Gastroallergic anisakiasis: immediate ... - Revista seaic

Alergol Inmunol Clin 2000;15:230-236
Mª C. López Serrano,
A. Alonso-Gómez,
Á. Moreno-Ancillo 1 ,
Á. Daschner,
J. Suárez de Parga 1
Allergy Section and
1
Endoscopy Unit, "La Paz"
General University Hospital.
Madrid, Spain
Original Article
Gastroallergic anisakiasis: immediate
hypersensitivity due to Anisakis simplex
infestation
In Spain, cases of anisakiasis were anecdotic up to 1995. In that year, however,
and led by Dr. Fernández de Corres, the Spanish allergologists became
fully aware of Anisakis simplex (AS) because of cases of allergic reaction
after the intake of "presumably" well-cooked fish with positive skin
tests and specific IgE to AS. The fundament of AS allergy appeared to reside
in the heat stability of AS antigens. Following the observation of several
cases of anaphylaxis with AS infestation, a prospective study was set
up in 1997 in the "La Paz" University Hospital. Patients were entered into
the study that came to the Emergency Outpatient Clinic with allergic or
gastrointestinal symptoms after the ingestion of seafoods or fish up to 48
hours earlier. If the gastrointestinal symptoms persisted, a gastroscopy was
performed. Over a period of 18 months, 120 patients were assessed who
complained of allergic symptoms; in 96 of them, AS was actually implicated.
Over those 18 months, and based on the allergic symptoms, 24 patients
were detected in whom one or more parasites were removed from their stomachs
(more parasites detected within 18 months than in the whole of
Spain since 1991). Vinegar-marinated herring and in some cases fresh hake
-presumably well-cooked- were the sources in most of the cases of parasitic
infestation. The authors coined for this condition the term gastroallergic
anisakiasis in order to differentiate it from gastric anisakiasis, as the hypersensitivity
symptoms after contact with the parasite were more intense and
severe than the gastric ones. The antigenic source appeared to be in most
cases the live parasite, and, furthermore, it appeared to require binding to
the submucosa in order to trigger the hypersensitivity reaction.
The next step in these patients with gastroallergic anisakiasis was to carry
out challenge tests with frozen, non-infective parasites. Tolerance was
confirmed in a number of patients, and from then onwards patients were
allowed to eat deep-frozen fish, with no problems ensuing. At that point,
allergy to heat-stable AS proteins appeared to be less frequent than previously
supposed, and it was surmised that the IgE-mediated response corresponded,
in most sensitised patients, to contact (luminal or asymptomatic
parasitic infestations) with the live parasite.
The past history of dietary intake, the clinical features, the skin test responses
and the serial quantitation of AS-specific IgE represent important key points in
the diagnosis. Cases of true Anisakis simplex allergy may indeed exist, but in
the light of the results of this prospective study they appear to be infrequent.
Key words: Anisakis simplex. Gastroallergic anisakiasis. Prospective study.
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Gastroallergic anisakiasis
Anisakiasis gastro-alérgica:
hipersensibilidad inmediata debida
a parasitación por Anisakis
simplex
En España, hasta 1995 los casos de anisakiasis eran anecdóticos.
Sin embargo, en 1995, los alergólogos españoles, de la
mano del grupo del Dr. Fernández de Corres, llegan al Anisakis
simplex (AS) por casos de reacciones alérgicas tras consumo
de pescado "presumiblemente" bien cocinado y con pruebas
cutáneas e IgE específica a AS positivas. La base de la
alergia al AS parecía estar en la termoestabilidad de antígenos
del AS. Tras observar algunos casos de anafilaxia con
parasitación por AS, en 1997 se inició en el Hospital Universitario
"La Paz" de Madrid un estudio prospectivo. Se introdujeron
pacientes que acudían a Urgencias con síntomas alérgicos
o gastrointestinales tras ingestión de productos de mar,
aceptando pacientes que hubieran tomado el alimento hasta
48 horas antes. Si el cuadro digestivo persistía se realizaba
endoscopia. En 18 meses se evaluaron 120 pacientes que
consultaron por síntomas alérgicos, de los cuales en 96 se implicó
verdaderamente al AS. En esos 18 meses, y sobre la base
de los síntomas de alergia, se detectaron 24 pacientes a los
que se extrajeron del estómago uno o más parásitos (más parásitos
hallados en sólo 18 meses que desde 1991 en España).
El boquerón en vinagre y, en algunos casos, la merluza fresca,
presumiblemente bien cocinada, fueron la fuente de la
mayoría de las parasitaciones. Los autores denominaron a esta
entidad anisakiasis gastro-alérgica, diferenciándola de la
anisakiasis gástrica dado que los síntomas de hipersensibilidad
tras el contacto con el parásito eran más intensos e importantes
que los gástricos. Parecía que, en su mayoría, era el
parásito vivo la fuente antigénica, y, más aún, que necesitaba
fijarse a la submucosa para producir la reacción de hipersensibilidad.
El paso siguiente en estos pacientes con anisakiasis
gastro-alérgica fue la provocación con parásitos congelados
no infectivos. Se confirmó su tolerancia en varios pacientes,
y a partir de entonces al resto se les permitió comer pescado
congelado sin suceder ningún problema. En ese punto, la
alergia a proteínas termoestables del AS parecía menos frecuente
de lo previamente supuesto, y se intuía que la respuesta
mediada por IgE en la mayoría de los pacientes sensibilizados
correspondía a contactos (parasitaciones en forma
luminal o asintomáticas) con el parásito vivo. El antecedente
dietético, la clínica, la respuesta a las pruebas cutáneas y la
medición seriada de IgE específica a AS son claves importantes
para el diagnóstico. Puede que existan casos de verdadera
alergia a AS, pero a la vista de los resultados del presente
estudio prospectivo deben ser infrecuentes.
Palabras clave: Anisakis simplex. Anisakiasis gastro-alérgica.
Estudio prospectivo.
INTRODUCTION
Anisakis simplex (AS) is a parasitic helminth included
in the Class Nematoda. Leucckart, in 1876, was the
first to describe a case of human infestation, in a Greenland
child. In 1960, Van Thiel identified the infesting parasite
as the stage III larva of Anisakis 1-5 . The taxonomy of
the genus Anisakis is a complex one. It is included in the
Class Nematoda, subclass Secernentea, order Ascaridida,
suborder Ascaridina, superfamily Ascaridoidea, family
Anisakidea. The subfamily Anisakinae includes the genus
Anisakis, with four recognised species: Anisakis simplex,
Anisakis physeris, Anisakis typica and Anisakis schupakovi
5 . All these species are usually parasitic in the stomach of
marine mammals. The life cycle of the parasite may include
one or more intermediate hosts. The ova of the adult parasites
are shed with the marine mammal’s faeces into the
water and continue there their development up to the stage
of infective larva. At this stage, the larva is some 0.35 mm
long and is ingested by a first host, usually planktonic
crustaceans, in which it develops further and attains a size
of about 5 mm. After a fish or a cephalopod has ingested
the crustacean host, the larvae develop into their third larval
stage and grow to about 2-3 cm in length. These larvae
may pass several times from one fish or cephalopod to
another one, but they do not complete their evolutive cycle
until they arrive into the stomach of a marine mammal.
There they attach themselves to the gastric wall and evolve
into the fourth larval stage and then into adult parasites,
thus completing their life cycle 1-5 .
Man is an aberrant host, as the larva cannot attain sexual
maturity in this environment. Man becomes infested
upon ingesting the larvae in raw or undercooked fish, but
also in smoked fish, semi-preserves, dried or marinated
fish (particularly vinegar-marinated), ceviche (a Peruvian
lemon-marinated fish preparation) or Japanese culinary delicacies
such as sushi or sashimi, which are prepared with
raw fish. The number of fish species reported to be pos-
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M. a C. López Serrano, et al
sibly infested is a veritable host, and includes cod, sardine,
herring, mackerel, salmon, hake, pollack, anchovy, whiting,
bonita and horse mackerel; the most frequently infested
cephalopod is the squid 6-9 .
Parasitic infestation of man by the live larvae is termed
anisakiasis or anisakidosis, and is particularly common
among the Japanese because of their habit of raw fish
consumption 10,11 .
By the year 1995, human Anisakis-related diseases
were differentiated into a number of clinical forms depending
on the affected region of the digestive tract. The
luminal form was considered to be caused only by Phocanema
larvae and to constitute a lesser stage in which
only asymptomatic adherence of the larvae occurred. In
these cases, the larvae die within a period of weeks and
are expelled with the faeces 12 . A further form was gastric
anisakiasis, caused by stage III larvae and characterised
by epigastric pain episodes 13-16 . If the parasite was not extracted,
the disease could progress towards the invasive
forms of subacute or chronic anisakiasis 17-20 . There had
also been some reports of polyarthritis 21,22 and some rare
cases of invasion of other organs such as the lung, liver,
spleen and pancreas 23 . In these cases of advanced anisakiasis,
IgE and eosinophils had been implicated in the
pathogenesis of the local lesions caused by the parasite
16,24-29 . Only occasionally had localised maculopapular
lesions or generalised urticaria been reported in these patients
13,23,30 .
At that time, and up to 1996, many cases had already
been reported in the Netherlands and occasional ones in
France, the United Kingdom and the USA 3,4,11,20,31,32 . In
Spain, only anecdotal cases of anisakiasis had been published
between 1991 and 1996 21,33-35 .
In 1995, Spanish allergologists finally began paying
attention to Anisakis-induced disease because of reported
cases of allergic reactions after the intake of presumably
well-cooked fish in association to positive skin tests and
specific IgE for Anisakis, while the investigations were negative
for the fish supposedly involved in the reaction. Some
authors postulated that the fundament of Anisakis simplex
allergy was the heat-stability of a number of antigens
that might be able to bind to the patients’ IgE and trigger
hypersensitivity symptoms upon the ingestion of cooked
fish 38-40 .
After having observed some cases of anaphylaxis
with Anisakis simplex infestation 42 , a prospective study was
begun in 1997 at the "La Paz" University Hospital in Madrid
(Spain).
MATERIAL AND METHODS
Patients were entered into the study who were seen
at the Emergency Outpatient Clinic because of
allergic or gastrointestinal symptoms after the ingestion
of fish or seafood, irrespective of the preparation,
and including patients who had eaten the suspect food
up to 48 hours earlier. Endoscopy was performed if the
digestive symptoms persisted for over 6-8 hours. In all
patients entered, skin tests were performed with Anisakis
extract, with a panel of different fishes and with
the particular fish or seafood apparently involved in
the reaction. The total serum and fish- and Anisakis
simplex-specific IgE levels were also measured during
the acute episode, and the total IgE and Anisakisspecific
IgE were again measured one month after the
reaction.
RESULTS
Over a period of 18 months, 120 patients consulting
because of allergic symptoms were studied; in 96 of them
Anisakis simplex was actually involved. The associated digestive
symptoms were mild or moderate in most patients,
so that endoscopy was performed only in 47 of them. In
that period 24 infested patients were detected in whom
one or more parasites were removed from the stomach at
endoscopy.
The patient population was divided into three
groups:
1) Patients who had undergone endoscopy and were
actually infested.
2) Patients who had undergone endoscopy and were
not infested.
3) Patients who had not undergone endoscopy.
Vinegar-marinated anchovies and, in some cases,
presumably well-cooked fresh hake were the sources of
most parasitic infestations.
The latency period of the allergic symptoms was variable,
with a mean latency of ca. 6 hours but with a range
between minutes and over 24 hours, and with no differences
between the three groups.
In many cases the digestive symptoms had already
subsided, and endoscopy was not performed.
The total serum and specific IgE levels were significantly
increased one month after contact with the parasite
in all three groups.
232

Gastroallergic anisakiasis
The statistical analysis of the characteristics of the
three patient groups suggests that they were composed of
similar patients.
CHALLENGE TESTS AND LATER DIET
Over the time of the study no clearly defined cases
were seen of patients having had symptoms either with
deep-frozen fish (industrial preparations) or with sufficiently
cooked fish preparations. It is an axiom in Allergology
that, when doubts arise as to a given allergen being
the cause of a given reaction, challenge tests with that
allergen are proposed, besides the usual in vitro assessments
and skin tests.
Live parasites were frozen until they became non-infective.
Challenge tests were then performed, initially giving
from 11 to 20 parasites to a total of 20 out of the 96
patients, with negative results. The challenge tests were
thereupon interrupted, and the remainder of the patients
were allowed to eat deep-frozen fish or seafoods; the tolerance
was repeatedly checked in successive six-monthly
visits and up to the time of writing. In a total of 76 patients
so investigated, no problem related to the ingestion
of deep-frozen fish has been detected until now. Twenty
patients were lost to follow-up, as they did not attend the
successive review visits.
DISCUSSION
In 1995, the conditions caused by Anisakis simplex
were differentiated into a number of clinical forms according
to the digestive tract region involved. Gastric anisakiasis
was caused by stage III larvae; in this particular
form the larvae reach the submucosa through the action of
peptidases, and induce epigastric pain due to the inflammatory
reaction of the viscus wall 13-16 . If the parasite(s) were
not extracted, the condition progressed to the subacute or
chronic anisakiasis form. The larvae might be able to traverse
the gastric or intestinal wall; the parenteral invasive
form resulting might cause granulomata or abscessification
in association to eosinophilia, fever, diarrhoea and abdominal
pain. This situation might mimic acute appendicular
episodes, but true appendicitis and episodes of intestinal
obstruction had also been reported 17-20 . Infrequent cases of
polyarthritis 21,22 and still rarer ones of distant organ invasion
(lung, liver, spleen and pancreas) 23 had also been described.
In these cases of anisakiasis, both the IgE and the
eosinophils had been implicated in the aetiopathogenesis
of the local lesions caused by the attachment of the parasites
16,24-29 . In the course of a first contact, the parasitic infestation
might induce a mild chronic inflammatory reaction
in the mucosa. The acute forms would then be due
to type I or type III hypersensitivity reactions in the digestive
tract in the course of secondary infestations 16,29,30 .
Only occasionally had localised maculopapular lesions
and generalised urticaria been reported in these patients
13,23,30 .
In Europe, and up to 1996, over 100 cases had been
reported in the Netherlands (collected between 1995 and
1968) 3,4,11 ; and there had been occasional case reports in
France, the United Kingdom and the USA from 1975 onwards
11,20,31,32 . In Spain, some six cases had been reported
between 1991 and 1996; cases of anisakiasis were anecdotal
at that time 21,33-35 , but from that year onwards the number
of reports increased progressively.
In 1995 the Spanish allergologists were made aware
of Anisakis-induced disease through cases of allergic reactions
after the ingestion of presumably well-cooked fish
with positive skin tests and specific IgE to Anisakis while
the studies were negative for the fish supposedly involved
in the reaction 36-41 . The reports of Anisakis simplex sensitisation
multiplied, and some confusion arose regarding the
value of some positive tests in patients describing no allergic
reaction at all, and of course no previous infestation
by Anisakis simplex (ca. 13%). For some authors, the basis
of Anisakis simplex allergy was to be found in the heatstability
of some antigens of the parasite, which would be
able to bind to the patients’ IgE and trigger hypersensitivity
symptoms upon the ingestion of cooked fish 38-40 .
After having observed a number of cases of anaphylaxis
associated to Anisakis simplex infestation 42 , a prospective
study was initiated at the "La Paz" University
Hospital in Madrid. Over a period of 18 months 120 patients
were assessed, who had consulted because of allergic
symptoms (in many cases life-threatening anaphylaxis
or anaphylactic shock); in 96 of them Anisakis simplex
was truly implicated in the reactions 43-49 . The associated digestive
symptoms were mild or moderate in most patients,
and for this reason only 47 patients underwent endoscopy.
To our surprise, over those 18 months, and based on the
allergic symptoms, 24 patients were detected in whom one
or more parasites were removed from their stomachs (almost
more parasites found over a period of 18 months
than in the whole of the Spanish literature between 1991
233

M. a C. López Serrano, et al
and that time). The very typical "boquerón en vinagre"
(vinegar-marinated anchovies) and in some cases presumably
well-cooked fresh hake were the sources of most
infestations. The latency period of the allergic symptoms
was quite variable, ranging between a few minutes and
over 24 hours. The average latency for the digestive
symptoms was similar, although they tended to occur
slightly earlier. No endoscopy was performed when the digestive
symptoms had already subsided at the time of seeing
the patient. The total serum IgE and the specific IgE
were found to be significantly increased one month after
the index contact 45,47,48 .
The statistical analyses suggested that the study population
was formed by similar patients, in whom in some
cases the parasite became attached to the gastric mucosa
for a time sufficient for triggering the allergic reaction;
however, its trend to then detach and be expelled does not
allow it to be detected in time at endoscopy. The authors
termed this particular condition gastroallergic anisakiasis"
42-51 , differentiating it from gastric anisakiasis, as the
hypersensitivity symptoms after contact with the parasite
were more intense and severe than the gastric ones. However,
in the course of the study period and also in a review
of previous suggestive cases from our Hospital no cases
were detected in which symptoms had arisen after consuming
industrially deep-frozen or sufficiently cooked fish.
In the light of this observation, it would appear that in
most cases the live parasite had been the antigen source,
and furthermore, that the parasite required attachment to
the submucosa in order to elicit the hypersensitivity reaction.
At this point in time, true allergy to heat-stable proteins
of Anisakis simplex appeared to be less frequent than
previously supposed, and it was thought that the IgE-mediated
response corresponded, in most of the sensitised patients,
to previous contacts with the live parasite (transient
infestation either in the luminal form or clinically asymptomatic).
Adhering to the diagnostic procedure usually applied
in Allergology whenever there is doubt about a given antigen
as the cause of a given reaction, the next step in these
patients with gastroallergic anisakiasis was challenge testing
with non-infective frozen parasites 50 . Tolerance was
confirmed in a number of patients, and from then onwards
the remainder of the patients were allowed to eat deep-frozen
fish, with no untoward problems arising.
The immunologic and inflammatory response to the
parasite may explain most of the clinical symptoms and
signs in anisakiasis. The parasite avails itself of proteases
in order to achieve attachment to the gastrointestinal mucosa.
It is quite possible that local factors such as preexisting
mucosal lesions, changes in gastrointestinal motility
or changes in the environmental pH may influence not
only the parasite’s ability to become attached but also the
duration of such attachment end even the possibility –rather
more remote, but already reported– of transmucosal
penetration. Once attached to the submucosa, the secretion
of proteins by the parasite sets in motion the defensive
response of the rich gastrointestinal lymphoid tissue. The
type of anti-parasite response in this case is predominantly
Th2. Thus, the expression pattern of cytokines such as IL-4
and IL-5 leads to chemotactic attraction of eosinophils and
to intestinal lymphoid tissue hyperplasia and also to a stimulation
to IgE production, with the subsequent increase
of the total and parasite-specific IgE levels 16,24-29,48 . Other
immunoglobulins are also produced and may in some cases
lead to immune-complex-mediated responses.
The symptomatology of anisakiasis would be mediated
mainly by this inflammatory response and in some cases
by the penetration of the parasite. If the response is
maintained only in the local gastric environment, acute
gastric anisakiasis will ensue. Further to this, the already
initiated immune response may induce distant hypersensitivity
symptoms mediated by IgE –and therefore allergic–,
which seem to be rather frequent: gastro-allergic anisakiasis.
Immune complexes might explain the articular manifestations
sometimes observed but, in the light of the published
reports, are rather infrequent. Subacute or chronic
anisakiasis is usually seen at the intestinal level, and the
inflammation (even though the parasite may have already
been expelled with the faeces) may induce mucosal changes
leading even to an acute abdomen. If the parasite still
remains within the digestive tract wall, or even achieves
its penetration, surgery will be required in most of these
cases. In very rare cases, penetration of the parasite leads
to its apparition in exceptional locations such as the lung,
the liver, the spleen or the pancreas.
In the cases of subacute or chronic anisakiasis, distant
hypersensitivity manifestations are infrequent.
The previous history of fish or seafood ingestion, the
clinical manifestations, the endoscopic and radiologic examination,
the response to the skin tests and the serial measurements
of the specific IgE Anisakis simplex antibodies
are important clues for the diagnosis.
Cases may exist of true Anisakis simplex allergy but,
in the light of the results of this prospective study, they
234

Gastroallergic anisakiasis
should not be particularly frequent. Challenge tests with
non-infective parasites should be the clue for diagnosis in
these cases, keeping in mind the importance of the subsequent
dietary restrictions 50,52 .
The best therapeutic measure for anisakiasis is
prophylaxis and prevention, avoiding the ingestion of raw
fish or of fish prepared in ways that do not extinguish the
viability of the larvae. Industrial smoking should achieve
temperatures of at least 60ºC for at least 10 minutes if it is
to be considered safe. The larvae may withstand conditions
such as 50 days at 2ºC, 60 days in vinegar, 6 days in formaldehyde,
or 2 hours at –20ºC. however, they are unable
to resist over 2 minutes at temperatures in excess of 60ºC.
The infestation rates of fish are high, ranging from
40 to 80% of the pieces examined depending on the species
6-9 . The prophylactic measure imposed by law within
the European Union, that is to compulsorily deep-freeze
any fish destined to commercialisation for raw consumption
to –20ºC for at least 24 hours, has dramatically reduced
the incidence of anisakiasis in many regions in Europe.
In Spain, the main problems resides in the lack of
information on the side of the home cooks or of the restauration
industry, so that the fish that has been bought
and prepared either raw or undercooked not necessarily
has complied with that ruling.
The observation by the Allergologists has only made
manifest (and put a name) one disease condition that has
probably existed for a long time 42-51 . Because of this renewed
vigilance, there is a continuing increase of the number
of cases reported in Spain, where preventive rulings
that do exist are not sufficiently applied.
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