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Canine babesiosis in Europe:

how many diseases?
Vesna Matijatko1, Marin Torti1 and Theo P. Schetters2
University of Zagreb, Faculty of Veterinary Medicine, Clinic for Internal Diseases, Heinzelova 55, 10000 Zagreb, Croatia
Merck Sharp & Dohme Animal Health, PO Box 31, 5830 AA Boxmeer, The Netherlands

Babesiosis, recognized since ancient times as an impor- separate species [5,6]. Different species of large and small
tant disease of livestock and more recently as an Babesia are shown in Table 1.
emerging disease in dogs worldwide, is caused by Babesia parasites are naturally transmitted only by
intraerythrocytic protozoa of the genus Babesia and ticks, and in the case of canine babesiosis there is a very
is transmitted by ticks. The pathophysiology of canine strong association between the Babesia species that is
babesiosis has been extensively studied but many ques- transmitted and the tick species (reviewed in [7]). As a
tions remain unanswered, especially regarding the di- consequence, the prevalence of babesiosis is dependent on
versity of disease manifestations in different European the presence of the tick vector in the environment (Table 2).
countries. Continued investigation of the similarities
and differences in host–parasite interplay in canine ba- Canine babesiosis in Europe
besiosis in different European countries should lead to a In Europe the predominant cause of canine babesiosis is B.
better understanding of the disease process, potentially canis, and clinical cases have been reported from Austria [8],
leading to better prediction of disease outcome and the Croatia [9,10], France [11], Germany [12], Hungary [13],
development of new treatment modalities. From the Italy [14], the Netherlands [15], Poland [16], Portugal [17],
European point of view it is important to conduct these Slovenia [18], Spain [19], Switzerland [20], and recently
studies on Babesia canis. Norway [21]. The disease can be clinically classified into
uncomplicated and complicated forms. Uncomplicated ba-
Canine babesiosis: a riddle yet to be solved besiosis has been suggested to be a consequence of anemia
In recent years, more and more cases of babesiosis in dogs resulting from hemolysis [22], whereas complicated canine
have been reported in Europe, and it appears that canine babesiosis may be a consequence of the development of
babesiosis is an emerging infectious disease. The parasite systemic inflammatory response syndrome (SIRS) and mul-
is transmitted by ticks, and migration of ticks to hitherto tiple organ dysfunction syndrome (MODS), both of which are
uninfested geographical areas could explain the increasing cytokine-mediated phenomena [22,23]. Clinical signs of
incidence of clinical cases in Europe. The clinical presen- uncomplicated babesiosis include pale mucous membranes,
tation of canine babesiosis is diverse and ranges from fever, anorexia, depression, splenomegaly, hypotension and
transient anorexia to a complex syndrome in which multi- water hammer pulse [24–27]. Clinical manifestations of the
ple organ systems are affected. Several factors play a role complicated form of babesiosis depend on the particular
in the development and outcome of the infection; these complications that develop. In Europe, a higher mortality
include the abundance of the tick vector, the percentage of rate is noted in countries that have reported complications
ticks that are infected, and the Babesia species involved. that are strikingly similar to those of the South African form
This review presents an update on canine babesiosis with a of babesiosis [28], namely MODS, cerebral babesiosis, shock,
focus on the clinical disease as manifested in Europe. rhabdomyolysis, acute renal failure (ARF), acute respirato-
ry distress syndrome (ARDS), acute liver dysfunction and
Babesia species that infect dogs acute pancreatitis (AP). The highest mortality rate is noted
Canine babesiosis is caused by apicomplexan parasites in Hungary where MODS is reported in 16% of cases,
that are classified either as large (5  2.5 mm) or small hepatopathy in 24%, AP in 6%, ARF in 30%, disseminated
Babesia (2  1.5 mm) [1]. Large Babesia canis was divided intravascular coagulation (DIC) in 17%, immune-mediated
into three different species, namely Babesia canis, Babesia hemolytic anemia (IMHA) in 8%, ARDS in 6%, and cerebral
rossi and Babesia vogeli [2]. Recently, a new large babesian babesiosis in 3% [29]. In Croatia the most common compli-
species, Babesia sp. (Coco) was discovered [3,4]. B. canis, B. cation was MODS (10%) [30]. It is interesting to note that
vogeli and B. rossi, previously considered to be subspecies within MODS the most common complication was ARF,
of B. canis, are identical morphologically but show great followed by hepatopathy, ARDS and cerebral babesiosis
variations in geographic distribution, vector specificity, [31,32]. In a study of B. canis infection in Croatia, a consid-
genetic characteristics and the clinical signs they induce erable number of dogs with hypotensive shock were
in dogs, and are therefore now widely considered to be observed [32]. In contrast to these findings, B. canis infection
in other European countries has only low mortality. For
example, in Poland the mortality rate is 3.9% and the most
Corresponding author: Matijatko, V. ( commonly reported complication is ARF [26], whereas in
1471-4922/$ – see front matter ß 2011 Elsevier Ltd. All rights reserved. doi:10.1016/ Trends in Parasitology, March 2012, Vol. 28, No. 3 99
Review Trends in Parasitology March 2012, Vol. 28, No. 3

Table 1. Groups of canine Babesia species hypothesis that virulence is indeed different between
Group Species Refs. strains of B. canis.
Large Babesia Babesia canis [76]
Babesia rossi [7] Genetic diversity
Babesia vogeli [3] With the development of molecular biological tools it be-
Babesia sp. (Coco) [4] came possible to analyze the diversity of B. canis strains at
Small Babesia Babesia gibsoni [87] the genetic level. Analysis of more than 90 isolates from
Babesia conradae [88] France revealed that based on diversity of the Bc28 gene,
Babesia microti-like (Theileria annae) [9,89,90] three genetically distinct groups could be defined, Bc28-A,
Bc28-B (predominant) and Bc28-3403 [38]. Similar analy-
sis of over 200 isolates from Central Europe revealed that
Spain and Italy the most common complication noted in B. only genetic groups Bc28-A and Bc28-B were prevalent,
canis-infected dogs is DIC [33,34]. In those countries MODS with a slight predominance of Bc28-A (B. Carcy, unpub-
has not been reported, and the mortality rate is significantly lished). The analysis did not allow a correlation with
lower. Indeed, it seems that in Spain the infection with virulence to be established; however, a correlation with
newly discovered small Babesia species results in a more functional protective immunity in vaccination challenge
severe disease (mortality rate 22%) that is associated with studies is apparent (discussed below).
ARF [35].
Antigenic diversity
Diversity among Babesia canis strains Vaccination challenge experiments have indicated that
Differences in virulence antigenic diversity is present in B. canis strains. Dogs
Differences in the clinical manifestations of disease may vaccinated with soluble parasite antigens (SPA) derived
reflect different Babesia strains. This is best evidenced in from the supernatant of in vitro cultures of B. canis strain
B. bovis, for which it has been possible to select for strains A parasites were protected against homologous challenge
that are less virulent than the parent strain. This selection infection, but not against challenge infection with a heter-
process involves repeated passage through splenecto- ologous B. canis strain B [39,40]. This indicates that there
mized calves and is being used in the production of live are functional antigenic differences between B. canis
vaccines against B. bovis in cattle [36]. In addition to strains [2]. Antigenic diversity may be related to allelic
differences in virulence, it was also shown that there diversity, where by different parasite clones express dis-
are antigenic differences between B. bovis strains. The tinct members of a particular protein family, such as the
occurrence of antigenically different strains has been MSA-1 and MSA-2 merozoite surface antigens [38]. Ho-
suggested to explain vaccination failures in Australia in mologous recombination during sexual stages in the tick
the period 1985–1990 [37]. Likewise, strain diversity in B. vector is likely to be the molecular mechanism involved in
canis could explain the variable clinical picture seen in the generation of such antigenic diversity, although gene
affected dogs in France [11]. Direct evidence of the exis- organization analysis suggests that other mechanisms
tence of strains of B. canis with variable virulence has may also contribute [41].
recently been reported from Poland. Based on differences
in part of the 18S ribosomal RNA gene, isolates of B. canis Antigenic variation
could be separated into two genetically different groups: A A further and distinct mechanism for the generation of
and B [17]. It was later shown that thrombocytopenia, one antigenic diversity takes place via a dynamic genetic pro-
of the first hematological signs of natural and experimen- cess operating at the clonal level. This phenomenon has
tal B. canis infection [11,27], was statistically different been described for several protozoan parasites, including
between the two genetic groups [26]. In addition, there was B. bovis [42], where antigenic molecules are not expressed
a strong correlation between the extent of thrombocytope- at the merozoite surface but are instead expressed at the
nia and increases in body temperature, accelerated pulse surface of the infected erythrocytes, and may therefore
rate and discoloration of urine. These data support the play a role in the specific adhesion of infected erythrocytes

Table 2. Geographic distribution of different Babesia species and their vectors

Species Geographic distribution Vector Refs. and comments
Babesia canis Europe, Asia Dermacentor reticulatus [6,9,13,16,91]
Babesia rossi Africa Haemaphysalis leachii [92]
Babesia vogeli Africa, Europe, Asia, Australia, Rhipicephalus sanguineus [5,6,9,17–19,93–97]
North and South America
Babesia sp. (Coco) United States Unknown [3]
Babesia gibsoni Worldwide Haemaphysalis sp. [7,87,89,98,99]
Rhipicephalus sp.
Babesia conradae California Rhipicephalus sanguineus? [90]
Babesia microti-like Southern Europe Most probably Ixodes hexagonus? Discovered 10 years ago in Spain and
(Theileria annae) named Babesia microti-like or Babesia
annae. Renamed Theileria annae based
on molecular phylogenetic analysis [9,19,88,100].

Review Trends in Parasitology March 2012, Vol. 28, No. 3

to the capillary endothelium of particular organs, a process detoxification systems of parasitic protozoa have been
termed sequestration. It is believed that this process plays identified and their roles in parasite survival have been
a role in sustaining low-level chronic infection in immune investigated [55]. The so-called ‘redox proteins’ were
animals, which helps to maintain immunity [43]. Although shown to be essential for the survival of protozoan para-
antigenic variation has not been shown for B. canis, low- sites. Furthermore, oxidative stress may negatively affect
level chronic infection occurs in dogs experimentally organ injury and overall survival [56]. Malondialdehyde is
infected with B. canis or B. vogeli parasites [44,45]. In an end product of polyunsaturated fatty acid oxygenation
the latter it was further shown that immunity in these dogs and is a reliable and commonly used biomarker for asses-
was prolonged compared to dogs treated after initial infec- sing lipid peroxidation [57]. Serum malondialdehyde
tion to clear the parasites [45]. In the field, dogs are faced levels were found to be elevated significantly in canine
with several antigenically diverse B. canis parasite fami- babesiosis [58].
lies of variable virulence, and these have evolved mecha- Products of oxidative stress may thus contribute to
nisms that allow survival in (partially) immune dogs. protective immune responses against the parasite if pro-
duced in optimal amounts [52,53], but can also contribute
Pathophysiology of the disease to pathogenesis when produced in excess [54]. Therefore,
Canine babesiosis is generally classified into uncomplicat- the important element for favorable outcome in babesiosis
ed and complicated forms. Whereas uncomplicated babe- may be the balance between oxidant and antioxidant
siosis appears to be a consequence of anemia, complicated processes.
canine babesiosis is characterized by pathologic changes in Different levels of parasitemia have been reported in
a number of organs (MODS). In recent years increasing numerous studies of canine babesiosis. Anemia in canine
numbers of researchers have proposed that a uniform babesiosis is not proportional to parasitemia [33,59,60].
mechanism leads to different clinical manifestations The established fact that the quantity of destroyed ery-
[22,28,46]. This is based on the hypothesis that SIRS throcytes is much higher than the degree of parasitemia
(leading to MODS) is a pathophysiological mechanism that suggests that destruction takes place of both parasitized
underlies the different presentations of babesiosis. Recent and unparasitized erythrocytes [61]. In one study, all
publications have shown that both uncomplicated and patients showed a level of parasitemia of below 1% [62].
complicated babesiosis due to B. canis are associated with Another study reported that higher levels of parasitemia
host inflammatory responses [27,46]. correlated with worse clinical scores [63], and the degree
of parasitemia was significantly higher in the dogs that
Uncomplicated babesiosis died. In an experimental study of canine babesiosis
Subjects infected with Babesia parasites develop anemia. caused by B. canis, all dogs developed low-grade para-
The mechanism that leads to the anemic state is complex sitemia (less than 1%) [27]. In studies of canine babesiosis
and involves erythrocyte depletion as a result of parasite in Croatia, all patients with uncomplicated babesiosis had
multiplication, hemodilution, localization in the spleen, a level of parasitemia below 1% (I. Kiš, Ph.D. Thesis,
(autoimmune) hemolysis, erythrophagocytosis and im- University of Zagreb, 2007). In a study in Croatia of septic
paired erythropoiesis [47]. Anemia may lead to tissue shock due to babesiosis, seven of 10 dogs had a level of
anoxia, and this is considered to be the hallmark of babe- parasitemia above 1%, whereas three had a level below
siosis [28]. There are indications that oxidative stress and 1% [32]. Given that all the dogs in this study died, it would
lipid peroxidation play a role in the pathogenesis of anemia seem that a low level of parasitemia does not guarantee a
in some protozoan diseases [48]. Excess lipid peroxidation favorable outcome, but that a level of parasitemia greater
in biological membranes compromises their structural than 1% is associated with poor outcome. One of the
integrity, with loss of fluidity, decrease in membrane po- proposed mechanisms that could lead to the development
tential and increased permeability to ions [49]. These of septic shock in babesiosis, and subsequently increase
changes can lead to rupture of the membrane and release the risk of poor outcome, is related to the parasite itself.
of cell contents [50]. Mata (M.M. Mata, M.V.Sc. Thesis, The association between a higher level of parasitemia and
Haryana Agriculture University, 1990) argued that lipid shock raises the question of whether the two are causally
peroxidation causes an accumulation of oxidative ions in related. In experimental B. canis infection, the onset of
red blood cells that causes their lysis. the acute phase reaction appeared to be related to the
Many parasites including protozoa are sensitive to oxi- infectious dose, although the acute phase response was
dative stress. Sensitivity to oxidative stress has been ultimately triggered in all cases, irrespective of dose [27].
reported in malaria [51], hepatozoonosis [52], tropical The arguments for the inflammatory response are sup-
theileriosis [53] and bovine babesiosis [54]. Reactive oxy- ported by the fact that acute-phase protein production is
gen species (ROS) and reactive nitrogen species (RNS) are increased in canine babesiosis and can be used as a
powerful oxidants and nitrating species that can inactivate predictive marker for disease risk and to monitor the
enzymes and initiate lipid peroxidation and nitration, response to treatment [46]. Nevertheless, the concentra-
which in turn lead to free-radical chain reactions that tion of C-reactive protein (CRP) did not show prognostic
further damage membranes, nucleic acids and proteins value because it was not associated with outcome in
[55]. These processes can ultimately lead to parasite death babesiosis caused by B. rossi [64].
[51,52]. As a defense mechanism, parasites produce com- The timing of the different triggers may lead to different
pounds and antioxidant enzymes that directly neutralize outcomes: high infectious doses trigger an early inflamma-
ROS and RNS. Over recent years, several antioxidant and tory response that could push the system out of balance.
Review Trends in Parasitology March 2012, Vol. 28, No. 3

However, severe parasitemia is unlikely to be the sole Bilirubin concentration is a much better indicator of liver
trigger of circulatory collapse in canine babesiosis, espe- damage, but is problematic in canine babesiosis because of
cially because some dogs with low levels of parasitemia are hemolysis. All these facts confirm the need to revise the
known to develop shock [27,32,63]. It has been suggested criteria for SIRS and MODS in veterinary medicine and to
that this response is triggered by SPA released into the develop a uniform and reliable scoring system for inflam-
plasma during infection [2,27]. matory responses (SIRS, MODS, sepsis, septic shock) to be
able to compare these conditions between different veteri-
Host inflammatory response nary centers or different countries.
Because babesiosis, as with human malaria caused by
Plasmodium falciparum, can be classified as protozoal Canine babesiosis – how many diseases?
sepsis [65,66], it was suggested that the inflammatory For a long time it was widely accepted that babesiosis caused
mechanisms in this disease are similar to those of other by B. rossi is a disease different from babesiosis caused by B.
septic conditions clinically characterized by SIRS and canis. Most importantly, with B. rossi infections there is a
MODS. This could explain similarities between various higher risk of developing complications and a significantly
diseases such as babesiosis, malaria, sepsis, multiple trau- higher rate of mortality [22,28,59,76,77]. By comparison,
ma and burns [22]. These similarities have provoked infection with B. canis was considered to cause a predomi-
scientists to revise the original definition of sepsis as being nantly mild disease with high seroprevalence ranges (20–
caused exclusively by bacteria. It is now considered that 85%) in endemic areas [9,78,79] and low rate of clinical
sepsis is SIRS with the confirmed presence of an infectious disease [80]. Reviewing the results of studies of babesiosis
agent in the blood [65]. SIRS is described in naturally caused by B. canis throughout Europe demonstrated a wide
occurring as well as in experimental canine babesiosis range of mortality rates, varying from 1.5 to 20%. The
[23,27,30], and although the role of SIRS in systemic highest mortality rates are found in Hungary (20%) [29]
inflammation and the development of MODS have not and Croatia (11–13.9%) (I. Kiš, Ph.D. Thesis, University of
been disputed, the criteria for defining SIRS remain con- Zagreb, 2007) [43], and the lowest in France (1.5%) [80]. The
troversial [67–72]. One flaw in the definition of SIRS is that reported mortality rate in the Netherlands is 17% [15] and
it might identify patients with systemic inflammatory 9% in Portugal [17], but these numbers should be inter-
disease, but the presence or absence of SIRS has little preted with caution. Regarding the study of canine babesio-
value in predicting outcome [73]. The cut-off values for the sis in the Netherlands, it is important to emphasize that
parameters of SIRS are a major issue in veterinary medi- because diagnosis of babesiosis in three of the four dogs that
cine because the normal values for temperature, heart rate died was only established postmortem, these animals there-
and respiratory rate vary in dogs, owing in part at least to fore did not receive any antibabesial treatment. For the
significant variations in their size [74]. This is especially a Netherlands study, diagnosis of babesiosis in three of the
problem in babesiosis because anemia, which is often four dogs that died was only established postmortem, and
present in canine babesiosis, significantly increases heart these animals therefore did not receive any antibabesial
and respiratory rate. Another problem regarding SIRS is treatment. Considering the fact that only one dog with
that a significant number of dogs with babesiosis are SIRS- confirmed babesiosis died in that study, the actual mortality
negative [23,30], and therefore could not be considered to rate was 5%. In addition, reported mortality rates for dogs
have sepsis according to current definitions. Because both with babesiosis in Portugal should be interpreted in light of
uncomplicated and complicated babesiosis appear to be the the fact that two of four dogs that died were euthanized
result of host inflammatory responses [27,46,64], in these without treatment, the third was infected with B. vogeli,
cases the concept of SIRS fails to identify patients with Erlichia canis and Leishmania infantum, and the fourth
demonstrated systemic inflammation. Moreover, some was infected with B. canis and Leishmania infantum. From
SIRS-negative dogs develop MODS [23,30]. SIRS, sepsis, these data, the actual mortality rate in Portugal for B. canis
severe sepsis and septic shock are clinical entities that are infection without coinfection was low. Therefore, B. canis
considered to represent the progression of the inflamma- disease in both the Netherlands and Portugal can be con-
tory response, and therefore an animal with babesiosis sidered to be mild.
that is both SIRS-negative and MODS-positive cannot be By contrast, the clinical manifestations, complications
clinically classified according to the present definitions. and mortality rate of B. canis infection in Hungary and
Multiple organ dysfunction syndrome is documented in Croatia are more similar to those of South African canine
canine babesiosis caused by B. rossi and B. canis [23,30,32]. babesiosis caused by B. rossi than to B. canis infections in
As emphasized for the concept of SIRS, the MODS criteria other European countries. Overall, it seems that canine
are also controversial. For example, the creatinine level babesiosis caused by B. canis in Europe is not a single
has been widely used for identifying renal failure. Howev- disease, and instead has at least two clinically different
er, prerenal azotemia with no structural kidney damage disease manifestations, one mild, in which multiple organ
can also lead to elevated serum creatinine concentrations, failure is absent, and a second that is severe and that is
and creatinine values are therefore insufficiently specific to generally complicated by MODS and hypotension. The an-
establish renal failure. In addition, in experimental B. swer to the question ‘why is it like this?’ might lie in the
canis infection it was shown that creatinine levels decrease parasite itself, the host, or in host–parasite interplay. Re-
in the early phase of the disease [27,75]. Liver failure is garding the parasite itself, it has been demonstrated that
commonly diagnosed from elevated concentrations of different Babesia species, subspecies or isolates can produce
liver enzymes, but this in our opinion is also not specific. disease of markedly different severity [77]. Moreover,
Review Trends in Parasitology March 2012, Vol. 28, No. 3

significant differences in disease outcome and prognosis the majority of these studies were carried out on dogs
have been observed following infection with different strains infected with B. rossi.
of a single species of Babesia (B. rossi) [81].
Regarding the host response, it was reported that in Concluding remarks
some human patients with malaria, organ system dysfunc- In summary, the balance between SIRS and CARS is of
tion may develop and evolve even after the parasites have utmost importance, and it would be prudent to investigate
been eradicated from the blood by specific therapy [82]. several pro- and anti-inflammatory mediators in the same
This observation supports the hypothesis that inflamma- samples before drawing conclusions regarding possible
tory mediators are involved because immunoinflammatory interactions and correlations between them. It will be
processes set in motion by fulminant infection may at times crucial to relate the outcome of canine babesiosis to the
be self-perpetuating, even when the parasites have been onset, magnitude and durations of SIRS and CARS (and
eliminated by treatment. It is clinically important to un- their elements). From the European point of view, it is
derstand that the proinflammatory state of the acute phase important to conduct these studies on B. canis. In addition,
response (SIRS) also initiates anti-inflammatory media- it will be important to conduct such studies in different
tors (compensatory anti-inflammatory response syndrome, European countries on patients with genetically charac-
CARS). The extent of the pro- and anti-inflammatory terized B. canis strains.
events should be balanced and proportional to the insult.
However, some factors (i.e. constitutional, genetic, and/or Acknowledgments
environmental) may generate an inadequate reaction Theo P. Schetters is Invited Professor at the Laboratoire de Biologie
Cellulaire et Moléculaire of the University of Montpellier 1, Montpellier
(over-reaction and under-reaction). The balance between
SIRS and CARS plays a crucial role in resolving the infec-
tion, but the pro- and anti-inflammatory mechanisms are References
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