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AnisakidosisDavidson H Hamer

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INTRODUCTIONHumans are accidental hosts to the intermediate larval stage of several species of zoonotic intestinal nematodes, which are acquired by the consumption of raw or undercooked marine fish or squid. Anisaki-dosis was first recognized more than 50 years ago in a patient in the Netherlands who presented with an eosinophilic intestinal lesion associated with severe abdominal pain. During the last two decades, these nematodes have been increasingly identified as causes of gastric, intestinal, and allergic syndromes in humans who have occupational exposure or frequently consume seafood.

Most human infections are caused by Anisakis simplex (also known as the herring worm) and Pseudoterranova decipiens (cod or seal worm) [1,2]. Other less common members of the family Anisakidae are the A. simplex complex (e.g. A. pegreffi) and the Pseudoterranova complex, as well as A. physeteris, Contracaecum spp. and Thynnascaris spp. The term anisakidosis refers to disease caused by any member of the family Anisakidae, whereas anisakiasis is caused by worms of the genus Anisakis and pseudoterranovosis by the genus Pseudoterranova.

EPIDEMIOLOGYThe annual incidence is greatest in Japan, where the consumption of raw fish is common. Of the approximately 20,000 reported cases worldwide, more than 90% occur in Japan [3]. Most other cases have been described in Korea and Europe, especially the Netherlands, Germany, France, Spain and Italy. During the last two decades, there have been increasing reports from the US, Canada, Brazil, Chile, Egypt

and New Zealand. The increase in prevalence of anisakidosis can be attributed to improved endoscopic diagnosis, increased consumption of raw or lightly cooked seafood, and larger populations of the defini-tive hosts [4]. While there have been approximately 60 cases reported in the US, anisakidosis is most likely greatly underdiagnosed and underreported.

Anisakidosis is associated with consuming raw, marinated, or incom-pletely cooked fish. In Japan, infections occur more frequently in coastal populations and in men aged 20 to 50 years. Fish served in sushi bars tend to be less contaminated or even free of Anisakis as sushi chefs are experts in identifying larval infestation. The risk of infection is greater with less-expensive marine fish such as cod, herring, mackerel and squid that are more frequently consumed at home or in local restaurants. The main fish species responsible for anisakiasis in Japan are mackerel and squid. In the Netherlands, herring is mainly responsible; in the US, Pacific salmon; and in Spain, pickled anchovies. Pseudoterranovosis rarely occurs in Japan and Europe. By contrast, it is more frequent in the US and Canada where P. decipiens is mainly transmitted by the Atlantic or Pacific cod, Pacific halibut, and red snapper.

Limited data from seafood markets suggest that substantial propor-tions of fish are infected with third-stage larvae (L3) of A. simplex. In Spain, greater infection rates in fish from the Atlantic Ocean are present than in those from the Mediterranean Sea. A substantial pro-portion of cod harvested in the Atlantic Ocean is infected with P. decipiens (Fig. 121.1).

l Humansareaccidentalhoststotheintermediatelarvaofmarinenematodes,especiallyAnisakis simplexandPseudoterranova decipiens

l Infectionresultsfromconsumptionofraworundertreatedmarinefishorsquid

l ThegreatestburdenofdiseaseisinJapanbutincreasedawarenessofanisakidosisandadventurouseatinghabitshaveresultedinagreaterworldwidedistributionofdisease

l Majorclinicalsyndromesincludegastric,intestinal,extraintestinal,andallergicanisakidosis

l Endoscopycanbeusedforbothdiagnosisandtreatmentofgastricanisakidosis

l Prolongedfreezing,flashfreezingatlowtemperatures,andadequatelycookingmarinefishareeffectiveforprevention

Key features

FIGURE 121.1 Pseudoterranova decipiens larvae embedded in the flesh of Atlantic cod.

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FIGURE 121.2 Life cycle of anisakids.

Humans become incidentalhosts through eating infectedraw or undercooked seafood

Diagnosis of gastric anisakiasis can bemade by endoscopy during which the ~2 cm larvae can be removed

Fish and squid maintain L3 larvae that are infectiveto humans and marine mammals

Marine mammals excreteunembryonated eggs

Infective stage

diagnostic stage

1

2b

2a

4

5

6

7

Eggs become embryonatedin water and L2 larvae formin the eggs

After the L2 larvae hatch fromeggs, they become free-swimming

Infected crustaceans are eaten by fish or squid.The third-stage larvae migrate into the viscera,peritoneal cavity and musculature of the secondintermediate host

When fish or squid containing L3 larvae are ingestedby marine mammals, the larvae molt twice and developinto adult worms. Adult worms produce eggs that areshed by marine mammals

i

i

d

d

3 Free-swimming larvae are ingestedby crustaceans and they mature into L3 larvae

NATURAL HISTORY, PATHOGENESIS, AND PATHOLOGYThe adult worm is found in the stomachs or intestines of marine mammals such as whales, dolphins, sea lions, and seals [5]. Eggs hatch in seawater to form free-living larvae (L2) that infect intermedi-ate hosts, usually crustaceans, e.g. krills (Fig. 121.2). Within the first intermediate host, the parasite matures into L3 larvae which are sub-sequently ingested by marine fish or squid, which serve as transport (second intermediate) hosts. The third-stage larvae migrate into the viscera, peritoneal cavity and musculature of this host. Ingestion of uncooked fish or squid by a marine mammal (final host) or humans (accidental hosts) leads to infection. The nematode larvae develop into fourth-stage larvae and then adults in the marine mammal final host.

Primary hosts for Anisakis are dolphins, porpoises, and whales. Primary hosts for P. decipiens are seals, walruses, and sea lions.

After ingestion of raw or undercooked saltwater fish by humans, the larvae embed themselves in the gastric or intestinal mucosa and then die. The burrowing or dead larva precipitates an intense hypersensitiv-ity reaction characterized by a granulomatous, eosinophilic tissue infiltrate. A Th2 immune response has been demonstrated in humans, with mucosal and submucosal inflammatory infiltrate composed of eosinophils and lymphocytes.

CLINICAL FEATURESThere are four major clinical syndromes in humans: gastric, intestinal, ectopic (or extra-gastrointestinal), and allergic [3]. Infection with P.

H U N T E R ’ S T R O P I C A L M E D I C I N E A N D E M E R G I N G I N F E C T I O U S D I S E A S E866

FIGURE  121.3 Third-stage larva of Anisakis simplex burrowing into the gastric mucosa. Surrounding erythema and edema of the mucosa are evident. (Endoscopic view courtesy of Drs Tomohiro Kato and Itaru O-I, Department of Medicine, Daini Hospital, Tokyo Women’s Medical University.)

A B

decipiens usually involves only the stomach and tends to be milder than disease due to Anisakis spp., which may cause symptomatic gastric or intestinal infections. Asymptomatic infections with Pseudo-terranova spp. may come to medical attention when the patient coughs up a live or dead worm. This usually occurs within 48 hours of the ingestion of infected fish and may be preceded by a sensation of feeling a worm crawling in the upper esophagus or pharynx, termed “tingling throat syndrome”.

Gastric anisakiasis is heralded by the abrupt (generally 1–12 hours after ingestion of raw fish) onset of severe epigastric pain, nausea, vomiting, and low-grade fever (Fig. 121.3). There is frequently leuko-cytosis with intense eosinophilia. Untreated gastric disease may lead to chronic, ulcer-like symptoms and can be more difficult to diagnose.

Intestinal anisakiasis is characterized by intermittent or constant abdominal pain that may be severe enough to result in peritoneal signs or a partial bowel obstruction. Symptoms may not appear until 5 to 7 days or longer after ingestion of the anisakid larvae. Intestinal infections predominantly occur in the terminal ileum; colonic or jejunal involvement is less common. Rare complications include small bowel obstruction, ileal stenosis, intussusception, intestinal per-foration, and pneumoperitoneum.

Ectopic, extra-gastrointestinal and intraperitoneal anisakiasis are less common complications which result from an anisakid larva penetrat-ing the full thickness of the stomach or intestine. This can lead to larval migration within the peritoneal cavity and, less commonly, the pleural cavity, mesentery, liver, pancreas, ovary, and subcutaneous tissue.

Anisakidosis may be associated with a strong allergic response [6]. Generally within 1 to 2 hours after the ingestion of infected fish, allergic reactions develop with manifestations ranging from urticaria and isolated angioedema to anaphylaxis. Allergic reactions are accom-panied by high levels of IgE including specific anti-A. simplex IgE. High levels of fish consumption and occupational exposure (e.g. fish processing) are associated with increased risk of allergy to A. simplex.

PATIENT EVALUATION, DIAGNOSIS, AND DIFFERENTIAL DIAGNOSISA history of recent consumption of raw or inadequately prepared fish or squid followed by the acute onset of epigastric or right lower quad-rant abdominal pain provide important diagnostic clues. Gastro-scopic or surgical removal and examination of the larva provides a definitive diagnosis of gastric anisakidosis. Besides directly visualizing the worm embedded in the gastric mucosa, endoscopy can reveal erythema, edema, erosions, a tumor-like nodule, or thickened gastric folds, which can suggest a diagnosis of lymphoma or gastric cancer.

Gastric anisakidosis can be misdiagnosed as a peptic ulcer, gastritis, or gastric carcinoma. As a result of the vague symptoms associated with intestinal infections, the differential diagnosis is broad and includes appendicitis, ileitis, diverticulitis, eosinophilic gastroenteri-tis, cholecystitis, colonic tumor, and inflammatory bowel disease. Extraintestinal infections may be confused with acute peritonitis, tuberculous peritonitis, and pancreatic cancer.

Detection of anti-A. simplex IgE by ELISA, latex agglutination, or other immunoassays can be used for the serodiagnosis of anisakiasis, but is not commercially available [6,7]. The diagnosis of allergy to A. simplex should be based on the following: a compatible history of allergic reactions after consumption or exposure to fish; positive skin-prick test; elevated specific anti-A. simplex IgE; and a lack of reaction to fish proteins. Multiplex PCR methods have been developed for identification of specific marine nematodes species in fish, but these are not available for human use.

TREATMENTEndoscopic extraction is the preferred treatment of gastric anisakido-sis unless the larva is spontaneously regurgitated. Surgical removal of the larvae may be necessary for intestinal or extraintestinal infections, especially if complications such as intestinal obstruction, appendici-tis, or peritonitis occur. If the diagnosis of intestinal anisakidosis can be established without the need for an invasive procedure, then con-servative, supportive therapy will often lead to clinical resolution. Limited evidence suggests that albendazole (400 to 800 mg daily for 6 to 21 days) is effective [8].

PREVENTIONThe best protection against anisakidosis is to avoid consumption of raw or inadequately cooked, marinated, or salted marine fish or squid. The risk of human infection can also be reduced by visual examination of fish, extraction of visible parasites, and removal of heavily parasitized fish from the market. Eviscerating fish as soon as possible after catch may decrease the number of larvae in the fish flesh by preventing migration from the intestinal tract into the edible mus-culature. Additional protective measures include thorough cooking, freezing at −20°C (−4°F) for 7 days, or blast freezing to −35°C (−31°F) for 15 hours or longer.

REFERENCES1. Audicana MT, Kennedy MW. Anisakis simplex: from obscure infectious worm

to inducer of immune hypersensitivity. Clin Microbiol Rev 2008;21:360–79.This review presents a comprehensive summary of the immunopathogenesis of anisakiasis.

2. McClelland G. The trouble with sealworms (Pseudoterranova decipiens species complex, Nematoda): a review. Parasitology 2002;124:S183–203.

3. Hochberg N, Hamer DH. Anisakidosis: perils of the deep. Clin Infect Dis 2010;51:806–12.This is a recently published comprehensive review of the epidemiology, clinical manifestations, treatment and prevention of anisakidosis.

4. Chai JY, Murrell KD, Lymbery AJ. Fish-borne parasitic zoonoses: Status and issues. Int J Parasitol 2005;35:1233–54.

5. Ishikura H, Kikuchi K, Nagasawa K, et al. Anisakidae and anisakidosis. Prog Clin Parasitol 1993;3:43–102.

6. Audicana MT, Ansotegui IJ, de Corres LF, Kennedy MW. Anisakis simplex: dangerous – dead and alive? Trends Parasitol 2002;18:20–5.This brief review provides an excellent overview of anisakiasis with an emphasis on the role of this parasite as a cause of food allergy in Spain and methods for diagnosis of allergy to A. simplex.

7. López-Serrano MC, Gomez AA, Daschner A, et al. Gastroallergic anisakiasis: findings in 22 patients. J Gastroenterol Hepatol 2000;15:503–6.

8. Pacios E, Arias-Diaz J, Zuloaga J, et al. Albendazole for the treatment of ani-sakiasis ileus. Clin Infect Dis 2005;41:1825–6.