Veterinary Parasitology 175 (2011) 193–206

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Veterinary Parasitology
journal homepage: www.elsevier.com/locate/vetpar

Review

Larval development of Toxocara canis in dogs

Thomas Schnieder ∗ , Eva-Maria Laabs, Claudia Welz
Institute for Parasitology, University of Veterinary Medicine, Buenteweg 17, D-30559 Hannover, Germany

a r t i c l e i n f o a b s t r a c t

Article history: The parasitic roundworm Toxocara canis is present in dog populations all over the world. Due
Received 25 June 2010 to its zoonotic potential, this roundworm is of special interest not only for veterinarians,
Received in revised form 7 October 2010
but also for medical practitioners. In the present review, current knowledge of infection
Accepted 12 October 2010
routes and the subsequent development of larvae within the canine host is summarised.
Furthermore, information about the clinical, pathological, enzymatic, haematological and
Keywords:
histopathological changes was collected, giving a broad overview of current knowledge
Toxocara canis
of the infection. Although the data collected over the years give an idea of what happens
Toxocarosis
Infection routes during the larval development of T. canis, many questions remain open. Nevertheless, it is
Larval development important that we continue our efforts to further understand the biology of this versatile
Prenatal infection and compelling parasite and try to improve and optimise strategies to prevent the infection
Zoonosis in dogs and thereby to protect humans from this infection.
© 2010 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
2. Larval development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
2.1. Oral infection with T. canis eggs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
2.1.1. The infective stage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
2.1.2. The first part of the migration route . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
2.1.3. The impact of age and acquired immunity on larval migration route . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
2.1.4. The impact of gender on prevalence of patent infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195
2.1.5. The influence of the infection dose on the course of infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
2.1.6. Development into adults . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
2.1.7. Somatic migration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
2.2. Oral infection through paratenic hosts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
2.3. Prenatal infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198
2.3.1. Reactivation of larvae during pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
2.3.2. Migration and development of larvae in the puppies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
2.4. Lactogenic infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
2.4.1. Distribution of larvae in the mammary glands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
2.5. Oral infection with juvenile intestinal larvae and periparturient immunosuppression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200
2.5.1. The putative impact of hormonal changes in bitches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
3. Pathological changes in the host during larval migration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201
3.1. Clinic and gross changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201

∗ Corresponding author. Tel.: +49 511 953 8711; fax: +49 511 953 8870.
E-mail address: Thomas.Schnieder@tiho-hannover.de (T. Schnieder).

0304-4017/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.vetpar.2010.10.027
194 T. Schnieder et al. / Veterinary Parasitology 175 (2011) 193–206

3.2. Haematological and enzymatic changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202

3.2.1. Anaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
3.2.2. Eosinophilia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
3.2.3. Increased liver enzyme levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
3.3. Histopathological changes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
4. Evasion of the immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
4.1. The antigenic coat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
4.2. The interaction of TES molecules with the immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204

1. Introduction examined the hair of 60 dogs in Ireland and the UK, with
the result that T. canis eggs were found in 25% of the cases.
Toxocara canis (Werner, 1782) is one of the most impor- Of these eggs, 78.9% were viable and 4.2% embryonated,
tant gastrointestinal helminths in dogs, with infections emphasising the potential infection risk from these eggs.
reported from all parts of the world. In Argentina, 16.35% These findings were supported by a study which exam-
of 1944 fresh dog faecal samples collected from both urban ined the hair of 100 stray dogs in Ireland with the result
and rural areas were positive for T. canis (Soriano et al., that 67% of the dogs were found to have T. canis eggs
2010). A study in Nigeria in 2007 reported 33.8% of 269 on their hair (Roddie et al., 2008b). These authors exam-
household dogs to be positive, with a prevalence of 51.4% ined not only dog hair for T. canis eggs but also fox hair,
in puppies up to 6 months (Sowemimo, 2007). Another revealing 28% of 87 foxes to be positive. 61.4% of these
Nigerian study determined the overall prevalence in 396 eggs were either viable or embryonating (Roddie et al.,
dogs to be 41%, with younger dogs being more suscepti- 2008a). In Turkey, Aydenizöz-Ozkayhan et al. (2008) found
ble to the infection (Ugbomoiko et al., 2008). A similarly T. canis eggs in the hair of 21.56% of 51 dogs. All the eggs
high infection rate (45.2%) was reported for 438 slaugh- were viable, 21% being either embryonating or embry-
tered dogs in abattoirs in a Chinese province, determined onated. Overgaauw et al. (2009) detected T. canis eggs in
by counting the adult worms (Dai et al., 2009). Several 12.2% of 148 fur samples of clinically healthy dogs. In this
studies confirm that T. canis infections are also common study, none of the eggs were viable. The actual impact
in the European canine population. A study performed in of T. canis eggs within dog fur on human health remains
Italy diagnosed 33.6% out of 295 dogs going to veterinary to be determined, but as pets literally share house and
clinics for whatever reason as T. canis positive (Habluetzel bed with their owners, this source of infection might be
et al., 2003). In Hannover, Germany, 2.2% of the faecal underestimated. The wide distribution of T. canis and its
samples from 1281 dogs examined as part of diagnostic importance as a zoonotic agent, causing visceral and ocular
services from 1998 to 2002 were positive for eggs of this larva migrans in humans, have led to an increasing inter-
parasite (Epe et al., 2004). A similar prevalence (2.1%) was est in the biology and epidemiology of this parasite. For
determined for the years 2003–2009 (unpublished data). efficient prevention of infections in dogs, understanding
In Serbia, Nikolic et al. (2008) examined stool samples its complex life cycle, including infections resulting from
from 151 household, stray, and military dogs, revealing a ingestion of either embryonated eggs from the environ-
prevalence as high as 30.5%, whereas 1159 faecal samples ment or larvae from infected paratenic hosts, as well as
tested in Northern Belgium showed a T. canis prevalence infections from vertical transmission (intrauterine or lac-
of 4.4% in household dogs (Claerebout et al., 2009). The togenic), is crucial. However, there are still unanswered
same study identified a prevalence of 26.3% in breeding questions concerning the life cycle of this nematode. In
kennel dogs. In the UK, Batchelor et al. (2008) included this review, current knowledge regarding larval develop-
4526 dogs with clinical signs of gastrointestinal disease in ment in dogs, mechanisms of larval reactivation from the
their prevalence study, with 1.4% being positive. In a recent tissue, immune evasion and pathological changes in organs
German study, out of 445 dogs taken in by animal shel- after invasion will be outlined and discussed. As some of
ters 2.5% of adult dogs were positive for T. canis, whereas the previous studies were published in German only, their
dogs up to 1 year of age were positive at a rate of 8.8% inclusion in this review might be of special interest.
(Rohen, 2009). In the Netherlands, a coproscopic preva-
lence of 4.4% of T. canis eggs was determined in 92 clinically 2. Larval development
healthy dogs (Overgaauw et al., 2009). However, the preva-
lences determined in the cited studies cannot be compared 2.1. Oral infection with T. canis eggs
directly to each other as the examined populations were
quite different. Nevertheless, T. canis is undeniably present 2.1.1. The infective stage
in the canine population worldwide, especially in young Eggs of T. canis are unembryonated when shed with
dogs. Working dogs and stray dogs seem to be at a higher the faeces. Under optimal conditions, i.e. temperatures
risk of getting infected than pet dogs (Nikolic et al., 2008). between 25 and 30 ◦ C and relative humidity of 85–95%,
Nonetheless, not only do excreted eggs in dog faeces and the development of the infective larval stage within the
contaminating soil provide a human infection risk, but also egg requires 9–15 days (Schacher, 1957; Okoshi and Usui,
do eggs attached to dog hair. Wolfe and Wright (2003) 1968). Nevertheless, depending on soil type and climatic
 T. Schnieder et al. / Veterinary Parasitology 175 (2011) 193–206
conditions, development can vary from 3 to 6 weeks up
to several months, and the infective stage in the egg
can remain viable for at least 1 year (Overgaauw, 1997).
Thereby, the infective larval stage is not, as was believed
for many years, the second larval stage but the third one,
which emerges after two moults in the egg (Araujo, 1972;
Brunaska et al., 1995).
2.1.2. The first part of the migration route
After ingestion by the host, eggs hatch in the duode-
num within 2–4 h. The released, infective larvae penetrate
the mucosa of the intestine (Webster, 1958b). The pen-
etration mechanism is as yet not fully understood.
However, an elastase-like protease was detected in larval
excretory–secretory (E/S) products (Robertson et al., 1989).
This protease might assist larvae in penetrating host tis-
sues, i.e. the intestinal mucosa, liver or kidney parenchyma
and the walls of blood vessels. Furthermore, direct
mechanical disruption is discussed (Parsons, 1987). After
penetrating the intestinal wall, larvae invade lymph ves-
sels and migrate to the mesenteric lymph nodes (Webster,
1958b). Thereafter, they travel in venous capillaries via the
portal circulation to the liver (Webster, 1958a). The major-
ity of the larvae reach the liver approximately 24 h post
infection (p.i.) (Webster, 1958a). Subsequently, within 12 h
most larvae continue to migrate, exiting the liver via Vena
cava, passing the heart and reaching the lung via the pul-
monary artery. The larvae occur there between 24 and 36 h
p.i., and numbers increase up to 96 h (Webster, 1958a).
Webster (1958b) demonstrated the passive haematoge-
nous transport by detecting T. canis larvae in the blood
of the heart as well as in the pulmonary artery 72 h post
infection. Those larvae which are trapped in capillaries and
cannot continue the migration remain in the liver. After
encapsulation, these larvae cause the mottled appearance
and the whitish spots characteristic of T. canis infection
(Webster, 1958a).
2.1.3. The impact of age and acquired immunity on larval
migration route
From the lung, larvae follow two different routes,
depending on the age and immune status of the host and
the infection dose. Firstly, they can penetrate the alveoli
wall and continue their migration via bronchioles and tra-
chea to the pharynx. Here they are swallowed and finally
grow into adult worms in the intestine. On the second
route, larvae again penetrate the alveoli wall and re-enter
the circulatory system, being distributed to the somatic tis-
sue (Webster, 1958b). Greve (1971) compared 3-week-,
3-month- and 1-year-old dogs from an ascarid-naïve
colony after experimental subcutaneous infection with T.
canis. In 3-week-old puppies almost all larvae had migrated
through the “tracheal migration” route. In contrast, in 3-
month- and 1-year-old dogs most larvae were discovered
in granulomes in the tissue. Therefore, it was concluded
that the likelihood of somatic migration progressively
increases from the age of 3 months onwards. Concurrently,
the development of larvae into adult ascarids decreases
(Greve, 1971; Oshima, 1976). This phenomenon is referred
to as age resistance, which is firstly based on the devel-
opment of immune competence and secondly on acquired
195
immunity (Barriga, 1988). Immunity is assumed to occur
on the one hand in the lung as a putative delayed type
hypersensitivity response (Dubey, 1978), affecting third-
stage larvae after reinfection (Oshima, 1976). On the other
hand, immunity is also located in the gastro-intestinal
tract, preventing the infective larval stage from penetrat-
ing the intestinal mucosa after reinfection. The restricted
penetration might be ascribed to an inflammatory allergic
reaction after the release of vasoactive amines by sensi-
bilised mastocytes (Soh and Kim, 1973), this possibly also
being the explanation for the catarrhal-haemorrhagic diar-
rhea described in reinfected dogs (Löwenstein, 1981). This
statement is supported by elevated gamma globulin val-
ues in the exudate and tissue of the intestine (Soh and
Kim, 1973). The degree of inhibition was examined by
Löwenstein (1981) who discovered that after reinfection
of lactating bitches with embryonated eggs, the distribu-
tion of larvae in the somatic tissue and the elimination
in the milk were 99% lower than in the group infected
only once. Zimmermann (1983) determined that a trickle
primary infection during 10 days resulted in a 28% lower
distribution of larvae compared to a single infection with
the same total number of embryonated eggs, thus demon-
strating the rapid development of the immune response.
Additionally, studies showed that acquired immunity
is stage specific against third stage larvae only. Juvenile
intestinal larvae (L4) introduced directly into the intestine
of previously immunised dogs were able to grow into adult
worms at a rate of 46–60%, whereas infective third stage
larvae implanted in a similar manner did not develop into
adults. Furthermore, no antibody response was detected
after implantation of fourth stage larvae (Fernando et al.,
1973). These results were confirmed by a study show-
ing that implantation of juvenile intestinal larval stages
in five 1- to 2-year-old male dogs, produced patent infec-
tions in all dogs. The same was achieved after a first and
a second retransplantation (Brunschön-Hellmich, 1987).
Furthermore, the immune system is unable to completely
eliminate tissue-arrested parasites. Possible reasons will be
discussed later on.
2.1.4. The impact of gender on prevalence of patent
infections
Some studies suggest that the migration route of the
parasite is influenced not only by age and immunity
but also by gender. It has been observed that patent
T. canis infections occur more frequently in adult male
dogs (older than 12 months old) than in females of the
same age (Ehrenford, 1957; Turner and Pegg, 1977). This
was discussed to be part of a survival strategy in terms
of evolution, as females spread the infection via reacti-
vated somatic tissue larvae to their offspring, whereas
Toxocara infections in males can only be distributed by
patent intestinal infections (Overgaauw, 1997). Webster
(1958a) also reported that more larvae migrate in the
somatic tissues of female dogs compared to those of male
dogs. In a survey with 1324 dogs, Ehrenford (1957) found
32.8% of the males in contrast to only 9.4% of the females to
be infected with adult T. canis. Furthermore, it was stated
that in male dogs there was no evidence of immunity
up to 36 months of age, whereas females showed an
196 T. Schnieder et al. / Veterinary Parasitology 175 (2011) 193–206
increasing immunity from 6 to 36 months (Ehrenford,
1957). No protective immunological response was
detected in 3 adult male greyhounds, which were repeat-
edly infected with 100–200 viable eggs and became patent
even though serum antibodies to the parasite surface
as well as to secreted antigens were detected (Maizels
and Meghji, 1984). Maizels and Meghji (1984) discussed
as possible reasons firstly a greater susceptibility of this
breed to certain parasite infections, secondly the gender
and thirdly the infection dose. In contrast, in another,
more recent, study, female dogs were reported to have a
higher prevalence (Bridger and Whitney, 2009). However,
the authors themselves acknowledge that the sample size
of 28 dogs with known sex was low. Thus, the results may
not be comparable to other studies. However, whether the
gender really influences the migration and development
of T. canis is doubtful, since most prevalence studies have
not seen any difference between male and female dogs
(Fontanarrosa et al., 2006; Daryani et al., 2009; Rohen,
2009; Gingrich et al., 2010).
2.1.5. The influence of the infection dose on the course of
infection
Comparing the course of infection after infection
with different numbers of infective eggs, it is obvi-
ous that the antigenic stimulus has an impact on the
development of protective immunity. Dubey (1978)
experimentally infected 45 ascarid-naïve 2-month-
old puppies and 6 adult dogs. In 24 out of 25 pups
infected with 10–1000 embryonated eggs a patent
infection was established. In contrast, no patent
infection was detectable in 20 puppies infected with
10,000 eggs. Furthermore, three of the six adult dogs (7,
10 and 52 months old) developed patent infections after
being fed with 100 embryonated eggs each (Dubey, 1978).
Similarly, a study on 18 beagles confirmed the results of
Maizels and Meghji (1984) that low infection doses, i.e. 100
embryonated eggs, cause patent infections also in older
dogs (Fahrion et al., 2008). Therefore, adult dogs considered
immune against T. canis infections were shown to develop
patent infections after reinfection if the number of infec-
tive larvae and thus the antigen stimulus is low. Thus, it
can be assumed that the number of adult dogs with patent
infections and the contamination of the environment with
eggs might be higher than so far assumed.
2.1.6. Development into adults
As mentioned above, the lung is the crucial organ in
which parting of the ways occurs: larvae migrate either
towards the intestine to establish a patent infection or
towards somatic tissue to become a larva migrans. To com-
plete their way to a patent infection, larvae penetrate the
alveoli and reach, after passing the bronchioles, the tra-
chea. After 7–9 days larvae can be detected in the trachea
and in the esophagus. The gastrointestinal tract is reached
7–15 days after infection (Sprent, 1958). From early stud-
ies it is hard to determine where larval moults actually
occur, because these authors considered the infective lar-
vae to be second stage larvae and described a total of
three moults. More recent knowledge, however, proves
that infective larvae in the egg are already third stage larvae
Fig. 1. T. canis larva leaving a lung vessel (Manhardt, 1980).
and only two moults occur inside the host (Araujo, 1972;
Brunaska et al., 1995). According to Webster (1958a) one
moult occurs either in the lungs and trachea or in the esoph-
agus, the next in the stomach, and a further one in the
duodenum. Schacher (1957) also reported about findings
of third and fourth stage larvae in the stomach and about
fourth and fifth stage larvae in the duodenum. Although
conclusive studies are missing, it may be assumed that the
first moult to L4 happens somewhere between entering the
bronchioles and passing the stomach.
Without any doubt the last moult to the preadult stage
(L5) takes place in the small intestine. When preadults
have matured, first eggs are shed approximately 4–5 weeks
p.i. in experimentally infected puppies (Webster, 1958a),
whereas in older hosts prepatency seems to be extended to
40 up to 56 days p.i. (Fahrion et al., 2008). It is believed that
each adult ascarid lives for 4 months on average (Parsons,
1987). Experimentally infected dogs are reported to expel
53% of their adult worm burden within a period of 8 days,
beginning 1 week after the onset of patency (Burke and
Roberson, 1979).
2.1.7. Somatic migration
As puppies mature, the disposition for tracheal migra-
tion and development of a patent infection falls to a low
level. Instead, most larvae re-enter the capillary system
to finally perform somatic migration. Many of the earlier
studies lack information about whether truly ascarid-naïve
animals have been used. To gain a better understanding of
the way larvae travel in the lung and thereafter in adult, so
far ascarid-naïve dogs, Manhardt (1980) injected 200,000
infective larvae into the Vena cephalica antebrachii of 1- to
3-year-old dogs. After 1 h p.i., 75% of the administered lar-
vae were recovered from the lung, whereas no larvae could
be detected in the arterial blood. In histological slides lar-
vae could be detected moving inside the lung vessels as
well as leaving them (Fig. 1). Furthermore, they were found
migrating freely in the interstitium and finally reaching the
lung alveoli (Fig. 2).
Somatic migration in the lung leads to many petechial
haemorrhages, giving the lung a stippled appearance
(Webster, 1958a; Manhardt, 1980). Manhardt’s (1980)
findings confirmed Oshima’s (1976) assumption that
somatic migration is performed by larvae which are
 T. Schnieder et al. / Veterinary Parasitology 175 (2011) 193–206
Fig. 2. T. canis larva in the lung, interstitial pneumonia (Institute for Par-
asitology, archive).
trapped in capillaries, causing them to penetrate the walls
and migrate through the tissue to re-enter the vascular sys-
tem. This somatic migration ability leads to the appearance
of larvae in organs close to the lung and in the pleural
cavity. Furthermore, Manhardt (1980) examined the kid-
ney more closely, an organ commonly highly affected by
T. canis larvae, but rarely showing serious organ failure.
Larvae leave the blood vessels within the cortex, leaving
small haemorrhages under the capsule of the kidney, and
start a somatic migration (Fig. 3). Some larvae penetrate the
urine canaliculi, being detectable up to the renal medulla
and even as far as in the urine itself, whereas most larvae
remain after a short somatic migration close under the cap-
sule where they are encapsulated in granulomes (Fig. 4).
Shortly after the start of the haematogenous transport, lar-
vae were also discovered between the fibrillae of the heart
muscle (Manhardt, 1980).
The time period in which most larvae were distributed
was determined as 24–72 h (Manhardt, 1980). At the same
time, the number of larvae in organs other than the lungs
increased correspondingly, as shown in Table 1. A surpris-
ing phenomenon was observed for the numbers counted
after 48 and 72 h in the front legs, which were higher than
in the hind legs at the same time. However, this difference
was no longer present at day 28 p.i.
Regarding the distribution of T. canis larvae in the body
of infected dogs, the vast majority of migrating larvae end
Fig. 3. T. canis larvae close to glomerula in the kidney capsule (Institute
for Parasitology, archive).
197
Fig. 4. T. canis larva encapsulated under the kidney capsule (Manhardt,
1980).
up in the skeletal muscles and the kidneys, but also the liver
and central nervous system are affected (Webster, 1958b;
Bosse et al., 1980; Manhardt, 1980). In addition, Manhardt
(1980) infected an adult bitch orally with 20,000 embry-
onated eggs. Based on the number of recovered larvae from
tissue samples, she calculated that 78.3% of the larvae were
contained within the skeletal muscles and 20.1% within the
kidneys. In dogs the brain is in general only affected by
low numbers of migrating larvae. After digestion of half of
the brain of one 3-month-old dog, Greve (1971) found only
7 larvae, whereas no larvae could be recovered in the 1-
year-old and the other 3-month-old dogs. This contrasts
to the situation in paratenic hosts, where the brain and the
eyes, directly connected via the Nervus opticus, are severely
affected.
2.2. Oral infection through paratenic hosts
Besides direct oral ingestion of eggs, dogs can also be
infected after ingestion of paratenic hosts which carry
T. canis larvae in their tissue. Paratenic hosts can be, among
others, birds (Okoshi and Usui, 1968), rodents, e.g. mice
(Sprent, 1953), but also rabbits (Sprent, 1955), pigs (Sasmal
et al., 2008), foxes (Saeed and Kapel, 2006), and humans (Ito
et al., 1986).
Paratenic hosts become infected by ingestion of embry-
onated eggs. There are reports of larvae staying alive for at
least 2 years in the tissue of mice, rats, guinea pigs and rab-
bits (Beaver, 1956) and surviving several weeks in frozen
carcasses of mice (Sprent, 1953). In chickens and pigeons
they were found to survive for at least 3 months (Beaver,
1956).
A number of studies showed that Toxocara infections
clearly induce behavioural changes in mice as a model for
paratenic hosts. Infected mice are less active and explo-
rative and less aversive to open areas. As a result they are
at a higher risk of being caught by predators than unin-
fected animals (Meyer zur Heyde, 1984; Cox and Holland,
1998, 2001; Hamilton et al., 2006).
After infection of dogs with paratenic hosts, Sprent
(1958) observed that in some cases intestinal infections
developed directly without tracheal migration. The most
likely reason for this was that larvae had already migrated
198 T. Schnieder et al. / Veterinary Parasitology 175 (2011) 193–206

Table 1
Number of larvae in organs, body cavities and excretions at different time points after injection of 200,000 T. canis larvae into the V. cephalica antebrachii
(Manhardt, 1980).

Hours/days p.i.

1h 12 h 24 h 48 h 72 h 28 days

Number of larvae in:

Lunga 175,637 135,860 96,531 47,058 6426 790
Diaphragma 0 1 7 353 86 312
Pleural cavity 0 0 22 20 0 1
Arterial blood 0 0 4 15 1 0

Skeletal musclesa , b 0 0 212 10,965 16,575 45,390

Kidneysa 0 0 422 10,348 12,100 18,136
Livera 0 0 62 2862 14,157 5943
Hearta 3 0 55 1944 1,077 2196
Braina 0 0 0 95 30 26
Peritoneal cavity 0 0 0 3 0 0
Tracheal mucus 0 1 9 15 14 0
Urine 0 0 0 2 0 0

Total number of larvae 175,640 135,862 97,324 73,680 50,466 72,794

a
The number of larvae was calculated from the artificial digestion of 50 g tissue sample and 200 g skeletal muscle, respectively, in relation to the
physiological organ weights of a beagle with a body weight of 15 kg.
b
The muscle sample (200 g) consisted of 50 g each of the following muscles: M. biceps dexter, M. biceps sinister, M. semitendinosus dexter, M. semitendinosus
sinister.

in the tissue of the previous host. Therefore, they had
already reached a stage of maturity sufficient for direct
development (Overgaauw, 1997). Warren (1969), however,
detected larvae also in the liver, lung, trachea, and esoph-
agus, therefore concluding that larvae released from mice
tissue also undergo tracheal migration in the dog. Herschel
(1981) fed infected mice to beagles and 72 h after ingestion
larvae were detected in the liver and lungs, in the arterial
blood as well as in other peripheral organs of one dog. After
feeding infected mice to dogs, a normal prepatent period
of 34–48 days was observed (Herschel, 1981).
2.3. Prenatal infection
The most important way of T. canis infection in dogs
is prenatal transmission, also known as transplacental or
intrauterine transmission. There are several reports stat-
ing that puppies post partum are commonly infected with
T. canis. This infection can be induced by feeding embry-
onated eggs (Shillinger and Cram, 1923) or subcutaneously
injecting “Belaskaris-larvae” (i.e. T. canis larvae) (Fülleborn,
1921) to pregnant bitches. Nonetheless, parenteral infec-
tion of puppies occurs not only after the infection of the
pregnant bitch but also through reactivation of somatic tis-
sue larvae from earlier infections (Yutuc, 1949; Webster,
1958b; Koutz et al., 1966). It is not known for sure yet
how long larvae can remain and survive in the tissue of
dogs. However, in a study on mice, larvae could be recov-
ered from the tissue up to 1 year post infection (Bardón
et al., 1994). In two abstract-like publications, Douglas
and Baker (1959a,b) refer to a study finding that 241 and
358 days after an infection of the bitch, prenatal infec-
tions still occurred. Furthermore, it was observed that a
bitch harbouring somatic larvae can infect puppies during
three consecutive pregnancies (Soulsby, 1983). Koutz et al.
(1966) also observed prenatal infections in foetuses from a
bitch which had not been experimentally infected but was
supposed to harbour somatic larvae from a previous nat-
ural infection. They further stated that the infection of the
bitch has to occur until a short period post conceptionem
to lead to prenatal infection of the foetuses. They came to
this conclusion as they were not able to detect larvae in the
progeny of bitches infected during 11–21 days post concep-
tionem, but indeed gave no further particulars about these
data. In contrast, the group of Bosse et al. (1980) was able to
induce prenatal infections in puppies at least until 7 days
ante partum.
In summary, this transmission mode is of major impor-
tance for puppies and may occur after reactivation of
somatic larvae from previous infections of the bitch as well
as from new infections during pregnancy.
After infecting the bitch, larvae can either migrate
directly to the offspring or remain in the somatic tissue
depending on the time point of infection. Douglas and
Baker (1959a,b) stated in two short notes that larvae do
not reach the foetuses before the 42nd day of pregnancy.
This was confirmed by Scothorn et al. (1965), who could
not find larvae in foetuses of a bitch on the 35th day of
pregnancy, but in 5 out of 6 foetuses of another bitch on
the 56th day of pregnancy. Both bitches were not infected
experimentally but assumed to be infected naturally prior
to the start of the experiments. In a further study, which
aimed to determine the time point of larvae appearing in
the foetuses more exactly, the first larva was detected in
one of six foetuses of an experimentally infected bitch on
the 43rd day of pregnancy (Koutz et al., 1966). From the
47th day onwards, all foetuses of infected bitches were
positive. No data are available about the time point when
somatic larvae are reactivated and actually start to migrate
to the foetuses. Regarding the way of transmission from the
bitch to the foetus, Webster (1958a) suggested that larvae
reach the placenta via the circulatory system and penetrate
the delicate layer of tissue which separates the maternal
and foetal blood. In the study by Scothorn et al. (1965),
which is at least partially included in the analyses of Koutz
et al. (1966), two larvae were found in the umbilical cord
 T. Schnieder et al. / Veterinary Parasitology 175 (2011) 193–206
tissue. Therefore, the umbilical cord is regarded as a central
transfer point between bitch and foetus in utero.
2.3.1. Reactivation of larvae during pregnancy
The mechanism how larvae are reactivated in the
somatic tissue of the bitch is still a matter of debate.
However, Webster (1958a) already supposed that this phe-
nomenon is connected to the changing hormone status.
In mice, which can also transmit T. canis infections
vertically, a clear decrease in tissue-arrested larvae after
application of prolactin was demonstrated (Oshima, 1961).
These results were confirmed in a recent study by Jin
et al. (2008), who observed that migration of larvae to the
mammary gland was triggered by prolactin. These find-
ings suggest that a similar path for reactivation might
also apply for dogs, although the transmission in mice
mainly occurs lactogenically (Baumm, 1980) rather than
prenatally. Regarding another also mainly lactogenically
transmitted parasite, Ancylostoma caninum, a study showed
that after administration of estrogen and progesterone to
a lactating bitch more larvae were shed in the milk than
beforehand (Stoye, 1973; Krause, 1975). A study on reacti-
vation of tissue-arrested third stage larvae of A. caninum
revealed that neither estrogen nor progesterone had a
direct effect on feeding/reactivation of these larvae. Pro-
lactin showed a stimulatory effect only at concentrations
approximately 1000× higher than physiological levels.
However, the two isoforms (1 and 2) of TGF-␤ led to signifi-
cant stimulatory effects on A. caninum larvae (Arasu, 2001).
Therefore, Arasu (2001) concluded that during pregnancy
host-derived TGF-␤ could act on a parasite-encoded recep-
tor which then causes the reactivation of somatic tissue
larvae. It had previously been shown that there is a strong
correlation between estrogen and the expression of TGF-␤2
in rats (Schneider et al., 1996). A recent study confirmed
that TGF-␤ also induces the reactivation of dauer larval
stages of Caenorhabditis elegans (Gallo and Riddle, 2009).
As C. elegans and A. caninum are allocated to the same clade
of nematodes, which is determined by the relatedness of
their 18S RNA sequences, these results indicate that the
reactivation of dauer stages might be preserved at least
between nematodes of clade V. Whether the same mecha-
nisms induce reactivation of T. canis, a clade III nematode,
remains to be investigated.
2.3.2. Migration and development of larvae in the
puppies
After reactivation of tissue-arrested larvae, they migrate
to the liver of the offspring, where they remain until birth
(Scothorn et al., 1965; Koutz et al., 1966; Stoye, 1976).
Stoye (1976) additionally found 0.4% of the recovered lar-
vae in organs other than the liver or lungs, namely in
muscles, the brain and kidneys. While he explains the
presence of larvae in the lung by the already started
migration, he interprets the larvae in other organs as
somatic larvae after migration or distribution, as described
in adult dogs. Post partum migration from the liver con-
tinues immediately. Larvae were already detectable in
the lungs 30 min post partum (Koutz et al., 1966). As
soon as larvae reach the lung they undergo a tracheal
migration. Koutz et al. (1966) noticed a variable migra-
199
tory behaviour with some larvae reaching the intestine
already 2 days post partum and others remaining 2.5
days in the liver before starting migration. Nevertheless,
within 3 days the majority of the larvae had reached the
lung. In all cases, larvae had reached the intestine by the
7th day post partum. There are different reports concern-
ing the duration of prepatency after prenatal infection:
21–30 days were described by Yutuc (1949) and 25–46
days by Douglas and Baker (1959a,b). Voßmann (1985),
however, found a prepatent period of 28 days. Subse-
quently, more than 70% of the adult worm burden of
puppies was expelled spontaneously 9–10 weeks post par-
tum (Voßmann, 1985).
2.4. Lactogenic infection
The lactogenic transmission is of rather subordinate
importance for the distribution of T. canis. Burke and
Roberson (1985a,b) compared the number of prenatally
and lactogenically transmitted infections. They experi-
mentally infected bitches 2–4 months before pregnancy.
Immediately post partum and before nursing, the pup-
pies were exchanged with newborn puppies of uninfected
bitches. After 4 weeks of nursing, the puppies were
necropsied and examined for T. canis infections. Therefore,
prenatal and lactogenic infections could be differentiated.
Only 2.3% of the total infection dose could be recovered,
98.5% of these having been transmitted prenatally and
only 1.5% lactogenically (Burke and Roberson, 1985a). After
infection at mid-pregnancy, Burke and Roberson (1985b)
recovered 29.2% of the infection dose from the pups. 95.5%
of these had been transmitted prenatally and only 4.5%
were transferred lactogenically. When the bitches were
infected 48 h post partum, a time point which excludes the
possibility of prenatal infection, 7.9% of the infection dose
could be recovered from the puppies.
Similar experiments were performed by Stoye (1976),
although he determined the number of larvae in the milk
instead of examining the puppies. After infection of a bitch
on the day of mating, he recovered 8.5% larvae of the initial
infection dose in total, 99.2% of which had been transmitted
prenatally to the puppies and only 0.8% having been found
in the bitch’s milk. Stoye (1976) also infected a bitch on the
day of birth, and recovered 9.5% of the infection dose from
the milk between the 4th and the 28th day post partum.
This was confirmed by Löwenstein (1981), who infected
lactating bitches 10 days post partum and recovered 9.5%
of larvae up to day 28 after infection.
Therefore, the prenatal route appears to be the most
important infection route for puppies. However, if a bitch
becomes infected post partum, the lactogenic transmis-
sion is another possibility for the parasite to infect new
hosts. Nevertheless, little is known about the development
of larvae in puppies after ingestion of the milk. With a long
prepatent period of 27–35 days after ingestion of larvae
with the milk (Bosse et al., 1980), a direct intestinal devel-
opment seems to be unlikely.
The course of larval shedding with the milk is widely
consistent. First larvae can already be detected within the
first days post partum. The number of larvae increases
then consistently until a maximum is reached approxi-
200 T. Schnieder et al. / Veterinary Parasitology 175 (2011) 193–206
Fig. 5. Larva in mammary gland alveoli (Manhardt, 1980).
mately 7–14 days post partum. During the first 2–3 weeks
post partum most infections of puppies occur. However,
after high infections shortly before or after birth, larvae
appear in the milk approximately 4–7 days after infec-
tion and can be found in the milk at least up to day 28
after infection (Stoye, 1976; Manhardt, 1980; Löwenstein,
1981).
2.4.1. Distribution of larvae in the mammary glands
To further examine the course of shedding with the milk
and the distribution of larvae in the mammary gland, on
the day of birth Manhardt (1980) infected bitches orally
with embryonated eggs or either intravenously, subcuta-
neously or intra-peritoneally with larvae. Afterwards, each
mammary gland complex was examined at different time
points up to 28 days p.i. In all experiments, except after sub-
cutaneous infection, shedding of larvae in the milk started
4 days p.i. However, after subcutaneous infection of larvae
into the flank close to the mammary gland, larvae reached
the milk and tissue already 1 day p.i., but only in the mam-
mary gland complex nearby. 1, 2, and 3 days later larvae
had also reached the neighbouring complexes but never
reached all of them. Therefore, Manhardt (1980) calculated
the speed of migration of larvae through tissues as 15 cm
in 24 h. Hence, she concluded that somatic migration of
T. canis larvae directly from the intestine via the peritoneal
cavity and abdominal wall might be conceivable to a certain
extent.
Histological examination of the mammary gland 8
days after oral infection with 100,000 embryonated eggs
showed that most larvae (565) were present, more or less
curled in the alveoli of the gland (Fig. 5), whereas only
few were detected in the mammary ducts (2), in the inter-
stitium (3), and in the peri-glandular conjunctive tissue
(4) (Manhardt, 1980). Larvae in the mammary ducts were
stretched and in the interstitium either stretched or in
a meander shape. Larvae in the peri-glandular conjunc-
tive tissue were already being encapsulated in granulomes
(Fig. 6). Larvae were found in all parts of the gland, mostly in
the alveoli and no larvae were detected in a vessel. Thus, it
was not possible to clarify whether larvae migrated mainly
haematogenously or somatically.
Fig. 6. Larva in the mammary gland, encapsulated in periglandular tissue
(Manhardt, 1980).
2.5. Oral infection with juvenile intestinal larvae and
periparturient immunosuppression
In the periparturient period bitches can suffer from
patent T. canis infections. This may be due to different
reasons. One possibility is that bitches can be infected
by juvenile intestinal larvae (L4) shed with the faeces
of the infected puppies (Sprent, 1961). While nursing
and cleaning their puppies, bitches ingest these larvae,
which directly develop into adult worms in the intes-
tine (Lloyd et al., 1983). This is possible because, as
mentioned beforehand, immunity in previously infected
bitches is stage specific and directed against third stage
larvae only. The time needed until eggs appear in the fae-
ces after this kind of infection was shown to be 9–12 days
(Brunschön-Hellmich, 1987). Another possibility would be
a spurious infection, which is caused by the accidental
ingestion of eggs shed in the faeces of the offspring, pass-
ing through the intestine of the bitch to reappear in her
faeces.
Additionally, a phenomenon called periparturient
immunosuppression may occur (Lloyd et al., 1983). It
is proven that pregnancy and lactation in dogs lead to
a reduced immunological responsiveness. This is dis-
played by a suppressed in vitro transformation of the
lymphocytes responding to phytomitogens and also a
suppressed T. canis-induced lymphocyte transformation.
Furthermore, eosinophilia commonly detected during a
T. canis infection is repressed during the periparturient
period (Lloyd et al., 1983). The immunosuppression might
allow tissue-arrested larvae and larvae of newly acquired
infections to perform tracheal migration and eventually
intestinal development. The relevance of immunosup-
pression for the development of patent infections in
bitches was confirmed by Lloyd et al. (1983), who were
able to induce a patent T. canis infection after admin-
istering high doses of corticosteroids to a 6-month-old
dog. The hypothesis of immunosuppression as a cause
of patent infections was also supported by the find-
ing of egg-producing adult worms in a bitch at a time
post partum which was too early to be caused by
ingestion of immature stages of the offspring (Sprent,
1961).
 T. Schnieder et al. / Veterinary Parasitology 175 (2011) 193–206 201

2.5.1. The putative impact of hormonal changes in

bitches
Evans et al. (1991) observed that bitches in the luteal
phase were three times more likely to have patent
infections compared to other groups (pregnant, spayed,
anoestrus, and previously injected with a progestagen).
Nonetheless, this was a field study based on routine visits
to veterinarians, with no definite knowledge of the back-
ground of the examined dogs. Regarding a possible relation
between luteal phase and patent infections, Overgaauw
et al. (1998) emphasise that after an infection during the
luteal phase, eggs would appear within the faeces 4–5
weeks later due to the prepatency period and therefore
would not be detected during the luteal phase. The group
(Overgaauw et al., 1998) addressed the impact of prolactin
Fig. 7. Adult ascarids penetrating a dog liver (Institute for Parasitology,
on T. canis infections in a more controlled study. The
archive).
prolactin levels of cyclic bitches, although increasing
during the luteal phase, remained low compared to those some were found in the liver parenchyma and in the bile
of pregnant dogs. A higher risk for patent T. canis infections ducts. The common bile duct was dilated and thickened.
during the luteal phase was not found. Anyhow, patent A single ascarid was even found penetrating through the
infections were also not detected in the two pregnant pancreatic duct. In the intestine several 100 adults were
bitches examined in that study. The authors raise the detected. This phenomenon occurs most often in pups after
question whether pseudopregnant bitches, which show a extensive prenatal infection. Moreover, a massive number
high prolactin level, would also develop patent infections of ascarids in the intestine of young dogs after prenatal
(Overgaauw et al., 1998). infection can lead not only to the typical pressure sensitive,
drum-shaped abdomen (Fig. 8) but also to developmental
3. Pathological changes in the host during larval
migration

3.1. Clinic and gross changes

Larval migration leads to tissue damage in the host

(Webster, 1958a). 24–72 h p.i. in some dogs bloody-
mucous enteritis might occur, caused by the penetration
of the intestinal wall by the larvae (Fernando, 1968). The
arrival of larvae in the lung can then be accompanied
by coughing and dyspnoea (Overgaauw, 1997). The final
intestinal colonisation usually does not cause more than
a limited to moderate enteritis, but in cases of massive
infection it can cause obstructions and ruptures of the
intestine (Webster, 1958a). Hayden and Van Kruiningen
(1975) compared a control group of dogs naturally infected
with T. canis and a group additionally infected three
times a week for 1 month with 3500 embryonated eggs
each time, totalling 50,000 eggs. The latter group was
considered superinfected. Lesions in the intestinal tract
of dogs naturally infected with T. canis were minimal,
whereas superinfected dogs had several white nodules in
the jejunum and petechiae in the pyloric mucosa.
A profound colonisation can also cause adult ascarids
to invade the bile ducts, perforate liver parenchyma and
finally enter the abdominal cavity through the liver capsule
(Fig. 7). Naturally, this incident leads to a generalised and
incurable peritonitis, which exacerbates if female ascarids
in the peritoneal cavity continue to produce and release
eggs (Dade and Williams, 1975). In the case report of
Dade and Williams (1975) on a 5-week-old puppy with
inappetence, depression, diarrhea and weakness, during
necropsy 21 adult ascarids were found in the peritoneal
cavity, 4 adults were apparently in the process of leaving Fig. 8. Typical drum-shaped abdomen of a puppy infected with T. canis
the liver as they were protruding from the capsule, and (Institute for Parasitology, archive).
202 T. Schnieder et al. / Veterinary Parasitology 175 (2011) 193–206
disorders such as cachexia, zero growth and also rachitic
symptoms (Bosse et al., 1980; Herschel, 1981; Voßmann,
1985). Voßmann (1985) infected four bitches 10 days ante
conceptionem with 20,000 embryonated eggs each. The
fifth bitch remained uninfected and therefore its puppies
served as a control group. Three of the infected bitches
were treated with fenbendazole to reduce the prenatal
infection, whereas one infected bitch was not treated and
therefore highly infected. All puppies from the untreated
bitch showed alternating obstipation and diarrhea, fur-
thermore vomiting, anaemia and rachitis. These puppies
subsequently died between the 22nd and the 49th days.
Necropsy revealed ascites, cachexia, anaemia and dilata-
tion and partial rupture of the proximal duodenum by a
ball of ascarids. The cause of death was most often rupture
of the intestinal wall and peritonitis after migration of
adult ascarids through the bile duct and parenchyma of
the liver. Puppies from treated bitches showed no typical
signs of toxocarosis, but with 4 kg, compared to the 7 kg
body weight of the uninfected control group at the end
of the study, a considerably reduced development of
body weight. Necropsy showed slight dilatation of the
proximal duodenum, a macroscopically thicker stomach
and intestinal wall and an activation of the lymphatic
system (Voßmann, 1985).
Among macroscopic lesions in other organs, red and
white spots in the liver distributed over all lobes occur
as well as petechiae and yellowish-white and red lesions
in the lungs. Kidneys often show typical white lesions
throughout the whole cortex (Hayden and Van Kruiningen,
1975; Manhardt, 1980; Herschel, 1981) (Fig. 9).
3.2. Haematological and enzymatic changes
3.2.1. Anaemia
Voßmann (1985) examined haematological changes in
puppies after prenatal infection and observed changes
in the red blood cell counts. Red blood cell counts are
physiologically low in newborn puppies and increase
Fig. 9. Typical white spots on the kidney (Institute for Parasitology,
archive).
approximately 6–8 weeks post partum to reach the values
in adult dogs. In contrast, puppies heavily infected with T.
canis showed further decreasing numbers of erythrocytes,
which were mostly caused by severe internal bleeding. Rea-
sons for the occurrence of internal bleeding were preadult
larvae migrating through the liver as well as perforation of
the intestine, caused by the massive load of adults. Moder-
ately infected puppies showed an increase of erythrocyte
counts from the 5th week onwards, but did not reach those
values of uninfected animals. In contrast, in adult bitches,
no changes in the red blood cell counts were observed after
infection with T. canis larvae (Zimmermann, 1983).
3.2.2. Eosinophilia
Also characteristic for T. canis infection is the
eosinophilia which starts at least on the 7th day post
infection, reaching its maximum approximately 14 days
post infection (Zimmermann, 1983). A similar time
course of eosinophilia is observed in prenatally infected
puppies from day 7 post partum on (Voßmann 1985).
Voßmann (1985) furthermore reported that the degree
of eosinophilia in prenatally infected puppies is almost
proportionate to the intensity of the infection. With the
commencement of egg shedding in the faeces the number
of eosinophils slowly decreased, returning to physiological
levels 42 days p.i. These data showed that the course of the
eosinophilia in prenatally infected pups is comparable to
that in experimentally infected adult dogs (Zimmermann,
1983).
3.2.3. Increased liver enzyme levels
During infection with T. canis not only changes in the
blood counts are observed but also enzymatic changes.
During the liver migration, the liver enzymes glutamate
dehydrogenase (GLDH) and alanine transaminase (ALT)
increased, reaching a maximum 14 days p.i. (Zimmermann,
1983). Afterwards, ALT remained on a high level for a cer-
tain time period, whereas GLDH returned to physiological
values after 14 days (Stobernack, 1988). After reinfection,
liver enzymes show an increase again even though it is
lower than after the primary infection (Zimmermann,
1983). Voßmann (1985) observed these two enzymes
in prenatally infected puppies to be elevated already at
birth up to 67 U/l for GLDH (physiological value up to
6.0 U/l) and 365 U/l for ALT (physiologically up to 55 U/l)
in highly infected puppies. The values returned to normal
1–2 weeks post partum. A second increase caused by adult
ascarids migrating through the liver and the peritoneal
cavity was detected shortly before the death of highly
infected puppies.
3.3. Histopathological changes
Webster (1958a) histologically examined the organs
affected by the parasite. Within this study, 72 h p.i. in the
liver parenchyma free larvae were detected as well as an
infiltration of leucocytes. During the following 24–48 h
the number of leucocytes increased continuously. Most
leucocytes were identified as eosinophils, monocytes and
also polymorphonuclear leucocytes. Webster (1958a)
reported a tendency of these cells to gather in nodules,
 T. Schnieder et al. / Veterinary Parasitology 175 (2011) 193–206
Fig. 10. Granuloma in the skeletal muscle (Institute for Parasitology,
archive).
sometimes surrounding a larva in their centre. These struc-
tures could be referred to as granulomes. Based on these
processes the tissue becomes necrotic, haemorrhages and
marked fatty degeneration of liver cells occur. After 10
days first signs of encapsulation marked by a thin fibrous
capsule were seen associated with the retreat of some
of the leucocytes. Finally, about 3 weeks p.i., Webster
(1958a) observed the beginning of a regenerative process
with fibrous tissue proliferation. Excessive infiltration
of lymphocytes, eosinophils and reticulum cells in the
liver was also observed in the study of Hayden and Van
Kruiningen (1975).
Webster (1958a) further examined the lung and also
found an infiltration with leucocytes, mainly eosinophils,
forming compact nodules. Infected dogs suffered from lob-
ular pneumonia and vascular congestion. Heavy infections,
which are not further specified by Webster (1958a), led
to serious pneumonia with exudate mainly comprising
mucus, blood cells, epithelial cells as well as larvae in the
alveoli and bronchioles. Furthermore, haemorrhages were
common and in some cases extensive tissue degeneration
was observed.
Dense aggregates of eosinophils were also found in the
intestinal wall, especially in the duodenum and jejunum
but also in the cecum and colon. Even mesenteric lymph
nodes had a few capsular and cortical granulomes (Hayden
and Van Kruiningen, 1975). Furthermore, Hayden and Van
Kruiningen (1975) observed mild to severe pyelitis in the
kidney in 3 out of 7 dogs and interstitial infiltrates of lym-
phocytes, plasma cells, eosinophils and histocytes in the
cortex of 2 dogs. Granulomes directly under the capsule of
the kidney were also described by Herschel (1981).
Therefore, it can be said that eosinophil infiltration and
granulomes were most pronounced in the liver, kidney and
lung (Hayden and Van Kruiningen, 1975). It is known that
larvae in skeletal muscles of paratenic hosts are enclosed
in granulomes (Parsons, 1987). Manhardt (1980) also made
this observation in the definitive host (Fig. 10), the central
nervous system being the only exception.
4. Evasion of the immune system
As outlined above, larvae migrate for several weeks, and
arrested larvae remain alive for at least several months in
203
the host tissue. Why therefore should the immune system
not be able to detect and to successfully eliminate these
larvae? Two ways of immune evasion have been suggested.
One hypothesis is that larvae reach a state of hypobiosis in
the tissue, where expression of the immune system stim-
ulating antigens is widely reduced. The other hypothesis
suggests an immunosuppression induced by T. canis larvae
which affects the function of T-helper cells. Consequently,
the host response to parasite antigens and the production
of specific antibodies is reduced (Overgaauw, 1997).
4.1. The antigenic coat
Many in vitro studies have been conducted to further
elucidate the mechanisms this parasite uses to evade the
host’s immune system. As hatched larvae can be main-
tained in vitro and excretory–secretory (E/S) antigens can
be collected, this stage is regarded as a model for stud-
ies on host–parasite-interactions (Maizels et al., 1987).
Smith et al. (1981) found that larvae are not recognised by
antibodies against E/S antigens at 37 ◦ C but are so when
kept at 2 ◦ C or at 37 ◦ C after preincubation with certain
antimetabolites. Both, low temperatures and antimetabo-
lites, led to a metabolic inhibition, which was displayed by
the ability of the antibodies to bind to the surface of the
larvae. Furthermore, when the temperature was increased
to 37 ◦ C or the antimetabolites were removed, binding of
fluorescence-labelled antibodies was again not detected.
Due to the fact that E/S antigens could be detected all over
the surface of metabolically inhibited larvae but not on the
surface of larvae kept at 37 ◦ C, it was concluded that the
whole outer larval surface was involved in the release of
E/S products (Smith et al., 1981). Smith et al. (1981) then
hypothesised that the ability to repeatedly shed E/S prod-
ucts on the entire surface could enable the larvae to contin-
uously remove antibodies attached to the surface. There-
fore, antibody-dependent cell adhesion reactions of the
host would effectively be prevented. This hypothesis was
confirmed by several authors. Badley et al. (1987) found out
that absorption of immune sera with E/S antigens removed
surface IgG but also C3, which implied that E/S antigens
have the ability to remove antibodies and serum compo-
nents necessary for direct complement fixation. Maizels
and Page (1990) found larvae to be bound by comple-
ments even up to C9. Furthermore, it was observed by using
electron microscopy that the single layer of granular epi-
cuticular material of larvae incubated with immune serum
for at least 30 min, thickened and condensed and that
the denser portion of the epicuticle frequently detached
from the surface. Together with the sheath-like layer also
eosinophils, containing vacuoles opening to the larval sur-
face, were detached. Therefore, no gross damage to larvae
could be seen after 30 min or after 12 h in culture with cells
and serum (Badley et al., 1987). The ability to repeatedly
shed attached antibodies and cells is maintained by high
production and expression of antigens, which contribute
to the surface layer, i.e. E/S antigens. Badley et al. (1987)
reported that the E/S antigen production totals quantities of
up to 8 ng per larvae and day. Maizels et al. (1984) reported
that within 1 h 25% of the surface antigens were released,
indicating the rapidity of this process.
204 T. Schnieder et al. / Veterinary Parasitology 175 (2011) 193–206
Maizels et al. (1984) further characterised the E/S
components from T. canis (TES). Five antigenic compo-
nents were identified and named after their molecular
weights in kDa: TES-32, TES-55, TES-70, TES-120 and
TES-400. All TES-molecules were found to contain more
than 40% carbohydrates, the majority of which were N-
acetylgalactosamine and galactose (Meghji and Maizels,
1986). All TES molecules were first secreted and then
formed the larval surface coat except for TES-400.
Page et al. (1992) examined the organs which might
be connected to the secretion of the major glycoproteins
of T. canis, using immunogold electron microscopy. It was
found that they are derived from two specialised organs
within the nematode organism. The two primary locations
were found to be the esophageal glands, which secrete their
products via the esophagus in the oral orifice, as well as a
large branched secretory cell, which has its opening to the
cuticle at an anterior secretory pore. Additionally, it was
found that TES-32 is synthesised separately in the cuticle
(Page et al., 1992).
4.2. The interaction of TES molecules with the immune
system
Loukas et al. (1999) found that TES-32 is a C-type lectin
having greater similarity to mammalian C-type lectins
than to the respective orthologues in C. elegans. As the
mammalian C-type lectins are involved in the immune
response, the authors supposed an immune evasive strat-
egy of the parasite based on the similarity to host immune
cell receptors. Subsequently, Loukas et al. (2000) showed
that binding of TES-70 and other TES to host proteins from
a canine cell line occurs in a calcium-dependent manner.
The interaction of T. canis E/S antigens with the immune
system was further documented in a recent study by
Giacomin et al. (2008a). Injected E/S antigens enhanced the
migration of Nippostrongylus cantonensis in IL-5 transgenic
mice, which have an innate resistance to N. cantonensis.
The authors confirmed the activation and consumption of
the complement factor C3 reported by Badley et al. (1987).
Additionally, they surmise a complement-independent
mechanism modulating the function of eosinophils, as the
resistance of the mice is not based on the complement
system (Giacomin et al., 2008b). However, the exact mech-
anism of the interactions of TES and eosinophils and other
immune cells remains unclear.
5. Conclusions
Holland and Smith (2006) referred to Toxocara as “The
Enigmatic Parasite”. There is no better way to precisely
characterise this fascinating nematode, and the present
state of knowledge even after decades of intense research,
still leaves many questions unanswered. Our present, more
stringent animal welfare considerations certainly exclude
any new attempts to solve the remaining mysteries of lar-
val development inside the host and help us to accept a
certain level of incomplete knowledge. More important
however is that despite a large number of highly efficient
anthelmintics, this zoonotic parasite still represents the
most prevalent nematode in dogs and that we understand
that intensive research is still required to improve control
strategies in dogs and to prevent transmission to humans.
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