Gnathostoma.full

CLINICAL MICROBIOLOGY REVIEWS, July 2009, p. 484–492 Vol. 22, No. 3 0893-8512/09/$08.00ϩ0 doi:10.1128/CMR.00003-09 Copyright © 2009, American Society for Microbiology. All Rights Reserved. Gnathostomiasis, Another Emerging Imported Disease Downloaded from http://cmr.asm.org/ on October 12, 2019 by guest Joanna S. Herman1* and Peter L. Chiodini1,2 Department of Clinical Parasitology, Hospital for Tropical Diseases, 3rd Floor, Mortimer Market, Capper Street, London WC1E 6JB, United Kingdom,1 and London School of Hygiene and Tropical Medicine, London, United Kingdom2 INTRODUCTION .......................................................................................................................................................484 EPIDEMIOLOGY .......................................................................................................................................................484 LIFE CYCLE AND MORPHOLOGY ......................................................................................................................485 CLINICAL FEATURES .............................................................................................................................................486 Cutaneous Gnathostomiasis..................................................................................................................................487 Visceral Disease ......................................................................................................................................................488 Pulmonary manifestations .................................................................................................................................488 Gastrointestinal manifestations........................................................................................................................488 Genitourinary manifestations ...........................................................................................................................488 Ocular ...................................................................................................................................................................488 Auricular manifestations ...................................................................................................................................488 CNS manifestations ............................................................................................................................................488 DIAGNOSIS ................................................................................................................................................................489 TREATMENT ..............................................................................................................................................................490 PREVENTION.............................................................................................................................................................491 ACKNOWLEDGMENTS ...........................................................................................................................................491 REFERENCES ............................................................................................................................................................491 INTRODUCTION Southeast Asia, Japan, and increasingly Latin America, partic- ularly Mexico. Previously, the disease was rarely seen outside International travel to the tropics has dramatically increased areas of endemicity; however, over the past decade, the num- over the past few decades, with a subsequent and significant ber of cases seen in countries where it is not endemic has increase in the number of patients presenting with tropical increased. Few clinicians outside areas of endemicity are fa- diseases in countries where such infections are not endemic. It miliar with the disease, and therefore diagnosis is often missed is estimated that 50 million residents of industrialized coun- or prolonged, with potentially serious consequences. The clas- tries travel annually to such areas (42, 44), which brings expo- sic triad of intermittent migratory swellings, eosinophilia, and sure to a broad range of pathogens rarely, if ever, encountered a history of travel to Southeast Asia or other areas of ende- at home. These may vary from short-lived, easily detected and micity should alert physicians to the possible diagnosis. Vis- treatable infections (e.g., gastrointestinal infections) to more ceral disease is more serious than the cutaneous manifestations exotic infections such as filarial and helminthic infections (e.g., and, in the case of central nervous system (CNS) disease, may loiasis, stronglyoidiasis, and schistosomiasis). Such infections be fatal. may be seen rarely by physicians in temperate climates, and therefore diagnosis can prove elusive if these infections are not This article describes the epidemiology, life cycle, clinical considered. Travelers are becoming ever more adventurous in features, diagnostic tools, treatment, and prevention of this choice of country, pursuit of remoteness and immersion in disease. local culture, which will frequently include eating all local delicacies (e.g., ceviche or “drunken crab”) without consider- EPIDEMIOLOGY ation of what organisms they might be harboring. Migration has also increased substantially over the past few decades, with Gnathostoma was first discovered in the stomach wall of a people from the tropics and subtropics settling in the West, tiger that died at London Zoo in 1836 (35) and was first and many come harboring parasites of which they are unaware. described in humans in 1889 in Thailand by G. M. R. Levinson (cited in references 5 and 24). The next case was not described Gnathostomiasis is a parasitic infection caused by the third- until 1934, and shortly after, its life cycle was elucidated (37). stage larvae of the helminths Gnathostoma spp., which are seen mostly in tropical and subtropical regions. It is a food-borne The foci of endemicity have been predominantly in Japan zoonosis and is endemic in areas where people eat raw fresh- and Southeast Asia, particularly Thailand, but the disease is water fish or shellfish, especially Thailand and other parts of also endemic in Cambodia, Laos, Myanmar, Indonesia, Phil- ippines, and Malaysia (Fig. 1). Cases have also been reported * Corresponding author. Mailing address: Department of Clinical in China, Sri Lanka, and India (41). In more recent years it has Parasitology, Hospital for Tropical Diseases, 3rd Floor, Mortimer become an increasing problem in Central and South America, Market, Capper Street, London WC1E 6JB, United Kingdom. Phone: particularly in Mexico (due to the consumption of ceviche [raw 020 7387 4411, ext. 5418. Fax: 020 7383 0041. E-mail: joherman fish marinated in lime]) (12, 39), and also in Guatemala, Peru, @doctors.org.uk. and Ecuador (14, 23). There have also reports of cases in Myanmar, Zambia, and, most recently, Botswana (6, 16, 17). 484

VOL. 22, 2009 PARASITOLOGIC AND CLINICAL ASPECTS OF GNATHOSTOMIASIS 485 FIG. 1. Map of countries with reported acquisition of gnathostomiasis. Downloaded from http://cmr.asm.org/ on October 12, 2019 by guest Changes in dietary habits are the main cause of expansion of and Japan were solely due to G. spinigerum. However, in the the geographical range of the disease. However, despite the early 1980s in Japan new cases appearing in urban areas were significant increase in the number of sushi bars in the West, found to be due to G. hispidum, with the infective larvae found there do not appear to be any data showing a causal increase in loaches (small freshwater fish) (29). in the disease. From the reports, it seems that the important factor is where the sushi is eaten rather than simply the con- Humans are accidental hosts in which the parasite fails to sumption itself. Nawa et al. (28) have suggested that the cases reach sexual maturity. The definitive hosts are dogs, cats, ti- tend to occur as a result of consumption of food from local gers, leopards, and probably other fish-eating mammals, where restaurants in countries where the disease is endemic and the adult worm lives coiled up in the wall of the stomach, where few regulations if any govern the sourcing or storage of producing a tumor-like mass. In the definitive hosts the adult fish for consumption. They suggest that such restaurants tend worm (which reaches 13 to 55 mm in length) releases eggs into to use cheaper local freshwater or brackish-water fish, in con- the stomach which are then passed in the feces. These embryo- trast to sushi bars and restaurants in the West, which primarily nate in freshwater and hatch to release first-stage larvae after use more expensive saltwater fish which are free of Gnathos- about 7 days, which are then ingested by the first intermediate toma spp. and harbor relatively few potentially transmissible host, a water flea or copepod (usually a species of the genus parasites. In the latter places there are very stringent rules Cyclops), where they develop into second-stage larvae (Fig. 2). governing food sourcing and preparation which have to be When infected Cyclops organisms are ingested by the second adhered to and are rigorously enforced (28). intermediate hosts (fish, eels, frogs, birds, and reptiles), the second-stage larvae are freed in the intestine and develop into LIFE CYCLE AND MORPHOLOGY third-stage larvae. These migrate through the tissues and en- cyst in the muscles of their transport hosts, where they remain The genus Gnathostoma belongs to the order Spirurida, one as infectious larvae. When eaten by an appropriate definitive of the largest groups of nematodes. These groups are charac- host, such as cats and dogs, the larvae are freed once more in terized biologically by requiring one or more intermediate the gastrointestinal tract, from where they migrate to the liver hosts in their life cycles. The genus has 12 species (11, 15, 29), and abdominal cavity. After about 4 weeks they return to the with only 4 recorded in humans: G. spinigerum, commonly stomach, invading the gastric wall, where they resemble a tu- found in wild and domestic cats and dogs in India, China, mor, with an aperture that connects to the gastric lumen Japan, and southeast Asia; G. hispidum, found in wild and through which eggs may later be released. Here they grow into domestic pigs in Europe, Asia, and Australia; G. doloresi, adults to complete their life cycle, usually within about 6 found in wild boars; and G. nipponicum, found in weasels in months. Eggs are released into the environment in the stool of Japan (15). Until the early 1980s, all cases of gnathostomiasis the host about 8 to 12 months after initial ingestion of the found in humans in the areas of endemicity in Thailand, China, infective third-stage larvae by the definitive host (15, 41, 51).

486 HERMAN AND CHIODINI CLIN. MICROBIOL. REV. FIG. 2. Life cycle of Gnathostoma spinigerum. (Adapted from an image from the CDC-DPDx [www.dpd.cdc.gov/dpdx/HTML/gnathostomiasis.htm].) Downloaded from http://cmr.asm.org/ on October 12, 2019 by guest Humans usually become infected with the third-stage larvae of CLINICAL FEATURES Gnathostoma spp. by eating raw or inadequately cooked fresh- The clinical features can be divided into immediate symp- water fish or other intermediate hosts such as snakes, frogs, toms, a cutaneous form, and a visceral form. Within 24 to 48 h and chickens. However, two alternative routes of infection have been suggested: ingestion of water containing infected FIG. 3. Photograph of a third-stage larva of Gnathostoma spini- copepods (thus taking the place of a second intermediate host) gerum, showing the entire larva (A) and the head with hooks (B). or by penetration of the skin of food handlers by third-stage larvae from infected meat (11). Symptoms in humans occur as the late third-stage larvae migrate through the tissues, causing intermittent symptoms of cutaneous or visceral larva migrans. The larvae have been observed to move at 1 cm/hour (14). The larvae usually measure up to 12.5 mm long and 1.2 mm wide and are reddish white in color (15). They are identified on the basis of several characteristic features, which include the shape of the body, the number of rows of hooks at the cephalic end, the number of hooks in each row, the character of the spines which cover the body, and the extent to which the body is covered by spines, which vary according to species (Fig. 3) (11). These rows of hooks enable the larva to lodge in the host tissues and are in part responsible for the mechanical damage that it inflicts on its host. Identification of the species present is important for epidemiological purposes, but treatment is the same for all species.

VOL. 22, 2009 PARASITOLOGIC AND CLINICAL ASPECTS OF GNATHOSTOMIASIS 487 FIG. 5. Magnetic resonance image of thigh with Gnathostoma sp. Downloaded from http://cmr.asm.org/ on October 12, 2019 by guest larva. (Reprinted from reference 25.) FIG. 4. Photograph showing cutaneous larva migrans due to Gna- excretions and secretions it produces, and the host’s immuno- thostoma spinigerum on the forehead (A) and shoulder (B). (Reprinted logical response. The substances released contain various com- from reference 17.) pounds, including one similar to acetylcholine, a “spreading factor” with hyaluronidase, a proteolytic enzyme, and a hemo- of ingestion of Gnathostoma organisms, patients may develop lytic substance, which have been demonstrated in various stud- nonspecific signs and symptoms such as malaise, fever, urti- ies in Japan in the 1950s (5, 24). These substances, in addition caria, anorexia, nausea, vomiting, diarrhea, and epigastric or to the mechanical damage, result in the characteristic hemor- right upper quadrant pain. These symptoms occur as the larva rhagic tracks that may be seen in the subcutaneous tissues in excysts and migrates through the stomach or intestinal wall and patients or in the viscera or CNS postmortem. the liver and may last for 2 to 3 weeks (15). A marked gener- alized eosinophilia usually develops in association with larval Cutaneous Gnathostomiasis penetration of the gastrointestinal wall, with reported levels of Ͼ50% of the total white cell count. The larval worm then Cutaneous gnathostomiasis is the most common manifesta- migrates to the skin through the subcutaneous tissue causing tion of infection and is known by several local names, e.g., the typical migratory swellings (cutaneous disease) and from Yangtze River’s edema and Shanghai’s rheumatism in China, here may penetrate into deeper tissues and viscera to involve tuao chid in Japan, and paniculitis nodular migratoria eosino- the lungs, eyes, ears, gastrointestinal and genitourinary sys- filica in Latin America. It typically presents with intermittent tems, and rarely, but often fatally, the CNS (visceral disease). migratory swellings, (nodular migratory panniculitis), usually The majority of infections result only in cutaneous disease, affecting the trunk or upper limbs. These nonpitting edema- within 3 to 4 weeks after ingestion of the larvae, but the onset tous swellings vary in size and may be pruritic, painful, or of symptoms may be delayed for months and even years (23, erythematous (Fig. 4 and 5). They usually occur within 3 to 4 41). As the chronic stage begins and the larva enters the sub- weeks of ingestion of the larvae, typically last 1 to 2 weeks, and cutaneous tissues, the eosinophilia and systemic features usu- are commonly due to only one larva, but on occasion infection ally subside. with two or more has been found (10, 41). The swellings are due to both mechanical damage from the larva and the host’s The exact pathogenicity of gnathostomiasis is uncertain, but immunological response to the parasite and its secretions. As it is thought that the symptoms are due to the combined effects the larva migrates, subcutaneous hemorrhages may be seen of mechanical damage secondary to the larva’s migration, the along its tracks, which are pathognomonic of gnathostomiasis and can help differentiate it from other causes of larva migrans, e.g., sparganosis or strongyloidiasis. Episodes of swelling slowly

488 HERMAN AND CHIODINI CLIN. MICROBIOL. REV. become less intense and shorter in duration, but in untreated ence of eosinophilia is less likely in ocular disease because the Downloaded from http://cmr.asm.org/ on October 12, 2019 by guest patients symptoms may recur intermittently for up to 10 to 12 eye is a privileged site, and it is usually mild if elevated at all years. (41). Other, less common manifestations of cutaneous gnathosto- Auricular manifestations. Various reports have described a miasis include a creeping eruption (which may be confused wide variety of manifestations, which include mastoiditis, sen- with cutaneous larva migrans), a skin abscess, or a nodule, sorineural hearing loss, and extrusion of the larva from the which tend to occur when the larva is migrating more super- external auditory canal, the soft palate, the cheek, the tip of ficially (41). In these cases the larva can often be excised. tongue, and the tympanic membrane (15, 41). Spontaneous extrusion of a larva from the subcutaneous tis- sues has also been described. If the migratory lesions are on CNS manifestations. Although gnathostomiasis was de- the face, there is a serious risk of CNS or ocular invasion. scribed in the 19th century, CNS involvement was proven only in the latter half of the 20th century, with the postmortem Visceral Disease finding of a gnathostoma larva in the cervical cord of a patient with eosinophilic encephalomyelitis in 1967 (9). In the subse- The Gnathostoma larva is highly invasive and motile and quent year the parasite was found on the surface of the cere- therefore can produce an extremely wide range of symptoms bral hemisphere and attached to the choroid plexus of the affecting virtually any part of the body. In noncerebral disease lateral ventricle in two patients with fatal meningoencephalitis. the larvae may continue to cause intermittent symptoms until There have been several case series of CNS disease, which has they die after about 12 years, if left untreated. increased understanding of the pathophysiology (5, 38). Com- pared to other forms of disease, the CNS form of the infection Pulmonary manifestations. Pulmonary symptoms that have carries the highest mortality, with reported rates of 8 to 25%, been attributed to infection with Gnathostoma spp. include and 30% of survivors having long-term sequelae (5, 38, 41). cough, pleuritic chest pain, heamoptysis, lobar consolidation or However, these data are from the era before the use of al- collapse, pleural effusions, and pneumo- or hydropneumotho- bendazole and ivermectin. rax (13, 27, 36, 41). In some cases expectoration of the larva has led to resolution of the symptoms. Most patients have had The main features of CNS involvement are a radiculomyeli- an accompanying eosinophilia, with a reported range of 30 to tis, radiculomyeloencephalitis, eosinophilic meningitis, and 72%, and when a pleural effusion has been present it has been subarachnoid hemorrhage. The hallmark symptoms are an eosinophilic in nature (41). Therefore, a triad of eosinophilia, acute onset of excruciating radicular pain and/or headache subcutaneous swellings, and unexplained eosinophilic pleural (subarachnoid hemorrhage or eosinophilic meningitis), with effusion with a history of appropriate exposure risk should alert subsequent paralysis of the extremities and/or cranial nerve the physician to a diagnosis of gnathostomiasis (15). palsies. The typical clinical picture can be explained by the migratory pathway of the parasite, which gains entry to the Gastrointestinal manifestations. Gastrointestinal manifes- spinal cord along nerve roots (cranial, cervical, thoracic, or tations are less common in humans but may present as sharp lumbar), causing intense radicular pain (or headache in the abdominal pains as the larva migrates through the liver and case of cranial nerve or cervical root involvement) which usu- spleen or as a chronic mass in the right lower quadrant. Less ally lasts from 1 to 5 days (5). This initial pain is typically commonly, there may be acute right iliac fossa pain with fever followed by a degree of paralysis ranging from weakness to mimicking acute appendicitis or intestinal obstruction. Infec- complete paralysis of one to four limbs (the most common tion has also been found as an incidental (and asymptomatic) being paraplegia of lower limbs) as the parasite ascends the finding at surgery for a different problem. Radiologically the spinal cord to the brain. Urinary retention is usual with radiculo- findings are of a thickened bowel wall with narrowing of the myelitis and radiculomyeloencephalitis. Cranial nerve palsies lumen (15). Histologically the lesions found at surgery are tend to occur after the onset of paralysis, and if multiple they consistent with eosinophilic granulomas, but macroscopically signify a poor prognosis. Cerebral involvement is usually indi- they resemble neoplastic lesions, which has led to inappropri- cated by a depressed consciousness level or coma, but inter- ate radical surgery. This can be avoided only by consideration estingly, mental confusion does not tend to occur (5, 38). of possible parasitic infection in the preoperative work-up of such patients. In some cases different CNS symptoms may occur, or cur- rent ones may reappear after a quiescent period due to further Genitourinary manifestations. Involvement of the genitouri- migration of the larva to another location within the CNS. This nary tract is uncommon, but hematuria and the passage of the most commonly occurs within the first 2 weeks of the onset of larva in the urine have been reported. Other symptoms attrib- the initial neurological deficit but may be seen as early as 6 h uted to Gnathostoma spp. include profuse vaginal bleeding, or as late as 1 month. cervicitis, balanitis, an adnexal mass, and hematospermia (15, 36, 41). The pathogenicity in the CNS is thought to be the same as that elsewhere in the body, with direct mechanical injury caus- Ocular. The eye is the only organ in which the larva may be ing the most damage due to tearing with or without destruction visualized, and therefore there are many more literature re- of the nerve tissue and its vascular structures, as well as in- ports of ocular involvement than of involvement of other or- flammation and destruction of tissue due to toxin production. gans (15). Eye involvement has led to symptoms of uveitis The hallmark signs of gnathostomiasis are hemorrhagic tracts, (usually anterior), iritis, intraocular hemorrhage, glaucoma, which have been well documented throughout the spinal cord retinal scarring, and detachment. The larva is usually be found and cerebral tissue postmortem (5, 24). Death occurs if vital in the anterior chamber and may be recovered intact, but there structures in the brain stem are invaded, which may occur are a few reports of intravitreal localization (3, 4). The pres- within 4 to 31 days following the onset of CNS symptoms, or if

VOL. 22, 2009 PARASITOLOGIC AND CLINICAL ASPECTS OF GNATHOSTOMIASIS 489 FIG. 6. (A) Hematoxylin- and eosin-stained cross-section of a Gnathostoma organism taken from a subcutaneous nodule above the right breast Downloaded from http://cmr.asm.org/ on October 12, 2019 by guest of a patient, showing the esophagus. Note the presence of cuticular spines (arrow). (B) Another hematoxylin- and eosin-stained cross-section of a Gnathostoma organism, taken from the same specimen as for panel A, showing the intestinal cells and characteristic large lateral chords (LC). (Panel A is from Diagnostix Pathology Laboratories LTD and the CDC-DPDx and panel B is from the CDC-DPDx [www.dpd.cdc.gov/dpdx /HTML/gnathostomiasis.htm].) the larva burrows through a cerebral arteriole, resulting in gration (as previously discussed), particularly in the skin or massive subarachnoid hemorrhage (5). In Thailand 6% of sub- subcutaneous tissues, but is not always present at other times, arachnoid hemorrhages in adults and 18% of those in children and its absence should not exclude the diagnosis. Eosinophilia are due to gnathostomiasis (50). of the cerebrospinal fluid (CSF) is also highly supportive of CNS disease, with reported levels of 5 to 94% and a total CSF The main differential diagnosis of CNS disease due to Gna- white cell count of up to 500/mm3 (range, 20 to 1420/mm3), thostoma is infection with Angiostrongylus catonensis, another but may also be found with several other parasites, e.g., highly prevalent parasite in southeast Asia. This may produce Angiostrongylus cantonensis, Toxocara canis, Strongyloides ster- a similar eosinophilic meningoencephalitis, but the acute nerve coralis, Ascaris lumbricoides, Paragonimus westermani, Fasciola root pain, signs of spinal cord compression, and hemorrhagic hepatica, and Trichinella spiralis and with schistosomiasis, or xanthochromic spinal fluid seen in gnathostomiasis are ab- neurocystercercosis, and other infections such as coccidiodo- sent with Angiostrongylus infection (38). The Gnathostoma mycosis and aspergillus infection (5, 21). Noninfectious condi- larva is more invasive than that of Angiostrongylus and there- tions involving the CNS should also be considered (e.g., lym- fore produces more frequent focal neurological signs. In con- phoma, particularly Hodgkin’s) (40). trast, the Angiostrongylus larva, which is considerably smaller (120 ␮m wide and 12 mm long) and usually multiple, more In the 1960s skin tests using intradermal injection of G. commonly causes a meningoencephalitis, and although neuro- spinigerum antigen were developed in Japan, but these were tropic, it is rarely fatal (21). later shown to lack adequate sensitivity and specificity (26, 48). Scientists in Japan then went on to be the first to develop a DIAGNOSIS serological test for the diagnosis, using crude somatic extract of adult Gnathostoma doloresi worms found locally (23). How- The triad of eosinophilia, migratory lesions, and obvious ever, this was hampered by cross-reactivity with other locally exposure risk are highly suggestive of the diagnosis of gnatho- found parasites, including Paragonimus westermani, Toxocara stomiasis. Exposure risk must include residence in or travel to canis, Anisakis, and Fasciola hepatica. Later it was found that an area of endemicity and consumption of food that potentially this was a problem particular to the G. doloresi antigen but contains the larval form of the parasite (raw or undercooked could be overcome if the G. spinigerum antigen was used in- fish [in particular swamp eels, catfish, sleeper perch, bream, stead (1, 48). Nile tilapia, butterfish, loaches, or snake-headed fish], frogs, chickens, cats, or dogs). Clinically, the main differential diag- Tests were improved by using antigen from the third-stage noses includes angiostrongyliasis, trichinosis, and cutaneous larvae (L3) of G. spinigerum instead of the adult worm, but larva migrans. cross-reactivity remained a problem with other parasitic infec- tions. Furthermore, the L3 antigen was found to be highly Before the advent of serology, the diagnosis was more often complex, with over 20 components, some of which reacted with made by the isolation of the larvae from the lesions they the sera of healthy controls (32). Tapchaisri and colleagues caused, but this is often difficult in migratory skin lesions, is found that a specific L3 antigen with a molecular mass of 24 clearly not practical for visceral disease, and is no longer re- kDa had the greatest specificity and reacted only with gnatho- quired (Fig. 6). stomiasis sera and not with those from other parasitic infec- Eosinophilia is frequently present during initial worm mi-

490 HERMAN AND CHIODINI CLIN. MICROBIOL. REV. tions (49). This subsequently formed the basis of the immuno- dose of 400 mg twice a day for 21 days (18, 30). Albendazole is Downloaded from http://cmr.asm.org/ on October 12, 2019 by guest blot and future trials on serodiagnosis (20). a broad-spectrum benzmidazole antihelminthic which has proven efficacy against intestinal helminths and also extraint- An enzyme-linked immunosorbent assay (ELISA) for L3 estinal helminthic infections such as opisthorchiasis, hydatid immunoglobulin G (IgG) antibody was also developed, but the disease, and cutaneous larva migrans. The principal mode of sensitivity was poor, ranging from 59 to 87%, with a specificity action for albendazole is by its inhibitory effect on tubulin of 79 to 96% (1, 22, 46). Nuchprayoon and colleagues then polymerization, with resultant loss of cytoplasmic microtu- showed that by using IgG subclasses rather than total IgG, the bules. The loss of these impairs glucose uptake, with subse- sensitivity and specificity of the ELISA could be improved. quent depletion of the organism’s glycogen stores resulting in This had been shown previously to improve the diagnosis for immobilization and death. Albendazole is poorly absorbed other parasitic infections such as ascariasis, leishmaniasis, and from the gastrointestinal tract (although it is absorbed better filariasis (33). Their study showed that IgG2 had the least than mebendazole) and is rapidly converted in the liver to its cross-reactivity (particularly with Angiostrongylus, the main dif- active primary metabolite, albendazole sulfoxide, prior to ferential diagnosis) and had a specificity of 88% and positive reaching the systemic circulation. Oral bioavailability appears predictive value of 93%, whereas IgG1 had the highest sensi- to be enhanced when albendazole is coadministered with a tivity (98%) and negative predictive value (94%). With the fatty meal (2). The drug has been found to be safe and rela- exception of IgG2, cross-reactivity was found with An- tively well tolerated, with the main side effects being nausea, giostrongylus cantonensis, hookworm, Strongyloides stercoralis, dizziness, headache, and occasionally abnormal liver function and Opisthorchis viverrini. They concluded that IgG1 antibody tests and a transient leukopenia. Additionally, albendazole ap- should be used as a screening test for those with presumptive pears to stimulate the outward migration of the larva, thus gnathostomiasis and that IgG2 antibody could be used to con- making it more accessible and possibly amenable to excision firm the diagnosis. A further extensive retrospective study of (19, 47). The reason for this migration is unknown, but it tends parasitic and nonparasitic diseases carried out over 7 years to occur 7 to 14 days after commencing treatment. confirmed these findings of a lack of cross-reactivity (P. De- kumyoy, personal communication). Ivermectin has also been investigated for use in the treat- ment of gnathostomiasis, and it seems that its efficacy is similar Currently a number of serological tests are available for the to that reported for albendazole (30). Ivermectin binds selec- diagnosis of gnathostomiasis. The most widely used in Europe tively with high affinity to glutamate-gated chloride ion chan- is an immunoblot to detect the specific 24-kDa band consid- nels which occur in invertebrate nerve and muscle cells. This ered diagnostic of gnathostomiasis. This is carried out at var- leads to an increase in the permeability of the cell membrane ious places, with the United Kingdom serology being sent to to chloride ions with hyperpolarization of the nerve or muscle the Hospital for Tropical Diseases, Mahidol University, cell, resulting in paralysis and death of the parasite (34). Iver- Bangkok, Thailand. The Swiss Tropical Institute (Basel, Swit- mectin may also interact with other ligand-gated chloride chan- zerland), also performs serological testing. However, currently nels, such as those gated by the neurotransmitter gamma- there are no commercial reagents available. aminobutyric acid. It is metabolized in the liver and has few side effects, the main one being dizziness, and is therefore Specific mention should be made of the diagnosis of CNS generally well tolerated. Ivermectin has been shown to be disease. The CSF typically shows an eosinophilia, with elevated effective as either a stat dose of 0.2 mg/kg or as doses of 0.2 opening pressure and protein level. The use of CSF serology is mg/kg on two consecutive days, and therefore adherence is not not routine, and there are no published data on its utility in this a problem (31). The studies involving ivermectin have had context. Magnetic resonance imaging has also been useful in fairly small sample sizes (n ϭ 17 to 21), and therefore its demonstrating the migratory lesions within the spinal cord (7, evaluation with a larger prospective study is needed. Of note is 43). The parasite produces high-signal intensity on T2 weight- that a potential issue of flaring of disease was found in a study ing and contrast enhancement on T1 weighting, which if static by Kraivichian et al., which showed that those in the ivermectin could be attributed to various vascular, neoplastic, inflamma- group experienced an exacerbation of cutaneous symptoms tory, or infectious causes. However, the migratory nature of compared with those in the albendazole group (19). This could such lesions would be consistent with the well-documented theoretically be a serious problem for visceral disease, in par- pathway of the Gnathostoma larva. Multiple sclerosis would ticular ocular and CNS disease, although no such occurrences also produce intermittent lesions on magnetic resonance im- have been reported. This raises the issue of steroid use, which aging, but this can be excluded by the absence of CSF oligo- for neurocystercercosis is used to prevent inflammation in sites clonal bands. which could potentially be hazardous. Theoretically this ratio- nale for use could be applied to CNS or ocular gnathostomi- TREATMENT asis; however, data are limited, and the only study to examine this (n ϭ 162) showed no definite benefit in those who received For many years there was no effective treatment for gnatho- oral or intravenous steroid treatment (38). stomiasis, and surgical excision of the larvae remained the only effective management. Various drugs were tried both in animal Initial treatment is not always successful, and second courses models and in humans without success, including thiabenda- of treatment have been needed in some cases. Either albenda- zole, praziquantel, metronidazole, diethylcarbamazine, and zole or ivermectin may be used in sequence in such patients, quinine (18). and both have been used with successful outcomes for initial treatment failures (8, 25). However in regions of endemicity it However, studies with albendazole in animal models were may be difficult to differentiate between treatment failure and promising, and a trial by Kraivichian et al. in 1992 (n ϭ 112) confirmed its efficacy in humans, with cure rates of Ͼ90% at a

VOL. 22, 2009 PARASITOLOGIC AND CLINICAL ASPECTS OF GNATHOSTOMIASIS 491 reinfection. A recent series reported by Strady et al., con- 7. Chandenier, J., J. Husson, S. Canaple, C. Gondry-Jouet, P. Dekumyoy, M. Downloaded from http://cmr.asm.org/ on October 12, 2019 by guest ducted with returning travelers outside areas of endemicity, Danis, G. Riveau, C. Hennequin, A. Rosa, and C. P. Raccurt. 2001. Medul- indicated that initial relapse occurred up to 7 months after lary gnathostomiasis in a white patient: use of immunodiagnosis and mag- treatment, and the maximum period between two relapses was netic resonance imaging. Clin. Infect. Dis. 32:E154–E157. 15 months, with the latter occurring in one patient with CNS disease (45). A pragmatic approach would be that if the patient 8. Chappuis, F., T. Farinelli, and L. Loutan. 2001. Ivermectin treatment of a was asymptomatic after 12 months of treatment, this would be traveler who returned from Peru with cutaneous gnathostomiasis. Clin. In- sufficient evidence of cure, particularly if supported by a res- fect. Dis. 33:E17–E19. olution of any eosinophilia and a decrease in ELISA levels. In the event of relapse, a new 12-month follow-up period should 9. Chitanondh, H., and L. Rosen. 1967. Fatal eosinophilic encephalomyelitis be commenced. caused by the nematode Gnathostoma spinigerum. Am. J. Trop. Med. Hyg. 16:638–645. Future trials would be useful to investigate the use of com- bined treatment with both albendazole and ivermectin and to 10. Daengsvang, S. 1949. Human gnathostomiasis in Siam with reference to the determine whether relapse rates are lower with combination method of prevention. J. Parasitol. 35:116–121. drugs than with monotherapy. 11. Daengsvang, S. 1981. Gnathostomiasis in Southeast Asia. Southeast Asian J. PREVENTION Trop. Med. Public Health. 12:319–332. Eradication of the organism is unlikely given its global dis- 12. Diaz-Camacho, S. P., M. Zazueta-Ramos, E. Ponce-Torrecillas, I. Osuna- tribution and expanding culinary tastes for exotic foods in the Ramirez, R. Castro-Velasquez, A. Flores-Gaxiola, J. Baquera Heredia, K. West. Therefore, control will be achieved only through educa- Willms, H. Akahane, K. Ogata, and Y. Nawa. 1998. Clinical manifestations tion campaigns to raise public awareness (22). Adequate cook- and immunodiagnosis of gnathostomasis in Culican, Mexico. Am. J. Trop. ing is the best way to ensure that the larvae are killed, although Med. Hyg. 59:908–915. freezing infected meat to Ϫ20°C for 3 to 5 days is also effective. However, the common practice in Mexico of marinating fresh 13. Dow, C., P. L. Chiodini, A. J. Haines, and S. M. Michelson. 1988. Human fish in lime juice is ineffective, and the organism has been gnathostomiasis. J. Infect. 17:147–149. found to be viable even after 5 days of immersion in lime juice (39). Public health education is essential to change the eating 14. Feinstein, R. J., and J. Rodriguez-Valdes. 1984. Gnathostomiasis or larva habits of people in areas with high levels of endemicity, and migrans profundus. J. Am. Acad. Dermatol. 11:738–740. travelers need to be aware of the potential consequences of eating local delicacies. The large variety and wide distribution 15. Guitierrez, Y. 2000. Diagnostic pathology of parasitic infections with clinical of animals that are intermediate hosts make it impossible to correlations, 2nd ed. Oxford University Press, Oxford, United Kingdom. eliminate the parasite, and therefore appropriate cooking methods and avoidance of raw or undercooked freshwater fish 16. Hale, D. C., L. Blumberg, and J. Frean. 2003. Case report: gnathostomiasis are the only measures that can be taken. However, while trav- in two travellers to Zambia. Am. J. Trop. Med. Hyg. 68:707–709. elers continue to seek the exotic and remote, gnathostomiasis will be seen with increasing frequency in the West and other 17. Herman, J. S., E. Wall, C. Van Tulleken, P. Godfrey-Faussett, R. L. Bailey, regions where it is not endemic, and it should be considered and P. L. Chiodini. 2009. Emergence of gnathostomiasis in Botswana in another emerging imported disease of which physicians should British tourists. Emerg. Infect. Dis. 15:594–597. be aware. 18. Kraivichian, P., M. Kulkumthorn, P. Yingyourd, P. Akarabovorn, and C. C. ACKNOWLEDGMENTS Paireepai. 1992. Albendazole for the treatment of human gnathostomiasis. Trans. R. Soc. Trop. Med. Hyg. 86:418–421. We thank Paron Dekumyoy for helpful discussion and Julie Watson and Patricia Lowe for use of photographic images. 19. Kraivichian, K., S. Nuchprayoon, P. Sitichalernchai, W. Chaicumpa, and S. Yentakam. 2004. Treatment of cutaneous gnathostomiasis with ivermectin. Peter Chiodini is supported by the UCL Hospitals Comprehensive Am. J. Trop. Med. Hyg. 71:623–628. Biomedical Research Centre Infection Theme. 20. Laummaunwai, P., K. Sawanyawisuth, P. M. Intapan, V. Chotmongkol, C. REFERENCES Wongkham, and W. Maleewong. 2007. 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