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Tick Bites, Alpha-Gal and “Late Night Anaphylaxis”

Tick Bites, Alpha-Gal and “Late Night Anaphylaxis”. Thomas A E Platts -Mills, MD PhD FRS University of Virginia Disclosures : We are grateful to NIAID for generous support: AI-20565 and UO1-100799-2 and to Thermo Fisher for grant support

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Tick Bites, Alpha-Gal and “Late Night Anaphylaxis”

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  1. Tick Bites, Alpha-Gal and “Late Night Anaphylaxis” Thomas A E Platts-Mills, MD PhD FRS University of Virginia Disclosures: We are grateful to NIAID for generous support: AI-20565 and UO1-100799-2 and to Thermo Fisher for grant support DrPlatts-Mills is a consultant for IBT/Viracor and speaker for ALK .

  2. 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

  3. Cetuximab Solid Phase* Measurement of IgE ab to Purified Allergens Using Streptavidin Solid Phase Fel d 1, mouse IgG, Der p 1, Lol p 1, Asian lady bug,retuximab, infliximab etc. Cetuximab + Biotin Streptavidin CAP plus ~5ugBiotinylated Cetuximab * Assay in parallel with standard curve gives results for anti-Cetuximab IgE in IU/ml.Erwin et al JACI ’05, Erwin et al JACI ’09.

  4. IgE Antibodies Binding to Cetuximab in Serum from 76 Case Subjects and 462 Controls Chung CH et al. N Engl J Med 2008;358:1109-1117

  5. Specificity of the IgE Antibodies That Cross-React with Cetuximab

  6. Glycosylation of cetuximab as shown in Chung et al ’08 and the true structure of the Fc fragment of IgG * Glycosylation Site Including α-gal and Sialic Acid Fab N-88 N-43 N-299 Glycosylation Site With Human Oligosaccharides Oligosaccharide Fc *Lammerts van Bueren, Rispens….. Platts-Mills, and Parren . IgE antibodies to galactose alpha-1,3-galactose do not bind to alpha-galactosylated glycans attached to the Fc domain of intact therapeutic mAbs. Nat Biotechnol 2011. *Roy Jefferis . Recombinant antibody therapeutics: the impact of glycosylation on mechanisms of action. Trends Pharmacol Sci, 30: 356-6 2

  7. Jez…& Steinkellner. Significant impact of single N-glycan residues on the biological activity of Fc-based antibody-like fragments. JBC. Epub May 2012. Oligosaccharides (in yellow)

  8. Commins and Platts-Mills; Current perspectives, JACI ‘09

  9. Karl Landsteiner Defined the ABO system and recognized the presence of other closely related “B like” oligosaccharides on mammalian cells which also gave rise to antibody responses in humans. Koike et al. Proc Nat Acad Sci 2006;104(2):559-564. See: Macher BA and Galili U. The AlphaGal epitope:a carbohydrate of unique evolutionary and clinical relevance, Biochim. Biophys. Acta, 1780:75-88. ‘08

  10. Tick Bite Causes Potentially-Deadly Allergic Reaction To Meat For Coppell Man June 26, 2013: CBS, Dallas/Fort Worth, Texas.

  11. Case report: problems with the “other white meat” • Ms. I.C., age 79 • Non-atopic, employed at UVA for >40 years • Two episodes of hives in May 2012 • June 2012 – ate pork for lunch and 3 hours later began itching, which progressed to hives, shortness of breath, and tongue swelling before she collapsed in the UVA hospital lobby with blood pressure of 60/45 • Received epinephrine, Benadryl, and Solu-Medrol • Admitted overnight • Serum tryptase: 36.5 (normal range <11.5 ng/ml)

  12. Exam. five hours after reaction and eight hours after eating pork

  13. Case report: problems with the “other white meat” • Ms. I.C., age 79 • June 2012: seen in clinic, fully recovered • IgE to alpha-gal: 82.7 IU/ml • Second visit: no further episodes • IgE to alpha-gal: 28.1 IU/ml; pork: 2.2; beef: 4.3; dog dander: 1.1; chicken and fish <0.1 • On further questioning she reported three tick bites earlier in the summer that had itched for about ten days.

  14. Delayed anaphylaxis to beef A Reactions to Cetuximab C D B Rocky mountain spotted fever Spread of the lone star tick Incidence rates (per 1,000,000 persons) 0 0.1-0.9 1.0-9.9 10.0-14.9 15.0+

  15. Changes in IgE ab to Alpha-gal (IU/ml) and in Total IgE (IU/ml) after multiple bites from larval ticks. ↓↓ 10/26/06 5/21/07 10/9/07 11/6/07 2/9/09 IgE to Alpha-gal 0.49 16.9 48.3 130 33 Total IgE#127 199 350 532 360 →Several bites from adult ticks May ‘07 →Multiple bites (~200) from seed ticks August ’07 Serum IgE ab assays 5/14/08: Cat 38, Dog 44, Beef 39, Pork 37.5; Chicken, Turkey, Cod, Dust Mite, Roach and Ragweed all <0.35 IU/ml #Total IgE of this subject had been consistently less than 200 IU/ml since 1980. * Odocoileus virginianusA.americanum T P-M Aug 7th 2007

  16. History of East Coast White tail deer. As was the case in most of North America, these deer were “nearly extirpated “ by 1900 as a Result of over-exploitation and loss of habitat to agriculture. In the Piedmont deer restoration Started in 1951 and the first open season for deer in the Piedmont was 1958. Since then numbers in Eastern North America have risen from 500,000 to greater than 2 million. South Carolina Department of Natural Resources. Web site accessed March 29th 2013

  17. Original image: CDC; modified by D.N. Gaines for VDH (Grand Rounds: June 13, 2012)

  18. Reports of Itch *The likelihood of Lyme disease infection decreased with >3 reports of tick-associated itch (odds ratio 0.14, 95% CI 0.94–0.03, p = 0.01).

  19. Tick bites as an occupational disease of park rangers! • Park rangers inevitably get tick bites, and in Virginia this often results in sensitization to alpha-gal. • However, this form of sensitization is not associated with asthma, and preliminary data suggests that alpha-gal is not inhaled.# A. Americanum biteat 48 hours # Commins et al. Galactose-alpha-1,3-galactose-specific IgE is associated with anaphylaxis but not asthma. AJRCCM. 2012;185:723. Courtesy Katherine Kocan, Oklahoma State

  20. The enigma of IgE B-cell memory in human subjects: J.Davies, T.Platts-Mills and R.Aalberse, JACI in press 2013

  21. Ecuadorian farm dog infested with cattle ticks

  22. H h AJRCCM on line Feb 2012 Patients presenting with anaphylaxis, or recurrent urticaria who have IgE specific for alpha-gal have normal lung function no increase in asthma symptoms and normal FeNO. This ectoparasite induced IgE response cross reacts with cat, can make major contributions to total IgE, and appears to be a model for IgE responses to parasites that do not create or increase the risk for asthma. The results explain previous enigmatic IgE antibodies to cat in a Kenyan village and in the ED in Virginia.

  23. Der Spiegel 49/2012, p. 138

  24. Alpha-gal cases have now been reported from: -Australia -Sweden -France -Germany -Spain -Japan -China -Zimbabwe -South Africa -England And more than a thousand cases in the USA Stockholm, Sweden: Marianne van Hage Borstel, Germany: Uta Jappe Berlin, Germany: Jorg Kleine-Tebbe Nancy, France: Anne Moneret-Vautrin, Sandrine Jacquenet

  25. Kennedy, Stallings, Platts-Mills,…, and Commins. Pediatrics. 2013;

  26. Three questions: with partial answers • Do the patients have IgE antibodies to red meat and if so what is the specificity of the antibodies • Why are these IgE antibodies present in this large region of the South East? • Why are the allergic reactions to red meat delayed for 3-6 hours?

  27. -Subject #FC-07: sIgE to alpha-gal = 9.3 IU/mL; Total IgE = 204 -6 hours after consuming 56g of pork prosciutto, subject released with (disappointing) mild itch and single hive

  28. Subject calls from car 30 minutes after being released and begins to experience progression of itching and “warmth to skin” Initial picture upon arrival home (approximately 7.5 hours after eating proscuitto)

  29. Approximately 45 minutes after arriving home

  30. FACS Detection of CD63, a marker of Basophil Activation -PE CD63 -PE Histamine nuclear membrane

  31. 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-03: 3.8 ng/ml (baseline) → 13.4ng/ml (2 hrs) → 18.3 ng/ml (4 hrs) • -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

  32. Gating Strategy Gating Strategy HLA-DR/lineage 1 FITC CD63 APC CD123 PerCP-Cy5.5 • Basophils • 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 CD 123

  33. Basophil CD63 expression after challenge with mammalian meat in a patient with IgE to alpha-gal [A] and two control subjects [B and C] Hour 4 Hour 5 Hour 0 Hour 1 Hour 2 Hour 3 A B C CD63 Flow cytometry of basophil activation, as measured by CD63 upregulation from baseline, at hourly time points after meat challenge in an patient with a positive history of delayed urticaria to mammalian meat and IgE to alpha-gal [A], a control subject who exhibited CD63 upregulation after consumption of mammalian meat [B], and a control subject whose basophils did not upregulate CD63 after challenge. Basophils were gated as lineage 1 (CD3, CD14, CD16, CD19, CD20, CD56) negative, HLA-DR negative, CD41 negative (to remove platelets), and CD123 positive. Expression of CD203c did not change significantly during challenge and is not shown. CD123 1.03% 2.63% 0.12% 43.8% 7.75% 22.0% 0.65% 0.62% 0.23% 30.7% 0.46% 61.5% 0.84% 1.37% 1.30% 0.21% 0.35% 0.19%

  34. Summary of Mammalian Meat Challenge Results in Subjects with or without IgE to alpha-gal

  35. Questions re meat Challenges The delay in reactions to red meat in patients with IgE to alpha-gal can be demonstrated in a monitored challenge. We have observed reactions that required treatment and were accompanied by a rise in both Histamine and Tryptase but which did not start until four hours after challenge. Activation of basophils in vivo follows the same time course as the clinical reactions but is also seen in some controls. The results suggest that the urticarial and anaphylactic reactions require activation of mast cells The results demonstrate that the particles that cause both basophil activation and symptoms take three or more hours to enter the circulation.

  36. Exercise induced anaphylaxis : 17 year old girl. George du Toit, Kate Swan, and Scott Commins Two severe episodes requiring epinephrine occurred during exercise and challenge tests confirmed that they only occurred after eating pork. =Serum test for pork positive in London. So ? Assay for IgE to Alpha-gal in Virginia negative. Serum Results IU/ml Beef <0.35 Wheat <0.35 Pork 16.2Cat 24.6 Lamb 7.3 Cat serum albumin 83. Milk 0.5 Dog serum albumin 44. Diagnosis: Pork-cat syndrome with Exercise induced reactions Hilger et al Allergy 52:179 and Postumus et al JACI, 2013 in press

  37. “Allergy to Mammalian Proteins: At the Borderline between Foreign and Self?” • 200 subjects allergic to animal dander • 30% had IgE specific for various species’ albumin • Of these subjects, most had IgE with a high level of cross-reactivity between cat, dog, and horse albumin. • A few albumin sensitized subjects demonstrated IgE highly specific for one species. Spitzauer S, et al.IgE cross-reactivities against albumins in patients allergic to animals. JACI. 1995;96:951.

  38. 8 cases (3 teenagers and 5 adults) of reactions to pork occurring within 1 hour • In 3 cases, reactions graded as anaphylaxis • Skin tests positive to cat and pork, but in most cases negative to beef • Serum assays positive for cat dander (3.74-155 IU/ml) and cat albumin (2.3-130 IU/ml) • Serum assays for alpha-gal negative in 7 out of 8 cases • JACI in press 2013

  39. Cat extract (and IgE assays) can be made from dander and/or epithelium, which contain many different proteins. Dander Epithelium Tick Bites** Case III Case I Case III Alpha-gal on a a protein (e.g., cat IgA*) Fel d 1 (uteroglobin) 18 kDa Fel d 2 (cat albumin) 69 kDa 200kDa 69 kDa Cross reacts Pork-albumin ! Cross reacts with all Non-primate mammals *Gronlund H, et al. The carbohydrate galactose-α-1,3-galactose is a major IgE-binding epitope on cat IgA. JACI. 2009; 123:1189. **Commins et al JACI 2011 Cat IgA is Fel d 5. See www.allergen.org.

  40. Conclusions i) Delayed anaphylaxis to red meat is now common in a large and increasing area of the “South Eastern” USA. ii) IgE antibodies to alpha-gal in the USA are primarily, if not exclusively, due to bites from Amblyomma americanum. iii)There are many possible causes of the increase but increased ticks is most likely. iv) Delay in reactions after eating red meat reflects delay in the correct form of the epitope entering the blood stream. v) Tick bites induce an IgG1 and IgE response, and may not influence the pre-existing IgG2 response : ie there are two “separate” responses to the same epitope.

  41. Colleagues: 2006-2012 University of Virginia Scott Commins Libby Kelly Peter Heymann Anubha Tripathi Jake Hosen Sharma Satinover Hayley James Lisa Workman Josh Kennedy Elizabeth Erwin/Ohio Matt Perzanowski/Columbia Gus Litonjua, Harvard Diane Gold, Harvard Africa and Europe Eva Ronmark, Sweden Bo Lundback, Sweden Lucy N’Ganga, Kenya Joseph Odiambo, Kenya Adnan Custovic, Manchester Alpha-Gal Research Christine Chung, Nashville BelooMirakhur, BMS Qinwei Zhou; ImClone Tina Hatley, Bentonville Dane McBride. Louis Matos. SajuEapen. .

  42. http://www.peta.org/b/thepetafiles/archive/2013/04/01/peta-release-meat-allergy-inducing-ticks.aspxhttp://www.peta.org/b/thepetafiles/archive/2013/04/01/peta-release-meat-allergy-inducing-ticks.aspx

  43. Alpha-gal cases have now been reported from: -Australia -Sweden -France -Germany -Spain -Japan -China -Zimbabwe -South Africa -England And more than a thousand cases in the USA Stockholm, Sweden: Marianne van Hage Borstel, Germany: Uta Jappe Berlin, Germany: Jorg Kleine-Tebbe Nancy, France: Anne Moneret-Vautrin, Sandrine Jacquenet

  44. 1000 100 10 1 0.35 0.35 0.1 Alpha-gal specific IgE titers in patients presenting to clinic with anaphylaxis or asthma AJRCCM 2012,185:723 Alpha-gal specific IgE (IU/mL) Red dots indicate subjects with a history of anaphylactic reactions Limit of detection • x 8 • x 13 • x 58 • x 55 Number <0.35 Cat in home No cat in home Asthma Controls Anaphylaxis, urticaria, or angioedema subjects

  45. Table II. Absorption of sera from pork-cat subjects using different mammalian albumins Posthumus J, et al. JACI. Epub 2013. 1. Add Sepharose-linked cat albumin to patient’s serum 2. Centrifuge to remove IgE bound to cat albumin beads after 4h incubation 3. Assay supernatant for IgE Ab using ImmunoCAP Absorption Technique: Cat albumin Sepharose IgE Ab

  46. IgE to Alpha-gal in Virginia can be a large part of Total IgE 30% 10% r = 0.60, p<0.001

  47. Specific IgE Titers in Three Different Food Allergy Syndromes **p<0.001 compared to each of the EoE food allergens

  48. IgE to Beef in Sera Strongly Positive for IgE to α-gal Beef α-gal

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