[Show abstract][Hide abstract] ABSTRACT: Rationale: Effective therapeutic interventions for chronic, idiopathic lung diseases remain elusive. Normalized T cell function is an important contributor to spontaneous resolution of pulmonary sarcoidosis. Upregulation of inhibitor receptors, such as Programmed Death-1 (PD-1) and its ligand, PD-L1, are important inhibitors of T cell function. Methods: Gene expression profiles of sarcoidosis and healthy control peripheral blood mononuclear cells (PBMC) were analyzed at baseline and follow up. Flow cytometry was used to measure ex-vivo expression of PD-1 and PD-L1 on systemic and bronchoalveolar lavage (BAL)-derived cells of sarcoidosis and control subjects, as well as the effects of PD-1 pathway blockade on cellular proliferation following T cell receptor (TCR) stimulation. Immunohistochemistry analysis for PD-1/PD-L1 expression was conducted on sarcoidosis, malignant and healthy control lung specimens. Measurements and Main Results: Microarray analysis demonstrates longitudinal increase in PDCD1 gene expression in sarcoidosis PBMC. IHC analysis revealed increased PD-L1 expression within sarcoidosis granulomas and lung malignancy, but was absent in healthy lungs. Increased numbers of sarcoidosis PD-1+ CD4+T cells are present systemically, compared to healthy controls (p<0.0001). Lymphocytes with reduced proliferative capacity exhibited increased proliferation with PD-1 pathway blockade. Longitudinal analysis of sarcoidosis subjects revealed reduced PD-1+ CD4+ T cells with spontaneous clinical resolution, but not with disease progression. Conclusions: Analogous to the effects in other chronic lung diseases, these findings demonstrate that the PD-1 pathway is an important contributor to sarcoidosis CD4+ T cell proliferative capacity and clinical outcome. Blockade of the PD-1 pathway may be a viable therapeutic target to optimize clinical outcomes.
Full-text · Article · Jul 2014 · American Journal of Respiratory and Critical Care Medicine
[Show abstract][Hide abstract] ABSTRACT: Objective:
To determine the feasibility of administering iloprost by inhalation in patients with mild atopic asthma.
Volunteers underwent supervised inhalation of iloprost in the clinic with measurement of spirometry and blood pressure for 2 hours. The volunteers then inhaled iloprost four times daily at a dose of 2.5 or 5 μg for 14 days. Spirometry, asthma questionnaires, peak flow diaries, measurement of methacholine responsiveness, and exhaled nitric oxide concentrations were obtained prior to and after the treatment period.
Chronic inhalation of iloprost (2.5-5 μg) did not alter spirometry or methacholine responsiveness.
Inhaled iloprost in carefully selected volunteers with mild asthma appears to be a suitable intervention to explore the effects of prostacyclin in human asthma.
No preview · Article · Oct 2012 · Journal of Asthma
[Show abstract][Hide abstract] ABSTRACT: Current asthma guidelines recommend assessing the level of a patient's asthma control. Consequently, there is increasing use of asthma control as an outcome measure in clinical research studies. Several composite assessment instruments have been developed to measure asthma control.
National Institutes of Health institutes and federal agencies convened an expert group to propose the most appropriate standardized composite score of asthma control instruments to be used in future asthma studies.
We conducted a comprehensive search of PubMed using both the National Library of Medicine's Medical Subject Headings and key terms to identify studies that attempted to develop and/or test composite score instruments for asthma control. We classified instruments as core (required in future studies), supplemental (used according to study aims and standardized), or emerging (requiring validation and standardization). This work was discussed at a National Institutes of Health-organized workshop convened in March 2010 and finalized in September 2011.
We identified 17 composite score instruments with published validation information; all had comparable content. Eight instruments demonstrated responsiveness over time; 3 demonstrated responsiveness to treatment. A minimal clinically important difference has been established for 3 instruments. The instruments have demographic limitations; some are proprietary, and their use could be limited by cost.
Two asthma composite score instruments are sufficiently validated for use in adult populations, but additional research is necessary to validate their use in nonwhite populations. Gaps also exist in validating instruments for pediatric populations.
No preview · Article · Mar 2012 · The Journal of allergy and clinical immunology
[Show abstract][Hide abstract] ABSTRACT: Acute asthma severity scores facilitate assessment and implementation of timely and appropriate therapy for pediatric patients but are complex and challenging for clinicians to use at the bedside.
To assess whether a simple, bedside acute asthma severity score comprising 3 standard clinical measures performs as well as more comprehensive asthma scores.
We prospectively enrolled participants 5 to 17 years of age with acute asthma exacerbations. We recorded 3 asthma scores at baseline and after 2 hours of treatment: the Pediatric Asthma Severity Score (PASS), the Pediatric Respiratory Assessment Measure (PRAM), and the RAD score (Respiratory rate; Accessory muscle use; Decreased breath sounds). We assessed each score for criterion validity in predicting baseline percent forced expiratory volume in 1 second (%FEV(1)) and for responsiveness in predicting change of %FEV(1) after 2 hours of treatment using multiple linear regression models adjusted for age, race, sex, and Global Initiative for Asthma chronic control.
Of 536 participants included for analyses, median age was 8.8 years, 60% were male, and 58% were African American. The 3 acute asthma scores demonstrated similar criterion validity to explain variation of baseline %FEV(1) (R(2): 0.434 [PASS]; 0.462 [PRAM]; 0.426 [RAD]), but none demonstrated clinically significant responsiveness to change in %FEV(1) (R(2): 0.109 [PASS]; 0.106 [PRAM]; 0.139 [RAD]).
The RAD score, comprising 3 routinely measured bedside clinical parameters, is a simple and easily used instrument for assessing the severity of an acute asthma exacerbation and has comparable criterion validity and improved responsiveness when compared with 2 more complex acute asthma scores.
No preview · Article · Jul 2011 · Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology
[Show abstract][Hide abstract] ABSTRACT: Acute asthma exacerbations are one of the most common reasons for paediatric emergency department visits and hospitalisations, and a relapse frequently necessitates repeat urgent care. While care plans exist, there are no acute asthma prediction rules (APRs) to assess severity and predict outcome. The primary objective of the Acute Asthma Severity Assessment Protocol study is to develop a multivariable APR for acute asthma exacerbations in paediatric patients. A prospective, convenience sample of paediatric patients aged 5-17 years with acute asthma exacerbations who present to an urban, academic, tertiary paediatric emergency department was enrolled. The study protocol and data analysis plan conform to accepted biostatistical and clinical standards for clinical prediction rule development. Modelling of the APR will be performed once the entire sample size of 1500 has accrued. It is anticipated that the APR will improve resource utilisation in the emergency department, aid in standardisation of disease assessment and allow physician and non-physician providers to participate in earlier objective decision making. The objective of this report is to describe the study objectives and detailed methodology of the Acute Asthma Severity Assessment Protocol study.
Full-text · Article · May 2011 · Emergency Medicine Journal
[Show abstract][Hide abstract] ABSTRACT: Purpose: Percent predicted forced expiratory volume in one second (%FEV1) is an accepted criterion standard for severity of airways obstruction in acute asthma, but is frequently not available in acute care settings. Accessory muscle use is a readily available, easily identifiable bedside physical finding. We sought to assess the severity-dependent relationship of pre-treatment accessory muscle use with both %FEV1 and disposition decision among pediatric patients with acute exacerbations.
Methods: We prospectively enrolled participants ages 5 to 17 years with asthma and signs or symptoms of an acute exacerbation who presented to our urban, tertiary care pediatric emergency department (PED). We defined accessory muscle use as any visible use of the scalene, sternocleidomastoid-suprasternal, intercostal or subcostal muscles. Accessory muscle use was quantified as none, one group, or two or more muscle groups. The clinical team made the disposition decision (hospitalization/discharge) and was blinded to %FEV1 values.
We compared pre-treatment accessory muscle use with simultaneous %FEV1 for participants meeting all American Thoracic Society (ATS) spirometry criteria, and with disposition for the entire cohort. We used the Kruskal-Wallis and Chi-square tests, respectfully, for these analyses, and adjusted for age, gender and race in a third, multivariable model.
Results: Between April, 2008, and December, 2009, 541 eligible patients were enrolled and 478 unique participants were included for analyses. Median age was 8.8 years (IQR 6.8, 11.5), 60% male, and 56% African-American; 75% were discharged to home, 17% admitted to the floor, and 8% to the PICU.
All participants attempted spirometry, and 257 (54%) met all ATS criteria. %FEV1 (IQR) was 76% (58, 87) in those without use of any, 49% (39, 63) in those with use of one, and 34% (24, 43) in those with use of two or more accessory muscle groups (P<0.001, Figure). Of the entire cohort (n=478), accessory muscle use was noted in 244 (51%). The clinical team hospitalized 28 (12%) of those without accessory muscle use, 37 (28%) of those with use of one group, and 54 (48%) of those with use of more than one group (p<0.001). Accessory muscle use remained associated with increased odds of hospitalization when adjusted for age, gender and race in the multivariable model (OR=4.57 95%CI: 2.78-7.49, P<0.001).
Conclusion: Accessory muscle use in pediatric patients with acute asthma exacerbations is associated with both decreased %FEV1 and with the decision for asthma hospitalization in a severity-dependent fashion. Accessory muscle use assessment is of value to clinicians because it is simple, low cost, relatively objective, and physiologically plausible, as it is indicative of increased work of breathing.
Figure: Top: Boxes comprise interquartile ranges with median lines. Fences are 1.5 x IQR beyond IQR bounds. Bottom: Disposition of entire study cohort according to accessory muscle use.
[Show abstract][Hide abstract] ABSTRACT: Nuclear factor kappa B (NF-kappa B) is a critical transcription factor for the production of many inflammatory cytokines. It is activated in the airway epithelium of human asthmatics and in mice after allergic stimulation. To examine the role of NF-kappa B activation in allergic inflammation, the authors generated transgenic mouse lines that allowed for the inducible stimulation of NF-kappa B in airway epithelial cells. After allergic sensitization with ovalbumin and alum, mice were challenged daily with ovalbumin aerosols and NF-kappa B was activated in airway epithelium by administration of doxycycline. Enhancement of airway epithelial NF-kappa B expression alone did not lead to increased airway responsiveness to methacholine. However, induction of epithelial NF-kappa B during allergic inflammation caused airway hyperresponsiveness, increased airway neutrophilic and lymphocytic inflammation and goblet cell hyperplasia. Accompanying the exaggerated inflammation was an increase in the cytokines granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-15, and KC. Interestingly, the counter regulatory interleukin, IL-10, was suppressed by NF-kappa B activation. The epithelial NF-kappa B dependent modulation of these cytokines provides a plausible explanation for the increased inflammation seen with overexpression of NF-kappa B. Modulation of airway epithelial NF-kappa B activation enhances the airway hyperresponsiveness and mucus secretion found in the mouse lung during allergic inflammation. NF-kappa B represents a potential target for pharmacologic intervention in human asthma.
Full-text · Article · Dec 2009 · Experimental Lung Research
[Show abstract][Hide abstract] ABSTRACT: To determine if African American and European American children with asthma admitted to an intensive care unit (ICU) had different characteristics, we conducted a retrospective chart review of asthma admissions to the region's only pediatric ICU.
A chart review was performed on 125 patients with asthma admitted to the pediatric critical care unit at Vanderbilt Children's Hospital. Descriptive statistics, clinical characteristics, and disparities in care were compared using either Fisher's exact tests or Wilcoxon ranksum tests.
Most of the children reported previous admissions to a pediatric ICU (63%) or a hospital (82%) for asthma. Despite this, only 48% of the children were taking inhaled corticosteroids before admission. Only 28% of the children reported being followed by an asthma specialist, but, of these, 97% were taking corticosteroids. There were no racial/ethnic disparities in medication use, treatment, or outcomes.
We found no racial/ethnic disparities in inpatient/outpatient medication usage, treatment, or outcomes between African American and European American children in our cohort. Recurrent admissions to the ICU among children with severe asthma are common, and inhaled corticosteroids usage is relatively low. Asthmatic children with ICU admissions should be followed and treated aggressively by an asthma specialist.
Preview · Article · Nov 2009 · Journal of the National Medical Association
[Show abstract][Hide abstract] ABSTRACT: African Americans are disproportionately affected by asthma. Social and economic factors play a role in this disparity, but there is evidence that genetic factors may also influence the development of asthma and response to therapy in African American children. Our hypothesis is that variations in asthma related genes contribute to the observed asthma disparities by influencing the response to asthma-specific therapy. In order to test this hypothesis, we characterized the clinical response to asthma-specific therapy in 107 African American children who presented to the emergency room in status asthmaticus, with a primary outcome indicator of length of time on continuous albuterol. Single locus analysis indicated that genotype variation in glutathione-dependent S-nitrosoglutathione reductase (GSNOR) is associated with a decreased response to asthma treatment in African American children. A post hoc multi-locus analysis revealed that a combination of four single nucleotide polymorphisms (SNPs) within GSNOR, adrenergic receptor beta 2, and carbamoyl phosphate synthetase-1 give a 70% predictive value for lack of response to therapy. This predictive model needs replication in other cohorts of patients with asthma, but suggests gene-gene interactions may have greater significance than that identified with single variants. Our findings also suggest that genetic variants may contribute to the observed population disparities in asthma.
No preview · Article · Jul 2009 · Pediatric Pulmonology
[Show abstract][Hide abstract] ABSTRACT: Invariant natural killer T (iNKT) cells produce cytokines that can influence the immune response to infection or allergen. Controversy surrounds their role in exacerbations of human atopic asthma.
To determine the effect of allergen challenge on iNKT cells' mobilization to the airways and blood and to establish the relationship between airway iNKT cells and bronchial sensitivity to methacholine and allergen in patients with atopic asthma.
We performed flow cytometry analysis for the iNKT cell receptor Va24 and V311 on bronchoalveolar lavage (BAL) cells at baseline and 24 hours after segmental antigen challenge (SAC) (n = 8) and on peripheral blood mononuclear cells (PBMCs) at baseline and 6 to 7 hours after inhaled allergen (n = 10). Challenges were performed using standardized protein allergens to which the participants were sensitive.
The number of BAL eosinophils increased 24 hours after SAC. The low mean (SEM) baseline percentage of iNKT cells in the population of BAL CD4' T cells remained unchanged 24 hours after SAC (0.035% [0.01%] vs 0.049% [0.02%]; n = 8; P = .50). Likewise, the mean (SEM) percentage of iNKT cells in PBMCs was unchanged after inhaled allergen provocation (0.068% [0.033%] vs 0.057% [0.026%]; n = 10; P = .10). No correlation was found between iNKT cells in BAL and the sensitivity to inhaled methacholine or allergen.
The percentages of both BAL and peripheral blood iNKT cells did not increase during allergen provoked asthmatic responses. Determination of iNKT cells in airway biopsy specimens would allow conclusively ruling against mobilization of iNKT cells in allergen-induced asthma exacerbation in humans.
No preview · Article · Jun 2009 · Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology
[Show abstract][Hide abstract] ABSTRACT: The Shanghai Women's Asthma and Allergy Study is the first population-based incidence study designed to assess the associations of dietary antioxidant intake and measures of oxidative stress and antioxidant enzyme activity with development of adult-onset asthma and allergic rhinitis. A total of 65,732 participants in the Shanghai Women's Health Study, an ongoing cohort study in seven districts of Shanghai, People's Republic of China, were recruited to the Shanghai Women's Asthma and Allergy Study from 2003 to 2007. Dietary intake was assessed in the parent study by using a validated and quantitative food frequency questionnaire at baseline recruitment and at the first biennial follow-up survey. Blood and urine samples were collected to measure baseline oxidative stress, antioxidant enzyme activity, and nutrient levels at the baseline survey. Incident asthma and allergic rhinitis were assessed by using a modification of the International Study of Asthma and Allergies in Childhood questionnaire during the biennial in-person survey of the Shanghai Women's Health Study. Diagnosis of asthma was confirmed by either methacholine challenge testing or test of reversibility to beta-agonists. Dietary antioxidant intake, plasma antioxidants, antioxidant enzymes, and urinary isoprostanes, a marker of oxidative stress, were measured prior to disease onset. This paper describes the study objectives, design, population demographics, and recruitment results.
Full-text · Article · Jul 2008 · American journal of epidemiology
[Show abstract][Hide abstract] ABSTRACT: To investigate changes in oxidant stress during and following acute asthma exacerbations, this study measured 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP (F(2)-IsoP-M), the major urinary metabolite of 15-F(2t)-IsoP, in eight asthmatic adults, during and following an asthma hospitalization. F(2)-IsoP-M concentrations at admission and follow-up were significantly higher than discharge (admission median: 4.12 ng/Cr mg, range 1.89-7.8; follow-up: 2.47 ng/Cr mg (1.56-6.86); discharge: 1.42 ng/Cr mg (0.7-4.44); both p<0.01), but not significantly different between admission and follow-up. F(2)-IsoP-M concentrations at follow-up were higher than a control group with stable asthma (0.68 ng/Cr mg (0.31-1.5), p=0.0008). In conclusion, asthma exacerbations requiring hospitalization are associated with 6-fold higher urinary F(2)-IsoP-M concentrations compared to stable asthmatics. F(2)-IsoP-M concentrations decreased significantly during hospitalization, but significant elevations 3 months following hospitalization suggest ongoing oxidative stress despite clinical improvement. Urinary F(2)-IsoP-M may be a clinically useful, simple non-invasive systemic measure of oxidative stress in asthmatics, providing information not captured by spirometry or symptoms.
No preview · Article · Sep 2007 · Free Radical Research
[Show abstract][Hide abstract] ABSTRACT: Although airway epithelial cells provide important barrier and host defense functions, a crucial role for these cells in development of acute lung inflammation and injury has not been elucidated. We investigated whether NF-kappaB pathway signaling in airway epithelium could decisively impact inflammatory phenotypes in the lungs by using a tetracycline-inducible system to achieve selective NF-kappaB activation or inhibition in vivo. In transgenic mice that express a constitutively active form of IkappaB kinase 2 under control of the epithelial-specific CC10 promoter, treatment with doxycycline induced NF-kappaB activation with consequent production of a variety of proinflammatory cytokines, high-protein pulmonary edema, and neutrophilic lung inflammation. Continued treatment with doxycycline caused progressive lung injury and hypoxemia with a high mortality rate. In contrast, inducible expression of a dominant inhibitor of NF-kappaB in airway epithelium prevented lung inflammation and injury resulting from expression of constitutively active form of IkappaB kinase 2 or Escherichia coli LPS delivered directly to the airways or systemically via an osmotic pump implanted in the peritoneal cavity. Our findings indicate that the NF-kappaB pathway in airway epithelial cells is critical for generation of lung inflammation and injury in response to local and systemic stimuli; therefore, targeting inflammatory pathways in airway epithelium could prove to be an effective therapeutic strategy for inflammatory lung diseases.
Full-text · Article · Jun 2007 · The Journal of Immunology
[Show abstract][Hide abstract] ABSTRACT: The allergic inflammation occurring in asthma is believed to be accompanied by the production of free radicals. To investigate the role of free radicals and the cells affected we turned to a murine model of allergic inflammation produced by sensitization to ovalbumin with subsequent aerosol challenge. We examined oxidant stress by measuring and localizing the sensitive and specific marker of lipid peroxidation, the F2-isoprostanes. F2-isoprostanes in whole lung increased from 0.30 +/- 0.08 ng/lung at baseline to a peak of 0.061 +/- 0.09 ng/lung on the ninth day of daily aerosol allergen challenge. Increased immunoreactivity to 15-F2t-IsoP (8-iso-PGF2alpha) or to isoketal protein adducts was found in epithelial cells 24 h after the first aerosol challenge and at 5 days in macrophages. Collagen surrounding airways and blood vessels, and airway and vascular smooth muscle, also exhibited increased immunoreactivity after ovalbumin challenge. Dietary vitamin E restriction in conjunction with allergic inflammation led to increased whole lung F2-isoprostanes while supplemental vitamin E suppressed their formation. Similar changes in immunoreactivity to F2-isoprostanes were seen. Airway responsiveness to methacholine was also increased by vitamin E depletion and decreased slightly by supplementation with the antioxidant. Our findings indicate that allergic airway inflammation in mice is associated with an increase in oxidant stress, which is most striking in airway epithelial cells and macrophages. Oxidant stress plays a role in the production of airway responsiveness.
No preview · Article · May 2006 · Free Radical Biology and Medicine
[Show abstract][Hide abstract] ABSTRACT: F2-isoprostanes are produced in vivo by nonenzymatic peroxidation of arachidonic acid esterified in phospholipids. Increased urinary and plasma F2-isoprostane levels are associated with a number of human diseases. These metabolites are regarded as excellent markers of
oxidant stress in vivo. Isoprostanes are initially generated in situ, i.e. when the arachidonate precursor is esterified in phospholipids, and they are subsequently released in free form. Although
the mechanism(s) responsible for the release of free isoprostanes after in situ generation in membrane phospholipids is, for the most part, unknown, this process is likely mediated by phospholipase A2 activity(ies). Here we reported that human plasma contains an enzymatic activity that catalyzes this reaction. The activity
associates with high density and low density lipoprotein and comigrates with platelet-activating factor (PAF) acetylhydrolase
on KBr density gradients. Plasma samples from subjects deficient in PAF acetylhydrolase do not release F2-isoprostanes from esterified precursors. The intracellular PAF acetylhydrolase II, which shares homology to the plasma enzyme,
also catalyzes this reaction. We found that both the intracellular and plasma PAF acetylhydrolases have high affinity for
esterified F2-isoprostanes. However, the rate of esterified F2-isoprostane hydrolysis is much slower compared with the rate of hydrolysis of other substrates utilized by these enzymes.
Studies using PAF acetylhydrolase transgenic mice indicated that these animals have a higher capacity to release F2-isoprostanes compared with nontransgenic littermates. Our results suggested that PAF acetylhydrolases play key roles in the
hydrolysis of F2-isoprostanes esterified on phospholipids in vivo.
Preview · Article · Mar 2006 · Journal of Biological Chemistry