Anisakis simplex and related worms are natural parasites

Transcription

1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2005;3: Anisakis Simplex Induced Small Bowel Obstruction After Fish Ingestion: Preliminary Evidence for Response to Parenteral Corticosteroids LAURA RAMOS,* CARMEN ALONSO,* MAR GUILARTE, JAIME VILASECA,* JAVIER SANTOS,* and JUAN RAMON MALAGELADA* *Digestive System Research Unit and Allergy Unit, Hospital Universitari Vall d Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain Background & Aims: Gastrointestinal anisakiasis, a fishborne zoonoses, may be acquired by humans after the ingestion of raw marine fish infested with larvae of the nematode Anisakis simplex. Because of the invasive nature of the parasite, inflammatory obstruction or perforation of the gut wall may result. Although rare, Anisakis-induced intestinal obstruction is becoming a growing public health problem in Mediterranean areas, such as Spain, with a high fish-intake based diet. Unawareness of this entity and nonspecific clinical symptoms, along with the lack of alternative therapeutic options other than conservative measures, may explain why half of these patients require abdominal laparotomy for diagnostic and therapeutic purposes. Methods: We describe a series of 8 patients with acute intestinal anisakiasis treated in our center from July 2001 to January Results: The first 3 patients underwent segmental ileal resection for imminent peritonitis. The remaining 5 patients were treated with intravenous 6-methylprednisolone (1 mg/kg/24 h) for 5 days with fast clinical and radiologic resolution in all 5 patients with no adverse reactions. Conclusions: Although preliminary, our data may suggest that parenteral corticosteroids could be a reasonable, inexpensive, and safe alternative in these patients to prevent intestinal resection. Anisakis simplex and related worms are natural parasites of a great variety of marine species. Adult forms of A simplex live in the digestive tract of marine mammals such as dolphins and whales. Fertilized eggs are excreted to seawater and infect copecods and small invertebrates where they become infective for fish and larger invertebrates. Human anisakiasis, a fish-borne zoonoses, may be acquired by humans after the ingestion of raw or undercooked seafoods infested with third- or fourth-stage larvae of the nematode A simplex. 1 The distribution of human anisakiasis is universal, but predominates in countries such as Japan, Peru, or The Netherlands where consumption of raw fish (sushi, sashimi, cebiche, smoked herring) is or has been very frequent. In Spain the first case was observed in Since then, the incidence of anisakiasis has increased dramatically, with hundreds of allergic responses and more than 50 cases of intestinal obstruction being reported in the past 10 years. 3 5 The main risk factor for the infection in the Spanish population is the ingestion of boquerones en vinagre (pickled anchovies, Engraulis encrasicholus), a traditional Spanish appetizer. Unfortunately, intestinal obstruction sometimes evolves to gut perforation or peritonitis despite usual conservative measures. In these cases surgical resection of the affected gut segment is mandatory because no other alternative treatments have been proven efficacious to prevent laparotomy. We describe 8 patients in whom small-bowel obstruction developed caused by acute intestinal anisakiasis. In 5 of the patients, early administration of parenteral corticosteroids prompted clinical and radiologic resolution and therefore emergency laparotomy was avoided. Patients and Methods All patients in this series ingested undercooked (patient 2 ingested cod) or raw fish (all other patients ingested pickled anchovies) in the week before admission. The first 3 patients underwent surgery because of the lack of response to conservative measures that included fasting, nasogastric aspiration, analgesia, and intravenous fluid therapy. After resolution of the intestinal obstruction in patient 4 with parenteral corticosteroids, we developed a treatment protocol for future patients with the aim of preventing surgical intervention. Thus, patients fulfilling inclusion criteria (ingestion of raw fish in the 4 days before admission and segmental intestinal obstruction on computed tomography [CT]) were prospectively treated in the first 24 hours after admission with 6-methylprednisolone (1 mg/kg/24 h, intravenous) for 5 days (patients 5 8). Abbreviations used in this paper: CT, computed tomography; Ig, immunoglobulin; SPT, skin prick test by the American Gastroenterological Association /05/$30.00 PII: /S (05)

2 668 RAMOS ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 7 Patient 1 A 32-year-old woman came to the emergency room after 3 days of abdominal pain, nausea, and constipation. Laboratory blood test results on admission are shown in Table 1. Plain abdominal radiographs showed dilated small-bowel loops with air-fluid levels. Thickening of the distal ileum (see Figure 1) and a small amount of free peritoneal fluid were seen on CT scan. The patient did not respond to conservative measures (increasing leukocytosis, progressive decrease of hematocrit, and signs of peritoneal irritation) and underwent segmental ileal resection hours after admission. Histopathologic examination revealed transmural eosinophil infiltration and the presence of A simplex. A skin prick test (SPT) with A simplex extract (1 mg/dl, IPI Laboratories, Madrid, Spain), total immunoglobulin (Ig)E and specific IgE titers against A simplex (CAP System Pharmacia, Uppsala, Sweden) were performed (Tables 1 and 2). Patient 2 A 34-year-old man developed generalized urticaria, facial angioedema, and shortness of breath immediately after fish consumption. Intramuscular corticosteroids (60 mg of 6-methyl-prednisolone in a single dose) were administered on admission at another hospital for anaphylaxis with clinical resolution in a few hours. Seven days later, he was admitted to our hospital after 96 hours of abdominal pain, nausea, and vomiting. Blood test results revealed leukocytosis and eosinophilia. Upper-gastrointestinal endoscopy showed acute gastric erosions. Plain abdominal radiographs showed dilated smallbowel loops without distal air. An abdominal CT scan showed narrowing of the proximal ileum, enlarged mesenteric nodes, and ascites. The patient did not improve on conservative measures for 24 hours (peritoneal irritation, progressive abdominal distention, decrease of hematocrit level) and an emergency laparotomy with small-bowel resection (18 cm) was performed. Examination of the excised gut segment showed eosinophilic enteritis but no parasite. The diagnosis of allergy to Anisakis and intestinal anisakiasis was corroborated by SPT and total and specific IgE titers (Tables 1 and 2). Patient 3 An 80-year-old man was admitted after 48 hours of diffuse abdominal pain and constipation. Leukocytosis was Table 1. Diagnostic Tests on Admission Patient White cells (cells/mm 3 ) Eosinophils (cells/mm 3 ) A simplex SPT 1 12, , , , , , , SPT, skin prick test. Figure 1. Abdominal CT scan showing thickening of the distal ileum. observed on blood tests. Abdominal plain films and a CT scan showed dilated small-bowel loops with a thickened distal jejunum. Because no improvement was observed on conservative measures, after 24 hours surgery was performed. A 15-cm stenotic segment was excised on laparotomy. Pathologic examination showed A simplex and intense eosinophilic infiltration of the gut wall. Other tests performed are shown in Tables 1 and 2. Patient 4 A 49-year-old man presented to the emergency room after 12 hours of abdominal pain, nausea, and vomiting. Diminished bowel sounds and diffuse tenderness were noted on physical examination. Leukocytosis was observed and abdominal CT scan showed dilated small-bowel loops, thickened proximal ileum, and free peritoneal liquid. Crohn s ileitis was suspected and 6-methylprednisolone (1 mg/kg/24 h, intravenous) was administered the first day. The day after, suspicion of anisakiasis was raised after the patient referred to frequent consumption of anchovies in vinegar and this was confirmed by SPT. Steroids were administered for up to 5 days. Seven days after admission, CT showed complete resolution and a colonoscopy with ileoscopy showed a normal ileum. Other results are shown in Tables 1 and 2. Patient 5 A 76-year-old man was brought to our hospital for abdominal pain and nausea initiated 24 hours after eating raw fish. Leukocytosis and eosinophilia were found. A CT scan showed thickening of the terminal ileum and free peritoneal liquid. The diagnosis of intestinal anisakiasis was corroborated by SPT and total and specific IgE titers (Tables 1 and 2). Scheduled treatment was given with complete clinical and radiologic resolution by day 5 after initiation. Patient 6 A 53-year-old woman was admitted because of 48 hours of colicky abdominal pain initiated after ingestion of

3 July 2005 ANISAKIS SIMPLEX 669 Table 2. Evolution of Total IgE (U/mL)/Specific IgE (KU/L) Months after admission Patient /40 88/ / / /77 281/ /27 188/16 137/ / / /22 148/16 56/6 27/4 13/2 6 44/14 11/4 7 62/28 122/92 99/75 44/19 26/ / / 100 NOTE. Normal serum values are as follows: total IgE 100 U/mL; specific IgE.35 KU/L. anchovies. Physical examination showed diffuse abdominal tenderness. Leukocytosis was present. Abdominal imaging showed thickened proximal ileal loops with luminal narrowing. Other tests performed are shown in Tables 1 and 2. The patient showed prompt clinical response to corticosteroids and abdominal CT showed a normal ileum 1 week later. Patient 7 A 62-year-old-man was admitted because of abdominal pain, nausea, and constipation. He had eaten anchovies in vinegar 48 hours before the onset of the symptoms. No leukocytosis was observed. An abdominal CT scan showed a thickened distal ileum. The diagnosis of intestinal anisakiasis was corroborated by SPT and total and specific IgE titers (Tables 1 and 2). Complete clinical and radiologic resolution was achieved within 5 days after steroid treatment. Patient 8 A 25-year-old man was admitted because of urticaria, abdominal pain, nausea, and vomiting 48 hours after consumption of raw anchovies. Leukocytosis was present. An abdominal CT scan showed enlargement of the distal ileum with narrowing of the intestinal lumen. Other results are shown in Tables 1 and 2. Complete clinical and radiologic resolution was obtained 4 days after steroid treatment. Results Of the 8 patients, 6 were men. The median age was 51 years (range, y). All patients had eaten undercooked or raw fish in the week before admission, mostly anchovies. Seven patients showed mild leukocytosis and in 2 patients (patients 2 and 5) eosinophilia was observed on admission. Increased levels of total IgE were present in 6 cases on the first blood test at the emergency ward. All patients showed increased specific IgE titers against A simplex. The SPT for A simplex was positive in all patients except patient 1. Image analysis (abdominal ultrasound or CT) confirmed small-intestinal obstruction in all patients. The first 3 patients in our series underwent segmental ileal resection for imminent peritonitis and in 2 patients parasite identification was achieved from the excised gut segment. The remaining 5 patients were treated prospectively with intravenous 6-methylprednisolone (1 mg/ kg/24 h) for 5 days with fast clinical and radiologic resolution in all 5 patients with no adverse reactions. Discussion The incidence of gastrointestinal anisakiasis is increasing worldwide and particularly in Spain, reaching 4 cases/100,000 inhabitants. 4 The origin of this increasing incidence is unknown, although physician awareness of the parasite and higher contamination of seawater by infested viscera thrown by fishermen after evisceration of their captures probably may contribute. 3 Herein, we report 8 cases observed at our institution in the Spanish region of Catalonia throughout a period of 24 months. Human anisakiasis comprise mostly allergic and digestive symptoms, although extradigestive manifestations also have been observed occasionally. Allergy to A simplex usually is manifested as an urticaria or angioedema starting 60 to 120 minutes after ingestion. 5 Remarkably, acute or recurrent anaphylactic responses affect more than 25% of the patients. Digestive syndromes may vary according to the gut segment involved, mostly the stomach or small intestine, and exceptionally the colon. 1,3,4 Gastric anisakiasis is the most common presentation in Japan, whereas intestinal anisakiasis is more frequent in Europe and North America. 1,3,5 The combination of digestive and allergic symptoms is frequent in gastric anisakiasis, but rare in the case of intestinal affectation. Two of our patients (patients 2 and 8) showed this combination. Intestinal anisakiasis may show up as an acute abdomen syndrome causing abdominal pain and distention, nausea, vomiting, constipation, and small-volume ascites resembling a peritonitis, appendicitis, or small-bowel

4 670 RAMOS ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 3, No. 7 obstruction. Acute forms involving the distal ileum are by far the most frequent and usually initiate in the first 72 hours after ingestion 6 as occurred in all our patients, although latency times of up to 10 days or longer have been described. In subacute or chronic presentations, patients may be asymptomatic or show nonspecific abdominal symptoms and the parasite may be found by chance during surgery. The pathogenesis is not well understood but worm as well as host defenses are critical. The nematode releases several proteases contained in the dorsal esophagic gland that can degrade the extracellular matrix, favoring tunnel formation and penetration into the gut wall. A metallo-aminopeptidase and a trypsinlike serine protease have been identified as part of the parasite tissue penetrating armamentarium. 7 9 Once the larva is fixed to the submucosa, a defensive host counterresponse is initiated. This immune response is dominated by Th2 lymphocytes and involves interleukin-4 and interleukin-5, enhanced IgE synthesis, hyperplasia of mast cells, and massive chemotaxis of eosinophils and other inflammatory cells. 10 Thickening of the gut wall caused by intensive transmural edema, narrowing of the intestinal lumen resulting in regional stenosis, and even perforation may appear. Other common pathologic features are mesenteritis, mesenteric adenopathies, and eosinophilic ascites. In acute phases of intestinal anisakiasis, blood tests usually show mild leukocytosis, increased levels of total IgE, and sometimes late eosinophilia. 1 Positive SPT for A simplex confirms sensitization to the parasite, but it is not diagnostic and can be negative even in the presence of the parasite as happened in patient 1 in our series. Specific IgE against A simplex is highly sensitive (100%) but not very specific (50%) because cross-reaction with other parasites (Ascaris, Toxocara, and Echinoccocus) and other unrelated microorganisms, insects, and plants occurs. 11 An antigen-capture enzyme-linked immunosorbent assay using O-deglycosilated antigen bound by the monoclonal-antibody UA3 is 100% sensitive and 100% specific, but not easily available. 11,12 Endoscopy cannot be considered as a diagnostic or therapeutic alternative in cases in which small intestine is affected because of obvious technical difficulties to reach the obstructed intestinal segment. However, ileoscopy sometimes is necessary to establish the differential diagnosis with other causes of distal regional enteritis. Imaging techniques such as ultrasound and computed tomography are useful to guide the diagnosis. Frequent findings are confined thickening of the gut wall, dilated small-bowel loops, marked edema of Kerkring s folds, and the presence of free peritoneal fluid, 13 signs that were present in all of our patients. Microscopically the lesions are characterized by intense edema and massive eosinophilic infiltration that may appear as a phlegmonous infiltrate and affect the whole intestinal wall. 1 Visualization and identification of the parasite is achieved in about 60% of cases, in 2 of 3 surgical specimens in our series, because the larva sometimes escape through the intestinal wall into the peritoneal cavity. 1 Although, conclusive and definitive diagnosis should be established only when the nematode is observed directly. The combination of consistent clinical, serologic, imaging, and pathologic data can be regarded as highly specific. This point can be shown by the second patient in our series. The parasite was not found in the gut wall but by the combination of an anaphylactic response to ingestion of undercooked fish, increased total IgE with high levels of specific IgE for A simplex, segmental ileal stenosis showing massive eosinophilic infiltration, and total recovery after surgical resection made other diagnostic possibilities (Table 3) very unlikely. 14,15 Although considered a benign disease by some investigators, 13 many of these patients undergo diagnostic laparotomy and segmental gut resection. 3,4 Whether this is caused by unawareness of anisakiasis or by the natural evolution of the disease is unclear. Antihelminthics may improve symptoms in some cases of chronic anisakiasis. 16 However, when intestinal obstruction is established no medical treatments other than conservative measures have been proven to be efficacious to prevent surgery. In our series 5 patients with acutely established intestinal obstruction by A simplex were treated with intravenous corticosteroids. We chose corticosteroids because of their well-known anti-inflammatory effect along with positive evidence showing temporal resolution of bowel obstruction in cases of advanced cancer and extremely low side effects in short therapeutic cycles. 17 There was a dramatic clinical and radiologic improvement in all 5 patients with ad integrum resolution, no need for surgery, and no adverse drug effects. Moreover, all patients were followed-up for at least a mean period of 10 months after Table 3. Differential Diagnosis of Anisakis-Induced Small-Bowel Obstruction Crohn s disease Primary eosinophilic gastroenteritis Postsurgical adherences Parasitic infections (Strongyloides, Ascaris, Toxocara, Ancylostoma) Tumors (lymphoma, leiomyoma, leiomyosarchoma) Bacterial infections (Yersinia, tuberculosis) Intussusception Granulomatous jejunoileitis Ischemia

5 July 2005 ANISAKIS SIMPLEX 671 the diagnosis. They were counseled on dietary measures and remained asymptomatic, showing a progressive decrease in total IgE and specific IgE for A simplex levels (Table 2). When compared with the first 3 patients in our series and with many other cases in the literature in which conservative treatment failed to prevent surgery, parenteral corticosteroids seem a very reasonable alternative. Moreover, although prospective and controlled trials are needed to corroborate our results, we are tempted to suggest the consideration of parenteral corticosteroids in cases of intestinal segmental obstruction, unless contraindicated, in which A simplex is suspected as the causative agent. Finally, we agree with other investigators that the best treatment of anisakiasis is prevention. Adequate manipulation and processing of fresh seafood, by cooking it at 60 C for at least 10 minutes, or freezing it at 20 C for at least 24 hours, already has been shown to kill the parasite (Directive 91/493/European Community) and thus to prevent digestive anisakiasis. In addition, public health authorities should promote adequate legislation and standards to protect the general public from this phenomenon. References 1. Ishikura H, Kikuchi K, Nagasawa K, et al. Anisakidae and anisakidosis. Prog Clin Parasitol 1993;3: Arenal Vera JJ, Marcos Rodriquez JL, Borrego Pintado MH, et al. Anisakiasis as a cause of acute appendicitis and rheumatologic picture: the first case in medical literature. Rev Esp Enferm Dig 1991;79: Lopez Penas D, Ramirez Ortiz LM, del Rosal Palomeque R, et al. Study of 13 cases of anisakiasis in the province of Cordoba. Med Clin (Barc) 2000;114: Repiso Ortega A, Alcantara Torres M, Gonzalez de Frutos C, et al. Gastrointestinal anisakiasis. Study of a series of 25 patients. Gastroenterol Hepatol 2003;26: Audicana MT, Ansotegui IJ, de Corres LF, et al. Anisakis simplex: dangerous dead and alive? Trends Parasitol 2002;18: Ishiguro A, Uno Y, Ishiguro Y, et al. Anisakiasis of the ileocecal valve. Gastrointest Endosc 2001;53: Sakanari JA, McKerrow JH. Identification of the secreted neutral proteases from anisakis simplex. J Parasitol 1990;76: Morris SR, Sakanari JA. Characterization of the serine protease and serine protease inhibitor from the tissue-penetrating nematode Anisakis simplex. J Biol Chem 1994;269: Hotez P, Cappello M, Hawdon J, et al. Hyaluronidases of the gastrointestinal invasive nematodes Ancylostoma caninum and Anisakis simplex: possible functions in the pathogenesis of human zoonoses. J Infect Dis 1994;170: del Pozo V, Arrieta I, Tunon T, et al. Immunopathogenesis of human gastrointestinal infection by Anisakis simplex. J Allergy Clin Immunol 1999;104: Lorenzo S, Iglesias R, Leiro J, et al. Usefulness of currently available methods for the diagnosis of Anisakis simplex allergy. Allergy 2000;55: Iglesias R, Leiro J, Santamarina MT, et al. Monoclonal antibodies against diagnostic Anisakis simplex antigens. Parasitol Res 1997;83: Ido K, Yuasa H, Ide M, et al. Sonographic diagnosis of small intestinal Anisakiasis. J Clin Ultrasound 1998;26: Walker NI, Croese J, Clouston AD, et al. Eosinophilic enteritis in Northeastern Australia. Pathology association with Ancylostoma caninum and implications. Am J Surg Pathol 1995;19: Van Laethem JL, Jacobs F, Braude P, et al. Toxocara canis infection presenting as eosinophilic ascites and gastroenteritis. Dig Dis Sci 1994;39: Moore D, Girdwood R, Chiodini PL. Treatment of anisakiasis with albendazol. Lancet 2002;360: Feuer DJ, Broadley KE. Corticosteroids for the resolution of malignant bowel obstruction in advanced gynaecological and gastrointestinal cancer. Cochrane Database Syst Rev 2000;2: CD Address requests for reprints to: Javier Santos, MD, Digestive System Research Unit, Hospital Universitari Vall d Hebron, Passeig Vall d Hebron , Barcelona, Spain. jsantos@vhebron. net; fax: (34)