Hemolymphatic/oncology

Hemolymphatic/Oncology
Blood Parasites in the Dog and Cat:
Haemobartonellosis:
Haemobartonella sp. are gram negative, non-acid fast, epicellular parasites of
erythrocytes. Haemobartonella canis and Haemobartonella felis are the species that
affect dogs and cats, respectively. Experimentally, cats have been reported to have a
subclinical infection with H. canis. Haemobartonella organisms contain both DNA and
RNA and replicate by binary fission. These organisms have not been cultivated outside
the host cells.
Haemobartonella felis

Etiology:

H. felis organisms appear as small, blue-staining cocci, rings and rods attached to
erythrocytes with polychrome-stained blood films. In thick blood slides, they appear as
cocci whereas on the thin, feathered edge of the blood smear they appear as rings and
rods. Organisms are 0.5 um in diameter and appear to be partially buried in indented foci
on the surface of the erythrocytes. Discoid, coccoid, rod-shaped and doughnut-shaped
organisms have been observed. The parasitized erythrocytes may lose the normal
biconcave shape and become spherocytes or stomatospherocytes.
Pathogenesis:

H. felis transmission is suspected to be by blood-sucking arthropods such as the flea,
although experimentally this mode of transmission has not been proven. H. felis can be
transmitted from an infected queen to her offspring but it is not known how this
transmission happens, whether it is in utero, during parturition or via nursing.
Transmission can be accomplished via blood transfusion from a “normal-appearing”
carrier cat to a non-infected recipient. Some cats have been noted to have cat bites
present and this may be a source of transmission. Stress due to other illness,
hospitalization or surgical procedures is also associated with clinical Haemobartonellosis.
FeLV is associated with H. felis infections and approximately 50% of cats with H. felis
are FeLV positive. It is suspected that FeLV may make cats more susceptible to H. felis
due to decreased immunity and ability to convert a latent H. felis infection into an active
one. But experimentally, it has been shown that H. felis infections can predispose cats to
FeLV infection. Cats infected with both H. felis and FeLV have more severe anemia and
clinical signs. There is no association of FIV infection with H. felis infections.
The severity of the disease produced by H. felis varies in cats that are mildly anemic
and without clinical signs to cats that are markedly depressed and die from severe
anemia. There are four stages of the disease: preparasitemic, acute, recovery, and carrier phases or stages. The preparasitemic phase is about 1 to 3 weeks after IV injection. The acute phase is the time from the first to the last episode of parasitemia which may last 1 month or more. Occasionally, cats die quickly after a massive parasitemia and declining packed cell volumes, early in the course of the disease. Parasites generally appear in the blood in a cyclical manner with the number of parasites increasing to a peak over 1 to 5 days, followed by a rapid decline. The synchronized disappearance of organisms can occur in 2 hours or less following a parasitemic episode. Few if any parasites are seen on the blood film for several days following an episode. A rapid decrease in PCV followed by a rapid increase in PCV may occur due to the appearance and disappearance of organisms. These fluctuations are probably associated with splenic sequestration of parasitized erythrocytes and with the later release of non-parasitized erythrocytes. In other instances, the PCV remains decreased or continues to decline for 1 or more days after a parasitemic episode due to erythrocyte destruction. Some damage to erythrocytes may be caused directly by the parasite, but immune-mediated injury appears to be more important. This may be due to antibodies produced against uncovered antigens in the altered erythrocyte membrane or due to direct antibody production against the organism. Direct Coomb’s tests may be positive 1 week after a parasitemia and may remain positive throughout the acute stage whether or not the parasites are present. Minimal intravascular hemolysis occurs with anemia usually due to extravascular erythrophagocytosis by macrophages in the spleen, liver, lungs and bone marrow. Without treatment, approximately one third of the cats with uncomplicated acute haemobartonellosis die due to the severe anemia. If the cat can mount a sufficient immune response to the organism and a regenerative bone marrow response in excess of the rate of erythrocyte destruction, recovery can occur. The recovery phase is the time from the last major parasitemia to the time when the PCV has stabilized within or close to the normal range. This may take one month or longer. In untreated cats that survive and go into the recovery phase, organisms are usually seen in low numbers in the blood but do not occur as discrete parasitemic episodes. Cats that recover from acute infections with H. felis usually remain chronically infected for months to years and possibly for life. Although the immune system picks off the organisms from the erythrocyte, intact organisms can survive inside phagocytic vacuoles of spleen and lung macrophages. These surviving organisms account for the indefinite, chronically infected state. These chronically infected, asymptomatic cats account for the carrier phase. The carrier cat may have a normal PCV or may have a mild regenerative anemia. Blood films may not reveal any organisms or low numbers of organisms. Carrier cats appear to be in a balanced state in which replication of organisms is balanced by phagocytosis and removal. Clinical Findings:Acute haemobartonellosis occurs in cats of all ages but may be seen more in young male cats due to their increased roaming and fighting behavior giving them greater exposure to the organism. Feline haemobartonellosis is usually a disease of individual cats but multiple infections in multicat households has been reported. Subclinical or latent infections may not produce any clinical signs but may cause a mild anemia. The most common clinical signs in sick cats are depression, weakness, anorexia, weight loss, paleness of mucous membranes and splenomegaly. Icteric mucous membranes may occassionally be noted. Clinical signs depend on the stage of the disease and how rapidly the anemia develops. With slow onset of anemia, weight loss may be the only outward sign and the cat may appear bright and alert. A rapid declining PCV and resulting severe anemia in a cat associated with severe parasitemia causes weight loss but with severe depression. Pyrexia is noted in 50% of the cats in the acute phase of the disease but is usually normal in all other phases. Hypothermia may be noted in severely affected cats that are moribound. Diagnosis: Blood smears that are stained with Wright-Giemsa stain or Diff-Quick staining may show organisms during the acute phase in about 50% of affected cats but are difficult to recognize in low numbers. Differentiation of H. felis organisms from Howell-Jolly bodies and Cytauxzoon parasites is essential. New methylene blue staining should be avoided due to the difficulty distinguishing the ribosomal material in reticulocytes from the H. felis organisms. Erythrophagocytosis by monocytes or macrophages may be present. The absence of identification of H. felis organisms on a blood smear does not rule out the disease. Complete Blood Counts show a decreased PCV below 20% and possibly as low as 10% by the time clinical signs are apparent. MCV may be normal and reticulocytes may not be increased in the patient with a rapidly declining PCV. Most cats show signs of regeneration by the time clinical signs are apparent and have an increased MCV, polychromasia and reticulocytosis (punctate reticulocytes) indicating a regenerative anemia. White blood cell counts are variable and not of diagnostic importance. Platelet counts are usually normal. Coomb’s test is often positive by the time the patient presents with clinical signs. Reagents made specifically for cats is needed for this test. Bone Marrow examination although rarely indicated in a regenerative anemia reveals a normal M:E ratio in the early stages but may be decreased in the later stages due to erythroid hyperplasia. The diagnosis of Haemobartonellosis in the cat is not ruled in or out by the identification of organisms. Currently there are no commercially available tests that can accurately identify H. felis organisms when the blood smear is negative. Immunofluorescent microscopy by trained individuals with access to proper equipment can be used in research. A PCR test for H. felis in the blood is available but no studies have been done as of yet to determine its accuracy. A diagnosis of Haemobartonellosis is made in a cat that presents clinically with a regenerative anemia, positive Coomb’s test, autoagglutination of refrigerated blood or erythrophagocytosis by blood monocytes. Other diseases such as autoimmune hemolytic anemia or FeLV-induced hemolytic anemia should also be considered. On the other
hand, positive identification of the H. felis organism in the blood does not necessarily
indicate that the clinical illness present is caused by the parasite since it may be observed
incidentally in carrier cats.
Treatment:
Tetracycline 20 mg/kg, TID, PO for 3 weeks. Adverse affects of tetracycline in cats are
fever, anorexia and possible liver toxicity. If these occur, a lower dosage or tetracycline
analog may be used.
Doxycycline is a tetracycline analog that may eliminate severe side effects seen with
tetracycline. It is given at a dosage of 5 mg/kg, BID, PO for 3 weeks.
Prednisolone is indicated in severely anemic cats to inhibit the erythrophagocytosis. A
dosage of 1-2 mg/kg, BID, PO is used initially and then tapered as the PCV increases and
then stabilizes. This is the same treatment as autoimmune hemolytic anemia since the
two diseases cannot be distinguished unless the organism is identified.
Blood transfusion is indicated in the severely anemic patient. Whole blood or packed
RBCs may be used after blood typing and cross-matching to a donor.
Prognosis:
Persistance of the parasite in recovered animals is the usual with most becoming
chronically infected and carriers. Stress may induce relapse episodes of parasitemia
resulting in clinical disease. Even so, the prognosis in recovered patients is considered
good for the long-term.
Prevention:
Eliminating blood-sucking arthropods from cats is recommended due to their suspicion in
transmission. Using blood donors that have been splenectomized and then evaluating
blood smears for 10 days thereafter is recommended.
Haemobartonella canis
Etiology:
H. canis organsms differ from H. felis organisms in that they more commonly form
chains that extend across the surface of the erythrocytes. However, individual organisms
may also appear as small dots, rods or rings. The chains of organisms frequently occur in
grooves or deep infoldings that can markedly distort the erythrocyte shape.
Pathogenesis: The brown dog tick Rhipicephalus sanguineus has been shown experimentally to transmit the disease. Transtadial and transovarian transmission in ticks has also been described which may indicate that the tick is an important reservoir as well as a vector for the infection. Blood transfusions from infected carrier donor dogs to non-infected recipients may occur but is of less concern in the dog since splenectomy of the recipient is usually required before clinical disease would occur. Haemobartonellosis has been documented in a litter of 4 week old puppies and caused death in two of the puppies. Indirect evidence of transmission of the infection in utero has been reported. Transmission by oral administration of infected blood has also been reported. In contrast to haemobartonellosis in cats, the majority of nonsplenectomized dogs infected with H. canis do not develop clinical evidence of the disease or become anemic. Most do not have sufficient enough organisms present to be detected on routine blood film examination. Cases have been described in nonsplenectomized dogs with concurrent Ehrlichia, Babesia, bacterial and viral infections. Haemobartonellosis has also occurred in dogs given immunosuppressive drugs and in dogs with splenic disease. Rare cases have been found in nonsplenectomized dogs that had no evidence of immunosuppression. Experimentally, the prepatent period after IV injection of infected blood into splenectomized dogs ranges from 1 or 2 days to 2 weeks or more. Some cases had rapidly developing anemia associated with a constant parasitemia. Death occurs in these dogs within a month after inoculation. In other dogs, the development of anemia is gradual and is a result of repetitive parasitemic episodes. Parasites may be observed in the blood for a week or more with a few intervening days when they are not observed. One to 2 months are required for the PCV and hemoglobin concentration to drop to minimum values and an equal time for them to return to normal. It appears that antibodies are produced against erythrocytes. Clinical Findings: Unless other disease is present, clinical signs are rarely present in nonsplenectomized dogs infected with H. canis. Experimentally, splenectomized dogs become listless and have pale mucous membranes as the anemia develops. Temperature and appetite are usually normal. Bilirubinuria may be present. Diagnosis:Blood smear examination usually identifies organisms when clinical evidence of anemia is seen. Usually chains of cocci are seen on the erythrocyte membrane in the anemic dog. Complete Blood Count usually reveals a decreased PCV that may be as low as 20% before clinical signs occur. Signs of regeneration are usually present by the time of presentation and consist of reticulocytosis, increased polychromasia and anisocytosis, circulating nucleated erythrocytes and frequent Howell-Jolly bodies. Spherocytosis may be seen. Macrocytosis may take more time to develop and may not be present initially. No consistent white blood cell abnormalities are noted. Neither icterus nor hemoglobinemia is recognized in uncomplicated cases. Coomb’s test may be positive and spherocytosis may be found on blood smears indicating the presence of anti-erythrocyte antibody. Diagnosis depends on the recognition of organisms in the blood and distinguishing them from artifacts such as basophilic stippling and Howell-Jolly bodies. Blood films should be inspected carefully for the organisms in anemic dogs after splenectomy. Treatment:Oxytetracycline, Tetracycline, Doxycycline and Chloramphenicol can be used for treatment. Oxytetracyline or Tetracycline can be used at a dosage of 20 mg/kg, TID, PO for 3 weeks. Doxycycline is used at a dosage of 5 mg/kg, BID, PO for 3 weeks. Chloramphenicol is used at a dosage of 20 mg/kg, BID, PO for 9 days with the recognition that bone marrow hypoplasia can be a side effect of this drug. Prednisone at immunosuppressive doses may be indicated in the severely anemic patient. Blood Transfusion may be indicated in the severely anemic patient. Prognosis: Dogs that recover from Haemobartonellosis probably have latent infections and remain carriers. Prevention: Elimination of blood-sucking arthropods. Iatrogenic transmission via blood transfusion is only of concern if the patient has been splenectomized. Splenectomizing blood donors and examining blood films for the organism for 10 days thereafter is recommended to rule out latent infections. Cytauxzoonosis Etiology: Cytauxzoon felis causes a usually fatal tick-borne blood protozoal disease of domestic cats and exotic felines. Cytauxzoonosis has been reported in many south central and southeastern states in the United States. The natural reservoir host appears to be the North American bobcat (Lynx rufus). Iatrogenic transmission of the disease from a Florida panther to a domestic cat has been reported. Life cycle: In the life cycle of C. felis, schizonts develop primarily within mononuclear phagocytes, first as indistinct vesicular structures within the cytoplasm of infected cells and later as large, distinct, nucleated schizonts that actively undergo division by schizogony and binary fission. The phagocytes line the lumens of the veins within almost every organ and become huge and numerous, often occluding the vessel like a thrombus. Later in the course of the disease, schizonts develop buds (merozoites) that separate and eventually fill the entire host cell. The host cell probably ruptures, releasing the merozoites into the blood or tissue fluid. Merozoites appear in macrophages 1 to 3 days before they are observed in erythrocytes. These organisms then invade uninfected erythrocytes and produce late-stage parasitemias that are detected on examination of blood films, usually 1 to 3 days before death. Transmission: Ticks are the likely natural vector for Cytauxzoon because most cases have been associated with the presence of ticks on the host. The tick, Dermacentor variabilis has been documented to transmit the disease from a bobcat to two domestic cats. Inoculation of blood from infected bobcats to domestic cats appeared to transmit only the erythrocytic piroplasm stage. Therefore, the fatal form of the disease is thought to occur only after tick transmitted infections. Amblyomma americanum, the Lone star tick, was suspected to transmit the disease in a Florida white tiger that died from the disease. The sporadic occurrence, short course of illness and usually fatal nature of the disease indicate that the domestic cat is likely an incidental dead-end host. However, there are a few reports of domestic cats surviving the disease. Pathogenesis: Rapid multiplication of the tissue phase of the parasite may cause mechanical obstruction of blood flow, especially through the lungs. By-products of tissue parasites may be toxic, pyrogenic, and vasoactive, whereas the blood phase may induce destruction and phagocytosis of erythrocytes. Disseminated intravascular coagulation (DIC) has been a complication in infected cats. Infected cats appear to die from a shock-like state. Clinical findings: Most cats present with the disease during the months of May through September. Geographic clusters of infection also seems to occur. Access to outdoor, wooded areas or any tick exposure history is typically noted. Anorexia, dyspnea, lethargy, dark urine, dehydration, depression, icterus, pale mucous membranes, anemic heart murmur, increased capillary refill time (>2 seconds) and fever (103-107 F) are seen clinically. . Hypothermia, recumbency and coma are clinical findings in terminally ill cats. The entire course of the disease usually is less than one week with most cats having a rapid onset and course of illness with death occurring in fewer than 5 days. Incubation periods in experimentally infected cats ranges between 5 to 20 days post-inoculum. Febrile periods may be followed by subnormal temperatures and onset of dyspnea noted by the cat having difficulty breathing. Cats usually die 2 or 3 days after a temperature peak. Clinical pathology abnormalities are normocytic, normochromic anemia, variable leukocyte counts but often leukopenia, thrombocytopenia, hyperbilirubinemia, hyperglycemia, hypoalbuminemia, hypocholesterolemia, hypokalemia, increased alanine aminotransferase (ALT) and bilirubinuria. Elevations in BUN, ammonia and liver enzymes may not occur until the febrile or comatose stages. Prolongation of PTT and PT with increased FDPs are present in cats with DIC. Diagnosis: Blood smear examination is used to demonstrate the piroplasms in erythrocytes from thin blood smears that are carefully prepared and stained with Wright’s or Geimsa stains. The piroplasms appear as round “signet ring” shaped bodies that are 1 to 1.5 um in diameter; bipolar oval “safety pin” forms 1x2 um; tetrad forms or anaplasmoid round “dots” less than 0.5 um in diameter. Piroplasm cytoplasm stains light blue and the nucleus dark red or purple. Number of parasitized cells ranges from cat to cat and with the stage of the disease. Single cells usually contain one piroplasm but pairs and tetrads may occur. Distinction from Haemobartonella and Babesia stages must be made. Bone marrow, spleen or lymphnode aspirates or impression smears may contain phagocytes containing tissue phase schizonts. Histopathologic evaluation of lung, lymph nodes, spleen, heart, and brain in cats that die are examined for parasites. Pathological findings: Gross findings in cats include dehydration, pallor, icterus, hydropericardium, enlarged, edematous and hemorrhagic lymph nodes, accentuated hepatic lobular pattern, intra-abdominal venous distention, splenomegaly, petechial and ecchymotic hemorrhages on the serosal surfaces of abdominal organs and lungs. The lungs are often congested and edematous with petechiae throughout. Minimal inflammatory reaction is present in affected tissues. Lumens of veins of the lungs, liver, lymph nodes and spleen are partially or completely occluded with large numbers of phagocytes containing schizonts. Treatment: Attempts to treat these cats have been unrewarding. Supportive care with intravenous fluid therapy is essential. Parvaquone, sodium thiacetarsamide, buparvaquone and tetracycline do not appear to be effective. One cat treated with fluids, enrofloxacin and tetracycline survived elimination of blood parasites. Most success in treatment has been with the carbanilide compounds diminazene aceturate or imidocarb dipropionate. One cat with DIC was treated with fluids, subcutaneous heparin, enrofloxacin and diminazene aceturate and had an immediate improvement in clinical state and eliminated the parasitemia by day 4 after treatment. Giving two sequential injections of diminazene is most efficacious. Another report of 2 cats in the same household were treated with diminazene alone and recovered. Imidocarb is given in two injections with a 2-week interval. Concurrent antibiotic therapy with first-generation cephalosporins for cats with leukopenia is recommended for the first 7-10 days. Whole blood transfusions are also indicated in the severely anemic patient and the patient in DIC. Diminazene binds to parasite kinetoplast DNA at sites rich in adenine-thymidine base pairs, inhibiting DNA replication and possibly inhibiting mitochondrial type II topoisomerase. Pharmacokinetics of diminazene have not been worked out in the cat. It persists in high concentrations in the liver and kidney of dogs for greater than 10 days after injection. Excretion of the compound is via the kidney. Metabolism extent is unknown. Toxicosis is reported in the dog as injury to liver, kidney, bladder, lungs, heart and brain. Side effects in cats treated are not reported. Clinical signs of fever and lethargy seen after the first few days of treatment in cats were considered effects from dying organisms . Dosage recommendation in the cat is 2 mg/kg. Not commercially available but many veterinary schools have it. Imidocarb dipropionate is a related aromatic diamidine. Dosages of 2 mg/kg and 5 mg/kg have been reported to treat Cytauxzoon infections in the cat. The lower dose (2 mg/kg) is recommended to reduce fatal complications. The injections are given intramuscularly (IM) twice with a 3 to 7 days interval. Atropine (0.05 mg/kg) may be given to control the adverse signs associated with parasympathomemetic events. Heparin is also advised (100-150 U/kg, SC, TID) while treating with diminazene or imidocarb. Is commerically available. Babesiosis Etiology: Babesiosis is a disease of worldwide significance caused by tick-borne hematozoan organisms. B. canis and B.gibsoni are the two species capable of natural infection in the dog. B. felis, B. cati, B. herpailuri and B. pantherae have been reported in cats. Dogs: B.canis is the more important of the two species that affect dogs. It is a large (2.4um x 5.0 um) piriform-shaped organism that may occur singly or paired within erythrocytes. Its range of coverage is wide including most of southern Europe; Africa; Asia; and North, Central and South America. Vector ticks include Rhipicephalus sanguineus, Dermacentor reticulatus, D. marginatus and H. leachi in natural conditions and D. andersoni and Hyalomma marginatum in experimental ones. B. gibsoni is a small, pleomorphic (1.0 um x 3.2 um) organism usually observed singly within erythrocytes. It is found primarily in northern Africa and the southern parts of Asia but is endemic in the southwestern United States. It is sporadically noted in areas near military bases, where military working dogs that have been transported around the world are housed. B. gibsoni’s geographical range correlates with that of the vector ticks, Haemaphysalis bispinosa and R. sanguineus. A trinomial nomenclature system for B. canis has been proposed due to serologic and cross-immunity studies as well as differences in pathogenicity and vectors. B. canis vogeli occurs in the tropical and subtropical regions of most continents and is transmitted by R. sanguineus. It is the least pathogenic of the strains and is the one found in the United States. B. canis canis occurs in Europe and parts of Asia and it has an intermediate pathogenicity. It is transmitted by ticks of the Dermacentor genus. B. canis rossi is the name of the highly pathogenic strain transmitted by H. leachi and is found in southern Africa. Cats: Feline babesiosis has not been studied extensively as the disease in dogs. B. felis is a highly pathogenic species found in southern Africa and the Sudan. B. cati is less pathogenic and found primarily in India. B. herpailuri and B. pantherae are large organisms of wild Felidae in Africa that have been transmitted experimentally to the domestic cat. There have been no cases of feline babesiosis reported in the United States. Epidemiology:In the United States, canine babesiosis occurs most commonly along the Gulf Coast and in the south, central and southwestern states. Arkansas, Arizona, Florida, and Oklahoma seem to be states where cases are most common. The seroprevalence is higher in adult dogs than in dogs less than one year of age. Prevalence within kennels has been noted to be highest in greyhounds and kennels with poor tick control programs. In kennels with intensive tick control programs, the prevalence is lower. Greyhounds have been noted to have a higher seroprevalence when compared to non-greyhound breeds in endemic areas. Outbreaks may occur and are usually localized to a small area or a kennel. Younger dogs, dogs less than one year of age are more susceptible to the infection. Dogs younger than 2 months old may be protected by maternally derived antibody. Age may not be a significant factor in the pathogenesis of clinical disease caused by B. gibsoni and the more virulent strains of B. canis. Pathogenesis: Transmission of babesias is by the bite of infected ixodid ticks. The adult female is the most important in transmission but all stages of the tick are likely to be infected. Once in the host, Babesia spp. attach to the erythrocyte membrane and are engulfed by endocytosis. Once in the erythrocyte, the red blood cell membrane disintegrates and the organism multiplies within the cytoplasm by binary fission, which results in merozoites. Up to 16 merozoites may be seen in a single red blood cell but they usually occur singly or paired. Ticks are then infected with merozoites by feeding on an infected animal. A complex life cycle involving transtadial and transovarial transmission occur which results in sporozoite formation in cells of the tick’s salivary glands. The infected ticks pass the sporozoites in the saliva into the host when they feed. Ticks must feed a minimum of 2 to 3 days for transmission of B. canis to occur. After infection, a significant host immune response occurs. The immune system does not appear able to completely clear the infection and recovered animals are usually chronic carriers. Poor humoral response is common in pups less than 8 months old.
There are two syndromes that can occur after infection with B.canis. One is
characterized by hemolytic anemia and the other by hypotensive shock and/or multiple
organ dysfunction. Parasitemia results in the increased osmotic fragility of erythrocytes,
hemolysis (often intravascular) and subsequent anemia. The severity of the anemia is not
proportional to the low degree of parasitemia usually observed. Direct parasitic damage
to the RBC contributes to the anemia as well as increased erythrophagocytic activity of
macrophages and secondary immune-system-induced damage after antierythrocyte
membrane antibodies are formed. Oxidative stress may also contribute to increased
susceptibility to phagocytosis. Soluble parasite proteases activate the kallikrein system
and induce fibronogen-like protein (FLP) formation which increases the “stickiness”
leading to further sludging of erythrocytes in the capillaries. The most severe sludging
seems to occur in the CNS and muscles. Rhabdomyolysis and acute renal failure have
been complications. Disseminated intravascular coagulation (DIC) can be a devistating
complication of canine babesiosis. Plasma kallikrein levels are elevated which can
activate the intrinsic cascade at factor XII. Thrombocytopenia is common especially in
B. gibsoni. It can be a result of DIC but is likely a result of immune-mediated platelet
destruction. Membranoproliferative glomerulonephritis is seen in some affected dogs
and may be 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 off-load oxygen. The tissue damage results in the release of cytokines
causing wide-spread inflammation and further damage to multiple organ systems.
Hypoxia appears to be more important than hemoglobinuria in producing kidney damage
in dogs experimentally infected.
Clinical Findings:
Dogs
Babesiosis may follow hyperacute, acute, chronic or subclinical courses. Most dogs in
the United States are subclinical carriers.
Hyperacute disease is uncommon but can have devastating consequences. It is
characterized by hypotensive shock, hypoxia, extensive tissue damage and vascular
stasis. Most dogs die with this form of babesiosis despite therapy. In the U.S. this form
is most common in puppies and has been reported in one adult Doberman pinscher after
surgical stress and blood transfusion from an infected greyhound blood donor. Shock,
coma, or death after less than a 1 day history of anorexia, lethargy, and hematuria may be
seen. Dogs with hyperacute disease usually are heavily parasitized and have a history of
heavy tick infestation.
Acute disease is characterized by anorexia, hemolytic anemia, thrombocytopenia,
lymphadenomegaly and splenomegaly. Lethargy, fever and vomiting are also common.
Fatalities may occur, especially in puppies or B. gibsoni-infected adults. Most animals
with acute disease recover with treatment. Hematuria and icterus may be present
particularly in B.canis-infected dogs. Immune-mediated hemolytic anemia and systemic
lupus erythematosus are the primary diseases that must be differentiated from this form
of babesiosis. A paradoxic phenomenon of intravascular hemolysis with
hemoconcentration despite normal plasma proteins is occassionally seen in dogs infected
with severely pathogenic strains of B. canis and has been termed “red biliary” and is
characterized by mucous membrane congestion and grossly visable hemoglobinemia
and/or hemoglobinuria. The hemoconcentration is characterized by a slightly increased
PCV and has been associated with neurological signs, acute renal failure, DIC and
pulmonary edema.
Chronic infections have been primarily reported in B. canis-infected dogs in southern
Africa and are characterized by intermittent fever, decreased appetite, and marked loss of
body condition. The chronic form may occur in B. gibonsoni-infected dogs in the U.S.
but has not been well documented.
Atypical signs and complications of Babesia infections have been reported and are
uncommon. Respiratory disease ranging from mild upper respiratory tract signs to
dyspnea; GI signs including vomiting, constipation, diarrhea and ulcerative stomatitis;
ascites and edema, especially periorbital, peripheral limb and scrotal edema; pulmonary
edema possibly related to adult respiratory distress syndrome with increased capillary
permeability may be seen and is often fatal. Rarely hemorrhages varying from petechiae
to ecchymotic patches may occur secondary to thrombocytopenia and DIC.
Musculoskeletal manifestations include Babesia-associated masticatory myositis, joint
swelling and back pain. Severe rhabdomyolysis may cause muscle pain, dark colored
urine, muscle tremors and abnormal gait. Acute renal failure is a rare complication
occuring in less than 3% in one report. CNS manifestations are referred to as “cerebral
babesiosis” and signs include seizures, weakness, ataxia and vestibular or cerebellar
signs. Sludging of the capillaries of the CNS with resultant tissue hypoxia is thought to
be the cause. Dual infections with Ehrlichia canis may be seen due to the same vector
causing transmission and therefore, overlapping clinical signs of both diseases may be
observed.
Subclinically infected dogs in the U.S. are present in certain populations. Greyhounds in
the U.S. have a high seroprevalance but adult dogs rarely show clinical signs. Parasites
will rarely be found on blood smears from asymptomatic carriers, making identification
of this group of dogs difficult without performing serologic screening tests. The primary
importance of this group of dogs may be in their role as a potential source of infection to
puppies in breeding colonies or as a source of infection through blood transfusion. Most
subclinical carriers will never show clinical signs of babesiosis, however, they may rarely
show signs when subjected to stress or to treatment with glucocorticoids.
Cats
Cats with naturally occurring babesiosis usually are younger than 2 years and may show
lethargy, anorexia, weakness, rough hair coat, or diarrhea. Fever and icterus are rarely
observed. Chronic anemia can be severe and is the underlying reason for clinical signs.
Diagnosis:
Clinical pathology abnormalities:

Dogs:
A mild, normocytic, normochromic anemia is noted in the first few days post infection
and then the anemia becomes macrocytic, hypochromic, and regenerative as the disease
progresses. Differentials to consider are IMHA, zinc or onion toxicity, clostridial
septicemia and GI hemorrhage mimicking a hemolytic anemia. Thrombocytopenia has a
high prevalence in dogs with babesiosis. Reticulocytosis is proportional to the severeity
of the anemia. Leukocyte abnormalities may include leukocytosis, neutrophilia,
neutropenia, lymphocytosis and eosinophilia. A leukomoid reaction similar to that seen
in immune-mediated hemolytic anemia may be seen. Autoagglutination of erythrocytes
in saline and a positive Coomb’s test may be noted making it difficult to distinguish from
IMHA if organisms are not present. Serum chemistry values are usually normal.
Hypokalemia in severely affected animals may be present due to decreased intake in diet.
Hyperkalemia and hypoglycemia are noted in severely affected animals. Dual infections
with Ehrlichia canis may have hyperglobulinemia. Azotemia and metabolic acidosis
may occur and contribute to morbidity and mortality. Hyperbilirubinemia is a consistent
finding in the acute disease caused by B. canis but not by B. gibsoni. Liver enzyme
activities may be increased during severe disease. Bilirubinuria, hemoglobinuria,
proteinuria, and granular casts may be observed on urinalysis.
Cats with B. felis have similar but less severe findings. The anemia is usually
macrocytic; hyperbilirubinemia is common; serum chemistry abnormalities are usually
restricted to mild increases in liver enzyme activities.
Definitive diagnosis of babesiosis is dependent on demonstration of organisms within
infected erythrocytes or positive serology. Blood smears should be made of blood
collected from peripheral capillary beds in the ear tip or nail bed to yield a higher number
of parasitized cells. Erythrocytes adjacent to the buffy coat are also more likely to be
infected. Phagocytized organisms may be found in neutrophils. Organisms may be more
easily detected in acute cases of babesiosis versus the chronically affected or carrier
animal.
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. Indirect Fluorescent Antibody testing is the most reliable and most
commonly used test. Although laboratory methods differ, in general a titer greater than
or equal to 80 to B. canis on a single sample is sufficient for diagnosis. A cut-off titer of
320 or greater has been determined to be a positive titer for B. gibsoni. Early in the
disease or very young dogs may be serologically negative, therefore making a paired
serum sample taken 2 weeks later necessary for evaluation of a rising titer. Cross-
reactivity between B. canis and B. gibsoni make parasite identification necessary to
differentiate between these two species. ELISA and dot-ELISA techniques for antibody
detection of these species is used in research. Dogs infected with B. gibsoni may have
false positive serologic test results for Toxoplasma gondii and Neospora caninum as well.
Therapy:

Dogs:
Dogs generally show improvement clinically within 24 hours of treatment with
antibabesial drugs. Unfortunately, of the most effective of the babesiacidal drugs,
diaminazene aceturate and phenamidine isethionate are not approved for use in the
United States. Diminazene aceturate is the most commonly used drug worldwide. It is
an aromatic diamidine derivative in the same class of drugs as phenamidine isethionate
and pentamidine isethionate. Diminazene aceturate is effective when given IM but
clearance of the organism is inconsistent even at higher doses. B.canis infections are
more responsive to Diminazene aceturate than B. gibsoni infections. Side effects in dogs
are pain and swelling at the injection site, GI irritation and neurological signs.
Pentamidine isethionate (Pentam300, Abbott Labs, Abbott Park, IL) has been approved
for use in the United States and is effective against both B. canis and B. gibsoni.
Although the drug has not been extensively studied, side effects known are injection site
pain, hypotension, tachycardia and vomiting.
Imidocarb dipropionate, a carbanilide member of the diaminidine family, is a very
effective drug against B.canis and has few side effects. It is available in the United States
and is also effective against Ehrlichia canis infections, therefore the drug of choice in
dual infections. It is less effective against B. gibsoni infections. At the suggested dose,
imidocarb eliminates the Babesia organism 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 6.0 mg/kg the day following a dose of diminazene at 3.5 mg/kg
has also been shown to clear infection. Side effects are uncommon and are related to an
anticholinesterase effect of the drug. Salivation, lacrimation, vomiting, diarrhea, muscle
tremor, restlessness, tachycardia and dypsnea can be seen. Pre-treatment with Atropine is
indicated to prevent the side effects.
Other drugs that may be of benefit are Quinuronium sulfate for B. canis infection, Trypan
blue (1% solution) for mild to moderate signs of B.canis infection or in patients with
severe clinical signs to avoid anticholinesterase side effects of imidocarb and the CNS
toxicity of other diamidines since it is less likely to aggravate shock or hypotension.
Metronidazole has been used with limited success in B. gibsoni infections.
Clindamycin is the treatment of choice for B. microti in humans and there have been
reports of its success in the treatment of canine babesiosis at 25-50 mg/kg per day.
Controlled trials evaluating the efficacy of clindamycin in dogs are needed.
Azithromycin and atovaquone are newer drugs that are effective against B.microti in
hamster models.
Doxycycline has been effective in preventing or reducing parasitemia when dogs were
being treated at the time of infection.
Cats: Treatment of feline babesiosis has not been well studied. The drug of choice is
Primaquine phosphate, an antimalarial compound given PO or as an IM injection. The
effective dose of 0.5 mg/kg is very close to the lethal dose of 1.0 mg/kg.
Supportive care is very important in the management of babesiosis and many will recover without specific antibabesiacidal therapy. IV fluids for dehydrated or shocky animals is indicated. Whole blood or packed red blood cells should be given to severely anemic patients. Transfusions may also normalize acid base status as well as arterial oxygen status. In severely metabolically acidic animals, sodium bicarbonate infusion may be needed. Treatment of concurrent stressors such as GI parasitism is important. Glucocorticoid use is contraversial. It may be indicated in the unresponsive case due to the immune system implicated as causing many of the clinical signs such as hemolytic anemia. Glucocorticoids may be needed at immunosuppressive doses for the short term. Long term glucocorticoids should be avoided. Glucocorticoid usage could result in more severe parasitemia shortly after initiated due to suppression of the monocyte-macrophage system and its role in clearing the parasite. Prevention:This is the key to avoiding the disease since drug therapies can be difficult to obtain. This is particularly important in the kennel situtation and in the kennels in southeast U.S., prevention may be all that is necessary to control outbreaks. Control of the vector tick is the objective. Frequent inspection of the hair coat and skin of each dog for ticks, serological testing of new animals brought into the kennel and then quarantined before introduction are advised. Flea and tick collars are reasonably effective for tick control when used with inspection, topical ascaracide application and environmental control. Fipronil (TopSpot, Frontline) appears to be effective as a topical product for tick control. A vaccine produced from cell culture derived exoantigens of B.canis is available in Europe. Efficacy of 70-100% has been reported with mild signs of the disease being seen in some of the animals vaccinated. Other studies have been less impressive. Vaccination appears to block the initiation of many of the severe pathological processes. Use of this vaccine in other geographical areas is limited due to the difference in strain antigenicity. Public Health Risk: There does not appear to be a Babesia that is host specific for humans, but mild infections in people have been reported as well as rare cases of severe illness and death. Humans are the accidental host when they are bitten by an infected tick. People with AIDS are especially at risk due to their immunologically compromised condition.

Source: http://www.cvm.okstate.edu/files/VMTH/Syllabi/VMED%207482%20Hemolymphatic%20Notes/Hemolymphatic%20VI.pdf