Gnathostomiasis: An Emerging Infection of Raw Fish Consumers in Gnathostoma Nematode-Endemic and Nonendemic Countries

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1 318 REVIEW Gnathostomiasis: An Emerging Infection of Raw Fish Consumers in Gnathostoma Nematode-Endemic and Nonendemic Countries James H. Diaz, MD, Dr PH Schools of Public Health and Medicine, Louisiana State University Health Sciences Center (LSUHSC) in New Orleans, New Orleans, LA, USA DOI: /jtm Background. Gnathostomiasis, a helminthic infection commonly reported in Southeast Asia and Latin America, may follow consumption of raw seafood infected with muscle-encysted larvae of Gnathostoma species nematodes. As a result of increasingly exotic tastes for local ethnic dishes, including raw seafood, some regions outside of gnathostome-endemic areas import live species for raw consumption. This may facilitate imported human gnathostomiasis or potentially the establishment of this zoonosis in formerly nonendemic regions. Traveling to a gnathostome-endemic area is no longer a criterion for diagnosis. The objectives of this review are to enhance clinician awareness of this infection by describing the behavioral risk factors for its acquisition, life-cycle, clinical manifestations, diagnosis, management, and prevention. Methods. Internet search engines were queried with the key medical subject heading words. Case reports, case series, epidemiological investigations, and laboratory studies were reviewed; high risk behaviors for gnathostomiasis were identified; and human cases were stratified as cutaneous gnathostomiasis, visceral gnathostomiasis, neurognathostomiasis, and ocular gnathostomiasis. Results. The greatest risk factors for gnathostomiasis included the consumption of raw freshwater seafood dishes in endemic regions and the consumption of raw imported or domestic seafood dishes in households and ethnic restaurants in many nonendemic regions. Conclusions. Gnathostomiasis is no longer a disease of returning travelers, and autochthonous cases may be anticipated to increase as a result of the importation of live Gnathostoma-infected species and the potential establishment of regional zoonoses of Gnathostoma-infected wild species. Since the eradication of gnathostomiasis is unlikely given the global distribution of Gnathostoma nematodes, the only effective preventive strategy is to educate persons in endemic and nonendemic areas that fish, eels, frogs, snakes, and birds must be cooked thoroughly first before eating and not eaten raw or marinated. The onset of migratory subcutaneous swellings with hyper-eosinophilia weeks to months after consuming raw seafood should provoke suspicion of gnathostomiasis. Gnathostomiasis is a food-borne helminthic infection that may follow the consumption of raw seafood infected with muscle-encysted larvae of Gnathostoma species nematodes. Gnathostomes have a complex life cycle that requires three hosts: (1) a freshwater copepod that ingests eggs shed by adults; (2) a wide range of fish and other aquatic intermediate hosts for larval maturation; and (3) definitive vertebrate hosts for adult development. The most important species causing human infections are Gnathostoma spinigerum and Gnathostoma hispidum. Travelers returning to their native countries from nations in Southeast Asia and Corresponding Author: James H. Diaz, MD, Dr PH, 2020 Gravier Street, Third Floor, New Orleans, LA 70112, USA. jdiaz@lsuhsc.edu Latin America with high incidence rates of gnathostomiasis and histories of consuming raw or marinated fish remain at the greatest risks of contracting gnathostomiasis and manifesting the classic presentation of intermittent, pruritic migratory swellings and peripheral eosinophilia within months to years. 1 The major foci for endemic gnathostomiasis remain in Southeast Asia (Thailand, Laos, Myanmar, Indonesia, Malaysia, and the Philippines) and in certain nations of Latin America where lime-juice marinated raw fish (sushi) or ceviche dishes are popular, especially Mexico, Colombia, Ecuador, and Peru. 1 Autochthonous gnathostomiasis has now been reported from several countries that are nonendemic for Gnathostoma species zoonoses. 2 Some cases have been attributed to the importation of live species for raw consumption, some with Gnathostoma infections International Society of Travel Medicine, Journal of Travel Medicine 2015; Volume 22 (Issue 5):

2 Gnathostomiasis 319 As a result, the objectives of this review were to describe the biology and life cycle of Gnathostoma nematodes and the behavioral risk factors for gnathostomiasis; and to describe the clinical manifestations, diagnosis, management, and prevention of human gnathostomiasis. Materials and Methods In order to describe the biology and life cycle of Gnathostoma nematodes and the epidemiology, clinical manifestations, diagnosis, management, and prevention of human gnathostomiasis, Internet search engines, including PubMed, Medline, Ovid, Google, and Google Scholar were queried with the key medical subject heading (MESH) words, Infections, helminthic; Helminthiasis, gnathostomiasis, gnathostomosis, neurognathostomiasis, ocular gnathostomiasis, visceral (hepatic) gnathostomiasis; Nematode parasites, Gnathostoma species. Case reports, case series, epidemiological investigations, and laboratory studies were reviewed; high-risk behaviors for gnathostomiasis were identified; human cases of gnathostomiasis were stratified as cutaneous gnathostomiasis, visceral (hepatic) gnathostomiasis, neurognathostomiasis, and ocular gnathostomiasis. Results The Epidemiology of Imported Gnathostomiasis Nawa and colleagues first noted that more imported gnathostomiasis cases occurred in travelers returning from countries where few regulations governed the selection and preparation of raw fish for consumption. 4 In many instances, cheaper freshwater fish, more likely to harbor infective Gnathostoma larvae, such as tilapia, bass, and trout, were used to prepare sashimi and ceviche dishes rather than more expensive, parasite-free saltwater fish. 4 In addition, Rojas-Molina and colleagues demonstrated that the common practice of marinating fresh fish in lime juice in the preparation of ceviche dishes in Latin America did not kill infective Gnathostoma larvae which could remain viable in muscle for up to 5 days. 5 During a 12-month study period, Moore and colleagues reported 16 cases of gnathostomiasis in travelers returning to London for treatment. 6 The median time from onset of symptoms to diagnosis was 12 months with a range of 3 weeks to 5 years, and the countries most frequently visited in order included India, Bangladesh, China, and Thailand. 6 In 2009, Strady and colleagues reported another series of 13 patients diagnosed in Paris with imported gnathostomiasis between 2000 and The median age was 38 years (range years), and the female-to-male ratio was Eleven of the 13 patients reported consuming raw fish, and all patients had recently traveled to endemic regions including 11 patients who returned from Southeast Asia (Cambodia, China, Laos, Myanmar, Japan, Sri Lanka, Thailand, and Vietnam) and 2 patients who returned from Mexico. 7 Autochthonous gnathostomiasis has now been reported from regions with low endemicity rates for Gnathostoma species zoonoses. 2 In addition to and as a direct result of increasingly exotic tastes among returned travelers and natives, many regions outside of Gnathostoma species-endemic regions now import live species for raw consumption, some with Gnathostoma infections. 3 The Taxonomy, Biology, and Life Cycle of Gnathostoma Species The genus Gnathostoma belongs to a large order of nematodes, Spirurida, with complex life cycles with two intermediate hosts. There are 13 recognized species, 6 of which can cause human infections (Table 1). Although veterinary parasitologists prefer the term gnathostomosis for gnathostome-caused veterinary diseases, medical parasitologists consistently use the term gnathostomiasis for gnathostome-caused human diseases. 8 The parasitic life cycles begin as adult worms (13 55 mm in length) encysted in the stomachs of definitive animal hosts release eggs that are shed in the hosts feces. The eggs develop in freshwater and hatch in about 7 days releasing first-stage larvae (L1). The L1 larvae are ingested by the first intermediate hosts, freshwater copepods (Cyclops species). The larval-infected copepods are ingested by a broad range of second intermediate hosts including fish, eels, frogs, snakes, and birds. L1 larvae develop into second-stage larvae (L2) in the gastrointestinal tract of the second intermediate or paratenic hosts and mature into third-stage larvae (L3) which encyst in their tissues. When L3 larvae are ingested by predatory, definitive hosts, typically wild and domestic felids and canids and other wild carnivores, they penetrate the gastrointestinal tract, migrate through the liver into the peritoneal cavity, and reenter the stomach in about 4 weeks to encyst, mature into adults within 6 months, and release eggs. The entire life cycle occurs within a period of 8 to 12 months. As accidental or dead-end hosts that do not support the nematode s reproductive life cycle, humans become infected by eating raw or undercooked second intermediate hosts that harbor muscle-encysted infective L3 larvae. 1,6 Although human transmission is typically by raw seafood consumption, two alternative routes of transmission have been described by Daengsvang: (1) ingestion of freshwater contaminated with L1-infected copepods and (2) direct skin penetration in food handlers by L3 larvae during the preparation of infected fish, frogs, or other second intermediate hosts. 9 The Clinical Manifestations of Gnathostomiasis The infective inoculum for gnathostomiasis is small and usually follows ingestion of only one infective, L3 larvae. 1,6 A prodrome of epigastric pain, nausea,

3 320 Diaz Table 1 Currently recognized Gnathostoma species, their geographic distributions, and definitive animal hosts Currently recognized Gnathostoma species (N = 13) Geographic distributions Definitive animal hosts Human infections reported (+) or not( ) (N = 6) Gnathostoma binucleatum Central and South America Wild and domestic cats and dogs + Gnathostoma doloresi Japan and Southeast Asia Wild and likely domestic pigs + Gnathostoma hispidum China, Korea, Japan, Southeast Asia, Wild and domestic pigs + Australia, and Central America Gnathostoma malaysiae Japan and Southeast Asia Rats + Gnathostoma nipponicum Japan and Korea Weasels + Gnathostoma spinigerum China, Japan, Southeast Asia, India, Central Wild and domestic cats and dogs + America, South America, and East Africa (Botswana, Zambia) Gnathostoma didephilis North America Opossums _ Gnathostoma lamothei North America and Central America Raccoons _ Gnathostoma procyonis North America and Central America Raccoons _ Gnathostoma miyazaki Japan, Southeast Asia, and North America Otters _ Gnathostoma socialis North America Mink _ Gnathostoma turgidum North America, Central America, and South Opossums and bears (North _ America America) Gnathostoma vietnamicum China, Southeast Asia Otters _ and vomiting begins shortly thereafter and lasts for 2 to 3 weeks before resolving. 1,6 This prodrome is felt to represent larval penetration of the intestines and portal venous migration to the liver. The prodrome is often dismissed as food poisoning, misdiagnosed as acute appendicitis or mesenteric adenitis, and usually underreported. 1 A prolonged incubation period then ensues with a median of 12 months (range 3 weeks to 5 years). 6 Invasive larval migration through tissues is aided by burrowing hooks which cause mechanical damage and by release of secretory proteins including hyaluronidases, hemolysins, and metalloproteinases. 10,11 The combined pathophysiological effects of mechanical tissue damage by burrowing L3 larvae and the inflammatory effects of larval secretory factors often result in the characteristic hemorrhagic worm tracks seen in the liver and brain during imaging studies and postmortem. 1,12 14 These same mechanisms are also responsible for the four clinical manifestations of gnathostomiasis: (1) cutaneous disease with intermittent migratory swellings and, less often, subcutaneous nodules containing an L3 larva; (2) visceral (hepatic) or gastrointestinal (eosinophilic gastritis) disease; (3) neurognathostomiasis (cerebral gnathostomiasis) with high case fatality rates (CFRs); and (4) ocular gnathostomiasis, the rarest manifestation of the larval migration Cutaneous gnathostomiasis is the most common manifestation of infection and typically presents with intermittent migratory subcutaneous swellings. In countries where gnathostomiasis is common, these migratory swellings have been referred to as Yangtze River edema (China), tuao chid (Japan), and paniculitis nodular migratoria eosinophilica (Latin America). 1 Subcutaneous swellings typically occur within weeks of ingestion of infective larvae, but may also occur months to years later and may recur in untreated cases for up to 10 to 12 years. 1,7 The systemic manifestations of gnathostomiasis are less common than the cutaneous manifestations and include eosinophilic gastritis, central nervous system (CNS) invasion with the highest CFRs of up to 32%, and ocular gnathostomiasis being reported rarely with only 24 cases reported by 2012, with 14 cases from India. 12,13 Pulmonary larval migration may be associated with cough, pleuritic chest pain, pleural effusions, hemoptysis, and accompanying peripheral hyper-eosinophilia (20% 72%). 1 Genitourinary manifestations are also uncommon, but passage of the larva in the urine accompanied by hematuria has been reported. 1 Although most autochthonous cases in nonendemic regions manifest themselves as migratory, cutaneous gnathostomiasis, Jarell and colleagues reported the case of a 45-year-old female who consumed sushi weekly in San Francisco and presented with a solitary, pruritic nodule on her abdomen that contained a gnathostome. 2 A work-up for systemic and target organ-specific gnathostomiasis was negative. 2 Table 2 describes the clinical manifestations of imported gnathostomiasis in a representative series of returning travelers over the reporting period, 1984 to ,15 28 Table 3 describes similar presenting clinical manifestations of locally acquired or autochthonous gnathostomiasis in low-endemicity regions over a more recent reporting period, 2009 to Table 4 describes the clinical and radioimaging characteristics of neurognathostomiasis and intraocular gnathostomiasis. 12,13 The Diagnosis of Gnathostomiasis G. spinigerum larvae are large, ranging from 2.5 to 12.5 mm in length and 0.5 to 1.2 mm in width, and can

4 Gnathostomiasis 321 Table 2 Selected reports of imported gnathostomiasis in returning travelers 6,15 28 Resident countries Countries (or regions) visited Gnathostoma species Presenting clinical manifestations Year reported Reference number United States (US) Laos Gnathostoma spinigerum Subcutaneous nodule on abdomen with extruding L3 larva US Southeast Asia Gnathostoma spinigerum Intermittent migratory subcutaneous swellings Germany Thailand Gnathostoma spinigerum Intermittent migratory subcutaneous swellings over right upper arm and chest with bilateral axillary lymph-adenopathy and eosinophilia Japan Myanmar (Burma) Gnathostoma malaysiae Two cases of slowly migrating pruritic and erythematous eruptions Germany Bangladesh Gnathostoma species Intermittent migratory swellings of the left hand and arm with eosinophilia Holland Southeast Asia Gnathostoma spinigerum Two cases of recurrent facial swellings; one case with eosinophilia Switzerland Peru Gnathostoma species Relapsing subcutaneous swellings Spain France United Kingdom (UK) Two cases: #1: Southeast Asia and #2: Mexico Five cases: Southeast Asia Four cases: #1: Hong Kong #2: Bangladesh #3: Southeast Asia #4: Borneo Gnathostoma species Two cases of intermittent subcutaneous swellings Gnathostoma hispidum Creeping eruptions (n = 3) Recurrent migratory swellings (n = 2) Subcutaneous nodule (n = 1) Hepatitis (n = 2) Gnathostoma species #1: recurring subcutaneous nodules on limbs #2: intermittent swellings right forearm and upper arm #3: eosinophilic gastritis #4: 4 3 cm lump in thigh US Two cases: Zambia Gnathostoma species Intermittent migratory swellings 24 Spain Two cases: Gnathostoma species #1: intermittent migratory 25 #1: Thailand #2: Mexico swellings #2: neuro-gnathostomiasis (eosinophilic menigoencephalitis) Germany Southeast Asia and Gnathostoma spinigerum Eosinophilic gastritis South Africa Holland, Germany Laos Gnathostoma species Intermittent migratory swellings UK Two cases: Botswana Gnathostoma spinigerum Gnathostoma spinigerum France GI = gastrointestinal. 13 cases: Southeast Asia Central America Gnathostoma species 9 cases: recurrent cutaneous manifestations 2 cases: GI gnathostomiasis 2 cases: neuro-gnathostomiasis 8 cases: had 13 relapses be visualized through the skin in cases of subcutaneous nodular gnathostomiasis and in the anterior chamber (iris) or retina in ocular gnathostomiasis. 1,11 In addition to recovery from skin, subcutaneous tissues, and CNS, G. spinigerum larvae have been recovered from the eyes, lungs, muscles, bladder, and gastrointestinal tract. 1,11 Neuroimaging studies are nonspecific and nonconfirmatory, but will complement serological studies for presumptive diagnoses of gnathostomiasis. Sithinamsuwan and Chairangsaris reported multiple, noncontrast enhancing worm-like lesions in both cerebral hemispheres and the cerebellum on magnetic resonance imaging (MRI) of the brain in an 18-year-old man who reported frequently consuming raw freshwater fish and presented with a 1-month history of migratory skin swellings followed by headache, ataxia, and left-sided hemiparesis. 14 The computerized tomogram

5 322 Diaz Table 3 Selected reports of autochthonous gnathostomiasis 2,29 35 Resident countries Countries (or regions) visited Gnathostoma species Presenting clinical manifestations Year reported Reference number Japan Japan Gnathostoma doloresi Autochthonous case of a subcutaneous nodule containing L3 larva Japan Japan Gnathostoma nipponicum Five autochthonous cases; all with intermittent migratory subcutaneous swellings containing L3 larvae on biopsy Japan Japan Gnathostoma hispidum Three autochthonous cases; all with intermittent migratory subcutaneous swellings containing L3 larvae on biopsy Mexico Mexico Gnathostoma doloresi Five autochthonous cases; all with intermittent migratory swellings on the trunk and face; all serologically positive China China Gnathostoma spinigerum Fever with intermittent creeping eruptions of erythematous plaques United States (US) US Gnathostoma species Solitary subcutaneous nodule on the abdomen that contained a gnathostome on biopsy Brazil Brazil Gnathostoma species Autochthonous case: intermittent migratory swellings Korea Korea Gnathostoma species Autochthonous case: facial intermittent migratory swellings (CT) of the brain was nonspecific and demonstrated cerebral edema only. 14 The authors concluded that MRI may provide better neuroimaging of cerebral larval migration in gnathostomiasis than CT, and that a combination of positive neuroimaging and immunoblot studies would be required for presumptive diagnosis of gnathostomiasis in cases in which larvae could not be recovered. 14 An enzyme-linked immunosorbent assay (ELISA) for L3 immunoglobulin G antibody has been developed as a screening test with poor sensitivity and cross-reactivity with several other nematodes. 1,36 In Asia and Europe, an immunoblot to detect the 24 kda L3 antigen band is diagnostic for gnathostomiasis. 1,5 Ribosomal DNA (rdna) sequencing has also been used as a tool for classification and phylogenetic analysis of gnathostomiasis in the Americas. 37 A major limitation in the diagnosis of gnathostomiasis is an inability to identify the infecting species of gnathostome for epidemiological purposes. 35,37 Even serological tests are often nonspecific for species identification due to inter-species antigenic cross-reactivity. 35,37 The Management of Gnathostomiasis The treatment of gnathostomiasis with albendazole is usually straightforward except in cases of neural larval migrans where brain edema could be aggravated by the host s inflammatory response to dying larvae. 13 In such cases, corticosteroids may be administered alone (prednisolone, 60 mg/day for 7 days) as the larvae migrate and then die naturally. 13 The reported efficacy of albendazole, 400 mg twice a day for 21 days, in the treatment of gnathostomiasis is over 90%, and a similar therapeutic efficacy has been reported for ivermectin, 0.2 mg/kg as a single dose, or 0.2 mg/kg on two consecutive days. 1,6,7 Of note, albendazole will stimulate the outward migration of the larva and make it more accessible to excisional biopsy and expert identification. 1 As in the case series reported by Moore and colleagues and Strady and colleagues, some patients may have a relapse and require a second course of albendazole and/or ivermectin therapy, with relapses often heralded by peripheral eosinophilia. 6,7 The Establishment of Regional Zoonotic Reservoirs of Gnathostoma Species and the Potential for Autochthonous Gnathostomiasis As a result of increasingly adventurous tastes among travelers and natives alike for local, ethnic dishes, including raw seafood, many regions outside of Gnathostoma species-endemic regions import live seafood species for raw consumption, some with Gnathostoma infections. 3 The ethnic cuisine industry is supported by domestic aquaculture that produces farm-raised freshwater fish, such as tilapia, trout, and bass, and by the increased importation of live freshwater seafood, such as Asian swamp eels (Monopterus spp.). 3 Although raw seafood dishes are typically prepared with saltwater species, freshwater species which harbor more parasites are also used in these dishes, such as lime-juice marinated tilapia or trout ceviche and eel-sashimi and sushi. 4,5

6 Gnathostomiasis 323 Table 4 Clinical and radioimaging characteristics of neurognathostomiasis and intraocular gnathostomiasis 12,13 (Adapted from Pillai and colleagues 12 and Katchanov and colleagues 13 ) Neurological and ocular syndromes CNS entry access for infective third stage (L3) larvae Clinical neurological and ophthalmological presentations Neuroradiological findings (CT and MRI) Radiculomyelitis/ myeloencephalitis Meningitis/ meningoencephalitis Subarachnoid hemorrhage Intracerebral hemorrhage Ocular gnathostomiasis Intervertebral foramina along spinal nerves and vessels Cranial nerve foramina along spinal nerves and vessels Intervertebral or neural foramina Intervertebral or neural foramina Posterior retina via branches of the central retinal artery Radiculopathy; spinal syndrome (paraplegia, neurogenic bladder, quadriplegia); may progress to myeloencephalitis Severe headache, meningismus (stiff neck), cranial nerve (abducens) palsies, focal neurologic signs, depressed consciousness Severe headache and meningeal signs Severe headache, sudden onset of focal neurologic signs Sudden unilateral loss of visual acuity without peripheral eosinophilia. The diagnosis is typically confirmed by surgical extraction of a motile L3 larva in the anterior chamber, often hooked on the iris. Due to the avascularity of the anterior chamber, the immune response may be minimal to absent; and serological tests, such as ELISA and the 24-kDa L3 antigen immunoblot, may be negative MRI: hyper-intensities and swelling of the spinal cord with gadolinium enhancement on T1 post-contrast images CT: parenchymal, subdural, or subarachnoid hyperintensities MRI: multiple worm-like T2-weighted hyper/ hypo-intensities in both hemispheres and cerebellum 3 mm diameter consistent with hemorrhagic worm tracks ± gadolinium enhancement CT: subdural or subarachnoid hyperintensities MRI: worm tracks possible CT: parenchymal hyperintensities MRI: worm tracks possible MRI: may confirm portal of entry in posterior retina by demonstrating retinal tear with choroidal hemorrhage near the optic disc CT = computerized tomogram; MRI = magnetic resonance imaging; ELISA = enzyme-linked immunosorbent assay. In 2014, biologists from the United States (US) Geological Survey detected Gnathostoma species infective-stage larvae in nearly 30% of imported Monopterus species Asian swamp eels and in 4.5% of locally caught Monopterus species freshwater swamp eels in three states. 3 The investigators concluded that consumption of imported swamp eels from Gnathostoma-endemic regions of Asia could transmit gnathostomiasis to humans in the United States and that autochthonous cases could also occur following consumption of raw, Gnathostoma-infected and locally caught freshwater eels of the same species. 3 Autochthonous cases of gnathostomiasis have now been described in Brazil and Korea following the consumption of raw, locally harvested freshwater fish. 34,35 The Prevention and Control of Gnathostomiasis The eradication of gnathostomiasis is very unlikely given the global distribution of Gnathostoma nematodes and the culinary tastes of residents and travelers to endemic regions. In addition, adventurous eating habits, including the consumption of marinated (ceviche) or raw (sashimi, sushi) fish, may also expose individuals to the intermediate hosts that cause gnathostomiasis. The only effective preventive strategy for gnathostomiasis is to educate persons in endemic and nonendemic areas that fish, eels, frogs, snakes, and birds must be cooked thoroughly first before eating and not eaten raw or marinated. Conclusions Gnathostomiasis is no longer confined solely to endemic regions and to returning travelers from gnathostome-endemic regions. Autochthonous cases in nonendemic regions may be anticipated to increase as a result of the importation of live Gnathostoma-infected species and the potential establishment of regional zoonoses of Gnathostoma-infected species. The onset of migratory subcutaneous swellings with hyper-eosinophilia weeks to months after consuming raw seafood should provoke suspicion of gnathostomiasis in all patients.

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