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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 genusBabesia.82,138,141

Babesiaorganisms 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 canisandBabesia gibsonihave been the two predominant species capable of naturally infecting a dog.

Strains of these organisms are found worldwide (Table 77-1). A smallBabesiaorganism resemblingB. gibsonihas

been described and may be a third species affecting dogs in California.32,75In Spain an organism resembling

Babesia microtiand tentatively being described as Theileria annaehas 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 pantheraehave been reported (see Table 77-1).82,141

Dogs

B. canisis 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 forB. canishas been

proposed.26,149,174

B. canis vogeliis the proposed name for the strain that is found in tropical and subtropicalregions of most continents and transmitted by the brown dog tickRhipicephalus sanguineus. It is the least

pathogenic of the three strains and is the one found in the United States.B. canis canisis the name proposed for

the strain in Europe and parts of Asia. It intermediately pathogenic and transmitted by ticks of theDermacentor

genus.B. canis rossiis the proposed name for the highly pathogenic strain that is found in South Africa and

transmitted byHeamaphysalis leachi. A large strain, a yet unclassifiedBabesia, was isolated from a dog with

hemolytic anemia, leukopenia, and thrombocytopenia.14a

B. gibsoniis 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 smallBabesiaspecies 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 toB. microtior Theileria, tentatively named Theileria annae, was found in the Pyrenean region

of Spain.172

A Spanish isolate ofB. equiwas identified in a dog.33

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Cats

Feline babesiosis has not been studied as extensively as the canine form.B. felisis a small, highly pathogenicstrain 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 ofB. canis canishave been amplified from the blood of three cats

from Spain and Portugal34

; however, no organisms were visualized.B. canisssp.presentiiwas identified in two

cats in Israel.9The ill cat was coinfected with feline immunodeficiency virus (FIV) andMycoplasma

haemominitum. No cases of feline babesiosis have been reported in the United States.B. herpailuriandB.

pantheraeare largeBabesiaorganisms 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 fromB. feliswas isolated

from lions (Panthera leo)in Kruger National Park.92

EPIDEMIOLOGY

B. canisandB. gibsoniare the two species that cause canine babesiosis worldwide (see Table 77-1).B. canis canis

is transmitted byDermacentor reticulatusin Europe, andB. canis vogeliis transmitted byR. sanguineusin many

temperate and tropical countries.B. canis rossiis transmitted byH. leachiin South Africa. Experimentally,B.

canisisolates have been transmitted byDermacentor andersoniandHyalomma marginatum.40,82

In the United

States, canine babesiosis caused byB. canis vogeliis 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 akennel. 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 ofB. canisinfections is suspected but unproven.47

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Table 77-1 Common BabesiaSpecies, 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?aR.

sanguineus?a

Hemolytic anemia or

chronic subclinical

infection with weight

loss and debilitation

Small Babesiaorganisms 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

Felined

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. canisssp.presentii Israel Large (2.7 1.7 m)

round to oval or

ring-shape

Unknown Profound anemia and

icterus or

nonsymptomatic

Humane



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Infectious Diseases of the Dog and Cat, 3rd EditionB. 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. divergenslike 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 forB. gibsonihave not been published; most evidence is

circumstantial.

b SomeB. gibsoniisolates are larger and have a heterogenous appearance resemblingB. canis,so PCR

testing gives the most reliable differentiation.

c Theileria annaehas been proposed as a new name for this organism.23,172

d Also includesB. 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]).



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Fig 77-1 Blood smears from dog with babesiosis. A, Pair of large, piriform-shape

merozoites of B. caniswithin erythrocytes. B, Individual merozoites of B.

gibsoniin erythrocytes (Wright stain, 1000). (Courtesy Ken Latimer,University of Georgia, Athens, Ga.)

Infections withB. gibsonioccur 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 ofB. gibsonicorrelated with that of

the suspected vector ticks,Haemaphysalis bispinosa, andR. sanguineus.

82

Haemaphysalis longicornisandH.leachiwere 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 bothR. sanguineus

andDermacentor 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 engorgedR. sanguineus;

however, infection could not be transovarially or transstadially transmitted to other dogs.167

Infections withB. gibsonioccur 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 toB. gibsonito 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 issuspected, 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 byB. gibsoni.

In kennels whereB. gibsoniinfections 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



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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 allBabesiaspecies. However, transmission via fomites has not beendocumented 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 resemblesBabesiaisolated

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 inR. sanguineus;however, transmission has

not been shown.167

The previously mentioned Spanish isolate ofBabesia(tentatively classified as T. annae) is closely related toB.

felis,B. microti, and isolates from wild felids in Africa.75,92,172

Based on ticks collected from infected dogs,Ixodeshexagonusis the suspected principal vector.

25

The characteristic geographic ranges established for the variousBabesiaspecies 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

ofBabesiain 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 withB. canis, all stages of the tick are likely to be infected.40

Of theBabesia

organisms that are not transmitted transovarially, larvae are not infected. Once in the host,Babesiaspecies 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. canismultiplies within the erythrocytes by repeated binary fission, creating merozoites. As

many as 16 merozoites ofB. canismay 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 ofB. canisto occur.96

Several differences in life cycles have been identified in non-B. canisinfections. Transovarial transmission in ticks

is not a feature ofB. gibsoniinfections. Furthermore, the California strain ofBabesiareplicates 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

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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 ofB. canisis likely and may result in weak

or fading puppies.20,47,139

In one instance,B. canisinfection 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 ofBabesiaorganisms 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

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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 differentiateinto 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'ssaliva. (Courtesy University of Georgia, Athens, Ga.)



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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 pathogenicB. canis rossiinfections 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.56Oxidative 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 withB. gibsoni, which may relate to oxidative damage from lipid

peroxidation.114

Increased urinary methemoglobinemia levels have been found in dogs with naturally occurringB.

canisinfections.90

Lipid peroxidation occurring duringBabesiainfection increases rigidity of parasitized and

nonparasitized erythrocytes and slows their passage through capillary beds. Soluble parasite proteases activate the



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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 byB. canis rossi.Babesiaproteases may induce increases in plasma

kallikrein levels, which can activate the intrinsic cascade at factor XII. Thrombocytopenia is common, especially

in dogs infected withB. 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 pathogenicBabesia

strains. Causes of hypoxia include anemia, shock, vascular stasis, excessive endogenous production of carbonmonoxide, 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 byB. canis

rossiinfection; 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.160Pulmonary, 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 inSouth Africa, is highly virulent and causes a hemolytic anemia or an acute overwhelming inflammatory

response.124

B. canis canisresults 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 vogeliresults in mild clinical

disease, generally without overt signs.

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Acute clinical signs are typical of initial infections withB. gibsoniand the more virulent strains ofB.

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 inB.gibsoni-infected adults, but most animals

with this acute disease recover with treatment. Hematuria and icterus may be noted, especially inB.

canis-infected dogs. The acute presentation is most typical ofB. gibsoniinfections encountered in Asia and

the United States andB. canisinfections 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 ofB. canisinfection are poorly characterized.63

Most infected dogs withB. canis

vogeliin the United States are subclinical carriers.140

Low-grade or subclinical manifestations can also be

seen with certain strains and more commonly withB. gibsoniinfections.

Specific Clinical Features

B. canis rossiin 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 withB. gibsoniinfections, fighting breeds such as bull terriers, American pit bull terriers, and

Staffordshire bull terriers had a higher prevalence ofB. canis rossiinfections, with high mortality

indicating increased susceptibility to or greater exposure risk of babesiosis.

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Table 77-2 Clinical Findings in Dogs with Babesiosis138

SPECTRUM DURATIONNonspecific 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 vogeliin 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 ofB. 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. gibsoniin Asia, Africa, Europe, the United States, and Australia

Typical clinical signs ofB. gibsoniinfection 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 ofthe complicating factors associated with otherBabesiainfections.

101

728

729

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Fig 77-4 Pale mucous membranes of pit bull dog with B. gibsoniinfection.

(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.)



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California isolate

Clinical signs of dogs affected by the CaliforniaBabesiaisolate have included lethargy, vomiting,elevated rectal temperature, and pale mucous membranes caused by anemia.

32Most infected animals have

developed acute severe hemolytic anemia and accompanying thrombocytopenia.

Spanish isolate

In Spain, disease caused by theB. 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 inB. canis rossiinfections 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.

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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 withB. canis rossiinfections.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.

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Acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is a severe and frequent catastrophic complication ofbabesiosis. 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

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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 severeB. canis rossiinfection 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.canisparasites 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

findingB. gibsonion 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 withglucocorticoids.

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

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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 withB. canisandEhrlichia

canisshowed 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 byB. canis

strains but not byB. gibsoni.61,156Liver enzyme activity may be increased during severe disease. Urinalysismay reveal bilirubinuria, hemoglobinuria, proteinuria, and granular casts. InB. canis rossiinfections 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.

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Cats

In feline babesiosis, which is caused byB. felis, the anemia is typically macrocytic, hypochromic, andregenerative.

130No 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 withB. felistypically 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. canisarelarge, piriform-shape organisms and usually exist singly or in pairs (see Fig. 77-1,A), whereas smaller single

intracellular organisms are likely to beB. gibsoni(see Fig. 77-1,B). Parasitemia is often low, especially inB.

canisinfected dogs, making thorough examination of thin blood smears necessary. WithB. canisinfections,

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 ofBabesia-parasitized erythrocytes and degree of reticulocytosis.9b,41,148

Inaddition, 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 detectingBabesiaparasites, 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 toB. canisthat 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 incriminatingB. gibsoniinfection.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 ofBabesiainfection exist. Cross-reactivity betweenB. canisandB. gibsonimake

parasite identification or PCR necessary to differentiate between the two species. However, very young dogs or

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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 withB. canisparasitemia 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.

15,123,156aUsing some tests

based on whole-cell antigens, dogs infected withB. gibsonimay have false-positive serologic test results for

Toxoplasma gondiiandNeospora caninumas well as forB. canis, especially at lower serum titers168

Recombinant-produced P50 protein ELISA testing has been more specific forB. gibsoniinfection 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 forBabesiacan 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 ofB. gibsoniandB.

canis.37a,58b,115a,76,135

Use of a seminested PCR allows for detection and differentiation ofB. gibsoniandB.

canisDNA in blood.11

PCR has been used to identify a thirdBabesiaspecies 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 toBabesia odocoileiandBabesia divergensin 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 inB. 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.

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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. canisorganisms

(Wright-Giemsa stain, 1100). (Courtesy Peter MacWilliams and Charles

W. Qualls, Jr., Stillwater, Okla.)



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THERAPY

Dogs

Dogs generally show clinical improvement within 24 hours of treatment with antibabesial drugs (Table 77-381

;

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 forB. canisinfection, 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. gibsoniinfections are less responsive to diminazene thanB. 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.

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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 Onced NA +++ ++ +

Phenamidine 1520 SC 24 2 +++ ++

isethionate (Lomadine,

Phenamidine)c

Pentamidine

isethionate (Pentam300)

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 ForB. canis,this dose is sufficient; forB. 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 againstB. canis.

g Only shown to reduce or prevent parasitemia in dogs that were infected during treatment.

h Effective againstB. microtiin people and hamsters. Also effective againstB. gibsoniin dogs when

both azithromycin and atovaquone are used in combination.14



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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 ofPneumocystis

pneumonia in people. The drug has been effective againstB. canisandB. gibsoni.81The 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 againstB.

canis.6,81

It is available in the United States (see Drug Formulary, Appendix 8). It is less effective againstB.

gibsoni. At the suggested dose (see Table 77-3), imidocarb eliminates theBabesiainfection 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. canisinfection

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 againstE. canisand is therefore the drug of choice in dual

infections.6It has protective prophylactic activity up to 6 weeks after a single injection.

155Side 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.1An 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 ofPneumocystis cariniipneumonia 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) inPlasmodiumspecies. Atovaquone and azithromycin are effective againstB. microtiin hamster

models57,159

andB. gibsoniin vitro and in vivo in dogs.98b

The combination has proved effective in treatingB.

gibsoniin 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 sterilizeB. gibsoniinfections or reduce the parasitemia below detectable limits.

Although additional studies on more strains are needed, this may be the treatment of choice forB. 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 forB. gibsoniinfection 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 withB. canisinfection.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 withB. 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.

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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 forB.

microtiin 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 ofB. gibsoniinfections 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 experimentalB. canisinfection 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. felisactivity.

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 oxygenstatus and acid-base balance inB. canis-infected dogs, as well as replaces subfunctional hemoglobin with

functional hemoglobin.

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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 withB. 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 controllingBabesiaparasitemia. 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 ofBabesiamakes prevention of

paramount importance. Preventive measures alone may be sufficient to controlB. canisoutbreaks 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 ofBabesiaare 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 againstB. canisbabesiosis 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 ofB. canisis 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

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protection was achieved using soluble parasite antigens from the EuropeanB. canis vogeliisolate and South

AfricanB. canis rossiisolate.129

Babesiaorganisms 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 forBabesiadaily

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 forB. 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 theB. caniscarrier 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 isB. gibsoni. Most reported cases ofB. gibsoniin 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 withB. gibsonito have recently been in fights with pit bull dogs.

10,93

It istherefore 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 uncharacterizedBabesiahave 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

NoBabesia

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 forBabesiaof animals when they are

bitten by infected ticks.B. microtiis the primary parasite affecting people in the northeast and upper Midwest ofthe United States (see Table 77-1). The vector tick isIxodes 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

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A severe form of human babesiosis is caused byB. divergensin Europe andB. equiin 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 toB. divergensMO1was isolated from a person in Missouri who had had a splenectomy and had a

fatal illness.52Babesiosis was also identified in Italy and Austria with a new strain (EU1) that was more closely

related toB. odocoileithanB. divergens.49

In both instances the people had previously had splenectomies and

developed characteristic signs of hemolytic anemia. Identical isolates ofBabesiahave been found inIxodes

ricinusticks 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

otherBabesia.74,120

Historic case reports of human babesiosis caused by domestic animal piroplasms such as

Babesia bovisorB. canishave 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 ofBabesia canis,

Babesia canissubsp.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 ofBabesia gibsoni(Asian genotype) andB. canisDNA 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 withBabesia canisand either treated or untreated with imidocarb dipropionate.

Vet Parasitol. 114, 2003, 453465.

22. Camacho, AT, Guitin, FJ, Pallas, E, et al.: Azotemia and mortality amongBabesia microti-like

infected dogs.J Vet Intern Med. 18, 2004, 141146.

32. Conrad, P, Thomford, J, Yamane, I, et al.: Hemolytic anemia caused byBabesia gibsoniinfection 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 gibsoniinfection 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 gibsoniinfection 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.

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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.


77 babesiosis

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