Guidelines in pathology induced by Anisakis Original Article

J. Domínguez Ortega,
C. Martínez-Cócera
Allergy Service, "San Carlos"
University Hospital,
Madrid, Spain.
Original Article
Alergol Inmunol Clin 2000;15:267-272
Guidelines in pathology induced by
Anisakis
Anisakiasis or anisakidosis is the infestation of man by the third larval
stage of the parasite Anisakis simplex. The frequency with which parasitised
fish is found in our environment and the alimentary habits regarding
fish lead to thinking that the incidence of anisakiasis cases among the population
is greater than the one reported until now. It is therefore necessary
to know the various forms of the disease, its diagnosis and –particulary
significant for the Allergologist– the therapeutic recommendations, including
the prior deep-freezing of the fish and/or the dietetic advice of avoiding
the ingestion of raw or undercooked fish. The present paper summarises
a number of basic points, a guideline, which may lead us to a better
knowledge and understanding of this parasitisation and, through this knowledge,
to achieve a better identification of cases. A further aim is to stress
that the exclusion from the diet of every and all kinds of fish is in most cases
unwarranted and unnecessary.
Key words: Anisakis simplex. Anisakiasis. Anisakidosis. Diagnosis. Treatment. Dietary
advice.
Guía de actuación en patología producida por
Anisakis
La anisakiasis o anisakidosis consiste en la parasitación del hombre por la
larva, en su tercer estadio de desarrollo, del parásito Anisakis simplex. La frecuencia
con que encontramos en nuestro medio pescado parasitado y los hábitos
de consumo del mismo, hacen suponer una mayor incidencia de casos en
la población que la comunicada hasta ahora. Es por ello imprescindible conocer
las diferentes formas clínicas de la enfermedad, su diagnóstico y, de modo
especialmente significativo para el alergólogo, las recomendaciones terapéuticas,
incluyendo la ultra-congelación previa del pescado y/o las normas dietéticas
de evitación del mismo, crudo o poco cocinado. Recogemos en este trabajo
unos puntos básicos, una guía de actuación, que nos aproxime a un mayor
conocimiento de esta parasitación y, con ello, lograr una mejor identificación
de los casos. Del mismo modo, se pretende destacar que la retirada de la dieta
de todo tipo de pescado es, en la mayoría de los casos innecesaria.
Palabras clave: Anisakis simplex. Anisakiasis. Anisakidosis. Diagnóstico. Tratamiento.
Consejo dietético.
267

J. Domínguez Ortega, et al
INTRODUCTION
Anisakiasis -or anisakidosis- represents the infestation
of man by the third larval development stage of the
parasite Anisakis simplex.
The high rate of fish consumption in Spain and the
rather high frequency of its consumption as raw or undercooked
preparations leads us to presume that the incidence
of disease conditions associated to contact with the Anisakis
simplex parasite is greater than the one reported up to
now. A better knowledge of the clinical forms of these
conditions on the side of the physician, and particularly so
on the side of the Allergologist, is a sine qua non requisite
for their correct diagnosis. The present concise guidelines
aim at serving as a basis for a better approach to these diseases.
The following general outline may be considered at
the time of approaching the diagnosis of the disease and
the ensuing therapeutic intervention:
1. Anamnesis
2. Initial complementary studies
a) Plain radiographies
b) Ultrasonography
c) Endoscopic procedures
3. Anatomopathological study
4. Immunoallergic study
a) Skin prick tests
b) Quantitation of the serum total IgE and specific
Anisakis simplex IgE levels
c) IgE immunoblot
d) Challenge tests
ANAMNESIS
A correct anamnesis is indispensable for a correct
diagnosis of the disease. A history of ingestion of raw or
undercooked cephalopods or fish (salted, smoked, marinated,
or insufficiently cooked in a microwave oven 1 ) up to
48-72 hours before the onset of symptoms is highly orientative.
Although a large number of potentially infested
species exist, as demonstrated by Sanmartín et al. in 18 of
23 species of fish from the Galician coast studied 2 , anchovies,
which are frequently consumed raw (marinated in vinegar),
and squid among the cephalopods, are frequently
implicated. However, in each geographic area a seasonal
cycle appears to exist in which the infestation of fish is
more frequent.
268
1600
1400
1200
1000
800
600
400
200
0
IgE IgE esp
Specific IgE
1 mes moth
3 meses moth
6 meses moth
Fig. 1. Evolution of the serum total and specific anti-Anisakis simplex
IgE. The graph reproduces the variations in the total and specific Anisakis
simplex IgE levels (mean values from a series of 12 patients
with intestinal anisakiasis assessed at our Service) after one, three
and six months of a strict fish-free diet.
A good organ, system and apparatus anamnesis
should be recorded, as there are several different clinical
pictures that may be encountered. Among the gastrointestinal
forms, the following ones should be borne in mind:
The luminal form is the one in which there is only
adherence of the parasite to the digestive mucosa; this
form is asymptomatic, and the larvae may be detected in
the faeces or the vomit.
The gastric form features epigastric pain, nausea and
occasionally vomiting. Cutaneous symptoms may also occur
in association to the gastric manifestations 3 . The symptoms
usually begin 24 to 48 hours after the ingestion.
The intestinal form mimics acute appendicitis, diverticulitis
or ileitis. This form features abdominal pain and
changes in the intestinal rhythm resembling an obstructive
episode 4-6 (due to the fact that in the affected area the intestinal
wall is covered by a fibrinous exsudate and thickened
by oedema). The ability to produce a number of proteases
(aminopeptidase, trypsine-like protease and several
hyaluronidases) that may attack and degrade macromolecules
and thus favour penetration enables the parasite larva
to perforate the gastrointestinal mucosa. It is thus even
possible to find true intestinal wall perforation leading to
peritoneal manifestations 7 . Extraintestinal forms (hepatic,
splenic and pulmonary) have been reported as well as totally
extradigestive ones (articular involvement, one case
of asthma 8 and one of occupational conjunctivitis due to
Anisakis sensitisation in a fishmonger 9 ).
There is a group of patients who report cutaneous
and systemic reactions after the ingestion of fish but tolerate
such ingestion at other times. These patients have been
included in the condition traditionally termed "Anisakis
allergy". Although the most frequent manifestation is urticaria,
angioedema and even anaphylactic shock have also

Fig. 2. Plain film of the abdomen in bipedestation. Air-fluid levels and
dilated intestinal loops can be seen.
been reported. In some cases, the cutaneous or anaphylactic
symptoms are associated to the digestive ones 10 .
LABORATORY DETERMINATIONS
As in many other disease conditions coursing with an
acute abdomen, the white blood cell differential count, although
it may on occasion show no changes, may evidence
a more or less marked leukocytosis with slight or moderate
neutrophilia or eosinophilia; a later increase of the eosinophil
count may be observed starting 24 hours after the onset
of the clinical symptoms. The blood biochemistry is
usually unremarkable unless complications of the intestinal
pseudo-obstruction itself occur (repeated vomiting, etc.).
Although at present not routinely measured, the serum Eosinophil
Cationic Protein (ECP) levels seem to be consistently
and markedly increased in this first phase, indicating
Guidelines for Anisakis-induced disease
a marked eosinophil activation and orienting the diagnostic
process towards an eosinophilic inflammatory infiltrate.
RADIOLOGY
The gastric forms evidence no recognised radiological
pattern. In the intestinal forms, the conventional radiology
(plain films of the abdomen) shows a pseudo-obstruction pattern,
with dilated small intestinal loops and air-fluid levels in
the lateral decubitus or bipedestation projections (Fig. 2).
The use of contrast media for imaging does not represent
a first choice, although images of wall thickening,
intestinal lumen narrowing with pseudotumour images,
"fingerprint" signs and, very rarely, radiolucent lineal areas
corresponding to the larvae may be seen.
In the ultrasonography, which is the imaging technique
of first choice in these cases, there is thickening of the intestinal
wall, free peritoneal fluid in variable quantities, narrowing
of the intestinal lumen and diminished peristaltism 11 .
ENDOSCOPY AND
ANATOMOPATHOLOGICAL STUDIES
The certainty diagnosis is provided by the visualisation
of the larva or larvae at gastroendoscopy or colonoscopy;
these procedures also allow the larvae to be removed and resolution
of the clinical condition ensues. Moderate to severe
mucosal oedema may be observed in the first two days after
infestation by the parasite, the severity of the clinical symptoms
and the endoscopic findings bearing a close relationship
to the duration of the condition 12 .
The anatomopathological study of a surgical specimen
will also allow the identification of Anisakis larvae. In the
early stage of the parasitic infestation there is oedema and
non-specific inflammatory infiltration; later stages invariably
evidence an eosinophilic infiltrate that may involve only the
mucosa, or also deeper layers of the intestinal wall (Figs. 4
and 5). Peritoneal involvement may be seen after perforation
of the intestinal wall by the parasite has occurred.
SKIN TESTS AND IGE DETERMINATIONS
Skin prick tests
The skin prick tests are usually performed with com-
269

J. Domínguez Ortega, et al
Fig. 3. Abdominal ultrasonography showing thickened walls of the
intestinal loops and free intraabdominal fluid.
mercial Anisakis simplex extracts at a 1-mg/ml concentration,
with both early (15 min) and late (24 h) readings. A
number of cases of anaphylaxis during skin prick testing
have been reported 13 .
The skin prick tests have low specificity, as they do
not discriminate between true positive results and cross-reactions
to other parasites such as Ascaris or Echinococcus.
The skin tests with a panel of different fish extracts
are consistently negative.
IgE quantitation
The serum levels of total IgE and Anisakis simplexspecific
IgE are assessed using the CAP-radioimmunoassay
technique. Increased levels of both are usually found
and their evolution has been observed to be associated, the
total and specific IgE levels decreasing together over time
if a fish- and cephalopod-free diet is instituted 14 (Fig. 1).
IgE, IgG and IgA immunoblot
These techniques are useful for the differentiation of
cross-reactions from true anisakiasis. Although no homogeneous
pattern is known to exist, in the first case (cross reactions)
the sera recognise exclusively intermediate-molecular weight
antigens when tested against the parasite proteins, while the
sera of patients with true Anisakis infestation will also recognise
low-molecular weight (14 - 30 kDa) antigens15 (Fig. 6).
These low molecular weight antigens are thought to correspond
to so-called secretory/excretory larval antigens
DIETETIC CONSIDERATIONS
When faced with a patient diagnosed of anisakiasis,
the question arises whether a strict fish-free diet is absolu-
270
Figs. 4 and 5. Histopathology study of the surgical specimen of a
patient with suspected anisakiasis. There is a marked eosinophyllic
infiltrate extending even into the muscular layer of the intestinal wall.
tely necessary, and even more so when fish represents a
basic alimentary component in many other conditions such
Fig. 6. IgE immunoblot (from the studies by Dr. Moneo and Dr. Fernández
de Corres). Several intermediate-molecular weight bands
(30 - 50 kDa) as well as other low-molecular weight ones (14 - 30
kDa) can be identified.

as coronary artery disease or in the treatment of morbid
obesity.
Some authors consider that repeated, sometimes
asymptomatic infestation may trigger a sensitisation to
protein antigens, inducing an IgE-mediated response and
thus the cutaneous or anaphylactic manifestations. These
authors recommend full avoidance of any fish or seafood
whatsoever.
However, an ever-increasing group of investigators
postulates that this condition actually represents an unusually
inadequate response to the parasite, similar to that
seen in other parasitoses such as echinococcosis (hydatid
cyst disease). The presence of the live parasite in the gastrointestinal
mucosa would then induce the release of secretory/excretory
antigens and an IgE-mediated response
to the parasitic infestation. In this context, a number of
groups in our own country are currently performing oral
challenge tests with lyophilised or frozen larvae both in
patients with "gastroallergic" anisakiasis 16 and in those
with only cutaneous and/or anaphylactic symptoms, and
their results lend support to the second theory.
MANAGEMENT
The management of the gastrointestinal forms of
Anisakis-induced disease should be conservative if extraction
of the larvae is not achieved, although even surgery
may become necessary in cases with intestinal perforation
and peritonitis.
In the cutaneous and/or anaphylactic forms, the management
should consist of immediate medical intervention
with administration of epinephrine, antihistamines and
parenteral corticosteroids in the same way as for any secondary
anaphylactic reaction of any aetiology.
However, it should be pointed out that the fundamental
basis of the management of this particular parasitic
infestation is that of prophylactic measures so as to prevent
the ingestion of the live parasite:
Avoidance of the ingestion of raw or poorly cooked
fish including salted, smoked, soused or marinated fish or
insufficiently-cooked fish preparations (microwave oven
or grill).
Deep-freezing the fish at -20ºC for at least 72 hours
prior to its preparation for consumption. Fish that has been
deep-frozen already in the fishing grounds should be preferred,
as this has been eviscerated at an early stage and
the possibility of parasites having passed into the flesh is
Guidelines for Anisakis-induced disease
consequently less. Any cooking of fish or cephalopods
should attain core temperatures of at least 60ºC.
Insisting on adequate legislation as to production and
marketing of fishery products, with strict health and sanitary
controls by the authorities concerned to guarantee
compliance. Such legislation has already been implemented
in the Netherlands, achieving a marked reduction in
the number of cases. Similar legislation exists also in
Spain, although the high rate of home-preparation of fish
may perhaps hinder its correct application.
REFERENCES
1. Cnut Blasco A, Labora Lóriz A, López de Torre J, Romeo Martínez
JA. Anisakiasis gástrica aguda por cocción insuficiente en horno microondas.
Med Clin 1996; 106: 317-318.
2. Sanmartín ML, Quintero P, Iglesias R, Santamaría MT, Leiro J,
Ubeira FM. Nemátodos parásitos en peces de las costas gallegas.
Madrid. Díaz de Santos, 1994; 31-37.
3. Alonso A, Daschner A, Moreno-Ancillo A. Anaphylaxis with Anisakis
simplex in the gastric mucosa. N Engl J Med 1997; 337: 350-351.
4. López Vélez R, García A, Barros C, Mazarbeitia F, Oñate JM. Anisakiasis
en España. Descripción de 3 casos. Enf Infecc Microbiol
Clin 1992; 10: 158-161.
5. Martín Cabanna J, Monturiol JM, Louredo A, Valentín Gamazo C,
Jiménez J, Jiménez P, Alcázar JA, Rueda JA, Quitans A. Abdomen
agudo y anisakiasis: a propósito de dos casos. Cir Esp 1994; 56
Supl 1: 265.
6. Gómez B, Tabar AI, Larrinaga B, Álvarez MJ, García BE, Olaguibel
JM. Eosinophilic gastroenteritis and Anisakis. Allergy 1998; 53:
1148-1154.
7. Arenal Vera JJ, Marcos Rodríguez JL, Borrego Pintado MH, Castro
L, Blanco Álvarez JL. Anisakiasis como causa de apendicitis aguda y
cuadro reumatológico: primer caso en la literatura médica. Rev Esp
Enf Digest 1991; 79: 355-358.
8. Armentia A, Lombardero M, Callejo A, Martín Santos JM, Gil FJ,
Vega J, Arranz ML, Martínez C. Occupational asthma by Anisakis
simplex. J Allergy Clin Immunol; 102: 831-4.
9. Añíbarro B, Seoane FJ. Occupational conjuctivitis caused by sensitization
to Anisakis simplex. J Allergy Clin Immunol 1998; 102: 331-
332.
10. Moreno-Ancillo A, Caballero MT, Cabañas R, Contreras J, Martín
Barroso JA, Barranco P, López Serrano MC. Allergic reactions to Anisakis
simplex parasiting seafood. Ann Allegy Asthma Immunol 1997;
79: 246-250.
11. Shirama M, Koga T, Ishibashi H, Uchida S, Ohta Y, Shimoda Y.
Intestinal anisakiasis: US in diagnosis. Radiology 1992; 185:789-
793.
12. Saburo Kakizoe, Hiroshi Kakizoe, Keiji Kakizoe, Yumiko Kakizoe,
Masumi Maruta, Tamako Kakizoe, Shinobu Kakizoe. Endoscopic
findings and Clinical Manifestation of Gastric Anisakiasis. Am J Gastroenterol
1995; 90: 761-763.
13. Carretero P, Rivas C, Todo P, Gómez B, Núñez C, Alday E, More-
271

J. Domínguez Ortega, et al
no I. Anafilaxia tras realización de prick-test a Anisakis simplex. Rev
Esp Alergol Inmunol Clin 1998; 13: 226-228.
14. Daschner A, Alonso Gómez A, Caballero T, Suárez de Parga JM,
López Serrano MC. Usefulness of early serial measurement of specific
and total immunoglobulin E in the diagnosis of gastroallergic anisakiasis.
Clin Exp Allergy 1999; 29: 1260-1264.
272
15. García M, Moneo I, Audícana MT, Del Pozo MD, Muñoz D, Fernández
E, Díez J, Etxenagusia MA, Ansotegui IJ, Fernández de Corres
L. The use of IgE immunoblotting as a diagnostic tool in Anisakis
simplex allergy. J Allergy Clin Immunol 1997; 99: 497-501
16. Alonso A, Moreno-Ancillo A, Daschner A, López Serrano MC.
Dietary assessment in five cases of allergic reactions due to gastroallergic
anisakiasis. Allergy 1999; 54: 517-520.