Alpha-gal allergy Presented by Pannipa Kittipongpattana, MD. March15, 2019

1. Red
Meat
Allergy
(Alpha-gal allergy)
Pannipa Kittipongpattana, M.D.
15 March 2019
Pediatric Allergy and Immunology Department
King Chulalongkorn Memorial Hospital

2. INTRODUCTION
Why am I interested in this topic?

3. Ann Allergy Asthma Immunol. 2006;97:39–43.
Cases from 1978-2003 from single university hospital, Tennessee, USA
Anaphylaxis from hymenoptera and immunotherapy were excluded
Idiopathic
59%
Food
22%
Drugs
11%
Etc
3%
Shellfish
34%
Peanuts
19%
Additives
11%
Tree
nuts
10%
Beef
6%
Others
30%
Exercise
5%

4. 218 cases from 2006-2016 from single university hospital, Tennessee, USA
Idiopathic
76, 34.9%
Probable cause
57, 26.1%
Definitive cause
85, 39%
Alpha-Gal
33%
Food
28%
Venom
19%
D. Pattanaik et al. Ann Allergy Asthma Immunol 121 (2018) 594−597
Mastocytosis
6%
Exercise
6%
Drugs
5%
Etc
3%

5. FIRST ENCOUNTER
How did Alpha-gal allergy come into clinical attention?

6. J Allergy Clin Immunol 2015;135:589-96.

7. Commins S. et.al. J Allergy Clin Immunol. 2011 May ; 127(5): 1286–1293.e6.
CETUXIMAB-INDUCED HYPERSENSITIVITY REACTIONS
Reported incidence in each study sites
Site total N incidence
Europe 329 1.2%
NE/W US 80 0%
US 400 0.5%
Southern US 88 22%
Reactions developed rapidly after or
during the first infusion

8. Chung CH, et al. N Engl J Med 2008; 358:1109-1117
California
Tennessee Boston

9. Chung CH, et al. N Engl J Med 2008; 358:1109-1117

10. Chung CH, et al. N Engl J Med 2008; 358:1109-1117

11. Commins S. et.al. J Allergy Clin Immunol. 2011 May ; 127(5): 1286–1293.e6.
What might explain regional difference in prevalence of IgE ?
Regional exposure
- Histoplasmosis
- Ameba
- Tick bites
- Coccidioidomycosis
- Nematodes
- Cestodes

12. THE ORIGIN
What actually is Alpha-gal?

13. “B-like
blood group”

14. J Proteomics. 2016 Mar 1;135:90-100.

15. J Proteomics. 2016 Mar 1;135:90-100.

16. Immunology. 2013 Sep;140(1):1-11

17. Allergenic
epitope in
cetuximab is
Alpha-Gal
Hypersensitivity
reaction is
mediated by
preformed-IgE
What shift B-
cell to produce
IgE ?
Why there is
regional
difference?

18. PIECES OF THE JIGSAW
How it’s all come together.

19. Meanwhile in Australia...

20. Report from Royal North Shore Hospital,
Sydney, New South Wales, Australia
2003-2007
25 Cases of red meat allergy
- 40% delay onset (> 4hr after ingestion)
- 68% severe reaction
- 44% more than 1 type of red meat
Beef > Lamb > Pork > Game
van Nunen SA, O’Connor KS, Clarke LR, Boyle RX, Fernando SL. An association
between tick bite reactions and red meat allergy in humans. Med J Aust 2009;190:510-1.

21. Med J Aust 2009;190:510-1.
Asia Pac Allergy. 2015 Jan;5(1):3-16
- All from Northern Beaches region, an endemic area of
Ixodes holocyclus (Paralysis tick)
- 24/25 reported large reaction to tick bite
- Tick bite preceded meat allergy by 1 - 6 months
- 29 control subjects (allergy to other food) also reported a
history of tick bite with no large reaction
Positive
Negative
Not done

22. “Novel association between tick bite reactions and red meat allergy.
We speculated that:
individuals are sensitised to tick salivary proteins
that are cross-reactive
with proteins found in various red meats.
”
van Nunen SA, O’Connor KS, Clarke LR, Boyle RX, Fernando SL. An association
between tick bite reactions and red meat allergy in humans. Med J Aust 2009;190:510-1.

23. Now, back to USA

24. Commins S. et.al. J Allergy Clin Immunol. 2009 Feb;123(2):426-33
University of Virginia Health System
4 patients with delayed anaphylaxis after red-meat
ingestion were test +ve for IgE to alpha-gal
Screen 243 patients → 15 more patients were IgE +ve
Another 5 patients with IgE +ve were sent from Missouri
Total 24 patients with +ve IgE to alpha-gal
all reported red-meat ingestion
3-6 hr prior to allergic reaction
Finding:
Delayed anaphylaxis to red-meat can be mediated by IgE to alpha-gal
Questions:
What induce production of these IgE?
Why are these reactions delayed?

25. SPT and intradermal test results in patients with IgE antibodies to α-gal.
Commins S. et.al. J Allergy Clin Immunol. 2009 Feb;123(2):426-33

26. Chung CH, et al. 2008 Commins S, et al. 2009van Nunen, et al. 2008 (first presentation)
Connecting the jigsaw...
cetuximab

27. +ve IgE to α-galNO IgE to α-gal
“3 researchers developed red-meat
allergy and recalled being bitten by a
tick weeks-months before”
J Allergy Clin Immunol 2015;135:589-96.

28. Tripathi A. et al. J Allergy Clin Immunol Pract 2014;2:259-65
https://www.cdc.gov/rmsf/stats/index.html
Incidence of Rocky Mountain spotted fever Distribution of Lone Star Tick

29. Alpha-gal & Lone Star Tick (Amblyomma americanum)
https://www.cdc.gov/rmsf/stats/index.html
Commins S. et.al. J Allergy Clin Immunol. 2011 May ; 127(5): 1286–1293.e6.

30. INFUSION OF CETUXIMAB
Summary of alpha-gal sensitization leading to clinical symptoms of red meat allergy
J Allergy Clin Immunol 2015;135:589-96.

31. Tick bite & Red-meat allergy around the world
Amblyomma americanum
Ixodes holocyclus
Ixodes ricinus
Ixodes cajennense
van Nunen S. Asia Pac Allergy 2015;5:3-16
Asia Pac Allergy. 2018 Jul;8(3):e31
Ixodes nipponensis
Haemaphysalis longicornis
Amblyomma sculptum

32. OPEN THE DOOR
How did the discovery advance our understanding?

33. Answers and new Question
What epitope cause IgE mediated reaction to cetuximab and red-meat?
→ Alpha-gal
What cause production of IgE specific to Alpha-gal?
→ likely tick-bite
Why is there a regional difference?
→ also tick-bite!
But
- HOW? → Hypotheses:
- Why are reactions delayed?

34. Hamsten C, et al. Allergy. 2013 Apr;68(4):549-52
Patient’s sera with IgE+ve Murine Ab to Alpha-gal
Control’s sera Irrelevant Ab
Araujo RN, et al. Int J Parasitol. 2016;46(3):213-20.
α1,3-GalT-KO
α1,3-GalT-KO
X 9 days
Amblyomma sculptum

35. Crispell G, et al. BioRxiv. Dec; 2018. doi: https://doi.org/10.1101/505776
UF un-fed, PF partially-fed, MG midgut, SG salivary gland

36. Answers and new Question
What epitope cause IgE mediated reaction to cetuximab and red-meat?
→ Alpha-gal
What cause production of IgE specific to Alpha-gal?
→ likely tick-bite
Why is there a regional difference?
→ also tick-bite!
But
- HOW? → Hypotheses:
- Why Delayed Reaction?

37. EMJ Allergy Immunol. 2018;3[1]:89-98.
The Glycolipid hypothesis

38. Curr Allergy Asthma Rep (2019) 19: 3

39. Curr Allergy Asthma Rep (2019) 19: 3

40. Arterioscler Thromb Vasc Biol. 2018;38:1665–9.
IgE to the mammalian oligosaccharide galactose-α-1,3-galactose is associated with increased atheroma
volume and plaques with unstable characteristics

41. PRACTICAL POINT

42. Red meat allergy
JAMA. 2018;319(4):332.
Asia Pac Allergy. 2015 Jan;5(1):3-16
https://foodallergycanada.ca/2016/07/know-signs-symptoms-anaphylaxis/
Symptoms: typical IgE-mediated reaction
DELAYED onset: 2-10 hr (mostly 3-6 hr)
May be in the middle of the night
Hard to realize “food allergy”
Factor:
ingestion
Typical onset of IgE mediated
food allergy: within 2 hr
Allergen: galactose-alpha-1,3-galactose
Found in most mammal meats
Some patients also allergic to:
milk, gelatine, and visceras
Etiology: certain tick-bite
Except: Old-world monkeys,
Apes, Humans
Heat stable

43. Diagnostic test
Skin-prick test with
commercial extract
DANDER
Determine if the patient is
sensitized to mammalian
meat only
r/o Pork-Cat syndrome
Determine milk tolerant
Prick-by-prick test
with fresh meat
Serum test for
IgE to alpha-gal
Oral food challenge
with 3-6 hr observation

44. Commins S. and Platts-Mills T. Curr Allergy Asthma Rep 2013;13:72–7
Pork-Cat syndrome
Comparison of cat exposure (direct or indirect) and the IgE response to cat-related
proteins in terms of epitope, cross–reactivity, and the allergic syndrome

45. Differ from alpha-gal allergy
- Rapid onset after ingestion
- Reactions usually occur with fresh, dried,
and smoked pork because albumin is heat
labile
J Allergy Clin Immunol Pract. 2018 Nov - Dec;6(6):1813-1823.
J Allergy Clin Immunol. 2001 Dec;108(6):881-90.
Pork-Cat syndrome (allergen: Fel d 2)

46. Natural history of Red meat allergy
● Not well studied
● Some evidence suggests that IgE to alpha-gal decrease over time (1-2 yr)
● Additional tick bites appear to increase the antibody level
Unpublished work from: Scott Commins, MD, Charles
Lane, MD, and Thomas Platts-Mills, MD, PhD.
IgE to alpha-gal and total IgE following tick bites
The chance of remission seems greater for
A. americanum than from I. holocyclus

47. Management
Asia Pac Allergy. 2015 Jan;5(1):3-16
Tripathi A. et al. J Allergy Clin Immunol Pract 2014;2:259-65
Food allergy: A practice parameter update—2014
● Avoid mammalian meats
includes mammalian organs and other products:
lard, suet, gelatin, pork rinds, and dairy products
● Avoid ticks bite
● Treatment of episodes

48. Take Home Messages
● IgE mediated reactions are usually rapid, but may be ‘delayed’
● Most allergenic epitopes are protein, but may be carbohydrate
● Tick-bite can trigger food allergy
http://thewordsofencouragement.com