Not every seafood allergy is allergy

Attilio Boner
University of
Verona, Italy
attilio.boner@univr.it
Introduction
Classification of Seafood
Seafood Allergy
Adverse Reactions to Foreign
Substances in Seafood
Adverse Reactions to Infectious Agents
that Contaminate Seafood
Recognition and Management
of Seafood Poisoning
Conclusion
Not every seafood “allergy” is allergy !

Bahna SL. Ann Allergy Asthma Immunol. 2016;117(5):458-461.
may present with similar symptoms
and often may be misdiagnosed as an allergy.
consumption of seafood adverse reactions
immune-mediated allergic reactions or nonimmunologic adverse

•Seafood is a general term that refers to any edible aquatic animal,
which includes thousands of different species.
The 2 commonly consumed groups:
fin fish and shellfish
bony (>95%) and cartilaginous.
mollusks and crustaceans
Classification of Seafood

Stephen JN, CEA 2017;47:300-312
• Reported prevalence ranges from self-reported rates of 5%
to challenge-proven rates of 0.1%.
• From current available data, it appears that there are significant
regional differences in rates of bony fish allergy, with higher
reported rates of bony fish allergy in regions with high consumption.
• Across European cities, approximately 0.2% of the population
is reported to be allergic to some type of fish.
• The populations of Portugal, Spain and Scandinavian are likely to be
the highest consumers of fish in Europe.
Fish allergy epidemiology: How common is it?

International prevalences of reported food allergies and
intolerances: comparisons arising from the European
Community Respiratory Health Survey (ECRHS)
1991-1994. Woods RK, Eur J Clin Nutr. 2001;55:298e304.
European Community
Respiratory Health Survey
(ECRHS).
17280 adults aged 20-44 y
from 15 countries
% adults reporting symptoms
with ingestion of
3 –
2 –
1 –
0 -
2.8%
shrimp
2.3%
oyster fish
2.2%

Sharp MF, Clin Rev Allergy Immunol. 2014;46(3):258-71.
Seafood allergy: Demographics and Prevalence
•In Europe, most of the populations based prevalence studies come from
Spain, Portugal, and the Scandinavian countries.
•Fish allergy in Norway is almost as common as allergy to egg among children,
while fish allergy is more common in children from Finland.
•In Spain fish allergy began predominantly before the second year of life.
•Over one third of sensitized children reported multiple fish allergy, most
probably due to the major cross-reactive fish allergen parvalbumin (Gad c 1).
•However, the majority of children demonstrated monosensitivity to one
or the other fish species.
•Children usually do not outgrow this type of food allergy.

Seafood allergy: Demographics and Prevalence
•In Europe, most of the populations based prevalence studies come from
Spain, Portugal, and the Scandinavian countries.
•Fish allergy in Norway is almost as common as allergy to egg among children,
while fish allergy is more common in children from Finland.
•In Spain fish allergy began predominantly before the second year of life.
•Over one third of sensitized children reported multiple fish allergy, most
probably due to the major cross-reactive fish allergen parvalbumin (Gad c 1).
•However, the majority of children demonstrated monosensitivity to one
or the other fish species.
•Children usually do not outgrow this type of food allergy.
populations with high consumption of anchovy and herring
species (rich in parvalbumin) might be of increased risk
of developing fish 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.
Mourad AA, Bahna SL. Fish-allergic patients may be able to eat fish.
Expert Rev Clin Immunol. 2015;11:419e430.
•Cross-reactivity between fin fish and shellfish is exceedingly rare.
Woo CK, Bahna SL. Not all shellfish “allergy” is allergy! Clin Transl Allergy.2011;1:3.
≠
Seafood allergy: Allergens

Finfish
*
* 90% of fish allergic patients reacts to this allergen,
present also in frogs
Allergy. 2004;59:653
Collagen
Seafood Allergens
≠

• The major heat-stable pan-fish allergen,
parvalbumin (PV), has been identified and
characterized for numerous fish species.
• There are very few reports of allergic reactions
to cartilaginous fish despite widespread consumption.
• PV consists of two distinct protein lineages, α and β.
• The α-lineage of this protein is predominant in muscle
tissue of cartilaginous fish (Chondrichthyes), while
β-PV is abundant in muscle tissue of bony fish (Osteichthyes).
• The low incidence of allergic reactions to ingested rays and sharks is
likely due to the lack of molecular similarity, resulting in reduced
immunological cross-reactivity between the two PV lineages.
Stephen JN, CEA 2017;47:300-312
Fish allergens
α
β
≠

Quantification of major allergen parvalbumin in 22 species of fish
by SDS-PAGE. Kobayashi Y, Food Chem. 2016;194:345-53.
•The allergenicity of fish is considered to correlate with the content of
parvalbumin, the major fish allergen.
•In this study application of the Sodium Dodecyl Sulphate - PolyAcrylamide
Gel Electrophoresis (SDS-PAGE) method to 22 species of fish revealed a
marked variation in parvalbumin content among fish.
•The parvalbumin content was found to be higher in
dorsal white muscle than in ventral white muscle,
in rostral part of white muscle than in caudal part
of white muscle and in white muscle than in dark muscle.
Large-sized migratory fish, such as salmon, swordfish and tuna,
were commonly very low in both parvalbumin content
and IgE reactivity.
+
- - --
+++ +++[parvalbumin]

Quantification of major allergen parvalbumin in 22 species of fish
by SDS-PAGE. Kobayashi Y, Food Chem. 2016;194:345-53.
•The allergenicity of fish is considered to correlate with the content of
parvalbumin, the major fish allergen.
•In this study application of the Sodium Dodecyl Sulphate - PolyAcrylamide
Gel Electrophoresis (SDS-PAGE) method to 22 species of fish revealed a
marked variation in parvalbumin content among fish.
•The parvalbumin content was found to be higher in
dorsal white muscle than in ventral white muscle,
in rostral part of white muscle than in caudal part
of white muscle and in white muscle than in dark muscle.
Large-sized migratory fish, such as salmon, swordfish and tuna,
were commonly very low in both parvalbumin content
and IgE reactivity.
+
- - --
+++ +++[parvalbumin]
prick by prick

Comparison of allergenicity and allergens between fish
white and dark muscles. Kobayashi A, Allergy.2006;61(3):357-63.
Heated extracts prepared
from both white and dark
muscles of 5 species of fish
and examined for reactivity
with IgE in fish-allergic
patients by enzyme-linked
immunosorbent assay
(ELISA) and for allergens by
immunoblotting.
Parvalbumin contents in
both white and dark muscles
determined by ELISA using
antiserum against mackerel
parvalbumin.
IgE reactivity of the pooled patient serum and
3 patient sera to the heated extracts
from white and dark muscles of:
sardine (1), yellowtail (2), horse mackerel (3),
red sea bream (4) and Pacific mackerel (5).

Comparison of allergenicity and allergens between fish
white and dark muscles. Kobayashi A, Allergy.2006;61(3):357-63.
Heated extracts prepared
from both white and dark
muscles of 5 species of fish
and examined for reactivity
with IgE in fish-allergic
patients by enzyme-linked
immunosorbent assay
(ELISA) and for allergens by
immunoblotting.
Parvalbumin contents in
both white and dark muscles
determined by ELISA using
antiserum against mackerel
parvalbumin.
IgE reactivity of the pooled patient serum and
3 patient sera to the heated extracts
from white and dark muscles of:
sardine (1), yellowtail (2), horse mackerel (3),
red sea bream (4) and Pacific mackerel (5).
The fish dark muscle
is less allergenic than
the white muscle,
because the same
allergen molecule
(parvalbumin) is
contained at much
lower levels in the
dark muscle than in
the white muscle.

Important variations in parvalbumin content in common
fish species: a factor possibly contributing to variable
allergenicity. Kuehn A, Int Arch Allergy Immunol 2010;153:359
Fish muscle extracts
were separated by SDS-
PAGE and parvalbumin
content was estimated by
densitometric band
quantification.
parvalbumin content ranged from:
 <0.05 mg for tuna,
 0.3-0.7 mg for mackerel,
 1-2.5 mg for salmon, trout and cod
 >2.5 mg per gram raw muscle for
carp, herring, anchovy and redfish
Variability in parvalbumin content is likely
to contribute to the variation in clinical
reactivity to different fish species.

Important variations in parvalbumin content in common
fish species: a factor possibly contributing to variable
allergenicity. Kuehn A, Int Arch Allergy Immunol 2010;153:359
Fish muscle extracts
were separated by SDS-
PAGE and parvalbumin
content was estimated by
densitometric band
quantification.
Variability in parvalbumin content is likely
to contribute to the variation in clinical
reactivity to different fish species.
if a subjects is
allergic to tunna it is
unlekely that he will
be able to tollerate
other fishes
while if he is allergic
to other fishes
(sarde, acciughe) he
may tollerate
tunna ?
parvalbumin content ranged from:
 <0.05 mg for tuna,
 0.3-0.7 mg for mackerel,
 1-2.5 mg for salmon, trout and cod
 >2.5 mg per gram raw muscle for
carp, herring, anchovy and redfish

Missing parvalbumin: implications in diagnostic testing for
tuna allergy. Lim DL, J Allergy Clin Immunol 2005;115:874–875.
Dissection of Thunnus tonggol
(Bleeker) for evaluation of
parvalbumin.
The fish was skinned and torso
sectioned transversely
into 6 portions (left).
Three of these sections,
the (1) rostral, (2) mid, and
(3) caudal portions, were further
divided into 3 parts,
dorsal (D) and ventral (V) white
muscle and middle red meat (right).
Parvalbumin was found
in the white muscle of tuna
and was absent in the red
(+) (-) (+)

Allergy to fish parvalbumins: studies on the cross-
reactivity of allergens from 9 commonly consumed fish.
Van Do T, J Allergy Clin Immunol 2005;116:1314–1320
To determine the allergenic
cross-reactivity between
9 commonly edible fish: cod,
salmon, pollack, mackerel, tuna,
herring, wolffish, halibut, and
flounder
Sera from 10 patients allergic
to fish and rabbit antisera
against 3 parvalbumins
(Gad c 1, Sal s 1, and The c 1)
herring, and wolffish contained the
most potent cross-reacting allergens,
whereas
•halibut, (pesci piatti)
•flounder, (platessa, sogliola)
•tuna, (tonno)
•mackerel (sgombro)
were the least allergenic
in the current study.
The latter could probably be tolerated
by some of the tested patients.

Allergy to fish parvalbumins: studies on the cross-
reactivity of allergens from 9 commonly consumed fish.
Van Do T, J Allergy Clin Immunol 2005;116:1314–1320
To determine the allergenic
9 commonly edible fish: cod,
salmon, pollack, mackerel, tuna,
herring, wolffish, halibut, and
flounder
Sera from 10 patients allergic
to fish and rabbit antisera
against 3 parvalbumins
(Gad c 1, Sal s 1, and The c 1)
herring, and wolffish contained the
most potent cross-reacting allergens,
whereas
•halibut, (pesci piatti)
•flounder, (platessa, sogliola)
•tuna, (tonno)
•mackerel (sgombro)
were the least allergenic
in the current study.
The latter could probably be tolerated
by some of the tested patients.
Anchovies also are rich
in parvalbumins

• In vitro or SPT cross-reactivity is not always predictive of in vivo
cross-sensitization and actual clinical allergy.
• Individuals sensitive to cod were also sensitized to salmon, whereas
Halibut (pesci piatti), flounder (passera, platessa), tuna and mackerel (sgombro) were found
to be the least cross-reactive.
• Allergies to cartilaginous fish are rarely reported, possibly due to
their low incidence, despite the fact that they are commonly consumed.
• While cross-reactions to both α- and β-PV were observed,
β-PV demonstrated significantly more IgE binding than α-PV.
Patterns of clinical cross-reactivity and tolerance
across fish species in fish-allergic individuals
Stephen JN, CEA 2017;47:300-312
β-PV > α-PV
β-PV

•Heating fish denatures collagen to form gelatin, which is water
soluble and can be easily digested by gastrointestinal enzymes.
•However, collagen in raw fish meat is water insoluble.
•The T-cell epitopes of collagen are likely to be resistant to digestion
by proteolytic enzymes; therefore, collagen can potentially induce
sensitization.
Fish collagen is an important panallergen
in the Japanese Population
Kobayashi Y. Allergy 2016;71:720-723
sashimi
or sushi

 Parvalbumin and intact
collagen purified from
the muscle and skin.
 Sera from 36 patients with
immediate hypersensitivity
reactions such as urticaria,
dyspnoea and anaphylactic
shock after ingestion
of raw and cooked fish.
 Pooled serum from
10 healthy volunteers.
% of Japanese patients with
fish allergy and sIgE for
50%
collagen paralbumin
50 –
40 –
30 –
20 –
10 –
00
44%
mackerel
sgombro

Cross-reactivity of Pacific mackerel
collagen to heated crude extracts
from 22 species of fish by the
competitive ELISA inhibition test.
Collagen is another panallergen of fishes

• Absorption of allergen across mucosa can be rapid,
and codfish proteins have been identified in the
sera of healthy individual within 10 min of consumption.
• The biological activity of the allergens was lost at pH 2.0,
but at pH 3.0, the protein patterns and
histamine-releasing capacity of the proteins
were maintained up to 2 h post-digestion.
• The increased pH was a result of antacid medication
leading to incomplete digestion and rapid uptake
of the allergens.
+
+
+
+
+
+
Changes in allergenicity related to exposure
Stephen JN, CEA 2017;47:300-312

•Tropomyosin is the major shellfish thermostable
allergen and is responsible for cross-reactivity
between members of the shellfish family,
particularly within the crustacean family.
•Newly described allergens 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.

Sensitization pattern of crustacean-allergic individuals
can indicate allergy to molluscs
Vidal C, Allergy 2015;70:1493–1496
 31 patients with anaphylaxis
to crustaceans
(14 with mollusc allergy
and 17 with mollusc tolerance).
 SPTs, sIgEs and SDS-PAGE
immunoblotting.
Patients with mollusc allergy
presented more frequently
(+) SPTs to molluscs
and
higher sIgE titles in response
to both molluscs and
crustaceans.
only
+

Vidal C, Allergy 2015;70:1493–1496
Positive likelihood ratios for the
identification of mollusc allergy
9 –
8 –
7 –
6 –
5 –
4 –
3 –
2 –
1 –
0
10 –
4.3
11 –
10.9
Shrimp-sIgE
of 1.57 kUA/l
rPen a1-sIgE
of 4.38 kUA/l
 31 patients with anaphylaxis
to crustaceans
(14 with mollusc allergy
and 17 with mollusc tolerance).
 SPTs, sIgEs and SDS-PAGE
immunoblotting.
rPen a 1
Tropomyosin,
Shrimp

Vidal C, Allergy 2015;70:1493–1496
•This study shows that patients with crustacean anaphylaxis and MA and
patients with isolated crustacean anaphylaxis (i.e.MT) represent two
different populations in clinical and immunological terms.
•According to our results, SPTs or prick by prick tests positive
to molluscs (clam, mussel, octopus or squid) indicate a risk
of reacting against mollusc ingestion in patients with crustacean anaphylaxis.
•In contrast, patients with SPTs positive to shrimp alone are less likely
to develop Mollusc Allergy.
•Likewise, patients with MA showed higher sIgE concentrations to molluscs
than did patients with MT.
•These results are consistent with a role of tropomyosin in Mollusc Allergy.

In vivo diagnosis with purified tropomyosin in mite
and shellfish allergic patients
Lopez-Matas MA. Ann Allergy Asthma Immunol 2016;116:538-543
850 patients
Mite allergic patients (M)
Shellfish allergic
patients (S)
Mite- and shellfish
allergic patients (MS) MITE
40 –
30 –
20 –
10 –
0
% patients with (+) SPT for tropomyosin
28.6%
2.7%
38.5%
SHELLFISH MITE AND
SHELLFISH
PATIENTS ALLERGIC to

850 patients
Mite allergic patients
patients
allergic patients MITE
40 –
30 –
20 –
10 –
0
28.6%
2.7%
38.5%
SHELLFISH MITE AND
SHELLFISH
Tropomyosin does not seem
to be a relevant mite
allergen in Spain, which also
holds true for other
European countries.
Moreover, in our population,
tropomyosin is not a
shellfish major allergen,
and it seems evident that
other shrimp and shellfish
allergens have to be
considered.

850 patients
patients
40 –
30 –
20 –
10 –
0
28.6%
2.7%
38.5%
SHELLFISH MITE AND
SHELLFISH
The group MS had the
highest prevalence to
tropomyosin sensitization
(38.5%), suggesting
that this value is
correlated with the
mites and shellfish
tropomyosins.

850 patients
patients
40 –
30 –
20 –
10 –
0
28.6%
2.7%
38.5%
SHELLFISH MITE AND
SHELLFISH
we can hypothesize that
in group MS the first
sensitizer were mites,
and after a period these
patients developed
allergy to shellfish.
1°
2°

Seafood allergy in children: a descriptive study.
Turner P, Ann Allerg Asthma Immunol 2011;106:494–501
167 children with
a history of definite
clinical reaction
to seafood and/or
positive food
challenge
•Over 50% of crustacean-allergic children
could tolerate non-crustacean fish.
•Sensitization to other fish species was very
common in fish-allergic children, with one
third reporting clinical reactions to at least
two species;
•16% developed symptoms to fish vapours.
•In children with allergy to tuna and/or
salmon, at least 21% were able
to tolerate the fish in a canned form.

Seafood allergy in children: a descriptive study.
Turner P, Ann Allerg Asthma Immunol 2011;106:494–501
167 children had a
history of definite
clinical reaction
to seafood and/or
positive food
challenge
•Over 50% of crustacean-allergic children
could tolerate non-crustacean fish.
•Sensitization to other fish species was very
common in fish-allergic children, with one
third reporting clinical reactions to at least
two species;
•16% developed symptoms to fish vapours.
•In children with allergy to tuna and/or
salmon, at least 21% were able
to tolerate the fish in a canned form.
consumption
of canned fish
was associated
with a reduction
in SPT size in
most patients,
implying that this
may have resulted
in the induction
of tolerance
in these patients

Cross-reactivity to fish and chicken meat:
a new clinical Syndrome
Kuehn A, Allergy 2016; 71:1772–1781.
 Patients with food
allergy to fish and
chicken meat (n = 29) or
chicken meat only (n = 7)
without sensitization
to hen’s eggs
•Chicken parvalbumin and
two new allergens, aldolase
and enolase, were identified
at 12, 40, and 50 kDa, respectively.
•They were recognized by sIgE
of 61%, 75%, and 83%
of all patient sera which were
in the majority of the cases
(+) for the fish homologues as well.

Cross-reactivity to fish and chicken meat:
a new clinical Syndrome
Kuehn A, Allergy 2016; 71:1772–1781.
 We identified 3 new chicken allergens, parvalbumin (Gal d 8), enolase
(Gal d 9), and aldolase (Gal d 10) and could show that these allergens,
which have homologues in fish, are responsible for the clinical
cross-reactivity between fish and chicken meat.
 We demonstrated different allergen contents in chicken breast, leg, and
wing samples leading to the conclusion that these tissues have
a variable allergenicity, not only for patients with food allergy
to fish and chicken meat but also for chicken meat-allergic
patients without concomitant fish allergy
 In cooked or roasted foods, enolase and aldolase were detectable in
chicken breast while parvalbumin was detectable in chicken legs and wings.
*
*
*

•There are multiple types of the major allergens parvalbumin in fish
and of tropomyosin in shellfish with no cross-reactivity between fish and
shelfish allergens.
•Allergenicity in these species is affected by processing
and tends to increase by heating but decrease with
canning, gastric acidity, and enzymes.
•The allergenicity of crustaceans appears to be higher than of mollusks,
followed by fish,
> >

•Most hypersensitivity reactions to seafood are IgE mediated
and are associated with rapid onset of symptoms, including
gastrointestinal, cutaneous, respiratory, or multiple organ
system symptoms, 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, or
inhalation.
Bahna SL. Adverse food reactions by skin contact. Allergy. 2004;59(suppl 78):66e70.
Ramirez DA Jr, Food hypersensitivity by inhalation. Clin Mol Allergy. 2009;7:4.

Seafood allergy: Clinical Features,
•The main clinical manifestations of allergic
reactions to fish include vomiting and diarrhea
while the most extreme form of reaction is
life-threatening anaphylactic shock.
•Patients with fish allergy can however also react
to aerosolized proteins generated by cooking or
processing of fish resulting in dyspnea, wheezing,
tightness of the throat, urticaria, edema, and
light headedness.
•raw fish allergens from an open-air fish market and
detected allergen concentrations ranging from 2 to 25 ng/m3,
very similar to the levels identified in the occupational
setting causing allergic sensitization.

•Diagnosis of fin fish or shellfish allergy is primarily based on the type,
onset, and course of symptoms, supported by a (+) SPTs results or sIgE
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 may 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.
Mourad AA, Fish-allergic patients may be able to eat fish. Expert Rev Clin Immunol. 2015;11:419e430.
X
X
OK
OK
Seafood allergy: Diagnosis

Diagnostic
decision tree
on how to
proceed from
the suspicion
of fish-related
allergic
symptoms,
Fish allergy:
in review.
Sharp MF, Clin Rev
Allergy Immunol.
2014;46(3):258-71.
* For cod–fish, a diagnostic level of
IgE that can predict clinical
reactivity in a US population, with
>95 % certainty, was identified as
20 KUA/l.
It is however questionable if this
seemingly high value can be
extrapolated to other fish species
and other populations as IgE values
as low as 1 kU/l could be determined
in patients with anaphylactic
reactions to pilchard (sardina) and
Anchovy (acciuga)
*

Stephen JN, CEA 2017;47:300-312
• The amount of fish ingested may be important for some individuals
with fish allergy.
• Moreover, important pan-fish allergens may vary in concentration
between fish.
• The fish ED10 eliciting dose to which 10% of an allergic population
would be expected to first clinically react is estimated to be 27 mg.
• Other factors may influence thresholds, such as impaired gastric
digestion. Codfish proteins digested in hypo-acidic conditions
(pH 3.0) were demonstrated to reduce the tolerance levels
between 10 to 30 times as compared to digestion at pH 2.0.
• A decision tree has been suggested to manage fish allergy in a stringent
manner that also takes into account adverse parasitic and toxin
reactions. Sharp MF, Clinic Rev Allergy Immunol 2014; 46:258–271
Diagnosis of fish allergy

•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.
Seafood allergy: Management

Induction of tolerance to different types of fish through
desensitization with hake D’Amelio C, PAI 2017;28:96-99
•A 6-year-old female who presented with generalized urticaria
after first eating fish (hake) at the age of 9 months and
later at the age of 12 months following the reintroduction
of small portions of different types of fish (hake and sole).
•She started suffering facial hives after being exposed to steam generated
while cooking tuna at her home since the age of six.
•Taking into account the clinical history, we decided
to perform oral immunotherapy (OIT) with the fish hake,
a white fish which is frequently consumed in our country.
nasello

Adverse Reactions to Foreign Substances in Seafood
*
*
*

Gastric Anisakiasis Images in clinical medicine
Baden LR, N Engl J Med 2016;375(7):e11
• A 36-year-old previously healthy
woman presented with a 2-day history
of severe chest pain and epigastric pain
associated with nausea and vomiting.
• The patient reported that she had
consumed uncooked salmon
approximately 2 hours before
the chest pain developed.
• Gastroscopy revealed multiple anisakis
larvae penetrating into the mucosa in
the esophagogastric junction, fundus,
upper body, middle body, and antrum
of the stomach. 11 larvae were
removed with endoscopic forceps,
after which the patient’s symptoms
resolved

•The disease caused by infection with live Anisakis larvae is called anisakiasis.
•Upon a primary exposure to a helminth, various degrees of inflammatory responses
are triggered in the host, characterized by the recruitment of inflammatory
effector cells such as neutrophils and eosinophils and changes in blood vessel
permeability and blood flow.
•Non-specific inflammation is minimal in most natural host–parasite systems but is
often enhanced in zoonotic infections where the host is unnatural or non-permissive,
and accordingly, infection with Anisakis species often induces a significant
eosinophilic inflammation during a primary infection.
•Anisakiasis usually presents as mild to severe abdominal pain, nausea, vomiting
and/or diarrhoea (which in many cases leads to the natural expulsion of the
parasite), appendicitis, bleeding, and is in some cases accompanied by allergic
reactions, such as hives (urticaria), angioedema, bronchospasm and even
anaphylactic shock.
Anisakiasis
Nieuwenhuizen NE, Curr Allergy Asthma Rep. 2014;14:455e461.

Allergy to Anisakis simplex and Anisakiasis
•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 (Anisakiasis).
•Gastrointestinal symptoms, urticaria, dermatitis, asthma and even
anaphylaxis may occur.
Daschner A, J Allergy Clin Immunol. 2000;105:176e181.
Seafood allergy: Anisakis simplex

Allergy to Anisakis simplex and Anisakiasis
•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 (Anisakiasis).
•Gastrointestinal symptoms, urticaria, dermatitis, asthma and even
anaphylaxis may occur.
Daschner A, J Allergy Clin Immunol. 2000;105:176e181.
Diagnosis and treatment are made by endoscopic confirmation
and surgical removal of the granulomas.

Prevention of Anisakiasis
•The best means of avoiding infection with
live Anisakis is to ensure that all fish meant
for consumption is deep-frozen (at −20 °C)
for at least 24 h
Garcia F et al. Freezing protects against allergy
to Anisakis simplex.
J Investig Allergol Clin Immunol. 2001;11:49–52.
or that
•fish is cooked for at least 10 min at 60 °C .
Audicana MT, Ansotegui IJ, de Corres LF, KennedyMW.
Anisakis simplex: dangerous—dead and alive?
Trends Parasitol. 2002;18:20–5.

Allergy to Anisakis simplex
•Anisakis simplex is a nematode that infests fish, crustacean and mollusks.
•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 nasello in Spain),
are notable for high rates of infestation.
AAITO-IFIACI Anisakis Consortium. Anisakis hypersensitivity in Italy: prevalence
and clinical features: a multicenter study. Allergy. 2011;66:1563-69.
•Larvae are susceptible to heating (>60C for 10 minutes) or freezing
(-20°C for 48 hours), but some of their allergens are resistant to cooking,
freezing, and partially to digestion.

•Anisakis simplex is a nematode that infests fish, crustacean and mollusks.
•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 nasello in Spain),
are notable for high rates of infestation.
AAITO-IFIACI Anisakis Consortium. Anisakis hypersensitivity in Italy: prevalence
and clinical features: a multicenter study. Allergy. 2011;66:1563-69.
•Larvae are susceptible to heating (>60C for 10 minutes) or freezing
(-20°C for 48 hours), but some of their allergens are resistant to cooking,
freezing, and partially to digestion.
Exposure to proteins from live or dead
Anisakis can cause allergic reactions.

•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.
•Diagnosis of Anisakis allergy currently relies on clinical symptoms, a history
of exposure to seafood and detection of Anisakis-sIgE or a (+) Anisakis SPT
in the absence of specific IgE to the fish or seafood itself.
The clinical history may be less clear when patients present with
chronic symptoms such as chronic urticaria, contact dermatitis,
asthma and rhino-conjunctivitis, particularly if they are atopic.
•Furthermore, detection of sIgE to Anisakis can also be due to immunologic
cross-reactivity to other helminths (e.g. Ascaris) or invertebrates such as
dust mites, cockroaches and shrimps.

•A better diagnostic test would therefore use component-resolved diagnosis,
including all known allergens of Anisakis, particularly those that do not
appear to cross-react with those of other species.
•Since particular allergens are associated with reactions to cooked fish,
this approach may also aid in dietary advice given to patients.
•Some patients with Anisakis allergy are able to tolerate a diet of frozen or
well-cooked fish, but some patients are sensitized to heat-stable allergens
and may react even to well-processed fish.
•Garcia F et al. Freezing protects against allergy to Anisakis simplex. J Investig Allergol Clin Immunol.
2001;11:49–52.
•Baeza ML et al. Characterization of allergens secreted by Anisakis simplex parasite: clinical relevance in
comparison with somatic allergens. Clin Exp Allergy. 2004;34:296–302.
•Moneo I et al. Isolation of a heat-resistant allergen from the fish parasite Anisakis simplex. Parasitol
Res. 2005;96:285–9.

Characterized allergens of Anisakis simplex
*
* a Pepsin- and Heat-Resistant Major Allergen ESP = excretory–secretory products

High prevalence of Anisakis simplex hypersensitivity
and allergy in Sicily, Italy
Heffler E, Ann Allergy Asthma Immunol 2016;116:146
15.4%
% patients sensitized
to A simplex
20 –
15 –
10 –
5 –
….0
30%
of patients
had
mono-
sensitization
to
A simplex.
 3419 consecutive
patients referred
to the allergy clinic
during a 22 mo-period.
 Sensitization
to A simplex by SPT.

Distribution of allergic symptoms
in patients allergic to Anisakis simplex.
patients referred
 Sensitization
gastrointestinal
oral allergy syndrome

Distribution of allergic symptoms
in patients allergic to Anisakis simplex.
patients referred
 Sensitization
gastrointestinal
Allergic symptoms
from A simplex ingestion
in raw or marinated fish
were quite frequent,
with symptoms
ranging from
to anaphylaxis.

Attilio Boner
University of
Verona, Italy
attilio.boner@univr.it
Introduction
Classification of Seafood
Seafood Allergy
Adverse Reactions to Foreign
Substances in Seafood
Adverse Reactions to Infectious
Agents that Contaminate Seafood
Recognition and Management
of Seafood Poisoning
Conclusion

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 manifestations 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 ventilatory failure.

Clostridium botulinum
Botulism is more likely to occur with certain preparations
characteristic of particular cultures and geographic
locations, such as
1) the whale meat mukluk in the Alaskan and Canadian Arctic,
2) rakish in Norway,
3) salted gray mullet feseikh in Egypt,
4) salted eviscerated whitefish kapchunka in Israel and New York City,
5) uncooked salmon ashbal in Iran,
6) fermented fish preserved in rice izushi in Japan, and
7) imported vacuum-packed whitefish in Europe.

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:
1) vomiting,
2) abdominal cramps, and
3) diarrhea usually within 24 hours of ingestion.

Vibrio vulnificus
•Vibrio vulnificus, a species of Gram-negative, motile, curved,
rod-shaped (bacillus), pathogenic bacteria of the genus Vibrio.
•It is present in marine environment as 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.
Jones MK, Infect Immun. 2009;77:1723e1733.

Vibrio vulnificus
•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 immunocompromised patients or associated liver disease.
Jones MK, Infect Immun. 2009;77:1723e1733.
•Diagnosis of V vulnificus 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 gastroenteritis
in the United States and is generally referred to as the misnomer
of stomach flu. Hall AJ, Emerg Infect Dis. 2013;19:1198e1205.
•Symptomatic illness usually occurs after ingestion
of contaminated raw food, including seafood.
•After an incubation period of 24 to 48 hours after ingestion 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, scombrotoxin,
or other vasoactive amines
(putrescine and cadaverine).
Hungerford JM. Toxicon. 2010;56:231e243.
Jantschitsch C,
J Am Acad Dermatol. 2011;65:246e247.
High histamine levels are formed by
bacterial proliferation on the surface
of fish that have been improperly
refrigerated.

•The spoiling bacteria (when bacteria breaks down the food, acids and other waste
products are created) can be Proteus, Escherichia coli, Salmonella, Morganella
morganii, Enterobacter aerogenes, Raoultella planticola, and Hafnia alvei.
•Histidine decarboxylase in these bacteria 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 decarboxylation
may also directly degranulate mast cells.

•Histamine development is more likely to occur in raw,
unfrozen fish.
Because the fish may appear and smell normal,
the consumer may not identify a problem before eating the fish.
•Once the bacteria have formed the enzyme
histidine decarboxylase, histamine production can
continue even if the bacteria are killed.
•Although cooking can inactivate both the enzyme and the bacteria,
the toxic factors produced are heat stable and, once formed,
are not destroyed by cooking, smoking, or freezing.

•The most commonly susceptible fish are in the Scombridae and
Scomberesocidae families, which include:
tuna,
mackerel,
blue fish,
anchovies,
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.

Histamine poisoning associated with eating tuna burgers.
Becker K. JAMA. 2001;285:1327-1330.
20 case-patients with 2 of the
following symptoms within
2 hours of eating tuna:
rash,
facial flushing,
vomiting,
diarrhea,
dyspnea,
a tight feeling in the throat,
headache,
a metallic or peppery taste
in the mouth.
All case-patients ate tuna:
18 ate tuna burgers,
2 ate salad containing tuna,
and 2 ate filets.
Tuna samples (available from 3
outbreaks) had histamine levels
above the FDA regulatory level
of 50 ppm (levels were
between 213 and 3245 ppm).

Becker K. JAMA. 2001;285:1327-1330.
rash,
facial flushing,
vomiting,
diarrhea,
dyspnea,
headache,
in the mouth.
In 19 cases, the tuna used
to prepare burgers or
salads was frozen and
thawed more than once
before serving.
Violations of
recommended temperature
controls were identified
in 2 of the 5 restaurants,
accounting
for 14 (64%)
cases.
and 2 ate filets.

Becker K. JAMA. 2001;285:1327-1330.
rash,
facial flushing,
vomiting,
diarrhea,
dyspnea,
headache,
in the mouth.
rapid chilling of fish on the
fishing vessel and
keeping the temperature
of the fish lower than 0°C
throughout storage and
distribution is the best
way to prevent histamine
formation.
This is lower than the
current FDA
recommendation of 5°C
and 2 ate filets.

Becker K. JAMA. 2001;285:1327-1330.
•Tuna can be especially vulnerable to temperature fluctuations because their
average body temperature when caught tends to be several degrees warmer
than that of other types of fish.
•Belly meat might have an increased susceptibility to bacterial contamination
during the evisceration process because of its proximity
to the fish gut cavity, where histamine-forming bacteria reside.
•Furthermore, thin pieces of fish, such as the belly meat used for ground
tuna and salads, might be more vulnerable to temperature fluctuations
than thicker tuna filets.
•Violation of storage and temperature controls are also more likely with tuna
used for salads and burgers, because pieces are stored over a longer period
than filets and exposed to multiple thawing and refreezing cycles.

Becker K. JAMA. 2001;285:1327-1330.
Histamine poisoning is a chemical intoxication with a short incubation period,
usually ranging from minutes to a few hours after ingestion.
Symptoms include:
•tingling and burning sensations around the mouth,
•headache,
•facial flushing and sweating,
•rash and itching on the upper body,
•abdominal cramps, nausea, vomiting, diarrhea,
•heart palpitations.
+
+

+
Becker K. JAMA. 2001;285:1327-1330.
Histamine poisoning is a chemical intoxication with a short incubation period,
usually ranging from minutes to a few hours after ingestion.
Symptoms include:
•tingling and burning sensations around the mouth,
•headache,
•facial flushing and sweating,
•rash and itching on the upper body,
•abdominal cramps, nausea, vomiting, diarrhea,
•heart palpitations.
Symptoms related to histamine
poisoning can also be similar to
those of coronary heart
disease, increasing the
possibility of an invasive medical
intervention if misdiagnosed.

Becker K. JAMA. 2001;285:1327-1330.
•In most persons, symptoms are self-limiting, although
histamine poisoning can be life-threatening in persons
with conditions such as asthma and heart disease.
•Some drugs, such as monoamine oxidase inhibitors,
can worsen or prolong an attack by inhibiting the
breakdown of histamine.
•Antihistamine medication such as diphenhydramine
and cimetidine often relieve symptoms.
•However, severe cases of toxicity can require
the same aggressive management as acute anaphylaxis.

Pufferfish Poisoning (pesce palla)
•Pufferfish tetrodotoxin can be present in porcupinefish,
globefish, blowfish, mola, ocean sunfish, triggerfish.
•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, dizziness, weakness,
paresthesias, loss of reflexes, hypotension, motor paralysis, and respiratory
failure.
flesh of pufferfish

Seafood Neurotoxin (paralytic shellfish poisoning)
•Seafood neurotoxins (saxitoxin and its derivatives) are produced
by cyanobacteria in fresh water and by dinoflagellates
(marine plankton) in seawater.
•Mollusks are more commonly implicated than crustaceans.
Pufferfish may be affected as well.
•Florida monitors the neurotoxin concentrations in pufferfish
along its east coast.
•Afflicted persons develop paresthesia and numbness within < 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.
Florida

Ciguatera Fish Poisoning
•The dinoflagellate Gambierdiscus toxicus in blue-green algae can infect
reef fish and produce ciguatoxin, maitotoxin, scaritoxin, and gambieric acid.
Lehane L. Ciguatera update. Med J Aust. 2000;172:176e179.
•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.
Blue green algae may
look like algae but
it’s actually bacteria

•The toxins are heat stable and lipid soluble and are more
in the fish head, viscera, roe(uova), 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.
Brett J, Pregabalin to treat ciguatera fish poisoning. Clin Toxicol (Phila). 2015;53:588.

•The toxins are heat stable and lipid soluble and are more
in the fish head, viscera, roe(uova), 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.
Brett J, Pregabalin to treat ciguatera fish poisoning. Clin Toxicol (Phila). 2015;53:588.
toxins interfere with the
function of nerve endings

Azaspiracid Shellfish Poisoning
•Azaspiracids are polyether marine toxins
possibly produced by dinoflagellate
and accumulate in various shellfish.
•Eating the affected shellfish causes severe acute gastrointestinal
symptoms that persist for 2 to 3 days.

•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 mechanism of action.
•The presence of similar symptoms in other individuals 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 reactions should be
higher in regions with seasonal algal blooms
and high levels of biotoxins or toxic algae.
Recognition and Management of Seafood Poisoning

•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

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.

Reactions to seafood can be allergic in nature to:
1) a known allergen in fin fish or shellfish or
2) can be attributable to something other than seafood protein,
such as contamination by other food allergens,
3) seafood parasite Anisakis simplex,
4) additives,
5) natural rubber latex, or
6) chemical contamination, or
7) seafood-associated toxins by bacterial action.
Not every seafood “allergy” is allergy: Conclusions

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;
1) nature and timing of the reaction,
2) type of item involved,
3) whether other members of the dining party also fell ill, and
4) patient’s own history of consuming these items.
These inquiries can help differentiate a likely
IgE-mediated reaction from a toxic one. or

Whenever allergy tests are performed and the results are negative
for the suspected seafood item, the physician should consider:
1. Anisakis simplex allergy if the seafood is from a highly infested
region.
2. seafood-associated toxins or botulism in individuals with neurologic
symptoms or when multiple consumers are affected,
3. if the fish tasted spoiled or is from a typical species, scombroid
poisoning should be considered.

Thank you
for your
attention
to the
story my
granpa
told you!
Mia Charlize Powell

Not every seafood allergy is allergy

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