**5.1 VLM syndrome**

In the 1950s, second-stage larvae of *T. canis* (now known to be third-stage larvae) were identified in the tissues of several children associated with the presence of clinical signs and a pathology that has since been known as VLM [35]. The associated syndrome in these children was characterized by extensive eosinophilia, hepatomegaly, splenomegaly, hypergammaglobulinemia, and chronic cough with eosinophilic pulmonary infiltration. VLM is more common in children (1–5 years) than in adults because they are more exposed to the infection through the ingestion of larvated eggs of *T. canis*, favored by factors such as living with puppies, poor hygienic habits, and pica [14, 36].

In humans, after ingestion of infective eggs, the larvae hatch in the small intestine and penetrate the intestinal wall, from which they are transported by the blood circulation to various organs, mainly the liver, heart, lungs, brain, muscle, and eyes [37]. In these organs, the larvae actively migrate, aided by proteases with which they cause tissue damage and exert a histophagous spoliating action (traumatic action). The migrating larvae do not continue their development; however, they remain dormant for several years, but they continue to secrete excretion-secretion antigens that induce an inflammatory response in some organs, such as the liver and spleen (hepatosplenomegaly), or are mediators of immunopathological alterations in other organs, such as the lung, where they produce eosinophilic pulmonary infiltration related to cough and persistent secretion [38].

Given the impossibility of carrying out studies in humans, experimental models have been developed in different species of paratenic hosts, such as primates [39], rabbits [40], rats [41], mice [42], and gerbils [43], where the sequence of pathophysiological and immunological events of VML have been studied. In these models, it has been observed that organ injuries can be acute or chronic. The acute phase is characterized by a severe inflammatory response that causes multifocal lesions with necrosis and vacuolization with polymorphonuclear infiltrate, mainly neutrophils with the presence of eosinophils in the liver and lungs. The chronic phase is characterized by the presence of granulomatous lesions with infiltrates of mononuclear cells, fibroblasts, and eosinophils, as well as the presence of fibrosis around the lesion with traces of calcification in the center of the lesions, which in some cases can be extensive. The main organs affected are the liver, lung, kidney, and brain (**Figure 2**). These lesions can be seen with or without the presence of the larva, which suggests the importance of the antigenic excretion-secretion products released by the larva in the tissues.

The clinical picture of VLM includes hyperleukocytosis (30,000–60,000 cells/ mm3), eosinophilia (14–90%), abdominal pain, enlargement of lymph nodes, hepatomegaly, splenomegaly, increased ishemagglutinins and liver enzymes, intermittent fever, cough, and bronchospasm, among others [44–47]. The severity of the condition

#### **Figure 2.**

*Lesions produced by* Toxocara canis *larvae in Mongolian gerbils (*Meriones unguiculatus*). A: lung with chronic granuloma. B: kidney with chronic granuloma with a larva trapped inside (L). C: larva in the pigmented layer of the retina with rupture of blood capillaries. D: larva the in brain with no apparent tissue reaction (photo credits: Dr. Alba-Hurtado).*

depends on the number of eggs ingested and the presence of larvae in critical places; although most patients recover and the signs subside with anthelmintic treatment, deaths from this infection have been reported [48, 49].

The diagnosis of VLM is based on the initial detection of antibodies against excretion-secretion antigens of *T. canis* by ELISA and its confirmation by Western blot in patients with eosinophilia, with high concentrations of serum IgE or with suggestive clinical manifestations. [50–52]. It has been proposed that the confirmatory diagnosis can be validated with the identification of a larva from a biopsy or by some molecular tests, such as PCR, DNA hybridization and restriction fragment length polymorphism, or sequencing of *Toxocara* ribosomal DNA; however, it is still in the of experimentation in animal models and is not available for humans [53]. Different tools, such as ultrasound (US), contrast-enhanced ultrasound (CEUS), contrastenhanced computed tomography (ceCT), contrast-enhanced magnetic resonance imaging (ceMRI) and positron emission tomography (PET), are currently used to obtain suggestive images of the main lesions in different human organs [49, 54].

#### **5.2 OLM syndrome**

This syndrome was first described by Wilder in 1950, who found nematode larvae (unidentified at the time) in 24 of 46 pseudogliomas in eyes enucleated for endophthalmitis with apparent retinoblastoma [55]. Nichols later identified the larvae as *T. canis* in sections from four out of five of the eyes examined by Wilder [56]. Although, it is currently accepted that *T. canis* larvae are the main etiologic agent of OLM, it has also been shown that T. cati can cause ocular infections in humans [57–59].

OLM is a disease that generally occurs in young patients. In a systematic review and meta-analysis of studies published internationally, it was observed that the highest infection rate was detected in the 1–25 mean age group; within this range, the highest prevalence occurred between 11 and 20 years of age and was higher in men than in women [34]. It has been shown that having contact with dogs, ownership of dogs or cats, exposure to soil, and consuming raw/undercooked meat can be risk factors for OLM [12, 26, 34, 60].

OLM is generally observed in the absence of clinical signs and symptoms of VLM; it is considered to occur in people initially exposed to a small number of larvae, so they do not mount a significant immune response (many patients with a clinical diagnosis of OLM are seronegative to *Toxocara*), and the larvae migrate freely through various organs and accidentally reach the eye [61, 62]. Observations in experimental models and some clinical evidence indicate that *Toxocara* larvae infect the eye by migrating through capillaries or directly from the brain through the optic nerve [63–66].

The lesions detected in the eyes of patients diagnosed with OLM have been granulomas located near the optic disc or intraretinal (see **Figure 2C**), posterior and peripheral retinochoroiditis, panuveitis, optic papillitis, uveitis, retinal deformation or detachment, idiopathic epiretinal membranes, infiltration of inflammatory cells in the humor vitreous, hemorrhagic lesions and neuroretinitis as a sequel to migration of larvae in the retina [60, 67–69]. The main clinical manifestations include poor visual acuity, vision loss, strabismus, leukorrhea, eye irritation, and endophthalmitis [58, 70]. In most cases, lesions occur in only one eye, although there are reports of bilateral conditions [70].

The initial diagnosis of OLM is based on clinical signs and observation of lesions with an ophthalmoscope in the fundus examination. Confirmation of the diagnosis can be made by the detection of antibodies against excretion-secretion antigens of *T. canis* by ELISA in the vitreous humor of the affected eye and the study of the lesions by ultrasound biomicroscopy (UBM) and optical coherence tomography (OCT) [71, 72].

### **5.3 Neurotoxocariosis**

The first report of the presence of an encapsulated larva of *T. canis* in the brain of a child was in 1951; originally, the larva was identified as probably *Ascaris lumbricus* [73]; later, this larva was identified as *T. canis* [74]. The damage produced by *Toxocara* larvae in the central nervous system (CNS) of humans has been widely discussed by many authors. The pathology depends on the number of larvae, the location of the larvae in the nervous system, the time postinfection, the immune response, and some intrinsic factors of the host. Most cases of neuro toxocariosis have been attributed to the presence of *T. canis* and, less frequently, to *T. cati*; however, the latter cannot be

ruled out in some neurological infections. In experimental models, a greater tendency for *T. canis* to migrate to the CNS than *T. cati* has been observed [75].

In humans, many *Toxocara* infections in the CNS can go unnoticed and do not produce manifestations; therefore, their frequency is unknown. Some autopsy studies have shown the presence of larvae in the leptomeninges, gray and white matter of the cerebrum, cerebellum, thalamus, and spinal cord, unrelated to previous neurological signs [76].

In experimental models, it has been shown that *T. canis* larvae in the CNS can produce areas of necrosis, loss of Purkinje cells, glial nerve fibers and nerve sheaths, granulomatous lesions, emorrhagic and exudative lesions, vasculitis with eosinophilic and lymphocytic infiltration, gliosis and hemosiderosis. Some larvae can be observed without any response around them (see **Figure 2D**) [76, 77].

The clinical pictures of neurotoxocariosis in humans rarely occur simultaneously with signs of VLM. Most clinical manifestations occur in adult men with an average age of 35–42 years. Clinical signs associated with neurotoxocariosis may be indicators of different neurological disorders, such as myelitis (sensation disorders such as tingling sensation or hypoesthesia to specific dermatomes; motor disorders such as sphincter disturbances and conus medullaris syndrome; autonomic disturbances such as bladder and bowel dysfunction, and erectile failure), encephalitis (focal deficits, confused state, seizure and cognitive disorders) or meningitis (headaches, stiff neck/neck pain, nausea or vomiting, and Kernig's/Brudzinski's sign). Fever may occur on some occasions, although this is not a constant sign [76, 78].

The association between *T. Canis* seropositivity and cognitive development is controversial and has been widely discussed by several authors. Some authors, such as Magnaval et al. [79], found no association between seropositivity and any recognizable neurological syndrome; however, other authors have shown an association between seropositivity and lower cognitive development in children; however, due to incomplete controls and low sample size, the results are not clear [80–83].

In this context, Walsh and Haseeb [84], conducted one of the most conclusive studies; they analyzed a sample of 3,949 children representative of the US child population. Seropositive to *T. canis* children scored significantly lower on the Scale for Children-Revised (WISC-R) and Wide Range Achievement Test-Revised (WRAT-R) than seronegative children. Moreover, this relationship was independent of socioeconomic status, ethnicity, sex, rural residence, cytomegalovirus infection and blood lead levels. These results show another facet of the importance of toxocariosis as a neglected infection.

The diagnosis of neurotoxocariosis is difficult because there is no characteristic clinical syndrome. Due to the lack of confirmatory diagnostic tests and the nonspecific nature of its symptoms, neurotoxocariosis is probably underdiagnosed. As there is no universally accepted criterion for the diagnosis of this syndrome, a comprehensive diagnosis must be considered that must include the broad spectrum of neurological manifestations (signs of meningitis, encephalitis, myelitis, and/or cerebral vasculitis), together with high titers of antibodies against *Toxocara* in cerebrospinal fluid and/or blood, eosinophilia in blood and/or cerebrospinal fluid, suggestive radiological images, the presence of risk factors and clinical and radiological improvement after anthelmintic therapy [54, 78, 85].

#### **5.4 Covert toxocariosis**

Taylor et al. [86] proposed the term covert toxocariosis to describe a new clinical entity of human toxocariosis. It is currently considered that covert toxocariosis is

#### *Toxocariosis: From a One Health Perspective DOI: http://dx.doi.org/10.5772/intechopen.104508*

characterized by nonspecific symptoms and signs that are not associated with the VLM, OLM,or neurotoxocariosis. Clinical manifestations include asthma, acute bronchitis, pneumonia, wheezing with or without Loeffler's syndrome, chronic urticaria or eczema, lymphadenopathy, myositis, and pseudorheumatoid syndrome, with or without eosinophilia.

The excretion-secretion antigens produced by *T. canis* during migration are strong stimulants of Th2-associated immune responses and the consequent induction of IL-4, IL-5, IL10, and IL-13. This cytokine profile induces an increase in the level of specific IgE-antibodies and eosinophilia, which are effectors to kill some larvae. These same effectors contribute to airway hypersensitivity and inflammation, associating chronic *T. canis* infection with allergic disorders such as asthma, allergic rhinitis, atopic dermatitis, and urticaria [87–89].

Asthma is a lung disease characterized by an exacerbation of the immune response in the airways to a variety of external stimuli, which produces inflammation, bronchospasm, and obstruction of the airways, which are reversible spontaneously or with treatment. Since years ago, several epidemiological and experimental studies have shown a significant relationship between *Toxocara* infection and the development of asthma, mainly in children [90–92]. Meta-analysis studies, where extensive collections of published data were made, have confirmed this association. Li et al. [93] using data from 723 asthmatic patients and 807 controls found a significantly higher prevalence of *T. canis* infection in patients with asthma than in controls (OR 3.36, P < .001). Aghaei et al. [87] using data from 872 asthmatics and 4597 non-asthmatics children, found an increased risk for asthma in children with *Toxocara* infection seropositivity (OR, 1.91; 95% CI, 1.47–2.47).

The exact mechanisms by which *Toxocara* infection induces asthma and other allergic disorders remain unclear. *Toxocara* larval migration has been associated with an intense immune response, which causes strong allergic inflammation involving the intestine, muscle, liver, kidney, and lung [43, 94]. An animal model study (mice) showed that previous infection with *T. canis* intensified the ovalbumin-induced allergic airway inflammatory response associated with elevated eosinophil counts and IgE antibody levels in bronchoalveolar fluid and increased expression of IL-4 mRNA in the lung [92]. Several authors have described skin manifestations associated with toxocariosis and the risk of seropositive patients presenting skin lesions [95]. Significant associations have been observed between *Toxocara* seropositivity and pruritus (OR = 4.1, P < 0.1) and chronic urticaria (OR = 6.9, P < 0.0001) [96, 97]. Some of these patients presented with symptoms of VLM or OLM; however, the majority had no signs of previous *Toxocara* infection. Similar to neurotoxocariosis, there is no specific diagnosis for the clinical symptoms of cutaneous toxocariosis, so the participation of *T. canis* as a producer of skin alterations has probably been underestimated.
