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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.

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Presentation on theme: "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."— Presentation transcript:

1 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

2 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

3 I. Background How oncologists helped uncover a novel food allergy

4 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

5 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. Regarding cetuximab HSR:

6 Measurement of IgE ab to Purified Allergens Using Streptavidin Solid Phase Streptavidin Solid Phase + Biotinylated “Allergen” “Allergen” of interest (cetuximab ) + Biotin Solid Phase* *Routine assay technique in parallel with Phadia standard curve gives results in IU/ml. Then add serum; wash; add labeled anti-IgE; detect chemilum.

7 IgE Antibodies Binding to Cetuximab in Sera from 76 Case Subjects and 462 Controls

8 Cetuximab ** Site not glycosylated N-88 N-43 N-299 Qian J, Liu T,…Zhou Q. Analytical Biochem, 2007. Typical Fc region oligos: core fucosylated biantennary oligos; no alpha-gal or NGNA

9 Specificity of the IgE Antibodies that Cross-React with Cetuximab Chung CH et al. N Engl J Med 2008;358:1109-1117

10 II. Defining a “new” food allergy

11 Specificity of the IgE Antibodies That Cross-React with Cetuximab Chung CH et al. N Engl J Med 2008;358:1109-1117

12 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

13 Skin Testing Results: Often <4mm SPT IntradermalPrick test Prick test performed using lancette and intradermal testing with 25 gauge needle in the same patient on a single clinic visit.

14 Patient data, presentation, symptom delay, and laboratory evaluation PatientAge /SexRace Symptoms ANA = Anaphylaxis AE = Angioedema U = Urticaria Time to Reaction (hours) Alpha-Gal IgE Titer (IU/mL) Beef IgE Titer (IU/mL) Total IgE Titer (IU/mL) E00144 / MWANA6 67.03.48157 E00880 / FWAE, U6 0.520.3545.9 E01826 / MWANA559.316.6274 E02274 / FWAE, U3 9.038.9066.6 E02647 / MWANA6 >10032.91081 E03056 / MWU4-6 80.615.8 709 E03155 / FWU4 68.926.2243 E03666 / MWU4-621.1 19.2262 E05445 / MWANA32.420.35244 E07650 / MWU4 9.253.24247 E11558 / FWANA2-4 >10047.81622 E12837 / MWU4-626.85.65886 E16239 / FWAE, U611.11.5130.5

15 Limit of detection ▼x1 ♦ x1 x3  x12  x11  x12  x1  x7 x1  x9 ♦ x4 FoodsInhalants Specific IgE Abs (IU/mL) r =0.81 r =0.98 CAP-RAST of Specific IgE Abs in Patients with anti-Gal IgE

16 Asthma (N = 68) Clinic controls (N = 59) No cat in home (N = 112) 0.35 0.1 1 10 100 1000 0.35 Alpha-gal specific IgE (IU/mL) Limit of detection x 8 x 13 x 58 x 55 Number <0.35 Cat in home (N = 96) Anaphylaxis/ urticaria subjects Alpha-gal specific IgE is associated with anaphylaxis but not asthma (Figure adapted from Commins, Kelly…Platts-Mills, AJRCCM, 2012) = Reactions include anaphylaxis

17 r = 0.60, p<0.001 30%10%

18 Sex (% male)69% Mean age at presentation (Range) 12 (4-17) Geometric Mean of Total IgE (95% CI)147 IU/mL (105-206 IU/mL) Symptoms at presentation Anaphylaxis*44% Gastrointestinal/ Oral 64% Urticaria92% Angioedema31% Average time to symptoms (Range)4.68 hrs (10 mins to 24 hrs) Tick exposure100% Redness and Itching at site of Tick bite 87% Tick borne illness#10% Emergency Department (ED) visits46%** Medications administered in EDEpinephrine (19%) Antihistamines (35%) Oral Steroids (19%) Parenteral Steroids (17%) IV Fluids (17%) Hospital Admissions8% IgE Ab to alpha-gal in kids (n=45)

19

20 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.

21 ‘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

22 III. Ticks. Really?

23 Geographical distribution of cetuximab hypersensitivity reactions As reported by O’Neil et al, JCO 2007

24 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

25 Geographical Incidence of Rocky Mountain Spotted Fever Data from CDC website for 2009; accessed 2/2011

26 Original image: CDC; modified by D.N. Gaines for Virginia Department of Health

27 Geographical range of Amblyomma americanum population Data from CDC website; accessed 10/2010

28 Geographical range of Amblyomma americanum population Data from CDC website; accessed 9/2012 welcome to the party

29 Bites from the larvae of Amblyomma or Dermacentor ticks and IgE ab to alpha-Gal. Test10/26/065/21/0710/9/07 11/6/07 * Cetuximab (alphaGal) 0.49 16.948.3 130 Total IgE 127 199350 532 Multiple bites by seed ticks are not uncommon in the Southeast. Photograph: August 23, 2007. * 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.

30 * Subject #1 Time course of IgE antibodies to alpha-gal and total IgE following episodes of multiple tick bites (red arrows)

31 Subject #2 Time course of IgE antibodies to alpha-gal and total IgE following episodes of multiple tick bites (red arrows)

32 * Subject #3 Time course of IgE antibodies to alpha-gal and total IgE following episodes of multiple tick bites (red arrows)

33 110100100010000 0.1 1 10 100 1000 Total IgE versus IgE to Alpha-Gal Total IgE (IU / mL) IgE to Alpha-Gal (IU / mL) Report tick or chigger bite(s) No history obtained for tick bite(s) Specifically deny tick bite(s) R= 0.78 P <0.001

34 R amblyommii?

35 IV. Delayed food allergy

36

37 -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

38 -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

39 -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

40 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)

41 Approximately 8.25 hours after eating prosciutto

42 Mammalian meat challenge Subject #FC-08: sIgE to alpha-gal = 30.3 IU/mL ; total IgE = 146 Before3hrs 45min after eating meat

43 Subject #FC-08: Mammalian meat challenge Diffuse urticaria appeared at 4hrs 15min after eating meat (left arm shown here)

44 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

45 Urticaria Time to symptoms (hrs:min) Treatment required Tryptase elevation Allergics (n=10) 7*/103:50 – 6:007/101**/9 Summary of Mammalian Meat Challenge Results in Subjects with IgE to alpha-gal *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

46 Gating Strategy HLA-DR/lineage 1 FITC CD63 APC CD123 PerCP-Cy5.5 CD 123 % of max Basophils Negative for Lineage Cocktail 1 (CD3, CD14, CD16, CD19,CD20, and CD56) HLA-DR Positive for CD123 (IL-3Ra) FcεRI (IgE receptor) IgE

47 FACS Detection of CD63, a marker of Basophil Activation nuclear membrane Histamine CD63 - APC APC-linked anti-CD63 ab IL-3 Rα PerCP-Cy5.5-linked anti- CD123 ab

48 1 hr 0.72% 2 hrs 0.54% 3 hrs 0.87% CD63 CD123 In vivo Basophil Activation during Mammalian Meat Challenge #FC-02 4 hrs - 16.11% 5 hrs - 14.12% 6 hrs - 5.12%

49 In vivo Basophil Activation during Mammalian Meat Challenge Baseline 1.96% 2 hrs 3.08% 4 hrs 1.8% 5 hrs 8.74% CD63 IgE -FC07 - sIgE to alpha-gal = 9.3 IU/mL; Total IgE = 204 -Whole blood was collected, fixed & stained

50 Delayed anaphylaxis Urticaria Time to symptoms (hrs:min) Treatment required Allergics 2/107/103:50 – 6:007/10 Controls 0/10 n/a0/10 Summary of Mammalian Meat Challenge Results in Subjects with or without IgE to alpha-gal Delayed anaphylaxis Urticaria Time to symptoms (hrs:min) Treatment required Basophil activation Allergics 2/106/103:50 – 6:007/108/10

51 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 Why the delay?

52 Thoracic duct blood stream The delivery of lipid to the circulation takes time (about 4 hours) VLDLIDLLDLHDL =Alpha-gal moiety, as a glycolipid Further conversion

53 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. Why the delay?

54 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 Conclusions

55 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


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