Background: Allergic bronchopulmonary aspergillosis (ABPA) is a disease with uncertain pathology.... more Background: Allergic bronchopulmonary aspergillosis (ABPA) is a disease with uncertain pathology. Studies have suggested a pathogenic role for TH2 cells. Previously, we demonstrated, in a small group of patients, that TH2 reactivity to a major Aspergillus fumigatus antigen was restricted by HLA-DR2 or HLA-DR5 alleles. Objectives: We sought to confirm whether susceptibility to ABPA is exclusively associated with HLA-DR locus and to investigate the involvement of HLA-DQ genes in the development of ABPA. Methods: Genomic DNA was extracted from patients with ABPA, patients without ABPA but with positive A fumigatus skin test responses and asthma or cystic fibrosis, and healthy control subjects. HLA-DR and HLA-DQ genes were detected by using low-resolution typing; high-resolution typing was done only on HLA-DR2– and HLA-DR5–positive individuals by using sequence-specific primers (PCR-SSP). Results: A significantly higher frequency of HLA-DR2 was observed in patients with ABPA versus those without ABPA (corrected P < .01) or healthy control subjects (corrected P < .01). Genotype analysis revealed that susceptibility to ABPA is associated with HLA-DR2 alleles DRB1*1503 and DRB1*1501 and, to a lesser extent, with the HLA-DR5 allele DRB1*1104. The presence of DR4 or DR7 alleles in non-DR2/5 patients with ABPA suggests that these alleles may also be contributing factors in this disease. Another striking observation was the significantly high frequency of HLA-DQ2 in patients without ABPA (67.4%) compared with patients with ABPA (20.5%) and normal control subjects (37.7%), suggesting that these alleles may confer protection in the population without ABPA. Conclusion: These genetic studies suggest that HLA-DR molecules DR2, DR5, and possibly DR4 or DR7 contribute to susceptibility while HLA-DQ2 contributes to resistance and that a combination of these genetic elements determines the outcome of ABPA in patients with cystic fibrosis and asthma. (J Allergy Clin Immunol 2000;106:723-9.)
Candida albicans (C. albicans) is a major nosocomial pathogen. We examined arachidonic acid (AA) ... more Candida albicans (C. albicans) is a major nosocomial pathogen. We examined arachidonic acid (AA) and cytokine production by monocytes stimulated with C. albicans. [14C]-AA labeled monocytes released 8.9 ±2.3% of the incorporated AA following stimulation with live C. albicans (C. albicans: monocyte of 16∶1) (P=0.0002). Prior studies indicate that solubleα-mannans andβ-glucans antagonize mannose andβ-glucan receptors, respectively. Preincubation of monocytes withα-mannan (100μg/ml) caused 45.8 ±5.7% inhibition of [14C]-AA release, whereasβ-glucan (100μg/ml) yielded 43.7 ±6.0% inhibition (Pβ (IL-1β), tumor necrosis factor-α (TNFα), interleukin-6 (IL-6) and interleukin-8 (IL-8). However, a-mannan orβ-glucan failed to inhibit IL-1β release. These data indicate that C. albicans induces monocytes to release AA and inflammatory cytokines. Furthermore, AA, but not cytokine liberation, is partially mediated by a-mannan andβ-glucan components of the fungus.
5-10% of asthma cases are poorly controlled chronically and refractory to treatment, and these se... more 5-10% of asthma cases are poorly controlled chronically and refractory to treatment, and these severe cases account for disproportionate asthma-associated morbidity, mortality, and health care utilization. While persons with severe asthma tend to have more airway obstruction, it is not known whether they represent the severe tail of a unimodal asthma population, or a severe asthma phenotype. We hypothesized that severe asthma has a characteristic physiology of airway obstruction, and we evaluated spirometry, lung volumes, and reversibility during a stable interval in 287 severe and 382 non-severe asthma subjects from the Severe Asthma Research Program. We partitioned airway obstruction into components of air trapping (indicated by FVC) and airflow limitation (indicated by FEV 1 /FVC). Severe asthma had prominent air trapping, evident as reduced FVC over the entire range of FEV 1 /FVC. This pattern was confirmed with measures of RV/TLC in a subgroup. In contrast, non-severe asthma did not exhibit prominent air trapping, even at FEV 1 /FVC<75% predicted. Air trapping also was associated with increases in total lung capacity and functional reserve capacity. After maximal bronchodilation, FEV 1 reversed similarly from baseline in severe and non-severe asthma, but the severe asthma classification was an independent predictor of residual reduction in FEV 1 after maximal bronchodilation. An increase in FVC accounted for most of the reversal of FEV 1 when baseline FEV 1 was <60% predicted. We conclude that air trapping is a characteristic feature of the severe asthma population, suggesting that there is a pathological process associated with severe asthma that makes airways more vulnerable to this component.
Rationale: Airway inflammation is common in severe asthma despite antiinflammatory therapy with c... more Rationale: Airway inflammation is common in severe asthma despite antiinflammatory therapy with corticosteroids. Lipoxin A 4 (LXA 4 ) is an arachidonic acid-derived mediator that serves as an agonist for resolution of inflammation. Objectives: Airway levels of LXA 4 , as well as the expression of lipoxin biosynthetic genes and receptors, in severe asthma. Methods: Samples of bronchoalveolar lavage fluid were obtained from subjects with asthma and levels of LXA 4 and related eicosanoids were measured. Expression of lipoxin biosynthetic genes was determined in whole blood, bronchoalveolar lavage cells, and endobronchial biopsies by quantitative polymerase chain reaction, and leukocyte LXA 4 receptors were monitored by flow cytometry. Measurements and Main Results: Individuals with severe asthma had significantly less LXA 4 in bronchoalveolar lavage fluids (11.2 6 2.1 pg/ml) than did subjects with nonsevere asthma (150.1 6 38.5 pg/ml; P , 0.05). In contrast, levels of cysteinyl leukotrienes were increased in both asthma cohorts compared with healthy individuals. In severe asthma, 15-lipoxygenase-1 mean expression was decreased fivefold in bronchoalveolar lavage cells. In contrast, 15-lipoxgenase-1 was increased threefold in endobronchial biopsies, but expression of both 5-lipoxygenase and 15-lipoxygenase-2 in these samples was decreased. Cyclooxygenase-2 expression was decreased in all anatomic compartments sampled in severe asthma. Moreover, LXA 4 receptor gene and protein expression were significantly decreased in severe asthma peripheral blood granulocytes. Conclusions: Mechanisms underlying pathological airway responses in severe asthma include lipoxin underproduction with decreased expression of lipoxin biosynthetic enzymes and receptors. Together, these results indicate that severe asthma is characterized, in part, by defective lipoxin counterregulatory signaling circuits.
Background-Asthma is a heterogeneous clinical disorder. Methods for objective identification of d... more Background-Asthma is a heterogeneous clinical disorder. Methods for objective identification of disease subtypes will focus on clinical interventions and help identify causative pathways. Few studies have explored phenotypes at a molecular level.
American Journal of Respiratory and Critical Care Medicine, 2007
Background: Severe asthma has been associated with severe exacerbations, lower lung function and ... more Background: Severe asthma has been associated with severe exacerbations, lower lung function and greater tissue inflammation. Previous studies have suggested that mutations in interleukin-4 receptor ␣ (IL4R␣) are associated with lower lung function, higher IgE, and a gain in receptor function. However, an effect on exacerbations and tissue inflammation has not been shown. Hypothesis: Allelic substitutions in IL4R␣ are associated with asthma exacerbations, lower lung function, and tissue inflammation, in particular to mast cells and IgE. Methods: Two well-characterized cohorts of subjects with severe asthma were analyzed for five single nucleotide polymorphisms (SNPs) in IL4R␣. These polymorphisms were compared with the history of severe asthma exacerbations and lung function. In the primary (National Jewish) cohort, these polymorphisms were also compared with endobronchial tissue inflammatory cells and local IgE. Results: In both cohorts, the presence of the minor alleles at E375A and Q551R, which were more common in African Americans, was associated with a history of severe exacerbations and lower lung function. In the National Jewish cohort, the C allele at E375A was associated with higher tissue mast cells and higher levels of IgE bound to mast cells. The significance for most of these associations remained when whites (the larger racial subgroup) were analyzed separately. Conclusions: SNPs in IL4R␣, which are more common in African Americans, are associated with severe asthma exacerbations, lower lung function, and increased mast cell-related tissue inflammation. Further studies of the impact of these mutations in African Americans and on receptor function are indicated.
The largest portion of the cost for asthma healthcare is due to hospitalizations. Improved method... more The largest portion of the cost for asthma healthcare is due to hospitalizations. Improved methods of healthcare delivery for patients with asthma are needed to prevent readmissions. From 1996 to 1999, 96 adult subjects (predominantly young African American women) hospitalized with an asthma exacerbation, who had a history of frequent healthcare use, were randomized to an asthma nurse specialist intervention (n ϭ 50) or a usual care group (n ϭ 46) for 6 months. Our aim was to decrease rates of readmissions within 6 months of hospital discharge, to reduce cost, and to improve health-related quality of life. Our results demonstrate a 60% reduction in total hospitalizations (31 readmissions in the intervention group and 71 in the control group, p ϭ 0.04), with no significant change in emergency department visits. Readmissions for asthma were reduced by 54% (21 vs. 42 in the control group; p ϭ 0.04). We found a marked reduction in lost work or school days: 246 versus 1,040 days in the control group (p ϭ 0.02). The intervention resulted in a substantial reduction in direct and indirect healthcare costs, saving $6,462 per patient (p ϭ 0.03). A brief intervention program focusing on high healthcare users with asthma can result in improved asthma control and reduced hospital use with substantial cost savings.
Morbidity and mortality due to asthma continues to increase despite advances in understanding the... more Morbidity and mortality due to asthma continues to increase despite advances in understanding the pathophysiology and treatment of the disease. We evaluated the potential risk factors for asthma morbidity and mortality in a large metropolitan city (St. Louis, MO) using small area geographic analysis. We found that the risk of hospitalization for children with asthma was 8.4 times greater (95% confidence interval [CI] 7.0-9.9) in lower socioeconomic zip code areas and 5.3 times greater (95% CI 4.7-5.9) in those zip codes with a higher percentage of African Americans. Similarly, the risk of death due to asthma was 6.4 times greater in the lower socioeconomic zip code areas (95% CI3.4-12.1). Lower socioeconomic status and African American race are strong risk factors for hospitalization and mortality from asthma. Public policy and healthcare resources need to be organized and directed more efficiently to this population.
Revisión de mru y mruv. El movimiento rectilíneo uniforme (mru) es un movimiento que se realiza c... more Revisión de mru y mruv. El movimiento rectilíneo uniforme (mru) es un movimiento que se realiza con velocidad constante, y la ecuación que permite representar ese movimiento es CAPÍTULO 1: : :
Background: Allergic bronchopulmonary aspergillosis (ABPA) is a disease with uncertain pathology.... more Background: Allergic bronchopulmonary aspergillosis (ABPA) is a disease with uncertain pathology. Studies have suggested a pathogenic role for TH2 cells. Previously, we demonstrated, in a small group of patients, that TH2 reactivity to a major Aspergillus fumigatus antigen was restricted by HLA-DR2 or HLA-DR5 alleles. Objectives: We sought to confirm whether susceptibility to ABPA is exclusively associated with HLA-DR locus and to investigate the involvement of HLA-DQ genes in the development of ABPA. Methods: Genomic DNA was extracted from patients with ABPA, patients without ABPA but with positive A fumigatus skin test responses and asthma or cystic fibrosis, and healthy control subjects. HLA-DR and HLA-DQ genes were detected by using low-resolution typing; high-resolution typing was done only on HLA-DR2– and HLA-DR5–positive individuals by using sequence-specific primers (PCR-SSP). Results: A significantly higher frequency of HLA-DR2 was observed in patients with ABPA versus those without ABPA (corrected P < .01) or healthy control subjects (corrected P < .01). Genotype analysis revealed that susceptibility to ABPA is associated with HLA-DR2 alleles DRB1*1503 and DRB1*1501 and, to a lesser extent, with the HLA-DR5 allele DRB1*1104. The presence of DR4 or DR7 alleles in non-DR2/5 patients with ABPA suggests that these alleles may also be contributing factors in this disease. Another striking observation was the significantly high frequency of HLA-DQ2 in patients without ABPA (67.4%) compared with patients with ABPA (20.5%) and normal control subjects (37.7%), suggesting that these alleles may confer protection in the population without ABPA. Conclusion: These genetic studies suggest that HLA-DR molecules DR2, DR5, and possibly DR4 or DR7 contribute to susceptibility while HLA-DQ2 contributes to resistance and that a combination of these genetic elements determines the outcome of ABPA in patients with cystic fibrosis and asthma. (J Allergy Clin Immunol 2000;106:723-9.)
Candida albicans (C. albicans) is a major nosocomial pathogen. We examined arachidonic acid (AA) ... more Candida albicans (C. albicans) is a major nosocomial pathogen. We examined arachidonic acid (AA) and cytokine production by monocytes stimulated with C. albicans. [14C]-AA labeled monocytes released 8.9 ±2.3% of the incorporated AA following stimulation with live C. albicans (C. albicans: monocyte of 16∶1) (P=0.0002). Prior studies indicate that solubleα-mannans andβ-glucans antagonize mannose andβ-glucan receptors, respectively. Preincubation of monocytes withα-mannan (100μg/ml) caused 45.8 ±5.7% inhibition of [14C]-AA release, whereasβ-glucan (100μg/ml) yielded 43.7 ±6.0% inhibition (Pβ (IL-1β), tumor necrosis factor-α (TNFα), interleukin-6 (IL-6) and interleukin-8 (IL-8). However, a-mannan orβ-glucan failed to inhibit IL-1β release. These data indicate that C. albicans induces monocytes to release AA and inflammatory cytokines. Furthermore, AA, but not cytokine liberation, is partially mediated by a-mannan andβ-glucan components of the fungus.
5-10% of asthma cases are poorly controlled chronically and refractory to treatment, and these se... more 5-10% of asthma cases are poorly controlled chronically and refractory to treatment, and these severe cases account for disproportionate asthma-associated morbidity, mortality, and health care utilization. While persons with severe asthma tend to have more airway obstruction, it is not known whether they represent the severe tail of a unimodal asthma population, or a severe asthma phenotype. We hypothesized that severe asthma has a characteristic physiology of airway obstruction, and we evaluated spirometry, lung volumes, and reversibility during a stable interval in 287 severe and 382 non-severe asthma subjects from the Severe Asthma Research Program. We partitioned airway obstruction into components of air trapping (indicated by FVC) and airflow limitation (indicated by FEV 1 /FVC). Severe asthma had prominent air trapping, evident as reduced FVC over the entire range of FEV 1 /FVC. This pattern was confirmed with measures of RV/TLC in a subgroup. In contrast, non-severe asthma did not exhibit prominent air trapping, even at FEV 1 /FVC<75% predicted. Air trapping also was associated with increases in total lung capacity and functional reserve capacity. After maximal bronchodilation, FEV 1 reversed similarly from baseline in severe and non-severe asthma, but the severe asthma classification was an independent predictor of residual reduction in FEV 1 after maximal bronchodilation. An increase in FVC accounted for most of the reversal of FEV 1 when baseline FEV 1 was <60% predicted. We conclude that air trapping is a characteristic feature of the severe asthma population, suggesting that there is a pathological process associated with severe asthma that makes airways more vulnerable to this component.
Rationale: Airway inflammation is common in severe asthma despite antiinflammatory therapy with c... more Rationale: Airway inflammation is common in severe asthma despite antiinflammatory therapy with corticosteroids. Lipoxin A 4 (LXA 4 ) is an arachidonic acid-derived mediator that serves as an agonist for resolution of inflammation. Objectives: Airway levels of LXA 4 , as well as the expression of lipoxin biosynthetic genes and receptors, in severe asthma. Methods: Samples of bronchoalveolar lavage fluid were obtained from subjects with asthma and levels of LXA 4 and related eicosanoids were measured. Expression of lipoxin biosynthetic genes was determined in whole blood, bronchoalveolar lavage cells, and endobronchial biopsies by quantitative polymerase chain reaction, and leukocyte LXA 4 receptors were monitored by flow cytometry. Measurements and Main Results: Individuals with severe asthma had significantly less LXA 4 in bronchoalveolar lavage fluids (11.2 6 2.1 pg/ml) than did subjects with nonsevere asthma (150.1 6 38.5 pg/ml; P , 0.05). In contrast, levels of cysteinyl leukotrienes were increased in both asthma cohorts compared with healthy individuals. In severe asthma, 15-lipoxygenase-1 mean expression was decreased fivefold in bronchoalveolar lavage cells. In contrast, 15-lipoxgenase-1 was increased threefold in endobronchial biopsies, but expression of both 5-lipoxygenase and 15-lipoxygenase-2 in these samples was decreased. Cyclooxygenase-2 expression was decreased in all anatomic compartments sampled in severe asthma. Moreover, LXA 4 receptor gene and protein expression were significantly decreased in severe asthma peripheral blood granulocytes. Conclusions: Mechanisms underlying pathological airway responses in severe asthma include lipoxin underproduction with decreased expression of lipoxin biosynthetic enzymes and receptors. Together, these results indicate that severe asthma is characterized, in part, by defective lipoxin counterregulatory signaling circuits.
Background-Asthma is a heterogeneous clinical disorder. Methods for objective identification of d... more Background-Asthma is a heterogeneous clinical disorder. Methods for objective identification of disease subtypes will focus on clinical interventions and help identify causative pathways. Few studies have explored phenotypes at a molecular level.
American Journal of Respiratory and Critical Care Medicine, 2007
Background: Severe asthma has been associated with severe exacerbations, lower lung function and ... more Background: Severe asthma has been associated with severe exacerbations, lower lung function and greater tissue inflammation. Previous studies have suggested that mutations in interleukin-4 receptor ␣ (IL4R␣) are associated with lower lung function, higher IgE, and a gain in receptor function. However, an effect on exacerbations and tissue inflammation has not been shown. Hypothesis: Allelic substitutions in IL4R␣ are associated with asthma exacerbations, lower lung function, and tissue inflammation, in particular to mast cells and IgE. Methods: Two well-characterized cohorts of subjects with severe asthma were analyzed for five single nucleotide polymorphisms (SNPs) in IL4R␣. These polymorphisms were compared with the history of severe asthma exacerbations and lung function. In the primary (National Jewish) cohort, these polymorphisms were also compared with endobronchial tissue inflammatory cells and local IgE. Results: In both cohorts, the presence of the minor alleles at E375A and Q551R, which were more common in African Americans, was associated with a history of severe exacerbations and lower lung function. In the National Jewish cohort, the C allele at E375A was associated with higher tissue mast cells and higher levels of IgE bound to mast cells. The significance for most of these associations remained when whites (the larger racial subgroup) were analyzed separately. Conclusions: SNPs in IL4R␣, which are more common in African Americans, are associated with severe asthma exacerbations, lower lung function, and increased mast cell-related tissue inflammation. Further studies of the impact of these mutations in African Americans and on receptor function are indicated.
The largest portion of the cost for asthma healthcare is due to hospitalizations. Improved method... more The largest portion of the cost for asthma healthcare is due to hospitalizations. Improved methods of healthcare delivery for patients with asthma are needed to prevent readmissions. From 1996 to 1999, 96 adult subjects (predominantly young African American women) hospitalized with an asthma exacerbation, who had a history of frequent healthcare use, were randomized to an asthma nurse specialist intervention (n ϭ 50) or a usual care group (n ϭ 46) for 6 months. Our aim was to decrease rates of readmissions within 6 months of hospital discharge, to reduce cost, and to improve health-related quality of life. Our results demonstrate a 60% reduction in total hospitalizations (31 readmissions in the intervention group and 71 in the control group, p ϭ 0.04), with no significant change in emergency department visits. Readmissions for asthma were reduced by 54% (21 vs. 42 in the control group; p ϭ 0.04). We found a marked reduction in lost work or school days: 246 versus 1,040 days in the control group (p ϭ 0.02). The intervention resulted in a substantial reduction in direct and indirect healthcare costs, saving $6,462 per patient (p ϭ 0.03). A brief intervention program focusing on high healthcare users with asthma can result in improved asthma control and reduced hospital use with substantial cost savings.
Morbidity and mortality due to asthma continues to increase despite advances in understanding the... more Morbidity and mortality due to asthma continues to increase despite advances in understanding the pathophysiology and treatment of the disease. We evaluated the potential risk factors for asthma morbidity and mortality in a large metropolitan city (St. Louis, MO) using small area geographic analysis. We found that the risk of hospitalization for children with asthma was 8.4 times greater (95% confidence interval [CI] 7.0-9.9) in lower socioeconomic zip code areas and 5.3 times greater (95% CI 4.7-5.9) in those zip codes with a higher percentage of African Americans. Similarly, the risk of death due to asthma was 6.4 times greater in the lower socioeconomic zip code areas (95% CI3.4-12.1). Lower socioeconomic status and African American race are strong risk factors for hospitalization and mortality from asthma. Public policy and healthcare resources need to be organized and directed more efficiently to this population.
Revisión de mru y mruv. El movimiento rectilíneo uniforme (mru) es un movimiento que se realiza c... more Revisión de mru y mruv. El movimiento rectilíneo uniforme (mru) es un movimiento que se realiza con velocidad constante, y la ecuación que permite representar ese movimiento es CAPÍTULO 1: : :
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