Toxocara species (Toxocariasis)

Parasitology

Life Cycle

Among the Nematodes belonging to the genus Toxocara, only 2 species, Toxocara canis and T. cati, are recognized as causative agents of human toxocaral disease (14, 54). Both ascarid helminths dwell in the upper digestive tract of their definitive hosts, which are canids and felids, respectively. Female worms may produce up to 200,000 eggs per day. Eggs passed in the feces are not infective and must be in the soil to become embryonated (64).

Swallowing of infective eggs by adult dogs rarely results in the presence of Toxocara in the digestive tract. The eggs hatch in the small intestine. The released larvae perforate the intestinal wall, enter a vessel, and travel through the liver and then the lungs into the left heart. They are propelled by the systemic circulation and finally bore through the capillary vessels, migrating into surrounding tissues where they may survive for years. When a bitch becomes pregnant, these dormant larvae are reactivated by hormonal stimuli and migrate transplacentally towards the fetus (42). Newly born puppies are therefore infected. This transplacental migration is apparently absent in cats. The main mode of contamination for kittens is the transmammary route involving larvae, which are found in the milk (22), whereas this mode is accessory for puppies.

When infective eggs are ingested by non-canid and non-felid species, a cycle similar to that depicted above is completed, leading to the presence of tissue-dwelling dormant larvae in the host organism, which remain infective for predators eating parasitized tissues. This status is referred to as paratenesis. When a dog or a cat preys upon an infected paratenic host, the larvae are liberated during digestion and complete their development in the alimentary tract (64). If the predator is not canine or feline, larvae released from the prey's tissues during the digestion process can migrate into the predator's organism in the same manner as in the primary paratenic host (150), thus explaining the foodborne route for human contamination, which is noted below in the “Epidemiology” section. The rate of dogs harboring adult Toxocara worms was found to be approximately 25% in Western countries during the seventies (11), but it has dramatically decreased due to a better information provided to dog's owners leading to higher frequency of deworming (126). The prevalence of infected cats varies from 6.4% in Germany (12) to 42% in Ireland (122).

Epidemiology

The remarkable fecundity of Toxocara spp. worms explains the high level of soil contamination with Toxocara eggs found in parks, playgrounds, and other public places. For example, the proportion of soil samples that are positive for T. canis eggs in parks and playgrounds has been reported to range from 15 to 78% (11). Moreover, Toxocara eggs have been recovered from salads and other raw vegetables taken from kitchen gardens (86, 159). Viable T. canis eggs are also present on dog hair, particularly in puppies, thus opening door for contamination of humans (6, 136).

Human toxocariasis remains primarily a soil-transmitted zoonosis, specifically a saprozoonosis according to the WHO’s classification (166). Geophagia and pica are high-risk behaviors, especially when coupled with the close proximity of under-wormed pets. Close contact with pets may also lead to contamination through a hand-to-mouth route. Large amounts of embryonated Toxocara may then be ingested, whereas the consumption of raw vegetables grown in contaminated kitchen gardens elicits small trickle infections. Socio-economic status, including sanitation levels, represents a further risk factor that can interact with the infectious power of contaminated soil. For example, in San Sebastian (Gipuzkoa province, Northwestern Spain), the seroprevalence of toxocariasis was found to be 0% amongst 2-5 year-old children from the middle-class vs. 37% in their counterparts from disadvantaged districts of the city (29). Climatic conditions also influence the transmission of human toxocariasis. Humid and warm climates represent ecosystems that are thought to be very favorable for the embryonation and the survival of Toxocara eggs in the soil (58). The impact of climate on toxocariasis transmission was demonstrated in two field surveys carried out on the Canary Islands and in Argentina Patagonia (52, 81). In the Canary Islands study, a significant difference was found between the positivity rates recorded in humid windward areas of the archipelago and those from drier  leeward areas. A significant correlation was discovered between the level of seroprevalence and De Martonne's aridity-humidity index, which was found also in the Patagonia study.

In addition to the role played by a contaminated soil or close contact with pets harboring Toxocara eggs on their fur, another type of transmission directly involving larvae, via a foodborne route can, also be involved in human toxocariasis. In the literature, cases of infection occurring after the consumption of raw or undercooked meat or offal from potential paratenic homeotherm hosts, such as chicken (120), cow (27) duck (73), lamb (141), pig (155) or rabbit (152), are reported. In Thessaly (Greece), antibodies against Toxocara spp.were found in 42.9% of sheep and 10.1% of goats (84), suggesting that the human use of raw or undercooked meat or offal from these small ruminants was a possible risk factor for acquiring toxocariasis.

Due to these various factors, human toxocariasis is one of the most common helminthiases in the world. Seroprevalence surveys carried out in Western countries showed that the positivity rate was between 2% and 5% amongst apparently healthy adults from urban settlements, whereas it ranged from 14.2% to 37% in rural areas (106).When a tropical wet climate is combined with a poor socio-economic status, the transmission level oftoxocariasis appears to be significantly higher, as the seroprevalence rate amongst children was found to be 47% in Salvador, Brazil (116), 63.2% in Bali (28) and 86.8% in the Marshall Islands (57), respectively. The rate was shown to peak at 92.8% in teenagers and adults in La Réunion (French Overseas Territories, Indian Ocean) (102).

Clinical Manifestations

It is now generally accepted that Toxocara infection elicits various syndromes in humans, which can be classified as either generalized forms, including major and minor syndromes, or compartmentalized forms (39, 106, 143, 146).       

The major generalized forms are represented by the so-called "visceral larva migrans" (VLM) syndrome, as defined by Beaver (14). This syndrome is caused by ingesting large amounts of embryonated eggs ofToxocara spp. and is generally reported in children living in poor socioeconomic conditions or in individuals suffering from mental retardation or severe psychiatric disorders, all of whom present with pica or geophagia. The visceral larva migrans syndrome is uncommon in Westernized, industrialized, countries. The clinical picture comprises an impairment of the general status that includes weight loss and fever along with asthmatic cough, wheezing, generalized lymphadenopathy, hepatomegaly and often Löffler’s infiltrates in chest X-ray photographs (14, 46).

The existence of milder forms of the disease, other than visceral larva migrans, was suspected due to the discrepancy between the high seroprevalence found in most countries and the low number of visceral larva migrans cases, with only 970 cases of visceral larva migrans recorded between 1952 and 1978 (46). In the mid-1980s, two studies were carried out simultaneously in French adults (66) and Irish children (156). They demonstrated that human toxocariasis was not a rare condition and generally assumed the features of a syndrome that included chronic weakness, digestive pain, various allergic signs – often conjunctival or cutaneous, such as itchy rash or pruritus – diffuse myalgias, an irritating cough, and, in children, sleeping and behavior disturbances. This clinical form was termed “covert toxocariasis",  first in Ireland and then in the English-speaking world, and “common toxocariasis” in France. Subsequently, toxocaral infection was found to be frequently associated with various allergy–related syndromes, including chronic urticaria (69), reactive arthritis (18, 133), or angio-edemas (30). Although numerous Toxocara-infected patients have difficulty breathing and therefore display an asthma-like condition (66), the relationship of toxocariasis with this major respiratory disease remained a matter of debate for years (31, 67) until a recent meta-analysis demonstrated the existence of a positive association between asthma and infection by Toxocara spp. larvae (90).

Compartmentalized forms of the disease include ocular and neurological toxocariasis. Ocular toxocariasis (OT) was described prior to visceral larva migrans (167). This for of the infection usually occurs in toddlers, young children, teenagers or young adults and is generally unilateral. The presence of a single larva in the eye wall or in close proximity induces chronic inflammation, and the immunological response to the soluble larval antigens released in a rather enclosed area plays a crucial role. The pathological outcome is anterior uveitis or, more often, posterior uveitis along with hyalitis and chorioretinitis. The opacification of the vitreous humor can be accompanied by deposits of immune complexes, often at the periphery, and by the development of fibrous traction bands that result in retinal detachment (4). If the larva is trapped in the eye membranes by the inflammatory reaction, a retinal granuloma can develop, often at the posterior pole. When large, it can cause bulging at the posterior pole, which resembles a retinoblastoma (8). The most common first sign is vision loss in the affected eye that increases quickly within days or a few weeks. Funduscopy and biomicroscopic examination often reveals uveitis, endophthalmitis (149), papillitis (15, 59) retinal granulomatous lesions (62), or inflammatory masses (snow-banks) in the peripheral vitreous (158). In some individuals these signs may wax and wane over a period of years. Many patients exhibit a subclinical infection and are diagnosed only during a routine eye examination (68, 170). Ocular toxocariasis is apparently an endemic disease in some areas, with an estimated incidence of 1 per 1,000 patients attending an ophthalmology consultation in Alabama (95). By relating that number to the population of the state, an annual incidence of 1 case per 100,000 persons was estimated (143). In Ireland, a survey involving 121,156 children revealed a rate of 9.7 per 100,000 (68).

Although Toxocara larvae readily migrate to the brains of experimentally infected laboratory animals, the involvement of central nervous system (CNS) in toxocariasis appears to be uncommon as less than 60 cases have been reported thus far in the English literature (23, 45, 53). Infection of the CNS by Toxocara spp. larvae causes non-specific illnesses such as meningitis, meningoencephalitis or transverse myelitis (23, 45, 51, 79, 160). Thus, the relationship between the observed symptoms and toxocariasis remains unclear in some cases (104). The involvement of toxocariasis as a primary cause of epilepsy is still a matter of debate, according to the results of a meta-analysis addressing this question (132).

Medical imaging techniques can be used to detect and localize granulomatous lesions caused by Toxocara larvae. Abdominal ultrasound revealed multiple hypoechoïc areas in the livers of 14 children who initially presented with hepatomegaly, eosinophilia and a positive Toxocara serology (7). Under computed tomography (CT), hepatic lesions appear as low-density areas (43, 77). In the CNS, more sensitive magnetic resonance imaging (MRI) revealed granulomas appearing as hyper-intense areas in proton-density and T2-weighted images, primarily located cortically or sub-cortically (23, 51, 125, 138). In patients who were diagnosed clinically and serologically as having ocular toxocariasis, ultrasound revealed a highly reflective peripheral mass, vitreous bands or membranes, and traction retinal detachment (161). These findings were consistent with those found by CT or MRI (96, 157). The more recent technique of spectral domain optical coherence tomography, which provides clear and continuous images from the retina to the sclera-choroidal interface, appears to be a valuable tool for the diagnosis and the post-treatment follow-up of ocular toxocariasis (4, 70).

Laboratory Diagnosis

Peripheral blood eosinophilia, though not specific to Toxocara infection, has been consistently associated with visceral larva migrans. In contrast, in patients with ocular toxocariasis, this laboratory finding is often absent (64), most likely due to the low larval burden (often a single larva) observed in children with ocular toxocariasis. In common and covert toxocariasis, blood eosinophilia can be absent in some patients. Other diagnostic tests should therefore be considered, the most valuable of which is determination of the concentration of serum total IgE (66, 108).

The definitive laboratory diagnosis of human toxocaral infection is made via histopathological examination of tissue specimens, including the liver (85), lungs, brain (72), vitreous (3) and enucleated eyes (115). In patients with ocular toxocariasis, a mobile larva or larval tract can be directly observed under the retina (117) but this finding requires confirmation through specific serological methods.

The most commonly utilized serological diagnostic test is an enzyme-linked immunosorbent assay (ELISA) employing excretory-secretory antigens from T. canis larvae maintained in vitro (34). The use of such antigens further increased both sensitivity and specificity of the ELISA (80). However, some cross-reactivity has been reported in sera from multiparasitized tropical patients (94). A positive ELISA for Toxocaracan be confirmed through western blotting (WB), which is as sensitive as ELISA, but more specific especially when bands from 24 to 35 kilodaltons are considered (99). The detection of immunoglobulin isotypes other than IgG, especially IgE and IgG4, can be helpful in the differential diagnosis of toxocariasis (101, 108, 163).

Serum ELISA for Toxocara-specific IgG was found to be less sensitive for the diagnosis of ocular toxocariasis than for other forms of the disease (65). The solution for this problem came from the generalization of anterior chamber paracentesis (ACP), which made immunodiagnosis using aqueous humor (AH) possible via TES-ELISA (17, 35) or WB (107). Both methods detect specific IgG. For neurological toxocariasis, immunodiagnosis can be carried out in CSF (104, 160). Immunodiagnosis using AH or CSF should be always coupled with serum testing. If the results are discordant, i.e., negative in serum but positive in AH or CSF, this finding indicates intraocular or intrathecal synthesis of specific anti-ES Ag IgG. When the serum and any aspirated fluid are simultaneously positive, the synthesis of specific IgG in the eye or CNS should be assessed using Reiber’s formula (134).

When interpreting a serological result, it should be kept in mind that Toxocara infection in humans is usually a benign, asymptomatic, and self-limiting condition. The numerous seropositive individuals detected through the screening of large populations in epidemiological surveys likely represent past rather than recent infections presenting limited pathological significance. Only patients with clinical signs consistent with toxocaral disease are candidates for therapy because current immunodiagnostic tests are not capable of distinguishing between current and past infection. Immunologic testing should be therefore accompanied by a blood eosinophil count and by the determination of serum total IgE.

A finding of both a peripheral eosinophilia and a positive serological test result is indicative of active toxocariasis. The diagnosis is less certain in individuals who lack eosinophilia but who present with one or more clinical signs of covert toxocariasis. In such cases an increase in the concentration of serum total IgE > 500 IU/ml provides further evidence of recent Toxocara infection. The detection of the eosinophil-cationic-protein (ECP) released by activated eosinophils (63) could also be helpful (108), due to the preferential accumulation of these cells in tissues (139).

Molecular diagnostic methods are hampered by several factors that have caused the search for Toxocara spp. DNA to mainly be restricted to fundamental investigations (60). These techniques have also been used to identify larval structures, e.g., in biopsies or in organ fragments from surgery or necropsies or in CSF, but this approach is not currently used in practice (23, 78). The detection of soluble DNA in blood or other fluids appears to be promising but is not routinely performed as yet (26).

Pathogenesis

In humans, after ingestion, Toxocara larvae achieve the same somatic course as in any paratenic mammal. The embryonated eggs hatch in small intestine where the released larvae perforate the wall. They then enter a blood vessel and go through the liver and lungs to the left heart where they are disseminated by the systemic circulation. After they went out the vessels, the parasites wander extensively in the surrounding tissues and have been found in the liver, lungs, heart, eye and brain (37, 167). They leave tracks of hemorrhage, necrosis and inflammatory cells, with eosinophils predominating. Larvae may be encapsulated, then destroyed inside granulomas by host's response. In the eye, where the migration of a single larva often is observed, this type of lesion tends to induce a total retinal detachment (115). The pathologic manifestations result from inflammation due to the immune response directed against the excretory-secretory antigens (TES-Ag). These antigens are released by the larvae from their outer epicuticle coat (92), which is readily sloughed off when bound by specific antibodies (127). They are a mix of glycoproteins including a potent allergenic component (153) which could be similar to the so-called TBA-1 (171).

The mechanism by which the organism clears up the larvae is not really known. In mice, eosinophils do not contribute to host resistance (38) since antibody-dependent cell cytolysis mediated both by eosinophils and specific IgE antibodies apparently is lacking (82). Trapping of larvae in the liver, as described in mice (128). could be the main way of elimination. Production of NO, which was found to be triggered in rats by contact of macrophages with antigens from T. canis larvae, could be the biochemical support for larval destruction (50). However, no immunopathological study of this liver trapping phenomenon has been carried out so far in humans. Some facts have been collected suggesting that intra-hepatic larval destruction could occur on a regular basis in subjects exposed to repeated infections. Amongst 310 children autopsied in a Brazilian hospital, the prevalence of hepatic granulomas due to toxocariasis was 3.2%, whereas the seroprevalence of the disease was 30-39% in children living in the same area (119).  

The intensity of the disease in humans results from the size of the inoculum and the repetition of the infections. A chronically elevated level of serum total IgE, what is common in patients having common toxocariasis (66, 108), was found to be a cause of skin allergy (76, 123). Patient's genotype would also be involved, since atopy seems to be a worsening factor, as suggested by studies including atopic and non-atopic children (20, 83, 116).

SUSCEPTIBILITY IN VITRO AND IN VIVO

There is only scarce information concerning the susceptibility of Toxocara larvae to drug treatment in animal hosts. Most tests have utilized T. canis infected mice and none have been conducted in vitro. When comparing the results of these tests, one must be concerned about the large size of inoculums used per kilogram body weight. For example, mice weighing about 35g were typically given 500 to 2,000 embryonated eggs corresponding to a dose of 1 to 4 million eggs for a human adult. This situation would only be encountered among children having an intense history of geophagia who live or play in a highly contaminated environment. In contrast, the number of Toxocara eggs required to produce toxocariasis in humans is likely to be much lower. For example, in 1959, a human volunteer was given orally about 100 T. canis embryonated eggs. His blood eosinophil count increased to 13,500 cells/mm3 on day 30 post-infection, and was still 6,150 cells/mm3 4.5 months later. He also developed a persistent cough (25). This syndrome was similar to that encountered in common or covert toxocariasis.

Rationale of Tests in Animal Models

In mice, a regimen in which a test drug is given on day 1-3 post-infection will assess its effects particularly on the hepato-pulmonary migratory phase of infection. In this model the animals are usually sacrificed by the 1st week post-infection. If treatment is given on day 4-6 p.i. and the animals are sacrificed by the 7th week post-infection, the drug's activity during the muscle and CNS migratory phase of infection can be assessed. The results of two studies (9, 55) confirmed that treatment on day 8, or later post-infection, is more effective against larvae in the muscles and brain.

The efficacy of various treatments has been assessed by using larval recovery methods from artificially digested tissues of infected mice and untreated controls. Some drugs, e. g., thiabendazole, had a negligible larvicidal effect but produced marked-inhibition of larval migration through the tissues (1). Drugs including levamisole, ivermectin, albendazole and fenbendazole caused significant larval retention in the liver, followed by the migration of very few larvae to muscles and brain of treated mice (2). Most larvae retained in the liver subsequently died and were not recoverable by day 35. However, these findings likely do not have any direct relevance for the treatment of humans, since treatment is likely to begin long after the peak of hepatic and pulmonary larval migration.

Assessment of the Efficacy of Various Drugs

Many animal experiments testing the larvicidal effects of drugs against Toxocara were performed in the 1970's and 1980's (1, 2, 33, 36, 55, 74, 121), but there have been few recent studies. In one such study, mice were infected once with T. canis larvae and treated on day 2, 14, 81, 87 or 123 post-infection, using several different drugs including albendazole, fenbendazole, flubendazole, oxibendazole, and ivermectin (55). Reductions in mean tissue larval counts of 98.8% or 100% were recorded after a 30-day course of fenbendazole at 750 mg/kg daily or albendazole at 220 mg/kg daily, respectively. A reduction of the larval counts by 88.2% or 81.1% was achieved using a 20-day course of flubendazole at 700 mg/kg daily or oxibendazole at 750 mg/kg daily, respectively. Ivermectin showed only moderate larvicidal potential. Another study assessed in vitro the activity of albendazole, along with that of six derivatives which were prodrugs, on the motility of Toxocara canis larvae. One of the prodrugs (A6 compound) was found to be 2-fold more active than native albendazole in aqueous solution (112). Whether Toxocara cati larvae, which are now also recognized to induce human disease (54) are sensitive to benzimidazoles was assessed in an avian model. Chickens infected using embryonated T. cati egg were treated with either albendazole or fenbendazole. The treatments started on day 123 p.i., and the duration was 30 days. Pathological examination of the liver, lungs, brain, and cardiac and skeletal muscles from sacrificed chickens did not reveal any T. cati larva, thus suggesting that T. cati larvae would be more sensitive to benzimidazoles than their T. caniscounterparts (124).

In these studies, the blood brain barrier was found to be permeable to the tested anthelmintics, but the daily doses administered were much higher than those recommended for human therapy. When mebendazole was tested in mice using a dose of 100 mg/kg daily, administered from 1 to 3 days post-infection, a 43% decrease in whole body larval counts was observed (9). Diethylcarbamazine administered intraperitoneally at 25 µg/kg for 3 days post-infection elicited an 84.7% reduction in larval recovery (33). An interesting possibility might be to use of liposomes with incorporated benzimidazole carbamate anthelmintics to provide sustained drug-release reservoirs and to enhance drug efficacy. In a mouse model, liposomized albendazole and fenbendazole were co-administered with liposomized immunomodulator glucan, and both embedded drugs were found to be more efficient than their saline-suspended counterparts (75). Similarly, testing of albendazole coupled with solid dispersions of high-molecular weight polyethylene glycol (PEG-6000) vs albendazole in aqueous solution (ABZ-W) in a murine model of toxocariasis showed a greater effect of the PEG-6000 formulation, which significantly decreased the number of larvae recovered from the liver or the lungs and ,particularly, from the brain (89).

ANTIPARASITIC THERAPY

General

Whether a person with toxocariasis is a candidate for treatment depends on the type and severity of clinical signs. For many years, anthelmintic therapy was considered as unnecessary or ineffective, especially for visceral larva migrans. This opinion was related, in part, to the large larval inoculum that probably occurs in some children with visceral larva migrans, the repeated infections that occur in some patients with poor hygiene and geophagia, and the lack of approved drugs for the of treatment of toxocariasis. However, the results of controlled and randomized trials indicate that anthelmintic treatment might be indicated, especially for the common and covert clinical forms of toxocariasis. Acute visceral larva migrans in children and adults is usually treated either symptomatically or with specific anthelmintic therapy. Individuals with  ocular toxocariasis  may be treated with anthelmintics, if successive courses of corticosteroids do not result in full recovery or if further visual loss is threatened (see below). Patients presenting with common  (106) or covert (156) toxocariasis along with a peripheral eosinophilia, are often treated conservatively, since these forms of the disease are usually self-limiting. Anthelmintic treatment is therefore, not started immediately, but might be considered for patients who remain symptomatic despite efforts to prevent re-infection with Toxocara eggs. Asymptomatic subjects presenting with a chronic eosinophilia and those with covert toxocariasis in the absence of eosinophilia, do not normally require any specific therapy. Whatever the clinical signs or treatment used it is important to remove infected children, especially those with geophagia or poor hygiene, from contaminated environments and particularly from any contact with undewormed puppies.

Drugs of Choice

Prospective randomized trials evaluating therapy for toxocariasis and the few that have been performed have occasionally used inconsistent dosages and suboptimal duration. Albendazole appears to be the tentative drug of choice, although the evidence for this recommendation is marginal. The optimal dose and duration of therapy remains to be established. We would recommend 10 mg/kg daily for 14 days. Although comparative trials have not been performed, mebendazole may be less effective than albendazole. If neither of these two benzimidazole agents is available or efficient, diethylcarbamazine is an alternative agent at a dose of 3-4 mg/kg daily for 21 days.

Benzimidazole Derivatives (listed by order of first use in humans)

These compounds bind selectively to parasite-tubulin, which differs from that found in mammalian cells, and prevents microtubule formation.

Thiabendazole  (2-thiazol-4yl)-IH benzimidazole)

Thiabendazole should be administered with a fatty meal because of poor solubility. The efficacy was assessed in three controlled randomized trials. Thiabendazole was given p. o. daily from 25 mg/kg (97) to 50 mg/kg (13, 151) for 3 days (13),  4 days  (13), 5 days (151) or 7 days (97). Improvement in clinical manifestations ranged from 50% (97) to 53% (151). Side-effects consisting of dizziness, nausea, and vomiting, were observed in 50%  (97) and 60%  (151) of patients. These same side-effects also commonly occurred with other uses of thiabendazole (154).

Thiabendazole treatment for human toxocariasis has been found moderately effective, but associated with a high rate of side effects, some of which may be severe. Cholestasis (135),  cholestatic hepatitis (48) or ductopenia (111, 145) have been reported following a 2-or 3-day treatment regimen with thiabendazole at a dose of 25 mg/kg/daily for strongyloïdiasis. The use of thiabendazole for treating toxocariasis therefore cannot be recommended.

Mebendazole (methyl-5-benzoyl-1H benzimidazol-2-ylcarbamate)

The drug is practically insoluble in water and should be administered with a fatty meal. However, large variations in plasma concentrations of active drug metabolites have been reported inpatients treated for hydatid disease or for toxocariasis (93, 98).

Various drug regimens for toxocariasis in adults have been tested in three controlled randomized trials. Mebendazole was given at 25 mg/kg body weight daily for 7 days  (97) or 20-25 mg/kg body weight daily for 3 weeks (103). A discontinuous regimen, namely 10-15 mg/kg b/w daily, 3 consecutive days in a week for 6 weeks, was tested versus placebo to assess the efficacy on dormant Toxocara larvae (100). In this study, the efficacy was found to be similar to that of placebo. The use of continuous therapy combined with a higher daily dose resulted in a 57 to 70% reduction in clinical manifestations (97, 103). Side effects consisting of weakness, dizziness, nausea, abdominal and gastric pain were mild and occurred in 9.6 to 17% of treated individuals (97,103). In the comparative study of mebendazole versus diethylcarbamazine, both drugs were similar in efficacy, but mebendazole had significantly fewer adverse effects than diethylcarbamazine (103).

Albendazole (methyl-5-propylthio-1H-benzimidazol-2-ylcarbamate)

Albendazole is poorly absorbed from the gastrointestinal tract and should be administered with a fatty meal. A controlled randomized study in which albendazole was given at 10 mg/kg body weight daily for 5 days, found clinical improvement in 47% of patients with toxocariasis (151). Sixty percent of patients complained about minor side-effects. In spite of these mixed results, a review of the recent literature found numerous anecdotal reports concerning a single case, and also open studies (4, 5, 10, 79, 142, 172) indicating that albendazole has become a commonly used drug for the treatment of toxocariasis, possibly due to the lack of major adverse reactions together with its wide availability in most countries. Albendazole when used at a daily dosage of 10 to 15 mg/kg for 14 days as recommended for trichinellosis (56) appeared to be effective and safe for toxocariasis and should be tested in future controlled studies.

Diethylcarbamazine  (diethyl-4-methylpiperazine-1-carboxamide)

This highly water-soluble compound has been the mainstay for filariasis chemotherapy since 1949. In the presence of specific antibodies, it enhances both the adherence and cytotoxicity of neutrophils and eosinophils to microfilariae by altering the parasite's surface layer (131). Also, diethylcarbamazine activates platelets that release free radicals. This action is antibody independent and triggered by a filarial excretory antigen (24). Moreover, diethylcarbamazine interferes with arachidonic acid metabolism and causes production of PGE2, PGE12, and thromboxane, in both the filarial parasite and its host (114). A direct anti-helmintic effect has also been demonstrated in vitro on Wuchereria bancrofti microfilariae characterized by morphological alterations such as loss of the microfilarial sheath and lysis of the cytoplasm together with the destruction of organelles and the formation of vacuoles (130).

In a controlled randomized study versus mebendazole, diethylcarbamazine was given at 3-4 mg/kg daily for 21 days. The therapeutic schedule started at 25 mg daily and the dose was progressively increased in an attempt to avoid adverse reactions due to parasite lysis. No antihistamine drugs were used. This regimen resulted in a 70% significant decrease in the severity of clinical signs. Twenty-eight percent of patients reported minor side-effects including increased weakness, dizziness, nausea, vomiting, or abdominal pain. These disturbances were dose-dependent and waned when the daily dosage was tapered. In 10% of subjects, a Mazzotti-like reaction (itching, urticaria, and/or edema) was observed, suggestive of accelerated larval lysis. One patient experienced severe gastric pain, and was taken off treatment. Overall adverse effects were significantly higher than with mebendazole (103). A consideration in the use of this compound is antagonism by corticosteroids that partially inhibit its mechanism of action (110). Therefore, diethylcarbamazine and corticosteroids must be given sequentially.

Special Situations

Ocular toxocariasis

No controlled clinical trials have been conducted to date for the treatment of ocular toxocariasis. However, results from case reports (15, 140) or open studies (4, 10, 41, 62, 67)  suggest that the use of corticosteroids to reduce inflammation is effective and may minimize permanent ocular damage caused by the local release of excretory-secretory antigens from larval migration in the eye. Should the use of oral and/or topical corticosteroids not produce the desired effect, specific anthelmintic treatment should then be considered. The effectiveness and indications for anthelmintic therapy alone remain unknown (144), and anecdotal case reports are rather sketchy. A concern in the treatment of patients with ocular toxocariasis with anthelmintics is that the cure may be worse than the disease. That is, the drug-induced death of an intra-ocular larva might produce an acute inflammatory response that can permanently damage the eye. One experiment in a primate model consisted of the intra-vitreal injection of live and dead T. canislarvae. It demonstrated that dead larvae caused little ocular reaction, whereas viable larvae often were surrounded by an acute inflammatory reaction or a chronic granuloma (164). Results from another study using a mouse model suggested that the inflammatory response was directed against Toxocara excretory-secretory antigens released from the larval cuticle, a phenomenon which is likely linked to parasite viability (61). The evidence from animal experiments suggests that treatment of choice for ocular toxocariasis should consist of the sequential use of corticosteroids followed by anthelmintics, in order to first reduce any inflammation that is present and then to kill the larvae. However, in a recent study, the simultaneous use of corticosteroids and albendazole in aqueous solution proved to be more efficient than corticosteroids or albendazole in aqueous solution alone (4). Further studies comparing the efficacy of these three therapeutic schedules are therefore needed.

In mice, diethylcarbamazine has been shown to accumulate in the brain and in the aqueous humor (64). Further circumstantial evidence regarding penetration of diethylcarbamazine into the eye comes from experience gained with its wide-spread use for the treatment of human onchocerciasis (32). Therefore diethylcarbamazine might be the better choice for treating ocular toxocariasis Since the action of diethylcarbamazine may be inhibited by corticosteroids (110), both drugs should not be given concurrently. In a collaborative multicenter trial of 19 patients with ocular toxocariasis treated with corticosteroids followed by diethylcarbamazine at 3-4 mg/kg/b/w daily for 21 days, 8 patients had good to excellent results. In contrast, 3 patients were treated with both drugs simultaneously; no improvement was seen in 2 patients after 2 months, while deterioration occurred in the third patient resulting in enucleation of the eye (Magnaval, unpublished data).

Whether the benzimidazole derivatives or their active metabolites penetrate well into the human eye has not been yet established by intraocular pharmacokinetic and pharmacodynamic studies. Thiabendazole was found in the aqueous and vitreous of a child treated for a toxocaral retinal granuloma at a dose of 25 mg/kg 90 minutes prior to surgery (109). The penetration of albendazole or metabolites would depend on blood-retinal barrier breakdown due to eye inflammation (148).

Neurologic Involvement

The treatment of patients with neurological toxocariasis has consisted of a combination of corticosteroids plus the following anthelmintics: albendazole (79, 118) diethylcarbamazine (79, 87), mebendazole (44), or thiabendazole (88). Diethylcarbamazine (138) or thiabendazole (132, 137) has been used as monotherapy, but the results of these studies have been equivocal. The treatment of choice, in our opinion, is corticosteroids, followed by diethylcarbamazine.

Immunosuppressed hosts (including HIV patients and transplant recipients)

Toxocara larvae do not multiply in paratenic hosts and no case of fulminant or disseminated toxocaral disease in an immunosuppressed patient has yet been reported.

Monotherapy or Combination Therapy

Unlike the situation for filariases, (e. g., bancroftiasis), where various combinations of albendazole, diethylcarbamazine, and ivermectin have been successfully tested, no combined drug regimen using two or more anthelmintics has been formally evaluated in patients with toxocariasis.

ADJUNCTIVE THERAPY

Serious or fatal complications in people caused by systemic larval migration, including heart failure due to endomyocardial fibrosis, myocarditis, pericarditis and cardiac tamponade, or lung involvement with a respiratory obstructive syndrome have been reported. Neurological migration of larvae may also be life-threatening. Patients presenting with such syndromes must be aggressively treated with anti-inflammatory and anthelmintic drugs, preferably in specialized infectious disease centers that have experience treating such patients. The most commonly used anti-inflammatory drugs for treating  ocular toxocariasis are corticosteroids, namely oral prednisone or prednisolone. The usual regimen is approximately 1 mg/kg daily for 1 month or more, if needed, then the dosage is tapered. Among physical methods, laser photocoagulation is indicated when a larva can be identified by direct visualization in the eye (59). Ocular granulomas can be treated with cryopexy (47, 173). Pars plana vitrectomy can be used to remove the epiretinal as well as the subretinal component of a Toxocara retinal granuloma (165). Such surgical techniques have also been performed in patients suffering from chronic toxocaral endophthalmitis unresponsive to intensive corticosteroid therapy, or that resulted in vitreoretinal or peripheral traction with retinal detachment (18). A larva can also be removed by vitrectomy (16, 117).

ENDPOINTS FOR MONITORING THERAPY

The evaluation of treatment efficacy for toxocariasis primarily relies upon the clinical response. Therefore, the point during the course of the infection at which the treatment is initiated as well as the frequency of follow-up examinations is critical. For example, when the efficacy of albendazole for the treatment of toxocariasis was evaluated (151), a significant clinical improvement was noticed between physical examinations performed at the 2nd and the 6th week of follow-up. This same improvement in clinical signs however, if observed more than 6 months after treatment might simply reflect the self-limiting natural course of most toxocaral infections (13). Based our experience in treating patients with common toxocariasis (97, 100, 103, 105) we suggest assessing the efficacy of treatment between the 4th and the 6th week after the end of treatment. The use of a quantitative clinical scoring system, as described in several controlled studies (100, 103) is helpful for statistical evaluations of drug efficacy.

Abnormal patterns (e.g., hypoechoic lesions) that can be detected by ultrasound or low-density areas observed by CT in the liver (77), or T2-weighted images visualized by MRI in the brain (138), usually resolve within 1 to 2 months following treatment. Therefore, these diagnostic modalities should be used along with clinical signs in assessment of treatment efficacy for toxocariasis.

Among non-specific laboratory tests, only eosinophil count appears helpful for post-treatment follow-up. In a controlled trial of toxocariasis comparing diethylcarbamazine with mebendazole, both induced a significant decrease in the mean eosinophil count within 1 month of treatment, whereas the serum total IgE concentration remained unchanged (103).

The detection of specific anti-Toxocara IgG by ELISA does not appear to be useful for monitoring therapy. When ELISA antibody titers were compared between treated and untreated children, the kinetics of specific anti Toxocara IgG was not affected by anthelmintic treatment (13, 49) or decreased very slowly (168). Conversely, the specific anti-Toxocara IgE serum concentration does seem to decrease significantly post-treatment if it is markedly elevated prior to therapy (49, 101) especially in atopic patients.

VACCINES

Indications

There is little need for a vaccine to prevent Toxocara infection in humans and none is currently being developed. While the prevalence of infection of children is high in some areas, most infections are subclinical and self-limiting. Also, there is no evidence that humoral or cell-mediated immunity will prevent a migrating larvae from reaching the eye where it can result in visual loss. In contrast, a vaccine to prevent the transplacental migration of T. canis larvae from a pregnant bitch to her puppies could reduce the prevalence of fecal shedding by puppies, thereby minimizing the risk of infection to children and other dogs. Since experiments done in a mouse model were unsatisfactory, further research is needed in the bitch before the full potential of a vaccine can be appreciated.

PREVENTION

General Measures

Whatever the clinical form of toxocariasis encountered and regardless of the treatment used, measures must be initiated to prevent reinfection, especially of children. The first step is to obtain a careful history to identify possible environmental and personal risk factors, especially the source of Toxocara eggs, behaviors such geophagia or poor personal hygiene, and lack of adequate parental supervision. Infected dogs or cats should be treated by a veterinarian, and contaminated soil removed, or the area closed so it is not accessible to children. Newborn puppies are often infected. Home-gardens should be fenced to prevent fecal contamination by dogs and cats. Produce gathered from possibly contaminated gardens should be thoroughly washed and the consumption of raw meat that could harbor Toxocara larvae should be avoided. Geophagia should be brought to the attention of an appropriate health provider for treatment. Personal hygiene also should be upgraded by encouraging hand-washing, especially prior to eating and discouraging hand to mouth activity at all times. Parents of affected children should be counseled about the risk factors for toxocariasis. Municipal ordinances to prevent pet dogs from entering parks and playgrounds and requiring owners to remove their pet s feces from public areas should be considered.

Prophylaxis by Anthelmintic Agents

Infections in Dogs and Cats

Anthelmintics which are used in veterinary medicine are classified in 3 groups: benzimidazoles/probenzimidazoles, tetrahydro¬pyrimidine /imidazothiazoles and macrocyclic lactones. In 2002, a new class was introduced, that was termed “cyclooctadepsipeptides”. Emodepside, a member of this class, is a semisynthetic derivate from a natural compound of the fungus Mycelia steriliathat parasitizes Camelia japonica leaves.  Table 1 indicates the drugs that are currently available and approved by the U.S. Food and Drug Administration or by National Agencies from European countries. Compounds are often associated in order to broaden the activity spectrum, so most of intestinal cestodes or nematodes, but also fleas, mange and the heartworm, Dirofilaria immitis, are now included in the target list.

Prophylaxis Schedule

Puppies should be routinely treated starting at 2 to 3 weeks of age (69). Further treatment should be given every two weeks until 12 weeks of age (147) to minimize environmental contamination with eggs. This treatment regimen is appropriate even if a fecal floatation examination is negative, since this test is not 100% sensitive, the cost of treatment is minimal, and there are very few side-effects of treatment. Adult dogs should be dewormed once or twice a year, except for bitches which should be treated before and one month after parturition. Treatment is also indicated after each estrus cycle.

There is no generally accepted specific recommendation for treatment of cats. However, based on the life cycle of T. cati kittens should be routinely treated at 4-6 weeks of age with a second treatment 2-3 weeks later. Adult cats should be dewormed following the schedule suggested for adult dogs.

CONTROVERSIES AND CAVEATS

Controversies

Toxocara larvae in the tissues of dogs and cats appear to be sensitive to anthelmintics. Since puppies are most often infected in utero by transplacental transmission of larvae, widespread treatment of pregnant bitches could reduce the prevalence of infected puppies and thereby, the incidence of human toxocariasis. Fenbendazole or albendazole given at 150 mg/kg for three days was reported to be 90% effective in reducing the somatic Toxocara larval burden of puppies (91). A regimen of fenbendazole at 50 mg/kg administered weekly from the 40th day of pregnancy and then to the puppies until 3 weeks of age, was also found to be effective (21). Concerning cats, an emodepside 2.14 % / praziquantel 8.58 % topical solution used during the late period of pregnancy was tested for the prevention and treatment of lactogenicToxocara cati infection appeared to be efficient (169).

However, no drug has so far been approved for this use and it is unlikely that such use will become widespread, since most pet dogs are obtained from private homes rather than from large commercial breeding kennels (129).

Ivermectin

Ivermectin, which is primarily a veterinary anthelmintic drug, has been used for the treatment of some human parasitic diseases. This macrocyclic lactone compound has been shown to be highly effective and improve significantly the prognosis for people with onchocerciasis, the cause of river blindness (19). Ivermectin has also been registered both in the European Union and the USA for treating strongyloïdiasis (113).  Physicians may therefore, be tempted to use ivermectin to treat human toxocariasis, particularly because the drug can be given in a single 12-mg dose and has few side effects. However, no controlled study of its efficacy for toxocariasis has been conducted. When tested on a series of 17 cases of common toxocariasis, ivermectin was only 40% effective in reducing clinical manifestations, and there was no significant decrease in the blood eosinophil count (105). Thus, ivermectin should not be used for the treatment of any form of toxocariasis until the question of its efficacy and safety has been evaluated with a controlled study.

Future Studies

Uncertainty exists for the drug of choice for toxocariasis and more rigorous controlled trials need to be performed using consistent and objective endpoints.

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Tables

Table 1 - Drugs for the Treatment of Ascarid Infections in Dogs and Cats *

Name	Route of administration	Range of efficacy	FDA-approved use  Species         Age/ Weight
Emodepside/ Praziquantel	topical	A, D, H, T **	cats	³ 500 g or 1.0 lb/0.4 kg
Emodepside/ Toltrazuril	oral	A, H, W, coccidia	dogs	³ 2 weeks of age or 1.0 lb/ 0.4 kg.
Eprinomectine / Praziquantel/ Fipronil	spot-on	A, H, W, ectoparasites	cats	³ 7 weeks of age or 0.6 kg.
Febantel/Pyrantel	oral	A, H, W.	dogs	³ 2 weeks of age
Febanel/ Praziquantel/ Pyrantel pamoate	oral	A, D, E, H, T, W	dogs	³ 3 weeks of age or 2.0 lb/ 1.0 kg
Fenbendazole	oral	A, D, H, T, W	dogs	no recommendation
Flubendazole	oral	A, H, T, W	dogs, cats	no recommendation
Levamisole/ Niclosamide	oral	A, H, T	dogs	³ 3 months of age *
Mebendazole	oral	A, H, W, T.	dogs, cats	no recommendation
Milbemycin oxime	oral	A, H, W. Dirofilaria	dogs	³ 2 weeks of age or 1.0 lb/ 0.4 kg
Milbemycin oxime/ Praziquantel	oral	A, D, H, T, W, Dirofilaria	dogs, cats	³ 2 weeks of age or 1.0 lb for dogs,³ 6 weeks of age or 1.0 lb/ 0.4 kgfor cats
Moxidectine oxime/ Imidaclopride	spot-on	A, H, W, fleas	dogs, cats	³ 7 weeks of age or 1.0 kg for dogs; ³ 9 weeks of age or 1.0 kgfor cats
Moxidectine oxime// Spinosad	oral	A, H, W, fleas	dogs	no recommendation
Nitroscanata	oral	A, D, H, T	dogs	³ 2 weeks of age *
Oxfendazole	oral	A, D, H, T, W	dogs	³ 2 weeks of age *
Piperazine salts	oral	A	dogs, cats
Pyrantel pamoate	oral	A, H.	dogs, cats	³ 2 weeks of age
Pyrantel pamoate/ Praziquantel	oral	A, D, H, T	cats	³ 4 weeks of age or ³ 1.5 lb.
Pyrantel pamoate/ Febantel/ Praziquantel	oral	A, D, T	dogs	³ 2 weeks of age
Pyrantel/ Oxantel/ Praziquantel	oral	A, D, H, T	dogs	³ 8 weeks of age or 1.0 kg
Selamectine	topical	A, H, fleas,Dirofilaria	dogs, cats	³ 6 weeks of age

* modified from recommendations to veterinarians: "How to prevent transmission of intestinal roundworms from pets to people"  CDC/NCID - AAVP.

** targets : A = ascarids (Toxocara and Toxascaris spp); D = flea tapeworm (Dipylidim caninum);  E = Echinococcus granulosus; H = hookworms (Ancylostoma and Uncinaria spp); T = taeniid tapeworms; W = whipworms (Trichuris vulpis)

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