Allergy and Immunology Fellow University of Virginia ...4/8/2019 1 Clinical and Immunologic...

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4/8/2019 1 Clinical and Immunologic Investigations into the α-Gal Syndrome Monica Gupta, MD Allergy and Immunology Fellow University of Virginia Medical Center Disclosures Speaker: None NIH Grant R37-AI-20565 (Platts-Mills) Assay support: Phadia/Thermo Fisher Patent on IgE assay to a-Gal (Platts-Mills)

Transcript of Allergy and Immunology Fellow University of Virginia ...4/8/2019 1 Clinical and Immunologic...

Page 1: Allergy and Immunology Fellow University of Virginia ...4/8/2019 1 Clinical and Immunologic Investigations into the α-Gal Syndrome Monica Gupta, MD Allergy and Immunology Fellow University

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Clinical and Immunologic Investigations into the α-Gal Syndrome

Monica Gupta, MDAllergy and Immunology FellowUniversity of Virginia Medical Center

Disclosures

◦ Speaker: None◦ NIH Grant R37-AI-20565 (Platts-Mills)◦ Assay support: Phadia/Thermo Fisher◦ Patent on IgE assay to a-Gal (Platts-Mills)

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Brief BackgroundGalactose-α-1,3-galactose (α-Gal) is an oligosaccharide that has been identified as a culprit allergen in both food and drug-related allergic reactions

It is expressed in non-primate mammals and is the target of IgE antibodies that cause reactions to red meat which can consist of urticaria, angioedema, or anaphylaxis 2-6 hours after ingestion of mammalian meat products

Brief Background

IgE sensitization to α-Gal occurs via tick bites which is supported by regional occurrence of cases

Commins et al. JACI, 2011

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Distribution of Cases of the α-Gal Syndrome to Red Meat in the United States

‡≥100 Cases

5-40 Cases

1-4 Cases

0 Cases

41-99 Cases

‡Cases diagnosed elsewhere

‡ ‡

Established lone star tick, CDC, 2007

Hamptons

ManhattanQueensBrooklyn

Questions going forward◦ Mechanisms whereby tick bites induce IgE to α-

Gal◦ Explanation for the characteristic delay in

symptom onset of 2-6 hours◦ Do our α-Gal patients, or asymptomatic

sensitized subjects in the community, have other diseases that are associated with IgE to α-Gal ◦ Clinical presentation of subjects with allergic

reactions related to α-Gal syndrome: e.g. -differences by age, sex or baseline atopy?

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Investigation of 261 cases presenting for evaluation of red meat allergyMethods:• 261 patients from Central Virginia were enrolled in an IRB-

approved observational study• All subjects self-reported allergic reactions (eg. urticaria,

anaphylaxis) to mammalian meat • Serum obtained, questionnaires completed• Assays were conducted for total IgE and IgE to a panel of

inhalant, food and venom allergens including α-Gal, beef, pork, cat, gelatin, cat serum albumin, and pork serum albumin using standard ImmunoCAP assays.

Demographics and characteristics of cohort

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Demographics and characteristics of cohort

*

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α-Gal Beef Pork Milk

P=0.009

P=0.20

P=0.42

P=0.68

% ≥0.35 IU/mL: 97% 93% 97% 93% 90% 89% 80% 74%Fisher’s, P value: 0.70 0.70 >0.99 0.51

A

Children vs Adults

Time of Symptom Onset in subjects reporting reactions to red meat

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α-Gal sIgE titers are similar in subjects whoreport early or delayed symptoms

Does a-Gal syndrome occurs equallyin those with and without traditional atopy?

Proposed mechanisms that could contribute to a-Gal sensitization

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1

10

100

1000

A NA A NA NAAα-Gal Beef Milk

% positive: 73% 78% 68% 75% 59% 54%χ2, P value:

P=0.83

P=0.08

P=0.11

0.32 0.19 0.42

Urticaria GI Anaphylaxis

α-Gal titers and symptoms are similar regardless of traditional atopy

*Atopy defined as sIgE ≥ 0.7 IU/mL to DM, Timothy grass, or Ragweed

COMPARISON OF CHARACTERISTICS OF THREE FORMS OF RED MEAT ALLERGY

Primary Beef Allergy

Pork-Cat Syndrome

α-Gal Syndrome

Clinical Features -Most commonly described in atopic children; subjects often have concomitant milk allergy

-Occurs in cat allergic subjects, and is most common in adolescence and early adulthood

-Relates to tick bites and can develop across life-span with no other history of atopy-Often has delayed symptom onset

Relevant Allergen(s) -Bovine Serum Albumin (Bos d 6),Immunoglobulin, etc.

-Albumin of cat cross-reacts with pork albumin

-Galactose-α-1,3-galactose (α-Gal)

Immunologic Features

-Often poly-sensitized to many food allergens

-Positive IgE to cat, cat serum albumin (Fel d 2), pork-Cross-reactivity to serum albumin to pork (Sus S 1)

-IgE to α- Gal, IgE to other mammalian extracts (beef, pork, milk, cat, dog)

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Component analysis of the 16 subjects who tested negative for IgE to α-Gal

α-Gal is the dominant cause of red meat allergy in children and

adults central VA

261 cases of self-reported red meat allergy

*

* 2 subjects who initially tested a-Gal positive also hadIgE signature suggestive of pork-cat syndrome

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Summary◦ Of the cohort, 95% were a-Gal cases◦ Presentation and immune response was similar in

children and adults◦ Most subjects report delayed symptom onset (ie,

>2hrs) but 16% reported symptoms earlier, and a-Gal sIgE responses were similar in these subjects◦ Consistent with the role of tick bites in the

acquisition of the syndrome, it was equally represented among subjects with and without traditional atopy

Conclusions• The α-Gal syndrome should be considered in

presentations of urticaria and/or anaphylaxis and/or GI cramping, particularly:• In areas where lone star ticks are endemic• In children and adults, and regardless of atopic

status• In those with delayed symptom onset, noting

symptoms can occur in less than 2 hours

• However, other forms of mammalian meat allergy, such as pork-cat syndrome and primary beef allergy should also be considered

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References◦ Chung CH, Mirakhur B, Chan E, Le QT, Berlin J, Morse M, et al. Cetuximab-induced anaphylaxis and IgE

specific for galactose-alpha-1,3-galactose. N Engl J Med. 2008;358(11):1109-17.

◦ Commins SP, James HR, Kelly LA, Pochan SL, Workman LJ, Perzanowski MS, et al. The relevance of tick bites to the production of IgE antibodies to the mammalian oligosaccharide galactose-alpha-1,3-galactose. J Allergy Clin Immunol. 2011;127(5):1286-93 e6.

◦ Commins SP, James HR, Stevens W, Pochan SL, Land MH, King C, et al. Delayed clinical and ex vivo response to mammalian meat in patients with IgE to galactose-alpha-1,3-galactose. J Allergy Clin Immunol. 2014;134(1):108-15.

◦ Commins SP, Satinover SM, Hosen J, Mozena J, Borish L, Lewis BD, et al. Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-alpha-1,3-galactose. J Allergy Clin Immunol. 2009;123(2):426-33.

◦ Wilson JM, Platts-Mills TAE. Meat allergy and allergens. Mol Immunol. 2018;100:107-12

◦ Wilson JM, Platts-Mills TAE. Red meat allergy in children and adults. Curr Opinion Immunol. 2019, In Press

◦ Wilson JM, Platts-Mills TAE. The oligosaccharide galactose-α-1,3-galactose and the α -Gal syndrome: insights from an epitope that is causal in IgE-mediated immediate and delayed anaphylaxis. EMJ Allergy Immunol. 2018;3(1):89-98.

◦ Wilson JM, Schuyler AJ, Schroeder N, Platts-Mills TA. Galactose-alpha-1,3-Galactose: Atypical Food Allergen or Model IgE Hypersensitivity? Curr Allergy Asthma Rep. 2017;17(1):8.

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Acknowledgements

Thomas Platts-Mills, MD, PhD, FAAAAI, FRSJeffrey Wilson, MD, PhDAlexander Schuyler, BS, BALisa Workman, BAEmily McGowan, MD, PhDJonathan Posthumus, MDHayley R. James, MDMaya Retterer, BABehnam Keshavarz, PhD

Scott Commins, MD, PhD

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Map of Lone Star Tick Distribution

www.cdc.gov

Characteristics Total

(n=261) Urgent Care

(n=166) Age at enrollment, median (range) 49 (5-82) 50 (6-82)

Sex, male (%) 120 (46%) 75 (45%)

Race, Caucasian 247 (95%) 158 (95%)

Symptom

Hives 242 (93%) 156 (94%)

Anaphylaxis 157 (60%) 122 (73%)

GI 167 (64%) 111 (67%) Only GI 9 (3%) 4 (2%)

Timing

0-<2hrs 41 (15%) 29 (17%)

≥ 2hrs 211 (81%) 132 (80%)

Not specified 9 (3%) 5 (3%)

Tick or chigger bite in last 10 yrs 255 (98%) 164 (99%)

Total IgE (IU/mL), GM (95%CI) 144 (125-166) 147 (124-174)

α-Gal

sIgE, n>0.35 (%) 245 (94%) 157 (95%)

sIgE, GM (95%CI) 17.7 (15-21) 18.5 (15-23)

% sIgE of total, GM (95%CI) 11.9 (10-14) 12.5 (11-15)

Demographics and characteristics of cohort