Q:

6/10/2014
I have a 10 year-old male patient who suffered anaphylaxis to salmon and he is now avoiding all finfish, as he should. There are no issues with shellfish. His Auvi-Q is with him at all times and both the patient and the family are well educated about food allergy. His mother asked me an interesting question that has never been posed to me before and so I would like your opinion.

He very much enjoys outdoor sports including fishing and his mother has asked me if he can handle fish, especially something like taking a fish off of the hook. My instincts say no. I am aware that tropomysin is the protein to which most patients are allergic but I still worry that in handling a fish, if the fish is wounded, and perhaps, splashes water in his mouth, he could have a problem. I also worry that he could touch his mouth after touching the fish and somehow have a problem.

I might just be an overprotective allergist-mom but I'd like your opinion please.

A:

Thank you for your inquiry.

Before directly answering your question, I think we need to shed some light on common misconceptions in regards to fish allergy. First of all, it is true that most allergists recommend avoidance of all fish in patients allergic to a single fish because there is crossreactivity. However, this crossreactivity is not universal, and it has been estimated that 50 percent of patients may demonstrate such crossreactivity (see previous entry posted on our website 10/23/2013 and abstracts copied below).

Secondly, tropomyosin is not an allergen in fish, but rather shellfish. Fish do not contain tropomyosin, and shellfish do not contain allergens found in fish. This is the reason that there is no crossreactivity between finfish and shellfish. Tropomyosin is the major allergen in shellfish, but the major allergen in fish is parvalbumin, and more recently discovered enolases. Again, see the abstracts copied below.

So, although I do not disagree with the recommendation to avoid all fish, one cannot conclude conclusively that your patient is at risk for anaphylaxis to any fish other than salmon. The reason I mention this is only because this fact plays a role in my direct answer (see below) to your question. The reason that we mentioned the tropomyosin issue is because we would not want the readers of this entry to be confused in this regard.

Having said this, there is no right or wrong answer as to whether or not your patient should avoid fish. My belief is that if you asked several allergists, you would get several dissenting opinions. The answer to that question depends upon non-quantitative factors such as how badly the child wants to fish, how mature he is at age 10, the anxiety level of his parents, et cetera. However, it is possible that a patient allergic to fish could have an anaphylactic reaction upon contact with fish either through a scratch or other wound, pricking the finger with the hook, et cetera. However, in my experience, if patients are careful, there is no problem in this regard, and I do not normally prohibit fishing in fish-sensitive individuals. We do instruct them to be careful when handling fish, avoiding any chance of sticking themselves with the hook, wearing gloves, et cetera. With these precautions, we have personally not had a "bad experience." However, I would certainly not in any way argue with the decision to disallow fishing in your patient. Again, there is not a "right or wrong" strategy. It is purely a judgment call.

Thank you again for your inquiry and we hope this response is helpful to you.

Fish allergy: potential cross-reactivity between fish
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Q:
10/23/2013
My question involves a 53 year-old man with a history of fish anaphylaxis as a child. The steam form cooking has caused SOB in the past. He remembers the fish exposure to be freshwater fish. He has been able to eat some ocean caught fish with no reactions. RAST for general Whitefish was negative. Is there a possibility that freshwater fish can cause anaphylaxis that the ocean caught fish would not?

A:
Thank you for your inquiry.

Your question highlights the issue of cross-reactivity between fish. We have dealt with this issue previously on our website, and I have copied below that entry along with our response for your convenience.

In direct answer to your question, yes. Many patients can eat certain fish whereas they react violently to others. There are no definitive data regarding cross-reactivity that we can apply to fish in order to guide patients in their choices, but what we do know is summarized in the entry copied below.

In regards to your patient, there should be no problem with his continuing to eat fish that he ingests without difficulty, but more than likely those which have caused a problem in the past will continue to do so.

Question:
3/6/2013
Please clarify the family in which salmon and tuna belong. Are they considered a whitefish or are they in a separate category? Thank you for your time.

Answer:
Thank you for your inquiry.

Tuna and salmon belong to different families of fish. Tuna is a member of the Scombridae family of fish. Salmon is in the Salmonidae family. However, I assume you are interested in potential allergen cross-reactivity between salmon and tuna, and family per se doesn't always define cross-reactivity. Unfortunately, cross-allergenicity between fish is quite complex and has not, to my knowledge, been conclusively defined. Copied for you below is an abstract of an article that has looked at this issue, and I think that the operative word in the conclusion is “probably.” Also the issue of cross-reactivity between fish is discussed in detail in the classic article looking at clinical cross-reactivity between foods by Sicherer (1). This article should be readily accessible to you through the allergist with whom you work via a subscription to The Journal of Allergy and Clinical Immunology. The point being, from reading this article, is that there is unpredictability as far as cross-reactivity is concerned. The only true test is an oral challenge.

However, in general, it would be expected that cross-reactivity between tuna and salmon is relatively rare, with salmon probably more commonly cross-reactive with cod, and tuna more commonly cross-reactive to other members of the scombroid family. However, these cross-reactivity patterns are only guidelines, and cannot be taken literally because there are definite exceptions. For example, in one Italian investigation, in children sensitive to cod, over 50% showed sensitivity to tuna (2).

In summary, salmon and tuna belong to different families of fish. However, the fact that they are in separate families does not rule out potential cross-reactivity, and there are no definitive data which would allow you to predict with accuracy as to whether or not clinical cross-reactivity would occur. Testing for specific IgE would of course be helpful, but an oral challenge would be the only completely reliable test to determine such cross-reactivity.

Thank you again for your inquiry and we hope this response is helpful to you.

J Allergy Clin Immunol. 2005 Dec;116(6):1314-20. Epub 2005 Oct 3.
Allergy to fish parvalbumins: studies on the cross-reactivity of allergens from 9 commonly consumed fish.
Van Do T, Elsayed S, Florvaag E, Hordvik I, Endresen C.
Source
Allergy Research Group, Laboratory of Clinical Biochemistry, Haukeland University Hospital, Bergen, Norway.
Abstract
Background: Fish-hypersensitive patients can probably tolerate some fish species while being allergic to others.
Objective: To determine the allergenic cross-reactivity between 9 commonly edible fish: cod, salmon, pollack, mackerel, tuna, herring, wolffish, halibut, and flounder.
Methods: Sera from 10 patients allergic to fish and rabbit antisera against 3 parvalbumins (Gad c 1, Sal s 1, and The c 1) were used. Cross-reactivity was investigated by SDS/PAGE and IgE immunoblotting, IgG ELISA, IgE ELISA inhibition, and skin prick test (SPT).
Results: Cod (Gad c 1), salmon (Sal s 1), pollack (The c 1), herring, and wolffish share antigenic and allergenic determinants as shown by immunoblots and IgE ELISA, whereas halibut, flounder, tuna, and mackerel displayed lowest cross-reactivities. The highest mean IgE ELISA inhibition percent of 10 sera was obtained by Gad c 1, followed by The c 1, herring, Sal s 1, wolffish, halibut, flounder, tuna, and mackerel with the least inhibition. Nine of the 10 patients showed positive SPT to cod, salmon, and pollack; 8 patients reacted to recombinant (r) Sal s 1. Positive SPTs to rGad c 1 and rThe c 1 were demonstrated in 1 patient.
Conclusion: Gad c 1, Sal s 1, The c 1, herring, and wolffish contained the most potent cross-reacting allergens, whereas halibut, flounder, tuna, and mackerel were the least allergenic in the current study. The latter could probably be tolerated by some of the tested patients.

References:
1. Sicherer SH. Clinical implications of cross-reactive food allergens. J Allergy Clin Immunol 2001; 108:881-890.

2. de Martino, M; Novembre, E; Galli, L; de Marco, A; Botarelli, P; Marano, E; Vierucci, A. Allergy to different fish species in cod-allergic children: In vivo and in vitro studies. J Allergy Clin Immunol; 1990; 86: 909-914.

Kuehn A1, Swoboda I2, Arumugam K1, Hilger C1, Hentges F3.
Fish Allergens at a Glance: Variable Allergenicity of Parvalbumins, the Major Fish Allergens. Front Immunol. 2014 Apr 22;5:179. eCollection 2014.
Abstract
Fish is a common trigger of severe, food-allergic reactions. Only a limited number of proteins induce specific IgE-mediated immune reactions. The major fish allergens are the parvalbumins. They are members of the calcium-binding EF-hand protein family characterized by a conserved protein structure. They represent highly cross-reactive allergens for patients with specific IgE to conserved epitopes. These patients might experience clinical reactions with various fish species. On the other hand, some individuals have IgE antibodies directed against unique, species-specific parvalbumin epitopes, and these patients show clinical symptoms only with certain fish species. Furthermore, different parvalbumin isoforms and isoallergens are present in the same fish and might display variable allergenicity. This was shown for salmon homologs, where only a single parvalbumin (beta-1) isoform was identified as allergen in specific patients. In addition to the parvalbumins, several other fish proteins, enolases, aldolases, and fish gelatin, seem to be important allergens. New clinical and molecular insights advanced the knowledge and understanding of fish allergy in the last years. These findings were useful for the advancement of the IgE-based diagnosis and also for the management of fish allergies consisting of advice and treatment of fish-allergic patients.

Clin Exp Allergy. 2013 Jul;43(7):811-22. doi: 10.1111/cea.12117.
Identification of enolases and aldolases as important fish allergens in cod, salmon and tuna: component resolved diagnosis using parvalbumin and the new allergens.
Kuehn A1, Hilger C, Lehners-Weber C, Codreanu-Morel F, Morisset M, Metz-Favre C, Pauli G, de Blay F, Revets D, Muller CP, Vogel L, Vieths S, Hentges F.
Author information
1Laboratory of Immunogenetics and Allergology, CRP-Santé, L-1526 Luxembourg, Luxembourg.
Abstract
Background: The majority of fish-allergic patients are sensitized to parvalbumin, known to be the cause of important IgE cross-reactivity among fish species. Little is known about the importance of fish allergens other than parvalbumin.
Objective: The aim of this study was to characterize hitherto undefined fish allergens in three commonly consumed fish species, cod, salmon and tuna, and to evaluate their importance for in vitro IgE-diagnosis in addition to parvalbumin and fish gelatin.
Methods: Sixty-two patients were diagnosed by clinical history, skin prick tests and specific IgE to fish extracts. Two new fish allergens from cod, salmon and tuna were identified by microsequencing. These proteins were characterized by immunoblot, ELISA and mediator release assay. Purified parvalbumin, enolase, aldolase and fish gelatin were used for quantification of specific IgE in ELISA.
Results: Parvalbumin and two other allergens of 50 and 40 kDa were detected in IgE-immunoblots of cod, salmon and tuna extracts by most patient sera. The 50 and 40 kDa proteins were identified as beta-enolase and fructose-bisphosphate aldolase A respectively. Both purified enzymes showed allergenic activity in the mediator release assay. Indeed, 72.6% of the patients were sensitized to parvalbumin, 20% of these had specific IgE to salmon parvalbumin only. IgE to enolases were found in 62.9% (0.5-95.0 kUA /L), to aldolases in 50.0% (0.4-26.0 kUA /L) and to fish gelatin in 19.3% (0.4-20.0 kUA /L) of the patients. Inter-species cross-reactivity, even though limited, was found for enolases and aldolases by IgE-inhibition ELISA.
Conclusions and Clinical Relevance: Fish enolase and aldolase have been identified as important new fish allergens. In fish allergy diagnosis, IgE to enolase and aldolase are especially relevant when IgE to parvalbumin are absent.

Cross reactivity between fish and shellfish.
[Article in Spanish]
Torres Borrego J1, Martínez Cuevas JF, Tejero García J.
Author information
1Unidad de Alergología y Neumología Pediátrica. Departamento de Pediatría. Hospital Universitario Materno-Infantil Reina Sofía. Córdoba. Spain.
Abstract
In Spain, fish allergy represents 18 % of all cases of food allergy in children while reactions caused by crustacea and mollusks account for 3.8 % and 1.6 % respectively. Cross-reactivity is defined as the recognition of distinct antigens by the same IgE antibody, demonstrable by in vivo and in vitro tests, which clinically manifests as reactions caused by antigens homologous to different species. Subclinical sensitization can also occur, giving rise to patients sensitized to particular fish or shellfish but who do not present symptoms on consumption.Cod and shrimp have been the models used to study allergy to fish and crustacea respectively. The major allergens responsible for cross-reactivity among distinct species of fish and amphibians are proteins that control calcium flow in the muscular sarcoplasm of these animals, called parvalbumins, with a molecular weight of approximately 12 kD and an isoelectric point of 4.75, resistant to the action of heat and enzymatic digestion. Recently, recombinant carp parvalbumin has been reproduced, confirming that this allergen contains 70 % of the IgE epitopes present in natural extract of cod, tuna and salmon, which makes it a valid tool in the diagnosis of patients with fish allergy. Moreover, this recombinant allergen could constitute the basis for the development of immunotherapy against food allergy. In the case of shellfish, a non-taxonomic group that includes crustacea and mollusks, the major allergen is tropomyosin, an essential protein in muscle contraction both in invertebrates and vertebrates. In invertebrates, tropomyosins, which have a molecular weight of between 38 and 41 kD, show great homology in their amino acid sequence and are the panallergens responsible for cross-reactions between crustacea, insects, mites, nematodes, and different classes of mollusks. It is estimated that 50 % of individuals allergic to some type of fish are at risk for reacting to a second species, while those allergic to some type of crustacea present a risk of 75 % due to the greater similarity among tropomyosins than among parvalbumins. In addition, up to 40 % of patients sensitized to one or more fish do not present symptoms on consuming other species, the best tolerated of which belong to the Scombroidea family (which includes tuna).

Sincerely,
Phil Lieberman, M.D.

AAAAI - American Academy of Allergy Asthma & Immunology