Anemias: Look out for vector-borne diseases

Q: Could you review anemias in cats?

A: Dr. Kristy Dowers gave an excellent lecture, "Causes of feline anemia: old and new," at the 2009 American College of Veterinary Internal Medicine Forum in Montreal. Here are some relevant points from it:

Anemia is a common blood abnormality in many species, including cats. Determining the regenerative nature of the anemia guides the work-up in cats. Regenerative anemias suggest blood loss or red-cell lysis. Red-cell lysis can be due to toxins, infectious agents, neoplasia (as a secondary immune-mediated phenomenon) or primary immune-mediated hemolytic anemia. Non-regenerative causes of anemia include iron deficiency, anemia of inflammatory disease, renal disease, bone-marrow disorders, neoplasia, infectious disease and immune-mediated disorders directed at erythrocyte precursors.

Presentation, historical findings

Classic signs of anemia include lethargy, weakness, inappetence, pale mucous membranes or icteric membranes if hemolysis is occurring. Given that infectious disease and neoplasia are two major rule-outs for anemia, fever may be present. Since many of the infectious agents are vector-borne, flea-and-tick exposure should be determined. Outdoor status increases the chance of contact with other cats and thereby exposure to the retroviral agents. Exposure to drugs or toxins such as onions and acetaminophen is important to ascertain. Other systemic signs, such as PU/PD with renal disease, can indicate the presence of other chronic diseases.

Diagnosis

A complete blood count, including reticulocyte count, will determine whether regenerative or non-regenerative anemia is present. Acute blood loss and red blood cell lysis will not be regenerative for two to four days, so clinical and clinicopathologic parameters should be taken into account when making an assessment of the regenerative nature of the anemia. Clinical evidence of bleeding and a low plasma protein should differentiate acute blood loss from hemolytic anemia. Spherocytes are difficult to identify in feline blood smears and are therefore not a reliable means to diagnose hemolytic anemia. Presence of reticulocytes and/or nucleated red blood cells and macrocytosis with or without autoagglutination can be diagnostic for regenerative anemia.

An iron-deficiency anemia will be characterized as microcytic anemia and FeLV-induced non-regenerative anemia will often be macrocytic anemia.

A thorough evaluation of blood smears can reveal intracellular or extracellular organisms. Presence of Heinz bodies may indicate an exposure to toxins that cause oxidative damage such as onions and propylene glycol. A direct Coombs' test may be performed, but a negative test does not rule out an immune-mediated anemia since its sensitivity and specificity are low in cats. An osmotic fragility test is indicated in breeds such as Abyssinians and Somalis which can have a hereditary erythrocyte membrane defect.

A serum chemistry panel is necessary to rule in or out other causes of anemia, such as renal disease and other systemic illnesses. Hyperbilirubinemia may be present if hemolysis is severe. Other abnormalities in the serum chemistry panel depend on the specific chronic disease, infectious agent or neoplastic process. FeLV antigen/FIV antibody testing should be done. Thoracic and abdominal radiographs (or abdominal ultrasound) should be performed to help rule out neoplasia.

Toxins

Various toxins and drugs are associated with hemolytic anemia in cats. Zinc, onions, propylene glycol, acetaminophen, methylene blue, methionine, methimazole and benzocaine preparations are a few of these agents. Most toxins will induce Heinz body formation and some, such as acetaminophen toxicity, cause methemoglobinemia as well. Supportive care is the primary therapy for Heinz body anemia.

Hemoplasmosis

Mycoplasma haemofelis, Candidatus M. haemominutum, and Candidatus M. turicensis are the organisms responsible for hemoplasmosis. Virulence is attributed primarily to M. haemofelis and Candidatus M. turicensis. This disease has worldwide distribution with rates of prevalence varying from 4 percent to 23 percent for M. haemofelis, depending on the location. Since the flea is the likely vector, prevalence rates vary according to climate, too. Other modes of transmission include blood transfusion (and by extension between cats if blood contamination occurs) and from the queen to her kittens (in utero or via lactation).

Clinical signs are those associated with anemia, and fever often is present. Identification of the gram-negative, epierythrocytic organisms on a blood smear is an unreliable means of diagnosis because of cyclic parasitemia, staining artifacts and sample handling. PCR for organismal DNA is the most sensitive and specific test for the haemoplasma organisms. The standard treatment is doxycycline (5 mg BID for 14 days), but there is substantial evidence that the fluoroquinolones are equally efficacious. In several studies, enrofloxacin (5-10 mg PO q 24 hrs for 14 days), marbofloxacin (2.75 mg PO q24 hrs), and pradofloxacin (a novel fluoroquinolone not yet available in the United States) have demonstrated clearance of the organism by PCR weeks to months after therapy. In cats in which organism clearance has not occurred, recrudescence during times of stress is possible.

Cytauxzoonosis

Cytauxzoon felis is a tick-borne protozoal organism that is predominantly found in the south central, southeastern and mid-Atlantic states. The bobcat is the primary reservoir host and Dermacentor variabilis is the presumed tick vector. These signet ring-shaped organisms are located within the red blood cell during the "erythrocytic phase" of the infection. C. felis invades monocytes/macrophages which are distributed to the tissue for the "tissue phase" or "leukocytic phase" of the disease. Schizont-engorged monocytes clog vessels and account for the multi-organ failure and rapid death, usually within one week, associated with cytauxzoonosis.

While anemia is considered 100 percent fatal in cats, recent reports of healthy carriers and cats that have survived suggest that aggressive therapy may improve survival rates. A presumptive diagnosis often is made on acute onset of clinical signs (severe lethargy, anorexia, icterus, dyspnea) in an endemic region with possible exposure to ticks. A definitive diagnosis can be made if the parasite is visualized within the RBCs; PCR is also now available. A promising combination of the anti-malarial drug atovaquone (15 mg/kg PO TID) and azithromycin (10 mg/kg PO Q24), in addition to aggressive supportive care and heparin, is currently being recommended. With this combination, a survival rate of 64 percent was reported.

Bartonellosis

Bartonella species have been implicated in multiple diseases in humans, dogs and cats. In cats, the primary infective species are B. henselae and B. clarridgeiae. In humans, B. bacilliformis causes a hemolytic anemia in which nearly 100 percent of RBCs are infected. Although this organism does not infect cats, a case of human hemolytic anemia caused by B. henselae has been reported.

Studies also have demonstrated the intraerythrocytic location of B. henselae in naturally infected cats using electron microscopy, making this organism a candidate for unexplained cases of feline anemia.

Recently, however, a retrospective study attempting to correlate Bartonella species with cases of hemolytic anemia found no significant prevalence differences in the healthy cats vs. anemic cats with a positive Bartonella PCR assay.

As with many high-prevalence diseases, it will be difficult to make the association between Bartonella species and anemia.

Ehrlichiosis

Ehrlichia and Anaplasma-like DNA have been amplified from naturally-infected cats and have been demonstrated to cause clinical signs in cats, including fever, lethargy, inappetence and, in some cases, anemia. Though these organisms are listed under hemolytic causes, the anemias in one case report were non-regenerative. Given the fact that ehrlichiosis in cats is uncommon and that only some of these cats had anemia, it is unnecessary to test routinely for these organisms in cats with anemia.

FeLV and FIV

FeLV can cause both non-regenerative and regenerative anemias. The latter may be due to concurrent infections with the haemoplasma organisms, but an immune-mediated process is also possible. FeLV antigen testing is therefore recommended for any cat presenting with hemolytic anemia. FIV infections are nearly always associated with a non-regenerative anemia. There are only a few controlled studies evaluating use of antiviral agents in these diseases and most show either no effect or are toxic. Feline interferon-? and human interferon-a showed some effect for FeLV and FIV, respectively.

Primary immune-mediated hemolytic anemia

There is a subset of cats with hemolytic anemia for which neoplasia, toxins and most infectious diseases have been ruled out, either by infectious disease assays or trial therapies with anti-bacterial agents. In one study of 19 cats, no identifiable infectious, neoplastic, or toxic could be found as a cause of their anemia.

A majority of these cats were Coombs' positive, suggesting that anti-erythrocyte antibodies were present. In another retrospective study of anemic cats whose blood was submitted for extensive infectious-disease testing, approximately 75 percent of cats with either non-regenerative or regenerative anemia and 60 percent with non-regenerative anemia were negative for all organisms tested. This would suggest that primary immune-mediated hemolytic anemia may be more common than previously thought.

Unfortunately, a definitive diagnosis may be difficult to obtain.

The direct Coombs' test appears to be neither specific nor sensitive in cats.

New techniques, such as flow cytometry and anti-erythrocyte antibody assays, may be helpful in identifying anti-erythrocyte antibodies in cats with primary hemolytic anemia but are currently not commercially available.

Therefore the diagnosis of primary immune-mediated hemolytic anemia cats is usually made by ruling out all other causes of anemia with an exhaustive work-up and trial therapy. Treatment with immunosuppressive doses of steroids is the mainstay of therapy.

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