Diagnosis, treatment of tick-borne diseases

Q: Please discuss diagnosis and treatment of tick-transmitted diseases in the United States.

A: Dr. Adam J. Birkenheuer gave an excellent lecture on "Hematological and Biochemical Changes in Tick-Transmitted Diseases" at the 2008 American College of Veterinary Internal Medicine Forum in San Antonio. Here are some relevant points from that lecture:

While many veterinarians diagnose dogs and cats with classic signs and presentations, those with atypical presentations often are missed. A missed diagnosis often results in therapies that can lead to persistent illness or, in some cases, actually worsen the outcome.

Many factors contribute to the emergence of tick-transmitted diseases, including climate change, urbanization, vector epidemiology, alternative forms of disease transmission, ease of animal transport and advanced diagnostic techniques.

Veterinarians need to be vigilant for tick-transmitted diseases, especially cases that don't respond to treatment and those in which "things just don't add up."

Babesiosis

Canine babesiosis is an emerging disease in North America and is typically caused either by Babesia gibsoni or Babesia canis vogeli. Babesia gibsoni is most commonly detected in American Pit Bull Terriers. Babesia canis is most commonly diagnosed in Greyhounds. In addition to tick transmission, infection via blood transfusions, dog fights and perinatal routes also occur.

Babesiosis can be acute or chronic in nature. There are variations in the clinical presentation depending on the species of piroplasm, age and breed of the host and presence of concurrent disease.

The most common hematologic findings are thrombocytopenia and anemia. Despite the fact that most veterinarians associate babesiosis with anemia, most studies demonstrate that thrombocytopenia is the most common hematologic abnormality in dogs. Thrombocytopenia is suspected to be immune-mediated (ITP).

The thrombocytopenia can be severe (< 50,000 plt/ul), but evidence of bleeding is rare. Some cases have had ITP without anemia. The anemia is primarily due to immune-mediated destruction and is often (> 85 percent) Coombs' positive. The degree of anemia is variable and can be severe (PCV < 10 percent), but some infected dogs have normal hematocrit. But no matter what the hematocrit, some degree of RBC regeneration is usually detected.

The effects on the leukon are variable and inconsistent. Some cases have a profound leukocytosis with a left shift that often accompanies a strong regenerative response. The most common abnormalities detected on a serum chemistry profile include mild increases in liver enzymes and hyperglobulinemia.

Other clinical signs include fever, lymphadenopathy, splenomegaly, pigmenturia and jaundice. A common misconception exists that all cases of babesiosis exhibit intravascular hemolysis. For B. gibsoni, the most commonly diagnosed form of Babesia in the United States, this seems to be a rare finding.

Microscopy or PCR can easily rule in babesiosis, but it is difficult to rule out babesiosis completely. Currently microscopy, PCR and serology are all considered to maximize your chances of identifying the infection. The organisms stain well with a modified Wright's stain.

Evaluation of capillary blood (ear or toenail) may improve parasite recovery. There is variable seroreactivity, so serology against both B. canis and B. gibsoni is warranted. Convalescent (three to four weeks) titers may be helpful in cases with acute onset of illness and low or negative acute titers. Seroreactivity of > 1:64 is suspicious for exposure in most laboratories.

PCR tests should be able to identify and differentiate all common canine Babesia species. PCR is the most accurate way to identify which species of Babesia is present. In one study, a single PCR test identified 85 percent of B. gibsoni and two consecutive PCR tests identified 100 percent.

Currently imidocarb dipropionate (6.6 mg/kg IM, repeat in two weeks) is the nation's only approved treatment for canine babesiosis. Atovaquone 13.5 mg/kg PO TID (with a fatty meal) and azithromycin 10 mg/kg PO Q24 in combination for 10 days has been shown to reduce or eliminate B. gibsoni (Asian) parasitemia as determined by PCR. A combination therapy of doxycycline, clindamycin and metronidazole has shown some promise in a small experimental study.

Babesia canis is likely to be cured by imidocarb dipropionate. Babesia gibsoni may be cured by atovaquone and azithromycin combination therapy. Other treatments may result in a clinical remission with persistent parasitemia. These dogs are at risk for recrudescence and may act as a reservoir. Two consecutive blood-smear evaluations and PCR six to eight weeks post-treatment confirms a cure.

Serology is unlikely to be helpful for short-term follow-up, since antibody titers may persist for months following treatment. Feline babesiosis has not been reported in the United States, but cats can be infected by Cytauxzoon felis.

Ehrlichiosis/anaplasmosis

Canine ehrlichiosis/anaplasmosis is caused by several different species of Ehrlichia/Anaplasma species. Those species reported in the United States include E. canis, E. ewingii, E. chaffeensis, A. phagocytophilum (E. equi) and A. platys (E. platys). Ehrlichiosis can be either acute or chronic. Most cases are recognized during the chronic stage.

The hematologic effects of ehrlichiosis/anaplasmosis can be variable, but the most common abnormality detected is thrombocytopenia. Despite the fact that many veterinarians suspect ehrlichiosis/anaplasmosis in dogs with any hemolytic anemia, a non-regenerative anemia is more commonly identified. Ehrlichiosis is only occasionally associated with a secondary IMHA.

Ehrlichiosis also can cause pancyto-penia. The effects on the leukon are variable. Both leukocytosis and leukopenia do occur. Lymphocytosis can be seen. The accompanying clinical signs often are vague, including fever, lethargy, anorexia, weight loss and vomiting. Bleeding tendencies such as epistaxis, petechia or ecchymosis also may be present. Hyperglobulinemia (polyclonal much more commonly than monoclonal), hypoalbuminemia, lymphadenopathy, proteinuria, polyarthritis (common with E. ewingii) and/or uveitis may be present.

The absence of thrombocytopenia does not rule out ehrlichiosis. Anaplasma platys only appears to cause thrombocytopenia and not systemic illness. Anaplasma phagocytophilum is associated with acute febrile illness in dogs and thrombocytopenia is a common finding. Co-infection with A. phagocytophilum and Borrelia burgdorferi has been associated with worse illness.

Serology is helpful in the diagnosis of ehrlichiosis/anaplasmosis. Acute and convalescent (three to four weeks) titers should be performed if the clinical signs are acute and initial titers are low or negative.

A four-fold change is consistent with ehrlichiosis/anaplasmosis. If the signs are chronic (> four weeks), then a single high titer is consistent with infection. In-house tests are not designed for diagnostic use but a positive test in conjunction with appropriate clinical findings is supportive of a diagnosis of ehrlichiosis/anaplasmosis.

The current in-house assays fail to detect antibodies against E. ewingii and cannot differentiate antibodies against A. phagocytophilum from those against A. platys. Occasionally a morula is identified in a white blood cell or platelet on a blood smear, but the parasitemia often is very low, so the sensitivity of microscopy is poor. The low levels of circulating organisms also can hamper PCR. A positive PCR test should rule in the presence of infection and identify which species is present. A negative PCR test does not rule out the possibility of ehrlichiosis. Therefore, the resolution of clinical signs in response to therapy remains an important "test."

Doxycycline (10 mg/kg/day for three to four weeks) is considered the treatment of choice. Other drugs that are reported to be effective include tetracycline, oxytetracycline, minocycline and chloramphenicol. Imidocarb dipropionate does not appear to be an effective treatment.

Resolution of clinical signs after therapy is probably the most important follow-up; further specific diagnostics for ehrlichiosis/anaplasmosis are not indicated.

Serology generally is a poor way to assess recovery because antibody titers may persist for months. If the animal is seroreactive and does not respond to therapy, the PCR should be performed because some species, such as E. chaffeensis, may not respond as well to therapy. If the PCR is negative, then an alternative diagnosis should be considered. Dogs do not appear to transmit infections to humans but can act as a sentinel for ehrlichiosis/anaplasmosis.

The clinical signs of feline ehrlichiosis appear similar to what is seen in dogs, and it should be considered when more common causes of disease are not apparent.

Bartonellosis

Bartonella vinsonii and B. henselae appear to be the primary causes of bartonellosis in dogs. The full spectrum of canine diseases caused by Bartonella species has yet to be elucidated. Bartonella species have been shown to be a cause of endocarditis and have been associated with granulomatous inflammation and hepatic disease in dogs.

Although polyarthritis has been confirmed only in a handful of cases of canine bartonellosis, lameness and stiffness are the most common presenting signs for dogs with confirmed Bartonella endocarditis, suggesting that it may be a more common finding.

Anemia and thrombocytopenia have been detected in nearly half of the dogs diagnosed with Bartonella vinsonii.

The pathogenicity of Bartonella infection in cats is unclear, and it has not consistently been found to have any specific or characteristic hematologic or biochemical effects. Some studies have detected an association between stomatitis and lymphadenopathy in cats co-infected with Bartonella and FIV, while other studies have not detected associations between Bartonella and clinical diseases in cats.

Serology is suggestive of exposure or infection. And positive PCR test results are indicative of current infection. PCR tests should help identify and differentiate which species of Bartonella are present. A combination of culture (BAPGM) and PCR appears to be an excellent method for the detection of Bartonella species. For unknown reasons, there are frequently discordant results between serological and molecular/bacteriologic assays, so a combination of these techniques is recommended.

The optimal treatment for bartonellosis is unknown. Currently animals are being treated with azithromycin (5-10 mg/kg PO Q24 for five days, then every other day for 45 days). Some cases have had additional clinical responses when rifampin was used in combination with the azithromycin.

Since the full spectrum of disease is unknown and a large percentage of normal animals can test positive for Bartonella, cautious interpretation of test results is warranted and consideration of alternative diagnoses when animal signs fail to resolve with treatment. Humans, especially immune-compromised people, have been infected with Bartonella.

Rocky Mountain Spotted Fever)

RMSF caused by Rickettsia rickettsii is an acute systemic disease of dogs and humans. It generally is seasonal (April to September) correlating with the tick Dermacentor species life cycle.

Thrombocytopenia is the most common hematologic abnormality (>85 percent). The degree of thrombocytopenia ranges from moderate (about 75,000 plt/ul) to severe (< 5,000 plt/ul).

The primary mechanism is consumption secondary to vasculitis, but there is some evidence for immune-mediated destruction. Leukocytosis is the second most common hematologic finding. The degree of leukocytosis can be severe (> 50,000 WBC/ul), and tends to increase along with the duration of the disease. RMSF commonly is not known to cause immune-mediated hemolytic anemia. The anemia associated with RMSF often is mild (PCV 25-30 percent). The hematologic effects rarely are seen without accompanying clinical signs, such as fever, lethargy, anorexia, pain, petechia, jaundice and neurologic signs. Common serum chemistry abnormalities identified in dogs with RMSF included hypoalbuminemia, hyponatremia and hyperbilirubinemia.

Serology helps in diagnosing RMSF. If signs are acute, then paired acute and convalescent (two to four weeks after the acute) titers should be submitted to the lab. A four-fold change is diagnostic for an active infection.

If the dog is sick > 10-14 days, then a single high titer (> 1:1024) is consistent with an active infection. Positive Immunofluorescence of skin biopsies or positive nested PCR results also indicate active infection. Response to therapy (doxycycline, tetracycline, enrofloxacin or chloramphenicol) is suggestive but not diagnostic.

Doxycycline (5 mg/kg BID or 10 mg/kg Q24), chloramphenicol (15-30 mg/kg TID), and enrofloxacin (5 mg/kg BID) for two weeks are effective treatments. Resistance has not been reported, so if signs persist after treatment an alternative diagnosis should be considered.

An accurate diagnosis is important, because the dog can serve as a sentinel for human infections. A convalescent titer is indicated even if the animal has responded to treatment. Resistant RMSF has not been reported. RMSF has not been reported in cats. Casual contact should not pose a major risk, but direct exposure is a potential. Also, common vector transmission is possible (sentinel).

Cytauxzoonosis

Cytauxzoonosis is an emerging infectious disease of cats in North America, caused by the protozoal parasite Cytauxzoon felis. It is transmitted via the tick vector Dermacentor variabilis and possibly other tick species such as Amblyomma americanum.

Cats typically present acutely, and historically the mortality rate is high (over 90 percent). More than 90 percent of the cases are diagnosed between April and September. Outdoor cats are at higher risk for infection, and there appear to be hyper-endemic areas of C. felis transmission. Bobcats appear to be the reservoir host and only rarely develop severe disease. Most cats die within five to seven days of the onset of clinical signs. The majority of clinical signs are due to obstruction of small vessels with schizont-laden macrophages, resulting in ischemia and thrombosis.

The most common signs are lethargy, depression and fever. Pancytopenia is the classic hematologic finding for cytauxzoonosis, but there may only be reductions of one or two cell lines in affected cats. Thrombocytopenia and leukopenia appear to be the most common hematologic abnormalities.

Hemolytic anemia is most prominent in seven to 14 days after presentation. Hyperbilirubinemia and increased serum ALT and ALP concentrations (often not proportional to the degree of hyperbilirubinemia) are common serum chemistry profile findings. Physical examination typically reveals fever and hepatosplenomegaly. Cats often are dyspneic, moribund, hypothermic and neurologic in the end stages of disease.

Cytologic diagnosis is the most common and rapid means of diagnosing cytauxzoonosis. The earliest stage of infection is the multiplication of schizonts in macrophages. These infected macrophages can be identified in tissue aspirates (particularly the liver, lung and spleen) or on the feathered edge of peripheral blood smears. These infected macrophages frequently are mistaken for platelet clumps and can measure nearly 100 microns in diameter.

In endemic areas hepatic aspirates may be warranted in highly suspicious cases.

The parasite also may be identified in red blood cells on Wright Giemsa-stained blood smears as the classic signet ring. There are no commercially available serologic tests. PCR is now available, sensitive and specific and can be performed rapidly to aid in the diagnosis or confirmation of cytauxzoonosis.

Supportive care with intravenous fluids and anticoagulants are the standard of care for the treatment of cytauxzoonosis.

Heparin is the anticoagulant of choice (100-300 U/kg SQ TID). Anti-protozoal therapies have been administered to cats with cytauxzoonosis but the effect on outcome is not clear because no controlled studies have been performed.

Imidocarb dipropionate (2 mg/kg IM once every two weeks) or diminazine aceturate have been recommended. Pre-treatment with atropine (0.05 mg/kg SQ once) appears to reduce the cholinergic side effects associated with imidocarb dipropionate. Atovaquone (10 mg/kg PO Q24) and azithro-mycin (15 mg/kg PO TID) combination therapy in combination for 10 days with aggressive supportive care appears to be a promising treatment with survival rates approaching 60 percent in an uncontrolled study.

Other antibiotics frequently are administered to cats with cytauxzoonosis, presumably to prevent secondary infections because many cats are neutropenic, although some antibiotics (doxycycline and clindamycin) do have anti-protozoal activity.

If cats survive more than seven days, the prognosis for long-term survival is excellent. Prospective testing of cats in the same household with infected cats has identified carriers.

Dr. Hoskins is owner of Docu-Tech Services. He is a diplomate of the American College of Veterinary Internal Medicine with specialities in small animal pediatrics. He can be reached at (225) 955-3252, fax: (214) 242-2200 or e-mail: jdhoskins@mindspring.com