Human toxocariasis

SUMMARY

Human toxocariasis is a globally prevalent zoonotic parasitic infection caused by larvae of Toxocara species, primarily Toxocara canis and Toxocara cati. Toxocariasis is commonly transmitted to humans through the ingestion of embryonated Toxocara eggs found in contaminated soil, water, or on surfaces contaminated with animal feces. Unlike in dogs and cats, humans are not definitive hosts for Toxocara spp., and, as a result, Toxocara larvae do not complete their life cycle in humans. Instead, following accidental oral ingestion of embryonated eggs, Toxocara larvae undergo an aberrant larval migratory cycle to various organs including the lungs, liver, muscles, and central nervous system, and do not return to the intestines to develop into mature adult worms. As the Toxocara larvae do not complete their life cycle in the human host, they will ultimately die in human tissue. This comprehensive systematic review of human toxocariasis analyzes and synthesizes existing research to provide a detailed and updated understanding of this zoonotic parasitic infection of global importance. This review provides an in-depth analysis of various aspects of toxocariasis, including its epidemiology, microbiology, pathogenesis, clinical manifestations, diagnostic methods, and treatment strategies.

INTRODUCTION

Human toxocariasis is a globally prevalent zoonotic parasitic infection caused by the larvae of Toxocara species, specifically Toxocara canis and Toxocara cati, the dog and cat roundworm. Toxocariasis poses a significant public health challenge owing to its widespread distribution and potential to cause a range of clinical manifestations in human hosts. The first diagnosis of human toxocariasis was described more than 60 years ago; however, human toxocariasis remains largely understudied, leading to large knowledge gaps in the literature. To date, various clinical syndromes have been recognized, including visceral larval migrans (VLM), neurotoxocariasis (NT), ocular toxocariasis (OT), and covert or common toxocariasis (CT) (1). It is likely that these manifestations are not totally separate entities, although the degree to which these clinical syndromes overlap remains unknown (2–5).

Dogs and cats are the definitive hosts of T. canis and T. cati. Humans are accidental hosts, incidentally infected with Toxocara spp. through ingestion of embryonated Toxocara eggs in contaminated soil/sand and water or through ingestion of infected definitive host tissue.

Because infection occurs via oral ingestion of eggs, food-borne transmission is also possible (6). Following ingestion of eggs, juvenile larvae are released from the egg and translocate across the gastrointestinal mucosa into the systemic circulation. Larvae travel to visceral compartments, most commonly the liver and the lungs, via the circulatory system. A high burden of larvae migrating through the host can lead to profound local and systemic inflammation. As a result, Toxocara larval migration can cause tissue damage via direct mechanical damage from the worm as well as through indirect activation of the host immune response. Unlike the human roundworm Ascaris lumbricoides, Toxocara larvae are unable to complete their necessary migratory cycle in the human host and thus are unable to mature into adult worms, reproduce, or release eggs. Instead, Toxocara larval development arrests in tissue and leads to a self-limited and often asymptomatic infection in humans (1, 6). However, in certain cases, particularly with high worm burden, larval migration and larval death in tissue can cause severe, life-long morbidity in humans. Toxocariasis in humans is classically divided into four main clinical syndromes: (i) VLM, (ii) NT, (iii) OT, and (iv) common or covert toxocariasis.

This comprehensive review of human toxocariasis synthesizes existing literature to provide a detailed and updated understanding of the epidemiology, microbiology, pathogenesis, clinical manifestations, diagnostic methods, and treatment strategies of human toxocariasis.

EPIDEMIOLOGY

Toxocariasis is prevalent worldwide, especially in regions with high feral or untreated dog and cat populations, particularly in resource-limited regions. It is estimated that 19% of the world’s population (1.4 billion) is seropositive (7); however, the true burden of disease globally remains unknown (8). In a recent review of Toxocara cases, the following seroprevalence was documented by World Health Organization regions: 37.7% (25.7%–50.6%) in Africa, 34.1% (20.2%–49.4%) in

Southeast Asia, 24.2% (16.0%–33.5%) in the Western Pacific, 22.8% (19.7%–26.0%) in the Americas, 10.5% (8.5%–12.8%) in Europe, and 8.2% (5.1%–12.0%) in the Eastern Mediterranean (7). Global variation, as well as in-country variation, may be secondary to socioeconomic resources, climate, and cultural approach to dogs and cats in each region (9, 10). In the USA, an estimated 5.1%–13% of children over age 6 are seropositive for Toxocara (11, 12). Toxocara in the USA disproportionately affects persons in contact with outdoor dogs and cats (13) as well as children, particularly children living in low-resource areas. In New York City boroughs, Toxocara egg prevalence in public spaces (i.e., public parks and playgrounds) was inversely related to the average income of the region (14). Furthermore, in a study conducted in Houston, Texas, Toxocara “hotspots” correlated to areas of poverty in the greater Houston region (15). Children, including those living in the USA are at particularly high risk of toxocariasis due to behaviors such as pica, particularly geophagia, leading to ingestion of soil/sand contaminated with Toxocara eggs as well as close contact with animals (16). Toxocariasis disproportionately affects children from underserved communities in the USA, with the highest prevalence of disease in non-Hispanic Black children (up to 21%) (11), particularly those living in the southern USA. Because millions of US children living in low-resource regions are exposed to Toxocara, toxocariasis likely represents one of the most important zoonotic pathogens contributing to childhood health disparities (17), including reduced cognitive function (18). Increased local and global surveillance is critical to gaining a greater understanding of not only the prevalence of disease but also to further delineate the risk factors and clinical outcomes associated with human toxocariasis (19).

PARASITOLOGY

Toxocara spp. is a helminthic parasite classified as a nematode or roundworm (20, 21). There are two primary species of Toxocara: T. canis and T. cati. Species differentiation can be challenging as both species release subspherical eggs with pitted surfaces (Fig. 1). However, the surface pitting on T. canis eggs is more coarse than the pitting on T. cati eggs (22). Furthermore, both species develop into large round worms that live in the intestines of both dogs and cats (23). Male worms measure 4 to 10 cm in length and approximately 2 mm in width, while females measure 5 to 18 cm in length and approximately 3 mm in width (Fig. 2) (24). Due to these similarities in gross appearance, species differentiation relies on molecular methods. Other Toxocara species, including T. vitulorum, T. pteropodis, T. mackerrasae, T. lyncus, T. apodemi, T. malaysiensis, and T. tanuki, among others, have been described in animal hosts (25, 26) and may have zoonotic potential.

Fig 1.

Toxocara spp. egg. Reprinted from reference 27 (CDC DPDx).

Fig 2.

(A) Toxocara canis larva hatching from an egg. (B) Toxocara canis adult male (top) and female (bottom). Reprinted from reference 27 (CDC DPDx).

In definitive hosts like cats and dogs, Toxocara spp. can be transmitted by ingestion of eggs, ingestion of infected tissue, transplacental transmission, and/or transmammary transmission (20, 27, 28). However, in humans, Toxocara spp. is transmitted via ingestion of either embryonated eggs containing stage 3 larvae (L3) or ingestion of uncooked infected paratenic host (i.e., chicken, sheep) tissue containing L3 larvae (Fig. 3) (27, 29). Eggs are released in the stool of the definitive hosts but not in accidental or paratenic hosts (i.e., humans). Adult female worms living in the definitive host can release up to 200,000 eggs per day. Once released in the stool of the definitive host, eggs are not immediately infective. Instead, they require a minimum of 2 weeks in the soil to support the development of the larvae into L3. Humans ingest embryonated L3 eggs through consumption of contaminated soil, water, or plants (29, 30). Once ingested, L3 hatch from the egg in the gastrointestinal tract and begin their transient, essential larval migration through host tissues by blood or lymphatic fluid to the liver and the lungs. Unlike in dogs and cats, the L3 do not return to the gastrointestinal tract in humans and thus do not develop into adult worms. Instead, the larvae remain in tissue where they can remain dormant and may incite a severe type 2 immune response (29). Infection in humans is self-limited; however, the host immune response to the larvae in tissue leads to a variety of clinical syndromes.

Fig 3.

Toxocara spp. lifecycle. Adapted from reference 27 (CDC DPDx).

CLINICAL MANIFESTATIONS

Toxocariasis causes a wide spectrum of clinical syndromes, ranging from asymptomatic infection to severe disease such as vision loss, seizure disorders, and multi-organ involvement. Most cases of toxocariasis are asymptomatic, as reflected by the large number of seropositive people in the USA (11), and the clinical manifestations depend on parasite load, host immune response, and the site of infection. Toxocariasis is classically described as four primary syndromes: VLM, NT, OT, and CT (1).

VLM

VLM occurs as a result of larval migration throughout the body into a variety of organ compartments. While VLM can occur at any age, the highest incidence is in children under 5 years, possibly due to higher incidence of behavior risk factors such as geophagia in this age group (31, 32). Symptoms occur due to both direct organ damage from larval migration as well as indirect damage from a resultant host immune response to larval death and include fever, malaise, weight loss, pulmonary symptoms, hepatomegaly, rash, and lymphadenopathy (33). Lung and liver tissue are the common destinations for larval migration; less commonly, cardiac and urinary systems can be involved. Peripheral and tissue-specific eosinophilia is often seen in conjunction with site-specific symptoms (34).

Toxocara-associated pulmonary disease

Pulmonary symptoms associated with toxocariasis include coughing, wheezing, and dyspnea. Asthma, acute bronchiolitis, or pneumonitis can occur because of larval migration through lung tissue and/or larval death in lung tissue (20). Severe clinical manifestations have also been described, such as eosinophilic pneumonia (35, 36). Allergic asthma is the most common symptomatic manifestation in the lungs, a chronic inflammatory disease associated with increased mucus secretion and bronchial hyperreactivity. Toxocara-induced allergic asthma is mediated by type 2 T helper (Th2) cells, which secrete IL-4, IL-5, and IL-13, and upregulation of IgE stimulating immune cell recruitment, eosinophil degranulation, and airway hyperreactivity (37). Multiple systematic reviews have concluded a positive association between previous Toxocara infection and increased risk of childhood asthma (38, 39). While this association has been explored in childhood asthma, the association between adult toxocariasis and asthma is less clear (40). Less common pulmonary manifestations of toxocariasis include pulmonary nodules (41).

Toxocariasis-associated liver disease

Larval migration through the liver and larval death can manifest as liver lesions on imaging in patients with VLM (42). Toxocara-induced liver lesions can appear similar to liver lesions from other nematode infections, like Fasciola hepatica infection, atypical bacterial infections, or malignancy (43, 44). Associated symptoms of hepatic involvement include fever, abdominal pain, and peripheral eosinophilia. Toxocara-induced liver lesions can evolve into pyogenic liver abscess (45–47) with histopathology showing eosinophilic infiltrates (48). Eosinophilic hepatitis with eosinophilic granulomas (49) and Charcot-Leyden crystals (50) has also been documented.

Toxocariasis-associated cardiac disease

While rare, a spectrum of cardiac manifestations from toxocariasis has been described in the literature. Myocarditis is the most commonly documented cardiac disease associated with toxocariasis (51–53), but other manifestations include pericarditis (54–56), Löeffler’s endocarditis (57), myocarditis (41, 58), heart failure, pericardial effusion (45), as well as cardiac tamponade (56) and associated thrombus (55, 57) have all been documented in the literature. Cardiac manifestations can range from incidental findings to acute decompensation from severe cardiac failure or tamponade. Histologically, eosinophilic inflammatory infiltrates, myocardial necrosis, subendocardial fibrosis, and granulomas are indicative of Toxocara VLM in the heart. Based on the common histopathology, the mechanism of cardiac diseases is likely from direct damage due to larval migration and indirect damage due to a compensatory immune response (59).

Other organ involvement in VLM

Genitourinary disease associated with toxocariasis has been described, including nephrotic syndrome (60–62) and eosinophilic cystitis (43, 63), and is often associated with peripheral eosinophilia (64). Additionally, allergic skin diseases such as atopy, eczema, and urticaria have been positively associated with Toxocara seropositivity, which is presumed to be due to histamine release from activated mast cells as a result of a Th2 immune response during larval migration and/or larval death in the human host (65, 66).

NT

The first case of neurotoxocariasis was reported in 1951 in a child with clinical and pathological findings consistent with an encapsulated larva in the central nervous system (CNS), initially concerning infection by the human roundworm Ascaris lumbricoides (67). It was not until 1966 that it was suggested that this disease was secondary to Toxocara canis instead of Ascaris (68). Since then, much more is known about the diverse neurological manifestations of human toxocariasis, ranging from acute meningoencephalitis (69, 70), myelitis (71), spinal abscess (72), optic neuritis, and cerebral vasculitis (73) to chronic morbid conditions such as epilepsy (74, 75), cognitive impairment, and behavior changes (76). Additionally, asymptomatic CNS infection has been documented (77).

Larval migration into the CNS most likely occurs via hematogenous spread. Acutely, NT can be associated with meningoencephalitis from migrating larvae causing mechanical damage and induction of the host immune response. Patients may present with fever, altered mental status, and focal neurological deficits. NT is also a known cause of epilepsy, particularly in children (78). Larval migration through the CNS can provoke inflammatory responses and disrupt neural functions, potentially triggering epileptic seizures. Toxocariasis-associated epilepsy may present with a range of seizure types, including generalized tonic-clonic, focal, or complex partial seizures.

Beyond epilepsy, NT may also contribute to cognitive deficits, including memory impairment, learning difficulties, executive dysfunction, and behavior changes such as irritability, hyperactivity, and emotional lability (79). Additionally, more recent studies suggest that NT could be a risk factor for neuropsychiatric conditions, including schizophrenia (80).

OT

Ocular nematode infections were first recognized in 1950 following enucleation of the eye in children diagnosed with retinoblastoma (81). These worms were later identified as Toxocara spp. (82). Toxocara larvae migrate through the circulation and into the periocular soft tissues of the posterior eye, where ocular damage occurs due to mechanical destruction and resultant host granulomatous immune reaction (10). Migration via the optic nerve and from the cerebrospinal fluid to the optic chiasm has been proposed and demonstrated in animal models but has not been confirmed in human disease (82–87).

OT typically presents as unilateral disease and classically affects children, typically older children, although recent studies have reported the condition in adults as well (88). The older age distribution in OT may reflect the natural history of chronic toxocariasis in the posterior eye and not necessarily recent infection (88). OT commonly presents as painless (pain is reported in up to 33% of cases) (88) unilateral vision loss associated with photophobia and “floaters.” Common ophthalmologic findings include vitreitis, posterior or intermediate uveitis (less likely anterior uveitis), traction retinal detachment, granuloma formation, endophthalmitis, optic neuropathy, and/or crystoid macular edema (2, 89). Granulomas are most often peripheral, but can be present on the optic nerve. Interestingly, while local ocular eosinophilia is common, peripheral eosinophilia is usually absent in OT (90). Advanced OT, also termed “pseudoretinoblastoma,” presents with leukocoria and, uncommonly, strabismus, mimicking retinoblastoma (91). The clinical outcome for the majority of patients with OT is permanent vision loss, leading to at least 70 people blinded by toxocariasis each year in the USA (90, 92).

Covert and common toxocariasis

Covert toxocariasis in children and common toxocariasis in adults are syndromes that occur in persons with positive serologic diagnostic assays that present with non-specific symptoms. In covert toxocariasis, recurrent abdominal pain is a common symptom, but anorexia, nausea, vomiting, lethargy, headaches, limb pains, sleep and behavior disturbances, and pneumonia can also occur (93, 94). In adults, common toxocariasis can manifest as weakness, pruritus, rash, abdominal pain, and dyspnea (95). Peripheral eosinophilia is generally present in 25% of patients with covert toxocariasis (96). Symptom resolution may take months to years; however, the long-term impact of covert toxocariasis remains largely unknown. Longitudinal studies on the natural history of covert toxocariasis following targeted treatment are needed.

DIAGNOSIS

While toxocariasis can be readily diagnosed in dogs and cats through examination of Toxocara eggs in fecal samples, toxocariasis remains a diagnostic challenge in humans. Toxocara larvae arrest in tissue and do not complete their life cycle in the human host. As a result, neither eggs, larvae, nor adult worms will be found in the stool of infected humans. Thus, diagnosis is largely dependent on exposure history, indirect laboratory blood tests, and the constellation of clinical symptoms.

A complete blood count with differential to evaluate for peripheral eosinophilia is often used initially to identify individuals with possible toxocariasis (97). Eosinophils are tissue-dwelling immune cells that can be elevated in persons with toxocariasis as larvae migrate through or arrest in viscera. In children with positive Toxocara enzyme linked immunosorbent assay (ELISA) living in Peru, 40% had peripheral eosinophilia, measured by absolute eosinophil count (AEC), in comparison to 19% of children with negative serology (98). Screening of adult blood donors in Brazil revealed that the majority of individuals with positive Toxocara ELISA assay also had elevated peripheral eosinophilia (99). Even in non-endemic regions, elevated AEC was identified in 50% of patients with positive Toxocara ELISA assays (100). Cases of severe peripheral eosinophilia with AEC over 5,000 cells/µL, consistent with severe secondary hypereosinophilia syndrome, have also been reported in persons with toxocariasis (101). However, the degree of peripheral eosinophilia is dependent on the larval burden and the site of larval migration. For instance, peripheral eosinophilia is typically absent in patients with OT (15, 34, 102). Thus, the absence of peripheral eosinophilia does not rule out toxocariasis, particularly in cases of NT and OT (103). Given the association of peripheral eosinophilia and human toxocariasis, Toxocara should be evaluated in all patients with risk factors and elevated AEC. In a study of adults presenting to clinical care for peripheral eosinophilia of unknown etiology in Seoul, Korea, toxocariasis was the most common diagnosis (representing over 50% of all cases of elevated AEC) and the AEC ranged from 510 to 31,840 cells/µL (34). Additional studies in Korea confirmed Toxocara as a common diagnosis for peripheral eosinophilia of unknown etiology in endemic regions (104, 105). Unfortunately, peripheral eosinophilia is a non-specific indicator of toxocariasis, and additional diagnostic assays are needed to further support the diagnosis.

Isohemagglutinins to A and B blood group antigens are another indirect marker of toxocariasis that can be used to support the diagnosis of human toxocariasis. Toxocara excretory-secretory (ES) products have A and B group antigens that cross-react with human isohemagglutinins (106), resulting in elevated levels of isohemagglutinins in individuals with VLM (107). While isohemagglutinin analysis is non-specific for human toxocariasis, utilization of this assay may be a helpful adjunct assay to complement serologic or, when feasible, molecular testing.

Serological tests on serum (or CSF in cases of NT) remain the most common tool for the diagnosis of toxocariasis. Like many helminths, Toxocara larvae secrete proteins and other molecules through their ES product during the migratory phase. The ES product aids in larval migration and interaction with the host immune response but can also be used to develop serologic immune assays (17, 108). Commercially available enzyme immunoassays (EIAs) detect host antibodies against T. canis L3 excretory-secretory (TES) antigens from serum. While TES EIAs are available in the USA, they do have several limitations. First, TES EIAs rely on crude ES product isolated from cultured Toxocara canis larvae for immunoassay development. Additionally, TES EIAs are generally qualitative assays measuring total serum IgG. TES EIA IgG can remain positive for years after infection and does not differentiate acute versus remote infection. In some laboratories, specifically the CDC, titers can be measured and followed serially. Per the CDC, a titer of ≥1:32 is considered positive (samples can be sent to the CDC through https://www.cdc.gov/infectious-diseases-labs/php/submission-form/?CDC_AAref_Val and by contacting Parasites Lab parasiteslab@cdc.gov) (27). A change in paired serologic assay titers and/or measurement of the avidity of Toxocara-specific IgG may provide insight into acute versus remote infection (109). However, these tests are not routinely available commercially.

Early studies evaluating the efficacy of TES EIA to diagnose human toxocariasis demonstrated nearly 100% sensitivity and specificity (110). However, more modern studies have shown that the TES EIA has an overall sensitivity of 78%. Furthermore, the sensitivity of the TES EIA for Toxocara syndromes such as OT is as low as 50%, although the sensitivity of TES EIA may be increased in OT by evaluating titers down to 1:2 if the clinical presentation is consistent with OT (111, 112). While the overall specificity of the TES EIA is approximately 92%, in regions endemic with other helminthic pathogens, particularly Ascaris, the specificity can be as low as 78% due to cross-reactivity with other helminth ES (78, 113). A positive TES EIA can be confirmed using a western blot to increase specificity (114); however, this assay is not readily available, relies on crude TES antigen, and is time-consuming. The use of native or crude TES in serologic assays including EIA and western blot is a significant limitation. Obtaining crude TES requires worm dissection and egg removal, followed by in vitro egg incubation, egg hatching, and larvae culture to obtain sufficient quantities of TES (3). The diagnostic limitations of TES-ELISA and western blot make the development of novel diagnostic assays, such as the use of recombinant proteins, a critical need in toxocariasis research (1, 115).

The use of recombinant T. canis (rTc) antigens may provide a breakthrough in human toxocariasis diagnosis by using high-throughput production of immunogenic antigens to incorporate into serologic assay instead of natural products (116). Identification of immunodominant antigens within the TES is a critical first step in developing rTc antigen-based immunoassays. Studies using immunoblotting and mass spectrometry have identified rTc-MUC3, rTc-TES-26, rTc-TES-32, and rTc-CTL4 (TES-70) as immunodominant proteins that, when used in IgG4 immunoassays, enhance both the specificity and sensitivity of the ELISA. A combination of rTc-TES-26 and rTc-CTL4 proteins increased the immunoassay sensitivity to 100% and specificity to 100% (117). Other studies using immunoscreening of sera from human subjects with toxocariasis against a T. canis larval cDNA library identified two C-type lectins (CTLs): Tc-CTL-1, also known as TES-32 and TES-30, and Tc-CTL-2. Both antigens were able to be expressed as recombinant proteins (rTc-CTL-1 and rTc-CTL-2) in an Escherichia coli system, integrated into an ELISA and western blot, and differentiated Toxocara infection from infection with other helminths in human sera (118). Furthermore, the testing performance of rTc-TES-120 expressed in both Pischia pastoris and Escherichia coli has been evaluated in 45 human samples with helminth infection and demonstrated 100% specificity for sera collected from Toxocara-infected humans (119). Other rTc proteins, including rTc-ASA, rTc-PDP, rTc-ASP, and rTc-TES-26, have been evaluated for potential use in immunoassays; however, continued investigation is warranted (120, 121). The efficacy of these rTc proteins in the diagnosis of human toxocariasis in adult patients versus pediatric patients has also been explored. Sera collected from children and adults were tested with rTc-TES-30- (Tc-CTL-1) and rTc-TES-120-based ELISA. There was no difference in the sensitivity of rTES-30 in children (81.8%) compared to adults (87%). However, rTc-TES-120 sensitivity was found to be reduced in children (63.6%) compared to adults (95.7%). Specificity for rTc-TES-30 and rTc-TES-120 was preserved at >94% for both children and adults (122). Other non-EIA-based immunoassay diagnostic platforms such as rapid diagnostic kits and multiplex assays using rTc proteins have shown promising results (123). Lateral flow assays specifically would provide a more rapid, low-cost field test, while Luminex multiplex bead-based assays would allow for testing of multiple antigens simultaneously. While these diagnostic assay platforms have shown promising results, more studies are needed to validate the assay performance (124, 125). Alternatively, rTc proteins such as rTc-TES-30 (Tc-CTL-1), which has shown high concordance with negative sera, could be used as confirmatory testing in western blots, reducing the reliance on natural Toxocara ES (126).

Investigation into the use of rTc chimeric polypeptides may add an additional benefit to recombinant protein-based immunoassays. Previous studies of Toxocara myosin heavy chain protein described only two immunodominant domains within the protein, suggesting that the combination of immunodominant domains within multiple proteins may enhance testing performance (127). Based on this premise, using an enhanced green fluorescent protein (eGFP) carrier-based system, antigenic rTc polypeptides from well-characterized recombinant proteins (TES-26, TES-32, TES-120, and myosin heavy chain) were expressed to produce a chimeric protein. Identification of T. canis polypeptides that have immune cross-reactivity to other helminth polypeptides was eliminated from the chimeric protein in order to enhance specificity. While the specificity of this chimeric protein was improved, the recombinant chimeric antigen had inferior sensitivity when compared to complete recombinant protein and TES-EIA (128). Further development and evaluation of chimeric proteins composed of rTc immunodominant polypeptides that are not conserved across helminth species is required.

Molecular tests such as stool polymerase chain reaction and serum circulating antigen are essential diagnostic tools used for the detection of Toxocara spp. in definitive hosts such as dogs and cats (25, 108, 129–131). However, as humans are non-patent hosts for the development of adult Toxocara worms in the intestines (larvae are trapped in tissue granulomas), these tools have limited use in humans except when used to test tissue samples by biopsy (i.e., liver tissue, brain tissue, cardiac tissue, ocular fluid) (25). Unfortunately, the lack of practical application of currently available molecular diagnostic assays in the diagnosis of human diseases limits their utility (132, 133).

Radiographic diagnosis is another adjunctive tool that can aid in the diagnosis of VLM, NT, and OT. In VLM, the use of abdominal ultrasound or computerized tomography (CT) scan of the abdomen and/or chest based on clinical symptoms may identify evidence of larval migrans. Visceral lesions identified radiographically by CT are typically ill-defined, ovoid lesions (44) consistent with eosinophilic granulomatous infiltrates and can be observed in any organ system, including lungs, liver, brain, heart, and eyes (134). In a study of adults with serologically diagnosed toxocariasis, 38% had one or more ovoid, hypoechoic lesions in the liver identified by abdominal ultrasound, and 68% had one or more ovoid, ill-defined lesions in the liver identified by CT scan. Radiographic lesions varied in size from <2 cm to >5 cm (42). Pulmonary lesions secondary to VLM are most commonly found in subpleural locations within the lower lungs but may be distributed randomly across multiple lobes (135, 136). In a study evaluating 63 patients with VLM, 57% had lesions identified in both lungs, and 49% had lesions in three or more lobes. Lesions were described most commonly as ill-defined ground glass opacities, solid nodules, or patchy consolidations and less likely as focal linear opacities (136). Cardiac magnetic resonance imaging (CMR) has been used in case reports to identify cases of Toxocara myocarditis, pericarditis, or endomyocardial fibrosis from direct larval migration and/or secondary hypereosinophilic infiltration. Case reports of Toxocara cardiac involvement have been described using CMR by evidence of elevated global T1 and T2 values (137) indicating myocardial edema or subendocardial enhancement from hypereosinophilia and the development of fibrosis (138).

Magnetic resonance imaging (MRI) of the brain, spine, and/or orbit may be useful in the diagnosis of NT and OT. Ocular imaging by ocular ultrasound or CT scan may demonstrate a temporal peripheral mass, a vitreous membrane extending between the posterior pole and the mass, and traction retinal detachment (109). Use of optical coherence tomography and fluorescein angiography in the diagnosis of OT has also been described (139, 140). MRI findings for cerebral NT are non-specific and can involve hyperintense lesions throughout the cerebrum, including cortical and extra-cortical lesions and leptomeningeal enhancement on T2 and fluid-attenuated inversion recovery (FLAIR) sequences. Obstructive hydrocephalus, vasculitis, and acute infarction have also been described using MRI and MRI angiography in cases of cerebral NT (103). In contrast, neuroimaging of patients with spinal NT demonstrates spinal cord edema and focal nodular enhancement on T2 and FLAIR sequences (103). In a case series of 17 patients with Toxocara myelitis, 15 of the 17 patients had fusiform enlargement of the spinal cord with isointense lesions on T1 and hyperintense signals on T2 and FLAIR sequence, and 16 out of 17 patients had focal, nodular lesions (the last patient had large diffusion lesions) following contrast (141).

THERAPEUTICS

Treatment regimens for human toxocariasis are dependent on the clinical syndrome and the severity of symptoms. Four drugs have been approved for the treatment of toxocariasis: three benzimidazoles (albendazole, mebendazole, thiabendazole) and diethylcarbamazine (DEC) (142). Albendazole emerged as the treatment of choice given its worldwide availability, low cost, favorable side effect profile, and adequate efficacy (142, 143). A variety of treatment durations have been evaluated, including 5 days (104, 144–146), 2 weeks (143), and 4–8 weeks (147). Many clinical experts and health organizations, including the CDC, recommend treatment of all symptomatic Toxocara syndromes with albendazole for 5 days (19, 97), while some experts suggest a longer treatment duration of 14 days (142). Albendazole can be given as 400 mg twice a day for 5 days for adults and children greater than 2 years of age (97). The dosing of albendazole in children less than 24 months old is unknown. The World Health Organization recommends a half-dose of albendazole (200 mg) for children less than 24 months old for deworming protocols (148); however, the American Academy of Pediatrics and CDC recommend standard dosing (400 mg twice daily) for all children regardless of age (97, 149). Albendazole is not approved for children less than 1 year but has been used anecdotally and in mass drug administration programs (150). It should be taken with fat-containing food to maximize absorption (151). Mebendazole 100–200 mg twice a day for 5 days is an alternative regimen (97).

Other drugs can be used to treat toxocariasis but have lower efficacy or worse side effects compared to albendazole. DEC has similar efficacy to albendazole and mebendazole but causes more severe adverse reactions (143, 152). In a trial comparing thiabendazole to albendazole, albendazole was associated with a higher cure rate (144). However, other studies have shown an 86% cure rate with thiabendazole (153). Ivermectin has not been shown to be effective (154).

Anthelmintic treatment in patients with asymptomatic toxocariasis remains controversial in the literature (34, 142). Additionally, the need for systemic anthelmintics for ocular toxocariasis remains controversial. If anthelmintic treatment is pursued, experts recommend treatment with albendazole due to elevated drug concentrations in the CNS compared to other benzimidazoles (155–157).

Corticosteroids should precede the use of anthelmintics in (i) VLM infection of the heart and/or VLM with severe peripheral eosinophilia; (ii) OT; and (iii) NT, in order to reduce profound immune cell recruitment and activation in tissues during anthelmintic therapy (158). Corticosteroids should be continued throughout the course of anthelmintic therapy and subsequently tapered. Management of secondary diseases such as asthma, vision loss, and epilepsy is largely supportive. The reduction of inflammation in OT is critical to reduce tractional forces leading to retinal detachment and can be achieved through topical, periocular depot injections, or systemic corticosteroids or steroid-sparing immunosuppressant medications if necessary (159, 160). If retinal detachment occurs, vitrectomy is the treatment of choice (161, 162). Steroids with or without albendazole, and ultimately vitrectomy, can be used for recurrent vitritis due to OT (163).

Novel therapeutics are needed to improve the treatment of toxocariasis, namely drugs that will reach adequate concentrations in host viscera. An albendazole prodrug was shown to have greater nematocidal effect in vitro compared to albendazole (164), and natural products such as naphthoquinones (165) and alkaloids (166, 167) have also been studied. Drug nanocarriers have been evaluated as well to increase benzimidazole delivery to tissues, including with lipid nanoparticles (168) and chitosan microparticles (169). Derivatives of benzimidazoles such as fenbendazole and other anthelmintic drugs continue to be evaluated for potential new therapeutic options against toxocariasis (170–174) but are not yet available.

GLOBAL BURDEN AND PREVENTION

Toxocariasis represents a common zoonotic infection with a high global burden. Given the impact of this disease, prevention strategies that utilize a multi-disciplinary “One-Health” approach are critical (17). Goals of preventive measures include environmental control measures, screening and treatment, and education (Table 1).

TABLE 1.

Strategies to prevent and control Toxocara spp. disease

	Environmental control	Screening and treatment	Education
Human	Washing hands after contact with animals or potentially contaminated dirt Decontaminating public objects in parks and daycares Reducing pica and geophagia in children	Appropriate screening in healthcare centers for children Prompt treatment of infections	Education regarding appropriate screening and treatment guidelines for healthcare professionals Comprehensive education program geared towards the public
Animal	Prompt disposal of pet waste Limiting stray animal access to public parks Limiting stray animal population	Appropriate screening and treatment in animal facilities Regular pet deworming	Education regarding appropriate screening and treatment for veterinary professionals

A comprehensive public education platform and campaign are necessary to inform communities about the various risks and preventive measures for Toxocara in both humans and animals. Educating pet owners on the importance of regularly deworming pets and frequently maintaining hygienic environments for both pets and humans is essential. Additionally, appropriate disposal of animal waste in public and private spaces, limiting the stray animal population, as well as limiting access to public parks by stray animals can drastically reduce transmission of Toxocara to humans (27). Individuals, as well as caregivers of young children, need to be educated on washing hands after contact with animals or contact with dirt that could be contaminated with animal waste. Reducing pica and raising awareness about the risk of placing objects from public spaces into the mouth can minimize the risk of infection in children (175).

Human and veterinary healthcare education plays a role in the prevention and awareness of Toxocara infections. Expanding the knowledge of human healthcare professionals regarding the epidemiology and clinical manifestations of Toxocara in humans can improve diagnosis, treatment, and patient outcomes through early diagnosis. Regulation of feral dogs and cats is necessary to prevent and control the spread of the parasite in the environment (176). Screening programs instituted in animal facilities as well as in veterinary healthcare centers may provide faster diagnosis and treatment of disease in animals (177). Early identification and treatment of infections in both animals and humans may impede the development of severe health issues within a community. By integrating these prevention strategies into public health programs, communities can reduce the risk of toxocariasis and increase the overall health of animal and human populations.

RESEARCH GAPS AND FUTURE DIRECTIONS

Toxocara is an underrecognized and underdiagnosed clinical disease causing chronic inflammation and systemic and localized syndromes which can lead to significant life-long morbidity. Diagnosis is limited by diagnostic assays with variable sensitivity and specificity that are reliant on resources that are not readily available. In highly endemic regions, the use of current diagnostic assays is further restricted by cross-reactivity with other helminths. New diagnostic assays that use recombinant proteins to reduce the reliance on scarce resources, as well as the identification of novel Toxocara antigens that improve sensitivity and specificity of diagnostic assays, are needed. Development of rapid diagnostic assays such as lateral flow tests is not currently available but is an important tool to identify cases within the community using minimal resources. Furthermore, early identification of clinical cases is stymied by lack of practitioner knowledge of the disease, including lack of awareness of diagnostic assays, clinical manifestations, and treatment interventions. Public health surveillance programs are needed to increase awareness of disease. Instituting mandatory reporting of human cases of toxocariasis would aid in heightening the awareness of the infection within a community. Additionally, active and passive surveillance animal programs that incorporate deworming of dogs and cats are critically needed to reduce disease in animals, which would ultimately lead to decreased disease in humans. Lastly, research that investigates potential vaccine targets for both animals and humans remains largely unfunded, restricting scientific advancement in preventative strategies.

Biographies

Dr. Susana Lopez-Alamillo is a physician and clinical researcher with over seven years of clinical research experience. She earned her medical degree from Universidad Popular Autónoma de Puebla. Dr. Lopez has held key research fellowships, including at the Instituto Nacional de Neurología y Neurocirugía in Mexico City, and as Research Coordinator at the Division of Cardiothoracic Transplantation and Circulatory Support at Baylor College of Medicine. She is currently the Clinical Research Lead at the National School of Tropical Medicine at Baylor College of Medicine and the Center for Vaccine Development at Texas Children's Hospital. Dr. Lopez has spent the last three years focusing on tropical diseases, driven by a passion to improve global health and address emerging threats. Her expertise in clinical research enables her to contribute to the advancement of knowledge and therapies in this field, with a goal of improving public health outcomes worldwide.

Pravallika Padyala is a pre-medical student at Baylor University pursuing a dual major in Biology and Business with a concentration in Global Health. She has held research positions at institutions including Texas Children’s Hospital, Baylor College of Medicine, and Baylor University. Her interest in this topic stems from her work in microbiology and infectious diseases at the National School of Tropical Medicine at Baylor College of Medicine, under the mentorship of Dr. Jill Weatherhead. Padyala is passionate about global health and aspires to become a physician committed to advancing healthcare through research and community-based initiatives.

Dr. Megan Carey is a pediatric infectious diseases fellow in the tropical medicine track at Baylor College of Medicine and Texas Children's Hospital. She has clinical expertise in global health, HIV, and is certified in tropical medicine and traveler's health from the American Society of Tropical Medicine and Hygiene. Her research in the Clinton Lab within the National School of Tropical Medicine focuses on therapeutics for zoonotic and emerging pathogens, specifically flavivirus vaccines. Her goal is to interrupt diseases causing generational poverty and improve outcomes for children worldwide.

Dr. Megan M. Duffey is an infectious diseases and tropical medicine specialist at Baylor College of Medicine. She received her MD from Medical College of Wisconsin and completed an Internal Medicine-Pediatrics residency at Indiana University School of Medicine and an Infectious Diseases fellowship with a focus in tropical medicine and global health at Baylor College of Medicine, where she is now faculty. She studies the epidemiology of emerging neglected tropical infections.

Dr. Jill E. Weatherhead is an adult and pediatric infectious disease physician-scientist at Baylor College of Medicine and Texas Children's Hospital. Her laboratory studies the interaction between parasitic worms and the host immune system to cause end-organ disease. She diagnoses and treats adult patients in the Harris Health System Tropical Medicine clinic and pediatric patients in the Texas Children's Hospital Tropical Medicine Clinic. She is the Director of the adult and pediatric infectious disease fellowship tropical medicine and global health track and the Assistant Dean of the National School of Tropical Medicine at Baylor College of Medicine.