Age of Asthma Onset Phenotype 
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.
doi:10.1164/rccm.201207-1270OC
PMCID: PMC3570651  PMID: 23204252
asthma; obesity; age of asthma onset; ADMA; arginine
3.  P2X7-Regulated Protection from Exacerbations and Loss of Control Is Independent of Asthma Maintenance Therapy 
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.
doi:10.1164/rccm.201204-0750OC
PMCID: PMC3570642  PMID: 23144325
asthma; P2X7; exacerbation; Asthma Clinical Research Network; corticosteroids
4.  Receptor Pre-Clustering and T cell Responses: Insights into Molecular Mechanisms 
T cell activation, initiated by T cell receptor (TCR) mediated recognition of pathogen-derived peptides presented by major histocompatibility complex class I or II molecules (pMHC), shows exquisite specificity and sensitivity, even though the TCR–pMHC binding interaction is of low affinity. Recent experimental work suggests that TCR pre-clustering may be a mechanism via which T cells can achieve such high sensitivity. The unresolved stoichiometry of the TCR makes TCR–pMHC binding and TCR triggering, an open question. We formulate a mathematical model to characterize the pre-clustering of T cell receptors (TCRs) on the surface of T cells, motivated by the experimentally observed distribution of TCR clusters on the surface of naive and memory T cells. We extend a recently introduced stochastic criterion to compute the timescales of T cell responses, assuming that ligand-induced cross-linked TCR is the minimum signaling unit. We derive an approximate formula for the mean time to signal initiation. Our results show that pre-clustering reduces the mean activation time. However, additional mechanisms favoring the existence of clusters are required to explain the difference between naive and memory T cell responses. We discuss the biological implications of our results, and both the compatibility and complementarity of our approach with other existing mathematical models.
doi:10.3389/fimmu.2014.00132
PMCID: PMC4012210  PMID: 24817867
T cell receptor; clustering; stochastic dynamics; signaling; naive T cells; memory T cells
5.  Genome-wide association studies of asthma indicate opposite immunopathogenesis direction from autoimmune diseases 
Background
Genome-wide association studies (GWASs) of asthma have consistently implicated the ORM1-like 3 and gasdermin B (ORMDL3-GSDMB), IL33, IL-1 receptor–like 1 and IL-18 receptor 1 (IL1RL1-IL18R1), RAD50-IL13, thymic stromal lymphopoietin and WD repeat domain 36 region (TSLP-WDR36), and HLA-DR/DQ regions.
Objective
A GWAS of asthma was performed in a non-Hispanic white population.
Methods
A GWAS was performed in 813 Severe Asthma Research Program/Collaborative Studies on the Genetics of Asthma/Chicago Asthma Genetics Study cases and 1564 control subjects. The GWAS results were compared with those of the published GWASs of autoimmune diseases.
Result
Multiple single nucleotide polymorphisms in the TNFAIP3 interacting protein 1 (TNIP1) gene, which interacts with TNFAIP3 and inhibits the TNF-α–induced nuclear factor κB inflammation pathway, were associated with asthma: rs1422673 (P = 3.44 × 10−7) and rs10036748 (P = 1.41 × 10−6, r2 = 0.67). rs1422673 was also associated with asthma in the published GABRIEL (P = .018) and EVE (P = 1.31 × 10−5) studies. The minor allele T of rs20541 in IL13 is the risk allele for asthma but the protective allele for psoriasis. The minor allele T of rs2395185 in HLA-DRA is the risk allele for asthma but the protective allele for ulcerative colitis. The minor allele A of rs2872507 in GSDMB is the protective allele for asthma but the risk allele for rheumatoid arthritis, Crohn disease, and ulcerative colitis. The T allele of rs10036748 in the TNIP1 gene is the minor protective allele for asthma but the minor or major risk allele for systemic lupus erythematosus and systemic sclerosis in non-Hispanic white or Chinese subjects, respectively.
Conclusions
Our study suggests that single nucleotide polymorphisms associated with both asthma and autoimmune diseases might have opposite effects on immunopathogenesis. (J Allergy Clin Immunol 2012;130:861-8.)
doi:10.1016/j.jaci.2012.04.041
PMCID: PMC3579216  PMID: 22694930
Asthma; genetics; genome-wide association study; TNFAIP3 interacting protein 1
6.  A detailed phenotypic analysis of immune cell populations in the bronchoalveolar lavage fluid of atopic asthmatics after segmental allergen challenge 
Background
Atopic asthma is characterized by intermittent exacerbations triggered by exposure to allergen. Exacerbations are characterized by an acute inflammatory reaction in the airways, with recruitment of both innate and adaptive immune cells. These cell populations as well as soluble factors are critical for initiating and controlling the inflammatory processes in allergic asthma. Detailed data on the numbers and types of cells recruited following allergen challenge is lacking. In this paper we present an extensive phenotypic analysis of the inflammatory cell infiltrate present in the bronchoalveolar lavage (BAL) fluid following bronchoscopically directed allergen challenge in mild atopic asthmatics.
Methods
A re-analysis of pooled data obtained prior to intervention in our randomized, placebo controlled, double blinded study (costimulation inhibition in asthma trial [CIA]) was performed. Twenty-four subjects underwent bronchoscopically directed segmental allergen challenge followed by BAL collection 48 hours later. The BAL fluid was analyzed by multi-color flow cytometry for immune cell populations and multi-plex ELISA for cytokine detection.
Results
Allergen instillation induced pro-inflammatory cytokines (IL-6) and immune modulating cytokines (IL-2, IFN-γ, and IL-10) along with an increase in lymphocytes and suppressor cells (Tregs and MDSC). Interestingly, membrane expression of CD30 was identified on lymphocytes, especially Tregs, but not eosinophils. Soluble CD30 was also detected in the BAL fluid after allergen challenge in adult atopic asthmatics.
Conclusions
After segmental allergen challenge of adult atopic asthmatics, cell types associated with a pro-inflammatory as well as an anti-inflammatory response are detected within the BAL fluid of the lung.
doi:10.1186/1710-1492-9-37
PMCID: PMC3848528  PMID: 24330650
T lymphocyte; CD30 expression; Segmental allergen challenge; Asthma
7.  Comparison of Physician-, Biomarker-, and Symptom-Based Strategies for Adjustment of Inhaled Corticosteroid Therapy in Adults With Asthma 
Context
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.
Objective
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.
Interventions
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.
Results
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).
Conclusion
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.
Trial Registration
clinicaltrials.gov Identifier: NCT00495157
doi:10.1001/2012.jama.10893
PMCID: PMC3697088  PMID: 22968888
8.  Genome-wide Ancestry Association Testing Identifies a Common European Variant on 6q14.1 as a Risk Factor for Asthma in African Americans 
Background
Genetic variants that contribute to asthma susceptibility may be present at varying frequencies in different populations, which is an important consideration and advantage for performing genetic association studies in admixed populations.
Objective
To identify asthma-associated loci in African Americans.
Methods
We compared local African and European ancestry estimated from dense single nucleotide polymorphism (SNP) genotype data in African American adults with asthma and non-asthmatic controls. Allelic tests of association were performed within the candidate regions identified, correcting for local European admixture.
Results
We identified a significant ancestry association peak on chromosomes 6q. Allelic tests for association within this region identified a SNP (rs1361549) on 6q14.1 that was associated with asthma exclusively in African Americans with local European admixture (OR=2.2). The risk allele is common in Europe (42% in the HapMap CEU) but absent in West Africa (0% in the HapMap YRI), suggesting the allele is present in African Americans due to recent European admixture. We replicated our findings in Puerto Ricans and similarly found that the signal of association is largely specific to individuals who are heterozygous for African and non-African ancestry at 6q14.1. However, we found no evidence for association in European Americans or in Puerto Ricans in the absence of local African ancestry, suggesting that the association with asthma at rs1361549 is due to an environmental or genetic interaction.
Conclusion
We identified a novel asthma-associated locus that is relevant to admixed populations with African ancestry, and highlight the importance of considering local ancestry in genetic association studies of admixed populations.
doi:10.1016/j.jaci.2012.03.045
PMCID: PMC3503456  PMID: 22607992
asthma; population structure; genome-wide association study; admixture mapping; ancestry association testing; admixed populations; African Americans; Puerto Ricans
9.  Elevated urinary leukotriene E4 levels are associated with hospitalization for pain in children with sickle cell disease 
American journal of hematology  2008;83(8):640-643.
Cysteinyl leukotrienes (CsyLTs) are inflammatory mediators produced by white blood cells. Leukotriene LTE4 is the stable metabolite of CsyLTs, which can be measured in urine. We tested two hypotheses among children with sickle cell disease (SCD): (1) baseline urinary LTE4 levels are elevated in children with SCD when compared with controls; and (2) baseline LTE4 levels are associated with an increased incidence rate of hospitalization for SCD-related pain. Baseline LTE4 levels were measured in children with SCD (cases) and children without SCD matched for age and ethnicity (controls). Medical records of cases were reviewed to assess the frequency of hospitalization for pain within 3 years of study entry. LTE4 levels were obtained in 71 cases and 22 controls. LTE4 levels were higher in cases compared with controls (median LTE4: 100 vs. 57 pg/mg creatinine, P < 0.001). After adjustment for age and asthma diagnosis, a greater incidence rate of hospitalization for pain was observed among children with SCD in the highest LTE4 tertile when compared with the lowest (114 vs. 52 episodes per 100 patient-years, P = 0.038). LTE4 levels are elevated in children with SCD when compared with controls. LTE4 levels are associated with an increased rate of hospitalizations for pain.
doi:10.1002/ajh.21199
PMCID: PMC3729258  PMID: 18506703
10.  The Impact of Self-Identified Race on Epidemiologic Studies of Gene Expression 
Genetic epidemiology  2011;35(2):93-101.
Although population differences in gene expression have been established, the impact on differential gene expression studies in large populations is not well understood. We describe the effect of self-reported race on a gene expression study of lung function in asthma. We generated gene expression profiles for 254 young adults (205 non-Hispanic whites and 49 African Americans) with asthma on whom concurrent total RNA derived from peripheral blood CD4+ lymphocytes and lung function measurements were obtained. We identified four principal components that explained 62% of the variance in gene expression. The dominant principal component, which explained 29% of the total variance in gene expression, was strongly associated with self-identified race (P<10−16). The impact of these racial differences was observed when we performed differential gene expression analysis of lung function. Using multivariate linear models, we tested whether gene expression was associated with a quantitative measure of lung function: pre-bronchodilator forced expiratory volume in one second (FEV1). Though unadjusted linear models of FEV1 identified several genes strongly correlated with lung function, these correlations were due to racial differences in the distribution of both FEV1 and gene expression, and were no longer statistically significant following adjustment for self-identified race. These results suggest that self-identified race is a critical confounding covariate in epidemiologic studies of gene expression and that, similar to genetic studies, careful consideration of self-identified race in gene expression profiling studies is needed to avoid spurious association.
doi:10.1002/gepi.20560
PMCID: PMC3718033  PMID: 21254216
ancestry; gene expression; population stratification; self-identified race
11.  Determinants of asthma after severe respiratory syncytial virus bronchiolitis 
Background
The development of asthma after respiratory syncytial virus (RSV) bronchiolitis has been demonstrated in case-control studies, although the determinants of post-RSV asthma remain undefined.
Objectives
We sought to evaluate the potential determinants of physician-diagnosed asthma after severe RSV bronchiolitis during infancy.
Methods
We enrolled 206 children during an initial episode of severe RSV bronchiolitis at 12 months of age or less in a prospective cohort study and followed these children for up to 6 years. In a subset of 81 children, we analyzed CCL5 (RANTES) mRNA expression in upper airway epithelial cells.
Results
Forty-eight percent of children had physician-diagnosed asthma before the seventh birthday. Independent determinants significantly associated with increased risk for physician-diagnosed asthma by the seventh birthday included maternal asthma (odds ratio [OR], 5.2; 95% CI, 1.7-15.9; P = .004), exposure to high levels of dog allergen (OR, 3.2; 95% CI, 1.3-7.7; P = .012), aeroallergen sensitivity at age 3 years (OR, 10.7; 95% CI, 2.1-55.0; P = .005), recurrent wheezing during the first 3 years of life (OR, 7.3; 95% CI, 1.2-43.3; P = .028), and CCL5 expression in nasal epithelia during acute RSV infection (OR, 3.8; 95% CI, 1.2-2.4; P < .001). White children (OR, 0.19; 95% CI, 0.04-0.93; P = .041) and children attending day care (OR, 0.18; 95% CI, 0.04-0.84; P = .029) had a decreased risk of physician-diagnosed asthma.
Conclusions
Approximately 50% of children who experience severe RSV bronchiolitis have a subsequent asthma diagnosis. The presence of increased CCL5 levels in nasal epithelia at the time of bronchiolitis or the development of allergic sensitization by age 3 years are associated with increased likelihood of subsequent asthma.
doi:10.1016/j.jaci.2012.02.010
PMCID: PMC3612548  PMID: 22444510
Bronchiolitis; respiratory syncytial virus; asthma; prospective cohort; CCL5
12.  Immune responses to self-antigens in asthma patients: Clinical and immuno-pathological implications 
Human Immunology  2012;73(5):511-516.
Asthma leads to chronic airway inflammation that shares pathological features of chronic rejection after lung transplantation. Due to significant role of autoimmunity in chronic rejection, we hypothesized that immunity to self-antigens may also be present in asthma. The goal was to define immune responses to self-antigens in patients with asthma. Blood and clinical data were collected from 99 asthmatics and 60 controls. Serum was analyzed for antibodies (Abs) to Collagen V (ColV) by ELISA and correlated with disease severity. Asthmatics' sera were tested in human protein array to determine immune responses to other self-antigens. Asthmatics had higher concentration of Abs to ColV (predominantly IgG isotype) compared to control (p < 0.01). These Abs correlated with severe asthma (p<0.01) and corticosteroid use (p=0.032). Additionally, Abs to novel self-antigens epidermal group factor receptor (EGFr), activin A type 1 receptor, and alpha-catenin (α-catenin) were detected in asthmatics. We conclude that Abs to self-antigens (ColV, EGFr, Activin A type 1 receptor, and α-catenin) are present in asthmatics sera correlating with clinical disease. Epithelial damage from airway inflammation during asthma may result in exposure of cryptic self-antigens or their determinants resulting in immune response to self-antigens and these may contribute to pathogenesis of asthma.
doi:10.1016/j.humimm.2012.02.010
PMCID: PMC3338898  PMID: 22386692
Asthma; Autoimmunity; Collagen V; epidermal growth factor receptor; Activin A type 1 receptor; alpha catenin
13.  Sleep Quality and Asthma Control and Quality of Life in Non-Severe and Severe Asthma 
Sleep & breathing = Schlaf & Atmung  2011;16(4):1129-1137.
Purpose
The effect of sleep quality on asthma control independent from common comorbidities like gastroesophageal reflux disease (GERD) and obstructive sleep apnea (OSA) is unknown. This study examined the association between sleep quality and asthma control and quality of life after accounting for OSA and GERD in non-severe (NSA) and severe (SA) asthma.
Methods
Cross-sectional data from 60 normal controls, 143 with NSA, and 79 with SA participating in the Severe Asthma Research Program was examined. Those who reported using positive airway pressure therapy or were at high risk for OSA were excluded.
Results
Both SA and NSA had poorer sleep quality than controls, with SA reporting the worst sleep quality. All asthmatics with GERD and 92% of those without GERD had poor sleep quality (p =.02). The majority (88%–100%) of NSA and SA participants who did not report nighttime asthma disturbances still reported having poor sleep quality. In both NSA and SA, poor sleep quality was associated with worse asthma control and quality of life after controlling for GERD and other covariates.
Conclusions
These results suggest that poor sleep quality is associated with poor asthma control and quality of life among asthmatics and cannot be explained by comorbid GERD and nighttime asthma disturbances.
doi:10.1007/s11325-011-0616-8
PMCID: PMC3617495  PMID: 22102290
Asthma control; Gastroesphogeal reflux disease; Sleep
14.  Severe Asthma 
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.
doi:10.1164/rccm.201107-1317PP
PMCID: PMC3297096  PMID: 22095547
asthma; remodeling; inflammation; bronchoscopy; imaging
16.  Lower levels of plasmacytoid dendritic cells in peripheral blood are associated with a diagnosis of asthma 6 years after severe respiratory syncytial virus bronchiolitis 
Background
Plasmacytoid dendritic cells (DC) play a crucial role in antiviral immunity and promoting Th1 polarization, possibly protecting against development of allergic disease.
Objective
Examination of the relationship between peripheral blood plasmacytoid DC levels and manifestations of asthma and atopy early in life.
Methods
We have isolated peripheral blood mononuclear cells (PBMC) from 73 children (mean age ± SD: 6.6 ± 0.5 years old) participating in the RSV Bronchiolitis in Early Life (RBEL) study. Flow cytometry was performed on PBMC detecting DC surface-markers: Blood Dendritic Cell Antigens (BDCA) 1, 3, and 2 which identify myeloid type 1, type 2, and plasmacytoid cells respectively. Total serum IgE, peripheral eosinophil count, and allergy skin tests were documented.
Results
45% (n=33) of study participants had physician-diagnosed asthma by 6 years of age. These children had significantly lower quantities (mean ± SD) of plasmacytoid DC than their non-asthmatic counterparts (1020 ± 921 vs. 1952 ± 1170 cells per 106 PBMC, p=0.003). We found significantly lower numbers of myeloid dendritic cells in children with asthma (3836 ± 2472 cells per 106 PBMC) compared with those without (4768 ± 2224 cells per 106 PBMC, p=0.02); however, this divergence was not significant after adjusting for covariates of age, gender, race, skin test reactivity, smoke exposure, and day care attendance. We did not identify any direct association between DC levels and markers of atopy: skin test reactivity, peripheral eosinophilia, and IgE level.
Conclusion
Children who are diagnosed with asthma after severe RSV bronchiolitis appear to have a relative deficiency of plasmacytoid DC in peripheral blood.
doi:10.1111/j.1399-3038.2008.00818.x
PMCID: PMC3515331  PMID: 19140903
dendritic cell; asthma; respiratory syncytial virus
17.  How Cytokines Co-occur across Asthma Patients: From Bipartite Network Analysis to a Molecular-Based Classification 
Journal of Biomedical Informatics  2011;44(Suppl 1):S24-S30.
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.
doi:10.1016/j.jbi.2011.09.006
PMCID: PMC3277832  PMID: 21986291
18.  Impact of Race on Asthma Treatment Failures in the Asthma Clinical Research Network 
Rationale: Recent studies suggest that people with asthma of different racial backgrounds may respond differently to various therapies.
Objectives: To use data from well-characterized participants in prior Asthma Clinical Research Network (ACRN) trials to determine whether racial differences affected asthma treatment failures.
Methods: We analyzed baseline phenotypes and treatment failure rates (worsening asthma resulting in systemic corticosteroid use, hospitalization, emergency department visit, prolonged decrease in peak expiratory flow, increase in albuterol use, or safety concerns) in subjects participating in 10 ACRN trials (1993–2003). Self-declared race was reported in each trial and treatment failure rates were stratified by race.
Measurements and Main Results: A total of 1,200 unique subjects (whites = 795 [66%]; African Americans = 233 [19%]; others = 172 [14%]; mean age = 32) were included in the analyses. At baseline, African Americans had fewer asthma symptoms (P < 0.001) and less average daily rescue inhaler use (P = 0.007) than whites. There were no differences in baseline FEV1 (% predicted); asthma quality of life; bronchial hyperreactivity; or exhaled nitric oxide concentrations. A total of 147 treatment failures were observed; a significantly higher proportion of African Americans (19.7%; n = 46) experienced a treatment failure compared with whites (12.7%; n = 101) (odds ratio = 1.7; 95% confidence interval, 1.2–2.5; P = 0.007). When stratified by treatment, African Americans receiving long-acting β-agonists were twice as likely as whites to experience a treatment failure (odds ratio = 2.1; 95% confidence interval, 1.3–3.6; P = 0.004), even when used with other controller therapies.
Conclusions: Despite having fewer asthma symptoms and less rescue β-agonist use, African-Americans with asthma have more treatment failures compared with whites, especially when taking long-acting β-agonists.
doi:10.1164/rccm.201103-0514OC
PMCID: PMC3361331  PMID: 21885625
asthma; long-acting β-agonist; African Americans; race; treatment failure
19.  Journal Allergy & Clinical Immunology Perspective: Lung imaging in Asthma: The picture is clearer 
Imaging of the lungs in patients with asthma has evolved dramatically over the last decade with sophisticated techniques, such as computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET) and single photon emission computed tomography (SPECT). New insights into current and future modalities for imaging in asthma and their application are discussed to potentially shed a clearer picture of the underlying pathophysiology of asthma, especially severe asthma, and the proposed clinical utility of imaging in this common disease.
doi:10.1016/j.jaci.2011.04.051
PMCID: PMC3187916  PMID: 21636118
asthma; imaging; CT chest; MRI
20.  Safety of Investigative Bronchoscopy in the Severe Asthma Research Program 
Background
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.
Objective
To prospectively evaluate changes in lung function and the frequency of adverse events related to investigative bronchoscopy.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.jaci.2011.02.042
PMCID: PMC3149754  PMID: 21496892
investigative bronchoscopy; safety; severe asthma; exacerbation
21.  A stochastic T cell response criterion 
The adaptive immune system relies on different cell types to provide fast and coordinated responses, characterized by recognition of pathogenic challenge, extensive cellular proliferation and differentiation, as well as death. T cells are a subset of the adaptive immune cellular pool that recognize immunogenic peptides expressed on the surface of antigen-presenting cells by means of specialized receptors on their membrane. T cell receptor binding to ligand determines T cell responses at different times and locations during the life of a T cell. Current experimental evidence provides support to the following: (i) sufficiently long receptor–ligand engagements are required to initiate the T cell signalling cascade that results in productive signal transduction and (ii) counting devices are at work in T cells to allow signal accumulation, decoding and translation into biological responses. In the light of these results, we explore, with mathematical models, the timescales associated with T cell responses. We consider two different criteria: a stochastic one (the mean time it takes to have had N receptor–ligand complexes bound for at least a dwell time, τ, each) and one based on equilibrium (the time to reach a threshold number N of receptor–ligand complexes). We have applied mathematical models to previous experiments in the context of thymic negative selection and to recent two-dimensional experiments. Our results indicate that the stochastic criterion provides support to the thymic affinity threshold hypothesis, whereas the equilibrium one does not, and agrees with the ligand hierarchy experimentally established for thymic negative selection.
doi:10.1098/rsif.2012.0205
PMCID: PMC3479899  PMID: 22745227
22.  Importance of hedgehog interacting protein and other lung function genes in asthma 
Background
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.
Objectives
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1016/j.jaci.2011.01.056
PMCID: PMC3105202  PMID: 21397937
Asthma; Genetics; Asthma severity; Meta-analysis; FEV1; FVC; FEV1/FVC; HHIP; FAM13A; PTCH1
23.  Obesity and asthma, an association modified by age of asthma onset 
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1016/j.jaci.2011.03.036
PMCID: PMC3128802  PMID: 21624618
Severe; asthma; obesity; SARP
24.  Airway Microbiota and Bronchial Hyperresponsiveness in Patients with Sub-optimally Controlled Asthma 
Background
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.
Objective
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1016/j.jaci.2010.10.048
PMCID: PMC3037020  PMID: 21194740
microbiome; bacteria; asthma; 16S rRNA; PhyloChip
25.  Asthma Friendly Pharmacies: A Model to Improve Communication and Collaboration among Pharmacists, Patients, and Healthcare Providers 
Pharmacists, with expertise in optimizing drug therapy outcomes, are valuable components of the healthcare team and are becoming increasingly involved in public health efforts. Pharmacists and pharmacy technicians in diverse community pharmacy settings can implement a variety of asthma interventions when they are brief, supported by appropriate tools, and integrated into the workflow. The Asthma Friendly Pharmacy (AFP) model addresses the challenges of providing patient-focused care in a community pharmacy setting by offering education to pharmacists and pharmacy technicians on asthma-related pharmaceutical care services, such as identifying or resolving medication-related problems; educating patients about asthma and medication-related concepts; improving communication and strengthening relationships between pharmacists, patients, and other healthcare providers; and establishing higher expectations for the pharmacist’s role in patient care and public health efforts. This article describes the feasibility of the model in an urban community pharmacy setting and documents the interventions and communication activities promoted through the AFP model.
doi:10.1007/s11524-010-9514-9
PMCID: PMC3042067  PMID: 21337057
Asthma; Community pharmacy; Pharmacists; Pharmaceutical care; Collaboration; Communication

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