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Understanding Steroid-Refractory Severe Asthma
Abstracts AB181
J ALLERGY CLIN IMMUNOL VOLUME 139, NUMBER 2
Isolated BAL Neutrophilia and Unimodal Airway Epithelial IL-13 Inducible Gene Signatures Characterize Children with Treatment-Resistant Asthma
Larry Borish, MD, FAAAAI1, Thomas J. Braciale, MD, PhD2, DebbieAnn Shirley, MD3, John W. Steinke, PhD, FAAAAI4, Sandford Williams, MS5, Karlyn Pollack, BS5, Brian J. Capaldo, PhD5, and W. Gerald Teague, MD6; 1University of Virginia Health System, Charlottesville, VA, 2University of Virginia Hospital, Charlottesville, VA, 3C, University of Virginia, Charlottesville, VA, 4Asthma and Allergic Diseases Center, Charlottesville, VA, 5University of Virginia, Charlottesville, VA, 6Child Health Research Center, University of Virginia School of Medicine, Charlottesville, VA. RATIONALE: Assessment of lung fluid inflammatory markers and infectious species is indicated to inform treatment decisions in children with problematic asthma. The purpose of this study was to examine prevailing granulocyte patterns, potential pathogens, and bronchial epithelial IL-13-inducible gene signatures in 119 children with poor asthma control despite high-dose ICS treatment. METHODS: Children underwent bronchoscopy with BAL for granulocyte counts, PCR for respiratory viruses, bacterial cultures, and bronchial brush (n554) for epithelial IL13- inducible signature gene expression by qPCR. RESULTS: Asthma severity spanned mild/moderate (34%), severe (41%), and very severe (25%). Isolated neutrophilia was the prevailing granulocyte pattern (43.7%), followed by pauci-granulocytic (35.3%), mixed granulocytic (17.6%), and isolated eosinophilia (3.4%). Children with BAL neutrophilia were younger, less allergen sensitized, but had an 8-fold greater detection of potential bacterial pathogens (40.0%) compared to other granulocyte patterns (p50.0001). Enterovirus detection was common (26%) and evenly distributed among the four patterns. The IL13inducible three gene mean signature was unimodal, did not have a clearTh2 HIGH versus LOW cut point, and was highest in children with mixed granuloyctes (p50.08). CONCLUSIONS: Isolated BAL neutrophilia is common in young children with poorly-controlled asthma, in an age group with less allergen sensitization but abundant potential bacterial and viral pathogens in the airspaces. Unlike studies of adults with milder asthma on low-dose ICS, we could not identify a bimodal pattern of Th2 HIGH and LOW gene expression profiles, likely due to the suppressive effects of high-dose corticosteroid treatment in our sample.
577
Understanding Steroid-Refractory Severe Asthma
Marc Gauthier, MD1, Mahesh Raundhal, PhD2, Tim Oriss, PhD2, Prabir Ray, PhD3, Sally E. Wenzel, MD, FAAAAI4, and Anuradha Ray, PhD3; 1 University of Pittsburgh Medical Center, PITTSBURGH, PA, 2University of Pittsburgh, PITTSBURGH, PA, 3University of Pittsburgh, Pittsburgh, PA, 4The University of Pittsburgh Asthma Institute at UPMC and the University of Pittsburgh School of Medicine, Department of Pulmonary, Allergy and Critical Care Medicine, Pittsburgh, PA. RATIONALE: Severe Asthma (SA) is marked by poor corticosteroid (CS) response and frequent exacerbations leading to high cost and morbidity. Prior work showed elevated levels of airway IFN-g in ;50% of SA which was associated with worse lung function in a mouse model. We investigated whether CS treatment in the setting of type-1 inflammation further consolidates the type-1 signature. METHODS: mRNA levels of CXCL10 (a recruiter for IFN-g-secreting Tcells) were measured by qPCR in a monocytic cell line, in lungs of mice subjected to mild and severe asthma models and in human bronchoalveolar-lavage (BAL) cells obtained through the Severe Asthma Research
Program (SARP). Glucocorticoid receptor (GR) function was determined by luciferase reporter assay. RESULTS: We treated cells with stimuli known to induce CXCL10 (IFNg (100 ng/ml) or LPS (10 ng/ml)) and dexamethasone at two time-points (pre-treatment simulating chronic CS treatment and simultaneous treatment simulating a CS burst). Dexamethasone inhibited LPS induction of CXCL10 at both time-points. Dexamethasone pre-treatment increased IFN-g induced CXCL10 while simultaneous treatment had no effect, despite no impact on GR function. Mouse studies showed increased CXCL10 expression in SA model unchanged by dexamethasone. Similar results were seen in human BAL cell samples. CONCLUSIONS: We observed increased IFN-g-induced CXCL10 expression with dexamethasone pre-treatment, potentially contributing to CS insensitivity. This finding was confirmed using a mouse model of SA and samples from SA patients maintained on high dose CS. These findings suggest that CS may further consolidate type-1 inflammation in severe asthmatics.
578
Improving Antibiotic Choice in Hospitalized Medical Patients Reporting Penicillin Allergy
Kimberly G. Blumenthal, MD1, Paige G. Wickner, MD, FAAAAI2, Shelley Hurwitz, PhD3, Nicholas Pricco, BS4, Alexandra E. Nee, BA5, Karl Laskowski, MD, MBA3, Erica S. Shenoy, MD, PhD6, and Rochelle P. Walensky, MD, MPH6; 1Division of Rheumatology, Allergy and Immunology, Department of Medicine, Massachusetts General Hospital, Boston, MI, 2Division of Rheumatology, Allergy and Immunology, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, 3 Department of Medicine, Brigham and Women’s Hospital, Boston, MA, 4University of Minnesota, Minneapolis, MN, 5New York Medical College, Valhalla, NY, 6Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA. RATIONALE: Reported penicillin allergy rarely reflects penicillin intolerance. Failure to address inpatient penicillin allergies results in more broad-spectrum antibiotic use, treatment failures, and adverse drug events. We aimed to determine the optimal approach to penicillin allergies among medical inpatients. METHODS: We evaluated internal medicine inpatients reporting penicillin allergy in three periods: (1) standard of care (SOC), (2) penicillin skin testing (ST), and (3) computerized guideline application with decision support (APP). The primary outcome was use of a penicillin or cephalosporin, comparing interventions to SOC using multivariable logistic regression. RESULTS: There were 625 patients: SOC 148, ST 278, and APP 199. Of 278 ST patients, 179 (64%) were skin test eligible; 43 (24%) received testing and none were allergic. In the APP period, there were 292 unique website views; 112 users (38%) completed clinical decision support. While ST period patients did not have an increased odds of penicillin or cephalosporin use overall (aOR 1.3 [95% CI 0.8, 2.0]), we observed a significant increased odds of penicillin or cephalosporin use overall in the APP period (aOR 1.8 [95% CI 1.1, 2.9]), and in a per protocol analysis of the skin tested subset (aOR 5.6 [95% CI 2.5, 12.4]). CONCLUSIONS: Both the computerized guideline with decision support and penicillin skin testing 2 when completed 2 increased use of penicillin and cephalosporin antibiotics among inpatients reporting penicillin allergy. While the skin tested subset showed an almost 6-fold impact, the computerized guideline significantly increased penicillin or cephalosporin use overall nearly 2-fold and was readily implemented.
SUNDAY
576
J ALLERGY CLIN IMMUNOL VOLUME 139, NUMBER 2
Isolated BAL Neutrophilia and Unimodal Airway Epithelial IL-13 Inducible Gene Signatures Characterize Children with Treatment-Resistant Asthma
Larry Borish, MD, FAAAAI1, Thomas J. Braciale, MD, PhD2, DebbieAnn Shirley, MD3, John W. Steinke, PhD, FAAAAI4, Sandford Williams, MS5, Karlyn Pollack, BS5, Brian J. Capaldo, PhD5, and W. Gerald Teague, MD6; 1University of Virginia Health System, Charlottesville, VA, 2University of Virginia Hospital, Charlottesville, VA, 3C, University of Virginia, Charlottesville, VA, 4Asthma and Allergic Diseases Center, Charlottesville, VA, 5University of Virginia, Charlottesville, VA, 6Child Health Research Center, University of Virginia School of Medicine, Charlottesville, VA. RATIONALE: Assessment of lung fluid inflammatory markers and infectious species is indicated to inform treatment decisions in children with problematic asthma. The purpose of this study was to examine prevailing granulocyte patterns, potential pathogens, and bronchial epithelial IL-13-inducible gene signatures in 119 children with poor asthma control despite high-dose ICS treatment. METHODS: Children underwent bronchoscopy with BAL for granulocyte counts, PCR for respiratory viruses, bacterial cultures, and bronchial brush (n554) for epithelial IL13- inducible signature gene expression by qPCR. RESULTS: Asthma severity spanned mild/moderate (34%), severe (41%), and very severe (25%). Isolated neutrophilia was the prevailing granulocyte pattern (43.7%), followed by pauci-granulocytic (35.3%), mixed granulocytic (17.6%), and isolated eosinophilia (3.4%). Children with BAL neutrophilia were younger, less allergen sensitized, but had an 8-fold greater detection of potential bacterial pathogens (40.0%) compared to other granulocyte patterns (p50.0001). Enterovirus detection was common (26%) and evenly distributed among the four patterns. The IL13inducible three gene mean signature was unimodal, did not have a clearTh2 HIGH versus LOW cut point, and was highest in children with mixed granuloyctes (p50.08). CONCLUSIONS: Isolated BAL neutrophilia is common in young children with poorly-controlled asthma, in an age group with less allergen sensitization but abundant potential bacterial and viral pathogens in the airspaces. Unlike studies of adults with milder asthma on low-dose ICS, we could not identify a bimodal pattern of Th2 HIGH and LOW gene expression profiles, likely due to the suppressive effects of high-dose corticosteroid treatment in our sample.
577
Understanding Steroid-Refractory Severe Asthma
Marc Gauthier, MD1, Mahesh Raundhal, PhD2, Tim Oriss, PhD2, Prabir Ray, PhD3, Sally E. Wenzel, MD, FAAAAI4, and Anuradha Ray, PhD3; 1 University of Pittsburgh Medical Center, PITTSBURGH, PA, 2University of Pittsburgh, PITTSBURGH, PA, 3University of Pittsburgh, Pittsburgh, PA, 4The University of Pittsburgh Asthma Institute at UPMC and the University of Pittsburgh School of Medicine, Department of Pulmonary, Allergy and Critical Care Medicine, Pittsburgh, PA. RATIONALE: Severe Asthma (SA) is marked by poor corticosteroid (CS) response and frequent exacerbations leading to high cost and morbidity. Prior work showed elevated levels of airway IFN-g in ;50% of SA which was associated with worse lung function in a mouse model. We investigated whether CS treatment in the setting of type-1 inflammation further consolidates the type-1 signature. METHODS: mRNA levels of CXCL10 (a recruiter for IFN-g-secreting Tcells) were measured by qPCR in a monocytic cell line, in lungs of mice subjected to mild and severe asthma models and in human bronchoalveolar-lavage (BAL) cells obtained through the Severe Asthma Research
Program (SARP). Glucocorticoid receptor (GR) function was determined by luciferase reporter assay. RESULTS: We treated cells with stimuli known to induce CXCL10 (IFNg (100 ng/ml) or LPS (10 ng/ml)) and dexamethasone at two time-points (pre-treatment simulating chronic CS treatment and simultaneous treatment simulating a CS burst). Dexamethasone inhibited LPS induction of CXCL10 at both time-points. Dexamethasone pre-treatment increased IFN-g induced CXCL10 while simultaneous treatment had no effect, despite no impact on GR function. Mouse studies showed increased CXCL10 expression in SA model unchanged by dexamethasone. Similar results were seen in human BAL cell samples. CONCLUSIONS: We observed increased IFN-g-induced CXCL10 expression with dexamethasone pre-treatment, potentially contributing to CS insensitivity. This finding was confirmed using a mouse model of SA and samples from SA patients maintained on high dose CS. These findings suggest that CS may further consolidate type-1 inflammation in severe asthmatics.
578
Improving Antibiotic Choice in Hospitalized Medical Patients Reporting Penicillin Allergy
Kimberly G. Blumenthal, MD1, Paige G. Wickner, MD, FAAAAI2, Shelley Hurwitz, PhD3, Nicholas Pricco, BS4, Alexandra E. Nee, BA5, Karl Laskowski, MD, MBA3, Erica S. Shenoy, MD, PhD6, and Rochelle P. Walensky, MD, MPH6; 1Division of Rheumatology, Allergy and Immunology, Department of Medicine, Massachusetts General Hospital, Boston, MI, 2Division of Rheumatology, Allergy and Immunology, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, 3 Department of Medicine, Brigham and Women’s Hospital, Boston, MA, 4University of Minnesota, Minneapolis, MN, 5New York Medical College, Valhalla, NY, 6Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA. RATIONALE: Reported penicillin allergy rarely reflects penicillin intolerance. Failure to address inpatient penicillin allergies results in more broad-spectrum antibiotic use, treatment failures, and adverse drug events. We aimed to determine the optimal approach to penicillin allergies among medical inpatients. METHODS: We evaluated internal medicine inpatients reporting penicillin allergy in three periods: (1) standard of care (SOC), (2) penicillin skin testing (ST), and (3) computerized guideline application with decision support (APP). The primary outcome was use of a penicillin or cephalosporin, comparing interventions to SOC using multivariable logistic regression. RESULTS: There were 625 patients: SOC 148, ST 278, and APP 199. Of 278 ST patients, 179 (64%) were skin test eligible; 43 (24%) received testing and none were allergic. In the APP period, there were 292 unique website views; 112 users (38%) completed clinical decision support. While ST period patients did not have an increased odds of penicillin or cephalosporin use overall (aOR 1.3 [95% CI 0.8, 2.0]), we observed a significant increased odds of penicillin or cephalosporin use overall in the APP period (aOR 1.8 [95% CI 1.1, 2.9]), and in a per protocol analysis of the skin tested subset (aOR 5.6 [95% CI 2.5, 12.4]). CONCLUSIONS: Both the computerized guideline with decision support and penicillin skin testing 2 when completed 2 increased use of penicillin and cephalosporin antibiotics among inpatients reporting penicillin allergy. While the skin tested subset showed an almost 6-fold impact, the computerized guideline significantly increased penicillin or cephalosporin use overall nearly 2-fold and was readily implemented.
SUNDAY
576