Feline Leukemia Virus and Related Diseases: Introduction

Feline Leukemia Virus and Related Diseases: Introduction
(Feline lymphoma and leukemia, Lymphosarcoma)

Etiology and Epidemiology

Pathogenesis

Disorders Caused by FeLV

Diagnosis

Treatment

Lymphoma Treatment

Prevention and Control

Zoonotic Risk

Despite the widespread use of vaccines, feline leukemia virus (FeLV) remains one of the most important causes of morbidity and mortality in cats. It causes a variety of malignancies, but persistent infection can also cause severe immunosuppression and profound anemia. The virus is present worldwide. In nature, FeLV infects domestic cats and a few other Felidae. In the laboratory, cells from a much wider range of species can be infected by some strains of the virus.

Etiology and Epidemiology:

FeLV is a retrovirus in the family Oncovirinae. Other oncoviruses include feline sarcoma virus, mouse leukemia viruses, and 2 human T-lymphotropic viruses. Although oncogenesis is one of their more dramatic effects, oncoviruses cause many other diseases, including degenerative, proliferative, and immunologic disorders.

There are 3 main FeLV subgroups of clinical importance. Subgroup A viruses are found in all naturally infected cats. FeLV-A, the original, archetypical form of the virus, is efficiently transmitted among cats. FeLV-A viruses tend to be less pathogenic than viruses of the other subgroups, but some strains cause severe immunosuppression. Almost all naturally infected cats are originally infected by FeLV-A. Within the infected cat, FeLV-A is sometimes altered to produce FeLV-B and FeLV-C viruses. FeLV-B is found in ~50% of naturally infected cats, along with FeLV-A. FeLV-A and FeLV-B together are more frequently associated with neoplastic diseases than is FeLV-A alone. FeLV-C viruses are isolated from only 1% of naturally infected cats, along with FeLV-A and sometimes both FeLV-A and FeLV-B. The presence of FeLV-C in an infected cat is strongly associated with the development of erythroid hypoplasia and consequent severe anemia. Viruses of all 3 subgroups are detected (but cannot be distinguished) by commonly used FeLV diagnostic test kits.

The incidence of FeLV infection is directly related to the population density of cats. Infection rates are highest in catteries and multicat households, especially when cats have access to the outdoors. In the USA, 1-2% of healthy stray urban cats are persistently viremic. Not surprisingly, much higher percentages of sick, “at risk” cats are found to be infected.

Persistently infected, healthy cats are the major reservoir of FeLV. Carriers excrete large quantities of virus in saliva. Lesser amounts of virus are excreted in tears, urine, and feces. Oronasal contact with infectious saliva or urine is the most likely mode of transmission. Nose-to-nose contact, mutual grooming, and shared litter trays and food dishes facilitate transmission. Bite wounds from infected cats are an efficient mode of transmission but occur relatively infrequently in cats kept indoors 100% of the time. Bites may be a more important mode of transmission in indoor-outdoor cats.

Age resistance is significant. Young kittens are much more susceptible than adults. The virus may be transmitted vertically (in utero or by milk) or horizontally (by secretions and excretions). Because FeLV is a fragile, enveloped virus and because of age resistance, horizontal transmission between adults usually requires prolonged, intimate contact. In addition, the dose required for oronasal transmission of the virus is relatively high.

Pathogenesis:

After oronasal inoculation, the virus first replicates in oropharyngeal lymphoid tissue. From there, virus is carried in blood mononuclear cells to spleen, lymph nodes, epithelial cells of the intestine and bladder, salivary glands, and bone marrow. Virus later appears in secretions and excretions of these tissues and in peripheral blood leukocytes and platelets. Viremia is usually evident 2-4 wk after infection. The acute stage of FeLV infection (2-6 wk after infection) is rarely detected. It is typically characterized by mild fever, malaise, lymphadenopathy, and blood cytopenias.

In ~70% of adult cats, viremia and virus shedding are transient, lasting only 1-16 wk. A few cats continue to shed virus in secretions for several weeks to months after they cease to be viremic. Virus may persist in bone marrow for a longer period, but even this latent, or sequestered, infection usually disappears within 6 mo. Some FeLV-exposed cats (~30%) do not mount an adequate immune response and go on to become persistently (ie, permanently) viremic. Persistently viremic cats develop fatal diseases after a variable time period.

Disorders Caused by FeLV:

FeLV-related disorders are numerous and include immunosuppression, neoplasia, anemia, immune-mediated diseases, reproductive problems, and enteritis.

The immunosuppression caused by FeLV is similar to that caused by feline immunodeficiency virus ( Viral-induced Immunodeficiencies). There is an increased susceptibility to bacterial, fungal, protozoal, and other viral infections. Numbers of neutrophils and lymphocytes in the peripheral blood of affected cats may be reduced, and those cells that are present may be dysfunctional. Many FeLV-positive cats have low blood concentrations of complement; this contributes to FeLV-associated immunodeficiency and oncogenicity because complement is vital for some forms of antibody-mediated tumor cell lysis. Much of the immunodeficiency caused by FeLV is thought to be due to the high degree of viral antigenemia.

Lymphoid or myeloid tumors (eg, lymphoma, lymphoid leukemia, erythremic myelosis) develop in up to 30% of cats persistently infected with FeLV. Although FeLV-negative (ie, nonviremic) cats also develop these tumors, they may still be induced by FeLV, as many negative cats with lymphoma have viral sequences that can be detected by immunohistochemistry and PCR. Such cats may have been previously infected with FeLV despite negative test results for the virus. The transient presence of FeLV could have triggered lymphoma. However, the persistence of FeLV antigen increases the risk of lymphoma by as much as 60-fold compared with an FeLV-negative cat. Lymphoma is the most frequently diagnosed malignancy of cats. Most American cats with mediastinal, multicentric, or spinal forms of lymphoma are FeLV-positive. However, in some parts of the world, these forms of lymphoma are becoming much less common, and the proportion occurring in FeLV-positive cats is decreasing. This may be related to effective control of FeLV. Renal and GI forms of lymphoma are more likely to be found in FeLV-negative cats.

Leukemia is a neoplastic proliferation of hematopoietic cells originating in the bone marrow. The cell lines that become neoplastic are neutrophils, basophils, eosinophils, monocytes, lymphocytes, megakaryocytes, and erythrocytes. In cats, the leukemias are strongly associated with FeLV infection and sometimes (but not always) associated with neoplastic cells circulating in the blood. Lymphoid leukemias are further divided as acute and chronic. Acute lymphocytic leukemia is characterized by lymphoblasts circulating in the blood. In chronic lymphocytic leukemia, there is an increased number of circulating lymphocytes that have normal morphology.

The anemia caused by FeLV is usually nonregenerative and normochromic. There is frequently an idiosyncratic macrocytosis. About 10% of FeLV-related anemias are hemolytic and regenerative. This form of anemia may be associated with hemobartonellosis or immune-mediated hemolysis, or both.

Immune complexes formed in the presence of moderate antigen excess can cause systemic vasculitis, glomerulonephritis, polyarthritis, and a variety of other immune disorders. In FeLV-infected cats, immune complexes form under conditions of antigen excess, because FeLV antigens are abundant and anti-FeLV IgG antibodies are sparse. These conditions are ideal for the development of immune-mediated disease.

Reproductive problems are common; 68-73% of infertile queens have been reported to be FeLV-positive, and 60% of queens that abort are FeLV-positive (although abortion is a relatively uncommon cause of feline infertility). Fetal death, resorption, and placental involution may occur in the middle trimester of pregnancy, presumably as a result of in utero infection of fetuses by virus transported across the placenta in maternal leukocytes. Occasionally, infected queens give birth to live, viremic kittens. Latently infected (ie, nonviremic) queens may pass virus on to their kittens in milk.

Enteritis, resembling feline panleukopenia both clinically and histopathologically, may develop. Clinical signs include anorexia, depression, vomiting, and diarrhea (which may be bloody). Because of the concurrent immunosuppression associated with FeLV infection, septicemia may develop. Evidence suggests that FeLV and feline panleukopenia virus may act synergistically to produce this syndrome.

Other disorders may also develop. FeLV occasionally causes a neuropathy leading to anisocoria, urinary incontinence, or hindlimb paralysis. Certain FeLV-induced lymphomas can produce identical clinical signs. If antineoplastic therapy is planned, it is important to distinguish neoplasia from neuropathy. FeLV can also cause quasineoplastic disorders such as multiple cartilaginous exostoses (osteochondromatosis).

Diagnosis:

Two types of tests are readily available for clinical use. The immunofluorescence assay (IFA) tests for the presence of FeLV structural antigens (eg, p27 or other core antigens) in the cytoplasm of cells suspected to be FeLV-infected. In clinical practice, peripheral blood smears are usually used for the IFA, but cytologic preparations of bone marrow or other tissues can also be used. The IFA is considered to be the most reliable but requires submission to a commercial laboratory, so results are delayed. IFA-positive cats are considered to be persistently viremic and have a poor longterm prognosis.

The more convenient ELISA can be performed in the veterinary clinic and tests for the presence of soluble FeLV p27. FeLV antigen may be present in the absence of intact, infectious viral particles because excess FeLV antigens are released from infected cells free of viral particles. The ELISA detects antigenemia rather than viremia. Several different test kits are available; most have sensitivities and specificities of 98%. Accuracy can be improved by running both the IFA and ELISA on the same cat.

Diagnosis of FeLV-induced neoplasia is similar to that of other tumors. Cytologic examination of fine-needle aspirates of masses, lymph nodes, body cavity fluids (eg, pleural effusion), and affected organs may reveal malignant lymphocytes. Bone marrow examination may reveal leukemic involvement, even when the peripheral blood appears normal. Biopsy and histopathologic examination of abnormal tissues is often necessary for diagnostic confirmation.

Treatment:

Ideally, an FeLV-infected cat would be identified early and treated to eradicate the retroviral infection before FeLV-related diseases had time to develop. Unfortunately, eradication of retroviral infections at any stage of disease is extremely difficult. Most infected cats are persistently viremic by the time infection is diagnosed.

Many treatments have been administered in an attempt to reverse viremia or decrease clinical signs associated with FeLV infection. Anecdotal reports of antiviral agents and immunotherapeutic agents reversing viremia, improving clinical signs, and prolonging survival are abundant. Controlled studies using naturally infected cats have been unable to substantiate a benefit from these therapies.

FeLV-positive cats can live without major diseases for several years. Stress and sources of secondary infection should be avoided. The cat should remain indoors 100% of the time to reduce the risk of exposure to infectious agents and to prevent transmission of the virus to other cats. Routine prophylactic care for FeLV-infected cats is more important than for uninfected cats. Routine vaccinations should be administered based on the risk to the cat, with rabies vaccinations given to comply with local laws. FeLV vaccinations should not be administered, as there is no evidence to suggest a benefit. Physical examinations focusing on external parasites, skin infections, dental disease, lymph node size, and body weight should be performed every 6 mo. Administration of an anthelmintic at these visits is recommended. All infected cats should be neutered. Owners should be advised to watch for signs of FeLV-related disease, particularly secondary infections. Therapy for such infections or other illnesses should be more aggressive and of longer duration, as the immunocompromised condition renders the cat less able to fight diseases naturally.

Lymphoma Treatment:

Feline lymphoma can be treated with cytotoxic drugs. These drugs may cause significant toxicities if not dosed and administered properly. (See also antineoplastic agents, Antineoplastic Agents: Introduction .) Most cytotoxic drugs are also carcinogens and must be handled properly. Before undertaking treatment with these drugs, veterinarians should familiarize themselves with proper dosing and administration, appropriate monitoring of the patient, toxicities and complications, and safe handling to prevent exposure of veterinary personnel and owners to the agents and their metabolites. Treated properly, most cats do not experience significant toxicities and enjoy a good quality of life.

About 50% of cats with lymphoma that are treated will obtain a complete remission (ie, no clinical evidence of disease). FeLV-negative cats that attain a complete remission live an average of 9 mo, and FeLV-positive cats have an average survival of 6 mo. Cats not treated or those not responding to treatment survive ~6 wk.

Many protocols for treatment of feline lymphoma have been published; most use similar drugs with differing schedules of administration. One widely used protocol consists of an intensive induction phase (vincristine 0.75 mg/m², IV, weekly for 4 wk, cyclophosphamide 300 mg/m², PO every 3 wk on the same day as vincristine, and prednisone 10 mg/cat, PO, sid throughout the protocol), followed by a less intensive maintenance phase (vincristine and cyclophosphamide given every 3 wk on the same day, prednisone continued daily). Treatment is continued for 1 yr or until relapse. With this protocol, 79% of cats attained remission and average survival was 150 days. Changing the maintenance protocol to doxorubicin 25 mg/m², IV, every 3 wk, provided an average remission of 281 days. When relapse occurs, the drug regimen can be changed and a second remission achieved; however, second remissions seldom last as long as the first.

Acute lymphocytic leukemia is treated with the same protocol as lymphoma, but only ~25% of cats obtain remission. For those that obtain remission, the average length is 7 mo. Chronic lymphocytic leukemia is best treated with chlorambucil (2 mg/cat, PO) and prednisone (40 mg/m², PO), given every other day on alternating days. Leukemias other than lymphocytic are rarely treated because the cats are extremely ill and very few respond to therapy.

Prevention and Control:

Testing should be mandatory in the following situations: 1) all kittens at their first veterinary visit, so the owners can be counseled regarding a cat that tests positive (as is routinely done for congenital abnormalities), 2) all cats prior to entering a household with existing uninfected cats, 3) all cats in an existing household prior to admission of a new, uninfected cat, and 4) all cats prior to their first FeLV vaccination.

FeLV vaccines are intended to protect cats against FeLV infection or, at least, to prevent persistent viremia. Types of vaccines include killed whole virus, subunit, and genetically engineered. Vaccines may vary in protective effect, and manufacturers’ claims and independent comparative studies should be carefully noted. Vaccines are indicated only for uninfected cats; there is no benefit in vaccinating an FeLV-positive cat. The cat’s risk, of exposure to FeLV-positive cats should be assessed, and vaccines used only for those cats at risk. Although the risk of tumor development is low, FeLV vaccines have been associated with the development of sarcomas at the vaccination site. Uninfected cats in a household with infected cats should be vaccinated; however, other means of protecting uninfected cats (eg, physical separation) should also be used. Constant exposure to FeLV-infected cats is likely to result in viral transmission regardless of vaccination status.

Zoonotic Risk:

Some strains of FeLV can be grown in human tissue cultures. This has led to concerns of possible transmission to humans. Several studies have addressed this concern; none have shown any evidence that any zoonotic risk exists.