Fish allergy.pdf

Fish allergy
Tharida Khongcharoensombat, MD
Division of Pediatric Allergy, Immunology
Department of Pediatrics, Faculty of Medicine
King Chulalongkorn Memorial Hospital
17 June 2022

Contents
• Fish Consumption and Allergy Prevalence
• Classification
• Fish product
• Fish allergen
• Cross reactivity
• Food processing and its impact on fish allergenicity
• Diagnosis
• Management
• Cross reactivity between fish, crustacean and mollusc
• Fish allergy and allergic disease

Introduction
• Each fish species may contain multiple isoforms of a given allergen that often
differ in their allergenicity
• Fish allergens belong to several protein families with different levels of stability
to food processing.
• Different preparation methods may contribute to specific sensitization
patterns to specific fish species and allergens in different geographic regions.
• Allergy can be elicited by proteins present in fish muscle, roe, skin or blood.
• < 1% of general population suffer from a fish allergy.
• Parvalbumin is the major fish allergen (prevalence rate 70-95%)
• The avoidance of all fish as a common management approach is usually not
necessary as many patients may be only sensitized to specific species and
allergens.
Kalic T, et al. Front Allergy. 2021 Oct 13;2:732178.
Molecular allergology user’s guide 2016

Introduction
• The most common type of hypersensitivity reactions to fish is IgE-
mediated fish allergy.
• Occur immediately after the exposure
• Variety of symptoms ranging from mild, including local urticaria and oral
allergy syndrome, to serious such as severe anaphylaxis
• Fish is one of the main causative agents of FPIAP, FPIES
• The diagnosis: more complex
• The variety of fish species
• The amount of allergens they contain
• The allergens’ degree of evolutionary distance to human homologs
• The fish processing methods which may alter allergen composition and
IgE-reactivity Kalic T, et al. Front Allergy. 2021 Oct 13;2:732178.

Fish Consumption and Allergy Prevalence
• Consumption of fish is steadily on the increase worldwide due to their high
nutritional value.
• Determining the prevalence of true fish allergy can be difficult as in many
cases immunological data are unavailable.
• Prevalence of fish allergy is estimated by
• Clinical history with the patients
• Evaluating questionnaires

Lowest

• Such studies carry the risk of overestimating the incidence of IgE-
mediated fish allergy as many allergy-like reactions may occur due to
other factors
• Scombroid poisoning
• Exposure to fish toxins
• Exposure to fish parasite Anisakis (in raw or marinated fish)
• Adverse reactions to fish mediated by non-IgE related mechanisms
Fish Consumption and Allergy Prevalence
Ruethers T, et al. Mol Immunol. 2018 Aug;100:28-57.

Classification

Classification
Cartilaginous fish
• Endoskeleton made of cartilage
• Reproduce internally
• Found primarily in marine water
Bony fish
• Endoskeleton made of stable cranial
bone
• Reproduce mostly externally
• Found in fresh and marine water
• Largest group of all vertebrates
consisting of 45 orders and over 435
families

Shark
Sawfish
Shark
Skate
Ray

Elephant fish
Rat fish Rabbit fish

Coelacanth
Lobe-finned fish
• Extinct
• Order coelacanths being the oldest
discovered order - having a continuous
presence for 100 million years

Ray-finned fish
• The largest subclass
• All edible bony fish
Order
Sole = ปลาลิ้นหมา
, ปลาช่อม่วง
Family Latidae
Asian seabass
ปลากระพงขาว
ปลาดุก

ปลานิล, ปลาทับทิม
Oreochromis niloticus

For an accurate diagnosis of fish allergy, the species most relevant for particular
geographic regions should be considered.
ปลานิล
ปลาดุก
ปลากระพงขาว

Fish product
Fish meat
• The largest allergenic activity resides in the muscle
• Food processing does not seem to affect the allergenic potency but the
allergen content which varies in different species.
• Parvalbumin, enolases, aldolases
Eggs, roe, caviar
• Typically consumed in raw form
• Fish egg allergens: limited data
• Parvalbumin are not present in fish eggs

Fish product
Fish gelatin
• Made from fish skins and bones
• May contain allergenicity
Isinglass
• From fish swim bladders
• Mainly contains collagen
Fish blood
• Use as additives or processing
aids
• Occupational asthma:
aerosolization of blood-derived
allergens during processing of fish
• Potential allergen: serum albumin
Food (beverages, candy, marshmallow), pharmaceutical (gel, capsules and coating),
biological (vaccines, SLIT), wound dressing, dental application product
Exempted from food labelling regulation

Fish allergen
The first discovered fish allergens
• Gad m 1: Atlantic cod
• Gad c1: Baltic cod

Fish allergen: Parvalbumin
• α-parvalbumins, β-parvalbumins and oncomodulins
• Like calmodulin and troponin C, parvalbumin is a member of the EF hand-
containing calcium binding protein superfamily.
• A key factor in regulating calcium homeostasis
• Transports calcium from troponin-C to the sarcoplasmic reticulum calcium
pump during muscle relaxation and plays a role in neuronal activity
• All major allergens from bony fish are β-parvalbumins.
• Highly cross reactive with parvalbumins from various fish species
• Highest in white fish followed by salmon and tuna
Anna Nowak-Wegrzyn, Middleton 9th edition

Sequence comparison of fish allergens
with homologs from other vertebrates
(A) β-parvalbumins compared with human and
and cartilaginous fish α-parvalbumins
(B) α-parvalbumins
• Low IgE-binding
• Minor allergens in chicken meat, frogs and crocodiles
(rare)
Frog
Chiken
Crocodile

Fish allergen: β-enolase
• α, β, and γ isoform
• Minor allergens
• Fish β-enolases show sequences identities > 80% with their human
homolog.
• Sequence identities between enolases from bony fish exceed 90%.

• Essential enzyme in glycolysis and gluconeogenesis
• There are three forms of class I aldolases: aldolase A, B, and C
• Aldolase A is preferentially expressed in muscle and brain.
• Minor allergens in several fish species such as cod (Gad m 3), salmon
(Sal s 3) and tuna (Thu a 3) and in chicken meat (Gal d 10).
Fish allergen: Aldolase A

(C) β-enolase (D) aldolase A compared with cartilaginous fish aldolase C

Tropomyosin
• Regulate morphogenesis, cell proliferation, vesicle trafficking,
biomechanics, and glucose metabolism.
• Muscle contractions: interaction of actin filaments with myosin motors
and actin binding proteins.
• Recently, salmon (Sal s 4) and catfish (Pan h 4) tropomyosins were
identified as heat-stable allergens that bound IgE from 6 to 32% of fish-
allergic patients’ sera, depending on the species and the isoform
• No data on cross reactivity between tropomyosins from different fish
are available it is expected to be high, given the 80–95% sequence
identities between these allergens.
Fish allergen: Minor allergen

(E) tropomyosin α1 (F) collagen type I α1 chain
Ore m 4 from tilapia = first
allergenic fish tropomyosin

Type I Collagen
• Cartilage, bones, tendons, and skin
• Bound IgE from 20% of fish-allergic patients
• Sensitization to fish gelatin, the denatured and partially hydrolyzed form
of type I collagen, was detected in a minority of fish-allergic patients
• High IgE cross-reactivity between gelatin from different fish species.
• No cross-reactive between fish and bovine.
• Explained by a considerable sequence divergence between
mammalian and fish type I collagens

Creatine Kinase
• A key enzyme of the cellular energy metabolism
• Found primarily in muscle and brain tissue
• Catfish (Pan h 7) and salmon (Sal s 7)
Triosephosphate Isomerase Triosephosphate isomerase (TIM)
• Catfish (Pan h 8) and salmon (Sal s 8)
Pyruvate Kinase Pyruvate kinase (PK)
• Catfish (Pan h 9)

Lactate Dehydrogenase Lactate dehydrogenase (LDH)
• Convert pyruvate to lactate
Glucose-6-Phosphate Isomerase
Glyceraldehyde-3-Phosphate Dehydrogenase

Vitellogenin
• The major egg yolk proteins and the source of nutrients required for the
development of the embryo of egg-laying vertebrates and invertebrates.
• Produced in the liver, provide or transport amino acids, lipids,
phosphorous, and calcium to the egg
• Onc k 5: chum salmon
• A major allergen for patients allergic to chum salmon roe
• Showed IgE-cross-reactivity with homologs from fish roe of other
salmonids.

Sensitization and clinical relevant
• Allergens from different fish species
frequently share between 50 and 75%
of sequence identities
• Parvalbumins are important cross-
reactivity markers (panallergen)
• Higher IgE-titers in patients of
broad as compared with those of
low cross-reactivity
• Cross-reactivity
• Broad 70%
• Limited 30%
primed by dietary conditions
(species, processing).
Klueber J, et al. Curr Treat Options Allergy. (2019) 6:322–37

Cox AL, et al. J Allergy Clin Immunol Pract. 2021 Jan;9(1):82-99.

Cross reactivity based on IgE testing, clinical history, questionnaires.
• Cross-reactivity among bony fishes and in most patients, tolerance to ray
• A Dutch study (n = 38) (Schulkes KJ, et al. Clin Transl Allergy. 2014)
• 59% of the fish-allergic patients had an allergy to all fish species ever
tried
• A Japanese study (n = 38) (Kobayashi Y, et al. Allergol Int. 2016)
• High cross-reactivity in 88% of the participants
• European cohort (n = 62) (Kuehn A, et al.Clin Exp Allergy. 2013)
• Mono-reactivity to salmonids (salmon, trout) was 12%.

• It is generally accepted that fish allergy sufferers have an approximately
50% chance of being cross-reactive to another fish species.
• Mono-sensitivity in tilapia and salmon has been reported.
• Different linear IgE-binding epitopes of parvalbumin from five fish
species (Atlantic cod, Atlantic salmon, Baltic cod, common carp, and chub
mackerel) have been characterized and probably contribute to species-
specific reactivity

• Allergenicity is dependent on two factors
• The allergenicity of the proteins
• The amount of the allergens present in the tissue
• A study by Kuehn et al. (Kuehn et al., 2014)
• The parvalbumin content may differ up to 48 fold between fish
species (0.2–11.2 mg of parvalbumin per gram of tissue) dependent on
• Size, Species, Type of fish (sedentary or migratory type)
• The parvalbumin content within one species can differ up to 7.4-fold
between different muscle parts
• Higher parvalbumin in dorsal and rostral compared to ventral and
caudal parts of fish muscle, respectively.
• Parvalbumin is more abundant in white compared to dark tissue.

Food processing
and its impact on fish allergenicity
• Various processing treatments are used in the preparation of fish and
products
• To increase the shelf-life
• Improve the taste, texture
• Remove pathogenic microorganisms
• The food processing techniques may alter allergen recognition by IgE
• Fragmentation of linear IgE epitopes
• Destruction of the conformational epitopes
• Generation of neoepitopes.
• Changes in allergenicity upon fish processing

Dasanayaka BP, et al. Crit Rev Food Sci Nutr. 2022;62(7):1951-1970.

Increase allergenicity Reduce allergenicity No effect
Frying Canning Drying
Cold smoking Salting Salting
Lye-treating High pressure process
Fermentation Lyophillization/
freeze drying
Irradiation Freezing
Enzyme catalyzed
Food processing

Yang H, et al. (Food Funct 2018)
• IgE reactivity of the parvalbumin from the Japanese scad (Decapterus
maruadsi)
• Retained after boiling, ultraviolet irradiation and ultrasonication
• Decreased upon Maillard reaction and pressure treatment
Kobayashi et al. (Allergol Int 2016)
• Demonstrated that collagen in fish extracts prepared from thermally
processed fish (heated to 100, 120, and 140◦C before the extract
preparation) retained its IgE-binding properties
• This demonstrates the importance of collagen as an allergen from
both raw and heated fish.
Food processing

• Several heat-labile fish allergens were described
• Aldolase A and β-enolase were described as allergens from cod,
salmon, catfish, tuna and carp.
• Due to the heat-sensitivity, patients sensitized exclusively to these
allergens may be able to consume thermally processed fish.
Food processing

Diagnosis
• Based on clinical assessment, skin prick test (SPT), serum specific-IgE
testing, and OFC.
A detailed history of the allergic episode, including
• Time and duration of the reaction
• Type and quantity of specific fish species
• Symptom characteristics involving skin, mucous membranes, cardiovascular,
respiratory, and neurologic system
• Prior history of a similar reaction
Skin prick test (SPT)
• Extract limited due to
• Lack of allergen standardization, lack of important allergens and the presence
of preservatives in the extracts
• Prick-to-prick tests Molecular allergology user’s guide 2016
Kalic T, et al. Front Allergy. 2021 Oct 13;2:732178

Specific-IgE
• In the widely used ImmunoCAP system (ThermoFisher Phadia), 28 fish
extracts but only 2 purified fish allergens are available for routine specific-
IgE quantification.
• Level of sIgE correlated with clinical reactivity to predict allergy to fish
• In US population
• sIgE level of 20 kUA/L to cod: predict allergy to this fish with 95%
certainty
• However, clinical reactions have been indicated for patients with
much lower IgE titer
Clinical history + elevated levels of allergen-specific IgE or a positive SPT result
is the foundation of fish allergy diagnosis.
Diagnosis
Kalic T, et al. Front Allergy. 2021 Oct 13;2:732178

Oral food challenge to confirm fish allergy
• Positive OFC usually correlates with a strong SPT result and high specific
IgE against fish.
• OFCs can be performed open, single-blind, or DBPCFC, the latter being
the gold standard for the diagnosis of fish allergy.
• OFC is useful not only for the diagnosis but also for avoiding
unnecessary dietary restrictions.
• Several studies used OFC to show that some patients with fish allergy may
tolerate certain fish types
Diagnosis

Molecular allergy diagnosis
• Utilizes purified natural or recombinant allergens instead of total extracts
• Allow for simultaneous quantification of IgE specific to many species and
may therefore reduce the number of required OFCs.
• Besides the major allergen parvalbumin, other allergen components
should be implemented to precisely determine the pattern of IgE
sensitization.
• One example of a recently introduced in vitro multiplex allergen test is
the ALEX2 Allergy Explorer (MacroArray Diagnostics).
• It contains: parvalbumins from 8 species, aldolase and enolase from
Atlantic cod, and whole extracts from 6 fish species.
Diagnosis

J. Čelakovská et al. food and agricultural immunology 2022, Vol 33, No. 1, 1-19

Clinical practice and Management
• Dietary avoidance of fish
• Administration of rescue medicine in case of accidental exposure to fish
or their allergens
• Patients with an allergy to one or more fish are advised to avoid most or
all fish species, a recommendation that in many cases turns out to be too
strict.
• It has been shown that patients with fish allergy can frequently eat
certain fish species.

• Therefore, it has been proposed to categorize patients with fish allergy
into three clusters
(A) polysensitized patients who respond to all types of fish on the basis
of cross-reactions of β-parvalbumin and often enolase and aldolase
(B) mono-sensitized patients with a selective allergic reaction to one
individual fish species based on a specific epitope of β-parvalbumin
(C) oligosensitized patients who respond to a number of specific fish
based on enolase and aldolase, without IgE for β-parvalbumin
• Depending on the specific cluster the patient belongs to, OFC for one or
more fish species can be performed with the aim to provide safe
alternatives for consumption.

Natural history of fish allergy (Data are scarce)
• The majority of reports suggesting long-term clinical reactivity.
• Many patients develop clinical fish allergy during childhood that persist during
adulthood
• One study (Dannaeus A, Clin Allergy. 1981)
• Only 15% of children outgrow their fish allergy within a period of 2 to 5 years.
• Retrospective study (Carvalho S, J Investig Allergol Clin Immunol. 2020)
• Up to 63% of patients may overcome fish allergy
• Prospective clinical study (Xepapadaki P, J Allergy Clin Immunol Pract. 2021)
• Tolerance of fish (cod) increased with age, ranging from 3.4% in preschool
children to over 45% in adolescents
Patients developing tolerance over time
should be identified to avoid unnecessary continuation of food restrictions

Occupational fish allergy
• Cooks have high exposure rates by skin contact, inhalation but also
ingestion.
• A great load with airborne fish proteins (up to 986 ng.m-3) including
allergens has been measured for the fish-processing environment.
• Cutaneous symptoms (contact urticaria, protein contact dermatitis),
allergic rhinitis and asthma are the most common symptoms.
• Preceding atopy and hand eczema are risk factors for fish
sensitization via the damaged skin barrier.
• Diagnostic work-up includes sIgE testing and skin tests (prick, prick-to-
prick) with diagnostic fish extracts or the native food.

• Rates of cross-reactivity between fish and shellfish are not
expected to be high due to differences in major allergens.
• Co-allergy to both fish and crustaceans was reported for
between 6 and 21% of patients with seafood allergy
Cross react between fish, crustacean and mollusc

Cross react between fish, crustacean and mollusc

Fish introduction and asthma
• Whether early introduction (before 12 months of age) does
contribute to prevent fish allergy still needs further investigation
• Including fish into the diet of young infants seems to reduce the
risk for developing asthma and allergic rhinitis.

• Study: birth cohort, Southeast Sweden
• N = 9,727
• Asthma until age 15-17 years = 948 (450 cases were atopic)
• Baseline questionnaire, food diary
• Covering timing of introduction of complementary foods during the first
year and duration of breastfeeding
• Result
• Introduction of fish before 43 weeks of age, as compared to later,
was associated with a lower risk of asthma, irrespective of atopic
classification.
Klingberg S, et al. Eur J Pediatr. 2019;178(3):395–402. 22.

Introduction of fish Vs risk of
developing asthma
• < 28 weeks
• ≥ 29 to < 43 weeks
• ≥ 43 weeks
• Both atopic and non-atopic
asthma
Decrease risk

Discussion and conclusion
• Early and intermediate introduction of fish (< 43 weeks)
• Associated with a decreased risk of asthma, irrespective of atopic
classification
• The high content of omega-3 long-chain polyunsaturated fatty acids
has been suggested to be involved in mechanisms behind the protection
from fish against atopic disease.
• A recent meta-analysis (Muley P, et al. J Allergy (Cairo) 2015:312052)(5 RCTs)
• Did not find any significant associations between omega-3
supplementation, starting in infancy, and the risk of asthma
• This indicates that there are probably other nutrients that are involved in
the protection from early fish introduction.
• Vitamin D and zinc, which are found in substantial amounts in fish have
been suggested to have impact on wheeze and asthma.

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