Pediatric Toxocariasis

Toxocariasis is caused by Toxocara canis (T. canis) and, less frequently, Toxocara catis (T. catis), which are intestinal nematodes (roundworms) found in dogs and cats, respectively. In humans, toxocariasis is considered an aberrant infection because humans are incidental hosts, as the parasites cannot successfully reach full maturity in the human body. Instead, the invasive larvae migrate for months through different organs until they are overcome by the human inflammatory reaction and die. The larvae can survive in tissues for at least 9 years and, possibly, for the entire life of the host.

Three clinical forms of toxocariasis are traditionally described; these are visceral larva migrans (VLM), ocular larva migrans (OLM), and covert toxocariasis (common toxocariasis).[1] A constellation of differing disease manifestations have been attributed to each of these clinical forms.[2]

Diagnosis is based on clinical and serologic findings. In addition to enzyme-linked immunosorbent assay (ELISA), polymerase chain reaction (PCR) is being researched as a possible diagnostic tool. Stool examination for Toxocara larvae is not a helpful diagnostic test for toxocariasis. Whether or not the infection should be treated and, if so, when and how it should be treated is controversial. The anthelmintic agents, mebendazole, thiabendazole, albendazole, and diethylcarbamazine, are medication options used in treatment. Corticosteroids also have a significant role in therapy. See the images below.

Most frequently, human toxocariasis is caused by T. canis, a nematode roundworm of the family Ascaridae. Adult T. canis female worms are usually found in young puppies and lactating female dogs. The adult T. canis female worms can excrete as many as 200,000 eggs per day. These eggs require about 2 to 5 weeks of optimal environmental conditions (temperatures of 10-35°C, high soil humidity) to develop from a noninfective unembryonated form to an infective embryonated egg. Embryonated eggs are resistant to freezing, moisture, and extreme pH levels.

When a dog ingests infective eggs, the eggs hatch into larvae in the proximal small intestine. The larvae then penetrate the intestinal wall, and gain access to the blood and lymphatic circulation. The larvae invade the dog’s liver, lungs, and other tissues. In most dogs, the larval maturation process is arrested in most tissues. However in the pregnant female, T. canis continues developing and migrates across the placenta, infecting canine fetuses. After the birth of the puppies, the larvae continue to mature migrating from the lungs to the gastrointestinal tract via the trachea. The larvae reach maturity in the puppies' intestinal tracts. Post-partum, the lactating female dog is re-infected while caring for her young. Therefore, the primary sources of T. canis eggs are puppies less than 3 months old and lactating female dogs.

Humans are paratenic hosts for T. canis. Paratenic hosts are transport hosts in which the larvae never mature into adult worms. The infection is acquired through ingestion of soil containing infective T. canis eggs. Theseeggs are found in areas where dogs defecate, such as playgrounds, outdoor public areas and dog parks. As much as 20-30% of soil samples from public parks and children's sandboxes are contaminated with Toxocara eggs. Infections acquired through ingestion of raw snails and raw lamb have also been reported.

The cat roundworm, T. catis, has a similar life cycle to T. canis. A noted difference is that vertical transmission is due to lactation more than transplacental transmission. Humans are paratenic hosts; however, there have been some cases reported of mature worm T. catis intestinal infections in children. Overall, T. catis causes fewer cases of human infection than T. canis, probably due to the defecation patterns of cats, which make environmental infestation less frequent. As such, this article focuses on T. canis infections.

Tissue damage in Toxocariasis is due to the host inflammatory reaction more than the infection itself. The larvae produce glycosylated proteins, usually referred to as Toxocara excretory-secretory (TES) antigens. These antigens induce a Th2-type CD4+ T-cell immune response characterized by production of interleukin 4 (IL-4) that promotes the switching of B-cell isotypes to the production of immunoglobulin E (IgE) and interleukin 5 (IL-5). These, in turn, promote eosinophil differentiation and vascular adhesion.

Although Toxocara organisms are the most common causes of visceral larva migrans (VLM) syndrome, case reports have cited other zoonotic nematodes that cause VLM, including Ascaris suum,[3] Baylisascaris procyonis (raccoon ascarid), and Lagochilascaris minor (opossum ascarid).

T. canis infections occur in canine animals throughout the world, as confirmed by seroepidemiologic studies. The prevalence of seropositivity varies not only from country to country but also in different regions within a country.[4] The real prevalence of toxocariasis is difficult to estimate because serologic diagnostic tests are performed only when the diagnosis is suspected, and most human Toxocara infections are asymptomatic.

United States data

Toxocariasis is a public health problem. The prevalence of infection in different communities is directly proportional to the infection rates among canines and the free access of dogs to public places. Obviously, the higher the rate of infected dogs and the easier their access to public places, the more easily humans are exposed to infective eggs. Because eggs need weeks in the soil to become infective, direct contact with young puppies is not a risk factor for acquiring disease. Young children are at higher risk because of their play habits and their tendency to have oral behaviors such as putting their fingers in their mouths. Children with geophagic pica (the compulsion to consume earth, soil, or clay), children who have contact with puppy litters, and children who are mentally challenged with abnormal oral behaviors are particularly at risk. In tropical climates, clay soil types, warm temperature and humidity favor the embryonization and viability of Toxocara eggs.

In the United States, the seroprevalence of children, as measured with enzyme-linked immunosorbent assay (ELISA) that employs TES antigens, varies from 4-8%. Seroprevalence is higher in Puerto Rico and the southeastern states and then in the western, mid-western and mid-Atlantic states. Black and Latino peoples have rates of 16-30%. Prevalence is also higher in underserved urban areas of the United States.[5] Immigrants from Latin America are also at risk for VLM.[6]

International data

The prevalence of human toxocariasis in tropical regions of the world is higher than in the United States.[7, 8, 9, 10, 11, 12] The highest seroprevalence ever recorded was in a village of Santa Lucia, West Indies. Here, the prevalence was 86% in children aged 6 months to 6 years. This community had an extraordinarily high rate of T. canis infection explained by peridomestic areas contaminated with canine waste and geophagic pica behavior among children. Serologic surveys in different countries reveal seropositivity rates of 19% in the Netherlands, 2.5% in Germany, 39% in Brazil, 5.8-36% in the Czech Republic, 0-37% in Spain, 5.2% in Cuba,[13, 14] 10.9 % in Jordan, 47.5% in Colombia, 81% in Nepal, and 13% in the Slovak Republic.[15]

A meta-analysis of 250 studies estimated that the global prevalence of anti-Toxocara serum antibodies is 19.0% (95% confidence interval [CI], 16.6-21.4%). The seroprevalence is highest in Africa (37.7%; CI, 25.7-50.6%) and lowest in the Eastern Mediterranean region (8.2%; CI, 5.1-12.0%).[16]

A study conducted in a tropical region of Venezuela illustrates the greater risk for disadvantaged sectors of society in acquiring this infection.[17] In this study, only 1.8% of middle-class urban subjects had positive findings, compared with 20% of urban-slum dwellers, 25% of rural farmers, and 35% of Amazon Indians. In Bolivia, toxocariasis was thought to be a significant cause of epilepsy, particularly partial epilepsy.

In an epidemiological, cross-sectional study in 252 schoolchildren (ages 1-12 years old) in Brazil, seroprevalence of IgG anti-Toxocara antibodies was found to be 15.5%. An ELISA test based on TES antigens was used to determine outcomes. Geophagic pica was associated with increased prevalence. Thorough hand-washing before meals was associated with decreased seroprevalence.[18]

Sex- and age-related demographics

Boys usually have higher seroprevalence than girls. This is probably related to differences in play behavior.

Individuals of all ages are at risk. VLM associated with severe symptoms occurs mainly in young children, age 18 months to 3 years old. Children within this age group who engage in geophagic pica have greater risk in an environment contaminated with Toxocara eggs. The infective worm burden along with the host response, determines the level of infestation and disease severity.[19] Overall, VLM is diagnosed primarily in children, age 1-7 years. OLM occurs more often in older children, adolescents and young adults.

Morbidity/mortality

Although sudden death due to T. canis infestation has been reported, mortality is unusual. The major morbid condition is decreased visual acuity caused by ocular larva migrans (OLM). Evidence suggests that toxocariasis may be a causative factor for allergic asthma.

The 3 clinical forms of toxocariasis traditionally described are the following:

Visceral larva migrans (VLM)

See the list below:

• General: VLM syndrome is characterized by bouts of fever, coughing wheezing and hepatomegaly. Serology shows leukocytosis, anemia, eosinophilia, hypergammaglobulinemia, and positive Toxocara titers. The patient usually has malaise, weakness, and non-specific abdominal symptoms. VLM is diagnosed mainly in children age 1-7 years old. Systemic disease in this age group rarely results in ocular disease. Many organ systems can be involved in VLM.

• Dermatologic:

  • Skin lesions, such as urticaria and nodules, have been described. Toxocariasis can cause chronic idiopathic urticaria, especially when associated with eosinophilia.

  • Wells syndrome is an eosinophilic cellulitis of unknown origin. A report described 2 cases with clinical and histologic features of Wells syndrome with positive anti-Toxocara titers.[20] Not only did the symptoms respond to treatment with albendazole, but the antibody titer also normalized.

  • Another study demonstrated the presence of T. canis antibodies in 65% of patients with chronic urticaria (n=51), as compared with 21% in controls (n=81), others found a seroprevalence of 20% in chronic urticaria (n=128) versus 13% in controls (n=236), a seroprevalence of 8% in chronic urticaria (n=110), a seroprevalence of 13% in children with the condition, and a seroprevalence of 30% in controls.[21]

  • Overall, studies citing toxocariasis as the cause of chronic urticaria are inconsistent.

• Pulmonary:

  • Wheezing is a common symptom of VLM.

  • History of a chronic cough (lasting for more than 3 weeks) of a paroxysmal character with greater severity at night and associated with recurrent wheezing is reported.[19]

  • Progression to eosinophilic pneumonia and respiratory failure can occur.

  • Severe pulmonary involvement correlates with other VLM symptoms such as fever, urticaria, pronounced eosinophilia.

  • VLM can be confused with lymphoma. A case report cites a 65-year-old previously healthy male who presented with a 2-week history of fever, night sweats, weight loss, eosinophilia, and a high erythrocyte sedimentation rate. Chest radiograph revealed bilateral hilar and mediastinal lymphadenopathy and discrete bilateral pleurisy. This clinical presentation made the diagnosis unclear for either VLM or lymphoma.[22]

• Hepatic:

  • VLM is usually associated with hepatomegaly.

  • Histology usually reveals granulomatous hepatitis.

  • Pyogenic liver abscess concomitant with Toxocara hepatitis has also been reported.

  • The spleen can be enlarged but this occurs less often than the liver.

• Lymphatic and lymphedema:

  • Generalized lymphadenopathy is an infrequent manifestation of toxocariasis. A 24-month-old boy in whom lymphedema was the main clinical manifestation of toxocariasis has been reported.[23]

  • There have been two cases of isolated eosinophilic ascites reported due to Toxocara.[24]

• Rheumatologic:

  • Frequently, manifestations such as arthralgias, monoarthritis, migratory cutaneous lesions, and small-vessel vasculitis coincidentally occur with VLM. Henoch-Schönlein purpura has been described in a 17-year-old male in association with anti-Toxocara IgG and IgE that spontaneously resolved.[25]

• Cardiac:

  • All layers of the heart can be affected. The most common cardiac presentation is myocarditis. Among the unusual manifestations described in the literature are Loeffler endomyocarditis (a restrictive cardiomyopathy)[26] and pericardial tamponade.[27]

• CNS:

  • Toxocariasis is a cause of eosinophilic meningitis, an aseptic meningitis in which the WBCs in the cerebrospinal fluid are primarily eosinophils.

  • Other less common entities described in association with VLM are encephalitis,[28] larval invasion of the brain parenchyma, seizures due to solitary mass lesions, static encephalopathy, arachnoiditis, and spinal cord lesions.[29]

Ocular larva migrans (OLM)[30]

• Ocular toxocariasis or OLM refers to eye (usually retinal) involvement during Toxocara infection. Larvae migrate to and invade the eyes, where they induce an eosinophilic inflammatory reaction.

• OLM can occur in patients after a diagnosed case of systemic disease with VLM, currently with VLM, or alone without clinical evidence of VLM

• Ocular toxocariasis is an uncommon disease that occurs primarily in young patients.[31] However, patients with OLM tend to be older (age 5-10 years old) than those with VLM (primarily age 1-4 years old).

• Males and females are affected equally. Patients can report a history of recent exposure to puppies or kittens. Parents may report geophagic pica behavior in their children.

• The disease is unilateral in most cases, with mild-to-moderate intermediate or diffuse inflammation. Bilateral involvement has been reported in adults.

• Cases of isolated OLM lack systemic symptoms, such as fever, cough, and abdominal pain, and do not have marked eosinophilia. The lack of symptoms with OLM as seen in VLM, suggest that visceral and ocular manifestations are separate clinical entities.[5] .

• Loss of visual acuity, leukocoria (white pupillary reflex), strabismus, and ocular pain are clinical findings.

  • There is no pathognomonic presentation for OLM.

  • Ophthalmological evaluation is fostered due to uveitis, endophthalmitis, strabismus or impaired vision.

  • Other presentations of OLM include endophthalmitis with secondary retinal detachment, retinal granulomas, uveitis, vitreous abscess, and optic neuritis.

  • These clinical findings can be mistaken for retinoblastoma. OLM has been cited as a cause of pseudo-retinoblastoma.

    • Tools to differentiate are ocular ultrasonography, serology ELISA for T. canis, and cytology of aqueous humor.[32]

• Among patients with uveitis, ocular toxocariasis is relatively uncommon. In a review of 2,185 patients with uveitis, OLM was the etiology in 22 patients (1%).[33] Of these 22 patients, the following findings were present.

  • Mean patient age was 16.5 years.

  • Inflammation was unilateral in 91% of cases.

  • The most common symptoms present in Toxocara uveitis were blurred vision (75%), pain or photophobia (33.3%), and ocular floaters (16.7%).

  • Presentation consisted of a granuloma in the peripheral retina in 50% of cases, granuloma in the macula in 25% of cases, and moderate-to-severe vitreous inflammation, mimicking endophthalmitis in 25% of cases.

  • Serum ELISA for antibodies to Toxocara was positive in 11 patients (50%), negative in 8 patients (36.4%), and unknown in 3 patients (13.6%).

  • Four patients tested for vitreous or aqueous ELISA showed positive titers (2 had negative serologic titers), confirming that seronegativity does not exclude the diagnosis.

  • The primary causes of vision loss were vitreitis, cystoid macular edema, and traction retinal detachment.

Covert toxocariasis

See the list below:

• Covert toxocariasis, also called common toxocariasis, refers to a less specific syndrome that was recognized with the wider use of serodiagnostic assays for Toxocara infection.

• Most cases of covert toxocariasis are asymptomatic.

• Symptoms, if present, tend to be mild and nonspecific such as chronic or recurrent abdominal pain, hepatomegaly, cough, sleep disturbances, headache, malaise, anorexia, and failure to thrive.

• Pulmonary wheezing may be the only presenting symptom.

• Eosinophilia is less frequent and less pronounced with this covert form than with VLM. Toxocara antibody titers are also lower.

Clinical manifestations

The clinical manifestations of T canis infections depend on the following factors:

• Number of infective eggs

• Duration of infection

• Anatomic location of the larvae

• Host immune response

See the list below:

• VLM

  • General: Systemic toxocariasis consists of wheezing, hepatomegaly, and, occasionally, mild abdominal tenderness.

  • Dermatologic: Urticaria and nodules are common. Cellulitis may occur in Wells syndrome.

  • Pulmonary: Wheezing is typical. Evidence of pleural effusions is rarely noted.

  • Hepatic: VLM is usually associated with hepatomegaly. Hepatosplenomegaly has been reported.

  • Lymphatic: Generalized lymphadenopathy is an infrequent manifestation.

  • Rheumatologic: Monoarthritis, migratory cutaneous lesions, and evidence of small-vessel vasculitis may be present.

  • Cardiac: Findings suggestive of myocarditis are the most common.

  • CNS: A stiff neck and focal neurologic signs may be present.

• OLM

  • Loss of visual acuity

  • Leukocoria

  • Strabismus

  • Secondary retinal detachment

  • Uveitis

  • Vitreous abscess

  • Optic neuritis

• Covert toxocariasis

  • Wheezing

  • Hepatomegaly

  • Abdominal tenderness

  • Failure to thrive

See the list below:

• The primary causes of toxocariasis are T canis and T catis.

• Toxocara species are not the only causes of OLM and VLM; others include Baylisascaris procyonis, Gnathostoma spinigerum, Trichinella spiralis, and Angiostrongylus and Anisakis species. Other causes include A suum (especially in Japan); Angiostrongylus cantonensis or Angiostrongylus costaricensis; and, much less commonly, ascarids from salt-water fishes, such as members of the genera Phocanema, Anisakis, and Contracaecum.

• Cutaneous larva migrans is caused by Ancylostoma duodenale.

Visceral larva migrans (VLM):

Visceral larva migrans (VLM) is usually suspected in a young child who presents with fever, wheezing, and hepatomegaly. A complete blood count (CBC) with differential reveals leukocytosis and marked eosinophilia (≤80%). Other nonspecific laboratory findings are hypergammaglobulinemia (particularly IgM) and elevated isohemagglutinin titers for antigens in blood groups A and B.

Titers for Toxocara are assessed using a specific enzyme-linked immunosorbent assay (ELISA). The Toxocara Excretory-Secretory (termed TES) ELISA uses an excretory or secretory antigen from the supernatants of in vitroT. canis larvae. With a cutoff dilution of 1:32, the sensitivity of TES ELISA is approximately 75%, and its specificity is close to 92%. Specificity may be lower in tropical populations because of cross-reactivity with other helminthic diseases. Western blotting appears to be more specific but is more labor-intensive. The major pitfall of serologic tests is that they cannot be used to distinguish between current and past infections.

Antigen-capture assays with monoclonal antibodies may be helpful in diagnosing current infection but their sensitivity and specificity are not ideal.

Presently, polymerase chain reaction (PCR) has been used to detect infection, but is limited to identify Toxocara species in the tissues of animal models.

The diagnosis of VLM can be definitively confirmed by finding larvae in the affected tissue via histologic examination or by assessing the digestion of tissue. Biopsy is rarely performed, and the larvae are not always found.

Ocular larva migrans (OLM):

The diagnosis of OLM usually relies on clinical findings as the serologic diagnosis tends to be problematic. Patients with OLM have TES ELISA titers that can be negative or lower than those values seen in patients with VLM. Considering a titer greater than 1:8 as indicative for infection, the TES ELISA is 90% sensitive and 91% specific for this clinical form of toxocariasis. Clinical correlation is warranted.

Titers of ocular vitreous and aqueous humor are elevated when compared to serum levels.[19]

Covert:

A definitive test for covert toxocariasis does not exist. Positive anti-Toxocara titers in the presence of malaise, chronic weakness, pulmonary symptoms, abdominal pain, or allergic signs accompanied by eosinophilia and absence of response to allergens, support this diagnosis.

Since the intestinal form of toxocariasis does not occur in humans, stool studies for ova and parasites are not helpful in the diagnosis of toxocariasis. Presence of other parasites in the stool indicates environmental and behavior risk factors for other parasitic disease.

Imaging studies in toxocariasis (VLM and OLM) depend on the body location of the disease.

• Chest radiography is indicated in patients with wheezing and eosinophilia in whom eosinophilic pneumonia is suspected. It can also identify pleural effusions and cardiac shadow enlargement.

• Echocardiography is used to evaluate myocardial function, which is depressed in myocarditis, and to identify the presence of pericardial fluid and intracardiac pseudotumors.

• Abdominal ultrasonography is a good screening test to identify hepatic granulomas.

• Ocular ultrasonography can be used to characterize T. canis ocular lesions.

• CT scans and MRI are also used to evaluate presence of ocular and/or CNS disease.

Biopsy of the involved tissue may be helpful.

When performed, biopsy of the affected tissues reveals granulomatous lesions containing large numbers of eosinophils and neutrophils and, rarely, the remnants of dead larvae.

Most patients with toxocariasis recover without therapy.

• In most cases, patients with VLM are treated with anthelmintic agents.

• Treatment with anthelmintic agents is indicated for severe complications, such as for patients with cerebral, cardiac, and/or pulmonary involvement.

• Anthelmintic treatment can induce an increased systemic inflammatory reaction, as such corticosteroids are sometimes used in conjunction with or without anthelminthic therapy.

• An experienced ophthalmologist must be involved in the immediate care of patients with suspected OLM. Treatment of OLM focuses on ocular steroid therapy (intraocular steroids) as opposed to anthelminthic treatment, as steroids have shown benefit for patients with concern of permanent vision loss. Ocular surgery may be recommended to prevent complications. The use of anthelminthic agents is not as clear.

• Treatment of covert toxocariasis should be individualized. The decision to treat depends on the age of the patient, severity of the symptoms, and certainty of the diagnosis.

Ocular surgical care may be necessary for OLM.

Infectious diseases specialists and ophthalmologists often are helpful. Other consultants may be needed, depending on the body tissues and organ systems affected with systemic infection.

Clarification and correction of the patient’s underlying cause of geophagic pica may prevent reinfection.

Activity limitation may be required in cases with cardiac involvement and/or ocular complications (such as retinal detachment).

Anthelmintic agents are used primarily for severe complications of VLM, such as cerebral, cardiac, and pulmonary involvement.

Class Summary

These eradicate the larvae. Parasite biochemical pathways are different from the human host, thus toxicity is directed to the parasite, egg, or larvae. Mechanism of action varies within the drug class. Antiparasitic actions may include the following:

- Inhibition of microtubules causes irreversible block of glucose uptake

- Tubulin polymerization inhibition

- Depolarizing neuromuscular blockade

- Cholinesterase inhibition

- Increased cell membrane permeability, resulting in intracellular calcium loss

- Vacuolization of the schistosome tegument

- Increased cell membrane permeability to chloride ions via chloride channels alteration

Diethylcarbamazine (Hetrazan)

The DOC in most textbooks, but the FDA does not list toxocariasis as an indication. It is obtained only through the manufacturer.

Thiabendazole (Mintezol)

Broad-spectrum anthelmintic drug; mechanism of action is unclear, but may inhibit the helminth-specific enzyme fumarate reductase.

Albendazole (Albenza)

Has poor PO bioavailability; absorption is enhanced by fatty meals; systemic anthelmintic effect is attributed to its sulfoxide metabolite; albendazole may induce its own metabolism.

Mebendazole (Vermox)

Synthetic broad-spectrum anthelmintic. Likely the drug for which the most experience exists and the safest drug in its class. Inhibits microtubule formation and causes glucose depletion in the worms.

The therapeutic responses of patients with VLM are evaluated clinically and by following peripheral blood eosinophil counts. Toxocara titers may not reflect the response to treatment.

Follow-up of OLM relies on the recommendations of the treating ophthalmologist. The evaluation of vitreous anti-Toxocara titers is a practical way of diagnosing, but not monitoring, the treatment response.

The signs and symptoms of covert toxocariasis lack specificity. Diagnosis may be confirmed by the disappearance of symptoms after anthelmintic treatment. If the patient's symptoms do not improve after treatment, expand on the differential diagnosis.

See the list below:

• The prevalence of human toxocariasis is a reflection of dogs' rates of infestation and their access to public places. Proper disposal of dog and cat feces is essential to lower infection rates.

• Prevention of toxocariasis is a public health issue and is important for both animals and humans.

  • In developed countries, prevention involves regulations that obligate pet owners to have veterinarians examine their pets for parasites. Anthelmintic treatment of puppies and kittens at age 2, 4, 6, and 8 weeks of age prevents the excretion of Toxocara eggs by mature worms acquired transplacentally or through mother’s milk. Regular deworming of dogs and cats during annual veterinary visits.

  • Restricting dogs from assessing places, such as playgrounds, where children may come in contact with animal excrement.

  • Pet owners should to clean up after their pets, to properly dispose of waste, and to clean pet play areas of waste, weekly. Encourage children not to play in areas where animals defecate.

  • Covering children’s sandboxes when not in use to prevent pet access.

  • Foster and model good hygiene practices, such as washing hands with soap and water after playing outside and/or playing with pets.[34]

• In underdeveloped countries, the situation is more complex due to poor basic sanitation infrastructure, such as access to clean water and functional sewage systems.

Complications depend on the human organ sites to which the larvae migrate.

In general, the prognosis for VLM and covert toxocariasis is good.

Prognosis in OLM depends on the pathology at the time of diagnosis. Blindness, usually unilateral, can result.

Proper hygiene and sanitation are probably the least expensive and most effective means of reducing parasitic diseases.

In countries in which the creation of good water and sewer systems is unrealistic, every effort should be made to educate the citizens about basic sanitation to diminish the rates of parasitic diseases.