Shellfish allergy Presented by Onnicha Chaisetsumpan, MD. October 21, 2022

1. Shellfish Allergy
Onnicha Chaisetsumpan, MD
Division of Allergy, Immunology and Rheumatology Unit,
Department of Pediatrics
King Chulalongkorn Memorial Hospital

2. Outline
•Classification
•Epidemiology
•Shellfish allergen
•Cross-reactivity
•Clinical manifestation
•Diagnosis
•Management

3. Classification of shellfish
Ruethers T, et al. Molecular immunology. 2018 Aug 1;100:28-57.

4. Classification of shellfish
Molecular Allergology User’s Guide 2.0 EAACI 2022.

5. Lee AJ, et al. APJAI 2012 Mar 1;30(1):3.

6. Classification of shellfish
Common name Scientific name Adult length Habitat
กุ้งฝอย Riceland prawn Macrobrachium
Lanchesteri
2-7 cm Freshwater
กุ้งขาว White leg Pacific shrimp
King prawn
Litopenaeus vannamei, formerly
Penaeus vannamei
23 cm Saltwater
กุ้งแชบ๊วย Banana shrimp Fenneropenaeus merguiensis 20-25 cm Saltwater
กุ้งกุลาดํา Black tiger prawn Penaeus monodon 18-25 cm Saltwater
กุ้งกุลาลาย Green tiger prawn Penaeus semisulcatus 10-18 cm. Saltwater
กุ้งก้ามกราม กุ้ง
แม่นํoา กุ้งนาง
Giant river prawn Macrobracium rosenbergii 13-31 cm Freshwater
กุ้งมังกร Spiny lobster Panulirus spp. >30 cm Saltwater
ล็อบสเตอร์ Lobster Nephropidae spp. >30 cm Saltwater
เครย์ฟิช Crayfish, small lobster,
freshwater lobster
Family: Astacidae, Cambaridae,
Parastacidae
Varies Freshwater
เคย Krill Order Euphausiacea 1.5 cm Saltwater
กุ้งฝอย
Courtersy Aj.Pannipa, MD

7. Classification of shellfish

8. Common name Scientific name Adult
length
Habitat
ปูแสม Mangrove crab Sesarma mederi 3-7 cm Freshwater
ปูจาก ปูแป้น Gren tidal crab Varuna litterata 3-7 cm Freshwater
ปูนา Ricefield crab Somanniathelphusa
spp.
Freshwater
ปูนํoาตก Waterfall crab
Stream crab
Laurnaudia
larnaudii
Freshwater
ปูขน/ไก่/ภูเขา Hairy leg
Mountain crab
Cardiosoma carnifex 8-20 cm Freshwater
ปูม้า ปูชัก Flower crab Portunus armatus 15-20 cm Saltwater
ปูทะเล ปูดํา ปูไข่ Giant mud crab Scylla serrata 24 cm Saltwater
ปูจักจั†น ปูกบ Red frog crab Ranina ranina 7-15 cm Saltwater
กัoงกระดาน Slipper lobster Thenus oritentalis 12-25 cm Saltwater
กัoงตั‡กแตน Mantis shrimp Oratosquailla nepa 11-14 cm Saltwater
Classification of shellfish
ปูนํoาตก ปูขน
ปูนา
ปูแสม
ปูจาก
กัoงกระดาน กัoงตั‡กแตน

9. Common name Scientific name Adult length Habitat
หอยชักตีน Wing shell Strombus canarium 3.5-5 cm Saltwater
หอยขม River snail Filopaludina martensi 2-4 cm Freshwater
หอยลาย Surf clam Paphia undulata 5-6 cm Saltwater
หอยแครง Cockle Anadara granosa 6-7 cm Saltwater
หอยตลับ Enamel venus shell Meretrix spp. 3-9 cm Saltwater
หอยเชลล์/พัด Scallop Amusium pleuronectes 7-15 cm Saltwater
หอยแมลงภู่ Green mussel Perna viridis 4-20 cm Freshwater
หอยนางรม Oyster Crassostrea spp. Varies Saltwater
หอยเป๋าฮืoอ Abalone Haliotis spp. Varies Saltwater
หมึกกล้วย Splendid squid Loligo duvauceli 20-35 cm
หมึกกระดอง Rainbow squid Sepia pharaonis 15-25 cm
หมึกหอม หมึกตะเภา Soft cuttlefish Sepistenthis
lessoniana
25-30 cm
หมึกยักษ์เล็ก Dollfus’s octopus Octopus dolifusi 6-12 cm
Classification of shellfish
หอยชักตีน หอยขม หอยเป๋าฮืoอ
Courtersy Aj.Pannipa, MD

10. Epidemiology
• Estimated prevalence of shellfish allergy:
up to 3% of population, depending on
geographical region
• Asia-Pacific > Europe and North America
• Asia-Pacific region: children 0.9-1.19%,
adolescents and adults 5.12-7.71%
Wai CY, et al. International journal of molecular sciences. 2020 Mar 23;21(6):2234.
Wong L, et al. Current Opinion in Allergy and Clinical Immunology. 2019 Jun 1;19(3):236-42.

11. Epidemiology
Molecular Allergology User’s Guide 2.0 EAACI 2022.
Lopata AL, et al. Clinical & Experimental Allergy. 2010 Jun;40(6):850-8.
• Prevalence in Asian populations is likely
to be more common than Western
• Onset of shellfish allergy often seen in
late childhood or adolescence
• Shellfish allergy is one of the leading
causes of food-induced anaphylaxis
• 42% in adults
• 12-20% in children

12. Shellfish allergen
Lopata Al, et al. Allergo journal. 2016 Nov;25(7):24-32.

13. • Bind along the length of actin and regulate cooperation of
troponin and myosin to control contraction of muscle fibers
• Highly stable and retains allergenicity despite thermal and
high-pressure processing
Major allergen
In adult
Major allergen
In children
Ruethers T, et al. Molecular
immunology. 2018 Aug 1;100:28-57.
Major allergen

14. Shellfish allergen
Molecular Allergology User’s Guide 2.0 EAACI 2022.

15. There are allergens in the shrimp
cephalothorax, absent or exist only
small amounts in muscular tissue
Rosa S, et al. Allergy. 2007 Jan;62(1):85-7.

16. • 3 patients with anaphylaxis after
ingestion of shrimp: sensitized to
allergen found in cephalothorax
• Hemocyanin: 75kDa, present
mainly in cephalothorax
Guillen D, et al. Annals of Allergy, Asthma & Immunology. 2014 Dec 1;113(6):674-5.

17. Hemocyanin
• 75kD subunit, hexameric structure
• First identified as allergen in the giant
freshwater shrimp
• Copper-containing, oxygen transport proteins
• Mainly found in hemolymph of invertebrate
animals
• Consumption of cephalothorax is common in
Asian populations
Shellfish allergen
Ruethers T, et al. Molecular immunology. 2018 Aug 1;100:28-57.

18. Shellfish allergen
Middleton’s Allergy Clinical and Practice 9th

19. Shellfish allergen
Middleton’s Allergy Clinical and Practice 9th

20. Shellfish allergen
Lee AJ, et al. APJAI 2012 Mar 1;30(1):3.

21. Shellfish allergen
Middleton’s Allergy Clinical and Practice 9th

22. Shellfish allergen
Lee AJ, et al. APJAI 2012 Mar 1;30(1):3.

23. Shellfish allergen
• Among crustacean: tropomyosin homology 88-100%
• Crustacean and insects, mites: tropomyosin
homology 78-98%
Ruethers T, et al. Molecular immunology. 2018 Aug 1;100:28-57.

24. Shellfish allergen
Ruethers T, et al. Molecular immunology. 2018 Aug 1;100:28-57.
• Crustacean and mollusk: tropomyosin homology 60%
• Among mollusk: tropomyosin homology 70-97%

25. Cross reactivity
Cox AL, et al. J Allergy Clin Immunol Pract. 2021 Jan;9(1):82-99.
Sicherer SH, et al. J Allergy Clin Immunol 2001;108:881-90

26. Cross reactivity
Food Allergy. Practice Parameter. 2014

27. Cross reactivity
• Among crustacean, between crustacean and mollusk, between crustaceans and
mollusk and mite or cockroaches
• High risk of pan-shellfish allergy cross-reactivity
• Some may be allergic to crustacean but tolerate mollusk, or exhibit species-specific
allergy
• Tropomyosin: coiled-coil molecule formed by two parallel alpha-helix
Molecular Allergology User’s Guide 2.0 EAACI 2022.

28. Cross reactivity
Middleton’s Allergy Clinical and Practice 9th
Molecular Allergology User’s Guide 2.0 EAACI 2022.

29. Cross reactivity
Molecular Allergology User’s Guide 2.0 EAACI 2022.

30. Clinical manifestation
Ruethers T, et al. Molecular immunology. 2018 Aug 1;100:28-57.

31. Type of consumption and exposure
• Fresh and cooked meat
• Food processing methods (thermal or pressure
treatment): not destroy most of allergens but may
enhance allergenicity
• Food additives
• Dried shrimp, shrimp paste as flavoring agents
• Potential source and cause of accidental consumption
to shellfish allergens
• Occupational exposure
• Airborne shellfish particulate matter
• Elicit upper and lower respiratory tract symptoms
• Fish parasites: Anisakis
Molecular Allergology User’s Guide 2.0 EAACI 2022.

32. Molecular Allergology User’s Guide 2.0 EAACI 2022.

33. Molecular Allergology User’s Guide 2.0 EAACI 2022.

34. Clinical manifestation
Ruethers T, et al. Molecular immunology. 2018 Aug 1;100:28-57.

35. Clinical manifestation
Non-immunological: adverse reactions to ingested shellfish (shellfish toxic
syndrome)
• Paralytic shellfish poisoning
• Neurotoxic shellfish poisoning
• Diarrhetic shellfish poisoning
• Amnesic shellfish poisoning
• Azaspiracids shellfish poisoning
• Adverse reactions to bacterial or viral contamination
• Presence of similar symptoms in others
who shared same meal
• Absence of prior reactions to same
shellfish
• Subsequent tolerance without symptoms
Ruethers T, et al. Molecular immunology. 2018 Aug 1;100:28-57.
Woo CK, et al. Clinical and Translational Allergy. 2011 Dec;1(1):1-7.

36. Clinical manifestation
• Typically, immediate onset, but rare late-phase reactions reported
• Occur within minutes to 2 hours following ingestion
• Severity of the reactions is variable even within the same individual
• Species-specific reactions
• Food preparation methods
• Part of shellfish consumed
• Presence of cofactors: alcohol, exercise, NSAIDs
• Food-dependent exercise-induced anaphylaxis (FDEIA)
• Culprit allergen: P75 homologue, fructose 1,6-bisphosphate aldolase (FBPA)
Ruethers T, et al. Molecular immunology. 2018 Aug 1;100:28-57.

37. Clinical manifestation
Phenotype FPIES
Acute FPIES
Chronic FPIES
Adult FPIES
Atypical FPIES
FPIES during
exclusive
breastfeeding
Ruethers T, et al. Molecular immunology. 2018 Aug 1;100:28-57.
Adult-onset food protein induced enterocolitis syndrome (FPIES)
• Clinical presentation distinct from typical IgE-mediated symptoms
• Profuse vomiting, typically between 1-3 hours after ingestion
• Diarrhea, pallor, floppiness, hypothermia and hypotension
• Shellfish and fish FPIES: most common form of FPIES in adults

38. • Diagnosis was established after a median of 8 reactions, delayed to
diagnosis median 8 years
• Symptoms of seafood FPIES
• 100% severe abdominal pain
• 76% vomiting
• Main criteria FPIES
• May not apply to adult population
• 64% diarrhea
• All negative SPT/sIgE
• Crustacean 60%, fish 48% and cephalopods and bivalves 20% each
Gonzalez P, J Allergy Clin Immunol 2018;7:670-2.

39. Natural history
• Natural history of shellfish allergy is not well described
• Persistent with low rates of development of tolerance
• Self-report resolution of shellfish: 3.9% over 5 years
• In general, childhood-onset allergy to seafood has
poor prognosis, with minority outgrowing food
allergies
• Adult-onset shellfish allergy is thought to be
persistent
• Most individuals allergic to one type of crustacean
(shrimp, lobster, crab) —> react to other crustacean
due to high homology
Zotova V, et al. JACI in practice. 2019 Feb 1;7(2):690-2.

40. • Overall 26 challenges, 6/13
(46%) challenges to Pm and
6/13 (46%) challenges to Mr
were negative
• At 10 years after diagnosis,
46% of patients had resolved
shrimp allergy
17 patients
were recruited
P.Monodon (Pm) M.rosenbergii (Mr)
Ittiporn S, et al. APJAI 2021 Dec 1;39(4):249-57.

41. Resolved shrimp allergy patients
had significantly smaller size
of shrimp skin test than
persistent shrimp allergy patients
at both diagnosis and follow-up
Ittiporn S, et al. APJAI 2021 Dec 1;39(4):249-57.

42. Diagnosis
Challenging due to extensive repertoire of species and high degree of cross reactivity
between major allergen, tropomyosin of different shellfish, house dust mite and
cockroach
• History: convincing clinical history
• Skin prick test
• Serum-specific IgE
• Oral food challenges: definitive diagnosis
Molecular Allergology User’s Guide 2.0 EAACI 2022.

43. Diagnosis: skin test
• Commercial shellfish extracts
• Reasonable results in case of highly abundant allergens; tropomyosin
• Limited value due to false negative responses in case of heat sensitive allergens (MLC) or
weak or non-cross-reactive allergens (arginine kinase)
• Lack of availability of commercial extracts for specific shellfish species consumed by the
patient; Asia-pacific, Southern hemisphere
• Prick-prick test
• Using fresh shellfish (with suspected offending food), species-specific
• No established PPV and NPV for determining the likelihood of clinical allergy
• Performed with caution and in setting experienced in the recognition and management of
anaphylaxis
Molecular Allergology User’s Guide 2.0 EAACI 2022.

44. Molecular Allergology User’s Guide EAACI 2016.

45. 68 children with history of shrimp allergy and skin prick tests positive to shrimp
Food challenge to P.monodon and M.rosenbergii
Skin prick test extract (raw)
• PmSPT: P.monodon
• MrSPT: M.rosenbergii
Prick to prick (cooked)
• PmPTP: P.monodon
• MrPTP: M.rosenbergii
Commercial extracts
(raw Penaeus aztecus)
Positive OFC to
both 47.06%
Positive OFC to
P.monodon 17.65%
Positive OFC to
M.rosenbergii 23.53%
Negative OFC
11.76%
Jirapongsananuruk O, et al. Clinical & Experimental Allergy. 2008 Jun;38(6):1038-47.
P. monodon
(seawater shrimp)
M. Rosenbergii
(freshwater shrimp)

46. Correlation between mean wheal
diameter (MWD)from ComSPT-
PmSPT, ComSPT-MrSPT, PmSPT-
PmPTP and MrSPT-MrPTP,
but not ComSPT-MrSPT were
observed
Jirapongsananuruk O, et al. Clinical & Experimental Allergy. 2008 Jun;38(6):1038-47.

47. MWD from MrSPT larger in patients with
positive > negative challenges to
M.rosenbergii (no significantly difference)
Jirapongsananuruk O, et al. Clinical & Experimental Allergy. 2008 Jun;38(6):1038-47.
MWD from PmSPT and PmPTP were significantly
larger in patients with positive > negative
challenges to P.monodon

48. Pm allergy group
• PmSPT with MWD 30 mm.= 80% positive
probability for positive challenges
• PmPTP with MWD 22.5 mm, and ComSPT 20 mm.
= 95% predictive probability
Mr allergy group
• MrSPT with MWD 30 mm.= 95% positive
probability for positive challenges
• Specific allergy to Pm or Mr confirmed by food
challenges
• SPT using crude extracts and PTP test are useful
tools
Jirapongsananuruk O, et al. Clinical & Experimental Allergy. 2008 Jun;38(6):1038-47.

49. Diagnosis: IgE testing
Whole shellfish extract
• Not high sensitivity and specificity, vary upon region
• Potentially false negative or low titers in individuals sensitized to low abundance
allergens
• Not represent the specific shellfish species consumed by patients
Purified allergen
• Tropomyosin: more specific, variable sensitivity
Molecular Allergology User’s Guide 2.0 EAACI 2022.

50. Immunology KCMH
Specific IgE to shrimp (f24)
(MI117)
Specific IgE to crab (f23)
(MI152)
Specific IgE to squid (f258)
(MI153)
Molecular Allergology User’s Guide 2.0 EAACI 2022.

51. Code f24 Shrimp
Latin name • Pandalus borealis
(กุ้งแดง)
• Penaeus monodon
(กุ้งกุลาดํา)
• Metapenaeopsis
barbata (กุ้งทราย)
• Metapenaeus
joyneri (กุ้งตะกาด)
Route of exposure Ingestion
Source material Boiled, frozen Atlantic
shrimp and raw, frozen
prawns from the Indo-
West-Pacific
Code f258 Squid
Latin name • Loligo edulis
• Loligo vulgaris
Code f58 Pacific squid
Latin name Todarodes pacificus
Source material Squid meat
Pandalus borealis
Penaeus monodon
Metapenaeopsis barbata
Metapenaeus joyneri
Code f23 Crab
Latin name Chinocetes spp.
Route of exposure Ingestion
Source material Boiled crab meat

52. Component resolved diagnosis (CRD)
• Tropomyosin-sIgE
• Better positive predictive value for clinical reactivity,
compared with SPT or whole extract sIgE
• Still significant percentage of patients who are
monosensitized to minor allergens without
concurrent sensitization to tropomyosin
• Pen a 1, Pen m1
• Others shrimp allergens: Pen m 2, Pen m 4,
hemocyanin- potential diagnostic marker for
occupational exposure and symptoms to shellfish
allergens
• Very limited mollusc allergens investigated for use in
component-resolved diagnostics
Molecular Allergology User’s Guide 2.0 EAACI 2022.

53. Ruethers T, et al. Molecular immunology. 2018 Aug 1;100:28-57.

54. Component resolved diagnosis (CRD)
Molecular Allergology User’s Guide 2.0 EAACI 2022.

55. BAT and EXiLE
Patients aged 5-50 years with shrimp allergy:
history of allergic reactions within 2 hours after
consumption over the past 5 years
DBPCFC
• Skin prick test with commercial shrimp extract
(ALK-Abelló)
• Specific IgE to shrimp (f24 and rPen a 1, f351)
• BAT to P.monodon protein extract and rPen m 1
• EXiLE test with P.monodon or rPen m 1
Wai CY, et al. JACI in practice. 2021 Jan 1;9(1):236-44.

56. BAT using shrimp extract showed highest AUC, Youden Index, likelihood ratio,
odds ratio when compared with other assays and tropomyosin diagnosis
Wai CY, et al. JACI in practice. 2021 Jan 1;9(1):236-44.

57. • BAT is more accurate diagnostic
markers for shrimp allergy than SPT and
shrimp sIgE
• EXiLE (IgE crosslinking-induced luciferase
expression) = good alternative to BAT
• Tropomyosin may not be the most
important shrimp allergen in Chinese
Wai CY, et al. JACI in practice. 2021 Jan 1;9(1):236-44.

58. Diagnosis: challenge tests
• Oral double-blind, placebo-controlled food challenge
• Gold standard to confirm diagnosis of shellfish allergy
• Uncertain diagnosis, to consume a potentially cross-reactive mollusk
• Variety of recommended full cumulative doses: up to 24 g of seafood
Molecular Allergology User’s Guide 2.0 EAACI 2022.
Bird JA, et al. The Journal of Allergy and Clinical Immunology: In Practice. 2020 Jan 1;8(1):75-90.

59. Diagnosis: skin test and sIgE testing
Wai CY, et al. Current Opinion in Allergy and Clinical Immunology. 2022 Jun 1;22(3):202-12
Gelis S, et al. Journal of investigational allergology & clinical immunology. 2020 Jul 21;30(6):409-20..

60. Molecular Allergology User’s Guide 2.0 EAACI 2022.

61. Management
• Advice and avoidance
• Generally, recommend to avoid all shellfish containing products due to high degree of likely
clinically relevant cross-reactivity
• Regardless of grade of shellfish processing
• Emergency action plans, use of personal adrenaline autoinjectors
• Not increased risk of allergic reactions to iodine
• Topical antiseptic: Betadine, Povidine, intravenous x-ray radio-contrast agents
• People with iodine allergy are not increased risk of seafood allergy
• Allergen-specific immunotherapy
Molecular Allergology User’s Guide 2.0 EAACI 2022.

62. Management
Wai CY, et al. International journal of molecular sciences. 2020 Mar 23;21(6):2234.
Wai CY, et al. Current Opinion in Allergy and Clinical Immunology. 2022 Jun 1;22(3):202-12.

63. 60 patients with shrimp allergy 20 normal control patients
Sublingual immunotherapy
• Shrimp allergen extracts 2 species (P.semisulcatus, M.stebbingi)
• Dilution: 1/5000, 1/500 and 1/50 w/v
• Each vial: 1 drop in 1st day, 2 drops in 2nd day, 3 drops in 3rd day,
4 drops in 4th day and 4 drops until the concentration finished
• Total IgE, sIgE, IgG, eosinophilia
• PEFR before and after therapy
• Efficacy of sublingual shrimp
immunotherapy were evaluated in 60
Egyptian shrimp allergic patients and
20 controls
• At 6 months after start treatment
• Significant reduction of allergic
symptoms
• Reduction in shrimp-specific IgE
with increased IgG
• AR= most responsive to
sublingual shrimp AIR > urticarial
and asthmatic patients
Objective: to evaluate the efficacy and tolerance of sublingual
shrimp immunotherapy in Egyptian patients allergic to shrimp
Refaat MM, et al. Food and Nutrition Sciences. 2014 Sep 5;2014.

64. • SPT, sIgE and DBPCFC to
confirm allergy to culprit foods
• Litopenaeus setiferus shrimp
(Northern white shrimp) flour
• Multiple-food-allergic patients were recruited to a multi-site
clinical trial between January 1 and November 30, 2016
• Positive SPT ≥6 mm. and/or sIgE >4 kU/L for each food, total IgE
<2000 kU/L
• Clinical reaction in DBPCFCs at ≤125 mg dose
Initial rapid desensitization
2-5 food allergens
Up-dosing q2-4wk
Maintenance ≥1 g each
Andorf S, et al. EClinicalMedicine. 2019 Jan 1;7:27-38.
Nguyen DT, et al. Pediatric Allergy and Immunology. 2022 Jan;33(1):e13679.

65. Total 70 patients —> 3 found to have shrimp allergy
Nguyen DT, et al. Pediatric Allergy and Immunology. 2022 Jan;33(1):e13679.

66. Clinical outcomes and adverse events
Nguyen DT, et al. Pediatric Allergy and Immunology. 2022 Jan;33(1):e13679.