All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB1 VOLUME 133, NUMBER 2
A Rare Presentation Of Surfactant Deficiency In a Term Neonate Therapeutic Equivalence Of Budesonide/Formoterol (BUD/FM) 1 Dr. Nisha N. Shah, MD1, Dr. Heena Shah, MD2, Dr. Kenneth Paris, 3 Breath-Actuated Inhaler (BAI) Compared With Bud/FM Pressurized MD, MPH3; 1LSU Health Sciences Center New Orleans, New Orleans, Metered-Dose Inhaler (pMDI) In Adults and Adolescents With LA, 2Louisiana State University, New Orleans, LA, 3LSU Health Sciences Moderate To Severe Asthma Center, New Orleans, New Orleans, LA. Kevin R. Murphy, MD1, Rajiv Dhand, MD2, Frank Trudo, MD3,Tom RATIONALE: It is important to consider non infectious, and non allergic Uryniak, MS3, Ajay Aggarwal, MD3; 1Boys Town National Research causes of chronic pulmonary inflammation in a term neonate. We describe Hospital, Boys Town, NE, 2Department of Medicine, University of a rare case of surfactant deficiency in a term neonate. Tennessee Graduate School of Medicine, 3AstraZeneca LP. METHODS: Surfactant protein C gene sequencing done at Johns Hopkins RATIONALE: To assess the therapeutic equivalence of BUD/FM DNA laboratory. 160/4.5mg delivered by BAI versus BUD/FM delivered by pMDI. RESULTS: A 5 week old full term female with a history of failure to METHODS: Adults and adolescents >_12 years of age with asthma and >_3 thrive, formula intolerance, intermittent tachypnea, hypoxia, and leuko- months daily use of inhaled corticosteroids were randomized to receive either cytosis presented to our hospital. The patient was born full term via BUD/FM BAI 2x160/4.5mg bid, BUD/FM pMDI 2x160/4.5mgbid,orBUD
Cesarean section without complication. Serial chest radiography showed pMDI 2x160mg bid in this 12-week, double-blind, multi-center, parallel- SATURDAY persistent bilateral lung infiltrates. An extensive workup showed no group study (NCT01360021). Inclusion required prebronchodilator FEV1 _ _ _ underlying cardiac, gastrointestinal, or infectious pathology. After 6 weeks >45–<85% of predicted normal, and reversibility of >12% in FEV1 (ages of hospitalization she continued to have leukocytosis, persistent hypoxia 12–17) or >_12% and 200 mL (ages >_18). Assay sensitivity required confirma- on room air, and poor weight gain on elemental formula. Allergic and tion of BUD/FM pMDI superiority to BUD pMDI. Therapeutic equivalence immunologic workup included negative skin prick testing to cow’s milk, between BUD/FM via pMDI and BAI was assessed by estimating the ratio of undetectable IgE to cow’s milk, normal immunoglobulin levels, and treatment effects (pre- and 60 minutes post-dose FEV1) using multiplicative normal lymphocyte subpopulations. A high resolution CT revealed analysis of covariance and baseline pre-dose FEV1 as a covariate. scattered ground glass opacities concentrated in the lower lobes. Lung RESULTS: Randomized patients (N5214) had a mean age of 42.7 years. biopsy revealed alveolar changes consistent with childhood interstitial The objective of demonstrating assay sensitivity was achieved as post-dose lung disease. Genetic testing ultimately revealed an inherited mutation in FEV1 for BUD/FM pMDI was superior to BUD pMDI (treatment effect the gene coding for surfactant C. ratio 1.10, 95% CI 1.06–1.14; P<.001). Demonstrating therapeutic CONCLUSIONS: A mutational surfactant deficiency can present in the equivalence objectives of BUD/FM BAI and pMDI were met for 60 minute term neonate and lead to the pro-inflammatory cascade causing chronic post-dose FEV1 (treatment effect ratio 1.01; 95% CI .97–1.05; P5.547) lung disease well studied in premature neonates. Childhood interstitial and pre-dose FEV1 (treatment effect ratio 1.03; 95% CI .99–1.08; lung diseases can be missed in the newborn period. Its non specific P5.131). Adverse event profiles were similar. presentation can mimic much more common causes of respiratory distress. CONCLUSIONS: BUD/FM 2x160/4.5mg bid delivered by BAI or pMDI Early intervention with steroid therapy can delay the progression of disease were therapeutically equivalent as shown by pre-dose FEV1 and 60 minute and improve quality of life. post-dose FEV1 treatment effect ratios. No differences in safety profiles were identified across the treatment groups. Relapse Of Severe Asthma Exacerbations After Cessation Of 2 Omalizumab Treatment – Real Life Data Effects of Budesonide/Formoterol (BUD/FM) Deliverd By Pressurized Dr. Izabela R. Kuprys-Lipinska, MD, PhD, Prof. Piotr Kuna, MD, PhD; 4 Metered-Dose Inhaler (pMDI) on Symptoms In African Americans and Dept. of Internal Medicine, Asthma and Allergy, Medical University in Caucasians With Moderate and Severe Asthma With and Without Lodz, Poland. Fixed Airway Obstruction (FAO) RATIONALE: Many clinical and observational studies demonstrated Donald P. Tashkin, MD1,BradleyE.Chipps,MD2, Frank Trudo, MD3; effectiveness of omalizumab (OMA) in the treatment of severe asthma, but 1David Geffen School of Medicine at UCLA, Los Angeles, CA, 2Capital the optimal duration of the therapy remains unknown. Allergy & Respiratory Disease Center, Sacramento, CA, 3AstraZeneca, METHODS: Here we present our clinical experience on OMA cessation Wilmington, DE. in routine practice. Due to new reimbursement criteria OMA therapy was RATIONALE: Effects of BUD/FM and BUD on symptoms in African- interrupted in 11 subjects (6 women/5 men) this year. The mean patients’ American and Caucasian moderate to severe asthma patients with and age is 50.7614.2 yrs, the mean severe asthma duration is 13.566.1 yrs. without FAO. The mean OCS dose (prednisone equivalent) before OMA therapy was METHODS: Two 12-week, double-blind studies randomized patients >_12 _ _ 23612.2 mg/day. Six subjects have near-fatal asthma exacerbations years and prebronchodilator FEV1 >45% and <85% predictedtobid BUD/FM recorded in their medical history. Patients received OMA according to 320/9mg pMDI or BUD 320mg pMDI in A: (2 of 5 arms [NCT00652002]) and the manufacturer recommendation. All had good response to OMA and B: ([NCT00702325] BUD/FM 320/9mgpMDIorBUD360mg dry powder asthma deterioration when doses were missed. The mean time of OMA inhaler [DPI]).FAO determination waspost-albuterol FEV1/FVC atscreening therapy was 67.7611.6 months.
ABS 5.2.0 DTD YMAI10627_proof 11 January 2014 3:05 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB2 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Long-Term Effectiveness Of Omalizumab Treatment In Thai Severe Effects Of Long-Term Treatment With Budesonide/Formoterol (BUD/ 5 Asthmatic Patients: A Real-Life Experience 7 FM) Delivered By Pressurized Metered-Dose Inhaler (pMDI) On Dr. Orapan Poachanukoon, MD1, Dr. Theerasak Kawamatawong2, Symptoms In African-American and Caucasian Patients With Dr. Atik Saengasapaviriya3, Dr. Chanchai Sittipunt4,Dr.Hiroshi Moderate To Severe Asthma With and Without Fixed Airway Chantaphakul, MD, FAAAAI5, Prof. Kittipong Maneechotesuwan6, Obstruction (FAO) Dr. Pintip Ngamchanyaporn7, Dr. Kunchit Piyavechviratana8,Dr.Apichart Randall Brown, MD, MPH1, Bradley E. Chipps, MD2, Donald P. Khanisap9, Dr. Siwasak Juthong10, Dr. Warangkana Rithirak11, Tashkin, MD3, Frank Trudo, MD4; 1Center for Managing Chronic Dr. Chaicharn Pothirat12, Dr. Watchara Boonsawat13; 1Thammasat University, Disease, University of Michigan School of Public Health, 2Capitol Pathumtani, Thailand, 2Ramathibodi Hospaital, Mahidol University, Taiwan, Allergy and Respiratory Disease Center, 3David Geffen School of 3Phramonkutklao hospital, Thailand, 4Chulalongkorn University, Thailand, Medicine at UCLA, Los Angeles, CA, 4AstraZeneca, Wilmington, DE. 5Chutuchak District, Chulalongkorn University Hospital, Bangkok, Thailand, RATIONALE: To assess the effects of long-term treatment with BUD/FM 6Siriraj Hospital, Mahidol University, Bangkok, Thailand, 7Ramathibodi and BUD on symptoms in moderate to severe African-American and Hospaital, Mahidol University, Thailand, 8Pramongkut Hospital, Sathorn, Caucasian asthma patients with and without FAO. Thailand, 9Thammasat University Hospital, Thailand, 10Faculty of Medicine, METHODS: Two 52-week double-blind studies randomized subjects >_12 11 _ Songklanakrin University, Thailand, Songklanakarind University, Thailand, years of age with prebronchodilator FEV1 >45% predicted (A: 12 13 _ Chiangmai University, Thailand, Srinagarind Hospital, Thailand. NCT00651768) or FEV1 >50% (B: NCT00419952) to bid BUD/FM RATIONALE: To evaluate the long-term effectiveness of omalizumab in 640/18mg, BUD/FM 320/9mg, or BUD 640mg pMDI 3:1:1 in A or ‘real-life’ setting among Thai asthmatic patients. BUD/FM 320/9mg or BUD 320mg pMDI 1:1 in B. FAO was determined
METHODS: A multi-center, non-interventional, observational study in by post-albuterol FEV1/FVC at screening
ABS 5.2.0 DTD YMAI10627_proof 11 January 2014 3:07 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB3 VOLUME 133, NUMBER 2
FDA Guidance-Designed Study Of The Effects Of Intranasal METHODS: 80 patients aged from 18 to 60 years old; 36 were 9 Triamcinolone Acetonide Aqueous (TAA-AQ) On Growth Velocity males (45%), 44 (55%) - females who received out-patient (GV) Of Children With Perennial Allergic Rhinitis (PAR) treatment using high doses of glucocorticosteroids (fluticasone Dr. David P. Skoner, MD; Temple University School of Medicine, propionate at a dose of 500-1000 mg/day) were studied. Patients Allegheny General Hospital, Pittsburgh, PA; West Penn Allegheny Health were divided into two groups. Group 1 uncontrolled patients with System, Pittsburgh, PA. severe asthma (12 subjects; 15%) who received standard treatment RATIONALE: Earlier studies of GV effects of intranasal corticosteroids according GINA plus roflumilast 500 mg for 1 month; Group 2 (INS) in children with PAR were designed poorly and yielded conflicting uncontrolled severe asthma patients who received standard treatment results, prompting FDA to publish a guidance on study design. (68 subjects; 85%). The level of control was assessed by the METHODS: Randomized, double-blind, placebo-controlled, parallel-group, AsthmaControl Questionnaire (ASQ-Juniper) Severity of symptoms multicenter study designed to evaluate the effect of once-daily TAA-AQ nasal was evaluated using a visual analogue scale with score ranging from spray 110 mg on GV of children with PAR aged 3-9 years, by stadiometry 0 points (no symptom) to 6 points (maximally expressed symptom). during 4- to 6-month baseline, 12-month treatment, and 2-month follow-up Spirometry was followed. periods. HPA-axis function was measured by urinary cortisol levels. RESULTS: 2 patients (17%) from Group 1 were withdrawn due to adverse SATURDAY RESULTS: 299 subjects were randomized, and 216 subjects completed the effects (insomnia). In Group 1: controlled disease course was achieved in 2 study (107 placebo; 109 TAA-AQ). In the primary analysis (modified ITT: patients (17%) (0.39 points by ASQ with a 2-fold increase of FEV1); 133 placebo, 134 TAA-AQ), LS mean GV during treatment was lower in the partially controlled course was achieved in 4 patients (33%) (1.35 points TAA-AQ group than in the placebo group (5.65 cm/year and 6.09 cm/year, according to ASQ with a 1.4-fold increase of FEV1), and no changes were respectively). The difference was -0.45 cm/year (95% CI: [-0.78, -0.11], observed in 2 patients. In Group 2: controlled course in 2 subjects (2.94%), p50.0096). Much of the difference started within the first 2 months of treat- partially controlled course in 12 subjects (17.64%) and uncontrolled ment and then stabilized thereafter. In the follow-up period, GV in the TAA- disease course in 54 subjects (79.4%). AQ group (6.59 cm/year) approached that during baseline (6.70 cm/year), CONCLUSIONS: Roflumilast as an adjunctive therapy in patients and the placebo group decreased slightly (5.89 cm/year versus 6.06 cm/year with uncontrolled severe asthma who have failed high dose inhaled during baseline). No clinically-relevant HPA-axis suppression was observed. corticosteroids helps to improve asthma control likely by impacting the CONCLUSIONS: This study, using rigorous FDA-recommended design neutrophilic inflammatory component of the disease. elements, demonstrated that TAA-AQ had a small, statistically significant effect on GV of 3-9 year-old children with PAR. GV effects of all INS The Potent and Selective CRTH2 Antagonist OC000459 Is should be tested using the same study design. 12 Effective In The Treatment Of Eosinophilic Asthma When Given Once Daily Extended Omalizumab Dosage Intervals and Efficacy Dr. Roy Pettipher1, Dr. Michael Perkins1, Dr. Lisa Pearce Collins1, Dr. Saraleen Benouni, MD1, Dr. Lee E. Sheinkopf, MD, 10 Dr. Mark Baillet2, Dr. Trevor Lewis3, Dr. Jan Steiner4, Prof. John Bell5, FAAAAI2, Dr. LanAnh T. Do, MD, FAAAAI3, Dr. Asif Rafi, MD2, Dr. Mark Payton1, Dr. Michael Hunter1; 1Atopix Therapeutics, Abingdon, Dr. Roger M. Katz, MD, FAAAAI2; 1UCLA, Los Angeles, CA, 2ucla, United Kingdom, 2S-Cubed, Abingdon, United Kingdom, 3TL-Wise los angeles, CA, 3ucla, Los Angeles, CA. Consulting, Cambridge, United Kingdom, 4Oxford Therapeutics Consul- RATIONALE: Xolair (Omalizumab) has been marketed for the past 10 ting, Brightwell-cum-Sotwell, United Kingdom, 5Medical Sciences years for the treatment of difficult to treat steroid dependent allergic asthma Division, Oxford, United Kingdom. in ages 12-70. We have followed 171 patients on Xolair and report on 40 RATIONALE: CRTH2 mediates activation of Th2 cells, eosinophils who have been on Xolair for 3+ years. and basophils in response to prostaglandin D . The CRTH2 antagonist METHODS: Prospective study and retrospective review of all patients 2 OC000459 reduced airway inflammation and improved lung function receiving Omalizumab for difficult to treat asthma ages 12-70. in moderate persistent asthma. The current study was conducted to RESULTS: 13 of these 40 patients have remained on their original dosing determine whether OC459 was effective when dosed once a day and schedules, whereas 27 have increased their dosage intervals from 1 to 16 enabled the definition of the patient phenotype most responsive to weeks between injections. The determining factors were base upon improved treatment. clinical response and or reduced need for concomitant medications. 11 of 13 METHODS: Adult subjects (% FEV 60-85% were randomized to patients on the initial protocol have completely reversed to normal FEV1 1 OC000459 (25 mg OD, 200 mg OD or 100 mg BID) or placebo for 12 and/or FEF 25%-75%, and 12 of 27 patients on advanced dosing have weeks (n5117-125 per group, Full Analysis Set (FAS)). The primary reverted to normal FEV1 and/or FEF 25%-75%. Patients between the ages of endpoint was change from baseline in pre-bronchodilator FEV and sec- 13-17 years were able to reverse FEV1 and/or FEF 25%-75% at an average of 1 ondary endpoints included ACQ, AQLQ(S), incidence of exacerbations 15.5 doses(range 10-20), ages 20-40 years by an average of 18 doses (range and respiratory infections. Change in FEV was studied in atopic subjects 12-28), ages 40-50 years by 21.6 (range 12-36) doses, and over 50 years by an 1 with blood eosinophilia >_250/ml. average of 26 doses (range 12-36). There were no significant differences RESULTS: The change in FEV in the pooled dose groups at endpoint was noted with respect to gender or pre-treatment IgE levels. 1 95 ml vs placebo (p50.024). In an atopic eosinophilic subgroup, an CONCLUSIONS: Treatment with Omalizumab is successful in reversing improvement in FEV of 220 ml was observed vs placebo (p50.005). In FEV1 and/or FEF 25%-75% by dosage #15 to 26 in many individuals. 1 atopic eeosinophilic subjects aged <40, an increase in FEV of 355 ml Younger patients were more likely to reverse. Dosing intervals of 1 was seen vs placebo (p50.007). Improvements in ACQ and AQLQ(S) Omalizumab can be increased up to every 16 weeks depending on were observed in the FAS and the atopic eosinophilic subgroup. In the individual responses with reversal and decreased medication usage. FAS there was a lower incidence of exacerbations (3.8% on OC000459 Effect Of Roflumilast On Asthma Control In Moderate and Severe vs 7.7% on placebo, p50.107) and respiratory infections (12.3% on 11 Asthma Patients OC000459 vs23.1% on placebo, p50.003) in subjects treated with Prof. V. A. Beloglazov1, Dr. Yuri Popenko1, Prof. Lawrence M. DuBuske, OC000459. MD, FAAAAI2; 1Crimean State Medical University, Ukraine, 2George CONCLUSIONS: OC000459 is a safe and effective treatment which Washington University School of Medicine, DC. achieved clinically meaningful improvements in lung function when dosed RATIONALE: This study investigates the effect of roflumilast as add-on once-a-day in allergic asthmatics with an eosinophil-dominant form of the therapy in patients with severe asthma. disease.
ABS 5.2.0 DTD YMAI10627_proof 11 January 2014 3:07 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB4 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Safety and Efficacy Of ARRY-502, a Potent, Selective, Oral CRTh2 RESULTS: Single-dose RNS60 caused neither bronchoconstriction nor 13 Antagonist, In Patients With Mild To Moderate Th2-Driven significant changes in blood chemistry, hematology, urinalysis, vital Asthma signs, or physical examinations. Subjects receiving RNS60 over 28 Sally E. Wenzel, MD, FAAAAI1, Robert Hopkins, Director of Clinical days reported mostly mild AEs including headache, dyspnea, and Operations2, Dr. Michael Saunders, MD, Senior Director of Drug Safety2, oropharyngeal pain. These subjects showed significant improvement in David Chantry, Senior Director of Translational Medicine and Cell peak flow (n514, p 5 0.004) and QOL scores (n514, p 5 0.01), and Biology2, Lisa Anderson, Clinical Research Manager2, Roger Aitchison, a positive trend in the Physician’s Global Assessment scores. In Senior BioStatistician2, Christine Eberhardt, Research Investigator2, Sta- combination with budesonide, no significant difference in % predicted cie Bell, Director of Clinical Pharmacology2, Dr. Jeremy Cole, MD, Prin- FEV1 appeared between groups. Low-dose budesonide + RNS60 was cipal Investigator3, Dr. James Wolfe, MD, Physician/Research as effective as high-dose budesonide in maintaining a steady FEV1. In Investigator4, Dr. Sheldon L. Spector, MD, FAAAAI5, Dr. Lawrence D. this group, the QOL index improved significantly (n526, p50.01) Sher, MD, FAAAAI6, Dr. Edward M. Kerwin, MD, FAAAAI7, compared to baseline, and 30% of subjects showed a 320% improve- Dr. Larry Burgess, PhD, Executive Director of Medicinal Chemistry2; ment in QOL score and inhaler usage compared to 18% of subjects 1University of Pittsburgh Medical Center NW, Pittsburgh, PA, 2Array Bio- in the high-budesonide + normal saline group. Pharma Inc., Boulder, CO, 3IPS Research Company, Oklahoma City, OK, CONCLUSIONS: RNS60 was safe and well tolerated when 4Allergy & Asthma Associates of Santa Clara County Research Center, nebulized alone or together with budesonide. Low-dose budesonide + San Jose, CA, 5California Allergy & Asthma Medical Group, Los An- RNS60 was as effective and safe as high-dose budesonide + normal geles, CA, 6Peninsula Research Associates, Rolling Hills Estates, CA, saline. 7 Allergy and Asthma Center of Southern OR, Medford, OR. Ò RATIONALE: Asthma is associated with mast cell activation and Tiotropium Respimat Add-On To Inhaled Corticosteroids 15 Improves Lung Function In Patients With Symptomatic Mild prostaglandin D2 (PGD2) generation. PGD2 exerts pro-inflammatory activity via chemoattractant receptor-homologous molecule expressed on Asthma: Results From A Phase III Trial 1 2 3 Th2 cells (CRTh2). Pierluigi Paggiaro , Dr. David M. G. Halpin, MD , Roland Buhl , 4 5 6 METHODS: The safety and efficacy of CRTh2 antagonist ARRY-502 Dr. Michael Engel, MD , Valentina Zubek , Zuzana Blahova , Dr. Petra 4 7 1 was studied in mild atopic asthmatic adults in a double-blind, placebo- Moroni-Zentgraf , Dr. Emilio Pizzichini ; University of Pisa, Pisa, Italy, 2 3 controlled 4 week Phase 2a study. Enrolled patients were free of Royal Devon & Exeter Hospital, Exeter, United Kingdom, Mainz 4 inhaled corticosteroids with an FEV1% predicted of 60-85% and University Hospital, Mainz, Germany, Boehringer Ingelheim 5 elevated Th2-associated biomarkers. The primary endpoint was change Pharma GmbH & Co. KG, Ingelheim Am Rhein, Germany, Boehringer 6 from baseline FEV1 compared to placebo. Secondary endpoints Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, Boehringer 7 included additional spirometric evaluations, measures of asthma con- Ingelheim RCV GmbH & Co. KG, Vienna, Austria, NUPAIVA (Asthma trol and two quality of life (QOL) assessments. Safety was evaluated Research Centre), Universidade Federal de Santa Catarina, Florianopolis, by incidence and severity of adverse events, vital signs, laboratory and Brazil. EKG parameters. RATIONALE: Despite currently available therapies and detailed RESULTS: Potential participants were screened and randomized guidelines, many people with mild asthma remain symptomatic; it is to receive 200 mg BID ARRY-502 (n 5 93) or matching placebo important to establish the efficacy and safety of new treatments in this (n 5 91). FEV1 improved 3.9% compared to placebo (Day 29, group. p 5 0.02). Asthma Control Questionnaire-7, ß-agonist use and METHODS: A Phase III, randomized, double-blind, parallel-group symptom free days improved compared to placebo (p < 0.001, trial (NCT01316380) evaluated the efficacy and safety of once-daily Ò m m p < 0.001 and p 5 0.07 respectively). Asthma and Rhinitis QOL tiotropium Respimat 5 g or 2.5 g versus placebo for 12 weeks m improved compared to placebo (p 5 0.012, p 5 0.007). ARRY-502 in patients with symptomatic asthma on low-dose ICS (200-400 g was well tolerated with less adverse events than placebo; notably, 13 budesonide equivalent). Primary endpoint: FEV1 peak(0-3h) response 5 (change from baseline) at 12 weeks. Secondary endpoints: trough patients experienced asthma exacerbations (ARRY-502, n 4; Ò Placebo, n 5 9). Differences in efficacy outcomes between ARRY- FEV1, FEV1 AUC(0-3h) and PEF (measured with the AM2+ device) 502 and placebo were numerically and statistically greater in Th2 high responses, and ACQ-7 score. m (baseline) participants (DFEV1 5 6.7%; p 5 0.008). RESULTS: Of 464 treated patients, 155 received tiotropium 5 g, 154 m CONCLUSIONS: These results support safety and efficacy of ARRY-502 tiotropium 2.5 g, and 155 placebo. Both tiotropium doses were superior to m in mild asthma patients and warrant further development. placebo in FEV1 peak(0-3h) response (adjusted mean difference: 5 g, 128 mL; 2.5 mg, 159 mL; both p<0.001) and trough FEV1 response (adjusted A Phase I Assessment Of Safety and Tolerability Of RNS60, a mean difference: 5 mg, 122 mL, p50.001; 2.5 mg, 110 mL, p50.003). 14 Novel Therapeutic Containing Charge-Stabilized Nanostructures FEV1 AUC(0-3h) response at each visit, versus placebo, significantly In Asthma favored tiotropium 5 mg(p50.009 to p<0.001) and tiotropium 2.5 mg
Supurna Ghosh, PhD, Andreas Kalmes, PhD, Jarrad Mock, Jocelyn (all p<0.001, except Day 1). Adjusted mean PEFAM and PEFPM responses, Sutherland, Richard Watson, MD; Revalesio Corporation, WA. versus placebo, each week, all favored tiotropium 5 mg (all p<0.001) and RATIONALE: Based on promising preclinical findings, we tested 2.5 mg (all p<0.003). Adjusted mean ACQ-7 score was similar across all RNS60, a novel therapeutic with charge-stabilized oxygen-based nano- arms (5 mg, 1.391; 2.5 mg, 1.438; placebo, 1.377). Adverse events were structures, in a two part Phase I study in asthma. predominantly mild or moderate and were balanced between treatment METHODS: Nebulized RNS60 was tested in a) healthy subjects and mild groups. asthmatics not receiving steroids (single dose) and b) mild-to-moderate CONCLUSIONS: Tiotropium RespimatÒ was effective and well asthmatics not receiving steroids (twice-daily, 28 days). Subsequently, tolerated in patients with symptomatic mild asthma despite low-dose mild-to-moderate asthmatics currently on steroid therapy were randomized ICS treatment. and switched to budesonide (High:0.5mg/day; Low:0.25mg/day) for 4 weeks, and treated with RNS60 + high-dose budesonide, RNS60 + low-dose budesonide, or normal saline + high-dose budesonide for another 4 weeks, twice daily.
ABS 5.2.0 DTD YMAI10627_proof 11 January 2014 3:07 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB5 VOLUME 133, NUMBER 2
Ò Tiotropium Respimat Add-On Therapy Reduces Airflow RATIONALE: Once-daily tiotropium RespimatÒ, a long-acting anti- 16 Obstruction In Patients With Symptomatic Moderate Asthma, cholinergic bronchodilator, has been shown in a Phase III program Independent Of TH2 Inflammatory Status to improve lung function and reduce severe exacerbation risk in severe Dr. Thomas B. Casale, MD, FAAAAI1, Dr. Eric Donn Bateman, MD2, asthma patients who remain symptomatic despite using ICS+LABA. Prof. Ronald Dahl, MD3, Dr. Emilio Pizzichini4, Dr. Mark L. Use of pre-trial leukotriene receptor antagonists (LTRAs) was not Vandewalker, MD5, Dr. Johann Christian Virchow6, Dr. Michael restricted; we analyzed whether pre-screening LTRA use affected Engel, MD7, Dr. Petra Moroni-Zentgraf7, Dr. Hendrik Schmidt8, Huib tiotropium RespimatÒ efficacy. A. M. Kerstjens9; 1Univeristy Of South Florida Morsani College Of METHODS: In two Phase III, replicate, randomized, double-blind, Medicine, Tampa, FL, 2University of Cape Town Lung Institute, Cape placebo-controlled, parallel-group trials (NCT00772538/NCT00776984), Town, South Africa, 3Odense University Hospital, Odense, Denmark, symptomatic patients received high-dose ICS+LABA and once-daily 4NUPAIVA (Asthma Research Centre), Universidade Federal de Santa tiotropium RespimatÒ 5 mg or placebo. LTRAs were permitted during 5 Catarina, Florianopolis, Brazil, Clinical Research of the Ozarks, run-in and treatment. Co-primary endpoints were peak and trough FEV1 Columbia, MO, 6University Clinic Rostock, Rostock, Germany, 7Boeh- response (difference from baseline) at 24 weeks. Subgroups were defined ringer Ingelheim Pharma GmbH & Co. KG, Ingelheim Am Rhein, by pre-screening LTRA use: ‘‘Yes’’/‘‘No’’. SATURDAY Germany, 8Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach RESULTS: Of 912 randomized patients, 205 reported pre-screening an der Riss, Germany, 9University Medical Center Groningen, University LTRA use, 200 reported use during the treatment period, and 187 of Groningen, Groningen, Netherlands. had efficacy data at week 24. Baseline characteristics were compa- RATIONALE: In patients with symptomatic asthma receiving ICS or rable between groups. Mean BMI in LTRA ‘‘Yes’’/‘‘No’’ groups: 27.8 2 2 ICS+LABA, Phase III studies have demonstrated improved lung kg/m and 28.3 kg/m , respectively. Mean % predicted FEV1 at Ò function with tiotropium Respimat , a once-daily long-acting anticho- baseline: 56% in both groups. Lung function responses improved linergic bronchodilator. The efficacy of some treatments (e.g. ICS and independent of LTRA use: peak FEV1 was 99650 mL (p50.049) omalizumab) appears higher in TH2-high phenotypes, but no specific in the LTRA ‘‘Yes’’ group, and 113628 mL (p<0.001) in the treatments are available that work equally well in both TH2-high LTRA ‘‘No’’ group (peak FEV1 improvements independent of and TH2-low phenotypes. We explored whether TH2 biomarker status concomitant LTRA use [interaction p-value50.6742]). Trough FEV1 influenced responses to tiotropium in patients with moderate symptom- (difference from placebo) was 90646 mL (p50.052) in the LTRA atic asthma. ‘‘Yes’’ group and 93625 mL (p<0.001) in the LTRA ‘‘No’’ group
METHODS: In two replicate Phase III, randomized, double-blind, (trough FEV1 improvements independent of concomitant LTRA use placebo-controlled, parallel-group trials (NCT01172808/NCT01172821), [interaction p-value50.5218]). patients with moderate symptomatic asthma, using medium-dose ICS CONCLUSIONS: Once-daily tiotropium RespimatÒ added to (400-800 mg budesonide equivalent), were administered once-daily ICS+LABA improves lung function in patients with severe symptomatic Ò tiotropium Respimat 5 mg or 2.5 mg, placebo, or salmeterol (active asthma, independent of initial LTRA use. comparator without inferential analysis). Co-primary endpoints included Close Correlation Between Month Of Birth and The Prevalence peak and trough FEV1 response (difference from baseline) at 24 weeks. 18 Of Bronchial Asthma In Schoolchildren In a Taiwanese Pre-planned analyses (pooled population) were performed in TH2-low and T 2-high subgroups defined at baseline as total serum IgE <_ or Population H 1 2 3 >430 mg/L or blood eosinophils <_ or >0.63109/L. Prof. Ho-Chang Kuo , Prof. Wei-Chiao Chang , Prof. Kuender D. Yang , 4 1 RESULTS: Of 1545 patients in the full analysis set who received Prof. Wei-Pin Chang ; Kaohsiung Chang Gung Memorial Hospital and 2 tiotropium or placebo, 915/1455 were reported with IgE >430 mg/L and Chang Gung University, Kaohsiung, Taiwan, Taipei Medical University, 3 300/1461 with an eosinophil count of >0.63109/L. Peak FEV improved Show Chwan Memorial Hospital in Chang Bing, Changhua, Taiwan, 1 4 with tiotropium versus placebo, independent of IgE (p<0.0001 both doses) Yuanpei University, Taiwan. RATIONALE: Allergic diseases such as bronchial asthma (BA), atopic and eosinophil count (p<0.0001 both doses). Trough FEV1 also improved with tiotropium versus placebo, independent of IgE (p<0.0001 both doses) dermatitis (AD), and allergic rhinitis (AR), are common inflammatory and eosinophil count (p<0.005 both doses). diseases. Season has been indicated to influence the development of CONCLUSIONS: Once-daily tiotropium RespimatÒ as add-on to ICS allergic diseases. reduces airflow obstruction in patients with moderate symptomatic asthma, METHODS: Data were collected from the National Insurance Research Database of Taiwan. Subjects were identified by at least two service claims independent of TH2 phenotype, and thus may potentially provide an important therapeutic option. for ambulatory care or one claim for inpatient care. All of the enrolled patients were aged from 7 to 15 years in 2010. In addition, total IgE and Ò Once-Daily Tiotropium Respimat Improves Lung Function In CAP allergen data were collected from patients in a cohort study. 17 Patients With Severe Symptomatic Asthma Independent Of RESULTS: The study enrolled 105,483 schoolchildren who were Leukotriene Modifier Use closely correlated in the birth of month and BA prevalence Prof. Ronald Dahl, MD1, Prof. Dennis E. Doherty2, Jonathan (x2518.167, p<0.001). Those born in May had a lower prevalence Corren, MD3, Dr. Jill Karpel4, Huib A. M. Kerstjens5, Dr. Michael of BA (7.21%, OR: 0.91, CI: 0.80-1.03), however, those born in Engel, MD6, Dr. Petra Moroni-Zentgraf6, Dr. Hendrik Schmidt7, October had a higher prevalence of BA (10.59%, OR: 1.16, CI: Dr. Shu Hashimoto, MD, PhD8; 1Odense University Hospital, Odense, 1.05-1.30). No significant associations between the prevalence of AD Denmark, 2Lexington VA Medical Center, University of Kentucky, or AR and the month of birth were found. In addition, we found Lexington, KY, 3University of California, Los Angeles, CA, 4North that children born in the autumn (August to October) had a higher Shore Medical Arts LLP, Great Neck, NY, 5University Medical prevalence of BA compared to those born in the spring (February to Center Groningen, University of Groningen, Groningen, Netherlands, April) (OR: 1.11, CI: 1.07-1.28). Markers of maternal and childhood 6Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim Am Rhein, allergies including IgE and CAP were detected in a cohort study. Germany, 7Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach Children who were born in the autumn had a higher level of CAP an der Riss, Germany, 8Nihon University School of Medicine, Tokyo, and total IgE levels. Japan. CONCLUSIONS: The findings of this study showed that the month of birth was closely correlated with the prevalence of BA and a higher level of CAP among young schoolchildren.
ABS 5.2.0 DTD YMAI10627_proof 11 January 2014 3:07 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB6 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Test-Retest Reliability Of The ISAAC Questionnaire For a Web- Trends In Prevalence Of Asthma and Allergies In 13-14 Year Old 19 Based Study 21 Children Between Two ISAAC Studies In Birjand City, Iran Dr. Koichi Yoshida, MD1, Dr. Yuichi Adachi, MD, PhD2, Dr. Mari Dr. Mohammad Fereidouni, MD, PhD1, Mrs. Shaghayeghsadat Nourani Sasaki, MD1, Dr. Mayumi Furukawa, MD1, Dr. Toshiko Itazawa, MD, hassankiadeh2; 1Asthma, Allergy & Immunology Research Center, PhD2, Dr. Koji Hashimoto, MD, PhD3, Dr. Hiroshi Odajima4, Dr. Akira Birjand University of Medical Sciences, Iran, 2Birjand university of Akasawa, MD, PhD1; 1Division of Allergy, Tokyo Metropolitan medical sciences. Children’s Medical Center, Tokyo, Japan, 2Department of Pediatrics, RATIONALE: Many studies have reported increase in prevalence of University of Toyama, Toyama, Japan, 3Department of Pediatrics asthma and allergies in modern and under developed countries. Many and Child Health, Nihon University School of Medicine, Tokyo, Japan, factors contribute to this increase but the main factors are different in 4Fukuoka National Hospital, Fukuoka, Japan. different societies and areas. Data about the change in prevalence and risk RATIONALE: The reliability of a web-based questionnaire for evaluating factors in each society is primary step for prevention and management of the prevalence of allergic diseases in children is unknown. The aim of our allergic diseases. The aim of this study was to evaluate the changes in study was to evaluate the test-retest reliability of the International Study of prevalence of asthma and other allergic diseases among 13-14 years old Asthma and Allergies in Childhood (ISAAC) questionnaire for a web survey. children in a Birjand city after 16 years. METHODS: We asked 150 parents and their 200 children aged 6 to12 METHODS: In a cross-sectional study, validated Persian version of years to complete the web-based ISAAC questionnaire via the internet ISAAC written questionnaire was used to evaluate prevalence of twice, with a one month interval. Reliability was assessed using the allergic symptoms among 13-14 years old students in March 2011. proportion of agreement and the kappa coefficient. The study protocol was The same questionnaire and protocol has been used in 1994 ISAAC approved by the independent review board of the Tokyo Metropolitan survey. 3320 and 3100 questionnaires were returned in 2011 and 1994 Children’s Medical Center. respectively. RESULTS: A total of 184 children (93 boys and 91 girls, mean age RESULTS: Out of the 3320 students, 3000 were participated in this 8.8 6 1.8 years) were analyzed. The proportion of agreement for the study. 56% were female and 44% were male.In comparison to 1994 question on asthma and nose/eye symptoms was more than 90%, whereas survey, prevalence of asthma has not been changed significantly (3.8% that for the questions on eczema was less than 90%. The kappa coefficients vs. 3.7% in 1994 and 2011 respectively); but prevalence of rhinitis (9.6% for the questions on current symptoms of wheeze, rhinoconjunctivitis and in the year 1994 versus 19.7% in 2011) and eczema (11.3% in 1994 eczema were 0.63, 0.64, and 0.55, respectively. The kappa coefficients for versus 26.8 in 2011) has been increased during the 16 years period the questions on asthma ever, pollinosis ever and eczema ever were 0.80, significantly. 0.78 and 0.48, respectively. CONCLUSIONS: The result of this study confirmed the low prevalence CONCLUSIONS: The web-based ISAAC questionnaire was as reliable for of asthma bus also showed that wheeze, nasal and ocular symptoms, as well the epidemiological survey. The reliability for the questions on eczema tended as eczema have been increased in a large extent. further studies need to to be lower than that for the questions on other allergic diseases. Further reveal the underlying factors for this increase. studies are needed to create web-based questionnaires using multimedia, which would lead to further improvement in the reliability of questionnaires. An Evaluation Of The Thai-Translated Version Of The Childhood Asthma Control Questionnaire (C- ACT) and The Composite Characteristics Of Adolescents With Undiagnosed Asthma In 22 Asthma Severity Index (CASI) Among Thai Asthmatic Children Rural Counties In Georgia 20 Dr. Benjarat Dardaranonda, MD; Department of Pediatrics, Faculty of Dr. Poneh Davoodi, MD1, Dr. Dennis Ownby, MD, FAAAAI2, 3 4 Medicine, Siriraj Hospital, Mahidol University, Bangkok, THAILAND, Ms. Suzanne Havstad, MA , Dr. Jennifer Waller, PhD , Dr. Christine Bangkok, Thailand. L. M. Joseph, PhD3, Dr. Martha Tingen, PhD4; 1Georgia Regents Univer- 2 RATIONALE: Asthma severity is reflected by several aspects of the sity, Division of Allergy-Immunology and Rheumatology, Georgia Regents disease, such as impairment of daily activity and risk of exacerbations. University, Augusta, GA, 3Department of Public Health Sciences, Henry 4 Asthma control is the main emphasis of current asthma treatment. The Ford Hospital, Detroit, MI, Georgia Regents University, Augusta, GA. relationship between the new Thai-translated version of the Childhood RATIONALE: Few studies have focused on undiagnosed asthma in Asthma Control Test (C-ACT), Composite Asthma Severity Index (CASI) adolescents from rural areas. Our study reflects the characteristics of and Exhaled Breath Temperature (EBT) to determine asthma control has adolescents living in rural Georgia who have respiratory symptoms of not been evaluated among Thai children. We herein study whether C-ACT asthma but without a physician diagnosis. and CASI can predict asthma control in children using the control level of METHODS: The Lung Health survey was completed by students in GINA as a gold standard. grades 9-11 attending 4 rural public Georgia high schools as part of the Puff METHODS: 21-item questionnaire of the new Thai-translated version of City clinical trial. Survey questions included many typical asthma respi- C-ACT was implemented to asthmatic children (age 4-11 years) and their ratory symptoms. Chi-square and t-tests were used to compare those with a caregivers. GINA, CASI and EBT were evaluated. doctor’s diagnosis or symptoms only on demographic and biological RESULTS: Eighty-three patients (52 boys) were recruited. The mean assessments including exhaled nitric oxide (eNO) and salivary cotinine. age+SD was 8.2 61.89 years. Median onset of disease was 2 years RESULTS: Of the 355 students that reported asthma symptoms, 144 (41%) (range 0.5-9 years). The C-ACT and CASI were able to differentiate students did not have a diagnosis of asthma. Those with symptoms only were controlled asthma from partly controlled/uncontrolled groups more likely to be African-American females, had a lower geometric mean (P < 0.001). A cut off point of < 22 of C-ACT scores provided eNO, were more likely to live in a rental home, and had little knowledge sensitivity 73.9%, specificity 96.7%, PPV 89.5%,NPV 90.6% to about asthma. In addition, they had higher salivary cotinine levels and were identify uncontrolled asthma with the area under the ROC curve of more likely to have a cotinine level consistent with current smoking. 0.91. For CASI, a cut-off point of >_ 4 yielded sensitivity 87%, CONCLUSIONS: Undiagnosed asthma is a frequent problem in specificity 68.3%, PPV 52.3%, NPV 93.2% with AUC50.88. adolescents from rural counties in Georgia. African-American females There was a high correlation between C-ACT and CASI (r 5 -0.68, and those who live in rental homes were less likely to have been given a p-value < 0.001). There was no correlation between EBT and doctor’s diagnosis of asthma. These results may indicate a trend to C-ACT,CASI or GINA level of control. underdiagnose adolescents who are from a lower socioeconomic status. CONCLUSIONS: The Thai version of C-ACT and CASI are useful tools Also, the lower eNO among these adolescents may be partially explained to predict asthma control in Thai children with good correlation among by their higher cotinine levels consistent with active smoking. these two scores.
ABS 5.2.0 DTD YMAI10627_proof 11 January 2014 3:07 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB7 VOLUME 133, NUMBER 2
Impact Of Change In Inhaled Corticosteroids/Long-Acting Infectious Asthma Trigger, Acq Score and Minirqlq Score 23 Beta Agonist Combination (ICS/LABA) Use On The Risk Of 25 Correlations Support The One Airway Hypothesis Asthma Exacerbations In Asthma Patients Within a Medical Dr. Amy Virojanapa, MD1, Ms. Phoebe Shah2, Mr. Arthur Omondi1, Group Dr. Efren L. Rael, MD, FAAAAI3; 1Penn State, Hershey Medical Center, Dr. Richard H. Stanford, PharmD, MS1, Saurabh Nagar, MS1, Dr. Xiwu Hershey, PA, 2UC San Diego, Vista, CA, 3Allergy/Immunology, Penn Lin, PhD1, Dr. Dick O’Connor, MD2; 1GlaxoSmithKline, 2Sharp State University College of Medicine, Hershey, PA. Rees-Stealy Medical Group, San Diego, CA. RATIONALE: Infections associated with asthma represent a challenge RATIONALE: An asthma medication ratio (AMR) >_0.5 has been shown in asthma management due to the multiplicity of pathogens linked to to predict future asthma exacerbations. This study explores the impact of asthma as well as the potential for mutation associated with rapid increasing or decreasing ICS/LABA use over a 7 year period on achieving replication and selection pressures due to antibiotic administration. Here AMR of >_0.5. we report amongst a cohort of asthmatics at a university based allergy, METHODS: Retrospective, observational study utilizing pharmacy and asthma, and immunology specialty clinic, correlations between patient medical claims from a medical group from 01/2003-12/2010. All patients reported infectious asthma triggers, quality of life scores correlating with >_1 asthma diagnosis (493.xx) and with >_1 asthma inhaled medication with both the upper and lower airways as well as objective data from SATURDAY dispensed in each year of eligibility were included. The mAMR 5 total ICS spirometry. controllers dispensed/total ICS controllers dispensed + albuterol dispensed. METHODS: After informed consent and IRB approval, 104 asthmatics, Proportion of ICS/LABA use was determined annually as number of ICS/ recruited to the study between 2011 and 2013 underwent clinical LABA canisters dispensed O sum of ICS/LABA and ICS dispensed. assessment including review of the MiniRQLQ and ACQ quality of Generalized linear mixed model (GLM) was used to assess the effect of life scores, assessment as to whether the asthma was triggered by sinus incremental change in ICS/LABA on mAMR over 7 yeasrs adjusting for infections, as well as spirometry. The independent sample t- test divided differences in resource utilization, time and asthma medication use. the cohort by ACQ scores into group 1 (ACQ < 1.50) and group RESULTS: 990 patients met all criteria mean age (6SD) of 35 (618) 2(> 1.50). years. About 15% of the patients used albuterol and oral corticosteroids RESULTS: 57 percent of group 2 subjects reported sinus infections during the identification period. Overall, mean mAMR increases over time triggered their asthma vs. 44% of subjects in group 1 (p50.03, 95% while mean albuterol decreases over time. Adjusting for covariates, a 10% CI 1-25%). Subjects in group 2 reported a productive cough as opposed to a increase in ICS/LABA use was associated with a 9% increase (adjusted OR dry cough, had a lower mean FEV1 of 78% vs 92% (p50.00); and a higher 1.09, 95% CI 1.06, 1.12) in the likelihood of achieving mAMR >_0.5 while a MiniRQLQ total score 38 vs 25 (p50.00, CI 8-18). 50% increase in ICS/LABA use was associated with a 53% (OR 1.53, 95% CONCLUSIONS: Asthmatics with self reported sinus infection trig- CI 1.31, 1.8) increased likelihood of obtaining mAMR >_0.5. gered asthma, represent a potential asthma phenotype with higher CONCLUSIONS: Increase in ICS/LABA use over time in a population of MiniRQLQ and ACQ scores as well as lower FEV1. Further studies asthma patients was significantly associated with a higher likelihood of are necessary. achieving a mAMR of >_0.5. (GSK FLT114941). Comprehensive Immunological and Clinical Features Of Common HLA-DRB1 Alleles, Levels Of Total IgE and IL-13 In Patients Of 26 Variable Immunodeficiency (CVID) 24 Bronchial Asthma From A Local Tertiary Care Hospital In Lahore, Dr. Varaz Bozoghlanian, MD1, Sudhanshu Agrawal, MS2, Sudhir Gupta, Pakistan MD, PhD, FAAAAI1; 1University of California, Irvine, Irvine, CA, Mr. Khursheed Javaid, MPhil; University of Health Sciences, Lahore, 2University of California, Irvine. Pakistan. RATIONALE: CVID is the most common primary immunodeficiency RATIONALE: The prevalence of asthma is 3.7% in Pakistan. In Pakistan, in adults. There is a lack of comprehensive analysis of all components some studies had been performed to determine MHC and disease of the immune system and major clinical features of CVID in one associations except bronchial asthma. Therefore, present study was publication. conducted to investigate the frequency of HLA-DRB1 alleles in patients METHODS: A retrospective chart review of 50 adults and children with of bronchial asthma. CVID was performed. Clinical parameters included: frequency and nature METHODS: The study was approved from ethical review boards of UHS of infections, associated diseases such as granulomatous disorders, and Shalamar Hospital. Fifty physician-diagnosed bronchial asthma malignancies, autoimmunity, and allergic diseases. Immunologic param- patients (between 18-40 years) with H/O allergy and 30 healthy subjects eters included: na€ıve, central and effector memory CD4 and CD8 T cells; were included. HLA-DRB1 alleles were determined by PCR, total IgE and na€ıve, IgM memory, switched memory, marginal zone, and CD21 B cells serum IL-13 levels were determined by ELISA. Results were analyzed by and plasmablasts; NK cells, complement components, and expression of applying appropriate statistical tests using SPSS (Statistical Package for BAFF-R and TACI on B cells. Social Sciences) version 20. RESULTS: CD21lowB cells were significantly (P<0.045) increased, and RESULTS: Mean of total serum IgE levels of bronchial asthma patients class switched memory B cells were significantly (P<0.02) decreased. was 861.6 6 559.2 IU/ml and it was 204.7 6 237 IU/ml in controls. On The expression of TACI on CD27+ B cells was higher than on na€ıve comparison there was statistically significant difference (p value 0.000). cells. A markedly decreased TACI expression was observed in 10% of Serum mean IL-13 levels of bronchial asthma patients were 1409.9 IU/ patients. Prevalence of overt and clinical hypothyroidism was 24%, ml and 390.7 IU/ml in controls. On comparison there was statistically and ANA titers >_ 1:160 were present in 17.6% of CVID. Composite significant difference (p value 0.000). Among the HLA-DRB1 alleles prevalence of autoimmune diseases was 36%, higher than reported in DR B1*12 had highest frequency in asthma patients, 23(42%) as compared the literature. Increased frequency of recurrent urinary tract infections, to controls 6(20%). There was no statistically significant difference was resistant organisms, pneumonias, and allergic diseases including rhinitis present between mean total IgE conc. of HLA- DR B1*12 positive and asthma were observed. (607.9 IU/ml) and HLA- DR B1*12 negative (518.4 IU.ml) asthma patients CONCLUSIONS: In CVID, common immune alterations appear to be an (p value 0.259). Mean IL-13 levels were statistically significant between increase in CD21low B cells and a decrease in class switched memory HLA- DR B1*12 positive and HLA- DR B1*12 negative asthma patients. B cells. A subset of CVID patients appears to have deficiency of TACI. CONCLUSIONS: It is concluded that HLA-DRB1*12 may be implicated Increased frequency of urinary tract infections in CVID is a novel in the development of bronchial asthma patients in Pakistan. observation.
ABS 5.2.0 DTD YMAI10627_proof 11 January 2014 3:07 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB8 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Clinical, Immunological and Genetic Spectrum Of Novel BTK A Devastating Outcome In Undiagnosed X-Linked 27 Gene Mutations In X-Linked Agammaglobulinemia Patients and 29 Agammaglobulinemiad A Call For Earlier Screening Female Carriers Dr. Karen Elizaeth Bruner, MD1, Dr. Anthony Infante, MD, PhD2; Dr. Regan Pyle, DO1, Dr. John B. Hagan, MD, FAAAAI1, Amanda 1Wilford Hall Ambulatory Surgical Center, Lackland AFB, TX, 2UT Martinez, MS1, Dr. Avni Y. Joshi, MD1, Dr. Thomas Boyce, MD1, Health Science Center San Antonio, San Antonio, TX. Dr. Gerald W. Volcheck, MD, FAAAAI2, Dr. Yesim Yilmaz- RATIONALE: X-linked agammaglobulinemia is a primary humoral Demirdag, MD3, Prof. Sami L. Bahna, MD, DrPH, FAAAAI4, immunodeficiency typically presenting in boys between the ages of 3 Dr. Roshini S. Abraham, PhD, FAAAAI1; 1Mayo Clinic, Rochester, MN, and 18 months. Common pediatric practice is to wait for a second 2Mayo Clinic and Foundation, Rochester, MN, 3Columbia University, New significant infection before initiating immunodeficiency work-up, which York, NY, 4LA State University Health Sciences Center, Shreveport, LA. can cause concerning delays in diagnosis. Here we present a case where RATIONALE: In X-linked agammaglobulinemia (XLA) though over 600 this delay lead to neurologically devastating results. mutations have been reported in the BTK gene, new mutations continue to METHODS: BTK DNA sequencing test performed by LabCorp. be identified and characterized. We report 18 novel mutations not RESULTS: Pt was initially hospitalized with Streptococcus pneumonia previously described in 30 male patients with a clinical phenotype of meningitis at 4 months. He had previously been healthy and after initial XLA as well as female carriers with male relatives. hospitalization experienced several viral upper respiratory infections METHODS: Btk protein was assessed by flow cytometry and mutation and a urinary tract infection but no sinusitis, otitis or pneumonia. He analysis with full-gene Sanger sequencing. then presented at 10 months of age with his second S. pneumoniae RESULTS: Of the 18 novel mutations, 9 were missense, 2 nonsense, 3 meningitis associated with multi-system organ failure. He suffered deletions leading to frameshift, 1 deletion and 1 frameshift duplication. significant neurologic sequelae including seizures, severe develop- Seven of the new mutations were identified in more than one individual, from mental delay and tube feeding-dependency. He was fully vaccinated. the same family or unrelated, male or female. Of all the mutations, 17% Lab evaluation was significant for flow cytometry demonstrating near (n53) were identified in patients diagnosed for the first time in adulthood absence of CD19+ B cells at 0.2% (absolute number 7/mm3), low (age range: 30-64y). Twenty of 23 male (9 normal, 11 reduced or absent IgG at 132 mg/dL with undetectable IgA and IgM. BTK sequencing protein) patients and 4 of the 7 female carriers had Btk protein analysis showed missense mutation confirming X-linked agammaglobulinemia. performed by flow cytometry. All female carriers had normal Btk protein He has had no further significant infections since initiating treatment expression. Of the 23 male patients, 20 had undetectable or <2% B cells with subcutaneous immunoglobulin. (B cell data not available for 3 patients). All but one of the male patients had CONCLUSIONS: This case highlights the concern for delayed hypogammaglobulinemia. All mutations were predicted to be deleterious. diagnosis of severe immunodeficiency. In this age of vaccinations, CONCLUSIONS: The spectrum of protein expression, B cell numbers readily available lab evaluation and universal newborn screening, and new gene defects enforces the necessity of detailed diagnostic work-up we urge the immunology community to recommend earlier immu- in patients suspected of having XLA, especially as several patients may be nodeficiency screening after the first serious bacterial infection in an diagnosed for the first time in mid-to-late adulthood. infant and advocate for the early detection of antibody deficiency by adding it to state newborn screening panels. CD19+CD27+CD43+CD70-CD5- B-1b Cells In Children With 28 Specific Antibody Deficiency, Specific Antibody Deficiency Genetic Basis Of CVID-Like Disease With Decreased IgG, and Common Variable Immunodeficiency 30 Dr. Kate Welch, MD1, Dr. Elena Resnick, MD2, Dr. Charlotte Dr. Kathryn D. Convers, MD1,2, Barbara Kariuki, MPH1, Dr. Alan Cunningham-Rundles, MD, PhD, FAAAAI3; 1Mt. Sinai Medical Center, Knutsen, MD, FAAAAI1,2; 1Saint Louis University School of Medicine, 2Mount Sinai School of Medicine, New York, NY, 3Mt. Sinai Medical Saint Louis, MO, 2Cardinal Glennon Children’s Medical Center, Saint Louis, Center, New York, NY. MO. RATIONALE: Common variable immunodeficiency (CVID) encom- RATIONALE: Recurrent or severe sinopulmonary infections with passes a heterogeneous group of immune disorders with varying Streptococcus pneumonia (Spn) are common complications in children phenotypic subclasses. It is defined by reduced serum levels of IgG, and with primary humoral immunodeficiencies, such as Specific Antibody reduced IgA and/or IgM (at least two standard deviations below the mean Deficiency (SAD) or Common Variable Immunodeficiency (CVID). B-1 for age) with poor antibody responses. There are many patients who are cells are subdivided by CD5 expression into two functionally distinct IgG deficient who do not meet criteria for true CVID but still manifest groups: CD5+ (B-1a) and CD5- (B-1b). B-1b cells produce IgG, IgA and clinical pathology of various organ systems, similar to CVID patients. The IgM antibodies to polysaccharide Spn. Recently, it has been described underlying genetics and immunopathogenesis of this spectrum of diseases that the percentage of B-1b cells was decreased in patients with SAD. are currently poorly understood. We aim to examine a cohort of patients METHODS: We characterized B-1b cell expression in our pediatric with clinical pathology similar to CVID and compare them genetically to patients with SAD, CVID, SAD with hypogammaglobulinemia (SAD- true CVID patients. IgG) and healthy controls, in conjunction with clinical and additional METHODS: We identified 19 patients followed in our immunology immunologic features. Peripheral blood mononuclear cells (PBMC) were clinic for CVID-like pathology who do not meet official diagnostic isolated by Ficol-Hypaque density centrifugation and fluorochrome criteria for CVID. These patients experience frequent bacterial infections stained for CD19, CD27, CD43, CD70 and CD5. Repeated gating was and some require intravenous immunoglobulin therapy. However, they performed; ultimately CD19+CD27+CD43+CD70- cells (B-1) were either do not have sufficient hypogammaglobulinemia or they maintain a analyzed as CD5+ (B-1a) or CD5-(B-1b) cells. The nonparametric relatively robust disease-specific antibody response such that they are not Kruskal-Wallace test was used for multiple comparisons. Post hoc analysis classified as CVID. These patients will be genotyped with SNP and CNV was performed using Dunn’s multiple comparison test. analysis and compared to 363 previously identified CVID control RESULTS: SAD and SAD-IgG (p<0.01), as well as CVID (p<0.001) subjects. patients had significantly decreased percentages of B-1b cells compared RESULTS: The genetic data is currently under analysis. to healthy controls. We found a significant correlation between decreased CONCLUSIONS: By analyzing the genetic differences of true CVID B-1b cell percentages and percentages of protective antibody titers to patients in comparison to those of a subclass of CVID-like IgG deficient polysaccharide Spn (p5 0.0001). patients, we hope to elucidate the complex genetic basis of this disease and CONCLUSIONS: Decreased B-1b B cells were identified in children with uncover loci for disease characteristics that determine the clinical SAD, SAD-IgG and CVID. A correlation exists between decreased B-1b phenotype of this immune disorder. cells and inadequate antibody responses to polysaccharide Spn.
ABS 5.2.0 DTD YMAI10627_proof 11 January 2014 3:07 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB9 VOLUME 133, NUMBER 2
A Case Of A CVID Patient and Rabies Exposure METHODS: Patients were identified using ICD-9 code 279.0 in 31 Dr. Hassan Nasir, DO1, Dr. Shahnaz Fatteh2; 1Nova Southeastern online medical records at Beth Israel Deaconess Medical Center University College of Osteopathic Medicine, Davie, FL; Larkin Commu- (BIDMC). 94 patients were selected based on IgG <700mg/dL or nity Hospital, Miami, FL, 2Larkin Community Hospital, South Miami, FL. subclass deficiency; IgA <60mg/dL or IgM <50mg/dL; if IgG>400mg/ RATIONALE: It is rare to find patients with CVID who are exposed to dL, demonstration of poor vaccine response. 13.8% (13/94) of patients Rabies. A key problem that is faced by patients with CVID and other met criteria (chest CT findings of GLILD or biopsy demonstrating similar patients, is that these patients cannot fully recognize vaccines due granulomas) for GLILD. This project was approved by the IRB at to impaired B Cell Differentiation. BIDMC. METHODS: A 57 year old male patient presents with a history of RESULTS: The following statistically significant differences were Hemochromatosis and CVID presented with chief complaint of recent found: Hemoglobin (CVID mean 13.16g/dL, SD 1.6; GLILD mean exposure to bats. Patient proceeded to go to the ER for further evaluation 11.79g/dL, SD 1.924; p50.00051); AST (CVID mean 28.17IU/L, SD regarding post-exposure prophylaxis. 14.15; GLILD mean 47.15IU/L, SD 20.29; p5.00008); Alkaline RESULTS: An Allergy and Immunology specialist was consulted in the Phosphatase (CVID mean 81.42IU/L, SD 34.15; GLILD mean emergency department, and the patient was given both the Rabies vaccine 200.5IU/L, SD 183.5; p50.000003); Total Bilirubin (CVID mean SATURDAY and Immunoglobulin immediately after exposure, and completed all 4 0.4054mg/dL, SD 0.224; GLILD mean 0.758mg/dL, SD 0.729; vaccines over 14 day period. The patient was subsequently followed up p50.0016); Albumin (CVID mean 4.29g/dL, SD 0.520; GLILD out-patient by allergy and immunology specialist and was found to have mean 3.88g/dL, SD 0.649; p50.0229); CD8+ T-cells (CVID mean tolerated vaccinations with no consequences. The patient showed no signs 851.38/uL, SD 210.11; GLILD mean 1045.43, SD 1668.04; or symptoms consistent with rabies infection and admitted to having no p50.0086); T-cell CD4/CD8 ratio (CVID mean 3.104, SD 2.28; side effects from the rabies vaccines and immunoglobulin’s. GLILD mean 1.14, SD 0.509; p50.029). CONCLUSIONS: Due to the unknown probability of a response to the CONCLUSIONS: Certain biochemical markers are more likely to be rabies vaccine by CVID patients, giving a patient the rabies vaccine alone associated with GLILD in CVID patients. Future work is needed may or may not be helpful. On the other hand due tothe extreme fatalityof the to develop odds ratios to guide GLILD screening. We are rabies virus, and due to the fact that a dead-inactivated vaccine will likely not currently beginning this step using data from other Harvard-affiliated harm a patient (Kopel, Oren et al. 2012), the current recommendation is that hospitals. the rabies vaccine should be given in the event that a patient is exposed to the Jacobsen Syndrome With Combined Variable rabies virus in a CVID patient along with Immunoglobulin. 34 Immunoddeficiency (CIVD) Common Variable Immunodeficiency In The Very Old Dr. Arnaldo C. Porto Neto, MD, PhD, FAAAAI, Dr. Julio Mella 32 Dr. Katherine E. Gundling, MD; UCSF, San Francisco, CA. Pierezan, Student, Dr. Joao Paulo Bordin, Student, Dr. Julia Noschang, RATIONALE: Common Variable Immundeficiency (CVID) is a Dr. Juliana Gotardo, Student, Dr. Juliana Moro, Student, Dr. Jorge Luigi primary immunodeficiency that is diagnosed in people of all ages. Orso, Student, Dr. Jamile Pedroni, Student and Dr. Jessica Zandona, We evaluated and diagnosed a patient to have CVID at the age of 92, Student; School of Medicine UPF, PASSO FUNDO, Brazil. which led us to realize that very little is known about CVID diagnosed RATIONALE: Jacobsen syndrome is a rare 11q terminal deletion disorder in the very old. associated with multiple dysmorphic features, short stature, psychomotor METHODS: We reviewed available data about the oldest patients known retardation, congenital heart disease, thrombocytopenia (Paris- Trosseau to have CVID, and researched the literature for information about the syndrome), genitourinary anomalies, ophthalmologic disorder and occa- oldest age at diagnosis of CVID. sional digital anomalies . While recurrent upper respiratory infections in RESULTS: Our literature search revealed little information on how these patients are common, life-threatening or opportunistic infections are CVID differs in the very old compared to younger patients, except few reported. that, almost by definition, they have not had the severe, life- METHODS: We report 15 year-old male diagnosed as having 11q23.3 threatening illnesses that shorten the lifespan of certain CVID terminal deletion at 4 years-old. He has experienced a multitude phenotypes. There is also little infomation available regarding age at of problems, include Paris-Trosseau syndrome, developmental delay, diagnosis in the later years. psychomotor retardation, gastroesophagal reflux, atrioventricular septal CONCLUSIONS: Whether due to delay of diagnosis or due to milder defect, agenesis of right kidney, food allergy, asthma and recurrent otitis disease, CVID can be diagnosed in patients of very advanced age. Our media and persistent sinopulmonary infections, requiring frequent and patient may be the oldest person ever diagnosed with CVID. Examination prolonged courses of antibiotic. In 2009 he was hospitalized by sepsis and of available databases revealed several patients in this age group, but endocarditis. whether there are distinct differences in comparison to younger patients is RESULTS: Immunologic evaluation: IgG5375mg/dl, IgM519mg/dl, 3 3 not clear. Our patient’s quality of life greatly improved after institution of IgA57mg/dl, CD195 77.2/mm ,CD25 1482/mm CD35 1436/ 3 3 3 IVIg and we propose that advanced age is not a contraindication to mm ,CD45 684/mm ,CD85693/mm and pneumococal antibody ti- receiving immunoglobulin. ters were nonresponsive (pre and pos vaccination), isohemagglutinins were low:, anti-A 1:4, platelets (18,000 to 83,000 in blood tests) . Clinical Predictors Of Granulomatous Disease In Common Treatment with IVIG has led to normalization of IgG levels and 33 Variable Immunodeficiency clinical improvement. Dr. Anna R. Wolfson, Dr. Anna Kovalszki; Beth Israel Deaconess CONCLUSIONS: A significant number of Jacobsen syndrome have Medical Center, Boston, MA. recurrent infections, there have been no reports to our knowlegde of CVID RATIONALE: 8-22% of patients with Common Variable or life-threatening in Brazil with this syndrome. It is therefore prudent that Immunodeficiency (CVID) will develop granulomatous lymphocytic Jacobsen syndrome patients have immunologic assessment in face of interstitial lung disease (GLILD). There are currently no screening recurrent infections. guidelines. Earlier detection of disease may result in improved morbidity and mortality. We set out to detect markers predictive of GLILD to aid in development of screening guidelines.
ABS 5.2.0 DTD YMAI10627_proof 11 January 2014 3:07 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB10 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Factors Predicting Long-Term Hypogammaglobulinemia In Pneumococcal Titer Levels: Comparison Of Patients Receiving 35 Lymphoma Survivors 37 Intravenous Immunoglobulin Vs. Subcutaneous Immunoglobulin Dr. Huifang Lu, MD, PhD1, Dr. Xerxes Pundole2; 1UT MD Anderson Dr. Pamella Abghari, MD1,2, Dr. Elizabeth A. Secord, MD, FAAAAI1,2, Cancer Center, Houston, TX, 2UT MD Anderson Cancer Center. Dr. Pavadee Poowuttikul, MD1,3; 1Children’s Hospital of Michigan RATIONALE: Long-term hypogammaglobulinemia has emerged as a Department of Allergy Immunology, Detroit, MI, 2Wayne State concern in lymphoma survivors. We conducted a study to identify factors University, Detroit, MI, 3Pediatrics- Allergy/Immunology Division, responsible for the delayed immune recovery. Wayne State University School of Medicine, Detroit, MI. METHODS: We retrospectively reviewed the medical records of 5160 RATIONALE: Immunoglobulin replacement is the mainstay treatment adults treated for lymphoma at our institution between January 1, 2001, and in patients with humoral immunodeficiency, yet a handful of patients December 31, 2005, and identified 361 patients whose disease was in continue to develop sinopulmonary infections while on therapy. We complete remission or who had been treatment-free for more than 2 years. hypothesized, based on incidental findings of low pneumococcal titers Patients for whom either baseline or post-treatment immunoglobulin G in several immunodeficiency patients, that there will be lower (IgG) concentrations were available were included. IgG concentrations pneumococcal titer levels after at least one year of subcutaneous were followed retrospectively until December 31, 2010. Multiple logistic immunoglobulin (SCIG) compared with intravenous immunoglobulin regression and propensity score analyses were conducted to determine (IVIG). which characteristics predicted hypogammaglobulinemia. METHODS: A preliminary retrospective chart review was completed on RESULTS: Of the 361 eligible patients, 185 had both baseline and 13 patients, with ongoing enrollment for future addition to the study post-treatment IgG concentrations, and 176 had only post-treatment IgG population. These patient’s ages ranged between 1-61 years and are concentrations. Approximately half of the patients had low IgG concen- currently receiving immunoglobulin replacement therapy. Pneumococcal trations (25% persistently low and 24% transiently low) after treatment. serotype titers obtained at least one year after initiating therapy were Chi-square and Fisher exact tests revealed that mature B-cell lymphoma compared between IVIG (8 patients) and SCIG (5 patients). (P50.0127), disease stage (P50.0004), rituximab-containing cytotoxic RESULTS: Preliminary comparison between the groups demonstrated chemotherapy regimens (P50.0073), and stem cell transplantation (SCT) more therapeutic pneumoccocal titers achieved (>_ 1.4) while on SCIG. An (P<0.0001) were significantly associated with low IgG concentrations. additional finding was that neither IVIG nor SCIG achieved therapeutic Regression analysis showed similar results and further revealed that titer levels in Pneumococcal serotype 4 and 9N. Lastly, SCIG also did not baseline IgG concentrations (odds ratio53.9 [1.5-10.6]) are important in achieve therapeutic levels of pneumococcal serotype 23F. predicting hypogammaglobulinemia. The results of the propensity score CONCLUSIONS: Our retrospective chart review demonstrated a greater analysis suggested that factors other than chemotherapy regimen type number of therapeutic pneumococcal titers with SCIG in comparison to contributed to hypogammaglobulinemia. IVIG. Other studies have also supported this finding by demonstrating that CONCLUSIONS: IgG concentrations before and after treatment should weekly SCIG maintained 10-20% higher trough levels of IgG when be carefully monitored to better predict hypogammaglobulinemia, compared to IVIG. especially in patients with advanced mature B-cell neoplasms and those that receive rituximab-containing cytotoxic chemotherapy and SCT. Hypogammaglobulinemia, Multiple Sclerosis, and Treatment 38 With Intravenous Gammaglobulin Assessment Of Benefits Of Scig Valued By Healthcare Providers Dr. Tiffany Dy, MD1, Dr. Arye Rubinstein, MD, FAAAAI2; 1Montefiore 36 and Patients: Survey Results Medical Center at Albert Einstein College of Medicine, Bronx, NY, Ms. Annette R. Zampelli, NP1, Ms. Carla M. Duff, CPNP, MSN2, 2Albert Einstein College of Medicine, Bronx, NY. Dr. Ann Bullinger, PharmD1; 1CSL Behring, LLC, King of Prussia, PA, RATIONALE: Patients with multiple sclerosis (MS) may have various 2University of South Florida, Tampa, FL. associated immune abnormalities, mainly affecting regulatory T cell RATIONALE: Healthcare providers (HCPs) and patients often have functions. Although hypogammaglobulinemia is not a common feature differing opinions regarding treatment efficacy, tolerability, and satisfac- of MS, several uncontrolled studies have shown a benefit of high dose tion in a variety of disease conditions. Surveys were developed to assess intravenous gammaglobulin (IVIG). Treatment with IVIG has been physician, nurse, and patient perceptions of subcutaneous immunoglobulin associated with improved brain MRI findings and stabilization of disease (SCIG) versus intravenous immunoglobulin (IVIG) therapy. course. We evaluated 3 patients with MS who were referred for evaluation METHODS: Surveys (28 questions) were administered at professional of frequent respiratory infections and found to have humoral immune conferences to nurses (n551) and physicians (n526) experienced with aberrations. The association between hypogammaglobulinemia and MS immunoglobulin therapy. Unbranded surveys (34 questions) were activity has not been described. distributed online by the Immune Deficiency Foundation to patients METHODS: A retrospective chart review was performed on 3 patients (n5131) with primary immunodeficiency receiving immunoglobulin diagnosed with MS and referred for an immunodeficiency evaluation. All 3 therapy. had evidence of hypogammaglobulinemia, and 1 was diagnosed with RESULTS: HCPs were asked what they thought their patients perceived as common variable immunodeficiency (CVID). the most important benefit of SCIG therapy compared with IVIG. RESULTS: All 3 patients had decreased IgG levels that were 2 standard Approximately 80% of physicians and nurses selected answers related to deviations below normal. One patient with recurrent sinopulmonary quality of life (QoL), rather than tolerability-related or cost benefits. infections had decreased IgM levels and poor antibody responses to Patient responses were aligned with those of HCPs; 84% reported that QoL Streptococcus pneumoniae and rubella. The other two patients had was better with SCIG therapy compared with IVIG. Interestingly, 60% of normal specific antibody titers but suffered from recurrent sinopulmo- responding patients considered SCIG therapy to be more efficacious than nary infections. One patient also experienced recurrent Clostridium IVIG, whereas 62% of physicians and 47% of nurses considered SCIG and difficile infections. Lymphocyte subsets and mitogenic responses were IVIG to be equally efficacious. A minority of patients found SCIG to be normal. There was no increase in circulating immune complexes or less efficacious (5%) or less tolerable (9%) than IVIG. Similar proportions autoimmune markers. Two patients received IVIG and demonstrated a of patients, physicians, and nurses considered SCIG therapy to be better significant decrease in frequency of infections and exacerbations of tolerated than IVIG (64%, 69%, and 65%, respectively). multiple sclerosis. CONCLUSIONS: Perceptions of HCPs were generally consistent with CONCLUSIONS: This case series demonstrates that MS patients with patient opinions regarding benefits of SCIG therapy versus IVIG, although hypogammaglobulinemia may experience a deterioration of concommitant patients tended to perceive a greater efficacy benefit from SCIG. A positive immunoregulatory aberrations and that IVIG may ameliorate disease impact on QoL was significantly valued by both HCPs and patients. exacerbations.
ABS 5.2.0 DTD YMAI10627_proof 11 January 2014 3:07 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB11 VOLUME 133, NUMBER 2
Selective IgM Deficiency Presenting As Cryptogenic Organizing Withdrawn 39 Pneumonia 41 Dr. Cory A. Lundberg, DO1, Dr. Taylor A. Banks, MD1, Dr. Cecilia High Prevalence Of Bronchiolitis In Children With Primary Mikita, MD, MPH, FAAAAI2, Dr. Jeffrey Mikita, MD1; 1Walter Reed Immunodeficies National Military Medical Center, Bethesda, MD, 2Walter Reed Army 42 Dr. Celia Pinto Fernandez1, Dr. Mar ıa Dolores Gurbindo Guti errez1, Medical Center, Bethesda, MD. Dr. Jose Manuel Zubeldia Ortuno, MD, PhD2, Dr. Mar ıa Elena RATIONALE: Selective IgM deficiency is a rare disorder that may Seoane Reula1; 1Gregorio Maran~on Universitary Hospital, Madrid, Spain, present with severe and recurrent infections. It is associated with atopic, 2Hospital Gregorio Maranon, Madrid, Spain. autoimmune, hematologic, and malignant disorders; however interstitial RATIONALE: Bronchiolitis is the most frequent lower respiratory tract lung disease is rare. We present a patient with selective IgM deficiency illness in the first two years of life. Children with primary identified after diagnosis of cryptogenic organizing pneumonia. immunodeficiencies(PIDs) seem to have an increased risk of developing METHODS: Clinical exams, imaging, biopsy, and immunologic severe RSV(respiratory syncytial virus) bronchiolitis. Nowadays there are laboratory evaluation. no studies in regards to this subject. Our objective was to estimate the RESULTS: 35 year old female with history of Hashimoto’s thyroiditis SATURDAY prevalence of bronchiolitis in PIDs children, attended in the Paediatric presented initially to pulmonology for evaluation of progressive dyspnea and Clinical Immunology and Allergy Unit in Gregorio Maran~on Hospital cough for 1 year. She was found to have reticulonodular opacities and (Madrid) from April 1st to July 30th 2013. bronchiectasis on high definition CT scan, and was diagnosed with METHODS: We included all PIDs confirmed patients that attended the cryptogenic organizing pneumonia after bronchoscopy and open lung biopsy. Pediatric Clinical Immunology Unit during this period. We reviewed their She was referred to allergy/immunology to evaluate a possible allergic medical histories to know if they had previous clinical history of bronchiolitis. component to her cough with positive skin prick testing to dust mite. Upon RESULTS: We cared 106 children with PIDs confirmed diagnosis. Fifty- further questioning, she endorsed multiple sinus infections prompting an five(51%) of them had had bronquiolitis. 47%(26/55) infants with bronchio- immune deficiency evaluation. Labs revealed decreased total IgM level of 27 litis and PIDs had required hospital admission. 75% had a positive SRV test. mg/dL with normal IgA and IgG. Flow cytometry demonstrated low normal 74 children with antibodies deficiency were reviewed, out of which CD4+ cells, normal CD8+ and NK cells. Isohemagglutinins were present, 52.7%(39/74) had suffered bronchiolitis. 46%(6/13) infants with well and antigen-specific IgG antibody responses to tetanus and pneumococcal defined immunodeficiency syndromes and 20%(1/5) of those with combined antigens were normal. Secondary hypogammaglobulinemia was excluded. T and B cell immunodeficiency had bronchiolitis. All the patients with Despite treatment, the patient continues to have cough but no new infections. complement defects (6/6), 50%(2/4) with phagocyte defects and none of the CONCLUSIONS: Selective IgM deficiency is a rare disorder that should children with autoinflammatory syndrome(4) had presented bronchiolitis. be considered in the work up of recurrent infections and bronchiectasis. CONCLUSIONS: Our PIDs patients had a higher prevalence (51%) than Interstitial lung disease in patients with hypogammaglobulinemia has been that observed in general paediatric population (10-25%). Almost half of described. An immune deficiency workup should be considered in patients them required hospital admission. Bronquiolitis was more common in presenting with interstitial lung disease, especially with associated antibodies deficiencies and complement defects than in other PIDs. Even autoimmune and atopic disease. though more thorough studies are needed, PIDs infants should be included 40 Withdrawn as another palivizumab indication, to prevent severe RSV infection.
ABS 5.2.0 DTD YMAI10627_proof 11 January 2014 3:07 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB12 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Three Cases Of Good's Syndrome A Rare Case Of Helicobacter Cellulitis In a Patient With 43 Dr. Whitney M. Rassbach, MD1, Dr. Charlotte Cunningham- 45 X-Linked Agammaglobulinemia Rundles, MD, PhD, FAAAAI2; 1Mount Sinai School of Medicine, New Dr. Nina Lakhani, MD1, Dr. Linda R. Taggart2, Dr. Henry Jakubovic3, York, NY, 2Mt. Sinai Medical Center, New York, NY. Dr. Stephen D. Betschel, MD1, Dr. Zafir Hussain4; 1University of Toronto, RATIONALE: Good’s syndrome is a rare association of combined B- and Division of Clinical Immunology and Allergy, Toronto, ON, Canada, 2Uni- T-cell immunodeficiency with benign thymoma. Opportunistic infections versity of Toronto, Divison of Infectious Diseases, Toronto, 3University of often arise prior to discovery of the immune defect. Toronto, Division of Laboratory Medicine and Pathology, Toronto, ON, Can- METHODS: A retrospective chart review was performed of three ada, 4Universityof Toronto, Division of Microbiology,Toronto, ON, Canada. patients with Good’s syndrome who experienced medical complica- RATIONALE: X-linked agammaglobulinemia (XLA) is a humoral tions. Delayed recognition of the immune defect occurred in each immune deficiency due to defects in Btk expression, leading to absence case. of mature B-lymphocytes, severe hypogammaglobulinemia and increased RESULTS: Case 1 is a 59 year-old woman who presented with chronic susceptibility to infection. Patients with XLA can develop cellulitis due to cough and painful oral lesions at age 48. A thymoma and hypogamma- Helicobacter species, an organism that is atypical for cellulitis and difficult globulinemia were discovered. She was treated with high-dose oral steroids to detect and eradicate. We report a case of Helicobacter cellulitis in a for cryptogenic organizing pneumonia and with mycophenolate mofetil for patient with XLA, highlighting the importance of recognizing its oral lichen planus. IVIG was instituted. She later had acute babesiosis, C. pathogenicity in patients with XLA, and challenges in diagnosis. difficilecolitis, breast cancer, and idiopathic inflammatory bowel disease. METHODS: Case report and literature review. Case 2 is a 70 year-old man with chronic obstructive pulmonary RESULTS: This20-year-oldmanwhoworked atawaterpark, wasdiagnosed disease who had a thymoma resected in 1991, with recurrence of the with XLA in infancy and started on replacement intravenous immunoglobulin thymoma and onset of chronic cough and recurrent pneumonia in 2005. infusions. At age 18, two years before diagnosis, he developed repeated Lung biopsy revealed PCP pneumonia with granulomatous reaction. episodes of cellulitis with persistent hyperpigmented woody induration of the Hypogammaglobulinemia was discovered in 2012 and IVIG started. He left leg. Following multiple courses of antibiotics, several skin biopsies were expired with lung failure in 2013. Case 3 describes a 55 year-old man performed however, cultures of specimens remained negative. Silver staining with Good’s syndrome in whom a 1 kg thymoma was discovered after of tissue revealed thin, elongated, curved organisms. Direct 16S ribosomal syncope due to left heart compression. One year later panhypogammaglo- RNA sequencing detected Helicobacter species, however further speciation bulinemia was discovered on evaluation for recurrent sinus infections. He was not possible. Given the rarity of this diagnosis, a literature review was subsequently had salmonella and campylobacter gastroenteritis followed undertaken. Treatment was initiated with intravenous imipenem and oral by a herpes zoster infection. doxycycline. Dramatic improvements in cellulitis and plaque regression were CONCLUSIONS: Good’s syndrome patients present with the unique noted. The optimal duration of therapy is unknown. combination of thymoma, absent B-cells and hypogammaglobulinemia. CONCLUSIONS: Helicobacter species infections are rare but important Cellular immunity is variably impaired. A high incidence of opportunistic causes of cellulitis in patients with XLA, and should be considered when infections is present. cellulitis is refractory. It has not been reported in other primary humoral immune deficiencies. Molecular approaches to diagnosis are often Immunological Analysis Of Primary Selective IgM Deficiency In required. Combination antibiotics and prolonged duration of therapy 44 Adults may be necessary for successful management. Ankmalika Louis, MD1, Sudhanshu Agrawal, MS2, Sudhir Gupta, MD3; 1University of California, Irvine, CA, 2University of California, Irvine, Neuropathy In Patients With Underlying Immunodeficiency 3University of California, Irvine. 46 Syndrome RATIONALE: Primary selective IgM deficiency is a rare disorder with Dr. Robyn Kreiner, MD, Dr. Arye Rubinstein, MD, FAAAAI; Albert increased susceptibility to infections and autoimmune diseases. There is a Einstein College of Medicine, Bronx, NY. lack of detailed immunological study in patients with primary selective RATIONALE: Anti-glutamic acid decarboxylase (GAD65) is an antibody IgM Deficiency. against the enzyme responsible for converting glutamic acid to GABA. GABA METHODS: Adult patients with primary selective IgM deficiency (serum is found in high concentrations in the cerebellum. Lack of GABA is believed IgM <2SD of mean) were studied for detailed immunological analysis. to result in cerebellar ataxia, stiffness of muscles and autoimmune diseases. CD3+ T cells, na€ıve, central and effector memory subsets of CD4+ and METHODS: A retrospective chart review was conducted of 6 patients 19 CD8+ T cell, Na€ıve B cells, transitional B cells, marginal zone B cells, IgM to 61 years old with an antibody deficiency disorder associated with memory B cells, switched memory B cells, CD21 low B cells, neuropathy. All patients had markedly elevated anti-GAD antibodies Plasmablasts, B1 cells, CXCR3+ B cells, and NK cells were analyzed ranging from 118 to >30,000 nmol/L (normal <1.0). Motor and/or sensory using specific antibodies and isotype controls, using multicolor flow neuropathy was diagnosed by clinical presentation and abnormal EMG or cytometry. In addition, lymphocyte proliferations to mitogens and skin biopsy for small fiber density. antigens, specific antibody response against pneumococci, and comple- RESULTS: All 6 had underlying immunodeficiency with varying degrees of ment components were analyzed. Exome sequencing was performed in hypogammaglobulinemia with poor to no antibody response to polysaccharide four subjects including one mother and daughter. antigens. In addition to neuropathy, 4 patients had other autoimmune diseases RESULTS: A significant increase in CD21low (P<0.009) and IgM including thyroiditis, myasthenia gravis and inflammatory bowel disease. All memory B cells (P<0.02), and a significant decrease (P<0.02) in patients’ autoimmune manifestations failed to respond to treatment with CXCR3+ na€ıve and memory B cells and of NK cells (P<0.04) were intravenous gammaglobulin (IVIG) doses tailored to their underlying observed. Approximately 50% of patients display poor specific immunodeficiency. They did respond to high dose IVIG as utilized for antibody response against pneumococci. T cell response to mitogens and treatment of Chronic Inflammatory Demyelinating Neuropathy (CIDP). There antigen were normal. Data of exome sequencing are currently being was marked improvement of neuropathy and anti-GAD antibodies decreased analyzed. to near normal levels. In 4 patients neuropathic symptoms relapsed as IVIG CONCLUSIONS: Primary selective IgM deficiency is associated dose decreased. 2 patients responded to addition of rituximab with improved predominantly with B cell defects including increased CD21low and control of neuropathy and further decrease of anti-GAD antibodies. IgM memory B cells, decreased CXCR3+ B cells, and impaired CONCLUSIONS: There are no cohort studies of patients with neuropathy specific antibody response to polysaccharide antigens. T cell functions in antibody immunodeficiency associated with elevated Anti-GAD appear to be preserved. Exome sequencing data might reveal a specific antibodies. Our cohort of 6 patients suggests a response to high dose gene defect. IVIG with/without additional treatment with rituximab.
ABS 5.2.0 DTD YMAI10627_proof 11 January 2014 3:07 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB13 VOLUME 133, NUMBER 2
Allergic Sensitization and Enviromental Exposures In Amish and Association Of Wheezing Illness With Respiratory Viruses In 47 Hutterite Children 49 Hospitalized Jordanian Children Dr. Mark Holbreich, MD, FAAAAI1, Ms. Michelle Stein, MS2, Olajumoke Fadugba, MD1, Eva Kathryn Miller, MD2, Najwa Khuri- Ms. Rebecca Anderson, MS3, Dr. Nervana Metwali, PhD4, Dr. Peter S. Bulos, MD, FIDSA, CIC3, Samir Faouri, MD3, Asem Shehabi, PhD4, Thorne, PhD4, Dr. Donata Vercelli, MD5, Dr. Erika Von Mutius, MD, Christopher Fonnesbeck, PhD1, Li Wang, MS1, John V. Williams, MD1, MSc6, Dr. Carole Ober, PhD3; 1Allergy and Asthma Consultants, Indian- Natasha Halasa, MD, MPH1; 1Vanderbilt University Medical Center, apolis, IN, 2The University of Chicago, Chicago, IL, 3University of Chi- Nashville, TN, 2Pediatric Allergy, Immunology, and Pulmonary Medicine, cago, Chicago, IL, 4University of Iowa, Iowa City, IA, 5The University of Vanderbilt University Medical Center, Nashville, TN, 3Jordan University Arizona, Tucson, AZ, 6University Children’s Hospital, Munich, Germany. Hospital, Jordan, 4University of Jordan, Jordan. RATIONALE: In separate studies of two US farming populations of central RATIONALE: Respiratory illness with wheezing is a major cause of European ancestry, we found marked differences in the prevalence of allergic morbidity in infants. The burden of disease attributable to viruses in sensitization between Indiana Amish and South Dakota Hutterite children hospitalized children in Amman, Jordan is not well characterized. We (7% vs. 40%). Here, we directly compared the prevalence of allergic aimed to determine the association of wheezing illness with respiratory sensitization and exposure to major inhaled allergens in these children. viruses in hospitalized Jordanian children. SATURDAY METHODS: 30 age- and sex-matched school children each were studied METHODS: We conducted a prospective viral surveillance study in in Nov (Amish) and Dec (Hutterite) 2012. Serum IgE (ImmunoCap; children <2 years of age admitted with respiratory symptoms and/or fever Phadia) to mite, cat, cockroach, mold, mouse urine protein and epithelium, at the government-run hospital, Al-Basheer. Surveillance was conducted mixed tree, and mixed grass allergens were measured. Atopy was defined from 3/16/2010-9/10/2012. Clinical and demographic data were collected. as IgE>3.5KU/L to >_1 allergen. Eight allergens (3 mite, cat, dog, Nasal/throat swabs were obtained, placed into lysis buffer, aliquoted, and cockroach, rat, mouse) were measured by multiplex immunoassay in frozen at -808C. Specimens were shipped to Vanderbilt and tested by airborne dust sampled from electrostatic dust collectors one month after real-time RT-PCR for respiratory syncytial virus (RSV), human their placement in 10 homes from each population. metapneumovirus (HMPV), human rhinovirus (HRV), influenza A and RESULTS: We confirmed atopy prevalence is 7% (2/30) among Amish and B, adenovirus, and parainfluenza viruses 1, 2, 3 (PIV1-3). 30% (9/30) among Hutterite children (P50.042). Common allergens were RESULTS: Viral data was available for 2429 out of 2433(99.8%) enrolled essentially undetectable in house dust from both groups, except for Mus m1, subjects. The median age was 3.5months, 60% were males, 56% had which was found more frequently (9 of 10 vs. 2 of 10 homes, P50.0054) wheezing on admission (heard on auscultation by a clinician). Nine hundred and at higher levels (median5210 vs.15ng/m2) in Amish compared to eighty children tested positive for RSV,892 HRV,316 adenovirus, 233 HMPV, Hutterite homes. However, Amish children had no IgE to mouse allergens. 97 PIV3, 31 PIV1 and 11 PIV2. The most commonly detected co-infection CONCLUSIONS: Differential exposure to common allergens per se does was RSV/HRV (n5243). Of subjects with wheezing vs. those without not explain the lower prevalence of allergic sensitization among Amish wheezing, 26% vs. 16% had RSVonly (p<0.001), 6% vs. 3% had HMPVonly compared to Hutterite children. However, the combination of high mouse (p50.001), and 15% vs. 20% had HRVonly (p<0.001), respectively. allergen exposure and lack of sensitization tothese allergens may reflecta mi- CONCLUSIONS: Subjects with wheezing were more likely than those crobial environment that promotes protection from atopy among the Amish. without wheezing to have RSV, HMPVand RSV/HRV co-infection. Those with wheezing were less likely to have HRV. Wheezing was not Association Between Asthma-Related Emergency Department significantly associated with other viruses. 48 Visits, Tree Pollen, Pollution and Humidity In The Bronx, 2001 - 2008 The Effect Of Obesity On Asthma Control As Measured By The Dr. Jennifer Toh, MD1, Dr. Mili Shum, MD2,3, Dr. Gabriele De Vos, MD4, 50 Asthma Control Test Tulsi Desai4, Priyank Patel4, Dr. Sunit Jariwala, MD1, Dr. David L. Dr. Aerik A. Williams, MD, MPH1, Dr. Mark S. Dykewicz, MD, Rosenstreich, MD, FAAAAI5; 1Albert Einstein/Montefiore Medical Center, FAAAAI2, Dr. Jason W. Caldwell, DO, FAAAAI1; 1Wake Forest New York, NY, 2Montefiore Medical Center, Bronx, NY, 3Weill Cornell University Baptist Medical Center, Winston Salem, NC, 2Saint Louis Medical College, New York, NY, 4Albert Einstein College of Medicine, University School of Medicine, St. Louis, MO. Bronx, NY, 5Albert Einstein/Montefiore Medical Center, Bronx, NY. RATIONALE: Obesity (Body Mass Index > 25) is associated with RATIONALE: To examine the contribution of air pollution, humidity, and poorer Asthma Control Questionnaire (ACQ) scores and more frequent tree pollen to asthma-related emergency department visits (AREDV) in a hospitalizations. Data suggest that the Asthma Control Test (ACT) is high asthma prevalence area, the New York City borough of the Bronx. preferable to the ACQ in clinical practice. There is limited data evaluating METHODS: We previously investigated daily adult and pediatric the association between ACT scores and obesity. AREDV at two Bronx hospitals (Montefiore- Moses and Weiler) through METHODS: This study was a retrospective chart review conducted at a the Clinical Looking Glass data analysis software. Daily counts for tree university hospital-based allergy and immunology practice. It was pollen from 3/2001 to 10/2008 were obtained from the Armonk counting approved by the Wake Forest Baptist Health Institutional Review Board. station located in close proximity to the Bronx. In the present study, we In a random fashion, charts of 51 adult asthmatic patients were categorized daily measurements of tree pollen, humidity, and air pollutants retrospectively reviewed to investigate the association between obesity (nitrogen dioxide and particulate matter 2.5) into quartiles, and then and ACT score. BMI and ACT scores were calculated as an average over compared these variables in relation to AREDV. the follow-up period. Asthma was defined according to NHLBI guidelines. RESULTS: From 2001-2008, therewere a total of 42,065 AREDVat the two RESULTS: We identified 22 patients with normal BMI and 29 obese hospitals. In each of the years, we observed a spring peak (May) in AREDV, patients. Mean follow up duration was 1.2 years in the normal BMI group which consistently overlapped with high tree pollen levels. However, our and 1.0 years in the obese group. Between the groups there was no analysis of tree pollen, humidity, and air pollutant measurements, revealed difference in gender, prevalence of reflux disease, prevalence of rhinitis, that the highest quartile of daily tree pollen counts resulted in consistently smoking history, and asthma medication regimen. Mean BMI was high AREDV,regardless of pollutant or humidity measurements. In contrast, significantly higher in the obese group compared to the normal BMI group on days when humidity and air pollution levels were high, but tree pollen (33.3 vs 21.9, p50.001). Mean ACT score was significantly lower in the counts were low, AREDV were not significantly increased. obese group compared to the normal BMI group (18.9 vs 21.3, p50.03). CONCLUSIONS: There is a large, spring increase in AREDV in the CONCLUSIONS: Compared to asthma patients with a normal BMI, Bronx that closely correlates with high tree pollen counts and is not obese asthma patients have a significantly lower ACT score with a mean significantly affected by humidity or air pollution levels. These findings score (18.9) consistent with asthma impairment. Weight loss should be may have prognostic value in anticipating increased asthma exacerbations. addressed at each visit with obese asthma patients.
ABS 5.2.0 DTD YMAI10627_proof 11 January 2014 3:07 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB14 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Perception Of Asthma Control Is Not Consistent With Reported atopy and recent wheeze was attenuated by markers of geohelminth 51 Symptom Frequency In Urban Adolescents infections. Emily C. Ledford1, Ms. Jean Curtin-Brosnan, MA2, Dr. Meredith C. CONCLUSIONS: Our data suggest that urban residence modifies the McCormack, MD3, Dr. Elizabeth Matsui, MD4; 1Johns Hopkins School association between HDM atopy and recent wheeze, and this effect is of Medicine, 2Johns Hopkins University, Baltimore, MD, 3The Johns explained partly by the presence of geohelminth infection markers. Hopkins Pulmonary, Baltimore, MD, 4The Johns Hopkins University School of Medicine, Baltimore, MD. Allergic Inflammation and Health Outcomes Of Comorbid Asthma 53 and Obesity In Inner-City Black and Hispanic Schoolchildren RATIONALE: The relationship between perception of asthma control 1,2 2,3 and reported symptom frequency among adolescents remains unclear. Dr. Perdita Permaul, MD , Dr. William J. Sheehan, MD , Mr. Carter Petty, MA3, Dr. Sachin N. Baxi, MD2,3, Dr. Jonathan M. Gaffin, MD, METHODS: 48 Baltimore adolescents (14-17y) with persistent asthma 2,3 2,3 were enrolled in an observational prospective study. A questionnaire MMSc , Dr. Lianne S. Kopel, MD , Dr. Watcharoot Kanchongkittiphon, MD, PhD3, Mrs. Chunxia Fu, MS4, Dr. Diane R. captured symptoms, rescue medication use, and perceived asthma control. 2,4 2,3 1 The reported frequency of symptoms, activity limitation, nocturnal Gold, MD, MPH , Dr. Wanda Phipatanakul, MD, MS, FAAAAI ; Di- awakenings, and albuterol use within the past two weeks were used to vision of Pediatric Allergy/Immunology, Massachusetts General Hospital, Boston, MA, 2Harvard Medical School, Boston, MA, 3Boston Children’s determine actual asthma control. Misperception of control was defined as 4 report of well-controlled asthma when the child’s asthma met NAEPP Hospital, Boston, MA, Channing Laboratory, Brigham and Women’s criteria for not well-controlled or poorly controlled asthma. Hospital, Boston, MA. RESULTS: 54.2% were female, 91.7% African American, and 85.4% had RATIONALE: The impact of obesity on asthma outcomes and its public insurance. At baseline, 75% perceived that their asthma was well relationship with allergic inflammation in inner-city black and Hispanic controlled, but 54% actually had well-controlled asthma. Adolescents who children is poorly understood. reported well-controlled asthma had fewer symptoms than those who METHODS: The School Inner City Asthma Study (SICAS) examines reported uncontrolled asthma (mean: 3.1 vs. 5.8 days/2 weeks, p50.008). urban classroom allergen exposures and asthma morbidity in students with At the baseline visit, among those who reported that their asthma was well- asthma. Allergen sensitization data is collected at baseline. Classroom controlled, 39% had symptom frequencies indicative of uncontrolled mouse allergen (Mus m 1) levels, linked to enrolled students, are collected asthma (means: 7.0 days symptoms, 4.9 days of albuterol). The proportion during the academic year. Asthma morbidity outcome measures are of adolescents who exhibited misperception of control decreased over time obtained every 3 months. Students are stratified by body mass index (22, 17, 3, and 1% at the 3, 6, 9, and 12 month visits, respectively; p50.004). percentile for age and sex. CONCLUSIONS: A substantial proportion of adolescents who perceived RESULTS: Of 303 enrolled students, 49% were normal weight, 50% that their asthma was well-controlled reported symptom frequencies overweight, and 34% obese. Participants were predominantly black (35%) indicative of uncontrolled asthma; however, their perception of asthma and Hispanic (37%). Mouse allergen levels and skin testing data were 5 control improved over time. These findings suggest that education about available in 257 students from 29 schools; 27% (N 70 students) were goals of asthma management and repeated follow-up may improve mouse sensitized. Among sensitized, no significant interaction between 5 adolescents’ ability to accurately assess and manage their asthma. obesity and mouse allergen exposure (p 0.82) when stratified by race (all races p>0.60) or as a main effect of obesity (p50.32) on asthma symptom Urban Residence Modifies The Association Between Atopy and days exists. However, obese black students had more symptom days 52 Wheeze compared to normal/overweight black students (3.59 vs. 2.25 vs. 2.09, Dr. Pablo F. Endara1, Dr. Phil J. Cooper2,3, Thomas A. E. Platts- p50.002) regardless of allergen sensitization and exposure, not seen in Mills, MD, PhD, FAAAAI4, Lisa J. Workman, BA4, Maritza Vaca5, Hispanic students. No significant interactions of obesity and race were Dr. Martha Chico6, Mauricio L. Barreto, PhD7, Prof. Laura Rodrigues8; seen when predicting positive skin tests, FeNO level, healthcare and 1Universidad San Francisco de Quito, 2St. George’s University, London, controller medication use. United Kingdom, 3Pontificia Universidad Catolica del Ecuador, 4Division CONCLUSIONS: Obesity is not a risk factor for allergic inflammation of Asthma, Allergy & Immunology, University of Virginia Health System, and subsequent asthma symptoms suggesting a non-Th2 obesity-asthma Charlottesville, VA, 5Laboratorio de FEPIS, Quinind e, Esmeraldas Province, phenotype. Obesity effects on asthma symptoms may vary by race, Ecuador, 6Laboratorio de Investigacion FEPIS, 7Instituto de Saude Coletiva, however, with obese black students having more symptom days than UFBa, Salvador, BA, Brazil, 8London School of Hygiene and Tropical Hispanics. Medicine. RATIONALE: The association between atopy and allergic disease appears to be stronger in affluent compared to non-affluent populations, an effect that may be explained by attenuation of atopy by environmental exposures. We hypothesized that urban residence could modify the association between atopy indicators and wheeze and identified environ- mental exposures contributing to this effect. METHODS: Two nested case-control studies were done among school- children living in rural communities and urban neighbourhoods in the Province of Esmeraldas-Ecuador. Cases were defined as children with parentally-reported wheeze in the last year and controls as children with no history of wheeze. We measured geohelminths in stool samples and atopy by the specific IgE and skin prick test (SPT) reactivity to aeroallergens. RESULTS: Atopy, particularly measured as specific IgE against house dust mite (HDM), was more strongly associated with recent wheeze in urban than rural schoolchildren: (urban, adj. OR 5.19, 95% CI 3.37-8.00, P<0.0001; rural, adj. OR 1.81, 95%CI 1.09-2.99, P50.02; interaction, P<0.001). Twice as many wheeze cases were explained by atopy in urban compared to rural children: SPT to HDM (urban 18.5% vs. rural 9.6%), and anti-HDM IgE (urban 26.5% vs. rural 10.5%). The association between
ABS 5.2.0 DTD YMAI10627_proof 11 January 2014 3:07 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB15 VOLUME 133, NUMBER 2
Targeted Education Of Adult Patients From An Inner City CONCLUSIONS: Although breastfeeding initiation and continuation in 54 Population At Risk For Non-Adherence With Asthma Therapy these inner-city mothers is lower than the national average, a substantial Dr. Edan Sarid, MD1, Dr. Rauno Joks, MD2; 1SUNY Downstate Medical proportion initiated breastfeeding in the hospital. Mothers with a history, Center, Center for Allergy and Asthma Research, Brooklyn, NY, 2Center diagnosis, or current asthma were more likely to breastfeed than for Allergy and Asthma Research at SUNY Downstate, Brooklyn, NY. non-asthmatics, but did not breastfeed longer. RATIONALE: Medication non-adherence contributes to the prevalence and significant morbidity and mortality of asthma in inner city adults. By Genetic Determinants Of Allergic Sensitization To Cockroach measuring the risk of non-adherence through the Adherence Estimator 56 Allergen In Children 1 2 2 (AE, Merck), we investigated the effects of targeted intervention Priya Tripathi, PhD , Xiumei Hong, PhD , Deanna Caruso, MS , 1 2 1 addressing the three parameters of concern, commitment and cost. Peisong Gao, MD, PhD , Dr. Xiaobin Wang, MD, MPH, ScD ; Division METHODS: The AE is a questionnaire that assigns a weighted numerical of Allergy & Clinical Immunology, Johns Hopkins University School of 2 score for concern regarding medication harm, commitment based on Medicine, Baltimore, MD, Johns Hopkins University School of Public perceived need of medications and perceived financial burden due to out- Health, Baltimore, MD. of-pocket expense. AE scores were measured for outpatient adults (n532) RATIONALE: Sensitization to cockroach allergen is one of the strongest SATURDAY with persistent asthma treated according to NHLBI EPR-3 guidelines in our risk factors for asthma, and there is likely a genetic basis. We sought allergy and asthma clinic. 16 of 32 (50%) were found to be at-risk (score>0) to identify genetic determinants for the development of cockroach and received targeted education addressing all three domains. 28 were sensitization in early childhood. available for follow up (at-risk n513, not-at-risk n515). Targeted education METHODS: We performed a nested case-control analysis for cockroach involved counseling and review of a distributed informational handout sensitization in Boston Birth Cohort. Cockroach sensitization was defined addressing medication risks, benefits of commitment and referral for financial by specific IgE (sIgE) to cockroach allergen (>0.1 IU/ml). Analysis was counseling. Change in median scores was used in statistical analysis. performed for 1188 tagging single nucleotide polymorphisms (SNPs) of 6 RESULTS: There was a significant decrease in total AE score between 247 candidate genes in 631 children (mean age: 8.7 2.5 years) consisting visit one (mean511, median511) and visit two (mean55, median50) in of 75 affected individuals and 556 controls. Significantly associated SNPs patients found to be at risk for non-adherence (p50.004). There was a were further analyzed using logistic regression analysis. significant decrease in patients non-adherent due to concerns about their RESULTS: By chi-square test, the allele frequency of 52 SNPs medication from visit one (mean58, median57) to visit two (mean53, significantly differ between those individuals with and without cockroach median50) (p50.008). Decreases in non-adherence due to commitment sensitization (P value<0.05). Of these, 11 SNPs showed P<0.01, including 5 5 and cost were not statistically significant. (p 5 0.5,1.0 respectively). SNPs in FLG (rs6587665, P 0.002), MMP8 (rs17099450, P 0.002), 5 5 CONCLUSIONS: Educational interventions targeting patients at risk for JAK3 (rs867174, P 0.003), JAK1 (rs10889502, P 0.005), IL4R 5 5 non-adherence significantly decreases this risk, especially that associated (rs4074570, P 0.007), and IL5R (rs3846133, P 0.007). When logistic with concerns about medication side effects. regression analysis was performed adjusted for age, gender, and ethnicity proportion, 10 SNPs remained significant, including the most significant Maternal Allergy and Asthma and Their Association With SNP rs867174 in JAK3 (P50.0003) and SNPs in CLCA (rs465611, 55 Breastfeeding In Inner-City Mothers In a Birth Cohort Study (URECA) P50.001), IL4R (rs3024647, P50.002), FLG (rs6587665, P50.008), Katy F. Jaffee, MS1, Dr. Cynthia Visness, PhD1,Dr.GeorgeT. and JAK1 (rs17127114, P50.009). O’Connor, MD2, Dr. Gordon R. Bloomberg, MD, FAAAAI3, Dr. Meyer CONCLUSIONS: Our findings suggest that JAK3, CLCA, IL4R, FLG, Kattan, MD4, Robert A. Wood, MD, FAAAAI5, Dr. Peter J. Gergen, MD, and JAK1 may be candidate genes for cockroach sensitization. However, MPH6, Dr. James E. Gern, MD, FAAAAI7; 1Rho, Inc., Chapel Hill, NC, none of these SNPs reach significance after Bonferroni correction, which 2Boston University School of Medicine, Boston, MA, 3Campus Box may need to be replicated in larger samples and in independent 8116, St. Louis Children’s Hospital, Saint Louis, MO, 4NewYork-Presbyte- populations. rian/Columbia, New York, NY, 5Johns Hopkins University Medical Center, Baltimore, MD, 6AAIB\DAIT\NIH, Bethesda, MD, 7University of Wisconsin School of Medicine and Public Health, Madison, WI. RATIONALE: The American Academy of Pediatrics recommends exclusive breastfeeding for 6 months and continued breastfeeding for the first year of life, and there is evidence that breastfeeding protects against allergies and asthma. Minority populations, such as URECA, typically have lower rates of breastfeeding than the general US population. There is little information, however, on whether maternal allergy or asthma is associated with the initiation or duration of breastfeeding. METHODS: MotherswereenrolledduringpregnancyintotheUrban Environment and Childhood Asthma (URECA) Study (N5606). We examine rates of breastfeeding initiation, breastfeeding duration, and characteristics of the breastfeeding mothers. Maternal race, age, and education were controlled for in models examining the effect of asthma and allergy status. RESULTS: Fifty-eight percent of URECA mothers initiated breastfeeding in the hospital, and average duration was 17 weeks. Maternal serum IgE levels, eczema and hayfever were not related to breastfeeding initiation, but mothers with asthma were more likely to initiate breastfeeding (current asthma: OR51.5 [1.0, 2.2], history of asthma: 1.7 [1.2, 2.4], diagnosed asthma: OR51.7 [1.2, 2.4]). Higher education (p<0.001), being married (p50.002), and ethnicity (Hispanic vs. non-Hispanic, p<0.001) were associated with a greater likelihood of breastfeeding initiation; income, C-section delivery and gestational age were not. Breastfeeding duration was longer among older mothers (p<0.001).
ABS 5.2.0 DTD YMAI10627_proof 11 January 2014 3:07 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB16 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Exhaled Nitric Oxide (FeNO) and Dust Mite (Der p1) Exposure material is limited and extracts are not commercially available in the 57 Are Significantly Higher In Asthmatic Children Living In Humid U.S. Thus, the purpose of this study was to investigate the culture and Environments life cycle of E. maynei. Dr. Miguel J. Lanz, MD, FAAAAI1, Benjamin Efaw2, Mirna Gonzalez1, METHODS: Fresh eggs were obtained from gravid adult female mites Dr. Ronald J. Harbeck, PhD2; 1AAADRS Clinical Research Center, Coral and held at either 238 or 308C and 75% RH. Larvae that emerged and the Gables, FL, 2National Jewish Health, Denver, CO. subsequent life stages were monitored daily to follow development through RATIONALE: The interaction of environmental exposure and airway the life cycle. Active life stages were fed a diet of lyophilized raw chicken inflammation in pediatric asthma is multi-factorial, but specific clinical egg and baker’s yeast (9:1, vol:vol) which maintains long-term cultures. relationships exists. We attempted to study allergens common to our RESULTS: Duration of development from egg to adult was 27.562.8 days patient population but who live in two distinctly different environments and 20.064.6 days at 238 and 308C, respectively. The length of the life and this effect on markers of airway inflammation. cycle for E. maynei was shorter compared to that previously reported for D. METHODS: A retrospective chart review of atopic asthmatic children farinae (35.664.4 days) and D. pteronyssinus (34.065.9 days) grown on who had a documented history of dust mite sensitivity by history and prick the same diet at 238C. However, development times for E. maynei were skin testing was performed. A total of 124 children (80 males, 44 females, comparable to those reported for D. farinae (17.561.2 days) and mean age of 8 years) had the following clinical indices analyzed: exhaled D. pteronyssinus (19.362.5 days) at 308C. nitric oxide (FeNO), serum eosinophils, total IgE, spirometry and indoor CONCLUSIONS: E. maynei can be grown at the same conditions as allergen dust sampling (MARIA) for Der p1 and Der f1 from bedrooms. D. farinae and D. pteronyssinus to produce material for preparation of Children with high exposures to humidity in their home environment allergen extracts. (n569) by history were compared to those with lower levels of exposures (n555). Emergency Department Visits For Asthma As a Function Of RESULTS: Significant differences were found between groups with 60 Pollen and Mold Spore Counts Dr. Stacey Galowitz, DO1,2, Dr. Christopher Chang, MD, PhD, higher levels of FeNO and Der p1 bedroom samples found in the more 1 3 1 humid environments, and a trend towards higher serum eosinophils was FAAAAI , Mr. Michael R. McDowell ; Alfred I duPont Hospital for Children, Wilmington, DE, 2Thomas Jefferson University Hospital, also found. Significant means between groups were FeNO (34ppb vs 3 27ppb, *p50.05), Der p1 levels (136 ng/ml vs. 60 ng/ml, *p<0.0001), and Philadelphia, PA, Air Quality Management, New Castle, DE. serum eosinophils (7.6% vs 5.8%, p<0.08). No differences in Der f1 RATIONALE: Previous epidemiologic studies have reported associations bedroom samples, serum total IgE, and spirometry were found between between pollen levels and asthma exacerbations. We examined whether groups. All of the inflammatory indices were elevated as expected since the pollen and mold spore counts in the vicinity of homes of children suffering children were all atopic asthmatics. from asthma contribute to emergency room (ER) visits to A.I. duPont CONCLUSIONS: These results reveal that asthmatic children living in Hospital for Children (AIDHC) for asthma. humid environments have higher allergen exposures of Der p1 which METHODS: We conducted a retrospective review of over 4,000 patients results in higher levels of FeNO. presenting to the AIDHC ER and either discharged or admitted with a diagnosis of asthma exacerbation between 2010 and 2013. We correlated Extraordinary Alternaria Mold Counts During a Severe Drought visits with thrice weekly pollen and mold spore counts recorded by the 58 Mr. James J. Anderson, MLT1, Dr. Linda B. Ford, MD, Delaware Department of Natural Resources and Environmental Control in FAAAAI2; 1Environmental Allergy/Oshtech, London, ON, Canada, New Castle, DE. The number of ER visits averaged over a 3-day period 2The Asthma & Allergy Center, P.C., Bellevue, NE. from -1 day to +1 day around each sampling was correlated with pollen and RATIONALE: We recorded unusually high counts of ‘‘dry’’type molds at mold counts. Only patients whose address was within a 30 mile radius of our Omaha NE station during the severe drought of 2012 which also the sampler were investigated. included the St. Louis MO area. RESULTS: Poisson regression model analysis showed no significant METHODS: The spore content of our Burkard samples (n546) collected correlation between total pollen counts and ER visits (p 5 0.11), but between August 1 and September 31, 2012, were analyzed and compared showed a significant negative correlation between total mold counts and to the two primary spore types reported at the St. Louis NAB station ER visits (p 5 0.01). A significantly positive correlation was seen (n545) for the same time period. specifically between Cladosporium counts and ER visits (p 5 0.02). RESULTS: Cladosporium and Alternaria were the primary spore types of Significantly more ER visits were seen in the Spring and Fall seasons the twenty very high (VH) counts (>49,999 spores/M3) collected at (p 5 0.001). Omaha. Seven of the VH counts were > 100,000/M3 and contained CONCLUSIONS: Our results suggest no statistically significant ‘‘high’’ (>12,999/M3) amounts of Alternaria spores. By comparison, there correlation between total pollen counts and asthma-related ER visits. were nine VH counts at St. Louis, and the primary spore types were A positive correlation was found for Spring and Fall seasons and Ascospores and Cladosporium. Cladosporium counts. Further studies should target the role of specific CONCLUSIONS: We recorded copious amounts of airborne spores of the aeroallergens in asthma exacerbations. major allergen Alternaria during the drought of 2012. The spores were particularly prominent during the week overlapping August and the first week of September.
Culture Of The House Dust Mite Euroglyphus Maynei To Produce 59 Allergen Material Dr. Larry G. Arlian, PhD, FAAAAI, DiAnn L. Vyszenski-Moher, MS, Dr. Marjorie S. Morgan, PhD, Jacqueline Neal, MS; Wright State University, Dayton, OH. RATIONALE: The house dust mite, Euroglyphus maynei, occurs in homes worldwide and may be more numerous than Dermatophagoides farinae and/or D. pteronyssinus. Many dust mite allergic patients are sensitive to E. maynei. E. maynei is the source of multiple allergens but few have been characterized nor has prevalence of sensitivities been well studied in dust mite allergic patients largely because E. maynei culture
ABS 5.2.0 DTD YMAI10627_proof 11 January 2014 3:07 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB17 VOLUME 133, NUMBER 2
Daily Ragweed Pollen Forecasting Airborne Alternaria Spore Levels In Kansas City Is Associated 61 Estelle Levetin, PhD, FAAAAI1, Lauren Howard, BS1,2; 1Univer- 63 With Climatic Changes sity of Tulsa, Tulsa, OK, 2University of Oklahoma, Oklahoma City, OK. Dr. David A. Jara, MD1, Dr. Charles Barnes, PhD2, Dr. Jay M. RATIONALE: Ambrosia pollen is an important aeroallergen in North Portnoy, MD, FAAAAI2, Dr. Minati Dhar, PhD3; 1Childrens Mercy America; the ability to predict daily pollen levels may provide an important Hospital, 2Children’s Mercy Hospital, Kansas City, MO, 3Children’s benefit for sensitive individuals. Mercy Hospital & Clinics, Kansas City, MO. METHODS: Airborne pollen has been collected since December 1986 RATIONALE: Fungi are often associated with warm, moist conditions. with a Burkard spore trap located on the roof of a building at the University However, Alternaria alternata, is frequently associated with more arid of Tulsa. Burkard slides were prepared and analyzed using standard areas of the world. To determine if in a temperate climate, Alternaria is procedures. Ambrosia pollen data and meteorological data from 1987 to more abundant during periods of low humidity and little rainfall we 2011 were used to develop a multiple regression model to predict pollen conducted the following study. levels for the following day. Model output was compared to the 2012 METHODS: Data was retrieved from the Kansas City mold and spore ragweed pollen levels. database for a 15 year period from 1998 to 2012. Data from the winter
RESULTS: Meteorological factors from the preceding day were found to months of November to February was excluded. Collections were taken SATURDAY be significantly related to the next day’s pollen count. Average temperature with a Burkard device atop a 5 story building in the urban center of the and relative humidity were found to be positively related and statistically metropolitan area. Slides were collected daily and evaluated by a NAB significant (p<0.0001 and p<0.005, respectively). The previous day’s certified counter for the presence of Alternaria spores using the 12 traverse pollen concentration was found to be highly predictive and positively method. Spore counts for 4 hour intervals were stored in an Access correlated (p<0.00001). Additional variables were tested to determine database and analyzed using Excel. importance, but were not significant. These variables included: average RESULTS: Alternaria spore counts varied from 0 to 112 during the period wind speed, minimum temperature, maximum temperature, precipitation, with a mean of 4.9 (SD 7.9). Alternaria counts showed a strong positive and temperature difference. The resulting model considers average correlation with temperature (r5 0.31) and a negative correlation with temperature, relative humidity, and previous day’s Ambrosia concentration humidity (r5 -0.12). There was no correlation with wind speed and wind as predictive factors for pollen forecasting (R250.7191, p<0.00001). direction and a negative correlation with daily rainfall (r5-0.08). There Model accuracy was tested using the 2012 Ambrosiaseason. There was was a strong correlation with rainfall during the previous month (r50.18) no significant difference between the means for observed and calculated and previous week (r50.39). values (t(152) 5 -0.563, p50.5742). CONCLUSIONS: Increased levels of Alternaria spores are related to CONCLUSIONS: This multiple regression model explains 72% of the times of warmer temperatures and lower humidity. Alternaria can take variability of Tulsa Ambrosia pollen levels. Further testing of this model in advantage of recent rainfall and enhanced growth conditions, but is also different geographical areas is needed to show the utility and possible able to adapt to drier climates. clinical benefits. Influence Of Meteorological Conditions On Mountain Cedar Conditions Affect Dust Mite Infestation Of Flour Samples In 64 Pollen 62 Tropical Area Landon Bunderson, PhD1,2, Peter Van De Water, PhD3, Jeffrey Dr. Theerapan Songnuy; Allergy and Immunology Division, Chulalong- Luvall, PhD4, Estelle Levetin, PhD, FAAAAI2; 1Iowa State University, korn University Medical School, Bangkok, Thailand. Ames, IA, 2University of Tulsa, Tulsa, OK, 3California State University, RATIONALE: Oral mite anaphylaxis is caused by ingestion of dust Fresno, Fresno, CA, 4NASA Marshall Space Flight Center, Huntsville, AL. mite-contaminated flour in sensitized subjects. The type of flour, RATIONALE: Juniperus ashei pollen is a major winter allergen in the storage temperature and relative humidity influence mite propagation. south central U.S. causing severe hay fever in sensitive individuals. The study aimed to investigate conditions affected the development of mite Understanding the influence of meteorological conditions on airborne in order to provide appropriate flour storage instruction in a tropical pollen can improve pollen forecasting. country. METHODS: Six Burkard samplers were located in Juniperus ashei METHODS: Dermatophagoides farinae(Der f) were inoculated in six woodlands in Oklahoma and Texas during the winters of 2009-2010 and types of cooking flour; two types of self-rising flour, plain wheat flour, 2010-2011. Burkard slides were analyzed to determine bihourly pollen tempura batter mix containing wheat flour, corn flour and tapioca starch. concentrations, as well as average daily concentration. Meteorological The samples were stored in different containers and kept in two conditions; data were obtained from NWS stations close to each Burkard sampler in at room temperature (mean temperature526.6;range 25-28.98C,mean Texas and Oklahoma Mesonet in Oklahoma. Backward multiple regression relative humidity569.6; range 60-77.3%) and in a refrigerator (mean analysis was used to determine meteorological conditions that influence temperature58.2; range 2-12.28C, mean relative humidity536.7; range pollen concentration. 22-51.4%) for 20 weeks. The analysis of Der f1 allergen levels was RESULTS: Pollen concentrations varied greatly across all sampling performed every 2 weeks by ELISA assay. locations. Highest seasonal average concentration (1,797 pollen/m3) was re- RESULTS: Der f1 allergen levels at 6 weeks were significantly higher corded in Junction, TX and lowest (538 pollen/m3) occurred in San Marcos, than baseline in both storage conditions regardless of container TX, both during the winter of 2009-2010. In addition, frequent nighttime types(P<0.001). The maximum levels of Derf1 were found at 8 weeks. peaks suggest long-distance dispersal is a common occurrence in the region. Comparing between the two storage conditions, room temperature storage Meteorological conditions were also highly variable, with the 2010-2011 enhanced growth of dust mites in all types of flour(P<0.001). Different season generally warmer and drier than 2009-2010. Regression analysis types of flour had different influence on mite propagation. Self-rising flours produced separate models for each location and each year. Temperature yielded the highest numbers of mites followed by tempura batter mix was the most important meteorological factor and a significant variable in containing wheat flour, plain wheat flour, corn flour and tapioca starch all hourly regression models and most daily models. The regression model respectively (P<0.01). that explained the greatest variability in daily pollen concentration was CONCLUSIONS: Both storage conditions and types of flour affect dust from Sonora, TX (R250.816, p<0.001) and included maximum T, average mite infestation. In tropical regions, cooking flour should be kept RH, maximum wind and precipitation as significant variables. refrigerate for no longer than 6 weeks in order to prevent significant mite CONCLUSIONS: No single regression model was appropriate for propagation. all locations. Pollen forecasts need to consider local meteorological conditions across the Juniperus ashei distribution.
ABS 5.2.0 DTD YMAI10627_proof 11 January 2014 3:07 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB18 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
A Post-Hoc Qualitative Analysis Of Real Time Heads-Up Pollen Unusual Timing For The Ragweed Ambrosia Pollen Peak In 65 Counting Versus Traditional Microscopic Counting In The 67 Vinnitsa, Ukraine Environmental Exposure Unit (EEU) Ms. Viktoria Rodinkova1, Ms. I. Motruk1, Ms. L. Slobodianiuk1, Ms. O. Ms. Lisa Steacy, BSc1, Mr. Terry Walker, BA1, Mr. Barnaby Hobsbawn1, Mazur1, Ms. O. Palamarchuk1, Prof. Lawrence M. DuBuske, MD, Mrs. Jenny Thiele, MSc2, Dr. Anne K. Ellis, MD, MSc, FAAAAI1,3; 1Al- FAAAAI2; 1Vinnitsa National Pirogov Memorial Medical University, lergy Research Unit, Kingston General Hospital, Kingston, ON, Canada, Ukraine, 2George Washington University School of Medicine, DC. 2Queens University, Kingston, ON, Canada, 3Departments of Medicine RATIONALE: Ragweed pollen now covers much of Ukraine and and Biomedical & Molecular Science, Queen’s University, Kingston, has been stable in the timing of peak pollen over the last 10 years. ON, Canada. In 2010 and 2013 in Ukraine ragweed had unusual timing of peak RATIONALE: A custom digital imagery method for real time pollination. identification and counting of pollen was qualitatively evaluated in the METHODS: Pollen counts were obtained at Vinnitsa National Pirogov Environmental Exposure Unit (EEU). Memorial Medical University in 2009-2011 on daily basis and in 2012 at a METHODS: Airborne grass pollen was collected in the EEU via a bi-hourly mode employing volumetric methods using a Burkard trap at 25 RotorodÒ impact sampler. The pollen grains on each sampling rod were meters height above ground. counted using both traditional and heads-up microscopy. The heads-up RESULTS: The first period of peak Ambrosia pollination are registered in technique incorporated a microscope camera to create an on-screen image Vinnitsa since 1999 is the third ten-day period of August with peaks seen of the sampling rod. Firstly, unique images were created by manually August 24 to 28; 2011 and 2012 peak August 25; 2010 and 2013 peak advancing the stage, without duplicating previously captured pollen grains. August 26; 2009 peak August 28.orresponding with a seasonal peak. The Well-defined, sharp images were obtained by fine focus and zoom second peak period occurs after September 5. In 1999, it was September combinations to enhance certainty and recognition speed. Secondly, using 5. In 2012, it was September 18 with amounts greater than the August a custom application, each pollen grain was identified and counted peak (200 p.g./m3 on September 18 versus 100 p.g./m3 August 25, on-screen by ‘‘pointand click’’or ‘‘screentouch’’,simultaneously counting 2012). 2010 and 2013 had rapid rising of the ragweed pollen counts the and permanently anchoring opaque dots to the pollen grain locations. second ten-day period of August, almost two weeks earlier than usual, Counts were stored in real time on a central database. exceeding the meaning seasonal maximum on August 27, 2010 (102 RESULTS: Increased clarity of the pollen grains resulted in higher p.g./m3 versus 76 p.g./m3). 2013 was characterized by significant pollen counting accuracy. Duplicate counting of pollen grains was eliminated by count increases to 82 p.g./m3 on August 11 and a peak of 92 p.g./m3 on digitally labelling counted grains. Additional need for manual counting August 27. devices, commonly associated with mechanical and human errors, was CONCLUSIONS: Early ragweed pollen count increases for the second eliminated. Error free counts can be obtained with increased speed, ten-day period of August can be explained by progressive environmental therefore, improving the overall efficiency of the process and the EEU changes perhaps induced by global warming with earlier pollen peaks and system as a whole. more prolonged pollination seasons. CONCLUSIONS: This validated heads-up counting technique will allow for an increased response time to changes in the EEU pollen levels. This Safety and Efficacy Of a 12-Week Maintenance Interval In advancement could also enhance pollen counting processes followed by 68 Patients Treated With Imported Fire Ant Immunotherapy 1 2 others using direct microscopy pollen counting techniques. Dr. Karla E. Adams, MD , Dr. Shayne Stokes, MD , Dr. Kevin M. White, MD1, Dr. Kirk H. Waibel, MD, FAAAAI3, Dr. Michael S. Tankers- Real-Time PCR Quantification Of Virginia Live Oak (Quercus ley, MD, FAAAAI4; 1Wilford Hall Ambulatory Surgical Center, Joint 66 virginiana) Pollen Base San Antonio, Lackland AFB, TX, 2Luke AFB, Glendale, AZ, 3Land- Dr. Mark C. Glaum, MD, PhD, FAAAAI1,2, Ms. Eileen Rifkin1, Dr. Jia- stuhl RMC, 4Wilford Hall Ambulatory Surgical Center, Joint Base San Wang Wang, PhD1, Dr. Richard F. Lockey, MD1,2, Dr. Dennis K. Ledford, Antonio, San Antonio, TX. MD, FAAAAI1,2; 1Division of Allergy and Immunology, Department of RATIONALE: The purpose of this longitudinal cohort study is to Internal Medicine, University of South Florida, Morsani College of determine the safety and efficacy of maintenance immunotherapy Medicine, Tampa, FL, 2James A. Haley Veterans’ Affairs Hospital, in imported fire ant (IFA) hypersensitive patients given at 12-week Tampa, FL. intervals. RATIONALE: Pollen counting methods require microscopic analysis that METHODS: Patients >_18 years with a history of IFA hypersensitivity is prone to subjective variability. This investigation utilized quantitative substantiated by history and skin testing were enrolled after completion of real-time PCR (qPCR) to attempt to develop a more accurate and >_3 months of IFAWBE maintenance injections (1:100 w/v, S. invicta/rich- standardized method to quantitate aeroallergens. teri mix, Hollister-Stier, Spokane, WA) and proof of efficacy via field sting METHODS: Three types of qPCR standard curves were generated with or sting challenge. Once enrolled, the next 3 injections were given at 6, 8 species-specific primers and a TaqMan probe from the Quercus virginiana and 12 week intervals with regular injections thereafter at 12 weeks. nitrate reductase gene. Grains were sonicated for DNA extraction prior to Annual sting challenges were administered. Study approval was obtained purification with silica spin-columns. The first curve was based on a serial through the institutional IRB. dilution of DNA extracted from dry pollen to determine the efficiency RESULTS: In this interim analysis, a total of 9 patients with a mean age and sensitivity of the qPCR. The second curve was based on a serial of 41.7 years (range 24-62 years) completed a mean of 13.8 months dilution of 100 mg of pollen to determine the reproducibility of the DNA (range 12-18 months) in the study. Mean duration of monthly mainte- extraction from decreasing pollen weights. The third curve was generated nance IFA WBE prior to study enrollment was 40.2 months (range 5-96 from absolute numbers of grains counted using a hemocytometer to months). During the study period, subjects received a median of 6 establish correlation between the quantification cycles (Cq) and pollen maintenance injections (range 5-8). There were no systemic reactions to number. IFA WBE injections during the study period. Three participants RESULTS: The R-squared values for the first, second and third types of cumulatively sustained 7 field stings during the study period without curves were 0.997, 0.982, and 0.990, respectively. The qPCR efficiency was systemic reaction. Eight subjects were compliant with the IFA sting 100%610% with a qPCR detection range from a single to 107 pollen grains. challenge 12 months after enrollment and none experienced a systemic CONCLUSIONS: The R-squared values and qPCR efficiency indicate reaction to the sting challenge. that the qPCR is highly specific and reproducible. The DNA extraction CONCLUSIONS: IFA WBE IT extended to a 12-week interval reproducibility and pollen count correlation are high. These techniques appears to be a safe and effective treatment option. This is an may be useful to count airborne oak pollen and other pollens. on-going study.
ABS 5.2.0 DTD YMAI10627_proof 11 January 2014 3:07 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB19 VOLUME 133, NUMBER 2
Epidemiology and Clinical Predictors Of Biphasic Reactions In include increasing recognition of anaphylaxis, improved management 69 Children With Anaphylaxis and a real increase in the prevalence of food allergy. Of note, the Waleed D. Alqurashi1, Ian Stiell2, Kevin Chan3, Gina Neto1, George age-distribution of fatal cases varies significantly according to the nature Wells4; 1Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada, of the eliciting agent, and raises important questions about the differences 2Ottawa Hospital Research Institute, Ottawa, ON, Canada, 3Hospital for in the pathogenesis of anaphylaxis between different triggers. Sick Children, Toronto, ON, Canada, 4University of Ottawa Heart Institute, Ottawa, ON, Canada. Dying From Allergies: A Profile Of Fatal Anaphylaxis In The 71 United States: 1999-2010 RATIONALE: Epidemiological data regarding biphasic reactions among 1 2,3 children is sparse. This study aims to investigate the prevalence and clinical Dr. Elina Jerschow, MD, MSc , Dr. Robert Yao-Wen Lin, FAAAAI , Ms. Moira Scaperotti, Medical Student4, Dr. Aileen McGinn, PhD4; predictors for the biphasic reaction in children presenting to the Emergency 1 Department (ED) with anaphylaxis. Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, 2New York Downtown Hospital, New York, NY, 3New York Medical METHODS: A multicenter retrospective cohort study was conducted for 4 ED visits from January - December 2010. All visits that satisfied College, Valhalla, NY, Albert Einstein College of Medicine, Bronx, NY. anaphylaxis diagnostic criteria of the NIAID/FAAN were included. We RATIONALE: Anaphylaxis-related deaths have not been well SATURDAY analyzed the predictors of biphasic reaction using univariate analysis and characterized in the US for recent years. We thus sought to analyze multiple logistic regression. features of fatal anaphylaxis in the US from 1999 to 2010. METHODS: Using the US Multiple Cause of Death Data and Census RESULTS: Out of 1,749 ED records reviewed, 484 visits fulfilled study 8 inclusion criteria. Median age was 4.8 years (IQR 2.1-11.1) and 314 data/estimates, mortality rates per 100 million (10 ) population were (64.9%) were male. Seventy one (14.7%) patients developed biphasic calculated for 1999-2010. Negative binomial regression models were reactions. Among those who had biphasic reactions, 35 (49.3%) the used to assess the predictor effects of age, sex, race (African American biphasic reaction was treated with epinephrine. We found five independent (AA), White, Hispanics and others), and region on anaphylactic deaths. predictors of biphasic reaction: age 6-9 years (OR 3.60; 95%CI 1.5-8.58), RESULTS: Among specified anaphylaxis causes, medications were the most time from onset of the anaphylactic reaction to ED presentation common cause of fatal anaphylaxis in the US, followed by venom and food. >90 minutes (OR 2.58; 95%CI 1.47-4.53), wide pulse pressure at triage* The most frequently specified culprit in drug anaphylaxis (DA) was (OR 2.92; 95%CI 1.69-5.04), treatment of the reaction with >1 dose of antibiotics, followed by radiocontrast. Overall mortality rates from DA nearly 8 8 5 epinephrine (OR 2.7; 95%CI 1.12-6.55), and administration of inhaled doubled: 33.2/10 (1999-2001) to 61.1/10 (2008-2010). AA race, age> 20 and more recent year were predictors of DA mortality (p<0.001). Venom Salbutamol in ED (OR 2.39; 95%CI 1.24-4.62). 8 CONCLUSIONS: Biphasic reactions seem to be associated with more anaphylaxis (VA) deaths were most common in white adult men (30.6/10 5 severe anaphylactic reactions. We identified five clinical predictors that population). White race, Age> 20, male gender and southern region were all predictors of VA mortality (p<0.001). Food anaphylaxis (FA) deaths could ultimately be used to identify patients who would benefit from 8 prolong ED or inpatient monitoring. In agreement with previous literature, were most common in AA men (11.3/10 population). AA race was a better we found no benefit of systemic steroids in preventing biphasic reactions. predictor (p<0.001) of FA deaths than was male gender (p<0.01). These findings may enable better utilization of ED resources and CONCLUSIONS: There are strong and disparate associations between counseling of patients and families after anaphylactic reactions. race and anaphylaxis mortality due to specific allergens. The striking increase in DA deaths may relate in part to enhanced diagnosis and/ or to Age As a Risk Factor For Fatal Food-Induced Anaphylaxis: An increased administration of medications and radiocontrast. 70 Analysis Of UK and Australian Fatal Food Anaphylaxis Data Dr. Paul J. Turner, FRACP, PhD1,2, Dr. Vibha Sharma, FRCPCH3, Prospective Study To Determine Risk Factors and Severity Of 4 72 Food-Induced Allergic Reactions In Children Prof. Mimi L. K. Tang, MD, PhD, FAAAAI , Ms. M. Hazel 1 1 5 3 Dr. Angela Tsuang, MD , Mr. Nikhil Menon, Medical student , Gowland, BA , Dr. Nigel Harper, MBChB, FRCA , Dr. Tomaz 1 3 3 Ms. Natasha Setia, Medical student , Mr. Larry Geyman, Medical Garcez, MRCP, FRCPath , Dr. Richard Pumphrey, FRCPath , 1 2 1 1 student , Ms. Christina Cherny , Dr. Anna H. Nowak-Wegrzyn, MD, Dr. Robert J. Boyle, MBChB, PhD ; Imperial College London, United 3 1 2 2 3 FAAAAI ; Mount Sinai School of Medicine, New York, NY, Cornell Kingdom, University of Sydney, Australia, Central Manchester 3 University Hospitals NHS Foundation Trust, United Kingdom, 4The University, Icahn School of Medicine at Mount Sinai, New York, NY. University of Melbourne, Melbourne, Australia, 5Allergy Action, United RATIONALE: To determine risk factors, severity, and treatment of Kingdom. food-induced allergic reactions in children in the outpatient setting from RATIONALE: Small case series suggest that teenagers and young adults prospective data. may be at higher risk of fatal food-induced anaphylaxis than other age METHODS: Children with diagnosis of food allergy were followed over 24 groups, but this has not been confirmed in large population-based datasets. months. 126 patients were contacted to document food exposures and reactions. METHODS: We extracted data from national databases for hospital RESULTS: Thirty eight percent of patients reported an allergic reaction. admissions and fatalities due to anaphylaxis in England and Wales for the The majority of reactions were caused by milk (39%), followed by peanut period 1992-2011, and cross-checked fatalities against a prospective fatal (16.3%), egg (8.2%) and tree nuts (6.1%). Exposure to milk (OR 40.4, CI 5.2- 5 anaphylaxis registry. We examined time trends and age distribution for 316.4, p<0.0001) or peanut (OR 7.3, CI 1.5-36.1, p 0.014) was shown to be fatal reactions caused by food, drugs and insect stings, and compared these associated with increased odds of having a reaction. Furthermore, milk and to equivalent data previously published from Australia. peanut were linked to more severe reactions (44.4%). 83% of reactions were RESULTS: Hospital admissions due to anaphylaxis admissions increased caused by ingestion. There was no difference in odds of having a reaction steadilyoverthe time periods studiedin boththe UK and Australia,but fatality whether one took a tiny bite versus full serving. 33% of patients with more rates have remained stable at around 0.04 (UK) and 0.05 (Aus) cases per severe reactions had recently exercised. The amount and form of food had no 100,000 population per annum. Fatalities and admissions were most association with severity of reaction. 4 out of the 48 reactions used common in older people for drug- and insect sting-induced anaphylaxis. epinephrine, and were all given by patient/parent, at the scene or at home. For food-triggered reactions, fatalities were most common in teenagers and 3 out of 4 had just previously exercised. Mean anaphylaxis score was 2.3 for 5 young adults, in both countries. These findings are not explained by those that used epinephrine, versus 1.3 for those that did not (p 0.003). 75% age-related differences in the prevalence of food anaphylaxis requiring of parents reported feeling comfortable using the epinephrine auto-injector. hospitalisation. CONCLUSIONS: Milk or peanut allergy is associated with increased CONCLUSIONS: In the UK and Australia, hospitalisations for anaphy- odds of having an allergic reaction and caused more severe reactions. The laxis have increased, but fatal anaphylaxis has not. Possible explanations amount and form of food was not associated with severity of reaction.
ABS 5.2.0 DTD YMAI10627_proof 11 January 2014 3:07 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB20 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Factors Associated With Increased Risk Of Anaphylaxis than the post-test score (8.79 6 1.3, P<0.0001) and follow-up score 73 Aylin Altan Riedel, PhD1, Erin Buysman, MS1, Dr. Ray A. (8.17 6 1.5, P<0.0001), with a significant difference between post-test and Wolf, PharmD2, Paul Cavanaugh, Jr, PhD3, Jerald Seare, MD1,Tim follow-up scores (P50.0086). Participants’ perceived confidence in Bancroft, PhD1; 1OPTUM, Prairie Eden, MN, 2Mylan Specialty L.P., diagnosing (P50.0003) or managing (P<0.001) anaphylaxis improved New Hope, PA, 3Mylan Specialty, Basking Ridge, NJ. from baseline to follow-up. The proportion of participants reporting RATIONALE: This study was designed to identify patient factors clinical experience with anaphylaxis or epinephrine autoinjector use did associated with an increased risk of an anaphylactic event. not change over time. METHODS: This retrospective claims analysis used medical and CONCLUSIONS: Allergist-led face-to-face educational intervention pharmacy claims data from 2011 and 2012 for commercial enrollees in a improves residents’ short-term knowledge and perceived confidence in large US health plan associated with Optum. Data from adult and pediatric diagnosing and/or managing anaphylaxis. Lack of clinical experience or patients with claims-based evidence of anaphylaxis during emergency educational reinforcement may contribute to the observed decreased department or inpatient visits were identified and compared with data from knowledge over time. Innovative educational interventions are needed to controls with no evidence of anaphylaxis. A 12-month baseline period was improve and maintain resident KAB. used to assess patients’ characteristics including history of allergies and conditions related to anaphylaxis, comorbidities, and healthcare resource Anaphylaxis Management Before and After Implementation Of 75 Guidelines In The Pediatric Emergency Department utilization and costs. Patient demographics and baseline characteristics 1 1 2 were compared between anaphylaxis cases and controls. Dr. Shilpa Desai , Dr. Rhett Lieberman , Stephen Wisniewski, PhD , Dr. Todd David Green, MD, FAAAAI1; 1Children’s Hospital of Pittsburgh RESULTS: Patients who experienced anaphylaxis and control individuals 2 were similar in age. However, as a cohort, patients who experienced of UPMC, Pittsburgh, PA, University of Pittsburgh. anaphylaxis were more likely to be <_6or>_45 years old compared RATIONALE: Despite growing use of practice guidelines in hospital with controls. In addition, patients who experienced anaphylaxis were systems, studies are needed to analyze clinical changes as a result of such significantly more likely to present with baseline allergies, asthma and guidelines. In May 2010, Children’s Hospital of Pittsburgh of UPMC, other respiratory conditions, and cardiovascular disease and to use implemented guidelines for anaphylaxis management in the emergency b-blockers and angiotensin-converting enzyme inhibitors compared department and inpatient wards. We examined outcome differences in with controls. Finally, patients who experienced anaphylaxis had anaphylaxis management following guideline initiation relative to significantly higher baseline healthcare resource utilization and total outcomes prior to the initiation of the guidelines. medical costs compared with controls ($25,520 vs $6639, respectively; METHODS: A retrospective chart review was performed on 234children P<0.001). (96 before pre and 138 post-guidelines) who received a diagnosis of CONCLUSIONS: Differences in demographics and baseline character- anaphylaxis in either the emergency department or inpatient unit at istics were observed between patients who experienced anaphylaxis and Children’s Hospital of Pittsburgh from 2007 to 2013. control individuals. Understanding these characteristics will facilitate the RESULTS: There was no statistical difference in age, race, gender or development of a risk score to help identify patients at increased risk of personal history of atopy between the groups examined before and after anaphylaxis. guideline implementation. Administration of epinephrine at the first hospital entry point increased from 37.9% pre to 64.3% post guidelines A Face-To-Face Educational Program By Allergists Can Improve (p50.008). Use of steroids, H1-blockers, albuterol, saline and glucagon as 74 Knowledge, Attitudes, and Behaviors (KAB) Of Internal adjunct therapies was unchanged. Use of H2-blockers increased slightly. Medicine, Pediatric, and Emergency Medicine Residents Hospitalization rates decreased from 62.5% before guidelines to 31.2% Dr. Artemio M. Jongco, III, MD, PhD, MPH1, Dr. Sheila Bina, MD2, (p<0.001), despite no significant change in the allergy consultation rate. Dr. Robert Sporter, MD3, Dr. Marie A. Cavuoto Petrizzo, MD, FAAAAI4, There was a significant increase in patients being discharged with Dr. Blanka M. Kaplan, MD, FAAAAI5, Dr. Susan Schuval, MD, anaphylaxis action plans, epinephrine autoinjector prescriptions, and FAAAAI6; 1Feinstein Institute for Medical Research, Manhasset, NY; outpatient allergy referrals. Cohen Children’s Medical Center of New York, Great Neck, NY, 2Stony CONCLUSIONS: Implementation of hospital-wide guidelines for the Brook University Hospital, Stony Brook, NY, 3Division of Allergy/Immu- management of anaphylaxis correlates with a statistically significant nology, Departments of Medicine and Pediatrics, Hofstra North Shore-LIJ increase in epinephrine administration and decreased hospitalization School of Medicine, 4ProHealth Care Associates LLP, Lake Success, NY, rate, as well as an increase in management plans that are in accordance 5Department of Pediatrics, Division of Allergy & Immunology, with AAAAI recommendations. Hofstra-North Shore-LIJ School of Medicine, Great Neck, NY, 6Stony Brook U Medical Cente, Stony Brook University Medical Center, Stony Brook, NY. RATIONALE: Effective interventions are needed to improve physician training regarding anaphylaxis. METHODS: Internal medicine, pediatric, and emergency medicine residents at two academic medical centers were recruited to participate in a longitudinal study of resident KAB regarding anaphylaxis. We hypothesized that KAB would improve after an allergist-led face-to-face educational intervention. An anonymous questionnaire queried partici- pants’ demographics, prior clinical experience, perceived competency and comfort with anaphylaxis diagnosis and treatment. A 10-item pre-test assessed baseline knowledge. Allergists presented a 45-minute evidence- based educational program, immediately followed by a similar post-test to evaluate short-term improvement. Another 10-item follow-up test assessed long-term retention twelve weeks later. RESULTS: A total of 159 residents participated in the pre-test, 152 in the post-test, and 86 in the follow-up. Data were combined in subsequent analyses as there were no significant differences in participant distribution by department over time. The mean pre-test score (7.31 6 1.5) was lower
ABS 5.2.0 DTD YMAI10627_proof 11 January 2014 3:07 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB21 VOLUME 133, NUMBER 2
Managing Anaphylaxis In Adults: A Review Of All Cases METHODS: As part of the Cross-Canada Anaphylaxis REgistry 76 Presenting In A Single Year At An Emergency Department (C-CARE), a software program was developed to record all cases of Dr. Yarden Yanishevsky, MD1, Dr. Ann Elaine Clarke, MD, MSc2,3, suspected allergic reactions treated by primary care paramedics. Data Dr. Sebastian La Vieille, MD4, Dr. Scott Delaney, MD5, Dr. Reza on demographics, reaction characteristics and management was collected Alizadehfar, MD1, Mr. Christopher Mill, BSc3, Dr. Lawrence for cases meeting the definition of anaphylaxis between May and August Joseph, PhD3, Dr. Judy Morris, MD, MSc6, Dr. Yuka Asai, MD3,7, 2013. Dr. Moshe Ben-Shoshan, MD, MSc1; 1Division of Paediatric Allergy RESULTS: Among 7, 950 ambulance calls of which 5,893 required and Clinical Immunology, Department of Paediatrics, McGill University transport, 31 anaphylaxis cases were identified [0.4%, 95%CI (0.3%, Health Center, Montreal, QC, Canada, 2Division of Allergy and Clinical 0.6%), and 0.5% (0.4%, 0.8%), respectively]. Median age was 42.3 years Immunology, Department of Medicine, McGill University Health Centre, (IQR 15. 9, 58.3) and 56.1% (95% CI 33.4%, 69.4%) were females. The Montreal, QC, Canada, 3Division of Clinical Epidemiology, Department most common triggers included venom [45.2% (31.0%, 62.4%)], food of Medicine, McGill University Health Centre, Montreal, QC, Canada, [25.8% (12.5%, 44.9%)], and drugs [16.1% (6.1%, 34.5%)]. The majority 4Food Directorate, Health Canada, Ottawa, ON, Canada, 5Department of reactions occurred at home [71.0% (51.8%, 85.1%)]. Among all of Emergency Medicine, McGill University Health Center, Montreal, reactions, 38.7% (22.4%, 57.7%) were severe and 51.6% (33.4%, SATURDAY QC, Canada, 6Department of Emergency Medicine, Hopital^ du Sacr e- 69.4%) were moderate. Epinephrine was administered in 29.0% (14.9%, Cœur, Montreal, QC, Canada, 7Division of Dermatology, Department of 48.2%) of cases before and 58.0% (39.3%, 74.9%) after ambulance arrival. Medicine, McGill University Health Centre, Montreal, QC, Canada. In 17.8% (6.8%, 37.6%) of moderate/severe reactions, epinephrine was not RATIONALE: To assess anaphylaxis rate and management in adults administered. presenting to an emergency department (ED). CONCLUSIONS: This is the first prospective study evaluating METHODS: As part of the Cross-Canada Anaphylaxis REgistry (C- anaphylaxis cases presenting to EMS. Anaphylaxis accounts for a CARE), charts of all ED visits to the Montreal General Hospital between substantial number of calls in Outaouais, Quebec. Most reactions are March 2011 and February 2012 were reviewed to identify anaphylaxis moderate or severe and almost one fifth of moderate/severe do not receive cases. Cases were identified based on ICD 10 coding for either anaphylaxis epinephrine. Although we have reported elsewhere that food is the major or allergic reaction and only cases fitting the definition of anaphylaxis were anaphylaxis trigger in Quebec emergency departments, venom is the major included. Multivariate logistic regressions were used to identify factors culprit in cases contacting the Quebec EMS during summer. associated with epinephrine use for moderate/severe cases. RESULTS: Among 37,730 ED visits, 98 anaphylaxis cases [0.26 %, (95% Anaphylaxis Management In A Pediatric Emergency Department 1,2 3,4 CI 0.21%, 0.32%)] were identified. Median age was 31.5 years (IQR 26.4, 78 Natasha Sidhu, MD , Stacie M. Jones, MD , Elizabeth 1,2 1,5 1,2 44.0) and 33.7% (95% CI 24.6%, 44.0%) were males. Food was responsible Storm, MD , Maria Melguizo castro , Todd Nick , Tonya Thompson, 1,2 1 for 63.3% (52.9%, 72.6%) of reactions, drugs for 18.4% (11.5%, 27.7%) MD ; University of Arkansas for Medical Sciences, Little Rock, AR, 2 3 and venom for 4.1% (1.3%, 10.7%). In 14.3% (8.3%, 23.1%), the trigger Arkansas Children’s Hospital, University of Arkansas for Medical 4 was unidentified. Among all cases 95.9% (89.3%, 98.7%) were moderate Sciences and Arkansas Children’s Hospital, Little Rock, AR, Arkansas 5 (difficulty breathing/stridor/wheezing) or severe (hypoxia/cyanosis/circu- Children’s Hospital Research Institute, Little Rock, AR, Arkansas latory collapse/incontinence/neurological symptoms). Prior to ED arrival, Children’s Hospital, Little Rock, AR. 25% (1.3%, 78.1%) of mild and 20.2% (12.9%, 30.0%) of moderate/severe RATIONALE: In 2006 the National Institute of Allergy and Infectious reactions received epinephrine compared to 25% (1.3%, 78.1%) and 39.4% Disease established evidence-based treatment guidelines for anaphylaxis. (22.9%, 42.4%) after arrival. In 51.1% (40.6%, 61.4%) of moderate/severe The purpose of our study was to evaluate provider adherence to guidelines- reactions, no epinephrine was given. In non-drug induced anaphylaxis, based management for anaphylaxis in a pediatric emergency-department epinephrine auto-injectors (EAI) were prescribed in 52.5 % (41.1%, (ED). 63.7%). Older individuals presenting with moderate/severe reactions METHODS: Retrospective chart-review conducted of patients (0-18 were less likely to receive epinephrine [Odds ratio5 0.96 (0.92, 0.99)]. years) presenting to the Arkansas Children Hospital ED from 2004- CONCLUSIONS: Given the striking underuse of epinephrine in 2011 for the treatment of anaphylaxis using ICD9-codes. Multiple anaphylaxis management, especially in older individuals, educational variables including demographics, allergen-source, and anaphylaxis- programs are required to better implement current guidelines. management were collected. Fisher’s exact test used to compare patients treated with intramuscular (IM) epinephrine in the pre- versus Anaphylaxis Cases Presenting To Primary Care Paramedics In post-guideline period. Relative risk (RR) computed for the likelihood 77 Quebec that patients received self-injectable epinephrine prescription and Ms. Nofar Kimchi1, Dr. Ann Elaine Clarke, MD, MSc2,3, Jocelyn allergy follow-up. Moisan4, Colette Lachaine5, Dr. Sebastian La Vieille, MD6, Dr. Yuka RESULTS: Total of 187 patients evaluated; median age 7 years Asai, MD3,7, Dr. Lawrence Joseph, PhD3,8, Mr. Christopher Mill, BSc3, (range 1-18 years), 67% male, 48% African-American. Food (44%) Dr. Moshe Ben-Shoshan, MD, MSc9,10; 1Technion American Medical and insect-stings (22%) were common allergens, while 29% had no Students Program, Israel, 2McGill University Health Centre, Montreal, identifiable allergen. Only 47% (n587) received epinephrine in the ED; Canada, 3Division of Clinical Epidemiology, Department of Medicine, 31% (n527) via the preferred IM-route. Comparing pre- (n561) versus McGill University Health Centre, Montreal, QC, Canada, 4Services post-guideline (n5126) period demonstrated increase in the usage of pr ehospitaliers d’urgence de l’Outaouais, Quebec, Canada, QC, Canada, the IM-route (6% versus 46%, p<0.001). Overall 61% (n5115) 5Direction adjointe de services pr ehospitaliers d’urgence, MSSS, Quebec, received epinephrine prescription (56% pre versus 64% post, p50.3). Canada, QC, Canada, 6Food Directorate, Health Canada, Ottawa, ON, Post-guideline patients were 1.24 times as likely to receive the Canada, 7Division of Dermatology, Department of Medicine, McGill prescription (RR 1.24, 95% CI 0.86-1.79). Only 45% (n585) received University Health Centre, Montreal, QC, Canada, 8Departments of an allergy-referral (41% pre versus 48% post, p50.4). ). Post-guideline Epidemiology and Biostatistics, McGill University, Montreal, Canada, patients were 1.13 times as likely to receive an allergy-referral (RR 9Division of Paediatric Allergy and Clinical Immunology, Department 1.13, 95% CI 0.86-1.47). of Paediatrics, McGill University Health Center, Montreal, QC, Canada, CONCLUSIONS: Provider utilization of IM epinephrine has improved 10Montreal Children’s Hospital, Montreal, Canada. since anaphylaxis-guidelines were published. However, more provider RATIONALE: To assess the percentage of anaphylaxis cases among all education is needed to improve overall adherence of guidelines in a emergency medical services (EMS) calls in Outaouais, Quebec, Canada pediatric ED. and characterize their triggers and management.
ABS 5.2.0 DTD YMAI10627_proof 11 January 2014 3:07 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB22 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Characteristics Of Anaphylaxis In a Pediatric Emergency Unit Anaphylaxis: Epidemiology and Treatment In The Emergency 79 Beatriz Ameiro, MD1, Blanca Noguerado, MD1, Gabriela 81 Department Zambrano, MD1, Cristina Morales, MD1, Miguel Guzm an, MD1, Mar ıa Dr. Judy Morris, MD, MSc1,2, Dr. Julie Lapointe1, Dr. Sebastien La L. Baeza, MD, PhD2, Alberto Alvarez-Perea, MD3; 1Hospital General Vieille, MD3, Dr. Harley Eisman, MD4,5, Dr. Reza Alizadehfar, MD6, Universitario Gregorio Maran~on, Allergy Departmen, Madrid, Spain, Ms. Emma Perkins, BSc7, Mr. Christopher Mill, BSc7, Dr. Lawrence 2Hospital General Universitario Gregorio Maran~on, Allergy Department, Joseph, PhD5,7, Dr. Ann Elaine Clarke, MD, MSc7,8, Dr. Moshe Madrid, Spain, 3Hospital Materno Infantil Gregorio Maran~on, Pediatric Ben-Shoshan, MD, MSc5,6; 1Department of Emergency Medicine, Hopital^ Allergy Department, Madrid, Spain. du Sacr e-Cœur, Montreal, QC, Canada, 2University of Montreal, RATIONALE: Incidence of anaphylaxis among adults in our area was Montreal, QC, Canada, 3Food Directorate, Health Canada, Ottawa, ON, estimated 0.08%. Our goal was to determine the incidence of anaphylaxis Canada, 4Montreal Children’s Hospital, Montreal, QC, Canada, 5McGill in a Pediatric Emergency Unit (PEU), the characteristics and management University, Montreal, QC, Canada, 6Division of Paediatric Allergy and of patients. Clinical Immunology, Department of Paediatrics, McGill University METHODS: An observational descriptive study was performed at the Health Center, Montreal, QC, Canada, 7Division of Clinical Epidemi- PEU of a third level Hospital in Madrid. Electronic clinical records from ology, Department of Medicine, McGill University Health Centre, Mon- March 2012 to March 2013 were searched for keywords related to allergic treal, QC, Canada, 8Division of Allergy and Clinical Immunology, diseases. All clinical histories were reviewed by allergists and considered Department of Medicine, McGill University Health Centre, Montreal, anaphylaxis if WAO criteria were fulfilled. QC, Canada. RESULTS: Eighty cases of anaphylaxis were attended at the PEU RATIONALE: The aim of this study, as part of the multicenter C-CARE (incidence 0.15%). Mean age 4.664.2 years, 56.1% boys, 69.7% were (Cross-Canada Anaphylaxis Registry) project, is to describe the atopic, of which 91.3% had previous food allergy. Patients presented characteristics of anaphylactic reactions and evaluate if treatment cutaneous symptoms (95%), respiratory (77.5%), digestive (57.5%) and guidelines are observed by treating physicians in Sacr e-Cœur Hospital. cardiovascular (30%). Signs of severity (Brown et al, 2004) were present in METHODS: A prospective cohort study was conducted in the emergency 11.3%. There were no fatalities. PEU physicians had diagnosed with department of Sacr e-Cœur Hospital, a university-affiliated, urban tertiary anaphylaxis only 51.2% of the cases. Other diagnosis were urticaria, care hospital, caring mostly for an adult population. For each anaphylaxis allergic reactions, angioedema. Diagnosis of anaphylaxis at PEU was more case recruited by the treating physician, a standardised questionnaire was frequently given to the most severe cases (p50,029). The most frequently completed. suspected cause of anaphylaxis was food (87.5%), mostly milk (36.4%) RESULTS: Between May 2012 and August 2013, 106 cases of egg (19.5%) and nuts (15.6%). Epinephrine was administered to 40% anaphylaxis were identified (83 prospectively and 23 through chart review) of patients, more often in those diagnosed with anaphylaxis (p<0,0001). from a total of 78,163 ED visits. The median age was 35.1 years (IQR Self-injectable epinephrine was prescribed in 3 cases. 28.1), and 61.3% were females. In our cohort, 86.8% of the patients were CONCLUSIONS: The incidence of anaphylaxis in children is almost 18 years or older. The most frequent allergens were: food 57.3% (95% twice that of adults at the emergency room. It is much more frequent in CI:47.9-66.7%), drugs 18.4% (95%CI:11.0-25.8%) and insect venom atopic children, mainly with previous food allergy. The correct diagnosis of 11.7% (95%CI:5.6-17.8%). A total of 68.9% (95%CI:60.1-77.7%) of the anaphylaxis increases the chances to receive epinephrine at the PEU. patients received epinephrine; 23.8% (95%CI:15.7-31.9%) prior to their arrival and 50.0% (95%CI:40.5-59.5%) received it in-hospital. As for other Characteristics Of Anaphylaxis and Angioedema In Pediatric treatments, 96.2% (92.6-99.8) of patients received H1 antihistamines, 80 Emergency Center 39.6% (95%CI:30.3-48.9) received H2 antihistamines and 87.7% 1 2 1 Dr. Jung Hyun Kwon , Dr. Hyun Sup Keum ; Departments of Pediatrics (95% CI:81.4-94.0%) received corticosteroids. In non drug-induced Ewha Womans University School of Medicine, Korea, Seoul, South anaphylaxis, 90.2% (95%CI:83.8-96.6) of patients were prescribed an 2 Korea, Departments of Pediatrics Ewha Womans University School of epinephrine auto-injector in hospital or already had one prescribed. Medicine, Korea, South Korea. CONCLUSIONS: This study helps to better define anaphylaxis charac- RATIONALE: Anaphylaxis and angioedema are serious allergic disease, teristics in our population. It reveals under-use and under-prescription of may cause death. Children who have symptoms of anaphylaxis and epinephrine, the primary, life-saving treatment for anaphylaxis and angioedema visit to the emergency center frequently. Some symptoms of inappropriate preferential use of corticosteroids and antihistamines. anaphylaxis share with that of angioedema and it is thought that these diseases are the spectrum of severe allergic reactions. We want to compare and distinguish the characteristics of two diseases. METHODS: We retrospectively analyzed patients under age 18 years old who were diagnosed with anaphylaxis and angioedema from May 2008 to May 2013 a single pediatric emergency center. Diagnosis of anaphylaxis and angioedema were in accordance with WAO (world allergy organiza- tion) guidelines and we evaluated their characteristics. RESULTS: Total 297 patients, included and their average age were 4.8 6 3.9 years. The cases of anaphylaxis were 79 and angioedema were 218. The age of anaphylaxis were significantly higher(6.6 6 4.9 years vs. 4.1 6 3.3 years, p<0.05). The most triggers were food both groups (83.1 % vs. 79.8 %) and the time to occurrence less than 30 minutes had significant differences (anaphylaxis 50.6 % vs. angioedema 24.8 %, p<0.05). The heart rate of anaphylaxis were significantly higher than angioedema (49.4 % vs. 36.2%, p<0.05). In anaphylaxis group, the cases of hypotension were 5 (6.3 %) and multiple organ involvement more than 3 organs were 20.6 %. After discharge, patients received Epi-pen were only 3.8 % of anaphylaxis. CONCLUSIONS: The age were higher and the onset time from trigger were shorter in anaphylaxis. Besides blood pressure, we should give attention to heart rate to pediatric patients with severe allergic reactions.
ABS 5.2.0 DTD YMAI10627_proof 11 January 2014 3:07 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB23 VOLUME 133, NUMBER 2
Anaphylaxis In An Upstate New York Emergency Department: Pattern Of Epinephrine Use and Referral Of Emergency 82 Triggers and Treatments 84 Department Personnel In A Korean Hospital Dr. Britta Sundquist, Dr. Jaison Jose, Dr. John Paige, Keith Sweeney, Dr. Jae Won Jeong1, Dr. Chansun Park2, Mi Young Kim3; 1Inje Michael Lavelle, Dr. Daniel Pauze, Dr. Denis Pauze, Dr. Kirsi M. University Ilsan PAIK Hospital, Goyang-si, South Korea, 2Haeunda Jarvinen; Albany Medical College, Albany, NY. PAIK Hospital, South Korea, 3Busan PAIK Hospital, South Korea. RATIONALE: The incidence of anaphylaxis is rising. We sought to assess RATIONALE: Doctors’ knowledge regarding the dose and route of anaphylaxis triggers and treatments in an academic emergency department administration of epinephrine for anaphylaxis management is still (ED) that serves an urban, suburban, and rural population. deficient. This study was performed to investigate the usage pattern of METHODS: A retrospective chart review on anaphylaxis cases over a injectable epinephrine among emergency department personnel of a 7-year period was performed. second level training hospital. RESULTS: We identified 134 anaphylactic reactions. Median age was 22 METHODS: A retrospective study was led from February 2012 to July years (range 7 months to 75 years), 62% were female and 33% were 2013. Emergency record ware evaluated by allergy team. Patients’ children. Sixty-nine reactions were coded as anaphylaxis; another 65 met symptoms, signs, and treatment were analyzed. the second symposium criteria for anaphylaxis. The triggers included: RESULTS: In 2 years, 79 cases of anaphylaxis were collected. Mean age SATURDAY foods (53%); drugs (31%); unknown (10%); insects (4%). Sixty-three 40619 years, 51.9% women, Median duration of observation was 3 hours. (46%) received epinephrine; multiple doses of epinephrine were given in 7 Epinephrine was administered to 48.1% patients (34.2% subcutaneously, of those reactions (11%). Food was a trigger in 40 of 63 (63%) reactions 50% intramuscular, 15.8% intravenous). Epinephrine injection was treated with epinephrine whereas only in 31 of 71 (44%) that were not dependent on shock signs (p50.01), but it was independent of anaphylaxis (p50.02). Only 22% of the first epinephrine doses were administered by severity grade (p>0.05). 77.2% of anaphylaxis patients were referred to parent/self. Twenty-one (16%) patients were hospitalized, six in the allergy specialist when he/she leaves the emergency room. intensive care unit. Nine (53%) patients who were admitted presented to CONCLUSIONS: In the Emergency department, anaphylaxis manage- ED within an hour of symptom onset, compared to only 39 (34%) of ment and epinephrine use was deficient as compared to Anaphylaxis patients who were not admitted (p50.046). There was also a trend for less management guideline. It is needed to pay more efforts to this serious issue. frequent administration of epinephrine prior to the ED among those who We believe that constant education of anaphylaxis management will were hospitalized (p50.09). lead to improved standards of anaphylaxis patient care in the emergency CONCLUSIONS: Food is the main trigger for anaphylaxis. Food-induced setting. anaphylaxis is more likely treated with epinephrine than anaphylaxis induced by other triggers. Patients who were admitted presented to the ED Characterisation Of Anaphylaxis In a Large UK City With An quicker and were less often treated with epinephrine prior to arrival than 85 Ethnically Diverse Population 1 2 1 those who were not admitted. Richard J. Buka , Richard J. Crossman , Cathryn Derbridge , Aarnoud P. Huissoon1, Scott Hackett1, Matthew W. Cooke1,2, Susan Dorrian1, Mami- The Clinical Characteristics Of Children and Adolescents With dipudi T. Krishna1; 1Birmingham Heartlands Hospital, Birmingham, 83 Anaphylaxis Who Visited 139 ERs In Korea In 2012 United Kingdom, 2University of Warwick, United Kingdom. Dr. Mi-Hee Lee1, Dr. Eun-Hee Chung2, Dr. Young-Shil Lim3; 1Depart- RATIONALE: Little is known about anaphylaxis in the non-white ment of Pediatrics, Seoul Women’s Hospital, Incheon, South Korea, population (NWP). Birmingham is the second largest city in UK with an 2Department of Pediatrics, National Medical Center, Seoul, South Korea, ethnically diverse population; 42% are ‘non-white’ as opposed to an 3Division of Chronic Disease Surveillance, Korea Centers for Disease overall proportion of 15% in England. East Birmingham is a relatively Control and Prevention, Osong, South Korea. deprived area with a high density of NWP (50%). RATIONALE: Anaphylaxis is severe life threatening, unpredictable METHODS: We retrospectively applied the World Allergy Organisation disease if not managed within appropriate time and medicines. The (WAO) diagnostic criteria to patients admitted to our emergency incidence, causative agents of anaphylaxis are varies through the world department in 2012. wide and also few epidemiologic studies in Korea. We aimed this study to RESULTS: Annual incidence of anaphylaxis in this population is report the clinical characteristics of children and adolescents with approximately 8.8 per 10000. 220 attendances fulfilled the WAO criteria, anaphylaxis who visited emergency room(ERs), in Korea in 2012. mean age 32.5 (6 22.4 SD). 53 (24%) were <_ 16 years and 88 (40%) were METHODS: We analyzed the National Emergency Department male. 97 (44%) were caucasian, 99 (45%) were south asian, and 24 (11%) Information System(NEDIS) records of 139 ERs of 0 to 18 years old had other ethnic origins. Incidence of anaphylaxis was 10.4/10000 and visiting with anaphylaxis in Korea in 2012. We evaluated age distribution, 8.2/10000 in the South Asian and Caucasian population respectively. clinical manifestations and symptoms, also management outcome. 98 (44.5%) cases were graded as severe, 13 (5.9%) developed a biphasic RESULTS: A total 847 patients were visiting ERs with discharge response and there was one fatality. Patients with a history of atopy were diagnosis of anaphylaxis code in ICD-10 during the year. And the male more likely to develop a severe episode (p50.0074). Acute serum to female ratio was 1.28:1. We divided patient into age specific group, tryptase was measured in 79 cases and was raised in 22 giving a 0;5month of age(3.8%), 6;11month of age(5.0%), 1;3 years of sensitivity of 25%. The main aetiology in those attending follow-up was age(20.6%), 4;6 years of age(10.0%), 7;12 years of age(21.0%), and food in children [n527(93.1%)] as opposed to idiopathic in adults 13;18 years of age(39.1%). The initial symptoms of patients were skin [n542(67.7%)]. rash(17.9%), dyspnea(11.5%) and urticaria(8.5%). The final diagnosis CONCLUSIONS: The overall incidence of anaphylaxis was modestly related food reaction were 3.1%, adverse effect of drug were 40.4%, greater than previously reported in other countries, and seems a significant unspecified anaphylactic shock were 55.5%. The outcomes of 606 (71.6%) problem in NWP of east Birmingham. Whilst food was the main trigger in patients were discharged, 167(19.7%) patients were hospitalized and children conforming to previous reports, idiopathic anaphylaxis was the 18(2.1%) patients were admitted to intensive care unit(ICU). There was no commonest aetiology in adults. patient who died at ERs but 1 patient was expired after admitted to ICU. CONCLUSIONS: This is the first retrospective nationwide study of anaphylaxis patients visiting ERs in Korea, even if ERs informations about medication and laboratory data were limit. This study would be a potential use and application of anaphylaxis related ERs surveillance data.
ABS 5.2.0 DTD YMAI10627_proof 11 January 2014 3:07 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB24 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Ten Years' Experience Of Anaphylaxis In a Single University Factors Associated With a Lower Probability Of Refilling An 86 Hospital In Korea 88 Epipen Auto-Injector In a Timely Manner Dr. Cheol-Woo Kim1, Jae Hwa Cho2; 1Inha University Hospital, Incheon, Erin Buysman, MS1, Dr. Ray A. Wolf, PharmD2, Paul Cavanaugh, Jr, South Korea, 2Inha University Hospital, South Korea. PhD3, Aylin Altan Riedel, PhD1, Tim Bancroft, PhD1; 1OPTUM, Prairie RATIONALE: Anaphylaxis is a life-threatening condition that requires Eden, MN, 2Mylan Specialty L.P., New Hope, PA, 3Mylan Specialty, urgent medical care and subsequent prophylactic intervention to prevent its Basking Ridge, NJ. recurrence. This study was performed to investigate the causes and clinical RATIONALE: Epinephrine auto-injectors (EAIs) should be replaced in a features of disease in adult patients with anaphylaxis. timely manner as potency of epinephrine decreases after 18 to 24 months. METHODS: A retrospective medical chart review was performed on the This study analyzed rates of, and patient factors associated with, timely patients who visited the outpatient clinic or inpatient ward of the adult refilling for EAIs in a managed care population. allergy department, and diagnosed with anaphylaxis between Jan 2003 and METHODS: This study used medical and pharmacy claims data from Dec 2012 in a single tertiary university hospital in Korea. adult and pediatric commercial enrollees with >_1 prescription fill for RESULTS: A total of 251 subjects with anaphylaxis were enrolled. Drug EpiPenÒ or EpiPen JrÒEAI between January 2007 and June 2011 who were (53.8%) was the most common cause of anaphylaxis, followed by enrolled 6 months before and >_18 months after the first claim. Patients were idiopathic (15.1%), food (12.0%), food-dependent exercise induced assigned to 3 cohorts: timely, late, and never refill. Patient characteristics (10.4%), insect stings (5.2%), and exercise (3.6%). The clinical were compared between those with timely refills and those without. manifestations were cutaneous (98.4%), respiratory (69.3%), cardio- RESULTS: Overall, 35.6% of patients refilled on time (n542,689), vascular (61.4%), and gastrointestinal (34.7%), respectively. Gradual rise whereas 15.0% of patients refilled late (n518,028) and 49.3% of patients in the number of patients with anaphylaxis was noted during study time, never refilled (n559,139). Timely refill rates were highest in patients and increased tendency of the number of anaphylaxis caused by drugs was <_5 years old, decreased from age 5 to 25, and increased with age in patients noted. Approximately 36.3% were classified as severe anaphylaxis. 25 and older. Patients with timely refills were more likely to experience Portable epinephrine auto-injector(s) was prescribed to 29.9% (75/251) anaphylaxis or allergic reaction to food before the index date, have of patients, but about half of the patients did not purchase auto-injector(s). respiratory conditions and viral infections, and have EAIs prescribed by a More than 2/3 of the patients with anaphylaxis were lost during follow-up pediatrician or an allergist. These patients were also less likely to present period. with hypertension and other cardiovascular conditions compared with CONCLUSIONS: Drug was the most common cause of anaphylaxis in those not refilling on time. adult patients, and the number of drug-induced anaphylaxis has been CONCLUSIONS: Differences were observed between those who had increased gradually. Because half of the prescription for epinephrine timely EAI refills and those who did not. These differences may be used to auto-injector(s) did not filled and significant number of patients lost to develop a risk score for early identification of patients who are unlikely to follow-up, more comprehensive therapeutic and educational approaches refill an EAI prescription. will be required to prevent recurrent development of anaphylaxis. Food-Induced Anaphylaxis: Recognition and Response In Ohio Incidence Of Anaphylaxis In a Vilnius Lithuania Hospital 89 Schools 87 Applying WAO Criteria Dr. Erica Glancy, MD1, Dr. Peter J. Mustillo, MD, FAAAAI2, Prof. Audra Blaziene1, Dr. Neringa Buterleviciute1, Viktorija Dr. Christine B. Cho, MD3, Dr. Rekha Raveendran, MD4, Dr. Daniel Paltarackiene2, Prof. Lawrence M. DuBuske, MD, FAAAAI3; 1Vilnius Scherzer, MD2; 1Cleveland Clinic, Cleveland, OH, 2Nationwide University Medical School, Lithuania, 2Vilnius university Medical Children’s Hospital, Columbus, OH, 3National Jewish Health, Denver, School, Lithuania, 3George Washington University School of Medicine, CO, 4Asthma and Allergy Center LLC, Washington, DC. Washington, DC. RATIONALE: Food allergies are the most common cause of anaphylaxis RATIONALE: Anaphylaxis is a life threatening condition. Little has been in children and epinephrine is the only medication available to reliably reported related to anaphylaxis incidence, causes or medical care in treat these reactions. Up to 18% of children have experienced a reaction at Lithuania. This study analyses the incidence of anaphylaxis using WAO school or daycare, and it is unknown how proficient childcare workers are criteria in a Vilnius, Lithuania hospital to evaluate trigger factors, patterns at managing anaphylaxis using an epinephrine auto-injector. We sought to of clinical reaction and management of anaphylaxis. examine the proficiency of childcare staff in our region in recognizing and METHODS: Data from patients hospitalized with anaphylaxis at the treating anaphylaxis, both before and after an educational intervention. Pulmonology and Allergology Department of Vilnius University Hospital METHODS: Ninety-four participants attending an Ohio school nursing over a 3 year period (2009 – 2012) were analyzed. 70 patients (38 (54.3%) conference were provided a questionnaire to evaluate their ability to women; 32 (45.7%) men), fulfilled WAO anaphylaxis criteria and were recognize and respond to anaphylaxis in food allergic children. They then included in the analysis. The mean age of patients was 47.31 6 17.63 demonstrated the use of an epinephrine auto-injector (EpiPen) and were (20–83) years old. Anaphylaxis diagnosis was not confirmed in 2 patients critiqued by a licensed physician. A food allergy action plan was used to after re-evaluation by WAO criteria. review the indications for use of epinephrine in the setting of anaphylaxis. RESULTS: The main triggers for anaphylaxis were drugs in 37.1% and Participants were asked to re-demonstrate the use of the EpiPen insect stings in 25.7% of cases. The etiology of anaphylaxis was confirmed immediately following the intervention and complete a follow-up for 9 (12.9%) patients: for 3 patients using provocation tests with drugs, questionnaire immediately following the intervention and at 6 months. and 6 patients having positive sIgE for the suspected trigger. RESULTS: Participants were often unclear about when and how to use Cardiovascular symptoms were the most frequent (64 cases (91.4%)), epinephrine. Following our intervention, participants were 5.1 times more followed by skin (59 cases (84.3%)) and respiratory (38 cases (54.3%)) likely to answer survey questions correctly and 2.5 times more likely to symptoms. Anaphylaxis resulted in hospitalization in summertime in over correctly use the EpiPen. There was no statistically significant difference in one thrid of patients (25 (35.7%)). 24 (34.3%) patients required treatment questionnaire performance between the immediate post-test period and at in the intensive care unit. 6 month follow-up. CONCLUSIONS: Summer was the season most commonly associated CONCLUSIONS: A significant percentage of school nurses in our region with anaphylaxis, likely related to insect stings. Drugs were the most are not proficient in recognizing and treating food-induced anaphylaxis but common causes of anaphylaxis, although many patients failed to have a performance can be improved using a simple, easily reproducible training cause identified. Cardiovascular involvement occurred frequently and intervention. intensive care unit treatment was often required.
ABS 5.2.0 DTD YMAI10627_proof 11 January 2014 3:07 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB25 VOLUME 133, NUMBER 2
Availability and Utilization Of Epinephrine In Utah Schools For H1 and H2 blockers, montelukast, ketotifen, high-dose systemic 90 The Management Of Anaphylaxis corticosteroids, mycophenolate mofetil, omalizumab and elimination Benjamin L. Wright, MD1, Michelle Fogg, BS2, Catherine diets. The patient ceased to have anaphylaxis and urticaria 10 days after Sparks, MSN, RN, NCSN3, Brian P. Vickery, MD, FAAAAI4, two doses of rituximab 1000 mg every 14 days. After 6 months, B cell Dr. Joseph L. Roberts, MD, PhD5, Yamini Virkud, MD, MA1, Mandy count normalized and the patient restarted chronic urticaria symptoms and Allison, MD, MSPH, MEd6; 1Duke University, Durham, NC, 2Utah IA every 3-7 days. Retreatment with two doses of rituximab 500 mg every Food Allergy Network, Salt Lake City, UT, 3Utah Department of Health, 14 days led again to full remission of anaphylaxis with follow-up of Salt Lake City, UT, 4University of North Carolina, Chapel Hill, NC, 5Duke 4 months after retreatment. University Medical Center, Durham, NC, 6University of Colorado Denver, CONCLUSIONS: This is the first report of successful treatment of IA Denver, CO. with rituximab. This case suggests B-cell depletion as a novel highly RATIONALE: Utah students are at risk for anaphylaxis in school due to: effective treatment for IA. lack of school nurses, adequately trained school staff and a standardized approach to food allergy emergency planning. Utah law allows trained Evaluation Of a Diagnostic Protocol For Perioperative
92 Anaphylaxis Due To Isosulfan Blue Dye Allergy SATURDAY individuals to administer unassigned epinephrine (UE) in an emergency. 1 2 METHODS: We developed and implemented an online curriculum Ms. Mary Grace Baker , Julia A. Cronin, MD , Dr. Larry Borish, MD, FAAAAI3, Dr. Monica G. Lawrence, MD4; 1University of Virginia School to train school staff to recognize and treat anaphylaxis. Later, we 2 5 of Medicine, Charlottesville, VA, University of Virginia, Division of administered an online survey to all Utah school nurses (n 189). 3 Thirty-seven participants (20%) providing care for 181 Utah schools Asthma, Allergy and Immunology, Charlottesville, VA, Asthma and Allergic Diseases Center, Carter Center for Immunology Research, (18%) were recruited. Participants reported availability of UE and any 4 anaphylactic reactions occurring over the past 5 years. University of Virginia, Charlottesville, VA, University of Virginia RESULTS: Availability of UE increased 140% following implementation Department of Medicine, Division of Asthma, Allergy and Immunology, of online training (61% of schools surveyed). Schools supervised by Charlottesville, VA. trained nurses were more likely to provide UE subsequently {OR 5.3, 95% RATIONALE: Although isosulfan blue dye allergy has been extensively CI (1.9,15.2)}. Of 38 reported cases of anaphylaxis, 44% occurred in the reported in the oncology literature, allergists face a diagnostic classroom; epinephrine was often given (61%) and sometimes unassigned challenge when presented with patients reporting perioperative (21%). Epinephrine was administered by ‘‘other staff’’ most frequently anaphylaxis following blue dye exposure as there is no standardized skin (61%) followed by teachers (14%) and parents (14%) in comparison to test protocol. school nurses (4%). In 22% of cases, no history of allergy was known. METHODS: A retrospective chart review of three patients who School officials usually called 9-1-1 (62%) and referred the patient to the experienced perioperative anaphylaxis during sentinel lymph node biopsy emergency department (91%). with positive exposure to isosulfan blue dye was performed to evaluate a CONCLUSIONS: Schools should provide access to UE. Parental diagnostic protocol for blue dye allergy. administration of epinephrine at school suggests a possible delay in RESULTS: All three patients developed symptoms of anaphylaxis appropriate treatment. In areas where numbers of school nurses are including hypotension, angioedema, laryngeal edema, urticaria, and inadequate, additional school staff should receive training in recognition wheezing 10 to 30 minutes following peritumoral injection of isosulfan and management of anaphylaxis. Provision of online training for school blue. While one patient was managed with diphenhydramine permitting staff increases availability and may increase effectiveness of UE. the completion of the procedure, the other two patients required treatment with epinephrine, prolonged intubation, and procedure delay. Allergy Induction Of Remission Of Frequent Idiopathic Anaphylaxis With testing in the outpatient setting was conducted in a stepwise fashion 91 Rituximab beginning with skin prick testing with a 1:10 dilution and then full strength Dr. Arturo Borzutzky, MD1, Dr. Pamela S. Morales, MD2, Dr. Veronica isosulfan blue and proceeding to intradermal testing with a 1:1000 and then Mezzano, MD3, Ms. Sofia Nussbaum4, A. Wesley Burks, MD, FAAAAI5; 1:100 dilution. Two patients had positive skin prick tests to full strength 1Division of Pediatrics, School of Medicine, Pontificia Universidad isosulfan blue and one had a positive intradermal test to a 1:100 dilution of Catolica de Chile, Santiago, Chile, 2Pediatric Rheumatology, Allergy isosulfan blue, permitting definitive diagnosis. None of the patients and Immunology Unit, Division of Pediatrics, School of Medicine, experienced adverse reactions to testing. Pontificia Universidad Catolica de Chile, Santiago, Chile, 3Department CONCLUSIONS: Anaphylaxis to isosulfan blue is an uncommon but of Rheumatology and Clinical Immunology, School of Medicine, clinically significant adverse event associated with sentinel lymph node Pontificia Universidad Catolica de Chile, Santiago, Chile, 4Universidad biopsy. The protocol evaluated is safe and effective at diagnosing isosulfan de San Sebastian, Santiago, Chile, 5University of North Carolina, Chapel blue dye allergy. Hill, NC. RATIONALE: Frequent idiopathic anaphylaxis (IA) is a severe allergic disease of unknown etiology, with no standardized safe and effective treatment. METHODS: Case report. RESULTS: We report an 18-year-old girl with asthma and allergic rhinitis who developed mild chronic urticaria and frequent episodes of anaphylaxis characterized by sudden-onset pruritus, erythema, hives, abdominal pain, diarrhea, stridor and wheezing. Anaphylaxis occured every 3-30 days during 16 months, presenting spontaneously or after eating, with no specific triggers. Several episodes were witnessed and confirmed by experienced allergists. All episodes were promptly relieved by intramuscular epinephrine. Several food challenges to suspicious foods or additives were negative. Laboratory studies showed elevated total IgE of 334 UI/ml. Systemic mastocytosis was ruled out with normal baseline serum total and free tryptase, negative D816V c-Kit mutation, and normal histopathology of skin nevi, bone marrow and stomach. Ga68-PET/CTand intraplatelet serotonin ruled out carcinoid. The patient failed to respond to
ABS 5.2.0 DTD YMAI10627_proof 11 January 2014 3:07 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB26 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Acute Serum Tryptase Elevation In ALTE - An Atypical Epicare (Epinephrine Pen Investigation: Compliance and 93 Manifestation Of Bullous Mastocytosis 95 Recommendations) Dr. Alexander Alvarez, MD1, Dr. Anne-Marie A. Irani, MD, FAAAAI2, Dr. Nisha S. Patel, MD1, Dr. Christopher Chang, MD, PhD, FAAAAI2, Dr. Lawrence B. Schwartz, MD, PhD, FAAAAI3; 1Virginia Common- Dr. Gang Ye, PhD3; 1Thomas Jefferson University, Philadelphia, PA, wealth University, 2Virginia Commonwealth University Health Systems, 2Alfred I duPont Hospital for Children, Wilmington, DE, 3Nemours, Richmond, VA, 3Virginia Commonwealth University, Richmond, VA. Orlando, FL. RATIONALE: Apparent Life-Threatening Events (ALTE) in infants may RATIONALE: Food allergy can cause anaphylaxis in children. include apnea, color change, or muscle flaccidity. We describe a case Epinephrine injection can be lifesaving and epinephrine autoinjectors associated with an elevated acute serum tryptase level, indicating mast cell should accompany the patient at all times. Compliance with this activation, in an infant with bullous mastocytosis. recommendation is unknown. We assessed whether food allergy patients METHODS: Serum tryptase is a known and specific marker for mast cell are adherent with carrying their Epipens and identified the barriers which activation. We discuss a case involving syncope due to mast cell activation. hinder this process. RESULTS: An 11 month-old male presented with recurrent episodes of METHODS: IRB approval was obtained. Subjects included food allergy syncope. At seven months of age he developed bullous, pruritic scalp patients who were provided with Epipens. A short survey was distributed in lesions, unresponsive to antibiotics. Dermatological exam showed a clinic and returned in a sealed envelope to maintain confidentiality. The positive Darier’s sign. At eight months he had an ALTE consisting of surveys were reviewed at the completion of our study. Factor analysis of flushing, flaccid weakness, and apnea leading to syncope. He responded to survey items was performed and logistic regression analysis was physical stimulation, and upon hospital arrival his vital signs were normal. conducted to examine the effect of each factor on the prevalence of Over a two month period he had four such episodes. A serum tryptase level carrying Epipens. obtained within four hours of one episode was elevated (193 ng/ml; Ref: RESULTS: Of those surveyed 63% had their Epipen(s) with them during 1-11.4 ng/ml). Subsequent testing confirmed an elevated baseline tryptase the visit and 54% reported that they always carry the Epipen(s). The most level (41 ng/ml). A bone marrow biopsy was pursued and was unremark- common reason for non-adherence was forgetfulness. Prompts as able. KIT Asp816Val mutation analysis was also negative. Treatment with reminders and having multiple sets of Epipens were the two most common antihistamines and montelukast improved his skin lesions and prevented interventions suggested. Patients with more Epipens were more likely to further syncopal episodes. carry them (p50.008) and those who state they always carry the Epipen(s) CONCLUSIONS: Apnea as a manifestation of anaphylaxis has been were more likely to have it at any given point in time (p<0.001). Epipen previously described, typically associated with cardiovascular collapse. teaching and food allergy action plans were not shown to increase Elevated tryptase levels in postmortem serum from SIDS victims has also adherence. been reported. Our case demonstrates mast cell activation during an ALTE CONCLUSIONS: We should continue educating our patients with in a patient with underlying bullous mastocytosis. This furthers the notion the tools we have in place. In addition, consider prescribing more sets that mast cell activation may manifest differently in infants than older of Epipens. Automatic prompts designed to remind patients to take children or adults. their Epipens prior to leaving the home may prove to be the most beneficial. Methodology For Identifying Patients Presenting With 94 Anaphylaxis Using Administrative Claims Data Confusion With Substituting Epinephrine Auto-Injectors: A Focus Jerald Seare, MD1, Erin Buysman, MS1, Dr. Ray A. Wolf, PharmD2, Paul 96 On Medication Counseling, Dispensing, and Patient Education Cavanaugh, Jr, PhD3, Aylin Altan Riedel, PhD1, Tim Bancroft, PhD1; Sonia Dhanjal, PharmD, Stacie Lampkin, PharmD, BCACP, AE-C; 1OPTUM, Prairie Eden, MN, 2Mylan Specialty L.P., New Hope, PA, D’Youville College School of Pharmacy, Buffalo, NY. 3Mylan Specialty, Basking Ridge, NJ. RATIONALE: Proper usage of epinephrine auto-injectors (EAIs) is RATIONALE: Claims databases are an efficient means to examine critical during a potentially life-threatening event. Four EAIs are currently chronic and acute conditions in large, geographically, and demographically marketed in the United States: EpiPenÒ EAI, Auvi-QÒ EAI, AdrenaclickÒ diverse populations. Research using these data requires appropriate EAI, and a generic product that may only be interchanged with methods for identifying target populations. The objective of this analysis Adrenaclick EAI. The US Food and Drug Administration (FDA) has as- was to create a replicable algorithm to identify patients with evidence of signed BX ratings to EAIs, indicating a lack of sufficient data available anaphylaxis in administrative claims databases. to make a determination of bioequivalence. The objective of this analysis METHODS: This retrospective analysis used medical and pharmacy was to assess healthcare professionals’, pharmacists’, and patients’ knowl- claims data from 2011 and 2012 for adult and pediatric commercial edge regarding the impact of unique designs and operating instructions for enrollees in a large US health plan associated with Optum. Anaphylactic EAIs. events were identified using the following algorithms: Algorithm 1ddiag- METHODS: A literature search was conducted focusing on the use of nosis of anaphylaxis in an emergency department (ED) or inpatient setting; epinephrine in anaphylaxis, patients’ attitudes toward EAIs, and Algorithm 2dreceived epinephrine or dopamine to treat allergic reaction comprehension of use of EAIs among healthcare professionals. with cardiovascular/respiratory compromise during an ED or inpatient Differences between the EAIs were assessed by researching the FDA’s visit; Algorithm 3dreceived epinephrine auto-injector prescription to treat Orange Book, products’ websites, and products’ package inserts. allergic reaction with cardiovascular/respiratory compromise after an ED RESULTS: Differences in shape, color, number of safety caps, packaging, or inpatient visit; and Algorithm 4devidence of allergic reaction plus dispensing, and instructions for use were observed between the different shock during an ED or inpatient visit. EAIs. Under certain conditions, pharmacists may substitute EAIs in 21 RESULTS: 5621 patients in the claims database had evidence of states despite a BX rating. Several studies were also identified that anaphylaxis and met the study inclusion criteria. Algorithms 1, 2, 3, and indicated a lack of patient training and education on the use of EAIs. In 4 were satisfied by 48.5%, 24.9%, 23.1%, and 16.9% of cases, respectively. addition, studies indicated that healthcare professionals could not properly CONCLUSIONS: These results indicate the ability of claim-based demostrate correct technique. algorithms to identify anaphylactic events requiring ED or inpatient care CONCLUSIONS: Currently, EAIs can be substituted in 21 states despite using insurance claims. Validation via medical chart review (underway) their BX rating. Healthcare professionals, pharmacists, and patients should will determine the sensitivity and specificity of these algorithms. Validated be aware of the numerous differences among EAIs and the negative impact algorithms will be valuable for future studies of this severe and life- substitution and inadequate education may have on adherence and proper threatening condition. usage during an anaphylactic event.
ABS 5.2.0 DTD YMAI10627_proof 11 January 2014 3:07 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB27 VOLUME 133, NUMBER 2
Omalizumab For a Case Of Monoclonal Mast Cell Activation Food Dependent Exercise Induced Anaphylaxis Treatment With 97 Syndrome With Recurrent Anaphylaxis 99 Specific Oral Tolerance Induction Using IFN-Gamma Dr. Amanda Jagdis1, Dr. Peter Vadas, MD, PhD2; 1University of Toronto, Dr. Jae Ho Lee, MD, PhD1, Dr. Sun Young You, MD2, Dr. Hye Young Faculty of Medicine, Toronto, ON, Canada, 2St. Michael’s Hospital, Han, MD3; 1Department of Pediatrics, Chungnam National University, Toronto, ON, Canada. Taejeon, South Korea, 2Department of Pediatrics, Taejeon, South Korea, RATIONALE: Monoclonal mast cell activation syndrome (MMCAS) is a 3Department of Pediatrics, School of Medicine, Chungnam National clonal mast cell disorder presenting with recurrent anaphylaxis due to mast University, Taejeon, South Korea. cell mediator release. Antihistamines, antileukotrienes and mast cell RATIONALE: Food dependent exercise induced anaphylaxis (FDEIA) stabilizers are used to prevent anaphylaxis, but control can be difficult to was induced by exercise within three or four hours after ingestion of achieve. Omalizumab is a humanized murine monoclonal antibody specific allergenic foods. There is no specific treatment method. The that binds free IgE in serum, preventing IgE binding to the surface of avoidance of allergenic food with exercise is the only way to treat the mast cells/basophils. There are only a few case reports on use of FEDIA. omalizumab in MMCAS. Here, we present a case of MMCAS with METHODS: The patient of FDEIAwas women. The blood test, skin prick recurrent unprovoked anaphylaxis responding to treatment with test and oral food challenge test were performed. FDEIAwas confirmed by SATURDAY omalizumab. food allergy provocation test at the low dose of wheat with exercise. The METHODS: n/a anaphylactic reactions were not occurred only by wheat intake or only by RESULTS: A 31 year old female presented with elevated baseline serum exercise. The severity scores of 0 became to more than 2000 after oral food tryptase and 6 multisystem anaphylactic reactions over 8 months. Bone challenge with exercise by running for ten minutes. The patient was treated marrow biopsy showed increased mast cells and a single cluster of mast with the method of specific oral tolerance induction (SOTI) using cells with positive mutational analysis for c-kit Asp816Val, confirming IFN-gamma. Exercise was accompanied every treatment just after intake MMCAS. Initial medications included: cetirizine 20mg daily, ranitidine of wheat during treatment. 150mg BID, montelukast 10mg daily, sodium cromoglycate 200mg TID. RESULTS: The treatment method of SOTI using IFN-gamma was In total, 20 unprovoked reactions occurred over 16 months, requiring effective for FDEIA. The exercise was accompanied after intake of emergency room (ER) treatment and >17 doses of epinephrine. wheat during the treatment. The tolerance to wheat was induced Ketotifen 4mg BID, tapering Prednisone courses and Plaquenil 200mg successfully. after treatment. The patient could take wheat freely without daily were added without improvement. Plaquenil was discontinued and problems. omalizumab initiated at 300mg q4 weeks 4 months ago. Omalizumab CONCLUSIONS: A patient of FDEIA was treated successfully with has been well tolerated and thus far the patient has had only one reaction, SOTI using IFN-gamma. This treatment method should be effective for the not requiring epinephrine. causative treatment of FDEIA. CONCLUSIONS: MMCAS can be associated with recurrent, unprovoked anaphylaxis despite maximal treatment. This case suggests that omalizu- Food Associated Exercise Induced Anaphylaxis Associated mab may be an effective adjunct to therapy in patients with MMCAS and 100 With Late Phase Skin Test Reactivity To Shrimp 1 2 1 life-threatening reactions refractory to maximal medical therapy. Dr. Marisol Nardi , Dr. Robert Yao-Wen Lin, FAAAAI ; New York Downtown Hospital, New York, 2New York Downtown Hospital, New Chlorhexidine Impregnated Central Venous Lines: A Potentially York, NY; Weill Cornell Medical College, New York, NY. 98 Avoidable Cause Of Severe Perioperative Anaphylaxis RATIONALE: Specific IgE typically identifies the offending food in food Dr. Aisha Ahmed, MD, Dr. Katherine E. Gundling, MD; UCSF, San dependent exercise induced anaphylaxis (FDEIA). We present a woman Francisco, CA. whose history was consistent with FDEIA where the culprit food allergen RATIONALE: Chlorhexidine use is becoming increasingly common in was identified only by a late phase skin test reaction. the health care setting, particularly in the perioperative setting. Its METHODS: Case report of an FDEIA patient studied with exercise anti-septic properties confer ubiquitous use, from pre-operative shower testing, mediator release, skin testing and ImmuncapTM. solutions to antiseptic skin preparation and urinary catheters and gels. An RESULTS: A 22 year-old woman reported urticaria and syncope while often overlooked source of exposure is in central venous catheters (CVCs), running after eating shrimp dumplings. There was associated pruritus, which, in the case of allergic individuals, can cause life-threatening chest tightness, nausea and vomiting. She had an history of allergic rhinitis anaphylaxis. and eczema. Prick skin tests(ST) and ImmunocapTM were positive for crab METHODS: First, we examine a near death reaction to chlorhexidine from a but negative for shrimp. Serum tryptase, plasma histamine, thyroid CVC placed in the OR after careful planning following a previous severe antibody levels and anti-Fc Epsilon receptor antibody levels were normal. anaphylaxis in the same setting. Second, we evaluate reported cases of Intradermal ST with crab and shrimp(at 1/10 prick test concentrations) perioperative anaphylaxis to determinewhether chlorhexidine allergic patients were performed 24 hours prior to an exercise challenge test(Modified can be identified preoperatively. Third, we analyze the range of hospital and Bruce protocol) and showed only significant wheal and flare reactions household products that might induce chlorhexidine sensitization. for crab. Elevated plasma histamine levels were observed immediately RESULTS: On two sequential attempts at surgery for malignant post-exercise(after achieving target heart rate) without allergic symptoms Schwannoma the patient experienced severe perioperative anaphylaxis or signs. Four hours after exercise testing, the prior day’s intradermal requiring prolonged resuscitation due to the unrecognized presence of shrimp and crab test sites enlarged to 13mm and 7mm respectively, chlorhexidine in the CVC. Each insertion of a CVC resulted in a large, were associated with significant pruritus(especially the shrimp site) and direct systemic exposure to the allergen. A review of chlorhexidine related persisted >1 day. perioperative anaphylaxis literature reveals that prior cutaneous reactions CONCLUSIONS: Intradermal skin test responses may be useful in to chlorhexidine products are not uncommon. FDEIA. The phenomenon herein described has parallels to red meat CONCLUSIONS: Perioperative anaphylaxis to chlorhexidine can be allergy in that intradermal not prick ST were diagnostic. We speculate that severe due to its unexpected presence in CVCs, which also confer an in this case, exercise and intradermal ST were both required to produce immediate, systemic antigenic exposure. We propose that all patients be optimal cutaneous mast cell activation. asked about previous cutaneous reactions prior to surgery, and that positive histories be clarified with chlorhexidine specific IgE, prick skin testing or complete avoidance of chlorhexidine perioperatively. We describe several important hospital and household products that might induce chlorhexidine sensitization.
ABS 5.2.0 DTD YMAI10627_proof 11 January 2014 3:07 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB28 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Idiopathic Capillary Leak Syndrome Pharmacokinetics Of Berberine, a Bioactive Compound In 101 Dr. Carl B. Lauter, MD, FAAAAI; William Beaumont 103 Butanol Purified Food Allergy Herbal Formula-2 Hospital. Dr. Nan Yang, PhD, MS1, Dr. Ying Song, MD1, Dr. Changda Liu, PhD1, RATIONALE: Capillary leak can be the underlying mechanism of a Sool Yeon Cho, PhD2, Dr. Xiu-Min Li, MD1; 1Pediatrics, Icahn School of number of clinical syndromes, especially in severe shock states including Medicine at Mount Sinai, New York, NY, 2Hematology, Icahn School of anaphylaxis. The hallmarks of the idiopathic capillary leak syndrome Medicine at Mount Sinai, New York City, NY. (ICLS) include edema, hypotension and hemoconcentration and can mimic RATIONALE: Food Allergy Herbal Formula 2 (FAHF-2) prevents type 1 allergic disorders. peanut-induced anaphylaxis in a murine peanut allergy model. Butanol METHODS: Two recent patients from the Beaumont Hospital allergy- extracted FAHF-2 named B-FAHF-2 is equally effective at only 20% of the immunology consultation service were diagnosed in the same month FAHF-2 dose. We found previously that berberine isolated from these (January 2012) with ICLS. Results of their evaluation and management formulas inhibit IgE production and basophil activation. The aim of this were compared to recent literature and subject reviews on this rare condi- study was to determine the pharmacokinetics of berberine. tion (about 150 cases). METHODS: Berberine standard and B-FAHF-2 were dissolved in RESULTS: Case #1 – A 41 year old Caucasian woman presented to our acetonitrile and several concentrations were analyzed by liquid-chroma- ER with edema, hypotension and hemoconcentration and a history of tography-mass-spectrometry (LC-MS). Calibration curves were generated repeated bouts of massive edema. Misdiagnosis of ‘‘allergic edema’’ led to by plotting the chromatographic peak area as a function of berberine overuse of steroids and iatrogenic adrenal insufficiency. concentrations. C3H/HeJ mice were randomly separated into three groups Case #2 – A 46 year Caucasian woman presented with massive edema and 12 mg of B-FAHF-2, 2 mg of berberine, and water were orally swings and orthostatic dizziness for OP consultation after the diagnosis of administered. Blood samples were collected at several time points after ICLS was suspected by a local nephrologist. feeding. In addition, the presence of berberine in sera from subjects in a Neither patient had an MGUS, both have ultimately required IVIG for controlled phase I FAHF-2 Study was also analyzed. All serum samples control of the illness. In both patients, the diagnosis was made after were protein-precipitated with acetonitrile and berberine was detected by extensive testing, which excluded other causes. LC-MS. CONCLUSIONS: ICLS is an uncommon potentially life threating RESULTS: The percentage of berberine present in B-FAHF-2 was condition which can mimic angioedema and anaphylaxis/anaphylaxis calculated to be 9.1 61.8%. Serum concentration-time curves of berberine shock. were plotted. Tmax was determined to be 60 minutes and the Cmaxwas 172.5 6 27.6 ng/mL. Berberine alone was absorbed at a lower rate than was Comprehensive Metabolomic Analysis Identifies Uric Acid As berberine in B-FAHF-2. Berberine was also detected in sera from patients 102 a Critical Mediator Of Peanut Sensitization receiving FAHF-2, but not placebo, in a phase I study. 1 2 Mr. Joshua Kong , Dr. Kenneth Chalcraft, PhD , Dr. Rodrigo Jimenez- CONCLUSIONS: Berberine is a bioactive compound in B-FAHF-2 and 1 2 Saiz, PhD , Mrs. Tina Walker-Fattouh , Dr. Susanna Goncharova, MD, other components composed in B-FAHF-2 may enhance berberine bio- 2 2 1 1 PhD , Dr. Brian McCarry, PhD , Dr. Manel Jordana, MD, PhD ; McMas- availability. ter Immunology Research Centre (MIRC), McMaster University, Hamil- ton, ON, Canada, 2McMaster University, Hamilton, ON, Canada. Anaphylaxis After Bitten By Domestic Hamster: A Case RATIONALE: The ontogeny of peanut allergy (PA) remains poorly 104 Report understood. We argued that an untargeted metabolomic analysis would be a Dr. Leila Borges, MD1, Dr. Danielle Bichueti Silva, MD2, Dr. Tessa Ra- useful hypothesis-generating tool to identify novel biomarkers, mediators chel Tranquilini Gonc¸alves, MD3, Dr. Rafael Rota, MD3, Camila Gonzaga and possibly therapeutic targets in PA. da Silva4, Dr. Danieli Hirari, MD4, Dr. Marcia Mallozi, MD5, Prof. Dirceu METHODS: Models of PA and anaphylaxis used in this study involved Sole, MD, PhD3; 1UNIFESP, Brazil, 2Universidade Federal de S~ao Paulo, either the oral administration of peanut along with cholera toxin or the S~ao Paulo, Brazil, 3Federal University of Sao Paulo, Sao Paulo, Brazil, topical application of peanut on tape-stripped skin. Liquid-chromatog- 4Federal University of S~ao Paulo, S~ao Paulo, Brazil, 5Federal University raphy mass-spectrometry (LC-MS) was performed to identify chemical of S~ao Paulo, Brazil. changes in the serum of mice undergoing sensitization and anaphylaxis. RATIONALE: Exotic pets have increased as domestic pets worldwide Flow cytometry as well as in vivo gain-of-function and loss-of-function that has facilitated the exposure to potential unknown allergenic antigens. immunological studies were used to determine the biological significance We report a woman who had an anaphylaxis after hamster’s bite. of particular molecules in sensitization. METHODS: A 36-years-old woman, biologist, was evaluated at our RESULTS: LC-MS followed by multivariant analysis showed that the outpatient allergy clinic after she was bitten by her hamster. She had been purine metabolism pathway was altered with elevated levels of uric acid diagnosed at childhood as having bronchial asthma and allergic rhinitis. In (UA) in sensitized mice. UA depletion using allopurinol and uricase fully the last 2 years she had a Siberian hamster (Phodopus sungorus) as pet. prevented the development of peanut-specific antibodies and the develop- Prior bites had occurred without any reaction. After 18 months of exposi- ment of anaphylaxis. Conversely, administration of UA crystals, either tion, she was bitten by the animal on hand and after 20 minutes experienced orally or subcutaneously, instead of cholera toxin or tape-stripping, local angioedema and dyspnea. She took dexchlorpheniramine and respectively, along with peanut induced allergic sensitization and anaphy- improved gradually after 30 minutes. Later episodes of hamster bites lactic phenotype. The immunostimulatory effect of UA and UA crystals is evolved with immediate hives and/or edema on the hand that spread to likely mediated through the activation of resident dendritic cells. the arm. CONCLUSIONS: We identified UA, released after damage to the mucosa RESULTS: Exams showed: positivity on prick-to-prick to hamster saliva; and/or skin, as a critical alarmin that facilitates the development of peanut negative for saline solution 0.9% and positive for histamine 10mg/ml; allergy and anaphylaxis. specific IgE hamster epithelium 5 0.69 kU/L. Patient was instructed to remove the pet from her house. CONCLUSIONS: Hamsters as pets or laboratory animals can cause anaphylaxis from immediate-type I allergy, as well as allergic rhinitis and bronchial asthma. However, the exact nature of the antigen in hamster’s saliva is not well known yet. This case of anaphylaxis secondary to hamster’s bite should alert emergency-room physicians that new sources of antigen from exotic pets have been becoming more common and can be potentially life threatening.
ABS 5.2.0 DTD YMAI10628_proof 11 January 2014 7:12 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB29 VOLUME 133, NUMBER 2
Gene Expression Profiling Of Food-Induced Anaphylaxis Children’s Hospital ED with anaphylaxis were contacted one year after 105 Associated With Non-Steroidal Anti-Inflammatory Drugs their presentation and queried on subsequent allergic reactions. (NSAIDs) RESULTS: Between April 2011 and April 2012, among 168 individuals Dr. Rosa M. Munoz-Cano, MD, PhD1,2, Dr. Joan Bartra, MD, PhD2, presenting with anaphylaxis,102 consented to further follow-up and 80 Dr. Jorg Scheffel, PhD1, Dr. Mariona Pascal, PhD3, Dr. Barbara completed the questionnaire. Demographic and clinical characteristics of Dema, PhD1, Dr. Antonio Valero, MD, PhD2, Dr. Ana Olivera, PhD1, anaphylaxis at recruitment were comparable between respondents and Prof. Cesar Picado, MD, PhD2, Dr. Juan Rivera, PhD1; 1National Institute non-respondents (i.e. 80 versus 22) Fifteen patients (18.8%) reported 29 of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National allergic reactions; 14 reactions in 11 patients met the definition of Institutes of Health, Bethesda, MD, 2Unitat d’Al.lergia. Servei de Neumo- anaphylaxis. Among those with recurrent anaphylaxis, median age was logia i Al.lergia Respiratoria. Hospital Clinic. Barcelona. Institut d’Inves- 3.1 years (IQR: 2.4, 7.2) and the majority were males [60.0% (95%CI, tigacions Biom ediques August Pi i Sunyer (IDIBAPS)., Barcelona, Spain, 32.9%, 82.5%)]. Demographic data and history of atopy did not differ 3Servei d’Immunologia, Centre de Diagnostic Biomedic. Hospital Clinic., substantially between those with and without recurrent anaphylaxis. Food Barcelona, Spain. was the principal trigger [92.9%, (64.2%, 99.6%)]. Anaphylaxis was either
RATIONALE: Lipid transfer protein (LTP), an abundant protein in fruits, moderate or severe. Only 35.7% (14.0%, 64.4%) of moderate/severe SATURDAY vegetables and nuts, is a major allergen linked to food anaphylaxis in reactions used an epinephrine-autoinjector outside of the ED and only 50% Mediterranean areas. However, anaphylaxis to LTP occurs in most patients (26.8%, 73.2%) were brought to the ED. All patients treated in the ED when non-steroidal anti-inflammatory drugs (NSAIDs) are also ingested. received epinephrine either in or outside of the ED. To better understand the underlying causes for the requirement of NSAID CONCLUSIONS: Recurrent anaphylaxis occurs in 13.8 % of those in a subset of LTP-induced anaphylaxis patients, we compared their gene with previous anaphylaxis. Although all episodes of recurrent anaphy- expression profile. laxis were moderate /severe, epinephrine auto-injectors were underused METHODS: Adult patients with a proven clinical history of LTP-induced prior to ED arrival and 50% of patients with anaphylaxis did not anaphylaxis were selected by positive skin prick test and serum-specific present to the ED. IgE to LTP, regardless of age or sex, excluding patients with allergy/ intolerance to NSAID alone. Whole-genome expression analysis (RNA Sensitization To Recombinant Allergens Of Hevea Brasilensis Seq) was performed in blood cells from 14 individuals with NSAIDs- 107 In Patients With Latex Anaphylaxis 1 1 related LTP-induced anaphylaxis (NLA), 7 NSAIDs-unrelated LTP- Dr. J. M. Escobar Montalvo, MD , Ms. A. Gomez Infante, MD , Dr. Silvia Mart ınez Blanco, MD2, Dr. R. Vives Conesa, MD1; 1Hospital induced anaphylaxis (LA) and 13 healthy controls. 2 RESULTS: Gene ontology analysis revealed that in patients with NLA, Universitario 12 de Octubre, Madrid, Spain, Hospital Universitario 12 genes related to cell death/survival/proliferation/development pathways de Octubre, Spain. were significantly upregulated. Additionally, genes related to adenosine RATIONALE: The study of Hevea brasilensis recombinant allergens in- metabolism and signaling, including adenosine receptor 3, were upregu- creases the diagnostic accuracy in the cases of latex allergy. The objective lated in these patients. Remarkably, we observed an enhanced expression of this study was to describe the sensitization profiles to Hevea brasilen- of genes involved in pathways activated by IFN-gamma and in IgG sisrecombinant allergens in patients diagnosed with latex anaphylaxis in receptor expression in the LA group, mirrored by the presence of LTP- the Service of Allergology of the Hospital Universitario 12 de Octubre dur- specific IgG in this group. ing 2012. CONCLUSIONS: These findings suggest that the differential activa- METHODS: Descriptive study of the sensitization profiles to latex tion of the IFN-gamma pathway and IgG receptors could play a role recombinant allergens in patients diagnosed with latex anaphylaxis was in LTP-induced anaphylaxis. Furthermore, adenosine signaling may performed. The analyzed variables were age, sex, atopy, pollinosis, prick have a role in the pathogenesis of LTP-induced anaphylaxis related test (SPT-latex) and specific immunoglobulin E for latex (IgE-latex) and to NSAIDs, in agreement with previous reports of adenosine receptor their recombinant allergens. Every serum was evaluated for 8 latex Ò gene polymorphisms associated with aspirin- induced asthma and recombinants using Phadia-ImmunoCAP 250. urticaria. RESULTS: During 2012, four cases of latex anaphylaxis were diagnosed. Three of them occurred during a surgical procedure and Recurrence Rates Of Anaphylaxis In Children the other case was after mucocutaneous contact. The study of other 106 Dr. Andrew O’Keefe, MD1,2, Dr. Yuka Asai, MD3,4, possible causes was performed with negative results. SPT-latex results Mr. Christopher Mill, BSc3, Dr. Harley Eisman, MD5, Dr. Sebastian La were positive in three cases. IgE-latex assays were positive in all the Vieille, MD6, Dr. Reza Alizadehfar, MD5,7, Ms. Emma Perkins, BSc3, cases (median 5 5,65 kUa/L; 6 5,5). In the perioperative anaphylaxis Dr. Lawrence Joseph, PhD3, Dr. Ann Elaine Clarke, MD, MSc3,8, cases, one patient was sensitized to r Hevb 8; a second one, to r Hevb Dr. Moshe Ben-Shoshan, MD, MSc5,9; 1McGill University, Montreal, 6.01 and r Hevb 6.02; and the third one, to r Hevb 8, r Hevb 6.01 and r Canada, QC, Canada, 2Division of Pediatric Allergy and Clinical Immu- Hevb 6.02. The patient with mucocutaneous contact anaphylaxis was nology, Montreal Children’s Hospital, Canada, 3Division of Clinical sensitized to r Hevb 6.01 and r Hevb6.02. The study of other recombi- Epidemiology, Department of Medicine, McGill University Health nants was negative. Centre, Montreal, QC, Canada, 4Division of Dermatology, Department CONCLUSIONS: In this latex anaphylaxis cases, only the assay of r Hevb of Medicine, McGill University Health Centre, Montreal, QC, Canada, 6.01, r Hevb 6.02, and r Hevb 8 had positive results. 5McGill University, Montreal, QC, Canada, 6Food Directorate, Health Canada, Ottawa, ON, Canada, 7Division of Paediatric Allergy and Clinical Immunology, Department of Paediatrics, McGill University Health Cen- ter, Montreal, QC, Canada, 8Montreal General Hospital, 9Montreal Chil- dren’s Hospital, Montreal, Canada. RATIONALE: To determine the recurrence rate of anaphylaxis in children presenting at the Emergency Department (ED). METHODS: As part of the Cross-Canada Anaphylaxis REgistry (C- CARE), parents of children identified prospectively at the Montreal
ABS 5.2.0 DTD YMAI10628_proof 11 January 2014 7:12 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB30 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Patients Monosensitised To Hev b 8 Performs Surgery Comparison Of Plasma Kallikrein Inhibition By The 108 Without Avoidance The Latex and Without Complications 110 Monoclonal Antibody Inhibitor DX-2930 To Endogenous Dr. Adriano Sa, MD1, Dr. Leila Borges, MD2, Dr. Nathalia Barroso3, C1-INH Dr. Luis Felipe C. Ensina, MD4, Ines Nunes5, Prof. Dirceu Sole, MD, Daniel Sexton, Jon Kenniston, Ryan Faucette, Andrew Nixon, Christo- PhD6; 1Federal University of S~ao Paulo, S~ao Paulo, Brazil, 2UNIFESP, pher TenHoor, Yung H. Chyung, Burt Adelman; Dyax Corp. Brazil, 3Federal University of Sao Paulo, 4Universidade Federal de S~ao RATIONALE: Inhibition of plasma kallikrein (pKal) is a viable Paulo, S~ao Paulo, Brazil, 5Federal University of S~ao P~aulo, 6Federal Uni- therapeutic option for hereditary angioedema (HAE). DX-2930 is a human versity of Sao Paulo, Sao Paulo, Brazil. monoclonal antibody inhibitor of plasma kallikrein (pKal) being devel- RATIONALE: Latex allergy is still a public health problem generating oped for the prophylactic treatment of HAE. This study compared expenses in your eviction. inhibition of pKal activity by DX-2930 to the endogenous pKal inhibitor METHODS: We report the case of a boy monosensitised to Hev b 8 C1-Inhibitor (C1-INH). (profilin) that underwent surgery without precautions for latex and without METHODS: Purified proteins were used to examine the in vitro enzyme complications. inhibition kinetics of C1-INH and DX-2930. Inhibition of pKal activity in RESULTS: Boy, 5 years old, with a history of perioral hyperemia since 6 human plasma was measured using a pKal-selective synthetic peptide sub- months after contact with various foods. No history of previous surgeries or strate or cleavage of high-molecular weight kininogen (HMWK) by reaction after contact with latex. The prick test with latex extract (IPI Western blot. Inhibition of cell bound pKal was examined using cultured ASAC Portugal) and latex gloves were negative. The specific IgE human umbilical vein endothelial cells (HUVEC). (ImmunoCAP Ò Thermo Fisher) to latex and its fractions (rHev b 1, 3, RESULTS: Enzyme inhibition kinetics experiments using purified 5, 6.01, 6.02, 8, 9 and 11) were positive only for the latex (1.0 KU / L) and proteins show that C1-INH has a relatively slow association rate constant its fractions: 1 (0.15 KU / L), 5 (0.19 KU / L), 6.02 (0.14 kU / L), 8 (2.85 kU (1.7 x 104 M-1s-1) compared to DX-2930 (3.4 x 106 M-1s-1). Consistent with
/ L), 9 (0.11 KU / L ) and 11 (0.16 KU / L). The prick to prick with all foods this result, the apparent IC50 observed upon adding exogenous C1-INH to reported was positive only for mango, watermelon and orange. The normal human plasma was approximately 100-fold higher than that of DX- triggering with latex glove (use test) and food were negative. The patient 2930. Using Western blot, we observed that stoichiometric additions of underwent surgery without avoidance of latex and without complications. DX-2930 were sufficient to prevent HMWK proteolysis by active pKal; We believe that this patient was sensitized only to the fraction Hev b 8 and, whereas significantly higher concentrations of C1-INH (e.g. 1 mM) were as already reported by other authors, the monosensitised to this fraction has required to block HMWK proteolysis. C1-INH bound HUVEC cell-asso- been shown to be asymptomatic. ciated pKal with > 200-fold less potency than DX-2930. CONCLUSIONS: The evaluation of sensitization to latex fractions CONCLUSIONS: This in vitro study demonstrates that DX-2930 is a showed crucial in the indication of procedure with or without latex. more potent inhibitor of circulating or cell-bound pKal than C1-INH. The kinetics and inhibitory properties of C1-INH provide a potential mech- Home Treatment With Conestat Alfa In Attacks Of Hereditary anism for why HAE attacks can occur at C1-INH levels that exceed ex- 109 Angioedema Due To C1-Inhibitor Deficiency pected levels of activated pKal. Henriette Farkas, MD, PhD, DSc1, Dr. Erika Szabo1, Dr. Dorottya Csuka, PhD2, Dr. Kinga Viktoria Kohalmi1, Dr. Zsuzsanna Zotter1, The Prophylactic Use Of C1 Esterase Inhibitor (BerinertÒ)In Dr. Lilian Varga, PhD1; 1Semmelweis University, Budapest, Hungary, 111 HAE Patients Undergoing Invasive Procedures 2Hungarian HAE Center, 3rd Department of Internal Medicine, Semmel- Rachel Harrison, BSc1, Stephanie Santucci, RN1, Genevieve weis University, Budapest, Hungary. Gavigan, MASc, MD2, William H. Yang, MD1,2; 1Allergy and Asthma RATIONALE: Conestat alfa, a recombinant C1-inhibitor concentrate Research Corp., Ottawa, ON, Canada, 2University of Ottawa Medical (rhC1-INH), is a novel therapeutic option for the acute treatment of HAE School, Ottawa, ON, Canada. due to C1-INH (HAE-C1-INH). RATIONALE: For a patient with Hereditary Angioedema (HAE), METHODS: We analyzed 42 edematous episodes requiring acute physiological and/or psychological stress can cause insufficient control treatment and occurring in 2 female HAE-C1-INH patients. The patients of local inflammatory pathways. This leads to complement and contact were treated at home with a dose 2100 U rhC1-INH per occasion. The system activation and excess bradykinin resulting in angioedema. patients recorded the time of rhC1-INH administration; the time to the Therefore, an invasive procedure or surgery can trigger an HAE attack; onset of improvement and to the complete resolution of symptoms; and this in turn can cause further medical complications and pose an added noted any side effects. Symptom severity and patient satisfaction were danger to the post-procedure patient. C1 inhibitor, BerinertÒ, was measured with a visual analogue scale (VAS). approved in the US and Canada in 2009 and 2010, respectively, for the RESULTS: 27 HAE attacks occurred in abdominal viscera, 1 in the upper treatment of acute attacks. In April 2013, BerinertÒ was approved in airways, 8 in subcutaneous and 6 in multiple locations. RhC1-INH was Europe for short-term prophylaxis prior to medical, dental, or surgical administered 53 (5-780) [median (min-max)] minutes after the onset of the procedures to prevent HAE attacks. Currently, BerinertÒ is not approved in attacks with a severity (upon injecting) of 66 (10-98) on a VAS. Clinical Canada or the US for prophylaxis. We aim to demonstrate the effectiveness symptoms improved within 30 (10-270) minutes, and the complete of C1 esterase inhibitor, BerinertÒ, as a prophylactic treatment for HAE resolution of symptoms took 420 (100-3525) minutes. The time between patients undergoing invasive procedures. the onset of the attack and the administration of rhC1-INH correlated with METHODS: We performed a retrospective chart review from our the time that symptoms stopped worsening (R50.3395, p50.0278), with Canadian Tertiary Care Allergy and Asthma Clinic of our entire database time to the complete resolution of symptoms (R50.4046, p50.0087), as of HAE patients. well as with the severity of the HAE attack (R50.3143, p50.0427). None RESULTS: Between 1997 and June 2013, we administered C1 esterase of the patients experienced a recurrence of the attack, or drug-related inhibitor for prophylactic use prior to invasive procedures. There were a systemic adverse events. The mean VAS score of patient satisfaction total of 26 procedures, performed on 13 patients. The 26 procedures was 93. breakdown as follows: 8 dental surgeries, 3 open heart surgeries, 8 other CONCLUSIONS: Home treatment with rhC1-INH was an effective and surgical procedures, 2 child birth, 5 invasive procedures In all 26 well-tolerated therapy for all types of HAE attacks. Early treatment of procedures, there was no incidence of post-procedure HAE attacks after attacks resulted in the better outcomes. prophylactic administration of C1 esterase inhibitor. CONCLUSIONS: We found that C1 esterase inhibitor (BerinertÒ) decreased the incidence of post-procedure HAE attacks and was an effective prophylactic treatment.
ABS 5.2.0 DTD YMAI10628_proof 11 January 2014 7:12 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB31 VOLUME 133, NUMBER 2
Self-Administration Of a Novel Subcutaneous Bradykinin B2 HAE In a Southern Louisiana Kindred: Novel Gene Mutations 112 Receptor Antagonist, Icatibant (FirazyrÒ), As An Effective 114 Dr. Adrian Casillas, MD, FAAAAI; Baylor College of Med- Treatment Option In Patients With Hereditary Angioedema icine, Houston, TX. (HAE) RATIONALE: Hereditary angioedema (HAE) is a rare, debilitating and Stephanie Santucci, RN1, Hoang Pham, MD 2016, BSc, BA2, Rachel life-threatening disease with an estimated prevalence of 1:10,000 to Harrison, BSc1, William H. Yang, MD1,2; 1Allergy and Asthma Research 1:50,000. The disease results from a defect in production or function of Corp., Ottawa, ON, Canada, 2University of Ottawa Medical School, the Serping 1 gene product, C-1 esterase inhibitor (C1INH) and is inherited Ottawa, ON, Canada. in an autosomal dominant manner. Several mutations have been described RATIONALE: HAE is a rare disease characterized by recurrent in HAE patients in the Serping 1 gene. angioedema attacks involving larynx, abdomen, extremities and various METHODS: A kindred of HAE patients was identified from Southern body parts. The reactions are by and large self-limited, but potentially, Louisiana. Buccal swab specimens were analyzed from a number of these could be fatal. Currently, the only approved treatment in Canada is an subjects by qualitative PCR to amplify all exons of the Serping 1 gene. Gene intravenous C1-esterase inhibitor infusion. However, intravenous therapy sequences were identified and compared to known Serping 1 gene sequences. can be challenging for those who have co-morbid disorders. Icatibant RESULTS: Two distinct kindreds were identified. Gene mutations in SATURDAY (FirazyrÒ)—an investigational drug pending approval in Canada— offers Serping 1 were identified as follows: administration through subcutaneous delivery. Through a special access 1. G to A mutation in exon 5 which would cause a mutation from program, here we present self-administered icatibant treatment on a female tryptophan to a stop codon that results in cleavage of the exon 5 PCR subject with Charcot -Marie-Tooth disease, a rare genetic, neuromuscular product into 2 smaller fragments. disorder, which limits her ability to self-administer intravenous therapy. 2. G to A mutation in exon 8 which causes a Valine to Methionine mutation METHODS: During each icatibant self-administration event, a diary and is predicted to generate a splice variant that may yield a larger-than- method was used to collect the following patient-reported outcomes: attack normal mRNA that codes for a protein with an altered carboxy-terminus. intensity, anatomical location & trigger, number of doses, onset of relief, time elapsed until complete resolution, and adverse reactions. CONCLUSIONS: The mutations identified present novel findings. There RESULTS: During 2012-2013, the patient logged a total of 10 events, in is one individual identified that is homozygous for the possible splice which she treated each attack with a single self-administered 30 mg dose of variant at intron 6. Further analysis will reveal if the homozygous state is icatibant via subcutaneous injection. She experienced moderate to severe indicative of a more severe form of HAE. abdominal and peripheral HAE attacks. Onsetof relief occurred within 15 – 30 Hereditary Angioedema Without C1 Inhibitor Deficiency: minutes and complete resolution occurred within 4-hours to 5-days. Adverse Observation Of Patients Homozygous For FXII GENE Mutation reactions were mild in severity, transient, and resolved without further 115 Christiane Stieber1, Camila Veronez2, Nathalia Cagini2, Elisabete Cor- intervention. They included local injection site reaction (100%), headache deiro3, Dr. Anete S. Grumach3, Rosemeire Constantino-Silva3, Joao Bo- (60%), fatigue (30%), feeling ‘‘fuzzy-brained’’ (30%), and hot flush (20%). sco Pesquero2, Sven Cichon4; 1Life & Brain Center and Institute of CONCLUSIONS: This case report provides supporting evidence for Human Genetics, University of Bonn, Germany, 2Federal University of icatibant as an effective, safe and viable subcutaneous therapeutic S~ao Paulo, Brazil, 3Faculty of Medicine ABC, Brazil, 4Division of Med- alternative to intravenous treatments for patients with HAE. ical Genetics, Department of Biomedicine, University of Basel, Current Medical Management Of Hereditary Angioedema Switzerland. 113 (HAE): Follow-Up To a Large Survey Of US Physicians RATIONALE: Hereditary Angioedema (HAE) without C1 inhibitor Dr. Marc A. Riedl, MD, MS1, Dr. Richard G. Gower, MD, FAAAAI2, (C1INH) deficiency was described in 2000 and heterozygous Factor XII Dr. Aleena Banerji, MD3; 1University of California, San Diego, La Jolla, (FXII) mutations in 2006. Due to the extremely low population frequencies CA, 2Marycliff Allergy Specialists, Spokane, WA, 3Division of Rheuma- of the mutations in the population, homozygous patients had never been tology, Allergy, and Immunology, Department of Medicine, Massachu- described before. We examined two consanguineous families with HAE setts General Hospital, Harvard Medical School, Boston, MA. without C1INH. RATIONALE: A physician survey conducted in the US between October METHODS: Patients were diagnosed by clinical history, positive familial 2009 and February 2010 revealed wide variability in HAE management. history, normal C4, quantitative and qualitative C1INH. Other associated The objectives of our follow-up survey were to evaluate the impact of causes were excluded. DNA samples were evaluated for the known several newly available treatment options and identify changes in HAE care. missense mutations in exon 9 of the coagulation factor XII gene. METHODS: Between March and June 2013, 6570 physicians were RESULTS: Family 1: index case is a 31 year old female showing first contacted via postal mail with email follow-up (from HAEA and ACAAI symptom at age 3. Her 61 year old father has subcutaneous edema; mailing lists), of whom 277 (4.2%) responded. Participants completed a 46- abdominal pain and laryngeal edema several times triggered by trauma. Six question online survey which was closely patterned after the initial survey. members of this family were evaluated and the father is homozygous. RESULTS: Compared with the prior survey, this follow-up survey found Homozygosity in the father, however, suggests that both parents were that the proportion of physicians reporting danazol as the preferred long- heterozygous carriers. Family 2: index case is a 49 year old female with term prophylaxis agent declined from 56% to 23% (P<0.00005); severe disease, two out of her 3 siblings are affected and 2 granddaughters conversely, C1-INH increased in this category (20% to 57%; P<0.00005). as well. Her 50 year old sister has also severe disease and she is The percentage of attacks self-treated at home increased from 8% to 27% homozygous for FXII mutation. The mutation (c.1032C aA)was identified (P<0.00005). Decreases were observed in ED visits (62% to 54%; for both. P5NS) and hospitalizations (13% to 3%; P50.0001) for HAE attacks. CONCLUSIONS: The two patients reported by us represent the first The percentage of patients perceived by physicians to be very satisfied patients presenting with homozygous FXII mutations. Our observations with HAE treatment increased from 13% to 40% (P<0.00005). suggest that homozygosity for these FXII activating mutations lead to Convenience was reported more frequently as an important treatment deci- the development of disease symptoms in males (heterozygous male car- sion driver for patients (27% vs 10%; P<0.00005), while side effects were riers normally do not develop disease symptoms) and a more severe disease cited less frequently (16% vs 42%; P<0.00005); in both surveys, cost/insur- phenotype in females compared to patients heterozygous for FXII ance coverage was the greatest driver in this category (43% and 46%). mutations. CONCLUSIONS: These findings confirm that current treatment options for HAE are allowing for higher rates of home treatment, decreased ED visits/hospitalizations and providing greater patient satisfaction.
ABS 5.2.0 DTD YMAI10628_proof 11 January 2014 7:12 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB32 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Hereditary Angioedema Without C1 Inhibitor Deficiency: miRs-16, -17, -19a, -20a, -26a, -28, -139-5p, -140, -328, and -384, were 116 Clinical Evaluation Of 67 Brazilian Patients confirmed by individual qPCR assays. Elisabete Cordeiro1, Camila Veronez2, Christiane Stieber3, Nathalia Ca- CONCLUSIONS: Circulating miRNAs can potentially serve as bio- gini2, Rosemeire Constantino-Silva1, Rozana Gonc¸alves4, Gustavo Fu- markers for predicting HAE attack frequency, and as new targets for saro4, Neusa Wandalsen1, Sven Cichon5, Joao Bosco Pesquero2, pharmacological intervention of HAE. Dr. Anete S. Grumach1; 1Faculty of Medicine ABC, Brazil, 2Federal Uni- ~ 3 Hereditary Angioedema In The Pediatric Patient versity of Sao Paulo, Brazil, Life & Brain Center and Institute of Human 1 4 118 Dr. Gregory H. Bennett, DO , Dr. Timothy J. Craig, DO, Genetics, University of Bonn, Germany, Federal University of Minas 2 1 2 Gerais, Brazil, 5Division of Medical Genetics, Department of Biomedi- FAAAAI ; Penn State Children’s Hospital, Hershey, PA, Penn State cine, University of Basel, Switzerland. University College of Medicine, Hershey, PA. RATIONALE: Hereditary Angioedema (HAE) without C1 inhibitor RATIONALE: Hereditary angioedema (HAE) is caused by the absolute (C1INH) deficiency was described in 2000 and clinical manifestations deficiency, or functional inactivity, of the C1 esterase inhibitor (a plasma are similar to HAE with C1INH deficiency, including laryngeal edema. We protein that prevents activation of bradykinin). The goal of this study was to report the evaluation of diagnosed in Brazil. develop a clinical profile of the pediatric patient at initial diagnosis of HAE. METHODS: Patients were diagnosed by clinical history, positive familial METHODS: Pediatric patients were identified as part of a retrospective history, normal C4, quantitative and qualitative C1INH. Other associated study with a database evaluating patients managed for HAE. We describe causes were excluded. DNA samples were evaluated for missense patients’ gender, age at initial diagnosis, initial presenting complaint, mutations on exon 9 of coagulation factor XII. airway involvement, history of atopic comorbidities, family history of RESULTS: Sixty seven patients (10M:57F) out of 9 families were HAE, and initial patient encounter setting. included. First symptoms were reported between 1–50 years of age RESULTS: Twenty nine (29) pediatric patients were identified with the (mean 23.2y) and 15/67 were asymptomatic. Diagnosis was performed diagnosis of HAE: sixteen (16) female and thirteen (13) male. The mean age between 1-79 years old (mean 15.9y). The following clinical manifesta- at initial presentation was 8.5 years; median age was 9 years; ages ranged tions were reported: subcutaneous edema 37/52 (71%), gastrointestinal from birth to eighteen years. The most common presenting symptom was 5 5 edema 35/52 (67,3%) and upper respiratory edema 19/52 (36%). swelling of the face (n 12) and upper extremity (n 12), followed by 5 5 Triggering factors were: contraceptives 14/52; trauma 20/52; stress 14/ abdominal pain (n 9), lower extremity swelling (n 5), and scrotal swelling 5 52; menses 9/52; pregnancy 7/52. Contraceptives interruption improved 5 (n 1). Three (3) patients reported no prior symptoms and were diagnosed patients. Complications were: laryngeal edema after dental therapy 2/52; due to a family history of HAE. Four (4) patients reported airway 5 pancreatitis 2/52; apendicectomy 2/52; uvulectomy 1/52; laparotomy 1/52. involvement. 72% (n 21) of patients reported a positive family history of 5 Therapy used was: danazol 2/52; tranexamic acid 6/52; oxandrolon 1/52, HAE; 48% (n 14) of patients reported concomitant atopic disease history. icatibant 1/52. Two families reported relatives who died due to asphyxia. CONCLUSIONS: Due to the availability of targeted and appropriate Genetic analysis identified the known FXIIgene mutation in five out of 9 medications for hereditary angioedema, therapy should be prescribed at the families. time of diagnosis so that the patient is adequately prepared to treat their first CONCLUSIONS: The absence of C1INH deficiency does not exclude HAE attack. HAE. The risk of asphyxia is relevant in these patients and therapy has to be Clinical Features Of Pediatric Hereditary Angioedema instituted. Factor XII mutation is present in approximately half of the 119 Shelby N. Elenburg, MD1, Amal H. Assa’ad, MD, FAAAAI2, investigated families. In these families, predictive genetic testing can be Dr. Jonathan A. Bernstein, MD, FAAAAI3, Maya Nanda, MD2; 1Univer- employed to identify females at risk and adapt care and treatment. sity of Tennessee Health Science Center, Memphis, TN, 2Cincinnati Chil- 3 Circulating Extracellular Micrornas In Hereditary dren’s Hospital Medical Center, Cincinnati, OH, Division of 117 Angioedema Immunology Allergy & Rheumatology, University of Cincinnati Medical Peisong Gao, MD, PhD1, Kenneth Witwer, PhD2, Melissa McA- Center, Cincinnati, OH. lexander2, Priya Tripathi, PhD1, Tamara Johnson3, Dr. Huamin Henry RATIONALE: There is a paucity of data describing the clinical course of Li, MD, PhD, FAAAAI3; 1Division of Allergy & Clinical Immunology, hereditary angioedema (HAE) in children. The purpose of this study was to Johns Hopkins University School of Medicine, Baltimore, MD, 2Johns identify and characterize children with HAE in our medical center. Hopkins Institute for NanoBioTechnology, Baltimore, MD, 3Institute for METHODS: Electronic medical records from the past 10 years at Asthma and Allergy, Chevy Chase, MD. Cincinnati Children’s Hospital Medical Center and Bernstein Allergy RATIONALE: Hereditary angioedema (HAE) with C1INH deficiency Group were searched for ICD-9 code 277.6 (Other deficiencies of has tremendously diverse clinical presentation. Despite the recent circulating enzyme), in patients less than 18 years of age. Exclusion advances in treatment, no reliable biomarkers are available for identifying criteria included laboratory data not supportive of type I or type II HAE, or patients with higher risk/potential for frequent attacks. We assessed age at diagnosis greater than 18 years. Chart review was performed to feasibility of using plasma microRNAs (miRNAs) as potential biomarkers ascertain the clinical presentation of patients, and missing data was for HAE attack frequency. collected by telephone interviews with patient families. Descriptive METHODS: Peripheral blood was collected from 3 separate groups (8 statistics were performed using SAS version 9.3. each): HAE patients with more than 12 attacks in the past 12 months; HAE RESULTS: Twenty-one patients were identified. The mean age was 13.6 patients with less than 6 attacks in the last 12 months; and healthy controls. years (2.9-24.4), 71% were male, 86% had an HAE family history and 95% Circulating miRNA was isolated from plasma. Profiling of 754 human were Caucasian. The mean age of symptom onset and diagnosis was 6.5 (2- miRNAs was done with the QuantStudio OpenArray platform. The top 10 12) and 6.3 years (1-16), respectively. Five patients diagnosed were still differentially expressed miRNAs were selected for validation by individual asymptomatic. The most common angioedema attack sites were abdom- qPCR assays. inal, peripheral and laryngeal, which occurred at least once in 70%, 55%, RESULTS: Members of the paralogous miR-17-92 clusters that are and 20% of children, respectively. The mean number of lifetime estrogen-sensitive are identified to be differentially expressed between hospitalizations and ER visits was 0.8 (0-6) and 1.4 (0-12), respectively. cases and controls. The largest differences were observed between controls Only 15% of patients required prophylaxis therapy. and the HAE with frequent attack group. Interestingly, miR-384 was CONCLUSIONS: In our pediatric HAE patient population, the age of detected by array almost exclusively in healthy controls but not in HAE onset is younger than the average age of 11.2 years previously reported, patients with frequent attacks. Differentially expressed miRNAs, including with abdominal being more common than peripheral attack sites.
ABS 5.2.0 DTD YMAI10628_proof 11 January 2014 7:12 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB33 VOLUME 133, NUMBER 2
A Case Series Of Seven Pediatric Patients Successfully Center, University of Mainz, Mainz, Germany, 21Internal Medicine 120 Treated With Ecallantide and Icatibant For Hereditary Department, Luigi Sacco Hospital, Milan, Italy, 22Peking Union Medical Angioedema College Hospital, Beijing, China, 23Biomedical Research Network on Heather Minto, MD1,2, Kelly M. Maples, MD1,2; 1Eastern Virginia Med- Rare Diseases (CIBERER, U754), Madrid, Spain. ical School, Norfolk, VA, 2Children’s Hospital of The King’s Daughters, RATIONALE: No specific HRQoL questionnaire for HAE-C1INH is Norfolk, VA. available. RATIONALE: Hereditary Angioedema (HAE) is a rare and potentially METHODS: Qualitative analysis of interviews to Spanish HAE-C1INH life-threatening disease. Over the last several years much progress has been patients and experts followed by a rating phase to assess content validity made in the treatment of acute exacerbations of HAE. Previous studies led to a draft version of the questionnaire (HAE-QoL). Cross-cultural have shown that ecallantide; a plasma kallikrein inhibitor, icatibant; a adaptation and an international rating phase with experts were performed. bradykinin B2 receptor blocker, and recombinant C1 inhibitor are effective Resulting version (IHAE-QoL v.1.1), a clinical questionnaire and SF-36v2 treatments in adolescents and adults. However, there are no FDA approved were internationally pilot tested (with retest in half of the sample one treatments for acute exacerbations of HAE in the pediatric population. month later). Data were analyzed with SPSS v.9.0. Criteria for item
METHODS: We report a case series of seven pediatric patients treated for omission were no response >10%, corrected homogeneity index (CHI) SATURDAY 23 HAE exacerbations at a children’s hospital. Demographics, type of <0.3 or factor loadings <0.4 in the exploratory factor analysis (EFA). HAE, age at time of the attack, treatment used, response to treatment and Those items with higher loadings per factor were selected. Psychometric adverse effects are reported. properties were assessed. RESULTS: Seven patients with HAE ages 5-17 were treated at our facility RESULTS: 61 patients and 16 experts participated in the Spanish phase for 23 HAE attacks. 6 patients have type 1 HAE and one patient has type 3 and 14 experts from 13 countries in the international rating phase. A HAE. 22 attacks were treated with ecallantide and 1 attack was treated with version of 44 items and 9 dimensions was obtained. 332 patients from 11 icatibant successfully, all without adverse reactions. countries participated in the pilot study (accurate data from 290 patients CONCLUSIONS: In our cohort of 7 pediatric HAE patients, ecallantide and 124 out of 128 retests). One item was deleted due to non-response > and icatibant have been effective for resolution of HAE attacks and appear 10%, 3 items because of a CHI <0.3 and 3 items due to insufficient loading. to be safe even in patients as young as 5. Further studies need to be done to The final version (IHAE-QoL v.2.0) includes 25 items addressing 7 extend the FDA approval of ecallantide and icatibant to pediatric patients. dimensions. Good coefficients and correlations were obtained: Cronbach s alpha 0.63-0.88, test-retest reliability 0.87, convergent validity with SF-36 IHAE-Qol: Specific Health-Related Quality Of Life (HRQoL) (PCS 0.63, MCS 0.53, p<0.01) and external criterion validity with 121 Questionnaire In Hereditary Angioedema Due To C1 Inhibitor presence of symptoms, maintenance treatment and psychiatric care Deficiency (HAE-C1INH) (p<0.001) among others. 1 2 Dr. Nieves Prior, MD , Prof. Eduardo Remor , Elia Perez- CONCLUSIONS: The IHAE-QoL shows good reliability and validity 3 4 Fernandez, MSc , Dr. Carmen Gomez-Traseira, MD , Dr. Magdalena Ju- evidences and is available in 13 languages. lia Caminoa, MD4, Francisco Gay a5, Prof. Werner Aberer, MD6, Dr. Olga Melcina Barrera, MD7, Dr. Stephen D. Betschel, MD8, Prof. Laurence Relationship Between Angioedema Attacks and Health- Bouillet, MD, PhD9, Prof. Anette Bygum, MD10, Henriette Farkas, MD, 122 Related Quality Of Life Outcomes In Patients With PhD, DSc11, Dr. Anete S. Grumach12, Dr. Vesna Grivcheva- Hereditary Angioedema (HAE) Panovska, MD, PhD13, Dr. Marcel Levi, MD14, Dr. Hilary Dr. Jeff Dayno, MD1, Dave P. Miller2, Ms. Emily Hautamaki, MPH3, Longhurst, MD15, Dr. Alejandro Malbran, MD16, Dr. Dumitru Scott Newcomer1, David Fitts1, Dr. William R. Lumry, MD, FAAAAI4,5; Moldovan, MD, PhD17, Dr. Gregor Porebski, MD18, Dr. Avner 1ViroPharma Incorporated, 2ICON Clinical Research, 3Oxford Outcomes, Reshef, MD19, Dr. Petra Staubach, MD20, Dr. Andrea Zanichelli, MD21, an ICON plc company, 4AARA Research Center, Dallas, TX, 5Allergy and Dr. Yu-xiang Zhi, MD22, Dr. Teresa Caballero, MD, PhD4,23; 1Hospital Asthma Specialists, Dallas, TX. Universitario Severo Ochoa, Madrid, Spain, 2Psychology Faculty, Univer- RATIONALE: In a post hoc analysis of data from a randomized, placebo- sidad Autonoma, Madrid, Spain, 3Hospital Universitario Fundacion controlled, cross-over study of nanofiltered C1 esterase inhibitor (human) Ò Alcorcon, Madrid, Spain, 4Allergy Department, Hospital La Paz Institute (Cinryze , C1 INH-nf), we quantified the relationship between angioe- for Health Research (IdiPaz), Madrid, Spain, 5Research Unit, Hospital La dema attacks (frequency, severity, and duration) and health-related quality Paz Institute for Health Research (IdiPaz), Madrid, Spain, 6Department of of life (HRQoL). Dermatology and Venereology, Medical University of Graz, Graz, Austria, METHODS: Twenty-two patients with HAE and >_2 attacks per month 7Institute of Pneumology and Allergy. San Fernando’s Hospital, Panama received 1000 U C1 INH-nf or placebo every 3 to 4 days for 12 weeks and City, Panama, 8University of Toronto, Division of Clinical Immunology then crossed over to the other treatment arm for a second 12-week period. and Allergy, Toronto, ON, Canada, 9National Reference Centre for An- Sixteen patients (aged 42615 years) completed the SF-36 questionnaire at gioedema, Internal Medicine Department, Grenoble University Hospital, the end of both periods. A linear mixed model accounting for within- Grenoble, France, 10Denmark HAE Centre, Department of Dermatology patient correlation was used to estimate SF-36 scores as a function of and Allergy Centre, Odense University Hospital, Odense, Denmark, period; age; sex; and attack frequency, severity (mild51, moderate52, and 11Hungarian HAE Center, 3rd Department of Internal Medicine, Semmel- severe53), or duration for that period. The model did not include study weis University, Budapest, Hungary, 12Department of Dermatology, treatment. School of Medicine, University of Sao Paulo, Sao Paulo, Brazil, 13Unit RESULTS: Mean attack severity had the strongest association with of Allergology and Clinical Immunology. Department of Dermatology. HRQoL and was statistically significant for 8 scales: physical function, role Medicine School University Sts Cyril and Methodius, Skopje, Macedonia, physical, bodily pain, social function, mental health, vitality, general 14Department of Internal Medicine, Academic Medical Center, University health, and the physical component summary score (PCS). The model of Amsterdam., Amsterdam, Netherlands, 15Barts Health NHS Trust, Lon- coefficient for PCS indicated that a 1-point reduction in attack severity (eg, don, United Kingdom, 16British Hospital of Buenos Aires, Buenos Aires, severe to moderate or moderate to mild) was associated with improvement Argentina, 17Department of Allergology–Immunology, Mures County of 8.51 units in PCS (p50.002). Attack frequency was significantly Hospital, Tirgu-Mures, Romania, 18Department of Clinical and Environ- associated with 5 of 10 SF-36 scales, and duration was associated with and mental Allergology, Jagiellonian University, Krakow, Poland, 19Allergy, 6 of 10 scales. Clinical Immunology & Angioedema Unit, Chaim Sheba Medical Center, CONCLUSIONS: Improvements in angioedema attack frequency, Tel Hashomer, Israel, 20Department of Dermatology, University Medical severity, and duration were each associated with improvements in HRQoL, with attack severity having the strongest effect.
ABS 5.2.0 DTD YMAI10628_proof 11 January 2014 7:12 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB34 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Health-Related Quality Of Life (HRQoL) In Adult Patients With 1Barts Health NHS Trust, London, United Kingdom, 2Department of 123 Hereditary Angioedema Due To C1 Inhibitor Deficiency (HAE- Dermatology and Allergy, Charit e – Universit€atsmedizin, Berlin, Ger- C1-INH) Assessed By SF-36v2 many, 3Shire, Eysins, Switzerland, 4Department of Dermatology and Ve- Dr. Teresa Caballero, MD, PhD1,2, Dr. Magdalena Julia Caminoa, MD1, nereology, Medical University of Graz, Graz, Austria, 5National Elia P erez-Fern andez, MSc3, Dr. Carmen Gomez-Traseira, MD1, Reference Centre for Angioedema, Internal Medicine Department, Greno- Dr. Anne Aabom, MD4, Prof. Werner Aberer, MD5, Dr. Stephen D. ble University Hospital, Grenoble, France, 6Dipartimento di Scienze Bio- Betschel, MD6, Prof. Anette Bygum, MD4, Dr. Dorottya Csuka, PhD7, Hen- mediche e Cliniche, Ospedale Luigi Sacco, Universit a degli Studi di riette Farkas, MD, PhD, DSc7, Dr. Maria Gomide, MD8, Dr. Adriane Milano, Milan, Italy, 7Allergy Department, Hospital La Paz Institute for Groffik, MD9,Dr.AneteS.Grumach8, Mrs. Iris Leivobich10, Health Research (IdiPaz), Madrid, Spain. Dr. Alejandro Malbran, MD11, Dr. Eniko Mihaly, MD12,Dr.Dumitru RATIONALE: Phase III icatibant trials showed most hereditary angioe- Moldovan, MD, PhD13, Dr. Krystyna Obtulowicz, MD14,Dr.Gregor dema (HAE) attacks were treated successfully with one injection of icatibant, Porebski, MD15, Mrs. Celina Rayonne16,Dr.AvnerReshef,MD10, a selective bradykinin B2 receptor antagonist. To date, there is a paucity of Dr. Petra Staubach, MD9, Dr. Michaela Wiednig, MD5, Maria Joao real-world data regarding icatibant reinjection for HAE type I and II attacks. Forjaz17,18, Dr. Nieves Prior, MD19; 1Allergy Department, Hospital La METHODS: Descriptive retrospective analyses of icatibant reinjection Paz Institute for Health Research (IdiPaz), Madrid, Spain, 2Biomedical were performed on Icatibant Outcome Survey (IOS; Shire, Eysins, Research Network on Rare Diseases (CIBERER, U754), Madrid, Spain, Switzerland [NCT01034969]) data (July 2009-December 2012). IOS is an in- 3Hospital Universitario Fundacion Alcorcon, Madrid, Spain, 4Denmark ternational observational study monitoring icatibant safety and effectiveness. HAE Centre, Department of Dermatology and Allergy Centre, Odense Uni- RESULTS: Icatibant was administered for 507 non-laryngeal attacks in versity Hospital, Odense, Denmark, 5Department of Dermatology and Vene- 155 patients with HAE type I or II. Patients self-administered icatibant in reology, Medical University of Graz, Graz, Austria, 6University of Toronto, 69.2% of attacks; a single injection was used for 93.3% of attacks. For Division of Clinical Immunology and Allergy, Toronto, ON, Canada, 7Hun- attacks requiring reinjection, the second injection was given a median of garian HAE Center, 3rd Department of Internal Medicine, Semmelweis Uni- 12.6 hours after the first, with 95.7% of second injections administered >_6 versity, Budapest, Hungary, 8Department of Dermatology, School of hours after the first. Symptoms resolved a median of 4.3 hours after second Medicine, University of Sao Paulo, Sao Paulo, Brazil, 9Department of Derma- injection. Logistic regression analysis showed no relationship between tology, University Medical Center, University of Mainz, Mainz, Germany, reinjection requirement and sex, weight, family history, administrator type, 10Allergy, Clinical Immunology & Angioedema Unit, Chaim Sheba Medical attack severity, attack frequency (<20 versus >_20 attacks/year), attack Center, Tel Hashomer, Israel, 11British Hospital of Buenos Aires, Buenos location or long-term prophylaxis usage (all p>0.05). One injection was Aires, Argentina, 12Department of Allergology–Immunology, Mures County used in: 95.1% (n5195/205) of attacks involving only skin; 90.3% Hospital, T ırgu-Mures, Romania, 13Department of Allergology–Immu- (n5215/238) of attacks involving only abdomen; 92.7% (n5290/313) of nology, Mures County Hospital, Tirgu-Mures, Romania, Tirgu-Mures, severe/very severe attacks; 91.2% (n5312/342) and 96.8% (n5120/124) Romania, 14Department of Clinical and Enviromental Medicine, Jagiellonian of attacks in patients with <20 and >_20 attacks/year, respectively. University, Krakow, Poland, 15Department of Clinical and Environmental CONCLUSIONS: In this real-world setting, most HAE attacks resolved Allergology, Jagiellonian University, Krakow, Poland, 16ReSolve Research with one icatibant injection. There was no distinct profile for patients or Solutions Inc., Whitby, Ontario, Canada, 17National School of Public Health, attacks requiring reinjection. Carlos III Institute of Public Health, Madrid, Spain, 18REDISSEC, Madrid, Spain, 19Hospital Universitario Severo Ochoa, Madrid, Spain. RATIONALE: HAE-C1-INH is a rare disease with high morbidity and life-threatening attacks, and a paucity of HRQoL studies. METHODS: A prospective international multicenter cohort study was performed in 11 countries. The SF-36 v2 generic HRQoL survey was self- administered to adult patients with HAE-C1-INH as part of the pilot study for the validation of IHAE-QoL. The recall period was 4 weeks. Subscales scores (PF, SF, RP, RE, MH, VT, BP, GH), Physical component summary (PCS) and Mental component Summary (MCS) were calculated. No data were imputed. For each of the subscales and the component summary scores, higher values indicate better HRQoL. RESULTS: 290 patients were included with the following distribution: Argentine 16; Austria 18; Brazil 34; Canada 21; Denmark 27; Germany 42; Hungary 38; Israel 9; Poland 22; Romania 19; Spain 44. Surveys were complete enough to compute PCS and MCS scales scores in 278 and 284 patients, respectively. PCS mean was 49.7 (country range: 42.5-50.4), MCS mean was 46.2 (country range: 37.8-53.3). The subscale means for the whole sample were: PF 82.5; SF 73.6; RP 72.8; RE 77.8; MH 65.8; VT 55.6; BP 59.7; GH 53.5. Sixty-six patientsreferredthey were somewhat worse or much worse than a year ago. PF, RP, BP, VT and PCS scores were significantly lower in females. PF, RP, RE, MH, VT, BP, GH, PCS and MCS scores were significantly higher in patients with higher socioeconomic level. CONCLUSIONS: There were important differences in HRQoL by country. HRQoL was worse in females and in patients with lower socioeconomic level.
The Icatibant Outcome Survey: Characteristics Of Patients 124 With Hereditary Angioedema Requiring Reinjection Dr. Hilary Longhurst, MD1, Prof. Marcus Maurer, MD2, Dr. Vincent Fabien, PhD3, Prof. Werner Aberer, MD4, Prof. Laurence Bouillet, MD, PhD5, Dr. Andrea Zanichelli, MD6, Dr. Teresa Caballero, MD, PhD7;
ABS 5.2.0 DTD YMAI10628_proof 11 January 2014 7:12 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB35 VOLUME 133, NUMBER 2
The Icatibant Outcome Survey: Characterizing Breakthrough injections were self-administered (70.9%). One icatibant injection was 125 Hereditary Angioedema Attacks In Patients Receiving Long- sufficient for 95.4% of self-administered and 91.9% of HCP-administered Term Prophylaxis attacks (2 outliers excluded). Self- and HCP-treated attacks were similar in Prof. Werner Aberer, MD1, Prof. Marcus Maurer, MD2, Prof. Laurence severity (proportion of attacks classed as severe and very severe: 69.7% Bouillet, MD, PhD3, Amandine Perrin4, Dr. Andrea Zanichelli, MD5, and 72.2%, respectively). The median time to administration was Dr. Teresa Caballero, MD, PhD6, Dr. Hilary Longhurst, MD7; 1Department significantly lower in self- vs HCP-treated attacks (1.5 vs 2.5 hours; of Dermatology and Venereology, Medical University of Graz, Graz, Austria, p50.015), and there was a trend toward reduced attack duration (7.5 vs 8.5 2Department of Dermatology and Allergy, Charit e – Universit€atsmedizin, hours; p50.138). Median time to resolution was similar for self- vs HCP- Berlin, Germany, 3National Reference Centre for Angioedema, Internal Med- administration (3.5 hours for both; p50.809). Median time to resolution icine Department, Grenoble University Hospital, Grenoble, France, 4Shire, and duration of attack were shorter for treatment administered within 2 Eysins, Switzerland, 5Dipartimento di Scienze Biomediche e Cliniche, Ospe- hours vs >2 hours of attack onset (p50.032 and p<0.0001, respectively). In dale Luigi Sacco, Universit a degli Studi di Milano, Milan, Italy, 6Allergy general, icatibant was well tolerated. Department, Hospital La Paz Institute for Health Research (IdiPaz), Madrid, CONCLUSIONS: Self-administration of icatibant enabled a shorter time
Spain, 7Barts Health NHS Trust, London, United Kingdom. to administration vs HCP-administration. Earlier icatibant administration SATURDAY RATIONALE: Long-term prophylaxis (LTP) reduces attack severity and (<2 hours) resulted in faster attack resolution. One icatibant injection was frequency in patients with hereditary angioedema (HAE), although sufficient to treat the majority of HAE attacks. breakthrough attacks occur. We compared outcomes in patients with HAE who were/were not receiving LTP and received icatibant for acute attacks. Most Hereditary Angioedema (HAE) Attacks Resolved After METHODS: The Icatibant Outcome Survey (IOS; Shire, Eysins, 127 One Icatibant Injection: Analysis Of FAST-3 Open-Label Switzerland [NCT01034969]) is an international, prospective, observational Extension Study Dr. William R. Lumry, MD, FAAAAI1, Jovanna Baptista, MS2, Dr. Marc study monitoring icatibant safety and effectiveness during long-term treat- 3 4 1 ment. Descriptive retrospective analyses were performed of IOS treatment A. Riedl, MD, MS , Dr. Timothy J. Craig, DO, FAAAAI ; Allergy and Asthma Specialists, Dallas, TX, 2Shire, Lexington, MA, 3University of data in patients who were/were not receiving LTP (July 2009–March 2013). 4 RESULTS: Six hundred and sixty six attacks were treated with icatibant in California, San Diego, La Jolla, CA, Penn State University College of 180 patients with HAE type I or II; 210 attacks (31.5%) occurred in 67 Medicine, Hershey, PA. patients on LTP (37.2%). Danazol was the most commonly used LTP RATIONALE: Single icatibant injections were effective in treating (52.9% of breakthrough attacks). Most attacks were treated successfully hereditary angioedema (HAE) attacks in the double-blind, placebo- with one icatibant injection (90.0% [189/210] with LTP, 91.7% [418/456] controlled phase of the For Angioedema Subcutaneous Treatment-3 study without LTP). In patients with/without LTP, median time to first injection (FAST-3; NCT00912093). The need for second or third injections was (2.0 versus 2.7 hours), attack duration (9.0 versus 8.8 hours), and time to analyzed post hoc using data from the open-label extension (OLE) phase resolution (4.0 hours for both) were similar (all p>0.05). In patients of FAST-3. experiencing <10 attacks/year who were receiving LTP compared with not METHODS: Adults with HAE type I or II, who received a single receiving LTP, median time to first injection was 5.1 versus 2.3 hours subcutaneous injection of icatibant 30 mg or placebo for an attack in the (p50.104) and 1.3 versus 2.2 hours (p50.574) for >_10 attacks/year. controlled phase of FAST-3, could receive up to 3 injections of open-label _ CONCLUSIONS: Real-world data show that outcomes were comparable icatibant, >6 hours apart, per subsequent abdominal, cutaneous or for acute HAE attacks treated with icatibant in patients who were/were not laryngeal attack in an OLE. Reinjection rates, median times to onset of _ receiving LTP. These results suggest that icatibant was an effective symptom relief (>50% reduction in patient-reported, composite visual treatment for breakthrough HAE attacks. analog scale [VAS] symptom score), and almost complete symptom relief (all VAS symptom scores <10 mm) were analyzed in the OLE. The Icatibant Outcome Survey: Rate and Impact Of Treatment RESULTS: In the OLE, 435 attacks in 82 patients were treated with one 126 By Self-Administration (n5415; 95.4%), two (n519; 4.4%) or three (n51; 0.2%) icatibant Dr. Dolores Hernandez Fernandez de Rojas, MD1, Dr. Ethel injections. Most attacks were successfully treated with one injection, Ib anez,~ MD1, Dr. Hilary Longhurst, MD2, Prof. Marcus Maurer, MD3, irrespective of age, sex, HAE type, attack severity or attack location. For Dr. Vincent Fabien, PhD4, Prof. Werner Aberer, MD5, Prof. Laurence attacks treated with one injection, median time from first injection to onset Bouillet, MD, PhD6, Dr. Andrea Zanichelli, MD7, Dr. Teresa Caballero, of symptom relief was 2.0 hours (n5410) and median time to almost MD, PhD8; 1IIS Hospital Universitario La Fe, Valencia, Spain, 2Barts complete symptom relief was 4.9 hours (n5382). For reinjections, time Health NHS Trust, London, United Kingdom, 3Department of Derma- between the first and second injection was >_12 hours for 75% of attacks, tology and Allergy, Charit e – Universit€atsmedizin, Berlin, Germany, with a median of 25.7 hours (n520). 4Shire, Eysins, Switzerland, 5Department of Dermatology and Venereol- CONCLUSIONS: Irrespective of patient or attack characteristics, most ogy, Medical University of Graz, Graz, Austria, 6National Reference HAE attacks were successfully treated with one icatibant injection, leading Centre for Angioedema, Internal Medicine Department, Grenoble Univer- to patient-reported symptom relief. sity Hospital, Grenoble, France, 7Dipartimento di Scienze Biomediche e Cliniche, Ospedale Luigi Sacco, Universit a degli Studi di Milano, Milan, Italy, 8Allergy Department, Hospital La Paz Institute for Health Research (IdiPaz), Madrid, Spain. RATIONALE: Icatibant, a selective bradykinin B2 receptor antagonist for the treatment of hereditary angioedema (HAE) attacks in adults, can be self-administered or healthcare professional- (HCP-) administered. This analysis compared HCP- and self-administration in a real-world setting. METHODS: The Icatibant Outcome Survey (IOS; Shire, Eysins, Switzerland [NCT01034969]) is an international observational study monitoring safety and effectiveness of icatibant treatment. Descriptive retrospective analyses were performed (July 2009-December 2012). RESULTS: Icatibant was used to treat 608 type I/II HAE attacks in 363 patients. Proportions of mild, moderate, severe, and very severe attacks were 7.2%, 22.8%, 46.9%, and 23.0%, respectively. Most icatibant
ABS 5.2.0 DTD YMAI10628_proof 11 January 2014 7:12 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB36 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Evaluation Of Icatibant Reinjection Of Laryngeal Hereditary infant was born healthy. Genetic analysis revealed a missense mutation in 128 Angioedema Attacks: A Pooled Analysis Of Three Phase III exon 6 of the SERPING1 gene, identified as c.939T>G or p.Phe291Leu. Open-Label Extension Studies CONCLUSIONS: We describe the successful and safe use of Icatibant, Jovanna Baptista, MS1, Dr. Jonathan A. Bernstein, MD, FAAAAI2, the only medication available in Brazil for acute HAE attacks, during Dr. William R. Lumry, MD, FAAAAI3, Dr. Marc A. Riedl, MD, MS4; pregnancy and immediately before cesarean delivery in a patient present- 1Shire, Lexington, MA, 2Division of Immunology Allergy & Rheuma- ing a novel genetic mutation in SERPING1 as a cause of HAE type I. tology, University of Cincinnati Medical Center, Cincinnati, OH, 3Allergy and Asthma Specialists, Dallas, TX, 4University of California, San Diego, Recombinant Human C1 Inhibitor Treatment Does Not Affect La Jolla, CA. 130 D-Dimer Levels and Is Not Associated With Thromboembolic RATIONALE: Laryngeal attacks of hereditary angioedema (HAE) may Events In HAE Patients Dr. Avner Reshef, MD1, Dr. Andrea Zanichelli, MD2, Dr. Hilary be fatal if undiagnosed and/or untreated. For Angioedema Subcutaneous 3 4 5 Treatment (FAST)-1 (NCT00097695), FAST-2 (NCT00500656) and Longhurst, MD , Yun Hardiman, MS , Anurag Relan, MD , C. Erik Hack, MD6; 1Allergy, Clinical Immunology & Angioedema Unit, Chaim FAST-3 (NCT00912093) Phase III studies demonstrated the efficacy and 2 safety of icatibant for HAE type I and II attacks. This post-hoc pooled anal- Sheba Medical Center, Tel Hashomer, Israel, Dipartimento di Scienze Biomediche e Cliniche, Ospedale Luigi Sacco, Universit a degli Studi di ysis evaluated laryngeal HAE attacks requiring icatibant reinjection in 3 open-label extensions (OLEs) of these studies. Milano, Milan, Italy, Barts Health NHS Trust, London, United Kingdom, 4Santarus Inc., San Diego, CA, 5Pharming Technologies BV, Leiden, METHODS: Up to three subcutaneous injections of icatibant 30 mg, 6 administered >_6 hours apart, could be given per attack during FAST OLEs. Netherlands, University Medical Center Utrecht, Utrecht, Netherlands. If symptoms worsened >48 hours after initial treatment, the attack was RATIONALE: Recommended management of acute hereditary angioe- considered new. Evaluations included patient-assessed symptom severity dema (HAE) includes therapy with exogenous C1 Inhibitor (C1INH). using a 5-point scale before treatment and 2 and 4 hours post-injection. Thromboembolic events (TEE) have been reported with some plasma- RESULTS: Analyses included 52 patients with 110 laryngeal attacks: 75 derived C1INH, but not with recombinant human C1INH (rhC1INH; (68.2%) mild/moderate and 35 (31.8%) severe attacks. 101 (91.8%), 8 >1000 administrations). This study evaluating safety and efficacy of (7.3%), and 1 (0.9%) attacks were treated with one, two, and three icatibant rhC1INH for acute HAE attacks included monitoring for TEE, and injections, respectively. Patient sex, age, HAE type (I/II), and attack assessments of D-dimer (DD) fibrin-degradation products and risk of severity did not influence need for reinjection. Median time (range) deep vein thrombosis (DVT). between attack onset and first injection was 4.5 (0.7-34.7) hours; 65.6% of METHODS: Seventy-four patients with acute HAE attacks were ran- domized 3:2 to receive 50 IU/kg rhC1INH or placebo. DD levels (presented first injections were administered <6 hours of attack onset. The second th th injection was given a median of 26.6 (6.3-41.8) hours after the first, with as median [25 -75 quartiles]) were assessed prior to, and 2-h and at Day 7 88.9% of second injections administered at >_12 hours. The majority of after study drug infusion. DVT risk was assessed using Wells Prediction laryngeal symptoms were absent/mild by 4 hours after the first injection Rule. (difficulty swallowing: 74.5%; voice change: 80.9% [110 attacks]). RESULTS: At baseline, overall median DD level was elevated (2149 m m CONCLUSIONS: Most laryngeal HAE attacks and symptoms resolved [480-5105] g/L; normal <540 g/L), and was higher in patients with with one icatibant injection. The need for icatibant reinjection for a single submucosal (abdominal, oropharyngeal-laryngeal, urogenital) attacks m 5 attack was infrequent. (3095 [890-10000] g/L; n 29) compared with subcutaneous (peripheral, facial) attacks (960 [450-4060] mg/L; n535). At baseline (1874 [475- Successful and Safe Use Of Icatibant For Life-Threatening 4568] mg/L rhC1INH; 2259 [586-7533] mg/L placebo) and 2-h post- 129 Angioedema Attack During Pregnancy In a Patient With infusion (2389 [760-4974] mg/L rhC1INH; 2550 [310-8410] mg/L Hereditary Angioedema Type I placebo), median DD levels were comparable across treatment groups; Dr. Karine Boufleur, MD1, Ms. Luana Delcaro1, Dr. Daniel L. medians had decreased by Day 7 in both groups (425 [232-3240] mg/L Cordeiro, MD1, Dr. Priscila B. Botelho Palhas, MD1, Dr. Janaina rhC1INH; 418 [246-2318] mg/L placebo). Wells Prediction Rule did not Fernandes de Melo Sousa, MD1, Dr. Tha ıs Mendonc¸a, MD1, Dr. Janaina identify any risk of DVT, nor were any TEE reported. Michele de Lima Melo, MD1, Dr. Gustavo Neppelenbroek, MD1, CONCLUSIONS: DD, an activation marker of coagulation/fibrinolysis, Prof. Wlly Sarti1, Dr. Adriana S. Moreno, PhD1, Dr. Luisa Karla P. Arruda, was elevated during HAE attacks compared with remissions, and was MD, PhD, FAAAAI2; 1Ribeirao Preto Medical School, University of Sao higher with submucosal compared with subcutaneous attacks. Elevated Paulo, Ribeirao Preto, Brazil, 2School of Medicine of Ribeirao Preto, DD levels were associated with acute HAE attacks, but not with rhC1INH Ribeirao Preto, Brazil. treatment. No TEEs were observed with rhC1INH. RATIONALE: Hereditary angioedema (HAE) is a rare disease caused by C1 inhibitor deficiency that may lead to upper airway edema and asphyxia. We describe the case of a patient with HAE who used Icatibant during pregnancy. METHODS: Case report of a 40-year-old patient with HAE type I who presented upper airway edema during pregnancy. C1-INH and C4 were measured by nephelometry. Sequencing of SERPING1 gene was per- formed from PCR-amplified genomic DNA. RESULTS: Patient s symptoms started in infancy, and diagnosis of HAE was made at age 25(C1-INH 5.0mg/dL, normal 14-30mg/dL; C4 0.04g/L, normal 0.1-0.4g/L). She was treated with Danazol. Patient expressed desire to have a child, and after discussing risks, danazol was switched to tranexamic acid and she became pregnant. At 32 and 35 weeks pregnancy, she had two attacks of dyspnea, hoarseness, dysphagia and sensation of upper airway obstruction, and Icatibant was successfully used due to life- threatening nature of symptoms. At week 36, she self-administrated Icatibant for severe abdominal pain, however it was due to labor, and after six hours she underwent cesarian section. Patient did not present angioedema or any complications during labor or postpartum and the
ABS 5.2.0 DTD YMAI10628_proof 11 January 2014 7:12 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB37 VOLUME 133, NUMBER 2
C1-Esterase Inhibitor Concentrate For Acute Attacks Of with an additional dose of rhC1INH was evaluated in studies where this 131 Laryngeal Edema In Hereditary Angioedema (HAE): Fixed was permitted. Response was defined as >_20 mm decrease in visual analog Dosing Vs Body Weight-Adjusted Dosing scale (VAS) scores at two consecutive time points occurring within 4h, and Konrad Bork, MD1, Dr. Jonathan A. Bernstein, MD, FAAAAI2, Henrike relapse was defined as response followed by worsening of symptoms Feuersenger3, Thomas Machnig3, Dr. Timothy J. Craig, DO, FAAAAI4; within 24h. New attacks occurring within 3 days of treatment were 1University of Mainz, Mainz, Germany, 2Division of Immunology Allergy summarized. & Rheumatology, University of Cincinnati Medical Center, Cincinnati, RESULTS: One hundred twenty seven patients were treated for 290 OH, 3CSL Behring GmbH, Marburg, Germany, 4Penn State University attacks; 13 of 280 attacks (5%) were treated with an additional dose of 50 College of Medicine, Hershey, PA. IU/kg, while 95% were treated with a single dose. Of the 290 attacks with RATIONALE: Plasma-derived C1-esterase inhibitor (pdC1-INH) is 24h follow up data, 263 (91%) responded within 4h and none were effective in treating hereditary angioedema (HAE). Currently, 2 dosing associated with relapse of symptoms. Of the 280 attacks with 3-day follow regimens are recommended: body weight-adjusted dosing with 20 U/kg up data, 260 (93%) attacks had no new attack symptoms during this time. and fixed dosing with 1000 U. Since laryngeal attacks can be life- CONCLUSIONS: Treatment with rhC1INH resulted in a high response threatening and correct dosing is important for a fast regression of rate and no relapses within 24h. Most attacks were treated effectively with SATURDAY symptoms, we compared the 2 dosing regimens. a single dose, with a low rate of new attacks over a 3-day period. METHODS: Data from I.M.P.A.C.T.2 (16 HAE patients treated with 20 U/kg pdC1-INH) were compared with data from a hospital database (20 Efficacy Of C1Inhibitor Concentrate (Berinert) For Severe patients treated with fixed doses of 500 or 1000 U). Endpoints of this 133 Angioedema Attacks Induced By Drugs Targeting The Renin- Angiotensin Aldosterone System comparison were ‘‘time to first symptom relief’’ (TSR) and ‘‘time to 1 2 complete attack resolution’’ (TRT). Differences were assessed by Prof. Laurence Bouillet , Dr. Bernard Floccard , Dr. Isabelle Boccon-Gi- bod3, Dr. Sebastien Trouiller4, Dr. Anne Du-Than5, Prof. Olivier Fain6; Wilcoxon tests. 1 2 RESULTS: The mean TSR (95% CI) was 53.4 min (31.6; 75.2) in the Grenoble university hospital, Grenoble, France, Lyon university hospi- tal, Lyon, France, 3Grenoble University Hospital, Grenoble, France, fixed-dose group and 31.5 min (21.1; 41.9) in the adjusted-dose group. This 4 5 5 Centre hospitalierd’Aurillac, Aurillac, France, Montpellier university difference was significant (p 0.019). The mean TRT (95% CI) was 22.4 h 6 (17.1; 27.6) in the fixed-dose group and 16.6 h (8.6; 24.5) in the adjusted- hospital, Montpellier, France, Jean Verdier universty hospital, Bondy, dose group. Also this difference was significant (p50.037). No significant France. differences in TRT and TSR were observed between fixed-doses of 500 vs RATIONALE: Angiotensin converting enzyme (ACE) inhibitors can 1000 U. Clinical trials showed that fixed doses of 1000 U required re- induce bradykinin mediated angioedema. This side effect affects 0.5-1% of dosing in 62% of laryngeal attacks (n5262). A single body weight- patients. Angiotensin receptor blockers (ARB) can also induce this side adjusted dose of 20 U/kg was effective for all laryngeal attacks (n548). effect but more rarely. The attack localizations are mainly the ENT and the CONCLUSIONS: The indirect comparison showed that body weight- face. The diagnosis must be done faster because, in the absence of specific adjusted dosing with 20 U/kg pdC1-INH provides faster treatment treatment, fatal issue can occur in 25% of the cases. response in acute laryngeal HAE attacks compared with fixed dosing METHODS: An observational study (COBRA) is handled by the National with 500 or 1000 U and should therefore be considered as preferred Reference Centre for Angioedema (CREAK) since 4 years. The purpose of treatment choice. this study is to evaluate the efficiency and the safety of Berinert in France. Every French patient treated with Berinert was been included in COBRA. Sustained Response Following Acute Treatment Of Hereditary We have investigated all case-reports of angioedema induced by drugs 132 Angioedema Attacks With Recombinant Human C1 Esterase targeting the renin angiotensin aldosterone system and treated by Berinert. Inhibitor RESULTS: 11 patients were reported: 54.5% were female. The median H. Henry Li, MD, PhD1, Dr. Marc A. Riedl, MD, MS2, Dr. Jonathan A. age was 62.2 (+/-6.6) years. All angioedema were isolated. The localiza- Bernstein, MD, FAAAAI3, Dr. William R. Lumry, MD, FAAAAI4, tion of the attacks were facial (5 patients) and/or laryngeal (9 patients). Dr. Avner Reshef, MD5, Dr. Dumitru Moldovan, MD, PhD6, Henriette 54.5% of drugs were an ACE inhibitor, 36.4% an ARB. One patient took Farkas, MD, PhD, DSc7, Dr. Gregor Porebski, MD8, Marcin ACE inhibitor and ARB. Patients were receiving drugs since 4 years (1 Stobiecki, MD9, Yun Hardiman, MS10, Anurag Relan, MD11, month to 15 years). All patients’ state worsened after injections of anti- Prof. Marco Cicardi, MD, PhD12; 1Institute for Asthma and Allergy, histamine and/or corticosteroids. The time of reaction after the injection of Chevy Chase, MD, 2University of California, San Diego, La Jolla, CA, 20U/Kg of Berinert was 97.5 min (30min-5 hours). Only one patient didn’t 3Division of Immunology Allergy & Rheumatology, University of Cincin- improve after the injection. No side effect was reported. ACE inhibitors nati Medical Center, Cincinnati, OH, 4AARA Research Center, Dallas, and ARB were discontinued. TX, 5Allergy, Clinical Immunology & Angioedema Unit, Chaim Sheba CONCLUSIONS: Berinert is a potential treatment for severe angioedema Medical Center, Tel Hashomer, Israel, 6Department of Allergology– attacks induced by drugs targeting the renin-angiotensin aldosterone Immunology, Mures County Hospital, Tirgu-Mures, Romania, system. Tirgu-Mures, Romania, 7Semmelweis University, Budapest, Hungary, 8Department of Clinical and Environmental Allergology, Jagiellonian University, Krakow, Poland, 9Jagiellonian University College, Krakow, Poland, 10Santarus Inc., San Diego, CA, 11Pharming Technologies BV, Leiden, Netherlands, 12Department of Internal Medicine, Luigi Sacco Hospital, Milan, Italy, Milan, Italy. RATIONALE: Hereditary angioedema (HAE) with C1 esterase inhibitor (C1INH) deficiency is characterized by recurrent attacks of tissue swelling. Recombinant human C1INH (rhC1INH) is effective in improving angioedema symptoms in HAE patients. This post-hoc analysis evaluated durability of response to rhC1INH by assessing the rate of relapse, the use of an additional rhC1INH dose following the initial dose, and new attack occurrences. METHODS: Data were evaluated from 4 studies on HAE attacks treated with an initial dose of 50 IU/kg rhC1INH. The proportion of attacks treated
ABS 5.2.0 DTD YMAI10628_proof 11 January 2014 7:12 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB38 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Professional Administration Costs In The US For On-Demand 1University of Cincinnati, Cincinnati, OH, 2Division of Immunology Al- 134 Therapy Of Hereditary Angioedema lergy & Rheumatology, University of Cincinnati Medical Center, Cincin- Thomas Machnig1, Mr. Art Zbrozek, RPh, MSc, MBA2; 1CSL Behring nati, OH, 3Vanderbilt University, Nashville, TN. GmbH, Marburg, Germany, 2CSL Behring LLC, King of Prussia, PA. RATIONALE: Angiotensin converting enzyme inhibitor angioedema RATIONALE: Currently, treatments for on-demand therapy of type I or II (ACEI-AE) can be life threatening without proper intervention. Kallikrein attacks of hereditary angioedema (HAE) have been approved in the United inhibitors (Ecallantide) have been reported to prevent or attenuate ACEI- States (US) either for self-administration at home, or administration in a AE but randomized controlled studies are lacking. health-care setting. Patients who require professional administration of METHODS: An IRB approved, triple blind, placebo controlled pilot therapy incur additional costs. These additional costs have not been study investigating the efficacy of Ecallantide vs. Placebo for ACEI-AE in reported previously for the US. two Emergency Department (ED) settings was performed. Fifty ACEI-AE METHODS: The OptumInsight Database (2012) was used to identify patients were randomized to receive 3 x 10mg Ecallantide or 3 x 10mg patients who received at-home professional services for HAE therapy Placebo subcutaneous injections. Inclusion criteria required no improve- administration. The Premier data base (2011-13) was used to identify ment or progression of swelling after therapy with corticosteroids and H1- patients who received on-demand HAE therapy in the emergency room and H2-antihistamines. The primary endpoint was eligibility for ED (ER). Cohort inclusion required reason for intervention to be coded for discharge in <_ 4 hours after treatment. HAE attack and evidence of HAE therapy administered. RESULTS: The mean age of Ecallantide (n526) and Placebo (n524) RESULTS: Mean (median) at-home professional administration costs patients was 56617 and 57617, respectively. The majority for both groups were $59 ($30) per episode by service codes (N5118) and $106 ($105) per were African American (Ecallantide522; Placebo523). The Female:Male episode for procedure codes (N527). Mean (median) ER administration ratio for Ecallantide was 11:15 and for Placebo was 15:9; 50% of costs were $578 ($399) per episode (N537). Ecallantide vs. 17% of Placebo patients were on an ACE < 6 months. CONCLUSIONS: Costs of professional administration of HAE therapy Baseline angioedema severity (mild, moderate or severe) was evenly are small in comparison to the costs of the actual therapies, but they may distributed between groups with the majority being moderate become decisive when comparing therapies that can be self-administered (Ecallantide5 69%; Placebo563%). The primary endpoint of ED vs. those requiring professional administration. Thus, it is important to discharge in <_4 hours was met by 8/26 (31%) Ecallantide vs. 5/24 (21%) consider costs of professional administration of HAE treatment for Placebo patients (difference in proportions 10.0%, 95% CI -14.1% to inclusion in economic analyses of HAE therapies. 34.0%). Overall Ecallantide was well tolerated by all subjects. CONCLUSIONS: Although not significant, Ecallantide appeared to Successful Administration Of C1Esterase Inhibitor (C1inh) In resolve ACEI-AE more frequently than Placebo, and it was well tolerated. 135 An Individual Anaphylactic To It These data support a phase III trial with sufficient power to confirm this 1 2 Dr. Arthur B. Vegh, MD, FAAAAI , Ms. Marni Sellers , Ms. Nancy observation. Boyden2, Ms. Jennifer Vegh2; 1University of Washington, Tacoma, WA, 2none, Tacoma, WA. Ecallantide In Treatment Of Type III Hereditary Angioedema RATIONALE: Hereditary angioedema (HAE) is a severe, sometimes life 137 Dr. Anil Nanda, MD1, Dr. Anita N. Wasan, MD2; 1Asthma and threatening, disease not responding to normal angioedema treatment. Allergy Center, Lewisville, TX; UT Southwestern Medical Center, Dallas, C1inh replacement can decrease attack severity/frequency but allergy to TX, 2Allergy and Asthma Center, Lansdowne, VA. this is considered a contraindication to re-administration. Nonetheless, the RATIONALE: Type I and Type II hereditary angioedema syndromes have need for the therapy is still present. been well characterized, and multiple treatment options exist. However, METHODS: Aggressive allergy pretreatment and slowing of administra- comparatively little is known about Type III hereditary angioedema (with tion to allow for readministration. normal C1 esterase inhibitor levels and function). We present a case of RESULTS: Patient is a 44-y S diagnosed with HAE Type II. Sister has this Type III hereditary angioedema successfully treated with ecallantide, a diagnosis and mother has h/o recurrent angioedema. Abdominal, throat, plasma kallikrein inhibitor. tongue, face, extremity swellings occurred 2-3 times a week. C1inh METHODS: Our patient was referred for evaluation and treatment of infusions and prn ecallantide have given marked benefit. Her exam was recurrent idiopathic angioedema symptoms. unremarkable. C4 levels have been unremarkable. C1 esterase functional RESULTS: A 72 year old woman with a family history of angioedema level (National Jewish) was 26% (74-174%). Repeated C1inh administra- presented with a two year history of recurrent angioedema of lips, tongue, tion resulted in episodes of increasingly severity: pruritus, chest tightness, and throat. Symptoms started after discontinuing tamoxifen, an estrogen dyspnea, and palpitations. Finally, with slowing the infusion to 4 hours receptor antagonist, which was used for a period of 10 years. She had been (diluting with saline), premedication with loratadine 20mg, montelukast treated with multiple antihistamines, steroids, and epinephrine with no 40mg, ranitidine 300mg, pt was able to tolerate the 3 times/week treatments, significant benefit. The patient had normal C1 inhibitor protein level (24 though noted fatigue. Unfortunately, over 2 1/2 years of this, she developed mg/dL), normal C1 inhibitor function (100%), normal C1Q level (5.3 mg/ recurrent lower abdominal and lower extremity bruising, arthralgias, and dL), and low-normal C4 level (16 mg/dL, range: 16-47). Based upon the facial erythema. ESR/CRP, autoimmune serologies, and etc. labs remained positive family history, female gender, and association with estrogen, a unremarkable. The skin and joint sxs resolved with stopping C1inh. clinical diagnosis of type III hereditary angioedema was made. As previous CONCLUSIONS: With slowing the C1inh administration to 4 hours, therapies had no clinical effect, the patient was started on ecallantide 30 mg premedication with montelukast 40mg, ranitidine 300mg, loratadine subcutaneously during acute attacks. Within one hour of therapy, the 20mg, along with slowing administration of C1inh to 4 hours, patient angioedema resolves completely. The frequency of episodes has decreased was able to tolerate 3 times/week infusions, but later arthralgias and from monthly to once every 6 months. The patient has had no side effects bruising necessitated discontinuation. We believe this may be the first case with ecallantide. report of successful continued C1inh readministration despite allergy. CONCLUSIONS: This case demonstrates a successful treatment of Type III Hereditary Angioedema with ecallantide. Future studies would be Evaluation Of DX-88 (Ecallantide) For Treatment Of useful in assessing the efficacy of ecallantide in other angioedema 136 Angiotensin Enzyme Inhibitor Induced Angioedema In The syndromes. Emergency Department Dr. Joseph Moellman, MD1, Dr. Jonathan A. Bernstein, MD, FAAAAI2, Ms. Kimberly Hart1, Dr. Sean Collins3, Dr. Christopher Lindsell1;
ABS 5.2.0 DTD YMAI10628_proof 11 January 2014 7:12 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB39 VOLUME 133, NUMBER 2
BCX4161, An Oral Kallikrein Inhibitor: Safety and Structural and Molecular Changes Caused By Mutations 138 Pharmacokinetic Results Of a Phase 1 Study In Healthy 141 Thr328Lys and Thr328Arg In FXII Associated With Hereditary Volunteers Angioedema With Normal C1 Inhibitor Dr. Phil Collis1, Dr. Melanie Cornpropst1, Dr. Jo Collier2, Dr. William Dr. Adriana S. Moreno, PhD1, Dr. Helen Arcuri, PhD2, Prof. Mario Sheridan1; 1BioCryst Pharmaceuticals, Durham, NC, 2Quotient Clinical, Palma, PhD3, Dr. Luisa Karla P. Arruda, MD, PhD, FAAAAI4; 1Ribeirao Nottingham, United Kingdom. Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil, RATIONALE: Plasma kallikrein is a proven target in the treatment of 2Institute of Investigation in Immunology iii, School of Medicine of the hereditary angioedema (HAE). We conducted a Phase 1 study to evaluate University of Sao Paulo, S~ao Paulo, Brazil, 3Biosciences Institute, State the safety and pharmacokinetics of BCX4161, a potent and selective University of S~ao Paulo, Rio Claro, Brazil, 4School of Medicine of Ri- inhibitor of plasma kallikrein. beirao Preto, Ribeirao Preto, Brazil. METHODS: Healthy males and females aged 18-50 years received (Part RATIONALE: Functional implications of mutations in F12gene in pa- 1) single oral doses (50, 125, 250, 500 or 1000mg) or (Part 2) 7 day dosing tients with HAE with normal C1 Inhibitor(C1-INH) remain controversial. (100, 200, 400 or 800 mg q8hrs) of BCX4161 or placebo. Safety was Our aim was to advance knowledge on the role of these mutations using evaluated through assessment of adverse events, laboratory analyses, vital molecular modeling tools. SATURDAY signs, ECGs and physical examinations. Serial BCX4161 plasma and urine METHODS: Three-dimensional structure models of Factor XII(FXII) and concentrations were measured and standard PK parameters were active FXII (FXIIa), with or without mutations, were constructed using calculated. MODELLER9v11. Interactions of Factor XIIa with C1-INH were RESULTS: 87 subjects, median age 31 years, median weight 75 Kg, 21% evaluated using PatchDock v1.3 for protein-protein docking. Molecular female, completed the study. There were no serious adverse events, and no dynamics simulations were carried out with GROMACS 4.5.5 software dose limiting adverse events or laboratory abnormalities. Ten of 12 package. subjects in the 800 mg q8hr cohort, including both placebo subjects, RESULTS: Mutations of Thr328 to positively charged and hydrophilic reported mild GI disturbance (loose stools, diarrhea, or flatulence) that residues Lys or Arg on FXII molecule cause disruption of a putative O- resolved after cessation of dosing. Drug exposure was dose proportional linked glycosylation site, and altered structural folding of the protein and through 400 mg q8hrs. In the 400 mg q8hr cohort on Day 7, the pre-dose conformation of the active site at residues His412, Asp461 and Ser563. geometric mean (CV%) BCX4161 concentration was 28.6 ng/mL (77%), Surface area around the active site increased from 3022 A2 to 3585 A2 and 2 post-dose Cmax 152 ng/mL (57%), and half-life 13 (33%) hours. BCX4161 3470A in the wild type as compared to the mutated Thr328Lys and AUC0-8 was 27% greater on Day 7 relative to Day 1. Thr328Arg proteins, respectively. Analysis of the free energy of dissocia- CONCLUSIONS: BCX4161 was generally safe and well tolerated. tion indicates that the complex FXIIa:C1-INH in the mutated proteins is Plasma concentrations met or exceeded the target range (25-40 ng/mL) more stable, with DGdiss of -0.2kcal/mol in the wild type form, and predicted for efficacy as a prophylactic intervention in HAE patients. A 3.3kcal/mol and 6.4kcal/mol in the Thr328Lys and Thr328Arg mutated phase 2a study of 400 mg TID oral BCX4161 is planned. proteins, respectively. CONCLUSIONS: C1INH is the major inhibitor of FXIIa, preventing Treatment Of Hereditary Angioedema At The Time Of activation of kinin pathways. We hypothesize that increased affinity of C1- 139 Prodromal Symptoms: International Survey Of Physicians INH to mutated FXIIa at the active site may favor binding of C1-INH to 1 2 1 Dr. Neelu Kalra, MD , Dr. Timothy J. Craig, DO, FAAAAI ; Penn State these forms of the molecule, rendering more of the activated wild type 2 Hershey Medical Center, Hershey, PA, Penn State University College of molecule free to trigger activation of kinin pathways, which in turn will Medicine, Hershey, PA. lead to increase in bradykinin production and angioedema. RATIONALE: Hereditary angioedema (HAE) is a rare life threatening disease characterized by painful and debilitating attacks of angioedema. In majority of patients HAE attacks are preceded by prodromal symptoms such as fatigue, rash and gastrointestinal symptoms. Treatment at the time of prodrome may prevent an attack and reduce morbidity and mortality associated with HAE. Physicians are hesitant to utilize this approach. The goal of this study is to understand barriers to this approach. METHODS: An internet based international survey was conducted of physicians with expertise in HAE. Information was collected regarding their experience with prodromal symptoms. A literature search (PubMed, Google) with term: HAE prodromal signs and symptoms was performed. RESULTS: A total of 65 physicians were contacted of which 43 participated. In our survey majority (>70%) of physicians follow more than 15 HAE patients, consider prodromal symptoms to be sensitive in predicting HAE attacks and agree that treating prodromes will lead to rapid response, reduced disability and better quality of life. However, very few (<12%) physicians use this approach due to lack of data about specificity of prodromal symptoms and difficulty identifying patients who would benefit from this approach. Literature suggests that prodromal symptoms are sensitive predictors of an impending attack, but specifity data are lacking. CONCLUSIONS: Treating HAE at the time of prodrome in patients who are able to predict HAE attacks may lead to reduced morbidity and mortality and improve quality of life. Major barrier to using this approach is lack of data on specificity. 140 Withdrawn
ABS 5.2.0 DTD YMAI10628_proof 11 January 2014 7:12 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB40 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Ludwig's Angina Masquerading As Angioedema Incidence and Treatment Of Angioedema In a Third Level 142 Dr. Lynn A. Wiens, MD, FAAAAI; Warren Clinic, Tulsa, OK. 144 Spanish Hospital RATIONALE: Angioedema (AE) can be a medical emergency. Acquired Marta Seoane, MD, Maria Elisa Caralli, MD, Sarah Micozzi, MD, Marta AE is a side effect of ACE inhibitors, but other conditions mimic the facial Elena Rodriguez-Mazariego, MD, Mar ıa L. Baeza, MD, PhD; Hospital swelling and upper airway obstruction found in AE. We present an adult General Universitario Gregorio Maran~on, Allergy Department, Madrid, with facial swelling, airway compromise, and initial diagnosis of AE Spain. secondary to ACE inhibitors, who was subsequently found to have RATIONALE: Corticosteroids and antihistamines are conventional drugs Ludwig’s angina (LA). LA is a cellulitis with the potential to obstruct for angioedema without urticaria (AE), but this treatment is inefficient in the airways, often requiring tracheotomy. some of them. The aim of the study was to determine the incidence and METHODS: Patient’s lisinopril was discontinued, ecallantide adminis- characteristics of patients with AE at the Emergency room (ER) of a third tered, triple antibiotics were initiated, and tracheostomy was eventually level Spanish Hospital and compare them to patients with AE-associated required. Surgical incision and drainage led to defervescence of his fever. urticaria (U-AE). Those with a poor or non-response to these treatments RESULTS: This patient was hospitalized for facial swelling unresponsive were quantified. to antihistamines, prednisone, and epinephrine. Respiratory compromise METHODS: Observational study from January-June 2013. Patients older required mechanical ventilation. Patient became febrile despite antibiotics than 14 years old, with AE, U-AE or Urticaria (UR) were included. and did not respond to 30mg of ecallantide. Surgical incision revealed RESULTS: At the ER, 74.411 patients were attended. Angioedema purulent material positive for methicillin-resistant Staphylococcus. without urticaria was found in 0.17%, U-AE in 0.15% (24.66 % of Laboratory evaluation revealed normal complement, C1q, C1 esterase, urticarial patients) and UR in 0.43%. Mean age and gender were similar in and serum tryptase. His fever and facial swelling promptly resolved after I all groups (AE: 37.0620.1 (SD) years, median: 44, U-AE: 42.21618.32, & D and he was discharged after removal of his tracheostomy. median: 40, UR 44.31619.80, median: 41, p50.336. Females 58.99%, CONCLUSIONS: We believe this is the first reported case of Ludwig’s 54.95% and 58.70% respectively (p50.69). The facial location was present angina presenting as facial edema and airway compromise similar to AE. in 98.45% of AE (14% tongue), pharyngolaryngeal edema appeared in Our patient suffered from poor dentition, likely accounting for his 44.96% and 28.68% had peripheral involvement. All U-AE patients cellulitis. The danger in LA is swelling that spreads internally, often responded satisfactorily to conventional drugs in the first few hours. compromising the upper airway. In this case, expedient consultation with However 6% of AE patients were non-responders. One of them received ENT resulted in a favorable surgical treatment. Clinicians should be icatibant, with a rapid response. diligent to evaluate other causes of AE even if the medical history suggests CONCLUSIONS: The incidence of AE is low but similar to the AE- ACE inhibitor-induced AE. associated Urticaria. It’s major location is facial, half of it associated to upper respiratory symptoms which endure additional risk. All patients with A Simple, Sensitive and Selective Fluorogenic Assay To U-AE responded to antihistamines and corticoids, while the 6% of isolated 143 Monitor Plasma Kallikrein Inhibitory Activity Of BCX4161 In angioedema were resistant. These are presumably kinins-mediated AE, Activated Plasma that need alternative drugs for treatment. Dr. Y. S. Babu1, Ms. Ramanda Wilson1, Dr. Jianwen Zhang1, Dr. Melanie Cornpropst2, Dr. Phil Collis2, Dr. William Sheridan2; 1BioCryst Pharma- Seasonal Increase In Angioedema In An Inner City Hospital ceuticals, Inc, Birmingham, AL, 2BioCryst Pharmaceuticals, Durham, 145 Center NC. Helen Zhou, BS, Dr. Ashlei Mathew, MD, Dr. Rauno Joks, MD; Center RATIONALE: Plasma kallikrein is a proven target in the treatment of for Allergy and Asthma Research, State University of New York Down- hereditary angioedema. BCX4161 is an orally bioavailable potent inhibitor state Medical Center, Brooklyn, NY. of plasma kallikrein. We developed a sensitive and selective assay to RATIONALE: We previously determined there is a significant seasonal determine kallikrein activity in activated plasma from normal and HAE increase in the presentation of angioedema during late spring and summer subjects. in our predominantly African American patient cohort. However, the cause METHODS: Normal human plasma, prekallikrein (PKK)-depleted for this seasonality has yet to be found. plasma, or PKK-depleted plasma reconstituted with human PKK or plasma METHODS: An IRB approved retrospective EMR chart review was from HAE patients was pre-incubated with varying doses of ellagic acid conducted of pediatric and adult patients treated in the emergency activator (EAA). Enzymatic activity was followed by measuring the department or as an inpatient at Kings County Hospital Center for fluorescence produced following cleavage of an exogenous kallikrein- angioedema, from January 2007 through July 2012. An in-depth chart specific substrate. The assay monitored kallikrein activity in plasma review for the probable cause of each episode of angioedema was collected from subjects dosed with BCX4161 in a phase I trial. performed. Chi square test was performed to determine if there was a RESULTS: N-carbobenzyloxy-phenylalanine-arginine-7-amino-4-meth- significant increase in angioedema attributed to medication or food in the ylcoumarin was identified as a sensitive and selective kallikrein substrate. summer months of June, July, and August, or the winter month of January. EAA-induced amidolytic activity (kallikrein activity) in normal human RESULTS: During these months, 108 patients (79 women, 36 men, mean plasma, was completely abolished in PKK-depleted plasma and restored in age 55620 yrs) were diagnosed with angioedema. Of these cases 76 were PKK—depleted plasma reconstituted with a physiologic concentration of attributed to medications, 14 were attributed to foods, and the remaining 18
PKK (25 mg/mL). Using this fluorogenic assay, the mean EC50 value of cases had unknown causes. There was no difference in the frequency of BCX4161 spiked into normal human plasma samples was 5.8nM. The presentation with angioedema attributed to medication (p50.14) or food
mean EC50 values for BCX4161 and C1INH spiked into HAE patient (p50.54) among the months surveyed. Interestingly, 16/18 or 89% of plasma samples were 13.7 and 213nM, respectively. After oral administra- episodes with unknown triggers occurred during the summer months. tion of BCX4161 to healthy subjects in a Phase 1 trial reported separately, CONCLUSIONS: Increase in summer angioedema without obvious there was a dose-dependent increase in plasma kallikrein inhibition, which trigger suggests a possible seasonal increase in non-food triggered correlated with the pharmacokinetic profile of BCX4161. histamine-mediated angioedema during this period. CONCLUSIONS: A sensitive and selective fluorogenic assay can monitor ex-vivo kallikrein activity in human plasma. This assay was used as a pharmacodynamic biomarker of drug effect to aid in dose selection for clinical trials.
ABS 5.2.0 DTD YMAI10628_proof 11 January 2014 7:12 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB41 VOLUME 133, NUMBER 2
Seeming Tongue Swelling Responding To Nebulized Aerochambers and Asthmatics: Do No Harm? 146 Ipratropium In An Individual With A Diagnosis Of Type III 148 Dr. Jack Leon-Max Mutnick, MD; Stevens Community Med- HAE (Hereditary Angioedema) ical Center, Morris, MN. Ms. Jennifer Vegh1, Dr. Arthur B. Vegh, MD, FAAAAI2, Ms. Nicholette RATIONALE: Spacers added to metered-dose inhalers improve delivery of Butler1; 1none, Tacoma, WA, 2University of Washington, Tacoma, WA. medication to lung tissue, but are spacers a harbinger for infection, especially RATIONALE: When a patient presentation doesn’t conform, reassess- in asthmatic patients already combatting inflammation in the lung? ment of mechanisms and dx need be done. We present a case of type III METHODS: In a single blind randomized pilot study patients diagnosed hereditary angioedema who self-induced what appeared to be tongue with asthma, according to current guidelines, were recruited to determine if swelling. the Advantage OptichamberÒ is a harbinger of microbial or fungal METHODS: Critical direct evaluation of an acute attack. organisms. Patients are started on a metered-dose inhaler (Mometasone/ RESULTS: 31 yS referred for HAE. She presented 3 1/2years ago with a 9 Formoterol) with the Advantage OptichamberÒ and are having the ‘‘spacer’’ yr h/o repeated episodes of swellings of the abdomen, tongue, and throat. cultured at three sites for bacterial/fungal organisms. Sensitivity of the This included ‘‘dozens’’ of intubations, a 3 month hospitalization and organisms to antibiotics or antifungal medications is also being evaluated. tracheostomy at a midwest university, a dx of HAE at Mayo Clinic despite Culture and sensitivity results are being accumulated at months 1, 4, and 10. SATURDAY unremarkable complement studies. Three months before seeing us, JM RESULTS: Early results show that after 1 month of therapy, cultures of the suffered repeated ED visits and 5 hospitalizations for swellings. Treatments: Advantage OptichamberÒ show organisms including Methicillin-resistant multiple different pain medications, IV corticosteroids, antihistamines with Staphylococcus epidermidis, Micrococcus luteus, Streptococcus para- inadequate benefit. Pt claimed, however, immediate IV diphenhydramine sanguinis, and gram positive rods. Staphylococcus epidermidis benefit. Fresh frozen plasma gave seemingly mild benefit in 3 hours. (Methicillin-resistant or –sensitive) shows almost a complete class- Examination: VS nl. Pulm: minimal course breath sounds. Her abdomen was resistance to the fluoroquinolones. Fungal results show rare alternaria spe- moderately distended and tender to mild palpation. Complement studies cies isolated. unremarkable. PFTs: NS improvement with BD but symptomatic benefit. CONCLUSIONS: As we develop improved therapies to treat and control Initial treatments: amitriptyline, albuterolHFA prn, tapering chronic nar- asthma, we must look beyond the ‘‘mouthpiece’’and consider the risks that cotics. C1 esterase inhibitor infusions and prn ecallantide with partial aerochambers present to our patients. Asthma exacerbations are serious benefit. Witnessing a tongue swelling, with the above h/o immediate diphen and not without complications, and one must question if aerochamber response (anticholinergic effect), neb. ipratropium was administered with devices should be impregnated with antibacterial/antifungal chemicals or rapid resolution of tongue and throat swelling. With inhaled cs, tiotropium, if these devices should also have a ‘‘shelf-life’’ considering the hazards her throat and tongue swellings have almost resolved. posed to patients, especially the concern for pulmonary infections due to CONCLUSIONS: We present a case of an individual with a dx of HAE these devices. with recurrent atypical bronchospasm giving a sensation of throat swelling and causing the patient to induce what appears to be tongue angioedema. Characterizing The Severe Asthma Population In The United 149 States: Claims-Based Analysis Of Three Treatment Cohorts In Cytokine Expression In a Case Of Cutaneous Mastocytosis The Year Prior To Treatment Escalation 147 With An Unusual Presentation Dr. Patrick W. Sullivan, PhD1, Dr. Jon Campbell, PhD2, Dr. Vahram Prof. Young Min Ahn, MD1, Prof. sang-Hoon Kim, Prof. Ho-jung Lee2, Ghushchyan, PhD2, Dr. Gary Globe, PhD3, Dr. Jeff Lange, PhD3,Dr.J Prof. Jai Youl Ro, PhD3; 1Department of Pediatrics, South Korea, Depart- Michael Woolley, PhD3; 1Regis University, 2University of Colorado Den- ment of Internal Medicine, South Korea, 2Department of Pathology, Eulji ver, 3Amgen, Inc., Thousand Oaks, CA. University School of Medicine, South Korea, 3Sungkyunkwan University RATIONALE: To describe demographics, employment, insurance, School of Medicine, South Korea. medication adherence and healthcare utilization of patients with severe RATIONALE: We experienced the case of a 10-year-old girl who asthma. presented with angioedma and facial nerve palsy possibly associated METHODS: This was an asthma cohort study (age 12-75 years) requiring with the cutaneous mastocytosis. Her recurrent angioedema has presented three initial claims within three months for omalizumab, high-intensity since 4 year of age which was exacerbated by spicy foods or certain drugs. corticosteroids (HICS; >_1000 mg/day fluticasone equivalent or oral Therefore this study aims to investigate the relationship between cutaneous prednisone), or high-dose inhaled corticosteroid (HDICS; >_500 to <1000 mastocytosis and patient serum cytokine expression during the episode of mg/day fluticasone equivalent) from 2002-2011.Adherence was assessed angioedema. using the annualized Medication Possession Ratio (MPR: % of year taking METHODS: Serum tryptase was checked. Skin biopsy was taken from the medication). scalp and trunk lesions for histological examination. The immunofluores- RESULTS: Of 70,343 patients, 1,046 initiated omalizumab, 24,319 cence stain with CD 117 and genetic examination of KIT mutation was initiated HICS, and 44,978 initiated HDICS. More severe cohorts done on the infiltrating cells in the dermis. Individual cytokines were (omalizumab, HICS, and HDICS, respectively) had higher pre-index determined by human ELISA kit. mean values for medical expenditures ($14,071; $12,030 and $7570), RESULTS: Serum tryptase levels were elevated at 4, 9, and 10 years old utilization (27 outpatient and 10 specialty care visits; 19 outpatient and 2 respectively (51.5, 72.9, and 30 ng/mL). Mast cells densely infiltrated entire specialty; 15 outpatient and 2 specialty), asthma-related prescription drugs dermis , extending into subcutaneous fat. C-KIT mutation at codon 816 was (11.74; 7.8; 5.17) and chronic comorbidities (2.68; 2.67 and 2.19). In the negative. MRI showed possible involvement of facial nerve course in both year prior to omalizumab treatment: 72% of patients were taking HICS side in temporal bone and no evidence of neurogenic tumor along 7th and (MPR 30%), 64% oral corticosteroids (MPR 13%), 33% HDICS (MPR 8thcranial nerve. Expression of inflammatory cytokines, such as TNF-a, 40%), 63% leukotrienes (MPR 54%) and 69% short-acting beta agonists TGF-b, IL-4, IL-5, IL-6, IL-13, was remarkably increased in patient’s serum (29%); these patients were more likely to be salaried, full-time employees versus those in normal serum and anti-inflammatory cytokine IL-10 was with commercial PPO/POS insurance. remarkably decreased in patient’s serum versus that in normal serum. CONCLUSIONS: Categorizing severe asthma patients by treatment CONCLUSIONS: Magnetic resonance image suggests that transient cohorts provides more granular focus augmenting GINA categorization. facial palsy is possibly caused by soft tissue swelling on parotid gland area Increased severity was associated with higher baseline healthcare expen- associated with mastocytosis. And that cutaneous mastocytosis may be ditures and utilization. Prior to omalizumab treatment, most patients were induced through down-regulating the expression of anti-inflammatory taking high doses of corticosteroids. The high utilization and polyphar- cytokine IL-10 and up-regulating the expression of various inflammatory macy burden may reflect failures in standard of care and its treatment cytokines. options prior to titrating to the next step of therapy.
ABS 5.2.0 DTD YMAI10628_proof 11 January 2014 7:12 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB42 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Impact Of Asthma On Child and Family Activities Among a Rhinitis and Asthma Exacerbation Revealing Large Pulmonary 150 Rural Cohort 152 Effusion and Pelvic Mass Dr. Allison J. Burbank1,2, Mallikarjuna Rettiganti, PhD1,2, Paige Dr. Jennifer Olivier, MD1, Dr. Laurianne G. Wild, MD, FAAAAI2; 1Tu- Fisher, BA3, Tamara T. Perry, MD1,2; 1University of Arkansas for Medical lane University School of Medicine, New Orleans, LA, 2Tulane Univer- Sciences, Little Rock, AR, 2Arkansas Children’s Hospital, Little Rock, sity, New Orleans, LA. AR, 3Drexel University School of Public Health, Philadelphia, PA. RATIONALE: Common complaints seen by the allergist may not always RATIONALE: We examined impact of pediatric asthma on child and be what they appear. It is important for the clinician to perform a thorough family activities in a rural, medically underserved US region. evaluation for proper treatment and avoid bad outcomes. We present a METHODS: Utilizing a standardized interview format, we obtained patient with a history of well-controlled rhinitis and asthma who sought demographic characteristics, asthma symptoms, healthcare utilization, and care status post a six-month duration of progressive, worsening symptoms. impact of disease among children residing in 12 rural Arkansas counties. Evaluation revealed a large, right pulmonary effusion and pelvic mass. RESULTS: Of the 290 participants, median age was 9 years, 52.9% male, METHODS: Chest radiograph, chest CT, and pelvic ultrasound. 82% African-American, 81% with state-funded insurance, and 44.7% with RESULTS: 33-year-old female presents to the allergy clinic for presumed annual household income <_$14,999. Asthma severity classification was asthma and rhinitis exacerbation. Six months prior, her symptoms were 13.4% intermittent, 23.1% mild-persistent, 29.7% moderate-persistent and well controlled. Her respiratory status declined such that she had difficulty 33.8% severe-persistent. Asthma control classification was 22.7% well- walking down the hall without getting short of breath. Albuterol four times controlled, 77.3% not well-controlled or very poorly-controlled. daily provided minimal relief. Nighttime symptoms were so severe that she Caregivers reported a mean 3.9 (5.2) acute visits and 1.7 (3.3) systemic would wake from ‘‘wheezing so loud.’’ Rhinitis symptoms of postnasal steroid bursts in the past 12 months. Controller medications were drip, rhinorrhea, and congestion contributed to her worsening respiratory prescribed for 61.3% of participants, but only 51.1% of caregivers reported symptoms. Decreased breath sounds over the anterior and posterior right giving controller medications as prescribed. 44.7% of children had lung fields were noted on physical exam. Diagnostic imaging revealed a reported limitations with moderate physical activities, 35.3% of caregivers large, right pleural effusion and large mass anterior to the uterus. reported that their child was frustrated about having asthma, and 51.5% Laboratory immunoglobulin, complete blood count, and complete meta- reported feeling frustrated about having to limit activities. 46.2% of bolic panel values were unremarkable. Patient was ultimately diagnosed caregivers reported losing sleep and 12% reported missing work or school with Meig’s Syndrome. in the past 2 weeks due to their child’s asthma. CONCLUSIONS: This case exemplifies the importance of a complete CONCLUSIONS: The majority of participants in this rural, African- evaluation of patients with common symptoms that may present to the American cohort had moderate-severe, uncontrolled asthma. Activity allergist/immunologist. limitations, lost caregiver sleep, and missed work/school were prevalent. Caregivers reported frustration due to underlying disease and activity Deprivation Is Longitudinally Associated With Incident limitations. These findings are likely compounded by inadequate controller 153 Childhood Asthma 1,2 2,3 medication prescribing and/or filling patterns in this medically under- Dr. Elinor Simons, MD, MS, FAAAAI , Dr. Sharon Dell, MD , 4,5 1,5 1 served region. Interventions specifically tailored for rural, underserved Dr. Rahim Moineddin, PhD , Dr. Teresa To, PhD ; Child Health Eval- 2 children are needed to translate guidelines-based asthma management. uative Sciences, Hospital for Sick Children, Toronto, ON, Canada, Clin- ical Epidemiology, Department of Health Policy, Management and Inhaled Asthma Medications: Highlighting The Differences In Evaluation, University of Toronto, Toronto, ON, Canada, 3Respiratory 151 Formulations and Use Medicine and Child Health Evaluative Sciences, Hospital for Sick Chil- Dr. Lachara Lvingston Livingston1, Dr. Gregory Michael Cowan, MD2, dren, Toronto, ON, Canada, 4Department of Family and Community Med- Dr. Richard F. Lockey, MD3; 1University of South Florida Morsoni Col- icine, University of Toronto, Toronto, ON, Canada, 5Institute for Clinical lege of Medicine, 2University of South Florida Morsani College of Med- Evaluative Sciences, Toronto, ON, Canada. icine, 3Division of Allergy and Immunology, Department of Internal RATIONALE: Although longitudinal studies have shown associations Medicine, University of South Florida Morsani College of Medicine between parental incomeand childhood asthma development, deprivation has and James A. Haley Veterans’ Affairs Hospital, Tampa, FL. been proposed as a more comprehensive measure of childhood socioeco- RATIONALE: There are 7 reliever and 12 controller inhalational nomic status and its associations with childhood asthma must be determined. medications available for use in the United States. Up to 94% of patients METHODS: Prospectively-collected administrative data from the with asthma use 1 or more of them incorrectly (Rootmensen, et al 2010). Institute for Clinical Evaluative Sciences (ICES) were evaluated for the METHODS: The manufacturer instructions and descriptions of reliever 1997-2003 birth cohorts of Toronto children. Neighbourhood material and controller inhaled medications were reviewed. Differences in prepa- deprivation was reported according to the Ontario Marginalization Index ration, administration and formulation were noted. criteria, including no high school graduation, lone parent families, RESULTS: Each of these medications has special instructions, unique government transfers, unemployment, low income, and homes needing packaging, methods for delivery, formulations, and techniques for use. Of major repairs. Incident asthma was defined by the time of entry into the the 7 reliever medications, 6 require priming and 5 agitation prior to use. Of Ontario Asthma Surveillance Information System (OASIS) database, the 12 controller medications, 7 need priming and 5 require agitation prior requiring 2 outpatient visits for asthma within 2 consecutive years or any to use. The need for repriming because of lack of use varies between 24 hospitalization for asthma. We calculated the risk of incident asthma for the hours and two weeks. Additional specific descriptions are provided two highest versus two lowest quintiles of neighbourhood deprivation regarding dry powder (6 controller medications), suspension (6 reliever using Cox proportional and discrete-time hazard models. and 3 controller medications) or solution formulations (1 reliever and 3 RESULTS: The OASIS criteria for asthma were met for 21% of the 326 383 controller medications), how they should be stored (all should be stored at children. After adjusting for sex, preterm delivery, obesity, and atopic room temperature), and special considerations noted by the manufacturer. conditions, children with high birth neighbourhood deprivation were at CONCLUSIONS: Allocations for patients, physicians, and other health- increased risk of asthma development [hazard ratio (HR) 1.11; 95% confi- care professionals about the various relievers and controllers used to treat dence interval (CI), 1.09-1.13] and asthma healthcare visits in the past year asthma is essential to appropriately treat and prevent exacerbations of (HR 1.09; 95% CI, 1.05-1.14), compared to children with low neighbourhood asthma. The information provided will increase the effective use and deprivation. Deprivation in each year of the child’s life was associated with improve patient asthma outcomes. increased odds of incident asthma (odds ratio 1.06; 95% CI, 1.04-1.08). CONCLUSIONS: Children living in neighbourhoods with high material deprivation are at increased risk of incident asthma and current asthma.
ABS 5.2.0 DTD YMAI10628_proof 11 January 2014 7:12 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB43 VOLUME 133, NUMBER 2
Use Of Asthma Control Indicators In Measuring Efficacy Of An Assessment Of Infection Rates and Health Resource Use 154 Inhaled Corticosteroids In Asthmatic Smokers: A Systematic 156 Among Primary Immunodeficiency Disorder (PIDD) Patients Review Prior To Diagnosis Ms. Claire E. Hayes, MPH, CHES, AE-C, Mr. Henry Nuss, PhD; Loui- Dr. Chris Rabbat, PhD, Ms. Diane Ito, MA, Ms. Yan Xiong, MS, siana State University Health Sciences Center School of Public Health, Dr. Josephine Li-McLeod, PhD; Baxter Healthcare Corporation, Westlake New Orleans, LA. Village, CA. RATIONALE: Across studies investigators have reached competing RATIONALE: It is hypothesized that undiagnosed PIDD may burden conclusions regarding the effectiveness of inhaled corticosteroids (ICS) both the patient with repeated infections and the healthcare system with on improving asthma control in smokers. We completed a systematic significant service utilization. This analysis assessed infection rates and review of literature on the use of asthma control indicators to 1. Determine healthcare utilization among patients in the years leading up to a PIDD how current research measures efficacy of ICS in asthmatic smokers as diagnosis. well as to 2. Determine if current research supports claims that asthmatic METHODS: This retrospective analysis utilized the Truven Marketscan smokers are resistant to the effects of ICS. Database, 2002-2012. Patients who had at least 1 inpatient or ER diagnosis
METHODS: On-line databases PubMed, CINAHL, and PsycINFO were or at least 2 outpatient diagnoses of PIDD (279.xx) and at least one of the SATURDAY searched using terms relating to asthma, tobacco use, and corticosteroid following PIDD diagnoses: 279.04, 279.01, 279.05, or 279.06 and 5 years effectiveness. Eligibility criteria included: Articles published between of continuous health plan enrollment were identified. The first PIDD 2005 and 2013, English language, human subjects, adults (19 and older), diagnosis (279.xx) was identified as the index date and data preceding the and studies using at least one indicator of control as a measure of ICS index date were examined. Incidence rates of pneumonia, sinusitis, effectiveness. The prevalence of asthma control indicators as well as bronchitis, otitis, as well as hospitalizations, outpatient visits and outcomes of individual studies were compiled and analyzed to determine outpatient drug utilization were analyzed. efficacy of ICS in patients. RESULTS: 1388 patients were undiagnosed with PIDD for at least 5 RESULTS: Twelve studies met search criteria. Seven of these used only 1 years, of these, 84 were undiagnosed for at least 10 years, suggesting that indicator to measure asthma control in smokers. Additionally, ICS was found many patients are undiagnosed for years. The average percent increase in to be effective for smokers in only 4 of these studies. ICS was found to be rates of pneumonia, sinusitis, bronchitis and otitis per year over the 10 effective in all studies which used at least 5 indicators to measure control. years prior to diagnosis were 39%, 20.4%, 20.2%, 14.2%, respectively. CONCLUSIONS: Inhaled corticosteroids are shown to improve asthma in Hospitalizations, outpatient visits and outpatient drug utilization increased smokers when multiple control indicators are used to measure effectiveness. on average 29.1%, 10.5% and 5.3% per year, respectively during the same Future studies should 1. Evaluate the effectiveness of ICS using multiple time frame. This considerable increase in infections and hospitalizations indicators of control, as well as 2. Monitor patient adherence to ICS in suggests the condition may be increasing in severity over time prior to studies when determining appropriate asthma therapies for smokers. diagnosis. CONCLUSIONS: The results suggest a more timely diagnosis of PIDD Evaluation Of a Medication Adherence Estimator Survey may substantially ease the burden for both patients and the healthcare 155 Compared To Exhaled Nitric Oxide (FeNO) Levels and system. Asthma Control Test In Difficult-To-Treat/Severe Pediatric Asthma Patients A Comparison Of Costs Between Outpatient Hospital, Clinic Jigar Patel1, Vanessa Y. Cavero, MD2, Amy Perkins, MS2, Heather 157 and Home Settings For Intravenous Immunoglobulin (IVIG) Minto, MD2, Maripaz B. Morales, MD2; 1Department of Pediatrics, Infusions Eastern Virginia Medical School, Norfolk, VA, 2Children’s Hospital of Dr. Xiaolan Ye, PhD, Ms. Diane Ito, MA, Ms. Yan Xiong, MS, The King’s Daughters, Norfolk, VA. Dr. Josephine Li-McLeod, PhD; Baxter Healthcare Corporation, Westlake RATIONALE: Many difficult-to-treat/severe pediatric asthma patients Village, CA. are non-adherent to inhaled corticosteroid (ICS) therapy, resulting in RATIONALE: Home-based infusion of IVIG therapy may be beneficial in increased hospitalizations and emergency department visits as well as terms of reduced costs compared to the outpatient hospital (OH) or clinic reduced lung function. There is a need to develop a practical clinical tool to setting. This analysis assessed cost differences between infusions con- assess adherence. ducted at home versus OH or clinic using data from a large, commercial METHODS: CHKD Allergy/Immunology Clinic recruited 45 partici- medical claims database. pants for a prospective observational study. Inclusion criteria: 7-18 years METHODS: Patients who had at least 3 months of continuous IVIG old, diagnosed asthma, prescribed high dose ICS (>_1000 mcg/day). claims were identified using J codes from the Truven Marketscan Participants and parents completed Asthma Control Test (ACT) and Database, years 2002 -2012. Those who switched their infusion site of Adherence Estimator (developed by Merck and validated in adult chronic care from the OH or the clinic to the home setting and had 3 or more IVIG disease population to assess medication non-adherence risk). FeNO was claims in each site of care were identified. Costs of care were compared measured. Charts were reviewed for demographics and medications. Data between the home and OH or clinic setting. Monthly costs were calculated were analyzed to obtain descriptive statistics and Spearman rank correla- for each site, and the ratio between monthly cost at home and monthly cost tion coefficients (rho). in the OH or clinic was calculated for each patient. Signed rank test was RESULTS: 53.3% (n524) of subjects had a high FeNO level (>_20ppb) used to determine statistical significance between sites. and 62.2% (n528) had poorly controlled asthma according to ACT; RESULTS: There were 83 and 79 patients who switched their IVIG however, only 8.9% (n54) were high risk for non-adherence. 55.6% infusion sites between clinic and home or OH and home, respectively. (n525) were also on Xolair step-up therapy. There was no significant linear Switching from OH to home infusions resulted in significantly lower relationship between FeNO and Adherence Score (rho5-0.01) or between median costs ($6,916 v $4,188). The median home-to-OH cost ratio was FeNO and ACT Score (rho5-0.12). These coefficients were neither 0.61 (p<0.0001), indicating the costs of care for the home-based infusions statistically significantly different from zero nor greater than -0.55 (all were significantly less than the OH setting. The differences in costs P>0.05). There was a very weak, negative association between Adherence between clinic and home were not significant. Score and ACT Score; rho5-0.32 was statistically significantly different CONCLUSIONS: In this study, switching patients on IVIG treatment from zero (P50.03) but was not significantly greater than -0.55 (P>0.05). from the OH to the home setting resulted in significant cost savings. CONCLUSIONS: Future studies should focus on constructing a medica- tion adherence questionnaire that can be validated in a larger pediatric asthma population.
ABS 5.2.0 DTD YMAI10628_proof 11 January 2014 7:12 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB44 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Differences In Infection Rates Between Outpatient Hospital, hospitalizations, ER visits and antibiotic prescriptions per person in the 158 Clinic and Home Infusion Settings For Patients With Primary past 6 months were 1.6, 2.4, and 4.4, respectively. Immunodeficiency Disorder (PIDD) CONCLUSIONS: Results suggest PIDD patients prior to treatment have Ms. Diane Ito, MA, Ms. Yan Xiong, MS, Dr. Xiaolan Ye, PhD, diminished HRQOL compared to the US general population and high rates Dr. Josephine Li-McLeod, PhD; Baxter Healthcare Corporation, Westlake of health service utilization, highlighting the significant HRQOL and HRU Village, CA. burden among these patients. RATIONALE: Home-based infusion of IVIG therapy compared to the outpatient hospital (OH) or clinic setting may be beneficial for PIDD Phadiatop - An Atopy Test With Optimal Allergen Composition patients due to the potentially reduced risk of exposure to infections. This 160 Relevant For Most Geographical Regions Kerstin M. Wall1, Monica Nor en1, Dr. Cathy Van Rooyen2; 1Thermo analysis compared infection rates among PIDD patients who infused in the 2 home, clinic or OH. Fisher Scientific, ImmunoDiagnostics, Uppsala, Sweden, Ampath Na- METHODS: Patients who had at least 1 inpatient or ER claim or at least 2 tional Reference Laboratory, Immunology, Pretoria, South Africa. outpatient claims with PIDD ICD-9 code 279.xx and had at least 6 months RATIONALE: Phadiatop is a single blood test with shown high efficiency of continuous IVIG claims from the same site of care (home, clinic or OH) to help clinicians identify or exclude atopy, an important step in any allergy were identified from the Truven Marketscan Database, years 2002 -2012. investigation. There may sometimes be concerns about false negative Incidence rates of pneumonia and bronchitis were calculated for each site Phadiatop results due to a potential lack of relevant local allergens. In this of care. Regression analyses were conducted to compare age and gender- study we investigated the performance of Phadiatop and evaluated the adjusted infection rates between sites. potential for clinical improvement by changing the allergen content to RESULTS: 2758 patients infused in the clinic, 2006 in the home, and 1919 reflect the main allergens in the population tested. in the OH setting. Pneumonia rates were 0.67, 0.55 and 1.04 and chronic METHODS: Sixty-eight Phadiatop positive and 78 Phadiatop negative bronchitis rates were 0.38, 0.24, and 0.59 for the clinic, home and OH blood samples from a private South African laboratory were analyzed with settings, respectively. After adjusting for age and gender, the rates of a new South African prototype, where the allergen composition was made pneumonia and bronchitis not otherwise specified (NOS) in the OH setting by local allergists and their expertise, as well as for IgE antibodies to all were found to be significantly higher than in the home (p50.008, single allergens included in the two tests. Positive samples could thus p50.0185, respectively). Rates of chronic bronchitis were found to be possibly be identified with the new prototype among the Phadiatop significantly higher in both clinic (p50.0144) and OH (p<0.0001) negatives and possibly a better performance among the positives, i.e. compared to home. Differences in rates of pneumonia and bronchitis revealing higher IgE antibody levels. The single allergen test results would NOS between home and clinic were not significant. help explain potential discrepancies. CONCLUSIONS: Home infusion is associated with significantly lower RESULTS: The new prototype did not test positive for any of the negative rates of pneumonia and bronchitis compared to the OH among PIDD Phadiatop samples, but negative for 3/68 (4.4%) of the positive Phadiatop patients. samples. In general higher IgE antibody levels were detected with Phadiatop compared with the prototype. Assessment Of The Quality Of Life and Health Resource CONCLUSIONS: In a selected South African population Phadiatop 159 Utilization Burden Among Patients With Primary tested positive for slightly more samples and no additional benefit was Immunodeficiency Disorder (PIDD) Prior To Treatment found by using a new South African mix with specifically selected local Dr. John M. Routes, MD, FAAAAI1, Dr. Beatriz Tavares Costa- allergens. A well designed atopy test containing allergens with broad Carvalho, MD2, Prof. Bodo Grimbacher, MD3, Dr. Kenneth Paris, MD, coverage can be efficient regardless of the local allergen profile. MPH4, Dr. Hans D. Ochs, MD5, Ms. Diane Ito, MA6, Ms. Yan Xiong, MS6, Dr. Josephine Li-McLeod, PhD6, Dr. Richard I. Schiff, Histamine Skin Reactivity Increased With Body Mass Index MD, PhD7; 1Medical College of Wisconsin, Milwaukee, WI, 2Federal 161 In Korean Children University of Sao Paulo, Brazil, 3Royal Free Hospital & University Col- Dr. Jeon Mi Lee, Dr. Ju Wan Kang, Dr. Hyung Ju Cho; Yonsei University lege, London, United Kingdom, 4LSU Health Sciences Center, New Or- College of Medicine. leans, New Orleans, LA, 5University of Washington, Seattle, WA, RATIONALE: Skin prick test is one of the major test to diagnose allergic 6Baxter Healthcare Corporation, Westlake Village, CA, 7Baxter BioSci- disease and histamine skin reactivity is used as a positive control for skin ence, Westlake Village, CA. prick test. However, the reactivity to histamine by itself is fairly different RATIONALE: PIDD patients often suffer from multiple infections and among individuals and the reason for the individual differences has not yet functional impairment prior to initiation of immunoglobulin (Ig) treatment, been clearly understood. Therefore we investigated various factors in which may negatively impact their health related quality of life (HRQOL) pediatric patients who had underwent skin prick test and found that body and result in high health resource utilization (HRU). This analysis focused mass index (BMI) is significantly associated with histamine skin reactivity. ; on assessing the potential HRQOL and HRU burden among PIDD patients METHODS: 411 children aged 7 8 years old (224 boys and 187 girls) before Ig therapy. were enrolled in this analysis and their medical record was reviewed METHODS: This was a prospective, observational study of newly retrospectively . Skin prick test was performed with common 26 allergens diagnosed PIDD patients requiring Ig therapy. Eligible patients were in Korea. Other variables such as sex, age, body mass index, parental recruited from the US, UK, and Brazil. Patients’ HRQOL was assessed at allergy history, and parental smoking were also obtained. Multivariate baseline prior to first infusion, using the SF-36 for adults and the Pediatric analysis was used to determine the association between those variables and Quality of Life Inventory (PedsQL) for children. Hospitalizations, ER the results of skin prick test. visits, and antibiotic use 6 months prior to enrollment were also collected. RESULTS: Wheal size to histamine skin test showed positive correlation RESULTS: A total of 30 patients have enrolled in the study to date (20 significantly with BMI (Spearman’s Rho 0.139, P-value 0.005) and this adults, 10 children). The mean baseline SF-36 Physical Component Score was also confirmed by multivariate analysis that was adjusted by sex, age, (35.82 vs. 50.0, p<0.0001) and Mental Component Score (38.17 vs. 50.0, parental allergy history, parental smoking, and allergic sensitization p50.0134) were significantly lower among the adult PIDD patients (coefficient 0,076, 95% confidence interval 0.023 – 0.128). compared to the US general population norms. Among children, the CONCLUSIONS: Skin response to histamine increases as body mass mean baseline PedsQLTotal Score was also significantly lower than the US index is higher. Therefore we should consider this association when general population (68.87 vs. 83.84, p50.0008). The mean rates of interpreting skin prick test result and further study with large population will suggest a new way to interpret skin prick test result according to BMI for diagnosing allergic disease with less error.
ABS 5.2.0 DTD YMAI10628_proof 11 January 2014 7:12 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB45 VOLUME 133, NUMBER 2
The Impact Of Component Resolved Diagnosis On Allergen- at 1mg/ml is unacceptable for certain devices. On average there was no 162 Specific Immunotherapy Prescription In Children With pain difference in the multi device group compared to the single tip Pollen-Related Allergic Rhinitis devices. Dr. Paolo Matricardi, MD1, Dr. Giovanna Stringari2, Prof. Carlo Caffar- elli2, Dr. Riccardo Asero, MD3, Dr. Arianna Dondi4, Dr. Salvatore Tri- Phenotypic Classification Of Allergen Polysensitization In 5 6 1 164 Geriatric Adults podi , The Italian Pediatric Allergy Network ; Charite, Berlin, 1 2 2 Dr. Rohit Divekar, MBBS, PhD , Dr. John B. Hagan, MD, FAAAAI , Germany, Pediatric Department, University of Parma, Parma, Italy, 2 1 3 4 Hirohito Kita, MD ; Division of Allergic Diseases, Mayo Clinic, Roches- Clinica San Carlo, Paderno Dugnano, Italy, Department of Pediatrics, 2 University of Bologna, Bologna, Italy, 5Pediatric Department, Ospedale ter, MN, Mayo Clinic, Rochester, MN. Sandro Pertini, Roma, Italy, 6. RATIONALE: Geriatric allergy patients contribute significantly to health RATIONALE: IgE molecular assays (Component resolved diagnosis, care utilization. Information regarding the phenotypic expression of CRD) have been proposed to improve SIT prescription and efficacy in polysensitization in elderly adults is limited. We sought to determine pollen polysensitized patients with allergic rhinitis. However, the impact of subphenotypes of allergic polysensitization in elderly patients and to
CRD on SIT prescription in children with pollen-AR has never been evaluate the potential relevance these subphenotypes may have on the SATURDAY measured. outcome and management of allergic disease. METHODS: Children (n5 1271, age 4-18 yrs) with pollen-AR who never METHODS: This was a retrospective study designed to characterize received SIT were recruited (2009-2011) in 16 Italian clinics. Clinical data multi-allergen sensitive adults over 65 years of age. Patients with two or were collected through questionnaires (ISAAC, ARIA, GINA) and SPT more positive skin tests to a uniform panel of allergens were selected. positivity (ALK, Denmark) to Grass, Cypress, Olive, Mugwort, Pellitory Unsupervised learning using Network analysis was performed on skin and Betulacee tested with allergenic extracts. IgE sensitization to Phl p1, prick test results to 43 allergens on 97 patients and the resultant layout Phl p5, Bet v1, Cup a1, Art v1, Ole e1, Par j2, Phl p7 (polcalcin) and Phl was analyzed for existence of discrete clusters. Phenotypic and clinical pa- p12 (profilin) was tested by ImmunoCAP (TFS, Sweden). SIT prescription rameters of these clusters were analyzed for individual differences. was first modeled on SPT results and then re-modeled considering also RESULTS: The resultant graphical layout suggested existence of four CRD according to GA2LEN-EAACI guidelines and the opinion of 14 distinct allergen clusters (C), C1 represented principal sensitivity to house allergists. dust mite and animal allergens (except cat), C2 was predominantly trees, RESULTS: No IgE to the respective major allergenic molecules were weeds (except ragweed) and cat sensitive, C3 was mold sensitive, while C4 detected among patients with clinically relevant sensitization to mugwort was characterized by high reactivity to grasses and ragweed. Some (66/99, 67%), betulaceae (241/436, 55%), pellitory (138/419, 33%), olive allergens with high grade and frequency of sensitization had higher (204/719, 28%), cypress (43/279, 15%), and grass (113/1081, 10%). SIT influence on the network (eg. Kentucky blue, Orchard grass, Dust mites, prescription or composition, first based on SPT only, was corrected after Aspergillus, cat etc). C1 and C4 were found to have higher medication CRD in 277/627 children (44%) eligible for SIT according to guidelines usage and asthma history. and in 554/1271 children (44%) examined by the pediatricians. CONCLUSIONS: There was a lack of homogeneity in pattern of CONCLUSIONS: SIT prescriptions based on clinical history and SPT sensitization suggesting existence of subphenotypes of polysensitized only, are susceptible to be modified after CRD in a large proportion of geriatric individuals. Members of a cluster tended to have higher reactivity children with pollen-AR living in a Mediterranean country. The hypothesis to other allergens of same cluster leading to an ‘allergen restricted that CRD-guided prescription improves SIT efficacy deserves to be tested. subphenotype’.
Randomized Evaluation Of Ten Allergy Skin Prick Test Analysis Of The Discordance Between Immunocap and Skin 163 Devices 165 Prick Test For Common Allergens In Patients With Allergic 1 Rhinitis Symptoms Dr. Yohalakshmi Chelladurai, MD, MPH , Prof. Robert G. 1 1 2 2 2 1 Dr. Do Yang Park , Prof. Hyun Jun Kim , Dr. Ju Wan Kang , Prof. Yoo Hamilton, PhD, D.ABMLI, FAAAAI , Dr. Jody R. Tversky, MD ; Johns 1 3 1 2 Suk Kim , Prof. Chang-Hoon Kim ; Ajou University School of Medi- Hopkins University Bloomberg School of Public Health, Johns Hopkins 2 3 University School of Medicine, Baltimore, MD. cine, Yonsei University College of Medicine, Department of Otorhino- RATIONALE: Allergen skin prick testing remains an essential tool for laryngology, Yonsei University College of Medicine, Seoul, South Korea. diagnosing atopic disease. Analytical precision needs to be determined for RATIONALE: To compare the results of SPT and ImmunoCAP and to several newer devices. analyze the factors that induces the discrepancy in 6 common allergens. METHODS: Ten single and multi tip skin prick devices from five METHODS: Ninety four consecutive adult patients who visited with manufacturers were evaluated. Twenty-four subjects were recruited to allergic rhinitis symptoms were enrolled. All participants had undergone place 768 skin tests. Histamine (1mg/ml and 6mg/ml) and control were both SPTand ImmunoCAP and the concordance/discordance of the results introduced at six randomized locations on the upper and lower arms. Wheal were evaluated. Four demographic & clinical factors were used to analyze and flare reactions were measured independently by two blinded the influence on each diagnostic method. technicians. High-resolution digital photographs were taken at 10, 15 RESULTS: Among 6 allergens, perennial allergen showed higher and 20 minutes. concordance rate, while seasonal allergens showed significant discordance RESULTS: Measurement of wheal and flare responses between trained between SPT and ImmunoCAP. In analyzing the perennial allergens, old technicians was highly correlated (R2 5 0.914). Average wheal size among age patients showed relatively higher discordance rate compared to devices ranged from 3.1mm (ComforTen) to 6.9 mm (UniTest PC) using younger age patients. In the analysis of seasonal allergens, patients 1mg/ml histamine (P<0.001), and 4.8mm (GreerPick) to 8.7mm (Sharp- whom concurrently sensitized with perennial allergens showed higher Test) using 6mg/ml histamine (P<0.001). False negative rate for discordance rate than patients only sensitized with seasonal allergens. ComforTen was 25% using 1mg/ml histamine. Specificity was greater CONCLUSIONS: In prescribing the diagnostic test of allergic rhinitis, than 99% except the Duotip-Test II at 95%. All devices were well tolerated clinicians should consider patient’s demographics and individual symp- with average pain less than 4 on a 10-point visual analog scale. Pain scores toms to obtain more accuracy in diagnosis. were higher on the forearm (P<0.01) and among women (P<0.01). The UniTest single device had the lowest pain score (1.9). The Multi-Test PC had the lowest pain among the multi tip devices (2.2). CONCLUSIONS: All ten skin prick devices yielded high sensitivity and specificity with exceedingly rare true false positives. The use of histamine
ABS 5.2.0 DTD YMAI10628_proof 11 January 2014 7:12 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB46 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Role Of House Dust Mites In Allergic and Non Allergic Nasal Modified Shuffled Blo t 5 Recombinant Allergen From Blomia 166 Diseases 168 Tropicalis Produces a Shift Of Antigenicity For Binding To Prof. Maged Refaat, MD1, Prof. Tarek Mansour1, Prof. Talaat Samny2, IgG4 Isotype Prof. Ahmed Zaki3, Prof. Eman Osman1, Dr. Eman Ezzat1, Dr. Eman Dr. Ernesto Taketomi, MD, PhD1, Mrs. B arbara Avila, MSc1, Ahmed1; 1Department of Allergy and Clinical immunology, Ain Shams Mrs. Karine Almeida, PhD1, Mrs. Deise Silva, PhD1, Prof. Odon ırio university, Cairo, Egypt, 2Department of ear, nose and throat diseases, Abrah~ao Junior, PhD2, Prof. Jair Cunha-Junior, PhD1; 1Federal University Ain Shams university, Cairo, Egypt, 3Department of pathology, Ain of Uberl^andia, Uberlandia, Brazil, 2Federal University of Triangulo Mine- Shams university, Cairo, Egypt. iro, Uberaba, Brazil. RATIONALE: House dust mites (HDM) release allergens which trigger RATIONALE: Blo t 5, a protein of 14 kDa, is the major allergen from atopic reactions and possess digestive enzymatic activity. The role of mites Blomia tropicalisand epidemiological studies have shown that up to 90% of in bronchial asthma and allergic rhinitis (AR) is well recognized, but its the symptomatic patients had strong IgE reactivity to this allergen. role in non allergic nasal diseases is unclear. In this study we investigated METHODS: Molecular biology approach was used to produce two the role of HDM in the pathogenesis of non allergic nasal diseases. constructs encoding the Blo t 5 full sequence (rBlo t 5) and another with a METHODS: Ain Shams Outpatients Allergy and ENT clinics recruited 60 modified shuffled sequence (mBlo t 5) to produce the respective recombinant subjects for a case control study .They were classified into 4 groups. A: 30 allergens. The immunoreactivity to both recombinantproteins were measured patients with non allergic nasal diseases. B: 20 patients had allergic rhinitis by ELISA using serum samples from atopic and non-atopic patients. due to HDM. C: 10 patients had allergic rhinitis with negative test for RESULTS: The molecular modeling analysis of these recombinant HDM. D: 10 healthy volunteers. All were subjected to history taking, proteins reveals a disruption of the major IgE binding epitope from Blo t Clinical examination with diagnostic nasal endoscopy, Skin prick test, 5 previously described. The antibodies levels and positivity to both rBlo t 5 Histopathological examination of nasal biopsies and Measurement of and mBlo t 5 were evaluated using a panel of serum samples of atopic Bt+, HDM enzymes in mucosal biopsy using the Api ZYM system. atopic Bt- and non-atopic patients. IgE levels and positivity to rBlo t 5 and RESULTS: There was no difference in HDM enzymes between non AR mBlo t 5 allergens were comparable in atopic Bt+ patients. A similar patients (A) compared to AR patients due to HDM (B),(p>0.05) , but with profile of IgG1 reactivity to recombinant allergens was found in both atopic highly significant increase in (A) than HDM negative AR patients (C) and and non-atopic patients. It is worth to note that a significant reduction on controls (D),(p<0.001).Enzymes were present highly significantly in (B) IgE reactivity (> 20%) occurred in 26% of Bt+ serum samples while 37% than (C) and (D),(p<0.001). The mucosal ulceration was more common in of samples showed increase on IgG4 reactivity. (A) 86.7%, than (B) and (C) 60%. Inflammation and eosinophilic CONCLUSIONS: The modified Blo t 5 allergen showed a shift of infiltration was more common in (B) and (C) than (A), (p<0.001). antigenicity for binding to IgG4, suggesting that structural features are CONCLUSIONS: HDM may share in the pathogenesis of non AR since important to reduce the immunoreactivity to IgE antibodies for minimizing most of HDM proteolytic enzymes were detected in non AR patients as the undesirable effects when it is employed in immunotherapy procedures. similar to AR patients due to HDM.
Immunogenicity and IgE Blocking Capacity Of a Mixture Of 167 Depigmented and Chemically Modified Allergens From Different Homologous Groups Dr. Victor Miguel Iraola, Mr. Jos e Ramon Leonor, Dr. Mar ıa Morales, Dr. Raquel Moya, Dr. M. Angeles Lopez Matas, Dr. Ma Teresa Gallego, Dr. Jeronimo Carn es; Laboratorios LETI, Tres Cantos, Spain. RATIONALE: Allergen immunotherapy (AIT) with mixture of allergen extracts from different homologous groups remains controversial. Successful AIT has been linked to a specific immune response and the production of blocking antibodies. The objectives of this study were to investigate the antibody response, and the induction of IgE-blocking antibodies by a depigmented-polymerized (Dpg-Pol) vaccine composed by a mixture of grasses and olive pollen extract. METHODS: Sera from New Zealand rabbits immunized with mixture (50%;50%) of Dpg-Pol of grasses (mixture of Dactylis glomerata, Festuca elatiorx Lolium perenne, Phleum pratense, Poa pratensis) and Olea euro- paea, were obtained. Specific IgG against the extracts was determined by ELISA and Immunoblot. The capacity of these induced antibodies to block the human-IgE binding sites was tested by ELISA, comparing the binding of IgE from a pool of human sera, after the incubation of extracts with rabbit’s immunized sera and their corresponding preimmune. RESULTS: The vaccine composed by a mixture of grass and olive pollen induced high and similar specific IgG antibody levels to both allergen extracts. The produced antibodies show the capacity to block human-IgE binding sites of both extracts, with percentages of IgE-inhibition higher than 80% (83.2 % for grasses and 85.1% for Olea). CONCLUSIONS: Dpg-Pol vaccines composed by a mixture of allergen extracts induce specific IgG-antibodies to each extract, which are able to block the binding sites of IgE present in serum samples of allergic patients. Specific immunogenicity is maintained after the mixture of depigmented and polymerized extracts and corroborates the immunological efficacy of the treatment.
ABS 5.2.0 DTD YMAI10628_proof 11 January 2014 7:12 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB47 VOLUME 133, NUMBER 2
Induction Of Arah2-Specific Memory B Cells Identified Using Exposure of mice to OVA-EPIT led to the generation of Th3 cells but not 169 a Novel Tetramer-Based Approach Occurs Early and iTregs in the MLN, and in contrast to OVA-OIT, this was not impaired by Transiently During Peanut Oral Immunotherapy prior sensitization. Dr. Sarita U. Patil, MD1,2, Dr. Adebola Ogunniyi, PhD3, Mr. Alex Ma4, CONCLUSIONS: De novo generation of gut regulatory T cells is sup- Ms. Alisa K. Brennan, BS5, Ms. Theadora Swenson, BA6, Mr. Agustin pressed in sensitized mice during OIT but remains intact during EPIT. Calatroni, MA, MS7, Dr. James Moon, PhD8, Dr. J. Christopher The functional role of Th3 cells and iTregs in tolerance induction in Love, PhD3, Wayne G. Shreffler, MD, PhD, FAAAAI1,6; 1Harvard Medi- food-induced anaphylaxis is currently being investigated. cal School, Boston, MA, 2Allergy and Immunology, Massachusetts Gen- eral Hospital, Boston, MA, 3Massachusetts Institute of Technology, Long Term Protection Against New Sensitization After Milk- 4 171 Epit In Mice Sensitized To Milk Is Mediated By Tregs Cambridge, MA, Massachusetts General Hospital, Charlestown, MA, 1 1 5Rush Medical College, Chicago, IL, 6Massachusetts General Hospital, Pierre Henri Benhamou, MD , Dr. Vincent Dioszeghy, PhD , 1 1 1 Boston, MA, 7Rho, Inc., Chapel Hill, NC, 8Harvard Medical School, Mrs. Emilie Puteaux , Mrs. Melanie Ligouis , Mrs. Veronique Dhelft , Mrs. Camille Plaquet1, Prof. Christophe Dupont, MD, PhD2, Lucie Mon- Charlestown, MA. 1 1 2 RATIONALE: Peanut oral immunotherapy (PNOIT) increases tolerance doulet, PhD ; DBV Technologies, Bagneux, France, Hopital Necker En- SATURDAY in some peanut allergic patients and has been correlated with specific IgG fants Malades, Paris, France. induction. However, the humoral immune response to peanut allergens RATIONALE: In a previous experiment in milk-sensitized mice, milk- during PNOIT and its mechanistic relationship to clinical outcomes specific epicutaneous immunotherapy (milk-EPIT) was also able to remains poorly characterized. decrease immune response to further sensitization (Mondoulet et al. METHODS: Peripheral mononuclear blood cells at multiple time points AAAAI, abstract 3944, 2013). The aim of this study was to evaluate the from PNOIT study participants (n522) as well as non-allergic controls mechanism and maintenance of this immune protection process. (n57) were stained with Arah2 tetramers and analyzed by flow cytometry. METHODS: Young BALB/c mice were orally sensitized to milk, then From a subset (n53), paired heavy and light chain variable regions from treated by EPIT or not (Sham) and 2 weeks later, sensitized to peanut Arah2+ B cells were cloned by single cell PCR and co-expressed. protein extracts (PPE). After PPE-sensitization, mice were exposed to a Specificity was evaluated by ImmunoCAP and protein microarray. peanut regimen (inducing eosinophilic inflammation in esophageal mucosa) two times, immediately and 2 months after the end of EPIT. In RESULTS: The frequency of Arah2+CD19+CD27+IgM- memory B cells + + per million CD19+ cells was similar at baseline in allergic and control a second experiment, CD4 CD25 regulatory T cells (Tregs) were isolated subjects (30.7 vs. 14.3, p50.1), but significantly increased during PNOIT from spleen of milk-sensitized mice after EPIT or Sham, and transferred to 82.1 (p50.01). The expansion of Arah2+ cells within the memory B cell into naive mice (recipient). Recipient mice were sensitized to peanuts compartment was transient, peaking at about 10 weeks during PNOIT and exposed to a peanut regimen. (p50.01), preceding the increase in specific IgG4 levels. Of the 118 cloned RESULTS: EPIT significantly decreased Th2 immune responses to milk immunoglobulins, 34% were IgM, 34% IgG, 31% IgA and 1% indeter- and increased Foxp3+Tregs. After sensitization to PPE, only the milk- minant. Enrichment for Arah2 specific clones was suggested by CDR3 EPIT group showed a significant increase of PPE-sIgG2a and no induction of PPE-sIgE with no significant esophageal eosinophilic infiltration after homology. All 5/5 of the recombinant antibodies cloned to date from class- 2 switched cells were confirmed to be Arah2 specific. PPE oral exposure (3 vs 27 eosinophils/mm in sham, p<0.01). The effect was maintained over 2 months after the end of immunotherapy at humoral CONCLUSIONS: Using affinity selection and single-cell BCR cloning, 2 we have demonstrated early, transient expansion of circulating class- level and eosinophil infiltration (7 vs 16 eosinophils/mm in sham, switched, antigen-specific memory B cells during PNOIT. This method- p<0.05). Tregs transfer to naive recipient mice protected from the sensiti- zation to peanuts and prevented from esophageal eosinophil infiltration (16 ology will likely provide novel insights into humoral mechanisms of 2 immunotherapy and the role of antigen-specific antibody induction in vs 57 eosinophils/mm in sham, p<0.05). tolerance. CONCLUSIONS: Milk-EPIT is able to prevent new sensitization via a Treg mechanism in a model of successive sensitization mimicking the De Novo Generation Of Gastrointestinal Regulatory T Cells In allergic march. 170 Response To OIT and EPIT Leticia Tordesillas, PhD1, Lucie Mondoulet, PhD2, Pierre Henri Benhamou, MD2, Hugh A. Sampson, MD, FAAAAI3, M. Cecilia Berin, PhD1; 1Icahn School of Medicine at Mount Sinai, New York, NY, 2DBV Technologies, Bagneux, France, 3Pediatrics, Icahn School of Med- icine at Mount Sinai, New York, NY. RATIONALE: Epicutaneous immunotherapy (EPIT) and oral immuno- therapy (OIT) are being investigated as approaches to induce desensitiza- tion or tolerance to food allergens. We hypothesized that these two approaches may differ in their capacity to induce gastrointestinal regulatory T cells (Tregs) in sensitized mice. METHODS: To examine de novo induction of Tregs, we transferred CFSE-labeled (na€ıve OVA-specific) DO11.10 cells into na€ıve or orally- or skin-sensitized mice. Mice were then exposed to ovalbumin (OVA) by the oral or epicutaneous route (using OVA-ViaskinÒ), and lymph nodes and spleens harvested at 7 days for phenotyping by flow cytometry. RESULTS: Oral exposure of na€ıve mice to OVA (OVA-OIT) led to the generation of a population of CFSE-low DO11.10 cells in the mesenteric lymph node (MLN) that were LAP+/Foxp3- (consistent with Th3 cells) as well as Foxp3+ cells (consistent with iTregs). De novo Th3 and iTreg induction in DO11 cells after OVA-OITwas significantly impaired in both orally- and skin-sensitized mice. Mice sensitized to peanut did not have impaired Th3 or iTreg induction in MLN after OVA-OIT, indicating that there is not a general defect in tolerance pathways in sensitized mice.
ABS 5.2.0 DTD YMAI10628_proof 11 January 2014 7:12 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB48 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Epicutaneous Immunotherapy-Induced Regulatory T Cells particularly in the context of accidental peanut overdose and cofactors such 172 Could Migrate To More Various Sites Of Allergen Exposure as fever, infection, menstruation and exercise. Patients require continuous Compared To Sublingual Or Subcutaneous Immunotherapy In follow-up while on maintenance treatment. Mice Sensitized To Peanut Dr. Vincent Dioszeghy, PhD1, Lucie Mondoulet, PhD1, Mrs. V eronique Evaluation Of The Immunological Mechanisms Involved In Dhelft1, Mrs. M elanie Ligouis1, Mrs. Emilie Puteaux1, Mrs. Camille Pla- 174 The Efficacy Of Sublingual Immunotherapy With Ltp (Pru p 3) 1 2 In Allergic Patients Sensitized To Food By Ltps quet , Prof. Christophe Dupont, MD, PhD , Pierre Henri Benhamou, 1 2 1 1 2 Dr. Francisca Gomez, MD, PhD , Dr. Enrique Gomez, MD, PhD , MD ; DBV Technologies, Bagneux, France, Hopital Necker Enfants 3 3 Malades, Paris, France. Dr. Maria J. Torres, MD, PhD , Mrs. Luisa Galindo, RN , Ms. Maria Do- lores Ruiz3, Dr. Inmaculada Dona,~ MD, PhD3, Mrs. Gador Bogas1, RATIONALE: In mice, epicutaneous immunotherapy (EPIT) increases 3 3 Foxp3+ regulatory T cells (Tregs) (Dioszeghy, J Immunol 2011). Tregs Dr. Paloma Campo, MD, PhD , Dr. Teresa Posadas , Dr. Miguel Blanca, MD, PhD3, Dr. Cristobalina Mayorga, PhD4; 1Allergy Service, could display distinct efficacy based on their expression of homing 2 molecules. The aim of this study was to evaluate homing receptors Carlos Haya Hospital, Spain, Research Laboratory, Carlos Haya Hospi- 3 expression by Tregs induced during EPIT compared to sublingual (SLIT) tal-FIMABIS, Spain, Allergy Service, Carlos Haya Hospital, Malaga, 4 or subcutaneous (SCIT) immunotherapy. Spain, Research Laboratory, Carlos Haya Hospital-FIMABIS, Malaga, METHODS: Mice were sensitized to peanuts and divided into 4 groups: Spain. EPIT, SLIT, SCIT and not treated (Sham). After 8 weeks of treatment with RATIONALE: In Southern Europe Pru p3 is primary sensitizer of fruit 100mg of peanut protein extract, the proportion of Tregs in spleen, inguinal and is responsible of severe reactions. Specific immunotherapy (SIT) and mesenteric lymph node (iLN or mLN) were evaluated and the brings a new perspective to treat those patients. There is a lack of expression of homing receptors by spleen Tregs was analyzed by flow knowledge regarding cellular responses that include changes in basophil cytometry. activation during the IT. We aim to analyse early changes in basophil RESULTS: EPIT, SLIT and SCIT increased Foxp3+ Tregs in spleen response to Pru p 3 and Ara h 9 after the first month of sublingual compared to Sham (p<0.001), EPIT more than SLIT (p<0.001) and SCIT immunotherapy (SLIT). (p<0.05). Concerning migration to the lung, expression of CCR4 was METHODS: Forty-six peach allergic patients confirmed by positive increased on Tregs induced by the three therapies whereas migration to the specific IgE determined by skin prick test or fresh peach (prick-by-prick), skin measured by CLA expression was increased only in EPIT and SCIT ImmunoCAP IgE and/or double blind placebo control food challenge with treated mice. Consistently only EPIT and SCIT increased Tregs level in peach. Basophil reactivity was determined by the basophil activation test m iLN (p<0.01). For gut homing, EPIT, SLIT and SCIT significantly (BAT) with Pru p3, Ara h9 at two concentrations, 1 and 0.1 g/ml, before increased Tregs in mLN compared to Sham (p<0.01) but only EPIT and after 1month. induced higher expression of CCR9 on spleen Tregs. Moreover, the RESULTS: Twenty one patients evaluated (45%) performed anaphylaxis expression of CXCR3, CCR6 and CCR8 was increased on EPIT-induced and 55% urticaria and/or angioedema, 82,6% showed sensitization to other Tregs but not in SLIT or SCIT. plant foods proteins and 69,5% showed sensitization to pollens. BAT was CONCLUSIONS: Larger and stronger expression of homing receptors on done in 25 patients with first month of SLIT completed. The 28% patients Tregs was achieved with EPIT compared to SLIT supporting the clinical have an increase of Pru p 3 reactivity. 36% patients showed same reactivity applications of EPIT in various allergies. after first month and 36% presented a decreased reactivity to Pru p3. Similar results were obtained for Ara h9. Anaphylactic Reactions After Peanut Oral Immunotherapy CONCLUSIONS: Preliminary result disclosed that percentage of patients 173 Noam Berlin1, Dr. Amanda Jagdis1, Carly Barron2, Sean Ma- who underwent changes in BATreactivity to Pru p3 and Ara h9 was similar. clachlan3, Mohana Giruparajah2, Nathan Leader4, Dennis Penn5, There have been no differential clinical pattern in the groups studied after Dr. Gordon L. Sussman, FAAAAI1; 1University of Toronto, Faculty of one month of SLIT. BAT shows good correlation between Pru p3 and Ara Medicine, Toronto, ON, Canada, 2Gordon Sussman Clinical Research h9. Inc., Toronto, ON, Canada, 3University of Ottawa, Faculty of Medicine, Ottawa, ON, Canada, 4University of Melbourne, Faculty of Medicine, Melbourne, Australia, 5MastCell Pharmaceuticals, Inc., Raleigh, NC. RATIONALE: The safety profile of peanut oral immunotherapy (OIT) requires further study as adverse allergic reactions are reported during both build-up and maintenance dosing. We evaluated reactions to peanut on maintenance dosing after completion of one year of peanut OIT. METHODS: 4 subjects (3M:1F) with history of peanut anaphylaxis (grade 2 and 3; peanut specific IgE > 100) underwent a 1-day rush oral peanut desensitization with up to 25mg peanut protein (pp), followed by biweekly doubling of tolerated doses for one year, then ongoing daily maintenance dosing (median 6 peanuts). Outcomes were assessed clinically after reactions and patients were followed after completing peanut OIT for 423 6 58 days on maintenance. RESULTS: Anaphylactic reactions occurred in 7 of 1692 (0.41%) maintenance OIT doses. Two (0.12%) episodes of anaphylaxis required epinephrine and three (0.18%) required hospitalization. Two (0.12%) anaphylactic reactions were due to accidental overdose. Four of seven (57%) reactions occurred in the presence of known cofactors of anaphylaxis including fever/infection (1/7) and exercise (3/7). One patient stopped maintenance OIT after an anaphylactic reaction occurring at maintenance dose #354 (250mg pp). Mild gastrointestinal reactions occurred in all 4 patients with varying frequencies. CONCLUSIONS: Maintenance dosing following peanut OIT is associ- ated with ongoing risk of adverse allergic reaction, including anaphylaxis,
ABS 5.2.0 DTD YMAI10628_proof 11 January 2014 7:12 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB49 VOLUME 133, NUMBER 2
Changes In IgE and IgG4 Epitopes After Milk Oral IL-17 Enhances TNF-a-Induced, But Not IL-1b-Induced, 175 Immunotherapy (OIT) 177 Expression Of Neutrophil-Associated Cytokines By Human Bel en de la Hoz Caballer, MD, PhD1, Mrs. Cristina Vlaicu1,Inmaculada Lung Tissue Cells Cerecedo Carballo, MD, PhD2,Monica Rodr ıguez-Alvarez, MD3, Dr. Maria Dr. Akio Matsuda, PhD, Dr. Kenichiro Motomura, MD, Dr. Tetsuo Carmen Di eguez Pastor, MD4, Montserrat Fern andez-Rivas, MD, PhD5, Shoda, MD, Dr. Kyoko Futamura, MD, PhD, Dr. Hirohisa Saito, MD, Javier Mart ınez-Botas, PhD1,6; 1Hospital Universitario Ramon y Cajal. Insti- PhD, Dr. Kenji Matsumoto, MD, PhD; Department of Allergy and Immu- tuto Ramon y Cajal para la Investigacion Sanitaria, Madrid, Spain, 2Hospital nology, National Research Institute for Child Health and Development, del Sureste, Arganda del Rey, Spain, 3Hospital Cl ınico San Carlos, Spain, Tokyo, Japan. 4Hospital Universitario 12 de Octubre, Spain, 5Hospital Cl ınico San Carlos, RATIONALE: Although mild to moderate bronchial asthma is charac- Madrid, Spain, 6CIBER de Fisiopatolog ıa de la Obesidad y Nutricion (CI- terized by eosinophilic inflammation, some severe patients are known to BEROBN), Instituto de Salud Carlos III, Madrid, Spain. have neutrophilic inflammation and increased numbers of IL-17-producing RATIONALE: The aim of the study was to describe changes in IgG4 and cells in the airway. We aimed to determine the effects of proinflammatory IgE epitopes over milk OIT. cytokines and IL-17 on human lung tissue cells.
METHODS: Sera from reactive milk allergic patients participating in an METHODS: Normal human lung-derived epithelial cells (NHBE) and SATURDAY OIT study were collected at baseline, at the end of build-up phase, and 6, 12 fibroblasts (NHLF), bronchial smooth muscle cells (BSMC) and micro- and 24 months after (maintenance phase). A peptide microarray immuno- vascular endothelial cells (HMVEC-L) were stimulated with TNF-a, IL- assay was performed using a 20 AA library of overlapping peptides (3- 1b and IL-17, alone and in combination, for 24 hours. Expression levels of offset) of a-s1-, a-s2-, b- and k-caseins and b-lactoglobulin. the mRNA and protein of neutrophil-associated cytokines were measured RESULTS: Twenty-four milk allergic patients completed OIT. Seven by qPCR and ELISA, respectively. C/EBPd activity was determined using patients refused OIT (controls). Among patients, median number of the EMSA assay. positive peptides at baseline was (IgE/IgG4): a-s1 19/20, a-s2 13.5/8, b- RESULTS: The following results were observed in each of four types of casein 16.5/26.5, k-casein 12/9 and b-lactoglobulin 7.5/3. Over time, there lung tissue cells. Although IL-17 itself did not induce the tested neutrophil- was a statistically significant increase in the number of IgG4 positive associated cytokines, it significantly enhanced TNF-a-induced, but not IL- peptides in a-s1-, a-s2-, k-caseins, and b-lactoglobulin and a decrease in 1b-induced, expression of such neutrophil-associated cytokines as G-CSF the number of IgE positive peptides of a-s1- and b-caseins. In OIT and IL-6. IL-17 showed the same pattern of enhancement in regard to C/ patients, statistically significant increase in signal intensity was identified EBPd activity, a transcription factor responsible for G-CSF and IL-6 in IgG4 in a-s1-casein: AA13-38, AA85-116, AA109-134, AA127-167; a- expression. s2-casein: AA16-47, AA76-98, AA124-143; k-casein: AA1-47, AA55-77, CONCLUSIONS: Our results suggest that IL-17 may be involved in the AA70-107, AA97-119, AA130-155, AA151-170; b-lactoglobulin: pathogenesis of neutrophilic inflammation in the airway, seen in patients AA40-71, AA61-95, AA97-119, AA109-128, AA115-134, AA130-155. with severe asthma, by modulating TNF-a-mediated, but not IL-1b- A significant decrease in IgE signal intensity was observed at 24 months in mediated, signaling. The enhancing effects of IL-17 are probably due to a-s1-casein AA70-92, AA118-137, b-casein AA34-53, AA52-74, AA activation of C/EBPd, which would be a novel therapeutic target, 103-128, AA 145-170 and k-casein AA58-77. No changes in controls. especially in patients with severe asthma. CONCLUSIONS: OIT induces changes in IgE and IgG4 selected epitopes during both, build-up and maintenance phases. Changes observed at 12 and Prostaglandin I2 Receptor (IP) Signaling Inhibits Alternaria- 24 months may show the duration of maintenance phase. 178 Induced IL-5 and IL-13 Expression Through Group 2 Innate Lymphoid Cells (ILC2) IL-33 and TSLP Mediate Chronic Eosinophilic Airway Dr. Shinji Toki, PhD, Kasia Goleniewska, Sara Reiss, MS, Dr. Weisong 176 Inflammation and IgE Antibody Production Induced by Zhou, PhD, Dr. R. Stokes Peebles, Jr, MD, FAAAAI; Vanderbilt Univer- Multiple Airborne Allergens sity School of Medicine, Nashville, TN. Koji Iijima, PhD1, Takao Kobayashi, PhD1, Kenichiro Hara, MD1,2, Gail RATIONALE: ILC2 are a critical source of Th2 cytokines such as IL-5 Kephart1, Hirohito Kita, MD1; 1Mayo Clinic, Rochester, MN, 2Gunma Uni- and IL-13 and have an important role in allergic airway inflammation. We versity Graduate School of Medicine, Maebashi, Gunma, Japan. reported that prostaglandin I2 (PGI2) inhibits dendritic cell function and RATIONALE: Exposure to airborne allergens may trigger a complex Th2 cytokine production, however, the effect of PGI2 on ILC2 function network of immune responses in the airways, resulting in asthma and is not known. We hypothesized that endogenous PGI2 –IP signaling de- allergic diseases. In this study, we investigated the immunologic mecha- creases ILC2 cytokine secretion. To test this hypothesis, we evaluated nisms involved in the pathological process induced by chronic exposure to the number of IL-5 and IL-13-expressing ILC2 by using WT and IPKO multiple airborne allergens. mice following airway Alternaria extract challenge. METHODS: Na€ıve Balb/c or C57BL/6 mice were exposed to a mixture of METHODS: BALB/c background WT and IPKO mice were challenged natural allergen extracts, including Alternaria, Aspergillus and house dust intranasally with Alternaria extract for 4 consecutive days. mite, and a model antigen, OVA (named ‘‘OAAH’’) for up to 8 weeks. To Bronchoalveolar lavage (BAL) fluid and lung were harvested at 24 hours investigate the mechanisms, IL-5- and IL-13- reporter mice and gene-defi- after the last challenge. Control mice were challenged with PBS. IL-5 and cient animals were used. IL-13 protein expression in the BAL fluid and lung homogenate were RESULTS: Allergens acted synergistically and induced robust eosino- measured by ELISA. IL-5 and IL-13-expressing ILC2 in lung were philic airway inflammation and specific IgE antibody production, which detected by flow cytometry. peaked at 4 weeks and culminated in airway remodeling at 8 weeks. When RESULTS: IPKO mice had significantly greater IL-5 and IL-13 protein IL-5venus and IL-13eGFP cytokine reporter mice were exposed to OAAH, expression following Alternaria challenge in both BAL fluid and lung IL-5- or IL-13-positive cells increased in both CD4+ T cell and type 2 homogenate compared to WT mice (p<0.05). Further IPKO mice had a innate lymphoid cell (ILC2) populations. The lung levels of IL-33 significantly greater number of lung ILC2 that expressed IL-5 and IL-13 increased quickly after OAAH exposure and continued to rise throughout following Alternaria challenge compared to WT mice (p<0.05). IL-5 or IL- the chronic phase of inflammation. Airway eosinophilia and production of 13-expressing CD3+ CD4+ cells were not detected in Alternaria challenged Th2 cytokines and IgE antibody were significantly inhibited in ST2-/- (i.e. lung at this time point. IL-33 receptor deficient) and TSLPR-/- mice but not in IL-1R1-/- mice. CONCLUSIONS: IPKO mice had significantly increased IL-5 and IL-13 CONCLUSIONS: Chronic airway exposure to allergens triggers a expression and number of IL-5 and IL-13-expressing ILC2 in the lung network of innate and adaptive type 2 immune responses, and IL-33 and following Alternaria challenge. This result suggests that endogenous PGI2 TSLP, but not IL-1a/b, play major roles in regulating the process. –IP signaling down-regulates ILC2 functions.
ABS 5.2.0 DTD YMAI10628_proof 11 January 2014 7:12 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB50 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Local Administration Of CCL28 Is Sufficient To Drive Airway Surrogate Biomarkers Of Eosinophilic Airway Inflammation In 179 Hyper-Responsiveness and Mucous Cell Metaplasia 181 Asthma: Quantitation Of Major Basic Protein-1 and Charcot- Dr. Becky Buelow, MD, Mrs. Desire Hunter, Dr. Mitchell H. Grayson, Leyden Crystal Protein/Galectin-10 In Induced Sputum MD, FAAAAI; Medical College of Wisconsin, Milwaukee, WI. Dr. Sharmilee M. Nyenhuis, MD, FAAAAI1,2, Mr. Preeth Alumkal, BS3, RATIONALE: Viral infections have been shown to increase risk for Dr. Jian Du, MD3, Brian Maybruck, PhD3, Mr. Mark Vinicky, BS3, developing asthma and atopic disease. Using murine parainfluenza virus Ms. Melissa Morales-Perez, BS3, Dr. Jerry A. Krishnan, MD, PhD4, type 1 (Sendai virus), we have shown development of post-viral atopic Dr. Steven J. Ackerman, PhD3; 1Jesse Brown VA Medical Center, Chi- disease depends upon production of CCL28. This chemokine is released cago, IL, 2MC 719, University of Illinois at Chicago, Chicago, IL, 3Uni- when IgE bound to Fc RI3 on lung conventional dendritic cells is cross- versity of Illinois at Chicago, Chicago, IL, 4University of Illinois at linked. CCL28 attracts IL-13 producing Th2 cells, leading to airway hyper- Chicag, Chicago, IL. responsiveness (AHR) and mucous cell metaplasia (MCM). We sought to RATIONALE: Airway inflammation is a central feature of asthma, and determine if CCL28, independent of viral infection, could drive AHR and induced sputum is being used to categorize it into eosinophilic (>_2% MCM. eosinophils) and non-eosinophilic (<2% eosinophils) to inform treatment METHODS: To prime for Th2 responses, C57BL/6 mice were given choices. Eosinophilic asthma has been associated with more exacerbations ovalbumin and alum i.p. on days -8 and -3. On day -1, baseline AHR was and differential responses to treatment. We sought to assess surrogate determined by a methacholine challenge with measurement of specific biomarkers of eosinophilic inflammation in induced sputum (currently airways resistance (sRaw) and conductance (sGaw) using a non-invasive determined by differential cell counts) in asthma with quantitative two-chamber plethysmography system. On days 0, 1, and 2, 0.1mg, 0.3mg, measurements of major basic protein-1 (MBP1) and CLC/Gal-10 1mg, or 3mg of CCL28 was administered intranasally. AHR was measured [Charcot Leyden Crystal (CLC) protein/Galectin-10]. again on day 3, as was MCM (by PAS staining). METHODS: 32 human subjects with mild to moderate asthma (n520) RESULTS: Only the 3mg dose of CCL28 led to significantly increased and healthy controls (n512; no lung disease) between the ages of 18-75 AHR (elevated sRaw, decreased sGaw; p<_0.05 compared to baseline values were recruited. Baseline characterizations of lung function and sputum for 20, 40 and 80 mg/ml doses of methacholine, n 5 3) and MCM (1.00+/- differential cell counts were performed. Induced sputum was analyzed for 0.44 PBS treatment versus 5.60+/-1.42 CCL28 treatment, mean+/-sem MBP1 and CLC/Gal-10 by sandwich-based ELISAs developed in our PAS+cells/mm BM; p50.031). laboratory. CONCLUSIONS: Administration of 3mg of CCL28 is sufficient to drive RESULTS: Sputum analysis revealed higher (p<0.001) levels of MBP1 development of AHR and MCM in the absence of a viral infection. Future and CLC/Gal-10 in asthmatics vs. healthy controls. Asthmatics with studies will focus on whether Th2 priming is essential for this effect, as eosinophilic inflammation (>_2% eosinophils) had higher levels of MBP1 well as the chronicity of the CCL28 induced AHR and MCM. (p50.02) and CLC/Gal-10 (p<0.001) compared to non-eosinophilic inflammation (<2% eosinophils). CLC/Gal-10 levels were highly corre- Mucosal Uric Acid Induces Interleukin 33 and Initiates Type 2 lated (r50.81, p<0.001, Spearman’s) with sputum eosinophils; MBP1 180 Immune Responses To Inhaled Protease Allergens approached significance (r50.4, p50.14). 1 2 2 Kenichiro Hara, MD , Koji Iijima, PhD , Takao Kobayashi, PhD , CONCLUSIONS: We found significant differences in MBP1 and CLC/ 3 3 2 Dr. Satoshi Seno , Dr. Ichiro Tojima , Gail Kephart , Dr. Manabu Gal-10 levels between asthmatics and healthy controls, and in asthmatics 1 1 1 Ueno , Dr. Toshitaka Maeno , Dr. Masahiko Kurabayashi , Hirohito with eosinophilic vs. non-eosinophilic airway inflammation. CLC/Gal-10 2 1 Kita, MD ; Gunma University Graduate School of Medicine, Maebashi, was strongly correlated with sputum eosinophils in asthmatics. These 2 3 Gunma, Japan, Mayo Clinic, Rochester, MN, Shiga University of Med- findings suggest that sputum CLC/Gal-10 and MBP1 may be useful ical Science, Otsu, Shiga, Japan. biomarkers for differentiation of eosinophilic airway inflammation in RATIONALE: Epithelium-derived cytokines, such as IL-33 and thymic asthma. Utilization of these biomarkers will help personalize therapies in stromal lymphopoietin (TSLP), play pivotal roles to induce type 2 immune asthma based on airway inflammatory endotype. responses and to mediate pathologic processes associated with asthma. However, the immunological mechanisms that initiate production of these cytokines are largely unknown. In this study, we sought to investigate the mechanisms involved in initiation of type 2 immune responses to airborne protease allergens. METHODS: Na€ıve mice were exposed intranasally to proteases or uric acid (UA) with or without a surrogate antigen, ovalbumin (OVA). The immunological mechanisms were analyzed by using gene-deficient and transgenic animals and pharmacologic approaches. RESULTS: IL-33 and TSLP were produced quickly in the lungs of na€ıve mice exposed to cysteine proteases, such as bromelain and papain. Protease-driven IL-33 mediated innate type 2 responses and sensitized na€ıve animals to an innocuous airway antigen, OVA. Importantly, upon exposure to proteases, UAwas rapidly released into the airway lumen, and removal of this endogenous UA by uricase attenuated type 2 immune responses. UA promoted production and extracellular release of IL-33 by airway epithelial cells in vitro, and administration of UA into the airways of na€ıve animals initiated IL-33 production and type 2 immune responses in vivo. Finally, a potent UA synthesis inhibitor, febuxostat, mitigated airway inflammation and asthma phenotypes that were caused by repeated expo- sure to natural airborne allergens. CONCLUSIONS: These findings provide mechanistic insights into the development of type 2 immunity to airborne protease allergens and identify UA as a central player in regulating this process in respiratory mucosa.
ABS 5.2.0 DTD YMAI10628_proof 11 January 2014 7:12 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB51 VOLUME 133, NUMBER 2
IL-35-Producing T Cells (iTR35) Inhibit Th2 Effector Function, expression TLR2 and CLDN1 while ZO-1 staining had an abnormal 182 Induce Infectious Tolerance and Are Elevated Following punctate pattern. Th2 cytokines inhibited Pam3C-dependent TJ barrier Grass Pollen Sublingual Immunotherapy recovery of tape-stripped human skin measured by TEER (P<0.01) and Dr. Mohamed H. Shamji, BSc, MSc, PhD1, Ms. Janice paracellular permeability (P<0.01). Layhadi, BSc(Hons)2, Mr. Alan Perera-web, BSc(Hons)2,3, Ms. Rachel CONCLUSIONS: Th2-skewed STAT6VT mice have reduced epidermal Yan, RN4, Prof. Stephen R. Durham, MA, MD FRCP5; 1Imperial College TLR2 expression and diminished TLR2-dependent epidermal barrier London, South Kensington, United Kingdom, 2Imperial College London, repair. Th2 cytokines also reduced TLR2-dependent epidermal barrier 3Medical Research Council and Asthma UK Centre for Allergic Mecha- repair in human skin. Inhibiting Th2 cytokines may improve epidermal nisms of Asthma, UK, 4Imperial College London, United Kingdom, barrier function in response to tissue injury or microbes. 5Imperial College London, London, United Kingdom. RATIONALE: iTR35 represents a novel subset of regulatory T cells. We Epicutaneous Sensitization To Food Allergens Induce IL-4- hypothesize that IL-35 suppresses grass pollen-specific Th2 responses and 184 Producing Cells and T Follicular Helper (Tfh) Cells In An IL-6 confers a regulatory phenotype on Th2 effector cells (infectious tolerance). and IL-1-Dependent Manner
Furthermore, IL-35 and iTR35 cells are induced following grass pollen Ritobrata Goswami, PhD, Leticia Tordesillas, PhD, M. Cecilia Berin, SATURDAY sublingual immunotherapy. PhD; Icahn School of Medicine at Mount Sinai, New York, NY. METHODS: Putative Th2 effector cells (CD4+ CD25- CD45RO+) from RATIONALE: Exposure to food allergens through skin contact has been grass pollen allergics (n58) were co-cultured with irradiated APCs and proposed to be a risk factor for sensitization. In mice, allergic sensitization 5mg/mL Phleum pratense extract in the presence/absence of rhIL-35. can occur via the skin in an adjuvant-dependent fashion. Adjuvanticity may Allergen-driven proliferative responses and Th2 cytokines were measured derive from microbial factors or food allergens themselves. We hypoth- by 3H-thymidine incorporation and Luminex MagPix assay, respectively. esized that innate responses elicited by food allergens from skin In a pilot cross-sectional study, levels of IL-35 and numbers of iTR35 cells keratinocytes or dendritic cells could contribute to allergic sensitization were quantified from 7 grass pollen sublingual immunotherapy (SLIT)- by promoting Th2 or Tfh responses. treated patients, 12 untreated allergic subjects (SAR) and 12 non-atopic METHODS: Mice were epicutaneously exposed (on depilatory-treated controls (NA). abdominal skin or directly on the ear pinnae) to peanut alone, or to RESULTS: IL-35 significantly suppressed grass pollen-driven prolifera- ovalbumin with staphylococcal enterotoxin B (SEB/OVA), prior to tive responses (p50.002) and IL-4, IL-5 and IL-13 concentrations in assessing innate and adaptive immune responses. Mouse primary kerati- culture supernatants (all p<0.001). IL-35-treated Th2 effector cells nocytes, and dendritic cells were stimulated with endotoxin-cleaned acquired iTR35 phenotype (mRNA IL-12p35: p50.001; EBI3, p50.002) peanut extract in vitro. and were also able to mediate suppression of T cell proliferation (p<0.001) RESULTS: Epicutaneous exposure to peanut alone, or SEB/OVA,induced and Th2 cytokine production (IL-4, IL-5, and IL-13, all p<0.02). This sensitization and anaphylaxis on re-challenge. Mouse keratinocytes suppression was reversed by neutralising antihuman IL-35 mAb (T cell respond to peanut with upregulated IL-1, IL-6, and IL-33 but not TSLP proliferation, p50.002; IL-4, IL-5 p<0.01). SLIT group had lower overall or IL-25. Dendritic cells respond to peanut with an upregulation of OX40L, retrospective seasonal symptom scores compared to SAR (p<0.01). but only in the presence of keratinocytes. In vivo, epicutaneous peanut Numbers of iTR35 cells and protein levels of IL-35 were significantly exposure induces an increase in IL-4 producing T cells, while SEB/OVA increased in the SLIT (p50.005, p50.008) and NA groups (p50.001, induces an increase in IL-4 and Tfh cells. Blocking IL-6 and IL-1 during p50.003) compared to the SAR group. SEB/OVA exposure diminishes IL-4 and Tfh responses. CONCLUSIONS: IL-35 mediates suppression of grass pollen-driven Th2 CONCLUSIONS: Epicutaneous exposure to peanut, or SEB/OVA, cell responses. iTR35 cells are induced following SLITand may contribute induces innate responses in keratinocytes and dendritic cells that support to immunologic and clinical tolerance. the differentiation of Th2 and Tfh cells. These findings support the hypothesis that environmental exposure to peanut may contribute to peanut Th2 Cytokines Inhibit Toll-Like Receptor 2 Mediated sensitization in healthy skin, while toxins commonly found on atopic 183 Epidermal Barrier Repair dermatitis skin may contribute to sensitization to weaker allergens. Takeshi Yoshida, PhD1, I-Hsin Kuo, PhD1, Anna De Benedetto, MD, FAAAAI1, Donald Y. M. Leung, MD, PhD, FAAAAI2, Lisa A. Beck, MD, FAAAAI1; 1University of Rochester Medical Center, Rochester, NY, 2National Jewish Health, Denver, CO. RATIONALE: Atopic dermatitis (AD) is characterized by Th2 inflam- mation and defects in epidermal tight junctions (TJ). We have shown that activating Toll-like receptor 2 (TLR2) on human keratinocytes enhances TJ integrity and AD epidermis has reduced expression of TLR2. These observations have led us to hypothesize that Th2 cytokines inhibit TLR2- mediated barrier repair. METHODS: We utilized the STAT6VT mouse, which expresses a constitutively active STAT6, resulting in enhanced expression of Th2 cytokines. TJ barrier recovery following tape-stripping was quantified using transepidermal water loss (TEWL) and epidermal expression of TLR2 and TJ protein measured. TJ barrier recovery of tape-stripped skin from STAT6VT and WT 6 stimulation with Pam3C (TLR1/2 agonist; ex vivo) was measured by transepithelial electrical resistance (TEER) and par- acellular permeability. Pam3C-dependent TJ barrier recovery was also examined in human skin explants post tape-stripping 6 Th2 cytokines. RESULTS: Barrier recovery (e.g. TEWL) following tape-stripping was impaired in STAT6VT mice (P<0.001). Pam3C enhanced TJ barrier recovery as measured by TEER (P<0.01) and paracellular permeability (P<0.01) in skin from WT, but not STAT6VT mice. Immunofluorescence staining of the epidermis from STAT6VT mice revealed reduced
ABS 5.2.0 DTD YMAI10628_proof 11 January 2014 7:12 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB52 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Enhanced Thymic Stromal Lymphopoietin-Induced in Clm1-/- mice, eosinophil accumulation was similar in wt and Clm1-/- 185 Eosinophil-Basophil Lineage Commitment In Atopic mice, due to hyperchemotactic responses of Clm1-/-eosinophils. Individuals CONCLUSIONS: This study highlights CLM-1 as a novel regulator of Claudia C. K. Hui, MSc1, Sina Rusta-Sallehy, BSc1, Dr. Ilan IL-33-induced eosinophil activation. These data contribute to the under- Asher, MD1, Delia Heroux, BSC1, Judah Aryeh Denburg, MD, FRCPC, standing of endogenous molecular mechanisms regulating IL-33-induced FAAAAI2; 1McMaster University, Hamilton, ON, Canada, 2Division of responses and may ultimately lead to receptor-based tools for future Clinical Immunology and Allergy, Department of Medicine, McMaster therapeutic intervention in IL-33-associated diseases. University, ON, Canada. RATIONALE: Seminal studies have highlighted a critical immunomod- Role Of Interleukine-33 In Rhinovirus-Induced Allergic ulatory role for thymic stromal lymphopoietin (TSLP) in allergic 187 Asthma Exacerbation inflammation, as well as TSLP effects on the differentiation of progenitors Dr. Marie Toussaint, DMV, PhD, Dr. Aran Singanayagam, MD, in animal models. We have previously shown that TSLP is sufficient to Prof. Sebastian L. Johnston, MD, PhD, Dr. Nathan Bartlett, PhD; Imperial induce the differentiation of human hemopoietic progenitors (HHP) into College London, London, United Kingdom. eosinophils and basophils, but the effect of atopic sensitization on TSLP- RATIONALE: Interleukin (IL)-33 is an important promoter of type 2 induced ‘in situ hemopoiesis’ has not been studied. helper (Th2) immune responses and potentially important in asthma. METHODS: Peripheral blood HHP derived from atopic and nonatopic Rhinovirus (RV)-induced asthma exacerbations are characterised by individuals were stimulated with TSLP and/or IL-3 and assessed for Eo/B increased Th2 immunity and allergic inflammation. We hypothesized colony forming units (CFU) by methylcellulose cultures, TSLPR expres- that RV infection of the allergic lung would increase IL-33 expression sion by flow cytometry, and cytokine/chemokine secretion by Luminex. which in turn would enhance Th2 responses and cause asthma RESULTS: HHP isolated from atopic individuals were functionally and exacerbation. phenotypically more responsive to TSLP than those from nonatopic METHODS: To model RV-induced asthma exacerbation mice were individuals. HHP derived from atopics produced significantly more Eo/B sensitised and challenged with house dust mite (HDM). For exacerbation CFU than those from nonatopics post IL-3- (p<0.05) and IL-3/TSLP- groups, mice were infected with RV 24 hours after final challenge. stimulation (p<0.001). Within the atopic group, TSLP increased the Responses in Bronchoalveolar lavage (BAL), serum, mediastinal lymph formation of IL-3-responsive Eo/B CFU (p<0.01). No differences in nodes (MLN), lung tissue and Airway hyperresponsivness (AHR) were TSLPR expression were observed in both groups at baseline or after IL-3- assessed after HDM challenges prior to infection and at days 1 and 4 post- stimulation; however, expression was significantly increased in atopic infection. IL-33 and Th2 cytokines (IL-4, IL-5 and IL-13) expression subjects post TSLP- (p<0.01) and IL-3/TSLP-stimulation (p<0.01). (ELISA) were measured in the total lung and in the BAL. Quantification of Overall, HHP derived from atopic individuals secreted higher levels of Th2 cytokines was also performed in the supernatant of MLN cells after in cytokines/chemokines (IL-1b, IL-6, IL-13, TNFa, CXLC8, CCL5, vitro HDM restimulation. CCL17) compared to HHP from nonatopic individuals. RESULTS: RV-induced exacerbation was characterised by increased CONCLUSIONS: This is the first study to demonstrate enhanced TSLP- eosinophilic airway inflammation (p<0.001), airway hyperresponsiveness mediated hemopoiesis ex vivo in relation to clinical atopic status. The ca- (p<0.001) and increased IgE serum levels (p<0.5) compared to uninfected pacity of human HHP to participate in TSLP-driven allergic inflammation HDM allergic mice. In allergen-challenged RV-infected mice, IL-33 and points to the potential importance of ‘in situ hemopoiesis’ in allergic IL-13 protein level in the total lung and the level of Th2 cytokine (IL-4; inflammation initiated at the epithelial surface. p<0.001, IL-5; p<0.5 and IL-13; p<0.001) in the supernatant of MLN cells, were also significantly increased (p<0.01, p<0.05) compared to CMRF35-Like Molecule 1 (CLM-1) Is Required For IL-33- control mice. 186 Induced Eosinophil Activation CONCLUSIONS: HDM allergic mice produced more IL-33 after RV Dr. Ariel Munitz, PhD1, Mrs. Dana Shik1, Mr. Itay Moshkovits2, infection compared to uninfected allergic mice. Increased IL-33 was Mrs. Danielle Karo-Atar1; 1Department of Clinical Microbiology and associated with increased Th2 immune responses and allergic airways Immunology, The Sackler School of Medicine, Tel-Aviv University, Tel inflammation. Aviv, Israel, 2Tel-Aviv University, Israel. RATIONALE: IL-33 is a potent activator of various cells involved in allergic inflammation including eosinophils and mast cells. Despite its critical role in Th2 disease settings, endogenous molecular mechanisms that may regulate IL-33-induced responses remain to be defined. We have recently shown that eosinophils express CMRF35-like molecule (CLM)-1. Yet, the role of CLM-1 in regulating eosinophil functions is still elusive. METHODS: CLM-1 and CLM-8 expression and cellular localization was assessed in murine bone marrow-derived and/or peritoneal cells at baseline and following IL-33 stimulation (flow cytometry, western blot). IL-33- induced mediator release and signaling were assessed in wild type (wt) and Clm1-/- cells and mice. RESULTS: BM-derived eosinophils express high levels of non-glycosy- lated CLM-1. IL-33 induced a rapid, specific, concentration- and time- dependent upregulation of CLM-1 in eosinophils (in-vitro and in-vivo). CLM-1 was required for IL-33-induced mediator release from eosinophils. CLM-1 co-localized to ST2 following IL-33 stimulation and was required for IL-33-induced NFkB and p38 phosphorylation. Th2 cytokine (e.g. IL- 5, IL-13) and chemokine (e.g. eotaxin) secretion was markedly decreased in IL-33-treated Clm1-/- mice. Subsequently, IL-33-challenged mice dis- played reduced infiltration of mast cells, macrophages, neutrophils and B cells. Despite the markedly impaired IL-33-induced eotaxin expression
ABS 5.2.0 DTD YMAI10628_proof 11 January 2014 7:12 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB53 VOLUME 133, NUMBER 2
TGF-beta1 Mobilizes Mesenchymal Stem Cells In Allergic hours post nasal allergen challenge (NAC) for B cell phenotyping by flow 188 Asthma cytometry. Ting Xu, MD1,2, Ling-Ling Xian, MD, PhD3, Yufeng Zhou, MD, PhD1, RESULTS: Allergic individuals trended towards decreased IL-10 mRNA Beverly Plunkett, MS1, Xu Cao, PhD3, Mei Wan, MD, PhD3, Peisong expression 5 hours post CpG stimulation (p50.06) compared to NA Gao, MD, PhD1; 1Division of Allergy & Clinical Immunology, Johns controls, whereas no difference in IL-10+ B cell frequency (p50.5) nor IL- Hopkins University School of Medicine, Baltimore, MD, 2Department 10 concentration (p50.24) was observed. Overall, AIT patients showed a of Respiratory Medicine, Southern Medical University, Guangzhou, trend towards increased proportions of IL-10+ B cells compared to SAR China, 3Department of Orthopedics Surgery, Johns Hopkins University (p50.06), whereas the SLIT group had significantly greater proportions School of Medicine, Baltimore, MD. of IL-10+ B cells and IL-10 concentrations relative to SAR (p50.0009 RATIONALE: Mesenchymal stem cells (MSCs) have been suggested to and p50.046). Following NAC, Breg subsets (CD19+CD24hiCD38hi, participate in airway repair/remodeling. Transforming growth factor b1 CD19+CD5hi, CD19+CD24hiCD27hi and CD19+CD25+) significantly (TGFb1) is critical in the recruitment of stem/progenitor cells for tissue increased in NA and AIT groups (all p<0.05), but not in the SAR group. repair, regeneration, and remodeling. We here sought to investigate CONCLUSIONS: Grass pollen immunotherapy is associated with an + whether TGFb1 plays a role in MSC migration in allergic asthma. increase in peripheral IL-10 B cells and appears to restore a normal pe- SATURDAY METHODS: MSC migration was examined by using conditioned me- ripheral regulatory B cell response following local nasal allergen chal- dium (ECM) from cockroach extract (CRE)-challenged human bronchial lenge, compatible to that observed in non-allergic controls. epithelial cells (HBECs) in air/liquid interface (ALI) culture. The involvement of TGFb1 in ECM-induced MSC migration was investigated Respiratory Syncytial Virus Induces IL-25 and IL-33 b 190 Production In The Lungs by using ECM containing TGF 1 neutralizing antibody or control IgG 1 2 1,2 1 antibody. Furthermore, the migration of MSCs to CRE-challenged airway Matthew T. Stier , Kasia Goleniewska , R. Stokes Peebles ; Depart- b ment of Pathology, Microbiology, and Immunology, Vanderbilt University and the effect of TGF on MSC migration were examined in nestin-GFP 2 transgenic mice. School of Medicine, Nashville, TN, Allergy, Pulmonary, and Critical RESULTS: MSC migration was significantly enhanced by ECM from Care Medicine, Department of Medicine, Vanderbilt University School cockroach extract-challenged HBECs when compared with those from un- of Medicine, Nashville, TN. challenged cells. The increased migration was inhibited by antibodies RATIONALE: Respiratory syncytial virus (RSV) is the leading cause of against TGFb1. Significant inhibition was also observed with TbR1 hospitalization in infants. Early, severe RSV infection is also a risk factor inhibitor use. MSCs from bone marrow of GFP-transgenic mice demon- for the subsequent development of asthma. RSV infects the airway strated their ability to differentiate into fibro/myo-fibroblasts. Furthermore, epithelium, causing mucus production, epithelial cell sloughing, peribron- when these isolated GFP+-MSCs were injected systematically, the number chiolar inflammation, and increased airway hyperresponsiveness. of migrated GFP+-MSCs into lung was significantly increased after CRE Epithelial-derived cytokines IL-25 and IL-33 stimulate IL-13 and mucus challenge. Significantly greater numbers of endogenous GFP+ cells were production in asthma models. RSV infection produces similar Th2-like observed in allergen-challenged lung of nestin-GFP transgenic mice phenotypes, suggesting a role for epithelial-derived cytokines in this when compared with those receiving saline alone. Interestingly, these system. We sought to analyze the role of IL-25 and IL-33 during RSV increased MSCs could be inhibited when TGFb1 neutralizing antibody infection. was utilized. METHODS: Six to eight week old BALB/c mice were infected with CONCLUSIONS: These results provide evidence supporting a role of 1.5E6 PFU of RSV clinical isolate strain 01/2-20 or vehicle. Mice were TGFb1 in MSC migration, suggesting the importance of MSCs in allergen harvested at 3hr, 6hr, 12hr, 24hr, 48hr, 72hr, and 96hr with the collection of induced airway repair/remodeling in asthma. left lung, right lung, and bronchoalveolar lavage fluid. Transcript levels were measured by quantitative PCR and normalized to GAPDH. Protein IL-10-Producing B Cells Are Increased After Grass Pollen concentrations were evaluated by ELISA (R&D DuoSet). 189 Immunotherapy Compared To Untreated Grass Pollen Allergic RESULTS: IL-25 transcript and protein were most abundant at 3 and 6 Controls: A Blinded Cross-Sectional Study hours post infection, respectively. Transcript and protein levels of IL-33 Mr. James E. G. Charlesworth1,2, Dr. Guy W. Scadding, MD1,2, peaked at 12 hours post infection. Dr. Aarif Eifan, MD2, Ms. Rachel Yan, RN2, Ms. Andrea CONCLUSIONS: These data suggest a role for IL-25 and IL-33 in the Goldstone, RN2, Dr. Moises A. Calderon, MD, PhD1,2, Prof. Stephen R. RSV-associated immune response, prompting the need for additional Durham, MA, MD, FRCP3,4, Dr. Mohamed H. Shamji, BSc, MSc, studies on these epithelial-derived cytokines in regard to viral clearance PhD5; 1Medical Research Council and Asthma UK Centre for Allergic and immunopathology. Mechanisms of Asthma, United Kingdom, 2Imperial College London, United Kingdom, 3Imperial College London, London, United Kingdom, 4Medical Research Council and Asthma UK Centre for Allergic Mecha- nisms of Asthma, London, United Kingdom, 5Imperial College London, South Kensington, United Kingdom. RATIONALE: Grass pollen immunotherapy (AIT) induces Foxp3 and/or IL-10-expressing regulatory T cells and increases in allergen-specific IgG4. We previously showed that in vitrostimulation with CpG induced IL- 10-competent B cells capable of suppressing Th2 responses. This study ex- amines IL-10-producing B cells (Bregs) during AIT. METHODS: 14 grass pollen allergics receiving AIT (8 subcutaneous (SCIT) and 6 sublingual (SLIT) patients), 14 untreated allergics (SAR) and 14 non-allergic (NA) controls were studied. Blood was drawn for quantification of IL-10-producing B cells following CpG stimulation by FluoroSpot assay. IL-10 supernatant concentrations were measured by ELISA and mRNA responses by qPCR. Blood was also obtained pre and 6
ABS 5.2.0 DTD YMAI10628_proof 11 January 2014 7:12 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB54 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Small-Molecule Inhibition Of Stat3 Prevents House-Dust-Mite development to regulate or prevent excessive expansion of the eosinophil 191 (HDM)-Induced Airway Inflammation By Blocking Lung lineage in parasitic and allergic diseases. Production Of Th17 and Th2 Cytokines Dr. Aries C. Gavino, MD, Dr. David J. Tweardy, MD; Baylor College of Multiplex Cytokine Analysis Of Cord Blood Non-Adherent Medicine, Houston, TX. 193 Mononuclear Cells From Infants With Attributable Atopic Risk Following Il-5 Stimulation RATIONALE: Alternative treatments are needed for steroid-resistant, 1 2 Th17-mediated asthma. Signal transducer and activator of transcription 3 Mrs. Jenny Thiele, MSc , Ms. Vanessa N. Omana, MSc , Dr. Anne K. Ellis, MD, MSc, FAAAAI3; 1Queens University, Kingston, ON, Canada, (Stat3) drives Th17 differentiation and is linked to Th17- and Th2- 2 3 mediated airway inflammation. We hypothesized that C188-9, a small- Queen’s University, ON, Canada, Allergy Research Unit, Kingston Gen- molecule probe that inhibits Stat3 activation, can prevent HDM-induced eral Hospital, Kingston, ON, Canada; Departments of Medicine and airway inflammation by blocking production of Th17- and Th2-type Biomedical & Molecular Science, Queen’s University, Kingston, ON, cytokines. Canada. METHODS: C57BL/6 mice were treated for 15 days: 10 mice (control) RATIONALE: Atopy is the predisposition of individuals to develop daily received vehicle 1 (PBS; 50 ul) intranasally (IN) and vehicle 2 (10% allergic diseases. It is thought that infants born to atopic mothers display DMSO + 50% PEG400 in 5% dextrose; 200 ul) intraperitoneally (IP); 10 altered cytokine profiles in umbilical cord blood (UCB). We aimed to mice daily received HDM (40 ug in PBS) IN and vehicle 2 IP; and 10 mice identify a cytokine profile that indicates atopic risk as early as delivery. 5 5 daily received HDM IN and C188-9 (50 mg/kg in vehicle) IP. Total (t) METHODS: UCB was collected at birth (n 10 atopic, n 6 non-atopic). Stat3, Stat3 phosphorylated on Y705 (pStat3), IL-4, IL-5, IL-13, and IL-17 Samples were depleted of erythrocytes followed by isolation of mono- levels were measured in protein extracts of right lungs using Luminex nuclear cells (MNCs), and temporarily cryo-preserved. Once thawed beads. Sections of paraformaldehyde-fixed, paraffin-imbedded left lungs samples were depleted of adherent cells. Non-adherent mononuclear cells were stained with Alcian Blue/PAS and examined microscopically. (NAMNCs) were incubated with human recombinant interleukin 5 (rhIL- RESULTS: As expected, HDM inhalation increased airway goblet cell 5; 1ng/ml) and the supernatants were collected at 0, 24, 48 and 72 hours post-stimulation. Supernatants were examined by Luminex xMAP tech- numbers 35-fold, airway epithelia thickness 5-fold, and subepithelial Ò smooth muscle thickness 3-fold (p<0.0001 for each), which was accom- nology. The MILLIPLEX High Sensitivity Human Cytokine Magnetic b panied by a 7-fold increase in the pStat3-to-tStat3 ratio, a 3-fold increase in Bead Kit (Millipore) was used to measure IL-1 , IL-2, IL-4, IL-6, IL-7, g a IL-17, a 100-fold increase in IL-4, a 4-fold increase in IL-5, and a 2-fold IL-8 IL-10 IL-1, IFN- , GM-CSF, and TNF- . increase in IL-13 (p<0.05 for each). Remarkably, C188-9 treatment RESULTS: IL-5 Stimulation of NAMNCs from atopic participants concurrent with HDM inhalation normalized each endpoint, decreasing resulted in significant up-regulation of IL-2, IL-4, IL-6 IL-8, IL-10, IL- a each to levels statistically indistinguishable from control mice. 12, GM-CSF and TNF- (P<0.05 compared to 0 hr control by repeated CONCLUSIONS: Stat3 activation is critical for HDM-induced Th2- and measures ANOVA). In NAMNCs from non-atopic participants, only IL-2, Th17-mediated airway inflammation and can be prevented by use of IL-7, and IL-8 were significantly up-regulated (P<0.05). In addition, the g C188-9. up-regulation of IFN- and IL-12 concentrations were significantly different at 48 and 72 hr post-stimulation in the atopic samples compared Differential Promoter Usage and Regulation Of The Human to the non-atopic samples, respectively (P<0.05, by Mann-Whitney test). 192 Interleukin-5 Receptor a (IL-5Ra) Gene In Developing CONCLUSIONS: These findings suggest there are cytokine level Eosinophil Progenitors differences between atopic and non-atopic samples following IL-5 Kimberly G. Laffey, BSc, Dr. Jian Du, MD, Dr. Steven J. Ackerman, stimulation, which could potentially be applied as a predictive measure PhD; University of Illinois at Chicago, Chicago, IL. for newborns. RATIONALE: IL-5Ra is a critical component of the IL-5 signaling pathway responsible for regulating the expansion of the eosinophil lineage for development of eosinophilia in allergic diseases, including asthma. IL- 5Ra has two promoters, P1 and P2, both functionally active in eosinophilic cell lines. However, their differential roles and regulation during the development of authentic eosinophil progenitors remain unexplored. METHODS: Human umbilical cord blood-derived CD34+progenitors un- der IL-5-induced eosinophil differentiation were transfected with IL-5Ra- P1 or -P2 promoter luciferase reporter vectors at various time points to assess their differential promoter activity. Chromatin immunoprecipitation (ChIP) was performed at corresponding time points to determine the dy- namic occupancy of these promoters by transcription factors implicated in IL-5Ra regulation during eosinophil development. RESULTS: The IL-5Ra-P1 promoter is active throughout IL-5-induced eosinophil differentiation of CD34+/IL-5Ra+progenitors. However, P2 promoter activity is suddenly induced on day 7, overtaking P1 activity, before being attenuated during continued eosinophil development. Peak P2 activity coincides with a dramatic induction in expression of the pre- dominant soluble IL-5Ra isoform mRNA. Correspondingly, quantitative ChIPs revealed that the two promoters exhibit differential occupancy by transcription factors GATA-1, PU.1 and/or the C/EBP family of transcrip- tion factors (a, b and ε). CONCLUSIONS: Human IL-5Ra-P1 and -P2 promoters are under differential regulation, mediated in part through dynamic and combinato- rial interactions of stage-specific transcription factors. The coincidental peak in P2 promoter activity and IL-5Ra soluble isoform mRNA suggest that the IL-5-binding soluble receptor isoform is induced during eosinophil
ABS 5.2.0 DTD YMAI10628_proof 11 January 2014 7:12 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB55 VOLUME 133, NUMBER 2
Association Of IL-33 With Atherogenic Cytokines: A Link vivo actions on various cells, both resident and inflammatory, resulting in 194 Between Allergic Disease and Atherosclerosis beneficial outcomes in tissue damaging disorders. Dr. Misu Paul, MD1, Dr. Allison B. Reiss, MD2, Dr. Steven Carsons, MD3, Dr. Luz S. Fonacier, MD, FAAAAI4, Dr. Iryna Voloshyna, Variation In mRNA Expresion Of GATA1 and PRG2 In Umbilical 2 1 196 Cord Blood Following IL-5 Stimulation PhD ; Section of Allergy and Clinical Immunology, Department of Med- 1 2 icine, Winthrop University Hospital, mineola, NY, 2Winthrop Research Ms. Vanessa N. Omana, MSc , Mrs. Jenny Thiele, MSc , Dr. Anne K. El- lis, MD, MSc, FAAAAI3; 1Queen’s University, ON, Canada, 2Queens Uni- Institute, Department of Medicine, Winthrop University Hospital, Mine- 3 ola, NY, 3Division of Rheumatology, Allergy and Immunology, Depart- versity, Kingston, ON, Canada, Departments of Medicine and Biomedical ment of Medicine, Winthrop University Hospital, Mineola, NY, 4Section & Molecular Science, Queen’s University, Kingston, ON, Canada. of Allergy and Clinical Immunology, Department of Medicine, Winthrop RATIONALE: GATA1 and PRG2 are key genes in eosinophil-lineage University Hospital, Mineola, NY. commitment. Our laboratory recently developed a multiplexed qPCR anal- RATIONALE: Previous work by our group indicated that interleukin (IL) ysis of GATA1 and PRG2 mRNA expression in non-adherent mononuclear —33 might play a dual role in allergic diseases functioning as an inducer of cells (NAMNCs) following IL-5 stimulation. We aimed to determine if dif- immune responses and promoting pro-atherogenic changes in lipid ferences exist in mRNA expression patterns of GATA1 and PRG2in the um- SATURDAY metabolism. We investigate here the effects of IL-33 on THP-1 macro- bilical cord blood (UCB) of infants with attributable risk of atopy. phage activation and relationships between IL-33 and other pro-and anti- METHODS: UCB was collected at birth and maternal atopic status 5 5 inflammatory cytokines in plasma of healthy (HC) and atopic patients (AP) confirmed by skin prick testing (SPT) (n 28 atopic, n 18 non-atopic). with allergic rhinitis and asthma. Mononuclear cells (MNCs) were isolated from the UCB samples, cryopre- METHODS: THP-1 human-macrophages were incubated for 24h under served, then later thawed and depleted of adherent cells. NAMNCs were the following conditions: (1) phosphate buffered saline control, (2) IL-33 at incubated with human recombinant interleukin 5 (rhIL-5; 1ng/mL) and concentrations of 5, 10, 20 and 50ng/ml. Cell culture supernatants and collected at 0, 24, 48 and 72 hours post-stimulation. Multiplex qPCR was plasma from atopic patients [AP] (n520) and healthy controls [HC] performed to measure GATA1 and PRG2mRNA expression at all time points. (n510) were analyzed for levels of IL-33, IFNg, TNFa, IL-1b, IL-17a, IL- RESULTS: Stimulation of cord blood NAMNCs with IL-5 resulted in 10, IL-2, IL-5 with Milliplex-kit. steady downregulation of GATA1 expression beginning at 24 hours. RESULTS: Exposure of THP-1 macrophages to IL-33 resulted in a Conversely, there was an upregulation of the PRG2 gene expression, as pre- concentration-dependent release of TNFa (393.7 pg/ml for 50ng/ml IL-33 viously demonstrated. However, there were no significant differences in vs. 208.7 pg/ml for control [P<0.05, n52]), IFNg (2.49 pg/ml vs. 1.7 pg/ the GATA1 and PRG2 gene expression patterns of UCB samples from in- 5 ml) and IL-1b (188.93 pg/ml vs. 110.9 pg/ml [P<0.05, n52]). Similar fants born to atopic mothers vs. non-atopics. (GATA1 P 0.2285, 0.3166, 5 pattern was detected in AP plasma compared to HC. Increasing concen- and 0.1174 24h, 48h and 72h, respectively; PRG2P 0.1663, 0.6285, and trations of IL-33 in plasma strongly correlated with levels of IFNg 0.7612 at 24h, 48h and 72h). (r50.85), TNFa (r50.9) and IL-17a (r50.94). CONCLUSIONS: In this study, multiplexed qPCR analysis of GATA1 CONCLUSIONS: IL—33 in-vitro and in AP plasma augments levels of and PRG2 mRNA expression showed no significant differences between the pro-inflammatory cytokines IFNg and TNFa. Strong correlation of infants born to atopic versus non-atopic mothers, but enhanced understand- IL-33 and IL-17 in AP is a possible link for IL-33 involvement in IL-17 ing of eosinophilopoesis in UCB. mediated activation of the adaptive T-cell response and inflammatory-cyto- Mast Cells Drive Tissue Inflammation By Producing IL-33 That g a kine induction. The known atheroma-promoting nature of IFN and TNF 197 Orchestrates a Unique Basophil Phenotype could explain pro-atherogenic properties of AP plasma. Dr. Chia-Lin Hsu, PhD, Dr. Paul Bryce, PhD; Division of Allergy-Immu- Modulation Of Human Basophil Degranulation By nology, Department of Medicine, Feinberg School of Medicine, North- 195 Geranylgeranyl Compounds western University, Chicago, IL. Dr. Yuko Nakase1, Dr. Masao Yamaguchi1, Dr. Naoya Sugimoto1, RATIONALE: Skin, an important environmental interface, protects Dr. Maho Suzukawa, MD2, Dr. Hiroyuki Tamiya1, Dr. Yasuhiro Kojima1, against allergens that can trigger local or systemic anaphylactic reactions Dr. Hisanao Yoshihara1, Dr. Michio Kuramochi1, Dr. Hidenori Arai1, in allergic individuals. Skin-resident mast cells drive an early edema Dr. Hiroyuki Nagase1, Dr. Ken Ohta1,2; 1Teikyo University School of followed by a late antigen-driven tissue inflammation (ADTI) character- Medicine, Tokyo, Japan, 2National Hospital Organization Tokyo National ized by inflammatory cell recruitment. While histamine is important for the Hospital, Tokyo, Japan. immediate edema after encountering the antigens, the mechanisms that RATIONALE: Diverse pharmacological actions of geranylgeranyl (GG) control the inflammatory cell influx are still unclear. compounds are only partially clarified so far. These compounds are METHODS: A passive cutaneous model was used to study the ADTI. reported to exert various beneficial effects in vivo on inflammatory diseases Mice were intradermally injected with PBS in one ear and DNP-specific at skin or lung, and protection at gastric mucosa. GG compounds can also IgE in the other followed by intravenous challenge with DNP-HSA. Ear modulate cellular functions in vitro, including enhancement of mast cell swelling was measured and cell infiltration was determined by flow degranulation. In this study, we assessed whether these compounds can cytometry. Murine bone marrow-derived basophils (BMBs) were gener- affect the activation of human basophils. ated in vitro by culturing with IL-3 and activated with IgE/DNP or IL-33. METHODS: Basophils were obtained from normal volunteers and RESULTS: In vitro, we showed that IgE/DNP primed BMBs to produce preincubated with geranylgeranylacetone (GGA) at 1 ml/ml for 15 min Th2-associated cytokines like IL-4 and CCL24, while IL-33 activated ba- at 37oC, washed, and stimulated with various secretagogues. sophils to secrete neutrophil-recruiting chemokines, such as IL-6, CXCL1 RESULTS: Degranulation of basophils induced by anti-IgE antibody or and CXCL2. In vivo, we showed that mast cell-derived IL-33 was sufficient PMA was significantly enhanced by GGA or geranylgeraniol. However, and necessary to induce the late phase ear swelling. ST2 and IL-6-express- These compounds failed to affect basophil histamine release evoked by ing basophils were also required for inflammatory cell recruitment. MCP-1 or ionophore A23187. Compounds with shorter structures such as Furthermore, it was H4R responsible for basophil recruitment. geranylacetone of farnesol did not alter basophil degranulation. CONCLUSIONS: Our finding indicated that mast cells acted as local Simvastatin, an inhibitor of intracellular generation of GG compounds, sensors in responding to foreign antigens. Histamine was produced suppressed basophil histamine release by anti-IgE antibody or PMA. immediately and basophils were recruited through H4R. Migrated CONCLUSIONS: These results suggest that human basophils are a target basophils were then activated by mast cell-derived IL-33 through ST2 and produced IL-6 to promote antigen-driven tissue inflammation by cell type of GG compounds. Although the precise role of their modulation + high of basophil functions is not clear, these compounds may orchestrate the in recruiting CD45 Gr-1 neutrophils.
ABS 5.2.0 DTD YMAI10628_proof 11 January 2014 7:12 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB56 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Differential Regulation Of Pro-Inflammatory Cytokine Asthma Severity and Expression Of CLC3 On Human 198 Expression Of Airway Smooth Muscle Cells (ASM) By 200 Peripheral Blood and Nasal Lavage Eosinophils Insulin, Glucose, and Rosiglitazone Devendra K. Agrawal, Rohit Gaurav, Againdra K. Bewtra; Departments Dr. Qura-Tul-Ain Rashid, MD1, Dr. Lata Kaphalia, PhD2, Dr. William J. of Biomedical Sciences and Internal Medicine, and Center for Clinical Calhoun, MD, FAAAAI3; 1Allergy and Immunology, University of Texas and Translational Science, Creighton University School of Medicine, Medical Branch, 2University of Texas Medical Branch, Galveston, 3Al- Omaha, NE. lergy And Immunology, University of Texas Medical Branch, Galveston, RATIONALE: We have reported the role of CLC3 in TGF-b-induced TX. migration and activation of eosinophils, and increased expression of RATIONALE: Insulin and glucose induce a pro-inflammatory phenotype CLC3b and CLC3e transcript variants on TGF-b and eotaxin-treated in inflammatory cells, but the effects on ASM, which themselves can eosinophils. Severity of asthma and corticosteroid treatment may deter- potently regulate inflammation, are not known. PPARg receptor activity mine the CLC3 expression on eosinophils. can modulate inflammatory responses. Therefore, we hypothesized that METHODS: Eosinophils were isolated from human venous blood (>99% ASM will express increased inflammatory cytokines in response to insulin, pure; >98%viable) with negative selection from healthy (n510), mild-to- and this response may be influenced by levels of glucose, and the PPARg moderate (n510) and moderate-to-severe (n510) allergic asthmatics. agonist rosiglitazone, which acts as an insulin sensitizer. Nasal washings were taken from respective groups. Q-PCR, Western blot, METHODS: Cultured primary ASM cells were stimulated with LPS and fluorescence microscopy were used to obtain outcome measures. (2uM) and treated with insulin (100 nM), glucose (300 mg/dl) and RESULTS: mRNA transcripts of CLC3 variants varied among groups rosiglitazone (25uM) for 24 hours. Supernatant was harvested and based on the severity of asthma and corticosteroid treatment. Eosinophils concentrations of 17 cytokines were measured by multiplex ELISA. from mild-to-moderate asthmatics had 5-6-fold increase in CLC3 mRNA Three-way ANOVAwas the primary statistical method. transcripts compared to healthy volunteers. However, moderate-to-severe RESULTS: Unsurprisingly, proximal pro-inflammatory cytokines were asthmatics on inhaled corticosteroid had 2-3-fold increase in CLC3 influenced to a greater degree than distal cytokines. As an example, IL-8 transcripts. The CLC3b and CLC3e transcripts were increased 5-7 and 6- expression was significantly increased by rosiglitazone from 3800 to 5700 8-fold in mild-to-moderate asthmatics, and in moderate-severe asthmatics pg/ml, whereas high glucose significantly decreased IL-8 from 5200 to increase by 4-5 and 3-4 fold, respectively. Protein expression of CLC3 also 4400 pg/ml. In the presence of insulin, rosiglitazone further increased IL-8 followed the same trend. Asthmatics nasal lavage contained multiple expression to 7900 pg/ml. In contrast, G-CSF and expression was eosinophils expressing different levels of CLC3 with increased expression significantly increased by rosiglitazone, but significantly decreased by in mild-to-moderate than moderate-to-severe asthmatic and no inflamma- insulin, whereas effects in the opposite direction were observed for TNF-a tory cells in healthy subjects. and IL-6 (augmented expression by insulin). CONCLUSIONS: The CLC3 expression on eosinophils correlates with CONCLUSIONS: Inflammatory cytokine expression in ASM cells is asthma severity. Reduction in CLC3 expression may be an additional modulated by glucose, insulin, and the PPARg agonist rosiglitazone. mechanism of corticosteroid effects in allergic airway inflammation. Insulin is generally pro-inflammatory. These data suggest that patients with Differential CLC3 expression on nasal eosinophils could be a biomarker abnormalities of glucose metabolic pathways, particularly hyperinsuline- of asthma severity and treatment with corticosteroids. mia, may have consequent effects on immune function and regulation of airway inflammation.
An Association Between Disease Severity and Levels Of 199 Low-Density Granulocytes In The Peripheral Blood Mononuclear Cell Fraction Of Asthma Subjects Dr. Mary C. Tobin, MD1,2, Dr. Jun Fu, PhD1, Ms. Paige Adeli, RN1, Dr. Larry L. Thomas, PhD1; 1Rush University Medical Center, Chicago, IL, 2University Consultants in Asthma and Allergy, Chicago, IL. RATIONALE: A neutrophil-like cell population termed low-density granulocytes (LDG) has previously been identified in association with disease activity in the peripheral blood mononuclear cells (PBMC) of patients with systemic lupus erythematosus (SLE). We report here that LDG levels are also significantly elevated in the PBMC of patients with moderate persistent or severe persistent asthma. METHODS: Levels of LDG in the PBMC of 20 non-asthmatic control subjects, 20 subjects with intermittent (I) or mild persistent (MiP) asthma, and 20 subjects with moderate persistent (MoP) or severe persistent (SP) asthma were quantified by polychromatic flow cytometry. RESULTS: The percentages of LDG were significantly elevated (7.4 6 10.8 %; mean 6 SD) in the PBMC of subjects with MoP/SP asthma compared to PBMC of control subjects (1.3 6 1.1 %) or subjects with I/ MiP asthma (2.1 6 2.2 %). A statistically significant increase in the number of LDG in the PBMC paralleled the increase in LDG percentage. The highest percentages (up to 39%) of LDG were observed in PBMC of four subjects with SP asthma. The LDG in all subjects expressed at least two-fold higher levels of CD15 (Lewis x) and, as reported previously, increased levels of CD11b and CD66b compared to neutrophils. CONCLUSIONS: These findings extend the association between LDG and disease severity reported previously for SLE to now include asthma and, thus, identify LDG as potentially new cells of interest in asthma severity.
ABS 5.2.0 DTD YMAI10628_proof 11 January 2014 7:12 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB57 VOLUME 133, NUMBER 2
The Interaction Of Bifidobacteria With Human Blood CONCLUSIONS: Based on publications to date, LAD2 cells have made a 201 Leukocytes substantial impact on the study of human mast cell biology. The NIAID Dr. Leonid P. Titov, MD, PhD1, Dr. A. S. Murashko2, Dr. Andrei Y. approach via MTAs or LAs to obtain cells and have queries addressed in a Hancharou3, Dr. N. A. Golovnyova3, Dr. E. I. Kolomiets3, timely fashion, should enable future research and become a model system Prof. Lawrence M. DuBuske, MD, FAAAAI4; 1Republican Scientific for other developed and available cell lines. and Practical Center for Epidemiology and Microbiology, Minsk, Belarus, 2Republican Scientific And Practical Center for Epidemiology and Micro- Non c-Kit Tyrosine Kinase Expression In Mast Cell Leukemia biology, Minsk, Belarus, 3Republican Scientific and Practical Center for 203 Dr. Joseph H. Butterfield, MD, FAAAAI; Mayo Clinic, Ro- Epidemiology and Microbiology, Minsk, Belarus, 4George Washington chester, MN. University School of Medicine, DC. RATIONALE: The c-kit Asp816Val mutation is present in all subclasses RATIONALE: Probiotics may possibly exert health benefits in enteric of systemic mastocytosis (SM), yet the clinical courses of patients differ infections, allergic and autoimmune diseases. There is great variation in the greatly. Treatment approaches based on inhibiting mutated c-kit have ability of different strains of Bifidobacterium to interact with the immune largely been ineffective, suggesting that additional tyrosine kinase genes cells. This study assesses the interaction of Bifidobacterium strains with could be overexpressed as well. SATURDAY human monocytes, neutrophils and lymphocytes. METHODS: Peripheral blood (PB) cells frozen in 1985 from a mast cell METHODS: 4 Bifidobacteria strains, as well as their cell walls and lysates leukemia (MCL) patient whose cells were the source for the HMC-1 cell were assessed. Bacterial cells labeled with FITC were used for the line were examined for expression of tyrosine kinase genes. After thawing phagocytosis assay and Reactive Oxygen Species production study by and short-term cell culture, RNA was isolated from these MCL-PB cells. neutrophils. Blood cells were cultured with bacterial cell walls and cell For control, peripheral blood cells remaining in a leukoreduction system lysates. Flow cytometry was used to determine cell surface markers from chamber from a plateletpheresis donor were used. Microarray analysis was monocytes and lymphocytes (CD80/CD14, CD69/CD3) and ELISA to conducted according to manufacturer’s instructions for the Affymetrix measure cytokines (TNF-a, INF-g). One Cycle Target Labeling and Control Reagents kit. Data was searched RESULTS: Inter-strain variations in the ability of Bifidobacteria to be for increased expression of receptor and non-receptor tyrosine kinase phagocytosed by neutrophils and monocytes were seen. The phagocytosis genes. 20 receptor TK families (58 genes) and 12 non-receptor TK families + of bifidobacteria by monocytes was lower than by neutrophils, while the (37 genes) were searched for increased expression (3 fold change) inter-strain variations were similar. High ability of bifidobacteria cell wall compared to control leukoreduction system chamber cells. components to activate neutrophils and stimulate the generation of reactive RESULTS: The highest expression (fold change) compared to control oxygen species was noted. Significant effects of bifidobacteria cell wall occurred among the receptor TKs (RTKs): v-kit (96.9-fold change), neuro- components on the expression of CD69 by lymphocytes were seen. trophin tyrosine kinase receptor type 1 (NTRK1) (33.18-fold change) and Bacterial cell walls enhanced the production of TNF-alpha and expression Tie-1 (22.01-fold change). Non-receptor TK expression was not as marked. of CD80 by macrophages, but not INF-gamma production by lymphocytes. The highest values were for protein tyrosine kinase (PTK)2 (6.83-fold CONCLUSIONS: There were significant immunomodulatory effects of change) and PTK6 (6.61-fold change). Several RTK families were under the bifidobacteria strains studied as well as their isolated cell walls. These expressed compared to control. results suggest the potential use of these bifidobacteria strains in CONCLUSIONS: Over-expression of multiple TK genes was detected in biotechnology to develop new immunomodulators or as prebiotics for the cells of this patient with MCL. treatment or prophylaxis of immunologic human diseases. Characterization Of Systemic Mastocytosis Patients Based Worldwide Impact Of LAD2 Mast Cell Line On Mast Cell 204 Solely On The Minor Criteria 202 Biology Research Dr. Anupama Ravi, MD, Dr. Joseph H. Butterfield, MD, FAAAAI; Mayo Arnold S. Kirshenbaum, MD, FAAAAI1, Amy Petrik, PhD2, Rosemary Clinic, Rochester, MN. Walsh, PhD2, Sury Vepa, PhD, JD3, Dean D. Metcalfe, MD, FAAAAI1; RATIONALE: As part of an ongoing review of systemic mastocytosis 1Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, MD, 2Technol- (SM) patients diagnosed solely on the minor criteria we report preliminary ogy Transfer and Intellectual Property Office, NIAID, NIH, Bethesda, findings on the occurrence of B and C findings. MD, 3Office of Technology Transfer, NIH, Rockville, MD. METHODS: With IRB approval a retrospective chart review of SM from RATIONALE: During culture of bone marrow-derived human mast cells, 1992 to 2013 is being conducted. Inclusion criteria require meeting at least we noticed a clone of human mast cells thriving with rhSCF. This clone, 3 of the minor criteria: greater than 25% mast cells are spindle-shaped or named LAD2, was FcepsilonRI+/CD117+ and capable of releasing beta- have atypical morphology, KIT D816V mutation, aberrant CD25 expres- hexosaminidase(20-60%), enabling study in lieu of primary mast cell sion on MC, and serum tryptase persistently >20 ng/ml. Exclusion criteria cultures. To study the impact of worldwide distribution, we determined the included: 1) meeting the major criterion of multifocal infiltrates of MC’s numbers of investigators and publications resulting from LAD2 use. (>15 MC’s/infiltrate) in tryptase-stained biopsy sections of bone marrow METHODS: Records maintained in our lab, Technology Transfer and or 2) meeting less than 3 minor criteria. Intellectual Property Office, and Office of Technology Transfer were RESULTS: To date five patients fulfilled the inclusion criteria (3 males and reviewed for investigator numbers and location, material transfer agree- 2 females). Three and two patients met 3 and 4 minor criteria, respectively. ments (MTAs) and licensing agreements (LAs). Journals and their impact Four patients also had biopsy-confirmed cutaneous mastocytosis. Four factors were obtained from PubMed.gov using the term LAD2. Data was patients had KIT D816V mutation. All five patients had spindle-shaped mast displayed in Excel format. cells with aberrant CD25 expression. Three, three, and one patient had a b a RESULTS: As outlined in handling instructions, LAD2 cultures were serum tryptase > 20 ng/mL, 24 hour urinary 11 -prostaglandin F2 maintained weekly, stored under N2 and thawed yearly for expansion and >1000ng/24 hr, and 24 hour urinary N-methyl-histamine > 200mcg/g Cr distribution to centers worldwide. Since 2001, over 300 MTAs and 50 LAs at time of referral, respectively. None of the patients revealed B findings have been approved. LAD2 cells were shipped to all continents, except indicative of high MC burden or C findings including cytopenias, skeletal Antarctica. Over 80 publications in journals with impact factors 1.31 to involvement, myeloproliferation, liver impairment, or weight loss. 13.21 were documented. Intended use included degranulation by new CONCLUSIONS: Our cohort of five SM patients solely meeting at least 3 molecules, degranulation inhibition, receptors/cell signaling and genetic minor criteria had no B or C findings suggesting they may be more likely to marker studies. Overall investigator satisfaction was positive based on ease have indolent disease and better prognosis. of obtaining cells, use/storage of cells, data duplication, and trouble- shooting of questions or problems.
ABS 5.2.0 DTD YMAI10629_proof 11 January 2014 3:14 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB58 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Basophil Activation Is a Reliable Biomarker Of Allergic CD49d-Expressing Neutrophils Are Found In The Nasal 205 Bronchopulmonary Aspergillosis (ABPA) In CF: One Year 207 Lavage During An Acute Upper Respiratory Illness Results Of a Longitudinal Cohort Study Dr. Jerome Sigua, MD, Dr. Mitchell H. Grayson, MD, FAAAAI, Dr. Yael Gernez, MD, PhD1,2, Mr. Jeffrey Waters2, Mrs. Colleen Dunn2, Dr. Pippa Simpson, PhD, Ms. Erika Buell, Mrs. Desire Hunter, Zoe Davies2, Dr. Rabindra Tirouvanziam3, Mrs. Cassie Everson2, Dr. John Dr. Dorothy S. Cheung, MD, FAAAAI; Medical College of Wisconsin, Tamaresis2, Prof. Leonore Herzenberg4, Dr. Richard B. Moss, MD5; Milwaukee, WI. 1Highland Hospital, San Francisco, 2Stanford University School of Med- RATIONALE: Severe respiratory viral infections are associated with an icine, Stanford, CA, 3Emory University School of Medicine, Department increased risk for development of asthma and atopic disease. We previously of Pediatrics, Atlanta, GA, 4stanford, School of Medicine, stanford, 5Stan- demonstrated that recruitment of CD49d-expressing neutrophils (CD49d+ ford University School of Medicine, Palo Alto, CA. PMN) were critical to the development of post-viral atopic disease in a mouse RATIONALE: A. fumigatus (Af) colonizes the airways of 35% of cystic model. We undertook this study to determine if CD49d+ PMN were recruited fibrosis (CF) patients, with some further progressing towards allergic bron- to human nasal mucosa with acute upper respiratory tract viral infections. chopulmonary aspergillosis (ABPA). We hypothesized that changes on METHODS: Subjects 5-50 years of age within 4 days of onset of acute basophil surface activation pattern could discriminate between CF patients respiratory infection symptoms were enrolled. Following consent, a brief with and without ABPA. medical history, rhinitis symptom score (SNOT-20 questionnaire), nasal METHODS: It is a longitudinal cohort study comparing blood basophil swab for viral PCR, and nasal lavage were obtained. At least 4 weeks later CD203c levels, which were measured at baseline and upon in vitro activation identical testing was performed (convalescent data). The frequency of with Af allergen, in CF-ABPApatients (n518) and in two control groups: CF CD49d+ PMN in the nasal lavages was determined by flow cytometry. patients colonized with Af but without ABPA (CF-AC; n517) and CF pa- RESULTS: Compared to convalescence, CD49d+ PMN were found more tients without Af colonization or ABPA (CF; n515). Patients were tested frequently in the nasal lavage during an acute respiratory illness (3.0% every six months and when ill with pulmonary exacerbation. [1.28-5.46] vs. 1.0% [0-1.92]; illness vs. convalescence; median [IQR], RESULTS: Basophil CD203c surface expression discriminated CF- p<0.0001, n528). SNOT-20 scores were higher during the acute illness ABPA from CF-AC and CF over time (repeated measures ANOVA as well (1.53 [0.94-1.99] vs. 0.38 [0.05-0.85]; p<0.0001). A positive viral p50.0003). Ex vivo stimulation with Af extract (optimal at 10 minutes PCR was found in 13 subjects (rhinovirus (n511), RSV (n51), or influ- exposure) or recombinant Asp f1 (optimal at 30 minutes) produced similar enza B (n51)), and all exhibited higher CD49d+ PMN frequencies during results without difference in categorization. CF-ABPA patients experi- the viral infection versus convalescence (2.76% [1.16-4.0] vs. 0% [0-0.93]; enced more pulmonary exacerbations, were more frequently co-infected p50.0025, n513). with P. aeruginosa, and had more diabetes than controls. CONCLUSIONS: These preliminary data demonstrate that the CD49d+ CONCLUSIONS: The blood basophil CD203c assay is a suitable PMN are increased in the nasal lavage during an acute viral respiratory diagnostic biomarker of ABPA in CF. infection. Further studies will need to be performed to see if the presence of these cells correlates with development of atopic disease. Exosomes Secretion By Eosinophils: A Possible Role In 206 Asthma Pathogenesis Estradiol Has a Negative Impact On The Anaphylactic Victoria Del Pozo, PhD1, Carla Mazzeo1, Ainara Rodriguez Marco2, Mar 208 Response In Mice, Independent From Mast Cell Del Mar FERNANDEZ-NIETO3, Maria Paz Zafra4, Veronica Sanz1, Degranulation Prof. Joaquin Sastre, MD, PhD, FAAAAI3; 1IIS-FJD and CIBERES, Valerie Hox, MD, PhD1,2, Avanti Desai1,GeethaniBandara,PhD1,Alas- 2IIS-FJD, 3Fundacion Jimenez Diaz, Madrid, Spain, 4IIS-Fundacion dair M. Gilfillan, PhD1, Dr. Michael Beaven, PhD3,Dr.AnaOlivera,PhD1, Jim enez D ıaz. Dean D. Metcalfe, MD, FAAAAI1; 1Laboratory of Allergic Diseases, RATIONALE: Eosinophils secrete cytotoxic granules which are involved NIAID, NIH, Bethesda, MD, 2Laboratory of Clinical Immunology, Depart- in initiation and propagation of diverse inflammatory responses as asthma. ment of Microbiology and Immunology, KULeuven, Leuven, Belgium, Our hypothesis is that some of these granules are exosomes which contain 3Laboratory of Molecular Immunology, NHLBI, NIH, Bethesda, MD. miRNAs and participate in the pathogenesis of these diseases. Our aims are RATIONALE: Epidemiologic studies indicate gender differences in the to characterize the eosinophils exosomes and to investigate their role in prevalence of allergic diseases, with adult women suffering more asthma. frequently from anaphylaxis. We hypothesized that female sex hormones METHODS: We study the capacity of eosinophils to generate intracellular alter the course of allergen-induced anaphylaxis in mice. precursors of exosomes (multivesicular bodies, MVBs) by electron, confocal METHODS: Passive systemic anaphylaxis was induced in male as well as and fluorescence microscopy and flow cytometry analysis. Eosinophils were in female mice that were either ovariectomized (OVX) or sham-operated. labelled with the specific marker of MVBs (Lysobiphosphatidic Acid, To investigate the role of estradiol (E2), we repeatedly injected na€ıve LBPA) and the reporter of endosomal vesicles (CD63). Exosomes derived female mice with the specific estrogen-receptor antagonist ICI 182,780. from eosinophils were characterized by Western Blot (WB), Nanoparticle Additionally, OVX mice were subcutaneously implanted with pellets Tracking Analysis (NTA) to estimate the size distribution and concentration, releasing either E2 or placebo. To explore the effect of E2 on mast cell flow cytometry and by electron microscopy images. degranulation in vivo, plasma histamine levels were determined after anti- RESULTS: We observed that eosinophils generate intracellular MVBs. It gen-challenge and anaphylactic reaction in response to histamine-chal- was confirmed by the colocalization of LBPA and CD63 in these vesicles. lenge was measured in OVX and sham-operated mice. In vitro antigen- This result was corroborated by electron microscopy images. Exosomes induced degranulation and cytokine production were evaluated in bone purified from eosinophils from healthy and asthmatic subjects were marrow and peritoneal derived mast cells, in the presence or absence of E2. CD63+. The amount of exosomes was increased after stimulation with RESULTS: Male mice as well as OVX female mice were less susceptible IFN-g. NTA showed that the size of eosinophils exosomes was into the to passive systemic anaphylaxis compared to sham-operated female mice characteristic exosomal range. Finally, we found that the exosomes and this effect was reversed by implantation of E2-pellets. Also, the production from asthmatic subjects was higher than healthy subjects. anaphylactic response in naive female mice was reduced after pre- CONCLUSIONS: Our findings provide the first evidence that eosinophils treatment with ICI 182,780. The effect was not accompanied by a decrease produce MVBs and secrete exosomes. It is possible that they have an in plasma histamine-levels after challenge. Mice that underwent OVX important implication in the pathogenesis of asthma. Moreover, they also showed a reduced anaphylactic response to histamine. E2 did not enhance could be considered as a future biomarker antigen-induced mast cell degranulation in vitro. CONCLUSIONS: E2 has a negative impact on anaphylaxis in mice, which is not due to increased mast cell degranulation.
ABS 5.2.0 DTD YMAI10629_proof 11 January 2014 3:14 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB59 VOLUME 133, NUMBER 2
Regulation Of Reactive Oxygen Species Production Involving increased greater intracellular ROS, and secretion of IL-8 and GRO-a in 209 Src Family Kinase In Siglec-8 Induced Eosinophil Cell Death hTLR4/MD2/CD14 overexpressing cells compared to null cells. Dr. Gen Kano, MD, PhD1, Bruce S. Bochner, MD, FAAAAI2, Dr. Nives CONCLUSIONS: RWPE has direct TLR4-dependent, endotoxin-inde- Zimmermann, MD, FAAAAI3; 1Kyoto Prefectural University of Medi- pendent effects on airways that include ROS generation, CXCL1/2 cine, Kyoto, Japan, 2Division of Allergy and Clinical Immunology, North- secretion and neutrophil recruitment. RWPE/TLR4 induced neutrophilic western University School of Medicine, Chicago, IL, 3Children’s Hospital inflammation promotes allergic airway inflammation by further increasing Medical Center, Cincinnati, OH. ROS levels in airways. RATIONALE: Siglec-8 is a surface receptor predominantly expressed on human eosinophils where its ligation induces cell death. Since Siglec-8 has LAMP1 and CD63 Expression In Mouse Mast Cells and Human intracellular tyrosine-based motifs, we hypothesized that Src family 211 Basophils Rendered Hyporesponsive By Antigen/IgE- Mediated Activation and Desensitization kinases (SFKs) are involved in cell death induced by Siglec-8 engagement. 1 METHODS: Human peripheral blood eosinophils were purified and Prof. Pedro Giavina-Bianchi, MD, PhD, FAAAAI , Dr. Matthieu Picard, MD2, Dr. Joana Caiado, MD2, Dr. Veronica Mezzano, MD2, incubated with anti-Siglec-8 monoclonal antibodies (mAb, agonist), IL-5, 2 1
Dr. Mariana C. Castells, MD, PhD, FAAAAI ; Clinical Imunnology SATURDAY and SFK pharmacological inhibitors. Reactive oxygen species (ROS) pro- 2 duction was determined by dihydrorhodamine (DHR) 123 labeling and and Allergy Division, University of Sao Paulo, Boston, MA, Division flow cytometry or a chemiluminescence method using Amplex red. of Rheumatology, Allergy and Immunology, Department of Medicine, Activation of SFK was determined using phospholuminex and Western Brigham and Women’s Hospital, Harvard Medical School, Boston, MA. blotting. RATIONALE: Rapid drug desensitization protocols have been developed RESULTS: We first performed the phospholuminex assay to broadly based on limited clinical evidence and in vitro models. The aim of this assess phosphorylation of SFKs (Lck, Lyn, Src, Yes, Fgr, Fyn, Blk and study is to determine the expression of markers of activation on murine Hck) in lysates from eosinophils stimulated with anti-Siglec-8 mAb 6 IL- mast cells (LAMP1) and on human basophils (CD63) during antigen/ 5. We found consistently increased levels of phosphorylated Fgr in the IgE-mediated desensitization and activation. cytoplasmic fraction of cells co-stimulated with anti-Siglec-8 and IL-5 for METHODS: Mouse bone marrow derived mast cells (BMMCs) sensitized 3 hours compared with cells stimulated with IL-5 alone. Western blotting with DNP (2,4-dinitrophenol)-IgE were activated or desensitzed to DNP (1 confirmed SFK phosphorylation. To test the involvement of SFKs in ROS ng). Desensitization was acheived by sequential doubling doses of DNP production and cell death, we used SFK inhibitors PP2 and dasatinib, both every 10 min starting at 1pg. After activation or desensitization, BMMCs of which completely inhibited eosinophil ROS production and cell death were rechallenged by an activating dose of DNP to assess hyporesponsive- induced by anti-Siglec-8 and IL-5 co-stimulation. ness. LAMP1 surface expression and ß-hexosaminidase (ß-Hex) release CONCLUSIONS: Phosphorylation of the SFK occurs in eosinophils co- were used as activation markers. Human basophils from mite sensitized stimulated with anti-Siglec-8 and IL-5, and SFK activity is required for patients were activated or desensitized with Dermatophagoides pteronyssi- ROS production and eosinophil cell death in co-stimulated cells. This is nus(0.2 AU). Activation was assessed by CD63 surface expression. unexpected given that Siglecs are traditionally believed to signal via RESULTS: LAMP-1 and CD63 expression were 9.72% and 19.25% after tyrosine phosphatases. desensitization and 36.77% and 56% after activation, indicating a decreased expression by 73.57% and 65.62% after desensitization, Ragweed Pollen Extract (RWPE)-Induces TLR4-Dependent respectively. Desensitized BMMCs released significantly less ß-Hex 210 Neutrophil Recruitment That Augments Allergic Airway than their activated controls (reduction of 58.89%). Mediator depletion Inflammation was ruled out as calcium ionophore induced a 35.83% and 41.13% Dr. Koa Hosoki, MD, PhD, Dr. Leopoldo Aguilera-Aguirre, PhD, release in previously activated and desensitized cells, respectively. Prof. Istvan Boldogh, PhD, Dr. Qian Sun, PhD, Prof. Sanjiv Sur, MD; Uni- Hyporesponsiveness after rechallenge was established by reduced ß-hex versity of Texas Medical Branch, Galveston, TX. release and LAMP-1 and CD63 expression. RATIONALE: Endotoxin induces neutrophil recruitment and modulates CONCLUSIONS: LAMP1 and CD63 expression are reduced during allergic airway inflammation. Recent human studies have also shown that antigen/IgE desensitization on murine mast cells and human basophils pollen extract challenge induces neutrophil recruitment independent of respectively compared to activation. These activation markers can be used endotoxin. The innate mechanisms of endotoxin-independent pollen- to assess hyporesponsiveness induced by antigen/IgE desensitization and induced neutrophil recruitment and contribution to allergic inflammation activation in murine mast cells and human basophils. have not been elucidated. METHODS: Endotoxin-free RWPE was used in all experiments. WT and TLR4KO mice were intranasally challenged with RWPE in the presence or absence of CXCR2 or Nf-kB NEMO binding domain inhibitor. BALF levels of neutrophils, CXCL1 and CXCL2 were quantified 16 h later. WT and TLR4KO mice were sensitized with 5 intranasal doses of RWPE with/without CXCR2 inhibitor, and challenged with RWPE to elucidate allergic airway inflammation. 293 Null cells and 293 cells stably overexpressing hTLR4/MD2/CD14 were stimulated with RWPE, and intracellular ROS generation and chemokine secretion were quantified. RESULTS: Intranasal RWPE challenge in WT mice increased recruitment of neutrophils, CXCL1 and CXCL2 secretion, and elevated GSSG levels. These effects were abrogated in TLR4KO mice, and attenuated by coadministration of CXCR2 or Nf-kB inhibitors, or antioxidants. Repeated administration of RWPE in WT mice followed by RWPE challenge induced eosinophilic inflammation and mucin secretion; these effects were abrogated by disruptingTLR4 and attenuated by co-admin- istering CXCR2 inhibitor during sensitizing doses of RWPE. RWPE
ABS 5.2.0 DTD YMAI10629_proof 11 January 2014 3:14 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB60 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Vectorial Exposure and Fusion Of Secretory Granule Content IgE–Mediated Mast Cell Responses Are Inhibited By Thymol- 212 At The Mast Cell Degranulatory Synapse 214 Mediated Activation-Induced Cell Death Dr. Nicolas Gaudenzio1, Mr. Regis Joulia2, Prof. Salvatore Valitutti2, Dr. Joshua B. Wechsler, MD1, Dr. Chia-Lin Hsu, PhD2, Dr. Paul Bryce, Dr. Eric Espinosa2; 1Stanford University, Stanford, CA, 2INSERM PhD2; 1Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, U1043, Toulouse, France. IL, 2Division of Allergy-Immunology, Department of Medicine, Feinberg RATIONALE: Mast cell granule secretion (‘‘degranulation’’) following School of Medicine, Northwestern University, Chicago, IL. stimulation is classically viewed as the disseminated release of pre-stored RATIONALE: Mast cells play a critical role in inflammatory skin mediators. However, whether mast cell can degranulate in a vectorial diseases through release of pro-inflammatory mediators; however, few fashion when triggered by localized stimuli is still an open question. therapies directly target these cells. In 1878, the use of topical Thymol, a METHODS: Experiments have been performed in a controlled atmo- now recognized potent agonist for Transient Receptor Potential (TRP) sphere using confocal laser scanning microscopy to visualize human mast channels, was first described to treat eczema and psoriasis. We sought to cell degranulation in real-time. Mast cells were allowed to interact with Ig- determine the mechanisms through which thymol may alter skin opsonized cells and degranulation was monitored using fluorochrome- inflammation. labelled avidin molecules. METHODS: We examined the effect of topical thymol on IgE-dependent RESULTS: We showed that release of granule content by live mast cells is responses using a mast cell–dependent passive cutaneous anaphylaxis associated with the retention of a substantial fraction of pre-stored (PCA) model as well as in vitro cultured mast cells. bioactive material on the cell surface. Degranulation induced by FcR- RESULTS: Thymol dose-dependently inhibited PCA when administered crosslinking resulted in the sustained formation of foci of granule topically 24 hours prior to antigen challenge but provoked an ear swelling exposure, which eventually fused to form a thick corona of bioactive response directly on application. This direct effect was associated with material on the cell surface. Interaction of mast cells with Ig-opsonized local mast cell degranulation and was absent in histamine-deficient and cells resulted in a dedicated area of granule exposure and fusion at the cell- mast cell-deficient mice. However, unlike with PCA responses, there was cell interface overlapping with the signaling area. Antibody-mediated no late phase swelling. In vitro, thymol directly trigged mast cell vectorial release of granule content also occurred upon infection by the degranulation, calcium flux, and cytokine mRNA via TRP-channel intracellular parasite Toxoplasma gondii. activation. However, no cytokine protein was produced. Instead, thymol CONCLUSIONS: Our results broaden current views of mast cell induced a significant increase in apoptotic cell death that was seen both in degranulation by showing that mast cells can display granule content on vitro and in vivo. their surface and form ‘‘degranulatory synapses’’ for localized secretion CONCLUSIONS: We propose that the efficacy of thymol in reducing and targeted defense mechanisms. IgE-dependent responses is through promotion of activation-induced apoptotic cell death of mast cells and that this likely explains the clinical Airway Tissue, But Not Luminal, Eosinophilia Is Related To benefits observed in early clinical reports. 213 The Magnitude Of Airway Hyperresponsiveness In a Transgenic Murine Model Of Cat Allergy Mechanisms Of Non-IgE-Mediated Uptake Of Antigen By Mr. Daniel M. Moldaver1, Dr. Mantej S. Bharhani1, Ms. Jennifer Wattie1, 215 Human Mast Cells Ms. Tarandeep Singh1, Ms. Melissa Babra1, Dr. Marianne van Hage, MD2, Dr. Brant Ward, MD, PhD, Ms. Sahar Lotfi-Emran, Dr. Lawrence B. Dr. Mark D. Inman, MD, PhD1, Dr. Mark Larch e, PhD1; 1McMaster Uni- Schwartz, MD, PhD, FAAAAI; Virginia Commonwealth University, versity, Hamilton, ON, Canada, 2Karolinska Institutet, Department of Me- Richmond, VA. dicina Solna, Clinical Immunology and Allergy Unit, Stockholm, Sweden. RATIONALE: Binding of antigen to IgE/FcεRI complexes on mast cells RATIONALE: We attempted to develop a model of cat dander-induced can lead to internalization of the bound antigen. Our lab previously allergic airways disease in a humanized (HLA DR4 transgenic) mouse demonstrated that human mast cells possess the ability to internalize strain. We hypothesized that inhaled challenge with increasing doses of antigens in the absence of specific IgE. However, the mechanisms of such allergen would be associated with increased airway hyperreactivity (AHR) uptake are unknown. We therefore investigated the mechanisms by which and eosinophilic infiltration of the airways. human mast cells sample antigens from their environment. METHODS: Female HLA DR4 transgenic mice (Taconic Farms; 5wks, METHODS: Primary human mast cells were obtained from discarded n55/group, three independent experiments) were sensitized via intraper- surgical samples and cultured in vitro, as previously described. Small itoneal injections of Fel d 1 in alum and inhalation of purified cat dander chemical inhibitors of endocytosis were used to determine the cellular extract (CDE) on days 21-25. The allergic response was recalled on days 51 mechanisms of antigen uptake by primary human mast cells in the absence & 52 by inhaled CDE challenge at various doses (0, 1, 5, 10, 20 & 30 mg). of IgE. RNA expression patterns (microarrays) and protein expression Forty-eight hours post intranasal challenge, airway responsiveness was (flow cytometry) of multiple known endocytic receptors were analyzed quantified during a nebulized methacholine challenge. Mice were then as indicated. Internalization of bound antibody was used to determine en- sacrificed and tissues collected. Eosinophils were quantified in the docytic receptor function. bronchoalevolar lavage (BAL) by Wright-Giemsa staining and the tissues RESULTS: Human mast cells internalize model antigens using a combi- by histology and flow cytometry. nation of macropinocytotic and dynamin-dependent mechanisms. Unlike RESULTS: Low dose intranasal challenge with CDE (1 mg) resulted in other antigen presenting cells, mast cells express a restricted assortment of significantly elevated (P < 0.05, one-way ANOVA & t-test) BAL endocytic receptors at baseline. One such receptor, DEC-205, is highly eosinophilia, but no AHR. Increasing doses of inhaled CDE were expressed at baseline, and increased expression is seen after treatment with associated with reduced BAL eosinophilia, exemplified by high dose interferon-g. Furthermore, DEC-205 is functional on mast cells, and groups being nearly indistinguishable from saline mice. At doses of 5 mg binding of the receptor to an anti-DEC-205 antibody leads to rapid CDE and above, both airway responsiveness and tissue eosinophilia were internalization of the receptor. significantly elevated compared to saline mice. CONCLUSIONS: Like other antigen presenting cells, human mast cells CONCLUSIONS: In a model of cat allergen-induced allergic airway are able to sample antigens from their environment using a combination of disease in HLA DR4 transgenic mice there was an inverse relationship macropinocytosis and receptor-mediated endocytosis. Such redundancy in between BAL eosinophilia and the magnitude of AHR and tissue the pathways for antigen uptake by mast cells argues for its importance in eosinophilia. human mast cell biology.
ABS 5.2.0 DTD YMAI10629_proof 11 January 2014 3:14 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB61 VOLUME 133, NUMBER 2
Human EMR1, An Eosinophil-Specific Surface Receptor Of Pittsburgh Asthma Institute at UPMC and the University of Pittsburgh 216 Unknown Function, Is Modulated In Vivo and In Vitro School of Medicine, Department of Pulmonary, Allergy and Critical Dr. Fanny Legrand1, Dr. Nenad Tomasevic2, Mrs. Michelle Makiya1, Care Medicine, 2The University of Pittsburgh Asthma Institute at Dr. Christopher Bebbington2, Dr. Amy D. Klion, MD1; 1National Insti- UPMC and the University of Pittsburgh School of Medicine, Department tutes of Health, Bethesda, MD, 2Allakos. of Pulmonary, Allergy and Critical Care Medicine, Pittsburgh, PA. RATIONALE: Human EMR1, an eosinophil-specific surface receptor of RATIONALE: Asthma biomarkers from a variety of sources have unknown function, is a novel therapeutic target for eosinophilic disorders. variable clinical utility, performance characteristics, and applicability. Although recent data have demonstrated decreased EMR1 surface Sputum mast cells (MC) have been identified in stable, asymptomatic expression and increased serum EMR1 levels in eosinophilic subjects, asthmatics, as well as more severe asthmatics. [Foresi, JACI, 1997; Fajt, little is known about the mechanism of EMR1 modulation. AAAAI, 2011] Little is known about the treatment response to steroids in METHODS: Eosinophil expression of EMR1, IL-5Ra, Siglec-8, CD69, sputum MCs from different subtypes of asthma. ECP and EPX mRNA was quantified by RT-PCR. Purified eosinophils METHODS: Induced sputum, lung function, exhaled nitric oxide and (n513) were stimulated in vitro with IL-5, GM-CSF, IL-33, eotaxin or questionnaire data was collected at baseline and two weeks after
SEB. EMR1 surface and mRNA expression was assessed at baseline and triamcinolone injection (40mg) from 10 asthmatics (6 non-severe, 4 SATURDAY following stimulation. Eosinophil activation was confirmed by upregula- severe) from the University of Pittsburgh site of the Severe Asthma tion of surface CD69 expression. Research Program. Subjects were classified as Th2 high or low based on RESULTS: EMR1 mRNA expression correlated with IL-5Ra and Siglec- peripheral blood eosinophilia (>_300/mL). Sputum tryptase was measured 8 mRNA expression in freshly purified eosinophils from eosinophilic by qPCR. Data was analyzed nonparametrically. patients (r50.66 and 0.67, P<.001, n521), but not in those from normal RESULTS: Th2 high asthmatics (n54) had significantly greater sputum controls (n512). Surface EMR1 expression decreased following 2 hours of tryptase mRNA at baseline than Th2 low [median(IQR) 27.5(14.2-696.4) stimulation with IL-5 in vitro (GM MFI 3475 vs. 3845; P<.05). A similar vs. 2.2(0-9.20), p50.01]. After triamcinolone, Th2 high asthmatics had trend was observed with GM-CSF stimulation (P50.057). EMR1 mRNA decreases in sputum tryptase mRNA vs. mixed responses in Th2 low was significantly increased after 6 hours stimulation with IL-5 and GM- asthma (p50.03). FEV1%predicted tended to increase following triam- CSF in all subjects. No consistent changes in EMR1 expression were cinolone in Th2 high compared to Th2 low asthma [median increase5 seen following stimulation with IL-33, eotaxin or SEB, although CD69 6.5% vs. 0.5%, p50.13]. expression was not significantly upregulated. CONCLUSIONS: Th2 high asthma (based on blood eosinophils) associ- CONCLUSIONS: Although EMR1 is highly expressed on eosinophils ated with higher basal levels of MC biomarkers. These higher levels from normal and eosinophilic donors, IL-5 stimulation causes a small but predicted both a reduction in MC marker mRNA and improvement in lung significant drop in surface expression accompanied by increased mRNA function. Changes in MC mRNA (and FEV1) in response to triamcinolone in expression, consistent with increased receptor turnover. Results to date Th2 low asthmatics were inconsistent. While asthmatics with persistent Th2- using other stimuli suggest that this phenomenon may be related to cell like inflammation may respond clinically to additional steroid therapy, other activation, as assessed by CD69 expression. therapies targeting alternate pathways may be needed in Th2 low asthma.
Cyclo-Oxygenase Inhibition Increases The Frequency Of Analyses Of IL-33-Producing Cells During Multiple Antigen 217 CD49d+ Neutrophils In The Bronchoalveolar Lavage (BAL) 219 Challenges In Murine Asthma During a Respiratory Viral Infection Dr. Takeshi Nabe1, Mr. Hiroki Wakamori1, Ms. Anna Takiguchi1, Ms. Jennifer A. Hass, Ms. Erika Buell, Mrs. Desire Hunter, Dr. Dorothy Mrs. Haruka Kida1, Prof. Susumu Ohya1, Dr. Nobuaki Mizutani2, S. Cheung, MD, FAAAAI, Dr. Mitchell H. Grayson, MD, FAAAAI; Med- Prof. Shin Yoshino2, Prof. David Chaplin3; 1Kyoto Pharmaceutical Uni- ical College of Wisconsin, Milwaukee, WI. versity, Kyoto, Japan, 2Kobe Pharmaceutical University, Kobe, Japan, RATIONALE: We utilized a well-characterized mouse model where 3University of Alabama at Birmingham, Birmingham, AL. paramyxoviral infection with Sendai virus (SeV) leads to atopic disease. RATIONALE: IL-33, a cytokine produced from the airway epithelial Development of this post-viral atopic disease depends upon accumulation cells, has been suggested to be involved in asthma pathogenesis by of CD49d+ neutrophils (PMN) in the BAL. We have shown that these PMN bridging between the acquired and innate immunity. However, cellular express CysLTR1, and CysLTR1 blockade reduces the frequency of these sources of IL-33 in the lung during progression of asthma pathogenesis cells in the BAL. We hypothesized that COX inhibition would increase the have not been defined. We analyzed cellular sources of IL-33 in the lung frequency of CD49d+ PMNs, which could lead to enhanced atopic disease during multiple antigen challenges in sensitized mice. development. METHODS: OVA+Al(OH)3-sensitized Balb/c mice were intratracheally METHODS: C57BL/6 mice were inoculated intranasally with SeV, and challenged with OVA for 3 times. Time-course changes in IL-33 amount indomethacin was given i.p. once (10 mg/kg) or daily (5 mg/kg) on days -1, in the lung homogenate and IL-33-positive cells in the lung were analyzed 0 or 1 post inoculation with SeV. Three days post SeV inoculation the ELISA and immunohistochemistry, respectively. Furthermore, intracel- frequency of CD49d+ PMN was determined in the BAL by flow cytometry. lular IL-33-positive cells in the single lung cell suspension were analyzed RESULTS: COX inhibition increased the frequency of CD49d+ PMNs in by flow cytometer. the BAL for both single and daily administrations of indomethacin. The RESULTS: (1) The first antigen challenge increased IL-33 level in the lung greatest effects were seen with administration one day after SeV for single homogenate. Furthermore, the three time antigen challenges amplified the dose (15.061.1% vs 25.562.2%; mean6SEM %CD49d+ PMN; vehicle IL-33 production. (2) Immunohistochemical analyses of the lung tissue versus indomethacin; p50.01; n53) and starting on day 0 for daily dose revealed that the main cellular source of IL-33 at the 1st challenge was the (16.961.2% vs 28.361.2%; p50.01; n53). epithelial cells. Additionally, inflammatory cells infiltrating the lung were CONCLUSIONS: COX inhibition results in a significant increase in also IL-33-positive at the 3rd challenge. (3) Flow cytometric analyses CD49d+ PMNs in the alveolar space with viral infection. Future studies showed that approximately 20% and 10% of the IL-33-producing cells at the will examine if there is a link between this increase in CD49d+ PMNs 3rd challenge were F4/80+ CD11c+ cells (alveolar macrophages) and I-A/I- and development of atopic diseases. E+ CD11c+ cells (conventional dendritic cells), respectively. CONCLUSIONS: It was demonstrated that both macrophages and High Blood Eosinophils Predict Reductions In Sputum Mast Cells conventional dendritic cells infiltrated into the lung and produced IL-33 and Lung Function In Response To Triamcinolone In Asthma 218 in response to the multiple antigen challenges. Dr. Merritt L. Fajt, MD1, Ms. Crystal Uvalle, BS1, Mr. John Trudeau, BA1, Sally E. Wenzel, MD, FAAAAI2; 1The University of
ABS 5.2.0 DTD YMAI10629_proof 11 January 2014 3:14 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB62 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Repeat Lipopolysaccharide Exposure Is Sufficient To Impair and intra-peritoneal inflammation which occur in this adjuvant-free mouse 220 Viral Induced Pro-Atopic, CD49d Expressing Neutrophil model of active anaphylaxis. Recruitment To The Lung Dr. Wei An, MD1,2, Ms. Jennifer A. Hass2, Ms. Erika Buell2, Mrs. Desire Functional Phenotype Of CD49d-Expressing Neutrophils Hunter2, Dr. Dorothy S. Cheung, MD, FAAAAI2, Dr. Mitchell H. Gray- 222 Differs Between Viral Infection and TLR Stimulation son, MD, FAAAAI2; 1Froedtert Hospital, Milwaukee, WI, 2Medical Col- Dr. Dorothy S. Cheung, MD, FAAAAI, Erika Buell, Mrs. Desire Hunter, lege of Wisconsin, Milwaukee, WI. Dr. Mitchell H. Grayson, MD, FAAAAI; Medical College of Wisconsin, RATIONALE: Severe respiratory viral infections increase the risk of Milwaukee, WI. developing asthma and atopic disease. In the Sendai virus (SeV) mouse RATIONALE: Using the Sendai virus (SeV) model, we have shown that a subset of CD49d expressing neutrophils (CD49d+ PMN) is critical for post- model, we demonstrated this risk depends upon the early recruitment of + CD49d expressing neutrophils to the lung. We also demonstrated that viral atopic disease development. Further, CD49d PMNs accumulate in single intranasal (i.n.) dose of lipopolysaccharide (LPS) prior to SeV the lungs and bronchoalveolar lavage (BAL) after repeated intranasal inoc- + ulation with a TLR9 agonist. We undertook this study to determine whether infection significantly reduced CD49d neutrophils in the bronchoalveolar + + lavage (BAL). The hygiene hypothesis suggests chronic microbial expo- TLR9 induced CD49d PMN and SeV induced CD49d PMN differ in sure prevents development of atopic disease. Our study investigated function. whether chronic LPS exposure would reduce SeV mediated CD49d+ METHODS: C57BL/6 mice were inoculated intranasally with either SeV neutrophil recruitment to the lung and BAL. on day 0 or the TLR 9 agonist ODN1826 on days 0, 1, and 2. On day 3, METHODS: C57BL6 mice were treated with daily LPS (3ug) i.n. starting single cell preparations from the lung and BAL were flow sorted for Gr1 3 or 1 days before or with SeV infection (day 0). On day 3 post-SeV, the and CD49d expression. Each cell fraction was cultured in media for 24 + hours and supernatants analyzed by an ELISA-based cytokine array. BAL and lung were isolated and the frequency of CD49 neutrophils deter- + mined by flow cytometry. RESULTS: CD49d PMNs from BAL of SeV infected mice express 6 6 6 RESULTS: In the BAL, CD49d+ neutrophils were reduced most signifi- higher levels of TNF (181.8 40.4 Vs. 15.2 7.4, mean sem pg/ml, p50.0016, n53), CCL2 (304.5698.4 Vs. 48.1624.8, p50.02, n53), cantly when LPS exposure was started one day prior to or the day of SeV – 6 6 6 and CCL5 (893062701 Vs. 68668, p50.008, n53) than CD49d infection (23.6 1.8%, 10.2 1.6% [0.0002], 10.5 2.2% [0.0037], + 6 6 + PMNs. This pattern held true in the lungs. In contrast, CD49d PMNs 17.4 3.6% [0.11]; mean sem percent CD49d neutrophils [p value versus – PBS] for PBS, LPS starting on day 0, -1, or -3; n>_3). In the lung, CD49d+ from TLR9 inoculated mice did not differ from CD49d PMNs except 6 6 5 neutrophils decreased regardless of LPS starting day (42.963.7%, for CCL5 in the lung (92.7 33.3 Vs. 6.7 1.6, n 3) and CCL2 in the 6 6 5 5 6 6 6 >_ BAL (75.5 10.1 Vs. 1.6 1.6, p 0.001, n 3). 18.7 2.0% [0.0003], 22.6 1.0% [0.013], 24.9 2.0% [0.0052]; n 3). + CONCLUSIONS: Chronic LPS exposure reduces SeV-mediated CD49d+ CONCLUSIONS: Although TLR9 stimulation resulted in robust CD49d neutrophil accumulation in the lung and the BAL, suggesting an interaction PMN accumulation in the lung and BAL, these cells appeared functionally indistinct from CD49d– PMNs. This is in contrast to SeV induced CD49d+ between the viral and hygiene hypotheses in driving atopic risk. Future – studies will explore whether chronic LPS exposure is sufficient to prevent PMNs, which are functionally distinct from CD49d PMNs. Therefore, the development of post-viral atopic disease. CD49d alone is insufficient to define the pro-atopic PMN subtype.
Important Role For Mast Cells But Not Basophils In An Mast Cells Preferentially Migrate To Denatured Collagens 221 Adjuvant-Free Model Of Active Anaphylaxis In Mice 223 Compared To Native Collagens 1 1 2 1 1 2 Thomas Kaido , Robert T. Reid , Anthony Montgomery , Richard Reid ; Dr. Laurent L. Reber, PhD , Dr. Hajime Karasuyama, MD, PhD , 1 2 Dr. Mindy Tsai, DMSc1, Dr. Stephen J. Galli, MD1; 1Stanford University The Banck Center, San Diego, CA, University of California San Diego, School of Medicine, Stanford, CA, 2Tokyo Medical and Dentistry Grad- San Diego, CA. uate School, Tokyo, Japan. RATIONALE: Mast cell hyperplasia occurs in afflicted skin, airways, and RATIONALE: Conflicting results have been obtained regarding the role joints of individuals with contact hypersensitivities, asthma, and autoim- of mast cells (MCs) and basophils in mouse models of active anaphylaxis mune disorders. As cell migration into tissues may be influenced by local and allergy. In part, this might reflect the choice of adjuvant used during degradation of the extracellular matrix during disease progression, we compared mast cell motility to native versus denatured collagens. sensitization, as various adjuvants might differentially influence the + production of various antibody isotypes. Moreover, the use of adjuvants METHODS: Mast cells derived from CD34 peripheral blood cells were can eliminate the need for contributions of MCs in certain models of added to plates or transwells coated with native or denatured collagens in allergic airway inflammation. We therefore developed an adjuvant-free the presence or absence of known mast cell activators. Cytoskeletal rear- mouse model of active anaphylaxis and assessed the contributions of MCs rangement of mast cells was visualized microscopically using fluor-labeled and basophils in this model. phalloidin. Function-blocking antibodies and antibodies specific to acti- METHODS: Wild-type (WT) and various mutant mice were sensitized vated integrins were used to determine the cell surface receptors involved intra-peritoneally (i.p.) with ovalbumin (OVA) (< 0.01 endotoxin unit per in mast cell adherence and migration. injection) at weekly intervals for 6 weeks and were challenged i.p. with RESULTS: Higher numbers of human mast cells migrated to denatured OVA two weeks later. collagens type I and II compared to native collagens I an II. Mast cells were RESULTS: OVA-sensitized C57BL/6J mice developed a strong immediate morphologically much more spread on denatured collagens than on native drop in body temperature (i.e., hypothermia) upon OVA challenge, and also collagens. Optimal mast cell migration was dependent on SCF and divalent exhibited intra-peritoneal inflammation, as assessed 3 days after challenge. manganese but was unaffected by other known mast cell activators. Mast Both the hypothermia and the intra-peritoneal inflammation were signifi- cells did not adhere or migrate to collagen type III. Function-blocking cantly reduced in MC- and basophil-deficient Cpa3-Cre; Mcl-1fl/fl mice, as antibodies to integrin avb3 inhibited adherence and migration of mast cells well as in MC-deficient KitW-sh/W-sh mice, but not in basophil-depleted to denatured collagens while antibodies to integrins a4,avb5,b1,orb2 did Mcpt8DTR mice. Engraftment of KitW-sh/W-sh mice with bone marrow-derived not. SCF plus divalent manganese activated the high-affinity state of integ- cultured MCs (BMCMCs) significantly enhanced the hypothermia response rin avb3 on mast cells. W-sh/W-sh CONCLUSIONS: Mast cells derived from human peripheral blood of such Kit mice to OVA challenge, and restored intra-peritoneal + inflammation to levels similar to those observed in WT mice. CD34 cells preferentially spread and migrate to denatured collagens via CONCLUSIONS: Taken together, our data indicate that MCs, but not an integrin avb3-dependent mechanism. basophils, play an important role in the development of the hypothermia
ABS 5.2.0 DTD YMAI10629_proof 11 January 2014 3:14 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB63 VOLUME 133, NUMBER 2
Expression Of The Transcription Factor E4BP4 In Human Tolerability Of Two Different Immunoglobulin Intravenous 224 Basophils 226 Product In Patients With Primary Immunodeficiency Disease Dr. Bettina M. Jensen, Mrs. Maria Gohr, Prof. Lars K. Poulsen, PhD, Amanda Skoskiewicz, MSN, CPNP1, Melanie M. Makhija, MD2, Ram- FAAAAI; Allergy Clinic, Copenhagen University Hospital - Gentofte, say L. Fuleihan, MD3; 1Ann & Robert H. Lurie Children’s Hospital of Hellerup, Denmark. Chicago, Chicago, IL, 2Division of Allergy & Immunology, Department RATIONALE: The cytokine IL-3 plays an important role for human of Pediatrics, Northwestern University Feinberg School of Medicine, Chi- basophil development, function and survival. IL-3 is also reported to cago, IL; Ann and Robert H. Lurie Children’s Hospital of Chicago, Chi- induce the expression of the transcription factor E4BP4, but it is not known cago, IL, 3Division of Allergy & Immunology, Department of whether E4BP4 is expressed in basophils and influences basophil Pediatrics, Northwestern University Feinberg School of Medicine, Ann responsiveness. The aim of this study was to determine whether human & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL; Division basophils express E4BP4 and if so, to compare the expression of E4BP4 of Allergy & Immunology, Department of Pediatrics, Northwestern Uni- with basophil histamine release. versity Feinberg School of Medicine, Chicago, IL. METHODS: Buffy coat blood (<6h) was analyzed for anti-IgE mediated RATIONALE: To determine the tolerability of two different immuno- histamine release. Basophils were purified by negative selection and globulin intravenous(IGIV) products in primary immunodeficiency SATURDAY purity was determined by Alcian blue. RNA was extracted (0.005-0.02 mg disease(PID) patients. RNA from 0.5 - 1 x 106 cells), and the corresponding cDNA analyzed METHODS: We reviewed the medical records of PID patients who by real-time PCR where E4BP4 expression was calculated as received two different IGIV products over the past 6 years because our 2-(CT(E4BP4) - CT(b-actin)). E4BP4 protein expression was visualized in basophil pharmacy changed the preferred brand between these products three times lysates (107cells/ml) by Western blot followed by ECL stain and X-ray film during this period. Both brands remained available if needed by a particular exposure. Protein band intensities were correlated to b-actin expression. patient. Inclusion criteria consisted of patients requiring treatment with RESULTS: We analyzed basophils from 14 donors and found E4BP4 immunoglobulin for PID who received both products at our ambulatory mRNA expression in all donors (2.33 6 2.42) despite a low basophil RNA infusion center. Patients who received only 1 of the products were level. Seven donors were also tested for E4BP4 protein expression and excluded. We collected information about product used, infusion rate, again all basophil preparations were found positive. Comparing the side effects and pre-medications used. expression of E4BP4 with anti-IgE mediated histamine release revealed RESULTS: Thirty patients met inclusion criteria. 3 patients had no a trend towards a positive correlation between E4BP4 protein expression reaction to either product. 5 patients did not tolerate either product. 13 and basophil releasability (r 5 0.37, p 5 0.42). patients tolerated one of the two products but not the other, divided equally CONCLUSIONS: Human basophils express the transcription factor between the two products (7/6). 25 patients required at least one pre- E4BP4 which might have an impact on basophil histamine release. medication including anti-histamines, steroids and/or analgesics. 1 patient required a slower infusion rate without pre-medications. Side effects Cross-Talk Between Human Mast Cells and Bronchial included: Headache in 13 patients, hives in 5, vomiting in 3, fever/chills in 225 Epithelial Cells In The Production Of Plasminogen Activator 2, diarrhea in 1, anaphylaxis in 1, and possible seizure in 1. b Inhibitor-1 Via TGF- 1 CONCLUSIONS: Side effects are common in PID patients receiving IGIV 1 1 Dr. Seong Ho Cho, MD , Dr. Sun Hye Lee, PhD , Dr. Atsushi but most can be controlled with pre-medications and slowing the rate of 2 1 1 Kato, PhD , Dr. Tetsuji Takabayashi, MD , Dr. Soon Shin , Dr. Robert infusion. Tolerability of an IGIV product appears to be patient dependent rather 1 1 P. Schleimer, PhD, FAAAAI ; Division of Allergy-Immunology, Depart- than product dependent. The availability of at least 2 different IGIV products ment of Medicine, Northwestern University Feinberg School of Medicine, allows for optimal treatment of patients to prevent or control untoward effects. Chicago, IL, 2Department of Medicine, Division of Allergy-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL. RATIONALE: Previous reports suggest that plasminogen activator inhibitor-1 (PAI-1) promotes airway fibrosis in human asthma and allergen-challenged mice and that human and mouse mast cells (MC) are an important source of PAI-1. In the present study we investigated MC- epithelial cell (EC) interactions in the production of PAI-1. METHODS: We stimulated the human MC line, LAD2, or primary cultured human MC (PCHMC) with IgE-receptor cross-linking and collected the resulting supernatants. We incubated the human bronchial EC line, BEAS-2B or normal human bronchial EC with the LAD2 supernatants and measured the level of PAI-1 by ELISA. RESULTS: When supernatants from IgE-stimulated LAD2 were added to BEAS-2B, there was an approximate 2-fold enhancement of PAI-1 production by BEAS-2B (237.0622.7 vs 129.8623.4 ng/ml, n54, P<0.05). When we treated the MC supernatants with a TGF-b1 neutral- izing antibody, the production of PAI-1 from BEAS-2B was almost completely abrogated (control 277.7623.2 vs IgE-stimulation 394.0637.6 vs IgE+anti-TGF-b1 284.7651.5 ng/ml, n54, P<0.05). Although TGF-b1 mRNA was constitutively expressed in resting LAD2, it was not highly induced by IgE receptor-mediated stimulation. Nonetheless, active TGF-b1 protein was significantly increased in LAD2 after IgE receptor cross-linking (89.4627.7 vs 12.6611.1 pg/ml, n53, P<0.05). Active TGF-b1 produced by PCHMC was significantly reduced in the presence of a chymase inhibitor, suggesting a role of MC chymase as an activator of human latent TGF-b1. CONCLUSIONS: This study indicates that stimulation of human MC by IgE cross-linking triggers activation of TGF-b1, at least in part via chymase, which in turn induces the production of PAI-1 by bronchial EC.
ABS 5.2.0 DTD YMAI10629_proof 11 January 2014 3:14 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB64 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Epinephrine Use In Positive Oral Food Challenges Performed reaction at school. All types of staff need to be prepared to recognize and 227 As Screening For Food Allergy Therapeutic Trials treat a reaction, including in children with previously undiagnosed allergy. Ms. Sally A. Noone, RN, MSN, CCRC1, Jaime Ross, RN2, Hugh A. This highlights the need for undesignated epinephrine and food allergy Sampson, MD, FAAAAI3, Dr. Julie Wang, MD, FAAAAI2; 1Icahn School education in schools. of Medicine at Mount Sinai, New York, NY, 2The Icahn School of Med- icine at Mount Sinai, New York, NY, 3Pediatrics, Icahn School of Medi- Early and Significant Improvement In The Intensity Of Allergic cine at Mount Sinai, New York, NY. 229 Rhinitis Symptoms After Treatment With Intranasal RATIONALE: Studies indicate that 9-12% of positive oral food Ciclesonide 200 Mcg Qd: Open Trial In Mexican Population Francisco Javier Saynes-Marin1, Araceli Arellano-Plancarte2, Jazmin challenges (OFCs) for confirming food allergies require treatment with 2 2 2 epinephrine. Epinephrine use for positive OFCs performed as screening for Chiu-Ugalde , Estefania Torres-Medina , Jose Antonio Vargas-Romero , 2,3 1 enrollment in therapeutic trials for food allergy has not been reported. Juan Carlos Lopez-Alvarenga ; Hospital Angeles Metropolitano, 2 METHODS: Outcomes of positive screening OFCs from two treatment Mexico City, Mexico, Medical Department, Takeda Mexico S.A. de 3 trials, Food Allergy Herbal Formula-2 (FAHF-2) and Milk Oral C.V., Edo. de Mex., Mexico, Direccion de Investigacion, Hospital Gen- Immunotherapy (MOIT), performed at Mount Sinai were reviewed. In eral de Mexico "Eduardo Liceaga", Mexico City, Mexico. the FAHF-2 study, 45 subjects had positive OFCs (mean age 16.6 years, RATIONALE: Ciclesonide (CIC) is a hypotonic intranasal corticosteroid indicated for seasonal and perennial allergic rhinitis (AR). CIC is 60% male). Median food specific IgE levels were (kUA/L): peanut 33.25, metabolized by esterases to desisobutyryl-ciclesonide, its active metabo- walnut 40.7, cashew 4.05, sesame 49.35, salmon 2.82, cod 1.94. Median 1 skin prick test (SPT) wheal was 9.0 mm. In the MOIT study, 29 subjects lite. Previously, we have presented preliminary results of this clinical trial, had positive OFCs (mean age 9.6 years, 74% male). Median milk specific showing favorable impact of CIC 200 mcg qd over typical AR symptoms (n5457). This report presents the final results with 1562 subjects. IgE was 29.1 kUA/L and median SPT was 8.5 mm. RESULTS: OFC outcomes were similar in these two studies. The mean METHODS: Phase IV,open-label, non-interventional study. Patients with _ dose at termination of OFC was 15.1% in FAHF-2 and 7.5% in MOIT. active AR, >12 yo, with at least 2-year history of AR were included. They Reactions were scored as mild (64%), moderate (33%) and severe (3%) received intranasal CIC 200mcg qd during 4 weeks. Severity of typical and according to the NCI-CTCAE v 4.03 grading system. Symptoms included: associated AR symptoms was reported by the patients using a 10cm VAS oral 89%, skin 46%, gastrointestinal 54%, respiratory (upper and lower) (mornings, before CIC). During day 1, symptom intensity (SI) was re- 57%, and cardiovascular 3%. Epinephrine was administered in 39%. Other corded before CIC (time 0), 4h and 12h after treatment. From days 2 to treatments included antihistamine 100%, steroids 16.2% and intravenous 7, SI was evaluated once daily; from weeks 2 to 4, SI was registered fluids 9%. only once a week. Statistical analysis was performed by MANOVA CONCLUSIONS: Subjects undergoing screening OFCs for enrollment in adjusted by age, gender and BMI. 6 5 6 therapeutic trials are highly sensitive and react at low levels of allergen RESULTS: Mean age was 34 10 (SD), mean BMI 25.6 4and56.7% exposure. These reactions tend to be more severe and require more were women. Significant early decrease in SI of typical AR symptoms (nasal- aggressive treatment than OFCs performed to assess natural tolerance to congestion, nasal-itching, runny-nose and sneezing) occurred after only 12h of food allergens. treatment (effect sizes 77.7%, 68% 66% and 75% respectively; p<0.001). Effect sizes were even more pronounced at day 5 (130%, 117% 117% and School Experience With Food Allergy Reactions Highlight 119% respectively; p<0.001), and continued until day 28 without reaching a 228 The Need For Training and Availability Of Epinephrine plateau. A similar trend was observed for associated AR symptoms. Mrs. Katherine A. Schmeissing, MS, RN1, Christine Szychlinski, APN, CONCLUSIONS: Intranasal CIC was effective in relieving AR symp- CPNP2, Dr. Jacqueline Pongracic, MD, FAAAAI1,3, Dr. Anne Marie toms in a Mexican population with active AR. 1Saynes-Marin FJ, et al. Singh, MD4; 1Ann & Robert H. Lurie Children’s Hospital of Chicago, JACI 2013;Vol.131(2)suppl,AB189. Chicago, IL, 2Division of Allergy & Immunology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, 3Division of Allergy & Viral Induced Ibuprofen Sensitivity Leading To Anaphylaxis In Immunology, Department of Pediatrics, Northwestern University Fein- 230 Preschool Aged Children berg School of Medicine, 4Division of Allergy & Immunology, Depart- Mrs. Jodi A. Shroba, RN, MSN CPNP, Ms. Kathryn Chojnacki; Chil- ment of Pediatrics, Northwestern University Feinberg School of dren’s Mercy Hospital. Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago, RATIONALE: NSAIDS are one of the most common classes of Chicago, IL. medications involved in adult hypersensitivity drug reactions, with RATIONALE: Schools must be prepared to handle food allergy ibuprofen accounting for up to 30% of recorded reactions. We report 3 emergencies. We sought to characterize how Illinois school nurses were cases of ibuprofen anaphylaxis in children. prepared to manage life-threatening food allergies in schools and to METHODS: From January to June of 2011, three preschool aged patients determine how often these emergencies were occurring. presented to one outpatient allergy clinic after treatment for anaphylaxis METHODS: We created a server-mounted questionnaire via following ingestion of ibuprofen. All three patients had preceding symptoms SurveyMonkey.com that solicited school description, the nurses’ experi- of viral or bacterial illness and had previously tolerated ibuprofen. All three ence with severe allergic reactions in schools, and a description of how required emergent care and hospitalization for observation. One of three each school prepares for these type of emergencies. Invitations to partici- families consented to oral challenge. Graded oral challenge to ibuprofen was pate were emailed to school nurses who had attended state sponsored done in clinic with a total of 150mg given orally. continuing education events in the previous year and during a food allergy RESULTS: Twenty minutes after last dose, the patient developed cough presentation at the Illinois Association of School Nurses (IASN) fall con- and wheeze and was treated with 4 puffs albuterol and montelukast10mg. ference in 2012. The survey was open for completion for 4 months. Fifty minutes following the final dose, he developed sneezing, nasal RESULTS: Four-hundred-sixty school personnel (422 school nurses and drainage, perioral redness, periorbital edema and hives. He was then given 38 school health aids) completed the survey. Although nurses most cetirizine 5mg and observed for a total of 2 hours post onset of reaction. All frequently give injectable epinephrine (75.8%), all types of staff admin- symptoms had resolved at time discharge. istered the medication (aides, teachers, administrators, etc). Epinephrine CONCLUSIONS: Viral infection in preschool aged children may pre- was not available in 42.9% of untreated severe reactions. Alarmingly, disposition certain susceptible children to ibuprofen sensitization. 21.6% of reactions were from previously unknown allergen. Consideration should be given to ibuprofen as a causative agent in children CONCLUSIONS: This study demonstrates that life-threatening food presenting with anaphylaxis at the time of a viral infection even when allergic reactions occur at school and many students have their first allergic ibuprofen has been previously tolerated.
ABS 5.2.0 DTD YMAI10629_proof 11 January 2014 3:14 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB65 VOLUME 133, NUMBER 2
Anthropomorphic Variations According To Clinical Pattern In The Proficiency Status In The Use Of Inhaler and The Effect Of 231 Cow's Milk Allergic Children 233 Education On Inhaler Technique Ms. Diana Colson1, Prof. Nicolas Kalach, MD, PhD2, Ms. Pascale Sou- Eun-Jung Jo, MD1, Jung-Ha Mok, MD1, Seung-Eun Lee, MD2, Mi-Hyun laines3, Prof. Christophe Dupont, MD, PhD3,4; 1Nutricia Nutrition Clini- Kim, MD1, Kwangha Lee, MD, PhD1, Ki-Uk Kim, MD, PhD1, Min-Ki que, Saint Ouen, France, 2Hopital^ Saint Vincent de Paul, Groupement des Lee, MD, PhD1, Hye-Kyung Park, MD, PhD1; 1Department of Internal Hospitaux de l’Institut Catholique de Lille (GH-ICL), Lille, France, 3Ho- Medicine, Pusan National University School of Medicine, Busan, South pital Necker Enfants Malades, Paris, France, 4DBV Technologies, Paris, Korea, 2Department of Internal Medicine, Pusan National University France. Yangsan Hospital, Yangsan, South Korea. RATIONALE: To investigate the long-term effects of feeding with amino- RATIONALE: The appropriate use of inhaler is effective in treatment of acid (AAF) or extensive whey hydrolysate-based formula (eWHF) on airway diseases such as asthma and COPD. We assessed the proficiency growth, clinical and allergic parameters in mono- and poly-allergic children. status of inhaler use, and compared with the accuracy of inhaler use after METHODS: A telephone survey analyzed retrospectively 515 consecu- correct education of inhaler technique. tive (2004-2010) children with digestive/cutaneous/respiratory symptoms METHODS: We evaluated the inhaler technique in out-patients using related to mono-allergy (cow’s milk protein) or poly-allergy (>_2 foods) in a inhalers over 1 year. Inhaler technique was assessed from 6 criteria: for SATURDAY food allergy reference center (Ars ene Cohort, n8DC-2009-955). Children metered dose inhaler (MDI), remove mouthpiece cover and shake, breathe were enrolled if having been fed for >_6mo with >_500mL/day of AAF out gently, trigger at the same time as breathing, breathe in slowly and (NeocateÒ/Neocate AdvanceÒ) or of eWHF (Pepti-JuniorÒ), in combi- deeply until full, hold breath for 10 sec, and mouth rinsing if it contains nation with an adapted elimination diet. Parental questionnaires provided corticosteroid; for dry powder inhaler (DPI), remove mouthpiece cover, information on height, weight, evolution of clinical manifestations and prime device, breathe out gently, breathe in quickly and deeply until full, allergens sensitization. Analyses retained 135 children, for whom infor- hold breath for 10 sec, and mouth rinsing if it contains corticosteroid. The mation was available at age 5.962.75 years (mean6SD). correct operation of each item scored 1 point, the entire score was 6 points. RESULTS: At survey, BMI (z-scores) in mono-allergic children was The technique was reassessed at the next visit. significantly higher than in poly-allergic children, p 0.04. BMI of mono- RESULTS: A total of 86 patients (65.55610.87 yrs, male 58.1%) were allergic males fed with AAF tended to be higher than in poly-allergic p enrolled. Their diagnoses were asthma (44.2%), chronic obstructive 0.09. BMI of poly-allergic males fed with AAF tended to be lower than pulmonary disease (41.9%), and overlap syndrome (12.8%). The duration in those fed with eWHF, p 0.057. BMI in children with respiratory sensi- of inhaler use was 4.9264.48 years (range, 1-20 years). Initial score of the tization and asthma was significantly higher than in those without respira- technique was 3.6561.57 for MDI and 4.1860.92 for DPI, it was not tory sensitization and asthma, p 0.05. In children fed with AAF, the associated with age, gender, diseases, and duration of inhaler use. After percentage of persistent respiratory symptoms was 2.0%, i.e. 6 times education on inhaler technique, the score improved significantly (MDI, smaller than after eWHF feeding 12.1%, p 0.032. 5.2961.49, P-value<0.001; DPI, 5.6260.69, P-value<0.001). CONCLUSIONS: In mono-allergic children BMI is higher than in poly- CONCLUSIONS: This study showed the inhaler technique was poor allergic. Children with respiratory sensitization and asthma have higher despite long-term inhaler use and repetitive training of inhaler use is BMI than ones with cutaneuos/digestive symptoms. The replacement important. formula used, AAF vs eWHF, might exert some influence. The Natural History Of Wheat Hypersensitivity In Thai Development and Piloting Of a Food Allergy Education 234 Children 232 Program For Parents Of Young Children Dr. Nunthana Siripipattanamongkol, MD; Mahidol University, Ms. Catherine Gillespie, RN, MN CAE1, Ms. Nancy Ross, RN, CAE1, Bangkok, Thailand. Dr. Nestor F. Cisneros, MD, FRCPC2, Dr. Allan Becker, MD, FRCPC3; RATIONALE: Wheat hypersensitivity is a common cause of food allergy 1Children’s Hospital, Winnipeg, MB, Canada, 2University of Manitoba, among Thai children. Although the prevalence is increasing, the natural Winnipeg, MB, Canada, 3University Of Manitoba, Winnipeg, MB, history of this disease varies among different countries. This study aimed to Canada. study the natural history of IgE-mediated wheat hypersensitivity and to RATIONALE: Having a severe food allergy is life-threatening, but it can define the predictors of wheat tolerance. also have a significant impact on child and caregiver quality of life. Our METHODS: The patients with a history of immediate allergic reactions purpose was to develop an education program to help parents of young after wheat ingestions, were enrolled. Skin prick test (SPT), serum specific children gain knowledge, skills and confidence for successfully managing IgE (SIgE) to wheat and v-5-gliadin were performed. The oral challenge to their child’s severe food allergy. wheat was done to determine wheat tolerance. METHODS: Program development included a comprehensive literature RESULTS: Forty patients, age 6 months to 12 years, were studied. The review; consultation with an adult education specialist; development of mean duration of follow-up was 24 months. The median age of wheat objectives, content and format; a program draft review by professional and tolerance was 76 months (range 39-113 months). The percentage of lay food allergy experts; program piloting with parents of children <6 years children who had wheat tolerance was 10% by the age of 2, 20% by the age with severe food allergy and program revision based on participant and of 4, 42% by the age of 5 and 77% by the age of 9. The significant predictors facilitator feedback. Food allergy self-efficacy, caregiver burden and auto- for wheat tolerance were SPT for wheat less than 3 mm of wheal diameter injector technique were evaluated pre-program. Some caregivers were also (HR 8.4), history of non-anaphylactic reaction to wheat (HR 5.1). In evaluated post program. contrast, the level of wheat SIgE, sex, age of onset, time from onset to RESULTS: A small group interactive program was developed for parents physician diagnosis, duration of breastfeeding, age of solid food introduc- of children with severe food allergies. Eighteen groups participated in the tion, atopic disease and food co-sensitization were not the predictors of pilot program between February 2011 and June 2012. Seventy-three wheat tolerance. families completed the program including 102 mothers, fathers and CONCLUSIONS: Forty percent of children with wheat hypersensitivity grandmothers. Most participants were very satisfied with the program develop tolerance by the age of 5. History of non-anaphylactic reaction to and would recommend it to others. Follow up on 21 families several wheat and SPT are helpful to predict wheat tolerance. months post program indicated for most caregivers a decrease in caregiver burden and an increase in self-efficacy. CONCLUSIONS: The program was well received and appears to have positive benefits for parents of children at risk for a severe reaction. Further evaluation for effectiveness is required.
ABS 5.2.0 DTD YMAI10629_proof 11 January 2014 3:14 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB66 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Development Of a Multidisciplinary Clinic To Improve Care Of the entire study. Twenty-six (44%) of the subjects were non-adherent to 235 Adolescent Asthmatic Patients either part or all of the 6 month study. Ms. Lila C. Kertz, MSN, RN, CPNP, AE-C; Washington University, St. CONCLUSIONS: Almost half of study participants had difficulties with Louis, MO. medication adherence in this 6 month study, suggesting that the RATIONALE: Emphasizing control of asthma by asthma specialists intervention may be too demanding. while coordinating health promotion and disease prevention in adolescent patients, as provided by adolescent medicine specialists, may lead to Adapting Waiting-List For Allergy By Health Care On-Line: diagnosis of under-recognized co-morbid conditions. 237 Coordination Between Providers and Allergist In The Public METHODS: Seventeen asthmatic patients age 15-18 years, followed by System Dr. Inmaculada Sanchez-Mach ın, MD1, Dr. Paloma Poza Guedes2, Washington University pediatric allergists, pulmonologists, and nurse 1 3 practitioners in asthma clinic were referred to the Partnership for Asthma Dr. Ruperto gonzalez Perez , Dr. Yvelise Barrios, MD, PhD , Dr. Victor 1 1 Control with Teens (PACT) combined asthma/adolescent medicine Matheu, MD ; Hospital del Torax-Ofra, Sta Cruz de Tenerife, Spain, 2 3 clinic. Hospital Ofra-Torax, santa cruz de tenerife, Spain, Hospital Universi- RESULTS: Adolescent asthmatic patients with varying asthma severity tario de Canarias, Tenerife, Spain. (intermittent (12%), mild-persistent (12%), moderate-persistent (41%), RATIONALE: Primary care is the largest provider of patients to allergic severe-persistent (35%); 65% with uncontrolled asthma) were referred to care. To date, patient’s request were sent by fax and quoted on the waiting- PACT Clinic by their asthma specialist. The Guidelines for Adolescent list in order of arrival. Better coordination between levels of care, enables Preventative Services screening tool was used for referral for evaluation of better management of waiting-lists. sexually transmitted infection (76%), contraception (59%), weight man- METHODS: Allergic diseases can range from asymptomatic to critical agement (53%), self-reported depression (35%), acne (29%), substance- sensitization, and unpredictable exacerbations may occur as exposure to Ò abuse (12%), dysmenorrhea (12%). 59% were female. 76% had Medicaid. allergens. DRAGO-AP (InterSystems-Ensemble ) program allows the Upon initial consultation in PACT Clinic, patients were screened for contact to the main provider: Primary Care with the allergist. They can depression using PHQ-9 Modified for Teens survey (29% positive). 80% of do consultation about allergy evaluation indication. The allergist has ac- these patients had severe persistent asthma, 20% moderate persistent; 60% cess to the data of patient’s history and answered shortly (48h). He deter- of had uncontrolled asthma. All patients with a positive survey were mines if the patient need consultation or not, how long should be cited in referred for psychological counseling. Interventions for all other condi- the waiting-list and under what conditions the patient should go to consul- tions were individualized, as determined by the adolescent pediatric nurse tation (i.e. antihistamines leave enough time to perform prick test). practitioner. Asthma control continued to be managed by the allergy/ RESULTS: From April 2012 to July 2013, 2 allergists attend this activity in pulmonary PNP, following 2007 Guidelines for Diagnosis and health north area of S/C de Tenerife. We evaluated 1,155 consultations. Management of Asthma. 12.12% didn’t need allergy assistance. The 28.98% of patients came CONCLUSIONS: The high percentage of adolescent asthmatics with properly prepared, so allergy study has been possible and discharged the moderate-severe persistent, uncontrolled asthma and positive PHQ-9 same day. Modified screen suggests there is need to screen, identify and treat depression CONCLUSIONS: as an approach to improve management of asthma in this population. 1. A better control of prioritization of patients on waiting-lists was achieved. Food Allergy Herbal Formula-2 (FAHF-2) – Adherence To 2. A decrease in the utilization of specialist healthcare services was 236 Treatment obtained. Jaime Ross, RN1, Suzanne K. Carlisle, RN, BSN, CCRP2, Maripaz 3. The patients were also better prepared for the first visit. Vazquez, RN, BSN, CDE3, Stacie M. Jones, MD4, Dr. Jacqueline 4. With the growing demand for allergology assistance, the telemedicine Pongracic, MD, FAAAAI5, Dr. Julie Wang, MD, FAAAAI1; 1The Icahn offers new ways to improve the coordination of care and the efficiency of School of Medicine at Mount Sinai, New York, NY, 2University of Arkan- the public system. sas for Medical Sciences, Little Rock, AR, 3Division of Allergy and Immunology, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, 4Slot 512-13, University of Arkansas for Medical Sciences, Little Rock, AR, 5Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL. RATIONALE: A novel treatment for food allergy developed using Traditional Chinese Medicine, food allergy herbal formula-2 (FAHF-2), is under investigation in a Phase II clinical trial. Adherence to treatment was assessed. METHODS: Subjects aged 12-45 years were randomized to receive active FAHF-2 or placebo, 10 tablets three times a day for 6 months (30 tablets daily). Subjects kept medication diaries and brought study medications to study visits. They were contacted every 2 weeks and study visits were conducted every 2 months. Data collected included number of tablets ingested (per diary), number returned, and number of days between study visits. Adherence was calculated based on number of tablets taken in relation to expected number taken during the study time frame. Adherence was defined by medication completion > 80%. RESULTS: Sixty eight subjects were enrolled into the study, median age was 16 years old (range 12-44 years), 61.7% male, and 86.7% Caucasian, 4.4% African American, 5.8% Asian, and 2.9% other. Of the 9 subjects who withdrew from the study, three were due to difficulties with medication compliance. Of the 59 subjects who completed 6 months of therapy, 16 (27%) were non-adherent for 1/3 of the study period, 8 (13.6%) were non-adherent for 2/3 of the study and 2 (3%) were non-adherent for
ABS 5.2.0 DTD YMAI10629_proof 11 January 2014 3:14 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB67 VOLUME 133, NUMBER 2
Aerobiology Of Texas Panhandle and Efficiency Of AHPCO Genetic Effect Of Single-Nucleotide Polymorphisms In The 238 Technology As Air Purifier, Surface Sterilizer In Food 240 PPARGC1B Gene On Airway Hyperreactivity In Asthmatic Patients Processing Dr. Jong-Sook Park, MD, Dr. Myung-Sin Kim, Dr. Sung-Woo Park, Dr. Nabarun K. Ghosh, PhD1, Dr. Constantine K. Saadeh, MD, Dr. An-Soo Jang, Dr. Choon-Sik Park, MD; Soonchunhyang University FAAAAI2, Dr. Jeff Bennert, PhD, CTN3, Ms. Griselda Estrada, BS1; Bucheon Hospital, Bucheon, South Korea. 1West Texas A&M University, Canyon, TX, 2Allergy ARTS ACCR, Ama- RATIONALE: PPARGC1B is a co-activator for the estrogen receptor, rillo, TX, 3AIR OASIS, Amarillo, TX. PPAR. Genetic association of the PPARGC1Bgene with the risk of asthma RATIONALE: Allergy and Asthma cases have doubled in Texas and airway hyperreactivity was investigated. Panhandle area since 2007. We have collected aeroallergen samples and METHODS: Genotyping was done in 264 controls and 949 asthmatics characterized for 14 years. We used a novel AHPCO or Advanced using single-base extension methods. PPARGC1B, CHRM2, and CHRM3 Hydrated Photocatalytic Oxidation technology to produce filter less air mRNA levels were measured using real-time PCR methodology. Dual purifier, surface sterilizer for cell phones and meat processing facilities. luciferase reporter assays were performed to functionally analyze METHODS: We have been analyzing the daily aeroallergen by using the +102525G>ASNPs on exon 5. coated Melinex tape from the Burkard Volumetric Spore Trap. Exposed, RESULTS: 18 SNPs and 1 insertion/deletion polymorphismwere identified, SATURDAY stained Melinex tape was observed under a BX-40 Olympus microscope. and 7 SNPs were genotyped. No significant difference existed in the We assessed the AHPCO Technology for potential uses as air purification distribution of SNPs and haplotypes between the asthmatics and controls. unit, surface sterilizer and net reduction of bacteria, fungi during food However, the allele frequency of -427C>T and +102525G>A;R265Q processing. A fiberglass chamber was built to evaluate the performance and showed a significant association with log-transformed PC20 methacholine safety of the air purifiers. Blood, Human cell culture and plant cells were values in the asthmatics (P 5 0.005–0.0004). Real-time PCR demonstrated exposed to the AO chamber and The UV chambers to compare the higher PPARGC1B mRNA levels in asthmatics having -427CC allele than exposures. Petriplates, meat, vegetables were placed in the chamber to in those having -427TT or CT alleles (P 5 0.048). The ratio of the mRNA assess the capacity of sterilization. Images were captured with FITC, expression for each PPARGC1B exon4-mRNA compared to the wild type TRITC Filters with a BX40 and SZ-CTV Olympus Microscopes and SEM. was similar in peripheral blood mononuclear cells carrying the RESULTS: 14 years’ aeroallergen data of Texas Panhandle revealed a +102525G>A allele. Dual luciferase reporter assays revealed that gradual shift in aeroallergen index with the warmer climate and a shift in +102525A allele caused higher activation of ERa with estrogen than flowering seasons. +102525G allele. The ratio of the CHRM2, CHRM3, and b2ADR mRNA CONCLUSIONS: Strong wind current, maximum number of feedlots and expression for +102525A of PPARGC1B /ERa co-transfected 293T cells dry-land agriculture and a gradual shift in flowering season– all contribute mRNA showed a significant up regulation when compared to +102525G to a high concentration of allergic cases among the residents of Texas of PPARGC1B /ERaco-tansfected 293T cells mRNA. Panhandle. AHPCO technology proved to be an efficient way to reduce CONCLUSIONS: Polymorphisms of +102525G>A on exon 5 of the aeroallergen and prevent contamination during food processing. PPARGC1B gene may affect the development of AHR through the modu- lation of PPARGC1B gene products. The PPARGC1B genotypes may IL-33 and IL1RL1 Single Nucleotide Polymorphisms and Their serve as genetic markers for AHR. 239 Association With Asthma Among Puerto Ricans Dr. Javier A. Mendez, MD, Dr. Sylvette Nazario, MD, Dr. Angel Laureano, MD, Dr. Adriana Baez, PhD, Ms. Bianca Rivera, PhDc; Univer- sity of Puerto Rico School of Medicine, San Juan, PR. RATIONALE: Puerto Ricans have the highest asthma prevalence and mortality rates among all ethnic groups in the United States. The cause of this health disparity has not been elucidated, but may reflect a high prevalence of genetic risk factors for asthma in this population. Multiple genes have been associated with asthma among other ethnic groups, but most attempts to replicate these findings among Puerto Ricans have been unsuccessful. The aim of this study was to test whether SNPs in IL-33 and IL1RL1, two components of the innate immunity, are associated with asthma among Puerto Ricans. METHODS: 41 asthmatic Puerto Ricans and 53 healthy controls were recruited for this case-control study. Saliva samples were obtained from each participant to analyze SNPs rs1921622 in IL1RL1 and rs1342326 in IL-33. SNP genotyping was performed using Real-time Polymerase Chain Reaction (PCR). Skin testing for common aeroallergens was performed on asthmatic subjects to determine atopic status. Associations between genetic variants of IL-33 and IL1RL1 with asthma and asthma phenotypes were performed using logistic regression models. RESULTS: Both alleles studied demonstrated Hardy-Weinberg equilib- rium (p<0.05). IL-33 gene variants were not associated with asthma (p50.83), allergic asthma (p50.62), or asthma severity (p50.08). Similarly, no associations were found between IL1RL1 gene variants with asthma (p50.48) or asthma phenotypes. CONCLUSIONS: The gene variants of IL-33 and IL1RL1 analyzed in this study do not confer an increased risk of asthma or asthma-associated phenotypes among Puerto Ricans.
ABS 5.2.0 DTD YMAI10629_proof 11 January 2014 3:14 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB68 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Polymorphisms In IL10, TGFB, TLR4, TLR8 and ADBR2 Genes p50.04). Differences in allele frequency were also observed between 241 Resulted Associated To Asthma In Brazilian Family Trio Study allergic and non-allergic phenotypes among racial and gender subgroups. Mrs. Isabel Rugu^e Genov, MD1, Mrs. Angela Falcai, PhD2, Dr. Lucila CONCLUSIONS: We have identified genetic variants within the hista- Camargo, MD3, Dr. Marcia Mallozi, MD4, Dr. Virginia Ferriani, MD, mine pathway associated with an allergic versus non-allergic asthma PhD5, Prof. Alessandra Pontillo, PhD6, Prof. Antonio Condino- phenotype. Further studies are needed to determine the functional Neto, MD, PhD7, Prof. Dirceu Sole, MD, PhD8; 1Federal University of significance of identified SNPs and their impact on antihistamine response S~ao Paulo, S~ao Paulo, Brazil, 2ICB USP, S~ao Paulo, Brazil, 3UNIFESP, in patients with asthma and allergic disease. S~ao Paulo, Brazil, 4Federal University of S~ao Paulo, Brazil, 5School of Association Of Polymorphism At The CD14 Promoter (CD14- Medicine of Ribeirao Preto - University of Sao Paulo, Brazil, 6University 243 C159T) With Atopic and Non-Atopic Asthma In Adults From of S~ao Paulo, Brazil, 7Institute of Biomedical Sciences, Department of Crimea, Ukraine Immunology, University of S~ao Paulo, Sao Paulo, Brazil, 8Federal Univer- Yuri Bisyuk1, Prof. V. A. Beloglazov1, Dr. A. I. Dubovyi1, Dr. L. K. Zna- sity of Sao Paulo, Sao Paulo, Brazil. menska1, Prof. Lawrence M. DuBuske, MD, FAAAAI2; 1Crimean State RATIONALE: Asthma is a complex chronic inflammatory lung disease that Medical University, Ukraine, 2George Washington University School of results from the interaction between genetic predisposition and environmental Medicine, DC. factors. In the past decade the role of innate immunity in the pathogenesis of RATIONALE: The CD14 gene is located on chromosome 5q31-32, asthma has been investigated. Recentlygenome-wide association studieshave considered a critical region for asthma. There may be an association of the identified several innate immunity genes that significantly contribute to CD14 C-159T SNP with atopic and non-atopic asthma . asthma. In this study we reported the results obtained from family-based METHODS: 229 atopic and 41 non-atopic persistent asthma patients were association analysis of single nucleotide polymorphisms (SNPs) previously assessed. All atopic asthma patients had positive skin prick test results to at associated to asthma in a Brazilian cohort of patients. least 1 allergen and total IgE level > 100 IU/mL. Diagnosis of asthma was METHODS: Fourteen SNPs in 10 innate immune genes with a defined role according to GINA 2012 Guidelines. The control group included 285 non- in asthma development (TNF, IL6, IL10, TGFB, IFNG, TLR4, TLR7, TLR8, atopic volunteers. The single nucleotide polymorphism of CD14 C-159T CD14, FLG) were analysed in 311 Brazilian patients with asthma (ages was detected by PCR. Patients and volunteers provided written informed ranging from 5 to 18 years old) and their parents. Polymorphisms in consent for the genetic study. ADBR2 were used to stratify the patients according to bronchodilator RESULTS: In atopic asthma patients the CC genotype was detected in 57 responsiveness. SNP genotyping were done using sequence-specific primers patients, CT in 146 and TT in 26. Non-atopic asthma patients had CC in 25, PCR or Real-Time PCR with allelic-specific assays. Allelic frequencies were CT in 9, and TT in 7. The control group had CC in 97, CT in 146, and TT in analysed with Transmission Disequilibrium Test using Haploview. 42. The allele frequencies were 57% (n5260) for the C allele and 43% RESULTS: Among the 16 SNPs analysed, six were associated with asthma (n5198) for the T allele in atopic asthma cases (OR, 0.89; 95% CI, 0.69- in our Brazilian families’ cohort. Nominally significant association was 1.14; P50.35), whereas 72% (n559) for the C allele and 28 % (n523) for identified for TGFB rs1800471 (p56.33exp-5), IL10 rs1800871 and the T allele in non-atopic asthma cases (OR, 1.74; 95% CI, 1.04-2.89; rs1800872 (p50.024 and 0.023, respectively), TLR4 rs4986790 P50.03). In controls, the distribution was 60% (n5340) for the C allele (p50.020), TLR8 rs2407992 (p50.024), and ADRB2 rs1042714 (p50.033). and 40% (n5230) for the T allele. CONCLUSIONS: Our results emphasize the fundamental role of innate CONCLUSIONS: The CD14-C159T polymorphism is associated with immune genetic background in the development of asthma. According to adult non-atopic asthma but not with adult atopic asthma in the Crimean previous studies, polymorphisms in anti-inflammatory genes (IL10, TGFB) Ukraine population. as well as in TLRs and in ADBR2 genes were associated to asthma also in The Utility Of Anti-Pneumococcal Antibody Measurement In Brazilian population. 244 Patients With Primary Immunodeficiency Receiving Immunoglobulin Genetic Variation Along The Histamine Pathway In Children Dr. Stephen Jolles, Dr. Adrian Heaps, Dr. Mo Moody, Dr. Rachel Jones; 242 With Allergic Vs. Non-Allergic Asthma University Hospital of Wales, Cardiff, United Kingdom. Dr. Sara Anvari, MD1, Dr. Carrie A. Vyhlidal, PhD2,Mo 2 2 RATIONALE: Total immunoglobulin (IgG) serum level may not always Rezaiekhaligh, MS , Dr. Hongying Dai, PhD , Dr. Bridgette L. Jones, MD, be sufficient to determine adequate IgG replacement in primary immuno- FAAAAI1,2; 1Children’s Mercy Hospital & Clinics, Division of Allergy, 2 deficiencies (PID), given the wide range of pretreatment IgG levels. Poor Asthma and Immunology, Kansas City, MO, Children’s Mercy Hospital vaccine responses are a diagnostic criterion and specific antibody & Clinics, Division of Pediatric Clinical Pharmacology, Kansas City, MO. measurement while on therapy may offer additional information. RATIONALE: Previous studies have suggested that antihistamines may METHODS: This single-center retrospective study investigated if total be therapeutic in some patients with asthma. Variation in genes along the and specific IgG antibody trough levels correlated with clinical features, in histamine production, response, and degradation pathway may be impor- particular, infection frequency (based on medical history and antibiotic tant in predicting response to antihistamines. We hypothesize that requirements). Patients with PID (N5103), initially diagnosed with low differences exist among single-nucleotide polymorphisms (SNPs) in genes IgG, IgA, and/or IgM, poor response to vaccination and chronic infections, involved in the histamine pathway between children with allergic versus treated with immunoglobulin replacement for >3 months were selected. non-allergic asthma. RESULTS: Levels of anti-Haemophilus influenzae type B and anti-tetanus 5 METHODS: Children 7-18 years of age (n 118) with asthma partici- antibodies were almost always above the protective thresholds. However, pated in this IRB-approved protocol and were classified as allergic or non- anti-pneumococcal antibody levels were above the protective threshold allergic based on allergy skin testing. DNA isolation and genotyping were (50 U/mL) in only 2/15 patients with IgG levels of <7 g/L, in 11/23 patients performed to detect known SNPs among genes (HDC, HNMT, DAO, with IgG levels of 7–9 g/L, and in most patients (52/65) with IgG levels of ε HRH1, HRH4 and, Fc RII) within the histamine pathway. Chi Square, >9 g/L. Patients with IgG levels of <7 g/L were more likely to have low Fisher’s Exact test and Cochran-Armitage Trend were used to test for as- levels of anti-pneumococcal IgG antibodies and showed an almost two- sociations between genotypes and allergic or non-allergic asthma. fold increase in infection frequency. Significance was determined by p <0.05. CONCLUSIONS: Higher IgG trough levels correlate with higher pneu- RESULTS: We observed differences in allele frequency between mococcal antibody titres but a proportion of patients had inadequate participants with allergic versus non-allergic asthma for 3 SNPs: HRH1- pneumococcal antibody levels despite reassuring trough IgG levels. A 5 17 C/T (25% allergic with T, 14% non-allergic with T, p 0.04); HNMT poor response to pneumococcal vaccination is used diagnostically and the 5 -464 C/T (70% allergic with T, 56% non-allergic with T, p 0.03); measurement of anti-pneumococcal antibody levels on replacement may add HNMT -1639 C/T (30% allergic with TT, 14% non-allergic with TT, additional information, alongside clinical findings, when optimising therapy.
ABS 5.2.0 DTD YMAI10629_proof 11 January 2014 3:14 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB69 VOLUME 133, NUMBER 2
Diagnostic Immunization With Bacteriophage UX 174 In phenotypes consistent with the spectrum of disease, similar regions on 245 Patients With Common Variable Immunodeficiency/ chromosomes 2 and 6 were also strongly associated. Hypogammaglobulinemia CONCLUSIONS: This study exposes new and unexplored regions of Dr. Lauren Smith, MD1, Dr. Rebecca H. Buckley, MD, FAAAAI1, interest within chromosomes 2 and 6 in the CVID population. Further study Dr. Patricia L. Lugar, MD, MS2; 1Department of Pediatrics, Duke Univer- of these areas may show new gene(s) that may contribute to the disease. sity Medical Center, Durham, NC, 2Duke University Medical Center, Durham, NC. Rule Of Different Memory Cells In Common Variable 247 Immunodeficiency and Specific Antibody Deficiency RATIONALE: The use of the T cell-dependent neoantigen bacteriophage 1 2 3 F Amer M. Khojah, MD , Oral Alpan, MD , Ameera Bukhari, MS ; X 174 has been described since the 1960s as a method to assess specific 1 antibody response in patients with primary immune deficiencies. We Umm Al Qura Univirsity, Makkah, Saudi Arabia; Inova Fairfax Hospital for children, Fall Church, VA, 2Amerimmune, LLC, VA; O&O ALPAN, reviewed a cohort of patients at Duke University Medical Center (DUMC) 3 who received immunization with bacteriophage and report the clinical LLC, Taif University, Saudi Arabia. utility and safety of the immunization, as well as patient characteristics. RATIONALE: SAD diagnosis relies on abnormal response to pneumo-
METHODS: A retrospective chart review was performed of all Duke coccal vaccine. The purpose of our study is finding a flow cytometry SATURDAY Immunology Clinic patients (pediatric and adult) who received immuni- marker for early detection of SAD. zation with bacteriophage, from 1976-2012. Subjects were selected for METHODS: Total of 361 subjects (205 adults and 156 children) were inclusion if their diagnosis at the time of bacteriophage was either included in study between 2010 and 2013. Patients with known immuno- presumed or confirmed common variable immunodeficiency (CVID), deficiency other than SAD and CVID were excluded. Subjects were hypogammaglobulinemia, transient hypogammaglobulinemia, or antibody divided into 3 groups (control, SAD, CVID) based on their immunoglob- deficiency unspecified. Follow up post-immunization was also recorded. ulin levels and their response to pneumococcal vaccines. Data was RESULTS: One hundred nineteen patients were identified, 29 adult and 90 analyzed using SPSS. pediatric patients. Diagnoses prior to bacteriophage were CVID (n593), RESULTS: We found that SAD and CVID have significant lower number hypogammaglobulinemia (n523), and antibody deficiency (n53). Post- of memory B-cell. Furthermore, we found that percentage of memory B- 5 immunization diagnoses were CVID (n563), hypogammaglobulinemia cell increases with age in control group (correlation coefficient 0.4, P (n516), unknown (n525), normal patient (n58), and other primary value 0.0001) but not CVID or SAD groups. However, Memory T-helper immune deficiency (n57). Seventy-four patients had abnormal bacterio- cell increases with age in all three groups (correlation coefficient 0.71-0.78, phage results, 31 were normal, and 14 were borderline. There were 257 P value 0.0001).There was direct correlation between memory B-cell and recorded administrations of the immunization. Data on reactions was CD4+ memory T-cell (correlation coefficient 0.39 with P value <0.0001), recorded for 205 immunizations. Fourteen immunizations were associated and this correlation was inversed in SAD (correlation coefficient -0.45 with with minor adverse events. Seventeen patients stopped their immune P value of 0.007). Using CD4+ memory T-cell to memory B-cell ratio of globulin replacement therapy based on reported immunization response. 4.5 as a marker for SAD had specificity of 98% but poor sensitivity of 31%. CONCLUSIONS: Bacteriophage FX 174 is a clinically useful and safe CONCLUSIONS: Our findings suggest that there is impaired correlation, method to assess antibody response in patients with suspected antibody- either developmentally or acquired through negative feedback, between mediated immune deficiencies, particularly those who are on immune CD4+ memory T-cell and memory B-cell in SAD patients. Using the ratio globulin replacement therapy at the time of immunization. of CD4+ memory T-cell to memory B-cell helps identifying distinct cluster of SAD patients and future research is need to evaluate its prognostic value. Immunochip Study Reveals Regions On Chromosomes 2 and 6 246 May Contribute To The Spectrum Of CVID Dr. Tracy Hwangpo, MD/PhD1, Ewa Szymanksa, PhD1, Mrs. Marsha Brand1, Dr. Peter Gregerson, MD2, Dr. Peter Burrows, PhD3, Dr. Elizabeth Brown, PhD4, Dr. Richard Reynolds, PhD5, Dr. Harry Schroeder, MD/PhD6; 1UAB, 2The Feinstein Institute for Medical Research, 3UAB, Department of Microbiology, 4UAB, Department of Epidemiology, 5UAB, Department of Medicine, 6UAB, Department of Medicine and Department of Microbiology, AL. RATIONALE: In our PID Clinic, we have cared for more than 300 patients with recurrent infections and depressed immunoglobulins. We have enrolled a majority of them in a protocol to identify regions within the genome that may contribute to the spectrum of their disease. We are interested in patients with CVID as well as a spectrum of patients who do not meet CVID criteria. METHODS: We included a total of 1,422 cases and controls of European American ancestry; of which, 81 were diagnosed with CVID, 84 with intermediate CVID (ICR), and 75 with RESPI. Relative risk was estimated using odds ratios and corresponding 95% confidence intervals as implemented in PLINK using log-additive models and linkage disequilib- rium was assessed using Haploview and LocusZoom. RESULTS: The strongest gene associations with CVID were mapped to several loci on chromosomes 2 and 6. Specifically, on chromosome 2, loci mapped to the genes that encode endonuclease ZRANB3 and the GTPase activating protein RAB3GAP1 were strongly associated with CVID compared to controls (p56.00X10-12 and 6.59x10-12, respectively). On chromosome 6, rs2523535, localized to HLA-B, was associated with CVID (p53.13x10-9). When we expanded our analysis to include all
ABS 5.2.0 DTD YMAI10629_proof 11 January 2014 3:14 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB70 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Evaluation of a Novel Missense Activation-Induced without SP-A for 1 hr, and then, 24 hr after virus removal, viral replication 248 Deaminase AID Mutation in a Child with Hyper IgM were determined by western blotting. Syndrome: Is it a Pathogenic Mutation? RESULTS: SP-A binds RV16 with an apparent Kd of 332.0 ng/ml. SP-A Dr. Ottavia M. Delmonte, MD1, Dr. Feilong Meng, PhD2, Dr. Frederick reduced the RV16-induced RNA synthesis for IFNB1, TLR3, RIG-1, IRF- Alt, PhD3, Dr. Luigi D. Notarangelo, MD4, Dr. Jolan E. Walter, MD, 7 and MDA-5 significantly. SP-A also reduced IL-8 secretion from BEAS PhD5; 1Pediatric Residency Program, Boston Children’s Hospital, Har- 2B cells by 75%. In addition, SP-A inhibited viral protein expression in H1 vard Medical School, Boston, MA, 2Howard Hughes Medical Institute, HeLa cells. Program in Cellular and Molecular Medicine and Immune Disease Insti- CONCLUSIONS: These data illustrate the novel anti-viral and anti- tute, Boston Children’s Hospital, Department of Genetcis, Harvard Med- inflammatory properties of SP-A which may play important role in ical School, Boston, MA, 3Howard Hughes Medical Institute, Program in reducing Rhinovirus-induced exacerbation of asthma and COPD. Cellular and Molecular Medicine and Immune Disease Institute, Boston Children’s Hospital, Department of Genetics, Harvard Medical School, The Home Microbiome and Childhood Asthma Boston, MA, 4Division of Immunology, Boston Children’s Hospital, Har- 250 Dr. Christina E. Ciaccio, MD, FAAAAI, Mr. Kevin vard Medical School, Boston, MA; The Manton Center for Orphan Dis- Kennedy, MPH, CIEC, Prof. Charles S. Barnes, PhD, Dr. Jay M. ease Research, Boston Children’s Hospital, Boston, MA, 5Division of Portnoy, MD, FAAAAI, Dr. Lanny J. Rosenwasser, MD, FAAAAI; Chil- Allergy/Immunology, Massachusetts General Hospital for Children, Har- dren’s Mercy Hospital, Kansas City, MO. vard Medical School, Boston, MA. RATIONALE: Exposure to microorganisms has repeatedly been found to RATIONALE: Hyper IgM Syndrome (HIGM) is a primary immunode- influence the development of atopic diseases, such as asthma. This ficiency associated with defects of CD40, CD40L, AID and UNG genes. In relationship has been best understood as an inverse correlation between the case of a novel mutation, genetic testing requires secondary confirma- microbial diversity and atopic disease. Innovative techniques have been tion such as functional studies to establish a link between the clinical developed that more comprehensively characterize microbial commu- phenotype and the mutation identified. nities. The aim of this study, therefore, was to characterize the home METHODS: Genetic screening of a 4-year-old boy with clinical features microbiota of asthmatics and non-asthmatics. of HIGM Syndrome resulted in a novel missense mutation in the AID gene METHODS: This cross-sectional analysis was performed as part of the (p.Ala132Pro). The mutation was located away from the core catalytic Kansas City Safe and Healthy Homes Partnership. The microbiome was 5 domain, but in an area highly conserved among species. The effect of the compared in the dust from homes of asthmatic children (n 16) and healthy 5 mutation on AID expression or function was unclear. Testing was controls (n 7). Dust samples were collected from home vacuum bags. undertaken to connect the novel mutation to an actual defect in AID, in DNA was extracted and bacterial 16s rRNA genes amplified. Bacterial vivo and in vitro. In vitro studies included compliment class switch recom- products were fragmented, biotin labeled, and hybridized to the PhyloChip bination (CSR) assay in AICDA-deficient murine B cells and Western blot Array. Phylochip Arrays were scanned using a GeneArray scanner. to detect protein stability. AID function in vivo was assessed by IgG level RESULTS: 1746 operational taxonomic units (OTUs) were found in each and switched memory B cell fraction. of the 23 samples. Bacterial genus richness did not differ in the homes of 5 RESULTS: Functional studies confirmed that the mouse AID A132P asthmatics and non-asthmatics (p 0.09). The Bray Curtis distance mutant cannot support CSR in AICDA-deficient murine B cells with retro- between samples demonstrated separation between the whole microbiome viral-delivered AID mutant proteins. The AID mutant results in a dysfunc- of the two groups. All of the top 12 OTUs isolated belonged to one of the tional unstable protein which cannot be detected with Western blot, five phyla, Cyanobacteria, Firmicutes, Actinobacteria, Proteobacteria, and suggesting that this conserved amino acid could be involved in protein Bacteroidetes and were all increased in abundance in the samples from 5 5 -6 folding and stability. In vivo, the very low amount of AID resulted in low homes of asthmatic children (p 0.001 to p 7.2 x 10 ). IgG level (<7 mg/dL) and a low fraction of class switched memory B cells CONCLUSIONS: These results suggest that home dust has a character- (<2%). istic microbiota which is disturbed in the homes of asthmatics. Further CONCLUSIONS: Link should be established with functional studies for investigations are needed to determine how home microbial exposures novel mutations, especially in case of missense mutations. influence the respiratory, skin, and gastrointestinal microbiomes of its inhabitants. Surfactant Protein A (SP-A) Reduces Human Rhinovirus 16 249 (RV16)-Induced Inflammatory Responses In Bronchial Epithelial Cells and Inhibits Viral Replication In H1-HeLa Cells Sasipa Tanyaratsrisakul, PhD1, Ying Wang, MD2, Monica Kraft, MD2, Mari Nakamura, MD1, Prof. Dennis R. Voelker, PhD1; 1Department of medicine, National Jewish Health, Denver, CO, 2Department of Medicine, Duke University Medical Center, Durham, NC. RATIONALE: RV16 is a major virus associating with exacerbation of asthma and chronic obstructive pulmonary disease (COPD). There is no vaccine or effective treatment available. SP-A is a protein of the bronchoalveolar compartment that binds to numerous pathogens and regulates innate immunity. We examined the direct interaction between SP-A and RV16 and the effects of the protein on virus elicited inflamma- tory cytokine production and viral replication in BEAS 2B and H1 HeLa cells. METHODS: SP-A was purified from bronchoalveolar lavage fluid of alveolar proteinosis patients. SP-A binding to solid phase RV16 was determined by ELISA. BEAS 2B cells were treated with RV16, MOI 10, with or without SP-A 40 ug/ml for 48 hrs. IL-8 secretion was determined by ELISA, and RNA levels of IFNB1, TLR3, RIG-1, IRF-7 and MDA-5 were measured by qPCR. H1 HeLa cells were pre-absorbed with RV16 with or
ABS 5.2.0 DTD YMAI10629_proof 11 January 2014 3:14 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB71 VOLUME 133, NUMBER 2
Effect Of Prenatal Antioxidant Intake On Infants' Respiratory between RSV strain A2 F and EGFR. Knockdown of EGFR in resulted in 251 Infection lower RSVentry and infectivity, independent of the RSV strain. When cells Dr. Eun Lee1, Seo Ah Hong2, Dr. Song I. Yang, MD1, Prof. Kyung Won were treated with an EGFR tyrosine kinase inhibitor, the infectivity of Kim, MD, PhD3, Prof. Youn Ho Shin4, Kang Mo Ahn5, Dr. Soo-Jong recombinant 2-20, but not A2, was reduced. Overexpression of EGFR Hong, MD, PhD1 and the COCOA study group. 1Department of Pediat- enhanced activity of the 2-20 F protein but not A2 F, and this fusion boost rics, Childhood Asthma Atopy Center, Research Center for Standization was EGFR signaling-independent. EGFR was expressed apically in of Allergic Diseases, Asan Medical Center, University of Ulsan College ciliated WD-PBECs, and anti-EGFR reduced yield of clinical isolate of Medicine, Seoul, Korea, 2Asan Institute for Life Sciences, University RSV in WD-PBECs. of Ulsan College of Medicine, Seoul, Korea, 3Department of Pediatrics, CONCLUSIONS: EGFR interacts with the RSV F protein, prominently Severance Children’s Hospital, College of Medicine, Yonsei University, with RSV 2-20 F. EGFR promotes RSV 2-20 F activity as well as RSV Seoul, Korea, Seoul, South Korea, 4Department of Pediatrics, CHA Med- entry and infectivity. We identified signaling-dependent and -independent ical Center, CHA University School of Medicine, Seoul, Korea, South Ko- roles of EGFR in the RSV life cycle. rea, 5Department of Pediatrics, Samsung Medical Center, Sungkyunkwan
Cluster Analysis Of An Inner-City Cohort Of Infant Wheezers SATURDAY University School of Medicine, Seoul, Korea, South Korea. 1 2 RATIONALE: Prenatal maternal diet may influence disease susceptibility 253 Dr. Monica B. Reddy, MD , Andrew H. Liu, MD , Allison Schiltz1,2, Mrs. Anna Forssen, MS2, Dr. Mary D. Klinnert, PhD1,2; 1Uni- of offspring with genetic backgrounds. The effect of prenatal antioxidant 2 intake on the development of respiratory tract infection (RTI) during versity of Colorado School of Medicine, National Jewish Health, Denver, infancy has not been studied. The interactions between prenatal antioxi- CO. dant intake and genetic factors on RTI susceptibility at 12- months of age RATIONALE: Inner-city life is associated with early childhood wheezing was evaluated. and disparately poor asthma outcomes, but distinct phenotypes of the METHODS: In the COhort for Childhood Origin of Asthma and Allergic preschool age associated with poor outcomes have not been described. Diseases (COCOA) birth cohort study, prenatal maternal diet was assessed METHODS: In the Childhood Asthma Prevention Study (NIAID, PI by administering a food frequency questionnaire. Infants’ cord blood was Klinnert), 119 Inner-City participants with recurrent wheezing in infancy genotyped for the CD14 (rs2569190), TLR4 (rs1927911), and GSDMB were followed from enrollment (age 9-24 months) to age 4 years, and had (rs4794820) polymorphisms by using the TaqMan method. complete data for a hierarchical cluster analysis to identify distinct RESULTS: High prenatal maternal intake of vitamin C, folate, and total wheezing phenotypes based on asthma symptoms (ATS-B questionnaire), fruit and vegetables associated weakly with the risk of RTI in offspring. In impulse oscillometry (IOS) measures of lung function before and after children with the major CD14 allele, high prenatal intake of vitamins A and albuterol, and atopy. Asthma outcomes also included spirometry and C, folate, fruits, and total fruits and vegetables associated with a lower RTI exacerbations (prednisone courses, ER/clinic visits, hospitalizations). risk (p-trend<0.05), whereas in infants with the minor alleles, high prenatal RESULTS: Five phenotypes were identified: ‘Atopic Wheezers’ (10% of intake of fruit increased the RTI risk (p-trend <0.05). In children with the cohort) demonstrated asthma symptoms, high IOS resistance, high major TLR4 allele, the risk of RTI revealed inverse linear associations with bronchodilator (BD) response, atopy, and hyperinflation by spirometry; high prenatal intake of vitamin C (p for interaction50.0268). High prenatal ‘Non-atopic Wheezers’ (50%) demonstrated asthma symptoms, but no intake of fruits and total FV reduced the risk of RTI in infants with the GA atopy; ‘Remitters’ (18%) were asymptomatic and had low IOS resistance; or AA genotype of GSDMB (p for interaction<0.05). ‘Transient Wheezers’ (10%) were asymptomatic but with low lung CONCLUSIONS: Prenatal antioxidant intake may reduce the risk of RTI volumes; and ‘Paradoxical Responders’ (12%) demonstrated an increase in infants, and this relationship may be modified by CD14, TLR4, and in IOS resistance after albuterol. Atopic and Non-atopic Wheezers had GSDMB polymorphisms. significantly more ER visits compared to Remitters (p<0.01), and Non- atopic Wheezers received significantly more prednisone bursts compared Epidermal Growth Factor Receptor (EGFR) Mediates Cell to Remitters (p<0.01). 252 Fusion and Infectivity Of Respiratory Syncytial Virus (RSV) CONCLUSIONS: A cluster analysis identified 5 distinct phenotypes in an Sujin Lee1,2, Michael G. Currier1,2, Anne L. Hotard1,2, Jia Meng1,2, Carla inner-city cohort of wheezing infants followed to age 4 years. Atopic Pretto1,2, Ultan F. Power3, Remi Villenave3, Michael D. Shields3,4, wheezers and Non-atopic wheezers had persistent symptoms, differing Michael H. Chi5, R. Stokes Peebles6, Martin L. Moore1,2; 1Department patterns of lung function, and severe exacerbations, while Remitters and of Pediatrics, Emory University, GA, 2Children’s Healthcare of Atlanta, Transient Wheezers improved. GA, 3Centre for Infection and Immunity, School of Medicine, Dentistry and Biomedical Science, Queens University Belfast, Northern Ireland, 4The Royal Belfast Hospital for Sick Children, Northern Ireland, 5Allergy, Pulmonary, and Critical Care Medicine; Department of Medicine; Vander- bilt University School of Medicine, TN, 6Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN. RATIONALE: We reported that RSV clinical isolate ‘‘2-20’’ fusion (F) protein is mucogenic in RSV-infected mice. Here, we hypothesized a cellular protein interacts with the RSV 2-20 F protein. METHODS: Cellular proteins binding to RSV were identified by screening and proteomics. Interaction of RSV F with epidermal growth factor receptor (EGFR) was confirmed by co-immunoprecipitation and immunoblotting. RSV entry and infection were quantified in BEAS-2B cells and stable BEAS-2B EGFR-knockdown cells. RSV F proteins and EGFR were overexpressed in 293T cells in a fusion assay. EGFR and RSV were localized using confocal microscopy, and the effect of EGFR blockade on RSV was determined in well-differentiated primary pediatric bronchial epithelial cells (WD-PBECs). RESULTS: We identified EGFR as an RSV F-binding protein. The interaction between RSV strain 2-20 F and EGFR was stronger than that
ABS 5.2.0 DTD YMAI10629_proof 11 January 2014 3:14 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB72 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
A Randomized, Multi-Center, NIH/NIAID Funded Study To treatment. Risk factors for food allergy among infants with eczema include 254 Assess The Immunogenicity Of FluzoneÒ Intradermal and maternal allergy (OR 1.3, 95% CI 1.1, 1.7) and East Asian ethnicity Intramuscular Vaccines In Atopic Dermatitis (ORfather east asian 2.3, 95% CI 1.4, 3.8). Donald Y. M. Leung, MD, PhD, FAAAAI1, Lisa A. Beck, MD, CONCLUSIONS: Infants with eczema across the clinical severity FAAAAI2, Dr. Jon M. Hanifin, MD, FAAAAI3, Dr. Lynda C. spectrum are at increased risk of IgE-mediated food allergy. The risk is Schneider, MD, FAAAAI4, Dr. Amy Paller, MD5, Dr. Gloria greatest among infants with early-onset and more severe eczema. Infants David, PhD6, Ms. Katherine Monti6, Mr. Brett Jepson6, Dr. Adriana Wein- with eczema could be targeted for advice about introduction of food and berg, MD7; 1National Jewish Health, Denver, CO, 2University of Roches- interventions to reduce the prevalence of food allergy. ter Medical Center, Rochester, NY, 3Oregon Health & Science University, Portland, OR, 4Boston Children’s Hospital, Boston, MA, 5Northwestern Exome Chip Genotyping Reveals Association With PDE4C and University Feinberg School of Medicine, Chicago, IL, 6Rho, Inc., Chapel 256 Atopic Dermatitis In Populations Of European and African Hill, NC, 7University of Colorado Heath Sci Ctr., Denver, CO. Descent Nicholas M. Rafaels1, Lili Huang, MPH1, Donald Y. M. Leung, MD, RATIONALE: Atopic dermatitis (AD) is associated with defective 2 3 immune responses. A subset of AD are colonized with Staphylococcus PhD, FAAAAI , Lisa A. Beck, MD, FAAAAI , Dr. Candelaria I. Vergara, MD, PhD1, Dr. Mark Boguniewicz, MD, FAAAAI2, Dr. Tissa aureus. This raises concerns that AD may have reduced immune responses 4 5 Ò Ò Hata, MD , Dr. Lynda C. Schneider, MD, FAAAAI , Dr. Jon M. to Fluzone Intradermal compared to intramuscular Fluzone . 6 7 METHODS: Hemagglutinin Inhibition Antibody (HAI) titers were Hanifin, MD, FAAAAI , Dr. Richard Gallo, MD, PhD ,Dr.Li Gao, MD, PhD1, Dr. Ingo Ruczinski, PhD8, Dr. Rasika A. measured at baseline and day 28 post-vaccination in 223 subjects with 1 1 1 AD (including a subset with S. aureuscolonization) and 135 non-atopic Mathias, ScD , Dr. Kathleen C. Barnes, PhD, FAAAAI ; Division of Al- lergy and Clinical Immunology, Department of Medicine, Johns Hopkins (NA) controls, following administration per label of either a single dose 2 3 Ò University, Baltimore, MD, National Jewish Health, Denver, CO, Uni- of the seasonal 2012–2013 Fluzone Intradermal or intramuscular 4 Ò versity of Rochester Medical Center, Rochester, NY, University of Cali- Fluzone vaccine. Analyses excluded subjects who were seroprotected 5 (HAI>_1:40) at baseline. fornia, San Diego, San Diego, CA, Boston Children’s Hospital, Boston, MA, 6Oregon Health & Science University, Portland, OR, 7Division of RESULTS: Seroprotection and seroconversion rates for all 3 influenza 8 strains (B, H1N1, and H3N2) were not significantly different for AD and Dermatology, University of California, San Diego, San Diego, CA, Johns NA subjects receiving intradermal vaccination. Seroprotection and Hopkins University School of Public Health, Baltimore, MD. seroconversion rates were similar for AD receiving intradermal vaccina- RATIONALE: Atopic dermatitis (AD) is a complex, heritable trait that is tion compared to AD receiving intramuscular vaccination. Following characterized by skin infections in a subset of patients. AD eczema intradermal vaccination, AD colonized with S. aureus had notably lower herpeticum (ADEH+) is a rare but serious complication of AD for which seroprotection and seroconversion rates to the B strain (12% vs 47%, common genetic determinants in candidate loci have been demonstrated. p<0.001; and 21% vs 51%, p50.002, respectively) and a lower seroconver- Given that variants in these genes do not fully explain known heritability of sion rate for H1N1(77% vs 95%, p50.029) compared to uncolonized AD. ADEH+, we used the HumanExome-12v1-1_A Illumina exome chip There were no notable differences for H3N2. There was no difference be- platform to identify rare functional coding variants associated with risk of tween S. aureuscolonized vs uncolonized AD following intramuscular AD and ADEH+. FluzoneÒ for any strain. METHODS: We genotyped 242,901 single nucleotide variants (SNVs) on CONCLUSIONS: We conclude that NA and AD subjects mounted 140 ADEH+, 170 ADEH-, and 161 non-atopic (NA) European ancestry similar immune responses to intradermal vaccination. Among AD sub- (EA) patients and 42 ADEH+, 168 ADEH-, and 161 NA African ancestry jects, the subset having S. aureus colonization exhibited reduced cutaneous (AA) patients. Genetic associations for risk of ADEH+ and AD were immune responses after FluzoneÒ Intradermal vaccination. determined using logistic regression for common variants (minor allele frequency (MAF)>_0.05) and Fisher’s exact test for rare variants Which Infants With Eczema Are At Risk Of Food Allergy? (MAF<0.05). 255 Results From A Population Based Study RESULTS: Exome chip genotyping revealed 6 and 8 SNVs associated Dr. Jana K. Eckert, PhD1, Dr. Pamela Martin, PhD1, Dr. Adrian with ADEH+ and AD respectively, in EA patients (P<2.8E-4, P<3.9E-4, Lowe, PhD1,3, Dr. Jennifer Koplin, PhD1, Prof. Shyamali respectively). In AA patients, we found replication for 4 and 5 SNVs Dharmage, MD, PhD1,3, Prof. Lyle Gurrin, PhD1,3, Prof. Mimi L. K. with ADEH+ and AD, respectively. The most significant replicated associ- Tang, MD, PhD FAAAAI4, Prof. Anne-Louise Ponsonby, PhD1, ation with AD was in PDE4C; rs2229228 (meta-analysis combining EA Dr. Melanie Matheson, PhD3, Dr. David Hill, MBBD, FRACP1, and AA: P51.7E-4), a possibly damaging missense variant. Prof. Katrina Jane Allen, MD, PhD, FAAAAI1,5; 1Murdoch Childrens CONCLUSIONS: Genotyping of the exome chip has revealed a novel Research Institute, Victoria, Australia, 3University of Melbourne, Victo- association with AD and ADEH+ in PDE4C. Phosphodiesterase type 4 ria, Australia, 4The University of Melbourne, Melbourne, Australia, (PDE4), identified here, has biological plausibility. Inhibitors have thera- 5Royal Children’s Hospital, Victoria, Australia. peutic potential to regulate immune response to inflammatory diseases, RATIONALE: The risk of food allergy among infants with eczema has including AD, and polymorphisms in the PDE4 gene pathway have been rarely been examined in whole population samples. We sought to associated with allergic disease (i.e., asthma). characterize the risk of challenge-proven food allergy across the spectrum of eczema present in the general population. METHODS: The prevalence of food allergy to peanut, egg white or sesame, measured by oral food challenge, was calculated for 12-month-old infants with or without eczema in the HealthNuts study, Melbourne, Australia. Eczema severity was characterized by age at eczema onset and strength of topical treatment required. 4453 infants were included in the analyses. RESULTS: One in five infants with eczema were allergic to peanut, egg white or sesame (prevalence 20.9%, 95% CI 19.0, 23.0), compared to one in twenty-five infants without eczema (4.1%, 95% CI 3.4, 4.9, p<0.001). The risk increased to one in two (50.9%, 95% CI 42.8, 58.9) for infants with early eczema onset who required doctor-prescribed topical corticosteroid
ABS 5.2.0 DTD YMAI10629_proof 11 January 2014 3:14 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB73 VOLUME 133, NUMBER 2
Exploring a Role for Laminin Proteins in the Pathogenesis of What Really Happens In The Home: The Medication 257 Atopic Dermatitis 259 Environment Of Urban, Minority Youth Erin J. Klaffky, MD, PhD, Rachana Agrawal, PhD, Judith A. Woodfolk, Dr. Molly Martin, MD, MAPP, Andrea A. Pappalardo, MD; Rush Uni- MBChB, PhD, FAAAAI; University of Virginia, Charlottesville, VA. versity Medical Center, Chicago, IL. RATIONALE: The skin of patients with atopic dermatitis (AD) contains a RATIONALE: To describe the asthma medication environment in the dense T-cell infiltrate and a microenvironment enriched in extracellular homes of urban minority youth, and to determine predictors of medication matrix (ECM) components. Normal T-cells produce the heterotrimeric use, technique, and asthma control in this high risk population. ECM component, laminin, and secrete several isoforms when activated METHODS: Baseline data from two cohorts of minority youth with (laminins 8-11). Individual laminin isofoms influence T-cell behavior asthma in Chicago were combined for cross-sectional analysis. Bilingual through engagement of surface integrins. Given that the role of laminins in research assistants (RAs) asked caregivers and children to self-report AD has largely been overlooked, we aimed to explore its relevance to medications using pictures and observed children’s asthma medicines and disease. inhaler technique. Adherence was determined using electronic actuation METHODS: Circulating skin-homing CD4+T-cells in AD patients and monitors and/or medication counters. non-allergic healthy controls were analyzed for expression of laminins RESULTS: The sample contained 162 mainly Latino (93%) youth ranging SATURDAY and surface integrins by flow cytometry using freshly isolated PBMCs. from 5-18 years old. Almost all were on public insurance (79%). Most had Immunofluorescent staining of skin biopsy specimens from AD patients uncontrolled asthma (69% in last 4-weeks, 79% in last 12-months). Only was performed to examine co-localization of laminin components with 25% had a spacer, 78% had a quick relief medicine, and 49% had any skin-infiltrating T-lymphocytes. controller. RA observations controllers showed good agreement with RESULTS: Circulating CLA+CD4+ T-cells predominantly expressed sur- parent self-report (kappa50.64) and child self-report (kappa50.57). face and intracellular laminin 11 (a5b2g1) in both AD patients and con- Children reported less parental help with medications (41%) than their trols. No differences between groups were detected in the profile of parents (53%) (kappa50.40). Only 6% of children with inhaled cortico- laminin binding integrins (a1-3, a6, b1) on circulating CLA+CD4+ T-cells. steroids (n554) took 4 doses/day. For the metered dose inhaler (n5141), In the dermis of AD skin, laminin a5 was highly expressed in perivascular 37% were able to properly demonstrate >_ 6 correct steps; 33% did not infiltrates and present on the surface of CLA+ T-cells. By contrast, dermal actuate the medicine. Improved medication technique was associated with skin from normal subjects displayed only rare cells expressing laminin a5 having an observed controller (p50.05), having a spacer (p50.01), more with variable numbers of CLA+T-cells. Expression of laminin g1 chains English spoken at home (p50.02), and caregiver education level (p50.01) within the basement membrane were comparable between diseased and but not with asthma control. normal skin. CONCLUSIONS: This rigorous evaluation of the medication home CONCLUSIONS: Laminin a5 is expressed by circulating CLA+ T-cells environment of high risk youth demonstrated that many families lack and skin-infiltrating T-cells, and is enriched at perivascular sites containing critical medications, devices, technique, and adherence for proper medical T cells in AD skin. These findings implicate laminin a5 in the formation of management of asthma. microstructures that promote inflammation in AD skin. Young, African American Adults With Asthma: What Matters Thymic Stromal Lymphopoietin and Interleukin-33 Promote 260 To Them? 258 Skin Inflammation and Containment Of Vaccinia Virus In A Dr. Aimee L. Speck, MD1, Dr. Belinda Nelson, PhD2, Mrs. S. Olivia Mouse Model Of Atopic Dermatitis Jefferson, MSW3, Dr. Alan P. Baptist, MD, MPH, FAAAAI1; 1University Dr. Michiko K. Oyoshi, PhD, MSc, Ms. Jacqueline Beaupr e, of Michigan, Division of Allergy and Clinical Immunology, Ann Arbor, Mr. Nicholas Venturelli, Raif S. Geha, MD; Division of Immunology, Bos- MI, 2University of Michigan, Health Behavior and Health Education, ton Children’s Hospital, Harvard Medical School, Boston, MA. School of Public Health, Ann Arbor, MI, 3University of Michigan, Depart- RATIONALE: Eczema Vaccinatum (EV) is a life threatening complica- ment of Health Behavior and Health Education, School of Public Health, tion of exposure to smallpox vaccination in patients with atopic dermatitis Ann Arbor, MI. (AD) characterized by dissemination of vaccinia virus (VV) in skin and RATIONALE: Asthma is a common chronic condition that demonstrates internal organs. Increased levels of thymic stromal lymphopoietin (TSLP) significant health disparities among minority populations. Little research and interleukin (IL)-33 are associated with AD. We examined the role of has focused on the management needs and preferences of young, African TSLP and IL-33 pathways on the response of mice to epicutaneous (EC) American adults with asthma; a population undergoing dramatic life sensitization with ovalbumin (OVA) and cutaneous VV inoculation at changes as they transition from adolescence to adulthood. sensitized skin site METHODS: Focus groups were conducted with African American adults METHODS: TSLPR-/- and IL-33 receptor ST2-/- mice on BALB/c back- (n534) between the ages of 18 and 30 years with a physician diagnosis of ground or wild-type (WT) controls were EC sensitized with OVAand inoc- asthma. Focus group sessions were audiotaped, transcribed verbatim, and ulated with 107 plaque-forming units of VV by scarification at the site of coded using constant comparative analysis. antigen sensitization. Cytokine mRNA expression was assessed by quanti- RESULTS: Six major domains were identified and some of the salient tative PCR, and skin histology was examined by H&E staining. themes included: changes in asthma management needs with the onset of RESULTS: EC sensitization of WT mice with OVA resulted in the adulthood, career limitations due to asthma, childcare interference with development of AD-like allergic skin inflammation as indicated by an asthma regimen adherence and difficulties with medication cost due to increase in epidermal thickness, dermal thickness, dermal eosinophil lapses in insurance coverage. Participants also reported feeling discour- infiltration, and Th2 cytokine mRNA expression. EC sensitization of aged when interacting with physicians as it related to their asthma care; yet TSLPR-/- or ST2-/- mice with OVA failed to elicit the aforementioned ageism and racism were not perceived. Despite poor medication regimen changes. The size of primary lesions, number of satellite lesions, dermal compliance, participants were overwhelmingly interested in participating cellular infiltration and mRNA expression of IL-17, IL-4, and IL-13 in asthma self-management programs and had strong preferences that such following VV inoculation of OVA sensitized skin were significantly programs be tailored specifically to young adults with special consider- decreased in TSLPR-/- and ST2-/- mice compared to WT controls. ation of the cultural experience of young African Americans with asthma. CONCLUSIONS: These results suggest that the epithelial cytokines CONCLUSIONS: Young, African American adults have specific barriers TSLP and IL-33 may play an important role in the development of AD and to optimal asthma care as well as distinctive ideas for self-management EV. Blocking TSLP or IL-33 may attenuate the severity of AD and EV. programs. It is important for the asthma care provider to identify and address these population and age-specific barriers in order to improve asthma outcomes and decrease health care disparities.
ABS 5.2.0 DTD YMAI10629_proof 11 January 2014 3:14 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB74 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Language Disparities Among Minority Patients with Poor from households with income >$70,000, children from households with 261 Asthma Control income <5$40,000 had 2.2 times (95% CI 1.1-4.4) and 2.1 times (95% CI Dr. Jose R. Zaragoza-Buxo, MD1, Dr. Efren L. Rael, MD, FAAAAI2; 1.2-3.5) the odds of being sensitized to environmental and food allergens, 1Penn State University College of Medicine, Hershey, PA, 2Allergy/ respectively. We found no significant association between mother’s level of Immunology, Penn State University College of Medicine, Hershey, PA. education and sensitization. RATIONALE: In 2011, 3.6 million Hispanic had asthma, and were 30 CONCLUSIONS: Children who are Black, Hispanic or members of percent more likely to be hospitalized for asthma flares. African-American households with low family income were more likely to be sensitized to were 20% more likely to have asthma than non-Hispanic Whites. We both environmental and food allergens. evaluate the associations between limited English proficiency, Emergency Department (ED) visits, and hospitalization on asthma control in Minority Unrecognized Allergic Rhinoconjunctivitis and Allergic groups. 263 Sensitization Among Latino Youth (GALA II Study) Ulysses Burley, MPH1, Dr. Joy Hsu, MD, MSCI2, Duanny Alva, MD- METHODS: After IRB consent was obtained, a telephone survey was 1 3 4 conducted in a cohort of randomly selected minority subjects of all ages IMG, MPH , Ms. Elizabeth Nguyen, BS , Ms. Lindsey Roth, MA , Dr. Joshua Galanter, MD4, Dr. Sam Oh, PhD, MPH4, Ms. Celeste with moderate to severe persistent asthma. Subjects were classified into 3 4 5 groups, English-proficient African-American (1), English proficient Eng, BS , Mr. Fred Lurmann, MS , Dr. Rajesh Kumar, MD, MS, FAAAAI6, Dr. Harold J. Farber, MD, MSPH7, Dr. Denise Hispanic (2) and non-English proficient Hispanic (3). 8 9 RESULTS: Of 30 patients contacted, 73% responded, 59% were Hispanic Serebrisky, MD , Dr. Luisa Borrell, DDS, PhD , Dr. Saunak Sen, PhD10, Dr. William Rodriguez-Cintron, MD11, Dr. Jose Rodriguez- and 41% were African Americans. Among Hispanics 38% where non- 12 4 English fluent and considered this to affect their asthma. Hispanics were Santana, MD , Dr. Esteban Gonza Burchard, MD, MPH , Prof. Pedro C. Avila, MD, FAAAAI1; 1Feinberg School of Medicine, Northwestern more likely to present to the ED during the last year as compared with 2 African Americans (53% vs. 11%), had more E.R. visits last year (3.5 vs. University, Chicago, IL, Department of Medicine, Division of Allergy- Immunology, Northwestern University Feinberg School of Medicine, Chi- 1), and had a 23% higher rate of hospitalization for asthma. Among group 3 3 subjects, 80% presented to the ED for asthma flares and 40% were cago, IL, Department of Medicine, University of California, San Fran- cisco, California, San Francisco, CA, 4Department of Medicine, hospitalized for an average of 2.5 days. Of group 2 subjects, 29% presented 5 to the ED for asthma flares and 6% were hospitalized for an average of 1.5 University of California, San Francisco, San Francisco, CA, Sonoma Technology, Inc., Petaluma, CA, 6Pediatric allergy, Ann & Robert H. days. 7 CONCLUSIONS: Language barrier is associated with increased ED Lurie Children’s Hospital of Chicago, Chicago, IL, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, 8Pediatric Pulmo- visits, hospitalizations for asthma among Hispanic patients in our cohort. 9 Further analysis is needed to asses social factors associated with asthma nary Division, Jacobi Medical Center, Bronx, NY, Department of Health management in minority populations. Sciences, Graduate Program in Public Health, Lehman College, City Uni- versity of New York, Bronx, NY, 10Department of Epidemiology and Race/Ethnicity and SES Are Predictors Of Allergic Biostatistics, University of California, San Francisco, San Francisco, 262 Sensitization To Environmental and Food Allergens CA, 11Veterans Caribbean Health Care System, San Juan, PR, 12Centro Dr. Amina Abdeldaim, MD1, Dr. Supinda Bunyavanich, MD, MPH2, de Neumologia Pediatrica, San Juan, PR. Ms. Sheryl Rifas-Shiman, MPH3, Thomas A. E. Platts-Mills, MD, PhD, RATIONALE: Allergic rhinoconjunctivitis (ARC) can be unrecognized FAAAAI4, Dr. Diane R. Gold, MD, MPH5, Dr. Carlos Camargo, Jr, and may impair school performance in children. We investigated ARC MD, DrPH6, Dr. Emily Oken, MD7, Dr. Matthew Gillman, MD, SM3, frequency in reportedly healthy Latino children. Dr. Augusto A. Litonjua, MD, MPH8; 1Channing Division of Network METHODS: Hispanic children aged 8-21 years were recruited as non- Medicine, Brigham and Women’s Hospital, MA, 2Division of Pediatric allergic control and asthmatic subjects from five cities in the mainland Allergy & Immunology, Department of Pediatrics, Icahn School of Med- United States (US) and Puerto Rico for the GALA II Study (2008-2011). icine at Mount Sinai, New York, NY, 3Harvard Medical School, Boston, Controls denied physician diagnosis of ARC at screening before under- MA, 4Division of Asthma, Allergy & Immunology, University of Virginia going a study visit when we administered an extensive questionnaire and Health System, Charlottesville, VA, 5Channing Laboratory, Brigham and performed skin prick test (SPT to 14 aeroallergens) and venipuncture. We Women’s Hospital, Boston, MA, 6Department of Emergency Medicine, used logistic regression to identify variables associated with atopy and Massachusetts General Hospital, Harvard Medical School, Boston, MA, ARC, adjusting for demographics, socioeconomic status, ethnicity, 7Harvard Medical School, 8Channing Division of Network Medicine, recruitment site, and smoking history. Brigham and Women’s Hospital, Boston, MA. RESULTS: Of 1552 control subjects (mean+SD age 5 13.9+3.6 RATIONALE: We investigated the relationship between race/ethnicity, years,43% males), 50% were of Mexican descent, 30% Puerto Rican, socioeconomic factors and allergen sensitization. and 20% other Latino ethnicity. Atopy based on >1 positive SPT was METHODS: In Project Viva, a prospective cohort study examining the present in 48% of subjects (n5743) and unrecognized ARC in 13% effects of prenatal and perinatal factors on maternal and child health, we (n5202), based on atopy plus questionnaire report of nasocular symptoms evaluated 605 children ages 6.7-10.6 years for specific IgE levels to in the absence of colds or flu. Sensitization to indoor allergens predomi- Alternaria, Aspergillus, cat and dog dander, cockroach, Dermatophagoides nated and testing for 7 allergens identified >95% of atopic subjects. farinae, ragweed, rye grass, egg white, milk, peanut, sesame, soybean and Mexicans were more often atopic than Puerto Ricans (51% vs. wheat. Predictors included mother-reported race/ethnicity of the child, 38%,p<0.0005), but fewer reported rhinoconjunctivitis (18% vs. household income and maternal education. Covariates included child’s 42%,p<0.0005). Logistic regression showed that atopy was associated age; sex; diagnosis of asthma, hay fever and eczema; and maternal history with male gender (odds ratio[OR]51.59; 95% confidence interval [1.23- of asthma and/or atopy. Logistic regression was utilized for the analyses. 2.04]), city living (OR51.58[1.02-2.46]), living in mainland US RESULTS: Among the children, 12(2%) were Asian, 104(17%) black, (OR52.49[1.94-3.19]), and in the Northeast region (OR52.87[1.85- 25(4%) Hispanic, 358(59%) white and 65(11%) other race/ethnicity. 4.44]). 353(62%) and 86(15%) came from households with income >$70,000 CONCLUSIONS: Atopy and allergic rhinoconjunctivitis were common and <5$40,000, respectively. 259(43%) were sensitized to any environ- in Latino children reportedly healthy. Unrecognized ARC might affect mental allergen and 168(28%) to any food allergen. Compared to white child quality of life or school performance. children, Hispanic children had 10.6 times the odds (95% CI 1.9-199) of having any environmental sensitization and black children had 2.2 times the odds (95% CI 1.3-3.6) of any food sensitization. Compared to children
ABS 5.2.0 DTD YMAI10629_proof 11 January 2014 3:14 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
J ALLERGY CLIN IMMUNOL Abstracts AB75 VOLUME 133, NUMBER 2
The Nasal NO Response To External Acoustic Energy: A Pilot Phenotyping Non-Allergic and Local Allergic Rhinitis 264 Study 266 Dr. Carmen Rondon, MD, PhD1, Dr. Paloma Campo, MD, Dennis Shusterman, MD, MPH; University of California, San Francisco, PhD1, Dr. Esther Barrionuevo Sanchez, MD1, Ms. Cristina De Leiva Mo- Richmond, CA. lina1, Dr. Leticia Herrero Lifona, MD, PhD1, Ms. Maria Auxiliadora Guer- RATIONALE: Acoustic stimulation (humming) facilitates NO diffusion rero1, Dr. Francisca Gomez, MD, PhD1, Dr. Natalia Blanca-Lopez, MD, from the paranasal sinuses into the nasal cavity. This acoustic response may PhD2, Dr. Gabriela Canto, MD, PhD2, Dr. Miguel Blanca, MD, PhD1; 1Al- be blunted in the presence of rhinosinusitis. To further standardize this test, lergy Service, Carlos Haya Hospital, M alaga, Spain, 2Allergy Service, we evaluated a prototype apparatus that applies external acoustic energy – Infanta Leonor Hospital, Madrid, Spain. as an alternative to humming – during negative pressure nasal NO RATIONALE: The detection of local allergic rhinitis (LAR) in patients sampling. previously misclassified as non-allergic rhinitis (NAR), highlights the need METHODS: Non-smoking, non-asthmatic volunteers underwent exhaled for a clinical phenotyping of NAR. The objectives of this study were the NO sampling, followed by nasal NO sampling under three conditions: 1) demographic-clinical phenotyping of NAR and LAR, and the identification unstimulated / ‘‘quiet’’(‘‘Q’’);2) with 128 Hz external acoustic stimulation of risk factors in LAR. at low intensity (64 dBA at 30 cm – ‘‘S1’’);and 3) with acoustic stimulation METHODS: A total of 140 NAR and 140 LAR patients were evaluated by SATURDAY at moderate intensity (78 dBA at 30 cm – ‘‘S2’’). Stimulated-to-quiet (S/Q) clinical history and demographic-clinical questionnaire. The local ethics nasal NO ratios were calculated using mean NO values from the 10 seconds committee approved the study, and all participants gave informed consent. following the initial pressure transient in each recording. RESULTS: NAR subjects were significantly older than LAR RESULTS: A total of 12 subjects (9 females; mean age, 43.7 years) (NAR:42.15616.75; LAR:29.51612.47; p50.002), and had lower asso- completed the study. Seven subjects gave histories consistent with rhinitis. ciation with female gender (OR50.50; 95% CI, 0.28-0.88; p50.015), Individual mean nasal NO levels ranged from 66-182 ppb under quiet family history of atopy (OR50.20; 95% CI, 0.09-0.45; p50.001), child- conditions, 106-386 ppb with low-amplitude acoustic stimulation, and hood onset (OR50.19; 95% CI, 0.10-0.38; p50.001), and urban household 122-750 ppb with moderate amplitude. The corresponding values for S/Q (OR50.44; 95% CI, 0.23-0.82; p50.009). NAR patients had higher ratio ranged from 1.07-2.70 (S1) and from 1.24-7.65 (S2). A paired analysis association with perennial rhinitis (OR52.39; 95% CI, 1.12-5.01, p5 of nasal NO levels across subjects showed a significant upward trend with 0.018) and urticaria (OR54.42; 95% CI, 1.37-14.29; p50.008), and lower increasing applied acoustic energy (p < 0.01). association to severe symptoms (OR50.18; 95% CI, 0.09-0.36; p50,001), CONCLUSIONS: Our results confirm the application of external acoustic conjunctivitis (OR50.51; 95% CI, 0.29-0.91; p50.022) and asthma stimulation as an alternative to humming in assessing acoustic mixing of (OR50.40; 95% CI, 0.20-0.80; p50.008) than LAR. Sneezing (78.9%) gases between the paranasal sinuses and nasal cavity. Use of this procedure was the main symptom in NAR, and itching (85.5%) in LAR. Female may form the basis for a screening test for sinusitis. gender, FHA, childhood onset, asthma, seasonal rhinitis and severe symptoms were identified as risk factors for the diagnosis of LAR, and Flagellin/Toll-Like Receptor 5 Induces Interleukin-17C In mucous rhinorrea, urticaria, and symptoms triggered by irritant odours as 265 Human Nasal Epithelia risk factor for NAR. 1 2 2 Dr. Hyun Jin Min , Dr. Tae-Hoon Kim , Su-Yeon Choi , Prof. Joo-Heon CONCLUSIONS: LAR and NAR showed different demographic and 1,2 1,3 1 Yoon , Prof. Chang-Hoon Kim ; Department of Otorhinolaryngology, clinical phenotypes. The identification of risk factors in LAR and NAR can 2 Yonsei University College of Medicine, Seoul, South Korea, Research be a useful tool for their clinical diagnosis. Center for Human Natural Defense System, Yonsei University College of Medicine, Seoul, South Korea, 3The Airway Mucus Institute, Yonsei Role Of Basophil Activation Test For Identifying Subjects University College of Medicine, Seoul, South Korea. 267 With Local Allergic Rhinitis RATIONALE: The family of Interleukin-17 (IL-17) cytokine is involved Dr. Paloma Campo, MD, PhD1, Dr. Carmen Rondon, MD, PhD1, in host defense responses and various inflammatory diseases. Many studies Dr. Enrique Gomez, PhD2, Dr. Esther Barrionuevo Sanchez1, Mrs. Luisa indicated that IL-17A and IL-17F play an important role in the Galindo, RN1, Mr. J. A. Huertas1, Dr. Cristobalina Mayorga, PhD2, pathogenesis of airway inflammatory diseases. Recently, it has been Dr. Miguel Blanca, MD, PhD1; 1Allergy Service, Carlos Haya Hospital, reported that IL-17C mediates innate immune responses against microbial M alaga, Spain, 2Research Laboratory for Allergic Diseases, Hospital infection and inflammation in mucosal epithelium. However, little is Regional Universitario de Malaga - IBIMA, M alaga, Spain. known about the expression and biological function of IL-17C in human RATIONALE: A previous pilot study showed the presence of allergen- airway epithelium. specific IgE in the surface of peripheral basophils in 50% of subjects with METHODS: in vitro expermental analysis with primary cultured normal confirmed local allergic rhinitis (LAR). However, this phenomenon was human nasal epithelial cells and in vivo analyisis of human nasal mucosal investigated in a small number of patients. The aim of this study is tissue confirming the presence of specific allergen activation of basophils, by RESULTS: In this study, we found that IL-17C mRNA expression was means of basophil activation test (BAT) in a large population of LAR strongly induced by inflammatory cytokines such as TNF-a or IL-1b and subjects sensitized to D. pteronyssinus (DP). bacterial flagellin, recognized by toll-like receptor 5 (TLR5), in primary METHODS: BATwith 5, 20 and 50 ng/mL of DP extract was performed in cultured normal human nasal epithelial (NHNE) cells. We also confirmed 86 subjects: 30 with LAR (positive NPT with DP, negative skin testing and that IL-17C protein production was enhanced by TNF-a, IL-1b and sIgE to DP), 32 with AR (positive NPT with DP, positive skin testing and flagellin. We demonstrated that pretreatment of neutralizing antibody sIgE to DP), 10 with NAR (negative NPT, skin testing and sIgE to DP, against TLR5 completely inhibited flagellin-induced IL-17C expression, alternaria, phleum and olive tree pollen) and 14 healthy controls (negative indicating elevated IL-17C expression is specifically mediated by flagellin/ NPT, negative skin testing and sIgE to DP). Local ethics’ committee TLR5 engagement. Moreover, IL-17C stimulation induced innate immune approved the study. responses including the expression of antibacterial peptides and proin- RESULTS: BATwith DP was positive in 28/32 of AR patients (88) and in flammatory cytokines in NHNE cells. 14/30 (47%) of LAR subjects. In healthy controls, 1/14 had a positive CONCLUSIONS: Taken together, these results show that IL-17C response (7%) and 1/10 NAR subjects had positive results (10%). BAT expression is enhanced in response to inflammation and flagellin/TLR5 sensitivity was 85% in AR patients and 50% in LAR with a specificity of activation and involved in inflammatory process in human nasal epithelial 93% for both groups. cells. Our findings suggest that IL-17C cytokine may play an important role CONCLUSIONS: Basophil activation test may be a useful tool to support in TLR5-dependent innate immune responses of human airway epithelia. the diagnosis of local allergic rhinitis.
ABS 5.2.0 DTD YMAI10629_proof 11 January 2014 3:14 pm All abstracts are strictly embargoed until the date of presentation at the 2014 Annual Meeting.
AB76 Abstracts J ALLERGY CLIN IMMUNOL
SATURDAY FEBRUARY 2014
Does Serum Leptin Differ Between Patients With Rhinitis Of Predictors Of Response To Glucocorticoids In 268 Allergic Vs Nonallergic Aetiology? 270 Hypereosinophilic Syndromes Prof. Ayse Fusun Kalpaklioglu, MD, Dr. Ayse Baccioglu, MD; Kirikkale Paneez Khoury, MD1, Annalise Abiodun, RN1, Kelli Williams, MD, University Faculty of Medicine Department of Allergic Diseases. MPH1, JeanAnne Ware, CRNP1, Nicole Holland-Thomas, MSN, RN2, RATIONALE: Leptin, is a 16-kD-adipocyte-derived-cytokine that may Dr. Amy D. Klion, MD1; 1National Institutes of Health, Bethesda, MD, play a critical role in airway inflammation. Leptin has rarely been 2SAIC-Frederick Inc., Bethesda, MD. evaluated in allergic rhinitis (AR), but not in rhinitis of different aetiology. RATIONALE: Glucocorticoids (GCs) are considered first line treatment We aimed to compare serum leptin levels between AR and nonallergic for PDGFRA-negative hypereosinophilic syndromes (HESs). Despite this, rhinitis (NAR), as well as contributing factors. little is known about clinical predictors of GC responsiveness in HES. METHODS: Patients were enrolled based on chronic nasal symptoms. Reliable predictors of the ultimate GC dose required for disease control Serum leptin levels (ng/mL) were analyzed with a solid-phase-enzyme- could lead to more rational selection of an initial dosing regimen and/or amplified-sensitivity-immunoassay (DIAsource Immunoassays S.A. quicker institution of alternative therapy in GC-resistant patients. Louvain-la-Neuve, Belgium). Total nasal symptom scores (TNSS), and METHODS: Response to glucocorticoids (GC), as defined by reduction body mass index (BMI, kg/m2) were evaluated. of the absolute eosinophil count (AEC) to below 1000/mm3and control of RESULTS: A total of 322 patients (64.6% F) with a mean age of symptoms, was assessed by retrospective chart review in 312 subjects eval- 29.47611.59yr, were recruited and grouped as AR (n:221) and NAR uated at our institution on an IRB-approved protocol to study eosinophilia. (n:101). Leptin levels were insignificantly higher in patients with NAR Demographic, clinical and laboratory parameters, as well as ultimate diag- (5.68 60.99ng/ml) than AR (4.2260.39ng/ml), as well as BMI. Although nosis, were evaluated to determine predictors of GC response. Multivariate leptin was significantly higher in females in both groups, its higher level in regression analyses are ongoing. patients with BMI>_25kg/m2, compared to patients with BMI<25kg/m2, RESULTS: A majority of subjects (80%) with eosinophilia responded to was significant only in AR (6.6261.1ng/ml, 3.56 60.45ng/ml, GC, with a median prednisone dose of 10.5 mg (range 1.5-80 mg). Subjects p50.004). Likewise, leptin was significantly correlated with age, BMI, who did not respond to GC had higher peak median absolute eosinophil and eye symptoms (r50.154, r50.165, r5-0.167), in allergic rhinitics. counts (9372 vs 4911, p50.0002), were more likely to have myeloprolif- Despite higher TNSS in AR, compared to NAR, neither severity/seasonal- erative-variant HES, splenomegaly, and had higher median serum LDH ity of symptoms, nor sensitization type were related with leptin levels. (305 vs. 202, p50.0011). The GC response rate in subjects with lympho- CONCLUSIONS: This preliminary study provides the first evidence of cytic variant HES was no different than the group as a whole, and no similar serum leptin levels in patients with allergic and nonallergic rhinitis. specific features characterized GC non-responders in this subgroup. Serum leptin levels were higher in female gender and obese rhinitics, with a CONCLUSIONS: Higher peak eosinophil counts, and other features of positive correlation with BMI in AR. These results suggest that leptin myeloproliferation, such as elevated LDH, splenomegaly, and molecular measurement have limited value as the sole diagnostic tool when evidence of myeloproliferative disease predicted lack of response to differentiating AR and NAR. GCs. These features should prompt early consideration of alternative LTC4, But Not LTD4 Or LTE4, Activates Platelets Through a therapies. 269 CysLT2R and P2Y12 Receptor-Dependent Pathway Dr. Joshua A. Boyce, MD, FAAAAI1,2, Dr. Tao Liu, PhD1,2, Dr. Hannah Cummings, PhD1,2; 1Harvard Medical School, Boston, MA, 2Brigham and Women’s Hospital, Division of Rheumatology, Immunology and Allergy, Boston, MA.
RATIONALE: Cysteinyl leukotrienes (cysLTs, LTC4,LTD4, and LTE4) are potent inflammatory mediators of airway and vascular inflammation by signaling through at least three specific cysLT receptors. Platelets ex- press cysLT receptors and play an important role in asthma and vascular inflammation. The adherence of platelets to granulocytes and monocytes amplifies the production of cysLTs. However, it has not been fully ad- dressed whether cysLTs activate platelets, nor which receptors are most essential. METHODS: Platelet Rich Plasma (PRP) was collected from mice and
stimulated with LTC4,LTD4,orLTE4. Samples were stained with anti- CD41 and anti-CD62P antibodies for flow cytometric analysis. Platelets activation was determined by the percentage of CD62P+ on CD41+ platelets.
RESULTS: WT platelets stimulated with LTC4 displayed a dose-depen- dent increase in surface CD62P expression, and released large quantities
of thromboxane and CXCL4. Neither LTD4 nor LTE4 caused any response. -/- The response to LTC4 was completely absent in the platelets from cysltr2 mice, and fully intact in the platelets from cysltr1-/-, gpr99-/-, and tpr-/- strains. Compared to the WT, platelets from p2ry12-/- mice showed mark- edly impaired induction of CD62P expression and mediator generation in
response to LTC4. WT platelets treated with apyrase (to degrade ADP) -/- showed a pattern of attenuated responses to LTC4 similar to p2ry12 mice. CONCLUSIONS: LTC4 activates mouse platelets by a pathway entirely dependent on the CysLT2R. Newly-formed LTC4 from granulocytes could induce platelets to adhere via CD62 and cause their secretion of inflamma-
tory mediators before conversion to LTD4 and LTE4.
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J ALLERGY CLIN IMMUNOL Abstracts AB77 VOLUME 133, NUMBER 2
Differential Proteomic Analysis Of Eosinophils From Patients RESULTS: While lung GR-a expression did not change, lung GR-b 271 With Glucocorticoid Responsive Or Resistant expression was increased almost 3.5 fold in the obese mice exposed to Hypereosinophilic Syndrome HDM in comparison to their lean counterparts exposed to HDM (p < 0.05). Konrad Pazdrak, MD, PhD1, Paneez Khoury, MD2, Kizhake V. CONCLUSIONS: In this novel model of HDM-induced asthma in obese Soman, PhD1, Nicole Holland-Thomas, MSN, RN3, Mrs. Michelle Ma- vs. lean mice, we demonstrate increased GR-b mRNA expression in obese kiya2, Christof Straub, PhD1, Zheng Wu, PhD1, Dr. Amy D. animals suggesting a mechanism for steroid resistance. The next step Klion, MD2, Alexander Kurosky, PhD1; 1University of Texas Medical would be to examine the pathogenesis and significance of GR-b up- Branch, Galveston, TX, 2National Institutes of Health, Bethesda, MD, regulation in order to propose new therapeutic targets. 3SAIC-Frederick Inc., Bethesda, MD. RATIONALE: Although glucocorticoids (GC) are the first line therapy Reduced EP2 Receptor Expression Accounts For for PDGFRA-negative hypereosinophilic syndrome (HES), GC alone are 273 Prostaglandin E2 Resistance In Nasal Polyp Fibroblasts insufficient to control eosinophilia and symptoms in <_15% of patients. To From Patients With Aspirin Exacerbated Respiratory begin to explore the mechanisms underlying GC-resistance in HES, Disease; Possible Role For Histone Acetylation In Control eosinophil proteomes from GC-responsive and GC-resistant patients Of EP2 Receptor Expression SATURDAY 1,2 3 were compared. Dr. Katherine N. Cahill, MD , Mr. Derek Thibault , Dr. Benjamin A. 3 4 METHODS: Peripheral blood eosinophils were isolated from 5 patients Raby, MD, MPH , Dr. Andrea Baccarelli, MD, MPH, PhD , Dr. Neil 2,3 1,2 with GC-responsive HES, defined as control of eosinophilia and symptoms Bhattacharyya, MD , Dr. Joshua A. Boyce, MD, FAAAAI , 1,2 1 with <_ 20 mg prednisone, and 3 patients with GC-resistant HES, defined as Dr. Tanya M. Laidlaw, MD, FAAAAI ; Brigham and Women’s Hospi- inability to reduce eosinophilia <1000/mL and control symptoms despite tal, Division of Rheumatology, Immunology and Allergy, Boston, MA, 2 3 prednisone >_ 60 mg daily. Two-dimensional polyacrylamide gel electro- Harvard Medical School, Boston, MA, Brigham and Women’s Hospital, 4 phoresis (2D-PAGE) combined with Sypro Ruby and Pro Q Diamond Boston, MA, Harvard School of Public Health, Boston, MA. fluorescence stain was used to detect differentially expressed and RATIONALE: Nasal polyposis is a hallmark of aspirin exacerbated phosphorylated proteins between the two groups. Differentially expressed respiratory disease (AERD). Fibroblasts from nasal polyps of subjects with proteins that were up or down-regulated at least 1.5 fold were identified AERD show reduced E Prostanoid (EP)2 receptor expression compared to using MALDI-TOF mass spectrometry and verified by Western blotting. aspirin tolerant (AT) controls. The molecular basis and functional conse- RESULTS: Among the 777 protein spots revealed by Sypro Ruby in 2D- quences of this reduced EP2 receptor expression are unknown. PAGE resolved eosinophil lysates, nineteen were differentially expressed (p METHODS: Fibroblasts were cultured from nasal polyps of subjects with 5 5 <_ 0.05, and fold change >_ 1.5). Principal Component Analysis showed that AERD (n 9), AT sinus disease (n 4), or from healthy middle turbinate 5 expression of these 19 spots could discriminate between GC responsive and control tissue (n 5), and proliferation rates were assessed in the presence GC-resistant patients. Pro Q Diamond phosphoprotein stain revealed 29 of forskolin, PGE2,oranEP2-selective agonist. Fibroblast EP2 protein differentially phosphorylated proteins. Mass spectrometric analysis of expression levels were measured by monoclonal EP2 antibody staining proteins excised from gels identified proteins known to be involved in cell and mRNA levels of EP2,EP4, mPGES-1 and COX-2 were measured motility, cytokine signaling and chromatin reorganization. before and after culture with trichostatin A (TSA). Histone acetylation CONCLUSIONS: Proteomic analysis identified differentially expressed (H3K27ac) and DNA methylation of PTGER2 and PTGS2 were assessed. and phosphorylated proteins in eosinophils from GC-resistant patients with RESULTS: AERD fibroblasts resisted the PGE2- and EP2-induced sup- 5 HES. These data suggest that eosinophils themselves may play a primary pression of proliferation (p <0.001) compared with fibroblasts from AT role in GC-resistance in HES. and healthy controls. Cell surface EP2 expression was lower in AERD fi- broblasts than in healthy controls (p50.001) and TSA incubation induced Glucocorticoid Receptor-a^ Up-Regulation In C57BL/6 Diet- EP2 mRNA levels in AERD. AERD fibroblasts demonstrated variable 272 Induced Obese Mice With House Dust Mite-Mediated Asthma levels of H3K27ac at the EP2 promoter, which correlated with baseline Dr. Jennifer Diaz, MD1,2, Dr. Malvika Solanki, MBBS, MPH3, EP2 mRNA expression and inversely correlated with induction of EP2 Dr. Xiangying Xue, MD3, Prodyot Chatterjee, PhD3, Dr. Madhu 3 4 mRNA by TSA. No differences in DNA methylation of PTGER2 or Gupta, MBBS , Dr. Vincent R. Bonagura, MD, FAAAAI , Christine PTGS2 were found. Metz, PhD3; 1Feinstein Institute for Medical Research, Manhasset, NY, CONCLUSIONS: AERD fibroblasts resist the EP2-dependent anti-prolif- 2Allergy and Immunology, North Shore-LIJ Health System, Great Neck, erative effects of PGE2 and express lower levels of surface EP2 receptor. NY, 3Feinstein Institute for Medical Research, NY, 4Division of Al- Levels of H3K27ac at the EP2 promoter correlate with baseline EP2 lergy/Immunology, Departments of Medicine and Pediatrics, Hofstra mRNA expression, supporting an epigenetic basis for impaired EP2 expres- North Shore-LIJ School of Medicine, Great Neck, NY. sion in AERD. RATIONALE: The obese asthmatic population is more likely to experience steroid-resistant asthma than their lean counterparts. We examined the potential role of the glucocorticoid receptor-beta (GR-b), an antagonist of glucocorticoid receptor-alpha (GR-a) activity, using a novel model of house dust mite-induced asthma in lean vs. obese mice. We hypothesized that increased GR-b expression in the setting of obesity may enhanced steroid resistance in asthma. METHODS: Mice (C57BL/6, males, 8-10/group) were fed either a regular or high fat (60% lard) chow. After 6 months, mice received either intranasal saline (Sal) or house dust mite (HDM) extract 5 days/week for 6 weeks. Animals were euthanized with pentobarbital/phenytoin. Lung tissue was flash frozen in liquid N2. Total RNA was isolated and used for SYBR green-based quantitative PCR (qPCR) with murine GR-a and GR-b-specific primers. Relative changes in gene expression were calcu- lated as fold-changes using the comparative Ct (DDCt) method using mu- rine HPRT1 as the housekeeping gene.
ABS 5.2.0 DTD YMAI10629_proof 11 January 2014 3:14 pm