https://orcid.org/0009-0001-7608-2706
Figures
Abstract
Human gnathostomiasis is a foodborne zoonotic nematode infection caused by the larval stage of Gnathostoma species. Although historically reported predominantly from Asia and America, cases are increasingly identified in previously non-endemic regions. The heterogeneous clinical presentation and diagnostic challenges likely contribute to underrecognition of the global disease burden. Current evidence is largely derived from case reports and case series, with a notable lack of prospective studies. To better delineate the epidemiological distribution and clinical characteristics of human gnathostomiasis, we systematically reviewed and analyzed the available literature. Most cases are reported from Asia and the Americas, with Thailand, Japan, and Mexico accounting for the highest numbers. Clinical manifestations are predominantly larva migrans syndromes, including cutaneous involvement (83.6% of cases), followed by neurological (7.7%), ocular (3.5%), and visceral (2.3%) presentations. Long-term sequelae are uncommon overall but occur frequently in ocular (51.8%) and neurological (32.2%) disease, the latter also being associated with a substantial case-fatality rate (33.9%). Diagnosis is based on exposure risk, most commonly consumption of raw fish (70.7%), as well as laboratory findings such as eosinophilia, positive serology, and, when feasible, histopathological confirmation. Treatment primarily relies on anthelmintic treatment with albendazole and/or ivermectin and, if feasible, surgical removal of larvae. Treatment success is highest with albendazole plus ivermectin combination therapy (86.7%) compared to monotherapy with albendazole (73.5%) or ivermectin (56.7%).
Author summary
Human gnathostomiasis is a tropical parasitic worm infection that humans usually acquire by eating raw or undercooked fish. While most infections are reported in Asia (especially Thailand and Japan) and America (especially Mexico), there are increasing reports of cases from countries where the disease was previously unknown. The symptoms are caused by the larval stages of Gnathostoma worms, which migrate through the human body after ingestion. Most commonly, the larvae migrate under the skin, but in general, almost any part of the body or organ can be affected. Treatment is with antiparasitic drugs, as surgical removal of the larvae is only possible if they migrate very superficially. Because symptoms can vary greatly, depending on the part of the body or organ affected, the disease is difficult to diagnose, and many cases may go undetected. Most of the available information about the disease comes from individual case reports and small case series, rather than large-scale studies. To better understand where the disease occurs and how it presents, is diagnosed, and is treated, we systematically reviewed and analyzed the published literature and combined the available data to obtain a clearer overall picture of this disease.
Citation: Frey S, Kuenzli E, Henning L, Bravo F, Nawa Y, Neumayr A (2026) Human gnathostomiasis – A systematic review and analysis of the literature. PLoS Negl Trop Dis 20(7): e0014546. https://doi.org/10.1371/journal.pntd.0014546
Editor: Maria Victoria Periago, Consejo Nacional de Investigaciones Cientificas y Tecnicas, Fundación Mundo Sano, ARGENTINA
Received: January 28, 2026; Accepted: July 2, 2026; Published: July 31, 2026
Copyright: © 2026 Frey et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: The author(s) received no specific funding for this work.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Human gnathostomiasis is a foodborne parasitic zoonosis caused by tissue-invasive spirurid nematode larvae of various Gnathostoma species. The parasite was first described in 1836 by Sir Richard Owen, who recovered the adult parasite from a gastric wall mass of a tiger which died at the London Zoological Gardens [1]. In 1889, the first human case was published, reporting the recovery of the parasite’s larval stage from a breast abscess of a female Thai patient [2]. The parasite’s complete life cycle was finally described by Prommas and Daengsvang in 1937 [3].
Life cycle
The life cycle of the Gnathostoma spp. typically requires two intermediate hosts and a definitive host (Fig 1). Definitive hosts are wild and domestic carnivorous or omnivorous mammals in which male and female adult worms (size: female: ~ 2–10 cm; male: ~ 1–6 cm) live in tumorous cavities they form (depending on the Gnathostoma species) in the hosts’ stomach, esophagus wall or urinary system. Adults mate and produce unembryonated eggs, which are shed in the host’s feces. Eggs become embryonated in fresh water and early first-stage larvae (EL1) hatch. Freshwater copepods (Cyclops spp.), which serve as first intermediate hosts, ingest the free-swimming EL1, and the larvae molt twice to become early third-stage larvae (EL3). Following ingestion of the copepod by a suitable second intermediate host (i.e., fish or amphibian), EL3 migrate into the tissues of the host where they develop into advanced third stage larvae (AL3) and encyst. The definitive host is infected by consumption of AL3 harboring second intermediate or paratenic hosts [4,5]. Fig 1 shows the parasite’s life cycle, Table 1 lists the typical intermediate and definitive host species of the human pathogenic Gnathostoma species, and Fig 2 shows some photographic examples of AL3 larvae.
(1) Unembryonated eggs are shed with the definitive host’s feces into fresh water; (2) Eggs embryonate and early first stage larva (EL1) develops and hatches; (3) Early first stage larva (EL1) infects first intermediate host and develops into early third stage larva (EL3); (4a) Early third stage larva develops in the second intermediate host into advanced third stage larva (AL3); (5) The definitive host is infected by consumption of AL3 harboring second intermediate (4a) or paratenic hosts (4b); (6) Adult parasites lodge and mate in tumorous cavities they form (depending on the Gnathostoma species) in the stomach or esophagus wall. [Fig 1 includes graphical silhouettes generated using OpenAI’s ChatGPT image generation system (GPT-5.5; available at: https://chatgpt.com/. Accessed July 13th, 2026)].
(A-D) Advanced third-stage larva (AL3) of Gnathostoma binucleatum encysted in the muscle tissue of a second intermediate host freshwater fish (the bottom scale in (B) and (D) depicts millimeters); (E) Advanced third-stage larva (AL3) of Gnathostoma binucleatum (length: ~ 1.5–2mm); (F) Characteristic cephalic region of the advanced third-stage larva (AL3) of Gnathostoma binucleatum covered by four transverse rows of cuticular spines and the adjacent body covered with transverse rows of flat spines [Images: Neumayr A].
To date, 14 valid species of the genus Gnathostoma are described [6,7], six are known to be human pathogenic (Table 1).
Humans are accidental dead-end hosts, classically acquiring the infection by the consumption of raw or undercooked meat of second intermediate or paratenic hosts [5,9]. In addition, drinking water containing infected copepods and handling meat from infected secondary intermediate hosts with bare hands are also considered possible routes of human infection [10,11]. Furthermore, the description of an infected 3-day-old infant suggests the possibility of intrauterine/perinatal transmission [12].
Epidemiology
Human gnathostomiasis is endemic mainly in Asia and the Americas. In Asia, most cases of human gnathostomiasis have been reported from Thailand (cumulatively more than 9,000 cases) and Japan (cumulatively more than 4,000 cases), but cases are documented across most of Asia (from India and Sri Lanka to China, the Philippines, and Indonesia) [6]. In the 1970s, gnathostomiasis was discovered to also be endemic in certain regions of Mexico [13] with more than 10,000 human cases reported since [6]. In 1979, human cases of gnathostomiasis emerged in Ecuador (with more than 2,000 cases reported since [6]) and following the first reported case series in 2001 [14], cases continue to also be reported from Peru [11,14–17]. Sporadically, cases are reported from other Latin American countries [18] and North America [19,20]. In Australia, the first suspected case of autochthonously acquired gnathostomiasis was reported in 1970 [21], followed by sporadic case reports since [22]. Although no cases of gnathostomiasis have been reported among the local African population to date, individual case reports of infections diagnosed in travelers returning from Africa indicate that the parasite is also present in sub-Saharan Africa [23–28]. In Europe, locally acquired gnathostomiasis is limited to two cases reported from Spain [29]. The high incidence of infection in certain regions is primarily attributable to specific regional dietary habits and typical local raw dishes, such as, e.g., koi pla in Thailand, koi ga in Vietnam, sashimi and sushi in Japan, and ceviche in Latin America.
Clinical presentation
In endemic areas, infections in humans are often so common that the disease is known by specific local names among the population: e.g., Tua-chid (Thailand), Choko-fushu (Japan), Rangoon tumor (Myanmar), Yangtze River edema or Shanghai rheumatism (China), Woodbury bug (Australia). The symptoms observed in human gnathostomiasis reflect the erratic tissue migration of AL3 in the accidental human host. Although AL3 larvae may mature to young adults in the human host, patency is not reached [30]. Since the life span of larvae is limited, the natural death of the parasite limits the duration of the infection. However, untreated human infection may last for several years, with symptoms lasting over 10 years [4] and up to 17 years [31] being reported. The larvae migrate through the host tissue without specific organ tropism at a speed of up to 3 cm per hour [6], with the migration path being reflected in the symptoms caused. In general, human gnathostomiasis primarily presents as cutaneous larva migrans (CLM) and visceral larva migrans (VLM) syndrome. CLM is characterized by subcutaneous migratory erythema or swellings in cases of deep tissue migration and by serpiginous creeping eruptions in cases of more superficial tissue migration (Fig 3). Gnathostoma spinigerum and G. binucleatum are reported to predominately cause migratory erythema and swellings with a predilection for the extremities and the face/head and symptoms lasting up to several years, while G. hispidum, G. nipponicum and G. doloresi predominantly present with serpiginous creeping eruptions with a predilection for the body trunk and symptoms being limited to a few months [6].
Examples of cutanous larva migrans (CLM) syndrome/ creeping eruptions in patients with Gnathostoma binucleatum infection: Depending on the depth of the parasite’s tissue migration, the morphology of the lesions ranges from erythematous swellings (A–D) to superficial serpiginous migration tracks (D–G). [Images: Neumayr A (A), Bravo F (B–G)].
VLM may affect any organ, including the central nervous system (CNS). Although CNS involvement is relatively rare, neural larva migrans (NLM; neurognathostomiasis) and ocular larva migrans (OLM; ocular gnathostomiasis) are feared due to the potentially serious consequences [32,33]. Interestingly, neurognathostomiasis is almost exclusively reported from Thailand and rarely from other countries, while ocular gnathostomiasis is almost equally reported in Thailand, Japan, India, Myanmar and Mexico [6].
Diagnostics
Diagnosing gnathostomiasis relies on plausible exposure history (epidemiology and source of infection), compatible clinical symptoms (primarily the clinical picture of CLM), and specific laboratory testing. Regards to the latter, a definitive diagnosis, relying on the identification of the parasite by microscopy in biopsy specimen is, besides the occasional spontaneous percutaneous emergence of the larva, only rarely possible. The presence of eosinophilia, in blood or tissue biopsies, may support the diagnosis of gnathostomiasis but is neither reliably sensitive nor specific. Histopathologic findings may demonstrate superficial and/or deep perivascular eosinophilic infiltrates, with eosinophils comprising up to 95% of inflammatory cells in later lesion stages [34]. In the majority of cases, the laboratory evidence is limited to indirect supportive serological tests, detecting Gnathostoma-specific antibodies in the patient’s serum [5]. Before modern serological assays became available in the 1970s, skin testing, based on the intracutaneous injection of purified AL3 antigen provoking a delayed-type (cell-mediated) hypersensitivity reaction in sensitized persons, was used in endemic areas [4,35]. With the development of immunodiagnostics, skin testing was replaced by ELISA and later by immunoblot (Western blot), which to date is the most widely used test. The immunoblot detects IgG antibodies in the patient’s serum, specifically targeting a 24 kDa polypeptide of G. spinigerum- and G. binucleatum-AL3 crude antigen extract (Fig 4) [36–40]. Although well established in endemic countries, the limited availability of serological tests in non-endemic countries often restricts the diagnostic options. Finally, although equally restricted with regards to availability, polymerase chain reaction (PCR) and sequencing techniques may also be helpful to establish the diagnosis and determine the causative Gnathostoma species in biopsy material [41,42].
(A) Western blot based on G. spinigerum third stage larva (AL3) crude antigen preparation: Lane 1: serum of a Laotian patient with G. spinigerum infection; Lane 2: negative control; (B) Western blot based on G. binucleatum third stage larva (AL3) crude antigen preparation: Lane 1: serum of a Peruvian patient with G. binucleatum infection, Lane 2: negative control.
Treatment and outcome
Besides the few cases where manual removal of very superficially migrating Gnathostoma larva allows for manual/surgical removal, the main treatment of human gnathostomiasis is medically, either with albendazole [43–46], with ivermectin, or with a combination of both drugs. Although failures of medical treatment are not infrequently observed [47] and frequently several rounds of treatment may be necessary to achieve cure, the prognosis of Gnathostoma-related CLM and VLM is generally good. The prognosis of Gnathostoma-related NLM and OLM is less favorable, as permanent sequelae and, in severe cases, even death can result.
With this systematic review and analysis of the literature on human gnathostomiasis, we aim to provide clinicians with a comprehensive summary of the available data, focusing on the clinically relevant core aspects of the disease.
Methods
This systematic review was registered prospectively in PROSPERO (CRD42024613813). A systematic literature search was performed of the databases CINAHL, Cochrane, EMBASE Elsevier, Medline, PubMed, Scopus and Web of Science on 14/Nov/2024 with the following search term ((Gnathostoma [Mesh] OR Gnathostomiasis [Mesh])) OR (Gnathostom* [tiab] OR “G. spinigerum” [tiab] OR “G. hispidum” [tiab] OR “G. doloresi” [tiab] OR “G. nipponicum” [tiab] OR “G. malaysiae” [tiab] OR “G. binucleatum” [tiab]) NOT (“Animals” [Mesh] NOT “Humans” [Mesh]), with adaptions according to the corresponding databases. A detailed description of the search strategy can be found in S1 Text. After duplicate removal through EndNote (version 21, 2013, Philadelphia, PA, Clarivate), Covidence (https://www.covidence.org/) and manually, all publications were pre-screened by title and abstract. All studies not concerning human gnathostomiasis or not matching the inclusion criteria (clinical cases with data on epidemiology, diagnostics, treatment or outcome) were excluded. All remaining studies were full text screened according to the inclusion criteria in the systematic review protocol and studies not matching were excluded. Non-retrievable studies, neither available through the corresponding journal, nor through library services nor direct contacting of the author were labelled “non retrievable” and excluded. In the full text review stage, the reference lists of the reviewed studies were checked for potentially eligible studies not detected earlier (snowball-search approach). If a review contained clinical data of cases from non-retrievable or foreign language sources, the data were included with the remark “as referenced in”. A second search was conducted on 20/Aug/2025 with the identical search string to detect and include the most recent publications. From the included studies, the following data were extracted: Author, publication title, publication date, journal, country of study, type of study, study period, language, number of gnathostomiasis cases, patients age, sex, country of acquisition, minimum incubation period, country of patients origin, autochthonous or imported case, expositional risk factors, preexisting medical conditions, immunosuppression, pregnancy, symptoms, duration of hospitalization, number of larvae, clinical syndrome (CLM, VLM, NLM, OLM), affected body part, laboratory values, diagnostic testing (serology, skin test, PCR), location of laboratory, histology, Gnathostoma species, imaging findings, treatment, treatment induced eruption, larva removal, used anthelmintic(s), dosage, duration, retreatment, side effects, relapse, number of relapses, outcome, complications, sequelae. Uncertainties during the review process were resolved by consulting a second reviewer. The used data extraction sheet can be found in S1 Table.
Results
Our search identified 4,939 publications, of which 319 proved eligible for inclusion in the review (Fig 5). The reference lists of the included publications and the PRISMA checklist for systematic reviews are available in S2 Text.
In the 319 reviewed papers, a total of 2,433 gnathostomiasis cases were reported. Considering the level of diagnostic certainty, we defined respective categories according to which these cases can be divided into 1,221 “possible cases” (Def.: compatible clinical picture), 1,016 “probable cases” (Def.: compatible clinical picture + positive serology), and 196 “confirmed cases” (Def.: detection of parasite by microscopy or by polymerase chain reaction (PCR) in biopsy).
In 16 patients, multiple lesions of migrating larvae were present at the same time. The reported number of lesions/larvae in these cases were: Nlesions/larvae (Npatients): 2 (10), 3 (1), 4 (2), 5 (2), 12 (1).
Discussion
Since the discovery of the parasite in 1889, the number of publications on human gnathostomiasis has increased slowly but steadily, peaking between 2000 and 2010 (Fig 6), the period during which most clinical treatment studies were also conducted. [44,50,51,53]. Most cases of gnathostomiasis in humans continue to be reported from the traditional high endemic regions in Asia and Latin America. Over the years, the sporadic reports of diagnosed infections in returning travelers [23–25,28] as well as autochthonous infections in regions previously considered non-endemic [21,22,26,29] have expanded the known geographic range of the parasite (Fig 7).
1 From South Africa a single suspected case of gnathostomiasis has been reported as personal communication [48]. [Map generated in R using the choroplethr package with basemap shapefiles obtained from Natural Earth Data (Link to source: https://www.naturalearthdata.com/downloads/; Link to terms of use: http://www.naturalearthdata.com/about/terms-of-use/)].
The level of diagnostic certainty of the reviewed cases of gnathostomiasis varies considerably. Among the reviewed 2433 clinical cases only 196 were “confirmed”, while 1016 were “probable” and 1221 “possible” cases. Since confirmation of gnathostomiasis in humans is limited to the few cases in which the parasite can be detected and diagnosed using direct methods (microscopy, PCR), it is not surprising that most cases remain unconfirmed, and the diagnosis based on the clinical picture and/or the indirect method of serology. The “probable” category is also at risk to misclassification bias, particularly in regions where cross-reactivity with other parasites is possible, which can potentially limit the comparability across studies. Furthermore, different assay types, antigen source and inconsistent availability of serology across regions further limits the accuracy of the classification. We assessed the possibility of a stratified subgroup analysis between “confirmed,” “probable,” and “possible” cases; however, the number of “confirmed” cases was largely insufficient to perform such an analysis. Consequently, it is possible that some of the “probable” or “possible” cases in the original publications were incorrectly classified as gnathostomiasis, which confounds the validity of our analyses. Although this limitation has to be acknowledged, we nevertheless consider our data set to be the best available.
The vast majority of human gnathostomiasis is caused by G. spinigerum (Fig 8) and primarily originate from Asia with some sporadic cases also being reported from Australasia and Africa. Although early morphological studies of larvae obtained by biopsy from patients in Mexico and Ecuador described the larvae to be similar to those of G. spinigerum [54–57] later molecular genetic analysis revealed that human gnathostomiasis in Mexico and Ecuador is exclusively caused by the morphologically very similar species G. binucleatum [58,59]. To date, G. binucleatum is the only known zoonotic Gnathostoma species prevalent in the Americas, and the second most frequent Gnathostoma species causing human gnathostomiasis [6]. In this regard, it should be noted that the latter fact is well reflected in Fig 7 (with the high number of cases reported from Mexico) but not in Fig 8. Fig 8 is based on ‘reported cases with available individual clinical data’ and as such data is missing for most cases reported from Mexico, these are not included in the figure. All other human pathogenic Gnathostoma spp. (Table 1) are considerably less frequent (Table 5) and, besides two reported human G. hispidum cases from Spain [29], exclusively reported from Asia.
As expected, raw fish was mostly cited as the suspected source of infection (Table 2), although the consumption of other intermediate and paratenic host species, as well as contaminated water (containing infected copepods), were also cited as suspected sources of infection.
The primary clinical manifestation of human gnathostomiasis is CLM caused by a single migrating larva. The concomitant presence of more than one migrating larva in a patient is overall rare and was reported in only 0.7% (16/2421) of the cases (Nlesions/larvae [Npatients]: 2 [10], 3 [1], 4 [2], 5 [2], 12 [1]).
Most CLM lesions manifest as subcutaneous swelling (73.4%) or serpiginous dermal tracks (9.7%), reflecting deeper or more superficial larval migration, respectively (Table 3).
Several species-specific differences in lesion morphology and anatomical patterns are described in the literature, but these narrative descriptions originate primarily from clinical experts, and the available data is rather sparse. CLM lesions due to G. spinigerum and G. binucleatum are described to present identically as intermittent migratory swelling (less frequent as serpiginous dermal tracks) primarily located on the peripheral extremities, the face and the head with symptoms persisting untreated over >1–4 years [6]. In contrast, CLM lesions due to G. hispidum, G. nipponicum and G. doloresi are described to mainly present as serpiginous dermal tracks (less frequently as migratory swelling) primarily located on the central chest, abdomen and the back with symptoms persisting untreated over <2–3 months [6]. To verify these species-specific differences described, we analyzed the reviewed cases respectively (Table 4, Figs 9 and 10). The available data do not allow for an assessment of the individual species-specific duration of symptoms and the limited number of non-spinigerum CLM cases restricts the strength of the analysis. However, our species-specific analysis of the anatomical pattern and lesion morphology nevertheless corresponds with the literature (Table 4, Figs 9 and 10).
(A) CLM lesions which descriptions allowed only for a rough assignment to the main anatomical regions of the body (N = 7325); (B) CLM lesions which descriptions allowed for a detailed assignment to anatomical subregions of the body (N = 565); [Body template adapted from an open source clipart (Link to source: https://openclipart.org/detail/314881/human-male-and-female-body-line-art)].
(A) G. spinigerum + G. binucleatum (N = 255 [G.s. 248, G.b. 7]); (B) G. hispidum + G. doloresi + G. nipponicum (N = 55 [G.h. 9, G.d. 37, G.n. 9]) [Note: G. malaysiae was not included, since data were restricted to a single case, see Table 5]; [Body template adapted from an open source clipart (Link to source: https://openclipart.org/detail/314881/human-male-and-female-body-line-art)].
Organ invasive larval migration beyond the tegument is seen in 16.4% of the cases (either consecutively following CLM or as primary manifestation; Table 5). These cases present with NLM (8.2%), either in the form of primary NLM (7.6%) or as consecutive NLM (0.6%) following CLM or OLM (Table 5), as OLM (3.5%), or as VLM (2.3%).
In the cases of VLM, any organ may be affected by migrating larvae with a diverse range of reported retrieval sites. Larvae are either removed surgically or detected by the patient in sputum or in urine (Fig 11). The high proportion of cases in which patients reported the expulsion of larvae in sputum and urine can be explained by the fact that the presence of larvae in sputum and urine is more likely to be noticed than, for example, the expulsion of larvae in stool. Given that surgical removal of larvae from the intestinal tract is reported relatively frequently, it can be assumed that the latter does occur but goes unnoticed. Looking at the reported sites where larvae are frequently surgically removed, the prominence and immediate proximity of the frequently reported organs (colon, stomach, greater omentum; Fig 11) plausibly reflects the natural anatomical route of larvae after peroral infection. Unlike in NLM and OLM, viscerally migrating larvae are considerably less likely to cause significant pathology, consequently leading to surgical removal and diagnosis. Considering that in all cases presenting with CLM, the larvae must have previously passed through visceral tissue, it appears plausible to assume that the VLM cases which do not progress to consecutive CLM are in a lot of cases not diagnosed.
With regards to NLM and OLM, the question arises as to whether the reported frequencies of these clinical syndromes are due to actual neurotropism of the parasite or simply to the fact that invasion of these anatomical structures leads to more severe symptoms and thus are more likely to be diagnosed. Gnathostomal NLM is predominantly reported in the G. spinigerum endemic areas of Southeast Asia and rarely elsewhere (Fig 12). As discussed above, CLM caused by G. spinigerum and CLM caused by G. binucleatum are reported to exhibit identical patterns in terms of anatomical predilection and the tendency to show predominantly deeper rather than superficial tissue migration. The higher tendency towards deeper tissue migration would be consistent with the tendency to cause more NLM (compared to Gnathostoma spp. showing more superficial tissue migration). It is therefore striking that NLM is reported almost exclusively in the G. spinigerum endemic areas of Southeast Asia, while it is virtually unknown in the G. binucleatum endemic areas of Latin America (to date, only three autochthonous NLM cases on the American continent have been described, two in the USA [60,61] and one in Brazil [62]). Thus, a species-specific neurotropism of G. spinigerum appears possible, but remains to be proven.
CLM, cutaneous larva migrans; NLM, neural larva migrans; OLM, ocular larva migrans; VLM, visceral larva migrans.
NLM cases can roughly be split into three clinical forms: a cerebral, a spinal and a combined form, depending on the location of the neuronal damage caused by the migrating larvae. Findings in the cerebral form mainly include headaches, meningism, cranial nerve palsies and subarachnoid hemorrhages, while the spinal form is mainly associated with radicular pain, paresthesia, paresis or plegia, and the combined form exhibits findings from both forms (Fig 13). The Gnathostoma larva reaches the central nervous system via tissue migration along nerve roots, causing radiculomyelitis. The larva then ascends along the spinal nerves and vessels into the brain, causing direct mechanical damage to the tissue. This can be seen as hemorrhagic tracts in neurologic imaging and often leads to subarachnoid hemorrhage with red blood cells (RBC) in the cerebrospinal fluid (CSF) [63–65]. In Southeast Asia, where most gnathostomal NLM cases are reported, the main differential diagnosis is cerebral angiostrongyliasis due to the neurotropic neuroinvasive larvae of the nematode Angiostrongylus cantonensis. Since A. cantonensis larvae are significantly smaller (450–600 x 20–30 µm), enter the brain via the bloodstream, and have a more limited lifespan (2–8 weeks), the clinical picture and the prognosis differ considerably. Cerebral angiostrongyliasis primarily presents as eosinophilic meningitis, radicular symptoms are uncommon, migratory tracks are typically not visible on imaging, the course is usually mild and self-limiting, and subarachnoid hemorrhage and sequelae are rare [65,66].
NLM, neural larva migrans.
In gnathostomal OLM, all anatomical parts of the eye may be affected (Table 6), but the reported frequency of affected ocular structures suggests that the larvae mostly enter the eye from the anterior periorbital soft tissue. This is also suggested by case reports describing pain and swellings around the eye before the onset of ocular symptoms [61,67–69] and matches the anatomic CLM distribution pattern of G. spinigerum and G. binucleatum showing a predilection for the face and particularly the periocular region (Fig 10). This may also explain why to date, G. spinigerum and G. binucleatum are the only Gnathostoma spp. reported to cause OLM. However, in cases where there were no previous CLM lesions on the face but bleeding in the retinal vessels, retinal holes or fundus scars were observed, eye invasion may also have occurred via the bloodstream [70–73]. Compared to NLM, the occurrence of OLM appears to be more evenly distributed in the endemic areas, with the exception of a noticeable clustering of OLM cases reported from India and more recently from Myanmar [74]. This is particularly strange because, in comparison, CLM is very rarely reported from these countries (Fig 12). The reported symptoms and pathologies associated with gnathostomal OLM result from the invasion and migration of the larvae and are diverse but non-specific (Table 7).
Like other tissue-invasive helminth infections, gnathostomiasis is often accompanied by blood eosinophilia. Although no universal threshold value exists to define eosinophilia, a widely accepted cut-off is ≥ 500 eosinophils/μl (≥0.5 × 10⁹ eosinophils/l) [75]. The considerably lower frequency of peripheral eosinophilia in OLM compared to CLM, VLM and NLM is likely explained by the fact that the ocular space is an immunological sanctuary containing very few immune cells (even less than in the CNS) and being separated from the rest of the body by the blood-retina barrier [76]. Thus, once inside the eye, the systemic eosinophilic stimulation caused by the tissue migration of the larva(e) apparently abates. Although the CNS is also considered an immune privileged site [77], we interestingly found that this apparently does not influence the systemic eosinophilic reaction (Table 8).
Definitive diagnosis of gnathostomiasis relies on identification of Gnathostoma larvae in biopsy specimen or when they spontaneously emerge from CLM lesions. Since this is limited to a relatively small proportion of cases, serology remains the most commonly reported diagnostic method (Table 9). Since in most of the publications reviewed the data on the serological tests used were largely insufficient or missing, we refrained from attempting any analysis. A detailed summary of gnathostoma-specific serological assays is beyond the scope of this review and can be found elsewhere [6], but we would like to highlight some core aspects. In the absence of commercially available serological assays, serological testing remains limited and largely restricted to academic institutions offering diagnostic laboratory services (e.g., the Department of Helminthology at Mahidol University, Bangkok, Thailand or the Diagnostic Centre at the Swiss Tropical and Public Health Institute, Basel, Switzerland). To date, most serological assays rely on preparations of crude antigen of AL3, harvested from second intermediate hosts. Cross-reactivity of anti-Gnathostoma antibodies in serological assays is observed [78], but not necessarily present. Thus, anti-Gnathostoma antibodies in a patient’s blood may not always be detectable by an assay prepared from crude antigen of a Gnathostoma species not identical to the one infecting the patient [40]. Serological assays based on recombinant Gnathostoma antigens as well as a point-of-care immunochromatographic assay have been developed and it is hoped that in the future such assays will become commercially available [79–81]. In general, however, it should always be borne in mind that serology is an indirect diagnostic method with incomplete sensitivity and specificity. Although it can support the diagnosis, it must always be interpreted with caution and in conjunction with epidemiological and clinical probability.
For cases in which larvae can be obtained by biopsy, or larvae spontaneously emerge from CLM lesions, we compiled a diagnostic bench aid to facilitate identifying the species (S1 File).
Since in most cases the larvae cannot be removed manually nor do they spontaneously emerge from the CLM lesions, treatment with albendazole and/or ivermectin is the primary treatment method. The most used regimens are albendazole 2 x 400 mg/day over 21 days, ivermectin 0.2 mg/kg over 1–2 days or the combination of both (Table 10). When looking on the most used regimens, the summarized treatment success rates in the reviewed cases was highest for albendazole and ivermectin combination therapy (86.7%), followed by albendazole monotherapy (73.5%), and lowest with ivermectin monotherapy (56.7%) (Table 11).
To date, six prospective clinical studies have evaluated the efficacy of anthelminthic therapy in gnathostomiasis (Table 12). All the six trials were conducted in Thailand (thus, concerned G. spinigerum) and five of them evaluated the efficacy of albendazole or ivermectin against placebo or against each other. No studies on combination therapy have been conducted to date. Compared to our merged data, the treatment success rates in these studies were overall higher, but in line with our data higher for albendazole monotherapy (93–94.1%) [43,44,51] and lower for ivermectin monotherapy (50–95.2%). Combined usage of albendazole and ivermectin appears promising; however, the apparent benefits of this combination therapy should be interpreted with caution, as the available evidence is based almost exclusively on retrospective case reports and case series without prospective comparative evaluation. Combination therapy therefore requires further validation in prospective controlled studies to examine its efficacy and optimal use.
Retreatment and sometimes even multiple cycles of retreatment may be necessary in the case of treatment failure (Table 11). In the absence of evidence for a best retreatment regimen, the most frequently adopted strategy is changing to the alternative drug, extending the duration of treatment, or opting for combination therapy (Table 11). In some cases, anthelmintic treatment has been reported to lead to more superficial migration of Gnathostoma larvae with the possibility to extract the parasite from a small erupting papule [44,51] or even the spontaneous emergence of the larva [82]. This phenomenon of treatment induced larval outward migration/ emergence has mainly been described with albendazole [52], but similar observations were also reported with ivermectin [44,51,83], under interferon alpha therapy in a hepatitis C patient [84], and following praziquantel treatment [85], although the latter two drugs lack evidence regarding a plausible mode of action against Gnathostoma larvae and, thus remain debatable.
Besides anthelminthic treatment adjunctive corticosteroid treatment is used to control cerebral inflammation and edema in cases of NLM [46]. In the absence of evidence from clinical trials this approach is based on plausible theoretical considerations and the successful use of corticosteroids in other inflammatory CNS processes, including parasitic infections like, e.g., cerebral angiostrongyliasis, neurocysticercosis and neuroschistosomiasis [86].
Infrequently the use of other anthelmintic drugs (i.e., mebendazole, thiabendazole, diethylcarbamazine, praziquantel) in human gnathostomiasis has been reported (Table 10), but clinical studies evaluating their effectiveness are lacking. The effectiveness of other benzimidazole compounds such as mebendazole and thiabendazole appears plausible due to their identical mode of action to albendazole, but thiabendazole is no longer marketed and the inferior tissue penetration of mebendazole compared to albendazole argues against its use. The reported use of diethylcarbamazine (DEC) in three cases appears to be based on an anticipated pan-nematode activity of the compound, which is primarily used to treat filarial infections [87] whereas the effectiveness of praziquantel against the nematode Gnathostoma is not plausible, since the compound shows a trematode-specific mode of action [87]. In the only cases reported to have received albendazole plus praziquantel (Table 10), gnathostomiasis was initially not suspected (the case was a tourist returning from Botswana), the antiparasitic treatment empirically chosen, and the diagnosis only latter established after the larva emerged from the skin [24].
We found reported cure rates of gnathostomal CLM and VLM of 94.2% and 100%, respectively and no sequelae reported in these cases (Table 13). However, in 5.8% of the reviewed gnathostomal CLM cases failure of anthelminthic treatment was reported, leading to recurrent/relapsing CLM lesions. The true recurrence/relapse rate of human gnathostomiasis is difficult to assess, since systematic long-term follow-up data is limited and in endemic areas distinguishing treatment failure from reinfection is problematic. In this context, a French cohort study in particular has contributed interesting data: 13 French travellers who had been infected in Southeast Asia (n = 11) and Mexico (n = 2) were followed up for a median of 15 months (6–49 months) after favourably responding to first-line treatment with albendazole (n = 12) or ivermectin (n = 1) [47]. Eight of the 13 patients (61.5%) sustained a total of 13 relapses (1–4 relapses per patient). The median interval between initial treatment and the first relapse was 2 months (range 1–7 months), the interval between successive relapses was 5–30 months [47]. The relapse rate of 54.2% we found among the reviewed CLM cases confirms that treatment failures are overall frequent. Nevertheless, despite the high frequency of CLM relapses, cases unresponsive to medical treatment were only reported in 5.8% of the reviewed cases and therefore relatively rare. The very low number of VLM and NLM cases compared to CLM does not allow to answer the question whether differences regarding the relapse rate exist between the different gnathostomal syndromes (Table 13). Due to the overall limited number of non-spinigerum infections, an analysis regarding potential differences in treatment success and failure rates between the different Gnathostoma species was not feasible. In patients who suffer multiple relapses and undergo repeated treatment, it ultimately remains unclear whether the therapy was finally effective or whether the absence of further relapses was due to the natural death of the larvae. Thus, the effectiveness of medical treatment may be overestimated. More recently, the observation of morphological changes in the tegumental structures of G. spinigerum larvae that survived albendazole treatment has led to the speculation that the parasite may possibly be capable of developing adaptive tolerance/resistance to the drug [88].
In gnathostomal OLM, the lack of reports of treatment failure (Table 13) and the high rate of sequelae (in 53.7% of cases) is not surprising, given that surgical removal of the larvae is the treatment of choice and defect healing of the highly sensitive ocular structures invaded by the larvae is to be expected.
Not surprisingly, the worst outcome is reported in gnathostomal NLM, with roughly one third of patients fully recovering, one third suffering from sequelae, and one third dying of the infection (Table 13).
We acknowledge that our systematic review has three main limitations: Firstly, the fact that our literature search may have not included all publications reporting on cases and studies of gnathostomiasis, particularly those in Thai or Japanese. As Thailand and Japan are high endemic regions, our language restriction may have influenced the analyses. Secondly, publication bias is an important limiting factor, as case reports and case series are more likely to describe more severe or unusual presentations. This may have resulted in overrepresentation of clinically striking manifestations and may have influenced estimates of disease severity, syndrome frequency, and treatment outcomes. Also the analyses on geographic distribution, syndrome frequency, and treatment patterns may have been influenced by the language restriction as well as publication bias. Thirdly, the already mentioned fact that the number of non-spinigerum cases was overall relatively small, limiting the species-specific analysis. Nevertheless, we hope that our analysis provides clinicians with a helpful overview of the clinically relevant aspects of human gnathostomiasis.
Supporting information
S3 Table. Reference list of included publications.
https://doi.org/10.1371/journal.pntd.0014546.s007
(XLSX)
References
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