No.

4 July 2009

www.cvbd.org
®
CVBD DIGEST
Canine babesiosis –
a never-ending story
Cutting-edge information brought to you by the CVBD® World Forum
 ® No.4 July 2009
CVBD DIGEST Canine babesiosis – a never-ending story

Introduction

When Bayer HealthCare, Animal Health Division, called for the 1st International
CVBD® Symposium in 2006, it was the first and initial step to address the global
threat of canine vector-borne diseases (CVBD®). This was based on the belief
that vector-borne diseases of the dog should be treated as one topic and dealt
with on a global level and in an interdisciplinary way. During the past years,
CVBD® have become a global issue and have even sparked public interest.
Many of the parasite-transmitted diseases affect humans as well as animals.
The dog as man’s best friend plays an important role – as dogs serve as host for
some of the zoonotic pathogens and are greatly affected by them.

At the first symposium, the participants agreed to form the CVBD® World
Forum. Besides gathering knowledge, the main task for this group of inter-
national experts has been to raise awareness for the specific regional risks of
CVBD® and to foster preventative measures. For this reason, the CVBD® World
Forum created a website (www.cvbd.org) to provide the veterinary practitioner
with cutting-edge and clinically relevant scientific information on CVBD®.

In the CVBD® Digest, relevant findings from CVBD® symposia are presented
periodically to veterinary practitioners. The Fourth International CVBD®
Symposium has taken place, yet again reviving the intense discussion about the
current trends and prospects. Canine babesiosis was one highlight during the
recent symposium. Meanwhile, experts from all over the world increasingly
recognize infection with Babesia spp. as one of the most important CVBD®. The
latest data shed light on the role of fighting dogs in disease transmission, and
how the suspected spread of tick vectors into moderate climate regions paved
the way for the subsequent protozoan parasite infection. However, even in non-
endemic regions veterinarians should be aware of the disease when dogs display
fever, anemia or thrombocytopenia after returning from endemic regions.
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No.4 July 2009
Canine babesiosis – a never-ending story CVBD DIGEST 3

Cutting-edge information brought to you by the CVBD World Forum

Canine babesiosis –
a never-ending story
Author: Friederike Krämer Two-host-life cycle and the Pit Bull
Institute for Parasitology, University of Veterinary Medicine paradox
Hannover, Germany

Babesiosis is the oldest tick-borne disease reported Generally, Babesia spp. possesses two types of hosts:
in domestic animals and recently has attracted even an invertebrate host (ixodid ticks) and a vertebrate
more interest in the field of canine vector-borne host. In the tick vector, Babesia gamonts fuse to
diseases (CVBD). Due to emerging or newly identi- zygotes that later, after sporogony, develop to
fied pathogens, canine babesiosis still presents sporozoites within the salivary glands of the tick.
a significant challenge to the practitioner. This is The female tick may pass the pathogens to its off-
especially true for diagnosis and therapy. spring (transovarial transmission). Sporozoites are
Besides new pathogen species, spreading of the injected into the vertebrate host together with the
disease to former non-endemic areas has been re- saliva during blood feeding and directly infect red
ported as a consequence of international travel and blood cells. In these cells, they develop into piro-
expansion of tick vector habitats. To keep up with plasms. Multiplication usually results in two (some-
this development, practitioners should be aware of a times four) daughter cells (merozoites), which leave
variety of clinical signs and the treatment procedure. the host cell and each enter another red cell. This
Control and prevention can be supported by contin- continues until the death of the vertebrate host,
uous use of ectoparasiticides that minimize blood- or until the immune system of the host terminates
feeding by repelling and killing the tick vectors. the process.
Over the last 10 years, Babesia gibsoni (see below)
Babesiosis is a parasitic infection caused by hemo- infections have been reported in many countries
tropic protozoa of the genus Babesia (Order: Piro- outside of Asia, predominantly in American Pit Bull
plasmida). The pathogen was discovered at the end Terrier-type dogs, in the absence of tick vectors.
of the 19th century by the Romanian scientist Victor There is now convincing evidence that these cases
Babes, who was investigating febrile hemoglobinuria have arisen due to biting and fighting between
in cattle.1 Only seven years after these initial descrip- infected and non-infected dogs.4,5 The fighting dogs
tions, B. canis was first described in dogs in Italy.2 themselves are considered to be the reservoir of
The protozoan infects erythrocytes of wild and this Babesia species6 and the massive injuries during
domestic animals worldwide and is transmitted fighting as well as the breed of dogs itself seem
by a variety of ticks, including the Brown Dog tick to foster this non-vectorial spreading. Due to the
(Rhipicephalus sanguineus) and different members worldwide popularity of this breed and similar ones,
of the Dermacentor genus. More than 100 Babesia it is speculated that B. gibsoni will eventually be
species are reported so far, infecting many mam- reported from all countries where (usually illegal)
malian and some avian species. Babesia spp. infec- dog fighting is practiced.6 Nevertheless, the vast
tions have probably been complicating the lives of majority of Babesia spp. transmission worldwide is
humans and their domestic livestock since antiquity. due to tick biting and blood feeding.
In the biblical book Exodus 9:3, a plague of the
cattle of the Egyptian Pharaoh Ramses II is described
that could have been red water fever of cattle
(caused by B. bovis), including hemoglobinuria as
a prevalent sign.3
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4 CVBD DIGEST No.4 July 2009
Canine babesiosis – a never-ending story

Canine babesiosis: Babesia or Theileria?

Historically, Babesia spp. in dogs were identified

by their morphological appearance in erythrocytes
of blood smears. All large forms (intraerythrocytic
merozoite stage measures 3 to 5 µm, i.e. half or more
of the diameter of a red blood cell, see Figure 1) were
designated B. canis in former times, whereas all small
forms (merozoites measuring 1 to 3 µm, i.e. less than
half the diameter of an erythrocyte, see Figure 2)
were thought to be B. gibsoni. Babesia canis was
categorized into three subspecies (B. canis canis,
B. canis rossi, B. canis vogeli) on the basis of cross-
immunity, serological testing, vector specificity and
molecular phylogeny.7,8 These subspecies are now Fig. 2 Babesia gibsoni within red blood cells: note how the
considered to be separate species.9,10 Another, organism occupies markedly less than half of the diame-
ter of the cell. With permission of P. Irwin, Murdoch, Australia.
fourth ‘large’ Babesia sp. (yet unnamed) has been
described recently in a number of dogs with clinical
signs and hematological parameters consistent with Babesia, once injected into the host, enter directly
babesiosis in North Carolina, USA (see Table 1).11,12 into red blood cells. In contrast, Theileria sporozoites
do not infect red blood cells but penetrate lympho-
cytes (or macrophages) where they develop into
schizonts. Theileria merozoites enter red blood cells
where they grow into piroplasms and multiply by
budding into four daughter cells, forming tetrads,
often in the shape of a Maltese cross. Further
differences exist in the developmental cycle within
the tick vector (transovarial transmission in Babesia
spp. versus transstadial transmission in Theileria
spp.). In summary, as soon as schizonts are seen, the
parasite in question is not considered to be Babesia
anymore; but whether it is a true Theileria also
depends on the cycle in the tick vector – a very vague
species classification.17
Three Theileria species have been isolated in the
blood of a small number of dogs in Europe in recent
Fig. 1 Babesia canis within a red blood cell: note the propor-
tion of the cell occupied by this large Babesia species. years (T. equi and T. annulata)18,19 and from 82 dogs
With permission of P. Bourdeau, Nantes, France. in South Africa (unnamed Theileria sp. related to
an isolate obtained from antelope)20 (see Table 1).
The status of B. gibsoni as the only small Babesia However, until more information is available, the
species in dogs had to be abandoned in favor of competence of the dog as a host for these piro-
three genetically and clinically distinct species plasms is uncertain; the clinical correlation is un-
causing canine diseases: B. gibsoni, B. conradae known, and neither intra- nor extraerthrocytic
(reported in dogs in the western United States),13,14 stages have so far been visualized6. At least for
and a B. microti-like piroplasm (named Theileria T. annae infection, severe hemolysis and azotemia
annae).15,16 Recently, reclassification of Babesia have been reported.16
species into Theileria species was carried out on the
basis of differences in the life cycle.
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No.4 July 2009
Canine babesiosis – a never-ending story CVBD DIGEST 5

Geographic
Size Species Synonyms Vector Comments
distribution
Large Babesia vogeli Babesia canis vogeli Rhipicephalus Wide range:
sanguineus tropical, subtropical
and Mediterranean
regions

Babesia canis Babesia canis canis Dermacentor spp. Europe

Babesia rossi Babesia canis rossi Haemaphysalis Sub-Saharan

elliptica (formerly Africa,
H. leachi) South Africa

Babesia sp. Unnamed large Unknown North Carolina,

Babesia sp., North USA
Carolina isolate

Small Babesia gibsoni Babesia gibsoni Haemaphysalis Asia including Outside Asia this
Asia strain longicornis Japan, sporadic infection is often
occurrence associated with
worldwide Pit Bull Terriers and
other fighting dogs

Babesia conradae In original reports Unknown Western USA,

described as specifically
B. gibsoni California

Theileria annae Babesia microti-like Ixodes hexagonus Spain, Portugal

Spanish isolate/ (putative)
piroplasm/agent

Theileria sp. Unnamed Theileria Unknown South Africa Molecular

sp., South African detection only
Theileria sp.

Theileria annulata Unknown Africa, Europe, Molecular

Asia detection only

Theileria equi Babesia equi Unknown Africa, Europe, Molecular

Asia detection only

Tab. 1: Piroplasm species of domestic dogs (modified after P. Irwin (6))

Worldwide distribution is abundant, an establishment of new disease foci is

possible. The distribution of babesiosis is changing
When assessing the distribution of the disease, Irwin continuously, mainly driven by the spreading of the
considered it useful to categorize the regional vectors within their ecological ranges (see Figure
prevalence and incidence at two levels: (i) regions 5a/b). As previously mentioned, this distribution is
where the specific parasite is well established (en- further augmented by a non-vectorial dog-to-dog
demic) and clinically recognized and (ii) regions transmission in the case of B. gibsoni. A summary of
where sporadic autochthonous infections or cases the geographical distribution of the different Babesia
associated with traveling dogs have been reported.6 species is listed in Table 1. B. vogeli with its ubiquitous
Nevertheless, practitioners working within regions vector the Brown Dog tick (Rhipicephalus sanguineus)
of the second type should bear in mind that not only is widely distributed throughout tropical and sub-
the disease may be imported by traveling dogs into tropical regions and is spreading into cooler latitudes.
their local region, but that, as long as the tick vector B. canis (sensu stricto), transmitted by Dermacentor
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6 CVBD DIGEST No.4 July 2009
Canine babesiosis – a never-ending story

spp. (see Figure 3), has already preceded this de- • B. vogeli is the least pathogenic of the three
velopment and is increasingly being discovered main large canine Babesia species. The infection
throughout central Europe. B. rossi, originally only causes subclinical to mild to moderate clinical
recorded in South Africa, has extended its range to disease.10,24 In puppies, severe to fatal hemolytic
the Sub-Saharan zone (e.g., Nigeria21 and Sudan22). anemia is common.25,26 Adult diseased dogs
The most important small Babesia species, B. gib- often have a concomitant disease or show
soni, was originally identified in a number of dif- predisposing factors as splenectomy, immuno-
ferent southern, eastern and southeastern Asian compromized conditions etc.
countries. Meanwhile, it has been reported in many • Acute B. canis infection is characterized by a
countries outside Asia in connection with American mild to severe disease, in which parasitemia is
Pit Bull Terrier-type dogs. Geographical information often low and does not necessarily correlate
on recently characterized small piroplasm species as with the severity of clinical illness.24 The main
well as the additional so far unnamed large Babesia acute clinical signs are dehydration, lethargy,
species is scarce (see Table 1), as all these have been anorexia and fever. At initial clinical exami-
detected so far in fairly limited areas of distribution. nation, the majority of dogs present with mild
to severe thrombocytopenia, hyperfibrinoge-
nemia, mild to moderate anemia, hemolysis and
neutropenia.25
• B. rossi infection is the most severe infection of
the three main large canine Babesia species.
A large proportion of dogs develop compli-
cations, some of which (hemoconcentration,
neurological signs, acute renal failure and pul-
monary edema) require early aggressive and
intensive treatment and carry a poor prognosis.27
The unnamed large Babesia sp. from North Carolina
Fig. 3 Dermacentor spp. (female D. reticulatus shown here) has been reported to be associated with non-
are vectors for Babesia canis. With permission of T. Naucke, specific illness (lethargy and anorexia), pigmenturia
Bonn, Germany
and mild fever, especially in splenectomized dogs.6
Concerning the small Babesia species, B. conradae is
considered to be more pathogenic than B. gibsoni,
Complex clinical signs due resulting in higher parasitemias and more severe
to species diversity anemia.14 T. annae infection in Spain is associated
with severe hemolysis and azotemia.16

The severity of babesiosis in dogs ranges from sub- The clinical consequences of chronic babesial infec-
clinical infection through the development of mild tion are unclear. Even though most dogs seem to
anemia to broad organ failure and death. The criti-
cal determinant of this variable pathogenesis is the
piroplasm species. Other factors such as age, immune
status, concurrent infections or illness should also be
considered. All species may cause pyrexia, anorexia,
splenomegaly, anemia and thrombocytopenia.6
The most common clinical signs during Babesia spp.
infections in dogs are hemolytic anemia (see Figure 4)
and thrombocytopenia. Hemolytic anemia in the
course of the infection can occur due to direct eryth-
rocyte lysis by replication of intracellular parasites or
intravascular and extravascular hemolysis.23 The clin-
ical signs and clinicopathological abnormalities vary in Fig. 4 Anemia, here shown in a dog, is one of the main
presenting signs of acute babesiosis.
their severity according to species and host:
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No.4 July 2009
Canine babesiosis – a never-ending story CVBD DIGEST 7

tolerate the state of premunity with few ill effects, of the infection.6 Treatment of small Babesia species
a risk of developing immune-mediated complica- infections, especially B. gibsoni, has been tested
tions and recrudescence of clinical disease in case with diverse combinations such as clindamycin,
of later immunocompromised conditions theore- metronidazole and doxycycline39 or azithromycin
tically remains.6 and atovaquone11 with reasonable clinical efficacy.
Generally, supportive therapy such as intravenous
A range of diagnostic tools fluids and blood transfusions should be employed
whenever necessary in both, large and small Babesia
During acute infection, microscopy is reasonably spp. infection. Besides these approaches to treat an
sensitive at detecting intraerythrocytic parasites in established Babesia infection, prevention is also of
Giemsa or Wright’s stained blood smears and re- major importance. This is especially the case for dogs
mains the simplest and most accessible diagnostic traveling into endemic areas but also for local
test.6 Molecular diagnostic tools (e.g., PCR) have animals, considering the transmission period.
greatly increased the sensitivity and specificity of
Babesia detection. However, low parasitemia can Vaccination and further prevention
result in a false-negative PCR.
The diagnosis of chronically infected reservoir dogs Vaccination against Babesia infection has been a
remains a significant challenge due to a very low, subject of discussion for a long time and is registered
often intermittent parasite burden.6 A higher de- in some countries. However, cross-immunity experi-
tection rate in chronically infected dogs might be ments have shown in provisional results that the
achieved by testing on more than one occasion, but antigenic differences between the large Babesia
the alternative, complementary use of serology is species have important implications for the devel-
nevertheless advisable.28,29 Due to the fact that opment of a vaccine, as there is none or no complete
B. gibsoni can be transmitted without tick vectors, cross-protection between the individual pathogens.
a history of biting should always be included in the A combination of soluble parasite antigens (SPA)
anamnesis. from both European B. canis and South African
Concerning serology, immunofluorescent antibody B. rossi in form of a vaccine offered greater protec-
testing (IFAT) has been the most widely supported tion against heterologous challenge.40 Currently,
serological diagnostic test for canine babesiosis over suitable immunodominant and protective antigens
the last 30 years.30,31 Besides the general limitation are also under investigation in Japan for use in
of serology to differentiate acute from chronic in- vaccines against B. gibsoni.41 Similarly, several drugs
fections and cross-reactions, subjectivity and inade- have been investigated for their prophylactic po-
quacy of large-scale screening have been limiting tential against babesiosis, but none has been consist-
factors of IFAT.32 Additionally to IFAT, research has ently reliable in this regard.6
been conducted in the field of antigen detection for As with other vector-transmitted diseases, the best
use in recombinant protein enzyme-linked im- prevention is achieved by avoiding exposure to the
munosorbent assays (ELISA).32–38 vector.6 This should be considered when deciding to
take a dog from non-endemic into (highly) endemic
Therapy lacking parasite elimination areas. The dog should be protected with broad-
spectrum ectoparasiticides with repellent properties,
In general, neither treatment nor the host immune such as the synthetic pyrethroid permethrin.42 Inside
response completely eliminate the infection. Ani- an endemic area, regular treatment during the trans-
mals thus become chronic carriers of the organism mission period, e.g. in the form of monthly spot-on
and potential reservoirs of infection. applications, supports the prevention of tick bites and
Imidocarb dipropionate and diminazine aceturate are thus potential Babesia spp. transmission. In Eurasia,
widely used anti-piroplasm drugs. Besides these the combination of imidacloprid and permethrin has
drugs, other compounds have been used with vary- proven activity against the vector of B. canis, Derma-
ing degrees of success for the management of clinical centor reticulatus. The combination also prevents
signs of piroplasmosis (quinuronium sulphate, trypan the biting of other vectors such as ticks, sand flies,
blue, pentamidine, phenamidine and parvaquone). mosquitoes and stable flies and therefore minimizes
At best, all these drugs result in amelioration of the interaction between host and vector. This in turn
clinical signs; they rarely achieve a true sterilization results in a decreased risk of CVBD transmission.
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8 CVBD DIGEST No.4 July 2009
Canine babesiosis – a never-ending story

BABESIOSIS OCCURRENCE MAP ASIA-PACIFIC

RUSSIA

KAZAKHSTAN
MONGOLIA
China-North
NORTH

KYRGYZST.
KOREA
UZBEK.
TADJIK. SOUTH

China-West China- KOREA PACIFIC

Central East JAPAN
AFGHAN.
OCEAN
PAKISTAN NEPAL
BHUTAN
China-South
BANGLAD. TAIWAN
INDIA LAOS
MYANMAR

VIETNAM
CAMBODIA
PHILIPPINES
THAILAND
MALAYSIA
SRI LANKA BRUNEI
MALDIVES

INDONESIA

Tshagos Isl. PAPUA

(U.K.) NEW
GUINEA

INDIAN OCEAN

AUSTRALIA

No occurrence
NEW ZEALAND
Endemic occurrence

Fig. 5a Babesiosis distribution based on recent scientific publications in Asia-Pacific.

Fig. 5: Canine babesiosis belongs to the so-called several CVBD including also babesiosis in Asia-Pacific
canine vector-borne diseases (CVBD). This group of (Fig. 5a) and Europe (Fig. 5b). In most countries, the
infectious diseases with worldwide importance com- corresponding map is available as a poster for the
prises the major infections transmitted by ticks, mos- veterinary practice; the interactive versions of the
quitoes or sand flies. Bayer HealthCare has collected Asia-Pacific and the Europe map can be found at
data from recent scientific publications to provide a www.cvbd.org.
comprehensive view of the endemic situation of
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No.4 July 2009
Canine babesiosis – a never-ending story CVBD DIGEST 9

BABESIOSIS OCCURRENCE MAP EUROPE

No occurrence
Endemic occurrence

Fig. 5b Babesiosis distribution based on recent scientific publications in Europe.

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CVBD DIGEST No.4 July 2009
Canine babesiosis – a never-ending story

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CVBD DIGEST No.4 July 2009
Canine babesiosis – a never-ending story

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