Not every seafood “allergy” is allergy!

1. Mini-Symposium - International Food Allergy Symposium
Not every seafood “allergy” is allergy!
Sami L. Bahna, MD, DrPH
Allergy & Immunology Section, Louisiana State University Health, Shreveport, Louisiana
A R T I C L E I N F O
Article history:
Received for publication March 22, 2016.
Received in revised form April 15, 2016.
Accepted for publication April 18, 2016.
Introduction
The increasing production and consumption of seafood has been
associated with increased adverse reactions that can be either
immune-mediated allergic reactions or nonimmunologic adverse
reactions; both may present with similar symptoms and often may
be misdiagnosed as an allergy. The objective of this report is to
describe various types of adverse reactions that can occur after
eating seafood and may be misdiagnosed as seafood allergy.
Classification of Seafood
Seafood is a general term that refers to any edible aquatic animal,
which includes thousands of different species. For the purpose of
this presentation, seafood will be limited to the 2 commonly
consumed groups, namely, fin fish and shellfish.1
Fin fish consists of
2 main subgroups: bony (>95%) and cartilaginous. Shellfish also
consists of 2 main subgroups: mollusks and crustaceans. Seafood
consumption has been popular worldwide because of its palat-
ability and promoted nutritional advantages. The largest consumer
is China, followed by Japan and the United States. In 2009, Ameri-
cans ate an average of 15.8 lb of fin fish and shellfish per capita, with
shrimp being the top choice at 4.1 lb.2
Seafood Allergy
Seafood is 1 of the top 8 allergens attributable to IgE-mediated
reactions and is a common cause of food-induced anaphylaxis.
Fin fish and shellfish have multiple, different allergens that are
distinct from one another. Cross-reactivity between fin fish and
shellfish is exceedingly rare (Table 1).1,3
There are multiple types of
the major allergens parvalbumin in fish and of tropomyosin in
shellfish. Allergenicity in these species is affected by processing and
tends to increase by heating and decrease with canning, gastric
acidity, and enzymes.
The allergenicity of crustaceans appears to be higher than of
mollusks, followed by fish, although there are limited high-quality
studies reporting this. In the United States, a telephone survey
revealed that 2% to 3% self-reported the presence of seafood allergy
(2.2% to shellfish and 0.6% to fish).4
Shellfish allergy in this sample
was reported to be much less prevalent in children than in adults
(0.5% vs 2.5%). In a decreasing frequency, the causative triggers of
reported allergy to shellfish were shrimp, crab, lobster, clam, oyster,
and mussel. In an international survey administered to 17,280
adults from 15 countries, symptoms attributed to seafood ingestion
were reported to be caused by shrimp in 2.3%, oyster in 2.3%, and
fish in 2.2%.5
The variation may reflect differences in regional
consumptions.
Most hypersensitivity reactions to seafood are IgE mediated and
are associated with rapid onset of symptoms, including gastroin-
testinal, cutaneous, respiratory, or multiple organ system symp-
toms, consistent with anaphylaxis. They are generally more severe
than the reactions to most other food allergens. Sensitization and
provocation can occur by ingestion, skin contact,6
or inhalation.7
Airborne allergen exposures are particularly abundant in the vi-
cinity of cooking seafood by boiling, steaming, or frying. Exposure
by skin contact can occur more in occupational settings, and the
manifestations are commonly cutaneous in the form of urticaria or
allergic contact dermatitis but can be respiratory or systemic.
Occupational asthma in seafood processers (eg, snow crab) has also
been described.
Tropomyosin is the major shellfish allergen and is responsible
for cross-reactivity between members of the shellfish family,
particularly within the crustacean family. Newly described aller-
gens and subtle differences in the structures of tropomyosin among
different species of shellfish could account for the discrepancy
between in vitro cross-antigenicity and clinical cross-allergenicity
in patients who may be sensitized to certain allergens, yet not
manifest clinical reactivity on ingestion of these cross-reactive
items.
The diagnosis of fin fish or shellfish allergy is primarily based on
the type, onset, and course of symptoms, supported by a positive
Reprints: Sami L. Bahna, MD, DrPH, Allergy & Immunology Section, Louisiana State
University Health, 1501 Kings Hwy, Shreveport, LA 71130-3932; E-mail: SBAHNA@
lsuhsc.edu.
Disclosures: Author has nothing to disclose.
Previous Presentation: Presented during the International Food Allergy Sympo-
sium by the American College of Allergy, Asthma & Immunology; November 5,
2015; San Antonio, Texas.
Contents lists available at ScienceDirect
http://dx.doi.org/10.1016/j.anai.2016.04.018
1081-1206/Ó 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Ann Allergy Asthma Immunol 117 (2016) 458e461

2. allergy skin test results or measurement of specific IgE level against
the item in question. Unless the reaction was life-threatening,
confirmation may require an oral food challenge test using the
same offending seafood item (and possibly preparation). The
physician should be aware that the patient may react to only certain
species of fin fish or shellfish or when it is prepared in a certain
method. Some patients my react to certain parts but not another,
such as the shell but not the meat, white muscle but not dark
muscle, or roe (caviar) but not the fish muscle.1
Management of seafood allergy is to practice strict elimination,
which in highly allergic individuals may include avoidance of
touching or being close to cooking vapors and having available self-
injectable epinephrine. Specific immunotherapy or other treatment
for seafood allergy is not currently available and will require the
development of effective and safe protocols, particularly for highly
allergic individuals.
Adverse Reactions to Foreign Substances in Seafood
It is common for adverse reactions without an immunologic
basis to food to be erroneously described or diagnosed as allergy
(Table 2). A typical clinical hypersensitivity reaction may occur not
to the seafood protein but to a foreign substance, such as another
hidden food protein, an additive, natural rubber latex, or a parasite.
The reaction may be nonimmunologic and caused by food
poisoning or attributable to infectious agents or a toxin contained
in the seafood. A large variety of toxins can be produced in fish or
shellfish by contaminating bacteria in items that are not properly
handled and stored. The specific toxins would depend on the
contaminating microorganism and the seafood species.
Allergy to Anisakis simplex
Anisakis simplex is a nematode that infests sea mammals.
Various species of seafood can act as intermediate hosts for the
larvae, which are approximately 2 cm long in size. Certain regions,
particularly Japan and Spain (45% of hake in Spain), are notable for
high rates of infestation.8
Larvae are susceptible to heating (>60C
for 10 minutes) or freezing (À20C for 48 hours), but their allergens
are resistant to cooking, freezing, and partially to digestion. Live
larvae in raw or undercooked seafood ingested by human are
usually ejected by vomiting and diarrhea or destroyed by digestion.
Ingested larvae not killed by one of these processes can attach to
mucosa and form granulomas. In addition to gastrointestinal
symptoms, systemic reactions may occur.9,10
Anisakis infection
should be considered in patients highly suspected of having had an
adverse reaction to seafood but who have had negative allergy test
results to seafood. Skin testing and specific IgE to the parasite itself
have inconsistent reliability.11
There is no effective anti-Anisakis
drug. Diagnosis and treatment are made by endoscopic confirma-
tion and surgical removal of the granulomas.
Adverse Reactions to Infectious Agents That Contaminate
Seafood
Clostridium botulinum
Foodborne botulism occurs on ingestion of food contaminated
by toxin secreted by Clostridium botulinum. The toxin is resistant to
freezing but destroyed by boiling for 10 minutes. Initial manifes-
tations of botulism are gastrointestinal symptoms, such as nausea,
vomiting, and diarrhea. Other initial symptoms can include dry
mouth, diplopia, blurred vision, and photophobia caused by loss of
pupillary light reflex. A symmetric descending flaccid paralysis may
occur that can potentially lead to respiratory failure.
Botulism is more likely to occur with certain preparations
characteristic of particular cultures and geographic locations, such
as the whale meat mukluk in the Alaskan and Canadian Arctic,
rakish in Norway, salted gray mullet feseikh in Egypt, salted evis-
cerated whitefish kapchunka in Israel and New York City, uncooked
salmon ashbal in Iran, fermented fish preserved in rice izushi in
Japan, and imported vacuum-packed whitefish in Europe.12
Staphylococcus aureus
Staphylococcus aureus can contaminate food during handling by
an infected person and the food then left at room temperature for
some time. The produced enterotoxin when ingested causes vom-
iting, abdominal cramps, and diarrhea usually within 24 hours of
ingestion.
Vibrio vulnificus
Vibrio vulnificus is part of the natural flora of warm coastal
waters worldwide and has been isolated from a variety of seafood,
including fish, shrimp, oysters, and clams. Consumption of
contaminated raw or undercooked seafood can result in fulminant
sepsis with ecchymoses and bullae.13
Illness typically begins within
1 to 3 days but may be delayed for 7 days. Although illness is rare, V
vulnificus in human is the leading cause of death related to seafood
consumption in the United States, particularly in immunocom-
promised patients or associated liver disease.13
Diagnosis of V vul-
nificus infection is by microbiologic culture. Treatment includes
antibiotics (doxycycline plus a cephalosporin) and supportive care.
Norovirus (Norwalk Virus)
Norovirus infection is the most common cause of acute gastro-
enteritis in the United States and is generally referred to as the
misnomer of stomach flu.14
Symptomatic illness usually occurs af-
ter ingestion of contaminated raw food, including seafood. After an
incubation period of 24 to 48 hours after ingestion, gastrointestinal
symptoms, such as nausea, vomiting and watery diarrhea, can
occur. Resolution of symptoms usually occurs within 1 to 3 days.
Scombroid Poisoning (Histamine Fish Poisoning)
Bacterial contamination from mishandling of fish results in
production of heat-resistant toxic substances, including histamine,
Table 1
Seafood Allergens
Allergen Finish Shellfish
Major Parvalbumins (numerous) Tropomyosins (numerous)
Other Aldolase
Enolase
Vitellogenin
Arginine kinase
Myosin light chain
Sarcoplasmic binding protein
Table 2
Adverse Reactions to Foreign Substances in Seafood
Hypersensitivity Poisoning
Contamination
Another food
Natural rubber latex
Additives
Parasite
Anisakis simplex
Chemicals
Infectious agents or toxins
Clostridium botulinum toxin
Staphylococcus aureus enterotoxin
Vibrio vulnificus
Norovirus
Specific seafood-associated toxins:
Scombroid poisoning (histamine, scombrotoxin)
Pufferfish poisoning (tetrodotoxin)
Neurotoxin poisoning (saxitoxin)
Ciguatera poisoning (ciguatoxin, maitotoxin,
scaritoxin, gambieric acid)
Azaspiracid poisoning
S.L. Bahna / Ann Allergy Asthma Immunol 117 (2016) 458e461 459

3. scombrotoxin, or other vasoactive amines (putrescine and cadav-
erine).15,16
The spoiling bacteria can be Proteus, Escherichia coli,
Salmonella, Morganella morganii, Enterobacter aerogenes, Raoultella
planticola, and Hafnia alvei. Histidine decarboxylase in these bac-
teria acts on histidine in fish muscle and generates histamine,
which can then be ingested. It has been proposed that a specific
scombrotoxin, cis-urocanic acid, produced from histidine decar-
boxylation may also directly degranulate mast cells, although there
is mixed evidence to substantiate this theory.15,17
The most commonly susceptible fish are in the Scombridae and
Scomberesocidae families, which include tuna, mackerel, blue fish,
anchovies, and herring. Affected fish may acquire a bitter and
peppery taste, although this may occur in normally tasting items as
well. Fish can be screened by a histamine detector, and there is a
permissible limit of less than 50 mg/kg in the United States and 100
to 200 mg/kg in Europe.18
According to the records of North Carolina Department of Health,
22 cases of histamine fish poisoning were reported during 8
months.19
The affected fish was consumed in restaurants in 21 cases
and at home in 1 case with fish that was kept unfrozen in the trunk
of a car for several hours. All patients ate tuna, in the form of a burger
in 18 (82%), salad in 2, and filet in 2. It was discovered that the
implicated fish was subjected to several freezing and thawing cycles
and that there were some irregularities in the storing temperature.
Pufferfish Poisoning
Pufferfish tetrodotoxin can be present in porcupinefish, globe-
fish, blowfish, mola, ocean sunfish, triggerfish.18,20
In 2014, an
outbreak from imported dried pufferfish occurred in Minneap-
olis.21
The toxin is produced outside the fish bodies by bacteria and
accumulates in fish liver, gonads, and skin. In Japan, fugu (prepared
from the flesh of pufferfish) is required to be prepared by chefs
trained and certified to be devoid of the potentially poisonous
parts. Within minutes to hours, individuals develop nausea, dizzi-
ness, weakness, paresthesias, loss of reflexes, hypotension, motor
paralysis, and respiratory failure.
Seafood Neurotoxin
Seafood neurotoxins (saxitoxin and its derivatives) are produced
by cyanobacteria in fresh water and by dinoflagellates in
seawater.22
Mollusks are more commonly implicated than crusta-
ceans. Fish (pufferfish) may be affected as well. Florida monitors the
neurotoxin concentrations in pufferfish along its east coast. Afflic-
ted persons develop paresthesia and numbness within less than 30
minutes of ingestion, first in the mouth and then in the face and
neck, followed by drowsiness, motor incoordination, and muscular
weakness that may progress to respiratory paralysis.
Ciguatera Fish Poisoning
The dinoflagellate Gambierdiscus toxicus in blue-green algae can
infect reef fish and produce ciguatoxin, maitotoxin, scaritoxin, and
gambieric acid.23
It is endemic in the Pacific and Caribbean regions.
Implicated fish include barracuda, amberjack, grouper, snapper,
and moray eel. In Hong Kong, outbreaks occurred every few years,
and the dominant fish switched from snapper to grouper.24
The toxins are heat stable and lipid soluble and are more in the
fish head, viscera, roe, and skin. Within 1 to 4 hours of consuming
the affected fish, symptoms develop as gastrointestinal (vomiting,
diarrhea, colic), neurologic (paresthesia, numbness, pruritus,
myalgia, arthralgia), and cardiovascular (bradycardia, hypotension).
Gastrointestinal symptoms subside within days of rehydration.
Cardiovascular symptoms respond to atropine and dopamine.
Neurologic symptoms may persist for weeks or months and may
respond to amitriptyline, nifedipine, gabapentin, or pregabalin.25
Azaspiracid Shellfish Poisoning
Azaspiracids are polyether marine toxins possibly produced by
dinoflagellate and accumulate in various shellfish.26
Eating the
affected shellfish causes severe acute gastrointestinal symptoms
that persist for 2 to 3 days.
Recognition and Management of Seafood Poisoning
Seafood poisoning may be underdiagnosed, particularly when
mild or when misdiagnosed or self-attributed as an allergy and a
proper history is not undertaken to differentiate a likely mecha-
nism of action. The presence of similar symptoms in other in-
dividuals who shared the same meal, absence of prior reactions to
the same seafood, and its subsequent tolerance without symptoms
should favor a toxic reaction. The level of suspicion for toxic re-
actions should be higher in regions with seasonal algal blooms and
high levels of biotoxins or toxic algae. Except in scombroid
poisoning, the toxin in most of these toxic syndromes does not alter
the taste or appearance of the seafood item, and it is not inactivated
by ordinary cooking. The most likely toxin will depend on the
seafood species (Table 3).
Treatment of these toxic syndromes is mainly supportive,
including respiratory support in patients with pending respiratory
failure. In acute cases, gastric emptying and administration of
activated charcoal have been recommended to prevent further
absorption of the toxins.
Conclusion
Reactions to seafood can be allergic in nature to a known
allergen in fin fish or shellfish or can be attributable to something
other than seafood protein, such as contamination by other food
allergens, the seafood parasite A simplex, additives, natural rubber
latex, chemical contamination, or seafood-associated toxins by
bacterial action. Clinicians are advised to take a careful history and
not assume allergy as the default mechanism for a reported adverse
reaction to a seafood item. A detailed history should be obtained
about the nature and timing of the reaction, the type of item
involved, whether other members of the dining party also fell ill,
Table 3
Most Likely Toxins According to the Seafood Species and Common Symptoms
Finfish or Shellfish Toxin Symptoms
Scombridae, scomberesocidae (tuna, mackerel, blue fish) Histamine, scombrotoxin Within 0.5e4 hours: flushing, pruritus, urticaria,
headache, dizziness, gastrointestinal, anaphylaxis.
Reef fish (amberjack, barracuda, moray eel) Ciguatoxins by Gambierdiscus toxicus Within 1e6 hours: gastrointestinal, paresthesia,
respiratory paralysis.
Pufferfish (blowfish, globefish, mola, ocean sunfish,
porcupinefish, triggerfish)
Tetrodotoxin by certain bacteria Within minutes to a few hours: gastrointestinal,
neurologic.
Crustacea (crab, crayfish, lobster, prawn, shrimp) Toxin by Vibrio parahaemolyticus Within 12e48 hours: gastrointestinal, fever, headache.
Mollusks (abalone, clam, cuttlefish, mussel, octopus, oyster,
scallop, snail, squid)
Saxitoxin by cyanobacteria or Gambierdiscus
toxicus
Within 30 minutes: by aerosolization: conjunctivitis,
rhinorrhea, cough; by ingestion: vomiting, diarrhea,
paresthesia.
S.L. Bahna / Ann Allergy Asthma Immunol 117 (2016) 458e461460

4. and the patient’s own history of consuming these items. These
inquiries can help differentiate a likely IgE-mediated reaction from
a toxic one.
Whenever allergy tests are performed and the results are
negative for the suspected seafood item, the physician should
consider A simplex allergy if the seafood is from a highly infested
region or of seafood-associated toxins or botulism in individuals
with neurologic symptoms or when multiple consumers are
affected. If the fish tasted spoiled or is from a typical species,
scombroid poisoning should be considered.
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