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Proton Pump Inhibitors (PPIs) May Modulate More Than Just Reflux in Chronic Rhinosinusitis with Nasal Polyps
Abstracts AB285
J ALLERGY CLIN IMMUNOL VOLUME 137, NUMBER 2
Chronic Rhinosinusitis Patients with Gastroesophageal Reflux Disease Have Significantly Higher Prevalence of Atopic Conditions
Erica L. Palmisano, MD1, Mohamed Benhammuda2, Arpita Mehta2, Mary C. Tobin, MD2, Christopher D. Codispoti, MD, PhD2, Sindhura Bandi, MD2, Pete Batra, MD3, Phillip LoSavio, MD3, Robert P. Schleimer, PhD4, Mahboobeh Mahdavinia, MD, PhD2; 1Allergy/ Immunology section, Department of Immunology and Microbiology, Rush University Medical Center, Chicago, IL, 2Department of Immunology and Microbiology, Allergy/Immunology Section, Rush University Medical Center, Chicago, IL, 3Department of Otorhinolaryngology-Head and Neck Surgery, Rush University Medical Center, Chicago, IL, 4Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL. RATIONALE: Chronic rhinosinusitis (CRS) is characterized by chronic inflammation in the nasal and paranasal sinus mucosal membranes and is associated with increased risk of gastroesophageal reflux disease (GERD). However the mechanism underlying the link between CRS and GERD and the risk factors for GERD in patients with CRS are unknown. METHODS: We investigated the diagnosis of GERD in a large cohort of patients with CRS between 2005-2015. The diagnosis of GERD was based on positive symptoms of heartburn/regurgitation plus response to empiric therapy with PPI. Cases with possible diagnosis without evidence for treatment or positive GI diagnostic results were excluded. Charts were then evaluated for presence or absence of asthma, allergic rhinitis, eczema and food allergy. Comparisons between groups were assessed by using logistic regression; all analyses were adjusted for age, gender and BMI. RESULTS: Our cohort included 1005 patients with documented diagnosis of CRS; 211(20.9%) had GERD. Patients with CRS and GERD were predominantly female, and had higher BMI and age compared to CRS without GERD. CRS and GERD patients had higher prevalence of asthma (47.4% vs 26.6%, p<0.05), food allergy (21.8% vs 10%, p<0.05), allergic rhinitis (36% vs 28.8%, p<0.05) and eczema (11.4% vs 6.4%,p<0.05) as compared to CRS patients without GERD. GERD in CRS patients was not associated with nasal polyps, loss of smell, need for increased surgical treatment or Lund-MacKay-score. CONCLUSIONS: CRS patients with GERD are more likely to have atopic conditions. This may indicate that comorbid GERD and atopic disease are risk factors for development of CRS.
930
Proton Pump Inhibitors (PPIs) May Modulate More Than Just Reflux in Chronic Rhinosinusitis with Nasal Polyps
Jin Young Min, MD, PhD1, Robert C. Kern, MD1, Christopher J. Ocampo, MD, PhD2, Whitney W. Stevens, MD, PhD2, Caroline P. E. Price1, Christopher F. Thompson, MD1, Tetsuya Homma, MD, PhD2, David B. Conley, MD1, Stephanie Shintani-Smith, MD1, Julia H. Huang1, Lydia Suh, BSc2, James E. Norton, MS2, Kathryn E. Hulse, PhD2, Atsushi Kato, PhD2, Robert P. Schleimer, PhD2, Bruce K. Tan, MD1; 1Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, IL, 2Department of Medicine, Division of AllergyImmunology, Northwestern University Feinberg School of Medicine, Chicago, IL. RATIONALE: Chronic rhinosinusitis with nasal polyps (CRSwNP) is frequently characterized by tissue eosinophilia but the relationship of eosinophilia to other type 2 biomarkers has not been explored. Furthermore, recent data suggesting PPIs modulate eotaxin-3 production in eosinophilic esophagitis may have therapeutic implications for CRSwNP. We sought to characterize levels of type 2 mediators and their relationship to tissue eosinophilia and radiographic severity in CRS. We further aimed to evaluate whether PPIs have therapeutic potential in CRS and identify possible mechanisms of action in airway epithelium. METHODS: Type 2 mediators in nasal tissue and lavage fluid from control and CRS patients were measured by Luminex assay. Human
sinonasal epithelial cells and BEAS-2B cells were stimulated with IL-13 in the presence and absence of PPIs. The effects of PPIs on IL-13-induced effects were measured by ELISA, qRT-PCR, and pH imaging. RESULTS: IL-13, eotaxin-2 and eotaxin-3 were highly elevated in CRSwNP compared to control and were correlated with tissue ECP and radiographic severity. CRS patients taking PPIs had significantly lower tissue eotaxin-2 and eotaxin-3 levels than those not taking PPIs. In vitro, 5 different PPIs and the competitive H+/K+-ATPase inhibitor SCH-28080 all significantly inhibited IL-13-induced eotaxin-3 release by airway epithelial cells. In addition, IL-13-induced eotaxin-3 expression was dependent on the presence of extracellular K+ and associated with a PPI sensitive efflux of H+ions. CONCLUSIONS: IL-13, eotaxin-2, and eotaxin-3 in tissue are potential biomarkers of eosinophilia and severity in CRSwNP. Inhibition of IL-13-induced eotaxin-3 by PPIs may provide therapeutic benefit in CRSwNP via a novel H+/K+-dependent mechanism.
931
Heterogenous Inflammation in Rhinosinusitis without Nasal Polyps
Chronic
Atsushi Kato, PhD1,2, Aiko I. Klingler, PhD3, Whitney W. Stevens, MD, PhD1, Anju T. Peters, MD1, Julie A. Poposki, MS1, Lydia Suh, BSc1, James E. Norton, MS1, Roderick G. Carter, BSc1, Kathryn E. Hulse, PhD3, Leslie C. Grammer, MD1, Robert P. Schleimer, PhD1,4, Stephanie S. Smith, MD2, David B. Conley, MD2, Robert C. Kern, MD2, Bruce K. Tan, MD2; 1Department of Medicine, Division of Allergy-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, 2Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, IL, 3Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 4Department of Otolaryngology, Northwestern University Feinberg School of Medicine. RATIONALE: Although chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by type 2 inflammation, the type of inflammation in non-polypoid CRS (CRSsNP) is controversial. In European studies, CRSsNP showed distinct type 1 inflammation in ethmoid tissue (ET), but not in studies of CRSsNP uncinate tissue (UT) in the US. We have found regional differences in the expression of innate host defense molecules in the sinuses leading us to hypothesize that inflammatory patterns may have similar regional variability. METHODS: We collected inferior turbinate (IT), UT, and ET from controls, CRSsNP and CRSwNP and nasal polyp tissue (NP). Tissue mRNA expression for type 1 (IFN-g), 2 (CLC, IL-13) and 3 (IL-17A) inflammatory markers was examined. RESULTS: Inflammatory signals in ET were stronger than in IT and UT, thus we focused on ET. The pattern of inflammation in CRSsNP ET (n559) was heterogenous, and there were no significant differences, except in levels of CLC mRNA, compared to controls (n520) and CRSwNP (n536). When thresholds using the 90th percentile of expression in controls were defined, 24%, 51% and 22% of CRSsNP ET showed type 1, 2 and 3 inflammation, respectively. In contrast, 81% and 83% of CRSwNP ETand NP had type 2 inflammation. Interestingly, several CRSsNP donors had mixed inflammation, and 10% showed all three types. Among CRSsNP patients, Lund-Mackay scores significantly correlated with type 2, but not type 1 or 3, inflammation. CONCLUSIONS: CRSsNP is a heterogenous disease in the US, and therefore distinct therapeutic strategies may need to be determined based on the type of inflammation.
MONDAY
929
J ALLERGY CLIN IMMUNOL VOLUME 137, NUMBER 2
Chronic Rhinosinusitis Patients with Gastroesophageal Reflux Disease Have Significantly Higher Prevalence of Atopic Conditions
Erica L. Palmisano, MD1, Mohamed Benhammuda2, Arpita Mehta2, Mary C. Tobin, MD2, Christopher D. Codispoti, MD, PhD2, Sindhura Bandi, MD2, Pete Batra, MD3, Phillip LoSavio, MD3, Robert P. Schleimer, PhD4, Mahboobeh Mahdavinia, MD, PhD2; 1Allergy/ Immunology section, Department of Immunology and Microbiology, Rush University Medical Center, Chicago, IL, 2Department of Immunology and Microbiology, Allergy/Immunology Section, Rush University Medical Center, Chicago, IL, 3Department of Otorhinolaryngology-Head and Neck Surgery, Rush University Medical Center, Chicago, IL, 4Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL. RATIONALE: Chronic rhinosinusitis (CRS) is characterized by chronic inflammation in the nasal and paranasal sinus mucosal membranes and is associated with increased risk of gastroesophageal reflux disease (GERD). However the mechanism underlying the link between CRS and GERD and the risk factors for GERD in patients with CRS are unknown. METHODS: We investigated the diagnosis of GERD in a large cohort of patients with CRS between 2005-2015. The diagnosis of GERD was based on positive symptoms of heartburn/regurgitation plus response to empiric therapy with PPI. Cases with possible diagnosis without evidence for treatment or positive GI diagnostic results were excluded. Charts were then evaluated for presence or absence of asthma, allergic rhinitis, eczema and food allergy. Comparisons between groups were assessed by using logistic regression; all analyses were adjusted for age, gender and BMI. RESULTS: Our cohort included 1005 patients with documented diagnosis of CRS; 211(20.9%) had GERD. Patients with CRS and GERD were predominantly female, and had higher BMI and age compared to CRS without GERD. CRS and GERD patients had higher prevalence of asthma (47.4% vs 26.6%, p<0.05), food allergy (21.8% vs 10%, p<0.05), allergic rhinitis (36% vs 28.8%, p<0.05) and eczema (11.4% vs 6.4%,p<0.05) as compared to CRS patients without GERD. GERD in CRS patients was not associated with nasal polyps, loss of smell, need for increased surgical treatment or Lund-MacKay-score. CONCLUSIONS: CRS patients with GERD are more likely to have atopic conditions. This may indicate that comorbid GERD and atopic disease are risk factors for development of CRS.
930
Proton Pump Inhibitors (PPIs) May Modulate More Than Just Reflux in Chronic Rhinosinusitis with Nasal Polyps
Jin Young Min, MD, PhD1, Robert C. Kern, MD1, Christopher J. Ocampo, MD, PhD2, Whitney W. Stevens, MD, PhD2, Caroline P. E. Price1, Christopher F. Thompson, MD1, Tetsuya Homma, MD, PhD2, David B. Conley, MD1, Stephanie Shintani-Smith, MD1, Julia H. Huang1, Lydia Suh, BSc2, James E. Norton, MS2, Kathryn E. Hulse, PhD2, Atsushi Kato, PhD2, Robert P. Schleimer, PhD2, Bruce K. Tan, MD1; 1Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, IL, 2Department of Medicine, Division of AllergyImmunology, Northwestern University Feinberg School of Medicine, Chicago, IL. RATIONALE: Chronic rhinosinusitis with nasal polyps (CRSwNP) is frequently characterized by tissue eosinophilia but the relationship of eosinophilia to other type 2 biomarkers has not been explored. Furthermore, recent data suggesting PPIs modulate eotaxin-3 production in eosinophilic esophagitis may have therapeutic implications for CRSwNP. We sought to characterize levels of type 2 mediators and their relationship to tissue eosinophilia and radiographic severity in CRS. We further aimed to evaluate whether PPIs have therapeutic potential in CRS and identify possible mechanisms of action in airway epithelium. METHODS: Type 2 mediators in nasal tissue and lavage fluid from control and CRS patients were measured by Luminex assay. Human
sinonasal epithelial cells and BEAS-2B cells were stimulated with IL-13 in the presence and absence of PPIs. The effects of PPIs on IL-13-induced effects were measured by ELISA, qRT-PCR, and pH imaging. RESULTS: IL-13, eotaxin-2 and eotaxin-3 were highly elevated in CRSwNP compared to control and were correlated with tissue ECP and radiographic severity. CRS patients taking PPIs had significantly lower tissue eotaxin-2 and eotaxin-3 levels than those not taking PPIs. In vitro, 5 different PPIs and the competitive H+/K+-ATPase inhibitor SCH-28080 all significantly inhibited IL-13-induced eotaxin-3 release by airway epithelial cells. In addition, IL-13-induced eotaxin-3 expression was dependent on the presence of extracellular K+ and associated with a PPI sensitive efflux of H+ions. CONCLUSIONS: IL-13, eotaxin-2, and eotaxin-3 in tissue are potential biomarkers of eosinophilia and severity in CRSwNP. Inhibition of IL-13-induced eotaxin-3 by PPIs may provide therapeutic benefit in CRSwNP via a novel H+/K+-dependent mechanism.
931
Heterogenous Inflammation in Rhinosinusitis without Nasal Polyps
Chronic
Atsushi Kato, PhD1,2, Aiko I. Klingler, PhD3, Whitney W. Stevens, MD, PhD1, Anju T. Peters, MD1, Julie A. Poposki, MS1, Lydia Suh, BSc1, James E. Norton, MS1, Roderick G. Carter, BSc1, Kathryn E. Hulse, PhD3, Leslie C. Grammer, MD1, Robert P. Schleimer, PhD1,4, Stephanie S. Smith, MD2, David B. Conley, MD2, Robert C. Kern, MD2, Bruce K. Tan, MD2; 1Department of Medicine, Division of Allergy-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, 2Department of Otolaryngology, Northwestern University Feinberg School of Medicine, Chicago, IL, 3Division of Allergy-Immunology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 4Department of Otolaryngology, Northwestern University Feinberg School of Medicine. RATIONALE: Although chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by type 2 inflammation, the type of inflammation in non-polypoid CRS (CRSsNP) is controversial. In European studies, CRSsNP showed distinct type 1 inflammation in ethmoid tissue (ET), but not in studies of CRSsNP uncinate tissue (UT) in the US. We have found regional differences in the expression of innate host defense molecules in the sinuses leading us to hypothesize that inflammatory patterns may have similar regional variability. METHODS: We collected inferior turbinate (IT), UT, and ET from controls, CRSsNP and CRSwNP and nasal polyp tissue (NP). Tissue mRNA expression for type 1 (IFN-g), 2 (CLC, IL-13) and 3 (IL-17A) inflammatory markers was examined. RESULTS: Inflammatory signals in ET were stronger than in IT and UT, thus we focused on ET. The pattern of inflammation in CRSsNP ET (n559) was heterogenous, and there were no significant differences, except in levels of CLC mRNA, compared to controls (n520) and CRSwNP (n536). When thresholds using the 90th percentile of expression in controls were defined, 24%, 51% and 22% of CRSsNP ET showed type 1, 2 and 3 inflammation, respectively. In contrast, 81% and 83% of CRSwNP ETand NP had type 2 inflammation. Interestingly, several CRSsNP donors had mixed inflammation, and 10% showed all three types. Among CRSsNP patients, Lund-Mackay scores significantly correlated with type 2, but not type 1 or 3, inflammation. CONCLUSIONS: CRSsNP is a heterogenous disease in the US, and therefore distinct therapeutic strategies may need to be determined based on the type of inflammation.
MONDAY
929