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Dissecting the Contributions of IL4 and IL13 to Allergen-Induced Diarrhea
S24 Abstracts
SATURDAY
J ALLERGY CLIN IMMUNOL FEBRUARY 2008
Predictors of Cold Severity and Cellular Responses in Nasal Lavage and Sputum Samples in Asthmatics Inoculated with Rhinovirus-16 (RV16) J. P. DeMore, A. Morin, R. Vrtis, C. A. Swenson, W. W. Busse, J. E. Gern; University of Wisconsin, Madison, WI. RATIONALE: Rhinovirus infections frequently cause exacerbations of asthma, but it is unclear how baseline airway inflammation and inflammatory responses during acute infections influence the outcomes of infection. METHODS: Forty mild persistent allergic asthmatic subjects and normal controls were experimentally inoculated with RV16. The cellularity of nasal lavage and sputum samples were analyzed in 35 subjects who developed RV16 colds. Evaluations were obtained at baseline, during the acute infection and during recovery. Asthma and cold symptom diaries assessed severity via validated questionnaire. RESULTS: Subjects, both asthmatics and normal controls, with detectable eosinophilia (1 eosinophil in 300 WBC) in sputum at baseline reported more severe symptoms with their colds (p 5 0.05). More asthmatics had detectable eosinophils in nasal lavage samples at baseline (63% vs 29% p 5 0.08), acute infection (80% vs 25% p 50.003), one week (70% vs 25% p 5 0.009) and 2 weeks (74% vs 25% p 5 0.03) compared with controls. In sputum, more asthmatics had detectable eosinophils at baseline (56% vs 8% p 5 0.05), acute infection (82% vs 31% p 5 0.02), one week (76% vs 21% p 5 0.008) but no significant difference at 2 weeks. The remaining cellularity of nasal lavage and sputum samples were similar except that asthmatics tended to have elevated neutrophils, lymphocytes and monocytes at 2 weeks post-inoculation. CONCLUSIONS: Individuals with detectable airway eosinophilia may experience more severe cold symptoms. This suggests that baseline airway inflammation may be an important predictor of respiratory outcomes with RV infection. Funding: NIH/NIAID P01 AI50500 and U19 AI070503-01
91
Rosado1, R. Cardenas1; 1FUNDACION HOSPITAL ALCORCON, ALCORCON, SPAIN, 2UNIVERSIDAD REY JUAN CARLOS, Alcorcon, SPAIN, 3UNIVERSIDAD REY JUAN CARLOS, ALCORCON, SPAIN. RATIONALE: We assess relationships among anaphylaxis severity and different clinical conditions. METHODS: In the years 2004-5 in the Emergency Unit of our hospital, there were 435 patients diagnosed of anaphylaxis. Cases of anaphylaxis were extracted from electronic clinical records using alpha-numeric strings which included characters used to nominate acute allergic syndromes. This strategy showed a sensitivity of 95% to detect cases of anaphylaxis among all episodes from Emergency Unit in March 2005. We follow Brown’s criterions (JACI 2004;114:371) to establish the severity of anaphylaxis episodes. This author separates anaphylaxis episodes as mild, moderate and severe, applying the criterion of the magnitude of odds ratios between different items and hypotension and hypoxia. Multivariate ordinal and binomial logistic regression was used to establish the predictors of anaphylaxis severity. Variables used in each logistic model were age, gender and anaphylaxis subtype. RESULTS: Out of 435 patients with anaphylaxis 51.03% were mild, 36.09% moderate and 12.87% were severe. The study showed older ages having higher severity (O.R. 1.01, CI95% 1.001-1.02, 20 years intervals). Food (O.R. 0.33, CI95% 0.16-0.71) and drug (O.R. 0.46, CI95% 0.22-0.98) anaphylaxis were associated to lower severity scores of anaphylaxis. Cardiovascular involvement was associated to older age groups (O.R. 1.03, CI95% 1.02-1.04), while lower respiratory involvement was more frequent in idiopathic anaphylaxis (O.R. 6.94, CI95% 2.79-17.27). CONCLUSIONS: Cardiovascular involvement appears more frequent among older patients with anaphylaxis, while food and drug anaphylaxis are related with less severe episodes anaphylaxis. Idiopathic anaphylaxis was associated with lower respiratory symptoms of anaphylaxis. Funding: Spanish Investigational Sanitary Fund, Fundacion Mutua Madrilen˜a
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Dissecting the Contributions of IL4 and IL13 to Allergen-Induced Diarrhea E. B. Brandt, A. Munitz, T. Orekhova, M. Mingler, F. D. Finkelman, M. E. Rothenberg; Cincinnati Chidren’s Hospital Medical Center, Cincinnati, OH. RATIONALE: Intestinal anaphylaxis (manifested by intestinal diarrhea) is dependent on IgE and mast cells; we aimed to define the Th2 cytokines involved in disease pathogenesis and their cellular targets. METHODS: We evaluated BALB/c wild-type mice and mice deficient in STAT6, IL-4, IL-13, IL-4Ra (common to type 1 and 2 IL-4Rs), IL-13Ra1 (part of the type 2 IL-4R) or IL-13Ra2 (a decoy receptor for IL-13) as well as mice that selectively lack IL-4Ra on smooth muscle cells. All mice were sensitized with OVA/alum and repeated intragastric OVA. RESULTS: STAT6-/- and IL-4-/- mice had much lower IgE levels than wild-type mice and were resistant to OVA-induced diarrhea; whereas, IL13-/- mice developed intestinal mastocytosis and diarrhea despite reduced IgE levels. Interestingly, lower IgE levels were observed in naı¨ve IL13-/- and IL13Ra1-/- mice, while elevated IgE levels were present in IL-13Ra2-/- mice. Accordingly, compared to wild type mice fewer OVA exposures were needed to develop diarrhea in IL-13Ra2-/- mice, while IL-13-/- and IL-13Ra1-/- mice had impaired development of allergic diarrhea. Prophylactic targeting of IL-4Ra (2 mg of anti-IL-4Ra mAb prior to initial intragastric OVA exposure) suppressed development of OVA-induced diarrhea, but delayed anti-IL-4Ra treatment (2 mg before the 5th, 6th and 7th OVA exposures) had little effect. Finally, selective deletion of IL-4Ra in smooth muscle cells significantly delayed diarrhea onset. CONCLUSIONS: These results establish that IL-4 (and to a lesser degree IL-13) and their signaling receptors promote allergen-induced diarrhea; direct effects on smooth muscle cells contribute to disease development.
93
Severity Of Anaphylaxis According To Causes And Demographic Characteristics M. Moro1, M. A. Tejedor1,2, J. Esteban3, M. Mugica1, C. Vila1, A.
The First Case of Anaphylactic Shock due to Sublingual Immunotherapy with Standardized Mites Allergens L. Blazowski; General Hospital Jaslo, Jaslo, POLAND. INTRODUCTION: Sublingual immunotherapy (SLIT) is home administration treatment without medical supervision and therefore the safety of this form of immunotherapy is especially important. CASE REPORT: A 16-year-old girl, with a history of perennial allergic rhinitis and well-controlled intermittent asthma due to house dust mites began SLIT with standardized extract of HDM (Stallergenes, France). In the 3rd year of SLIT after 3 week break in maintenance dose (10 drops, 100 IR/ml), with unknown reason the girl administered herself 60 drops (100 IR/ml) of allergen extract, equivalent of 26.9 mg of house dust mites allergen. Within 5 minutes generalized pruritus, flushing and generalized urticaria developed, and the girl became dyspneic, began wheezing and shivering followed by double short collapse. Emergency team was called. The doctor found: blood pressure 70/40 mmHg, heart rate 160/min, weak pulse, generalized urticaria, mild asthma symptoms. The girl was sleepy but conscious. Doctor gave methylprednisone i.v., aminophylline i.v., intravenous fluids and oxygen. After several minutes she was admitted to Hospital Emergency Department when she suddenly became unconscious without pulse and blood pressure. She received epinephrine i.m., oxygen, corticosteroids, intravenous fluids and was transferred to Intensive Care Unit, where she recovered during one day. CONCLUSIONS: The case leads to reconfirm the safety of sublingual immunotherapy schedule with large dose of allergen without up-dosing phase and expands the education and monitoring field of SLIT patients. Funding: Self-funded
SATURDAY
J ALLERGY CLIN IMMUNOL FEBRUARY 2008
Predictors of Cold Severity and Cellular Responses in Nasal Lavage and Sputum Samples in Asthmatics Inoculated with Rhinovirus-16 (RV16) J. P. DeMore, A. Morin, R. Vrtis, C. A. Swenson, W. W. Busse, J. E. Gern; University of Wisconsin, Madison, WI. RATIONALE: Rhinovirus infections frequently cause exacerbations of asthma, but it is unclear how baseline airway inflammation and inflammatory responses during acute infections influence the outcomes of infection. METHODS: Forty mild persistent allergic asthmatic subjects and normal controls were experimentally inoculated with RV16. The cellularity of nasal lavage and sputum samples were analyzed in 35 subjects who developed RV16 colds. Evaluations were obtained at baseline, during the acute infection and during recovery. Asthma and cold symptom diaries assessed severity via validated questionnaire. RESULTS: Subjects, both asthmatics and normal controls, with detectable eosinophilia (1 eosinophil in 300 WBC) in sputum at baseline reported more severe symptoms with their colds (p 5 0.05). More asthmatics had detectable eosinophils in nasal lavage samples at baseline (63% vs 29% p 5 0.08), acute infection (80% vs 25% p 50.003), one week (70% vs 25% p 5 0.009) and 2 weeks (74% vs 25% p 5 0.03) compared with controls. In sputum, more asthmatics had detectable eosinophils at baseline (56% vs 8% p 5 0.05), acute infection (82% vs 31% p 5 0.02), one week (76% vs 21% p 5 0.008) but no significant difference at 2 weeks. The remaining cellularity of nasal lavage and sputum samples were similar except that asthmatics tended to have elevated neutrophils, lymphocytes and monocytes at 2 weeks post-inoculation. CONCLUSIONS: Individuals with detectable airway eosinophilia may experience more severe cold symptoms. This suggests that baseline airway inflammation may be an important predictor of respiratory outcomes with RV infection. Funding: NIH/NIAID P01 AI50500 and U19 AI070503-01
91
Rosado1, R. Cardenas1; 1FUNDACION HOSPITAL ALCORCON, ALCORCON, SPAIN, 2UNIVERSIDAD REY JUAN CARLOS, Alcorcon, SPAIN, 3UNIVERSIDAD REY JUAN CARLOS, ALCORCON, SPAIN. RATIONALE: We assess relationships among anaphylaxis severity and different clinical conditions. METHODS: In the years 2004-5 in the Emergency Unit of our hospital, there were 435 patients diagnosed of anaphylaxis. Cases of anaphylaxis were extracted from electronic clinical records using alpha-numeric strings which included characters used to nominate acute allergic syndromes. This strategy showed a sensitivity of 95% to detect cases of anaphylaxis among all episodes from Emergency Unit in March 2005. We follow Brown’s criterions (JACI 2004;114:371) to establish the severity of anaphylaxis episodes. This author separates anaphylaxis episodes as mild, moderate and severe, applying the criterion of the magnitude of odds ratios between different items and hypotension and hypoxia. Multivariate ordinal and binomial logistic regression was used to establish the predictors of anaphylaxis severity. Variables used in each logistic model were age, gender and anaphylaxis subtype. RESULTS: Out of 435 patients with anaphylaxis 51.03% were mild, 36.09% moderate and 12.87% were severe. The study showed older ages having higher severity (O.R. 1.01, CI95% 1.001-1.02, 20 years intervals). Food (O.R. 0.33, CI95% 0.16-0.71) and drug (O.R. 0.46, CI95% 0.22-0.98) anaphylaxis were associated to lower severity scores of anaphylaxis. Cardiovascular involvement was associated to older age groups (O.R. 1.03, CI95% 1.02-1.04), while lower respiratory involvement was more frequent in idiopathic anaphylaxis (O.R. 6.94, CI95% 2.79-17.27). CONCLUSIONS: Cardiovascular involvement appears more frequent among older patients with anaphylaxis, while food and drug anaphylaxis are related with less severe episodes anaphylaxis. Idiopathic anaphylaxis was associated with lower respiratory symptoms of anaphylaxis. Funding: Spanish Investigational Sanitary Fund, Fundacion Mutua Madrilen˜a
92
94
Dissecting the Contributions of IL4 and IL13 to Allergen-Induced Diarrhea E. B. Brandt, A. Munitz, T. Orekhova, M. Mingler, F. D. Finkelman, M. E. Rothenberg; Cincinnati Chidren’s Hospital Medical Center, Cincinnati, OH. RATIONALE: Intestinal anaphylaxis (manifested by intestinal diarrhea) is dependent on IgE and mast cells; we aimed to define the Th2 cytokines involved in disease pathogenesis and their cellular targets. METHODS: We evaluated BALB/c wild-type mice and mice deficient in STAT6, IL-4, IL-13, IL-4Ra (common to type 1 and 2 IL-4Rs), IL-13Ra1 (part of the type 2 IL-4R) or IL-13Ra2 (a decoy receptor for IL-13) as well as mice that selectively lack IL-4Ra on smooth muscle cells. All mice were sensitized with OVA/alum and repeated intragastric OVA. RESULTS: STAT6-/- and IL-4-/- mice had much lower IgE levels than wild-type mice and were resistant to OVA-induced diarrhea; whereas, IL13-/- mice developed intestinal mastocytosis and diarrhea despite reduced IgE levels. Interestingly, lower IgE levels were observed in naı¨ve IL13-/- and IL13Ra1-/- mice, while elevated IgE levels were present in IL-13Ra2-/- mice. Accordingly, compared to wild type mice fewer OVA exposures were needed to develop diarrhea in IL-13Ra2-/- mice, while IL-13-/- and IL-13Ra1-/- mice had impaired development of allergic diarrhea. Prophylactic targeting of IL-4Ra (2 mg of anti-IL-4Ra mAb prior to initial intragastric OVA exposure) suppressed development of OVA-induced diarrhea, but delayed anti-IL-4Ra treatment (2 mg before the 5th, 6th and 7th OVA exposures) had little effect. Finally, selective deletion of IL-4Ra in smooth muscle cells significantly delayed diarrhea onset. CONCLUSIONS: These results establish that IL-4 (and to a lesser degree IL-13) and their signaling receptors promote allergen-induced diarrhea; direct effects on smooth muscle cells contribute to disease development.
93
Severity Of Anaphylaxis According To Causes And Demographic Characteristics M. Moro1, M. A. Tejedor1,2, J. Esteban3, M. Mugica1, C. Vila1, A.
The First Case of Anaphylactic Shock due to Sublingual Immunotherapy with Standardized Mites Allergens L. Blazowski; General Hospital Jaslo, Jaslo, POLAND. INTRODUCTION: Sublingual immunotherapy (SLIT) is home administration treatment without medical supervision and therefore the safety of this form of immunotherapy is especially important. CASE REPORT: A 16-year-old girl, with a history of perennial allergic rhinitis and well-controlled intermittent asthma due to house dust mites began SLIT with standardized extract of HDM (Stallergenes, France). In the 3rd year of SLIT after 3 week break in maintenance dose (10 drops, 100 IR/ml), with unknown reason the girl administered herself 60 drops (100 IR/ml) of allergen extract, equivalent of 26.9 mg of house dust mites allergen. Within 5 minutes generalized pruritus, flushing and generalized urticaria developed, and the girl became dyspneic, began wheezing and shivering followed by double short collapse. Emergency team was called. The doctor found: blood pressure 70/40 mmHg, heart rate 160/min, weak pulse, generalized urticaria, mild asthma symptoms. The girl was sleepy but conscious. Doctor gave methylprednisone i.v., aminophylline i.v., intravenous fluids and oxygen. After several minutes she was admitted to Hospital Emergency Department when she suddenly became unconscious without pulse and blood pressure. She received epinephrine i.m., oxygen, corticosteroids, intravenous fluids and was transferred to Intensive Care Unit, where she recovered during one day. CONCLUSIONS: The case leads to reconfirm the safety of sublingual immunotherapy schedule with large dose of allergen without up-dosing phase and expands the education and monitoring field of SLIT patients. Funding: Self-funded