Infectious Diseases of The Dog and Cat, 3rd Edition: CHAPTER 77 Babesiosis

Infectious Diseases of the Dog and Cat, 3rd Edition
CHAPTER 77 Babesiosis
Joseph Taboada
Remo Lobetti
Canine babesiosis (piroplasmosis) is an important worldwide, tickborne disease caused by hemoprotozoan parasites
of the genus Babesia.
82,138,141
Babesia organisms primarily cause erythrocyte destruction, and the severity of illness
can range from a relatively mild to a fatal disease. Although hemolytic anemia is the hallmark of infection, numerous
variations exist and complications involving multiple organs may develop.
ETIOLOGY
Babesia canis and Babesia gibsoni have been the two predominant species capable of naturally infecting a dog.
Strains of these organisms are found worldwide (Table 77-1). A small Babesia organism resembling B. gibsoni has
been described and may be a third species affecting dogs in California.
32,75
In Spain an organism resembling
Babesia microti and tentatively being described as Theileria annae has been described in dogs.
172,173
Babesia equi
has been isolated from dogs in Spain.
33
In cats, Babesia felis, Babesia cati, Babesia herpailuri, Babesia leo, and
Babesia pantherae have been reported (see Table 77-1).
82,141
Dogs
B. canis is a large (2.4 m 5 m), piriform-shape organism that exists singly or paired within erythrocytes
(Fig. 77-1, A). Its expansive geographic range includes most of southern Europe, Africa, Asia, North America,
Central America, and South America. Based on genetic, serologic, and cross-immunity studies, as well as
differences in pathogenicity and vectors, a trinomial nomenclature system for B. canis has been
proposed.
26,149,174
B. canis vogeli is the proposed name for the strain that is found in tropical and subtropical
regions of most continents and transmitted by the brown dog tick Rhipicephalus sanguineus. It is the least
pathogenic of the three strains and is the one found in the United States. B. canis canis is the name proposed for
the strain in Europe and parts of Asia. It intermediately pathogenic and transmitted by ticks of the Dermacentor
genus. B. canis rossi is the proposed name for the highly pathogenic strain that is found in South Africa and
transmitted by Heamaphysalis leachi. A large strain, a yet unclassified Babesia, was isolated from a dog with
hemolytic anemia, leukopenia, and thrombocytopenia.
14a
B. gibsoni is a small, pleomorphic (1 m 3.2 m) organism usually observed singly within erythrocytes (see
Fig. 77-1, B). Initially, it was found primarily in northern Africa and the southern parts of Asia but has now
been found in Australia, Europe, and the United States.
Other small Babesia species have been isolated from clinically ill dogs. The organisms were likely acquired
from ticks that fed on infected wildlife reservoirs. In the western United States an unnamed species similar to
the CA1 strain that infects people in the region causes hemolytic anemia in dogs.
75
Another unnamed species
closely related to B. microti or Theileria, tentatively named Theileria annae, was found in the Pyrenean region
of Spain.
172
A Spanish isolate of B. equi was identified in a dog.
33
77
77.1
77.1.1
CHAPTER 77 Babesiosis Page 1 of 29
Cats
Feline babesiosis has not been studied as extensively as the canine form.B. felis is a small, highly pathogenic
strain that infects domestic cats in southern Africa and the Sudan. Infection of domestic cats primarily has been
identified in the strip along the coast of South Africa.
68,119
The other small strain,B. cati, is less pathogenic and
found primarily in India. Genetic sequences of B. canis canis have been amplified from the blood of three cats
from Spain and Portugal
34
; however, no organisms were visualized. B. canis ssp. presentii was identified in two
cats in Israel.
9
The ill cat was coinfected with feline immunodeficiency virus (FIV) and Mycoplasma
haemominitum. No cases of feline babesiosis have been reported in the United States. B. herpailuri and B.
pantherae are large Babesia organisms of wild Felidae in Africa and have been transmitted experimentally to
the domestic cat.
82
A small piroplasm (B. leo) similar to but serologically distinct from B. felis was isolated
from lions (Panthera leo) in Kruger National Park.
92
EPIDEMIOLOGY
B. canis and B. gibsoni are the two species that cause canine babesiosis worldwide (see Table 77-1). B. canis canis
is transmitted by Dermacentor reticulatus in Europe, and B. canis vogeli is transmitted by R. sanguineus in many
temperate and tropical countries. B. canis rossi is transmitted by H. leachi in South Africa. Experimentally, B.
canis isolates have been transmitted by Dermacentor andersoni and Hyalomma marginatum.
40,82
In the United
States, canine babesiosis caused by B. canis vogeli is most common along the Gulf Coast and in the southern,
central, and southwestern states. Reported prevalence has ranged from 3.8% to 59%.
140
The seroprevalence is
higher in adult dogs than in dogs younger than 1 year.
15
In a serosurvey of dogs in Florida, 46% of 393
greyhounds were seropositive. The prevalence within kennels ranged from 17% to 100%; the lower prevalence
was noted in kennels with more intensive tick control. None of 50 adult pet dogs that were not greyhounds
surveyed were seropositive, implicating both environment and breed susceptibility as factors in determining
seroprevalence in endemic areas.
140
Outbreaks may occur and are often localized to a relatively small area or to a
kennel. Veterinarians in one practice may see affected dogs often, whereas neighboring practices in the same area
may not see any at all.
138
Transplacental transmission of B. canis infections is suspected but unproven.
47
725
77.1.2
77.2
Table 77-1 Common Babesia Species, Vectors, and Distribution
SPECIES
GEOGRAPHIC
DISTRIBUTION
TYPICAL
MORPHOLOGIC
CHARACTERISTICS
RECOGNIZED TICK
VECTORS CLINICAL FINDINGS
Canine
Babesia canis vogeli Africa, Asia, Central
America, South
America, North
America, northern and
central Europe, Australia,
Large (2.43 45 m),
single or paired piriform
bodies
Rhipicephalus
sanguineus, Hyalomma
plumbeum (?)
Mild disease with
inapparent clinical signs;
more severe in young
animals
B. canis canis Europe, foci in Asia Large (2.43 45 m),
bodies
Dermacentor reticulates Transient parasitemia
and organ congestion
B. canis rossi South Africa Large (2.43 45 m),
bodies
Haemaphysalis leachi Highly virulent
hemolytic or immune
disease
Babesia (large strain)
14a
North Carolina Large (2.55 m) Unknown Hemolytic anemia,
thrombocytopenia,
leukopenia
B. gibsoni (many strain
variants)
Asia, including Japan, Sri
Lanka, Malaysia, and
India; northern and
eastern Africa; Australia;
midwestern and eastern
United States; southern
Europe
Small (12 34 m),
usually single annular
bodies (signet rings)
b
Haemaphysalis
bispinosa?
a
R.
sanguineus?
a
Hemolytic anemia or
chronic subclinical
infection with weight
loss and debilitation
Small Babesia organisms California Small (1 2.5 m),
usually single;
occasional maltese
crosses
Unknown (suspect
wildlife reservoir)
Hemolytic anemia
B. microti-like (Theileria
annae)
c
Northwestern Spain Small (1 2.5 m),
usually single
Ixodes hexagonus?
(suspect wildlife
reservoir)
Severe hemolytic
anemia, some animals
develop renal failure
B. equi (Spain isolate 1) Spain Small (1 2.5 m)
usually single
Unknown Hemolytic anemia
Feline
d
B. felis Africa, southern Asia,
Europe
Small (0.9 0.7 m),
single or paired annular
bodies
Unknown Hemolytic anemia with
chronic course; seen in
domestic cats in South
Africa
B. herpailuri Africa, South America? Large (1 2.5 m),
bodies
Unknown Isolated from
jaguarundi (Herpailurus
yagurundi) in South
America
B. cati Indian subcontinent Small (1 1.5 m),
bodies
Unknown Isolated from Indian
wildcat (Felis catus)
B. canis ssp. presentii Israel Large (2.7 1.7 m)
round to oval or
ring-shape
Unknown Profound anemia and
icterus or
nonsymptomatic
Human
e
B. microti North America:
northeastern United
States and Great Lakes
region; Europe
Small, pleomorphic
bodies
North America: I.
scapularis; Europe: I.
trianguliceps, I. ricinus
Hemolytic anemia,
fever, chills, mild or
subclinical anemia
B. divergens Europe Small, pleomorphic
bodies
I. ricinus Hemolytic anemia, more
severe than B. microti,
often in those that have
had a splenectomy
B. divergens like North America:
Washington state,
Missouri (MO1),
Kentucky
Small, pleomorphic
bodies, high-level
parasitemia
Unknown Hemolytic anemia, more
severe than B microti,
often in those that have
had a splenectomy
B. odocoilei-like (EU1) Austria, Italy Small, pleomorphic
bodies, occasional
maltese crosses
Unknown Fever, hemolytic anemia
in those that have had a
splenectomysplenectomy
B. gibsoni-like (CA1
CA4)
North America:
California
Ring forms and tetrads Dermacentor? (identical
isolates from deer and
bighorn sheep)
Hemolytic anemia
severe if
immunosuppressed or
have had a splenectomy
B. gibsoni-like, WA-1,
CA5 CA6
North America:
Washington state,
California
Ring forms and tetrads Dermacentor? (only
infects hamsters, not
dogs)
145
Hemolytic anemia
?, Association as a tick vector has not been proved but is suspected.
a Definitive studies identifying vectors for B. gibsoni have not been published; most evidence is
circumstantial.
b Some B. gibsoni isolates are larger and have a heterogenous appearance resembling B. canis, so PCR
testing gives the most reliable differentiation.
c Theileria annae has been proposed as a new name for this organism.
23,172
d Also includes B. pantherae, which has been isolated from a leopard cat (Panthera pardus) in Kenya,
and a small piroplasm that has been isolated from lions (Panthera leo) in the Kruger National Park,
South Africa.
92
e People are thought to be accidental hosts for babesias of reservoir animal hosts (e.g., B. microti
[rodents], B. divergens [cattle]).
Fig 77-1 Blood smears from dog with babesiosis. A, Pair of large, piriform-shape
merozoites of B. canis within erythrocytes. B, Individual merozoites of B.
gibsoni in erythrocytes (Wright stain, 1000). (Courtesy Ken Latimer,
University of Georgia, Athens, Ga.)
Infections with B. gibsoni occur throughout the world, and the insidious nature of this infection has allowed the
inadvertent transport of the organism from Asia to other areas. Definitive proof identifying the vectors in this
infection is lacking. In its original endemic area of Asia, the geographic range of B. gibsoni correlated with that of
the suspected vector ticks, Haemaphysalis bispinosa, and R. sanguineus.
82
Haemaphysalis longicornis and H.
leachi were also incriminated in some areas. Most of the isolations have been from dogs in the eastern and
midwestern regions of the United States. Transmission studies proving vector competence for both R. sanguineus
and Dermacentor variabilis, both of which are found in the United States, have been unsuccessful or
inconclusive.
167
Various stages of the parasite were found in the salivary glands of engorged R. sanguineus;
however, infection could not be transovarially or transstadially transmitted to other dogs.
167
Infections with B. gibsoni occur sporadically in the United States, most often in American Staffordshire and
American pit bull terriers or dogs that have been in fights with them.
10,13,60,93
The identified strains are those
likely imported from Asian countries. American pit bull terriers in Australia have also been found to have the
imported infections,
70,108
and isolated infections have been reported in Europe.
157
Although seroprevalence shows
exposure to B. gibsoni to be highest in adult dogs, those younger than 1 year are most susceptible to clinical
illness.
63
Because pups and many dogs within the same breed are infected, transmission from dam to offspring is
suspected, although an exact mode of transmission is uncertain. Dogs younger than 2 months may be protected by
maternal antibodies. Younger age is not a significant factor in the severity of clinical disease caused by B. gibsoni.
In kennels where B. gibsoni infections have been problematic, nonvector transmission is suspected. The high
prevalence of babesiosis among American pit bull terriers in many countries is likely a result of breed
susceptibility and environmental factors that lead to extensive exposure to vector ticks.
10,93
In addition, fighting
may play a role in transmissionthrough bite wounds and intermingling of blood, through saliva, or through
ingested blood.
10,98
Dogs who became infected after fighting with infected dogs developed clinical signs of illness
within 2 weeks. Sharing instruments for surgery, such as those used for tail docking, and reusing needles for
vaccinations can result in transmission of all Babesia species. However, transmission via fomites has not been
documented in the previously mentioned kennels, so fighting is still considered the most likely mechanism of
infection.
Small-strain (CA1) organisms reported in California infect various dog breeds in different housing situations, and
older dogs have a greater prevalence of seropositivity.
166
The parasite most closely resembles Babesia isolated
from mule deer (Odocoileus hemionus) and bighorn sheep (Ovis canadensis nelsoni) in the western United
States.
75
It was also similar to the WA1-type strains, which have been isolated from people in the western United
States.
75,120,121
Babesial developmental stages have been detected in R. sanguineus; however, transmission has
not been shown.
167
The previously mentioned Spanish isolate of Babesia (tentatively classified as T. annae) is closely related to B.
felis, B. microti, and isolates from wild felids in Africa.
75,92,172
Based on ticks collected from infected dogs, Ixodes
hexagonus is the suspected principal vector.
25
The characteristic geographic ranges established for the various Babesia species is based on close vector
relationships. Because of the international transport of dogs and cats, new infections may be reported any time
they are identified in new areas. In addition, exposure of these infected animals to vectors in new regions may
allow the infection to become established in new vectors and hosts. Furthermore, people and animals are
becoming exposed to new pathogens as they settle and reproduce in new environments in which sylvatic cycles
between vectors and their reservoir hosts exist. This has been apparent with the increasing number of new isolates
of Babesia in people and animals.
Babesias are transmitted through the bite of infected ixodid ticks (Fig. 77-2). The adult female tick is most
important in transmission, but with B. canis, all stages of the tick are likely to be infected.
40
Of the Babesia
organisms that are not transmitted transovarially, larvae are not infected. Once in the host, Babesia species attach
to the erythrocyte membrane and are engulfed by endocytosis.
58
Once in the erythrocyte, the red blood cell
membrane that surrounds the parasite disintegrates, and all subsequent stages are in direct contact with the host
cell cytoplasm. B. canis multiplies within the erythrocytes by repeated binary fission, creating merozoites. As
many as 16 merozoites of B. canis may be seen in a single erythrocyte, but they most commonly exist singly or in
pairs. Ticks are infected by ingesting merozoites during feeding. A complex life cycle involving transtadial and
transovarial transmission results in sporozoite formation in cells of the tick's salivary glands.
40,58
When infected
ticks feed, the sporozoites are passed with saliva into the circulation of the host. The tick must feed a minimum of
2 to 3 days for transmission of B. canis to occur.
96
Several differences in life cycles have been identified in non-B. canis infections. Transovarial transmission in ticks
is not a feature of B. gibsoni infections. Furthermore, the California strain of Babesia replicates into tetrads or
Maltese crosses and does not undergo binary fission.
PATHOGENESIS
The pathogenic sequence of events in babesiosis is summarized in Fig. 77-3. After infection, a significant host
immune response usually is generated. The immune system does not appear able to completely eliminate the
77.3
infection, and animals that recover are usually chronic carriers of the parasite. Poor humoral immune response is
common in pups younger than 8 months. Transplacental transmission of B. canis is likely and may result in weak
or fading puppies.
20,47,139
In one instance, B. canis infection was diagnosed in a 36-hour-old greyhound pup that
was born to a seropositive bitch. The pup's hematocrit (HCT) was lower than the levels of its four littermates.
139
The pathogenicity of Babesia organisms is determined primarily by the species and strain involved.
125,149,163
Host
factors, such as the age of the host and the immunologic response generated against the parasite or vector tick, are
also important.
151
Infected erythrocytes incorporate parasite antigens into their surface and induce antibodies in
the host that opsonize the erythrocytes, which leads to removal of infected erythrocytes by the
mononuclear-phagocyte system. Splenectomy makes the anemia and parasitemia more severe.
24
725
727
Fig 77-2 Life cycle of B. canis. A, Sporozoites of the organism enter the blood
following tick feeding, and infect erythrocytes by focal host erythrocyte
membrane invagination and dissolution. B, The organisms differentiate
into merozoites, and then (C) pleomorphic trophozoites (forms). These
divide within erythrocytes by binary fission causing eventual cell lysis.
The asexual reproduction (merogony) also produces more merozoites
(D) which infect new erythrocytes. If infected erythrocytes are ingested
by ticks (E), organisms appear in the tick gut about 10 hours after
feeding. F, They differentiate into gametes which penetrate the tick gut
epithelium fuse to form a zygote. G, The zygote penetrates the gut,
enters the hemolymph, and migrates to the salivary gland tissue. H,
Sporozoite replication occurs within the salivary gland and cells become
filled and they eventually bud from the surface epithelium into the tick's
saliva. (Courtesy University of Georgia, Athens, Ga.)
Fig 77-3 Proposed pathogenesis of canine babesiosis.
Two syndromes, one characterized by hemolytic anemia and the other by multiple-organ dysfunction syndrome
(MODS), account for most of the clinical signs observed in animals with babesiosis (see Fig. 77-2).
62,63
MODS
has primarily been associated with the most pathogenic B. canis rossi infections found in South Africa and often
causes intravascular hemolysis. Parasitemia results in osmotically fragile erythrocytes, hemolysis, and subsequent
anemia.
94
However, the severity of anemia is not proportional to the low degree of parasitemia usually observed.
Direct parasitic damage contributes to the anemia. However, induction of serum hemolytic factors, increased
erythrophagocytic activity of macrophages, and damage induced by the secondary immune system after formation
of antierythrocyte membrane antibodies are also important to the pathogenesis.
3-5,107,109,111,112
Serum from
infected dogs inhibits erythrocyte 5-nucleosidase, which can lead to the accumulation of cyclic nucleotides and
may contribute to erythrocyte damage.
56
Oxidative stress is another possible cause of damage to erythrocytes that
also results in increased susceptibility to phagocytosis.
110
Increased production of superoxide has been
demonstrated in erythrocytes infected with B. gibsoni, which may relate to oxidative damage from lipid
peroxidation.
114
Increased urinary methemoglobinemia levels have been found in dogs with naturally occurring B.
canis infections.
90
Lipid peroxidation occurring during Babesia infection increases rigidity of parasitized and
nonparasitized erythrocytes and slows their passage through capillary beds. Soluble parasite proteases activate the
kallikrein system and induce fibrinogen-like protein (FLP) formation. The FLPs make erythrocytes more sticky,
leading to additional erythrocytes sludging in the capillaries. Vascular stasis from sludging of parasitized cells and
erythrocyte stroma within capillary beds is thought to contribute to the acute anemia and many of the other
potential clinical signs. The most severe sludging appears to occur in the central nervous system (CNS) and
muscles.
163
Rhabdomyolysis and acute renal failure have been complications of babesiosis.
64,91
Thrombocytopenia alone is observed in many cases of babesiosis and may relate to immune or coagulatory
consumption of platelets from hemolytic or vascular injury. Abnormal coagulation results are not found in many
dogs.
45
However, overt disseminated intravascular coagulation (DIC) can be a devastating complication of the
severe forms of canine babesiosis caused by B. canis rossi. Babesia proteases may induce increases in plasma
kallikrein levels, which can activate the intrinsic cascade at factor XII. Thrombocytopenia is common, especially
in dogs infected with B. gibsoni. This condition can be a result of DIC but is also likely a result of
immune-mediated platelet destruction. Membranoproliferative glomerulonephritis is seen in some infected dogs
and may have an immune-mediated pathogenesis.
Tissue hypoxia is an important contributor to many of the clinical signs caused by the most pathogenic Babesia
strains. Causes of hypoxia include anemia, shock, vascular stasis, excessive endogenous production of carbon
monoxide, parasitic damage to hemoglobin, and decreased ability of hemoglobin to offload oxygen from
Babesia-infected dogs.
63,90
Hypoxia appears to be more important than hemoglobinuria in damaging the kidneys
of experimentally infected dogs.
91
Lactic acid generation from tissue hypoxia is considered the main reason for
metabolic acidosis that develops in animals with babesiosis.
84
Respiratory alkalosis results partly from
compensation but more directly from hyperventilation caused by hypoxemia.
Many atypical signs or complications can develop in animals with babesiosis, especially if caused by B. canis
rossi infection; they cannot be directly explained by hemolysis but appear to be the result of the host inflammatory
response. The resultant tissue damage probably causes the release of cytokines, which would be expected to
support widespread inflammation and additional damage to multiple organs.
63
MODS complications resulting
from the so-called systemic inflammatory response syndrome (SIRS) have been acute renal failure, hepatopathy,
immune-mediated hemolysis, pulmonary edema, rhabdomyolysis, and cerebral dysfunction.
160
Pulmonary, CNS,
and renal complications were associated with a higher rate of mortality.
CLINICAL FINDINGS
Dogs
General Features
Babesiosis may have a hyperacute, an acute, a chronic, or a subclinical course (Table 77-2). Acute disease
characterized by fever and lethargy, and acute anemia is the most common clinical syndrome, whereas the
hyperacute presentation characterized by extensive tissue damage is rare.
32,38
B. canis rossi, prevalent in
South Africa, is highly virulent and causes a hemolytic anemia or an acute overwhelming inflammatory
response.
124
B. canis canis results in a low-level parasitemia (less than 1%), and clinical disease is associated
with congestion of organs of the mononuclear phagocyte system.
127
B. canis vogeli results in mild clinical
disease, generally without overt signs.
727
728
77.4
77.4.1
77.4.1.1
Acute clinical signs are typical of initial infections with B. gibsoni and the more virulent strains of B.
canis.
19,32
Acute disease is characterized by anorexia, hemolytic anemia, thrombocytopenia,
lymphadenomegaly, and splenomegaly.
2,61,63
Anorexia, lethargy, fever, and vomiting are also common.
Fatalities may occur, especially in puppies and occasionally in B. gibsoni-infected adults, but most animals
with this acute disease recover with treatment. Hematuria and icterus may be noted, especially in B.
canis-infected dogs. The acute presentation is most typical of B. gibsoni infections encountered in Asia and
the United States and B. canis infections encountered in Africa, Australia, and southern Europe.
Immune-mediated hemolytic anemia (IMHA) and systemic lupus erythematosus are the primary diseases that
must be differentiated from this form of babesiosis.
Chronic manifestations of B. canis infection are poorly characterized.
63
Most infected dogs with B. canis
vogeli in the United States are subclinical carriers.
140
Low-grade or subclinical manifestations can also be
seen with certain strains and more commonly with B. gibsoni infections.
Specific Clinical Features
B. canis rossi in South Africa
B. canis rossi is the most virulent form of canine babesiosis. Two general and severe manifestations have
been described.
124
Clinical disease is often correlated with the degree of parasitemia.
127

Thrombocytopenia is a consistent finding in babesiosis and may be considered a screening test.
73
Severely
anemic dogs had hypoxic hepatic disease and increased concentrations of serum urea without creatinine.
Nonanemic dogs had severe azotemia and electrolyte disturbances. Hypoglycemia was a common finding
in virulent canine babesiosis and was common in dogs with mental depression or other neurologic signs.
72

As with B. gibsoni infections, fighting breeds such as bull terriers, American pit bull terriers, and
Staffordshire bull terriers had a higher prevalence of B. canis rossi infections, with high mortality
indicating increased susceptibility to or greater exposure risk of babesiosis.
77.4.1.2
77.4.1.2.1
Table 77-2 Clinical Findings in Dogs with Babesiosis
138
SPECTRUM DURATION
Nonspecific Signs Hyperacute Symptoms
Anorexia Hypothermia
Lethargy Shock
Weakness Coma
Pyrexia Disseminated intravascular coagulation
Weight loss
Atypical Signs Metabolic acidosis
Ascites Death
Edema Acute Symptoms
Constipation Hemolytic anemia
Diarrhea Icterus
Ulcerative stomatitis Splenomegaly
Hemorrhage Lymphadenopathy
Congested mucous membranes Vomiting
Chronic Symptoms
Polycythemia Intermittent pyrexia
Ocular and nasal discharge Partial anorexia
Respiratory distress Loss of body condition
Masticatory myositis Lymphadenopathy
Temporomandibular joint pain
Back pain
CNS signs
Seizures
Ataxia
Paresis
B. canis vogeli in greyhounds in the United States
The prevalence of babesiosis among greyhounds in the United States is high.
140
The likely organism
affecting greyhounds is the Gulf Coast strain of B. canis vogeli, which rarely causes clinical disease in
adults. No evidence suggests that these dogs are more susceptible than other breeds after experimental
inoculation.
31
B. gibsoni in Asia, Africa, Europe, the United States, and Australia
Typical clinical signs of B. gibsoni infection are intermittent fever, pale mucous membranes (Fig. 77-4),
decreased appetite, and marked loss of body condition.
27
A low-grade or compensated hemolytic anemia
and variable thrombocytopenia may be observed with laboratory testing. The chronic form of the disease
has been frequently observed, especially in the United States. Dogs develop mild fever, pale mucous
membranes, splenomegaly (Fig. 77-5), hepatomegaly, lymphadenomegaly, and lethargy without many of
the complicating factors associated with other Babesia infections.
101
728
729
77.4.1.2.2
77.4.1.2.3
Fig 77-4 Pale mucous membranes of pit bull dog with B. gibsoni infection.
(Courtesy University of Georgia, Athens, Ga.)
Fig 77-5 Ultrasonographic appearance of spleen from dog with B. gibsoni
infection. (Courtesy University of Georgia, Athens, Ga.)
California isolate
Clinical signs of dogs affected by the California Babesia isolate have included lethargy, vomiting,
elevated rectal temperature, and pale mucous membranes caused by anemia.
32
Most infected animals have
developed acute severe hemolytic anemia and accompanying thrombocytopenia.
Spanish isolate
In Spain, disease caused by the B. microti-like agent (and being called T. annae) is associated with pale
mucosae, weakness, hemoglobinuria, tachycardia, tachypnea, and elevated rectal temperature caused by
regenerative hemolytic anemia and thrombocytopenia that in some cases was accompanied by renal
failure.
23,24,46,172
In animals with renal failure, nonregenerative anemia, azotemia, and proteinuria with
high urine protein/creatinine ratios was found.
22
Uncomplicated Babesiosis
Canine babesiosis can be classified clinically as uncomplicated or complicated. The course and severity of
the disease depends on the virulence of the infecting organism and the host's immunocompetency.
Coinfections with other organisms can create a confusing clinical illness and cause immunosuppression.
147
Animals with uncomplicated babesiosis typically have clinical signs relating to acute hemolysis, including
fever, anorexia, depression, pale mucous membranes, splenomegaly, and water-hammer pulse. This form can
be further classified as mild, moderate, or severe according to the severity of the anemia. Mild,
uncomplicated babesiosis case can progress to become severe complicated babesiosis with life-threatening
anemia.
Complicated Babesiosis
The clinical manifestations of complicated babesiosis are not easily explained by the hemolytic disease
process. The development of many clinical or laboratory abnormalities often correlates with a greater degree
of parasitemia. Rare complications include gastrointestinal (GI) disturbances, myalgia, ocular involvement,
upper respiratory signs, cardiac involvement, necrosis of the extremities, fluid accumulation, and the chronic
form of the disease. Overlap among the different categories of the complications can also occur.
Complications are most frequently reported in B. canis rossi infections in dogs from South Africa.
Acute renal failure
Acute renal failure (ARF) associated with babesiosis typically includes symptoms of anuria or oliguria
despite adequate rehydration but is an uncommon complication. Evidence of renal damage, reflected on
urinalysis by the presence of proteinuria, casts, and renal tubular epithelial cells, is common in
complicated and uncomplicated cases but does not necessarily predict renal failure. An elevated serum
urea alone is an unreliable indicator of renal insufficiency in animals with babesiosis, as a
disproportionate rise in urea (compared with creatinine) has been related to catabolism of lysed
erythrocytes.
35a
Renal failure is diagnosed on the basis of ongoing evaluation of urine volume, urinalysis,
and degree of azotemia.
77.4.1.2.4
77.4.1.2.5
77.4.1.3
77.4.1.4
77.4.1.4.1
Acute intrinsic renal impairment without overt ARF occurs in humans with malariaa clinical picture
very similar to canine babesiosis. Renal tubular epithelial and other cells in the urine sediment, enzymuria,
proteinuria, and variable azotemia have been observed in dogs with B. canis rossi infections.
91
ARF was
also documented in numerous dogs in the same study.
Cerebral babesiosis
Cerebral babesiosis is defined as the concurrent presence of neurologic signs in an animal with babesiosis.
The signs, typical of peracute onset, include a combination of incoordination, hind-quarter paresis, muscle
tremors, nystagmus, anisocoria, intermittent loss of consciousness, seizures, stupor, coma, aggression,
paddling, or voca-lization.
63
Pathologic changes in the brain are congestion, macroscopic and microscopic
hemorrhages, sequestration of parasitized erythrocytes in capillary beds, and pavementing of parasitized
cells against the endothelium.
Coagulopathy
The most consistent hemostatic abnormality in babesiosis is profound thrombocytopenia, which is a
routine finding in complicated and uncomplicated cases, but clinically apparent hemorrhages are
relatively rare. DIC has been reported in animals with babesiosis; however, confirmation of DIC in
animals with babesiosis is difficult because of the nature of the underlying disease process and the
reported unreliability of the human fibrin degradation product test.
63
Clinical signs of DIC are difficult to
recognize until hemorrhages develop in the hypocoagulable phase. In the hypercoagulable phase, signs are
related to microthrombi-induced organ dysfunction.
Icterus and hepatopathy
In some cases of babesiosis, icterus, elevated liver enzyme levels, and elevated bile acid levels develop,
which indicate a liver insult.
102
Whether the insult is caused by inflammatory cytokines, hypoxic damage,
or a combination of these is not known. Icterus does not solely appear to be caused by hemolysis or
hepatic obstruction. Therefore liver dysfunction appears to be at least contributory. Histologic changes
usually associated with icterus include diffuse and periportal lesions, whereas icteric dogs with babesiosis
have a centrilobular lesion. However, it is possible that the liver has a diffuse, mild or moderate lesion that
does not cause histologic changes but is severe enough to cause a functional change. Hypoxic insults are
known to cause diffuse hepatocellular swelling, thus the hypoxia in severe babesiosis may be severe
enough to cause a transient hepatopathy.
Immune-mediated hemolytic anemia
Immune-mediated hemolysis is an increased destruction of erythrocytes caused by erythrocyte-membrane
associated antibodies. This destruction can either be primary, in which the membrane is normal, or
secondary, in which the membrane is altered and recognized as foreign. Secondary destruction is assumed
to occur in babesiosis.
146
The cardinal feature of babesiosis-associated IMHA is continuing hemolysis
despite successful antibabesial treatment. Diagnosis is confirmed by finding autoagglutination with saline
dilution of blood, detection of spherocytosis, or both. The Coombs test cannot be used to confirm a
diagnosis because uncomplicated cases and cases complicated with IMHA have a positive test result.
729
730
77.4.1.4.2
77.4.1.4.3
77.4.1.4.4
77.4.1.4.5
Acute respiratory distress syndrome
Acute respiratory distress syndrome (ARDS) is a severe and frequent catastrophic complication of
babesiosis. Typical clinical signs are a sudden increase in respiratory rate (which may be caused by other
factors, such as pyrexia and acidosis), dyspnea, moist cough, and blood-tinged frothy nasal discharge. The
diagnosis of ARDS is based on the presence of diffuse pulmonary infiltrates on thoracic radiography,
hypoxemia from ventilation-perfusion mismatch, normal pulmonary capillary wedge pressure, and
reduced pulmonary compliance.
39
In most clinical situations, pulmonary wedge pressure, blood-gas
analysis, and compliance cannot be measured. Thus diagnosis depends on the recognition of risk factors
for ARDS, thoracic radiographs, and exclusion of other causes of pulmonary edema, particularly
cardiogenic causes and fluid overload. Excluding fluid overload is particularly important in animals with
oliguric renal failure. Fluid loads that can be tolerated by normal dogs may fatally exacerbate pulmonary
edema in ARDS.
Hemoconcentration
The paradoxical phenomenon of severe intravascular hemolysis combined with hemoconcentration
constitutes the syndrome red biliary. The clinical features are congested mucous membranes, visible
hemoglobinemia, hemoglobinuria, or all of these and high-normal or elevated hematocrit levels.
63

Hemoconcentration has been associated with other complications, such as cerebral babesiosis, DIC, ARF,
and ARDS. Hemoconcentration in babesiosis is thought to be a result of reduction in blood volume as a
result of fluid shifts from the vascular to the extravascular compartment. Because plasma protein
concentrations are normal, plasmarather than a filtrate of plasmashifts from the vasculature. The
widespread increase in capillary permeability, which occurs in SIRS, may play an important role in the
pathogenesis. Concurrent hypoalbuminemia may relate to a loss of albumin into the interstitium because
of lost endothelial integrity associated with SIRS.
Hypotension
Dogs with severe and complicated babesiosis are frequently in a state of collapse and clinical shock.
Shock can resemble the hyperdynamic phase of septic shock. In a study, it was shown that hypotension
occurs frequently in dogs with babesiosis, and the presence and severity of hypotension increases with
increased disease severity.
66
The presence of hypotension in a large proportion of dogs with complicated
babesiosis is consistent with the hypothesis that inflammatory mechanisms play a major role in this
disease and can result in a sepsislike state. It is likely that hypotension in animals with babesiosis is a
combination of vasodilation, reduced vascular volume caused by increased vascular permeability,
dehydration, or all of these and myocardial depression. Hypotension can play a role in the
pathophysiologic symptoms of the disease because it has been hypothesized to facilitate parasite
sequestration.
Cardiac changes
In one study, dogs with complicated and concurrent IMHA-babesiosis had significantly higher cardiac
troponin I and T concentrations.
87
In this study, dogs with babesiosis developed important
electrocardiogram (ECG) changes such as heart blocks, ventricular premature complexes (VPCs), and
77.4.1.4.6
77.4.1.4.7
77.4.1.4.8
77.4.1.4.9
prolonged QRS changes and ST segment changes. However, most of the changes were not associated with
severity, outcome, and cardiac troponin levels. The exception was the presence of VPCs because a
correlation was found between troponin concentrations and VPCs. Cardiac histologic changes reported in
the study were hemorrhage, necrosis, inflammatory infiltrate, and fibrosis.
Acute pancreatitis
A retrospective study reported acute pancreatitis as a complication of canine babesiosis.
103
In this study,
four dogs had histologic evidence of pancreatitis, and another 16 dogs had serum amylase elevations,
lipase activity elevations, or both of a magnitude that supported a diagnosis of acute pancreatitis. The
median time of pancreatitis diagnosis was 2.5 days postadmission, with primarily young (a median age 3
years), sexually intact dogs being affected. The development of pancreatitis was unrelated to the degree of
anemia at time of admission. In addition to pancreatitis, 80% of dogs had other babesial complications,
namely icterus, ARDS, IMHA, renal failure, hemoconcentration, and cerebral syndrome. Acute
pancreatitis may represent the previously reported gut form of babesiosis.
Acid-base disturbances
Dogs with severe B. canis rossi infection have an arterial pH that varies from acidemia to alkalemia.
84
A
high anion gap metabolic acidosis is present in many dogs, whereas almost all have concurrent metabolic
acidosis and respiratory alkalosis. The severity of these abnormalities could not be linked to clinical
outcome.
Subclinical Infections
Subclinically infected dogs are common in certain populations.
98c
Greyhounds in the United States have a
very high seroprevalence of disease, but adult dogs rarely show clinical signs. Likewise, American pit bull
terriers appear to have a high prevalence of infection based on polymerase chain reaction (PCR) studies.
93
B.
canis parasites are rarely found on blood smears from asymptomatic carriers, making identification of this
group of dogs difficult without performing serologic screening tests or PCR. A slightly higher likelihood of
finding B. gibsoni on blood smears from asymptomatic American pit bull terriers exists if the clinician
examines the smears very thoroughly. However, serology and PCR are also more sensitive screening tools in
this population of dogs. The primary importance of this group of dogs may be in their role as a potential
source of infection to susceptible puppies in breeding colonies or as a source of infection through blood
transfusion or fighting.
38,140
Babesiosis can be a significant and underdiagnosed cause of morbidity and
mortality of puppies from breeding colonies located in endemic areas. The seroprevalence among adults in
affected kennels often is higher than 75% and can serve as a serologic marker for the disease. In comparison,
the seroprevalences are typically less than 20% in well-managed kennels from endemic areas where anemic
puppies are less likely to be encountered.
140
Most subclinical carriers never show clinical signs of
babesiosis; however, although rare, they may have symptoms when subjected to stress or treated with
glucocorticoids.
19,97
Cats
The reports of clinical infection in domestic cats have been predominantly from South Africa. Cats with
naturally occurring babesiosis usually are younger than 3 years and have no breed or sex predilection. Affected
730
731
77.4.1.4.10
77.4.1.4.11
77.4.1.5
77.4.2
cats generally have lethargy, anorexia, weakness, a rough hair coat, or diarrhea.
68
Fever and icterus are less
common. Anemia can be severe and is the underlying reason for the clinical signs. The disease is chronic, and
signs may not be apparent until a later stage of illness. Cats usually adapt to the anemia and may have only mild
clinical signs until they experience the stress of a physical examination or diagnostic evaluation.
104

Complications of the hemolytic anemia included hepatopathy, pulmonary edema, renal failure, CNS signs, and
concurrent infections.
DIAGNOSIS
Clinical Laboratory Findings
Dogs
The primary differential diagnoses for acute uncomplicated babesiosis are hemolytic states such as parasitic,
immune-mediated, oxidative, and traumatic insults to erythrocytes and GI hemorrhage mimicking a
hemolytic anemia. The clinical pathologic changes are nonspecific; the primary hematologic abnormalities
are anemia and thrombocytopenia.
2,61,99,113
The prevalence of thrombocytopenia is higher than that in dogs
with ehrlichiosis. A mild, normocytic, normochromic anemia is generally noted in the first few days after
infection, and the anemia then becomes macrocytic, hypochromic, and regenerative as the disease
progresses. The reticulocytosis is proportional to the severity of the anemia. Uncommonly, a relative
polycythemia with normal plasma protein concentration may be noted.
63
Leukocyte abnormalities are
inconsistently observed but may include leukocytosis, neutrophilia, neutropenia, lymphocytosis, and
eosinophilia.
61,113
A leukemoid response similar to that in cases of IMHA is occasionally seen.
86

Autoagglutination of erythrocytes in saline was noted in 21% of 134 dogs with babesiosis in one study, and
almost 85% of infected dogs were positive on direct antiglobulin (Coombs) test in another, making it
difficult to differentiate the disease from IMHA if organisms are not apparent.
63
Thrombocytopenia is
generally a feature of canine babesiosis, regardless of whether concurrent anemia is present.
147
Serum chemistry values are usually normal. Hypokalemia may be found in severely affected animals but is
probably nonspecific because of decreased potassium intake. Hyperkalemia and hypoglycemia were noted in
severely affected animals in one study.
61
Dogs with mild and severe babesiosis have low total serum protein
and albumin levels, albumin/globulin ratios, and -globulin levels. They also have an acute-phase response
characterized by elevated 1-acid glycoproteins.
89
A study of dual infections with B. canis and Ehrlichia
canis showed that the prevalence of hyperglobulinemia was higher in dogs with dual infections than in dogs
infected with a single infection caused by either organism.
99
Azotemia and metabolic acidosis are common
in animals with severe intravascular hemolysis and appear to contribute to morbidity and mortality. More
severely affected animals have high serum transaminase and alkaline phosphatase activity and increased
serum bilirubin levels. Hyperbilirubinemia is a consistent finding during acute disease caused by B. canis
strains but not by B. gibsoni.
61,156
Liver enzyme activity may be increased during severe disease. Urinalysis
may reveal bilirubinuria, hemoglobinuria, proteinuria, and granular casts. In B. canis rossi infections in
anemic South African dogs, animals can develop hypoxic hepatic disease with an increased serum urea and
profound leukocytosis with a left shift.
124
Nonanemic dogs may have severe azotemia, marked electrolyte
changes, and in some cases, leukopenia.
77.5
77.5.1
77.5.1.1
Cats
In feline babesiosis, which is caused by B. felis, the anemia is typically macrocytic, hypochromic, and
regenerative.
130
No characteristic change in total or differential leukocyte counts occurs, and thrombocytopenia
is an inconsistent finding. The in-saline agglutination test may also be positive.
130
Cats infected with B. felis typically have elevated hepatic cytosol enzyme activity and total bilirubin
concentrations. Serum protein values are primarily normal, but polyclonal hyperglobulinemia can occur. Renal
parameters are unaffected. Although various electrolyte abnormalities were reported, no consistent pattern was
found.
130
Microscopic Identification
The definitive diagnosis of babesiosis depends on demonstration of organisms within infected erythrocytes,
amplification of babesial DNA extracted from infected blood or tissue, or positive serology results. B. canis are
large, piriform-shape organisms and usually exist singly or in pairs (see Fig. 77-1, A), whereas smaller single
intracellular organisms are likely to be B. gibsoni (see Fig. 77-1, B). Parasitemia is often low, especially in B.
canisinfected dogs, making thorough examination of thin blood smears necessary. With B. canis infections,
blood collected from the peripheral capillary beds of the ear tip or nail bed may yield higher numbers of
parasitized cells.
61
Erythrocytes adjacent to the buffy coat of centrifuged specimens are also more likely to be
infected because the organism favors reticulocytes that have higher levels of nucleic acids, amino acids, and
adenosine triphosphate (ATP) and lower levels of glutathione.
169,170
Occasionally, phagocytized organisms and
erythrocyte fragments are seen in neutrophils. Although the organisms within erythrocytes may be numerous in
some acutely infected animals, they are rarely evident in chronically infected or asymptomatic carriers.
Evaluation of stained slides can be tedious and requires a significant time commitment on the part of the
laboratory technician. Flow cytometric techniques correlate closely with conventional light microscopic
techniques for identification of Babesia-parasitized erythrocytes and degree of reticulocytosis.
9b,41,148
In
addition, the methods of concentrating and staining of buffy coat improve the sensitivity of parasite
detection.
100
Electron microscopy can also be used by research laboratories to better characterize the
parasite.
122
Serologic Testing
Because of the difficulties in detecting Babesia parasites, especially in chronic carriers, immunodiagnostics
may be used to screen for infected hosts. Serodiagnostics have proved reliable as a method of indirect parasite
detection in either patent or occult infections that have been present long enough for an immune response to be
generated.
123,158
For canine babesiosis, the indirect fluorescent antibody (FA) test is probably the most specific
and most commonly used test for detection of babesial antibody.
123
Although laboratory methods differ,
generally titers to B. canis that are greater than or equal to 1:80 on a single sample are sufficient for diagnosis.
A cut-off titer of 1:320 or greater has been established for incriminating B. gibsoni infection.
168
A titer level of
1:1280 or greater has been considered as the cut-off to increase certainty for incrimination of infection in some
serologic studies.
168
Titers to multiple species must be measured if serology is performed in geographic areas
where more than one type of Babesia infection exist. Cross-reactivity between B. canis and B. gibsoni make
parasite identification or PCR necessary to differentiate between the two species. However, very young dogs or
731
732
77.5.2
77.5.3
77.5.4
dogs tested early in the disease course may be serologically negative, making it necessary to evaluate
convalescing serum in some cases.
15
Antibodies were not detected in 36% of dogs with B. canis parasitemia in
one study.
15
Enzyme-linked immunosorbent assay (ELISA) and dot-ELISA techniques for antibody detection
have been developed. ELISA results are much more sensitive and less specific than those from indirect FA.
ELISA testing is used more for seroepidemiologic studies than clinical diagnosis.
15,123,156a
Using some tests
based on whole-cell antigens, dogs infected with B. gibsoni may have false-positive serologic test results for
Toxoplasma gondii and Neospora caninum as well as for B. canis, especially at lower serum titers
168

Recombinant-produced P50 protein ELISA testing has been more specific for B. gibsoni infection than
immunoblotting and indirect FA testing.
42,156a
Nucleic Acid Detection
Because organisms vary or are infrequent in blood smears, genetic methods are the most sensitive and specific
means of detecting infection. Genus-specific screening for Babesia can be performed by PCR of DNA extracted
from blood samples.
7,44
Species identification can then be accomplished by comparing small subunit (SSU)
ribosomal RNA (rRNA) gene sequences found with known sequences of B. gibsoni and B.
canis.
37a,58b,115a,76,135
Use of a seminested PCR allows for detection and differentiation of B. gibsoni and B.
canis DNA in blood.
11
PCR has been used to identify a third Babesia species endemic to the western portion of
the United States,
76,93
a new strain from a dog in North Carolina,
14a
and another species from northwestern
Spain.
172
PCR also detected an organism similar to Babesia odocoilei and Babesia divergens in ticks from dogs
in Japan.
59
PATHOLOGIC FINDINGS
Pathologic findings include staining of tissues with hemoglobin or bilirubin, hepatosplenomegaly,
lymphadenopathy, and kidneys that are a dark-reddish color.
150
Edema and hemorrhage, which may indicate
vascular injury and poor tissue oxygenation in severely affected dogs, are often most severe in the lungs. Large
numbers of parasitized erythrocytes may be noted in capillary beds, especially in the brain (Fig. 77-6).
Nonparasitized cells often line the endothelial surface with parasitized cells sludged in the lumen. Microthrombi of
many tissues may be evident in animals exhibiting signs of DIC. Large numbers of parasitized cells are often
evident in the spleen. Impression smears of the spleen may substantiate the diagnosis of babesiosis at necropsy.
Organisms can be found in erythrocytes within the microvasculature (Fig. 77-7). Nonspecific findings include
erythroid hyperplasia in the bone marrow, extramedullary hematopoiesis of the liver and spleen, mononuclear
phagocyte system hyperplasia, and centrolobular necrosis of the liver. Vasculitis has been observed in B. gibsoni
infections and is associated with hepatitis and lymphadenitis with multifocal deposits of IgM in inflamed arteries
and renal glomeruli.
162
In chronic cases of canine babesiosis and cases of feline babesiosis, the only gross finding
may be splenomegaly.
77.5.5
77.6
Fig 77-6 Cerebral vessel filled with numerous erythrocytes parasitized by B. canis
(H and E stain, 1200). (Courtesy Charles W. Qualls, Jr., Stillwater, Okla.)
Fig 77-7 Impression smear of spleen obtained at necropsy from naturally infected
dog. Numerous erythrocytes contain one or more B. canis organisms
(Wright-Giemsa stain, 1100). (Courtesy Peter MacWilliams and Charles
W. Qualls, Jr., Stillwater, Okla.)
THERAPY
Dogs
Dogs generally show clinical improvement within 24 hours of treatment with antibabesial drugs (Table 77-3
81
;
see the Drug Formulary, Appendix 8, for additional information). Few drugs have been shown to eliminate the
parasites, and most dogs surviving the acute hemolytic crisis develop premunition in which a delicate balance
exists between their immune response and the persistent parasite. Unfortunately, two of the most effective of
the babesiacidal drugs for B. canis infection, diminazene aceturate and phenamidine isethionate, are not
approved for use in the United States. Diminazene aceturate is the most commonly used drug worldwide.
80
It is
an aromatic diamidine derivative in the same class of drugs as phenamidine isethionate and pentamidine
isethionate. Diminazene aceturate is effective when given intramuscularly (IM), although clearance of infection
is inconsistent even at higher doses. B. gibsoni infections are less responsive to diminazene than B. canis
infections. Dogs are more susceptible to the toxic effects of the drug than other species. Side effects include
pain and swelling at the injection site, GI irritation, and neurologic manifestations.
732
733
77.7
77.7.1
Table 77-3 Selected Babesiacidal Compounds Used in the Treatment of Canine
and Feline Babesiosis
ORGANISM
GENERIC (BRAND)
a
DOSE
(mg/kg)
b
ROUTE INTERVAL
(HOURS)
DURATION
(DAYS)
BABESIA
CANIS
BABESIA
GIBSONI
BABESIA
FELIS
Imidocarb dipropionate 56.6 IM Once Repeat in 14 +++ +
(Imizol) 7.5 IM Once NA
Diminazene aceturate
(Berenil, Ganaseg)
c
3.55 IM
Once
d
NA +++ ++ +
Phenamidine 1520 SC 24 2 +++ ++
isethionate (Lomadine,
Phenamidine)
c
Pentamidine
isethionate (Pentam
300)
e
16.5 IM 24 2 ++ ++ ?
Quinuronium sulfate
(Acaprin)
0.25 SC 48 2 ++
Trypan blue 10 IV Once NA ++
Primaquine phosphate
(Primaquine)
0.5 PO 24 13 ? +++
1 mg per
cat
IM 36 6 +++
Clindamycin (Antirobe,
Cleocin)
f
12.525 PO 12 710 ? ? ?
Doxycycline
(Vibramycin)
g
10 PO 12 710 + ? ?
Azithromycin
(Zithromax)
h
10 PO 24 10 ? +++ ?
Atovaquone (Mepron)
h
13.3 PO 8 10 ? +++ ?
Quinuronium sulfate
(Acaprin)
0.25 SC 48 2 ++ ? ?
IM, Intramuscular; SC, subcutaneous; IV, intravenous; PO, by mouth; +++, very good; ++, good; +, fair to poor; , not
effective; ?, unknown; NA, not applicable.
a For specific information on each drug, see Drug Formulary, Appendix 8.
b Dose per administration at specified interval.
c Drugs not approved for use in the United States. Available in other countries as oxopirvedine (trade
name Merial, Lyon, France), where it is combined with antihistamine, oxomemazine.
d For B. canis, this dose is sufficient; for B. gibsoni, repeat dose in 24 hours. These total dosages of 7
mg/kg or higher are associated with an increased risk of neurotoxicity.
e Orphan drugs.
f Anecdotal evidence for effectiveness against B. canis.
g Only shown to reduce or prevent parasitemia in dogs that were infected during treatment.
h Effective against B. microti in people and hamsters. Also effective against B. gibsoni in dogs when
both azithromycin and atovaquone are used in combination.
14
Phenamidine isethionate is available in many countries as a licensed drug for treatment of canine babesiosis.
Pentamidine isethionate (trade name Pentam 300; Abbott Labs, Abbott Park, Ill.) has been approved for use in
the United States by the Food and Drug Administration as an orphan drug for treatment of Pneumocystis
pneumonia in people. The drug has been effective against B. canis and B. gibsoni.
81
The drug has not been as
extensively studied as the other diaminidines. Side effects include injection site pain, hypotension, tachycardia,
and vomiting.
A carbanilide member of the diaminidine family, imidocarb dipropionate, is an effective drug against B.
canis.
6,81
It is available in the United States (see Drug Formulary, Appendix 8). It is less effective against B.
gibsoni. At the suggested dose (see Table 77-3), imidocarb eliminates the Babesia infection and eliminates the
infectivity of ticks engorging on treated animals for up to 4 weeks after treatment. A single dose of 7.5 mg/kg
or a single dose of 6 mg/kg the day following a dose of diminazene at 3.5 mg/kg has also been shown to clear
infections.
117
A dose of 7 mg/kg imidocarb given on days 15 and 27 following experimental B. canis infection
cleared infection but inhibited the protective response associated with gradual recovery, making the animals
more susceptible to reinfection parasitemia than untreated control dogs.
18
Because PCR was not performed and
antibody titers persisted, immune stimulation caused by premunition caused by subclinical persistence of the
parasite is possible. Imidocarb is also effective against E. canis and is therefore the drug of choice in dual
infections.
6
It has protective prophylactic activity up to 6 weeks after a single injection.
155
Side effects are
uncommon and thought to be related to an anticholinesterase effect of the drug. They include transient
salivation, lacrimation, vomiting, diarrhea, muscle tremor, restlessness, tachycardia, and dyspnea.
1
An overdose
of 10 times the proper amount resulted in hepatic necrosis and death in one dog.
77
Atovaquone is an antiprotozoal drug approved for the treatment of Pneumocystis carinii pneumonia in human
patients with the human immunodeficiency virus (HIV). The mechanism of action is not completely
understood, but the site of action appears to be inhibition of electron transport at the cytochrome bc 1 complex
(Complex III) in Plasmodium species. Atovaquone and azithromycin are effective against B. microti in hamster
models
57,159
and B. gibsoni in vitro and in vivo in dogs.
98b
The combination has proved effective in treating B.
gibsoni in a pilot study involving a small number of dogs with naturally acquired infection.
14a
Atovaquone
(13.3 mg/kg given orally every 8 hours) and azithromycin (10 mg/kg given orally once daily) were given for 10
days. The treatment appeared to sterilize B. gibsoni infections or reduce the parasitemia below detectable limits.
Although additional studies on more strains are needed, this may be the treatment of choice for B. gibsoni
infections in dogs. Atovaquone is difficult to obtain in some countries, and the expense can be much greater
than that of other treatments. Recrudescence of infection was observed greater than 30 days following
atovaquone monotherapy for B. gibsoni infection in dogs.
98a
Increased resistance to the drug was found by in
vitro testing. For this reason, it should always be used in combination with other drugs.
Quinuronium sulfate has been effective in treating dogs with B. canis infection.
78
Dogs showed clinical
improvements within 24 to 48 hours of treatment.
Trypan blue (1% solution) is effective in treating dogs with mild to moderate signs of infection with B. canis
(see Table 77-3).
67,133
It has also been recommended for patients with severe infections because it lacks the
anticholinergic properties of imidocarb and the CNS toxicity of the other diamidines.
81
Trypan blue does not
clear infections and results in bluish discoloration of tissues and plasma.
733
734
Aggressive supportive care and clindamycin (25 mg/kg given orally every 12 hours for 7 to 21 days) has been
recommended if the specific antibabesial drugs are not available. Clindamycin is the treatment of choice for B.
microti in people, and numerous anecdotal reports describe success in treating canine babesiosis at 25 to 50
mg/kg/day. However, many infected dogs recover completely without specific babesiacidal therapy if adequate
supportive measures are taken, making interpretation of uncontrolled treatment observations difficult.
Clindamycin proved effective in managing the acute complications of B. gibsoni infections in experimentally
infected dogs but did not clear the organisms.
164
Clindamycin at 25 mg/kg given orally every 12 hours for 7 to
21 days after infection resolved anemia and other clinical findings. However, no significant differences were
found between treated and untreated dogs in parasitemia levels or antibabesial IgG titers. Nevertheless,
morphologic changes in circulating parasites showed degenerative changes. Levels of parasitemia fluctuated in
subsequent monitoring in both groups; however, treated dogs had stronger humoral and cell-mediated immune
responses against the parasite. Clindamycin was also ineffective compared with oxytetracycline or diminazene
for treating experimental B. canis infection in mice.
8
Doxycycline has been effective in preventing or reducing parasitemia in dogs that were being treated at the time
of infection.
155
Cats
Treatment of feline babesiosis has not been as critically evaluated as its canine counterpart.
81
Most babesiacidal
drugs appear to be ineffective. Primaquine phosphate, an antimalarial compound, administered orally or as an
IM injection, is effective and currently the drug of choice (see Table 77-3). However, the effective dose, 0.5
mg/kg, is very close to the lethal dose of 1 mg/kg. In experimental studies, rifampicin and
trimethoprim-sulfadiazine were not as effective as primaquine.
118
Danofloxacin, enrofloxacin, and
buparvaquone had no anti-B. felis activity.
Blood Transfusions
Blood transfusions are usually indicated in severe, uncomplicated cases and complicated cases involving a
life-threatening anemia. The decision to transfuse is based on clinical signs, history, and hematologic test
results. Clinical signs that would indicate the need for transfusion are tachycardia, tachypnea, water-hammer
pulse, weakness, and collapse. The acuteness of onset and the degree of red cell regeneration should also be
taken into consideration. The hematocrit is the most commonly used indicator of anemia, but red cell count and
hemoglobin can also be used. No HCT has been established at which a transfusion should be given, because it
must be evaluated in conjunction with the clinical signs and history. Generally a transfusion is considered when
the HCT is 15% or lower and is always indicated when the HCT is 10% or lower. The degree of parasitemia is
not an important deciding factor because it often bears little relation to the degree of anemia. Packed red cells
are the component of choice for babesiosis. The administration of the plasma component of whole blood is
unnecessary in the majority of dogs with babesiosis and can place the patient at risk of volume overload. If
rehydration is required, crystalloid replacement solutions are preferable. Fresh whole blood improves oxygen
status and acid-base balance in B. canis-infected dogs, as well as replaces subfunctional hemoglobin with
functional hemoglobin.
77.7.2
77.7.3
Supportive Care
Ongoing supportive therapy should be based on a thorough patient assessment and ongoing monitoring,
appropriate laboratory testing, and accepted therapeutic principles for the complications that may be present.
Whether glucocorticoids are indicated is controversial. The immune system is implicated in many of the clinical
manifestations of canine babesiosis, especially the hemolytic anemia. In one study, 20% of dogs with B. canis
infection had hemolytic anemias that were not responsive to antibabesial therapy alone.
63
Treatment with
immunosuppressive doses of glucocorticoids is sometimes necessary. However, long-term use is probably not
indicated, and in most dogs the glucocorticoid dosage can be tapered over 2 to 3 weeks. This therapy may
predispose the animals to other infections and has the potential to induce babesial relapse.
97
The
monocyte-macrophage system is important in controlling Babesia parasitemia. Reduction in this system's
function often results in more severe parasitemia shortly after glucocorticoids are initiated.
PREVENTION
General Guidelines
The difficulty in obtaining specific therapeutic compounds for treatment of Babesia makes prevention of
paramount importance. Preventive measures alone may be sufficient to control B. canis outbreaks in kennels in
the southeastern United States. The primary means of prevention is control of the vector tick.
134
Frequent
inspection of the skin and hair coat for ticks is important because it takes a minimum of 2 to 3 days of feeding
for transmission of the parasite to occur. New animals should be serologically tested, treated, and quarantined
before being introduced into a colony. Flea and tick collars, although not very effective for flea control, are
reasonably effective for tick control when used with inspection, topical ascaricide application, and
environmental control. Fipronil (trade names TopSpot, Frontline; Merial, Iselin, N.J.) appears to be effective as
a topical product for tick control.
Premunition (subclinical infection) is important in controlling clinical signs of disease in areas where more
virulent strains of Babesia are endemic.
117
In these areas, completely clearing infections may not be desirable.
The role premunition plays in immunity in areas where less virulent strains are endemic is not known.
Duration of protective immunity against B. canis babesiosis is limited. Antibody titers gradually decline
between 3 and 5 months after infection.
149,154
Dogs are protected against homologous infection within 5 to 8
months after infection.
156
Cross-protection between strains does not occur, and seropositivity is no guarantee of
protection against heterologous challenge.
A vaccine produced from cell-culturederived exoantigens of B. canis is available in Europe.
106
An efficacy of
70% to 100% has been reported, with the disease occasionally seen in the vaccinates generally being mild.
105

Other field studies have been less impressive. Vaccination does not prevent infection but appears to block
initiation of many of the pathologic processes involved in disease pathogenesis (see Fig. 77-3).
125,126
Vaccines
may limit the parasitemia, reduction in HCT, and development of splenomegaly.
125
Differences in strain
antigenicity substantially limit the usefulness of the commercial vaccine in other areas. However, heterologous
734
735
77.7.4
77.8
77.8.1
protection was achieved using soluble parasite antigens from the European B. canis vogeli isolate and South
African B. canis rossi isolate.
129
Babesia organisms can be transmitted by transfusion, making control in a blood donor colony especially
important.
38,136
All prospective canine blood donors should be serologically tested for babesiosis. Positive
animals should be identified and culled from the program because seropositivity overestimates the infection rate
but provides a safer zone for eliminating potential carriers. PCR also offers a fairly sensitive way to detect
carriers. When PCR is not available, splenectomy has been used to increase the likelihood of finding parasites
in animals with occult infection and therefore is indicated. Blood smears should be examined for Babesia daily
for 2 weeks after splenectomy and then periodically thereafter.
Babesiosis in Greyhounds and American Pit Bull Terriers
Of the 16,000 greyhounds that were adopted through rescue leagues in 1995, 20% to 60% were likely to have
positive serotest results for B. canis. Much of this screening was done before the availability of PCR, and
serologic testing results likely overestimate the true prevalence of infection. This concern about babesiosis
developing in adopted greyhounds is common among adopting owners, greyhound rescue organizations, and
veterinarians. The question of what to do with these animals is not an easy one to answer. The likelihood of the
adopted greyhound developing clinical babesiosis is low, as is the likelihood of the dog serving as an
epidemiologic significant source of spread of the disease. However, the risk to other dogs is great if the infected
animal is placed in a breeding kennel in which dogs are housed together and tick control is not adequate or if
the animal is used as a canine blood donor. A single IM dose of imidocarb dipropionate at 7.5 mg/kg apparently
eliminates the B. canis carrier status. This approach should be considered in situations in which risk of spread is
likely. In other situations, the owner should be made aware of the seropositive status so that should clinical
signs consistent with babesiosis arise, the attending veterinarian can be alerted to the possibility of the disease.
The organism affecting American pit bull terriers is B. gibsoni. Most reported cases of B. gibsoni in the
southeastern United States have been associated with American pit bull terriers. It is common for dogs that are
not pit bull dogs and are infected with B. gibsoni to have recently been in fights with pit bull dogs.
10,93
It is
therefore important to include questions about recent fights in the history when evaluating a dog for hemolytic
anemia.
PUBLIC HEALTH CONSIDERATIONS
Babesiosis is a significant tickborne zoonosis of people found throughout Europe and in the northeast and upper
Midwest of the United States, and isolated cases of uncharacterized Babesia have been reported in Africa and
Mexico.
74
The majority of infections are mild or asymptomatic; however, some result in severe illness and death.
People who have had a splenectomy or are older (older than 55 years) are especially at risk.
36,120
No Babesia
organism has been identified that is host specific for people. Sylvan cycles with wild animal reservoirs occur in
nature. As for other tickborne zoonoses, people serve as accidental hosts for Babesia of animals when they are
bitten by infected ticks.B. microti is the primary parasite affecting people in the northeast and upper Midwest of
the United States (see Table 77-1). The vector tick is Ixodes scapularis (dammini), the vector tick of Lyme
borreliosis (see Chapter 45). The hemolytic disease with flulike symptoms is usually mild and self-limiting or
easily managed with clindamycin and quinine. As in dogs, complications of the disease occur in people that have
had a splenectomy or have other immunosuppressive illnesses.
48,52,53
77.8.2
77.9
A severe form of human babesiosis is caused by B. divergens in Europe and B. equi in the United States. This
form of the disease usually occurs in people who have had a splenectomy and is often fatal. An organism closely
related to B. divergensMO1was isolated from a person in Missouri who had had a splenectomy and had a
fatal illness.
52
Babesiosis was also identified in Italy and Austria with a new strain (EU1) that was more closely
related to B. odocoilei than B. divergens.
49
In both instances the people had previously had splenectomies and
developed characteristic signs of hemolytic anemia. Identical isolates of Babesia have been found in Ixodes
ricinus ticks from Slovenia, indicating a more widespread distribution of this organism in Europe.
A syndrome of severe anemia that has been reported in people who have had a splenectomy occurs in the western
United States.
121,120
Genetic analysis has shown that this northern California and Washington strain (WA1) is
more closely related to (but distinct from) the ilerial species and the California strain of piroplasm in dogs than to
other Babesia.
74,120
Historic case reports of human babesiosis caused by domestic animal piroplasms such as
Babesia bovis or B. canis have not been well documented.
54
However, domestic animals are a source of exposure
to the ticks, which may harbor other organisms more likely to infect humans.
Suggested Readings
*
* See the CD-ROM for a complete list of references.
9. Baneth, G, Kenny, MJ, Tasker, S, et al.: Infection with a proposed new subspecies of Babesia canis,
Babesia canis subsp. presentii, in domestic cats. J Clin Microbiol. 42, 2004, 99105.
11. Birkenheuer, AJ, Levy, MG, Breitschwerdt, EB: Development and evaluation of a seminested PCR for
detection and differentiation of Babesia gibsoni (Asian genotype) and B. canis DNA in canine blood
samples. J Clin Microbiol. 1, 2003, 41724177.
18. Brando, LP, Hagiwara, MK, Myiashiro, SI: Humoral immunity and reinfection resistance in dogs
experimentally inoculated with Babesia canis and either treated or untreated with imidocarb dipropionate.
Vet Parasitol. 114, 2003, 453465.
22. Camacho, AT, Guitin, FJ, Pallas, E, et al.: Azotemia and mortality among Babesia microti-like
infected dogs. J Vet Intern Med. 18, 2004, 141146.
32. Conrad, P, Thomford, J, Yamane, I, et al.: Hemolytic anemia caused by Babesia gibsoni infection in
dogs. J Am Vet Med Assoc. 199, 1991, 601605.
73. Kettner, F, Reyers, F, Miller, D: Thrombocytopenia in canine babesiosis and its clinical usefulness. J S
Afr Vet Assoc. 74, 2003, 6368.
93. Macintire, DK, Boudreaux, MK, West, GD, et al.: Babesia gibsoni infection among dogs in the
southeastern United States. J Am Vet Med Assoc. 220, 2002, 325329.
108. Muhlnickel, CJ, Jefferies, R, Morgan-Ryan, UM, et al.: Babesia gibsoni infection in three dogs in
Victoria. Aust Vet J. 80, 2002, 606610.
Uncited references
118a. Penzhorn, BL, Schoeman, T, Jacobson, LS: Feline babesiosis in South Africa, a review. Ann NY Acad
Sci. 1026, 2004, 183186.
735
736
77.10
77.11
160. Welzl, C, Leisewitz, AL, Jacobson, LS, et al.: Systemic inflammatory response syndrome and
multiple-organ damage/dysfunction in complicated canine babesiosis. J S Afr Vet Assoc. 72, 2001, 158162.

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