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Increasing risk factors for imported and domestic Gnathostomiasis in the United States.

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[R], and Google Scholar[R], were queried with the key medical subject heading (MESH) words, "infections, helminthic; Helminthiasis, gnathosomiasis, neurognathostomiasis; nematode parasites, Gnathostoma species." Case reports, case series, epidemiological investigations, and laboratory studies were reviewed; high-risk behaviors for gnathostomiasis were identified, and human cases of gnathostomiasis were stratified as cutaneous gnathostomiasis, visceral gnathostomiasis, neurognathostomiasis, and ocular gnathostomiasis.

RESULTS

The Epidemiology of Gnathostomiasis

Travelers returning to the US from nations in Southeast Asia and Latin America with high incidence rates of gnathostomiais and histories of consuming raw or marinated fish are at the greatest risks of contracting gnathostomiasis and manifesting the classic triad of intermittent, pruritic migratory swellings and peripheral eosinophilia within months to years. (3) The greatest foci for endemicity for gnathostomiasis are still in Southeast Asia (Thailand, Laos, Myanmar, Indonesia, Malaysia, and the Philippines) more so than in China, India, and Japan; and in specific nations of Latin America where ceviche dishes are popular, especially Mexico, Colombia, Ecuador, and Peru. (3)

Nawa et al. 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. (2) In many instances, cheaper freshwater fish, more likely to harbor infective Gnathostoma larvae, such as tilapia and brook trout, are used to prepare sashimi and ceviche dishes rather than more expensive, parasite-free saltwater fish. (2) In addition, Rojas-Molina and co-investigators 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 five days. (4)

During a twelve-month study period, Moore et al. reported sixteen cases of gnathostomiasis in travelers returning to London for prolonged treatment with oral albendazole. (5) The median time from onset of symptoms to diagnosis was twelve months with a range of three weeks to five years. The countries most frequently visited in order included India, Bangladesh, China, and Thailand. (5) In this case series, only three patients recalled eating raw fish. (5) In 2009, Strady et al. reported another series of thirteen patients diagnosed in Paris with imported gnathostomiasis between 2000 and 2004.6 The median age was 38 years (range 27-60 years), and the female-to-male ratio was 1.6.6 Eleven of the thirteen patients reported consuming raw fish, and all patients had recently traveled to endemic regions including eleven patients who returned from Southeast Asia (Cambodia, China, Laos, Myanmar, Japan, Sri Lanka, Thailand, and Vietnam) and two patients who returned from Mexico. (6) Nine patients presented with cutaneous gnathostomiasis, two with visceral (gastrointestinal) gnathostomiasis, and two with signs of neurognathostomiasis. (6) The median interval between symptom onset and treatment with albendazole (n = 12) or ivermectin (n = 1) was 3.5 months, and eight patients relapsed within a median of two months (range 1-7 months) after initial treatment. (6) The authors concluded that imported gnathostomiasis was typically cutaneous, and that relapses were common after initial treatment with recommended antihelminthics. (6)

The infective inoculum for gnathostomiasis is very small, usually only one more often than two or more infective, third stage larvae. (3,5) As soon as the raw secondary intermediate or paratenic host containing infective larvae is ingested and reaches the stomach, a syndrome of severe epigastric pain, nausea, and vomiting begins and lasts for two to three weeks, before resolving completely. (3,5) This prodrome is often dismissed as transient food poisoning, misdiagnosed as acute appendicitis or mesenteric adenitis, and usually under-reported. (3) This prodrome is felt to be consistent with larval penetration of the intestinal wall and larval migration through the portal venous system to the liver. (3) A prolonged incubation period then ensues, with a median interval of twelve months (range three weeks to five years). (5) Ultimately, one or more larvae may reemerge seeking to mature in any tissue and causing cutaneous, visceral, ocular, or neurognathostomiasis, or any combination of larva migrans. (3)

The Biology and Life Cycle of Gnathostoma Species

The genus Gnathostoma belongs to a large order of nematodes, Spirurida, and currently has thirteen recognized species; six of which can cause human infections. Gnathostoma nematodes are maintained in a zoonosis of regional mammalian host reservoirs and have complex life cycles with two intermediate hosts (Figure 1). The life cycles begin as eggs are released by adults worms (13-55 mm in length) encysted in the stomachs of definitive animal hosts and shed in the hosts' feces. The eggs develop in freshwater and hatch after about seven days, releasing release first-stage larvae. The first-stage 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. First-stage larvae (L1) 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 infective third-stage 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 abdominal cavity, and reenter the stomach in about four weeks. Third-stage larvae encyst in the stomach, mature over six months into adult worms in gastric tumor-like masses, and release eggs through apertures connected to the gastric lumen. The entire life cycle occurs within a period of eight to twelve 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, such as fish, eels, frogs, snakes, or chicken, that harbor muscle-encysted infective third stage larvae. Although human transmission is typically by raw seafood consumption, two alternative routes of transmission have been described: (1) ingestion of freshwater contaminated with first-stage larvae infected copepods; and (2) direct skin penetration in food handlers by third stage larvae during the preparation of infected fish, frogs, or other second intermediate hosts (Figure 1). (8)

The Pathophysiology of Gnathostomiasis

Specialized anatomic structures and secretory proteins make Gnathostoma nematodes highly mobile and deeply invasive. The infective third stage larvae are up to 12.5 mm long and 1.2 mm wide and reddish-brown in color with a curved tail and a head end capped by several rows of hooks for tissue burrowing (Figure 2). The cuticular anatomy, body shape, and number of rows of hooks on the head permit microscopic identification of different species for epidemiological purposes.

Invasive larval migration through tissues is aided by the burrowing hooks which cause mechanical damage and the release of secretory proteins. (9,10) These secretory proteins include hyaluronidases, hemolysins, and metalloproteinases, which spread open tissue planes and induce host immunological reactions, including vasodilation and peripheral hyper-eosinophilia in some cases. (9,10)

Peripheral eosinophilia, however, is not a constant finding in gnathostomiasis and is often absent in ocular gnathostomiasis because of the avascularity of the anterior chamber. (11) Moore et al reported peripheral eosinophilia in seven of sixteen patients (forty-four percent) treated for gnathostomiasis and concluded that peripheral eosinophilia could not be relied upon as a screening tool for gnathostomiasis, but could serve as a reliable marker of relapse in cases with eosinophilia at baseline. (5)

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 post mortem. (3,12) 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 disease; (3) neurognathostomiasis with high case fatality rates; and (4) ocular gnathostomiasis, the rarest manifestation of the larval migration.

The Clinical Manifestations of Gnathostomiasis

Cutaneous gnathostomiasis is the most common manifestation of infection and typically presents with intermittent migratory swellings, known as nodular migratory panniculitis, usually on the trunk or the upper arms. These swellings result from the mechanical migration with tissue damage and secretory proteins with host inflammatory responses of usually one larva and may leave tracks of visible subcutaneous hemorrhage. (3) 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 ten to twelve years. (3,8) A less common manifestation of cutaneous gnathostomiasis is a superficial nodule containing an L3 larva. 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). (3)

The visceral manifestations of gnathostomiasis are less common than the cutaneous manifestations with central nervous system (CNS) invasion having the highest case fatality rates (CFR) and ocular gnathostomiasis being reported rarely with only twenty-four cases in 2011, mostly from India. (7,11) As the infective larva migrates through the liver or spleen, acute abdominal pain or palpable masses may develop and mimic acute appendicitis or intestinal obstruction. (3) Pulmonary larval migration will be associated with cough, pleuritic chest pain, pleural effusions, hemoptysis, and accompanying peripheral hypereosinophilia (twenty to seventy-two percent). (3) Genitourinary manifestations are also uncommon, but passage of the larva in the urine accompanied by hematuria has been reported. (3) The main clinical and diagnostic imaging features of neurognathostomiasis are compared in Table 2 and are also accompanied by peripheral hypereosinophilia. (7) The CFR for neurognathostomiasis has been reported to be as high as thirty-two percent. (7) The main clinical and diagnostic imaging features of ocular gnathostomiasis are also described in Table 1 and are rarely accompanied by eosinophilia. (11)

The Diagnosis of Gnathostomiasis

G. spinigerum larvae are large, ranging from 2.5-12.5 mm in length and 0.5-1.2 mm in width; and can be visualized through the skin in cases of subcutaneous nodular gnathostomiasis and in the anterior chamber or retina in ocular gnathostomiasis. (3,11) The definitive diagnosis of gnathostomiasis can only be made by recovery of the larvae or by expert identification of the larvae in tissues. 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. (3,11) Neuroimaging studies are nonspecific and non-confirmatory, but compliment serological studies for presumptive diagnoses of gnathostomiasis. Sithinamsuwan and Chairangsaris reported multiple, non-contrast enhancing worm-like lesions in both cerebral hemispheres and the cerebellum on magnetic resonance imaging (MRI) of the brain in an eighteen-year-old man presenting with a one-month history of migratory skin swellings followed by headache, ataxia, and left-sided hemiparesis. (12) The computerized tomogram (CT) of the brain was non-specific and demonstrated cerebral edema only. (12) The patient reported consuming raw freshwater fish in his diet, and the immunoblot assay of CSF identified reactive antibodies to a specific 24-kDa band diagnostic of gnathostomiasis. (12) 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 for definitive diagnosis. (12) 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. (3,13) In Asia and Europe, an immunoblot to detect the 24-kDa L3 antigen band is diagnostic for gnathostomiasis. (3) Ribosomal DNA (rDNA) sequencing has been used to identify the Gnathostoma species that can cause gnathostomiasis in the Americas, and may offer a more definitive diagnostic tool than neuroimaging and the 24-kDa immunoblot assay. (14)

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. (7) In such cases, corticosteroids may be administered alone (prednisolone, 60 mg per day for seven days) as the larvae migrate and then die naturally. (7) The reported efficacy of albendazole, 400 mg twice a day for twenty-one days, in the treatment of gnathostomiasis is over ninety percent, and a similar therapeutic efficacy has been reported for ivermectin, 0.2 mg/kg as a single dose, or 0.2 mg/kg on 2 consecutive days. (3,5,6) Of note, albendazole will stimulate the outward migration of the larva and make it more accessible to excisional biopsy and expert identification. (3) As in the case series reported by Moore et al and Strady et al, some patents may relapse and require a second course of albendazole and/or ivermectin therapy, with relapses often heralded by peripheral eosinophilia. (3,5) Moore et al concluded that a lack of migratory symptom recurrence within a median incubation period of 12 months and the resolution of peripheral and CSF eosinophilia should be accepted as presumptive evidence of cure of gnathostomiasis. (5)

The Prevention and Control of Gnathostomiasis in the United States

The eradication of gnathostomiasis is unlikely given the global distribution of Gnathostoma nematodes and the increasingly exotic culinary tastes of both US residents and travelers to endemic regions. Current "survivor" television programs and movies often feature the consumption of raw fish, frogs, and snakes; all of which can serve as second intermediate or paratenic hosts that can cause gnathostomiasis. In addition to "survivor" programming, adventurous and exotic eating habits, including the consumption of marinated (ceviche) or raw (sashimi, sushi) fish, may also expose individuals to the intermediate hosts that cause gnathostomiasis. Prevention strategies for gnathostomiasis include: (1) educating citizens and travelers in endemic areas that fish, eels, frogs, snakes, and chicken must be cooked thoroughly first and not eaten raw or marinated; and (2) seeking medical care immediately for evaluation of migratory subcutaneous swellings. As noted, Gnathostoma larvae may remain viable for up to five days after total immersion in lime juice. (2)

CONCLUSIONS

Gnathostomiasis is a food-borne zoonotic helminthic infection, commonly described in Asia and Latin America that may follow the consumption of raw fish, eels, amphibians, and reptiles infected with muscle-encysted larvae of Gnathostoma species nematodes. After an inoculum of as little as one infective larva and a prolonged incubation period of months to years, most infections are characterized by intermittent migratory swellings due to subdermal larval migration. Less commonly, larval migration to the CNS may result in radiculomyelopathy or eosinophilic meningoencephalitis with high case fatality rates; or larval migration to the eye with resulting blindness in untreated cases. Since neither rDNA sequencing nor the 24-kDa immunoblot assays are uniformly available for laboratory diagnoses, clinicians should rely on combinations of history of exposure in endemic regions, positive neuroimaging, and parasite identification in tissues for definitive diagnoses of gnathostomiasis in most cases.

The only effective strategies for gnathostomiasis include: (1) educating citizens in the US and travelers abroad in endemic areas that fish, eels, frogs, snakes, and chicken must be cooked thoroughly first and not eaten raw or marinated; and (2) seeking medical care immediately for evaluation of migratory subcutaneous swellings.

REFERENCES

(1.) Cole RA, Choudhury A, Nico LG, Griffin KM. Gnathostoma spp. in live Asian swamp eels (Monopterus spp.) from food markets and wild populations, US. Emerg Infect Dis 2014;20:634-642.

(2.) Nawa Y, Hatz C, Blum J. Sushi delights and parasites: the risks of fish-borne and foodborne parasitic zoonoses in Asia. Clin Infect Dis 2005; 41:1297-1303.

(3.) Herman JS, Chiodini PL. Gnathostomiasis, another emerging imported disease. Clin Microbiol Rev 2009;22:484-492.

(4.) Rojas-Molina N, Pedraza-Sanchez S, Torres-Bibiano B, et al. Gnathostomiasis, an emerging foodborne zoonotic disease in Acapulco, Mexico. Emerg Infect Dis 1999;5:264-266.

(5.) Moore DAJ, McCroddan J, Dekumyoy P, Chiodini PL. Gnathostomiasis: An emerging imported disease. Emerg Infect Dis 2003;9:647-650.

(6.) Strady C, Dekumyoy P, Clement-Rigolet M, et al. Long-term follow-up of imported gnathostomiasis shows frequent treatment failure. Am J Trop Med Hyg 2009;80:33-35.

(7.) Katchanov J, Sawanyawisuth K, Chotmongkol V, Nawa Y. Neurognathostomiasis, a neglected parasitosis of the central nervous system. Emerg Infect Dis 2011;17:1174-1180.

(8.) Daengsvang S. Gnathostomiasis in Southeast Asia. Southeast Asia J Trop Med Public Health 1981;12:319-332.

(9.) Tort J, Brindley PJ, Knox D, et al. Proteinases and associated genes of parasitic helminthes. Adv Parasitol 1999;43:161-266.

(10.) Uparanukraw P, Morakote N, Harnnoi T, et al. Molecular coding of a gene encoding matrix metalloproteinase-like protein from Gnathostoma spinigerum. Parasitol Res 2001;87:751-757.

(11.) Pillai GS, Kumar A, Radhakrishnan N, Maniyelil J, et al. Intraocular gnathostomiasis: report of a case and review of literature. Am J Trop Med Hyg 2012;86:620-623.

(12.) Sithinamsuwan P, Chairangsaris P. Ganthostomiasis--Neuroimaging of larval migration. N Engl J Med. 2005;352:188-189.

(13.) Tapchaisri P, Nopparatana C, Chaicumpa W, Setasuban P. Intradermal reaction with Gnathostoma spinigerum antigen. Jpn J Parasitol 1991;21: 315-319.

(14.) Almeyda-Artigas RJ, Bargues MD, Mas-Coma S. ITS-2 rDNA sequencing of Gnathostoma species (nematoda) and elucidation of the species causing human gnathostomiasis in the Americas. J Parasitol 2000;86:537-544.

Dr. Diaz is associated with the Schools of Public Health, Program in Environmental and Occupational Health Sciences, and Medicine, Department of Anesthesiology, Louisiana State University Health Sciences Center (LSUHSC) in New Orleans, LA.

Table 1. Clinical and Radioimaging Characteristics of
Neurognathostomiasis and Intraocular Gnathostomiasis
(Adapted from Katchanov J et al 7, and Pillai GS et al)

Neurological           CNS entry access for    Clinical neurological &
And ocular            infective third stage        ophthalmological
syndromes                  (L3) larvae              presentations

Radiculomyelitis/         Intervertebral        Radiculopathy; spinal
Myeloencephalitis     foramina along spinal     syndrome (paraplegia,
                         nerves & vessels        neurogenic bladder,
                                                  quadriplegia); may
                                                     progress to
                                                  myeloencephalitis.

Meningitis/           Cranial nerve foramina   Severe headache, menin-
Meningoencephalitis   along spinal nerves &      gismus (stiff neck),
                             vessels           cranial nerve (abducens)
                                                    palsies, focal
                                                  neurologic signs,
                                               depressed consciousness.

Subarachnoid            Intervertebral or          Severe headache,
Hemorrhage               neural foramina           meningeal signs.

Intracerebral           Intervertebral or      Severe headache, sudden
Hemorrhage               neural foramina            onset of focal
                                                  neurologic signs.

Ocular                 Posterior retina via     Sudden unilateral loss
gnathostomiasis          branches of the       of visual acuity without
                      central retinal artery   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.

Neurological               Neuroradiological
And ocular                      findings
syndromes                     (CT and MRI)

Radiculomyelitis/        MRI: Hyper-intensities
Myeloencephalitis       & swelling of the spinal
                          cord with gadolinium
                           enhancement on T1
                         post-contrast images.

Meningitis/                 CT: parenchymal,
Meningoencephalitis           subdural, or
                              subarachnoid
                           hyperintensities.
                        MRI: multiple worm-like
                              T2-weight-ed
                       hyper/hypo-intensities in
                           both hemispheres &
                      cerebellum [greater than or
                        equal to] 3 mm diameter
                      consistent with hemorrhagic
                          worm tracks [+ or-]
                        gadolinium enhancement.

Subarachnoid          CT: subdural or subarachnoid
Hemorrhage                 hyperintensities.
                       MRI: worm tracks possible.

Intracerebral               CT: parenchymal
Hemorrhage                 hyperintensities.
                       MRI: worm tracks possible.

Ocular                  MRI: may confirm portal
gnathostomiasis          of entry in posterior
                        retina by demonstrating
                      retinal tear with choroidal
                          hemorrhage near the
                              optic disc.
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Author:Diaz, James H.
Publication:The Journal of the Louisiana State Medical Society
Article Type:Report
Geographic Code:1USA
Date:Sep 1, 2015
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