Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
It’s Nothing to Sneeze At – An Update in Allergy Virginia Chapter ACP Annual Meeting 2013 Scott P. Commins Division of Allergy and Clinical Immunology Disclosures We are grateful for generous support from the Oakey Food Allergy Fund These studies were carried out with generous support from the NIH-NIAID (K08 AI085190 & R21 AI087985) Disclosure: Up-to-Date card I. Background How oncologists helped uncover a novel food allergy High incidence of hypersensitivity reactions to cetuximab infusions in mid-Missouri: Association with prior history of atopy R. Owera, A. Gill, S. Haddadin, R. Khozouz and M. C. Perry University of Missouri Columbia, Columbia, MO Abstract, 2008 ASCO Annual Meeting Proceedings, Vol 26, No 15S, 2008:20747 Regarding cetuximab HSR: The story got stranger as O’Neil talked to more oncologists. He heard that a colleague in Nashville, Tennessee, was finding the same problem. But when O’Neil spoke to oncologists from other areas of the country, they didn’t know what he was talking about. A prominent colorectal oncologist in New York “thought we were lying or crazy,” O’Neil recalls. From “A Mysterious Allergy Afflicts the South” by Sheila Read in Endeavors, 24:2, 2-3, 2008. Measurement of IgE ab to Purified Allergens Using Streptavidin Solid Phase “Allergen” of interest (cetuximab) + Biotin Streptavidin Solid Phase + Biotinylated “Allergen” Solid Phase* Then add serum; wash; add labeled anti-IgE; detect chemilum. *Routine assay technique in parallel with Phadia standard curve gives results in IU/ml. IgE Antibodies Binding to Cetuximab in Sera from 76 Case Subjects and 462 Controls Cetuximab N-88 N-43 * * Site not glycosylated N-299 Typical Fc region oligos: core fucosylated biantennary oligos; no alpha-gal or NGNA Qian J, Liu T,…Zhou Q. Analytical Biochem, 2007. Specificity of the IgE Antibodies that Cross-React with Cetuximab Chung CH et al. N Engl J Med 2008;358:1109-1117 II. Defining a “new” food allergy Specificity of the IgE Antibodies That Cross-React with Cetuximab Chung CH et al. N Engl J Med 2008;358:1109-1117 JACI, February 2009 -24 patients -Virginia & Missouri - Symptoms delayed 3-6 hours after eating mammalian meat - Prick skin test often less than 4mm - Intradermal skin test positive Skin Testing Results: Often <4mm SPT Prick test Intradermal Prick test performed using lancette and intradermal testing with 25 gauge needle in the same patient on a single clinic visit. Patient data, presentation, symptom delay, and laboratory evaluation Symptoms Time to Alpha-Gal Beef IgE Total IgE ANA = Anaphylaxis Reaction IgE Titer Titer Titer AE = Angioedema U = Urticaria (hours) (IU/mL) (IU/mL) (IU/mL) ANA 6 67.0 3.48 157 Patient Age /Sex Race E001 44 / M W E008 80 / F W AE, U 6 0.52 0.35 45.9 E018 26 / M W ANA 5 59.3 16.6 274 E022 74 / F W AE, U 3 9.03 8.90 66.6 E026 47 / M W ANA 6 >100 32.9 1081 E030 56 / M W U 4-6 80.6 15.8 709 E031 55 / F W U 4 68.9 26.2 243 E036 66 / M W U 4-6 21.1 19.2 262 E054 45 / M W ANA 3 2.42 0.35 244 E076 50 / M W U 4 9.25 3.24 247 E115 58 / F W ANA 2-4 >100 47.8 1622 E128 37 / M W U 4-6 26.8 5.65 886 E162 39 / F W AE, U 6 11.1 1.51 30.5 CAP-RAST of Specific IgE Abs in Patients with anti-Gal IgE Foods Inhalants r =0.81 r =0.98 10 1 ▼x1 ♦x1 Be ef Po Limit of detection x3 x12 x11 x12 x1 x7 ♦x4 x1 x9 s yG ras ite tM Tim oth Du s Do g 1 Fe ld Ca t Fis h rke y Tu ke n Ch ic mb La rk a-G a l 0.1 Alp h Specific IgE Abs (IU/mL) 100 Alpha-gal specific IgE is associated with anaphylaxis but not asthma 1000 (Figure adapted from Commins, Kelly…Platts-Mills, AJRCCM, 2012) Alpha-gal specific IgE (IU/mL) = Reactions include anaphylaxis 100 10 1 Limit of detection 0.35 Number <0.35 •x8 • x 13 • x 58 • x 55 Asthma (N = 68) Clinic controls (N = 59) 0.1 Cat in home No cat in home (N = 96) (N = 112) Anaphylaxis/ urticaria subjects 30% r = 0.60, p<0.001 10% IgE Ab to alpha-gal in kids (n=45) Sex (% male) 69% Mean age at presentation (Range) Geometric Mean of Total IgE (95% CI) 12 (4-17) 147 IU/mL (105-206 IU/mL) Symptoms at presentation Anaphylaxis* 44% Gastrointestinal/ Oral Urticaria 64% Angioedema 31% 92% Average time to symptoms (Range) 4.68 hrs (10 mins to 24 hrs) Tick exposure 100% Redness and Itching at site of Tick bite Tick borne illness# Emergency Department (ED) visits Medications administered in ED Hospital Admissions 87% 10% 46%** Epinephrine (19%) Antihistamines (35%) Oral Steroids (19%) Parenteral Steroids (17%) IV Fluids (17%) 8% IgE Ab to alpha-gal in kids (n=45) Delayed symptoms induced by oral exposure to mammalian proteins in patients with IgE ab to alpha-gal. • Despite high titer IgE antibodies that bind epitopes on a range of mammalian proteins including beef, pork and lamb: – No awareness of immediate response in the mouth (i.e. no lip swelling or tingling). – Anaphylaxis occurring after eating beef starts with skin itching 3-6 hours later. – Skin prick tests generally <4mm in diameter while intradermals often ≥8mm. ‘Delayed’ food allergy? • Food allergy symptoms classically occur immediately (OAS), up to 2 hours after eating • No mention of ‘delayed’ symptoms that can be attributed to food in common allergy texts III. Ticks. Really? Geographical distribution of cetuximab hypersensitivity reactions As reported by O’Neil et al, JCO 2007 Distribution of known cases of delayed anaphylaxis to mammalian meat Dots = single cases Smaller stars = 5 to 24 cases within a state Larger stars = states with 25 or more cases Geographical Incidence of Rocky Mountain Spotted Fever Data from CDC website for 2009; accessed 2/2011 Original image: CDC; modified by D.N. Gaines for Virginia Department of Health Geographical range of Amblyomma americanum population Data from CDC website; accessed 10/2010 Geographical range of Amblyomma americanum population welcome to the party Data from CDC website; accessed 9/2012 Bites from the larvae of Amblyomma or Dermacentor ticks and IgE ab to alpha-Gal. Photograph: August 23, 2007. Test 10/26/06 5/21/07 10/9/07 11/6/07* Cetuximab (alphaGal) 0.49 16.9 48.3 130 Total IgE 127 199 350 532 •Multiple bites by seed ticks are not uncommon in the Southeast. *Titers:Total 262, Beef 19.2 Pork 10.1,Cat 17.5,Dog 19.8, IU/ml. Chicken, Turkey, Roach, Dust Mite and Ragweed all <0.35 IU/ml. Time course of IgE antibodies to alpha-gal and total IgE following episodes of multiple tick bites (red arrows) Subject #1 * Time course of IgE antibodies to alpha-gal and total IgE following episodes of multiple tick bites (red arrows) Subject #2 Time course of IgE antibodies to alpha-gal and total IgE following episodes of multiple tick bites (red arrows) * Subject #3 Total IgE versus IgE to Alpha-Gal Report tick or chigger bite(s) IgE to Alpha-Gal (IU / mL) 1000 R= 0.78 P <0.001 100 No history obtained for tick bite(s) 10 Specifically deny tick bite(s) 1 0.1 1 10 100 Total IgE (IU / mL) 1000 10000 R amblyommii? IV. Delayed food allergy -FC02 - sIgE to alpha-gal = 22.4 IU/mL; Total IgE = 109 -4:22 after consuming meat, symptoms began as itching & hive on hand; second hive appeared on arm -Given AH and observed -FC02 - sIgE to alpha-gal = 17.6 IU/mL; Total IgE = 184 -Whole blood was collected, fixed & stained -3:54 after consuming meat, symptoms began as itching, flushing and progressed: ultimately requiring epinephrine -Subject #FC-07: sIgE to alpha-gal = 9.3 IU/mL; Total IgE = 204 -Whole blood was collected, fixed & stained -6 hours after consuming 56g of pork prosciutto, subject released with (disappointing) mild itch and single hive Subject calls from car 30 minutes after being released to report progression of itching and “warmth to skin” Initial picture upon arriving home (approximately 7.5 hours after eating pork prosciutto) Approximately 8.25 hours after eating prosciutto Mammalian meat challenge Subject #FC-08: sIgE to alpha-gal = 30.3 IU/mL ; total IgE = 146 Before 3hrs 45min after eating meat Subject #FC-08: Mammalian meat challenge Diffuse urticaria appeared at 4hrs 15min after eating meat (left arm shown here) Mammalian meat challenge Subject #FC-10: sIgE to alpha-gal = 29.1 IU/mL ; total IgE = 201 4hrs 25min after eating mammalian meat: pruritus followed by urticaria on right flank Summary of Mammalian Meat Challenge Results in Subjects with IgE to alpha-gal Allergics (n=10) Urticaria Time to symptoms (hrs:min) Treatment required Tryptase elevation 7*/10 3:50 – 6:00 7/10 1**/9 *Two subjects received epinephrine (i.e., these reactions are probably better defined as delayed anaphylaxis to mammalian meat) **Tryptase: -Subject FC-08: 4.2ng/mL (baseline) → 18.2ng/mL (4 hrs) → 20.1 ng/mL (5 hrs) -Subject FC-10: 4.9 (baseline) → 6.2 (4 hrs) → 9.9 (5 hrs) → 10.7 (6 hrs) -No tryptase measurements were performed in subject FC-06 CD63 APC HLA-DR/lineage 1 FITC Gating Strategy Gating Strategy CD123 PerCP-Cy5.5 Negative for • Lineage Cocktail 1 (CD3, CD14, CD16, CD19,CD20, and CD56) • HLA-DR Positive for • CD123 (IL-3Ra) • FcεRI (IgE receptor) • IgE % of max Basophils CD 123 FACS Detection of CD63, a marker of Basophil Activation PerCP-Cy5.5-linked antiCD123 ab APC-linked anti-CD63 ab CD63 -APC IL-3 Rα Histamine nuclear membrane In vivo Basophil Activation during Mammalian Meat Challenge 1 hr 0.72% 2 hrs 0.54% 3 hrs 0.87% CD63 CD123 4 hrs - 16.11% 5 hrs - 14.12% 6 hrs - 5.12% #FC-02 In vivo Basophil Activation during Mammalian Meat Challenge Baseline 1.96% CD63 IgE 2 hrs 3.08% 5 hrs 8.74% 4 hrs 1.8% -FC07 - sIgE to alpha-gal = 9.3 IU/mL; Total IgE = 204 -Whole blood was collected, fixed & stained Summary of Mammalian Meat Challenge Results in Subjects with or without IgE to alpha-gal Urticaria Time to symptoms (hrs:min) Treatment required 2/10 7/10 3:50 – 6:00 7/10 0/10 0/10 n/a 0/10 Delayed anaphylaxis Allergics Controls Allergics Delayed anaphylaxis 2/10 Urticaria Time to symptoms (hrs:min) Treatment required Basophil activation 6/10 3:50 – 6:00 7/10 8/10 Why the delay? • The answer could be fat. Recall that fat is absorbed differently from protein or carbohydrates in a process that takes 3-4 hrs to enter the blood stream The delivery of lipid to the circulation takes time (about 4 hours) VLDL IDL LDL HDL Further conversion Thoracic duct blood stream =Alpha-gal moiety, as a glycolipid Why the delay? • The answer could be long-chain triglycerides associated with chylomicrons. Studies suggest LCT enhance dietary antigen absorption into the circulation via chylomicron formation. • The answer could be the nature of a carbohydrate-based food allergy. Conclusions • The report of delayed reactions occurring 3-6 hours after eating mammalian meat has been confirmed on multiple occasions and at two medical centers • In subjects with IgE to alpha-gal, basophil activation in vivo coincides with the appearance of clinical symptoms • Lack of basophil activation before 4 hours suggests that there is delayed appearance of the antigen into the bloodstream Uva Hayley James Susan Mozzicato Lisa Workman Alicia Clark Judith Woodfolk Walter Oliveira Whitney Stevens Shama Satinover Libby Kelly Peter Heymann Amy Stallings Julia Wisniewski Josh Kennedy Anubha Tripathi Jonathon Posthumus Contributors Barrett Lewis Michael Land Joey Lane Heather Gütekünst Jane Purser Gary Rakes Madeline Dillon Tina Hatley Luis Matos Saju Eapen Dane McBride Joseph Belleau Harold Moessner Marty Fiser Eddie Shields