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Effectiveness of Interventions to Maintain Penicillin Allergy Label Removal As Part of an Inpatient Penicillin Allergy Testing Protocol
Abstracts AB183
J ALLERGY CLIN IMMUNOL VOLUME 139, NUMBER 2
Effectiveness of Interventions to Maintain Penicillin Allergy Label Removal As Part of an Inpatient Penicillin Allergy Testing Protocol
Sheenal V. Patel, MD1, Scott A. Tarver, PharmD2, Kristin S. Alvarez, PharmD1,2, Kristin E. Lutek, PharmD2, James Schlebus2, and David A. Khan, MD, FAAAAI1; 1University of Texas Southwestern Medical Center, Dallas, TX, 2Parkland Health and Hospital System, Dallas, TX. RATIONALE: In patients with negative penicillin allergy testing, studies have shown high rates of persistence or redocumentation of the penicillin allergy label in the range of 36-49%. We evaluated the effectiveness of interventions used to maintain penicillin allergy label removal as part of an inpatient penicillin allergy testing program. METHODS: A retrospective chart review was conducted for adult patients who had a penicillin allergy label removed after testing negative on penicillin skin testing followed by amoxicillin challenge. The effect of three interventions on the maintenance of penicillin allergy label removal was evaluated: 1. pharmacist counseling at the time of negative testing; 2. pharmacist counseling at post-discharge follow-up; and 3. a best practice advisory alert in the electronic medical record (EMR) at the time of attempted redocumentation of the penicillin allergy. RESULTS: Between November 2014 and April 2016, 170 patients had negative penicillin allergy tests and follow-up within our health system at least 90 days later. The median follow-up time was 268 days and 17 patients (10%) had redocumentation of a penicillin allergy as follows: 11/ 97 (11.3%) patients who received only intervention 1; 0/10 patients who received interventions 1 and 2; 5/37 (13.5%) patients who received interventions 1, 2, and 3; and 1/26 (3.8%) patients who received interventions 1 and 3. CONCLUSIONS: Pharmacist counseling after a negative penicillin allergy test in our program showed lower rates of redocumentation than previously reported. Post-discharge counseling and EMR alerts may further improve this rate but a larger sample and longer follow-up is needed to confirm these findings.
583
Regulation of the Asthma-Associated Genes GSDMB and ORMDL3 Is Primarily Determined By Genotype That Is Mediated through DNA Methylation
Parul H. Kothari, MD, PhD, Weiliang Qiu, PhD, Damien C. CroteauChonka, PhD, Vincent J. Carey, PhD, and Benjamin A. Raby, MD, MPH; Brigham and Women’s Hospital, Boston, MA. RATIONALE: The most consistently replicated asthma-susceptibility locus is 17q21. Both genotype and methylation have been associated with candidate gene expression in this region, but their interrelationship remains poorly defined. METHODS: We studied two independent subpopulations from the Asthma BRIDGE cohort: 293 and 264 subjects with data from whole blood (WB) and CD4+ T cells, respectively. We performed association testing of ZPBP2, GSDMB and ORMDL3 gene expression with proximally situated SNPs and CpG marks, using linear regression analyses and accounting for potential confounders. We conducted mediation analysis with the causal inference test (CIT) for all significant (false discovery rate [FDR] < 0.05) SNPs and CpG sites. RESULTS: Of 1638 SNP-probe and 265 CpG-probe pairs tested, associations with either GSDMB or ORMDL3, but not ZPBP2, were replicated in both cohorts for 171 SNPs and 6 CpG sites. Increased ORMDL3 gene expression was associated with (i) asthma-associated SNPs, including the putative functional variant rs12936231 and (ii) decreased methylation of CpG sites, such as cg12655416 (all FDRs < 1e-6). CIT consistently supported a model whereby the observed effect of genotype on GSDMB or ORMDL3 gene expression was mediated through methylation. For example, in the WB and CD4+ T cell cohorts both the probability of rs12936231 genotype being independent of ORMDL3 mRNA levels after
adjusting for cg12655416 methylation and the overall mediation analyses were significant (all FDRs < 3e-3). CONCLUSIONS: 17q21 asthma-susceptibility genotypes increase GSDMB and ORMDL3 gene expression by reducing local CpG methylation, offering an intriguing new direction for molecular therapeutics in asthma: targeting of risk-mediating methylation marks.
584
Eosinophils Promote Emphysematous Lesions in a Mouse Model of Chronic Type 2 Lung Inflammation
Alfred Doyle, PhD1, William Lesuer1, Saif Pasha1, Nancy Lee, PhD2, James J. Lee, PhD2, Kelly Shim1, Justin Frere1, Jake Kloeber1, and Joseph Neely1; 1Mayo Clinic, Scottsdale, AZ, 2Mayo Clinic Arizona, Scottsdale, AZ. RATIONALE: Eosinophils are a potentially significant source of IL-13. IL-13 has been shown to activate macrophages leading to the expression of proteinases linked to the development of emphysematous lesions. We hypothesized that the lung eosinophilia associated with type 2 inflammation contributes to the enlargement of airspaces associated with chronic lung inflammation. METHODS: Lung samples from a mouse model of chronic type 2 inflammation (I5/hE2) were assessed for gene expression levels by microarray and protein levels by ELISA. Lung elastance was assessed using a Flexivent apparatus. Lung sections were assessed for emphysematous lesions by measurement of mean septal distance. Culture supernatants of isolated eosinophils and alveolar macrophage were assessed by ELISA. Eosinophil deficient (PHIL), and MMP-12-/- mice were crossed with I5/ hE2 animals to assess eosinophil-dependent mechanisms leading to the enlargement of airspaces. RESULTS: Microarray identified MMP-12 as the most upregulated gene in the lungs of I5/hE2 mice relative to eosinophil-deficient PHIL/I5/hE2 mice. Indeed, ELISA of bronchoalveolar lavage showed that lung MMP-12 levels in I5/hE2 mice were dependent on eosinophils. We showed, in vitro, that eosinophil-derived IL-13 promoted alveolar macrophage MMP-12 production. Our data also show that emphysematous lesions identified in the lungs of I5/hE2 mice were dependent on eosinophils and the induced MMP-12 expression. CONCLUSIONS: Eosinophil-derived IL-13 promotes alveolar macrophage MMP-12 production. More importantly, a mouse model of chronic severe type 2 lung inflammation exhibits emphysematous lesions that are dependent on eosinophils and MMP-12. These findings suggest an underappreciated mechanism by which eosinophils contribute to the pathologies linked with severe asthma, COPD, and ACOS patients.
SUNDAY
582
J ALLERGY CLIN IMMUNOL VOLUME 139, NUMBER 2
Effectiveness of Interventions to Maintain Penicillin Allergy Label Removal As Part of an Inpatient Penicillin Allergy Testing Protocol
Sheenal V. Patel, MD1, Scott A. Tarver, PharmD2, Kristin S. Alvarez, PharmD1,2, Kristin E. Lutek, PharmD2, James Schlebus2, and David A. Khan, MD, FAAAAI1; 1University of Texas Southwestern Medical Center, Dallas, TX, 2Parkland Health and Hospital System, Dallas, TX. RATIONALE: In patients with negative penicillin allergy testing, studies have shown high rates of persistence or redocumentation of the penicillin allergy label in the range of 36-49%. We evaluated the effectiveness of interventions used to maintain penicillin allergy label removal as part of an inpatient penicillin allergy testing program. METHODS: A retrospective chart review was conducted for adult patients who had a penicillin allergy label removed after testing negative on penicillin skin testing followed by amoxicillin challenge. The effect of three interventions on the maintenance of penicillin allergy label removal was evaluated: 1. pharmacist counseling at the time of negative testing; 2. pharmacist counseling at post-discharge follow-up; and 3. a best practice advisory alert in the electronic medical record (EMR) at the time of attempted redocumentation of the penicillin allergy. RESULTS: Between November 2014 and April 2016, 170 patients had negative penicillin allergy tests and follow-up within our health system at least 90 days later. The median follow-up time was 268 days and 17 patients (10%) had redocumentation of a penicillin allergy as follows: 11/ 97 (11.3%) patients who received only intervention 1; 0/10 patients who received interventions 1 and 2; 5/37 (13.5%) patients who received interventions 1, 2, and 3; and 1/26 (3.8%) patients who received interventions 1 and 3. CONCLUSIONS: Pharmacist counseling after a negative penicillin allergy test in our program showed lower rates of redocumentation than previously reported. Post-discharge counseling and EMR alerts may further improve this rate but a larger sample and longer follow-up is needed to confirm these findings.
583
Regulation of the Asthma-Associated Genes GSDMB and ORMDL3 Is Primarily Determined By Genotype That Is Mediated through DNA Methylation
Parul H. Kothari, MD, PhD, Weiliang Qiu, PhD, Damien C. CroteauChonka, PhD, Vincent J. Carey, PhD, and Benjamin A. Raby, MD, MPH; Brigham and Women’s Hospital, Boston, MA. RATIONALE: The most consistently replicated asthma-susceptibility locus is 17q21. Both genotype and methylation have been associated with candidate gene expression in this region, but their interrelationship remains poorly defined. METHODS: We studied two independent subpopulations from the Asthma BRIDGE cohort: 293 and 264 subjects with data from whole blood (WB) and CD4+ T cells, respectively. We performed association testing of ZPBP2, GSDMB and ORMDL3 gene expression with proximally situated SNPs and CpG marks, using linear regression analyses and accounting for potential confounders. We conducted mediation analysis with the causal inference test (CIT) for all significant (false discovery rate [FDR] < 0.05) SNPs and CpG sites. RESULTS: Of 1638 SNP-probe and 265 CpG-probe pairs tested, associations with either GSDMB or ORMDL3, but not ZPBP2, were replicated in both cohorts for 171 SNPs and 6 CpG sites. Increased ORMDL3 gene expression was associated with (i) asthma-associated SNPs, including the putative functional variant rs12936231 and (ii) decreased methylation of CpG sites, such as cg12655416 (all FDRs < 1e-6). CIT consistently supported a model whereby the observed effect of genotype on GSDMB or ORMDL3 gene expression was mediated through methylation. For example, in the WB and CD4+ T cell cohorts both the probability of rs12936231 genotype being independent of ORMDL3 mRNA levels after
adjusting for cg12655416 methylation and the overall mediation analyses were significant (all FDRs < 3e-3). CONCLUSIONS: 17q21 asthma-susceptibility genotypes increase GSDMB and ORMDL3 gene expression by reducing local CpG methylation, offering an intriguing new direction for molecular therapeutics in asthma: targeting of risk-mediating methylation marks.
584
Eosinophils Promote Emphysematous Lesions in a Mouse Model of Chronic Type 2 Lung Inflammation
Alfred Doyle, PhD1, William Lesuer1, Saif Pasha1, Nancy Lee, PhD2, James J. Lee, PhD2, Kelly Shim1, Justin Frere1, Jake Kloeber1, and Joseph Neely1; 1Mayo Clinic, Scottsdale, AZ, 2Mayo Clinic Arizona, Scottsdale, AZ. RATIONALE: Eosinophils are a potentially significant source of IL-13. IL-13 has been shown to activate macrophages leading to the expression of proteinases linked to the development of emphysematous lesions. We hypothesized that the lung eosinophilia associated with type 2 inflammation contributes to the enlargement of airspaces associated with chronic lung inflammation. METHODS: Lung samples from a mouse model of chronic type 2 inflammation (I5/hE2) were assessed for gene expression levels by microarray and protein levels by ELISA. Lung elastance was assessed using a Flexivent apparatus. Lung sections were assessed for emphysematous lesions by measurement of mean septal distance. Culture supernatants of isolated eosinophils and alveolar macrophage were assessed by ELISA. Eosinophil deficient (PHIL), and MMP-12-/- mice were crossed with I5/ hE2 animals to assess eosinophil-dependent mechanisms leading to the enlargement of airspaces. RESULTS: Microarray identified MMP-12 as the most upregulated gene in the lungs of I5/hE2 mice relative to eosinophil-deficient PHIL/I5/hE2 mice. Indeed, ELISA of bronchoalveolar lavage showed that lung MMP-12 levels in I5/hE2 mice were dependent on eosinophils. We showed, in vitro, that eosinophil-derived IL-13 promoted alveolar macrophage MMP-12 production. Our data also show that emphysematous lesions identified in the lungs of I5/hE2 mice were dependent on eosinophils and the induced MMP-12 expression. CONCLUSIONS: Eosinophil-derived IL-13 promotes alveolar macrophage MMP-12 production. More importantly, a mouse model of chronic severe type 2 lung inflammation exhibits emphysematous lesions that are dependent on eosinophils and MMP-12. These findings suggest an underappreciated mechanism by which eosinophils contribute to the pathologies linked with severe asthma, COPD, and ACOS patients.
SUNDAY
582